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The case for "connected health" at home
Many technologies have emerged to monitor, interact with, and support patients at home and change home health care delivery.1–5 This trend coincides with the explosion of consumer digital and mobile products such as “smartphones” and has brought with it many different names, such as telehealth, telemedicine, e-medicine, remote monitoring, “virtual” care, digital health, mobile medicine, interactive health, and distance health. Many of these terms and concepts raise concerns for those who value traditional expressions of caring, physical diagnosis, touch, and presence in health care. However, these new technologies may present opportunities to find ways to enhance humanism in home health care. This potential may be most evident among patients with serious chronic illness and their families, who often struggle 168 hours a week but find their access to help limited to brief visits at times convenient for the provider.
While our health care system offers heroic acute-care treatments for hundreds of life-threatening maladies, we seem to fall short in helping those with serious ongoing needs whose care must be coordinated over time and across health care venues. Thinking in terms of “connected health” may provide a more holistic nomenclature that suggests the bond between technology and the opportunity for closer personal relationships.6–8
OPPORTUNITIES
Can technology better connect our home health patients and families to care during the “white space,”9 between our visits? Can we use new mobile and digital technologies to improve care for the seriously chronically ill? We have the technology to turn many challenges into opportunities in the next decade. For example:
- Can we change our visit-based model of home health care to a model that provides 24/7 “inbound” multichannel access to home health care teams along with proactive “outbound” support between visits in the form of multimedia health education and virtual encounters? Can this free up time for longer visits targeted toward higher-risk and higher-complexity scenarios that require extensive team leadership and care coordination?
- Can “smart” home monitoring be integrated into home-based long-term care for patients who have dementia, fall risks, other safety issues, or unaddressed limitations in activities of daily living to increase independence and quality of life and reduce institutionalization while decreasing cost of care and accommodating workforce constraints?10
- How do we apply clinician-to-clinician and clinician-to-patient videoconferencing and other connected health approaches to increase home health patient access to specialized, but hard-to-find, clinicians for consultative and direct-care services?
- Can emerging technologies accelerate the shift in care whereby most acute care for exacerbations of chronic illness and other common acute scenarios move from hospitals into home-based models of acute care, such as “Hospital at home”?11
- To what extent can apps and other technologies provide self-management support to truly deliver the home health care version of the automatic teller machine? For example, diabetes self-management support tools provide patients feedback about their disease based on information input into mobile devices.12 Can this be expanded in a way that dramatically increases access, especially for vulnerable groups that have been hard to reach, while also decreasing costs?
- Can we improve the home health care experience by using connected health concepts to improve transparency, minimize common scheduling delays and annoyances, and empower patients while they are receiving care?
REAL-WORLD BARRIERS
Despite the opportunities, barriers remain for innovative providers. With few exceptions, there is no direct third-party reimbursement for care that comes through a device rather than the front door. Medicare does not reimburse home health providers for services outside of a visit, but specific guidance has been issued that clarifies some of the opportunities:
An HHA (Home Health Agency) may adopt telehealth technologies that it believes promote efficiencies or improve quality of care…. An HHA may not substitute telehealth services for Medicare-covered services ordered by a physician. However, if an HHA has telehealth services available to its clients, a doctor may take their availability into account when he or she prepares a plan…. If a physician intends that telehealth services be furnished while a patient is under a home health plan of care, the services should be recorded in the plan of care along with the Medicare covered home health services to be furnished.13
Thus, there is no reimbursement for telehealth services, but if telehealth is part of a physician-directed plan of care, it may be included if it promotes home health quality and efficiency. Beyond reimbursement, there are other regulatory barriers. If monitoring or other digital or virtual services are provided across state lines, the clinicians involved in a regional or national “command center” likely must meet the licensure requirements (or obtain waivers) for every jurisdiction in which their patients reside. Providers should seek counsel regarding the extent to which new devices and software need to be approved by the US Food and Drug Administration before being deployed. And, as with all health-related communication, it is essential that information transmitted in nontraditional ways be secure, private, and compliant with all mandated standards for privacy. Finally, if the technology or service is rolled out in a fashion that could be construed as a “gift” or “freebie” for marketing purposes rather than a tool to improve clinical outcomes and health care value, then there may be a risk that the approach runs afoul of laws to prevent undue inducements.
In addition to reimbursement and regulatory concerns, there are technical barriers to fully realizing the connected health opportunities in home care. Even if patients are provided with devices, there is variability in internet connectivity or bandwidth in any given home. Providing devices with built-in cellular capabilities can reduce these barriers, but cellular data coverage varies across different geographies. High-quality health care videoconferencing tends to require more bandwidth than that provided in the typical “3G” connection. Use of existing cable television connections, which are almost ubiquitous, is another option, but it typically requires a more customized set-up than consumer mobile devices with cellular and wireless capabilities. If the services were delivered or coordinated by the cable provider, some of these inconveniences might be resolved.
As with most innovation, there is no “cookbook,” and there is limited and conflicting evidence in the clinical sciences literature to guide best practices. Organizations that commit to using technology to improve the quality and efficiency of care will experience fits and starts before they find the right types and “doses” of technology in their new care models. The home health community should beware of these frustrations leading to undue skepticism, like that of Newsweek author Clifford Stoll, who in 1995 infamously wrote about the developing internet:
…today, I’m uneasy about this [trend]…. Visionaries see a future of telecommuting workers, interactive libraries and multimedia classrooms. They speak of electronic town meetings and virtual communities. Commerce and business will shift from offices and malls to networks and modems. And the freedom of digital networks will make government more democratic. Baloney. Do our computer pundits lack all common sense? The truth is no online database will replace your daily newspaper … no computer network will change the way government works.14
Like the internet of 15 years ago, mobile and digital technologies are now changing how people live and relate to one another and how businesses function. It is unlikely that the impact of these technologies on health care will be fully elucidated by controlled trials that consider incremental changes to existing care models and workflows. Rather, innovative providers and the next generation of clinicians that “grew up,” with mobile devices as part of their lives will create new home care workflows and care realities. Home health providers can use these technologies to better connect their patients and find new ways to reduce suffering, increase health and independence, and improve the care experience while lowering costs and increasing value. The individuals and organizations that seize the moment and “answer” these key questions in connected health with successful new approaches to care will be the winners of the future. There is such an opportunity to make a difference.
- Chen HF, Kalish MC, Pagan JA. Telehealth and hospitalizations for Medicare home healthcare patients. Am J Manag Care 2011; 17 (6 Spec No.):e224–e230.
- Gellis ZD, Kenaley B, McGinty J, Bardelli E, Davitt J, Ten Have T Outcomes of a telehealth intervention for homebound older adults with heart or chronic respiratory failure: a randomized controlled trial [published online ahead of print January 11, 2012]. Gerontologist 2012; 52:541–552. 10.1093/geront/gnr134
- Baker LC, Johnson SJ, Macaulay D, Birnbaum H. Integrated telehealth and care management program for Medicare beneficiaries with chronic disease linked to savings. Health Aff (Millwood) 2011; 30:1689–1697.
- Franko OI, Bhola S. iPad apps for orthopedic surgeons. Orthopedics 2011; 34:978–981.
- The smartphone will see you now: “apps” and devices are turning cell phones into tools for health. Harv Heart Lett 2011; 22:3.
- Barr PJ, McElnay JC, Hughes CM. Connected health care: the future of health care and the role of the pharmacist [published online ahead of print August 4, 2010]. J Eval Clin Pract 2012; 18:56–62. 10.1111/j.1365-2753.2010.01522x
- O’Neill SA, Nugent CD, Donnelly MP, McCullagh P, McLaughlin J. Evaluation of connected health technology. Technol Health Care 2012; 20:151–167.
- Ziebland S, Wyke S. Health and illness in a connected world: how might sharing experiences on the internet affect people’s health? Milbank Q 2012; 90:219–249.
- Dobson A. Personal communication. 2011.
- Dreyfus D. Smart-home technology for persons with disabilities. Am Fam Physician 2009; 80:233.
- Leff B, Burton L, Mader SL, Naughton B, et al. Hospital at home: feasibility and outcomes of a program to provide hospital-level care at home for acutely ill older patients. Ann Intern Med 2005; 143:798–808.
- Quinn CC, Shardell MD, Terrin ML, et al. Cluster-randomized trial of a mobile phone personalized behavioral intervention for blood glucose control [published online ahead of print July 25, 2011]. Diabetes Care 2011; 34:1934–1942. 10.2337/dc11-0366
- Medicare Home Health Agency Manual. Section 201.13, Tele-health. Centers for Medicare & Medicaid Services Web site. http://www.cms.gov/Regulations-and-Guidance/Guidance/Transmittals/downloads/R298HHA.pdf. Published January 22, 2002. Accessed September 18, 2012.
- Stoll C. The Internet? Bah! Newsweek 1995; 125 February 27:41.
Many technologies have emerged to monitor, interact with, and support patients at home and change home health care delivery.1–5 This trend coincides with the explosion of consumer digital and mobile products such as “smartphones” and has brought with it many different names, such as telehealth, telemedicine, e-medicine, remote monitoring, “virtual” care, digital health, mobile medicine, interactive health, and distance health. Many of these terms and concepts raise concerns for those who value traditional expressions of caring, physical diagnosis, touch, and presence in health care. However, these new technologies may present opportunities to find ways to enhance humanism in home health care. This potential may be most evident among patients with serious chronic illness and their families, who often struggle 168 hours a week but find their access to help limited to brief visits at times convenient for the provider.
While our health care system offers heroic acute-care treatments for hundreds of life-threatening maladies, we seem to fall short in helping those with serious ongoing needs whose care must be coordinated over time and across health care venues. Thinking in terms of “connected health” may provide a more holistic nomenclature that suggests the bond between technology and the opportunity for closer personal relationships.6–8
OPPORTUNITIES
Can technology better connect our home health patients and families to care during the “white space,”9 between our visits? Can we use new mobile and digital technologies to improve care for the seriously chronically ill? We have the technology to turn many challenges into opportunities in the next decade. For example:
- Can we change our visit-based model of home health care to a model that provides 24/7 “inbound” multichannel access to home health care teams along with proactive “outbound” support between visits in the form of multimedia health education and virtual encounters? Can this free up time for longer visits targeted toward higher-risk and higher-complexity scenarios that require extensive team leadership and care coordination?
- Can “smart” home monitoring be integrated into home-based long-term care for patients who have dementia, fall risks, other safety issues, or unaddressed limitations in activities of daily living to increase independence and quality of life and reduce institutionalization while decreasing cost of care and accommodating workforce constraints?10
- How do we apply clinician-to-clinician and clinician-to-patient videoconferencing and other connected health approaches to increase home health patient access to specialized, but hard-to-find, clinicians for consultative and direct-care services?
- Can emerging technologies accelerate the shift in care whereby most acute care for exacerbations of chronic illness and other common acute scenarios move from hospitals into home-based models of acute care, such as “Hospital at home”?11
- To what extent can apps and other technologies provide self-management support to truly deliver the home health care version of the automatic teller machine? For example, diabetes self-management support tools provide patients feedback about their disease based on information input into mobile devices.12 Can this be expanded in a way that dramatically increases access, especially for vulnerable groups that have been hard to reach, while also decreasing costs?
- Can we improve the home health care experience by using connected health concepts to improve transparency, minimize common scheduling delays and annoyances, and empower patients while they are receiving care?
REAL-WORLD BARRIERS
Despite the opportunities, barriers remain for innovative providers. With few exceptions, there is no direct third-party reimbursement for care that comes through a device rather than the front door. Medicare does not reimburse home health providers for services outside of a visit, but specific guidance has been issued that clarifies some of the opportunities:
An HHA (Home Health Agency) may adopt telehealth technologies that it believes promote efficiencies or improve quality of care…. An HHA may not substitute telehealth services for Medicare-covered services ordered by a physician. However, if an HHA has telehealth services available to its clients, a doctor may take their availability into account when he or she prepares a plan…. If a physician intends that telehealth services be furnished while a patient is under a home health plan of care, the services should be recorded in the plan of care along with the Medicare covered home health services to be furnished.13
Thus, there is no reimbursement for telehealth services, but if telehealth is part of a physician-directed plan of care, it may be included if it promotes home health quality and efficiency. Beyond reimbursement, there are other regulatory barriers. If monitoring or other digital or virtual services are provided across state lines, the clinicians involved in a regional or national “command center” likely must meet the licensure requirements (or obtain waivers) for every jurisdiction in which their patients reside. Providers should seek counsel regarding the extent to which new devices and software need to be approved by the US Food and Drug Administration before being deployed. And, as with all health-related communication, it is essential that information transmitted in nontraditional ways be secure, private, and compliant with all mandated standards for privacy. Finally, if the technology or service is rolled out in a fashion that could be construed as a “gift” or “freebie” for marketing purposes rather than a tool to improve clinical outcomes and health care value, then there may be a risk that the approach runs afoul of laws to prevent undue inducements.
In addition to reimbursement and regulatory concerns, there are technical barriers to fully realizing the connected health opportunities in home care. Even if patients are provided with devices, there is variability in internet connectivity or bandwidth in any given home. Providing devices with built-in cellular capabilities can reduce these barriers, but cellular data coverage varies across different geographies. High-quality health care videoconferencing tends to require more bandwidth than that provided in the typical “3G” connection. Use of existing cable television connections, which are almost ubiquitous, is another option, but it typically requires a more customized set-up than consumer mobile devices with cellular and wireless capabilities. If the services were delivered or coordinated by the cable provider, some of these inconveniences might be resolved.
As with most innovation, there is no “cookbook,” and there is limited and conflicting evidence in the clinical sciences literature to guide best practices. Organizations that commit to using technology to improve the quality and efficiency of care will experience fits and starts before they find the right types and “doses” of technology in their new care models. The home health community should beware of these frustrations leading to undue skepticism, like that of Newsweek author Clifford Stoll, who in 1995 infamously wrote about the developing internet:
…today, I’m uneasy about this [trend]…. Visionaries see a future of telecommuting workers, interactive libraries and multimedia classrooms. They speak of electronic town meetings and virtual communities. Commerce and business will shift from offices and malls to networks and modems. And the freedom of digital networks will make government more democratic. Baloney. Do our computer pundits lack all common sense? The truth is no online database will replace your daily newspaper … no computer network will change the way government works.14
Like the internet of 15 years ago, mobile and digital technologies are now changing how people live and relate to one another and how businesses function. It is unlikely that the impact of these technologies on health care will be fully elucidated by controlled trials that consider incremental changes to existing care models and workflows. Rather, innovative providers and the next generation of clinicians that “grew up,” with mobile devices as part of their lives will create new home care workflows and care realities. Home health providers can use these technologies to better connect their patients and find new ways to reduce suffering, increase health and independence, and improve the care experience while lowering costs and increasing value. The individuals and organizations that seize the moment and “answer” these key questions in connected health with successful new approaches to care will be the winners of the future. There is such an opportunity to make a difference.
Many technologies have emerged to monitor, interact with, and support patients at home and change home health care delivery.1–5 This trend coincides with the explosion of consumer digital and mobile products such as “smartphones” and has brought with it many different names, such as telehealth, telemedicine, e-medicine, remote monitoring, “virtual” care, digital health, mobile medicine, interactive health, and distance health. Many of these terms and concepts raise concerns for those who value traditional expressions of caring, physical diagnosis, touch, and presence in health care. However, these new technologies may present opportunities to find ways to enhance humanism in home health care. This potential may be most evident among patients with serious chronic illness and their families, who often struggle 168 hours a week but find their access to help limited to brief visits at times convenient for the provider.
While our health care system offers heroic acute-care treatments for hundreds of life-threatening maladies, we seem to fall short in helping those with serious ongoing needs whose care must be coordinated over time and across health care venues. Thinking in terms of “connected health” may provide a more holistic nomenclature that suggests the bond between technology and the opportunity for closer personal relationships.6–8
OPPORTUNITIES
Can technology better connect our home health patients and families to care during the “white space,”9 between our visits? Can we use new mobile and digital technologies to improve care for the seriously chronically ill? We have the technology to turn many challenges into opportunities in the next decade. For example:
- Can we change our visit-based model of home health care to a model that provides 24/7 “inbound” multichannel access to home health care teams along with proactive “outbound” support between visits in the form of multimedia health education and virtual encounters? Can this free up time for longer visits targeted toward higher-risk and higher-complexity scenarios that require extensive team leadership and care coordination?
- Can “smart” home monitoring be integrated into home-based long-term care for patients who have dementia, fall risks, other safety issues, or unaddressed limitations in activities of daily living to increase independence and quality of life and reduce institutionalization while decreasing cost of care and accommodating workforce constraints?10
- How do we apply clinician-to-clinician and clinician-to-patient videoconferencing and other connected health approaches to increase home health patient access to specialized, but hard-to-find, clinicians for consultative and direct-care services?
- Can emerging technologies accelerate the shift in care whereby most acute care for exacerbations of chronic illness and other common acute scenarios move from hospitals into home-based models of acute care, such as “Hospital at home”?11
- To what extent can apps and other technologies provide self-management support to truly deliver the home health care version of the automatic teller machine? For example, diabetes self-management support tools provide patients feedback about their disease based on information input into mobile devices.12 Can this be expanded in a way that dramatically increases access, especially for vulnerable groups that have been hard to reach, while also decreasing costs?
- Can we improve the home health care experience by using connected health concepts to improve transparency, minimize common scheduling delays and annoyances, and empower patients while they are receiving care?
REAL-WORLD BARRIERS
Despite the opportunities, barriers remain for innovative providers. With few exceptions, there is no direct third-party reimbursement for care that comes through a device rather than the front door. Medicare does not reimburse home health providers for services outside of a visit, but specific guidance has been issued that clarifies some of the opportunities:
An HHA (Home Health Agency) may adopt telehealth technologies that it believes promote efficiencies or improve quality of care…. An HHA may not substitute telehealth services for Medicare-covered services ordered by a physician. However, if an HHA has telehealth services available to its clients, a doctor may take their availability into account when he or she prepares a plan…. If a physician intends that telehealth services be furnished while a patient is under a home health plan of care, the services should be recorded in the plan of care along with the Medicare covered home health services to be furnished.13
Thus, there is no reimbursement for telehealth services, but if telehealth is part of a physician-directed plan of care, it may be included if it promotes home health quality and efficiency. Beyond reimbursement, there are other regulatory barriers. If monitoring or other digital or virtual services are provided across state lines, the clinicians involved in a regional or national “command center” likely must meet the licensure requirements (or obtain waivers) for every jurisdiction in which their patients reside. Providers should seek counsel regarding the extent to which new devices and software need to be approved by the US Food and Drug Administration before being deployed. And, as with all health-related communication, it is essential that information transmitted in nontraditional ways be secure, private, and compliant with all mandated standards for privacy. Finally, if the technology or service is rolled out in a fashion that could be construed as a “gift” or “freebie” for marketing purposes rather than a tool to improve clinical outcomes and health care value, then there may be a risk that the approach runs afoul of laws to prevent undue inducements.
In addition to reimbursement and regulatory concerns, there are technical barriers to fully realizing the connected health opportunities in home care. Even if patients are provided with devices, there is variability in internet connectivity or bandwidth in any given home. Providing devices with built-in cellular capabilities can reduce these barriers, but cellular data coverage varies across different geographies. High-quality health care videoconferencing tends to require more bandwidth than that provided in the typical “3G” connection. Use of existing cable television connections, which are almost ubiquitous, is another option, but it typically requires a more customized set-up than consumer mobile devices with cellular and wireless capabilities. If the services were delivered or coordinated by the cable provider, some of these inconveniences might be resolved.
As with most innovation, there is no “cookbook,” and there is limited and conflicting evidence in the clinical sciences literature to guide best practices. Organizations that commit to using technology to improve the quality and efficiency of care will experience fits and starts before they find the right types and “doses” of technology in their new care models. The home health community should beware of these frustrations leading to undue skepticism, like that of Newsweek author Clifford Stoll, who in 1995 infamously wrote about the developing internet:
…today, I’m uneasy about this [trend]…. Visionaries see a future of telecommuting workers, interactive libraries and multimedia classrooms. They speak of electronic town meetings and virtual communities. Commerce and business will shift from offices and malls to networks and modems. And the freedom of digital networks will make government more democratic. Baloney. Do our computer pundits lack all common sense? The truth is no online database will replace your daily newspaper … no computer network will change the way government works.14
Like the internet of 15 years ago, mobile and digital technologies are now changing how people live and relate to one another and how businesses function. It is unlikely that the impact of these technologies on health care will be fully elucidated by controlled trials that consider incremental changes to existing care models and workflows. Rather, innovative providers and the next generation of clinicians that “grew up,” with mobile devices as part of their lives will create new home care workflows and care realities. Home health providers can use these technologies to better connect their patients and find new ways to reduce suffering, increase health and independence, and improve the care experience while lowering costs and increasing value. The individuals and organizations that seize the moment and “answer” these key questions in connected health with successful new approaches to care will be the winners of the future. There is such an opportunity to make a difference.
- Chen HF, Kalish MC, Pagan JA. Telehealth and hospitalizations for Medicare home healthcare patients. Am J Manag Care 2011; 17 (6 Spec No.):e224–e230.
- Gellis ZD, Kenaley B, McGinty J, Bardelli E, Davitt J, Ten Have T Outcomes of a telehealth intervention for homebound older adults with heart or chronic respiratory failure: a randomized controlled trial [published online ahead of print January 11, 2012]. Gerontologist 2012; 52:541–552. 10.1093/geront/gnr134
- Baker LC, Johnson SJ, Macaulay D, Birnbaum H. Integrated telehealth and care management program for Medicare beneficiaries with chronic disease linked to savings. Health Aff (Millwood) 2011; 30:1689–1697.
- Franko OI, Bhola S. iPad apps for orthopedic surgeons. Orthopedics 2011; 34:978–981.
- The smartphone will see you now: “apps” and devices are turning cell phones into tools for health. Harv Heart Lett 2011; 22:3.
- Barr PJ, McElnay JC, Hughes CM. Connected health care: the future of health care and the role of the pharmacist [published online ahead of print August 4, 2010]. J Eval Clin Pract 2012; 18:56–62. 10.1111/j.1365-2753.2010.01522x
- O’Neill SA, Nugent CD, Donnelly MP, McCullagh P, McLaughlin J. Evaluation of connected health technology. Technol Health Care 2012; 20:151–167.
- Ziebland S, Wyke S. Health and illness in a connected world: how might sharing experiences on the internet affect people’s health? Milbank Q 2012; 90:219–249.
- Dobson A. Personal communication. 2011.
- Dreyfus D. Smart-home technology for persons with disabilities. Am Fam Physician 2009; 80:233.
- Leff B, Burton L, Mader SL, Naughton B, et al. Hospital at home: feasibility and outcomes of a program to provide hospital-level care at home for acutely ill older patients. Ann Intern Med 2005; 143:798–808.
- Quinn CC, Shardell MD, Terrin ML, et al. Cluster-randomized trial of a mobile phone personalized behavioral intervention for blood glucose control [published online ahead of print July 25, 2011]. Diabetes Care 2011; 34:1934–1942. 10.2337/dc11-0366
- Medicare Home Health Agency Manual. Section 201.13, Tele-health. Centers for Medicare & Medicaid Services Web site. http://www.cms.gov/Regulations-and-Guidance/Guidance/Transmittals/downloads/R298HHA.pdf. Published January 22, 2002. Accessed September 18, 2012.
- Stoll C. The Internet? Bah! Newsweek 1995; 125 February 27:41.
- Chen HF, Kalish MC, Pagan JA. Telehealth and hospitalizations for Medicare home healthcare patients. Am J Manag Care 2011; 17 (6 Spec No.):e224–e230.
- Gellis ZD, Kenaley B, McGinty J, Bardelli E, Davitt J, Ten Have T Outcomes of a telehealth intervention for homebound older adults with heart or chronic respiratory failure: a randomized controlled trial [published online ahead of print January 11, 2012]. Gerontologist 2012; 52:541–552. 10.1093/geront/gnr134
- Baker LC, Johnson SJ, Macaulay D, Birnbaum H. Integrated telehealth and care management program for Medicare beneficiaries with chronic disease linked to savings. Health Aff (Millwood) 2011; 30:1689–1697.
- Franko OI, Bhola S. iPad apps for orthopedic surgeons. Orthopedics 2011; 34:978–981.
- The smartphone will see you now: “apps” and devices are turning cell phones into tools for health. Harv Heart Lett 2011; 22:3.
- Barr PJ, McElnay JC, Hughes CM. Connected health care: the future of health care and the role of the pharmacist [published online ahead of print August 4, 2010]. J Eval Clin Pract 2012; 18:56–62. 10.1111/j.1365-2753.2010.01522x
- O’Neill SA, Nugent CD, Donnelly MP, McCullagh P, McLaughlin J. Evaluation of connected health technology. Technol Health Care 2012; 20:151–167.
- Ziebland S, Wyke S. Health and illness in a connected world: how might sharing experiences on the internet affect people’s health? Milbank Q 2012; 90:219–249.
- Dobson A. Personal communication. 2011.
- Dreyfus D. Smart-home technology for persons with disabilities. Am Fam Physician 2009; 80:233.
- Leff B, Burton L, Mader SL, Naughton B, et al. Hospital at home: feasibility and outcomes of a program to provide hospital-level care at home for acutely ill older patients. Ann Intern Med 2005; 143:798–808.
- Quinn CC, Shardell MD, Terrin ML, et al. Cluster-randomized trial of a mobile phone personalized behavioral intervention for blood glucose control [published online ahead of print July 25, 2011]. Diabetes Care 2011; 34:1934–1942. 10.2337/dc11-0366
- Medicare Home Health Agency Manual. Section 201.13, Tele-health. Centers for Medicare & Medicaid Services Web site. http://www.cms.gov/Regulations-and-Guidance/Guidance/Transmittals/downloads/R298HHA.pdf. Published January 22, 2002. Accessed September 18, 2012.
- Stoll C. The Internet? Bah! Newsweek 1995; 125 February 27:41.
Innovative models of home-based palliative care
As the prevalence of serious illness among the elderly population has increased, interest in palliative care has grown as an approach to care management that is patient-centered and focused on quality of life. Case management that employs palliative care has the potential to alleviate unnecessary pain and suffering for patients while they concurrently pursue life-prolonging therapy. Palliative care can be provided across the continuum of care, involving multiple health care providers and practitioners.
Home health care, while often used as a postacute care provider, also can provide longitudinal care to elderly patients without a preceding hospitalization. Home health providers often act as central liaisons to coordinate care while patients are at home, particularly chronically ill patients with multiple physician providers, complex medication regimens, and ongoing concerns with independence and safety in the home.
Home health care can play a critical role in providing palliative care and, through innovative programs, can improve access to it. This article provides context and background on the provision of palliative care and explores how home health can work seamlessly in coordination with other health care stakeholders in providing palliative care.
WHAT IS PALLIATIVE CARE?
Palliative care means patient- and family-centered care that optimizes quality of life by anticipating, preventing, and treating suffering. Palliative care throughout the continuum of illness involves addressing physical, intellectual, emotional, social, and spiritual needs and [facilitating] patient autonomy, access to information, and choice.1
At its core, palliative care is a field of medicine aimed at alleviating the suffering of patients. As a “philosophy of care,” palliative care is appropriate for various sites of care at various stages of disease and all ages of patients. While hospice care is defined by the provision of palliative care for patients at the end of life, not all palliative care is hospice care. Rather, palliative care is an approach to care for any patient diagnosed with a serious illness that leverages expertise from multidisciplinary teams of health professionals and addresses pain and symptoms.
Palliative care addresses suffering by incorporating psychosocial and spiritual care with consideration of patient and family needs, preferences, values, beliefs and cultures. Palliative care can be provided throughout the continuum of care for patients with chronic, serious, and even life-threatening illnesses.1 To a degree, all aspects of health care can potentially address some palliative issues in that health care providers ideally combine a desire to cure the patient with a need to alleviate the patient’s pain and suffering.
Although the Medicare program recognizes the potential breadth of palliative care, the hospice benefit is relatively narrow. Consistent with the depiction in the Figure,2 the Medicare hospice benefit is limited to care that is focused on “comfort, not on curing an illness”3 (emphasis added). The Medicare hospice benefit is available to Medicare beneficiaries who: (1) are eligible for Medicare Part A; (2) have a doctor and hospice medical director certifying that they are terminally ill and have 6 months or less to live if their illness runs its normal course; (3) sign a statement choosing hospice care instead of other Medicare-covered benefits to treat their terminal illness (although Medicare will still pay for covered benefits for any health problems that are not related to the terminal illness); and (4) get care from a Medicare-certified hospice program.3
There are, however, clear benefits to providing palliative care outside of the Medicare hospice benefit. In particular, patients with serious illnesses may have more than 6 months to live if their illness runs its normal course. Patients who may die within 1 year due to serious illness can benefit from palliative care. Furthermore, some patients would like to continue to pursue curative treatment of their illnesses, but would benefit from a palliative care approach. By providing palliative care in the context of a plan of care with the patient’s physician, the patient and family can comprehensively make decisions and obtain support that enables access to appropriate treatments while allowing enhanced quality of life through symptom management.
WHO CAN PROVIDE PALLIATIVE CARE?
Palliative care can be provided in any care setting that has been accredited or certified to provide care, including those that are upstream from hospice along the continuum of care. Hospitals, nursing homes, and home health agencies can provide palliative care.
The Joint Commission, a nonprofit accrediting organization, currently accredits or certifies more than 17,000 organizations or programs across the care continuum, including hospitals, nursing homes, home health agencies, and hospices. Within the scope of the home care accreditation program, hospices and home health agencies are evaluated by certified field representatives to determine the extent to which their services meet the standards established by The Joint Commission. These standards are developed with input from health care professionals, providers, subject matter experts, consumers, government agencies (including the Centers for Medicare & Medicaid Services [CMS]) and employers. They are informed by scientific literature and expert consensus and approved by the board of commissioners.
The Joint Commission also has a certification program for palliative care services provided in hospitals and has certified 21 palliative care programs at various hospitals in the United States.
The Joint Commission’s Advanced Certification Program for Palliative Care recognizes hospital inpatient programs that demonstrate exceptional patient-and family-centered care and optimize quality of life for patients (both adult and pediatric) with serious illness. Certification standards emphasize:
- A formal, organized, palliative care program led by an interdisciplinary team whose members are experts in palliative care
- Leadership endorsement and support of the program’s goals for providing care, treatment and services
- Special focus on patient and family engagement
- Processes that support the coordination of care and communication among all care settings and providers
- The use of evidence-based national guidelines or expert consensus to guide patient care
The certification standards cover program management, provision of care, information management, and performance improvement. The standards are built on the National Consensus Project’s Clinical Practice Guidelines for Quality Palliative Care2 and the National Quality Forum’s National Framework and Preferred Practices for Palliative and Hospice Care Quality.4 Many of the concepts contained in the standards for inpatient palliative care have their origins in hospice care.
In addition to palliative care accreditation programs, certification in palliative care for clinicians is also possible. The American Board of Medical Specialties approved the creation of hospice and palliative medicine as a subspecialty in 2006. The National Board of Certification of Hospice and Palliative Nurses offers specialty certification for all levels of hospice and palliative care nursing. The National Association of Social Workers also offers an advanced certified hospice and palliative social worker (ACHP-SW) certifcation for MSW-level clinicians. These certification programs establish qualifications and standards for the members of a palliative care team.
Subject to federal and state requirements that regulate the way health care is provided, hospitals, nursing homes, home health agencies, and hospices are able to provide palliative care to patients who need such care.5,6
WHAT IS HOME HEALTH’S ROLE IN PROVIDING PALLIATIVE CARE?
Many Medicare-certified home health agencies also operate Medicare-approved hospice programs. Home health agencies have a heightened perspective on patients’ palliative care needs. Because of the limited nature of the Medicare hospice benefit, home health agencies have built palliative care programs to fill unmet patient needs. Home health agencies often provide palliative care to patients who may be ineligible for the hospice benefit or have chosen not to enroll in it. These programs are particularly attractive to patients who would like to pursue curative treatment for their serious illnesses or who are expected to live longer than 6 months.
Home health patients with advancing or serious illness or chronic illness are candidates for a palliative care service. For these patients, the burden of their illness continues to grow as distressing symptoms begin to more regularly impact their quality of life. As they continue curative treatment of their illness, they would benefit from palliative care services that provide greater relief of their symptoms and support advanced care planning. Palliative care interventions become an integrated part of the care plan for these patients. Home health agencies serving patients with chronic or advancing illnesses will see care benefits from incorporating palliative care into their team’s skill set.
Two innovative examples of home health–based programs that include a palliative care component have been reported in peer-reviewed literature to date: Kaiser Permanente’s In-Home Palliative Care program and Sutter Health’s Advanced Illness Management (AIM) program.7–10
Kaiser Permanente’s In-Home Palliative Care Program
Kaiser Permanente (KP) established the TriCentral Palliative Care Program in 1998 to achieve balance for seriously ill patients facing the end of life who were caught between “the extremes of too little care and too much.”11 KP began the program after discovering that patients were underusing their existing hospice program. The TriCentral Palliative Care program is an outpatient service, housed in the KP home health department and modeled after the KP hospice program with three key modifications designed to encourage timely referrals to the program:
- Physicians are asked to refer a patient if they “would not be surprised if this patient died in the next year.” Palliative care patients with a prognosis of 12 months or less to live are accepted into the program.
- Improved pain control and symptom management are emphasized, but patients do not need to forgo curative care as they do in hospice programs.
- Patients are assigned a palliative care physician who coordinates care from a variety of health care providers, preventing fragmentation.
The program has five core components that are geared toward enhanced quality of care and patient quality of life. These core components are:
- An interdisciplinary team approach, focused on patient and family, with care provided by a core team consisting of a physician, nurse, and social worker, all with expertise in pain control, other symptom management, and psychosocial intervention
- Home visits by all team members, including physicians, to provide medical care, support, and education as needed by patients and their caregivers
- Ongoing care management to fill gaps in care and ensure that the patient’s medical, social, and spiritual needs are being met
- Telephone support via a toll-free number and after-hours home visits available 24 hours a day, 7 days a week as needed by the patient
- Advanced-care planning that empowers patients and their families to make informed decisions and choices about end-of-life care11
Assessments of the program’s results in a randomized controlled trial8 and a comparative study9 showed that patient satisfaction increased; patients were more likely to die at home in accordance with their wishes; and emergency department (ED) visits, inpatient admissions, and costs were reduced (Table 1).
Sutter Health AIM Program
Sutter Health in northern California, in collaboration with its home care and hospice affiliate, Sutter Care at Home, initiated a home health–based program, Advanced Illness Management (AIM), in 2000 in response to the growing population of patients with advanced illness who needed enhanced care planning and symptom management. This program served patients who met the Medicare eligibility criteria for home health, had a prognosis of 1 year or less, and were continuing to seek treatment or cure for their illness. These patients frequently lacked awareness of their health status, particularly as it related to choices and decisions connected to the progression and management of their conditions. They also were frequently receiving uncoordinated care through various health channels, resulting in substandard symptom management. As a result, patients tended to experience more acute episodes that required frequent use of “unwanted and inappropriate care at the end of life, and they, their families, and their providers were dissatisfied.”12
As the AIM program matured, it incorporated a broader care management model, including principles of patient/caregiver engagement and goal setting, self-management techniques, ongoing advanced care planning, symptom management, and other evidence-based practices related to care transitions and care management. The program connects with the patient’s network of care providers and coordinates the exchange of realtime information about the current status of care plans and medication, as well as the patient’s defined goals. This more comprehensive model of care for persons with advanced illness has achieved improved adherence to patient wishes and goals, reductions in unnecessary hospital and ED utilization, and higher patient/caregiver and provider satisfaction than usual care.
Today, AIM is not primarily a palliative care program. Rather, it provides a comprehensive approach to care management that moves the focus of care for advanced illness out of the hospital and into the home/community setting. AIM achieves this through integrating the patient’s “health system.”
This integration occurs through formation of an interdisciplinary team comprised of the home care team, representative clinicians connected to the hospital, and providers of care for the patient. This expanded team, then, becomes the AIM care management team that is trained on the principles of AIM and its interventions. With this enhanced level of care coordination and unified focus on supporting the patient’s personal health goals, the AIM program serves as a “health system integrator” for the vulnerable and costly population of people with advanced chronic illness.
Inpatient palliative care is a separate and distinct systemwide priority at Sutter Health and, because of this, AIM collaborates closely with the inpatient palliative care teams to ensure that patients experience a seamless transition from hospital to home. There, AIM staff work with patients and families over time to clarify and document their personal values and goals, then use these to develop and drive the care plan. Armed with clearer appreciation of the natural progression of illness, both clinically and practically, coupled with improved understanding of available options for care, most choose to stay in the safety and comfort of their homes and out of the hospital. These avoided hospitalizations are the primary source of AIM’s considerable cost savings.
Patients eligible for AIM are those with clinical, functional, or nutritional decline; with multiple hospitalizations, ED visits, or both within the past 12 months; and who are clinically eligible for hospice but have chosen to continue treatment or have not otherwise made the decision to use a hospice model of care. Once the patient is enrolled, the AIM team works with the patient, the family, and the physician on a preference-driven plan of care. That plan is shared with all providers supporting the patient and is regularly updated to reflect changes in the patient’s evolving choices as illness advances. This tracking of goals and preferences over time as illness progresses has been a critical factor in improving outcomes, especially those related to adherence or honoring a patient’s personal goals.
The AIM program started as a symptom management and care planning intervention for Medicare-eligible home health patients. The program has evolved over time into a pivotal fulcrum by which to engage or create an interdisciplinary focus and skill set across sites and providers of care in an effort to improve the overall outcomes for patients with advancing illness. In 2009, the AIM program began geographically expanding its home health–based AIM teams across 12 counties surrounding the San Francisco Bay area and the greater Sacramento region in northern California. The program now coordinates care with more than 17 hospitals and all of the large Sutter-affiliated medical groups, and it serves approximately 800 patients per day.
The AIM program has yielded significant results in terms of both quality of care and cost savings. Preliminary data on more than 300 AIM patients surveyed from November 2009 through September 2010 showed significant reductions in unnecessary hospitalizations and inpatient direct care costs (Table 2).12 Survey data also showed significant improvements in patient, family, and physician satisfaction when late-stage patients were served through AIM rather than through home care by itself.12
The Sutter Health AIM program recently received a Health Care Innovation Award from the Center for Medicare & Medicaid Innovation (CMMI) because of the program’s ability to “improve care and patient quality of life, increase physician, caregiver, and patient satisfaction, and reduce Medicare costs associated with avoidable hospital stays, ED visits, and days spent in intensive care units and skilled nursing facilities.”13 The $13 million CMMI grant will help expand AIM to the entire Sutter Health system. It is estimated that the program will save $29,388,894 over 3 years.13
CONCLUSION: CHALLENGES AND OPPORTUNITIES FOR THE US HEALTH CARE SYSTEM
The basic objective of AIM and programs like it is to move the focus of care for people with advanced illness out of the hospital and into home and community. This fulfills the Triple Aim vision set forth in 2008 by former CMS Administrator Don Berwick14:
- Improving health by reducing inpatient care that does not achieve person-centered goals or reduce overall mortality
- Improving care by basing it on the values and goals of people dealing with serious chronic illness
- Reducing costs by preventing unwanted hospital care
Sutter Health, a system that is on its way to becoming fully clinically integrated, was a logical choice for launching AIM because its hospitals are forming relationships with physician groups and home care providers. This integration process is supported nationally by CMS and CMMI, which are promoting new models of care and reimbursement such as accountable care organizations (ACOs) and bundled payments.
Nonintegrated hospitals and other provider groups can move in this same direction. AIM establishes key care coordination roles in each setting of care such as in hospitals and physician offices, as well as in the home care–based team and providers. The AIM care model emphasizes close coordination of clinical activities and communications, and integrates these with hospital and medical group operations. These provider groups can move strategically toward becoming “virtual ACOs” by coordinating care for people with advanced illness, who comprise the most vulnerable and costly segment of the US population and increasingly impact Medicare expenditures.
Changes in federal policy will be needed to facilitate national implementation of AIM-like programs. If ACOs and bundled payments were to be implemented overnight, the person-centered, cost-saving advantages of AIM would be obvious. However, until shared risk/shared savings models replace fee-for-service reimbursement, new payment policies will be needed on an interim basis to cover the costs of currently nonreimbursed care management services. This could be arranged through a per-enrollee-per-month payment or shared savings models tied to specific quality and utilization outcomes.
Simplification of regulatory requirements to better serve persons with advancing illness and to reduce the burden on providers operating such programs would be valuable. The pattern or progression of advancing chronic illness requires ongoing coordination in order to maintain a higher quality of life and symptom management. Current regulations and requirements foster an episodic focus in the home, as well in the hospital and physician’s office, which is not in alignment with the experience of persons living with advancing illness.
- Centers for Medicare & Medicaid Services. Medicare and Medicaid program: conditions of participation. Federal Register 2008; 73:32088–32219.
- Clinical Practice Guidelines for Quality Palliative Care. 2nd ed. Pittsburgh, PA: National Consensus Project for Quality Palliative Care. National Consensus Project Web site. http:www.nationalconsensusproject.org. Published 2009. Accessed December 12, 2012.
- Medicare hospice benefits. Centers for Medicare & Medicaid Services Web site. http://www.medicare.gov/publications/pubs/pdf/02154.pdf. Revised August 2012. Accessed November 14, 2012.
- A national framework and preferred practices for palliative and hospice care quality. A consensus report. National Quality Forum Web site. http://www.qualityforum.org/Publications/2006/12/A_National_Framework_and_Preferred_Practices_for_Palliative_and_Hospice_Care_Quality.aspx. Published 2006. Accessed December 12, 2012.
- Michal MH, Pekarske MSL. Palliative care checklist: selected regulatory and risk management considerations. National Hospice and Palliative Care Organization Web site. http://www.nhpco.org/fles/public/palliativecare/pcchecklist.pdf. Published April 17, 2006. Accessed November 14, 2012.
- Raffa CA. Palliative care: the legal and regulatory requirements. National Hospice and Palliative Care Organization Web site. http://www.nhpco.org/files/public/palliativecare/legal_regulatorypart2.pdf. Published December 22, 2003. Accessed November 14, 2012.
- In-home palliative care allows more patients to die at home, leading to higher satisfaction and lower acute care utilization and costs. Agency for Healthcare Research and Quality Health Care Innovations Exchange Web site. http://www.innovations.ahrq.gov/content.aspx?id=2366. Published March 2, 2009. Updated November 07, 2012. Accessed November 14, 2012.
- Brumley R, Enguidanos S, Jamison P, et al. Increased satisfaction with care and lower costs: results of a randomized trial of in-home palliative care. J Am Geriatr Soc 2007; 55:993–1000.
- Enguidanos SM, Cherin D, Brumley R. Home-based palliative care study: site of death, and costs of medical care for patients with congestive heart failure, chronic obstructive pulmonary disease, and cancer. J Soc Work End Life Palliat Care 2005; 1:37–56.
- Brumley RD, Enguidanos S, Cherin DA. Effectiveness of a home-based palliative care program for end-of-life. J Palliat Med 2003; 6:715–724.
- Brumley RD, Hillary K. The TriCentral Palliative Care Program Toolkit. 1st ed. MyWhatever Web site. http://www.mywhatever.com/cifwriter/content/22/fles/sorostoolkitfnal120902.doc. Published 2002. Accessed November 14, 2012.
- Meyer H. Innovation profile: changing the conversation in California about care near the end of life. Health Aff 2011; 30:390–393.
- Health Care Innovation Awards. Center for Medicare & Medicaid Innovation Web site. http://innovations.cms.gov/initiatives/Innovation-Awards/california.html. Accessed November 14, 2012.
- Berwick DJ, Nolan TW, Whittington J. The triple aim: care, health, and cost. Health Aff 2008; 27:759–769.
As the prevalence of serious illness among the elderly population has increased, interest in palliative care has grown as an approach to care management that is patient-centered and focused on quality of life. Case management that employs palliative care has the potential to alleviate unnecessary pain and suffering for patients while they concurrently pursue life-prolonging therapy. Palliative care can be provided across the continuum of care, involving multiple health care providers and practitioners.
Home health care, while often used as a postacute care provider, also can provide longitudinal care to elderly patients without a preceding hospitalization. Home health providers often act as central liaisons to coordinate care while patients are at home, particularly chronically ill patients with multiple physician providers, complex medication regimens, and ongoing concerns with independence and safety in the home.
Home health care can play a critical role in providing palliative care and, through innovative programs, can improve access to it. This article provides context and background on the provision of palliative care and explores how home health can work seamlessly in coordination with other health care stakeholders in providing palliative care.
WHAT IS PALLIATIVE CARE?
Palliative care means patient- and family-centered care that optimizes quality of life by anticipating, preventing, and treating suffering. Palliative care throughout the continuum of illness involves addressing physical, intellectual, emotional, social, and spiritual needs and [facilitating] patient autonomy, access to information, and choice.1
At its core, palliative care is a field of medicine aimed at alleviating the suffering of patients. As a “philosophy of care,” palliative care is appropriate for various sites of care at various stages of disease and all ages of patients. While hospice care is defined by the provision of palliative care for patients at the end of life, not all palliative care is hospice care. Rather, palliative care is an approach to care for any patient diagnosed with a serious illness that leverages expertise from multidisciplinary teams of health professionals and addresses pain and symptoms.
Palliative care addresses suffering by incorporating psychosocial and spiritual care with consideration of patient and family needs, preferences, values, beliefs and cultures. Palliative care can be provided throughout the continuum of care for patients with chronic, serious, and even life-threatening illnesses.1 To a degree, all aspects of health care can potentially address some palliative issues in that health care providers ideally combine a desire to cure the patient with a need to alleviate the patient’s pain and suffering.
Although the Medicare program recognizes the potential breadth of palliative care, the hospice benefit is relatively narrow. Consistent with the depiction in the Figure,2 the Medicare hospice benefit is limited to care that is focused on “comfort, not on curing an illness”3 (emphasis added). The Medicare hospice benefit is available to Medicare beneficiaries who: (1) are eligible for Medicare Part A; (2) have a doctor and hospice medical director certifying that they are terminally ill and have 6 months or less to live if their illness runs its normal course; (3) sign a statement choosing hospice care instead of other Medicare-covered benefits to treat their terminal illness (although Medicare will still pay for covered benefits for any health problems that are not related to the terminal illness); and (4) get care from a Medicare-certified hospice program.3
There are, however, clear benefits to providing palliative care outside of the Medicare hospice benefit. In particular, patients with serious illnesses may have more than 6 months to live if their illness runs its normal course. Patients who may die within 1 year due to serious illness can benefit from palliative care. Furthermore, some patients would like to continue to pursue curative treatment of their illnesses, but would benefit from a palliative care approach. By providing palliative care in the context of a plan of care with the patient’s physician, the patient and family can comprehensively make decisions and obtain support that enables access to appropriate treatments while allowing enhanced quality of life through symptom management.
WHO CAN PROVIDE PALLIATIVE CARE?
Palliative care can be provided in any care setting that has been accredited or certified to provide care, including those that are upstream from hospice along the continuum of care. Hospitals, nursing homes, and home health agencies can provide palliative care.
The Joint Commission, a nonprofit accrediting organization, currently accredits or certifies more than 17,000 organizations or programs across the care continuum, including hospitals, nursing homes, home health agencies, and hospices. Within the scope of the home care accreditation program, hospices and home health agencies are evaluated by certified field representatives to determine the extent to which their services meet the standards established by The Joint Commission. These standards are developed with input from health care professionals, providers, subject matter experts, consumers, government agencies (including the Centers for Medicare & Medicaid Services [CMS]) and employers. They are informed by scientific literature and expert consensus and approved by the board of commissioners.
The Joint Commission also has a certification program for palliative care services provided in hospitals and has certified 21 palliative care programs at various hospitals in the United States.
The Joint Commission’s Advanced Certification Program for Palliative Care recognizes hospital inpatient programs that demonstrate exceptional patient-and family-centered care and optimize quality of life for patients (both adult and pediatric) with serious illness. Certification standards emphasize:
- A formal, organized, palliative care program led by an interdisciplinary team whose members are experts in palliative care
- Leadership endorsement and support of the program’s goals for providing care, treatment and services
- Special focus on patient and family engagement
- Processes that support the coordination of care and communication among all care settings and providers
- The use of evidence-based national guidelines or expert consensus to guide patient care
The certification standards cover program management, provision of care, information management, and performance improvement. The standards are built on the National Consensus Project’s Clinical Practice Guidelines for Quality Palliative Care2 and the National Quality Forum’s National Framework and Preferred Practices for Palliative and Hospice Care Quality.4 Many of the concepts contained in the standards for inpatient palliative care have their origins in hospice care.
In addition to palliative care accreditation programs, certification in palliative care for clinicians is also possible. The American Board of Medical Specialties approved the creation of hospice and palliative medicine as a subspecialty in 2006. The National Board of Certification of Hospice and Palliative Nurses offers specialty certification for all levels of hospice and palliative care nursing. The National Association of Social Workers also offers an advanced certified hospice and palliative social worker (ACHP-SW) certifcation for MSW-level clinicians. These certification programs establish qualifications and standards for the members of a palliative care team.
Subject to federal and state requirements that regulate the way health care is provided, hospitals, nursing homes, home health agencies, and hospices are able to provide palliative care to patients who need such care.5,6
WHAT IS HOME HEALTH’S ROLE IN PROVIDING PALLIATIVE CARE?
Many Medicare-certified home health agencies also operate Medicare-approved hospice programs. Home health agencies have a heightened perspective on patients’ palliative care needs. Because of the limited nature of the Medicare hospice benefit, home health agencies have built palliative care programs to fill unmet patient needs. Home health agencies often provide palliative care to patients who may be ineligible for the hospice benefit or have chosen not to enroll in it. These programs are particularly attractive to patients who would like to pursue curative treatment for their serious illnesses or who are expected to live longer than 6 months.
Home health patients with advancing or serious illness or chronic illness are candidates for a palliative care service. For these patients, the burden of their illness continues to grow as distressing symptoms begin to more regularly impact their quality of life. As they continue curative treatment of their illness, they would benefit from palliative care services that provide greater relief of their symptoms and support advanced care planning. Palliative care interventions become an integrated part of the care plan for these patients. Home health agencies serving patients with chronic or advancing illnesses will see care benefits from incorporating palliative care into their team’s skill set.
Two innovative examples of home health–based programs that include a palliative care component have been reported in peer-reviewed literature to date: Kaiser Permanente’s In-Home Palliative Care program and Sutter Health’s Advanced Illness Management (AIM) program.7–10
Kaiser Permanente’s In-Home Palliative Care Program
Kaiser Permanente (KP) established the TriCentral Palliative Care Program in 1998 to achieve balance for seriously ill patients facing the end of life who were caught between “the extremes of too little care and too much.”11 KP began the program after discovering that patients were underusing their existing hospice program. The TriCentral Palliative Care program is an outpatient service, housed in the KP home health department and modeled after the KP hospice program with three key modifications designed to encourage timely referrals to the program:
- Physicians are asked to refer a patient if they “would not be surprised if this patient died in the next year.” Palliative care patients with a prognosis of 12 months or less to live are accepted into the program.
- Improved pain control and symptom management are emphasized, but patients do not need to forgo curative care as they do in hospice programs.
- Patients are assigned a palliative care physician who coordinates care from a variety of health care providers, preventing fragmentation.
The program has five core components that are geared toward enhanced quality of care and patient quality of life. These core components are:
- An interdisciplinary team approach, focused on patient and family, with care provided by a core team consisting of a physician, nurse, and social worker, all with expertise in pain control, other symptom management, and psychosocial intervention
- Home visits by all team members, including physicians, to provide medical care, support, and education as needed by patients and their caregivers
- Ongoing care management to fill gaps in care and ensure that the patient’s medical, social, and spiritual needs are being met
- Telephone support via a toll-free number and after-hours home visits available 24 hours a day, 7 days a week as needed by the patient
- Advanced-care planning that empowers patients and their families to make informed decisions and choices about end-of-life care11
Assessments of the program’s results in a randomized controlled trial8 and a comparative study9 showed that patient satisfaction increased; patients were more likely to die at home in accordance with their wishes; and emergency department (ED) visits, inpatient admissions, and costs were reduced (Table 1).
