Personalized healthcare is the tailoring of medical management and patient care to the individual characteristics of each patient. This is achieved by incorporating the genetic and genomic makeup of an individual and his or her family medical history, environment, health-related behaviors, culture, and values into a complete health picture that can be used to customize care. Another level of personalization, often called personalized medicine, involves the selection of drug therapy through the use of tests to determine the genes and gene interactions that can reliably predict an individual’s response to a given therapy. This white paper focuses largely on the use of personalized healthcare as a risk prediction tool.

CURRENT STATUS OF PERSONALIZED HEALTHCARE

Practitioners and consumers in today’s healthcare setting do not yet fully recognize the potential benefits of personalized healthcare (Table 1¹). Further, proposals for reform tend to be reactive rather than proactive. Family history is well validated as a tool to predict risk for disease, but, in some instances, genomic information may enhance risk prediction provided by family history. The trial-and-error approach now used to treat disease is costly, but genomic testing has the potential to save money through more effective use of diagnostic tests, counseling about medical management based on gene test results, and prescribing of medications.

The case for personalized healthcare: Seeking value

To fully appreciate the need to advance the adoption of personalized healthcare into the delivery of medicine, one must consider the operation of our current healthcare system and its inefficiencies in terms of delivery and cost, its imprecision in the selection of therapies, and its inability to optimize outcomes. The framework of the US healthcare system as it is now constructed is expensive, disease-directed (instead of health- and wellness-directed), fragmented, and complex. While gross domestic product (GDP) in the United States has increased by approximately 3% per year,² the compounded growth rate of healthcare expenditures is 6.1% per year. Healthcare in the aggregate now represents 17.6% of GDP and 27% of spending by the federal government and consumes 28% of the average household’s discretionary spending, surpassed only by housing.³

Personalized healthcare can potentially address the need for value consistent with the healthcare system’s prominent share of the US economy. The growth in healthcare spending is certain to be a target of the newly created Joint Select Committee on Deficit Reduction (created by the Budget Control Act of 2011), which is tasked with deficit reduction of at least $1.5 trillion over a 10-year period.

The need to address healthcare costs has been recognized in the Patient Protection and Affordable Care Act, a central feature of which is the creation of integrated health systems that pay for value based on quality, cost containment, and consumer experience. The legislation was enacted to transform healthcare in a variety of ways to make it more sustainable. The Patient Protection and Affordable Care Act seeks to end fragmentation by expanding the use of information technology to reorganize the delivery system and to prevent errors, shifting from volume-based incentives to incentives based on performance and outcomes, and rewarding effective healthcare delivery measures and good patient outcomes.

A shift from reactive to proactive

The premise behind personalized healthcare is the potential for more efficient healthcare, with the assumption that efficiency translates to lower cost and improved patient care.

Although healthcare reform is most often referred to in the context of improving access to care through insurance coverage mandates, true healthcare reform shifts current healthcare models from the practice of reactive medicine to the practice of proactive medicine, in which the tools of personalized healthcare (ie, genetics, genomics, and other molecular diagnostics) enable not only better quality of care but also less expensive care.

Several personalized tools have long been accepted into mainstream medicine. Two examples are the family history, which is the least expensive and most available genetic evaluation tool, and ABO blood typing for safe transfusions (as ABO blood types are alleles of a gene). In fact, much of what is now considered mainstream medical management was at one time considered new. To allow further evolution of medical practice, our challenge is to open our minds to the possibility that personalized proactive medicine can improve healthcare.

The new vision: More precise management

The trial-and-error approach to treating disease is inefficient and costly. Many drugs are effective for only about 50% of patients, often leading to switching or intensification of therapy that requires multiple patient visits.

Personalized medicine considers pharmacokinetic and other characteristics in selection of drug dosages. Genomic testing has the potential to provide clearer insight into the more successful use of currently available medicines. Treatment decisions (ie, drug and drug dosage choice) made on the basis of pharmacogenomic testing should increase adherence through greater effectiveness and fewer adverse drug reactions.

A massive amount of waste is related to pharmaceutical nonadherence and noncompliance. The New England Healthcare Institute has estimated that medication nonadherence costs the healthcare system $290 billion annually.⁴ Methodologies targeted at individual patients to improve adherence to drug regimens could save the healthcare system a tremendous amount of money.

Cancer management as a model for personalized healthcare. Personalization of therapy is especially suited to cancer management, given that the response to nonspecific cancer chemotherapy is suboptimal in most patients yet exposes them to adverse effects.⁵ Large-scale sequencing of human cancer genomes is rapidly changing the understanding of cancer biology and is identifying new targets in difficult-to-treat diseases and causes of drug resistance. Applying this information can achieve cost savings by avoiding the use of treatments that are ineffective in particular patients.

Overexpression of genetic mutations renders some cancers less susceptible to certain treatments, but has opened the door to individualized molecularly guided treatment strategies. For example, among patients with non–small cell lung cancer, mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain predict response to EGFR tyrosine kinase inhibitors, and anaplastic lymphoma kinase (ALK) inhibitors induce response in patients harboring a mutation in EML4-ALK genes. The recognition that human epidermal growth factor receptor (HER)-2 overexpression as a result of ERBB2 gene amplification occurs in as many as 20% of human breast cancers paved the way for the development of HER-2–targeted therapies. Patients with advanced colorectal cancer whose tumors express the KRAS gene mutation do not benefit from an EGFR inhibitor, whereas those with wild-type KRAS have improved survival with EGFR inhibitor treatment.⁶

 

BARRIERS TO THE APPLICATION OF PERSONALIZED HEALTHCARE

The availability and potential of personalized healthcare services and technology is not universally recognized or appreciated by consumers and clinicians. This lack of awareness contributes to a shortage of public support and limited demand for such services. Other barriers include misperceptions regarding the impact of personalized healthcare on disease management, limited incentives to use the available technology, and a knowledge gap among healthcare providers.

Lack of awareness and support

As applications of personalized healthcare advance to the point of clinical relevance, it is important to consider strategies for effective implementation into healthcare practice. Personalized healthcare, when more fully implemented, promises to accelerate the progress that healthcare reform hopes to achieve.

A major challenge to widespread adoption of personalized healthcare is limited recognition by the public and some healthcare providers that personalized healthcare can help to achieve better value. For personalized medicine to be embraced, the concept of “helix to health,” or translation of knowledge to the clinical setting, must resonate with the general public. Despite lack of public and provider awareness, the Personalized Medicine Coalition (PMC) has documented the existence of 56 personalized treatment and diagnostic products. Further, more than 200 product labels now recommend genetic testing prior to use to identify likely responders or inform of the influence of genetic variation on safety and effectiveness.

Consumers’ confidence in the efficacy and safety of medicines they take might contribute to the absence of public support for personalized healthcare. Similarly, despite the availability of genomic tests and tools, many physicians who might be advocates for personalized healthcare do not see the relevance of genomic medicine to their practices in terms of direct benefit to patient care.⁷

Apart from clinicians and consumers, support is also weak among health insurers and employers, even though the return on investment for personalized healthcare may be profound. Payers await the economic outcomes data that are crucial for their commitment to personalized healthcare. In addition, some have concerns about the ethical implications of personalized healthcare (see “Managing Genomic Information Responsibly”).

Perception of impact on treatment and prevention

A frequent criticism of genomics in medicine is that a genetic diagnosis does not help with patient management. In fact, surveillance and management of patients and family members often changes in response to a genetic diagnosis; knowing which gene is involved personalizes medical management. An example is the management of hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch syndrome, which is the most common form of hereditary colon cancer. For a person with HNPCC, the lifetime risk of developing colorectal cancer is approximately 80%. Lynch syndrome is caused by germline mutations in one of three major mismatch repair (MMR) genes (MLH1, MSH2, and MSH6), and it predisposes to other cancers—uterine, stomach, and ovarian—as well. In women with Lynch syndrome, the lifetime risk for uterine cancer is 40%, compared with 4% in the general population.

At least 90% of patients with Lynch syndrome can be detected through MMR testing via microsatellite instability (MSI) or immunohistochemistry (IHC).⁸ MSI is a cellular phenotype that indicates a deficiency in at least one DNA MMR protein.

Although 5-fluorouracil–based chemo therapy is the standard of care for treatment of colorectal cancer, it confers no survival advantage in patients with MMR-IHC null (lack of expression of the gene) or MSI-high sporadic colorectal cancer.^9,10 Knowing the status of MMR proteins, therefore, would alter the decision regarding neoadjuvant and adjuvant chemotherapy.

Perception of value

Implementation of pharmacogenomics into clinical practice has lagged. One major reason is the lack of an obvious business model for a product that may only be required once in an individual patient’s lifetime.¹¹

A second barrier to integration lies in the limited demand for pharmacogenomics from physicians. This may be related partly to limited expertise in genetics among many physicians and to significant pushback from payers against today’s costs. Without reimbursement, little incentive exists for pharmacogenomics diagnostics. The incentive for physicians is further depressed, perhaps appropriately, when randomized controlled studies fail to demonstrate improved clinical outcomes with the use of pharmacogenomicbased treatment strategies. Two such examples are genotype-guided warfarin dosing, which failed in a randomized controlled trial to improve the proportion of international normalized ratios in the therapeutic range,¹² and dosing of clopidogrel based on platelet reactivity, which did not improve outcomes after percutaneous coronary intervention compared with standard dosing in a randomized double-blind clinical trial.¹³

A significant delay in obtaining the results of pharmacogenomics testing, which also postpones the prescribing encounter, is another major drawback.

A knowledge gap persists

At present, delivery of personalized healthcare is not part of the usual training of physicians and other healthcare providers who are the gatekeepers of medicine. Few medical schools incorporate human and medical genetics, genomics, and pharmacogenomics into their curricula. Genetics is inadequately emphasized in residency curricula outside of pediatrics, family medicine, and obstetrics/gynecology.