Sutter Health AIM Program
Sutter Health in northern California, in collaboration with its home care and hospice affiliate, Sutter Care at Home, initiated a home health–based program, Advanced Illness Management (AIM), in 2000 in response to the growing population of patients with advanced illness who needed enhanced care planning and symptom management. This program served patients who met the Medicare eligibility criteria for home health, had a prognosis of 1 year or less, and were continuing to seek treatment or cure for their illness. These patients frequently lacked awareness of their health status, particularly as it related to choices and decisions connected to the progression and management of their conditions. They also were frequently receiving uncoordinated care through various health channels, resulting in substandard symptom management. As a result, patients tended to experience more acute episodes that required frequent use of “unwanted and inappropriate care at the end of life, and they, their families, and their providers were dissatisfied.”12
As the AIM program matured, it incorporated a broader care management model, including principles of patient/caregiver engagement and goal setting, self-management techniques, ongoing advanced care planning, symptom management, and other evidence-based practices related to care transitions and care management. The program connects with the patient’s network of care providers and coordinates the exchange of realtime information about the current status of care plans and medication, as well as the patient’s defined goals. This more comprehensive model of care for persons with advanced illness has achieved improved adherence to patient wishes and goals, reductions in unnecessary hospital and ED utilization, and higher patient/caregiver and provider satisfaction than usual care.
Today, AIM is not primarily a palliative care program. Rather, it provides a comprehensive approach to care management that moves the focus of care for advanced illness out of the hospital and into the home/community setting. AIM achieves this through integrating the patient’s “health system.”
This integration occurs through formation of an interdisciplinary team comprised of the home care team, representative clinicians connected to the hospital, and providers of care for the patient. This expanded team, then, becomes the AIM care management team that is trained on the principles of AIM and its interventions. With this enhanced level of care coordination and unified focus on supporting the patient’s personal health goals, the AIM program serves as a “health system integrator” for the vulnerable and costly population of people with advanced chronic illness.
Inpatient palliative care is a separate and distinct systemwide priority at Sutter Health and, because of this, AIM collaborates closely with the inpatient palliative care teams to ensure that patients experience a seamless transition from hospital to home. There, AIM staff work with patients and families over time to clarify and document their personal values and goals, then use these to develop and drive the care plan. Armed with clearer appreciation of the natural progression of illness, both clinically and practically, coupled with improved understanding of available options for care, most choose to stay in the safety and comfort of their homes and out of the hospital. These avoided hospitalizations are the primary source of AIM’s considerable cost savings.
Patients eligible for AIM are those with clinical, functional, or nutritional decline; with multiple hospitalizations, ED visits, or both within the past 12 months; and who are clinically eligible for hospice but have chosen to continue treatment or have not otherwise made the decision to use a hospice model of care. Once the patient is enrolled, the AIM team works with the patient, the family, and the physician on a preference-driven plan of care. That plan is shared with all providers supporting the patient and is regularly updated to reflect changes in the patient’s evolving choices as illness advances. This tracking of goals and preferences over time as illness progresses has been a critical factor in improving outcomes, especially those related to adherence or honoring a patient’s personal goals.
The AIM program started as a symptom management and care planning intervention for Medicare-eligible home health patients. The program has evolved over time into a pivotal fulcrum by which to engage or create an interdisciplinary focus and skill set across sites and providers of care in an effort to improve the overall outcomes for patients with advancing illness. In 2009, the AIM program began geographically expanding its home health–based AIM teams across 12 counties surrounding the San Francisco Bay area and the greater Sacramento region in northern California. The program now coordinates care with more than 17 hospitals and all of the large Sutter-affiliated medical groups, and it serves approximately 800 patients per day.
The AIM program has yielded significant results in terms of both quality of care and cost savings. Preliminary data on more than 300 AIM patients surveyed from November 2009 through September 2010 showed significant reductions in unnecessary hospitalizations and inpatient direct care costs (Table 2).12 Survey data also showed significant improvements in patient, family, and physician satisfaction when late-stage patients were served through AIM rather than through home care by itself.12
The Sutter Health AIM program recently received a Health Care Innovation Award from the Center for Medicare & Medicaid Innovation (CMMI) because of the program’s ability to “improve care and patient quality of life, increase physician, caregiver, and patient satisfaction, and reduce Medicare costs associated with avoidable hospital stays, ED visits, and days spent in intensive care units and skilled nursing facilities.”13 The $13 million CMMI grant will help expand AIM to the entire Sutter Health system. It is estimated that the program will save $29,388,894 over 3 years.13
CONCLUSION: CHALLENGES AND OPPORTUNITIES FOR THE US HEALTH CARE SYSTEM
The basic objective of AIM and programs like it is to move the focus of care for people with advanced illness out of the hospital and into home and community. This fulfills the Triple Aim vision set forth in 2008 by former CMS Administrator Don Berwick14:
- Improving health by reducing inpatient care that does not achieve person-centered goals or reduce overall mortality
- Improving care by basing it on the values and goals of people dealing with serious chronic illness
- Reducing costs by preventing unwanted hospital care
Sutter Health, a system that is on its way to becoming fully clinically integrated, was a logical choice for launching AIM because its hospitals are forming relationships with physician groups and home care providers. This integration process is supported nationally by CMS and CMMI, which are promoting new models of care and reimbursement such as accountable care organizations (ACOs) and bundled payments.
Nonintegrated hospitals and other provider groups can move in this same direction. AIM establishes key care coordination roles in each setting of care such as in hospitals and physician offices, as well as in the home care–based team and providers. The AIM care model emphasizes close coordination of clinical activities and communications, and integrates these with hospital and medical group operations. These provider groups can move strategically toward becoming “virtual ACOs” by coordinating care for people with advanced illness, who comprise the most vulnerable and costly segment of the US population and increasingly impact Medicare expenditures.
Changes in federal policy will be needed to facilitate national implementation of AIM-like programs. If ACOs and bundled payments were to be implemented overnight, the person-centered, cost-saving advantages of AIM would be obvious. However, until shared risk/shared savings models replace fee-for-service reimbursement, new payment policies will be needed on an interim basis to cover the costs of currently nonreimbursed care management services. This could be arranged through a per-enrollee-per-month payment or shared savings models tied to specific quality and utilization outcomes.
Simplification of regulatory requirements to better serve persons with advancing illness and to reduce the burden on providers operating such programs would be valuable. The pattern or progression of advancing chronic illness requires ongoing coordination in order to maintain a higher quality of life and symptom management. Current regulations and requirements foster an episodic focus in the home, as well in the hospital and physician’s office, which is not in alignment with the experience of persons living with advancing illness.
As the prevalence of serious illness among the elderly population has increased, interest in palliative care has grown as an approach to care management that is patient-centered and focused on quality of life. Case management that employs palliative care has the potential to alleviate unnecessary pain and suffering for patients while they concurrently pursue life-prolonging therapy. Palliative care can be provided across the continuum of care, involving multiple health care providers and practitioners.
Home health care, while often used as a postacute care provider, also can provide longitudinal care to elderly patients without a preceding hospitalization. Home health providers often act as central liaisons to coordinate care while patients are at home, particularly chronically ill patients with multiple physician providers, complex medication regimens, and ongoing concerns with independence and safety in the home.
Home health care can play a critical role in providing palliative care and, through innovative programs, can improve access to it. This article provides context and background on the provision of palliative care and explores how home health can work seamlessly in coordination with other health care stakeholders in providing palliative care.
WHAT IS PALLIATIVE CARE?
Palliative care means patient- and family-centered care that optimizes quality of life by anticipating, preventing, and treating suffering. Palliative care throughout the continuum of illness involves addressing physical, intellectual, emotional, social, and spiritual needs and [facilitating] patient autonomy, access to information, and choice.1
At its core, palliative care is a field of medicine aimed at alleviating the suffering of patients. As a “philosophy of care,” palliative care is appropriate for various sites of care at various stages of disease and all ages of patients. While hospice care is defined by the provision of palliative care for patients at the end of life, not all palliative care is hospice care. Rather, palliative care is an approach to care for any patient diagnosed with a serious illness that leverages expertise from multidisciplinary teams of health professionals and addresses pain and symptoms.
Palliative care addresses suffering by incorporating psychosocial and spiritual care with consideration of patient and family needs, preferences, values, beliefs and cultures. Palliative care can be provided throughout the continuum of care for patients with chronic, serious, and even life-threatening illnesses.1 To a degree, all aspects of health care can potentially address some palliative issues in that health care providers ideally combine a desire to cure the patient with a need to alleviate the patient’s pain and suffering.
Although the Medicare program recognizes the potential breadth of palliative care, the hospice benefit is relatively narrow. Consistent with the depiction in the Figure,2 the Medicare hospice benefit is limited to care that is focused on “comfort, not on curing an illness”3 (emphasis added). The Medicare hospice benefit is available to Medicare beneficiaries who: (1) are eligible for Medicare Part A; (2) have a doctor and hospice medical director certifying that they are terminally ill and have 6 months or less to live if their illness runs its normal course; (3) sign a statement choosing hospice care instead of other Medicare-covered benefits to treat their terminal illness (although Medicare will still pay for covered benefits for any health problems that are not related to the terminal illness); and (4) get care from a Medicare-certified hospice program.3
There are, however, clear benefits to providing palliative care outside of the Medicare hospice benefit. In particular, patients with serious illnesses may have more than 6 months to live if their illness runs its normal course. Patients who may die within 1 year due to serious illness can benefit from palliative care. Furthermore, some patients would like to continue to pursue curative treatment of their illnesses, but would benefit from a palliative care approach. By providing palliative care in the context of a plan of care with the patient’s physician, the patient and family can comprehensively make decisions and obtain support that enables access to appropriate treatments while allowing enhanced quality of life through symptom management.
WHO CAN PROVIDE PALLIATIVE CARE?
Palliative care can be provided in any care setting that has been accredited or certified to provide care, including those that are upstream from hospice along the continuum of care. Hospitals, nursing homes, and home health agencies can provide palliative care.
The Joint Commission, a nonprofit accrediting organization, currently accredits or certifies more than 17,000 organizations or programs across the care continuum, including hospitals, nursing homes, home health agencies, and hospices. Within the scope of the home care accreditation program, hospices and home health agencies are evaluated by certified field representatives to determine the extent to which their services meet the standards established by The Joint Commission. These standards are developed with input from health care professionals, providers, subject matter experts, consumers, government agencies (including the Centers for Medicare & Medicaid Services [CMS]) and employers. They are informed by scientific literature and expert consensus and approved by the board of commissioners.
The Joint Commission also has a certification program for palliative care services provided in hospitals and has certified 21 palliative care programs at various hospitals in the United States.
The Joint Commission’s Advanced Certification Program for Palliative Care recognizes hospital inpatient programs that demonstrate exceptional patient-and family-centered care and optimize quality of life for patients (both adult and pediatric) with serious illness. Certification standards emphasize:
- A formal, organized, palliative care program led by an interdisciplinary team whose members are experts in palliative care
- Leadership endorsement and support of the program’s goals for providing care, treatment and services
- Special focus on patient and family engagement
- Processes that support the coordination of care and communication among all care settings and providers
- The use of evidence-based national guidelines or expert consensus to guide patient care
The certification standards cover program management, provision of care, information management, and performance improvement. The standards are built on the National Consensus Project’s Clinical Practice Guidelines for Quality Palliative Care2 and the National Quality Forum’s National Framework and Preferred Practices for Palliative and Hospice Care Quality.4 Many of the concepts contained in the standards for inpatient palliative care have their origins in hospice care.
In addition to palliative care accreditation programs, certification in palliative care for clinicians is also possible. The American Board of Medical Specialties approved the creation of hospice and palliative medicine as a subspecialty in 2006. The National Board of Certification of Hospice and Palliative Nurses offers specialty certification for all levels of hospice and palliative care nursing. The National Association of Social Workers also offers an advanced certified hospice and palliative social worker (ACHP-SW) certifcation for MSW-level clinicians. These certification programs establish qualifications and standards for the members of a palliative care team.
Subject to federal and state requirements that regulate the way health care is provided, hospitals, nursing homes, home health agencies, and hospices are able to provide palliative care to patients who need such care.5,6
WHAT IS HOME HEALTH’S ROLE IN PROVIDING PALLIATIVE CARE?
Many Medicare-certified home health agencies also operate Medicare-approved hospice programs. Home health agencies have a heightened perspective on patients’ palliative care needs. Because of the limited nature of the Medicare hospice benefit, home health agencies have built palliative care programs to fill unmet patient needs. Home health agencies often provide palliative care to patients who may be ineligible for the hospice benefit or have chosen not to enroll in it. These programs are particularly attractive to patients who would like to pursue curative treatment for their serious illnesses or who are expected to live longer than 6 months.
Home health patients with advancing or serious illness or chronic illness are candidates for a palliative care service. For these patients, the burden of their illness continues to grow as distressing symptoms begin to more regularly impact their quality of life. As they continue curative treatment of their illness, they would benefit from palliative care services that provide greater relief of their symptoms and support advanced care planning. Palliative care interventions become an integrated part of the care plan for these patients. Home health agencies serving patients with chronic or advancing illnesses will see care benefits from incorporating palliative care into their team’s skill set.
Two innovative examples of home health–based programs that include a palliative care component have been reported in peer-reviewed literature to date: Kaiser Permanente’s In-Home Palliative Care program and Sutter Health’s Advanced Illness Management (AIM) program.7–10
Kaiser Permanente’s In-Home Palliative Care Program
Kaiser Permanente (KP) established the TriCentral Palliative Care Program in 1998 to achieve balance for seriously ill patients facing the end of life who were caught between “the extremes of too little care and too much.”11 KP began the program after discovering that patients were underusing their existing hospice program. The TriCentral Palliative Care program is an outpatient service, housed in the KP home health department and modeled after the KP hospice program with three key modifications designed to encourage timely referrals to the program:
- Physicians are asked to refer a patient if they “would not be surprised if this patient died in the next year.” Palliative care patients with a prognosis of 12 months or less to live are accepted into the program.
- Improved pain control and symptom management are emphasized, but patients do not need to forgo curative care as they do in hospice programs.
- Patients are assigned a palliative care physician who coordinates care from a variety of health care providers, preventing fragmentation.
The program has five core components that are geared toward enhanced quality of care and patient quality of life. These core components are:
- An interdisciplinary team approach, focused on patient and family, with care provided by a core team consisting of a physician, nurse, and social worker, all with expertise in pain control, other symptom management, and psychosocial intervention
- Home visits by all team members, including physicians, to provide medical care, support, and education as needed by patients and their caregivers
- Ongoing care management to fill gaps in care and ensure that the patient’s medical, social, and spiritual needs are being met
- Telephone support via a toll-free number and after-hours home visits available 24 hours a day, 7 days a week as needed by the patient
- Advanced-care planning that empowers patients and their families to make informed decisions and choices about end-of-life care11
Assessments of the program’s results in a randomized controlled trial8 and a comparative study9 showed that patient satisfaction increased; patients were more likely to die at home in accordance with their wishes; and emergency department (ED) visits, inpatient admissions, and costs were reduced (Table 1).
Sutter Health AIM Program
Sutter Health in northern California, in collaboration with its home care and hospice affiliate, Sutter Care at Home, initiated a home health–based program, Advanced Illness Management (AIM), in 2000 in response to the growing population of patients with advanced illness who needed enhanced care planning and symptom management. This program served patients who met the Medicare eligibility criteria for home health, had a prognosis of 1 year or less, and were continuing to seek treatment or cure for their illness. These patients frequently lacked awareness of their health status, particularly as it related to choices and decisions connected to the progression and management of their conditions. They also were frequently receiving uncoordinated care through various health channels, resulting in substandard symptom management. As a result, patients tended to experience more acute episodes that required frequent use of “unwanted and inappropriate care at the end of life, and they, their families, and their providers were dissatisfied.”12
As the AIM program matured, it incorporated a broader care management model, including principles of patient/caregiver engagement and goal setting, self-management techniques, ongoing advanced care planning, symptom management, and other evidence-based practices related to care transitions and care management. The program connects with the patient’s network of care providers and coordinates the exchange of realtime information about the current status of care plans and medication, as well as the patient’s defined goals. This more comprehensive model of care for persons with advanced illness has achieved improved adherence to patient wishes and goals, reductions in unnecessary hospital and ED utilization, and higher patient/caregiver and provider satisfaction than usual care.
Today, AIM is not primarily a palliative care program. Rather, it provides a comprehensive approach to care management that moves the focus of care for advanced illness out of the hospital and into the home/community setting. AIM achieves this through integrating the patient’s “health system.”
This integration occurs through formation of an interdisciplinary team comprised of the home care team, representative clinicians connected to the hospital, and providers of care for the patient. This expanded team, then, becomes the AIM care management team that is trained on the principles of AIM and its interventions. With this enhanced level of care coordination and unified focus on supporting the patient’s personal health goals, the AIM program serves as a “health system integrator” for the vulnerable and costly population of people with advanced chronic illness.
Inpatient palliative care is a separate and distinct systemwide priority at Sutter Health and, because of this, AIM collaborates closely with the inpatient palliative care teams to ensure that patients experience a seamless transition from hospital to home. There, AIM staff work with patients and families over time to clarify and document their personal values and goals, then use these to develop and drive the care plan. Armed with clearer appreciation of the natural progression of illness, both clinically and practically, coupled with improved understanding of available options for care, most choose to stay in the safety and comfort of their homes and out of the hospital. These avoided hospitalizations are the primary source of AIM’s considerable cost savings.
Patients eligible for AIM are those with clinical, functional, or nutritional decline; with multiple hospitalizations, ED visits, or both within the past 12 months; and who are clinically eligible for hospice but have chosen to continue treatment or have not otherwise made the decision to use a hospice model of care. Once the patient is enrolled, the AIM team works with the patient, the family, and the physician on a preference-driven plan of care. That plan is shared with all providers supporting the patient and is regularly updated to reflect changes in the patient’s evolving choices as illness advances. This tracking of goals and preferences over time as illness progresses has been a critical factor in improving outcomes, especially those related to adherence or honoring a patient’s personal goals.
The AIM program started as a symptom management and care planning intervention for Medicare-eligible home health patients. The program has evolved over time into a pivotal fulcrum by which to engage or create an interdisciplinary focus and skill set across sites and providers of care in an effort to improve the overall outcomes for patients with advancing illness. In 2009, the AIM program began geographically expanding its home health–based AIM teams across 12 counties surrounding the San Francisco Bay area and the greater Sacramento region in northern California. The program now coordinates care with more than 17 hospitals and all of the large Sutter-affiliated medical groups, and it serves approximately 800 patients per day.
The AIM program has yielded significant results in terms of both quality of care and cost savings. Preliminary data on more than 300 AIM patients surveyed from November 2009 through September 2010 showed significant reductions in unnecessary hospitalizations and inpatient direct care costs (Table 2).12 Survey data also showed significant improvements in patient, family, and physician satisfaction when late-stage patients were served through AIM rather than through home care by itself.12
The Sutter Health AIM program recently received a Health Care Innovation Award from the Center for Medicare & Medicaid Innovation (CMMI) because of the program’s ability to “improve care and patient quality of life, increase physician, caregiver, and patient satisfaction, and reduce Medicare costs associated with avoidable hospital stays, ED visits, and days spent in intensive care units and skilled nursing facilities.”13 The $13 million CMMI grant will help expand AIM to the entire Sutter Health system. It is estimated that the program will save $29,388,894 over 3 years.13
CONCLUSION: CHALLENGES AND OPPORTUNITIES FOR THE US HEALTH CARE SYSTEM
The basic objective of AIM and programs like it is to move the focus of care for people with advanced illness out of the hospital and into home and community. This fulfills the Triple Aim vision set forth in 2008 by former CMS Administrator Don Berwick14:
- Improving health by reducing inpatient care that does not achieve person-centered goals or reduce overall mortality
- Improving care by basing it on the values and goals of people dealing with serious chronic illness
- Reducing costs by preventing unwanted hospital care
Sutter Health, a system that is on its way to becoming fully clinically integrated, was a logical choice for launching AIM because its hospitals are forming relationships with physician groups and home care providers. This integration process is supported nationally by CMS and CMMI, which are promoting new models of care and reimbursement such as accountable care organizations (ACOs) and bundled payments.
Nonintegrated hospitals and other provider groups can move in this same direction. AIM establishes key care coordination roles in each setting of care such as in hospitals and physician offices, as well as in the home care–based team and providers. The AIM care model emphasizes close coordination of clinical activities and communications, and integrates these with hospital and medical group operations. These provider groups can move strategically toward becoming “virtual ACOs” by coordinating care for people with advanced illness, who comprise the most vulnerable and costly segment of the US population and increasingly impact Medicare expenditures.
Changes in federal policy will be needed to facilitate national implementation of AIM-like programs. If ACOs and bundled payments were to be implemented overnight, the person-centered, cost-saving advantages of AIM would be obvious. However, until shared risk/shared savings models replace fee-for-service reimbursement, new payment policies will be needed on an interim basis to cover the costs of currently nonreimbursed care management services. This could be arranged through a per-enrollee-per-month payment or shared savings models tied to specific quality and utilization outcomes.
Simplification of regulatory requirements to better serve persons with advancing illness and to reduce the burden on providers operating such programs would be valuable. The pattern or progression of advancing chronic illness requires ongoing coordination in order to maintain a higher quality of life and symptom management. Current regulations and requirements foster an episodic focus in the home, as well in the hospital and physician’s office, which is not in alignment with the experience of persons living with advancing illness.
- Centers for Medicare & Medicaid Services. Medicare and Medicaid program: conditions of participation. Federal Register 2008; 73:32088–32219.
- Clinical Practice Guidelines for Quality Palliative Care. 2nd ed. Pittsburgh, PA: National Consensus Project for Quality Palliative Care. National Consensus Project Web site. http:www.nationalconsensusproject.org. Published 2009. Accessed December 12, 2012.
- Medicare hospice benefits. Centers for Medicare & Medicaid Services Web site. http://www.medicare.gov/publications/pubs/pdf/02154.pdf. Revised August 2012. Accessed November 14, 2012.
- A national framework and preferred practices for palliative and hospice care quality. A consensus report. National Quality Forum Web site. http://www.qualityforum.org/Publications/2006/12/A_National_Framework_and_Preferred_Practices_for_Palliative_and_Hospice_Care_Quality.aspx. Published 2006. Accessed December 12, 2012.
- Michal MH, Pekarske MSL. Palliative care checklist: selected regulatory and risk management considerations. National Hospice and Palliative Care Organization Web site. http://www.nhpco.org/fles/public/palliativecare/pcchecklist.pdf. Published April 17, 2006. Accessed November 14, 2012.
- Raffa CA. Palliative care: the legal and regulatory requirements. National Hospice and Palliative Care Organization Web site. http://www.nhpco.org/files/public/palliativecare/legal_regulatorypart2.pdf. Published December 22, 2003. Accessed November 14, 2012.
- In-home palliative care allows more patients to die at home, leading to higher satisfaction and lower acute care utilization and costs. Agency for Healthcare Research and Quality Health Care Innovations Exchange Web site. http://www.innovations.ahrq.gov/content.aspx?id=2366. Published March 2, 2009. Updated November 07, 2012. Accessed November 14, 2012.
- Brumley R, Enguidanos S, Jamison P, et al. Increased satisfaction with care and lower costs: results of a randomized trial of in-home palliative care. J Am Geriatr Soc 2007; 55:993–1000.
- Enguidanos SM, Cherin D, Brumley R. Home-based palliative care study: site of death, and costs of medical care for patients with congestive heart failure, chronic obstructive pulmonary disease, and cancer. J Soc Work End Life Palliat Care 2005; 1:37–56.
- Brumley RD, Enguidanos S, Cherin DA. Effectiveness of a home-based palliative care program for end-of-life. J Palliat Med 2003; 6:715–724.
- Brumley RD, Hillary K. The TriCentral Palliative Care Program Toolkit. 1st ed. MyWhatever Web site. http://www.mywhatever.com/cifwriter/content/22/fles/sorostoolkitfnal120902.doc. Published 2002. Accessed November 14, 2012.
- Meyer H. Innovation profile: changing the conversation in California about care near the end of life. Health Aff 2011; 30:390–393.
- Health Care Innovation Awards. Center for Medicare & Medicaid Innovation Web site. http://innovations.cms.gov/initiatives/Innovation-Awards/california.html. Accessed November 14, 2012.
- Berwick DJ, Nolan TW, Whittington J. The triple aim: care, health, and cost. Health Aff 2008; 27:759–769.
- Centers for Medicare & Medicaid Services. Medicare and Medicaid program: conditions of participation. Federal Register 2008; 73:32088–32219.
- Clinical Practice Guidelines for Quality Palliative Care. 2nd ed. Pittsburgh, PA: National Consensus Project for Quality Palliative Care. National Consensus Project Web site. http:www.nationalconsensusproject.org. Published 2009. Accessed December 12, 2012.
- Medicare hospice benefits. Centers for Medicare & Medicaid Services Web site. http://www.medicare.gov/publications/pubs/pdf/02154.pdf. Revised August 2012. Accessed November 14, 2012.
- A national framework and preferred practices for palliative and hospice care quality. A consensus report. National Quality Forum Web site. http://www.qualityforum.org/Publications/2006/12/A_National_Framework_and_Preferred_Practices_for_Palliative_and_Hospice_Care_Quality.aspx. Published 2006. Accessed December 12, 2012.
- Michal MH, Pekarske MSL. Palliative care checklist: selected regulatory and risk management considerations. National Hospice and Palliative Care Organization Web site. http://www.nhpco.org/fles/public/palliativecare/pcchecklist.pdf. Published April 17, 2006. Accessed November 14, 2012.
- Raffa CA. Palliative care: the legal and regulatory requirements. National Hospice and Palliative Care Organization Web site. http://www.nhpco.org/files/public/palliativecare/legal_regulatorypart2.pdf. Published December 22, 2003. Accessed November 14, 2012.
- In-home palliative care allows more patients to die at home, leading to higher satisfaction and lower acute care utilization and costs. Agency for Healthcare Research and Quality Health Care Innovations Exchange Web site. http://www.innovations.ahrq.gov/content.aspx?id=2366. Published March 2, 2009. Updated November 07, 2012. Accessed November 14, 2012.
- Brumley R, Enguidanos S, Jamison P, et al. Increased satisfaction with care and lower costs: results of a randomized trial of in-home palliative care. J Am Geriatr Soc 2007; 55:993–1000.
- Enguidanos SM, Cherin D, Brumley R. Home-based palliative care study: site of death, and costs of medical care for patients with congestive heart failure, chronic obstructive pulmonary disease, and cancer. J Soc Work End Life Palliat Care 2005; 1:37–56.
- Brumley RD, Enguidanos S, Cherin DA. Effectiveness of a home-based palliative care program for end-of-life. J Palliat Med 2003; 6:715–724.
- Brumley RD, Hillary K. The TriCentral Palliative Care Program Toolkit. 1st ed. MyWhatever Web site. http://www.mywhatever.com/cifwriter/content/22/fles/sorostoolkitfnal120902.doc. Published 2002. Accessed November 14, 2012.
- Meyer H. Innovation profile: changing the conversation in California about care near the end of life. Health Aff 2011; 30:390–393.
- Health Care Innovation Awards. Center for Medicare & Medicaid Innovation Web site. http://innovations.cms.gov/initiatives/Innovation-Awards/california.html. Accessed November 14, 2012.
- Berwick DJ, Nolan TW, Whittington J. The triple aim: care, health, and cost. Health Aff 2008; 27:759–769.
Accountable care and patient-centered medical homes: Implications for office-based practice
The passage of the Patient Protection and Affordable Care Act will profoundly affect the way physicians—particularly those engaged in primary care—practice medicine. Clinicians and their colleagues will be obliged to meet government-mandated performance quality measures while achieving cost efficiencies. Two concepts are central to the implementation of reform in the US health care system: accountable care organizations (ACOs) and the patient-centered medical home (PCMH). To get some perspective on what these changes mean for the practicing clinician, Cleveland Clinic Journal of Medicine (CCJM) interviewed David Longworth, MD, who chairs the Cleveland Clinic Medicine Institute and directs strategy and implementation of Cleveland Clinic ACO-related activities.
CCJM: Please explain briefly the concept of PCMH.
Dr. Longworth: PCMH is not a new concept; first advanced by the American Academy of Pediatrics in 1967,1 it represents a model of care in which an individual patient has a primary relationship with one provider who manages and coordinates the different aspects of the patient’s health care. The provider collaborates with a team of health care professionals. The concept caught on about a decade ago when a consortium of family medicine organizations and ultimately industry, including IBM, endorsed the concept. IBM and others created the Primary Care Consortium and began to drive the concept of PCMH.
Increasingly, care delivered through PCMH is team-based. The team coordinates the patient’s care and, when appropriate, enlists specialists or subspecialists to provide necessary components of care, all while maintaining responsibility for care coordination across the continuum of care. The medical home model provides an opportunity for enhanced access and care coordination utilizing care outside of the office walls, such as through retail clinics, eVisits, online diagnostic services, phone and electronic communication, and house call services.
Patient-centered medical homes are springing up across the country. In 2008, the National Committee for Quality Assurance (NCQA) developed criteria for recognition of PCMHs.2 It scored the sophistication of medical homes at three levels, level 1 being the lowest and level 3 the highest. Between 2008 and the end of 2010, NCQA had recognized more than 1,500 PCMHs. According to the latest figures, more than 3,000 practices have now earned PCMH recognition from the NCQA.3
At Cleveland Clinic, pilot projects at three family health centers that cover 60,000 persons have recently been rolled out with the goal of determining the model of team care that yields the highest value, with value defined by the equation of quality over cost. Ideally, higher quality is delivered at lower cost to increase value.
CCJM: What are the goals of ACOs?
Dr. Longworth: The term “accountable care,” first used in 2006 by Elliot Fisher, Dartmouth Institute of Health Policy and Clinical Practice,6 expresses the idea that health care organizations be accountable for the care they deliver, with the three-part aim of better health for populations, better care for individuals, and reduced cost inefficiencies without compromised care.
With accountable care, institutions take on risk with the expectation that they will improve quality but reduce costs, and if they reduce costs and achieve certain quality targets for populations of patients, they will share in the savings accrued. The Affordable Care Act laid the groundwork for creation of ACOs. The regulation for ACOs released by the Centers for Medicare & Medicaid Services (CMS) became effective in January 2012.7,8 Many health care organizations opposed the rule for reasons related to complexity, prescriptiveness, onerous detail around governance and marketing, and shared savings arrangements, among others. The final rule addressed many of these concerns and enabled the creation of the first wave of ACOs.8 At present, 153 ACOs have been approved by CMS.9 Other ACOs funded by commercial payers are also being formed in many locations.
For ACOs to be effective, I believe that the cornerstone of management has to be PCMHs.
CCJM: You mentioned that institutions will take on risk. What kind of risk are you referring to?
Dr. Longworth: Added value must be rewarded with sustainable payment models. There are two payment models in the final ACO rule from CMS. Both models require 3-year commitments and both require involvement of primary care physicians. One model for organizations that want to stick a toe in the water has no downside risk and modest potential for gain if they hit certain quality and cost targets. For those organizations that are further along and want to assume risk, the second option is a shared savings/risk payment model, which creates greater incentives for efficiency and quality. In the shared savings/risk model, the ACO can retain a portion of savings if it meets performance and expenditure benchmarks based on its performance during the previous 3 years. It is also at risk for loss if expenditures are greater than a certain amount compared with benchmark expenditures. Ultimately, the final destination for ACOs will be a risk of loss if they don’t perform.
CCJM: How can these two structures—PCMHs and ACOs—optimize the use of home health?
Dr. Longworth: Home health, which is part of the postacute care continuum, will be vitally important for managing individuals and populations of patients as we move toward PCMHs and ACOs. Coordination of care will require communication between home health services and the primary care physicians who are integral to PCMHs. There will have to be an emphasis on transitions of care, from the hospital to home, from skilled nursing facilities to home, and so forth.
Accountable care organizations are responsible for a population of patients, and ACOs receive a fixed amount of money per year to cover an individual life in that population. Thus, managing quality and controlling cost is the name of the game no matter where the patient is in the health care continuum— the office, the emergency room, the hospital, a skilled nursing facility, or a home health setting. For some chronic diseases, managing patients in the home health setting may be vitally important to prevent unnecessary trips to the emergency room and hospital readmissions, thereby reducing expenditures while providing quality care.
CCJM: Do you expect an increase in the number of PCMHs and ACOs to increase the demand for home health services?
Dr. Longworth: Given the necessity of optimizing quality at lower cost, I anticipate a push to deliver as much care as we can in the least expensive “right” setting, which might be the home in some situations. Certainly, we don’t want to send patients home prematurely only to have them return to emergency departments or hospitals, but I think the demand for home health will increase as we try to decrease the number of days in skilled nursing facilities, which are expensive, and to move care from skilled nursing facilities to the home setting.
CCJM: Is there evidence that integrated delivery models such as PCMHs deliver value?
Dr. Longworth: The Patient-Centered Primary Care Collaborative demonstrated quality improvements in selected outcomes domains while also realizing savings through reductions in admissions, emergency department visits, skilled nursing facility days, and pharmacy costs.10
CCJM: What challenges do PCMHs and ACOs present to home health agencies and the way they provide services, and how will these challenges affect patients and clinicians?
Dr. Longworth: One challenge will be communication between home health services and primary care providers during transitions of care. A second will be managing costs for home health, which entails leveraging new technologies such as in-home devices and telemedicine to provide optimal and ideal monitoring of patients at the lowest potential cost. Home health, like other players along the care continuum, will face increasing scrutiny regarding quality metrics. Home health agencies will likely need to distinguish themselves from one another on the basis of performance measures such as emergency department utilization, unnecessary hospital readmissions, medication errors, and quality of service to patients as well as to primary care providers.
CCJM: How does personalized health care fit into the PCMH model?
Dr. Longworth: Personalized health care, which includes the use of genetic testing in certain situations, is an emerging field that is still in its infancy. Like PCMHs, personalized health care is proactive rather than reactive. Application of personalized health care can help deliver value with better prediction of disease and appropriate use of targeted therapies to improve outcomes for certain individuals. Such individualized treatment not only enables higher quality of care but wiser use of resources. For instance, genetic markers can be used to predict drug metabolism and adverse drug events for certain medications. In the field of oncology, the expression of genetic mutations in certain tumor types can help identify patients most likely to respond to specific targeted therapies. In these ways, personalized health care is patient-centered health care. As part of its proactive nature, personalized health care, beyond genetic testing, also implies advance planning of appointments with a focus on chronic care and keeping patients in the care system.
CCJM: How does participation in a PCMH or an ACO benefit the primary care provider? Are there any disadvantages to participation?
Dr. Longworth: In the current fee-for-service world, primary care physicians and all providers are paid on a widget-by-widget basis. Some primary care physicians and other specialists fear moving to this new world in which they will ultimately be accountable for quality and cost. Not everyone has embraced the concept, but I do think it is inevitable. Primary care physicians especially will be under increasing pressure to care for populations as opposed to individual patients. They will need to redesign the care delivery model to provide team-based, proactive care focusing on the highest-risk patients to try to keep them out of the emergency department and hospital. There will also be a greater emphasis on wellness moving forward, in an attempt to prevent the development of chronic diseases such as diabetes and obesity in individual patients and populations. All of these changes represent a different paradigm for the delivery of care, compared with the present model.
The benefit of participation for a primary care physician depends on the structure of an ACO, particularly the amount of personal financial liability an individual practitioner might have. In a staff-model, fixed-salary institution, primary care physicians would probably be more immune to financial liability than they would in other markets or other compensation models in which salary can fluctuate.
CCJM: What are some of the barriers to ACO implementation that are relevant to office-based practice, and how can they be overcome?
Dr. Longworth: There are a number of barriers to ACOs and true PCMHs. The barriers revolve around redefining workflows and moving away from reactive care—a physician-centric model in which a patient comes into the office with a problem and the physician reacts—to proactive care with the goal being to recognize how the patient is doing over time to prevent unnecessary trips to the emergency department and, ultimately, hospitalization. It is a fundamentally different mindset that involves proactive outreach targeted at high-risk patients whose chronic diseases are managed through a team-based approach. An essential feature of primary care practice will be care coordinators who will manage and proactively anticipate the needs of medically complex, high-risk patients who use a disproportionately large share of services.
In addition, a greater emphasis on wellness will be necessary to prevent the development of chronic diseases such as diabetes, obesity, and hypertension in the large segment of the population that is reasonably healthy.
CCJM: What steps can a clinician take to prepare his or her practice for ACO implementation?
Dr. Longworth: Small practices will be challenged. It is difficult to imagine accountable care without an electronic health record. To understand the population, the practitioner will need to do continuous performance management, which can’t be done without access to data from a population of patients. An increasing number of physicians are aligning with organizations that have the necessary infrastructure to provide the myriad data required to measure quality, to enable continuous improvement in performance, and to enhance the patient experience. Small practices may not have the resources to complete the administrative work necessary to become part of an ACO.
There are ways to align with an ACO that do not constitute full employment; for example, the Cleveland (Ohio) Quality Alliance has aligned with community-based physicians to provide informatics support. Linking with larger organizations that have the resources to provide quality measurement and contracting support will permit smaller community-based physicians’ practices to be part of the game.
CCJM: What steps should PCMHs and ACOs take to leverage and optimize home health services among other parts of the medical neighborhood?
Dr. Longworth: Frankly, the postacute continuum is a challenge for most systems across the country because postacute care is fragmented. Our strategy at Cleveland Clinic is to identify and align with preferred providers of home health services. The criteria that I look for are commitment to quality and transparency, service that is oriented to both patients and PCMHs, and openness to innovation for leveraging health care technology to deliver care at the best value. Home health providers need to think about how to best accomplish these results to position themselves to partner with ACOs.
CCJM: How do PCMHs and ACOs apply to special patient populations and their needs? Is there a population that’s best suited for the medical home model?
Dr. Longworth: Certain populations of higher-risk patients are ideally suited to home health coupled with chronic disease management using care coordinators. Some examples are children with asthma and children with intellectual and developmental disabilities (eg, autism) who have high utilization of emergency services. Another population is patients with heart failure who are often in and out of the emergency department and hospital; there has been a concerted effort to reduce 30-day readmission rates, which are as high as 30%, for this group. (Also see “Home-based care for heart failure: Cleveland Clinic’s ‘Heart Care at Home’ transitional care program”)
CCJM: What are the specific expectations for patient involvement in the PCMH setting?
Dr. Longworth: Our challenge lies in how best to motivate patients and engage them in their own care, especially patients who have chronic diseases. We all struggle to resolve the engagement question. Coaching and patient engagement are functions of PCMHs and at every point along the care continuum. Home health providers can serve as health coaches to promote adherence to medications, healthy lifestyles, and follow-up visits with patients’ doctors—these all need to happen to better engage patients. How to engage patients and motivate them to be more involved in their health is a basic challenge.
CCJM: Along similar lines, how can home health providers work with physicians to achieve patient-centered care?
Dr. Longworth: They can communicate early when they think that things are amiss, serve as health coaches, create technologic solutions that enhance efficiency of communication, and anticipate care needs of patients in the home setting.
CCJM: How might bundling affect the financial picture of PCMHs and patient care?
Dr. Longworth: When one talks about bundling, the devil is in the definition. In bundling, one gets paid for an episode of service. So, for example, a total knee replacement might be compensated by a 30-day bundle that covers only the surgery and the immediate postoperative period. Or it might be a 90-day bundle that includes hospitalization and perhaps some days in skilled nursing facility, but ideally transitioning from hospital to home. In the latter example, the bundle, or the total payment, will be split between the hospital and the home care services. If home health is included in a bundle, there will be tremendous pressure on the home health service to prevent readmission and emergency room visits and to eliminate waste of care. Home health’s vulnerability will depend upon how a bundle is defined for specific service.
CCJM: Who defines the terms of the bundle?
Dr. Longworth: Whoever is applying for the bundle—usually, a health care system, hospital, or ACO. It may be that home health services will subcontract for a fat fee in order to immunize themselves against risk, and shift all of the risk to the contracting organization. If I were a home health provider, I might try to minimize my own risk, but still offer my services at a price that is financially viable.
- Sia C, Tonniges TF, Osterhus E, Taba S. History of the medical home concept. Pediatrics 2004; 113 suppl 5:1473–1478.
- National Committee for Quality Assurance. Standards and Guidelines for Physician Practice Connections ®—Patient-Centered Medical Home (PPC-PCMH™). http://www.ncqa.org/Portals/0/Programs/Recognition/PCMH_Overview_Apr01.pdfPublished 2008. Accessed September 17, 2012.
- White paper. NCQA ’s Patient-centered medical home (PCMH) 2011. National Committee for Quality Assurance Web site. http://www.ncqa.org/Portals/0/Newsroom/PCMH%202011%20White%20Paper_4.6.12.pdf. Published 2011. Accessed September 17, 2012.
- 2011 annual report. National Committee for Quality Assurance Web site. http://www.ncqa.org/Portals/0/Publications/Resource%20Library/Annual%20Report/2011_Annual_Report.pdf. Published 2011. Accessed September 17, 2012.
- National Committee for Quality Assurance patient-centered medical home 2011. National Committee for Quality Assurance Web site http://www.ncqa.org/Portals/0/PCMH2011%20withCAHPSInsert.pdf. Published 2011. Accessed September 17, 2012.
- Fisher ES, Staiger DO, Bynum JP, Gottlieb DJ. Creating accountable care organizations: the extended hospital medical staff [published online ahead of print December 5, 2006]. Health Aff (Millwood) 2007; 26:w44–w57. 10.1377/hlthaff.26.1.w44
- Accountable care organizations: improving care coordination for people with Medicare. A U.S. Department of Health & Human Services Web site. www.HealthCare.gov/news/factsheets/accountablecare03312011a.html. Published March 31, 2011. Updated March 12, 2012. Accessed November 20, 2012.
- Centers for Medicare & Medicaid Services (CMS), HHS. Medicare program; Medicare shared savings program: accountable care organizations. Final rule. Fed Regist 2011; 76 212:67802–67990.
- Fact Sheets. CMS names 88 new Medicare shared savings accountable care organizations. A Centers for Medicare & Medicaid Services (CMS) Web site. http://www.cms.gov/apps/media/press/factsheet.asp?Counter=4405&intNumPerPage=10&checkDate=1&checkKey=&srchType=1&numDays=90&srchOpt=0&srchData=&keywordType=All&chkNewsType=6&intPage=&showAll=1&pYear=1&year=2012&desc=&cboOrder=date. Published July 9, 2012. Accessed November 20, 2012.
- Grumbach K, Grundy P. Outcomes of implementing patient centered medical home interventions: a review of the evidence from prospective evaluation studies in the United States. Patient-Centered Primary Care Collaborative Web site. http://www.pcpcc.net/fles/evidence_outcomes_in_pcmh.pdf. Published November 16, 2010. Accessed November 20, 2012.
The passage of the Patient Protection and Affordable Care Act will profoundly affect the way physicians—particularly those engaged in primary care—practice medicine. Clinicians and their colleagues will be obliged to meet government-mandated performance quality measures while achieving cost efficiencies. Two concepts are central to the implementation of reform in the US health care system: accountable care organizations (ACOs) and the patient-centered medical home (PCMH). To get some perspective on what these changes mean for the practicing clinician, Cleveland Clinic Journal of Medicine (CCJM) interviewed David Longworth, MD, who chairs the Cleveland Clinic Medicine Institute and directs strategy and implementation of Cleveland Clinic ACO-related activities.
CCJM: Please explain briefly the concept of PCMH.
Dr. Longworth: PCMH is not a new concept; first advanced by the American Academy of Pediatrics in 1967,1 it represents a model of care in which an individual patient has a primary relationship with one provider who manages and coordinates the different aspects of the patient’s health care. The provider collaborates with a team of health care professionals. The concept caught on about a decade ago when a consortium of family medicine organizations and ultimately industry, including IBM, endorsed the concept. IBM and others created the Primary Care Consortium and began to drive the concept of PCMH.
Increasingly, care delivered through PCMH is team-based. The team coordinates the patient’s care and, when appropriate, enlists specialists or subspecialists to provide necessary components of care, all while maintaining responsibility for care coordination across the continuum of care. The medical home model provides an opportunity for enhanced access and care coordination utilizing care outside of the office walls, such as through retail clinics, eVisits, online diagnostic services, phone and electronic communication, and house call services.
Patient-centered medical homes are springing up across the country. In 2008, the National Committee for Quality Assurance (NCQA) developed criteria for recognition of PCMHs.2 It scored the sophistication of medical homes at three levels, level 1 being the lowest and level 3 the highest. Between 2008 and the end of 2010, NCQA had recognized more than 1,500 PCMHs. According to the latest figures, more than 3,000 practices have now earned PCMH recognition from the NCQA.3
At Cleveland Clinic, pilot projects at three family health centers that cover 60,000 persons have recently been rolled out with the goal of determining the model of team care that yields the highest value, with value defined by the equation of quality over cost. Ideally, higher quality is delivered at lower cost to increase value.
CCJM: What are the goals of ACOs?
Dr. Longworth: The term “accountable care,” first used in 2006 by Elliot Fisher, Dartmouth Institute of Health Policy and Clinical Practice,6 expresses the idea that health care organizations be accountable for the care they deliver, with the three-part aim of better health for populations, better care for individuals, and reduced cost inefficiencies without compromised care.
With accountable care, institutions take on risk with the expectation that they will improve quality but reduce costs, and if they reduce costs and achieve certain quality targets for populations of patients, they will share in the savings accrued. The Affordable Care Act laid the groundwork for creation of ACOs. The regulation for ACOs released by the Centers for Medicare & Medicaid Services (CMS) became effective in January 2012.7,8 Many health care organizations opposed the rule for reasons related to complexity, prescriptiveness, onerous detail around governance and marketing, and shared savings arrangements, among others. The final rule addressed many of these concerns and enabled the creation of the first wave of ACOs.8 At present, 153 ACOs have been approved by CMS.9 Other ACOs funded by commercial payers are also being formed in many locations.
For ACOs to be effective, I believe that the cornerstone of management has to be PCMHs.
CCJM: You mentioned that institutions will take on risk. What kind of risk are you referring to?
Dr. Longworth: Added value must be rewarded with sustainable payment models. There are two payment models in the final ACO rule from CMS. Both models require 3-year commitments and both require involvement of primary care physicians. One model for organizations that want to stick a toe in the water has no downside risk and modest potential for gain if they hit certain quality and cost targets. For those organizations that are further along and want to assume risk, the second option is a shared savings/risk payment model, which creates greater incentives for efficiency and quality. In the shared savings/risk model, the ACO can retain a portion of savings if it meets performance and expenditure benchmarks based on its performance during the previous 3 years. It is also at risk for loss if expenditures are greater than a certain amount compared with benchmark expenditures. Ultimately, the final destination for ACOs will be a risk of loss if they don’t perform.
CCJM: How can these two structures—PCMHs and ACOs—optimize the use of home health?
Dr. Longworth: Home health, which is part of the postacute care continuum, will be vitally important for managing individuals and populations of patients as we move toward PCMHs and ACOs. Coordination of care will require communication between home health services and the primary care physicians who are integral to PCMHs. There will have to be an emphasis on transitions of care, from the hospital to home, from skilled nursing facilities to home, and so forth.
Accountable care organizations are responsible for a population of patients, and ACOs receive a fixed amount of money per year to cover an individual life in that population. Thus, managing quality and controlling cost is the name of the game no matter where the patient is in the health care continuum— the office, the emergency room, the hospital, a skilled nursing facility, or a home health setting. For some chronic diseases, managing patients in the home health setting may be vitally important to prevent unnecessary trips to the emergency room and hospital readmissions, thereby reducing expenditures while providing quality care.
CCJM: Do you expect an increase in the number of PCMHs and ACOs to increase the demand for home health services?
Dr. Longworth: Given the necessity of optimizing quality at lower cost, I anticipate a push to deliver as much care as we can in the least expensive “right” setting, which might be the home in some situations. Certainly, we don’t want to send patients home prematurely only to have them return to emergency departments or hospitals, but I think the demand for home health will increase as we try to decrease the number of days in skilled nursing facilities, which are expensive, and to move care from skilled nursing facilities to the home setting.
CCJM: Is there evidence that integrated delivery models such as PCMHs deliver value?
Dr. Longworth: The Patient-Centered Primary Care Collaborative demonstrated quality improvements in selected outcomes domains while also realizing savings through reductions in admissions, emergency department visits, skilled nursing facility days, and pharmacy costs.10
CCJM: What challenges do PCMHs and ACOs present to home health agencies and the way they provide services, and how will these challenges affect patients and clinicians?
Dr. Longworth: One challenge will be communication between home health services and primary care providers during transitions of care. A second will be managing costs for home health, which entails leveraging new technologies such as in-home devices and telemedicine to provide optimal and ideal monitoring of patients at the lowest potential cost. Home health, like other players along the care continuum, will face increasing scrutiny regarding quality metrics. Home health agencies will likely need to distinguish themselves from one another on the basis of performance measures such as emergency department utilization, unnecessary hospital readmissions, medication errors, and quality of service to patients as well as to primary care providers.
CCJM: How does personalized health care fit into the PCMH model?
Dr. Longworth: Personalized health care, which includes the use of genetic testing in certain situations, is an emerging field that is still in its infancy. Like PCMHs, personalized health care is proactive rather than reactive. Application of personalized health care can help deliver value with better prediction of disease and appropriate use of targeted therapies to improve outcomes for certain individuals. Such individualized treatment not only enables higher quality of care but wiser use of resources. For instance, genetic markers can be used to predict drug metabolism and adverse drug events for certain medications. In the field of oncology, the expression of genetic mutations in certain tumor types can help identify patients most likely to respond to specific targeted therapies. In these ways, personalized health care is patient-centered health care. As part of its proactive nature, personalized health care, beyond genetic testing, also implies advance planning of appointments with a focus on chronic care and keeping patients in the care system.
CCJM: How does participation in a PCMH or an ACO benefit the primary care provider? Are there any disadvantages to participation?
Dr. Longworth: In the current fee-for-service world, primary care physicians and all providers are paid on a widget-by-widget basis. Some primary care physicians and other specialists fear moving to this new world in which they will ultimately be accountable for quality and cost. Not everyone has embraced the concept, but I do think it is inevitable. Primary care physicians especially will be under increasing pressure to care for populations as opposed to individual patients. They will need to redesign the care delivery model to provide team-based, proactive care focusing on the highest-risk patients to try to keep them out of the emergency department and hospital. There will also be a greater emphasis on wellness moving forward, in an attempt to prevent the development of chronic diseases such as diabetes and obesity in individual patients and populations. All of these changes represent a different paradigm for the delivery of care, compared with the present model.
The benefit of participation for a primary care physician depends on the structure of an ACO, particularly the amount of personal financial liability an individual practitioner might have. In a staff-model, fixed-salary institution, primary care physicians would probably be more immune to financial liability than they would in other markets or other compensation models in which salary can fluctuate.
CCJM: What are some of the barriers to ACO implementation that are relevant to office-based practice, and how can they be overcome?
Dr. Longworth: There are a number of barriers to ACOs and true PCMHs. The barriers revolve around redefining workflows and moving away from reactive care—a physician-centric model in which a patient comes into the office with a problem and the physician reacts—to proactive care with the goal being to recognize how the patient is doing over time to prevent unnecessary trips to the emergency department and, ultimately, hospitalization. It is a fundamentally different mindset that involves proactive outreach targeted at high-risk patients whose chronic diseases are managed through a team-based approach. An essential feature of primary care practice will be care coordinators who will manage and proactively anticipate the needs of medically complex, high-risk patients who use a disproportionately large share of services.
In addition, a greater emphasis on wellness will be necessary to prevent the development of chronic diseases such as diabetes, obesity, and hypertension in the large segment of the population that is reasonably healthy.
CCJM: What steps can a clinician take to prepare his or her practice for ACO implementation?
Dr. Longworth: Small practices will be challenged. It is difficult to imagine accountable care without an electronic health record. To understand the population, the practitioner will need to do continuous performance management, which can’t be done without access to data from a population of patients. An increasing number of physicians are aligning with organizations that have the necessary infrastructure to provide the myriad data required to measure quality, to enable continuous improvement in performance, and to enhance the patient experience. Small practices may not have the resources to complete the administrative work necessary to become part of an ACO.
There are ways to align with an ACO that do not constitute full employment; for example, the Cleveland (Ohio) Quality Alliance has aligned with community-based physicians to provide informatics support. Linking with larger organizations that have the resources to provide quality measurement and contracting support will permit smaller community-based physicians’ practices to be part of the game.
CCJM: What steps should PCMHs and ACOs take to leverage and optimize home health services among other parts of the medical neighborhood?
Dr. Longworth: Frankly, the postacute continuum is a challenge for most systems across the country because postacute care is fragmented. Our strategy at Cleveland Clinic is to identify and align with preferred providers of home health services. The criteria that I look for are commitment to quality and transparency, service that is oriented to both patients and PCMHs, and openness to innovation for leveraging health care technology to deliver care at the best value. Home health providers need to think about how to best accomplish these results to position themselves to partner with ACOs.
CCJM: How do PCMHs and ACOs apply to special patient populations and their needs? Is there a population that’s best suited for the medical home model?
Dr. Longworth: Certain populations of higher-risk patients are ideally suited to home health coupled with chronic disease management using care coordinators. Some examples are children with asthma and children with intellectual and developmental disabilities (eg, autism) who have high utilization of emergency services. Another population is patients with heart failure who are often in and out of the emergency department and hospital; there has been a concerted effort to reduce 30-day readmission rates, which are as high as 30%, for this group. (Also see “Home-based care for heart failure: Cleveland Clinic’s ‘Heart Care at Home’ transitional care program”)
CCJM: What are the specific expectations for patient involvement in the PCMH setting?
Dr. Longworth: Our challenge lies in how best to motivate patients and engage them in their own care, especially patients who have chronic diseases. We all struggle to resolve the engagement question. Coaching and patient engagement are functions of PCMHs and at every point along the care continuum. Home health providers can serve as health coaches to promote adherence to medications, healthy lifestyles, and follow-up visits with patients’ doctors—these all need to happen to better engage patients. How to engage patients and motivate them to be more involved in their health is a basic challenge.
CCJM: Along similar lines, how can home health providers work with physicians to achieve patient-centered care?
Dr. Longworth: They can communicate early when they think that things are amiss, serve as health coaches, create technologic solutions that enhance efficiency of communication, and anticipate care needs of patients in the home setting.
CCJM: How might bundling affect the financial picture of PCMHs and patient care?
Dr. Longworth: When one talks about bundling, the devil is in the definition. In bundling, one gets paid for an episode of service. So, for example, a total knee replacement might be compensated by a 30-day bundle that covers only the surgery and the immediate postoperative period. Or it might be a 90-day bundle that includes hospitalization and perhaps some days in skilled nursing facility, but ideally transitioning from hospital to home. In the latter example, the bundle, or the total payment, will be split between the hospital and the home care services. If home health is included in a bundle, there will be tremendous pressure on the home health service to prevent readmission and emergency room visits and to eliminate waste of care. Home health’s vulnerability will depend upon how a bundle is defined for specific service.
CCJM: Who defines the terms of the bundle?
Dr. Longworth: Whoever is applying for the bundle—usually, a health care system, hospital, or ACO. It may be that home health services will subcontract for a fat fee in order to immunize themselves against risk, and shift all of the risk to the contracting organization. If I were a home health provider, I might try to minimize my own risk, but still offer my services at a price that is financially viable.
The passage of the Patient Protection and Affordable Care Act will profoundly affect the way physicians—particularly those engaged in primary care—practice medicine. Clinicians and their colleagues will be obliged to meet government-mandated performance quality measures while achieving cost efficiencies. Two concepts are central to the implementation of reform in the US health care system: accountable care organizations (ACOs) and the patient-centered medical home (PCMH). To get some perspective on what these changes mean for the practicing clinician, Cleveland Clinic Journal of Medicine (CCJM) interviewed David Longworth, MD, who chairs the Cleveland Clinic Medicine Institute and directs strategy and implementation of Cleveland Clinic ACO-related activities.
CCJM: Please explain briefly the concept of PCMH.
Dr. Longworth: PCMH is not a new concept; first advanced by the American Academy of Pediatrics in 1967,1 it represents a model of care in which an individual patient has a primary relationship with one provider who manages and coordinates the different aspects of the patient’s health care. The provider collaborates with a team of health care professionals. The concept caught on about a decade ago when a consortium of family medicine organizations and ultimately industry, including IBM, endorsed the concept. IBM and others created the Primary Care Consortium and began to drive the concept of PCMH.
Increasingly, care delivered through PCMH is team-based. The team coordinates the patient’s care and, when appropriate, enlists specialists or subspecialists to provide necessary components of care, all while maintaining responsibility for care coordination across the continuum of care. The medical home model provides an opportunity for enhanced access and care coordination utilizing care outside of the office walls, such as through retail clinics, eVisits, online diagnostic services, phone and electronic communication, and house call services.
Patient-centered medical homes are springing up across the country. In 2008, the National Committee for Quality Assurance (NCQA) developed criteria for recognition of PCMHs.2 It scored the sophistication of medical homes at three levels, level 1 being the lowest and level 3 the highest. Between 2008 and the end of 2010, NCQA had recognized more than 1,500 PCMHs. According to the latest figures, more than 3,000 practices have now earned PCMH recognition from the NCQA.3
At Cleveland Clinic, pilot projects at three family health centers that cover 60,000 persons have recently been rolled out with the goal of determining the model of team care that yields the highest value, with value defined by the equation of quality over cost. Ideally, higher quality is delivered at lower cost to increase value.
CCJM: What are the goals of ACOs?
Dr. Longworth: The term “accountable care,” first used in 2006 by Elliot Fisher, Dartmouth Institute of Health Policy and Clinical Practice,6 expresses the idea that health care organizations be accountable for the care they deliver, with the three-part aim of better health for populations, better care for individuals, and reduced cost inefficiencies without compromised care.
With accountable care, institutions take on risk with the expectation that they will improve quality but reduce costs, and if they reduce costs and achieve certain quality targets for populations of patients, they will share in the savings accrued. The Affordable Care Act laid the groundwork for creation of ACOs. The regulation for ACOs released by the Centers for Medicare & Medicaid Services (CMS) became effective in January 2012.7,8 Many health care organizations opposed the rule for reasons related to complexity, prescriptiveness, onerous detail around governance and marketing, and shared savings arrangements, among others. The final rule addressed many of these concerns and enabled the creation of the first wave of ACOs.8 At present, 153 ACOs have been approved by CMS.9 Other ACOs funded by commercial payers are also being formed in many locations.
For ACOs to be effective, I believe that the cornerstone of management has to be PCMHs.
CCJM: You mentioned that institutions will take on risk. What kind of risk are you referring to?
Dr. Longworth: Added value must be rewarded with sustainable payment models. There are two payment models in the final ACO rule from CMS. Both models require 3-year commitments and both require involvement of primary care physicians. One model for organizations that want to stick a toe in the water has no downside risk and modest potential for gain if they hit certain quality and cost targets. For those organizations that are further along and want to assume risk, the second option is a shared savings/risk payment model, which creates greater incentives for efficiency and quality. In the shared savings/risk model, the ACO can retain a portion of savings if it meets performance and expenditure benchmarks based on its performance during the previous 3 years. It is also at risk for loss if expenditures are greater than a certain amount compared with benchmark expenditures. Ultimately, the final destination for ACOs will be a risk of loss if they don’t perform.
CCJM: How can these two structures—PCMHs and ACOs—optimize the use of home health?
Dr. Longworth: Home health, which is part of the postacute care continuum, will be vitally important for managing individuals and populations of patients as we move toward PCMHs and ACOs. Coordination of care will require communication between home health services and the primary care physicians who are integral to PCMHs. There will have to be an emphasis on transitions of care, from the hospital to home, from skilled nursing facilities to home, and so forth.
Accountable care organizations are responsible for a population of patients, and ACOs receive a fixed amount of money per year to cover an individual life in that population. Thus, managing quality and controlling cost is the name of the game no matter where the patient is in the health care continuum— the office, the emergency room, the hospital, a skilled nursing facility, or a home health setting. For some chronic diseases, managing patients in the home health setting may be vitally important to prevent unnecessary trips to the emergency room and hospital readmissions, thereby reducing expenditures while providing quality care.
CCJM: Do you expect an increase in the number of PCMHs and ACOs to increase the demand for home health services?
Dr. Longworth: Given the necessity of optimizing quality at lower cost, I anticipate a push to deliver as much care as we can in the least expensive “right” setting, which might be the home in some situations. Certainly, we don’t want to send patients home prematurely only to have them return to emergency departments or hospitals, but I think the demand for home health will increase as we try to decrease the number of days in skilled nursing facilities, which are expensive, and to move care from skilled nursing facilities to the home setting.
CCJM: Is there evidence that integrated delivery models such as PCMHs deliver value?
Dr. Longworth: The Patient-Centered Primary Care Collaborative demonstrated quality improvements in selected outcomes domains while also realizing savings through reductions in admissions, emergency department visits, skilled nursing facility days, and pharmacy costs.10
CCJM: What challenges do PCMHs and ACOs present to home health agencies and the way they provide services, and how will these challenges affect patients and clinicians?
Dr. Longworth: One challenge will be communication between home health services and primary care providers during transitions of care. A second will be managing costs for home health, which entails leveraging new technologies such as in-home devices and telemedicine to provide optimal and ideal monitoring of patients at the lowest potential cost. Home health, like other players along the care continuum, will face increasing scrutiny regarding quality metrics. Home health agencies will likely need to distinguish themselves from one another on the basis of performance measures such as emergency department utilization, unnecessary hospital readmissions, medication errors, and quality of service to patients as well as to primary care providers.
CCJM: How does personalized health care fit into the PCMH model?
Dr. Longworth: Personalized health care, which includes the use of genetic testing in certain situations, is an emerging field that is still in its infancy. Like PCMHs, personalized health care is proactive rather than reactive. Application of personalized health care can help deliver value with better prediction of disease and appropriate use of targeted therapies to improve outcomes for certain individuals. Such individualized treatment not only enables higher quality of care but wiser use of resources. For instance, genetic markers can be used to predict drug metabolism and adverse drug events for certain medications. In the field of oncology, the expression of genetic mutations in certain tumor types can help identify patients most likely to respond to specific targeted therapies. In these ways, personalized health care is patient-centered health care. As part of its proactive nature, personalized health care, beyond genetic testing, also implies advance planning of appointments with a focus on chronic care and keeping patients in the care system.
CCJM: How does participation in a PCMH or an ACO benefit the primary care provider? Are there any disadvantages to participation?
Dr. Longworth: In the current fee-for-service world, primary care physicians and all providers are paid on a widget-by-widget basis. Some primary care physicians and other specialists fear moving to this new world in which they will ultimately be accountable for quality and cost. Not everyone has embraced the concept, but I do think it is inevitable. Primary care physicians especially will be under increasing pressure to care for populations as opposed to individual patients. They will need to redesign the care delivery model to provide team-based, proactive care focusing on the highest-risk patients to try to keep them out of the emergency department and hospital. There will also be a greater emphasis on wellness moving forward, in an attempt to prevent the development of chronic diseases such as diabetes and obesity in individual patients and populations. All of these changes represent a different paradigm for the delivery of care, compared with the present model.
The benefit of participation for a primary care physician depends on the structure of an ACO, particularly the amount of personal financial liability an individual practitioner might have. In a staff-model, fixed-salary institution, primary care physicians would probably be more immune to financial liability than they would in other markets or other compensation models in which salary can fluctuate.
CCJM: What are some of the barriers to ACO implementation that are relevant to office-based practice, and how can they be overcome?
Dr. Longworth: There are a number of barriers to ACOs and true PCMHs. The barriers revolve around redefining workflows and moving away from reactive care—a physician-centric model in which a patient comes into the office with a problem and the physician reacts—to proactive care with the goal being to recognize how the patient is doing over time to prevent unnecessary trips to the emergency department and, ultimately, hospitalization. It is a fundamentally different mindset that involves proactive outreach targeted at high-risk patients whose chronic diseases are managed through a team-based approach. An essential feature of primary care practice will be care coordinators who will manage and proactively anticipate the needs of medically complex, high-risk patients who use a disproportionately large share of services.
In addition, a greater emphasis on wellness will be necessary to prevent the development of chronic diseases such as diabetes, obesity, and hypertension in the large segment of the population that is reasonably healthy.
CCJM: What steps can a clinician take to prepare his or her practice for ACO implementation?
Dr. Longworth: Small practices will be challenged. It is difficult to imagine accountable care without an electronic health record. To understand the population, the practitioner will need to do continuous performance management, which can’t be done without access to data from a population of patients. An increasing number of physicians are aligning with organizations that have the necessary infrastructure to provide the myriad data required to measure quality, to enable continuous improvement in performance, and to enhance the patient experience. Small practices may not have the resources to complete the administrative work necessary to become part of an ACO.
There are ways to align with an ACO that do not constitute full employment; for example, the Cleveland (Ohio) Quality Alliance has aligned with community-based physicians to provide informatics support. Linking with larger organizations that have the resources to provide quality measurement and contracting support will permit smaller community-based physicians’ practices to be part of the game.
CCJM: What steps should PCMHs and ACOs take to leverage and optimize home health services among other parts of the medical neighborhood?
Dr. Longworth: Frankly, the postacute continuum is a challenge for most systems across the country because postacute care is fragmented. Our strategy at Cleveland Clinic is to identify and align with preferred providers of home health services. The criteria that I look for are commitment to quality and transparency, service that is oriented to both patients and PCMHs, and openness to innovation for leveraging health care technology to deliver care at the best value. Home health providers need to think about how to best accomplish these results to position themselves to partner with ACOs.
CCJM: How do PCMHs and ACOs apply to special patient populations and their needs? Is there a population that’s best suited for the medical home model?
Dr. Longworth: Certain populations of higher-risk patients are ideally suited to home health coupled with chronic disease management using care coordinators. Some examples are children with asthma and children with intellectual and developmental disabilities (eg, autism) who have high utilization of emergency services. Another population is patients with heart failure who are often in and out of the emergency department and hospital; there has been a concerted effort to reduce 30-day readmission rates, which are as high as 30%, for this group. (Also see “Home-based care for heart failure: Cleveland Clinic’s ‘Heart Care at Home’ transitional care program”)
CCJM: What are the specific expectations for patient involvement in the PCMH setting?
Dr. Longworth: Our challenge lies in how best to motivate patients and engage them in their own care, especially patients who have chronic diseases. We all struggle to resolve the engagement question. Coaching and patient engagement are functions of PCMHs and at every point along the care continuum. Home health providers can serve as health coaches to promote adherence to medications, healthy lifestyles, and follow-up visits with patients’ doctors—these all need to happen to better engage patients. How to engage patients and motivate them to be more involved in their health is a basic challenge.
CCJM: Along similar lines, how can home health providers work with physicians to achieve patient-centered care?
Dr. Longworth: They can communicate early when they think that things are amiss, serve as health coaches, create technologic solutions that enhance efficiency of communication, and anticipate care needs of patients in the home setting.
CCJM: How might bundling affect the financial picture of PCMHs and patient care?
Dr. Longworth: When one talks about bundling, the devil is in the definition. In bundling, one gets paid for an episode of service. So, for example, a total knee replacement might be compensated by a 30-day bundle that covers only the surgery and the immediate postoperative period. Or it might be a 90-day bundle that includes hospitalization and perhaps some days in skilled nursing facility, but ideally transitioning from hospital to home. In the latter example, the bundle, or the total payment, will be split between the hospital and the home care services. If home health is included in a bundle, there will be tremendous pressure on the home health service to prevent readmission and emergency room visits and to eliminate waste of care. Home health’s vulnerability will depend upon how a bundle is defined for specific service.
CCJM: Who defines the terms of the bundle?
Dr. Longworth: Whoever is applying for the bundle—usually, a health care system, hospital, or ACO. It may be that home health services will subcontract for a fat fee in order to immunize themselves against risk, and shift all of the risk to the contracting organization. If I were a home health provider, I might try to minimize my own risk, but still offer my services at a price that is financially viable.
- Sia C, Tonniges TF, Osterhus E, Taba S. History of the medical home concept. Pediatrics 2004; 113 suppl 5:1473–1478.
- National Committee for Quality Assurance. Standards and Guidelines for Physician Practice Connections ®—Patient-Centered Medical Home (PPC-PCMH™). http://www.ncqa.org/Portals/0/Programs/Recognition/PCMH_Overview_Apr01.pdfPublished 2008. Accessed September 17, 2012.
- White paper. NCQA ’s Patient-centered medical home (PCMH) 2011. National Committee for Quality Assurance Web site. http://www.ncqa.org/Portals/0/Newsroom/PCMH%202011%20White%20Paper_4.6.12.pdf. Published 2011. Accessed September 17, 2012.
- 2011 annual report. National Committee for Quality Assurance Web site. http://www.ncqa.org/Portals/0/Publications/Resource%20Library/Annual%20Report/2011_Annual_Report.pdf. Published 2011. Accessed September 17, 2012.
- National Committee for Quality Assurance patient-centered medical home 2011. National Committee for Quality Assurance Web site http://www.ncqa.org/Portals/0/PCMH2011%20withCAHPSInsert.pdf. Published 2011. Accessed September 17, 2012.
- Fisher ES, Staiger DO, Bynum JP, Gottlieb DJ. Creating accountable care organizations: the extended hospital medical staff [published online ahead of print December 5, 2006]. Health Aff (Millwood) 2007; 26:w44–w57. 10.1377/hlthaff.26.1.w44
- Accountable care organizations: improving care coordination for people with Medicare. A U.S. Department of Health & Human Services Web site. www.HealthCare.gov/news/factsheets/accountablecare03312011a.html. Published March 31, 2011. Updated March 12, 2012. Accessed November 20, 2012.
- Centers for Medicare & Medicaid Services (CMS), HHS. Medicare program; Medicare shared savings program: accountable care organizations. Final rule. Fed Regist 2011; 76 212:67802–67990.
- Fact Sheets. CMS names 88 new Medicare shared savings accountable care organizations. A Centers for Medicare & Medicaid Services (CMS) Web site. http://www.cms.gov/apps/media/press/factsheet.asp?Counter=4405&intNumPerPage=10&checkDate=1&checkKey=&srchType=1&numDays=90&srchOpt=0&srchData=&keywordType=All&chkNewsType=6&intPage=&showAll=1&pYear=1&year=2012&desc=&cboOrder=date. Published July 9, 2012. Accessed November 20, 2012.
- Grumbach K, Grundy P. Outcomes of implementing patient centered medical home interventions: a review of the evidence from prospective evaluation studies in the United States. Patient-Centered Primary Care Collaborative Web site. http://www.pcpcc.net/fles/evidence_outcomes_in_pcmh.pdf. Published November 16, 2010. Accessed November 20, 2012.
- Sia C, Tonniges TF, Osterhus E, Taba S. History of the medical home concept. Pediatrics 2004; 113 suppl 5:1473–1478.
- National Committee for Quality Assurance. Standards and Guidelines for Physician Practice Connections ®—Patient-Centered Medical Home (PPC-PCMH™). http://www.ncqa.org/Portals/0/Programs/Recognition/PCMH_Overview_Apr01.pdfPublished 2008. Accessed September 17, 2012.
- White paper. NCQA ’s Patient-centered medical home (PCMH) 2011. National Committee for Quality Assurance Web site. http://www.ncqa.org/Portals/0/Newsroom/PCMH%202011%20White%20Paper_4.6.12.pdf. Published 2011. Accessed September 17, 2012.
- 2011 annual report. National Committee for Quality Assurance Web site. http://www.ncqa.org/Portals/0/Publications/Resource%20Library/Annual%20Report/2011_Annual_Report.pdf. Published 2011. Accessed September 17, 2012.
- National Committee for Quality Assurance patient-centered medical home 2011. National Committee for Quality Assurance Web site http://www.ncqa.org/Portals/0/PCMH2011%20withCAHPSInsert.pdf. Published 2011. Accessed September 17, 2012.
- Fisher ES, Staiger DO, Bynum JP, Gottlieb DJ. Creating accountable care organizations: the extended hospital medical staff [published online ahead of print December 5, 2006]. Health Aff (Millwood) 2007; 26:w44–w57. 10.1377/hlthaff.26.1.w44
- Accountable care organizations: improving care coordination for people with Medicare. A U.S. Department of Health & Human Services Web site. www.HealthCare.gov/news/factsheets/accountablecare03312011a.html. Published March 31, 2011. Updated March 12, 2012. Accessed November 20, 2012.
- Centers for Medicare & Medicaid Services (CMS), HHS. Medicare program; Medicare shared savings program: accountable care organizations. Final rule. Fed Regist 2011; 76 212:67802–67990.
- Fact Sheets. CMS names 88 new Medicare shared savings accountable care organizations. A Centers for Medicare & Medicaid Services (CMS) Web site. http://www.cms.gov/apps/media/press/factsheet.asp?Counter=4405&intNumPerPage=10&checkDate=1&checkKey=&srchType=1&numDays=90&srchOpt=0&srchData=&keywordType=All&chkNewsType=6&intPage=&showAll=1&pYear=1&year=2012&desc=&cboOrder=date. Published July 9, 2012. Accessed November 20, 2012.
- Grumbach K, Grundy P. Outcomes of implementing patient centered medical home interventions: a review of the evidence from prospective evaluation studies in the United States. Patient-Centered Primary Care Collaborative Web site. http://www.pcpcc.net/fles/evidence_outcomes_in_pcmh.pdf. Published November 16, 2010. Accessed November 20, 2012.
AGA releases new medical position statement on constipation
Assessment of colonic transit in a patient presenting with constipation is recommended only after excluding a defecatory disorder and after treatment with laxatives and first-line pharmacologic agents fails, or after pelvic floor training in those with a defecatory disorder fails, according to a new medical position statement from the American Gastroenterological Association.
This recommendation is in contrast to the previous AGA medical position statement on constipation, which called for earlier assessment for colonic transit.
The change is one of only three substantive changes to the statement, which is published in the January issue of Gastroenterology; the others are the use of GRADE (Grading of Recommendations Assessment, Development, and Evaluation), which rates for each recommendation, its strength and quality of evidence, and the inclusion of newer agents; and deletion of certain older agents in treatment recommendations.
The colonic transit assessment recommendation is based in part on concerns about potential long-term side effects associated with newer agents that might be prescribed in patients with slow colonic transit.
"At present, the medical approaches used for managing normal and slow-transit constipation are similar. However, the major pharmacological trials in chronic constipation did not assess if the response to therapy is influenced by colonic transit. While newer agents may also be considered without assessing colonic transit, the long-term side effects, if any, of these agents are unknown and exposure to such potential risks might be more appropriate in patients with the more severe forms of constipation associated with slow transit," according to the statement.
Also, up to 50% of all patients with defecatory disorders have slow colonic transit as well, thus slow colonic transit does not exclude a defecatory disorder – and it also does not alter the management of defecatory disorders.
As for the approach to assessing for slow transit once a defecatory disorder is excluded, the statement says, "consideration should be given to assessing colonic transit by radiopaque markers, scintigraphy, or a wireless motility capsule in patients with persistent symptoms on laxatives."
Identifying slow colonic transit can reassure patients about the pathophysiology of their symptoms and also can serve as an objective marker for documenting response to treatment and provide physicians with the appropriate rationale for prescribing newer, often more expensive treatments.
Recommendations in the AGA statement that address the initial clinical assessment of constipation include the following:
• When feasible, medications that can cause constipation should be discontinued before further testing is initiated. This is a "strong" recommendation based on low-quality evidence.
• A careful digital rectal examination, including assessment of pelvic floor motion during simulated evacuation, is preferable to a cursory examination without these maneuvers and should be performed prior to referral for anorectal manometry. A normal exam, however, does not exclude defecatory disorders. This is a "strong" recommendation based on moderate-quality evidence.
The recommendations also address testing to assess medical causes of constipation. In addition to colonic transit testing, after ruling out a defecatory disorder, other recommended tests to assess for medical causes of constipation include a complete red blood count. Metabolic tests such as glucose, calcium, and sensitive thyroid-stimulating hormone are necessary only when other clinical features warrant these tests, and a colonoscopy and an imaging procedure for colonic lesions is only necessary in the presence of "alarm features," including blood in the stool, anemia, and weight loss, for medically refractory constipation or when age-appropriate colon cancer screening has not been performed. Anorectal manometry and a rectal balloon expulsion are indicated in those who fail to respond to laxatives but defecography only when anorectal manometry and a rectal balloon expulsion are inconclusive for defecatory disorders. All of these are "strong" recommendations based on low- or moderate-quality evidence.
Initial medical management, according to the statement, should include:
• A therapeutic trial of fiber supplementation and/or osmotic or stimulant laxatives after discontinuing medications that can cause constipation and after performing blood and other tests as guided by clinical features, but before anorectal testing.
• Use of long-term laxatives for normal and slow-transit constipation.
• Anorectal testing in patients who do not respond to these measures.
• Pelvic floor retraining by biofeedback therapy rather than laxatives in those with defecatory disorders.
These are all "strong" recommendations based on moderate- or high-quality evidence.
As for treatments to consider in patients who fail to respond to initial approaches, the AGA says that newer agents, such as lubiprostone and linaclotide, should be considered in those with normal or slow transit constipation who fail to respond to simple laxatives. Based on the GRADE ratings, this is a "weak" recommendation (implying that benefits, risks, and the burden of intervention are balanced among several legitimate management options or that appreciable uncertainty exists, and is based on moderate-quality evidence).
Also, when symptoms persist despite an adequate trial of biofeedback therapy – which improves symptoms in more than 70% of patients with defecatory disorders – anorectal tests and colonic transit should be reevaluated. This is a "strong" recommendation based on low-quality evidence.
Subtotal colectomy, as opposed to chronic laxative therapy, should be considered in those with symptomatic slow-transit constipation without a defecatory disorder, and colonic intraluminal testing should be considered to document colonic motor dysfunction prior to colectomy. These are weak recommendations based on moderate-quality evidence.
Finally, suppositories or enemas, rather than oral laxatives alone, should be considered in those with refractory pelvic floor dysfunction. This is a weak recommendation based on low-quality evidence.
These recommendations, drafted by a medical position panel and ultimately approved by the AGA Institute Governing Board, were published in conjunction with a technical review, which provides the rationale for the recommendations included in the statement.
AGA Institute Medical Position Panel members listed the following disclosures: Dr. Anthony Lembo reported serving as a consultant to, and serving as an advisory board member for Ironwood Pharmaceuticals and Forest Laboratories; Dr. Spencer D. Dorn reported serving as a consultant to Ironwood Pharmaceuticals and Forest Laboratories, and receiving research support from these companies, as well as from Synergy Pharmaceutical and Takeda Pharmaceuticals; Dr. A. E. Bharucha reported having a financial interest in a new technology related to anal manometry and serving a consultant for Helsin Therapeutics and Asubio Pharmaceuticals.
Assessment of colonic transit in a patient presenting with constipation is recommended only after excluding a defecatory disorder and after treatment with laxatives and first-line pharmacologic agents fails, or after pelvic floor training in those with a defecatory disorder fails, according to a new medical position statement from the American Gastroenterological Association.
This recommendation is in contrast to the previous AGA medical position statement on constipation, which called for earlier assessment for colonic transit.
The change is one of only three substantive changes to the statement, which is published in the January issue of Gastroenterology; the others are the use of GRADE (Grading of Recommendations Assessment, Development, and Evaluation), which rates for each recommendation, its strength and quality of evidence, and the inclusion of newer agents; and deletion of certain older agents in treatment recommendations.
The colonic transit assessment recommendation is based in part on concerns about potential long-term side effects associated with newer agents that might be prescribed in patients with slow colonic transit.
"At present, the medical approaches used for managing normal and slow-transit constipation are similar. However, the major pharmacological trials in chronic constipation did not assess if the response to therapy is influenced by colonic transit. While newer agents may also be considered without assessing colonic transit, the long-term side effects, if any, of these agents are unknown and exposure to such potential risks might be more appropriate in patients with the more severe forms of constipation associated with slow transit," according to the statement.
Also, up to 50% of all patients with defecatory disorders have slow colonic transit as well, thus slow colonic transit does not exclude a defecatory disorder – and it also does not alter the management of defecatory disorders.
As for the approach to assessing for slow transit once a defecatory disorder is excluded, the statement says, "consideration should be given to assessing colonic transit by radiopaque markers, scintigraphy, or a wireless motility capsule in patients with persistent symptoms on laxatives."
Identifying slow colonic transit can reassure patients about the pathophysiology of their symptoms and also can serve as an objective marker for documenting response to treatment and provide physicians with the appropriate rationale for prescribing newer, often more expensive treatments.
Recommendations in the AGA statement that address the initial clinical assessment of constipation include the following:
• When feasible, medications that can cause constipation should be discontinued before further testing is initiated. This is a "strong" recommendation based on low-quality evidence.
• A careful digital rectal examination, including assessment of pelvic floor motion during simulated evacuation, is preferable to a cursory examination without these maneuvers and should be performed prior to referral for anorectal manometry. A normal exam, however, does not exclude defecatory disorders. This is a "strong" recommendation based on moderate-quality evidence.
The recommendations also address testing to assess medical causes of constipation. In addition to colonic transit testing, after ruling out a defecatory disorder, other recommended tests to assess for medical causes of constipation include a complete red blood count. Metabolic tests such as glucose, calcium, and sensitive thyroid-stimulating hormone are necessary only when other clinical features warrant these tests, and a colonoscopy and an imaging procedure for colonic lesions is only necessary in the presence of "alarm features," including blood in the stool, anemia, and weight loss, for medically refractory constipation or when age-appropriate colon cancer screening has not been performed. Anorectal manometry and a rectal balloon expulsion are indicated in those who fail to respond to laxatives but defecography only when anorectal manometry and a rectal balloon expulsion are inconclusive for defecatory disorders. All of these are "strong" recommendations based on low- or moderate-quality evidence.
Initial medical management, according to the statement, should include:
• A therapeutic trial of fiber supplementation and/or osmotic or stimulant laxatives after discontinuing medications that can cause constipation and after performing blood and other tests as guided by clinical features, but before anorectal testing.
• Use of long-term laxatives for normal and slow-transit constipation.
• Anorectal testing in patients who do not respond to these measures.
• Pelvic floor retraining by biofeedback therapy rather than laxatives in those with defecatory disorders.
These are all "strong" recommendations based on moderate- or high-quality evidence.
As for treatments to consider in patients who fail to respond to initial approaches, the AGA says that newer agents, such as lubiprostone and linaclotide, should be considered in those with normal or slow transit constipation who fail to respond to simple laxatives. Based on the GRADE ratings, this is a "weak" recommendation (implying that benefits, risks, and the burden of intervention are balanced among several legitimate management options or that appreciable uncertainty exists, and is based on moderate-quality evidence).
Also, when symptoms persist despite an adequate trial of biofeedback therapy – which improves symptoms in more than 70% of patients with defecatory disorders – anorectal tests and colonic transit should be reevaluated. This is a "strong" recommendation based on low-quality evidence.
Subtotal colectomy, as opposed to chronic laxative therapy, should be considered in those with symptomatic slow-transit constipation without a defecatory disorder, and colonic intraluminal testing should be considered to document colonic motor dysfunction prior to colectomy. These are weak recommendations based on moderate-quality evidence.
Finally, suppositories or enemas, rather than oral laxatives alone, should be considered in those with refractory pelvic floor dysfunction. This is a weak recommendation based on low-quality evidence.
These recommendations, drafted by a medical position panel and ultimately approved by the AGA Institute Governing Board, were published in conjunction with a technical review, which provides the rationale for the recommendations included in the statement.
AGA Institute Medical Position Panel members listed the following disclosures: Dr. Anthony Lembo reported serving as a consultant to, and serving as an advisory board member for Ironwood Pharmaceuticals and Forest Laboratories; Dr. Spencer D. Dorn reported serving as a consultant to Ironwood Pharmaceuticals and Forest Laboratories, and receiving research support from these companies, as well as from Synergy Pharmaceutical and Takeda Pharmaceuticals; Dr. A. E. Bharucha reported having a financial interest in a new technology related to anal manometry and serving a consultant for Helsin Therapeutics and Asubio Pharmaceuticals.
Assessment of colonic transit in a patient presenting with constipation is recommended only after excluding a defecatory disorder and after treatment with laxatives and first-line pharmacologic agents fails, or after pelvic floor training in those with a defecatory disorder fails, according to a new medical position statement from the American Gastroenterological Association.
This recommendation is in contrast to the previous AGA medical position statement on constipation, which called for earlier assessment for colonic transit.
The change is one of only three substantive changes to the statement, which is published in the January issue of Gastroenterology; the others are the use of GRADE (Grading of Recommendations Assessment, Development, and Evaluation), which rates for each recommendation, its strength and quality of evidence, and the inclusion of newer agents; and deletion of certain older agents in treatment recommendations.
The colonic transit assessment recommendation is based in part on concerns about potential long-term side effects associated with newer agents that might be prescribed in patients with slow colonic transit.
"At present, the medical approaches used for managing normal and slow-transit constipation are similar. However, the major pharmacological trials in chronic constipation did not assess if the response to therapy is influenced by colonic transit. While newer agents may also be considered without assessing colonic transit, the long-term side effects, if any, of these agents are unknown and exposure to such potential risks might be more appropriate in patients with the more severe forms of constipation associated with slow transit," according to the statement.
Also, up to 50% of all patients with defecatory disorders have slow colonic transit as well, thus slow colonic transit does not exclude a defecatory disorder – and it also does not alter the management of defecatory disorders.
As for the approach to assessing for slow transit once a defecatory disorder is excluded, the statement says, "consideration should be given to assessing colonic transit by radiopaque markers, scintigraphy, or a wireless motility capsule in patients with persistent symptoms on laxatives."
Identifying slow colonic transit can reassure patients about the pathophysiology of their symptoms and also can serve as an objective marker for documenting response to treatment and provide physicians with the appropriate rationale for prescribing newer, often more expensive treatments.
Recommendations in the AGA statement that address the initial clinical assessment of constipation include the following:
• When feasible, medications that can cause constipation should be discontinued before further testing is initiated. This is a "strong" recommendation based on low-quality evidence.
• A careful digital rectal examination, including assessment of pelvic floor motion during simulated evacuation, is preferable to a cursory examination without these maneuvers and should be performed prior to referral for anorectal manometry. A normal exam, however, does not exclude defecatory disorders. This is a "strong" recommendation based on moderate-quality evidence.
The recommendations also address testing to assess medical causes of constipation. In addition to colonic transit testing, after ruling out a defecatory disorder, other recommended tests to assess for medical causes of constipation include a complete red blood count. Metabolic tests such as glucose, calcium, and sensitive thyroid-stimulating hormone are necessary only when other clinical features warrant these tests, and a colonoscopy and an imaging procedure for colonic lesions is only necessary in the presence of "alarm features," including blood in the stool, anemia, and weight loss, for medically refractory constipation or when age-appropriate colon cancer screening has not been performed. Anorectal manometry and a rectal balloon expulsion are indicated in those who fail to respond to laxatives but defecography only when anorectal manometry and a rectal balloon expulsion are inconclusive for defecatory disorders. All of these are "strong" recommendations based on low- or moderate-quality evidence.
Initial medical management, according to the statement, should include:
• A therapeutic trial of fiber supplementation and/or osmotic or stimulant laxatives after discontinuing medications that can cause constipation and after performing blood and other tests as guided by clinical features, but before anorectal testing.
• Use of long-term laxatives for normal and slow-transit constipation.
• Anorectal testing in patients who do not respond to these measures.
• Pelvic floor retraining by biofeedback therapy rather than laxatives in those with defecatory disorders.
These are all "strong" recommendations based on moderate- or high-quality evidence.
As for treatments to consider in patients who fail to respond to initial approaches, the AGA says that newer agents, such as lubiprostone and linaclotide, should be considered in those with normal or slow transit constipation who fail to respond to simple laxatives. Based on the GRADE ratings, this is a "weak" recommendation (implying that benefits, risks, and the burden of intervention are balanced among several legitimate management options or that appreciable uncertainty exists, and is based on moderate-quality evidence).
Also, when symptoms persist despite an adequate trial of biofeedback therapy – which improves symptoms in more than 70% of patients with defecatory disorders – anorectal tests and colonic transit should be reevaluated. This is a "strong" recommendation based on low-quality evidence.
Subtotal colectomy, as opposed to chronic laxative therapy, should be considered in those with symptomatic slow-transit constipation without a defecatory disorder, and colonic intraluminal testing should be considered to document colonic motor dysfunction prior to colectomy. These are weak recommendations based on moderate-quality evidence.
Finally, suppositories or enemas, rather than oral laxatives alone, should be considered in those with refractory pelvic floor dysfunction. This is a weak recommendation based on low-quality evidence.
These recommendations, drafted by a medical position panel and ultimately approved by the AGA Institute Governing Board, were published in conjunction with a technical review, which provides the rationale for the recommendations included in the statement.
AGA Institute Medical Position Panel members listed the following disclosures: Dr. Anthony Lembo reported serving as a consultant to, and serving as an advisory board member for Ironwood Pharmaceuticals and Forest Laboratories; Dr. Spencer D. Dorn reported serving as a consultant to Ironwood Pharmaceuticals and Forest Laboratories, and receiving research support from these companies, as well as from Synergy Pharmaceutical and Takeda Pharmaceuticals; Dr. A. E. Bharucha reported having a financial interest in a new technology related to anal manometry and serving a consultant for Helsin Therapeutics and Asubio Pharmaceuticals.
Depressive symptoms doubled risk of Crohn's disease in women
Depressive symptoms were associated with a doubling of the risk of Crohn’s disease in two large prospective cohorts of women, Dr. Ashwin N. Ananthakrishnan and his colleagues reported in the January issue of Clinical Gastroenterology and Hepatology (2013;11:57-62).
For women with recent and past episodes of depressive symptoms, the associations with the development of Crohn’s disease were significant, and were stronger for those with recent depression. The effect sizes were "in the same range we found for current smoking, oral contraceptive use, and NSAID use," all of which are known risk factors for Crohn’s disease, said Dr. Ananthakrishnan of Massachusetts General Hospital and Harvard Medical School, both in Boston, and his associates.
Video Source: American Gastroenterological Association YouTube channe
"Our findings support the potential importance of a biopsychosocial model in the pathogenesis of Crohn’s disease, and suggest the need for further studies on the effect of depression and stress on immune function and regulation," they noted.
Depression and life stress long have been thought to contribute to immune dysfunction and to influence both the risk for and the course of immune-mediated disorders such as Crohn’s. But until now, few studies have examined the role of mood in the onset of Crohn’s disease and ulcerative colitis, and those that did so were retrospective, failed to adjust for possible confounders, and assessed only the occurrence of major life stressors rather than the presence of depressive symptoms.
To address these shortcomings, the investigators examined the link between depressive symptoms and later onset of Crohn’s disease and ulcerative colitis using data from the prospective Nurses Health Study I and II. NHS I enrolled 121,700 female registered nurses who were 30-55 years old at baseline in 1976, and NHS II enrolled 116,686 female RNs aged 25-42 years at baseline in 1989.
For this study, Dr. Ananthakrishnan and his colleagues analyzed data for 152,461 of these participants in the two NHS cohorts. A total of 170 developed incident Crohn’s disease and 203 developed incident ulcerative colitis during follow-up.
Depressive symptoms were assessed several times in both the NHS I and II subjects using the five-question Mental Health Index (MHI-5), a subscale of the Short Form 36 health status survey. The participants received scores ranging from 1 to 100; 16,986 women (11% of the study population) received scores of 0-52, indicating the presence of depressive symptoms.
Subjects who scored from 86 to 100 composed the reference group.
The data were adjusted to account for numerous covariates that might influence risk for Crohn’s disease and ulcerative colitis, including the subjects’ race/ethnicity; smoking status; weight; menopausal status; and use of oral contraceptives, hormone therapy, and aspirin or NSAIDs.
There was a significant and linear increase in the risk of developing Crohn’s disease as MHI-5 scores decreased. Compared with the reference group, women with an MHI-5 score of 76-85 had a hazard ratio for Crohn’s disease of 1.38, those with an MHI-5 score of 53-75 had an HR of 1.59, and women with depressive symptoms and a score of 0-52 had an HR of 2.36.
No such association was seen between depressive symptoms and ulcerative colitis.
To account for the possibility that the study subjects’ depressed mood might be due to as-yet undiagnosed GI symptoms, the researchers performed a "lag" analysis excluding all cases of Crohn’s and ulcerative colitis that developed within 2 years of MHI-5 assessment. The results were unchanged in this analysis, they said.
The investigators also performed a sensitivity analysis restricted only to cases of Crohn’s disease that developed after 1996, when the NHS subjects first were routinely questioned about their use of antidepressant medications. Adjusting for the use of these drugs only slightly attenuated the strong association between depressive symptoms and Crohn’s disease.
"Preliminary animal and human studies suggest that treating depression through administration of antidepressants, or through improvement in coping mechanisms, could reduce risk of disease relapse. Whether similar interventions can also influence risk of disease onset, particularly among individuals with genetic susceptibility for Crohn’s disease or ulcerative colitis, merits further study," Dr. Ananthakrishnan and his associates said.
This study was supported by the American Gastroenterological Association, the Crohn’s and Colitis Foundation of America, the Broad Foundation, and the National Institutes of Health. Dr. Ananthakrishnan reported no potential financial conflicts of interest; his associates reported ties to Policy Analysis, Bayer HealthCare, Millennium Pharmaceuticals, and Pfizer.
Depressive symptoms were associated with a doubling of the risk of Crohn’s disease in two large prospective cohorts of women, Dr. Ashwin N. Ananthakrishnan and his colleagues reported in the January issue of Clinical Gastroenterology and Hepatology (2013;11:57-62).
For women with recent and past episodes of depressive symptoms, the associations with the development of Crohn’s disease were significant, and were stronger for those with recent depression. The effect sizes were "in the same range we found for current smoking, oral contraceptive use, and NSAID use," all of which are known risk factors for Crohn’s disease, said Dr. Ananthakrishnan of Massachusetts General Hospital and Harvard Medical School, both in Boston, and his associates.
Video Source: American Gastroenterological Association YouTube channe
"Our findings support the potential importance of a biopsychosocial model in the pathogenesis of Crohn’s disease, and suggest the need for further studies on the effect of depression and stress on immune function and regulation," they noted.
Depression and life stress long have been thought to contribute to immune dysfunction and to influence both the risk for and the course of immune-mediated disorders such as Crohn’s. But until now, few studies have examined the role of mood in the onset of Crohn’s disease and ulcerative colitis, and those that did so were retrospective, failed to adjust for possible confounders, and assessed only the occurrence of major life stressors rather than the presence of depressive symptoms.
To address these shortcomings, the investigators examined the link between depressive symptoms and later onset of Crohn’s disease and ulcerative colitis using data from the prospective Nurses Health Study I and II. NHS I enrolled 121,700 female registered nurses who were 30-55 years old at baseline in 1976, and NHS II enrolled 116,686 female RNs aged 25-42 years at baseline in 1989.
For this study, Dr. Ananthakrishnan and his colleagues analyzed data for 152,461 of these participants in the two NHS cohorts. A total of 170 developed incident Crohn’s disease and 203 developed incident ulcerative colitis during follow-up.
Depressive symptoms were assessed several times in both the NHS I and II subjects using the five-question Mental Health Index (MHI-5), a subscale of the Short Form 36 health status survey. The participants received scores ranging from 1 to 100; 16,986 women (11% of the study population) received scores of 0-52, indicating the presence of depressive symptoms.
Subjects who scored from 86 to 100 composed the reference group.
The data were adjusted to account for numerous covariates that might influence risk for Crohn’s disease and ulcerative colitis, including the subjects’ race/ethnicity; smoking status; weight; menopausal status; and use of oral contraceptives, hormone therapy, and aspirin or NSAIDs.
There was a significant and linear increase in the risk of developing Crohn’s disease as MHI-5 scores decreased. Compared with the reference group, women with an MHI-5 score of 76-85 had a hazard ratio for Crohn’s disease of 1.38, those with an MHI-5 score of 53-75 had an HR of 1.59, and women with depressive symptoms and a score of 0-52 had an HR of 2.36.
No such association was seen between depressive symptoms and ulcerative colitis.
To account for the possibility that the study subjects’ depressed mood might be due to as-yet undiagnosed GI symptoms, the researchers performed a "lag" analysis excluding all cases of Crohn’s and ulcerative colitis that developed within 2 years of MHI-5 assessment. The results were unchanged in this analysis, they said.
The investigators also performed a sensitivity analysis restricted only to cases of Crohn’s disease that developed after 1996, when the NHS subjects first were routinely questioned about their use of antidepressant medications. Adjusting for the use of these drugs only slightly attenuated the strong association between depressive symptoms and Crohn’s disease.
"Preliminary animal and human studies suggest that treating depression through administration of antidepressants, or through improvement in coping mechanisms, could reduce risk of disease relapse. Whether similar interventions can also influence risk of disease onset, particularly among individuals with genetic susceptibility for Crohn’s disease or ulcerative colitis, merits further study," Dr. Ananthakrishnan and his associates said.
This study was supported by the American Gastroenterological Association, the Crohn’s and Colitis Foundation of America, the Broad Foundation, and the National Institutes of Health. Dr. Ananthakrishnan reported no potential financial conflicts of interest; his associates reported ties to Policy Analysis, Bayer HealthCare, Millennium Pharmaceuticals, and Pfizer.
Depressive symptoms were associated with a doubling of the risk of Crohn’s disease in two large prospective cohorts of women, Dr. Ashwin N. Ananthakrishnan and his colleagues reported in the January issue of Clinical Gastroenterology and Hepatology (2013;11:57-62).
For women with recent and past episodes of depressive symptoms, the associations with the development of Crohn’s disease were significant, and were stronger for those with recent depression. The effect sizes were "in the same range we found for current smoking, oral contraceptive use, and NSAID use," all of which are known risk factors for Crohn’s disease, said Dr. Ananthakrishnan of Massachusetts General Hospital and Harvard Medical School, both in Boston, and his associates.
Video Source: American Gastroenterological Association YouTube channe
"Our findings support the potential importance of a biopsychosocial model in the pathogenesis of Crohn’s disease, and suggest the need for further studies on the effect of depression and stress on immune function and regulation," they noted.
Depression and life stress long have been thought to contribute to immune dysfunction and to influence both the risk for and the course of immune-mediated disorders such as Crohn’s. But until now, few studies have examined the role of mood in the onset of Crohn’s disease and ulcerative colitis, and those that did so were retrospective, failed to adjust for possible confounders, and assessed only the occurrence of major life stressors rather than the presence of depressive symptoms.
To address these shortcomings, the investigators examined the link between depressive symptoms and later onset of Crohn’s disease and ulcerative colitis using data from the prospective Nurses Health Study I and II. NHS I enrolled 121,700 female registered nurses who were 30-55 years old at baseline in 1976, and NHS II enrolled 116,686 female RNs aged 25-42 years at baseline in 1989.
For this study, Dr. Ananthakrishnan and his colleagues analyzed data for 152,461 of these participants in the two NHS cohorts. A total of 170 developed incident Crohn’s disease and 203 developed incident ulcerative colitis during follow-up.
Depressive symptoms were assessed several times in both the NHS I and II subjects using the five-question Mental Health Index (MHI-5), a subscale of the Short Form 36 health status survey. The participants received scores ranging from 1 to 100; 16,986 women (11% of the study population) received scores of 0-52, indicating the presence of depressive symptoms.
Subjects who scored from 86 to 100 composed the reference group.
The data were adjusted to account for numerous covariates that might influence risk for Crohn’s disease and ulcerative colitis, including the subjects’ race/ethnicity; smoking status; weight; menopausal status; and use of oral contraceptives, hormone therapy, and aspirin or NSAIDs.
There was a significant and linear increase in the risk of developing Crohn’s disease as MHI-5 scores decreased. Compared with the reference group, women with an MHI-5 score of 76-85 had a hazard ratio for Crohn’s disease of 1.38, those with an MHI-5 score of 53-75 had an HR of 1.59, and women with depressive symptoms and a score of 0-52 had an HR of 2.36.
No such association was seen between depressive symptoms and ulcerative colitis.
To account for the possibility that the study subjects’ depressed mood might be due to as-yet undiagnosed GI symptoms, the researchers performed a "lag" analysis excluding all cases of Crohn’s and ulcerative colitis that developed within 2 years of MHI-5 assessment. The results were unchanged in this analysis, they said.
The investigators also performed a sensitivity analysis restricted only to cases of Crohn’s disease that developed after 1996, when the NHS subjects first were routinely questioned about their use of antidepressant medications. Adjusting for the use of these drugs only slightly attenuated the strong association between depressive symptoms and Crohn’s disease.
"Preliminary animal and human studies suggest that treating depression through administration of antidepressants, or through improvement in coping mechanisms, could reduce risk of disease relapse. Whether similar interventions can also influence risk of disease onset, particularly among individuals with genetic susceptibility for Crohn’s disease or ulcerative colitis, merits further study," Dr. Ananthakrishnan and his associates said.
This study was supported by the American Gastroenterological Association, the Crohn’s and Colitis Foundation of America, the Broad Foundation, and the National Institutes of Health. Dr. Ananthakrishnan reported no potential financial conflicts of interest; his associates reported ties to Policy Analysis, Bayer HealthCare, Millennium Pharmaceuticals, and Pfizer.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Major Finding: Women with depressive symptoms and an MHI-5 score of 0-52 had a hazard ratio of 2.36 for Crohn’s disease.
Data Source: An analysis of data on 152,461 subjects in the Nurses Health Study I and II.
Disclosures: This study was supported by the American Gastroenterological Association, the Crohn’s and Colitis Foundation of America, the Broad Foundation, and the National Institutes of Health. Dr. Ananthakrishnan reported no potential financial conflicts of interest; his associates reported ties to Policy Analysis, Bayer HealthCare, Millennium Pharmaceuticals, and Pfizer.
Human papillomavirus vaccine: Safe, effective, underused
The vaccines against human papillomavirus (HPV) are the only ones designed to prevent cancer caused by a virus1,2—surely a good goal. But because HPV is sexually transmitted, HPV vaccination has met with public controversy.3 To counter the objections and better protect their patients’ health, primary care providers and other clinicians need a clear understanding of the benefits and the low risk of HPV vaccination—and the reasons so many people object to it.3
In this article, we will review:
- The impact of HPV-related diseases
- The basic biologic features of HPV vaccines
- The host immune response to natural HPV infection vs the response to HPV vaccines
- The clinical efficacy and safety of HPV vaccines
- The latest guidelines for HPV vaccination
- The challenges to vaccination implementation
- Frequently asked practical questions about HPV vaccination.
HPV-RELATED DISEASES: FROM BOTHERSOME TO DEADLY
Clinical sequelae of HPV infection include genital warts; cancers of the cervix, vulva, vagina, anus, penis, and oropharynx; and recurrent respiratory papillomatosis.4–6
Genital warts
HPV types 6 and 11 are responsible for more than 90% of the 1 million new cases of genital warts diagnosed annually in the United States.7–10
Bothersome and embarrassing, HPV-related genital warts can cause itching, burning, erythema, and pain, as well as epithelial erosions, ulcerations, depigmentation, and urethral and vaginal bleeding and discharge.11,12 Although they are benign in the oncologic sense, they can cause a good deal of emotional and financial stress. Patients may feel anxiety, embarrassment,13 and vulnerability. Adolescents and adults who have or have had genital warts need to inform their current and future partners or else risk infecting them—and facing the consequences.
Direct health care costs of genital warts in the United States have been estimated to be at least $200 million per year.14
Cervical cancer
Cervical cancer cannot develop unless the cervical epithelium is infected with one of the oncogenic HPV types. Indeed, oncogenic HPV is present in as many as 99.8% of cervical cancer specimens.15 HPV 16 and 18 are the most oncogenic HPV genotypes and account for 75% of all cases of cervical cancer. Ten other HPV genotypes account for the remaining 25%.16
In 2012, there were an estimated 12,170 new cases of invasive cervical cancer in the United States and 4,220 related deaths.17 The cost associated with cervical cancer screening, managing abnormal findings, and treating invasive cervical cancer in the United States is estimated to be $3.3 billion per year.18
Although the incidence and the mortality rates of cervical cancer have decreased more than 50% in the United States over the past 3 decades thanks to screening,19 cervical cancer remains the second leading cause of death from cancer in women worldwide. Each year, an estimated 500,000 women contract the disease and 240,000 die of it.20
Anal cancer
A recent study indicated that oncogenic HPV can also cause anal cancer, and the proportion of such cancers associated with HPV 16 or HPV 18 infection is as high as or higher than for cervical cancers, and estimated at 80%.21
The incidence of anal cancer is increasing by approximately 2% per year in both men and women in the general population,22 and rates are even higher in men who have sex with men and people infected with the human immunodeficiency virus.23
Hu and Goldie24 estimated that the lifetime costs of caring for all the people in the United States who in just 1 year (2003) acquired anal cancer attributable to HPV would total $92 million.
Oropharyngeal cancer
HPV types 16, 18, 31, 33, and 35 also cause oropharyngeal cancer. HPV 16 accounts for more than 90% of cases of HPV-related oropharyngeal cancer.25
Chaturvedi et al6 tested tissue samples from three national cancer registries and found that the number of oropharyngeal cancers that were HPV-positive increased from 16.3% in 1984–1989 to 71.7% in 2000–2004, while the number of HPV-negative oropharyngeal cancers fell by 50%, paralleling the drop in cigarette smoking in the United States.