The resulting knowledge gap is a fundamental factor in the lack of interest in using genomics in clinical medicine. Educating consumers and physicians at all levels, including specialty societies as well as insurers, will be key to expanding utilization of personalized healthcare. Educating payers and providing them with more data on economic outcomes associated with personalized healthcare will be necessary for adoption into clinical practice; implementation will lag as long as reimbursement decisions do not support personalized approaches to medicine.

As DNA sequencing technology has become less expensive and more powerful, companies have begun to market personal genomic testing. As a result, patients who use these services will increasingly want to discuss the results with their physicians. A significant number of clinicians are unfamiliar with personal genomic testing and emerging genetic testing options. In one survey of physicians who attended educational sessions that discussed recent developments in clinical genetics, only 37% indicated that they were familiar with recent genetic research that affected their patients.¹⁴

Targeted education will enhance physicians’ understanding of probabilities and risk estimates from the use of genomic testing; it will also improve recognition of potential causes of patient anxiety, gene variants of unknown significance, and follow-up tests and procedures that can add to expense. Nonphysician healthcare providers (ie, nurses and physician assistants) of direct care also will benefit from education.

 

INTEGRATING PERSONALIZED HEALTHCARE INTO CLINICAL PRACTICE

Practice standardization and an overhaul of the health information technology (HIT) infrastructure are needed if we are to reap the potential benefits of personalized healthcare. Creative approaches to practitioner education, which are being used in some institutions, must become more widespread. Similarly, the models for successful integration of personalized healthcare that have been achieved in some settings also can be implemented in other institutions.

Data collection and integration must be prioritized

Personalized healthcare can be both predictive and preventive, but moving past the disruptive phase of personalized healthcare will require a radical transformation of the healthcare “ecosystem” and HIT infrastructure.

Although data collection in the current system is extensive, data sharing and data management are inadequate. The pace at which HIT links clinical and genetic information must be accelerated. HIT will expedite innovation and implementation of personalized healthcare, allowing greater integration of data to permit improved data analysis capability. The ultimate goal is to create an interoperable system that connects these data across hospitals and clinicians to help clinicians interpret genomic and other risk information to better inform patient care.

Fully integrated health systems support better coordination of care and optimize the treatment of individual patients: linking research findings, treatment guidelines, treatment outcomes based on genetic profiles, and the individual patient’s own genetic profile will help to personalize treatments. Genomic information added to an individual’s electronic medical record along with improved data-sharing will facilitate clinicians’ ability to retrieve outcomes data based on patient characteristics.

Care models must be standardized, evidence-based practices must be executed, and care must be coordinated yet decentralized. In this way, clinicians can use the electronic medical record as an interoperable patient record to determine a personalized pathway to patient management. Standardization reduces variability in practice and permits seamless execution of care. Automation is imperative to achieving standardization, irrespective of the care supervisor. Investments must therefore be made to stimulate electronic medical record decision support.

In addition, larger data sets will be needed to identify the types of patients likely to respond to a treatment. Ideal data sets would be large enough to have adequate statistical power, be publicly available, standardize the collection of data with respect to response to therapy and toxicity, and contain data on concomitant collections of biologic samples.

Reimbursement must keep pace with medical advances

Payer willingness to reimburse for genomic tests and treatments will determine the pace of integration of personalized healthcare into clinical practice. Evidence that enhanced value can be derived from personalized approaches to medicine must be generated before personalized healthcare gains widespread acceptance by payers.

In addition, care-coordinated models must be developed to promote a value-based agenda that facilitates physician accountability and encourages clinical integration.

Innovative approaches are needed to educate providers

Development of point-of-care tools. Because information overload and lack of time are obstacles to clinicians’ efforts to incorporate genomic information into clinical practice, emphasis must be placed on genomic applications that have demonstrated utility. Engaging busy clinicians with point-of-care tools will maximize the relevance of the genomic information they receive and encourage effective use of their time. Decision-making should be supported through automatic risk assessment and management recommendations.

Educational tools. The National Coalition for Health Professional Education in Genetics (NCHPEG) was borne out of the recognition that the pace of genomic discovery far exceeds the pace at which healthcare providers can be educated. Its vision is to improve healthcare through informed use of genomic resources. NCHPEG is a member-based organization whose stakeholders include professional societies, hospitals, advocacy groups, and industry; it attempts to identify the specific educational needs for particular target audiences and then address these needs. It achieves its goals through the use of point-of-care tools and educational programs for continuing medical education credit.

One NCHPEG tool is the Pregnancy and Health Profile, which is a risk assessment and screening tool that attempts to improve the identification of women and babies at risk of developing genetic disease. It collects personal and family history information, performs a risk assessment for the clinician, and provides clinical decision support and education.

Another example of an educational tool is the “Genes to Society” curriculum initiated by The Johns Hopkins University School of Medicine in August 2009. The curriculum is being used as “the foundation for the scientific and clinical career development of future physicians.”¹⁵

Using personal genomic testing for education. The number of direct-to-consumer genomic tests is growing, and their market penetration will only increase as the cost of supplying a personal genome continues to decline. Whole genome scanning is being offered with the promise of identifying genetic predisposition to multiple diseases.

Participation in personal genomic testing may be a useful educational tool. Medical students, residents, and practicing physicians who participate in testing may be better equipped to advise patients about the processes involved and the potential utility and limitations of direct-to-consumer genotyping.¹⁴

Some companies that offer direct-to-consumer genomic testing provide telephone support from genetic counselors to help clients and their healthcare providers manage genetic information. Counselor services include identifying hereditary risks and reviewing diagnostic, preventive, and early-detection options.

Implementing pharmacogenomics into practice: Decision support systems are needed

A genomic decision support system that guides medication prescribing is needed to implement pharmacogenomic diagnostics. For such a system to achieve the goal of selecting the best medication for each individual, it must do the following:

• Test all polymorphisms relevant to the prescribing of any medication
• Be completed with no out-of-pocket cost to the patient
• Be performed before the patient requires the medication
• Provide results that will be interpreted as part of an individualized pharmacogenomics consult.¹¹

Many useful pharmacogenomic tests are based on cytochrome P450 metabolism phenotypes that are responsible for variance in response to drugs metabolized by this pathway. Others use human leukocyte antigen screening for hypersensitivity reactions to abacavir, carbamazepine, and allopurinol. Examples of pharmacogenomics tests appear in Table 2.

The 1200 Patients Project, a pilot research study under way at the Center for Personalized Therapeutics at the University of Chicago, is attempting to demonstrate the feasibility of incorporating pharmacogenomic testing into routine clinical practice for medication treatment decisions. DNA samples from patients who are taking at least one prescription medication are being tested for differences in genes that may suggest greater effectiveness or an increased risk of side effects from certain medications.

 

 

Solutions in practice

Cleveland Clinic’s genetics-based management of Lynch syndrome, the integration of genetics services during patient appointments at Cleveland Clinic, and a coordinated approach at The Ohio State University Medical Center are examples of practical applications of personalized healthcare.

Colorectal cancer management. One example of a personalized approach to medicine that improves health outcome while achieving cost savings is the genetics-based approach to HNPCC (Lynch syndrome) at Cleveland Clinic.

Early identification of Lynch syndrome by screening all colorectal cancer patients has been shown to save $250,000 per life-year gained in the United States.¹⁶ All colorectal cancers resected at the Cleveland Clinic main campus are routinely screened for MSI and IHC, and the process is embedded into the routine pathology workflow. With the patients’ foreknowledge, a gastrointestinal cancer genetics counselor scans the list of MSI and IHC results each week. Patients who are MSI-high or IHC-null are invited to receive genetic counseling and consider germline single-gene testing guided by the IHC results. With this active approach, patient uptake is 80%; in comparison, with a passive approach (MSI/IHC results are placed in the pathology report), the uptake is 14%¹⁷ (B. Leach and C. Eng, unpublished data, 2011).The successful application of the active approach requires the close cooperation of multiple disciplines, including members of the Cleveland Clinic Genomic Medicine, Pathology & Laboratory Medicine, and Digestive Disease Institutes.¹⁸

Integrating genetics-based care at Cleveland Clinic. Time delays for genetics services and limited collaboration with managing physicians who are not genetics specialists reduces genetics-based access and availability. Broad access to genetics clinical services is a means of clinical integration of genetics-enabled care. Providing patients and healthcare providers with easy access and short wait times is vital for clinical integration of genetics-enabled personalized healthcare.

As part of a patient-centered focus on medicine, clinical genetics services have been integrated throughout Cleveland Clinic. The system has two genetics clinics at its main campus and has embedded multiple genetics satellites within its nongenetics clinics, easing access. Genetics counselors are stationed in the same areas of practice as referring providers. Although patient encounters have increased at the medical genetics clinic in the Genomic Medicine Institute, genetics consultations no longer require an extra trip to the clinic since they are integrated into existing appointments. With this approach, large numbers of patients can be seen with no wait times.

Coordinated care at The Ohio State University Medical Center. The Center for Personalized Health Care at The Ohio State University Medical Center (OSUMC) embraces a systems-based care-coordinated model that improves care by executing standardized processes and automating routine tasks. The Institute for Systems Biology, which was established to develop genomics, wellness, and chronic disease biomarkers, collaborates with OSUMC on pilot projects in chronic disease, including cancer.

The OSUMC has a closed system in which it is the payer, employer, and provider of healthcare. This closed system serves as an ideal testing ground for reform. Goals include intervention in disease before symptoms appear and maintenance of wellness. The data from these demonstration projects should facilitate adoption of personalized healthcare by improving physician acceptance of personalized approaches and satisfying payers that personalized healthcare is cost-effective.

Personalized healthcare is the tailoring of medical management and patient care to the individual characteristics of each patient. This is achieved by incorporating the genetic and genomic makeup of an individual and his or her family medical history, environment, health-related behaviors, culture, and values into a complete health picture that can be used to customize care. Another level of personalization, often called personalized medicine, involves the selection of drug therapy through the use of tests to determine the genes and gene interactions that can reliably predict an individual’s response to a given therapy. This white paper focuses largely on the use of personalized healthcare as a risk prediction tool.