Hu and Goldie24 estimated that the total lifetime cost for all new HPV-related oropharyngeal cancers that arose in 2003 would come to $38.1 million.24
Vulvar and vaginal cancers
HPV 16 and 18 are also responsible for approximately 50% of vulvar cancers and 50% to 75% of vaginal cancers.4,5
Recurrent respiratory papillomatosis
HPV 6 and 11 cause almost all cases of juvenile- and adult-onset recurrent respiratory papillomatosis.26 The annual cost for surgical procedures for this condition in the United States has been estimated at $151 million.27
HPV VACCINES ARE NONINFECTIOUS AND NONCARCINOGENIC
Currently, two HPV vaccines are available: a quadrivalent vaccine against types 6, 11, 16, and 18 (Gardasil; Merck) and a bivalent vaccine against types 16 and 18 (Cervarix; Glaxo-SmithKline). The quadrivalent vaccine was approved by the US Food and Drug Administration (FDA) in 2006, and the bivalent vaccine was approved in 2009.28,29
Both vaccines contain virus-like particles, ie, viral capsids that contain no DNA. HPV has a circular DNA genome of 8,000 nucleotides divided into two regions: the early region, for viral replication, and the late region, for viral capsid production. The host produces neutralizing antibodies in response to the L1 capsid protein, which is different in different HPV types.
In manufacturing the vaccines, the viral L1 gene is incorporated into a yeast genome or an insect virus genome using recombinant DNA technology (Figure 1). Grown in culture, the yeast or the insect cells produce the HPV L1 major capsid protein, which has the intrinsic capacity to self-assemble into virus-like particles.30–33 These particles are subsequently purified for use in the vaccines.34
Recombinant virus-like particles are morphologically indistinguishable from authentic HPV virions and contain the same typespecific antigens present in authentic virions. Therefore, they are highly effective in inducing a host humoral immune response. And because they do not contain HPV DNA, the recombinant HPV vaccines are noninfectious and noncarcinogenic.35
VACCINATION INDUCES A STRONGER IMMUNE RESPONSE THAN INFECTION
HPV infections trigger both a humoral and a cellular response in the host immune system.
The humoral immune response to HPV infection involves producing neutralizing antibody against the specific HPV type, specifically the specific L1 major capsid protein. This process is typically somewhat slow and weak, and only about 60% of women with a new HPV infection develop antibodies to it.36,37
HPV has several ways to evade the host immune system. It does not infect or replicate within the antigen-presenting cells in the epithelium. In addition, HPV-infected keratinocytes are less susceptible to cytotoxic lymphocytic-mediated lysis. Moreover, HPV infection cause very little tissue destruction. And finally, natural cervical HPV infection does not result in viremia. As a result, antigen-presenting cells have no chance to engulf the virions and present virion-derived antigen to the host immune system. The immune system outside the epithelium has limited opportunity to detect the virus because HPV infection does not have a blood-borne phase.38,39
The cell-mediated immune response to early HPV oncoproteins may help eliminate established HPV infection.40 In contrast to antibodies, the T-cell response to HPV has not been shown to be specific to HPV type.41 Clinically, cervical HPV infection is common, but most lesions go into remission or resolve as a result of the cell-mediated immune response.40,41
In contrast to the weak, somewhat ineffective immune response to natural HPV infection, the antibody response to HPV vaccines is rather robust. In randomized controlled trials, almost all vaccinated people have seroconverted. The peak antibody concentrations are 50 to 10,000 times greater than in natural infection. Furthermore, the neutralizing antibodies induced by HPV vaccines persist for as long as 7 to 9 years after immunization.42 However, the protection provided by HPV vaccines against HPV-related cervical intraepithelial neoplasia does not necessarily correlate with the antibody concentration.43–47
Why does the vaccine work so well?
Why are vaccine-induced antibody responses so much stronger than those induced by natural HPV infection?
The first reason is that the vaccine, delivered intramuscularly, rapidly enters into blood vessels and the lymphatic system. In contrast, in natural intraepithelial infection, the virus is shed from mucosal surfaces and does not result in viremia.48
In addition, the strong immunogenic nature of the virus-like particles induces a robust host antibody response even in the absence of adjuvant because of concentrated neutralizing epitopes and excellent induction of the T-helper cell response.35,49,50
The neutralizing antibody to L1 prevents HPV infection by blocking HPV from binding to the basement membrane as well as to the epithelial cell receptor during epithelial microabrasion and viral entry. The subsequent micro-wound healing leads to serous exudation and rapid access of serum immunoglobulin G (IgG) to HPV virus particles and encounters with circulatory B memory cells.
Furthermore, emerging evidence suggests that even very low antibody concentrations are sufficient to prevent viral entry into cervical epithelial cells.46–48,51–53
THE HPV VACCINES ARE HIGHLY EFFECTIVE AND SAFE
The efficacy and safety of the quadrivalent and the bivalent HPV vaccines have been evaluated in large randomized clinical trials.23,28,29,54,55 Table 1 summarizes the key findings.
The Females United to Unilaterally Reduce Endo/ectocervical Disease (FUTURE I)54 and FUTURE II28 trials showed conclusively that the quadrivalent HPV vaccine is 98% to 100% efficacious in preventing HPV 16- and 18-related cervical intraepithelial neoplasia, carcinoma in situ, and invasive cervical cancer in women who had not been infected with HPV before. Similarly, the Papilloma Trial against Cancer in Young Adults (PATRICIA) concluded that the bivalent HPV vaccine is 93% efficacious.29
Giuliano et al55 and Palefsky et al23 conducted randomized clinical trials of the quadrivalent HPV vaccine for preventing genital disease and anal intraepithelial neoplasia in boys and men; the efficacy rates were 90.4%55 and 77.5%.23
A recent Finnish trial in boys age 10 to 18 found 100% seroconversion rates for HPV 16 and HPV 18 antibodies after they received bivalent HPV vaccine.56 Similar efficacy has been demonstrated for the quadrivalent HPV vaccine in boys.57
Adverse events after vaccination
After the FDA approved the quadrivalent HPV vaccine for girls in 2006, the US Centers for Disease Control and Prevention (CDC) conducted a thorough survey of adverse events after immunization from June 1, 2006 through December 31, 2008.58 There were about 54 reports of adverse events per 100,000 distributed vaccine doses, similar to rates for other vaccines. However, the incidence rates of syncope and venous thrombosis were disproportionately higher, according to data from the US Vaccine Adverse Event Reporting System. The rate of syncope was 8.2 per 100,000 vaccine doses, and the rate of venous thrombotic events was 0.2 per 100,000 doses.58
There were 32 reports of deaths after HPV vaccination, but these were without clear causation. Hence, this information must be interpreted with caution and should not be used to infer causal associations between HPV vaccines and adverse outcomes. The causes of death included diabetic ketoacidosis, pulmonary embolism, prescription drug abuse, amyotrophic lateral sclerosis, meningoencephalitis, influenza B viral sepsis, arrhythmia, myocarditis, and idiopathic seizure disorder.58
Furthermore, it is important to note that vasovagal syncope and venous thromboembolic events are more common in young females in general.59 For example, the background rates of venous thromboembolism in females age 14 to 29 using oral contraceptives is 21 to 31 per 100,000 woman-years.60
Overall, the quadrivalent HPV vaccine is well tolerated and clinically safe. Postlicensure evaluation found that the quadrivalent and bivalent HPV vaccines had similar safety profiles.61
Vaccination is contraindicated in people with known hypersensitivity or prior severe allergic reactions to vaccine or yeast or who have bleeding disorders.
HPV VACCINATION DOES MORE THAN PREVENT CERVICAL CANCER IN FEMALES
The quadrivalent HPV vaccine was licensed by the FDA in 2006 for use in females age 9 to 26 to prevent cervical cancer, cervical cancer precursors, vaginal and vulval cancer precursors, and anogenital warts caused by HPV types 6, 11, 16, and 18. The CDC’s Advisory Committee on Immunization Practices (ACIP) issued its recommendation for initiating HPV vaccination for females age 11 to 12 in March 2007. The ACIP stated that the vaccine could be given to girls as early as age 9 and recommended catch-up vaccinations for those age 13 to 26.62,63
The quadrivalent HPV vaccine was licensed by the FDA in 2009 for use in boys and men for the prevention of genital warts. In December 2010, the quadrivalent HPV vaccine received extended licensure from the FDA for use in males and females for the prevention of anal cancer. In October 2011, the ACIP voted to recommend routine use of the quadrivalent HPV vaccine for boys age 11 to 12; catch-up vaccination should occur for those age 13 to 22, with an option to vaccinate men age 23 to 26.
These recommendations replace the “permissive use” recommendations from the ACIP in October 2009 that said the quadrivalent HPV vaccine may be given to males age 9 to 26.64 This shift from a permissive to an active recommendation connotes a positive change reflecting recognition of rising oropharyngeal cancer rates attributable to oncogenic, preventable HPV, rising HPV-related anal cancer incidence, and the burden of the disease in female partners of infected men, with associated rising health care costs.
The bivalent HPV vaccine received FDA licensure in October 2009 for use in females age 10 to 25 to prevent cervical cancer and precursor lesions. The ACIP included the bivalent HPV vaccine in its updated recommendations in May 2010 for use in girls age 11 to 12. Numerous national and international organizations have endorsed HPV vaccination.65–71
Table 2 outlines the recommendations from these organizations.
HPV VACCINATION RATES ARE STILL LOW
HPV vaccine offers us the hope of eventually eradicating cervical cancer. However, the immunization program still faces many challenges, since HPV vaccination touches on issues related to adolescent sexuality, parental autonomy, and cost. As a result, HPV immunization rates remain relatively low in the United States according to several national surveys. Only 40% to 49% of girls eligible for the vaccine received even one dose, and of those who received even one dose, only 32% to 53.3% came back for all three doses.72–75 Furthermore, indigent and minority teens were less likely to finish the three-dose HPV vaccine series.
Why are the vaccination rates so low?
Parental barriers. In one survey,73 reasons that parents gave for not having their daughters vaccinated included:
- Lack of knowledge of the vaccine (19.4%)
- Lack of perceived need for the vaccine (18.8%)
- Belief that their daughter was not sexually active (18.3%)
- Clinician not recommending vaccination (13.1%).
In an effort to improve HPV vaccination rates,41 several states proposed legislation for mandatory HPV vaccination of schoolgirls shortly after licensure of the quadrivalent HPV vaccine.3 Since then, we have seen a wave of public opposition rooted in concerns and misinformation about safety, teenage sexuality, governmental coercion, and cost. Widespread media coverage has also highlighted unsubstantiated claims about side effects attributable to the vaccine that can raise parents’ mistrust of vaccines.76 Concerns have also been raised about a threat to parental autonomy in how and when to educate their children about sex.77
Moreover, the vaccine has raised ethical concerns in some parents and politicians that mandatory vaccination could undermine abstinence messages in sexual education and may alter sexual activity by condoning risky behavior.78 However, a recent study indicated that there is no significant change in sexual behavior related to HPV vaccination in young girls.79
In 2012, Mullins et al80 also found that an urban population of adolescent girls (76.4% black, 57.5% sexually experienced) did not feel they could forgo safer sexual practices after first HPV vaccination, although the girls did perceive less risk from HPV than from other sexually transmitted infections after HPV vaccination (P < .001).80 Inadequate knowledge about HPV-related disease and HPV vaccine correlated with less perceived risk from HPV after vaccination among the girls, and a lack of knowledge about HPV and less communication with their daughters about HPV correlated with less perceived risk from HPV in the mothers of the study population.81
Health-care-provider barriers. Physician endorsement of vaccines represents a key predictor of vaccine acceptance by patients, families, and other clinicians.82–84 In 2008, a cross-sectional, Internet-based survey of 1,122 Texas pediatricians, family practice physicians, obstetricians, gynecologists, and internal medicine physicians providing direct patient care found that only 48.5% always recommended HPV vaccination to girls.74 Of all respondents, 68.4% were likely to recommend the vaccine to boys, and 41.7% agreed with mandated vaccination. Thus, more than half of the physicians were not following the current recommendations for universal HPV vaccination for 11- to -12-year-olds.
In a survey of 1,013 physicians during the spring and summer of 2009, only 34.6% said they always recommend HPV vaccination to early adolescents, 52.7% to middle adolescents, and 50.2% to late adolescents and young adults.85 Pediatricians were more likely than family physicians and obstetrician-gynecologists to always recommend HPV vaccine across all age groups (P < .001). Educational interventions targeting various specialties may help overcome physician-related barriers to immunization.85
Financial barriers. HPV vaccine, which must be given in three doses, is more expensive than other vaccines, and this expense is yet another barrier, especially for the uninsured.86 Australia launched a government-funded program of HPV vaccination (with the quadrivalent vaccine) in schools in 2007, and it has been very successful. Garland et al87 reported that new cases of genital warts have decreased by 73% since the program began, and the rate of high-grade abnormalities on Papanicolaou testing has declined by a small but significant amount.
For HPV vaccination to have an impact on public health, vaccination rates in the general population need to be high. In order to achieve these rates, we need to educate our patients on vaccine safety and efficacy and counsel vaccine recipients about the prevention of sexually transmitted infections and the importance of regular cervical cancer screening after age 21. Clinicians can actively “myth-bust” with patients, who may not realize that the vaccine should be given despite a history of HPV infection or abnormal Pap smear.
FREQUENTLY ASKED QUESTIONS
What if the patient is late for a shot?
The current recommended vaccination schedule for the bivalent and quadrivalent HPV vaccines is a three-dose series administered at 0, 2, and 6 months, given as an intramuscular injection, preferably in the deltoid muscle. The minimal dosing interval is 4 weeks between the first and second doses and 12 weeks between the second and third doses.
The vaccines use different adjuncts with different specific mechanisms for immunogenicity; therefore, it is recommended that the same vaccine be used for the entire three-dose series. However, if circumstances preclude the completion of a series with the same vaccine, the other HPV vaccine may be used.63 Starting the series over is not recommended.
Long-term studies demonstrated clinical efficacy 8.5 years after vaccination.47 Amnestic response by virtue of activation of pools of memory B cells has been demonstrated, suggesting the vaccine may afford lifelong immunity.88
Is a pregnancy test needed before HPV vaccination?
The ACIP states that pregnancy testing is not required before receiving either of the available HPV vaccines.
A recent retrospective review of phase III efficacy trials and pregnancy registry surveillance data for both vaccines revealed no increase in spontaneous abortions, fetal malformations, or adverse pregnancy outcomes.89 Data are limited on bivalent and quadrivalent HPV vaccine given within 30 days of pregnancy and subsequent pregnancy and fetal outcomes. Both vaccines have been assigned a pregnancy rating of category B; however, the ACIP recommends that neither vaccine be given if the recipient is known to be pregnant. If pregnancy occurs, it is recommended that the remainder of the series be deferred until after delivery.62
It is not known whether the vaccine is excreted in breast milk. The manufacturers of both the bivalent and quadrivalent HPV vaccines recommend caution when vaccinating lactating women.30,31
Can HPV vaccine be given with other vaccines?
In randomized trials, giving the bivalent HPV vaccine with the combined hepatitis A, hepatitis B, meningococcal conjugate and the combined tetanus, diphtheria, and acellular pertussis vaccines did not interfere with the immunogenic response, was safe, and was well tolerated.90,91 Coadministration of the quadrivalent HPV vaccine has been studied only with hepatitis B vaccine, with similar safety and efficacy noted.
The ACIP recommends giving HPV vaccine at the same visit with other age-appropriate immunizations to increase the likelihood of adherence to recommended vaccination schedules.62
Is HPV vaccination cost-effective?
Kim and Goldie86 performed a cost-effectiveness analysis of HPV vaccination of girls at age 12 and catch-up vaccination up to the ages of 18, 21, and 26. For their analysis, they considered prevention of cancers associated with HPV types 16 and 18, of genital warts associated with types 6 and 11, and of recurrent respiratory papillomatosis. They also assumed that immunity would be lifelong, and current screening practices would continue.
They calculated that routine vaccination of 12-year-old girls resulted in an incremental cost-effective ratio of $34,900 per quality-adjusted life-year (QALY) gained. A threshold of less than $50,000 per QALY gained is considered reasonably cost-effective, with an upper limit of $100,000 considered acceptable.92
In the same analysis by Kim and Goldie,86 catch-up vaccination of girls through age 18 resulted in a cost of $50,000 to $100,000 per QALY gained, and catch-up vaccination of females through age 26 was significantly less cost-effective at more then $130,000 per QALY gained. The vaccine was also significantly less cost-effective if 5% of the population was neither screened nor vaccinated, if a 10-year booster was required, and if frequent cervical cancer screening intervals were adopted.
This analysis did not include costs related to the evaluation and treatment of abnormal Pap smears and cross-protection against other HPV-related cancers.
The cost-effectiveness of HPV vaccination depends on reaching more girls at younger ages (ideally before sexual debut) and completing the three-dose schedule to optimize duration of immunity.92 Appropriate modification of the current recommendations for the intervals of cervical cancer screening for vaccinated individuals will further improve the cost-effectiveness of vaccination. The inclusion of male vaccination generally has more favorable cost per QALY in scenarios in which female coverage rates are less than 50%93 and among men who have sex with men.94
TO ERADICATE CERVICAL CANCER
Given the remarkable efficacy and expected long-term immunogenicity of HPV vaccines, we anticipate a decline in HPV-related cervical cancer and other related diseases in the years to come. However, modeling studies predicting the impact of HPV vaccination suggest that although substantial reductions in diseases can be expected, the benefit, assuming high vaccination rates, will not be apparent for at least another decade.95 Furthermore, the current HPV vaccines contain only HPV 16 and 18 L1 protein for cancer protection and, therefore, do not provide optimal protection against all oncogenic HPV-related cancers.
The real hope of eradicating cervical cancer and all HPV-related disease relies on a successful global implementation of multivalent HPV vaccination, effective screening strategies, and successful treatment.
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- af Geijersstam V, Kibur M, Wang Z, et al. Stability over time of serum antibody levels to human papillomavirus type 16. J Infect Dis 1998; 177:1710–1714.
- Safaeian M, Porras C, Schiffman M, et al; Costa Rican Vaccine Trial Group. Epidemiological study of anti-HPV16/18 seropositivity and subsequent risk of HPV16 and -18 infections. J Natl Cancer Inst 2010; 102:1653–1662.
- Tindle RW. Immune evasion in human papillomavirus-associated cervical cancer. Nat Rev Cancer 2002; 2:59–65.
- Scott M, Nakagawa M, Moscicki AB. Cell-mediated immune response to human papillomavirus infection. Clin Diagn Lab Immunol 2001; 8:209–220.
- Roden R, Wu TC. Preventative and therapeutic vaccines for cervical cancer. Expert Rev Vaccines 2003; 2:495–516.
- Wang SS, Hildesheim A. Chapter 5: Viral and host factors in human papillomavirus persistence and progression. J Natl Cancer Inst Monogr 2003; 31:35–40.
- De Carvalho N, Teixeira J, Roteli-Martins CM, et al. Sustained efficacy and immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine up to 7.3 years in young adult women. Vaccine 2010; 28:6247–6255.
- Harper DM, Franco EL, Wheeler CM, et al; HPV Vaccine Study group. Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet 2006; 367:1247–1255.
- Villa LL, Costa RL, Petta CA, et al. High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up. Br J Cancer 2006; 95:1459–1466.
- Villa LL, Ault KA, Giuliano AR, et al. Immunologic responses following administration of a vaccine targeting human papillomavirus Types 6, 11, 16, and 18. Vaccine 2006; 24:5571–5583.
- Smith JF, Brownlow M, Brown M, et al. Antibodies from women immunized with Gardasil cross-neutralize HPV 45 pseudovirions. Hum Vaccin 2007; 3:109–115.
- Rowhani-Rahbar A, Mao C, Hughes JP, et al. Longer term efficacy of a prophylactic monovalent human papillomavirus type 16 vaccine. Vaccine 2009; 27:5612–5619.
- Stanley M. HPV - immune response to infection and vaccination. Infect Agent Cancer 2010; 5:19.
- Stanley M. Pathology and epidemiology of HPV infection in females. Gynecol Oncol 2010; 117(suppl 2):S5–S10.
- Yan M, Peng J, Jabbar IA, et al. Activation of dendritic cells by human papillomavirus-like particles through TLR4 and NF-kappaB-mediated signalling, moderated by TGF-beta. Immunol Cell Biol 2005; 83:83–91.
- Roberts JN, Buck CB, Thompson CD, et al. Genital transmission of HPV in a mouse model is potentiated by nonoxynol-9 and inhibited by carrageenan. Nat Med 2007; 13:857–861.
- Kines RC, Thompson CD, Lowy DR, Schiller JT, Day PM. The initial steps leading to papillomavirus infection occur on the basement membrane prior to cell surface binding. Proc Natl Acad Sci USA 2009; 106:20458–20463.
- Day PM, Kines RC, Thompson CD, et al. In vivo mechanisms of vaccine-induced protection against HPV infection. Cell Host Microbe 2010; 8:260–270.
- Garland SM, Hernandez-Avila M, Wheeler CM, et al; Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) I Investigators. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med 2007; 356:1928–1943.
- Giuliano AR, Palefsky JM, Goldstone S, et al. Efficacy of quadrivalent HPV vaccine against HPV Infection and disease in males. N Engl J Med 2011; 364:401–411.
- Petäjä T, Keränen H, Karppa T, et al. Immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in healthy boys aged 10–18 years. J Adolesc Health 2009; 44:33–40.
- Reisinger KS, Block SL, Lazcano-Ponce E, et al. Safety and persistent immunogenicity of a quadrivalent human papillomavirus types 6, 11, 16, 18 L1 virus-like particle vaccine in preadolescents and adolescents: a randomized controlled trial. Pediatr Infect Dis J 2007; 26:201–209.
- Slade BA, Leidel L, Vellozzi C, et al. Postlicensure safety surveillance for quadrivalent human papillomavirus recombinant vaccine. JAMA 2009; 302:750–757.
- Block SL, Brown DR, Chatterjee A, et al. Clinical trial and post-licensure safety profile of a prophylactic human papillomavirus (types 6, 11, 16, and 18) l1 virus-like particle vaccine. Pediatr Infect Dis J 2010; 29:95–101.
- Farmer RD, Lawrenson RA, Thompson CR, Kennedy JG, Hambleton IR. Population-based study of risk of venous thromboembolism associated with various oral contraceptives. Lancet 1997; 349:83–88.
- Labadie J. Postlicensure safety evaluation of human papilloma virus vaccines. Int J Risk Saf Med 2011; 23:103–112.
- Markowitz LE, Dunne EF, Saraiya M, Lawson HW, Chesson H, Unger ER; Centers for Disease Control and Prevention (CDC). Quadrivalent human papillomavirus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2007; 56:1–24.
- Centers for Disease Control and Prevention (CDC). FDA licensure of bivalent human papillomavirus vaccine (HPV2, Cervarix) for use in females and updated HPV vaccination recommendations from the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2010; 59:626–629.
- Centers for Disease Control and Prevention (CDC). FDA licensure of quadrivalent human papillomavirus vaccine (HPV4, Gardasil) for use in males and guidance from the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2010; 59:630–632.
- World Health Organization (WHO). Weekly Epidemiological Record (WER). January 2009; 84:1–16. http://www.who.int/wer/2009/wer8401_02/en/index.html. Accessed November 12, 2012.
- Saslow D, Castle PE, Cox JT, et al. American Cancer Society guideline for human papillomavirus (HPV) vaccine use to prevent cervical cancer and its precursors. CA Cancer J Clin 2007; 57:7–28.
- Committee opinion no. 467: human papillomavirus vaccination. Obstet Gynecol 2010; 116:800–803.
- American College of Physicians. ACP Guide to Adult Immunization. 4th ed. 2011:58–60. http://immunization.acponline.org/. Accessed November 12, 2012.
- Vaughn JA, Miller RA. Update on immunizations in adults. Am Fam Physician 2011; 84:1015–1020.
- American Academy of Pediatrics Committee on Infectious Diseases. Prevention of human papillomavirus infection: provisional recommendations for immunization of girls and women with quadrivalent human papillomavirus vaccine. Pediatrics 2007; 120:666–668.
- Friedman L, Bell DL, Kahn JA, et al. Human papillomavirus vaccine: an updated position statement of the Society for Adolescent Health and Medicine. J Adolesc Health 2011; 48:215–216.
- Centers for Disease Control and Prevention (CDC). National and state vaccination coverage among adolescents aged 13 through 17 years--United States, 2010. MMWR Morb Mortal Wkly Rep 2011; 60:1117–1123.
- Dorell CG, Yankey D, Santibanez TA, Markowitz LE. Human papillomavirus vaccination series initiation and completion, 2008–2009. Pediatrics 2011; 128:830–839.
- Kahn JA, Cooper HP, Vadaparampil ST, et al. Human papillomavirus vaccine recommendations and agreement with mandated human papillomavirus vaccination for 11-to-12-year-old girls: a statewide survey of Texas physicians. Cancer Epidemiol Biomarkers Prev 2009; 18:2325–2332.
- Schwartz JL, Caplan AL, Faden RR, Sugarman J. Lessons from the failure of human papillomavirus vaccine state requirements. Clin Pharmacol Ther 2007; 82:760–763.
- Cooper LZ, Larson HJ, Katz SL. Protecting public trust in immunization. Pediatrics 2008; 122:149–153.
- Olshen E, Woods ER, Austin SB, Luskin M, Bauchner H. Parental acceptance of the human papillomavirus vaccine. J Adolesc Health 2005; 37:248–251.
- Zimmerman RK. Ethical analysis of HPV vaccine policy options. Vaccine 2006; 24:4812–4820.
- Al Romaih WRR, Srinivas A, Shahtahmasebi S, Omar HA. No significant change in sexual behavior in association with human papillomavirus vaccination in young girls. Int J Child Adolesc Health 2011; 4:1–5.
- Mullins TL, Zimet GD, Rosenthal SL, et al. Adolescent perceptions of risk and need for safer sexual behaviors after first human papillomavirus vaccination. Arch Pediatr Adolesc Med 2012; 166:82–88.
- Middleman AB, Tung JS. School-located immunization programs: do parental p predict behavior? Vaccine 2011; 29:3513–3516.
- Samoff E, Dunn A, VanDevanter N, Blank S, Weisfuse IB. Predictors of acceptance of hepatitis B vaccination in an urban sexually transmitted diseases clinic. Sex Transm Dis 2004; 31:415–420.
- Gnanasekaran SK, Finkelstein JA, Hohman K, O’Brien M, Kruskal B, Lieu T. Parental perspectives on influenza vaccination among children with asthma. Public Health Rep 2006; 121:181–188.
- Daley MF, Crane LA, Chandramouli V, et al. Influenza among healthy young children: changes in parental attitudes and predictors of immunization during the 2003 to 2004 influenza season. Pediatrics 2006; 117:e268–e277.
- Vadaparampil ST, Kahn JA, Salmon D, et al. Missed clinical opportunities: provider recommendations for HPV vaccination for 11–12 year old girls are limited. Vaccine 2011; 29:8634–8641.
- Kim JJ, Goldie SJ. Health and economic implications of HPV vaccination in the United States. N Engl J Med 2008; 359:821–832.
- Garland SM, Skinner SR, Brotherton JM. Adolescent and young adult HPV vaccination in Australia: achievements and challenges. Prev Med 2011; 53(suppl 1):S29–S35.
- Rowhani-Rahbar A, Alvarez FB, Bryan JT, et al. Evidence of immune memory 8.5 years following administration of a prophylactic human papillomavirus type 16 vaccine. J Clin Virol 2012; 53:239–243.
- Forinash AB, Yancey AM, Pitlick JM, Myles TD. Safety of the HPV bivalent and quadrivalent vaccines during pregnancy (February) Ann Pharmacother 2011; [epub ahead of print]
- Wheeler CM, Harvey BM, Pichichero ME, et al. Immunogenicity and safety of human papillomavirus-16/18 AS04-adjuvanted vaccine coadministered with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine and/or meningococcal conjugate vaccine to healthy girls 11 to 18 years of age: results from a randomized open trial. Pediatr Infect Dis J 2011; 30:e225–e234.
- Pedersen C, Breindahl M, Aggarwal N, et al. Randomized trial: immunogenicity and safety of coadministered human papillomavirus-16/18 AS04-adjuvanted vaccine and combined hepatitis A and B vaccine in girls. J Adolesc Health 2012; 50:38–46.
- Eichler HG, Kong SX, Gerth WC, Mavros P, Jönsson B. Use of costeffectiveness analysis in health-care resource allocation decisionmaking: how are cost-effectiveness thresholds expected to emerge? Value Health 2004; 7:518–528.
- Chesson HW. HPV vaccine cost-effectiveness: updates and review. Presentation before the Advisory Committee on Immunization Practices (ACIP), June 22, 2011. Atlanta, GA: US Department of Health and Human Services, CDC; 2011. http://www.cdc.gov/vaccines/recs/acip/downloads/mtg-slides-jun11/07-5-hpv-cost-effect.pdf. Accessed August 31, 2012.
- Kim JJ. Targeted human papillomavirus vaccination of men who have sex with men in the USA: a cost-effectiveness modelling analysis. Lancet Infect Dis 2010; 10:845–852.
- Cuzick J, Castañón A, Sasieni P. Predicted impact of vaccination against human papillomavirus 16/18 on cancer incidence and cervical abnormalities in women aged 20–29 in the UK. Br J Cancer 2010; 102:933–939.
The vaccines against human papillomavirus (HPV) are the only ones designed to prevent cancer caused by a virus1,2—surely a good goal. But because HPV is sexually transmitted, HPV vaccination has met with public controversy.3 To counter the objections and better protect their patients’ health, primary care providers and other clinicians need a clear understanding of the benefits and the low risk of HPV vaccination—and the reasons so many people object to it.3
In this article, we will review:
- The impact of HPV-related diseases
- The basic biologic features of HPV vaccines
- The host immune response to natural HPV infection vs the response to HPV vaccines
- The clinical efficacy and safety of HPV vaccines
- The latest guidelines for HPV vaccination
- The challenges to vaccination implementation
- Frequently asked practical questions about HPV vaccination.
HPV-RELATED DISEASES: FROM BOTHERSOME TO DEADLY
Clinical sequelae of HPV infection include genital warts; cancers of the cervix, vulva, vagina, anus, penis, and oropharynx; and recurrent respiratory papillomatosis.4–6
Genital warts
HPV types 6 and 11 are responsible for more than 90% of the 1 million new cases of genital warts diagnosed annually in the United States.7–10
Bothersome and embarrassing, HPV-related genital warts can cause itching, burning, erythema, and pain, as well as epithelial erosions, ulcerations, depigmentation, and urethral and vaginal bleeding and discharge.11,12 Although they are benign in the oncologic sense, they can cause a good deal of emotional and financial stress. Patients may feel anxiety, embarrassment,13 and vulnerability. Adolescents and adults who have or have had genital warts need to inform their current and future partners or else risk infecting them—and facing the consequences.
Direct health care costs of genital warts in the United States have been estimated to be at least $200 million per year.14
Cervical cancer
Cervical cancer cannot develop unless the cervical epithelium is infected with one of the oncogenic HPV types. Indeed, oncogenic HPV is present in as many as 99.8% of cervical cancer specimens.15 HPV 16 and 18 are the most oncogenic HPV genotypes and account for 75% of all cases of cervical cancer. Ten other HPV genotypes account for the remaining 25%.16
In 2012, there were an estimated 12,170 new cases of invasive cervical cancer in the United States and 4,220 related deaths.17 The cost associated with cervical cancer screening, managing abnormal findings, and treating invasive cervical cancer in the United States is estimated to be $3.3 billion per year.18
Although the incidence and the mortality rates of cervical cancer have decreased more than 50% in the United States over the past 3 decades thanks to screening,19 cervical cancer remains the second leading cause of death from cancer in women worldwide. Each year, an estimated 500,000 women contract the disease and 240,000 die of it.20
Anal cancer
A recent study indicated that oncogenic HPV can also cause anal cancer, and the proportion of such cancers associated with HPV 16 or HPV 18 infection is as high as or higher than for cervical cancers, and estimated at 80%.21
The incidence of anal cancer is increasing by approximately 2% per year in both men and women in the general population,22 and rates are even higher in men who have sex with men and people infected with the human immunodeficiency virus.23
Hu and Goldie24 estimated that the lifetime costs of caring for all the people in the United States who in just 1 year (2003) acquired anal cancer attributable to HPV would total $92 million.
Oropharyngeal cancer
HPV types 16, 18, 31, 33, and 35 also cause oropharyngeal cancer. HPV 16 accounts for more than 90% of cases of HPV-related oropharyngeal cancer.25
Chaturvedi et al6 tested tissue samples from three national cancer registries and found that the number of oropharyngeal cancers that were HPV-positive increased from 16.3% in 1984–1989 to 71.7% in 2000–2004, while the number of HPV-negative oropharyngeal cancers fell by 50%, paralleling the drop in cigarette smoking in the United States.
Hu and Goldie24 estimated that the total lifetime cost for all new HPV-related oropharyngeal cancers that arose in 2003 would come to $38.1 million.24
Vulvar and vaginal cancers
HPV 16 and 18 are also responsible for approximately 50% of vulvar cancers and 50% to 75% of vaginal cancers.4,5
Recurrent respiratory papillomatosis
HPV 6 and 11 cause almost all cases of juvenile- and adult-onset recurrent respiratory papillomatosis.26 The annual cost for surgical procedures for this condition in the United States has been estimated at $151 million.27
HPV VACCINES ARE NONINFECTIOUS AND NONCARCINOGENIC
Currently, two HPV vaccines are available: a quadrivalent vaccine against types 6, 11, 16, and 18 (Gardasil; Merck) and a bivalent vaccine against types 16 and 18 (Cervarix; Glaxo-SmithKline). The quadrivalent vaccine was approved by the US Food and Drug Administration (FDA) in 2006, and the bivalent vaccine was approved in 2009.28,29
Both vaccines contain virus-like particles, ie, viral capsids that contain no DNA. HPV has a circular DNA genome of 8,000 nucleotides divided into two regions: the early region, for viral replication, and the late region, for viral capsid production. The host produces neutralizing antibodies in response to the L1 capsid protein, which is different in different HPV types.
In manufacturing the vaccines, the viral L1 gene is incorporated into a yeast genome or an insect virus genome using recombinant DNA technology (Figure 1). Grown in culture, the yeast or the insect cells produce the HPV L1 major capsid protein, which has the intrinsic capacity to self-assemble into virus-like particles.30–33 These particles are subsequently purified for use in the vaccines.34
Recombinant virus-like particles are morphologically indistinguishable from authentic HPV virions and contain the same typespecific antigens present in authentic virions. Therefore, they are highly effective in inducing a host humoral immune response. And because they do not contain HPV DNA, the recombinant HPV vaccines are noninfectious and noncarcinogenic.35
VACCINATION INDUCES A STRONGER IMMUNE RESPONSE THAN INFECTION
HPV infections trigger both a humoral and a cellular response in the host immune system.
The humoral immune response to HPV infection involves producing neutralizing antibody against the specific HPV type, specifically the specific L1 major capsid protein. This process is typically somewhat slow and weak, and only about 60% of women with a new HPV infection develop antibodies to it.36,37
HPV has several ways to evade the host immune system. It does not infect or replicate within the antigen-presenting cells in the epithelium. In addition, HPV-infected keratinocytes are less susceptible to cytotoxic lymphocytic-mediated lysis. Moreover, HPV infection cause very little tissue destruction. And finally, natural cervical HPV infection does not result in viremia. As a result, antigen-presenting cells have no chance to engulf the virions and present virion-derived antigen to the host immune system. The immune system outside the epithelium has limited opportunity to detect the virus because HPV infection does not have a blood-borne phase.38,39
The cell-mediated immune response to early HPV oncoproteins may help eliminate established HPV infection.40 In contrast to antibodies, the T-cell response to HPV has not been shown to be specific to HPV type.41 Clinically, cervical HPV infection is common, but most lesions go into remission or resolve as a result of the cell-mediated immune response.40,41
In contrast to the weak, somewhat ineffective immune response to natural HPV infection, the antibody response to HPV vaccines is rather robust. In randomized controlled trials, almost all vaccinated people have seroconverted. The peak antibody concentrations are 50 to 10,000 times greater than in natural infection. Furthermore, the neutralizing antibodies induced by HPV vaccines persist for as long as 7 to 9 years after immunization.42 However, the protection provided by HPV vaccines against HPV-related cervical intraepithelial neoplasia does not necessarily correlate with the antibody concentration.43–47
Why does the vaccine work so well?
Why are vaccine-induced antibody responses so much stronger than those induced by natural HPV infection?
The first reason is that the vaccine, delivered intramuscularly, rapidly enters into blood vessels and the lymphatic system. In contrast, in natural intraepithelial infection, the virus is shed from mucosal surfaces and does not result in viremia.48
In addition, the strong immunogenic nature of the virus-like particles induces a robust host antibody response even in the absence of adjuvant because of concentrated neutralizing epitopes and excellent induction of the T-helper cell response.35,49,50
The neutralizing antibody to L1 prevents HPV infection by blocking HPV from binding to the basement membrane as well as to the epithelial cell receptor during epithelial microabrasion and viral entry. The subsequent micro-wound healing leads to serous exudation and rapid access of serum immunoglobulin G (IgG) to HPV virus particles and encounters with circulatory B memory cells.
Furthermore, emerging evidence suggests that even very low antibody concentrations are sufficient to prevent viral entry into cervical epithelial cells.46–48,51–53
THE HPV VACCINES ARE HIGHLY EFFECTIVE AND SAFE
The efficacy and safety of the quadrivalent and the bivalent HPV vaccines have been evaluated in large randomized clinical trials.23,28,29,54,55 Table 1 summarizes the key findings.
The Females United to Unilaterally Reduce Endo/ectocervical Disease (FUTURE I)54 and FUTURE II28 trials showed conclusively that the quadrivalent HPV vaccine is 98% to 100% efficacious in preventing HPV 16- and 18-related cervical intraepithelial neoplasia, carcinoma in situ, and invasive cervical cancer in women who had not been infected with HPV before. Similarly, the Papilloma Trial against Cancer in Young Adults (PATRICIA) concluded that the bivalent HPV vaccine is 93% efficacious.29
Giuliano et al55 and Palefsky et al23 conducted randomized clinical trials of the quadrivalent HPV vaccine for preventing genital disease and anal intraepithelial neoplasia in boys and men; the efficacy rates were 90.4%55 and 77.5%.23
A recent Finnish trial in boys age 10 to 18 found 100% seroconversion rates for HPV 16 and HPV 18 antibodies after they received bivalent HPV vaccine.56 Similar efficacy has been demonstrated for the quadrivalent HPV vaccine in boys.57
Adverse events after vaccination
After the FDA approved the quadrivalent HPV vaccine for girls in 2006, the US Centers for Disease Control and Prevention (CDC) conducted a thorough survey of adverse events after immunization from June 1, 2006 through December 31, 2008.58 There were about 54 reports of adverse events per 100,000 distributed vaccine doses, similar to rates for other vaccines. However, the incidence rates of syncope and venous thrombosis were disproportionately higher, according to data from the US Vaccine Adverse Event Reporting System. The rate of syncope was 8.2 per 100,000 vaccine doses, and the rate of venous thrombotic events was 0.2 per 100,000 doses.58
There were 32 reports of deaths after HPV vaccination, but these were without clear causation. Hence, this information must be interpreted with caution and should not be used to infer causal associations between HPV vaccines and adverse outcomes. The causes of death included diabetic ketoacidosis, pulmonary embolism, prescription drug abuse, amyotrophic lateral sclerosis, meningoencephalitis, influenza B viral sepsis, arrhythmia, myocarditis, and idiopathic seizure disorder.58
Furthermore, it is important to note that vasovagal syncope and venous thromboembolic events are more common in young females in general.59 For example, the background rates of venous thromboembolism in females age 14 to 29 using oral contraceptives is 21 to 31 per 100,000 woman-years.60
Overall, the quadrivalent HPV vaccine is well tolerated and clinically safe. Postlicensure evaluation found that the quadrivalent and bivalent HPV vaccines had similar safety profiles.61
Vaccination is contraindicated in people with known hypersensitivity or prior severe allergic reactions to vaccine or yeast or who have bleeding disorders.
HPV VACCINATION DOES MORE THAN PREVENT CERVICAL CANCER IN FEMALES
The quadrivalent HPV vaccine was licensed by the FDA in 2006 for use in females age 9 to 26 to prevent cervical cancer, cervical cancer precursors, vaginal and vulval cancer precursors, and anogenital warts caused by HPV types 6, 11, 16, and 18. The CDC’s Advisory Committee on Immunization Practices (ACIP) issued its recommendation for initiating HPV vaccination for females age 11 to 12 in March 2007. The ACIP stated that the vaccine could be given to girls as early as age 9 and recommended catch-up vaccinations for those age 13 to 26.62,63
The quadrivalent HPV vaccine was licensed by the FDA in 2009 for use in boys and men for the prevention of genital warts. In December 2010, the quadrivalent HPV vaccine received extended licensure from the FDA for use in males and females for the prevention of anal cancer. In October 2011, the ACIP voted to recommend routine use of the quadrivalent HPV vaccine for boys age 11 to 12; catch-up vaccination should occur for those age 13 to 22, with an option to vaccinate men age 23 to 26.
These recommendations replace the “permissive use” recommendations from the ACIP in October 2009 that said the quadrivalent HPV vaccine may be given to males age 9 to 26.64 This shift from a permissive to an active recommendation connotes a positive change reflecting recognition of rising oropharyngeal cancer rates attributable to oncogenic, preventable HPV, rising HPV-related anal cancer incidence, and the burden of the disease in female partners of infected men, with associated rising health care costs.
The bivalent HPV vaccine received FDA licensure in October 2009 for use in females age 10 to 25 to prevent cervical cancer and precursor lesions. The ACIP included the bivalent HPV vaccine in its updated recommendations in May 2010 for use in girls age 11 to 12. Numerous national and international organizations have endorsed HPV vaccination.65–71
Table 2 outlines the recommendations from these organizations.
HPV VACCINATION RATES ARE STILL LOW
HPV vaccine offers us the hope of eventually eradicating cervical cancer. However, the immunization program still faces many challenges, since HPV vaccination touches on issues related to adolescent sexuality, parental autonomy, and cost. As a result, HPV immunization rates remain relatively low in the United States according to several national surveys. Only 40% to 49% of girls eligible for the vaccine received even one dose, and of those who received even one dose, only 32% to 53.3% came back for all three doses.72–75 Furthermore, indigent and minority teens were less likely to finish the three-dose HPV vaccine series.
Why are the vaccination rates so low?
Parental barriers. In one survey,73 reasons that parents gave for not having their daughters vaccinated included:
- Lack of knowledge of the vaccine (19.4%)
- Lack of perceived need for the vaccine (18.8%)
- Belief that their daughter was not sexually active (18.3%)
- Clinician not recommending vaccination (13.1%).
In an effort to improve HPV vaccination rates,41 several states proposed legislation for mandatory HPV vaccination of schoolgirls shortly after licensure of the quadrivalent HPV vaccine.3 Since then, we have seen a wave of public opposition rooted in concerns and misinformation about safety, teenage sexuality, governmental coercion, and cost. Widespread media coverage has also highlighted unsubstantiated claims about side effects attributable to the vaccine that can raise parents’ mistrust of vaccines.76 Concerns have also been raised about a threat to parental autonomy in how and when to educate their children about sex.77
Moreover, the vaccine has raised ethical concerns in some parents and politicians that mandatory vaccination could undermine abstinence messages in sexual education and may alter sexual activity by condoning risky behavior.78 However, a recent study indicated that there is no significant change in sexual behavior related to HPV vaccination in young girls.79
In 2012, Mullins et al80 also found that an urban population of adolescent girls (76.4% black, 57.5% sexually experienced) did not feel they could forgo safer sexual practices after first HPV vaccination, although the girls did perceive less risk from HPV than from other sexually transmitted infections after HPV vaccination (P < .001).80 Inadequate knowledge about HPV-related disease and HPV vaccine correlated with less perceived risk from HPV after vaccination among the girls, and a lack of knowledge about HPV and less communication with their daughters about HPV correlated with less perceived risk from HPV in the mothers of the study population.81
Health-care-provider barriers. Physician endorsement of vaccines represents a key predictor of vaccine acceptance by patients, families, and other clinicians.82–84 In 2008, a cross-sectional, Internet-based survey of 1,122 Texas pediatricians, family practice physicians, obstetricians, gynecologists, and internal medicine physicians providing direct patient care found that only 48.5% always recommended HPV vaccination to girls.74 Of all respondents, 68.4% were likely to recommend the vaccine to boys, and 41.7% agreed with mandated vaccination. Thus, more than half of the physicians were not following the current recommendations for universal HPV vaccination for 11- to -12-year-olds.
In a survey of 1,013 physicians during the spring and summer of 2009, only 34.6% said they always recommend HPV vaccination to early adolescents, 52.7% to middle adolescents, and 50.2% to late adolescents and young adults.85 Pediatricians were more likely than family physicians and obstetrician-gynecologists to always recommend HPV vaccine across all age groups (P < .001). Educational interventions targeting various specialties may help overcome physician-related barriers to immunization.85
Financial barriers. HPV vaccine, which must be given in three doses, is more expensive than other vaccines, and this expense is yet another barrier, especially for the uninsured.86 Australia launched a government-funded program of HPV vaccination (with the quadrivalent vaccine) in schools in 2007, and it has been very successful. Garland et al87 reported that new cases of genital warts have decreased by 73% since the program began, and the rate of high-grade abnormalities on Papanicolaou testing has declined by a small but significant amount.
For HPV vaccination to have an impact on public health, vaccination rates in the general population need to be high. In order to achieve these rates, we need to educate our patients on vaccine safety and efficacy and counsel vaccine recipients about the prevention of sexually transmitted infections and the importance of regular cervical cancer screening after age 21. Clinicians can actively “myth-bust” with patients, who may not realize that the vaccine should be given despite a history of HPV infection or abnormal Pap smear.
FREQUENTLY ASKED QUESTIONS
What if the patient is late for a shot?
The current recommended vaccination schedule for the bivalent and quadrivalent HPV vaccines is a three-dose series administered at 0, 2, and 6 months, given as an intramuscular injection, preferably in the deltoid muscle. The minimal dosing interval is 4 weeks between the first and second doses and 12 weeks between the second and third doses.
The vaccines use different adjuncts with different specific mechanisms for immunogenicity; therefore, it is recommended that the same vaccine be used for the entire three-dose series. However, if circumstances preclude the completion of a series with the same vaccine, the other HPV vaccine may be used.63 Starting the series over is not recommended.
Long-term studies demonstrated clinical efficacy 8.5 years after vaccination.47 Amnestic response by virtue of activation of pools of memory B cells has been demonstrated, suggesting the vaccine may afford lifelong immunity.88
Is a pregnancy test needed before HPV vaccination?
The ACIP states that pregnancy testing is not required before receiving either of the available HPV vaccines.
A recent retrospective review of phase III efficacy trials and pregnancy registry surveillance data for both vaccines revealed no increase in spontaneous abortions, fetal malformations, or adverse pregnancy outcomes.89 Data are limited on bivalent and quadrivalent HPV vaccine given within 30 days of pregnancy and subsequent pregnancy and fetal outcomes. Both vaccines have been assigned a pregnancy rating of category B; however, the ACIP recommends that neither vaccine be given if the recipient is known to be pregnant. If pregnancy occurs, it is recommended that the remainder of the series be deferred until after delivery.62
It is not known whether the vaccine is excreted in breast milk. The manufacturers of both the bivalent and quadrivalent HPV vaccines recommend caution when vaccinating lactating women.30,31
Can HPV vaccine be given with other vaccines?
In randomized trials, giving the bivalent HPV vaccine with the combined hepatitis A, hepatitis B, meningococcal conjugate and the combined tetanus, diphtheria, and acellular pertussis vaccines did not interfere with the immunogenic response, was safe, and was well tolerated.90,91 Coadministration of the quadrivalent HPV vaccine has been studied only with hepatitis B vaccine, with similar safety and efficacy noted.
The ACIP recommends giving HPV vaccine at the same visit with other age-appropriate immunizations to increase the likelihood of adherence to recommended vaccination schedules.62
Is HPV vaccination cost-effective?
Kim and Goldie86 performed a cost-effectiveness analysis of HPV vaccination of girls at age 12 and catch-up vaccination up to the ages of 18, 21, and 26. For their analysis, they considered prevention of cancers associated with HPV types 16 and 18, of genital warts associated with types 6 and 11, and of recurrent respiratory papillomatosis. They also assumed that immunity would be lifelong, and current screening practices would continue.
They calculated that routine vaccination of 12-year-old girls resulted in an incremental cost-effective ratio of $34,900 per quality-adjusted life-year (QALY) gained. A threshold of less than $50,000 per QALY gained is considered reasonably cost-effective, with an upper limit of $100,000 considered acceptable.92
In the same analysis by Kim and Goldie,86 catch-up vaccination of girls through age 18 resulted in a cost of $50,000 to $100,000 per QALY gained, and catch-up vaccination of females through age 26 was significantly less cost-effective at more then $130,000 per QALY gained. The vaccine was also significantly less cost-effective if 5% of the population was neither screened nor vaccinated, if a 10-year booster was required, and if frequent cervical cancer screening intervals were adopted.
This analysis did not include costs related to the evaluation and treatment of abnormal Pap smears and cross-protection against other HPV-related cancers.
The cost-effectiveness of HPV vaccination depends on reaching more girls at younger ages (ideally before sexual debut) and completing the three-dose schedule to optimize duration of immunity.92 Appropriate modification of the current recommendations for the intervals of cervical cancer screening for vaccinated individuals will further improve the cost-effectiveness of vaccination. The inclusion of male vaccination generally has more favorable cost per QALY in scenarios in which female coverage rates are less than 50%93 and among men who have sex with men.94
TO ERADICATE CERVICAL CANCER
Given the remarkable efficacy and expected long-term immunogenicity of HPV vaccines, we anticipate a decline in HPV-related cervical cancer and other related diseases in the years to come. However, modeling studies predicting the impact of HPV vaccination suggest that although substantial reductions in diseases can be expected, the benefit, assuming high vaccination rates, will not be apparent for at least another decade.95 Furthermore, the current HPV vaccines contain only HPV 16 and 18 L1 protein for cancer protection and, therefore, do not provide optimal protection against all oncogenic HPV-related cancers.
The real hope of eradicating cervical cancer and all HPV-related disease relies on a successful global implementation of multivalent HPV vaccination, effective screening strategies, and successful treatment.
The vaccines against human papillomavirus (HPV) are the only ones designed to prevent cancer caused by a virus1,2—surely a good goal. But because HPV is sexually transmitted, HPV vaccination has met with public controversy.3 To counter the objections and better protect their patients’ health, primary care providers and other clinicians need a clear understanding of the benefits and the low risk of HPV vaccination—and the reasons so many people object to it.3
In this article, we will review:
- The impact of HPV-related diseases
- The basic biologic features of HPV vaccines
- The host immune response to natural HPV infection vs the response to HPV vaccines
- The clinical efficacy and safety of HPV vaccines
- The latest guidelines for HPV vaccination
- The challenges to vaccination implementation
- Frequently asked practical questions about HPV vaccination.
HPV-RELATED DISEASES: FROM BOTHERSOME TO DEADLY
Clinical sequelae of HPV infection include genital warts; cancers of the cervix, vulva, vagina, anus, penis, and oropharynx; and recurrent respiratory papillomatosis.4–6
Genital warts
HPV types 6 and 11 are responsible for more than 90% of the 1 million new cases of genital warts diagnosed annually in the United States.7–10
Bothersome and embarrassing, HPV-related genital warts can cause itching, burning, erythema, and pain, as well as epithelial erosions, ulcerations, depigmentation, and urethral and vaginal bleeding and discharge.11,12 Although they are benign in the oncologic sense, they can cause a good deal of emotional and financial stress. Patients may feel anxiety, embarrassment,13 and vulnerability. Adolescents and adults who have or have had genital warts need to inform their current and future partners or else risk infecting them—and facing the consequences.
Direct health care costs of genital warts in the United States have been estimated to be at least $200 million per year.14
Cervical cancer
Cervical cancer cannot develop unless the cervical epithelium is infected with one of the oncogenic HPV types. Indeed, oncogenic HPV is present in as many as 99.8% of cervical cancer specimens.15 HPV 16 and 18 are the most oncogenic HPV genotypes and account for 75% of all cases of cervical cancer. Ten other HPV genotypes account for the remaining 25%.16
In 2012, there were an estimated 12,170 new cases of invasive cervical cancer in the United States and 4,220 related deaths.17 The cost associated with cervical cancer screening, managing abnormal findings, and treating invasive cervical cancer in the United States is estimated to be $3.3 billion per year.18
Although the incidence and the mortality rates of cervical cancer have decreased more than 50% in the United States over the past 3 decades thanks to screening,19 cervical cancer remains the second leading cause of death from cancer in women worldwide. Each year, an estimated 500,000 women contract the disease and 240,000 die of it.20
Anal cancer
A recent study indicated that oncogenic HPV can also cause anal cancer, and the proportion of such cancers associated with HPV 16 or HPV 18 infection is as high as or higher than for cervical cancers, and estimated at 80%.21
The incidence of anal cancer is increasing by approximately 2% per year in both men and women in the general population,22 and rates are even higher in men who have sex with men and people infected with the human immunodeficiency virus.23
Hu and Goldie24 estimated that the lifetime costs of caring for all the people in the United States who in just 1 year (2003) acquired anal cancer attributable to HPV would total $92 million.
Oropharyngeal cancer
HPV types 16, 18, 31, 33, and 35 also cause oropharyngeal cancer. HPV 16 accounts for more than 90% of cases of HPV-related oropharyngeal cancer.25
Chaturvedi et al6 tested tissue samples from three national cancer registries and found that the number of oropharyngeal cancers that were HPV-positive increased from 16.3% in 1984–1989 to 71.7% in 2000–2004, while the number of HPV-negative oropharyngeal cancers fell by 50%, paralleling the drop in cigarette smoking in the United States.
Hu and Goldie24 estimated that the total lifetime cost for all new HPV-related oropharyngeal cancers that arose in 2003 would come to $38.1 million.24
Vulvar and vaginal cancers
HPV 16 and 18 are also responsible for approximately 50% of vulvar cancers and 50% to 75% of vaginal cancers.4,5
Recurrent respiratory papillomatosis
HPV 6 and 11 cause almost all cases of juvenile- and adult-onset recurrent respiratory papillomatosis.26 The annual cost for surgical procedures for this condition in the United States has been estimated at $151 million.27
HPV VACCINES ARE NONINFECTIOUS AND NONCARCINOGENIC
Currently, two HPV vaccines are available: a quadrivalent vaccine against types 6, 11, 16, and 18 (Gardasil; Merck) and a bivalent vaccine against types 16 and 18 (Cervarix; Glaxo-SmithKline). The quadrivalent vaccine was approved by the US Food and Drug Administration (FDA) in 2006, and the bivalent vaccine was approved in 2009.28,29
Both vaccines contain virus-like particles, ie, viral capsids that contain no DNA. HPV has a circular DNA genome of 8,000 nucleotides divided into two regions: the early region, for viral replication, and the late region, for viral capsid production. The host produces neutralizing antibodies in response to the L1 capsid protein, which is different in different HPV types.
In manufacturing the vaccines, the viral L1 gene is incorporated into a yeast genome or an insect virus genome using recombinant DNA technology (Figure 1). Grown in culture, the yeast or the insect cells produce the HPV L1 major capsid protein, which has the intrinsic capacity to self-assemble into virus-like particles.30–33 These particles are subsequently purified for use in the vaccines.34
Recombinant virus-like particles are morphologically indistinguishable from authentic HPV virions and contain the same typespecific antigens present in authentic virions. Therefore, they are highly effective in inducing a host humoral immune response. And because they do not contain HPV DNA, the recombinant HPV vaccines are noninfectious and noncarcinogenic.35
VACCINATION INDUCES A STRONGER IMMUNE RESPONSE THAN INFECTION
HPV infections trigger both a humoral and a cellular response in the host immune system.
The humoral immune response to HPV infection involves producing neutralizing antibody against the specific HPV type, specifically the specific L1 major capsid protein. This process is typically somewhat slow and weak, and only about 60% of women with a new HPV infection develop antibodies to it.36,37
HPV has several ways to evade the host immune system. It does not infect or replicate within the antigen-presenting cells in the epithelium. In addition, HPV-infected keratinocytes are less susceptible to cytotoxic lymphocytic-mediated lysis. Moreover, HPV infection cause very little tissue destruction. And finally, natural cervical HPV infection does not result in viremia. As a result, antigen-presenting cells have no chance to engulf the virions and present virion-derived antigen to the host immune system. The immune system outside the epithelium has limited opportunity to detect the virus because HPV infection does not have a blood-borne phase.38,39
The cell-mediated immune response to early HPV oncoproteins may help eliminate established HPV infection.40 In contrast to antibodies, the T-cell response to HPV has not been shown to be specific to HPV type.41 Clinically, cervical HPV infection is common, but most lesions go into remission or resolve as a result of the cell-mediated immune response.40,41
In contrast to the weak, somewhat ineffective immune response to natural HPV infection, the antibody response to HPV vaccines is rather robust. In randomized controlled trials, almost all vaccinated people have seroconverted. The peak antibody concentrations are 50 to 10,000 times greater than in natural infection. Furthermore, the neutralizing antibodies induced by HPV vaccines persist for as long as 7 to 9 years after immunization.42 However, the protection provided by HPV vaccines against HPV-related cervical intraepithelial neoplasia does not necessarily correlate with the antibody concentration.43–47
Why does the vaccine work so well?
Why are vaccine-induced antibody responses so much stronger than those induced by natural HPV infection?
The first reason is that the vaccine, delivered intramuscularly, rapidly enters into blood vessels and the lymphatic system. In contrast, in natural intraepithelial infection, the virus is shed from mucosal surfaces and does not result in viremia.48
In addition, the strong immunogenic nature of the virus-like particles induces a robust host antibody response even in the absence of adjuvant because of concentrated neutralizing epitopes and excellent induction of the T-helper cell response.35,49,50
The neutralizing antibody to L1 prevents HPV infection by blocking HPV from binding to the basement membrane as well as to the epithelial cell receptor during epithelial microabrasion and viral entry. The subsequent micro-wound healing leads to serous exudation and rapid access of serum immunoglobulin G (IgG) to HPV virus particles and encounters with circulatory B memory cells.
Furthermore, emerging evidence suggests that even very low antibody concentrations are sufficient to prevent viral entry into cervical epithelial cells.46–48,51–53
THE HPV VACCINES ARE HIGHLY EFFECTIVE AND SAFE
The efficacy and safety of the quadrivalent and the bivalent HPV vaccines have been evaluated in large randomized clinical trials.23,28,29,54,55 Table 1 summarizes the key findings.
The Females United to Unilaterally Reduce Endo/ectocervical Disease (FUTURE I)54 and FUTURE II28 trials showed conclusively that the quadrivalent HPV vaccine is 98% to 100% efficacious in preventing HPV 16- and 18-related cervical intraepithelial neoplasia, carcinoma in situ, and invasive cervical cancer in women who had not been infected with HPV before. Similarly, the Papilloma Trial against Cancer in Young Adults (PATRICIA) concluded that the bivalent HPV vaccine is 93% efficacious.29
Giuliano et al55 and Palefsky et al23 conducted randomized clinical trials of the quadrivalent HPV vaccine for preventing genital disease and anal intraepithelial neoplasia in boys and men; the efficacy rates were 90.4%55 and 77.5%.23
A recent Finnish trial in boys age 10 to 18 found 100% seroconversion rates for HPV 16 and HPV 18 antibodies after they received bivalent HPV vaccine.56 Similar efficacy has been demonstrated for the quadrivalent HPV vaccine in boys.57
Adverse events after vaccination
After the FDA approved the quadrivalent HPV vaccine for girls in 2006, the US Centers for Disease Control and Prevention (CDC) conducted a thorough survey of adverse events after immunization from June 1, 2006 through December 31, 2008.58 There were about 54 reports of adverse events per 100,000 distributed vaccine doses, similar to rates for other vaccines. However, the incidence rates of syncope and venous thrombosis were disproportionately higher, according to data from the US Vaccine Adverse Event Reporting System. The rate of syncope was 8.2 per 100,000 vaccine doses, and the rate of venous thrombotic events was 0.2 per 100,000 doses.58
There were 32 reports of deaths after HPV vaccination, but these were without clear causation. Hence, this information must be interpreted with caution and should not be used to infer causal associations between HPV vaccines and adverse outcomes. The causes of death included diabetic ketoacidosis, pulmonary embolism, prescription drug abuse, amyotrophic lateral sclerosis, meningoencephalitis, influenza B viral sepsis, arrhythmia, myocarditis, and idiopathic seizure disorder.58
Furthermore, it is important to note that vasovagal syncope and venous thromboembolic events are more common in young females in general.59 For example, the background rates of venous thromboembolism in females age 14 to 29 using oral contraceptives is 21 to 31 per 100,000 woman-years.60
Overall, the quadrivalent HPV vaccine is well tolerated and clinically safe. Postlicensure evaluation found that the quadrivalent and bivalent HPV vaccines had similar safety profiles.61
Vaccination is contraindicated in people with known hypersensitivity or prior severe allergic reactions to vaccine or yeast or who have bleeding disorders.
HPV VACCINATION DOES MORE THAN PREVENT CERVICAL CANCER IN FEMALES
The quadrivalent HPV vaccine was licensed by the FDA in 2006 for use in females age 9 to 26 to prevent cervical cancer, cervical cancer precursors, vaginal and vulval cancer precursors, and anogenital warts caused by HPV types 6, 11, 16, and 18. The CDC’s Advisory Committee on Immunization Practices (ACIP) issued its recommendation for initiating HPV vaccination for females age 11 to 12 in March 2007. The ACIP stated that the vaccine could be given to girls as early as age 9 and recommended catch-up vaccinations for those age 13 to 26.62,63
The quadrivalent HPV vaccine was licensed by the FDA in 2009 for use in boys and men for the prevention of genital warts. In December 2010, the quadrivalent HPV vaccine received extended licensure from the FDA for use in males and females for the prevention of anal cancer. In October 2011, the ACIP voted to recommend routine use of the quadrivalent HPV vaccine for boys age 11 to 12; catch-up vaccination should occur for those age 13 to 22, with an option to vaccinate men age 23 to 26.
These recommendations replace the “permissive use” recommendations from the ACIP in October 2009 that said the quadrivalent HPV vaccine may be given to males age 9 to 26.64 This shift from a permissive to an active recommendation connotes a positive change reflecting recognition of rising oropharyngeal cancer rates attributable to oncogenic, preventable HPV, rising HPV-related anal cancer incidence, and the burden of the disease in female partners of infected men, with associated rising health care costs.
The bivalent HPV vaccine received FDA licensure in October 2009 for use in females age 10 to 25 to prevent cervical cancer and precursor lesions. The ACIP included the bivalent HPV vaccine in its updated recommendations in May 2010 for use in girls age 11 to 12. Numerous national and international organizations have endorsed HPV vaccination.65–71
Table 2 outlines the recommendations from these organizations.
HPV VACCINATION RATES ARE STILL LOW
HPV vaccine offers us the hope of eventually eradicating cervical cancer. However, the immunization program still faces many challenges, since HPV vaccination touches on issues related to adolescent sexuality, parental autonomy, and cost. As a result, HPV immunization rates remain relatively low in the United States according to several national surveys. Only 40% to 49% of girls eligible for the vaccine received even one dose, and of those who received even one dose, only 32% to 53.3% came back for all three doses.72–75 Furthermore, indigent and minority teens were less likely to finish the three-dose HPV vaccine series.
Why are the vaccination rates so low?
Parental barriers. In one survey,73 reasons that parents gave for not having their daughters vaccinated included:
- Lack of knowledge of the vaccine (19.4%)
- Lack of perceived need for the vaccine (18.8%)
- Belief that their daughter was not sexually active (18.3%)
- Clinician not recommending vaccination (13.1%).
In an effort to improve HPV vaccination rates,41 several states proposed legislation for mandatory HPV vaccination of schoolgirls shortly after licensure of the quadrivalent HPV vaccine.3 Since then, we have seen a wave of public opposition rooted in concerns and misinformation about safety, teenage sexuality, governmental coercion, and cost. Widespread media coverage has also highlighted unsubstantiated claims about side effects attributable to the vaccine that can raise parents’ mistrust of vaccines.76 Concerns have also been raised about a threat to parental autonomy in how and when to educate their children about sex.77
Moreover, the vaccine has raised ethical concerns in some parents and politicians that mandatory vaccination could undermine abstinence messages in sexual education and may alter sexual activity by condoning risky behavior.78 However, a recent study indicated that there is no significant change in sexual behavior related to HPV vaccination in young girls.79
In 2012, Mullins et al80 also found that an urban population of adolescent girls (76.4% black, 57.5% sexually experienced) did not feel they could forgo safer sexual practices after first HPV vaccination, although the girls did perceive less risk from HPV than from other sexually transmitted infections after HPV vaccination (P < .001).80 Inadequate knowledge about HPV-related disease and HPV vaccine correlated with less perceived risk from HPV after vaccination among the girls, and a lack of knowledge about HPV and less communication with their daughters about HPV correlated with less perceived risk from HPV in the mothers of the study population.81
Health-care-provider barriers. Physician endorsement of vaccines represents a key predictor of vaccine acceptance by patients, families, and other clinicians.82–84 In 2008, a cross-sectional, Internet-based survey of 1,122 Texas pediatricians, family practice physicians, obstetricians, gynecologists, and internal medicine physicians providing direct patient care found that only 48.5% always recommended HPV vaccination to girls.74 Of all respondents, 68.4% were likely to recommend the vaccine to boys, and 41.7% agreed with mandated vaccination. Thus, more than half of the physicians were not following the current recommendations for universal HPV vaccination for 11- to -12-year-olds.
In a survey of 1,013 physicians during the spring and summer of 2009, only 34.6% said they always recommend HPV vaccination to early adolescents, 52.7% to middle adolescents, and 50.2% to late adolescents and young adults.85 Pediatricians were more likely than family physicians and obstetrician-gynecologists to always recommend HPV vaccine across all age groups (P < .001). Educational interventions targeting various specialties may help overcome physician-related barriers to immunization.85
Financial barriers. HPV vaccine, which must be given in three doses, is more expensive than other vaccines, and this expense is yet another barrier, especially for the uninsured.86 Australia launched a government-funded program of HPV vaccination (with the quadrivalent vaccine) in schools in 2007, and it has been very successful. Garland et al87 reported that new cases of genital warts have decreased by 73% since the program began, and the rate of high-grade abnormalities on Papanicolaou testing has declined by a small but significant amount.
For HPV vaccination to have an impact on public health, vaccination rates in the general population need to be high. In order to achieve these rates, we need to educate our patients on vaccine safety and efficacy and counsel vaccine recipients about the prevention of sexually transmitted infections and the importance of regular cervical cancer screening after age 21. Clinicians can actively “myth-bust” with patients, who may not realize that the vaccine should be given despite a history of HPV infection or abnormal Pap smear.
FREQUENTLY ASKED QUESTIONS
What if the patient is late for a shot?
The current recommended vaccination schedule for the bivalent and quadrivalent HPV vaccines is a three-dose series administered at 0, 2, and 6 months, given as an intramuscular injection, preferably in the deltoid muscle. The minimal dosing interval is 4 weeks between the first and second doses and 12 weeks between the second and third doses.
The vaccines use different adjuncts with different specific mechanisms for immunogenicity; therefore, it is recommended that the same vaccine be used for the entire three-dose series. However, if circumstances preclude the completion of a series with the same vaccine, the other HPV vaccine may be used.63 Starting the series over is not recommended.
Long-term studies demonstrated clinical efficacy 8.5 years after vaccination.47 Amnestic response by virtue of activation of pools of memory B cells has been demonstrated, suggesting the vaccine may afford lifelong immunity.88
Is a pregnancy test needed before HPV vaccination?
The ACIP states that pregnancy testing is not required before receiving either of the available HPV vaccines.
A recent retrospective review of phase III efficacy trials and pregnancy registry surveillance data for both vaccines revealed no increase in spontaneous abortions, fetal malformations, or adverse pregnancy outcomes.89 Data are limited on bivalent and quadrivalent HPV vaccine given within 30 days of pregnancy and subsequent pregnancy and fetal outcomes. Both vaccines have been assigned a pregnancy rating of category B; however, the ACIP recommends that neither vaccine be given if the recipient is known to be pregnant. If pregnancy occurs, it is recommended that the remainder of the series be deferred until after delivery.62
It is not known whether the vaccine is excreted in breast milk. The manufacturers of both the bivalent and quadrivalent HPV vaccines recommend caution when vaccinating lactating women.30,31
Can HPV vaccine be given with other vaccines?
In randomized trials, giving the bivalent HPV vaccine with the combined hepatitis A, hepatitis B, meningococcal conjugate and the combined tetanus, diphtheria, and acellular pertussis vaccines did not interfere with the immunogenic response, was safe, and was well tolerated.90,91 Coadministration of the quadrivalent HPV vaccine has been studied only with hepatitis B vaccine, with similar safety and efficacy noted.
The ACIP recommends giving HPV vaccine at the same visit with other age-appropriate immunizations to increase the likelihood of adherence to recommended vaccination schedules.62
Is HPV vaccination cost-effective?
Kim and Goldie86 performed a cost-effectiveness analysis of HPV vaccination of girls at age 12 and catch-up vaccination up to the ages of 18, 21, and 26. For their analysis, they considered prevention of cancers associated with HPV types 16 and 18, of genital warts associated with types 6 and 11, and of recurrent respiratory papillomatosis. They also assumed that immunity would be lifelong, and current screening practices would continue.
They calculated that routine vaccination of 12-year-old girls resulted in an incremental cost-effective ratio of $34,900 per quality-adjusted life-year (QALY) gained. A threshold of less than $50,000 per QALY gained is considered reasonably cost-effective, with an upper limit of $100,000 considered acceptable.92
In the same analysis by Kim and Goldie,86 catch-up vaccination of girls through age 18 resulted in a cost of $50,000 to $100,000 per QALY gained, and catch-up vaccination of females through age 26 was significantly less cost-effective at more then $130,000 per QALY gained. The vaccine was also significantly less cost-effective if 5% of the population was neither screened nor vaccinated, if a 10-year booster was required, and if frequent cervical cancer screening intervals were adopted.
This analysis did not include costs related to the evaluation and treatment of abnormal Pap smears and cross-protection against other HPV-related cancers.
The cost-effectiveness of HPV vaccination depends on reaching more girls at younger ages (ideally before sexual debut) and completing the three-dose schedule to optimize duration of immunity.92 Appropriate modification of the current recommendations for the intervals of cervical cancer screening for vaccinated individuals will further improve the cost-effectiveness of vaccination. The inclusion of male vaccination generally has more favorable cost per QALY in scenarios in which female coverage rates are less than 50%93 and among men who have sex with men.94
TO ERADICATE CERVICAL CANCER
Given the remarkable efficacy and expected long-term immunogenicity of HPV vaccines, we anticipate a decline in HPV-related cervical cancer and other related diseases in the years to come. However, modeling studies predicting the impact of HPV vaccination suggest that although substantial reductions in diseases can be expected, the benefit, assuming high vaccination rates, will not be apparent for at least another decade.95 Furthermore, the current HPV vaccines contain only HPV 16 and 18 L1 protein for cancer protection and, therefore, do not provide optimal protection against all oncogenic HPV-related cancers.
The real hope of eradicating cervical cancer and all HPV-related disease relies on a successful global implementation of multivalent HPV vaccination, effective screening strategies, and successful treatment.
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- Harper DM, Franco EL, Wheeler CM, et al; HPV Vaccine Study group. Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet 2006; 367:1247–1255.
- Villa LL, Costa RL, Petta CA, et al. High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up. Br J Cancer 2006; 95:1459–1466.
- Villa LL, Ault KA, Giuliano AR, et al. Immunologic responses following administration of a vaccine targeting human papillomavirus Types 6, 11, 16, and 18. Vaccine 2006; 24:5571–5583.
- Smith JF, Brownlow M, Brown M, et al. Antibodies from women immunized with Gardasil cross-neutralize HPV 45 pseudovirions. Hum Vaccin 2007; 3:109–115.
- Rowhani-Rahbar A, Mao C, Hughes JP, et al. Longer term efficacy of a prophylactic monovalent human papillomavirus type 16 vaccine. Vaccine 2009; 27:5612–5619.
- Stanley M. HPV - immune response to infection and vaccination. Infect Agent Cancer 2010; 5:19.
- Stanley M. Pathology and epidemiology of HPV infection in females. Gynecol Oncol 2010; 117(suppl 2):S5–S10.
- Yan M, Peng J, Jabbar IA, et al. Activation of dendritic cells by human papillomavirus-like particles through TLR4 and NF-kappaB-mediated signalling, moderated by TGF-beta. Immunol Cell Biol 2005; 83:83–91.
- Roberts JN, Buck CB, Thompson CD, et al. Genital transmission of HPV in a mouse model is potentiated by nonoxynol-9 and inhibited by carrageenan. Nat Med 2007; 13:857–861.
- Kines RC, Thompson CD, Lowy DR, Schiller JT, Day PM. The initial steps leading to papillomavirus infection occur on the basement membrane prior to cell surface binding. Proc Natl Acad Sci USA 2009; 106:20458–20463.
- Day PM, Kines RC, Thompson CD, et al. In vivo mechanisms of vaccine-induced protection against HPV infection. Cell Host Microbe 2010; 8:260–270.
- Garland SM, Hernandez-Avila M, Wheeler CM, et al; Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) I Investigators. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med 2007; 356:1928–1943.
- Giuliano AR, Palefsky JM, Goldstone S, et al. Efficacy of quadrivalent HPV vaccine against HPV Infection and disease in males. N Engl J Med 2011; 364:401–411.
- Petäjä T, Keränen H, Karppa T, et al. Immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in healthy boys aged 10–18 years. J Adolesc Health 2009; 44:33–40.
- Reisinger KS, Block SL, Lazcano-Ponce E, et al. Safety and persistent immunogenicity of a quadrivalent human papillomavirus types 6, 11, 16, 18 L1 virus-like particle vaccine in preadolescents and adolescents: a randomized controlled trial. Pediatr Infect Dis J 2007; 26:201–209.
- Slade BA, Leidel L, Vellozzi C, et al. Postlicensure safety surveillance for quadrivalent human papillomavirus recombinant vaccine. JAMA 2009; 302:750–757.
- Block SL, Brown DR, Chatterjee A, et al. Clinical trial and post-licensure safety profile of a prophylactic human papillomavirus (types 6, 11, 16, and 18) l1 virus-like particle vaccine. Pediatr Infect Dis J 2010; 29:95–101.
- Farmer RD, Lawrenson RA, Thompson CR, Kennedy JG, Hambleton IR. Population-based study of risk of venous thromboembolism associated with various oral contraceptives. Lancet 1997; 349:83–88.
- Labadie J. Postlicensure safety evaluation of human papilloma virus vaccines. Int J Risk Saf Med 2011; 23:103–112.
- Markowitz LE, Dunne EF, Saraiya M, Lawson HW, Chesson H, Unger ER; Centers for Disease Control and Prevention (CDC). Quadrivalent human papillomavirus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2007; 56:1–24.
- Centers for Disease Control and Prevention (CDC). FDA licensure of bivalent human papillomavirus vaccine (HPV2, Cervarix) for use in females and updated HPV vaccination recommendations from the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2010; 59:626–629.
- Centers for Disease Control and Prevention (CDC). FDA licensure of quadrivalent human papillomavirus vaccine (HPV4, Gardasil) for use in males and guidance from the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2010; 59:630–632.
- World Health Organization (WHO). Weekly Epidemiological Record (WER). January 2009; 84:1–16. http://www.who.int/wer/2009/wer8401_02/en/index.html. Accessed November 12, 2012.
- Saslow D, Castle PE, Cox JT, et al. American Cancer Society guideline for human papillomavirus (HPV) vaccine use to prevent cervical cancer and its precursors. CA Cancer J Clin 2007; 57:7–28.
- Committee opinion no. 467: human papillomavirus vaccination. Obstet Gynecol 2010; 116:800–803.
- American College of Physicians. ACP Guide to Adult Immunization. 4th ed. 2011:58–60. http://immunization.acponline.org/. Accessed November 12, 2012.
- Vaughn JA, Miller RA. Update on immunizations in adults. Am Fam Physician 2011; 84:1015–1020.
- American Academy of Pediatrics Committee on Infectious Diseases. Prevention of human papillomavirus infection: provisional recommendations for immunization of girls and women with quadrivalent human papillomavirus vaccine. Pediatrics 2007; 120:666–668.
- Friedman L, Bell DL, Kahn JA, et al. Human papillomavirus vaccine: an updated position statement of the Society for Adolescent Health and Medicine. J Adolesc Health 2011; 48:215–216.
- Centers for Disease Control and Prevention (CDC). National and state vaccination coverage among adolescents aged 13 through 17 years--United States, 2010. MMWR Morb Mortal Wkly Rep 2011; 60:1117–1123.
- Dorell CG, Yankey D, Santibanez TA, Markowitz LE. Human papillomavirus vaccination series initiation and completion, 2008–2009. Pediatrics 2011; 128:830–839.
- Kahn JA, Cooper HP, Vadaparampil ST, et al. Human papillomavirus vaccine recommendations and agreement with mandated human papillomavirus vaccination for 11-to-12-year-old girls: a statewide survey of Texas physicians. Cancer Epidemiol Biomarkers Prev 2009; 18:2325–2332.
- Schwartz JL, Caplan AL, Faden RR, Sugarman J. Lessons from the failure of human papillomavirus vaccine state requirements. Clin Pharmacol Ther 2007; 82:760–763.
- Cooper LZ, Larson HJ, Katz SL. Protecting public trust in immunization. Pediatrics 2008; 122:149–153.
- Olshen E, Woods ER, Austin SB, Luskin M, Bauchner H. Parental acceptance of the human papillomavirus vaccine. J Adolesc Health 2005; 37:248–251.
- Zimmerman RK. Ethical analysis of HPV vaccine policy options. Vaccine 2006; 24:4812–4820.
- Al Romaih WRR, Srinivas A, Shahtahmasebi S, Omar HA. No significant change in sexual behavior in association with human papillomavirus vaccination in young girls. Int J Child Adolesc Health 2011; 4:1–5.
- Mullins TL, Zimet GD, Rosenthal SL, et al. Adolescent perceptions of risk and need for safer sexual behaviors after first human papillomavirus vaccination. Arch Pediatr Adolesc Med 2012; 166:82–88.
- Middleman AB, Tung JS. School-located immunization programs: do parental p predict behavior? Vaccine 2011; 29:3513–3516.
- Samoff E, Dunn A, VanDevanter N, Blank S, Weisfuse IB. Predictors of acceptance of hepatitis B vaccination in an urban sexually transmitted diseases clinic. Sex Transm Dis 2004; 31:415–420.
- Gnanasekaran SK, Finkelstein JA, Hohman K, O’Brien M, Kruskal B, Lieu T. Parental perspectives on influenza vaccination among children with asthma. Public Health Rep 2006; 121:181–188.
- Daley MF, Crane LA, Chandramouli V, et al. Influenza among healthy young children: changes in parental attitudes and predictors of immunization during the 2003 to 2004 influenza season. Pediatrics 2006; 117:e268–e277.
- Vadaparampil ST, Kahn JA, Salmon D, et al. Missed clinical opportunities: provider recommendations for HPV vaccination for 11–12 year old girls are limited. Vaccine 2011; 29:8634–8641.
- Kim JJ, Goldie SJ. Health and economic implications of HPV vaccination in the United States. N Engl J Med 2008; 359:821–832.
- Garland SM, Skinner SR, Brotherton JM. Adolescent and young adult HPV vaccination in Australia: achievements and challenges. Prev Med 2011; 53(suppl 1):S29–S35.
- Rowhani-Rahbar A, Alvarez FB, Bryan JT, et al. Evidence of immune memory 8.5 years following administration of a prophylactic human papillomavirus type 16 vaccine. J Clin Virol 2012; 53:239–243.
- Forinash AB, Yancey AM, Pitlick JM, Myles TD. Safety of the HPV bivalent and quadrivalent vaccines during pregnancy (February) Ann Pharmacother 2011; [epub ahead of print]
- Wheeler CM, Harvey BM, Pichichero ME, et al. Immunogenicity and safety of human papillomavirus-16/18 AS04-adjuvanted vaccine coadministered with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine and/or meningococcal conjugate vaccine to healthy girls 11 to 18 years of age: results from a randomized open trial. Pediatr Infect Dis J 2011; 30:e225–e234.
- Pedersen C, Breindahl M, Aggarwal N, et al. Randomized trial: immunogenicity and safety of coadministered human papillomavirus-16/18 AS04-adjuvanted vaccine and combined hepatitis A and B vaccine in girls. J Adolesc Health 2012; 50:38–46.
- Eichler HG, Kong SX, Gerth WC, Mavros P, Jönsson B. Use of costeffectiveness analysis in health-care resource allocation decisionmaking: how are cost-effectiveness thresholds expected to emerge? Value Health 2004; 7:518–528.
- Chesson HW. HPV vaccine cost-effectiveness: updates and review. Presentation before the Advisory Committee on Immunization Practices (ACIP), June 22, 2011. Atlanta, GA: US Department of Health and Human Services, CDC; 2011. http://www.cdc.gov/vaccines/recs/acip/downloads/mtg-slides-jun11/07-5-hpv-cost-effect.pdf. Accessed August 31, 2012.
- Kim JJ. Targeted human papillomavirus vaccination of men who have sex with men in the USA: a cost-effectiveness modelling analysis. Lancet Infect Dis 2010; 10:845–852.
- Cuzick J, Castañón A, Sasieni P. Predicted impact of vaccination against human papillomavirus 16/18 on cancer incidence and cervical abnormalities in women aged 20–29 in the UK. Br J Cancer 2010; 102:933–939.
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- Lacey CJ, Lowndes CM, Shah KV. Chapter 4: Burden and management of non-cancerous HPV-related conditions: HPV-6/11 disease. Vaccine 2006; 24(suppl 3):S3/35–S3/41.
- Derkay CS. Task force on recurrent respiratory papillomas. A preliminary report. Arch Otolaryngol Head Neck Surg 1995; 121:1386–1391.
- FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007; 356:1915–1927.
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- Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Whitehouse Station, NJ. Patient information about Gardasil (human papillomavirus quadrivalent type 6,11,16 and 18 vaccine, recombinant. http://www.gardasil.com/. Accessed November 12, 2012.
- GlaxoSmithKline Biologicals, Rixensart, Belgium. Highlights of prescribing information. Cervarix (human papillomavirus bivalent type 16 and 18 vaccine, recombinant. http://us.gsk.com/products/assets/us_cervarix.pdf. Accessed November 12, 2012.
- Zhou J, Sun XY, Stenzel DJ, Frazer IH. Expression of vaccinia recombinant HPV 16 L1 and L2 ORF proteins in epithelial cells is sufficient for assembly of HPV virion-like particles. Virology 1991; 185:251–257.
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- Schiller JT, Lowy DR. Papillomavirus-like particles and HPV vaccine development. Semin Cancer Biol 1996; 7:373–382.
- Harro CD, Pang YY, Roden RB, et al. Safety and immunogenicity trial in adult volunteers of a human papillomavirus 16 L1 virus-like particle vaccine. J Natl Cancer Inst 2001; 93:284–292.
- af Geijersstam V, Kibur M, Wang Z, et al. Stability over time of serum antibody levels to human papillomavirus type 16. J Infect Dis 1998; 177:1710–1714.
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- Tindle RW. Immune evasion in human papillomavirus-associated cervical cancer. Nat Rev Cancer 2002; 2:59–65.
- Scott M, Nakagawa M, Moscicki AB. Cell-mediated immune response to human papillomavirus infection. Clin Diagn Lab Immunol 2001; 8:209–220.
- Roden R, Wu TC. Preventative and therapeutic vaccines for cervical cancer. Expert Rev Vaccines 2003; 2:495–516.
- Wang SS, Hildesheim A. Chapter 5: Viral and host factors in human papillomavirus persistence and progression. J Natl Cancer Inst Monogr 2003; 31:35–40.
- De Carvalho N, Teixeira J, Roteli-Martins CM, et al. Sustained efficacy and immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine up to 7.3 years in young adult women. Vaccine 2010; 28:6247–6255.
- Harper DM, Franco EL, Wheeler CM, et al; HPV Vaccine Study group. Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet 2006; 367:1247–1255.
- Villa LL, Costa RL, Petta CA, et al. High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up. Br J Cancer 2006; 95:1459–1466.
- Villa LL, Ault KA, Giuliano AR, et al. Immunologic responses following administration of a vaccine targeting human papillomavirus Types 6, 11, 16, and 18. Vaccine 2006; 24:5571–5583.
- Smith JF, Brownlow M, Brown M, et al. Antibodies from women immunized with Gardasil cross-neutralize HPV 45 pseudovirions. Hum Vaccin 2007; 3:109–115.
- Rowhani-Rahbar A, Mao C, Hughes JP, et al. Longer term efficacy of a prophylactic monovalent human papillomavirus type 16 vaccine. Vaccine 2009; 27:5612–5619.
- Stanley M. HPV - immune response to infection and vaccination. Infect Agent Cancer 2010; 5:19.
- Stanley M. Pathology and epidemiology of HPV infection in females. Gynecol Oncol 2010; 117(suppl 2):S5–S10.
- Yan M, Peng J, Jabbar IA, et al. Activation of dendritic cells by human papillomavirus-like particles through TLR4 and NF-kappaB-mediated signalling, moderated by TGF-beta. Immunol Cell Biol 2005; 83:83–91.
- Roberts JN, Buck CB, Thompson CD, et al. Genital transmission of HPV in a mouse model is potentiated by nonoxynol-9 and inhibited by carrageenan. Nat Med 2007; 13:857–861.
- Kines RC, Thompson CD, Lowy DR, Schiller JT, Day PM. The initial steps leading to papillomavirus infection occur on the basement membrane prior to cell surface binding. Proc Natl Acad Sci USA 2009; 106:20458–20463.
- Day PM, Kines RC, Thompson CD, et al. In vivo mechanisms of vaccine-induced protection against HPV infection. Cell Host Microbe 2010; 8:260–270.
- Garland SM, Hernandez-Avila M, Wheeler CM, et al; Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) I Investigators. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med 2007; 356:1928–1943.
- Giuliano AR, Palefsky JM, Goldstone S, et al. Efficacy of quadrivalent HPV vaccine against HPV Infection and disease in males. N Engl J Med 2011; 364:401–411.
- Petäjä T, Keränen H, Karppa T, et al. Immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in healthy boys aged 10–18 years. J Adolesc Health 2009; 44:33–40.
- Reisinger KS, Block SL, Lazcano-Ponce E, et al. Safety and persistent immunogenicity of a quadrivalent human papillomavirus types 6, 11, 16, 18 L1 virus-like particle vaccine in preadolescents and adolescents: a randomized controlled trial. Pediatr Infect Dis J 2007; 26:201–209.
- Slade BA, Leidel L, Vellozzi C, et al. Postlicensure safety surveillance for quadrivalent human papillomavirus recombinant vaccine. JAMA 2009; 302:750–757.
- Block SL, Brown DR, Chatterjee A, et al. Clinical trial and post-licensure safety profile of a prophylactic human papillomavirus (types 6, 11, 16, and 18) l1 virus-like particle vaccine. Pediatr Infect Dis J 2010; 29:95–101.
- Farmer RD, Lawrenson RA, Thompson CR, Kennedy JG, Hambleton IR. Population-based study of risk of venous thromboembolism associated with various oral contraceptives. Lancet 1997; 349:83–88.
- Labadie J. Postlicensure safety evaluation of human papilloma virus vaccines. Int J Risk Saf Med 2011; 23:103–112.
- Markowitz LE, Dunne EF, Saraiya M, Lawson HW, Chesson H, Unger ER; Centers for Disease Control and Prevention (CDC). Quadrivalent human papillomavirus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2007; 56:1–24.
- Centers for Disease Control and Prevention (CDC). FDA licensure of bivalent human papillomavirus vaccine (HPV2, Cervarix) for use in females and updated HPV vaccination recommendations from the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2010; 59:626–629.
- Centers for Disease Control and Prevention (CDC). FDA licensure of quadrivalent human papillomavirus vaccine (HPV4, Gardasil) for use in males and guidance from the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2010; 59:630–632.
- World Health Organization (WHO). Weekly Epidemiological Record (WER). January 2009; 84:1–16. http://www.who.int/wer/2009/wer8401_02/en/index.html. Accessed November 12, 2012.
- Saslow D, Castle PE, Cox JT, et al. American Cancer Society guideline for human papillomavirus (HPV) vaccine use to prevent cervical cancer and its precursors. CA Cancer J Clin 2007; 57:7–28.
- Committee opinion no. 467: human papillomavirus vaccination. Obstet Gynecol 2010; 116:800–803.
- American College of Physicians. ACP Guide to Adult Immunization. 4th ed. 2011:58–60. http://immunization.acponline.org/. Accessed November 12, 2012.
- Vaughn JA, Miller RA. Update on immunizations in adults. Am Fam Physician 2011; 84:1015–1020.
- American Academy of Pediatrics Committee on Infectious Diseases. Prevention of human papillomavirus infection: provisional recommendations for immunization of girls and women with quadrivalent human papillomavirus vaccine. Pediatrics 2007; 120:666–668.
- Friedman L, Bell DL, Kahn JA, et al. Human papillomavirus vaccine: an updated position statement of the Society for Adolescent Health and Medicine. J Adolesc Health 2011; 48:215–216.
- Centers for Disease Control and Prevention (CDC). National and state vaccination coverage among adolescents aged 13 through 17 years--United States, 2010. MMWR Morb Mortal Wkly Rep 2011; 60:1117–1123.
- Dorell CG, Yankey D, Santibanez TA, Markowitz LE. Human papillomavirus vaccination series initiation and completion, 2008–2009. Pediatrics 2011; 128:830–839.
- Kahn JA, Cooper HP, Vadaparampil ST, et al. Human papillomavirus vaccine recommendations and agreement with mandated human papillomavirus vaccination for 11-to-12-year-old girls: a statewide survey of Texas physicians. Cancer Epidemiol Biomarkers Prev 2009; 18:2325–2332.
- Schwartz JL, Caplan AL, Faden RR, Sugarman J. Lessons from the failure of human papillomavirus vaccine state requirements. Clin Pharmacol Ther 2007; 82:760–763.
- Cooper LZ, Larson HJ, Katz SL. Protecting public trust in immunization. Pediatrics 2008; 122:149–153.
- Olshen E, Woods ER, Austin SB, Luskin M, Bauchner H. Parental acceptance of the human papillomavirus vaccine. J Adolesc Health 2005; 37:248–251.
- Zimmerman RK. Ethical analysis of HPV vaccine policy options. Vaccine 2006; 24:4812–4820.
- Al Romaih WRR, Srinivas A, Shahtahmasebi S, Omar HA. No significant change in sexual behavior in association with human papillomavirus vaccination in young girls. Int J Child Adolesc Health 2011; 4:1–5.
- Mullins TL, Zimet GD, Rosenthal SL, et al. Adolescent perceptions of risk and need for safer sexual behaviors after first human papillomavirus vaccination. Arch Pediatr Adolesc Med 2012; 166:82–88.
- Middleman AB, Tung JS. School-located immunization programs: do parental p predict behavior? Vaccine 2011; 29:3513–3516.
- Samoff E, Dunn A, VanDevanter N, Blank S, Weisfuse IB. Predictors of acceptance of hepatitis B vaccination in an urban sexually transmitted diseases clinic. Sex Transm Dis 2004; 31:415–420.
- Gnanasekaran SK, Finkelstein JA, Hohman K, O’Brien M, Kruskal B, Lieu T. Parental perspectives on influenza vaccination among children with asthma. Public Health Rep 2006; 121:181–188.
- Daley MF, Crane LA, Chandramouli V, et al. Influenza among healthy young children: changes in parental attitudes and predictors of immunization during the 2003 to 2004 influenza season. Pediatrics 2006; 117:e268–e277.
- Vadaparampil ST, Kahn JA, Salmon D, et al. Missed clinical opportunities: provider recommendations for HPV vaccination for 11–12 year old girls are limited. Vaccine 2011; 29:8634–8641.
- Kim JJ, Goldie SJ. Health and economic implications of HPV vaccination in the United States. N Engl J Med 2008; 359:821–832.
- Garland SM, Skinner SR, Brotherton JM. Adolescent and young adult HPV vaccination in Australia: achievements and challenges. Prev Med 2011; 53(suppl 1):S29–S35.
- Rowhani-Rahbar A, Alvarez FB, Bryan JT, et al. Evidence of immune memory 8.5 years following administration of a prophylactic human papillomavirus type 16 vaccine. J Clin Virol 2012; 53:239–243.
- Forinash AB, Yancey AM, Pitlick JM, Myles TD. Safety of the HPV bivalent and quadrivalent vaccines during pregnancy (February) Ann Pharmacother 2011; [epub ahead of print]
- Wheeler CM, Harvey BM, Pichichero ME, et al. Immunogenicity and safety of human papillomavirus-16/18 AS04-adjuvanted vaccine coadministered with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine and/or meningococcal conjugate vaccine to healthy girls 11 to 18 years of age: results from a randomized open trial. Pediatr Infect Dis J 2011; 30:e225–e234.
- Pedersen C, Breindahl M, Aggarwal N, et al. Randomized trial: immunogenicity and safety of coadministered human papillomavirus-16/18 AS04-adjuvanted vaccine and combined hepatitis A and B vaccine in girls. J Adolesc Health 2012; 50:38–46.
- Eichler HG, Kong SX, Gerth WC, Mavros P, Jönsson B. Use of costeffectiveness analysis in health-care resource allocation decisionmaking: how are cost-effectiveness thresholds expected to emerge? Value Health 2004; 7:518–528.
- Chesson HW. HPV vaccine cost-effectiveness: updates and review. Presentation before the Advisory Committee on Immunization Practices (ACIP), June 22, 2011. Atlanta, GA: US Department of Health and Human Services, CDC; 2011. http://www.cdc.gov/vaccines/recs/acip/downloads/mtg-slides-jun11/07-5-hpv-cost-effect.pdf. Accessed August 31, 2012.
- Kim JJ. Targeted human papillomavirus vaccination of men who have sex with men in the USA: a cost-effectiveness modelling analysis. Lancet Infect Dis 2010; 10:845–852.
- Cuzick J, Castañón A, Sasieni P. Predicted impact of vaccination against human papillomavirus 16/18 on cancer incidence and cervical abnormalities in women aged 20–29 in the UK. Br J Cancer 2010; 102:933–939.
KEY POINTS
- Two HPV vaccines are available: a quadrivalent vaccine against HVP types 6, 11, 16, and 18, and a bivalent vaccine against types 16 and 18.
- HPV causes cervical cancer, genital warts, oropharyngeal cancer, anal cancer, and recurrent respiratory papillomatosis, creating a considerable economic and health burden.
- The host immune response to natural HPV infection is slow and weak. In contrast, HPV vaccine induces a strong and long-lasting immune response.
- The HPV vaccines have greater than 90% efficacy in preventing cervical dysplasia and genital warts that are caused by the HPV types the vaccine contains. They are as safe as other common prophylactic vaccines.
- HPV vaccination has been challenged by public controversy over the vaccine’s safety, teenage sexuality, mandatory legislation, and the cost of the vaccine.
A short story of the short QT syndrome
Sudden cardiac death in a young person is a devastating event that has puzzled physicians for decades. In recent years, many of the underlying cardiac pathologies have been identified. These include structural abnormalities such as hypertrophic cardiomyopathy and nonstructural disorders associated with unstable rhythms that lead to sudden cardiac death.
The best known of these “channelopathies” are the long QT syndromes, which result from abnormal potassium and sodium channels in myocytes. Recently, interest has been growing in a disorder that may carry a similarly grim prognosis but that has an opposite finding on electrocardiography (ECG).
Short QT syndrome is a recently described heterogeneous genetic channelopathy that causes both atrial and ventricular arrhythmias and that has been documented to cause sudden cardiac death.
In 1996, a 37-year-old woman from Spain died suddenly; ECG several days earlier had shown a short QT interval of 266 ms.1 Two years later, an unrelated 17-year-old American woman undergoing laparoscopic cholecystectomy suddenly developed atrial fibrillation with a rapid ventricular response.1 Her QT interval was 225 ms. Her brother had a QT interval of 240 ms, and her mother’s was 230 ms. The patient’s maternal grandfather had a history of atrial fibrillation, and his QT interval was 245 ms. These cases led to the description of this new clinical syndrome (see below).2
CLINICAL FEATURES
Short QT syndrome has been associated with both atrial and ventricular arrhythmias. Atrial fibrillation, polymorphic ventricular tachycardia, and ventricular fibrillation have all been well described. Patients who have symptoms usually present with palpitations, presyncope, syncope, or sudden or aborted cardiac death.3,4
ELECTROCARDIOGRAPHIC FEATURES
The primary finding on ECG is a short QT interval. However, others have been noted (Figure 1):
Short or absent ST segment
This finding is not merely a consequence of the short QT interval. In 10 patients with short QT syndrome, the distance from the J point to the peak T wave ranged from 80 to 120 ms. In 12 healthy people whose QT interval was less than 320 ms, this distance ranged from 150 ms to 240 ms.5
Tall and peaked T wave
A tall and peaked T wave is a common feature in short QT syndrome. However, it was also evident in people with short QT intervals who had no other features of the syndrome.5
QT response to heart rate
Normally, the QT interval is inversely related to the heart rate, but this is not true in short QT syndrome: the QT interval remains relatively fixed with changes in heart rate.6,7 This feature is less helpful in the office setting but may be found with Holter monitoring by measuring the QT interval at different heart rates.
BUT WHAT IS CONSIDERED A SHORT QT INTERVAL?
In clinical practice, the QT interval is corrected for the heart rate by the Bazett formula:
Corrected QT (QTc) = [QT interval/square root of the RR interval]
Review of ECGs from large populations in Finland (n = 10,822), Japan (n = 12,149), the United States (n = 79,743), and Switzerland (n = 41,676) revealed that a QTc value of 350 ms in males and 365 ms in females was 2.0 standard deviations (SD) below the mean.8–11 However, a QTc less than the 2.0 SD cutoff did not necessarily equal arrhythmogenic potential. This was illustrated in a 29-year follow-up study of Finnish patients with QTc values as short as 320 ms, in whom no arrhythmias were documented.8 Conversely, some patients with purported short QT syndrome had QTc intervals as long as 381 ms.12
Similar problems with uncertainty of values have plagued the diagnosis of long QT syndrome.13 The lack of reference ranges and the overlap between healthy and affected people called for the development of a scoring system that involves criteria based on ECG and on the clinical evaluation.14,15
ESTABLISHING THE DIAGNOSIS OF SHORT QT SYNDROME
Clearly, the diagnosis of short QT syndrome can be challenging to establish. The first step is to rule out other causes of a short QT interval.
Differential diagnosis of short QT interval
In addition to genetic channelopathies, other causes of short QT interval must be ruled out before entertaining the diagnosis of short QT syndrome.
- Hypercalcemia is the most important of these: there is usually an accompanying prolonged PR interval and a wide QRS complex16
- Hyperkalemia17
- Acidosis17
- Increased vagal tone17
- After ventricular fibrillation (thought to be related to increased intracellular calcium)18
- Digitalis use19
- Androgen use.20
Interestingly, a shorter-than-expected QT interval was noted in patients with chronic fatigue syndrome.21
Which interval to use: QT or QTc?
Unfortunately, most population-based studies that searched for a short QT interval on ECG have used QTc as the main search parameter.8–11 As already mentioned, in patients with short QT syndrome, the QT interval is, uniquely, not shortened if the heart beats faster. In contrast, the QTc often overestimates the QT interval in patients with short QT syndrome, especially when the heart rate is in the 80s to 90s.16
In a review of cases of short QT syndrome worldwide, Bjerregaard et al22 found that the QT interval ranged from 210 ms to 340 ms with a mean ± 2 SD of 282 ± 62 ms. On the other hand, the QTc ranged from 248 ms to 345 ms with a mean ± 2 SD of 305 ± 42 ms.
Therefore, correction formulas (such as the Bazett formula) do not perform well in ruling in the diagnosis of short QT syndrome—and they do even worse in ruling it out.16,22
To establish a diagnosis of short QT syndrome in someone with prior evidence of atrial or ventricular fibrillation, a QT interval less than 340 ms or a QTc less than 345 ms is usually sufficient.22 In borderline cases in which the QT interval is slightly longer, some experts recommend other tests, although strong evidence validating their predictive value does not exist. These tests include genotyping, analysis of T wave morphology, and electrophysiologic studies.16
Recently, Gollob et al23 proposed a scoring system for short QT syndrome (Table 1). After reviewing the literature and comparing the diagnostic markers, the investigators determined diagnostic criteria that, when applied to the previously reported cases, were able to identify 58 (95.08%) of 61 patients with short QT syndrome (ie, a sensitivity of 95%).
For patients with intermediate probability, the authors recommended continued medical and ECG surveillance as well as ECGs for first-degree relatives, to further clarify the diagnosis.
Again, a principal caveat about this system is that it relies on the QTc interval rather than the QT interval to diagnose short QT syndrome.
THE SCOPE OF THE DISEASE
In a recent review of the literature, Gollob et al23 found a total of 61 cases of short QT syndrome reported in English. The cohort was predominantly male (75.4%), and most of the symptomatic patients presented during late adolescence and early adulthood. However, there have been reports of infants (4 and 8 months old), and of a man who presented for the first time at the age of 70. Of note, the authors only considered short QT syndrome types 1, 2, and 3 (see below) in their search for cases.
Whether the syndrome is truly this rare or, rather, whether many physicians are not aware of it is still to be determined. In addition, it is possible that incorrectly measuring the QT interval contributes to the lack of identification of this entity. Both of these factors were implicated in the rarity of reported long QT syndrome early after its discovery.14,15
MUTATIONS IN CARDIAC ION CHANNELS
Five distinct genetic defects have been associated with short QT syndrome. As in long QT syndrome, these give rise to subtypes of short QT syndrome, which are numbered 1 to 5 (see below).
The cardiac action potential
To understand how the mutations shorten the QT interval, we will briefly review of the cardiac myocyte action potential.24 In nonpacemaker cells of the heart, the activation of the cell membrane initiates a series of changes in ion channels that allow the movement of ions along an electrical gradient. This movement occurs in five phases and is repeated with every cardiac cycle (Figure 2).
In phase 0, the cardiac cell rapidly depolarizes.
Repolarization occurs in phases 1, 2, and 3 and is largely a function of potassium ions leaving the cell. During phase 2, calcium and sodium ions enter the cell and balance the outward potassium flow, creating the “flat” portion of the repolarization curve. Phase 3 is the main phase of repolarization in which the membrane potential rapidly falls back to its resting state (–90 mV). During phases 1 and 2, the cell membrane is completely refractory to stimulation, whereas phase 3 is divided into three parts:
- The effective refractory period: the cell is able to generate a potential that is too weak to be propagated
- The relative refractory period: the cell can respond to a stimulus that is stronger than normal
- The supernormal phase: the last small portion of phase 3, in which a less-than-normal stimulus can yield a response in the cell.
In phase 4, the cell is completely repolarized, and the cycle can start again.
Five types of short QT syndrome
Short QT syndrome 1. In 2004, Brugada et al25 identified the first mutation that causes abnormal shortening of the action potential duration. In contrast to the mutations that underlie long QT syndrome, this mutation actually causes a gain of function in the gene coding the rapidly acting delayed potassium current (IKr) channel proteins KCNH2 or HERG. Potassium leaving at a more rapid rate causes the cell to repolarize more quickly and shortens the QT interval. The clinical syndrome associated with KCNH2 gene gain-of-function mutation is called short QT syndrome 1.
Short QT syndromes 2 and 3. Other IK (potassium channel) proteins have been implicated as well. Gain-of-function mutations in the KCNQ1 and KCNJ2 genes are believed to account for short QT syndromes 2 and 3, respectively. KCNQ1 codes for the IKs protein, and KCNJ2 codes for the IK1 protein.26,27
Short QT syndromes 4 and 5 were identified by Antzelevitch et al,28 who described several patients who had a combination of channel abnormalities and ECG findings. Their ECGs showed “Brugada-syndrome-like” ST elevation in the right precordial leads, but with a short QT interval. These new syndromes were found to be associated with genetic abnormalities distinct from those of Brugada syndrome and other short QT syndromes. These abnormalities involved loss-of-function mutations in the CACNA1C gene (which codes for the alpha-1 subunit of the L-type cardiac calcium channel) and in the CACNB2 gene (which codes for the beta-2b subunit of the same channel). The two defects correspond to the clinical syndromes short QT syndrome 4 and short QT syndrome 5, respectively.28
MECHANISM OF ARRHYTHMOGENESIS IN SHORT QT SYNDROME
The myocardium is made of different layers: the epicardium, the endocardium, and the middle layer of myocytes composed mainly of M cells. Cells in the different layers differ in the concentration of their channels and can be affected differently in various syndromes. When cells in one or two of the layers repolarize at a rate different from cells in another layer, they create different degrees of refractoriness, which establishes the potential for reentry circuits to form.