CURRENT STATUS OF PERSONALIZED HEALTHCARE

Practitioners and consumers in today’s healthcare setting do not yet fully recognize the potential benefits of personalized healthcare (Table 1¹). Further, proposals for reform tend to be reactive rather than proactive. Family history is well validated as a tool to predict risk for disease, but, in some instances, genomic information may enhance risk prediction provided by family history. The trial-and-error approach now used to treat disease is costly, but genomic testing has the potential to save money through more effective use of diagnostic tests, counseling about medical management based on gene test results, and prescribing of medications.

The case for personalized healthcare: Seeking value

To fully appreciate the need to advance the adoption of personalized healthcare into the delivery of medicine, one must consider the operation of our current healthcare system and its inefficiencies in terms of delivery and cost, its imprecision in the selection of therapies, and its inability to optimize outcomes. The framework of the US healthcare system as it is now constructed is expensive, disease-directed (instead of health- and wellness-directed), fragmented, and complex. While gross domestic product (GDP) in the United States has increased by approximately 3% per year,² the compounded growth rate of healthcare expenditures is 6.1% per year. Healthcare in the aggregate now represents 17.6% of GDP and 27% of spending by the federal government and consumes 28% of the average household’s discretionary spending, surpassed only by housing.³

Personalized healthcare can potentially address the need for value consistent with the healthcare system’s prominent share of the US economy. The growth in healthcare spending is certain to be a target of the newly created Joint Select Committee on Deficit Reduction (created by the Budget Control Act of 2011), which is tasked with deficit reduction of at least $1.5 trillion over a 10-year period.

The need to address healthcare costs has been recognized in the Patient Protection and Affordable Care Act, a central feature of which is the creation of integrated health systems that pay for value based on quality, cost containment, and consumer experience. The legislation was enacted to transform healthcare in a variety of ways to make it more sustainable. The Patient Protection and Affordable Care Act seeks to end fragmentation by expanding the use of information technology to reorganize the delivery system and to prevent errors, shifting from volume-based incentives to incentives based on performance and outcomes, and rewarding effective healthcare delivery measures and good patient outcomes.

A shift from reactive to proactive

The premise behind personalized healthcare is the potential for more efficient healthcare, with the assumption that efficiency translates to lower cost and improved patient care.

Although healthcare reform is most often referred to in the context of improving access to care through insurance coverage mandates, true healthcare reform shifts current healthcare models from the practice of reactive medicine to the practice of proactive medicine, in which the tools of personalized healthcare (ie, genetics, genomics, and other molecular diagnostics) enable not only better quality of care but also less expensive care.

Several personalized tools have long been accepted into mainstream medicine. Two examples are the family history, which is the least expensive and most available genetic evaluation tool, and ABO blood typing for safe transfusions (as ABO blood types are alleles of a gene). In fact, much of what is now considered mainstream medical management was at one time considered new. To allow further evolution of medical practice, our challenge is to open our minds to the possibility that personalized proactive medicine can improve healthcare.

The new vision: More precise management

The trial-and-error approach to treating disease is inefficient and costly. Many drugs are effective for only about 50% of patients, often leading to switching or intensification of therapy that requires multiple patient visits.

Personalized medicine considers pharmacokinetic and other characteristics in selection of drug dosages. Genomic testing has the potential to provide clearer insight into the more successful use of currently available medicines. Treatment decisions (ie, drug and drug dosage choice) made on the basis of pharmacogenomic testing should increase adherence through greater effectiveness and fewer adverse drug reactions.

A massive amount of waste is related to pharmaceutical nonadherence and noncompliance. The New England Healthcare Institute has estimated that medication nonadherence costs the healthcare system $290 billion annually.⁴ Methodologies targeted at individual patients to improve adherence to drug regimens could save the healthcare system a tremendous amount of money.

Cancer management as a model for personalized healthcare. Personalization of therapy is especially suited to cancer management, given that the response to nonspecific cancer chemotherapy is suboptimal in most patients yet exposes them to adverse effects.⁵ Large-scale sequencing of human cancer genomes is rapidly changing the understanding of cancer biology and is identifying new targets in difficult-to-treat diseases and causes of drug resistance. Applying this information can achieve cost savings by avoiding the use of treatments that are ineffective in particular patients.

Overexpression of genetic mutations renders some cancers less susceptible to certain treatments, but has opened the door to individualized molecularly guided treatment strategies. For example, among patients with non–small cell lung cancer, mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain predict response to EGFR tyrosine kinase inhibitors, and anaplastic lymphoma kinase (ALK) inhibitors induce response in patients harboring a mutation in EML4-ALK genes. The recognition that human epidermal growth factor receptor (HER)-2 overexpression as a result of ERBB2 gene amplification occurs in as many as 20% of human breast cancers paved the way for the development of HER-2–targeted therapies. Patients with advanced colorectal cancer whose tumors express the KRAS gene mutation do not benefit from an EGFR inhibitor, whereas those with wild-type KRAS have improved survival with EGFR inhibitor treatment.⁶

 

BARRIERS TO THE APPLICATION OF PERSONALIZED HEALTHCARE

The availability and potential of personalized healthcare services and technology is not universally recognized or appreciated by consumers and clinicians. This lack of awareness contributes to a shortage of public support and limited demand for such services. Other barriers include misperceptions regarding the impact of personalized healthcare on disease management, limited incentives to use the available technology, and a knowledge gap among healthcare providers.

Lack of awareness and support

As applications of personalized healthcare advance to the point of clinical relevance, it is important to consider strategies for effective implementation into healthcare practice. Personalized healthcare, when more fully implemented, promises to accelerate the progress that healthcare reform hopes to achieve.

A major challenge to widespread adoption of personalized healthcare is limited recognition by the public and some healthcare providers that personalized healthcare can help to achieve better value. For personalized medicine to be embraced, the concept of “helix to health,” or translation of knowledge to the clinical setting, must resonate with the general public. Despite lack of public and provider awareness, the Personalized Medicine Coalition (PMC) has documented the existence of 56 personalized treatment and diagnostic products. Further, more than 200 product labels now recommend genetic testing prior to use to identify likely responders or inform of the influence of genetic variation on safety and effectiveness.

Consumers’ confidence in the efficacy and safety of medicines they take might contribute to the absence of public support for personalized healthcare. Similarly, despite the availability of genomic tests and tools, many physicians who might be advocates for personalized healthcare do not see the relevance of genomic medicine to their practices in terms of direct benefit to patient care.⁷

Apart from clinicians and consumers, support is also weak among health insurers and employers, even though the return on investment for personalized healthcare may be profound. Payers await the economic outcomes data that are crucial for their commitment to personalized healthcare. In addition, some have concerns about the ethical implications of personalized healthcare (see “Managing Genomic Information Responsibly”).

Perception of impact on treatment and prevention

A frequent criticism of genomics in medicine is that a genetic diagnosis does not help with patient management. In fact, surveillance and management of patients and family members often changes in response to a genetic diagnosis; knowing which gene is involved personalizes medical management. An example is the management of hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch syndrome, which is the most common form of hereditary colon cancer. For a person with HNPCC, the lifetime risk of developing colorectal cancer is approximately 80%. Lynch syndrome is caused by germline mutations in one of three major mismatch repair (MMR) genes (MLH1, MSH2, and MSH6), and it predisposes to other cancers—uterine, stomach, and ovarian—as well. In women with Lynch syndrome, the lifetime risk for uterine cancer is 40%, compared with 4% in the general population.

At least 90% of patients with Lynch syndrome can be detected through MMR testing via microsatellite instability (MSI) or immunohistochemistry (IHC).⁸ MSI is a cellular phenotype that indicates a deficiency in at least one DNA MMR protein.

Although 5-fluorouracil–based chemo therapy is the standard of care for treatment of colorectal cancer, it confers no survival advantage in patients with MMR-IHC null (lack of expression of the gene) or MSI-high sporadic colorectal cancer.^9,10 Knowing the status of MMR proteins, therefore, would alter the decision regarding neoadjuvant and adjuvant chemotherapy.

Perception of value

Implementation of pharmacogenomics into clinical practice has lagged. One major reason is the lack of an obvious business model for a product that may only be required once in an individual patient’s lifetime.¹¹

A second barrier to integration lies in the limited demand for pharmacogenomics from physicians. This may be related partly to limited expertise in genetics among many physicians and to significant pushback from payers against today’s costs. Without reimbursement, little incentive exists for pharmacogenomics diagnostics. The incentive for physicians is further depressed, perhaps appropriately, when randomized controlled studies fail to demonstrate improved clinical outcomes with the use of pharmacogenomicbased treatment strategies. Two such examples are genotype-guided warfarin dosing, which failed in a randomized controlled trial to improve the proportion of international normalized ratios in the therapeutic range,¹² and dosing of clopidogrel based on platelet reactivity, which did not improve outcomes after percutaneous coronary intervention compared with standard dosing in a randomized double-blind clinical trial.¹³

A significant delay in obtaining the results of pharmacogenomics testing, which also postpones the prescribing encounter, is another major drawback.

A knowledge gap persists

At present, delivery of personalized healthcare is not part of the usual training of physicians and other healthcare providers who are the gatekeepers of medicine. Few medical schools incorporate human and medical genetics, genomics, and pharmacogenomics into their curricula. Genetics is inadequately emphasized in residency curricula outside of pediatrics, family medicine, and obstetrics/gynecology.

The resulting knowledge gap is a fundamental factor in the lack of interest in using genomics in clinical medicine. Educating consumers and physicians at all levels, including specialty societies as well as insurers, will be key to expanding utilization of personalized healthcare. Educating payers and providing them with more data on economic outcomes associated with personalized healthcare will be necessary for adoption into clinical practice; implementation will lag as long as reimbursement decisions do not support personalized approaches to medicine.

As DNA sequencing technology has become less expensive and more powerful, companies have begun to market personal genomic testing. As a result, patients who use these services will increasingly want to discuss the results with their physicians. A significant number of clinicians are unfamiliar with personal genomic testing and emerging genetic testing options. In one survey of physicians who attended educational sessions that discussed recent developments in clinical genetics, only 37% indicated that they were familiar with recent genetic research that affected their patients.¹⁴

Targeted education will enhance physicians’ understanding of probabilities and risk estimates from the use of genomic testing; it will also improve recognition of potential causes of patient anxiety, gene variants of unknown significance, and follow-up tests and procedures that can add to expense. Nonphysician healthcare providers (ie, nurses and physician assistants) of direct care also will benefit from education.