It is believed that in short QT syndrome the endocardial cells and M cells repolarize faster than the epicardial cells, predisposing to reentry and arrhythmias. This accentuation of “transmural dispersion of repolarization” accounts for arrhythmogenesis in short QT syndrome as well as in long QT syndrome and the Brugada syndromes. The difference between these syndromes appears to be the layer or area of the myocardium that is affected more by the channelopathy (the M cells in long QT syndrome and the epicardium of the right ventricle in the Brugada syndrome).29
WHEN TO THINK OF SHORT QT SYNDROME
In any survivor of sudden cardiac death, the QT interval should be thoroughly scrutinized, and family members should undergo ECG. Patients in whom a short QT interval is incidentally discovered and for which other reasons are ruled out (see differential diagnosis) should be encouraged to have family members undergo ECG. Other potential patients are young people who develop atrial fibrillation and patients who have idiopathic ventricular fibrillation.4
TREATMENT AND PROGNOSIS
Evidence-based recommendations for the management of short QT syndrome do not yet exist, mainly because the number of patients identified to date is small.
Implantable cardioverter-defibrillators
Although placing an implantable cardioverter-defibrillator (ICD) seems to be warranted in patients who experience ventricular fibrillation, ventricular tachycardia, or aborted cardiac death, or in patients who have a family history of the same symptoms, the best management option is less clear for patients who have no symptoms and no family history.30 In addition, some patients may not want an ICD or may even not qualify for this therapy.
A unique problem with ICDs in short QT syndrome stems from one of the syndrome’s main features on ECG: the tall and peaked T wave that closely follows the R wave can sometimes be interpreted as a short R-R interval, provoking an inappropriate shock from the ICD.31
For the above reasons, we strongly encourage consulting a center with expertise in QT-interval-related disorders before placing an ICD in a patient suspected of having short QT syndrome.
Antiarrhythmic drugs
Prolongation of the QT interval (and the effective refractory period) with drugs has been an interesting area of research. Gaita et al32 studied the effect of four antiarrhythmics—flecainide (Tambocor), sotalol (Betapace), ibutilide (Corvert), and quinidine—in six patients with short QT syndrome. Only quinidine was associated with significant QT prolongation, from 263 ± 12 ms to 362 ms ± 25 ms. This resulted in a longer ventricular effective refractory period (> 200 ms), and ventricular fibrillation was no longer inducible during provocative testing.
In a recent study of long-term outcomes of 53 patients with short QT syndrome, Giustetto et al33 noticed that none of the patients taking quinidine, including those with a history of cardiac arrest, had any further arrhythmsic events. On the other hand, the incidence of arrhythmic events during the follow-up was 4.9% per year in patients not taking this drug. Quinidine had a stronger effect on the QT interval in patients with the HERG mutation than in those without.
RESEARCH MAY LEAD TO A BETTER UNDERSTANDING OF OTHER DISEASES
The short QT syndrome is one of the most recently recognized cardiac channelopathies associated with malignant arrhythmias. As with long QT syndrome, research in short QT syndrome may lead to a better understanding of the pathogenesis of more common but still poorly understood arrhythmias such as lone atrial fibrillation and idiopathic ventricular fibrillation.
- The Short QT Syndrome http://www.shortqtsyndrome.org/short_qt_history.htm. Accessed October 30, 2012.
- Gussak I, Brugada P, Brugada J, et al. Idiopathic short QT interval: a new clinical syndrome? Cardiology 2000; 94:99–102.
- Giustetto C, Di Monte F, Wolpert C, et al. Short QT syndrome: clinical findings and diagnostic-therapeutic implications. Eur Heart J 2006; 27:2440–2447.
- Viskin S, Zeltser D, Ish-Shalom M, et al. Is idiopathic ventricular fibrillation a short QT syndrome? Comparison of QT intervals of patients with idiopathic ventricular fibrillation and healthy controls. Heart Rhythm 2004; 1:587–591.
- Anttonen O, Junttila MJ, Maury P, et al. Differences in twelve-lead electrocardiogram between symptomatic and asymptomatic subjects with short QT interval. Heart Rhythm 2009; 6:267–271.
- Redpath CJ, Green MS, Birnie DH, Gollob MH. Rapid genetic testing facilitating the diagnosis of short QT syndrome. Can J Cardiol 2009; 25:e133–e135.
- Wolpert C, Schimpf R, Giustetto C, et al. Further insights into the effect of quinidine in short QT syndrome caused by a mutation in HERG. J Cardiovasc Electrophysiol 2005; 16:54–58.
- Anttonen O, Junttila MJ, Rissanen H, Reunanen A, Viitasalo M, Huikuri HV. Prevalence and prognostic significance of short QT interval in a middle-aged Finnish population. Circulation 2007; 116:714–720.
- Funada A, Hayashi K, Ino H, et al. Assessment of QT intervals and prevalence of short QT syndrome in Japan. Clin Cardiol 2008; 31:270–274.
- Mason JW, Ramseth DJ, Chanter DO, Moon TE, Goodman DB, Mendzelevski B. Electrocardiographic reference ranges derived from 79,743 ambulatory subjects. J Electrocardiol 2007; 40:228–234.
- Kobza R, Roos M, Niggli B, et al. Prevalence of long and short QT in a young population of 41,767 predominantly male Swiss conscripts. Heart Rhythm 2009; 6:652–657.
- Itoh H, Sakaguchi T, Ashihara T, et al. A novel KCNH2 mutation as a modifier for short QT interval. Int J Cardiol 2009; 137:83–85.
- Vincent GM, Timothy KW, Leppert M, Keating M. The spectrum of symptoms and QT intervals in carriers of the gene for the long-QT syndrome. N Engl J Med 1992; 327:846–852.
- Schwartz PJ. Idiopathic long QT syndrome: progress and questions. Am Heart J 1985; 109:399–411.
- Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria for the long QT syndrome. An update. Circulation 1993; 88:782–784.
- Bjerregaard P, Nallapaneni H, Gussak I. Short QT interval in clinical practice. J Electrocardiol 2010; 43:390–395.
- Maury P, Extramiana F, Sbragia P, et al. Short QT syndrome. Update on a recent entity. Arch Cardiovasc Dis 2008; 101:779–786.
- Kontny F, Dale J. Self-terminating idiopathic ventricular fibrillation presenting as syncope: a 40-year follow-up report. J Intern Med 1990; 227:211–213.
- Cheng TO. Digitalis administration: an underappreciated but common cause of short QT interval. Circulation 2004; 109:e152.
- Hancox JC, Choisy SC, James AF. Short QT interval linked to androgen misuse: wider significance and possible basis. Ann Noninvasive Electrocardiol 2009; 14:311–312.
- Naschitz J, Fields M, Isseroff H, Sharif D, Sabo E, Rosner I. Shortened QT interval: a distinctive feature of the dysautonomia of chronic fatigue syndrome. J Electrocardiol 2006; 39:389–394.
- Bjerregaard P, Collier JL, Gussak I. Upper limits of QT/QTc intervals in the short QT syndrome. Review of the world-wide short QT syndrome population and 3 new USA families. Heart Rhythm 2008; 5:AB43.
- Gollob MH, Redpath CJ, Roberts JD. The short QT syndrome: proposed diagnostic criteria. J Am Coll Cardiol 2011; 57:802–812.
- Shih HT. Anatomy of the action potential in the heart. Tex Heart Inst J 1994; 21:30–41.
- Brugada R, Hong K, Dumaine R, et al. Sudden death associated with short-QT syndrome linked to mutations in HERG. Circulation 2004; 109:30–35.
- Bellocq C, van Ginneken AC, Bezzina CR, et al. Mutation in the KCNQ1 gene leading to the short QT-interval syndrome. Circulation 2004; 109:2394–2397.
- Priori SG, Pandit SV, Rivolta I, et al. A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene. Circ Res 2005; 96:800–807.
- Antzelevitch C, Pollevick GD, Cordeiro JM, et al. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation 2007; 115:442–449.
- Antzelevitch C. Heterogeneity and cardiac arrhythmias: an overview. Heart Rhythm 2007; 4:964–972.
- Lunati M, Bongiorni MG, Boriani G, et al. Linee guida AIAC 2006 all’impianto di pacemaker, dispositivi per la resincronizzazione cardiaca (CRT) e defibrillatori automatici impiantabili (ICD). GIAC 2005; 8:1–58.
- Schimpf R, Wolpert C, Bianchi F, et al. Congenital short QT syndrome and implantable cardioverter defibrillator treatment: inherent risk for inappropriate shock delivery. J Cardiovasc Electrophysiol 2003; 14:1273–1277.
- Gaita F, Giustetto C, Bianchi F, et al. Short QT syndrome: pharmacological treatment. J Am Coll Cardiol 2004; 43:1494–1499.
- Giustetto C, Schimpf R, Mazzanti A, et al. Long-term follow-up of patients with short QT syndrome. J Am Coll Cardiol 2011; 58:587–595.
Sudden cardiac death in a young person is a devastating event that has puzzled physicians for decades. In recent years, many of the underlying cardiac pathologies have been identified. These include structural abnormalities such as hypertrophic cardiomyopathy and nonstructural disorders associated with unstable rhythms that lead to sudden cardiac death.
The best known of these “channelopathies” are the long QT syndromes, which result from abnormal potassium and sodium channels in myocytes. Recently, interest has been growing in a disorder that may carry a similarly grim prognosis but that has an opposite finding on electrocardiography (ECG).
Short QT syndrome is a recently described heterogeneous genetic channelopathy that causes both atrial and ventricular arrhythmias and that has been documented to cause sudden cardiac death.
In 1996, a 37-year-old woman from Spain died suddenly; ECG several days earlier had shown a short QT interval of 266 ms.1 Two years later, an unrelated 17-year-old American woman undergoing laparoscopic cholecystectomy suddenly developed atrial fibrillation with a rapid ventricular response.1 Her QT interval was 225 ms. Her brother had a QT interval of 240 ms, and her mother’s was 230 ms. The patient’s maternal grandfather had a history of atrial fibrillation, and his QT interval was 245 ms. These cases led to the description of this new clinical syndrome (see below).2
CLINICAL FEATURES
Short QT syndrome has been associated with both atrial and ventricular arrhythmias. Atrial fibrillation, polymorphic ventricular tachycardia, and ventricular fibrillation have all been well described. Patients who have symptoms usually present with palpitations, presyncope, syncope, or sudden or aborted cardiac death.3,4
ELECTROCARDIOGRAPHIC FEATURES
The primary finding on ECG is a short QT interval. However, others have been noted (Figure 1):
Short or absent ST segment
This finding is not merely a consequence of the short QT interval. In 10 patients with short QT syndrome, the distance from the J point to the peak T wave ranged from 80 to 120 ms. In 12 healthy people whose QT interval was less than 320 ms, this distance ranged from 150 ms to 240 ms.5
Tall and peaked T wave
A tall and peaked T wave is a common feature in short QT syndrome. However, it was also evident in people with short QT intervals who had no other features of the syndrome.5
QT response to heart rate
Normally, the QT interval is inversely related to the heart rate, but this is not true in short QT syndrome: the QT interval remains relatively fixed with changes in heart rate.6,7 This feature is less helpful in the office setting but may be found with Holter monitoring by measuring the QT interval at different heart rates.
BUT WHAT IS CONSIDERED A SHORT QT INTERVAL?
In clinical practice, the QT interval is corrected for the heart rate by the Bazett formula:
Corrected QT (QTc) = [QT interval/square root of the RR interval]
Review of ECGs from large populations in Finland (n = 10,822), Japan (n = 12,149), the United States (n = 79,743), and Switzerland (n = 41,676) revealed that a QTc value of 350 ms in males and 365 ms in females was 2.0 standard deviations (SD) below the mean.8–11 However, a QTc less than the 2.0 SD cutoff did not necessarily equal arrhythmogenic potential. This was illustrated in a 29-year follow-up study of Finnish patients with QTc values as short as 320 ms, in whom no arrhythmias were documented.8 Conversely, some patients with purported short QT syndrome had QTc intervals as long as 381 ms.12
Similar problems with uncertainty of values have plagued the diagnosis of long QT syndrome.13 The lack of reference ranges and the overlap between healthy and affected people called for the development of a scoring system that involves criteria based on ECG and on the clinical evaluation.14,15
ESTABLISHING THE DIAGNOSIS OF SHORT QT SYNDROME
Clearly, the diagnosis of short QT syndrome can be challenging to establish. The first step is to rule out other causes of a short QT interval.
Differential diagnosis of short QT interval
In addition to genetic channelopathies, other causes of short QT interval must be ruled out before entertaining the diagnosis of short QT syndrome.
- Hypercalcemia is the most important of these: there is usually an accompanying prolonged PR interval and a wide QRS complex16
- Hyperkalemia17
- Acidosis17
- Increased vagal tone17
- After ventricular fibrillation (thought to be related to increased intracellular calcium)18
- Digitalis use19
- Androgen use.20
Interestingly, a shorter-than-expected QT interval was noted in patients with chronic fatigue syndrome.21
Which interval to use: QT or QTc?
Unfortunately, most population-based studies that searched for a short QT interval on ECG have used QTc as the main search parameter.8–11 As already mentioned, in patients with short QT syndrome, the QT interval is, uniquely, not shortened if the heart beats faster. In contrast, the QTc often overestimates the QT interval in patients with short QT syndrome, especially when the heart rate is in the 80s to 90s.16
In a review of cases of short QT syndrome worldwide, Bjerregaard et al22 found that the QT interval ranged from 210 ms to 340 ms with a mean ± 2 SD of 282 ± 62 ms. On the other hand, the QTc ranged from 248 ms to 345 ms with a mean ± 2 SD of 305 ± 42 ms.
Therefore, correction formulas (such as the Bazett formula) do not perform well in ruling in the diagnosis of short QT syndrome—and they do even worse in ruling it out.16,22
To establish a diagnosis of short QT syndrome in someone with prior evidence of atrial or ventricular fibrillation, a QT interval less than 340 ms or a QTc less than 345 ms is usually sufficient.22 In borderline cases in which the QT interval is slightly longer, some experts recommend other tests, although strong evidence validating their predictive value does not exist. These tests include genotyping, analysis of T wave morphology, and electrophysiologic studies.16
Recently, Gollob et al23 proposed a scoring system for short QT syndrome (Table 1). After reviewing the literature and comparing the diagnostic markers, the investigators determined diagnostic criteria that, when applied to the previously reported cases, were able to identify 58 (95.08%) of 61 patients with short QT syndrome (ie, a sensitivity of 95%).
For patients with intermediate probability, the authors recommended continued medical and ECG surveillance as well as ECGs for first-degree relatives, to further clarify the diagnosis.
Again, a principal caveat about this system is that it relies on the QTc interval rather than the QT interval to diagnose short QT syndrome.
THE SCOPE OF THE DISEASE
In a recent review of the literature, Gollob et al23 found a total of 61 cases of short QT syndrome reported in English. The cohort was predominantly male (75.4%), and most of the symptomatic patients presented during late adolescence and early adulthood. However, there have been reports of infants (4 and 8 months old), and of a man who presented for the first time at the age of 70. Of note, the authors only considered short QT syndrome types 1, 2, and 3 (see below) in their search for cases.
Whether the syndrome is truly this rare or, rather, whether many physicians are not aware of it is still to be determined. In addition, it is possible that incorrectly measuring the QT interval contributes to the lack of identification of this entity. Both of these factors were implicated in the rarity of reported long QT syndrome early after its discovery.14,15
MUTATIONS IN CARDIAC ION CHANNELS
Five distinct genetic defects have been associated with short QT syndrome. As in long QT syndrome, these give rise to subtypes of short QT syndrome, which are numbered 1 to 5 (see below).
The cardiac action potential
To understand how the mutations shorten the QT interval, we will briefly review of the cardiac myocyte action potential.24 In nonpacemaker cells of the heart, the activation of the cell membrane initiates a series of changes in ion channels that allow the movement of ions along an electrical gradient. This movement occurs in five phases and is repeated with every cardiac cycle (Figure 2).
In phase 0, the cardiac cell rapidly depolarizes.
Repolarization occurs in phases 1, 2, and 3 and is largely a function of potassium ions leaving the cell. During phase 2, calcium and sodium ions enter the cell and balance the outward potassium flow, creating the “flat” portion of the repolarization curve. Phase 3 is the main phase of repolarization in which the membrane potential rapidly falls back to its resting state (–90 mV). During phases 1 and 2, the cell membrane is completely refractory to stimulation, whereas phase 3 is divided into three parts:
- The effective refractory period: the cell is able to generate a potential that is too weak to be propagated
- The relative refractory period: the cell can respond to a stimulus that is stronger than normal
- The supernormal phase: the last small portion of phase 3, in which a less-than-normal stimulus can yield a response in the cell.
In phase 4, the cell is completely repolarized, and the cycle can start again.
Five types of short QT syndrome
Short QT syndrome 1. In 2004, Brugada et al25 identified the first mutation that causes abnormal shortening of the action potential duration. In contrast to the mutations that underlie long QT syndrome, this mutation actually causes a gain of function in the gene coding the rapidly acting delayed potassium current (IKr) channel proteins KCNH2 or HERG. Potassium leaving at a more rapid rate causes the cell to repolarize more quickly and shortens the QT interval. The clinical syndrome associated with KCNH2 gene gain-of-function mutation is called short QT syndrome 1.
Short QT syndromes 2 and 3. Other IK (potassium channel) proteins have been implicated as well. Gain-of-function mutations in the KCNQ1 and KCNJ2 genes are believed to account for short QT syndromes 2 and 3, respectively. KCNQ1 codes for the IKs protein, and KCNJ2 codes for the IK1 protein.26,27
Short QT syndromes 4 and 5 were identified by Antzelevitch et al,28 who described several patients who had a combination of channel abnormalities and ECG findings. Their ECGs showed “Brugada-syndrome-like” ST elevation in the right precordial leads, but with a short QT interval. These new syndromes were found to be associated with genetic abnormalities distinct from those of Brugada syndrome and other short QT syndromes. These abnormalities involved loss-of-function mutations in the CACNA1C gene (which codes for the alpha-1 subunit of the L-type cardiac calcium channel) and in the CACNB2 gene (which codes for the beta-2b subunit of the same channel). The two defects correspond to the clinical syndromes short QT syndrome 4 and short QT syndrome 5, respectively.28
MECHANISM OF ARRHYTHMOGENESIS IN SHORT QT SYNDROME
The myocardium is made of different layers: the epicardium, the endocardium, and the middle layer of myocytes composed mainly of M cells. Cells in the different layers differ in the concentration of their channels and can be affected differently in various syndromes. When cells in one or two of the layers repolarize at a rate different from cells in another layer, they create different degrees of refractoriness, which establishes the potential for reentry circuits to form.
It is believed that in short QT syndrome the endocardial cells and M cells repolarize faster than the epicardial cells, predisposing to reentry and arrhythmias. This accentuation of “transmural dispersion of repolarization” accounts for arrhythmogenesis in short QT syndrome as well as in long QT syndrome and the Brugada syndromes. The difference between these syndromes appears to be the layer or area of the myocardium that is affected more by the channelopathy (the M cells in long QT syndrome and the epicardium of the right ventricle in the Brugada syndrome).29
WHEN TO THINK OF SHORT QT SYNDROME
In any survivor of sudden cardiac death, the QT interval should be thoroughly scrutinized, and family members should undergo ECG. Patients in whom a short QT interval is incidentally discovered and for which other reasons are ruled out (see differential diagnosis) should be encouraged to have family members undergo ECG. Other potential patients are young people who develop atrial fibrillation and patients who have idiopathic ventricular fibrillation.4
TREATMENT AND PROGNOSIS
Evidence-based recommendations for the management of short QT syndrome do not yet exist, mainly because the number of patients identified to date is small.
Implantable cardioverter-defibrillators
Although placing an implantable cardioverter-defibrillator (ICD) seems to be warranted in patients who experience ventricular fibrillation, ventricular tachycardia, or aborted cardiac death, or in patients who have a family history of the same symptoms, the best management option is less clear for patients who have no symptoms and no family history.30 In addition, some patients may not want an ICD or may even not qualify for this therapy.
A unique problem with ICDs in short QT syndrome stems from one of the syndrome’s main features on ECG: the tall and peaked T wave that closely follows the R wave can sometimes be interpreted as a short R-R interval, provoking an inappropriate shock from the ICD.31
For the above reasons, we strongly encourage consulting a center with expertise in QT-interval-related disorders before placing an ICD in a patient suspected of having short QT syndrome.
Antiarrhythmic drugs
Prolongation of the QT interval (and the effective refractory period) with drugs has been an interesting area of research. Gaita et al32 studied the effect of four antiarrhythmics—flecainide (Tambocor), sotalol (Betapace), ibutilide (Corvert), and quinidine—in six patients with short QT syndrome. Only quinidine was associated with significant QT prolongation, from 263 ± 12 ms to 362 ms ± 25 ms. This resulted in a longer ventricular effective refractory period (> 200 ms), and ventricular fibrillation was no longer inducible during provocative testing.
In a recent study of long-term outcomes of 53 patients with short QT syndrome, Giustetto et al33 noticed that none of the patients taking quinidine, including those with a history of cardiac arrest, had any further arrhythmsic events. On the other hand, the incidence of arrhythmic events during the follow-up was 4.9% per year in patients not taking this drug. Quinidine had a stronger effect on the QT interval in patients with the HERG mutation than in those without.
RESEARCH MAY LEAD TO A BETTER UNDERSTANDING OF OTHER DISEASES
The short QT syndrome is one of the most recently recognized cardiac channelopathies associated with malignant arrhythmias. As with long QT syndrome, research in short QT syndrome may lead to a better understanding of the pathogenesis of more common but still poorly understood arrhythmias such as lone atrial fibrillation and idiopathic ventricular fibrillation.
Sudden cardiac death in a young person is a devastating event that has puzzled physicians for decades. In recent years, many of the underlying cardiac pathologies have been identified. These include structural abnormalities such as hypertrophic cardiomyopathy and nonstructural disorders associated with unstable rhythms that lead to sudden cardiac death.
The best known of these “channelopathies” are the long QT syndromes, which result from abnormal potassium and sodium channels in myocytes. Recently, interest has been growing in a disorder that may carry a similarly grim prognosis but that has an opposite finding on electrocardiography (ECG).
Short QT syndrome is a recently described heterogeneous genetic channelopathy that causes both atrial and ventricular arrhythmias and that has been documented to cause sudden cardiac death.
In 1996, a 37-year-old woman from Spain died suddenly; ECG several days earlier had shown a short QT interval of 266 ms.1 Two years later, an unrelated 17-year-old American woman undergoing laparoscopic cholecystectomy suddenly developed atrial fibrillation with a rapid ventricular response.1 Her QT interval was 225 ms. Her brother had a QT interval of 240 ms, and her mother’s was 230 ms. The patient’s maternal grandfather had a history of atrial fibrillation, and his QT interval was 245 ms. These cases led to the description of this new clinical syndrome (see below).2
CLINICAL FEATURES
Short QT syndrome has been associated with both atrial and ventricular arrhythmias. Atrial fibrillation, polymorphic ventricular tachycardia, and ventricular fibrillation have all been well described. Patients who have symptoms usually present with palpitations, presyncope, syncope, or sudden or aborted cardiac death.3,4
ELECTROCARDIOGRAPHIC FEATURES
The primary finding on ECG is a short QT interval. However, others have been noted (Figure 1):
Short or absent ST segment
This finding is not merely a consequence of the short QT interval. In 10 patients with short QT syndrome, the distance from the J point to the peak T wave ranged from 80 to 120 ms. In 12 healthy people whose QT interval was less than 320 ms, this distance ranged from 150 ms to 240 ms.5
Tall and peaked T wave
A tall and peaked T wave is a common feature in short QT syndrome. However, it was also evident in people with short QT intervals who had no other features of the syndrome.5
QT response to heart rate
Normally, the QT interval is inversely related to the heart rate, but this is not true in short QT syndrome: the QT interval remains relatively fixed with changes in heart rate.6,7 This feature is less helpful in the office setting but may be found with Holter monitoring by measuring the QT interval at different heart rates.
BUT WHAT IS CONSIDERED A SHORT QT INTERVAL?
In clinical practice, the QT interval is corrected for the heart rate by the Bazett formula:
Corrected QT (QTc) = [QT interval/square root of the RR interval]
Review of ECGs from large populations in Finland (n = 10,822), Japan (n = 12,149), the United States (n = 79,743), and Switzerland (n = 41,676) revealed that a QTc value of 350 ms in males and 365 ms in females was 2.0 standard deviations (SD) below the mean.8–11 However, a QTc less than the 2.0 SD cutoff did not necessarily equal arrhythmogenic potential. This was illustrated in a 29-year follow-up study of Finnish patients with QTc values as short as 320 ms, in whom no arrhythmias were documented.8 Conversely, some patients with purported short QT syndrome had QTc intervals as long as 381 ms.12
Similar problems with uncertainty of values have plagued the diagnosis of long QT syndrome.13 The lack of reference ranges and the overlap between healthy and affected people called for the development of a scoring system that involves criteria based on ECG and on the clinical evaluation.14,15
ESTABLISHING THE DIAGNOSIS OF SHORT QT SYNDROME
Clearly, the diagnosis of short QT syndrome can be challenging to establish. The first step is to rule out other causes of a short QT interval.
Differential diagnosis of short QT interval
In addition to genetic channelopathies, other causes of short QT interval must be ruled out before entertaining the diagnosis of short QT syndrome.
- Hypercalcemia is the most important of these: there is usually an accompanying prolonged PR interval and a wide QRS complex16
- Hyperkalemia17
- Acidosis17
- Increased vagal tone17
- After ventricular fibrillation (thought to be related to increased intracellular calcium)18
- Digitalis use19
- Androgen use.20
Interestingly, a shorter-than-expected QT interval was noted in patients with chronic fatigue syndrome.21
Which interval to use: QT or QTc?
Unfortunately, most population-based studies that searched for a short QT interval on ECG have used QTc as the main search parameter.8–11 As already mentioned, in patients with short QT syndrome, the QT interval is, uniquely, not shortened if the heart beats faster. In contrast, the QTc often overestimates the QT interval in patients with short QT syndrome, especially when the heart rate is in the 80s to 90s.16
In a review of cases of short QT syndrome worldwide, Bjerregaard et al22 found that the QT interval ranged from 210 ms to 340 ms with a mean ± 2 SD of 282 ± 62 ms. On the other hand, the QTc ranged from 248 ms to 345 ms with a mean ± 2 SD of 305 ± 42 ms.
Therefore, correction formulas (such as the Bazett formula) do not perform well in ruling in the diagnosis of short QT syndrome—and they do even worse in ruling it out.16,22
To establish a diagnosis of short QT syndrome in someone with prior evidence of atrial or ventricular fibrillation, a QT interval less than 340 ms or a QTc less than 345 ms is usually sufficient.22 In borderline cases in which the QT interval is slightly longer, some experts recommend other tests, although strong evidence validating their predictive value does not exist. These tests include genotyping, analysis of T wave morphology, and electrophysiologic studies.16
Recently, Gollob et al23 proposed a scoring system for short QT syndrome (Table 1). After reviewing the literature and comparing the diagnostic markers, the investigators determined diagnostic criteria that, when applied to the previously reported cases, were able to identify 58 (95.08%) of 61 patients with short QT syndrome (ie, a sensitivity of 95%).
For patients with intermediate probability, the authors recommended continued medical and ECG surveillance as well as ECGs for first-degree relatives, to further clarify the diagnosis.
Again, a principal caveat about this system is that it relies on the QTc interval rather than the QT interval to diagnose short QT syndrome.
THE SCOPE OF THE DISEASE
In a recent review of the literature, Gollob et al23 found a total of 61 cases of short QT syndrome reported in English. The cohort was predominantly male (75.4%), and most of the symptomatic patients presented during late adolescence and early adulthood. However, there have been reports of infants (4 and 8 months old), and of a man who presented for the first time at the age of 70. Of note, the authors only considered short QT syndrome types 1, 2, and 3 (see below) in their search for cases.
Whether the syndrome is truly this rare or, rather, whether many physicians are not aware of it is still to be determined. In addition, it is possible that incorrectly measuring the QT interval contributes to the lack of identification of this entity. Both of these factors were implicated in the rarity of reported long QT syndrome early after its discovery.14,15
MUTATIONS IN CARDIAC ION CHANNELS
Five distinct genetic defects have been associated with short QT syndrome. As in long QT syndrome, these give rise to subtypes of short QT syndrome, which are numbered 1 to 5 (see below).
The cardiac action potential
To understand how the mutations shorten the QT interval, we will briefly review of the cardiac myocyte action potential.24 In nonpacemaker cells of the heart, the activation of the cell membrane initiates a series of changes in ion channels that allow the movement of ions along an electrical gradient. This movement occurs in five phases and is repeated with every cardiac cycle (Figure 2).
In phase 0, the cardiac cell rapidly depolarizes.
Repolarization occurs in phases 1, 2, and 3 and is largely a function of potassium ions leaving the cell. During phase 2, calcium and sodium ions enter the cell and balance the outward potassium flow, creating the “flat” portion of the repolarization curve. Phase 3 is the main phase of repolarization in which the membrane potential rapidly falls back to its resting state (–90 mV). During phases 1 and 2, the cell membrane is completely refractory to stimulation, whereas phase 3 is divided into three parts:
- The effective refractory period: the cell is able to generate a potential that is too weak to be propagated
- The relative refractory period: the cell can respond to a stimulus that is stronger than normal
- The supernormal phase: the last small portion of phase 3, in which a less-than-normal stimulus can yield a response in the cell.
In phase 4, the cell is completely repolarized, and the cycle can start again.
Five types of short QT syndrome
Short QT syndrome 1. In 2004, Brugada et al25 identified the first mutation that causes abnormal shortening of the action potential duration. In contrast to the mutations that underlie long QT syndrome, this mutation actually causes a gain of function in the gene coding the rapidly acting delayed potassium current (IKr) channel proteins KCNH2 or HERG. Potassium leaving at a more rapid rate causes the cell to repolarize more quickly and shortens the QT interval. The clinical syndrome associated with KCNH2 gene gain-of-function mutation is called short QT syndrome 1.
Short QT syndromes 2 and 3. Other IK (potassium channel) proteins have been implicated as well. Gain-of-function mutations in the KCNQ1 and KCNJ2 genes are believed to account for short QT syndromes 2 and 3, respectively. KCNQ1 codes for the IKs protein, and KCNJ2 codes for the IK1 protein.26,27
Short QT syndromes 4 and 5 were identified by Antzelevitch et al,28 who described several patients who had a combination of channel abnormalities and ECG findings. Their ECGs showed “Brugada-syndrome-like” ST elevation in the right precordial leads, but with a short QT interval. These new syndromes were found to be associated with genetic abnormalities distinct from those of Brugada syndrome and other short QT syndromes. These abnormalities involved loss-of-function mutations in the CACNA1C gene (which codes for the alpha-1 subunit of the L-type cardiac calcium channel) and in the CACNB2 gene (which codes for the beta-2b subunit of the same channel). The two defects correspond to the clinical syndromes short QT syndrome 4 and short QT syndrome 5, respectively.28
MECHANISM OF ARRHYTHMOGENESIS IN SHORT QT SYNDROME
The myocardium is made of different layers: the epicardium, the endocardium, and the middle layer of myocytes composed mainly of M cells. Cells in the different layers differ in the concentration of their channels and can be affected differently in various syndromes. When cells in one or two of the layers repolarize at a rate different from cells in another layer, they create different degrees of refractoriness, which establishes the potential for reentry circuits to form.
It is believed that in short QT syndrome the endocardial cells and M cells repolarize faster than the epicardial cells, predisposing to reentry and arrhythmias. This accentuation of “transmural dispersion of repolarization” accounts for arrhythmogenesis in short QT syndrome as well as in long QT syndrome and the Brugada syndromes. The difference between these syndromes appears to be the layer or area of the myocardium that is affected more by the channelopathy (the M cells in long QT syndrome and the epicardium of the right ventricle in the Brugada syndrome).29
WHEN TO THINK OF SHORT QT SYNDROME
In any survivor of sudden cardiac death, the QT interval should be thoroughly scrutinized, and family members should undergo ECG. Patients in whom a short QT interval is incidentally discovered and for which other reasons are ruled out (see differential diagnosis) should be encouraged to have family members undergo ECG. Other potential patients are young people who develop atrial fibrillation and patients who have idiopathic ventricular fibrillation.4
TREATMENT AND PROGNOSIS
Evidence-based recommendations for the management of short QT syndrome do not yet exist, mainly because the number of patients identified to date is small.
Implantable cardioverter-defibrillators
Although placing an implantable cardioverter-defibrillator (ICD) seems to be warranted in patients who experience ventricular fibrillation, ventricular tachycardia, or aborted cardiac death, or in patients who have a family history of the same symptoms, the best management option is less clear for patients who have no symptoms and no family history.30 In addition, some patients may not want an ICD or may even not qualify for this therapy.
A unique problem with ICDs in short QT syndrome stems from one of the syndrome’s main features on ECG: the tall and peaked T wave that closely follows the R wave can sometimes be interpreted as a short R-R interval, provoking an inappropriate shock from the ICD.31
For the above reasons, we strongly encourage consulting a center with expertise in QT-interval-related disorders before placing an ICD in a patient suspected of having short QT syndrome.
Antiarrhythmic drugs
Prolongation of the QT interval (and the effective refractory period) with drugs has been an interesting area of research. Gaita et al32 studied the effect of four antiarrhythmics—flecainide (Tambocor), sotalol (Betapace), ibutilide (Corvert), and quinidine—in six patients with short QT syndrome. Only quinidine was associated with significant QT prolongation, from 263 ± 12 ms to 362 ms ± 25 ms. This resulted in a longer ventricular effective refractory period (> 200 ms), and ventricular fibrillation was no longer inducible during provocative testing.
In a recent study of long-term outcomes of 53 patients with short QT syndrome, Giustetto et al33 noticed that none of the patients taking quinidine, including those with a history of cardiac arrest, had any further arrhythmsic events. On the other hand, the incidence of arrhythmic events during the follow-up was 4.9% per year in patients not taking this drug. Quinidine had a stronger effect on the QT interval in patients with the HERG mutation than in those without.
RESEARCH MAY LEAD TO A BETTER UNDERSTANDING OF OTHER DISEASES
The short QT syndrome is one of the most recently recognized cardiac channelopathies associated with malignant arrhythmias. As with long QT syndrome, research in short QT syndrome may lead to a better understanding of the pathogenesis of more common but still poorly understood arrhythmias such as lone atrial fibrillation and idiopathic ventricular fibrillation.
- The Short QT Syndrome http://www.shortqtsyndrome.org/short_qt_history.htm. Accessed October 30, 2012.
- Gussak I, Brugada P, Brugada J, et al. Idiopathic short QT interval: a new clinical syndrome? Cardiology 2000; 94:99–102.
- Giustetto C, Di Monte F, Wolpert C, et al. Short QT syndrome: clinical findings and diagnostic-therapeutic implications. Eur Heart J 2006; 27:2440–2447.
- Viskin S, Zeltser D, Ish-Shalom M, et al. Is idiopathic ventricular fibrillation a short QT syndrome? Comparison of QT intervals of patients with idiopathic ventricular fibrillation and healthy controls. Heart Rhythm 2004; 1:587–591.
- Anttonen O, Junttila MJ, Maury P, et al. Differences in twelve-lead electrocardiogram between symptomatic and asymptomatic subjects with short QT interval. Heart Rhythm 2009; 6:267–271.
- Redpath CJ, Green MS, Birnie DH, Gollob MH. Rapid genetic testing facilitating the diagnosis of short QT syndrome. Can J Cardiol 2009; 25:e133–e135.
- Wolpert C, Schimpf R, Giustetto C, et al. Further insights into the effect of quinidine in short QT syndrome caused by a mutation in HERG. J Cardiovasc Electrophysiol 2005; 16:54–58.
- Anttonen O, Junttila MJ, Rissanen H, Reunanen A, Viitasalo M, Huikuri HV. Prevalence and prognostic significance of short QT interval in a middle-aged Finnish population. Circulation 2007; 116:714–720.
- Funada A, Hayashi K, Ino H, et al. Assessment of QT intervals and prevalence of short QT syndrome in Japan. Clin Cardiol 2008; 31:270–274.
- Mason JW, Ramseth DJ, Chanter DO, Moon TE, Goodman DB, Mendzelevski B. Electrocardiographic reference ranges derived from 79,743 ambulatory subjects. J Electrocardiol 2007; 40:228–234.
- Kobza R, Roos M, Niggli B, et al. Prevalence of long and short QT in a young population of 41,767 predominantly male Swiss conscripts. Heart Rhythm 2009; 6:652–657.
- Itoh H, Sakaguchi T, Ashihara T, et al. A novel KCNH2 mutation as a modifier for short QT interval. Int J Cardiol 2009; 137:83–85.
- Vincent GM, Timothy KW, Leppert M, Keating M. The spectrum of symptoms and QT intervals in carriers of the gene for the long-QT syndrome. N Engl J Med 1992; 327:846–852.
- Schwartz PJ. Idiopathic long QT syndrome: progress and questions. Am Heart J 1985; 109:399–411.
- Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria for the long QT syndrome. An update. Circulation 1993; 88:782–784.
- Bjerregaard P, Nallapaneni H, Gussak I. Short QT interval in clinical practice. J Electrocardiol 2010; 43:390–395.
- Maury P, Extramiana F, Sbragia P, et al. Short QT syndrome. Update on a recent entity. Arch Cardiovasc Dis 2008; 101:779–786.
- Kontny F, Dale J. Self-terminating idiopathic ventricular fibrillation presenting as syncope: a 40-year follow-up report. J Intern Med 1990; 227:211–213.
- Cheng TO. Digitalis administration: an underappreciated but common cause of short QT interval. Circulation 2004; 109:e152.
- Hancox JC, Choisy SC, James AF. Short QT interval linked to androgen misuse: wider significance and possible basis. Ann Noninvasive Electrocardiol 2009; 14:311–312.
- Naschitz J, Fields M, Isseroff H, Sharif D, Sabo E, Rosner I. Shortened QT interval: a distinctive feature of the dysautonomia of chronic fatigue syndrome. J Electrocardiol 2006; 39:389–394.
- Bjerregaard P, Collier JL, Gussak I. Upper limits of QT/QTc intervals in the short QT syndrome. Review of the world-wide short QT syndrome population and 3 new USA families. Heart Rhythm 2008; 5:AB43.
- Gollob MH, Redpath CJ, Roberts JD. The short QT syndrome: proposed diagnostic criteria. J Am Coll Cardiol 2011; 57:802–812.
- Shih HT. Anatomy of the action potential in the heart. Tex Heart Inst J 1994; 21:30–41.
- Brugada R, Hong K, Dumaine R, et al. Sudden death associated with short-QT syndrome linked to mutations in HERG. Circulation 2004; 109:30–35.
- Bellocq C, van Ginneken AC, Bezzina CR, et al. Mutation in the KCNQ1 gene leading to the short QT-interval syndrome. Circulation 2004; 109:2394–2397.
- Priori SG, Pandit SV, Rivolta I, et al. A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene. Circ Res 2005; 96:800–807.
- Antzelevitch C, Pollevick GD, Cordeiro JM, et al. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation 2007; 115:442–449.
- Antzelevitch C. Heterogeneity and cardiac arrhythmias: an overview. Heart Rhythm 2007; 4:964–972.
- Lunati M, Bongiorni MG, Boriani G, et al. Linee guida AIAC 2006 all’impianto di pacemaker, dispositivi per la resincronizzazione cardiaca (CRT) e defibrillatori automatici impiantabili (ICD). GIAC 2005; 8:1–58.
- Schimpf R, Wolpert C, Bianchi F, et al. Congenital short QT syndrome and implantable cardioverter defibrillator treatment: inherent risk for inappropriate shock delivery. J Cardiovasc Electrophysiol 2003; 14:1273–1277.
- Gaita F, Giustetto C, Bianchi F, et al. Short QT syndrome: pharmacological treatment. J Am Coll Cardiol 2004; 43:1494–1499.
- Giustetto C, Schimpf R, Mazzanti A, et al. Long-term follow-up of patients with short QT syndrome. J Am Coll Cardiol 2011; 58:587–595.
- The Short QT Syndrome http://www.shortqtsyndrome.org/short_qt_history.htm. Accessed October 30, 2012.
- Gussak I, Brugada P, Brugada J, et al. Idiopathic short QT interval: a new clinical syndrome? Cardiology 2000; 94:99–102.
- Giustetto C, Di Monte F, Wolpert C, et al. Short QT syndrome: clinical findings and diagnostic-therapeutic implications. Eur Heart J 2006; 27:2440–2447.
- Viskin S, Zeltser D, Ish-Shalom M, et al. Is idiopathic ventricular fibrillation a short QT syndrome? Comparison of QT intervals of patients with idiopathic ventricular fibrillation and healthy controls. Heart Rhythm 2004; 1:587–591.
- Anttonen O, Junttila MJ, Maury P, et al. Differences in twelve-lead electrocardiogram between symptomatic and asymptomatic subjects with short QT interval. Heart Rhythm 2009; 6:267–271.
- Redpath CJ, Green MS, Birnie DH, Gollob MH. Rapid genetic testing facilitating the diagnosis of short QT syndrome. Can J Cardiol 2009; 25:e133–e135.
- Wolpert C, Schimpf R, Giustetto C, et al. Further insights into the effect of quinidine in short QT syndrome caused by a mutation in HERG. J Cardiovasc Electrophysiol 2005; 16:54–58.
- Anttonen O, Junttila MJ, Rissanen H, Reunanen A, Viitasalo M, Huikuri HV. Prevalence and prognostic significance of short QT interval in a middle-aged Finnish population. Circulation 2007; 116:714–720.
- Funada A, Hayashi K, Ino H, et al. Assessment of QT intervals and prevalence of short QT syndrome in Japan. Clin Cardiol 2008; 31:270–274.
- Mason JW, Ramseth DJ, Chanter DO, Moon TE, Goodman DB, Mendzelevski B. Electrocardiographic reference ranges derived from 79,743 ambulatory subjects. J Electrocardiol 2007; 40:228–234.
- Kobza R, Roos M, Niggli B, et al. Prevalence of long and short QT in a young population of 41,767 predominantly male Swiss conscripts. Heart Rhythm 2009; 6:652–657.
- Itoh H, Sakaguchi T, Ashihara T, et al. A novel KCNH2 mutation as a modifier for short QT interval. Int J Cardiol 2009; 137:83–85.
- Vincent GM, Timothy KW, Leppert M, Keating M. The spectrum of symptoms and QT intervals in carriers of the gene for the long-QT syndrome. N Engl J Med 1992; 327:846–852.
- Schwartz PJ. Idiopathic long QT syndrome: progress and questions. Am Heart J 1985; 109:399–411.
- Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria for the long QT syndrome. An update. Circulation 1993; 88:782–784.
- Bjerregaard P, Nallapaneni H, Gussak I. Short QT interval in clinical practice. J Electrocardiol 2010; 43:390–395.
- Maury P, Extramiana F, Sbragia P, et al. Short QT syndrome. Update on a recent entity. Arch Cardiovasc Dis 2008; 101:779–786.
- Kontny F, Dale J. Self-terminating idiopathic ventricular fibrillation presenting as syncope: a 40-year follow-up report. J Intern Med 1990; 227:211–213.
- Cheng TO. Digitalis administration: an underappreciated but common cause of short QT interval. Circulation 2004; 109:e152.
- Hancox JC, Choisy SC, James AF. Short QT interval linked to androgen misuse: wider significance and possible basis. Ann Noninvasive Electrocardiol 2009; 14:311–312.
- Naschitz J, Fields M, Isseroff H, Sharif D, Sabo E, Rosner I. Shortened QT interval: a distinctive feature of the dysautonomia of chronic fatigue syndrome. J Electrocardiol 2006; 39:389–394.
- Bjerregaard P, Collier JL, Gussak I. Upper limits of QT/QTc intervals in the short QT syndrome. Review of the world-wide short QT syndrome population and 3 new USA families. Heart Rhythm 2008; 5:AB43.
- Gollob MH, Redpath CJ, Roberts JD. The short QT syndrome: proposed diagnostic criteria. J Am Coll Cardiol 2011; 57:802–812.
- Shih HT. Anatomy of the action potential in the heart. Tex Heart Inst J 1994; 21:30–41.
- Brugada R, Hong K, Dumaine R, et al. Sudden death associated with short-QT syndrome linked to mutations in HERG. Circulation 2004; 109:30–35.
- Bellocq C, van Ginneken AC, Bezzina CR, et al. Mutation in the KCNQ1 gene leading to the short QT-interval syndrome. Circulation 2004; 109:2394–2397.
- Priori SG, Pandit SV, Rivolta I, et al. A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene. Circ Res 2005; 96:800–807.
- Antzelevitch C, Pollevick GD, Cordeiro JM, et al. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation 2007; 115:442–449.
- Antzelevitch C. Heterogeneity and cardiac arrhythmias: an overview. Heart Rhythm 2007; 4:964–972.
- Lunati M, Bongiorni MG, Boriani G, et al. Linee guida AIAC 2006 all’impianto di pacemaker, dispositivi per la resincronizzazione cardiaca (CRT) e defibrillatori automatici impiantabili (ICD). GIAC 2005; 8:1–58.
- Schimpf R, Wolpert C, Bianchi F, et al. Congenital short QT syndrome and implantable cardioverter defibrillator treatment: inherent risk for inappropriate shock delivery. J Cardiovasc Electrophysiol 2003; 14:1273–1277.
- Gaita F, Giustetto C, Bianchi F, et al. Short QT syndrome: pharmacological treatment. J Am Coll Cardiol 2004; 43:1494–1499.
- Giustetto C, Schimpf R, Mazzanti A, et al. Long-term follow-up of patients with short QT syndrome. J Am Coll Cardiol 2011; 58:587–595.
KEY POINTS
- Short QT syndrome is a genetic disease described initially in young patients who had atrial fibrillation or who died suddenly with no apparent structural heart disease.
- The diagnosis is established by the finding of a short QT interval. However, other factors including personal and family history are also important in establishing the diagnosis.
- The current recommendations for managing patients with short QT syndrome are not evidence-based. We encourage consultation with centers that have special interest in QT-interval-related disorders.
- Placement of an implantable cardioverter-defibrillator is considered the standard of care, especially in survivors of sudden cardiac death, ventricular fibrillation, or ventricular tachycardia. Unfortunately, a higher incidence of inappropriate shocks adds to the challenges of managing this potentially deadly disease.
Advanced heart failure: Transplantation, LVADs, and beyond
Patients with advanced heart failure far outnumber the hearts available for transplantation. Partly as a consequence of this shortage, left-ventricular assist devices (LVADs) are being used more widely.
This article is an update on options for managing severe, advanced heart failure, with special attention to new developments and continuing challenges in heart transplantation and LVADs.
THE PREVALENCE OF HEART FAILURE
About 2.6% of the US population age 20 and older have heart failure—some 5.8 million people. Of these, about half have systolic heart failure.1 Patients with systolic heart failure can be classified by degree of severity under two systems:
The New York Heart Association (NYHA) classifies patients by their functional status, from I (no limitation in activities) to IV (symptoms at rest). NYHA class III (symptoms with minimal exertion) is sometimes further broken down into IIIa and IIIb, with the latter defined as having a recent history of dyspnea at rest.
The joint American College of Cardiology and American Heart Association (ACC/AHA) classification uses four stages, from A (high risk of developing heart failure, ie, having risk factors such as family history of heart disease, hypertension, or diabetes) to D (advanced heart disease despite treatment). Patients in stage D tend to be recurrently hospitalized despite cardiac resynchronization therapy and drug therapy, and they cannot be safely discharged without specialized interventions. The options for these patients are limited: either end-of-life care or extraordinary measures such as heart transplantation, long-term treatment with inotropic drugs, permanent mechanical circulatory support, or experimental therapies.2
The estimated number of people in ACC/AHA stage D or NYHA class IV is 15,600 to 156,000. The approximate number of heart transplants performed in the United States each year is 2,100.3
WHICH AMBULATORY PATIENTS ARE MOST AT RISK?
The range for the estimated number of patients with advanced heart failure (NYHA class IIIb or IV) is wide (see above) because these patients may be hard to recognize. The most debilitated patients are obvious: they tend to be in the intensive care unit with end-organ failure. However, it is a challenge to recognize patients at extremely high risk who are still ambulatory.
The European Society of Cardiology4 developed a definition of advanced chronic heart failure that can help identify patients who are candidates for the transplant list and for an LVAD. All the following features must be present despite optimal therapy that includes diuretics, inhibitors of the renin-angiotensin-aldosterone system, and beta-blockers, unless these are poorly tolerated or contraindicated, and cardiac resynchronization therapy if indicated:
- Severe symptoms, with dyspnea or fatigue at rest or with minimal exertion (NYHA class III or IV)
- Episodes of fluid retention (pulmonary or systemic congestion, peripheral edema) or of reduced cardiac output at rest (peripheral hypoperfusion)
- Objective evidence of severe cardiac dysfunction (at least one of the following): left ventricular ejection fraction less than 30%, pseudonormal or restrictive mitral inflow pattern on Doppler echocardiography, high left or right ventricular filling pressure (or both left and right filling pressures), and elevated B-type natriuretic peptides
- Severely impaired functional capacity demonstrated by one of the following: inability to exercise, 6-minute walk test distance less than 300 m (or less in women or patients who are age 75 and older), or peak oxygen intake less than 12 to 14 mL/kg/min
- One or more hospitalizations for heart failure in the past 6 months.
Treadmill exercise time is an easily performed test. Hsich et al5 found that the longer patients can walk, the lower their risk of death, and that this variable is about as predictive of survival in patients with systolic left ventricular dysfunction as peak oxygen consumption, which is much more cumbersome to measure.
The Seattle Heart Failure Model gives an estimate of prognosis for ambulatory patients with advanced heart failure. Available at http://depts.washington.edu/shfm/, it is based on age, sex, NYHA class, weight, ejection fraction, blood pressure, medications, a few laboratory values, and other clinical information. The model has been validated in numerous cohorts,6 but it may underestimate risk and is currently being tested in clinical trials (REVIVE-IT and ROADMAP; see at www.clinicaltrials.gov).
Recurrent hospitalization is a simple predictor of risk. A study of about 7,000 patients worldwide found that after hospitalization with acute decompensated heart failure, the strongest predictor of death within 6 months was readmission for any reason within 30 days of the index hospitalization (Starling RC, unpublished observation, 2011). Any patient with heart failure who is repeatedly hospitalized should have a consultation with a heart failure specialist.
INOTROPIC THERAPY FOR BRIDGING
Inotropic drugs, which include intravenous dobutamine (Dobutrex) and milrinone (Primacor), are used to help maintain end-organ function until a patient can obtain a heart transplant or LVAD.
Inotropic therapy should not be viewed as an alternative to heart transplantation or device implantation. We inform patients that inotropic therapy is purely palliative and may actually increase the risk of death, which is about 50% at 6 months and nearly 100% at 1 year. A patient on inotropic therapy who is not a candidate for a transplant or for an assist device should be referred to a hospice program.7
CARDIAC TRANSPLANTATION: SUCCESSES, CHALLENGES
Survival rates after heart transplantation are now excellent. The 1-year survival rate is about 90%, the 5-year rate is about 70%, but only about 20% survive 20 years or longer.8,9 The prognosis is not as good as for combined heart-lung transplantation patients.
Age is an important factor and is a contentious issue: some medical centers will not offer transplantation to patients over age 65. Others regard age as just another risk factor, like renal dysfunction or diabetes.
Quality of life after heart transplantation is excellent: patients are usually able to return to work, regardless of their profession.
The leading cause of death after heart transplantation is malignancy, followed by coronary artery vasculopathy, then by graft failure. Some patients develop left ventricular dysfunction and heart failure of unknown cause. Others develop antibody-mediated rejection; in recent years this has been more promptly recognized, but treatment remains a challenge.
Acute rejection, which used to be one of the main causes of death, now has an extremely low incidence because of modern drug therapies. In a US observational study currently being conducted in about 200 patients receiving a heart transplant (details on CTOT-05 at www.clinicaltrials.gov), the incidence of moderate rejection during the first year is less than 10% (Starling RC, unpublished observation). But several concerns remain.
Adverse effects of immunosuppressive drugs continue to be problematic. These include infection, malignancy, osteoporosis, chronic kidney toxicity, hypertension, and neuropathy.
Renal dysfunction is one of the largest issues. About 10% of heart transplant recipients develop stage 4 kidney disease (with a glomerular filtration rate < 30 mL/min) and need kidney transplantation or renal replacement therapy because of the use of calcineurin inhibitors for immunosuppression.10
Coronary artery vasculopathy was the largest problem when heart transplantation began and continues to be a major concern and focus of research.11,12 Case 1 (below) is an example of the problem.
Case 1: Poor outcome despite an ideal scenario
A 57-year-old businessman had dilated cardiomyopathy and progressive heart failure for 10 years. He was listed for transplantation in 2008 and was given an LVAD (HeartMate II, Thoratec Corp, Pleasanton, CA) as a bridge until a donor heart became available.
In 2009, he received a heart transplant under ideal conditions: the donor was a large 30-year-old man who died of a gunshot wound to the head in the same city in which the patient and transplant hospital were located. Cardiopulmonary resuscitation was not performed, and the cold ischemic time was just a little more than 3 hours. Immune indicators were ideal with a negative prospective cross-match.