 

INTEGRATING PERSONALIZED HEALTHCARE INTO CLINICAL PRACTICE

Practice standardization and an overhaul of the health information technology (HIT) infrastructure are needed if we are to reap the potential benefits of personalized healthcare. Creative approaches to practitioner education, which are being used in some institutions, must become more widespread. Similarly, the models for successful integration of personalized healthcare that have been achieved in some settings also can be implemented in other institutions.

Data collection and integration must be prioritized

Personalized healthcare can be both predictive and preventive, but moving past the disruptive phase of personalized healthcare will require a radical transformation of the healthcare “ecosystem” and HIT infrastructure.

Although data collection in the current system is extensive, data sharing and data management are inadequate. The pace at which HIT links clinical and genetic information must be accelerated. HIT will expedite innovation and implementation of personalized healthcare, allowing greater integration of data to permit improved data analysis capability. The ultimate goal is to create an interoperable system that connects these data across hospitals and clinicians to help clinicians interpret genomic and other risk information to better inform patient care.

Fully integrated health systems support better coordination of care and optimize the treatment of individual patients: linking research findings, treatment guidelines, treatment outcomes based on genetic profiles, and the individual patient’s own genetic profile will help to personalize treatments. Genomic information added to an individual’s electronic medical record along with improved data-sharing will facilitate clinicians’ ability to retrieve outcomes data based on patient characteristics.

Care models must be standardized, evidence-based practices must be executed, and care must be coordinated yet decentralized. In this way, clinicians can use the electronic medical record as an interoperable patient record to determine a personalized pathway to patient management. Standardization reduces variability in practice and permits seamless execution of care. Automation is imperative to achieving standardization, irrespective of the care supervisor. Investments must therefore be made to stimulate electronic medical record decision support.

In addition, larger data sets will be needed to identify the types of patients likely to respond to a treatment. Ideal data sets would be large enough to have adequate statistical power, be publicly available, standardize the collection of data with respect to response to therapy and toxicity, and contain data on concomitant collections of biologic samples.

Reimbursement must keep pace with medical advances

Payer willingness to reimburse for genomic tests and treatments will determine the pace of integration of personalized healthcare into clinical practice. Evidence that enhanced value can be derived from personalized approaches to medicine must be generated before personalized healthcare gains widespread acceptance by payers.

In addition, care-coordinated models must be developed to promote a value-based agenda that facilitates physician accountability and encourages clinical integration.

Innovative approaches are needed to educate providers

Development of point-of-care tools. Because information overload and lack of time are obstacles to clinicians’ efforts to incorporate genomic information into clinical practice, emphasis must be placed on genomic applications that have demonstrated utility. Engaging busy clinicians with point-of-care tools will maximize the relevance of the genomic information they receive and encourage effective use of their time. Decision-making should be supported through automatic risk assessment and management recommendations.

Educational tools. The National Coalition for Health Professional Education in Genetics (NCHPEG) was borne out of the recognition that the pace of genomic discovery far exceeds the pace at which healthcare providers can be educated. Its vision is to improve healthcare through informed use of genomic resources. NCHPEG is a member-based organization whose stakeholders include professional societies, hospitals, advocacy groups, and industry; it attempts to identify the specific educational needs for particular target audiences and then address these needs. It achieves its goals through the use of point-of-care tools and educational programs for continuing medical education credit.

One NCHPEG tool is the Pregnancy and Health Profile, which is a risk assessment and screening tool that attempts to improve the identification of women and babies at risk of developing genetic disease. It collects personal and family history information, performs a risk assessment for the clinician, and provides clinical decision support and education.

Another example of an educational tool is the “Genes to Society” curriculum initiated by The Johns Hopkins University School of Medicine in August 2009. The curriculum is being used as “the foundation for the scientific and clinical career development of future physicians.”¹⁵

Using personal genomic testing for education. The number of direct-to-consumer genomic tests is growing, and their market penetration will only increase as the cost of supplying a personal genome continues to decline. Whole genome scanning is being offered with the promise of identifying genetic predisposition to multiple diseases.

Participation in personal genomic testing may be a useful educational tool. Medical students, residents, and practicing physicians who participate in testing may be better equipped to advise patients about the processes involved and the potential utility and limitations of direct-to-consumer genotyping.¹⁴

Some companies that offer direct-to-consumer genomic testing provide telephone support from genetic counselors to help clients and their healthcare providers manage genetic information. Counselor services include identifying hereditary risks and reviewing diagnostic, preventive, and early-detection options.

Implementing pharmacogenomics into practice: Decision support systems are needed

A genomic decision support system that guides medication prescribing is needed to implement pharmacogenomic diagnostics. For such a system to achieve the goal of selecting the best medication for each individual, it must do the following:

• Test all polymorphisms relevant to the prescribing of any medication
• Be completed with no out-of-pocket cost to the patient
• Be performed before the patient requires the medication
• Provide results that will be interpreted as part of an individualized pharmacogenomics consult.¹¹

Many useful pharmacogenomic tests are based on cytochrome P450 metabolism phenotypes that are responsible for variance in response to drugs metabolized by this pathway. Others use human leukocyte antigen screening for hypersensitivity reactions to abacavir, carbamazepine, and allopurinol. Examples of pharmacogenomics tests appear in Table 2.

The 1200 Patients Project, a pilot research study under way at the Center for Personalized Therapeutics at the University of Chicago, is attempting to demonstrate the feasibility of incorporating pharmacogenomic testing into routine clinical practice for medication treatment decisions. DNA samples from patients who are taking at least one prescription medication are being tested for differences in genes that may suggest greater effectiveness or an increased risk of side effects from certain medications.

 

 

Solutions in practice

Cleveland Clinic’s genetics-based management of Lynch syndrome, the integration of genetics services during patient appointments at Cleveland Clinic, and a coordinated approach at The Ohio State University Medical Center are examples of practical applications of personalized healthcare.

Colorectal cancer management. One example of a personalized approach to medicine that improves health outcome while achieving cost savings is the genetics-based approach to HNPCC (Lynch syndrome) at Cleveland Clinic.

Early identification of Lynch syndrome by screening all colorectal cancer patients has been shown to save $250,000 per life-year gained in the United States.¹⁶ All colorectal cancers resected at the Cleveland Clinic main campus are routinely screened for MSI and IHC, and the process is embedded into the routine pathology workflow. With the patients’ foreknowledge, a gastrointestinal cancer genetics counselor scans the list of MSI and IHC results each week. Patients who are MSI-high or IHC-null are invited to receive genetic counseling and consider germline single-gene testing guided by the IHC results. With this active approach, patient uptake is 80%; in comparison, with a passive approach (MSI/IHC results are placed in the pathology report), the uptake is 14%¹⁷ (B. Leach and C. Eng, unpublished data, 2011).The successful application of the active approach requires the close cooperation of multiple disciplines, including members of the Cleveland Clinic Genomic Medicine, Pathology & Laboratory Medicine, and Digestive Disease Institutes.¹⁸

Integrating genetics-based care at Cleveland Clinic. Time delays for genetics services and limited collaboration with managing physicians who are not genetics specialists reduces genetics-based access and availability. Broad access to genetics clinical services is a means of clinical integration of genetics-enabled care. Providing patients and healthcare providers with easy access and short wait times is vital for clinical integration of genetics-enabled personalized healthcare.

As part of a patient-centered focus on medicine, clinical genetics services have been integrated throughout Cleveland Clinic. The system has two genetics clinics at its main campus and has embedded multiple genetics satellites within its nongenetics clinics, easing access. Genetics counselors are stationed in the same areas of practice as referring providers. Although patient encounters have increased at the medical genetics clinic in the Genomic Medicine Institute, genetics consultations no longer require an extra trip to the clinic since they are integrated into existing appointments. With this approach, large numbers of patients can be seen with no wait times.

Coordinated care at The Ohio State University Medical Center. The Center for Personalized Health Care at The Ohio State University Medical Center (OSUMC) embraces a systems-based care-coordinated model that improves care by executing standardized processes and automating routine tasks. The Institute for Systems Biology, which was established to develop genomics, wellness, and chronic disease biomarkers, collaborates with OSUMC on pilot projects in chronic disease, including cancer.

The OSUMC has a closed system in which it is the payer, employer, and provider of healthcare. This closed system serves as an ideal testing ground for reform. Goals include intervention in disease before symptoms appear and maintenance of wellness. The data from these demonstration projects should facilitate adoption of personalized healthcare by improving physician acceptance of personalized approaches and satisfying payers that personalized healthcare is cost-effective.

Personalized healthcare is the tailoring of medical management and patient care to the individual characteristics of each patient. This is achieved by incorporating the genetic and genomic makeup of an individual and his or her family medical history, environment, health-related behaviors, culture, and values into a complete health picture that can be used to customize care. Another level of personalization, often called personalized medicine, involves the selection of drug therapy through the use of tests to determine the genes and gene interactions that can reliably predict an individual’s response to a given therapy. This white paper focuses largely on the use of personalized healthcare as a risk prediction tool.

CURRENT STATUS OF PERSONALIZED HEALTHCARE

Practitioners and consumers in today’s healthcare setting do not yet fully recognize the potential benefits of personalized healthcare (Table 1¹). Further, proposals for reform tend to be reactive rather than proactive. Family history is well validated as a tool to predict risk for disease, but, in some instances, genomic information may enhance risk prediction provided by family history. The trial-and-error approach now used to treat disease is costly, but genomic testing has the potential to save money through more effective use of diagnostic tests, counseling about medical management based on gene test results, and prescribing of medications.

The case for personalized healthcare: Seeking value

To fully appreciate the need to advance the adoption of personalized healthcare into the delivery of medicine, one must consider the operation of our current healthcare system and its inefficiencies in terms of delivery and cost, its imprecision in the selection of therapies, and its inability to optimize outcomes. The framework of the US healthcare system as it is now constructed is expensive, disease-directed (instead of health- and wellness-directed), fragmented, and complex. While gross domestic product (GDP) in the United States has increased by approximately 3% per year,² the compounded growth rate of healthcare expenditures is 6.1% per year. Healthcare in the aggregate now represents 17.6% of GDP and 27% of spending by the federal government and consumes 28% of the average household’s discretionary spending, surpassed only by housing.³

Personalized healthcare can potentially address the need for value consistent with the healthcare system’s prominent share of the US economy. The growth in healthcare spending is certain to be a target of the newly created Joint Select Committee on Deficit Reduction (created by the Budget Control Act of 2011), which is tasked with deficit reduction of at least $1.5 trillion over a 10-year period.

The need to address healthcare costs has been recognized in the Patient Protection and Affordable Care Act, a central feature of which is the creation of integrated health systems that pay for value based on quality, cost containment, and consumer experience. The legislation was enacted to transform healthcare in a variety of ways to make it more sustainable. The Patient Protection and Affordable Care Act seeks to end fragmentation by expanding the use of information technology to reorganize the delivery system and to prevent errors, shifting from volume-based incentives to incentives based on performance and outcomes, and rewarding effective healthcare delivery measures and good patient outcomes.

A shift from reactive to proactive

The premise behind personalized healthcare is the potential for more efficient healthcare, with the assumption that efficiency translates to lower cost and improved patient care.

Although healthcare reform is most often referred to in the context of improving access to care through insurance coverage mandates, true healthcare reform shifts current healthcare models from the practice of reactive medicine to the practice of proactive medicine, in which the tools of personalized healthcare (ie, genetics, genomics, and other molecular diagnostics) enable not only better quality of care but also less expensive care.

Several personalized tools have long been accepted into mainstream medicine. Two examples are the family history, which is the least expensive and most available genetic evaluation tool, and ABO blood typing for safe transfusions (as ABO blood types are alleles of a gene). In fact, much of what is now considered mainstream medical management was at one time considered new. To allow further evolution of medical practice, our challenge is to open our minds to the possibility that personalized proactive medicine can improve healthcare.

The new vision: More precise management

The trial-and-error approach to treating disease is inefficient and costly. Many drugs are effective for only about 50% of patients, often leading to switching or intensification of therapy that requires multiple patient visits.

Personalized medicine considers pharmacokinetic and other characteristics in selection of drug dosages. Genomic testing has the potential to provide clearer insight into the more successful use of currently available medicines. Treatment decisions (ie, drug and drug dosage choice) made on the basis of pharmacogenomic testing should increase adherence through greater effectiveness and fewer adverse drug reactions.

A massive amount of waste is related to pharmaceutical nonadherence and noncompliance. The New England Healthcare Institute has estimated that medication nonadherence costs the healthcare system $290 billion annually.⁴ Methodologies targeted at individual patients to improve adherence to drug regimens could save the healthcare system a tremendous amount of money.

Cancer management as a model for personalized healthcare. Personalization of therapy is especially suited to cancer management, given that the response to nonspecific cancer chemotherapy is suboptimal in most patients yet exposes them to adverse effects.⁵ Large-scale sequencing of human cancer genomes is rapidly changing the understanding of cancer biology and is identifying new targets in difficult-to-treat diseases and causes of drug resistance. Applying this information can achieve cost savings by avoiding the use of treatments that are ineffective in particular patients.

Overexpression of genetic mutations renders some cancers less susceptible to certain treatments, but has opened the door to individualized molecularly guided treatment strategies. For example, among patients with non–small cell lung cancer, mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain predict response to EGFR tyrosine kinase inhibitors, and anaplastic lymphoma kinase (ALK) inhibitors induce response in patients harboring a mutation in EML4-ALK genes. The recognition that human epidermal growth factor receptor (HER)-2 overexpression as a result of ERBB2 gene amplification occurs in as many as 20% of human breast cancers paved the way for the development of HER-2–targeted therapies. Patients with advanced colorectal cancer whose tumors express the KRAS gene mutation do not benefit from an EGFR inhibitor, whereas those with wild-type KRAS have improved survival with EGFR inhibitor treatment.⁶

 

BARRIERS TO THE APPLICATION OF PERSONALIZED HEALTHCARE

The availability and potential of personalized healthcare services and technology is not universally recognized or appreciated by consumers and clinicians. This lack of awareness contributes to a shortage of public support and limited demand for such services. Other barriers include misperceptions regarding the impact of personalized healthcare on disease management, limited incentives to use the available technology, and a knowledge gap among healthcare providers.

Lack of awareness and support

As applications of personalized healthcare advance to the point of clinical relevance, it is important to consider strategies for effective implementation into healthcare practice. Personalized healthcare, when more fully implemented, promises to accelerate the progress that healthcare reform hopes to achieve.

A major challenge to widespread adoption of personalized healthcare is limited recognition by the public and some healthcare providers that personalized healthcare can help to achieve better value. For personalized medicine to be embraced, the concept of “helix to health,” or translation of knowledge to the clinical setting, must resonate with the general public. Despite lack of public and provider awareness, the Personalized Medicine Coalition (PMC) has documented the existence of 56 personalized treatment and diagnostic products. Further, more than 200 product labels now recommend genetic testing prior to use to identify likely responders or inform of the influence of genetic variation on safety and effectiveness.

Consumers’ confidence in the efficacy and safety of medicines they take might contribute to the absence of public support for personalized healthcare. Similarly, despite the availability of genomic tests and tools, many physicians who might be advocates for personalized healthcare do not see the relevance of genomic medicine to their practices in terms of direct benefit to patient care.⁷

Apart from clinicians and consumers, support is also weak among health insurers and employers, even though the return on investment for personalized healthcare may be profound. Payers await the economic outcomes data that are crucial for their commitment to personalized healthcare. In addition, some have concerns about the ethical implications of personalized healthcare (see “Managing Genomic Information Responsibly”).

Perception of impact on treatment and prevention

A frequent criticism of genomics in medicine is that a genetic diagnosis does not help with patient management. In fact, surveillance and management of patients and family members often changes in response to a genetic diagnosis; knowing which gene is involved personalizes medical management. An example is the management of hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch syndrome, which is the most common form of hereditary colon cancer. For a person with HNPCC, the lifetime risk of developing colorectal cancer is approximately 80%. Lynch syndrome is caused by germline mutations in one of three major mismatch repair (MMR) genes (MLH1, MSH2, and MSH6), and it predisposes to other cancers—uterine, stomach, and ovarian—as well. In women with Lynch syndrome, the lifetime risk for uterine cancer is 40%, compared with 4% in the general population.

At least 90% of patients with Lynch syndrome can be detected through MMR testing via microsatellite instability (MSI) or immunohistochemistry (IHC).⁸ MSI is a cellular phenotype that indicates a deficiency in at least one DNA MMR protein.

Although 5-fluorouracil–based chemo therapy is the standard of care for treatment of colorectal cancer, it confers no survival advantage in patients with MMR-IHC null (lack of expression of the gene) or MSI-high sporadic colorectal cancer.^9,10 Knowing the status of MMR proteins, therefore, would alter the decision regarding neoadjuvant and adjuvant chemotherapy.

Perception of value

Implementation of pharmacogenomics into clinical practice has lagged. One major reason is the lack of an obvious business model for a product that may only be required once in an individual patient’s lifetime.¹¹

A second barrier to integration lies in the limited demand for pharmacogenomics from physicians. This may be related partly to limited expertise in genetics among many physicians and to significant pushback from payers against today’s costs. Without reimbursement, little incentive exists for pharmacogenomics diagnostics. The incentive for physicians is further depressed, perhaps appropriately, when randomized controlled studies fail to demonstrate improved clinical outcomes with the use of pharmacogenomicbased treatment strategies. Two such examples are genotype-guided warfarin dosing, which failed in a randomized controlled trial to improve the proportion of international normalized ratios in the therapeutic range,¹² and dosing of clopidogrel based on platelet reactivity, which did not improve outcomes after percutaneous coronary intervention compared with standard dosing in a randomized double-blind clinical trial.¹³

A significant delay in obtaining the results of pharmacogenomics testing, which also postpones the prescribing encounter, is another major drawback.

A knowledge gap persists

At present, delivery of personalized healthcare is not part of the usual training of physicians and other healthcare providers who are the gatekeepers of medicine. Few medical schools incorporate human and medical genetics, genomics, and pharmacogenomics into their curricula. Genetics is inadequately emphasized in residency curricula outside of pediatrics, family medicine, and obstetrics/gynecology.

The resulting knowledge gap is a fundamental factor in the lack of interest in using genomics in clinical medicine. Educating consumers and physicians at all levels, including specialty societies as well as insurers, will be key to expanding utilization of personalized healthcare. Educating payers and providing them with more data on economic outcomes associated with personalized healthcare will be necessary for adoption into clinical practice; implementation will lag as long as reimbursement decisions do not support personalized approaches to medicine.

As DNA sequencing technology has become less expensive and more powerful, companies have begun to market personal genomic testing. As a result, patients who use these services will increasingly want to discuss the results with their physicians. A significant number of clinicians are unfamiliar with personal genomic testing and emerging genetic testing options. In one survey of physicians who attended educational sessions that discussed recent developments in clinical genetics, only 37% indicated that they were familiar with recent genetic research that affected their patients.¹⁴

Targeted education will enhance physicians’ understanding of probabilities and risk estimates from the use of genomic testing; it will also improve recognition of potential causes of patient anxiety, gene variants of unknown significance, and follow-up tests and procedures that can add to expense. Nonphysician healthcare providers (ie, nurses and physician assistants) of direct care also will benefit from education.

 

INTEGRATING PERSONALIZED HEALTHCARE INTO CLINICAL PRACTICE

Practice standardization and an overhaul of the health information technology (HIT) infrastructure are needed if we are to reap the potential benefits of personalized healthcare. Creative approaches to practitioner education, which are being used in some institutions, must become more widespread. Similarly, the models for successful integration of personalized healthcare that have been achieved in some settings also can be implemented in other institutions.