Laboratory results after transplantation included creatinine 1.7 mg/dL (normal 0.6–1.2 mg/dL), low-density lipoprotein cholesterol 75 mg/dL, high-density lipoprotein cholesterol 64 mg/dL, and triglycerides 90 mg/dL.
The patient was given immunosuppressive therapy with cyclosporine (Neoral), mycophenolate (CellCept), and prednisone. Because his creatinine level was high, he was also perioperatively given basiliximab (Simulect), a monoclonal antibody to the alpha chain (CD25) of the interleukin-2 receptor. (In a patient who has poor renal function, basilixumab may help by enabling us to delay the use of calcineurin inhibitors.) He also received simvastatin (Zocor) 10 mg.
Per Cleveland Clinic protocol, he underwent 13 biopsy procedures during his first year, and each was normal (grade 0 or 1R). Evaluation by cardiac catheterization at 1 year showed some irregularities in the left anterior descending artery, but a stent was not deemed necessary. Also, per protocol, he underwent intravascular ultrasonography, which revealed abnormal thickness in the intima and media, indicating that coronary artery disease was developing, although it was nonobstructive.
Two months after this checkup, the patient collapsed and suddenly died while shopping. At autopsy, his left anterior descending artery was found to be severely obstructed.
Coronary artery vasculopathy is still a major problem
This case shows that coronary artery vasculopathy may develop despite an ideal transplantation scenario. It remains a large concern and a focus of research.
Coronary vasculopathy develops in 30% to 40% of heart transplant recipients within 5 years, and the incidence has not been reduced by much over the years. However, probably fewer than 5% of these patients die or even need bypass surgery or stenting, and the problem is managed the same as native atherosclerosis. We perform routine annual cardiac catheterizations or stress tests, or both, and place stents in severely blocked arteries.
THE DONOR SHORTAGE: CHANGING HOW HEARTS ARE ALLOCATED
The number of patients receiving a heart transplant in the United States—about 2,000 per year—has not increased in the past decade. The European Union also has great difficulty obtaining hearts for people in need, and almost every transplant candidate there gets mechanical support for some time. The gap between those listed for transplant and the number transplanted each year continues to widen in both the United States and Europe.
All transplant candidates are assigned a status by the United Network of Organ Sharing (UNOS) based on their medical condition. The highest status, 1A, goes to patients who are seriously ill, in the hospital, on high doses of inotropic drugs (specific dosages are defined) and mechanical circulatory support such as an LVAD, and expected to live less than 1 month without a transplant. Status 1B patients are stable on lower-dose inotropic therapy or on mechanical support, and can be in the hospital or at home. Status 2 patients are stable and ambulatory and are not on inotropic drugs.
In July 2006, UNOS changed the rules on how patients are prioritized for obtaining an organ. The new rules are based both on severity of illness (see above) and geographic proximity to the donor heart—local, within 500 miles (“zone A”) or within 500 to 1,000 miles (“zone B”). The order of priority for donor hearts is:
- Local, status 1A
- Local, status 1B
- Zone A, status 1A
- Zone A, status 1B
- Local, status 2
- Zone B, status 1A
- Zone B, status 1B
- Zone A, status 2.
As a result of the change, donor hearts that become available in a particular hospital do not necessarily go to a patient in that state. Another result is that status 2 patients, who were previously the most common transplant recipients, now have much less access because all status 1 patients within 500 miles are given higher priority. Since the change, only 8% of hearts nationwide go to status 2 patients, which is 67% fewer than before. At the same time, organs allocated to status 1A patients have increased by 26%, and their death rates have fallen.3
The new allocation system is a positive change for the sickest patients, providing quicker access and a reduction in waiting-list mortality.13 The drawback is that status 2 patients who are less ill are less likely to ever receive an organ until their condition worsens.
Heart transplant outcomes are publicly reported
The Scientific Registry of Transplant Recipients publicly reports heart transplant outcomes (www.srtr.org). For any transplant center, the public can learn the number of patients waiting for a transplant, the death rate on the waiting list, the number of transplants performed in the previous 12 months, the waiting time in months, and observed and risk-adjusted expected survival rates. A center that deviates from the expected survival rates by 10% or more may be audited and could lose its certification.
Also listed on the Web site is the percentage of patients who receive a support device before receiving a transplant. This can vary widely between institutions and may reflect the organ availability at the transplant center (waiting times) or the preferences and expertise of the transplantation team. We believe that the mortality rate on the waiting list will be reduced with appropriate use of LVADs as a bridge to transplantation when indicated. We have now transitioned to the use of the improved continuous-flow LVADs and rarely maintain patients on continuous inotropic therapy at home to await a donor organ.
MECHANICAL CIRCULATORY SUPPORT: BRIDGE OR DESTINATION?
Mechanical circulatory support devices are increasingly being used to sustain patients with advanced heart failure. Currently at Cleveland Clinic, more LVADs are implanted than hearts are transplanted.
Mechanical circulatory support is indicated for patients who are listed for transplant to keep them functioning as well as possible while they are waiting (bridge to transplant). For others it is “destination therapy”: they are not candidates for a transplant, but a device may improve and prolong the rest of their life.
Case 2: A good outcome despite a poor prognosis
A 71-year-old man was rejected for transplantation by his local hospital because of his age and also because he had pulmonary artery hypertension (78/42 mm Hg; reference range 15–30/5–15 mm Hg) and creatinine elevation (3.0 mg/dL; reference range 0.6–1.5 mg/dL). Nevertheless, he did well on a mechanical device and was accepted for transplantation by Cleveland Clinic. He received a transplant and is still alive and active 14 years later.
Comment. Determining that a patient is not a good transplantation candidate is often impossible. Putting the patient on mechanical support for a period of time can often help clarify whether transplantation is advisable. Probably most patients who receive mechanical support do so as a bridge to decision: most are acutely ill and many have organ dysfunction, pulmonary hypertension, and renal insufficiency. After a period of support, they can be assessed for suitability for transplantation.
LVADs continue to improve
Many devices are available for mechanical circulatory support.14 In addition to LVADs, there are right-ventricular assist devices (RVADs), and devices that simultaneously support both ventricles (BiVADs). Total artificial hearts are also available, as are acute temporary percutaneous devices. These temporary devices—TandemHeart (CardiacAssist, Pittsburgh, PA) and Impella (Abiomed, Danvers, MD)—can be used before a long-term mechanical device can be surgically implanted.
LVADs are of three types:
- Pulsatile volume-displacement pumps, which mimic the pumping action of the natural heart. These early devices were large and placed in the abdomen.
- Continuous axial-flow pumps, which do not have a “heartbeat.” These are quieter and lighter than the early pumps, and use a turbine that spins at 8,000 to 10,000 rpm.
- Continuous centrifugal-flow pumps. These have a rotor spinning at 2,000 to 3,000 rpm, and most of them are magnetically powered and suspended.
The superiority of LVADs over medical therapy was clearly shown even in early studies that used pulsatile LVADs.15 The results of such studies and the increased durability of the devices have led to their rapidly expanded use.
The newer continuous-flow pumps offer significant improvements over the old pulsatile-flow pumps, being smaller, lighter, quieter, and more durable (Table 1). A 2007 study of 133 patients on a continuous axial-flow LVAD (HeartMate II) found that 76% were still alive after 6 months, and patients had significant improvement in functional status and quality of life.16 In a postapproval study based on registry data, HeartMate II was found superior to pulsatile pumps in terms of survival up to 12 months, percentage of patients reaching transplant, and cardiac recovery. Adverse event rates were similar or lower for HeartMate II.17
Another study compared a continuousflow with a pulsatile-flow LVAD for patients who were ineligible for transplantation. Survival at 2 years was 58% with the continuousflow device vs 24% with the pulsatile-flow device (P = .008).18 Since then, postmarket data of patients who received an LVAD showed that 85% are still alive at 1 year.19 This study can be viewed as supporting the use of LVADs as destination therapy.
Quality of life for patients receiving an LVAD has been excellent. When biventricular pacemakers for resynchronization therapy first became available, distances on the 6-minute walk test improved by 39 m, which was deemed a big improvement. LVAD devices have increased the 6-minute walk distance by 156 m.20
Adverse events with LVADs have improved, but continue to be of concern
Infections can arise in the blood stream, in the device pocket, or especially where the driveline exits the skin. As devices have become smaller, driveline diameters have become smaller as well, allowing for a better seal at the skin and making this less of a problem. Some centers report the incidence of driveline infections as less than 20%, but they continue to be a focus of concern.18
Stroke rates continue to improve, although patients still require intensive lifelong anticoagulation. The target international normalized ratio varies by device manufacturer, ranging from 1.7 to 2.5.
Bleeding. Acquired von Willebrand syndrome can develop in patients who have an LVAD, with the gastrointestinal system being the most frequent site of bleeding.21
Device thrombosis occurs very rarely (2%–3%) but is very serious and may require pump exchange.
Mechanical malfunction. As duration of therapy lengthens, problems are arising with aging devices, such as broken wires or short circuits. New-generation pumps have markedly improved durability and reliability.
Good data are kept on device outcomes
The Interagency for Mechanically Assisted Circulatory Support (INTERMACS) maintains a national registry of patients with a mechanical circulatory support device to treat advanced heart failure. It was jointly established in 2006 by the National Heart, Lung, and Blood Institute, Centers for Medicare and Medicaid Services (CMS), the US Food and Drug Administration, and others. Reporting to INTERMACS is required for CMS reimbursement.
The INTERMACS database now has about 4,500 patients at 126 medical centers and is yielding useful information that is published in annual reports.22 The 2011 report focused on the experience with mechanical circulatory support as destination therapy and showed that patients who receive continuousflow pumps have significantly better survival rates than those with pulsatile-flow pumps.23 An earlier report showed that the level of illness at the time of implantation predicts survival24; this information now drives cardiologists to try to improve patient status with a temporary support device or intra-aortic balloon pump before implanting a durable device. The sickest patients (INTERMACS level 1) have the poorest outcomes, and centers now do fewer implantations in patients in this category. We have learned this important lesson from the INTERMACS registry.
The new devices have received a lot of media attention, and patient accrual has increased steadily as the devices have been approved.
On November 20, 2012, the US Food and Drug Administration approved the HeartWare Ventricular Assist System (HeartWare, Framingham, MA) for heart failure patients awaiting a transplant.
FUTURE DIRECTIONS
PROCEED II is an ongoing global clinical trial comparing the outcomes with donor hearts transported in standard cold storage to those transported in an experimental transport device that pumps the heart under physiologic conditions. If proven effective, this device could allow long-distance transport of donor hearts and expand the donor population.
A prospective, randomized study is now enrolling patients to evaluate induction therapy with rituximab (Rituxan) plus conventional immunosuppression (tacrolimus [Prograf], mycophenolate, steroid taper) vs placebo induction plus conventional immunosuppression. The study will enroll 400 patients (200 to each treatment arm) at 25 sites and will have a 36-month accrual period with 12-month follow-up (see http://clinicaltrials.gov/show/NCT01278745). The study is based on data in primates that found that eliminating B cells with an anti-CD20 drug before transplantation markedly reduced the incidence of coronary artery vasculopathy.
- Lloyd-Jones D, Adams RJ, Brown TM, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2010 update: a report from the American Heart Association. Circulation 2010; 1221:e46–e215.
- Jessup M, Abraham WT, Casey DE, et al. 2009 focused update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 2009; 119:1977–2016.
- 2009 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1999–2008. U.S. Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation, Rockville, MD.
- Metra M, Ponikowski P, Dickstein K, et al; Heart Failure Association of the European Society of Cardiology. Advanced chronic heart failure: a position statement from the Study Group on Advanced Heart Failure of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2007; 9:684–694.
- Hsich E, Gorodeski EZ, Starling RC, Blackstone EH, Ishwaran H, Lauer MS. Importance of treadmill exercise time as an initial prognostic screening tool in patients with systolic left ventricular dysfunction. Circulation 2009; 119:3189–3197.
- Gorodeski EZ, Chu EC, Chow CH, Levy WC, Hsich E, Starling RC. Application of the Seattle Heart Failure Model in ambulatory patients presented to an advanced heart failure therapeutics committee. Circ Heart Fail 2010; 3:706–714.
- Gorodeski EZ, Chu EC, Reese JR, Shishehbor MH, Hsich E, Starling RC. Prognosis on chronic dobutamine or milrinone infusions for stage D heart failure. Circ Heart Fail 2009; 2:320–324.
- Taylor DO, Stehlik J, Edwards LB, et al. Registry of the International Society for Heart and Lung Transplantation: Twenty-sixth official adult heart transplant report—2009. J Heart Lung Transplant 2009; 28:1007–1022.
- Stehlik J, Edwards LB, Kucheryavaya AY, et al. The registry of the International Society for Heart and Lung Transplantation: twenty-seventh official adult heart transplant report—2010. J Heart Lung Transplant 2010; 29:1089–1103.
- Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med 2003; 349:931–940.
- Kobashigawa JA, Katznelson S, Laks H, et al. Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med 1999; 340:272–277. Erratum in: N Engl J Med 1999; 340:976.
- Eisen HJ, Tuzcu EM, Dorent R, et al. Everolimus for the prevention of allograft rejection and vasculopathy in cardiactransplant recipients. N Engl J Med 2003; 349:847–858.
- Singh TP, Almond CS, Taylor DO, Graham DA. Decline in heart transplant wait list mortality in the United States following broader regional sharing of donor hearts. Circ Heart Fail 2012; 5:249–258.
- Baughman KL, Jarcho JA. Bridge to life—cardiac mechanical support. N Engl J Med 2007; 357:846–849.
- Rose EA, Gelijns AC, Moskowitz AJ, et al; Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) Study Group. Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med 2001; 345:1435–1443.
- Miller LW, Pagani FD, Russell SD, et al; HeartMate II Clinical Investigators. Use of a continuous-flow device in patients awaiting heart transplantation. N Engl J Med 2007; 357:885–896.
- Starling RC, Naka Y, Boyle AJ, et al. Results of the post-U.S. Food and Drug Administration-approval study with a continuous flow left ventricular assist device as a bridge to heart transplantation: a prospective study using the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support). J Am Coll Cardiol 2011; 57:1890–1898.
- Slaughter MS, Rogers JG, Milano CA, et al; HeartMate II Investigators. Advanced heart failure treated with continuous-flow left ventricular assist device. N Engl J Med 2009; 361:2241–2251.
- John R, Naka Y, Smedira NG, et al. Continuous flow left ventricular assist device outcomes in commercial use compared with the prior clinical trial. Ann Thorac Surg 2011; 92:1406–1413.
- Starling RC. Improved quantity and quality of life: a winning combination to treat advanced heart failure. J Am Coll Cardiol 2010; 55:1835–1836.
- Uriel N, Pak SW, Jorde UP, et al. Acquired von Willebrand syndrome after continuous-flow mechanical device support contributes to a high prevalence of bleeding during long-term support and at the time of transplantation. J Am Coll Cardiol 2010; 56:1207–1213.
- Kirklin JK, Naftel DC, Kormos RL, et al. The fourth INTERMACS annual report: 4,000 implants and counting. J Heart Lung Transplant 2012; 31:117–126.
- Kirklin JK, Naftel DC, Kormos RL, et al. Third INTERMACS Annual Report: the evolution of destination therapy in the United States. J Heart Lung Transplant 2011; 30:115–123.
- Kirklin JK, Naftel DC, Kormos RL, et al. Second INTERMACS annual report: more than 1,000 primary left ventricular assist device implants. J Heart Lung Transplant 2010; 29:1–10.
SUGGESTED READING
Costanzo MR, Dipchand A, Starling R, et al; International Society of Heart and Lung Transplantation Guidelines. The International Society of Heart and Lung Transplantation guidelines for the care of heart transplant recipients. J Heart Lung Transplant 2010; 29:914–956.
Mehra MR, Kobashigawa J, Starling R, et al. Listing criteria for heart transplantation: International Society for Heart and Lung Transplantation guidelines for the care of cardiac transplant candidates–2006. J Heart Lung Transplant 2006; 25:1024–1042.
Slaughter MS, Pagani FD, Rogers JG, et al; HeartMate II Clinical Investigators. Clinical management of continuous flow left ventricular assist devices in advanced heart failure. J Heart Lung Transplant 2010; 29(4 suppl):S1–S39.
Patients with advanced heart failure far outnumber the hearts available for transplantation. Partly as a consequence of this shortage, left-ventricular assist devices (LVADs) are being used more widely.
This article is an update on options for managing severe, advanced heart failure, with special attention to new developments and continuing challenges in heart transplantation and LVADs.
THE PREVALENCE OF HEART FAILURE
About 2.6% of the US population age 20 and older have heart failure—some 5.8 million people. Of these, about half have systolic heart failure.1 Patients with systolic heart failure can be classified by degree of severity under two systems:
The New York Heart Association (NYHA) classifies patients by their functional status, from I (no limitation in activities) to IV (symptoms at rest). NYHA class III (symptoms with minimal exertion) is sometimes further broken down into IIIa and IIIb, with the latter defined as having a recent history of dyspnea at rest.
The joint American College of Cardiology and American Heart Association (ACC/AHA) classification uses four stages, from A (high risk of developing heart failure, ie, having risk factors such as family history of heart disease, hypertension, or diabetes) to D (advanced heart disease despite treatment). Patients in stage D tend to be recurrently hospitalized despite cardiac resynchronization therapy and drug therapy, and they cannot be safely discharged without specialized interventions. The options for these patients are limited: either end-of-life care or extraordinary measures such as heart transplantation, long-term treatment with inotropic drugs, permanent mechanical circulatory support, or experimental therapies.2
The estimated number of people in ACC/AHA stage D or NYHA class IV is 15,600 to 156,000. The approximate number of heart transplants performed in the United States each year is 2,100.3
WHICH AMBULATORY PATIENTS ARE MOST AT RISK?
The range for the estimated number of patients with advanced heart failure (NYHA class IIIb or IV) is wide (see above) because these patients may be hard to recognize. The most debilitated patients are obvious: they tend to be in the intensive care unit with end-organ failure. However, it is a challenge to recognize patients at extremely high risk who are still ambulatory.
The European Society of Cardiology4 developed a definition of advanced chronic heart failure that can help identify patients who are candidates for the transplant list and for an LVAD. All the following features must be present despite optimal therapy that includes diuretics, inhibitors of the renin-angiotensin-aldosterone system, and beta-blockers, unless these are poorly tolerated or contraindicated, and cardiac resynchronization therapy if indicated:
- Severe symptoms, with dyspnea or fatigue at rest or with minimal exertion (NYHA class III or IV)
- Episodes of fluid retention (pulmonary or systemic congestion, peripheral edema) or of reduced cardiac output at rest (peripheral hypoperfusion)
- Objective evidence of severe cardiac dysfunction (at least one of the following): left ventricular ejection fraction less than 30%, pseudonormal or restrictive mitral inflow pattern on Doppler echocardiography, high left or right ventricular filling pressure (or both left and right filling pressures), and elevated B-type natriuretic peptides
- Severely impaired functional capacity demonstrated by one of the following: inability to exercise, 6-minute walk test distance less than 300 m (or less in women or patients who are age 75 and older), or peak oxygen intake less than 12 to 14 mL/kg/min
- One or more hospitalizations for heart failure in the past 6 months.
Treadmill exercise time is an easily performed test. Hsich et al5 found that the longer patients can walk, the lower their risk of death, and that this variable is about as predictive of survival in patients with systolic left ventricular dysfunction as peak oxygen consumption, which is much more cumbersome to measure.
The Seattle Heart Failure Model gives an estimate of prognosis for ambulatory patients with advanced heart failure. Available at http://depts.washington.edu/shfm/, it is based on age, sex, NYHA class, weight, ejection fraction, blood pressure, medications, a few laboratory values, and other clinical information. The model has been validated in numerous cohorts,6 but it may underestimate risk and is currently being tested in clinical trials (REVIVE-IT and ROADMAP; see at www.clinicaltrials.gov).
Recurrent hospitalization is a simple predictor of risk. A study of about 7,000 patients worldwide found that after hospitalization with acute decompensated heart failure, the strongest predictor of death within 6 months was readmission for any reason within 30 days of the index hospitalization (Starling RC, unpublished observation, 2011). Any patient with heart failure who is repeatedly hospitalized should have a consultation with a heart failure specialist.
INOTROPIC THERAPY FOR BRIDGING
Inotropic drugs, which include intravenous dobutamine (Dobutrex) and milrinone (Primacor), are used to help maintain end-organ function until a patient can obtain a heart transplant or LVAD.
Inotropic therapy should not be viewed as an alternative to heart transplantation or device implantation. We inform patients that inotropic therapy is purely palliative and may actually increase the risk of death, which is about 50% at 6 months and nearly 100% at 1 year. A patient on inotropic therapy who is not a candidate for a transplant or for an assist device should be referred to a hospice program.7
CARDIAC TRANSPLANTATION: SUCCESSES, CHALLENGES
Survival rates after heart transplantation are now excellent. The 1-year survival rate is about 90%, the 5-year rate is about 70%, but only about 20% survive 20 years or longer.8,9 The prognosis is not as good as for combined heart-lung transplantation patients.
Age is an important factor and is a contentious issue: some medical centers will not offer transplantation to patients over age 65. Others regard age as just another risk factor, like renal dysfunction or diabetes.
Quality of life after heart transplantation is excellent: patients are usually able to return to work, regardless of their profession.
The leading cause of death after heart transplantation is malignancy, followed by coronary artery vasculopathy, then by graft failure. Some patients develop left ventricular dysfunction and heart failure of unknown cause. Others develop antibody-mediated rejection; in recent years this has been more promptly recognized, but treatment remains a challenge.
Acute rejection, which used to be one of the main causes of death, now has an extremely low incidence because of modern drug therapies. In a US observational study currently being conducted in about 200 patients receiving a heart transplant (details on CTOT-05 at www.clinicaltrials.gov), the incidence of moderate rejection during the first year is less than 10% (Starling RC, unpublished observation). But several concerns remain.
Adverse effects of immunosuppressive drugs continue to be problematic. These include infection, malignancy, osteoporosis, chronic kidney toxicity, hypertension, and neuropathy.
Renal dysfunction is one of the largest issues. About 10% of heart transplant recipients develop stage 4 kidney disease (with a glomerular filtration rate < 30 mL/min) and need kidney transplantation or renal replacement therapy because of the use of calcineurin inhibitors for immunosuppression.10
Coronary artery vasculopathy was the largest problem when heart transplantation began and continues to be a major concern and focus of research.11,12 Case 1 (below) is an example of the problem.
Case 1: Poor outcome despite an ideal scenario
A 57-year-old businessman had dilated cardiomyopathy and progressive heart failure for 10 years. He was listed for transplantation in 2008 and was given an LVAD (HeartMate II, Thoratec Corp, Pleasanton, CA) as a bridge until a donor heart became available.
In 2009, he received a heart transplant under ideal conditions: the donor was a large 30-year-old man who died of a gunshot wound to the head in the same city in which the patient and transplant hospital were located. Cardiopulmonary resuscitation was not performed, and the cold ischemic time was just a little more than 3 hours. Immune indicators were ideal with a negative prospective cross-match.
Laboratory results after transplantation included creatinine 1.7 mg/dL (normal 0.6–1.2 mg/dL), low-density lipoprotein cholesterol 75 mg/dL, high-density lipoprotein cholesterol 64 mg/dL, and triglycerides 90 mg/dL.
The patient was given immunosuppressive therapy with cyclosporine (Neoral), mycophenolate (CellCept), and prednisone. Because his creatinine level was high, he was also perioperatively given basiliximab (Simulect), a monoclonal antibody to the alpha chain (CD25) of the interleukin-2 receptor. (In a patient who has poor renal function, basilixumab may help by enabling us to delay the use of calcineurin inhibitors.) He also received simvastatin (Zocor) 10 mg.
Per Cleveland Clinic protocol, he underwent 13 biopsy procedures during his first year, and each was normal (grade 0 or 1R). Evaluation by cardiac catheterization at 1 year showed some irregularities in the left anterior descending artery, but a stent was not deemed necessary. Also, per protocol, he underwent intravascular ultrasonography, which revealed abnormal thickness in the intima and media, indicating that coronary artery disease was developing, although it was nonobstructive.
Two months after this checkup, the patient collapsed and suddenly died while shopping. At autopsy, his left anterior descending artery was found to be severely obstructed.
Coronary artery vasculopathy is still a major problem
This case shows that coronary artery vasculopathy may develop despite an ideal transplantation scenario. It remains a large concern and a focus of research.
Coronary vasculopathy develops in 30% to 40% of heart transplant recipients within 5 years, and the incidence has not been reduced by much over the years. However, probably fewer than 5% of these patients die or even need bypass surgery or stenting, and the problem is managed the same as native atherosclerosis. We perform routine annual cardiac catheterizations or stress tests, or both, and place stents in severely blocked arteries.
THE DONOR SHORTAGE: CHANGING HOW HEARTS ARE ALLOCATED
The number of patients receiving a heart transplant in the United States—about 2,000 per year—has not increased in the past decade. The European Union also has great difficulty obtaining hearts for people in need, and almost every transplant candidate there gets mechanical support for some time. The gap between those listed for transplant and the number transplanted each year continues to widen in both the United States and Europe.
All transplant candidates are assigned a status by the United Network of Organ Sharing (UNOS) based on their medical condition. The highest status, 1A, goes to patients who are seriously ill, in the hospital, on high doses of inotropic drugs (specific dosages are defined) and mechanical circulatory support such as an LVAD, and expected to live less than 1 month without a transplant. Status 1B patients are stable on lower-dose inotropic therapy or on mechanical support, and can be in the hospital or at home. Status 2 patients are stable and ambulatory and are not on inotropic drugs.
In July 2006, UNOS changed the rules on how patients are prioritized for obtaining an organ. The new rules are based both on severity of illness (see above) and geographic proximity to the donor heart—local, within 500 miles (“zone A”) or within 500 to 1,000 miles (“zone B”). The order of priority for donor hearts is:
- Local, status 1A
- Local, status 1B
- Zone A, status 1A
- Zone A, status 1B
- Local, status 2
- Zone B, status 1A
- Zone B, status 1B
- Zone A, status 2.
As a result of the change, donor hearts that become available in a particular hospital do not necessarily go to a patient in that state. Another result is that status 2 patients, who were previously the most common transplant recipients, now have much less access because all status 1 patients within 500 miles are given higher priority. Since the change, only 8% of hearts nationwide go to status 2 patients, which is 67% fewer than before. At the same time, organs allocated to status 1A patients have increased by 26%, and their death rates have fallen.3
The new allocation system is a positive change for the sickest patients, providing quicker access and a reduction in waiting-list mortality.13 The drawback is that status 2 patients who are less ill are less likely to ever receive an organ until their condition worsens.
Heart transplant outcomes are publicly reported
The Scientific Registry of Transplant Recipients publicly reports heart transplant outcomes (www.srtr.org). For any transplant center, the public can learn the number of patients waiting for a transplant, the death rate on the waiting list, the number of transplants performed in the previous 12 months, the waiting time in months, and observed and risk-adjusted expected survival rates. A center that deviates from the expected survival rates by 10% or more may be audited and could lose its certification.
Also listed on the Web site is the percentage of patients who receive a support device before receiving a transplant. This can vary widely between institutions and may reflect the organ availability at the transplant center (waiting times) or the preferences and expertise of the transplantation team. We believe that the mortality rate on the waiting list will be reduced with appropriate use of LVADs as a bridge to transplantation when indicated. We have now transitioned to the use of the improved continuous-flow LVADs and rarely maintain patients on continuous inotropic therapy at home to await a donor organ.
MECHANICAL CIRCULATORY SUPPORT: BRIDGE OR DESTINATION?
Mechanical circulatory support devices are increasingly being used to sustain patients with advanced heart failure. Currently at Cleveland Clinic, more LVADs are implanted than hearts are transplanted.
Mechanical circulatory support is indicated for patients who are listed for transplant to keep them functioning as well as possible while they are waiting (bridge to transplant). For others it is “destination therapy”: they are not candidates for a transplant, but a device may improve and prolong the rest of their life.
Case 2: A good outcome despite a poor prognosis
A 71-year-old man was rejected for transplantation by his local hospital because of his age and also because he had pulmonary artery hypertension (78/42 mm Hg; reference range 15–30/5–15 mm Hg) and creatinine elevation (3.0 mg/dL; reference range 0.6–1.5 mg/dL). Nevertheless, he did well on a mechanical device and was accepted for transplantation by Cleveland Clinic. He received a transplant and is still alive and active 14 years later.
Comment. Determining that a patient is not a good transplantation candidate is often impossible. Putting the patient on mechanical support for a period of time can often help clarify whether transplantation is advisable. Probably most patients who receive mechanical support do so as a bridge to decision: most are acutely ill and many have organ dysfunction, pulmonary hypertension, and renal insufficiency. After a period of support, they can be assessed for suitability for transplantation.
LVADs continue to improve
Many devices are available for mechanical circulatory support.14 In addition to LVADs, there are right-ventricular assist devices (RVADs), and devices that simultaneously support both ventricles (BiVADs). Total artificial hearts are also available, as are acute temporary percutaneous devices. These temporary devices—TandemHeart (CardiacAssist, Pittsburgh, PA) and Impella (Abiomed, Danvers, MD)—can be used before a long-term mechanical device can be surgically implanted.
LVADs are of three types:
- Pulsatile volume-displacement pumps, which mimic the pumping action of the natural heart. These early devices were large and placed in the abdomen.
- Continuous axial-flow pumps, which do not have a “heartbeat.” These are quieter and lighter than the early pumps, and use a turbine that spins at 8,000 to 10,000 rpm.
- Continuous centrifugal-flow pumps. These have a rotor spinning at 2,000 to 3,000 rpm, and most of them are magnetically powered and suspended.
The superiority of LVADs over medical therapy was clearly shown even in early studies that used pulsatile LVADs.15 The results of such studies and the increased durability of the devices have led to their rapidly expanded use.
The newer continuous-flow pumps offer significant improvements over the old pulsatile-flow pumps, being smaller, lighter, quieter, and more durable (Table 1). A 2007 study of 133 patients on a continuous axial-flow LVAD (HeartMate II) found that 76% were still alive after 6 months, and patients had significant improvement in functional status and quality of life.16 In a postapproval study based on registry data, HeartMate II was found superior to pulsatile pumps in terms of survival up to 12 months, percentage of patients reaching transplant, and cardiac recovery. Adverse event rates were similar or lower for HeartMate II.17
Another study compared a continuousflow with a pulsatile-flow LVAD for patients who were ineligible for transplantation. Survival at 2 years was 58% with the continuousflow device vs 24% with the pulsatile-flow device (P = .008).18 Since then, postmarket data of patients who received an LVAD showed that 85% are still alive at 1 year.19 This study can be viewed as supporting the use of LVADs as destination therapy.
Quality of life for patients receiving an LVAD has been excellent. When biventricular pacemakers for resynchronization therapy first became available, distances on the 6-minute walk test improved by 39 m, which was deemed a big improvement. LVAD devices have increased the 6-minute walk distance by 156 m.20
Adverse events with LVADs have improved, but continue to be of concern
Infections can arise in the blood stream, in the device pocket, or especially where the driveline exits the skin. As devices have become smaller, driveline diameters have become smaller as well, allowing for a better seal at the skin and making this less of a problem. Some centers report the incidence of driveline infections as less than 20%, but they continue to be a focus of concern.18
Stroke rates continue to improve, although patients still require intensive lifelong anticoagulation. The target international normalized ratio varies by device manufacturer, ranging from 1.7 to 2.5.
Bleeding. Acquired von Willebrand syndrome can develop in patients who have an LVAD, with the gastrointestinal system being the most frequent site of bleeding.21
Device thrombosis occurs very rarely (2%–3%) but is very serious and may require pump exchange.
Mechanical malfunction. As duration of therapy lengthens, problems are arising with aging devices, such as broken wires or short circuits. New-generation pumps have markedly improved durability and reliability.
Good data are kept on device outcomes
The Interagency for Mechanically Assisted Circulatory Support (INTERMACS) maintains a national registry of patients with a mechanical circulatory support device to treat advanced heart failure. It was jointly established in 2006 by the National Heart, Lung, and Blood Institute, Centers for Medicare and Medicaid Services (CMS), the US Food and Drug Administration, and others. Reporting to INTERMACS is required for CMS reimbursement.
The INTERMACS database now has about 4,500 patients at 126 medical centers and is yielding useful information that is published in annual reports.22 The 2011 report focused on the experience with mechanical circulatory support as destination therapy and showed that patients who receive continuousflow pumps have significantly better survival rates than those with pulsatile-flow pumps.23 An earlier report showed that the level of illness at the time of implantation predicts survival24; this information now drives cardiologists to try to improve patient status with a temporary support device or intra-aortic balloon pump before implanting a durable device. The sickest patients (INTERMACS level 1) have the poorest outcomes, and centers now do fewer implantations in patients in this category. We have learned this important lesson from the INTERMACS registry.
The new devices have received a lot of media attention, and patient accrual has increased steadily as the devices have been approved.
On November 20, 2012, the US Food and Drug Administration approved the HeartWare Ventricular Assist System (HeartWare, Framingham, MA) for heart failure patients awaiting a transplant.
FUTURE DIRECTIONS
PROCEED II is an ongoing global clinical trial comparing the outcomes with donor hearts transported in standard cold storage to those transported in an experimental transport device that pumps the heart under physiologic conditions. If proven effective, this device could allow long-distance transport of donor hearts and expand the donor population.
A prospective, randomized study is now enrolling patients to evaluate induction therapy with rituximab (Rituxan) plus conventional immunosuppression (tacrolimus [Prograf], mycophenolate, steroid taper) vs placebo induction plus conventional immunosuppression. The study will enroll 400 patients (200 to each treatment arm) at 25 sites and will have a 36-month accrual period with 12-month follow-up (see http://clinicaltrials.gov/show/NCT01278745). The study is based on data in primates that found that eliminating B cells with an anti-CD20 drug before transplantation markedly reduced the incidence of coronary artery vasculopathy.
Patients with advanced heart failure far outnumber the hearts available for transplantation. Partly as a consequence of this shortage, left-ventricular assist devices (LVADs) are being used more widely.
This article is an update on options for managing severe, advanced heart failure, with special attention to new developments and continuing challenges in heart transplantation and LVADs.
THE PREVALENCE OF HEART FAILURE
About 2.6% of the US population age 20 and older have heart failure—some 5.8 million people. Of these, about half have systolic heart failure.1 Patients with systolic heart failure can be classified by degree of severity under two systems:
The New York Heart Association (NYHA) classifies patients by their functional status, from I (no limitation in activities) to IV (symptoms at rest). NYHA class III (symptoms with minimal exertion) is sometimes further broken down into IIIa and IIIb, with the latter defined as having a recent history of dyspnea at rest.
The joint American College of Cardiology and American Heart Association (ACC/AHA) classification uses four stages, from A (high risk of developing heart failure, ie, having risk factors such as family history of heart disease, hypertension, or diabetes) to D (advanced heart disease despite treatment). Patients in stage D tend to be recurrently hospitalized despite cardiac resynchronization therapy and drug therapy, and they cannot be safely discharged without specialized interventions. The options for these patients are limited: either end-of-life care or extraordinary measures such as heart transplantation, long-term treatment with inotropic drugs, permanent mechanical circulatory support, or experimental therapies.2
The estimated number of people in ACC/AHA stage D or NYHA class IV is 15,600 to 156,000. The approximate number of heart transplants performed in the United States each year is 2,100.3
WHICH AMBULATORY PATIENTS ARE MOST AT RISK?
The range for the estimated number of patients with advanced heart failure (NYHA class IIIb or IV) is wide (see above) because these patients may be hard to recognize. The most debilitated patients are obvious: they tend to be in the intensive care unit with end-organ failure. However, it is a challenge to recognize patients at extremely high risk who are still ambulatory.
The European Society of Cardiology4 developed a definition of advanced chronic heart failure that can help identify patients who are candidates for the transplant list and for an LVAD. All the following features must be present despite optimal therapy that includes diuretics, inhibitors of the renin-angiotensin-aldosterone system, and beta-blockers, unless these are poorly tolerated or contraindicated, and cardiac resynchronization therapy if indicated:
- Severe symptoms, with dyspnea or fatigue at rest or with minimal exertion (NYHA class III or IV)
- Episodes of fluid retention (pulmonary or systemic congestion, peripheral edema) or of reduced cardiac output at rest (peripheral hypoperfusion)
- Objective evidence of severe cardiac dysfunction (at least one of the following): left ventricular ejection fraction less than 30%, pseudonormal or restrictive mitral inflow pattern on Doppler echocardiography, high left or right ventricular filling pressure (or both left and right filling pressures), and elevated B-type natriuretic peptides
- Severely impaired functional capacity demonstrated by one of the following: inability to exercise, 6-minute walk test distance less than 300 m (or less in women or patients who are age 75 and older), or peak oxygen intake less than 12 to 14 mL/kg/min
- One or more hospitalizations for heart failure in the past 6 months.
Treadmill exercise time is an easily performed test. Hsich et al5 found that the longer patients can walk, the lower their risk of death, and that this variable is about as predictive of survival in patients with systolic left ventricular dysfunction as peak oxygen consumption, which is much more cumbersome to measure.
The Seattle Heart Failure Model gives an estimate of prognosis for ambulatory patients with advanced heart failure. Available at http://depts.washington.edu/shfm/, it is based on age, sex, NYHA class, weight, ejection fraction, blood pressure, medications, a few laboratory values, and other clinical information. The model has been validated in numerous cohorts,6 but it may underestimate risk and is currently being tested in clinical trials (REVIVE-IT and ROADMAP; see at www.clinicaltrials.gov).
Recurrent hospitalization is a simple predictor of risk. A study of about 7,000 patients worldwide found that after hospitalization with acute decompensated heart failure, the strongest predictor of death within 6 months was readmission for any reason within 30 days of the index hospitalization (Starling RC, unpublished observation, 2011). Any patient with heart failure who is repeatedly hospitalized should have a consultation with a heart failure specialist.
INOTROPIC THERAPY FOR BRIDGING
Inotropic drugs, which include intravenous dobutamine (Dobutrex) and milrinone (Primacor), are used to help maintain end-organ function until a patient can obtain a heart transplant or LVAD.
Inotropic therapy should not be viewed as an alternative to heart transplantation or device implantation. We inform patients that inotropic therapy is purely palliative and may actually increase the risk of death, which is about 50% at 6 months and nearly 100% at 1 year. A patient on inotropic therapy who is not a candidate for a transplant or for an assist device should be referred to a hospice program.7
CARDIAC TRANSPLANTATION: SUCCESSES, CHALLENGES
Survival rates after heart transplantation are now excellent. The 1-year survival rate is about 90%, the 5-year rate is about 70%, but only about 20% survive 20 years or longer.8,9 The prognosis is not as good as for combined heart-lung transplantation patients.
Age is an important factor and is a contentious issue: some medical centers will not offer transplantation to patients over age 65. Others regard age as just another risk factor, like renal dysfunction or diabetes.
Quality of life after heart transplantation is excellent: patients are usually able to return to work, regardless of their profession.
The leading cause of death after heart transplantation is malignancy, followed by coronary artery vasculopathy, then by graft failure. Some patients develop left ventricular dysfunction and heart failure of unknown cause. Others develop antibody-mediated rejection; in recent years this has been more promptly recognized, but treatment remains a challenge.
Acute rejection, which used to be one of the main causes of death, now has an extremely low incidence because of modern drug therapies. In a US observational study currently being conducted in about 200 patients receiving a heart transplant (details on CTOT-05 at www.clinicaltrials.gov), the incidence of moderate rejection during the first year is less than 10% (Starling RC, unpublished observation). But several concerns remain.
Adverse effects of immunosuppressive drugs continue to be problematic. These include infection, malignancy, osteoporosis, chronic kidney toxicity, hypertension, and neuropathy.
Renal dysfunction is one of the largest issues. About 10% of heart transplant recipients develop stage 4 kidney disease (with a glomerular filtration rate < 30 mL/min) and need kidney transplantation or renal replacement therapy because of the use of calcineurin inhibitors for immunosuppression.10
Coronary artery vasculopathy was the largest problem when heart transplantation began and continues to be a major concern and focus of research.11,12 Case 1 (below) is an example of the problem.
Case 1: Poor outcome despite an ideal scenario
A 57-year-old businessman had dilated cardiomyopathy and progressive heart failure for 10 years. He was listed for transplantation in 2008 and was given an LVAD (HeartMate II, Thoratec Corp, Pleasanton, CA) as a bridge until a donor heart became available.
In 2009, he received a heart transplant under ideal conditions: the donor was a large 30-year-old man who died of a gunshot wound to the head in the same city in which the patient and transplant hospital were located. Cardiopulmonary resuscitation was not performed, and the cold ischemic time was just a little more than 3 hours. Immune indicators were ideal with a negative prospective cross-match.
Laboratory results after transplantation included creatinine 1.7 mg/dL (normal 0.6–1.2 mg/dL), low-density lipoprotein cholesterol 75 mg/dL, high-density lipoprotein cholesterol 64 mg/dL, and triglycerides 90 mg/dL.
The patient was given immunosuppressive therapy with cyclosporine (Neoral), mycophenolate (CellCept), and prednisone. Because his creatinine level was high, he was also perioperatively given basiliximab (Simulect), a monoclonal antibody to the alpha chain (CD25) of the interleukin-2 receptor. (In a patient who has poor renal function, basilixumab may help by enabling us to delay the use of calcineurin inhibitors.) He also received simvastatin (Zocor) 10 mg.
Per Cleveland Clinic protocol, he underwent 13 biopsy procedures during his first year, and each was normal (grade 0 or 1R). Evaluation by cardiac catheterization at 1 year showed some irregularities in the left anterior descending artery, but a stent was not deemed necessary. Also, per protocol, he underwent intravascular ultrasonography, which revealed abnormal thickness in the intima and media, indicating that coronary artery disease was developing, although it was nonobstructive.
Two months after this checkup, the patient collapsed and suddenly died while shopping. At autopsy, his left anterior descending artery was found to be severely obstructed.
Coronary artery vasculopathy is still a major problem
This case shows that coronary artery vasculopathy may develop despite an ideal transplantation scenario. It remains a large concern and a focus of research.
Coronary vasculopathy develops in 30% to 40% of heart transplant recipients within 5 years, and the incidence has not been reduced by much over the years. However, probably fewer than 5% of these patients die or even need bypass surgery or stenting, and the problem is managed the same as native atherosclerosis. We perform routine annual cardiac catheterizations or stress tests, or both, and place stents in severely blocked arteries.
THE DONOR SHORTAGE: CHANGING HOW HEARTS ARE ALLOCATED
The number of patients receiving a heart transplant in the United States—about 2,000 per year—has not increased in the past decade. The European Union also has great difficulty obtaining hearts for people in need, and almost every transplant candidate there gets mechanical support for some time. The gap between those listed for transplant and the number transplanted each year continues to widen in both the United States and Europe.
All transplant candidates are assigned a status by the United Network of Organ Sharing (UNOS) based on their medical condition. The highest status, 1A, goes to patients who are seriously ill, in the hospital, on high doses of inotropic drugs (specific dosages are defined) and mechanical circulatory support such as an LVAD, and expected to live less than 1 month without a transplant. Status 1B patients are stable on lower-dose inotropic therapy or on mechanical support, and can be in the hospital or at home. Status 2 patients are stable and ambulatory and are not on inotropic drugs.
In July 2006, UNOS changed the rules on how patients are prioritized for obtaining an organ. The new rules are based both on severity of illness (see above) and geographic proximity to the donor heart—local, within 500 miles (“zone A”) or within 500 to 1,000 miles (“zone B”). The order of priority for donor hearts is:
- Local, status 1A
- Local, status 1B
- Zone A, status 1A
- Zone A, status 1B
- Local, status 2
- Zone B, status 1A
- Zone B, status 1B
- Zone A, status 2.
As a result of the change, donor hearts that become available in a particular hospital do not necessarily go to a patient in that state. Another result is that status 2 patients, who were previously the most common transplant recipients, now have much less access because all status 1 patients within 500 miles are given higher priority. Since the change, only 8% of hearts nationwide go to status 2 patients, which is 67% fewer than before. At the same time, organs allocated to status 1A patients have increased by 26%, and their death rates have fallen.3
The new allocation system is a positive change for the sickest patients, providing quicker access and a reduction in waiting-list mortality.13 The drawback is that status 2 patients who are less ill are less likely to ever receive an organ until their condition worsens.
Heart transplant outcomes are publicly reported
The Scientific Registry of Transplant Recipients publicly reports heart transplant outcomes (www.srtr.org). For any transplant center, the public can learn the number of patients waiting for a transplant, the death rate on the waiting list, the number of transplants performed in the previous 12 months, the waiting time in months, and observed and risk-adjusted expected survival rates. A center that deviates from the expected survival rates by 10% or more may be audited and could lose its certification.
Also listed on the Web site is the percentage of patients who receive a support device before receiving a transplant. This can vary widely between institutions and may reflect the organ availability at the transplant center (waiting times) or the preferences and expertise of the transplantation team. We believe that the mortality rate on the waiting list will be reduced with appropriate use of LVADs as a bridge to transplantation when indicated. We have now transitioned to the use of the improved continuous-flow LVADs and rarely maintain patients on continuous inotropic therapy at home to await a donor organ.
MECHANICAL CIRCULATORY SUPPORT: BRIDGE OR DESTINATION?
Mechanical circulatory support devices are increasingly being used to sustain patients with advanced heart failure. Currently at Cleveland Clinic, more LVADs are implanted than hearts are transplanted.
Mechanical circulatory support is indicated for patients who are listed for transplant to keep them functioning as well as possible while they are waiting (bridge to transplant). For others it is “destination therapy”: they are not candidates for a transplant, but a device may improve and prolong the rest of their life.
Case 2: A good outcome despite a poor prognosis
A 71-year-old man was rejected for transplantation by his local hospital because of his age and also because he had pulmonary artery hypertension (78/42 mm Hg; reference range 15–30/5–15 mm Hg) and creatinine elevation (3.0 mg/dL; reference range 0.6–1.5 mg/dL). Nevertheless, he did well on a mechanical device and was accepted for transplantation by Cleveland Clinic. He received a transplant and is still alive and active 14 years later.
Comment. Determining that a patient is not a good transplantation candidate is often impossible. Putting the patient on mechanical support for a period of time can often help clarify whether transplantation is advisable. Probably most patients who receive mechanical support do so as a bridge to decision: most are acutely ill and many have organ dysfunction, pulmonary hypertension, and renal insufficiency. After a period of support, they can be assessed for suitability for transplantation.
LVADs continue to improve
Many devices are available for mechanical circulatory support.14 In addition to LVADs, there are right-ventricular assist devices (RVADs), and devices that simultaneously support both ventricles (BiVADs). Total artificial hearts are also available, as are acute temporary percutaneous devices. These temporary devices—TandemHeart (CardiacAssist, Pittsburgh, PA) and Impella (Abiomed, Danvers, MD)—can be used before a long-term mechanical device can be surgically implanted.
LVADs are of three types:
- Pulsatile volume-displacement pumps, which mimic the pumping action of the natural heart. These early devices were large and placed in the abdomen.
- Continuous axial-flow pumps, which do not have a “heartbeat.” These are quieter and lighter than the early pumps, and use a turbine that spins at 8,000 to 10,000 rpm.
- Continuous centrifugal-flow pumps. These have a rotor spinning at 2,000 to 3,000 rpm, and most of them are magnetically powered and suspended.
The superiority of LVADs over medical therapy was clearly shown even in early studies that used pulsatile LVADs.15 The results of such studies and the increased durability of the devices have led to their rapidly expanded use.
The newer continuous-flow pumps offer significant improvements over the old pulsatile-flow pumps, being smaller, lighter, quieter, and more durable (Table 1). A 2007 study of 133 patients on a continuous axial-flow LVAD (HeartMate II) found that 76% were still alive after 6 months, and patients had significant improvement in functional status and quality of life.16 In a postapproval study based on registry data, HeartMate II was found superior to pulsatile pumps in terms of survival up to 12 months, percentage of patients reaching transplant, and cardiac recovery. Adverse event rates were similar or lower for HeartMate II.17
Another study compared a continuousflow with a pulsatile-flow LVAD for patients who were ineligible for transplantation. Survival at 2 years was 58% with the continuousflow device vs 24% with the pulsatile-flow device (P = .008).18 Since then, postmarket data of patients who received an LVAD showed that 85% are still alive at 1 year.19 This study can be viewed as supporting the use of LVADs as destination therapy.
Quality of life for patients receiving an LVAD has been excellent. When biventricular pacemakers for resynchronization therapy first became available, distances on the 6-minute walk test improved by 39 m, which was deemed a big improvement. LVAD devices have increased the 6-minute walk distance by 156 m.20
Adverse events with LVADs have improved, but continue to be of concern
Infections can arise in the blood stream, in the device pocket, or especially where the driveline exits the skin. As devices have become smaller, driveline diameters have become smaller as well, allowing for a better seal at the skin and making this less of a problem. Some centers report the incidence of driveline infections as less than 20%, but they continue to be a focus of concern.18
Stroke rates continue to improve, although patients still require intensive lifelong anticoagulation. The target international normalized ratio varies by device manufacturer, ranging from 1.7 to 2.5.
Bleeding. Acquired von Willebrand syndrome can develop in patients who have an LVAD, with the gastrointestinal system being the most frequent site of bleeding.21
Device thrombosis occurs very rarely (2%–3%) but is very serious and may require pump exchange.
Mechanical malfunction. As duration of therapy lengthens, problems are arising with aging devices, such as broken wires or short circuits. New-generation pumps have markedly improved durability and reliability.
Good data are kept on device outcomes
The Interagency for Mechanically Assisted Circulatory Support (INTERMACS) maintains a national registry of patients with a mechanical circulatory support device to treat advanced heart failure. It was jointly established in 2006 by the National Heart, Lung, and Blood Institute, Centers for Medicare and Medicaid Services (CMS), the US Food and Drug Administration, and others. Reporting to INTERMACS is required for CMS reimbursement.
The INTERMACS database now has about 4,500 patients at 126 medical centers and is yielding useful information that is published in annual reports.22 The 2011 report focused on the experience with mechanical circulatory support as destination therapy and showed that patients who receive continuousflow pumps have significantly better survival rates than those with pulsatile-flow pumps.23 An earlier report showed that the level of illness at the time of implantation predicts survival24; this information now drives cardiologists to try to improve patient status with a temporary support device or intra-aortic balloon pump before implanting a durable device. The sickest patients (INTERMACS level 1) have the poorest outcomes, and centers now do fewer implantations in patients in this category. We have learned this important lesson from the INTERMACS registry.
The new devices have received a lot of media attention, and patient accrual has increased steadily as the devices have been approved.
On November 20, 2012, the US Food and Drug Administration approved the HeartWare Ventricular Assist System (HeartWare, Framingham, MA) for heart failure patients awaiting a transplant.
FUTURE DIRECTIONS
PROCEED II is an ongoing global clinical trial comparing the outcomes with donor hearts transported in standard cold storage to those transported in an experimental transport device that pumps the heart under physiologic conditions. If proven effective, this device could allow long-distance transport of donor hearts and expand the donor population.
A prospective, randomized study is now enrolling patients to evaluate induction therapy with rituximab (Rituxan) plus conventional immunosuppression (tacrolimus [Prograf], mycophenolate, steroid taper) vs placebo induction plus conventional immunosuppression. The study will enroll 400 patients (200 to each treatment arm) at 25 sites and will have a 36-month accrual period with 12-month follow-up (see http://clinicaltrials.gov/show/NCT01278745). The study is based on data in primates that found that eliminating B cells with an anti-CD20 drug before transplantation markedly reduced the incidence of coronary artery vasculopathy.
- Lloyd-Jones D, Adams RJ, Brown TM, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2010 update: a report from the American Heart Association. Circulation 2010; 1221:e46–e215.
- Jessup M, Abraham WT, Casey DE, et al. 2009 focused update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 2009; 119:1977–2016.
- 2009 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1999–2008. U.S. Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation, Rockville, MD.
- Metra M, Ponikowski P, Dickstein K, et al; Heart Failure Association of the European Society of Cardiology. Advanced chronic heart failure: a position statement from the Study Group on Advanced Heart Failure of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2007; 9:684–694.
- Hsich E, Gorodeski EZ, Starling RC, Blackstone EH, Ishwaran H, Lauer MS. Importance of treadmill exercise time as an initial prognostic screening tool in patients with systolic left ventricular dysfunction. Circulation 2009; 119:3189–3197.
- Gorodeski EZ, Chu EC, Chow CH, Levy WC, Hsich E, Starling RC. Application of the Seattle Heart Failure Model in ambulatory patients presented to an advanced heart failure therapeutics committee. Circ Heart Fail 2010; 3:706–714.