Data collection and integration must be prioritized

Personalized healthcare can be both predictive and preventive, but moving past the disruptive phase of personalized healthcare will require a radical transformation of the healthcare “ecosystem” and HIT infrastructure.

Although data collection in the current system is extensive, data sharing and data management are inadequate. The pace at which HIT links clinical and genetic information must be accelerated. HIT will expedite innovation and implementation of personalized healthcare, allowing greater integration of data to permit improved data analysis capability. The ultimate goal is to create an interoperable system that connects these data across hospitals and clinicians to help clinicians interpret genomic and other risk information to better inform patient care.

Fully integrated health systems support better coordination of care and optimize the treatment of individual patients: linking research findings, treatment guidelines, treatment outcomes based on genetic profiles, and the individual patient’s own genetic profile will help to personalize treatments. Genomic information added to an individual’s electronic medical record along with improved data-sharing will facilitate clinicians’ ability to retrieve outcomes data based on patient characteristics.

Care models must be standardized, evidence-based practices must be executed, and care must be coordinated yet decentralized. In this way, clinicians can use the electronic medical record as an interoperable patient record to determine a personalized pathway to patient management. Standardization reduces variability in practice and permits seamless execution of care. Automation is imperative to achieving standardization, irrespective of the care supervisor. Investments must therefore be made to stimulate electronic medical record decision support.

In addition, larger data sets will be needed to identify the types of patients likely to respond to a treatment. Ideal data sets would be large enough to have adequate statistical power, be publicly available, standardize the collection of data with respect to response to therapy and toxicity, and contain data on concomitant collections of biologic samples.

Reimbursement must keep pace with medical advances

Payer willingness to reimburse for genomic tests and treatments will determine the pace of integration of personalized healthcare into clinical practice. Evidence that enhanced value can be derived from personalized approaches to medicine must be generated before personalized healthcare gains widespread acceptance by payers.

In addition, care-coordinated models must be developed to promote a value-based agenda that facilitates physician accountability and encourages clinical integration.

Innovative approaches are needed to educate providers

Development of point-of-care tools. Because information overload and lack of time are obstacles to clinicians’ efforts to incorporate genomic information into clinical practice, emphasis must be placed on genomic applications that have demonstrated utility. Engaging busy clinicians with point-of-care tools will maximize the relevance of the genomic information they receive and encourage effective use of their time. Decision-making should be supported through automatic risk assessment and management recommendations.

Educational tools. The National Coalition for Health Professional Education in Genetics (NCHPEG) was borne out of the recognition that the pace of genomic discovery far exceeds the pace at which healthcare providers can be educated. Its vision is to improve healthcare through informed use of genomic resources. NCHPEG is a member-based organization whose stakeholders include professional societies, hospitals, advocacy groups, and industry; it attempts to identify the specific educational needs for particular target audiences and then address these needs. It achieves its goals through the use of point-of-care tools and educational programs for continuing medical education credit.

One NCHPEG tool is the Pregnancy and Health Profile, which is a risk assessment and screening tool that attempts to improve the identification of women and babies at risk of developing genetic disease. It collects personal and family history information, performs a risk assessment for the clinician, and provides clinical decision support and education.

Another example of an educational tool is the “Genes to Society” curriculum initiated by The Johns Hopkins University School of Medicine in August 2009. The curriculum is being used as “the foundation for the scientific and clinical career development of future physicians.”¹⁵

Using personal genomic testing for education. The number of direct-to-consumer genomic tests is growing, and their market penetration will only increase as the cost of supplying a personal genome continues to decline. Whole genome scanning is being offered with the promise of identifying genetic predisposition to multiple diseases.

Participation in personal genomic testing may be a useful educational tool. Medical students, residents, and practicing physicians who participate in testing may be better equipped to advise patients about the processes involved and the potential utility and limitations of direct-to-consumer genotyping.¹⁴

Some companies that offer direct-to-consumer genomic testing provide telephone support from genetic counselors to help clients and their healthcare providers manage genetic information. Counselor services include identifying hereditary risks and reviewing diagnostic, preventive, and early-detection options.

Implementing pharmacogenomics into practice: Decision support systems are needed

A genomic decision support system that guides medication prescribing is needed to implement pharmacogenomic diagnostics. For such a system to achieve the goal of selecting the best medication for each individual, it must do the following:

• Test all polymorphisms relevant to the prescribing of any medication
• Be completed with no out-of-pocket cost to the patient
• Be performed before the patient requires the medication
• Provide results that will be interpreted as part of an individualized pharmacogenomics consult.¹¹

Many useful pharmacogenomic tests are based on cytochrome P450 metabolism phenotypes that are responsible for variance in response to drugs metabolized by this pathway. Others use human leukocyte antigen screening for hypersensitivity reactions to abacavir, carbamazepine, and allopurinol. Examples of pharmacogenomics tests appear in Table 2.

The 1200 Patients Project, a pilot research study under way at the Center for Personalized Therapeutics at the University of Chicago, is attempting to demonstrate the feasibility of incorporating pharmacogenomic testing into routine clinical practice for medication treatment decisions. DNA samples from patients who are taking at least one prescription medication are being tested for differences in genes that may suggest greater effectiveness or an increased risk of side effects from certain medications.

 

 

Solutions in practice

Cleveland Clinic’s genetics-based management of Lynch syndrome, the integration of genetics services during patient appointments at Cleveland Clinic, and a coordinated approach at The Ohio State University Medical Center are examples of practical applications of personalized healthcare.

Colorectal cancer management. One example of a personalized approach to medicine that improves health outcome while achieving cost savings is the genetics-based approach to HNPCC (Lynch syndrome) at Cleveland Clinic.

Early identification of Lynch syndrome by screening all colorectal cancer patients has been shown to save $250,000 per life-year gained in the United States.¹⁶ All colorectal cancers resected at the Cleveland Clinic main campus are routinely screened for MSI and IHC, and the process is embedded into the routine pathology workflow. With the patients’ foreknowledge, a gastrointestinal cancer genetics counselor scans the list of MSI and IHC results each week. Patients who are MSI-high or IHC-null are invited to receive genetic counseling and consider germline single-gene testing guided by the IHC results. With this active approach, patient uptake is 80%; in comparison, with a passive approach (MSI/IHC results are placed in the pathology report), the uptake is 14%¹⁷ (B. Leach and C. Eng, unpublished data, 2011).The successful application of the active approach requires the close cooperation of multiple disciplines, including members of the Cleveland Clinic Genomic Medicine, Pathology & Laboratory Medicine, and Digestive Disease Institutes.¹⁸

Integrating genetics-based care at Cleveland Clinic. Time delays for genetics services and limited collaboration with managing physicians who are not genetics specialists reduces genetics-based access and availability. Broad access to genetics clinical services is a means of clinical integration of genetics-enabled care. Providing patients and healthcare providers with easy access and short wait times is vital for clinical integration of genetics-enabled personalized healthcare.

As part of a patient-centered focus on medicine, clinical genetics services have been integrated throughout Cleveland Clinic. The system has two genetics clinics at its main campus and has embedded multiple genetics satellites within its nongenetics clinics, easing access. Genetics counselors are stationed in the same areas of practice as referring providers. Although patient encounters have increased at the medical genetics clinic in the Genomic Medicine Institute, genetics consultations no longer require an extra trip to the clinic since they are integrated into existing appointments. With this approach, large numbers of patients can be seen with no wait times.

Coordinated care at The Ohio State University Medical Center. The Center for Personalized Health Care at The Ohio State University Medical Center (OSUMC) embraces a systems-based care-coordinated model that improves care by executing standardized processes and automating routine tasks. The Institute for Systems Biology, which was established to develop genomics, wellness, and chronic disease biomarkers, collaborates with OSUMC on pilot projects in chronic disease, including cancer.

The OSUMC has a closed system in which it is the payer, employer, and provider of healthcare. This closed system serves as an ideal testing ground for reform. Goals include intervention in disease before symptoms appear and maintenance of wellness. The data from these demonstration projects should facilitate adoption of personalized healthcare by improving physician acceptance of personalized approaches and satisfying payers that personalized healthcare is cost-effective.

A 55-year-old woman has come to the clinic because of clear rhinorrhea and nasal congestion, which occur year-round but are worse in the winter. She reports that at times her nose runs continuously. Nasal symptoms have been present for 4 to 5 years but are worsening. The clear discharge is not associated with sneezing or itching. Though she lives with a cat, her symptoms are not exacerbated by close contact with it.

One year ago, an allergist performed skin testing but found no evidence of allergies as a cause of her rhinitis. A short course of intranasal steroids did not seem to improve her nasal symptoms.

The patient also has hypertension, hypothyroidism, and hot flashes due to menopause; these conditions are well controlled with lisinopril (Zestril), levothyroxine (Synthroid), and estrogen replacement. She has no history of asthma and has had no allergies to drugs, including nonsteroidal anti-inflammatory drugs (NSAIDs.)

How should this patient be evaluated and treated?

COMMON, OFTEN OVERLOOKED

Many patients suffer from rhinitis, but this problem can be overshadowed by other chronic diseases seen in a medical clinic, especially during a brief office visit. When a patient presents with rhinitis, a key question is whether it is allergic or nonallergic.

This review will discuss the different forms of nonallergic rhinitis and their causes, and give recommendations about therapy.

RHINITIS: ALLERGIC OR NONALLERGIC?

While allergic rhinitis affects 30 and 60 million Americans annually, or between 10% to 30% of US adults,¹ how many have nonallergic rhinitis has been difficult to determine.

In a study in allergy clinics, 23% of patients with rhinitis had the nonallergic form, 43% had the allergic form, and 34% had both forms (mixed rhinitis).² Other studies have suggested that up to 52% of patients presenting to allergy clinics with rhinitis have nonallergic rhinitis.³

Over time, patients may not stay in the same category. One study found that 24% of patients originally diagnosed with nonallergic rhinitis developed positive allergy tests when retested 3 or more years after their initial evaluation.⁴

Regardless of the type, untreated or uncontrolled symptoms of rhinitis can significantly affect the quality of life.

All forms of rhinitis are characterized by one or more of the following symptoms: nasal congestion, clear rhinorrhea, sneezing, and itching. These symptoms can be episodic or chronic and can range from mild to debilitating. In addition, rhinitis can lead to systemic symptoms of fatigue, headache, sleep disturbance, and cognitive impairment and can be associated with respiratory symptoms such as sinusitis and asthma.¹

Mechanisms are mostly unknown

While allergic rhinitis leads to symptoms when airborne allergens bind with specific immunoglobulin E (IgE) in the nose, the etiology of most forms of nonallergic rhinitis is unknown. However, several mechanisms have been proposed. These include entopy (local nasal IgE synthesis with negative skin tests),⁵ nocioceptive dysfunction (hyperactive sensory receptors),⁶ and autonomic nervous system abnormalities (hypoactive or hyperactive dysfunction of sympathetic or parasympathetic nerves in the nose).⁷

Does this patient have an allergic cause of rhinitis?

When considering a patient with rhinitis, the most important question is, “Does this patient have an allergic cause of rhinitis?” Allergic and nonallergic rhinitis have similar symptoms, making them difficult to distinguish. However, their mechanisms and treatment differ. By categorizing a patient’s type of rhinitis, the physician can make specific recommendations for avoidance and can initiate treatment with the most appropriate therapy. Misclassification can lead to treatment failure, multiple visits, poor adherence, and frustration for patients with uncontrolled symptoms.

Patients for whom an allergic cause cannot be found by allergy skin testing or serum specific IgE immunoassay (Immunocap/RAST) for environmental aeroallergens are classified as having nonallergic rhinitis.

 

CLUES POINTING TO NONALLERGIC VS ALLERGIC RHINITIS

Nonallergic rhinitis encompasses a range of syndromes with overlapping symptoms. While tools such as the Rhinitis Diagnostic Worksheet are available to help differentiate allergic from nonallergic rhinitis, debate continues about whether it is necessary to characterize different forms of rhinitis before initiating treatment.⁸

The diagnosis of nonallergic rhinitis depends on a thorough history and physical examination. Key questions relate to the triggers that bring on the rhinitis, which will assist the clinician in determining which subtype of rhinitis a patient may be experiencing and therefore how to manage it. Clues:

• Patients with nonallergic rhinitis more often report nasal congestion and rhinorrhea, rather than sneezing and itching, which are predominant symptoms of allergic rhinitis.
• Patients with nonallergic rhinitis tend to develop symptoms at a later age.
• Common triggers of nonallergic rhinitis are changes in weather and temperature, food, perfumes, odors, smoke, and fumes. Animal exposure does not lead to symptoms.
• Patients with nonallergic rhinitis have few complaints of concomitant symptoms of allergic conjunctivitis (itching, watering, redness, and swelling).
• Many patients with nonallergic rhinitis find that antihistamines have no benefit. Also, they do not have other atopic diseases such as eczema or food allergies and have no family history of atopy.

PHYSICAL FINDINGS

Some findings on physical examination may help distinguish allergic from nonallergic rhinitis.

• Patients with long-standing allergic rhinitis may have an “allergic crease,” ie, a horizontal wrinkle near the tip of the nose caused by frequent upward wiping. Another sign may be a gothic arch, which is a narrowing of the hard palate occurring as a child.
• In allergic rhinitis, the turbinates are often pale, moist, and boggy with a bluish tinge.
• 
  Findings such as a deviated nasal septum, discolored nasal discharge, atrophic nasal mucosa, or nasal polyps should prompt consideration of the several subtypes of nonallergic rhinitis (Table 1).

CASE CONTINUED

Our patient’s symptoms can be caused by many different factors. Allergic triggers for rhinitis include both indoor and outdoor sources. The most common allergens include cat, dog, dust mite, cockroach, mold, and pollen allergens. The absence of acute sneezing and itching when around her cat and her recent negative skin-prick tests confirm that the rhinitis symptoms are not allergic.

In this patient, who has symptoms throughout the year but no allergic triggers, consideration of the different subtypes of nonallergic rhinitis may help guide further therapy.

SUBTYPES OF NONALLERGIC RHINITIS

Vasomotor rhinitis

Vasomotor rhinitis is thought to be caused by a variety of neural and vascular triggers, often without an inflammatory cause. These triggers lead to symptoms involving nasal congestion and clear rhinorrhea more than sneezing and itching. The symptoms can be sporadic, with acute onset in relation to identifiable nonallergic triggers, or chronic, with no clear trigger.

Gustatory rhinitis, for example, is a form of vasomotor rhinitis in which clear rhinorrhea occurs suddenly while eating or while drinking alcohol. It may be prevented by using nasal ipratropium (Atrovent) before meals.

Irritant-sensitive vasomotor rhinitis. In some patients, acute vasomotor rhinitis symptoms are brought on by strong odors, cigarette smoke, air pollution, or perfume. When asked, most patients easily identify which of these irritant triggers cause symptoms.

Weather- or temperature-sensitive vasomotor rhinitis. In other patients, a change in temperature, humidity, or barometric pressure or exposure to cold or dry air can cause nasal symptoms.⁹ These triggers are often hard to identify. Weather- or temperature-sensitive vasomotor rhinitis is often mistaken for seasonal allergic rhinitis because weather changes occur in close relation to the peak allergy seasons in the spring and fall. However, this subtype does not respond as well to intranasal steroids.⁹

Other nonallergic triggers of vasomotor rhinitis may include exercise, emotion, and sexual arousal (honeymoon rhinitis).¹⁰

Some triggers, such as tobacco smoke and perfume, are easy to avoid. Other triggers, such as weather changes, are unavoidable. If avoidance measures fail or are inadequate, medications (described below) can be used for prophylaxis and symptomatic treatment.

Drug-induced rhinitis

Drugs of various classes are known to cause either acute or chronic rhinitis. Drug-induced rhinitis has been divided into different types based on the mechanism involved.¹¹

The local inflammatory type occurs in aspirin-exacerbated respiratory disease, which is characterized by nasal polyposis with chronic rhinosinusitis, hyposmia, and moderate to severe persistent asthma. Aspirin and other NSAIDs induce an acute local inflammation, leading to severe rhinitis and asthma symptoms. Avoiding all NSAID products is recommended; aspirin desensitization may lead to improvement in rhinosinusitis and asthma control.

The neurogenic type of drug-induced rhinitis can occur with sympatholytic drugs such as alpha receptor agonists (eg, clonidine [Cat-apres]) and antagonists (eg, prazosin [Minipress]).¹¹ Vasodilators, including phosphodiesterase-5 inhibitors such as sildenafil (Viagra), can lead to acute rhinitis symptoms (“anniversary rhinitis”).

Unknown mechanisms. Many other medications can lead to rhinitis by unknown mechanisms, usually with normal findings on physical examination. These include beta-blockers, angiotensin-converting enzyme inhibitors, calcium channel blockers, exogenous estrogens, oral contraceptives, antipsychotics, and gabapentin (Neurontin).

Correlating the initiation of a drug with the onset of rhinitis can help identify offending medications. Stopping the suspected medication, if feasible, is the first-line treatment.

Rhinitis medicamentosa, typically caused by overuse of over-the-counter topical nasal decongestants, is also classified under drug-induced rhinitis. Patients may not think of nasal decongestants as medications, and the physician may need to ask specifically about their use.

On examination, the nasal mucosa appears beefy red without mucous. Once a diagnosis is made, the physician should identify and treat the original etiology of the nasal congestion that led the patient to self-treat.

Patients with rhinitis medicamentosa often have difficulty discontinuing use of topical decongestants. They should be educated that the withdrawal symptoms can be severe and that more than one attempt at quitting may be needed. To break the cycle of rebound congestion, topical intranasal steroids should be used, though 5 to 7 days of oral steroids may be necessary.¹

Cocaine is a potent vasoconstrictor. Its illicit use should be suspected, especially if the patient presents with symptoms of chronic irritation such as frequent nosebleeds, crusting, and scabbing.¹²

Infectious rhinitis

One of the most common causes of acute rhinitis is upper respiratory infection.

Acute viral upper respiratory infection often presents with thick nasal discharge, sneezing, and nasal obstruction that usually clears in 7 to 10 days but can last up to 3 weeks. Acute bacterial sinusitis can follow, typically in fewer than 2% of patients, with symptoms of persistent nasal congestion, discolored mucus, facial pain, cough, and sometimes fever.

Chronic rhinosinusitis is a syndrome with sinus mucosal inflammation with multiple causes. It is clinically defined as persistent nasal and sinus symptoms lasting longer than 12 weeks and confirmed with computed tomography (CT).¹³ The CT findings of chronic rhinosinusitis include thickening of the lining of the sinus cavities or complete opacification of the pneumatized sinuses.

Major symptoms to consider for diagnosis include facial pain, congestion, obstruction, purulent discharge on examination, and changes in olfaction. Minor symptoms are cough, fatigue, headache, halitosis, fever, ear symptoms, and dental pain.

Treatment may involve 3 or more weeks of an oral antibiotic and a short course of an oral steroid, a daily nasal steroid spray, or both oral and nasal steroids. Most patients can be managed in the primary care setting, but they can be referred to an ear, nose, and throat specialist, an allergist, or an immunologist if their symptoms do not respond to initial therapy.

 

 

Nonallergic rhinitis eosinophilic syndrome

Patients with nonallergic rhinitis eosinophilic syndrome (NARES) are typically middle-aged and have perennial symptoms of sneezing, itching, and rhinorrhea with intermittent exacerbations. They occasionally have associated hyposmia (impaired sense of smell).¹ The diagnosis is made when eosinophils account for more than 5% of cells on a nasal smear and allergy testing is negative.

Patients may develop nasal polyposis and aspirin sensitivity.¹ Entopy has been described in some.¹⁴

Because of the eosinophilic inflammation, this form of nonallergic rhinitis responds well to intranasal steroids.