- Gorodeski EZ, Chu EC, Reese JR, Shishehbor MH, Hsich E, Starling RC. Prognosis on chronic dobutamine or milrinone infusions for stage D heart failure. Circ Heart Fail 2009; 2:320–324.
- Taylor DO, Stehlik J, Edwards LB, et al. Registry of the International Society for Heart and Lung Transplantation: Twenty-sixth official adult heart transplant report—2009. J Heart Lung Transplant 2009; 28:1007–1022.
- Stehlik J, Edwards LB, Kucheryavaya AY, et al. The registry of the International Society for Heart and Lung Transplantation: twenty-seventh official adult heart transplant report—2010. J Heart Lung Transplant 2010; 29:1089–1103.
- Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med 2003; 349:931–940.
- Kobashigawa JA, Katznelson S, Laks H, et al. Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med 1999; 340:272–277. Erratum in: N Engl J Med 1999; 340:976.
- Eisen HJ, Tuzcu EM, Dorent R, et al. Everolimus for the prevention of allograft rejection and vasculopathy in cardiactransplant recipients. N Engl J Med 2003; 349:847–858.
- Singh TP, Almond CS, Taylor DO, Graham DA. Decline in heart transplant wait list mortality in the United States following broader regional sharing of donor hearts. Circ Heart Fail 2012; 5:249–258.
- Baughman KL, Jarcho JA. Bridge to life—cardiac mechanical support. N Engl J Med 2007; 357:846–849.
- Rose EA, Gelijns AC, Moskowitz AJ, et al; Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) Study Group. Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med 2001; 345:1435–1443.
- Miller LW, Pagani FD, Russell SD, et al; HeartMate II Clinical Investigators. Use of a continuous-flow device in patients awaiting heart transplantation. N Engl J Med 2007; 357:885–896.
- Starling RC, Naka Y, Boyle AJ, et al. Results of the post-U.S. Food and Drug Administration-approval study with a continuous flow left ventricular assist device as a bridge to heart transplantation: a prospective study using the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support). J Am Coll Cardiol 2011; 57:1890–1898.
- Slaughter MS, Rogers JG, Milano CA, et al; HeartMate II Investigators. Advanced heart failure treated with continuous-flow left ventricular assist device. N Engl J Med 2009; 361:2241–2251.
- John R, Naka Y, Smedira NG, et al. Continuous flow left ventricular assist device outcomes in commercial use compared with the prior clinical trial. Ann Thorac Surg 2011; 92:1406–1413.
- Starling RC. Improved quantity and quality of life: a winning combination to treat advanced heart failure. J Am Coll Cardiol 2010; 55:1835–1836.
- Uriel N, Pak SW, Jorde UP, et al. Acquired von Willebrand syndrome after continuous-flow mechanical device support contributes to a high prevalence of bleeding during long-term support and at the time of transplantation. J Am Coll Cardiol 2010; 56:1207–1213.
- Kirklin JK, Naftel DC, Kormos RL, et al. The fourth INTERMACS annual report: 4,000 implants and counting. J Heart Lung Transplant 2012; 31:117–126.
- Kirklin JK, Naftel DC, Kormos RL, et al. Third INTERMACS Annual Report: the evolution of destination therapy in the United States. J Heart Lung Transplant 2011; 30:115–123.
- Kirklin JK, Naftel DC, Kormos RL, et al. Second INTERMACS annual report: more than 1,000 primary left ventricular assist device implants. J Heart Lung Transplant 2010; 29:1–10.
SUGGESTED READING
Costanzo MR, Dipchand A, Starling R, et al; International Society of Heart and Lung Transplantation Guidelines. The International Society of Heart and Lung Transplantation guidelines for the care of heart transplant recipients. J Heart Lung Transplant 2010; 29:914–956.
Mehra MR, Kobashigawa J, Starling R, et al. Listing criteria for heart transplantation: International Society for Heart and Lung Transplantation guidelines for the care of cardiac transplant candidates–2006. J Heart Lung Transplant 2006; 25:1024–1042.
Slaughter MS, Pagani FD, Rogers JG, et al; HeartMate II Clinical Investigators. Clinical management of continuous flow left ventricular assist devices in advanced heart failure. J Heart Lung Transplant 2010; 29(4 suppl):S1–S39.
- Lloyd-Jones D, Adams RJ, Brown TM, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2010 update: a report from the American Heart Association. Circulation 2010; 1221:e46–e215.
- Jessup M, Abraham WT, Casey DE, et al. 2009 focused update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 2009; 119:1977–2016.
- 2009 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1999–2008. U.S. Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation, Rockville, MD.
- Metra M, Ponikowski P, Dickstein K, et al; Heart Failure Association of the European Society of Cardiology. Advanced chronic heart failure: a position statement from the Study Group on Advanced Heart Failure of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2007; 9:684–694.
- Hsich E, Gorodeski EZ, Starling RC, Blackstone EH, Ishwaran H, Lauer MS. Importance of treadmill exercise time as an initial prognostic screening tool in patients with systolic left ventricular dysfunction. Circulation 2009; 119:3189–3197.
- Gorodeski EZ, Chu EC, Chow CH, Levy WC, Hsich E, Starling RC. Application of the Seattle Heart Failure Model in ambulatory patients presented to an advanced heart failure therapeutics committee. Circ Heart Fail 2010; 3:706–714.
- Gorodeski EZ, Chu EC, Reese JR, Shishehbor MH, Hsich E, Starling RC. Prognosis on chronic dobutamine or milrinone infusions for stage D heart failure. Circ Heart Fail 2009; 2:320–324.
- Taylor DO, Stehlik J, Edwards LB, et al. Registry of the International Society for Heart and Lung Transplantation: Twenty-sixth official adult heart transplant report—2009. J Heart Lung Transplant 2009; 28:1007–1022.
- Stehlik J, Edwards LB, Kucheryavaya AY, et al. The registry of the International Society for Heart and Lung Transplantation: twenty-seventh official adult heart transplant report—2010. J Heart Lung Transplant 2010; 29:1089–1103.
- Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med 2003; 349:931–940.
- Kobashigawa JA, Katznelson S, Laks H, et al. Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med 1999; 340:272–277. Erratum in: N Engl J Med 1999; 340:976.
- Eisen HJ, Tuzcu EM, Dorent R, et al. Everolimus for the prevention of allograft rejection and vasculopathy in cardiactransplant recipients. N Engl J Med 2003; 349:847–858.
- Singh TP, Almond CS, Taylor DO, Graham DA. Decline in heart transplant wait list mortality in the United States following broader regional sharing of donor hearts. Circ Heart Fail 2012; 5:249–258.
- Baughman KL, Jarcho JA. Bridge to life—cardiac mechanical support. N Engl J Med 2007; 357:846–849.
- Rose EA, Gelijns AC, Moskowitz AJ, et al; Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) Study Group. Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med 2001; 345:1435–1443.
- Miller LW, Pagani FD, Russell SD, et al; HeartMate II Clinical Investigators. Use of a continuous-flow device in patients awaiting heart transplantation. N Engl J Med 2007; 357:885–896.
- Starling RC, Naka Y, Boyle AJ, et al. Results of the post-U.S. Food and Drug Administration-approval study with a continuous flow left ventricular assist device as a bridge to heart transplantation: a prospective study using the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support). J Am Coll Cardiol 2011; 57:1890–1898.
- Slaughter MS, Rogers JG, Milano CA, et al; HeartMate II Investigators. Advanced heart failure treated with continuous-flow left ventricular assist device. N Engl J Med 2009; 361:2241–2251.
- John R, Naka Y, Smedira NG, et al. Continuous flow left ventricular assist device outcomes in commercial use compared with the prior clinical trial. Ann Thorac Surg 2011; 92:1406–1413.
- Starling RC. Improved quantity and quality of life: a winning combination to treat advanced heart failure. J Am Coll Cardiol 2010; 55:1835–1836.
- Uriel N, Pak SW, Jorde UP, et al. Acquired von Willebrand syndrome after continuous-flow mechanical device support contributes to a high prevalence of bleeding during long-term support and at the time of transplantation. J Am Coll Cardiol 2010; 56:1207–1213.
- Kirklin JK, Naftel DC, Kormos RL, et al. The fourth INTERMACS annual report: 4,000 implants and counting. J Heart Lung Transplant 2012; 31:117–126.
- Kirklin JK, Naftel DC, Kormos RL, et al. Third INTERMACS Annual Report: the evolution of destination therapy in the United States. J Heart Lung Transplant 2011; 30:115–123.
- Kirklin JK, Naftel DC, Kormos RL, et al. Second INTERMACS annual report: more than 1,000 primary left ventricular assist device implants. J Heart Lung Transplant 2010; 29:1–10.
SUGGESTED READING
Costanzo MR, Dipchand A, Starling R, et al; International Society of Heart and Lung Transplantation Guidelines. The International Society of Heart and Lung Transplantation guidelines for the care of heart transplant recipients. J Heart Lung Transplant 2010; 29:914–956.
Mehra MR, Kobashigawa J, Starling R, et al. Listing criteria for heart transplantation: International Society for Heart and Lung Transplantation guidelines for the care of cardiac transplant candidates–2006. J Heart Lung Transplant 2006; 25:1024–1042.
Slaughter MS, Pagani FD, Rogers JG, et al; HeartMate II Clinical Investigators. Clinical management of continuous flow left ventricular assist devices in advanced heart failure. J Heart Lung Transplant 2010; 29(4 suppl):S1–S39.
KEY POINTS
- After heart transplantation, survival rates are high and quality of life is excellent, although coronary artery disease, renal dysfunction, and the need for immunosuppressive drugs are ongoing challenges.
- Changes in donor heart allocation made in 2006 more strongly favor the sickest patients and have reduced the rate of mortality on the waiting list.
- Continuous-flow left-ventricular assist devices offer many advantages over the older pulsatile-flow devices, including improved outcomes, smaller size, less noise, and greater durability.
- Inotropic therapy is purely palliative and should not be viewed as an alternative to heart transplantation or device implantation.
When do Raynaud symptoms merit a workup for autoimmune rheumatic disease?
Indications that Raynaud phenomenon may be the presenting manifestation of a systemic autoimmune rheumatic disease are older age at onset (ie, over age 30), male sex, asymmetric involvement, and prolonged and painful attacks that can be severe enough to cause ischemic digital ulceration or gangrene (Figure 1).
Hence, chronic and severe digital ischemia causing ulceration or infarction differentiates secondary from primary Raynaud phenomenon and should prompt an investigation for an autoimmune rheumatic process. When taking the history, the clinician should seek clues to an underlying autoimmune condition, such as arthralgia, heartburn, dysphagia, shortness of breath, cough, and should examine the patient for telltale signs such as puffy hands and fingers, sclerodactyly, digital pitting scars, loss of fingertip pulp tissue, telangiectasias, and calcinosis.
CLUES TO PRIMARY VS SECONDARY RAYNAUD PHENOMENON
A diagnostic algorithm of digital ischemia (Figure 2) illustrates the range of presentations and possible causes. In Raynaud phenomenon, cold temperature and emotional stress provoke reversible color changes of the fingers and toes. Intense vasospasm of the digital arteries produces three well-defined phases1: white (pallor resulting from vasospasm), blue (dusky cyanosis due to deoxygenation of static venous blood) (Figure 1), and red (reactive hyperemia after the restoration of blood flow). However, only about 60% of patients have all three color changes. The attacks are associated with paresthesias, an uncomfortable feeling of coldness in the fingers, and ischemic pain.
Primary Raynaud phenomenon
Primary or idiopathic Raynaud phenomenon is seen in 5% to 10% of the general population. It more commonly affects women ages 15 to 30, is generally mild, involves the digits symmetrically, and is sometimes familial. An increase in alpha-2 adrenergic responses in the digital vessels leads to arterial vasospasm, an exaggerated physiologic response to cold temperatures.2 Geographic variability in prevalence likely represents differences in mean outdoor temperatures,3 which is in part why attacks of primary Raynaud phenomenon tend to be worse in the winter months.4
Secondary Raynaud phenomenon
Raynaud phenomenon also often occurs in certain autoimmune rheumatic diseases (secondary Raynaud phenomenon): for example, it is seen in scleroderma (90% to 95% of patients), mixed connective tissue disease (85%), systemic lupus erythematosus (40%), antisynthetase syndrome (40%), and sometimes in patients with other autoimmune rheumatic diseases. It may also be seen in hematologic disorders (cryoglobulinemia, cryofibrinogenemia, paraproteinemias, cold agglutinin disease, and polycythemia rubra vera), and it can also result from environmental and occupational exposures (frostbite, use of vibrating tools) and from exposure to certain drugs and toxins, such as polyvinyl chloride (Figure 2).
Acrocyanosis, a benign neurohormonal condition, should be included in the differential diagnosis for Raynaud phenomenon. Raynaud phenomenon is episodic, whereas acrocyanosis leads to persistent cyanosis of the acral body parts (fingers, toes) that is exacerbated by cold temperatures. However, the trophic skin changes, localized pain, and ulceration are not seen in acrocyanosis.
NAILFOLD CAPILLAROSCOPY: A KEY PART OF THE WORKUP
Nailfold capillaroscopy should be part of the evaluation of patients with Raynaud phenomenon (Figure 3), as it is one of the most reliable tests for distinguishing between primary and secondary Raynaud phenomenon.5 The sensitivity of the American College of Rheumatology classification criteria for systemic sclerosis increases significantly with the addition of nailfold capillary abnormalities.6,7
A stereomicroscope or videocapillaroscope is usually recommended to evaluate nailfold capillary morphology,5 but if such equipment is not available, a regular ophthalmoscope (with the lens set at 20 diopters or higher for better resolution) can serve the purpose at the bedside.8 A drop of mineral oil is placed on the nailfold to improve the image resolution, as it makes the horny layer of the cuticle transparent.
Abnormal patterns include dilated and enlarged capillary loops, disorganized capillaries, “dropouts” (avascular areas), microhemorrhages, and arborized capillaries (Figure 3).5 At no additional cost, the presence of these microvascular changes would add to the suspicion of secondary Raynaud phenomenon (negative predictive value of 93%).9 In addition, evolving capillaroscopic changes can be seen during follow-up visits, indicating the progressive nature of the microvasculopathy seen in these autoimmune rheumatic diseases.10
ADDITIONAL TESTING
If an underlying autoimmune rheumatic disease is suspected, laboratory testing should include a complete blood cell count, an erythrocyte sedimentation rate, and an antinuclear antibody (ANA) assay. If the ANA assay is negative, no further testing is usually necessary; however, a positive test should alert the clinician to consider an underlying autoimmune rheumatic process (negative predictive value of 93%).9 In a patient presenting with Raynaud phenomenon, a positive ANA test (even in the absence of other symptoms) warrants more frequent follow-up, urinalysis, and perhaps referral to a rheumatologist.
In the case of a positive ANA test, before ordering additional autoantibody tests, it is useful to consider the relevant non-Raynaud clinical manifestations. Indiscriminate ordering of a battery of autoantibodies should be avoided because of significant added cost and because it is not likely to provide additional information to guide management.
On the other hand, these more specific antibody tests may be of value in confirming the diagnosis suggested by the clinical profile of specific autoimmune rheumatic diseases, eg, anti-double-stranded DNA11 and anti-Smith12 antibodies for lupus, anti-topoisomerase I (Scl-70) and anti-centromere antibodies for scleroderma, 13 and anti-synthetase (eg, anti-Jo-1) antibodies for autoimmune myositis.14,15
- Raynaud M. On local asphyxia and symmetrical gangrene of the extremities (1862), and new research on the nature and treatment of local asphyxia of the extremities (1872).Barlow T, trans. Selected monographs (121). London: New Sydenham Society, 1988.
- Boin F, Wigley FM. Understanding, assessing and treating Raynaud’s phenomenon. Curr Opin Rheumatol 2005; 17:752–760.
- Maricq HR, Carpentier PH, Weinrich MC, et al. Geographic variation in the prevalence of Raynaud’s phenomenon: a 5-region comparison. J Rheumatol 1997; 24:879–889.
- Wigley FM. Clinical practice. Raynaud’s phenomenon. N Engl J Med 2002; 347:1001–1018.
- Cutolo M, Pizzorni C, Sulli A. Capillaroscopy. Best Pract Res Clin Rheumatol 2005; 19:437–452.
- Lonzetti LS, Joyal F, Raynauld JP, et al. Updating the American College of Rheumatology preliminary classification criteria for systemic sclerosis: addition of severe nailfold capillaroscopy abnormalities markedly increases the sensitivity for limited scleroderma. Arthritis Rheum 2001; 44:735–736.
- Hudson M, Taillefer S, Steele R, et al. Improving the sensitivity of the American College of Rheumatology classification criteria for systemic sclerosis. Clin Exp Rheumatol 2007; 25:754–757.
- Anders HJ, Sigl T, Schattenkirchner M. Differentiation between primary and secondary Raynaud’s phenomenon: a prospective study comparing nailfold capillaroscopy using an ophthalmoscope or stereomicroscope. Ann Rheum Dis 2001; 60:407–409.
- Spencer-Green G. Outcomes in primary Raynaud phenomenon: a meta-analysis of the frequency, rates, and predictors of transition to secondary diseases. Arch Intern Med 1998; 158:595–600.
- Wong ML, Highton J, Palmer DG. Sequential nailfold capillary microscopy in scleroderma and related disorders. Ann Rheum Dis 1988; 47:53–61.
- Weinstein A, Bordwell B, Stone B, Tibbetts C, Rothfield NF. Antibodies to native DNA and serum complement (C3) levels. Application to diagnosis and classification of systemic lupus erythematosus. Am J Med 1983; 74:206–216.
- Craft J. Antibodies to snRNPs in systemic lupus erythematosus. Rheum Dis Clin North Am 1992; 18:311–335.
- Weiner ES, Hildebrandt S, Senécal JL, et al. Prognostic significance of anticentromere antibodies and anti-topoisomerase I antibodies in Raynaud’s disease. A prospective study. Arthritis Rheum 1991; 34:68–77.
- Miller FW, Twitty SA, Biswas T, Plotz PH. Origin and regulation of a disease-specific autoantibody response. Antigenic epitopes, spectrotype stability, and isotype restriction of anti-Jo-1 autoantibodies. J Clin Invest 1990; 85:468–475.
- Ghirardello A, Zampieri S, Tarricone E, et al. Clinical implications of autoantibody screening in patients with autoimmune myositis. Autoimmunity 2006; 39:217–221.
Indications that Raynaud phenomenon may be the presenting manifestation of a systemic autoimmune rheumatic disease are older age at onset (ie, over age 30), male sex, asymmetric involvement, and prolonged and painful attacks that can be severe enough to cause ischemic digital ulceration or gangrene (Figure 1).
Hence, chronic and severe digital ischemia causing ulceration or infarction differentiates secondary from primary Raynaud phenomenon and should prompt an investigation for an autoimmune rheumatic process. When taking the history, the clinician should seek clues to an underlying autoimmune condition, such as arthralgia, heartburn, dysphagia, shortness of breath, cough, and should examine the patient for telltale signs such as puffy hands and fingers, sclerodactyly, digital pitting scars, loss of fingertip pulp tissue, telangiectasias, and calcinosis.
CLUES TO PRIMARY VS SECONDARY RAYNAUD PHENOMENON
A diagnostic algorithm of digital ischemia (Figure 2) illustrates the range of presentations and possible causes. In Raynaud phenomenon, cold temperature and emotional stress provoke reversible color changes of the fingers and toes. Intense vasospasm of the digital arteries produces three well-defined phases1: white (pallor resulting from vasospasm), blue (dusky cyanosis due to deoxygenation of static venous blood) (Figure 1), and red (reactive hyperemia after the restoration of blood flow). However, only about 60% of patients have all three color changes. The attacks are associated with paresthesias, an uncomfortable feeling of coldness in the fingers, and ischemic pain.
Primary Raynaud phenomenon
Primary or idiopathic Raynaud phenomenon is seen in 5% to 10% of the general population. It more commonly affects women ages 15 to 30, is generally mild, involves the digits symmetrically, and is sometimes familial. An increase in alpha-2 adrenergic responses in the digital vessels leads to arterial vasospasm, an exaggerated physiologic response to cold temperatures.2 Geographic variability in prevalence likely represents differences in mean outdoor temperatures,3 which is in part why attacks of primary Raynaud phenomenon tend to be worse in the winter months.4
Secondary Raynaud phenomenon
Raynaud phenomenon also often occurs in certain autoimmune rheumatic diseases (secondary Raynaud phenomenon): for example, it is seen in scleroderma (90% to 95% of patients), mixed connective tissue disease (85%), systemic lupus erythematosus (40%), antisynthetase syndrome (40%), and sometimes in patients with other autoimmune rheumatic diseases. It may also be seen in hematologic disorders (cryoglobulinemia, cryofibrinogenemia, paraproteinemias, cold agglutinin disease, and polycythemia rubra vera), and it can also result from environmental and occupational exposures (frostbite, use of vibrating tools) and from exposure to certain drugs and toxins, such as polyvinyl chloride (Figure 2).
Acrocyanosis, a benign neurohormonal condition, should be included in the differential diagnosis for Raynaud phenomenon. Raynaud phenomenon is episodic, whereas acrocyanosis leads to persistent cyanosis of the acral body parts (fingers, toes) that is exacerbated by cold temperatures. However, the trophic skin changes, localized pain, and ulceration are not seen in acrocyanosis.
NAILFOLD CAPILLAROSCOPY: A KEY PART OF THE WORKUP
Nailfold capillaroscopy should be part of the evaluation of patients with Raynaud phenomenon (Figure 3), as it is one of the most reliable tests for distinguishing between primary and secondary Raynaud phenomenon.5 The sensitivity of the American College of Rheumatology classification criteria for systemic sclerosis increases significantly with the addition of nailfold capillary abnormalities.6,7
A stereomicroscope or videocapillaroscope is usually recommended to evaluate nailfold capillary morphology,5 but if such equipment is not available, a regular ophthalmoscope (with the lens set at 20 diopters or higher for better resolution) can serve the purpose at the bedside.8 A drop of mineral oil is placed on the nailfold to improve the image resolution, as it makes the horny layer of the cuticle transparent.
Abnormal patterns include dilated and enlarged capillary loops, disorganized capillaries, “dropouts” (avascular areas), microhemorrhages, and arborized capillaries (Figure 3).5 At no additional cost, the presence of these microvascular changes would add to the suspicion of secondary Raynaud phenomenon (negative predictive value of 93%).9 In addition, evolving capillaroscopic changes can be seen during follow-up visits, indicating the progressive nature of the microvasculopathy seen in these autoimmune rheumatic diseases.10
ADDITIONAL TESTING
If an underlying autoimmune rheumatic disease is suspected, laboratory testing should include a complete blood cell count, an erythrocyte sedimentation rate, and an antinuclear antibody (ANA) assay. If the ANA assay is negative, no further testing is usually necessary; however, a positive test should alert the clinician to consider an underlying autoimmune rheumatic process (negative predictive value of 93%).9 In a patient presenting with Raynaud phenomenon, a positive ANA test (even in the absence of other symptoms) warrants more frequent follow-up, urinalysis, and perhaps referral to a rheumatologist.
In the case of a positive ANA test, before ordering additional autoantibody tests, it is useful to consider the relevant non-Raynaud clinical manifestations. Indiscriminate ordering of a battery of autoantibodies should be avoided because of significant added cost and because it is not likely to provide additional information to guide management.
On the other hand, these more specific antibody tests may be of value in confirming the diagnosis suggested by the clinical profile of specific autoimmune rheumatic diseases, eg, anti-double-stranded DNA11 and anti-Smith12 antibodies for lupus, anti-topoisomerase I (Scl-70) and anti-centromere antibodies for scleroderma, 13 and anti-synthetase (eg, anti-Jo-1) antibodies for autoimmune myositis.14,15
Indications that Raynaud phenomenon may be the presenting manifestation of a systemic autoimmune rheumatic disease are older age at onset (ie, over age 30), male sex, asymmetric involvement, and prolonged and painful attacks that can be severe enough to cause ischemic digital ulceration or gangrene (Figure 1).
Hence, chronic and severe digital ischemia causing ulceration or infarction differentiates secondary from primary Raynaud phenomenon and should prompt an investigation for an autoimmune rheumatic process. When taking the history, the clinician should seek clues to an underlying autoimmune condition, such as arthralgia, heartburn, dysphagia, shortness of breath, cough, and should examine the patient for telltale signs such as puffy hands and fingers, sclerodactyly, digital pitting scars, loss of fingertip pulp tissue, telangiectasias, and calcinosis.
CLUES TO PRIMARY VS SECONDARY RAYNAUD PHENOMENON
A diagnostic algorithm of digital ischemia (Figure 2) illustrates the range of presentations and possible causes. In Raynaud phenomenon, cold temperature and emotional stress provoke reversible color changes of the fingers and toes. Intense vasospasm of the digital arteries produces three well-defined phases1: white (pallor resulting from vasospasm), blue (dusky cyanosis due to deoxygenation of static venous blood) (Figure 1), and red (reactive hyperemia after the restoration of blood flow). However, only about 60% of patients have all three color changes. The attacks are associated with paresthesias, an uncomfortable feeling of coldness in the fingers, and ischemic pain.
Primary Raynaud phenomenon
Primary or idiopathic Raynaud phenomenon is seen in 5% to 10% of the general population. It more commonly affects women ages 15 to 30, is generally mild, involves the digits symmetrically, and is sometimes familial. An increase in alpha-2 adrenergic responses in the digital vessels leads to arterial vasospasm, an exaggerated physiologic response to cold temperatures.2 Geographic variability in prevalence likely represents differences in mean outdoor temperatures,3 which is in part why attacks of primary Raynaud phenomenon tend to be worse in the winter months.4
Secondary Raynaud phenomenon
Raynaud phenomenon also often occurs in certain autoimmune rheumatic diseases (secondary Raynaud phenomenon): for example, it is seen in scleroderma (90% to 95% of patients), mixed connective tissue disease (85%), systemic lupus erythematosus (40%), antisynthetase syndrome (40%), and sometimes in patients with other autoimmune rheumatic diseases. It may also be seen in hematologic disorders (cryoglobulinemia, cryofibrinogenemia, paraproteinemias, cold agglutinin disease, and polycythemia rubra vera), and it can also result from environmental and occupational exposures (frostbite, use of vibrating tools) and from exposure to certain drugs and toxins, such as polyvinyl chloride (Figure 2).
Acrocyanosis, a benign neurohormonal condition, should be included in the differential diagnosis for Raynaud phenomenon. Raynaud phenomenon is episodic, whereas acrocyanosis leads to persistent cyanosis of the acral body parts (fingers, toes) that is exacerbated by cold temperatures. However, the trophic skin changes, localized pain, and ulceration are not seen in acrocyanosis.
NAILFOLD CAPILLAROSCOPY: A KEY PART OF THE WORKUP
Nailfold capillaroscopy should be part of the evaluation of patients with Raynaud phenomenon (Figure 3), as it is one of the most reliable tests for distinguishing between primary and secondary Raynaud phenomenon.5 The sensitivity of the American College of Rheumatology classification criteria for systemic sclerosis increases significantly with the addition of nailfold capillary abnormalities.6,7
A stereomicroscope or videocapillaroscope is usually recommended to evaluate nailfold capillary morphology,5 but if such equipment is not available, a regular ophthalmoscope (with the lens set at 20 diopters or higher for better resolution) can serve the purpose at the bedside.8 A drop of mineral oil is placed on the nailfold to improve the image resolution, as it makes the horny layer of the cuticle transparent.
Abnormal patterns include dilated and enlarged capillary loops, disorganized capillaries, “dropouts” (avascular areas), microhemorrhages, and arborized capillaries (Figure 3).5 At no additional cost, the presence of these microvascular changes would add to the suspicion of secondary Raynaud phenomenon (negative predictive value of 93%).9 In addition, evolving capillaroscopic changes can be seen during follow-up visits, indicating the progressive nature of the microvasculopathy seen in these autoimmune rheumatic diseases.10
ADDITIONAL TESTING
If an underlying autoimmune rheumatic disease is suspected, laboratory testing should include a complete blood cell count, an erythrocyte sedimentation rate, and an antinuclear antibody (ANA) assay. If the ANA assay is negative, no further testing is usually necessary; however, a positive test should alert the clinician to consider an underlying autoimmune rheumatic process (negative predictive value of 93%).9 In a patient presenting with Raynaud phenomenon, a positive ANA test (even in the absence of other symptoms) warrants more frequent follow-up, urinalysis, and perhaps referral to a rheumatologist.
In the case of a positive ANA test, before ordering additional autoantibody tests, it is useful to consider the relevant non-Raynaud clinical manifestations. Indiscriminate ordering of a battery of autoantibodies should be avoided because of significant added cost and because it is not likely to provide additional information to guide management.
On the other hand, these more specific antibody tests may be of value in confirming the diagnosis suggested by the clinical profile of specific autoimmune rheumatic diseases, eg, anti-double-stranded DNA11 and anti-Smith12 antibodies for lupus, anti-topoisomerase I (Scl-70) and anti-centromere antibodies for scleroderma, 13 and anti-synthetase (eg, anti-Jo-1) antibodies for autoimmune myositis.14,15
- Raynaud M. On local asphyxia and symmetrical gangrene of the extremities (1862), and new research on the nature and treatment of local asphyxia of the extremities (1872).Barlow T, trans. Selected monographs (121). London: New Sydenham Society, 1988.
- Boin F, Wigley FM. Understanding, assessing and treating Raynaud’s phenomenon. Curr Opin Rheumatol 2005; 17:752–760.
- Maricq HR, Carpentier PH, Weinrich MC, et al. Geographic variation in the prevalence of Raynaud’s phenomenon: a 5-region comparison. J Rheumatol 1997; 24:879–889.
- Wigley FM. Clinical practice. Raynaud’s phenomenon. N Engl J Med 2002; 347:1001–1018.
- Cutolo M, Pizzorni C, Sulli A. Capillaroscopy. Best Pract Res Clin Rheumatol 2005; 19:437–452.
- Lonzetti LS, Joyal F, Raynauld JP, et al. Updating the American College of Rheumatology preliminary classification criteria for systemic sclerosis: addition of severe nailfold capillaroscopy abnormalities markedly increases the sensitivity for limited scleroderma. Arthritis Rheum 2001; 44:735–736.
- Hudson M, Taillefer S, Steele R, et al. Improving the sensitivity of the American College of Rheumatology classification criteria for systemic sclerosis. Clin Exp Rheumatol 2007; 25:754–757.
- Anders HJ, Sigl T, Schattenkirchner M. Differentiation between primary and secondary Raynaud’s phenomenon: a prospective study comparing nailfold capillaroscopy using an ophthalmoscope or stereomicroscope. Ann Rheum Dis 2001; 60:407–409.
- Spencer-Green G. Outcomes in primary Raynaud phenomenon: a meta-analysis of the frequency, rates, and predictors of transition to secondary diseases. Arch Intern Med 1998; 158:595–600.
- Wong ML, Highton J, Palmer DG. Sequential nailfold capillary microscopy in scleroderma and related disorders. Ann Rheum Dis 1988; 47:53–61.
- Weinstein A, Bordwell B, Stone B, Tibbetts C, Rothfield NF. Antibodies to native DNA and serum complement (C3) levels. Application to diagnosis and classification of systemic lupus erythematosus. Am J Med 1983; 74:206–216.
- Craft J. Antibodies to snRNPs in systemic lupus erythematosus. Rheum Dis Clin North Am 1992; 18:311–335.
- Weiner ES, Hildebrandt S, Senécal JL, et al. Prognostic significance of anticentromere antibodies and anti-topoisomerase I antibodies in Raynaud’s disease. A prospective study. Arthritis Rheum 1991; 34:68–77.
- Miller FW, Twitty SA, Biswas T, Plotz PH. Origin and regulation of a disease-specific autoantibody response. Antigenic epitopes, spectrotype stability, and isotype restriction of anti-Jo-1 autoantibodies. J Clin Invest 1990; 85:468–475.
- Ghirardello A, Zampieri S, Tarricone E, et al. Clinical implications of autoantibody screening in patients with autoimmune myositis. Autoimmunity 2006; 39:217–221.
- Raynaud M. On local asphyxia and symmetrical gangrene of the extremities (1862), and new research on the nature and treatment of local asphyxia of the extremities (1872).Barlow T, trans. Selected monographs (121). London: New Sydenham Society, 1988.
- Boin F, Wigley FM. Understanding, assessing and treating Raynaud’s phenomenon. Curr Opin Rheumatol 2005; 17:752–760.
- Maricq HR, Carpentier PH, Weinrich MC, et al. Geographic variation in the prevalence of Raynaud’s phenomenon: a 5-region comparison. J Rheumatol 1997; 24:879–889.
- Wigley FM. Clinical practice. Raynaud’s phenomenon. N Engl J Med 2002; 347:1001–1018.
- Cutolo M, Pizzorni C, Sulli A. Capillaroscopy. Best Pract Res Clin Rheumatol 2005; 19:437–452.
- Lonzetti LS, Joyal F, Raynauld JP, et al. Updating the American College of Rheumatology preliminary classification criteria for systemic sclerosis: addition of severe nailfold capillaroscopy abnormalities markedly increases the sensitivity for limited scleroderma. Arthritis Rheum 2001; 44:735–736.
- Hudson M, Taillefer S, Steele R, et al. Improving the sensitivity of the American College of Rheumatology classification criteria for systemic sclerosis. Clin Exp Rheumatol 2007; 25:754–757.
- Anders HJ, Sigl T, Schattenkirchner M. Differentiation between primary and secondary Raynaud’s phenomenon: a prospective study comparing nailfold capillaroscopy using an ophthalmoscope or stereomicroscope. Ann Rheum Dis 2001; 60:407–409.
- Spencer-Green G. Outcomes in primary Raynaud phenomenon: a meta-analysis of the frequency, rates, and predictors of transition to secondary diseases. Arch Intern Med 1998; 158:595–600.
- Wong ML, Highton J, Palmer DG. Sequential nailfold capillary microscopy in scleroderma and related disorders. Ann Rheum Dis 1988; 47:53–61.
- Weinstein A, Bordwell B, Stone B, Tibbetts C, Rothfield NF. Antibodies to native DNA and serum complement (C3) levels. Application to diagnosis and classification of systemic lupus erythematosus. Am J Med 1983; 74:206–216.
- Craft J. Antibodies to snRNPs in systemic lupus erythematosus. Rheum Dis Clin North Am 1992; 18:311–335.
- Weiner ES, Hildebrandt S, Senécal JL, et al. Prognostic significance of anticentromere antibodies and anti-topoisomerase I antibodies in Raynaud’s disease. A prospective study. Arthritis Rheum 1991; 34:68–77.
- Miller FW, Twitty SA, Biswas T, Plotz PH. Origin and regulation of a disease-specific autoantibody response. Antigenic epitopes, spectrotype stability, and isotype restriction of anti-Jo-1 autoantibodies. J Clin Invest 1990; 85:468–475.
- Ghirardello A, Zampieri S, Tarricone E, et al. Clinical implications of autoantibody screening in patients with autoimmune myositis. Autoimmunity 2006; 39:217–221.
Right upper-abdominal pain in a 97-year-old
A 97-year-old man has had right upper-abdominal pain intermittently for 2 weeks. He has hypertension, stage IV chronic kidney disease, chronic obstructive pulmonary disease, and constipation. He has never had abdominal surgery.
He describes his pain as mild and dull. It does not radiate to the right lower quadrant or the back and is not aggravated by eating. He reports no fever or changes in appetite or bowel habits during the last 2 weeks. His body temperature is 36.8°C, blood pressure 114/68 mm Hg, heart rate 86 beats per minute, and respiratory rate 16 times per minute.
On physical examination, his abdomen is soft with no guarding and with hypoactive bowel sounds. No Murphy sign is noted. Hemography shows a normal white blood cell count of 7.8 × 109/L) (reference range 4.5–11.0). Serum biochemistry studies show an alanine transaminase level of 23 U/L (5–50) and a lipase level of 40 U/L (12–70); the C-reactive protein level is 0.5 mg/dL (0.0–1.0). A sitting chest radiograph shows a focal gas collection over the right subdiaphragmatic area (Figure 1).
Q: Based on the information above, which is most likely the cause of this man’s upper-abdominal pain?
- Perforated viscera
- Diverticulitis
- Chilaiditi syndrome
- Subdiaphragmatic abscess
- Emphysematous cholecystitis
A: The workup of this patient did not indicate active disease, so the subphrenic gas on the radiograph most likely is the Chilaiditi sign. This is a benign finding that, in a patient with gastrointestinal symptoms (nausea, vomiting, constipation, upper-abdominal pain), is labeled Chilaiditi syndrome.
CHILAIDITI SIGN AND SYNDROME
The Chilaiditi sign1 describes a benign, incidental radiologic finding of subphrenic gas caused by interposition of colonic segments (or small intestine in rare cases) between the liver and the diaphragm. The radiologic finding is called the Chilaiditi sign if the patient is asymptomatic or Chilaiditi syndrome if the patient has gastrointestinal symptoms, as our patient did. The Chilaiditi sign is reportedly found in 0.02% to 0.2% of all chest and abdominal films.
Chilaiditi syndrome has a male predominance.2 Predisposing factors include an atrophic liver, laxity of the hepatic or the transverse colon suspension ligament, abnormal fixation of the mesointestine, and diaphragmatic weakness. Other factors include advanced age; a history of abdominal surgery, adhesion, or intestinal obstruction3; chronic lung disease; and cirrhosis.4
Management is usually conservative, with a prokinetic agent or enema for constipation, and bed-rest or bowel decompression as needed, unless complications occur. Our patient’s extreme age, underlying chronic pulmonary disease, and constipation predisposed him to this rare gastrointestinal disorder.
In this patient, pain in the right upper quadrant initially suggested an inflammatory disorder involving the liver, gallbladder, and transverse or ascending colon. Right upper-quadrant pain with radiologic evidence of subphrenic air collection further raises suspicion of pneumoperitoneum from diverticulitis, bowel perforation, or gas-forming abscess. However, this patient’s normal transaminase level, low C-reactive protein value, and prolonged symptom course made hepatitis, cholecystitis, diverticulitis, and subdiaphragmatic abscess less likely. Nonetheless, severe intra-abdominal pathology can sometimes manifest with only minor symptoms in very elderly patients. Consequently, the main concern in this scenario was whether he had minor and undetected perforated viscera causing pneumoperitoneum with an indolent course, or rather a benign condition such as Chilaiditi syndrome causing pain and subphrenic air.
IS IT CHILAIDITI SYNDROME OR PNEUMOPERITONEUM?
Chilaiditi syndrome and perforated viscera both involve subphrenic air, but they differ radiologically and clinically. Radiologically, identification of haustra or plicae circulares within the gas collection or fixed subphrenic air upon postural change indicates the Chilaiditi sign and favors Chilaiditi syndrome as the origin of the symptoms. Pneumoperitoneum from perforated viscera is more likely if the abnormal gas collection changes its position upon postural change. Abdominal ultrasonography can also assist in diagnosis by showing a fixed air collection around the hepatic surface in the Chilaiditi sign. Definite radiologic diagnosis can be reached through abdominal computed tomography. Clinically, these two disorders may manifest different severity, as perforated viscera often mandate surgical attention, whereas Chilaiditi syndrome seldom requires surgical treatment (25% of cases).2
Patients with the Chilaiditi sign also may develop abdominal pathology other than Chilaiditi syndrome per se. In our patient, the subphrenic air displayed a faint contour of bowel segments. His symptom course, benign physical examination, and the lack of laboratory evidence of other intra-abdominal pathology led us to suspect Chilaiditi syndrome as the cause of his abdominal pain. A normal leukocyte count and stable vital signs made the diagnosis of a major life-threatening condition extremely unlikely. Subsequently, abdominal sonography done at the bedside disclosed fixed colonic segments between the liver and the diaphragm. No hepatic or gallbladder lesions were detected. Chilaiditi syndrome was confirmed.
TAKE-HOME MESSAGE
As seen in this case, the accurate diagnosis rests on a careful physical examination and laboratory evaluation but, most importantly, on sound clinical judgment. Right upper-quadrant pain is often encountered in primary care practice and has many diagnostic possibilities, including benign, self-limited conditions such as Chilaiditi syndrome. It is vital to distinguish between benign conditions and severe life-threatening disorders such as hollow organ perforation so as not to operate on patients who can be managed conservatively.
- Chilaiditi D. Zur Frage der Hepatoptose und Ptose in allegemeinen in Anschluss an drei Fälle von temporärer, partieller Lebersverlagerung. Fortschr Geb Röntgenstr Nuklearmed Erganzungsband 1910; 16:173–208.
- Saber AA, Boros MJ. Chilaiditi’s syndrome: what should every surgeon know? Am Surg 2005; 71:261–263.
- Lo BM. Radiographic look-alikes: distinguishing between pneumoperitoneum and pseudopneumoperitoneum. J Emerg Med 2010; 38:36–39.
- Fisher AA, Davis MW. An elderly man with chest pain, shortness of breath, and constipation. Postgrad Med J 2003; 79:180,183–184.
A 97-year-old man has had right upper-abdominal pain intermittently for 2 weeks. He has hypertension, stage IV chronic kidney disease, chronic obstructive pulmonary disease, and constipation. He has never had abdominal surgery.
He describes his pain as mild and dull. It does not radiate to the right lower quadrant or the back and is not aggravated by eating. He reports no fever or changes in appetite or bowel habits during the last 2 weeks. His body temperature is 36.8°C, blood pressure 114/68 mm Hg, heart rate 86 beats per minute, and respiratory rate 16 times per minute.
On physical examination, his abdomen is soft with no guarding and with hypoactive bowel sounds. No Murphy sign is noted. Hemography shows a normal white blood cell count of 7.8 × 109/L) (reference range 4.5–11.0). Serum biochemistry studies show an alanine transaminase level of 23 U/L (5–50) and a lipase level of 40 U/L (12–70); the C-reactive protein level is 0.5 mg/dL (0.0–1.0). A sitting chest radiograph shows a focal gas collection over the right subdiaphragmatic area (Figure 1).
Q: Based on the information above, which is most likely the cause of this man’s upper-abdominal pain?
- Perforated viscera
- Diverticulitis
- Chilaiditi syndrome
- Subdiaphragmatic abscess
- Emphysematous cholecystitis
A: The workup of this patient did not indicate active disease, so the subphrenic gas on the radiograph most likely is the Chilaiditi sign. This is a benign finding that, in a patient with gastrointestinal symptoms (nausea, vomiting, constipation, upper-abdominal pain), is labeled Chilaiditi syndrome.
CHILAIDITI SIGN AND SYNDROME
The Chilaiditi sign1 describes a benign, incidental radiologic finding of subphrenic gas caused by interposition of colonic segments (or small intestine in rare cases) between the liver and the diaphragm. The radiologic finding is called the Chilaiditi sign if the patient is asymptomatic or Chilaiditi syndrome if the patient has gastrointestinal symptoms, as our patient did. The Chilaiditi sign is reportedly found in 0.02% to 0.2% of all chest and abdominal films.
Chilaiditi syndrome has a male predominance.2 Predisposing factors include an atrophic liver, laxity of the hepatic or the transverse colon suspension ligament, abnormal fixation of the mesointestine, and diaphragmatic weakness. Other factors include advanced age; a history of abdominal surgery, adhesion, or intestinal obstruction3; chronic lung disease; and cirrhosis.4
Management is usually conservative, with a prokinetic agent or enema for constipation, and bed-rest or bowel decompression as needed, unless complications occur. Our patient’s extreme age, underlying chronic pulmonary disease, and constipation predisposed him to this rare gastrointestinal disorder.
In this patient, pain in the right upper quadrant initially suggested an inflammatory disorder involving the liver, gallbladder, and transverse or ascending colon. Right upper-quadrant pain with radiologic evidence of subphrenic air collection further raises suspicion of pneumoperitoneum from diverticulitis, bowel perforation, or gas-forming abscess. However, this patient’s normal transaminase level, low C-reactive protein value, and prolonged symptom course made hepatitis, cholecystitis, diverticulitis, and subdiaphragmatic abscess less likely. Nonetheless, severe intra-abdominal pathology can sometimes manifest with only minor symptoms in very elderly patients. Consequently, the main concern in this scenario was whether he had minor and undetected perforated viscera causing pneumoperitoneum with an indolent course, or rather a benign condition such as Chilaiditi syndrome causing pain and subphrenic air.
IS IT CHILAIDITI SYNDROME OR PNEUMOPERITONEUM?
Chilaiditi syndrome and perforated viscera both involve subphrenic air, but they differ radiologically and clinically. Radiologically, identification of haustra or plicae circulares within the gas collection or fixed subphrenic air upon postural change indicates the Chilaiditi sign and favors Chilaiditi syndrome as the origin of the symptoms. Pneumoperitoneum from perforated viscera is more likely if the abnormal gas collection changes its position upon postural change. Abdominal ultrasonography can also assist in diagnosis by showing a fixed air collection around the hepatic surface in the Chilaiditi sign. Definite radiologic diagnosis can be reached through abdominal computed tomography. Clinically, these two disorders may manifest different severity, as perforated viscera often mandate surgical attention, whereas Chilaiditi syndrome seldom requires surgical treatment (25% of cases).2
Patients with the Chilaiditi sign also may develop abdominal pathology other than Chilaiditi syndrome per se. In our patient, the subphrenic air displayed a faint contour of bowel segments. His symptom course, benign physical examination, and the lack of laboratory evidence of other intra-abdominal pathology led us to suspect Chilaiditi syndrome as the cause of his abdominal pain. A normal leukocyte count and stable vital signs made the diagnosis of a major life-threatening condition extremely unlikely. Subsequently, abdominal sonography done at the bedside disclosed fixed colonic segments between the liver and the diaphragm. No hepatic or gallbladder lesions were detected. Chilaiditi syndrome was confirmed.
TAKE-HOME MESSAGE
As seen in this case, the accurate diagnosis rests on a careful physical examination and laboratory evaluation but, most importantly, on sound clinical judgment. Right upper-quadrant pain is often encountered in primary care practice and has many diagnostic possibilities, including benign, self-limited conditions such as Chilaiditi syndrome. It is vital to distinguish between benign conditions and severe life-threatening disorders such as hollow organ perforation so as not to operate on patients who can be managed conservatively.
A 97-year-old man has had right upper-abdominal pain intermittently for 2 weeks. He has hypertension, stage IV chronic kidney disease, chronic obstructive pulmonary disease, and constipation. He has never had abdominal surgery.
He describes his pain as mild and dull. It does not radiate to the right lower quadrant or the back and is not aggravated by eating. He reports no fever or changes in appetite or bowel habits during the last 2 weeks. His body temperature is 36.8°C, blood pressure 114/68 mm Hg, heart rate 86 beats per minute, and respiratory rate 16 times per minute.
On physical examination, his abdomen is soft with no guarding and with hypoactive bowel sounds. No Murphy sign is noted. Hemography shows a normal white blood cell count of 7.8 × 109/L) (reference range 4.5–11.0). Serum biochemistry studies show an alanine transaminase level of 23 U/L (5–50) and a lipase level of 40 U/L (12–70); the C-reactive protein level is 0.5 mg/dL (0.0–1.0). A sitting chest radiograph shows a focal gas collection over the right subdiaphragmatic area (Figure 1).
Q: Based on the information above, which is most likely the cause of this man’s upper-abdominal pain?
- Perforated viscera
- Diverticulitis
- Chilaiditi syndrome
- Subdiaphragmatic abscess
- Emphysematous cholecystitis
A: The workup of this patient did not indicate active disease, so the subphrenic gas on the radiograph most likely is the Chilaiditi sign. This is a benign finding that, in a patient with gastrointestinal symptoms (nausea, vomiting, constipation, upper-abdominal pain), is labeled Chilaiditi syndrome.
CHILAIDITI SIGN AND SYNDROME
The Chilaiditi sign1 describes a benign, incidental radiologic finding of subphrenic gas caused by interposition of colonic segments (or small intestine in rare cases) between the liver and the diaphragm. The radiologic finding is called the Chilaiditi sign if the patient is asymptomatic or Chilaiditi syndrome if the patient has gastrointestinal symptoms, as our patient did. The Chilaiditi sign is reportedly found in 0.02% to 0.2% of all chest and abdominal films.
Chilaiditi syndrome has a male predominance.2 Predisposing factors include an atrophic liver, laxity of the hepatic or the transverse colon suspension ligament, abnormal fixation of the mesointestine, and diaphragmatic weakness. Other factors include advanced age; a history of abdominal surgery, adhesion, or intestinal obstruction3; chronic lung disease; and cirrhosis.4
Management is usually conservative, with a prokinetic agent or enema for constipation, and bed-rest or bowel decompression as needed, unless complications occur. Our patient’s extreme age, underlying chronic pulmonary disease, and constipation predisposed him to this rare gastrointestinal disorder.
In this patient, pain in the right upper quadrant initially suggested an inflammatory disorder involving the liver, gallbladder, and transverse or ascending colon. Right upper-quadrant pain with radiologic evidence of subphrenic air collection further raises suspicion of pneumoperitoneum from diverticulitis, bowel perforation, or gas-forming abscess. However, this patient’s normal transaminase level, low C-reactive protein value, and prolonged symptom course made hepatitis, cholecystitis, diverticulitis, and subdiaphragmatic abscess less likely. Nonetheless, severe intra-abdominal pathology can sometimes manifest with only minor symptoms in very elderly patients. Consequently, the main concern in this scenario was whether he had minor and undetected perforated viscera causing pneumoperitoneum with an indolent course, or rather a benign condition such as Chilaiditi syndrome causing pain and subphrenic air.
IS IT CHILAIDITI SYNDROME OR PNEUMOPERITONEUM?
Chilaiditi syndrome and perforated viscera both involve subphrenic air, but they differ radiologically and clinically. Radiologically, identification of haustra or plicae circulares within the gas collection or fixed subphrenic air upon postural change indicates the Chilaiditi sign and favors Chilaiditi syndrome as the origin of the symptoms. Pneumoperitoneum from perforated viscera is more likely if the abnormal gas collection changes its position upon postural change. Abdominal ultrasonography can also assist in diagnosis by showing a fixed air collection around the hepatic surface in the Chilaiditi sign. Definite radiologic diagnosis can be reached through abdominal computed tomography. Clinically, these two disorders may manifest different severity, as perforated viscera often mandate surgical attention, whereas Chilaiditi syndrome seldom requires surgical treatment (25% of cases).2
Patients with the Chilaiditi sign also may develop abdominal pathology other than Chilaiditi syndrome per se. In our patient, the subphrenic air displayed a faint contour of bowel segments. His symptom course, benign physical examination, and the lack of laboratory evidence of other intra-abdominal pathology led us to suspect Chilaiditi syndrome as the cause of his abdominal pain. A normal leukocyte count and stable vital signs made the diagnosis of a major life-threatening condition extremely unlikely. Subsequently, abdominal sonography done at the bedside disclosed fixed colonic segments between the liver and the diaphragm. No hepatic or gallbladder lesions were detected. Chilaiditi syndrome was confirmed.
TAKE-HOME MESSAGE
As seen in this case, the accurate diagnosis rests on a careful physical examination and laboratory evaluation but, most importantly, on sound clinical judgment. Right upper-quadrant pain is often encountered in primary care practice and has many diagnostic possibilities, including benign, self-limited conditions such as Chilaiditi syndrome. It is vital to distinguish between benign conditions and severe life-threatening disorders such as hollow organ perforation so as not to operate on patients who can be managed conservatively.
- Chilaiditi D. Zur Frage der Hepatoptose und Ptose in allegemeinen in Anschluss an drei Fälle von temporärer, partieller Lebersverlagerung. Fortschr Geb Röntgenstr Nuklearmed Erganzungsband 1910; 16:173–208.
- Saber AA, Boros MJ. Chilaiditi’s syndrome: what should every surgeon know? Am Surg 2005; 71:261–263.
- Lo BM. Radiographic look-alikes: distinguishing between pneumoperitoneum and pseudopneumoperitoneum. J Emerg Med 2010; 38:36–39.
- Fisher AA, Davis MW. An elderly man with chest pain, shortness of breath, and constipation. Postgrad Med J 2003; 79:180,183–184.
- Chilaiditi D. Zur Frage der Hepatoptose und Ptose in allegemeinen in Anschluss an drei Fälle von temporärer, partieller Lebersverlagerung. Fortschr Geb Röntgenstr Nuklearmed Erganzungsband 1910; 16:173–208.
- Saber AA, Boros MJ. Chilaiditi’s syndrome: what should every surgeon know? Am Surg 2005; 71:261–263.
- Lo BM. Radiographic look-alikes: distinguishing between pneumoperitoneum and pseudopneumoperitoneum. J Emerg Med 2010; 38:36–39.
- Fisher AA, Davis MW. An elderly man with chest pain, shortness of breath, and constipation. Postgrad Med J 2003; 79:180,183–184.