Immunologic causes

Systemic diseases can affect the nose and cause variable nasal symptoms that can be mistaken for rhinitis. Wegener granulomatosis, sarcoidosis, relapsing polychondritis, midline granulomas, Churg-Strauss syndrome, and amyloidosis can all affect the structures in the nose even before manifesting systemic symptoms. Granulomatous infections in the nose may lead to crusting, bleeding, and nasal obstruction.¹

A lack of a response to intranasal steroids or oral antibiotics should lead to consideration of these conditions, and treatment should be tailored to the specific disease.

Occupational rhinitis

Occupational exposure to chemicals, biologic aerosols, flour, and latex can lead to rhinitis, typically through an inflammatory mechanism. Many patients present with associated occupational asthma. The symptoms improve when the patient is away from work and worsen throughout the work week.

Avoiding the triggering agent is necessary to treat these symptoms.

Hormonal rhinitis

Hormonal rhinitis, ie, rhinitis related to metabolic and endocrine conditions, is most commonly associated with high estrogen states. Nasal congestion has been reported with pregnancy, menses, menarche, and the use of oral contraceptives.¹⁵ The mechanism for congestion in these conditions still needs clarification.

When considering drug therapy, only intranasal budesonide (Rhinocort) has a pregnancy category B rating.

While hypothyroidism and acromegaly have been mentioned in reviews of nonallergic rhinitis, evidence that these disorders cause nonallergic rhinitis is not strong.^16,17

Structurally related rhinitis

Anatomic abnormalities that can cause persistent nasal congestion include nasal septal deviation, turbinate hypertrophy, enlarged adenoids, tumors, and foreign bodies. These can be visualized by simple anterior nasal examination, nasal endoscopy, or radiologic studies. If structural causes lead to impaired quality of life or chronic rhinosinusitis, then consider referral to a specialist for possible surgical treatment.

Clear spontaneous rhinorrhea, with or without trauma, can be caused by cerebrospinal fluid leaking into the nasal cavity.¹⁸ A salty, metallic taste in the mouth can be a clue that the fluid is cerebrospinal fluid. A definitive diagnosis of cerebrospinal fluid leak is made by finding beta-2-transferrin in nasal secretions.

Atrophic rhinitis

Atrophic rhinitis is categorized as primary or secondary.

Primary (idiopathic) atrophic rhinitis is characterized by atrophy of the nasal mucosa and mucosal colonization with Klebsiella ozaenae associated with a foul-smelling nasal discharge.^19,20 This disorder has been primarily reported in young people who present with nasal obstruction, dryness, crusting, and epistaxis. They are from areas with warm climates, such as the Middle East, Southeast Asia, India, Africa, and the Mediterranean.

Secondary atrophic rhinitis can be a complication of nasal or sinus surgery, trauma, granulomatous disease, or exposure to radiation.²¹ This disorder is typically diagnosed with nasal endoscopy and treated with daily saline rinses with or without topical antibiotics.²¹

CASE CONTINUED

Questioned further, our patient says her symptoms are worse when her husband smokes, but that she continues to have congestion and rhinorrhea when he is away on business trips. She notes that her symptoms are often worse on airplanes (dry air with an acute change in barometric pressure), with weather changes, and in cold, dry environments. Symptoms are not induced by eating.

We note that she started taking lisinopril 2 years ago and conjugated equine estrogens 8 years ago. Review of systems reveals no history of facial or head trauma, polyps, or hyposmia.

The rhinitis and congestion are bilateral, and she denies headaches, acid reflux, and conjunctivitis. She has a mild throat-clearing cough that she attributes to postnasal drip.

On physical examination, her blood pressure is 118/76 mm Hg and her pulse is 64. Her turbinates are congested with clear rhinorrhea. The rest of the examination is normal.

AVOID TRIGGERS, PRETREAT BEFORE EXPOSURE

While treatment for nonallergic rhinitis varies according to the cause, there are some general guidelines for therapy (Figure 1).

People with known environmental, non-immunologic, and irritant triggers should be reminded to avoid these exposures if possible.

If triggers are unavoidable, patients can pretreat themselves with topical nasal sprays before exposure. For example, if symptoms occur while on airplanes, then intranasal steroids or antihistamine sprays should be used before getting on the plane.

 

 

Many drugs available

Fortunately, many effective drugs are available to treat nonallergic rhinitis. These have few adverse effects or drug interactions.

Intranasal steroid sprays are considered first-line therapy, as there are studies demonstrating effectiveness in nonallergic rhinitis.²² Intranasal fluticasone propionate (Flonase) and beclomethasone dipropionate (Beconase AQ) are approved by the US Food and Drug Administration (FDA) for treating nonallergic rhinitis. Intranasal mometasone (Nasonex) is approved for treating nasal polyps.

Nasal steroid sprays are most effective if the dominant nasal symptom is congestion, but they have also shown benefit for rhinorrhea, sneezing, and itching.

Side effects of nasal steroid sprays include nasal irritation (dryness, burning, and stinging) and epistaxis, the latter occurring in 5% to 10% of patients.²³

Intranasal antihistamines include azelastine (Astelin, Astepro) and olopatadine (Patanase). They are particularly useful for treating sneezing, congestion, and rhinorrhea.²⁴ Astelin is the only intranasal antihistamine with FDA approval for nonallergic rhinitis.

Side effects of this drug class include bitter taste (with Astelin), sweet taste (with Astepro), headache, and somnolence.

Oral antihistamines such as loratadine (Claritin), cetirizine (Zyrtec), and fexofenadine (Allegra) are now available over the counter, and many patients try them before seeking medical care. These drugs may be helpful for those bothered by sneezing. However, no study has demonstrated their effectiveness for nonallergic rhinitis.²⁵ First-generation antihistamines may help with rhinorrhea via their anticholinergic effects.

Ipratropium, an antimuscarinic agent, decreases secretions by inhibiting the nasal parasympathetic mucous glands. Intranasal ipratropium 0.03% (Atrovent 0.03%) should be considered first-line if the dominant symptom is rhinorrhea. Higher-dose ipratropium 0.06% is approved for rhinorrhea related to the common cold or allergic rhinitis. Because it is used topically, little is absorbed. Its major side effect is nasal dryness.

Decongestants, either oral or topical, can relieve the symptoms of congestion and rhinorrhea in nonallergic rhinitis. They should only be used short-term, as there is little evidence to support their chronic use.

Phenylpropanolamine, a decongestant previously found in over-the-counter cough medicines, was withdrawn from the market in 2000 owing to concern that the drug, especially when used for weight suppression, was linked to hemorrhagic stroke in young women.^26,27 Other oral decongestants, ie, pseudoephedrine and phenylephrine, are still available, but there are no definitive guidelines for their use. Their side effects include tachycardia, increase in blood pressure, and insomnia.

Nasal saline irrigation has been used for centuries to treat rhinitis and sinusitis, despite limited evidence of benefit. A Cochrane review concluded that saline irrigation was well tolerated, had minor side effects, and could provide some relief of rhinosinusitis symptoms either as the sole therapeutic measure or as adjunctive treatment.²⁸ Hypertonic saline solutions, while possibly more effective than isotonic saline in improving mucociliary clearance, are not as well tolerated since they can cause nasal burning and irritation. Presumed benefits of saline irrigation are clearance of nasal secretions, improvement of nasociliary function, and removal of irritants and pollen from the nose.

A strategy

Initial therapy (Table 2) should be based on the presentation. If the patient has a limited response to the therapy at follow-up in 2 to 4 weeks, the physician should consider using adjunctive medications, address patient adherence and technique, and reassess the accuracy of the initial diagnosis. At this point, one can consider referral to a specialist such as an allergist or otolaryngologist, especially if there are comorbid conditions such as asthma or polyps.

Imaging the sinuses with CT, which has replaced standard nasal radiography, may help if one is concerned about chronic rhinosinusitis, nasal polyps, or other anatomic condition that could contribute to persistent symptoms. Cost and radiation exposure should enter into the decision to obtain this study because a diagnosis based on the patient’s report of symptoms may be equally accurate.^29,30

CASE CONTINUED

Our patient has a number of potential causes of her symptoms. Exposure to second-hand tobacco smoke at home and to the air in airplanes could be acute triggers. Weather and temperature changes could explain her chronic symptoms in the spring and fall. Use of an angiotensin-converting enzyme inhibitor (in her case, lisinopril) and estrogen replacement therapy may contribute to perennial symptoms, but the onset of her nonallergic rhinitis does not correlate with the use of these drugs. There are no symptoms to suggest chronic rhinosinusitis or anatomic causes of her symptoms.

This case is typical of vasomotor rhinitis of the weather- or temperature-sensitive type. This diagnosis may explain her lack of improvement with intranasal steroids, though adherence and spray technique should be assessed. At this point, we would recommend trying topical antihistamines daily when chronic symptoms are present or as needed for acute symptoms.

A 55-year-old woman has come to the clinic because of clear rhinorrhea and nasal congestion, which occur year-round but are worse in the winter. She reports that at times her nose runs continuously. Nasal symptoms have been present for 4 to 5 years but are worsening. The clear discharge is not associated with sneezing or itching. Though she lives with a cat, her symptoms are not exacerbated by close contact with it.

One year ago, an allergist performed skin testing but found no evidence of allergies as a cause of her rhinitis. A short course of intranasal steroids did not seem to improve her nasal symptoms.

The patient also has hypertension, hypothyroidism, and hot flashes due to menopause; these conditions are well controlled with lisinopril (Zestril), levothyroxine (Synthroid), and estrogen replacement. She has no history of asthma and has had no allergies to drugs, including nonsteroidal anti-inflammatory drugs (NSAIDs.)

How should this patient be evaluated and treated?

COMMON, OFTEN OVERLOOKED

Many patients suffer from rhinitis, but this problem can be overshadowed by other chronic diseases seen in a medical clinic, especially during a brief office visit. When a patient presents with rhinitis, a key question is whether it is allergic or nonallergic.

This review will discuss the different forms of nonallergic rhinitis and their causes, and give recommendations about therapy.

RHINITIS: ALLERGIC OR NONALLERGIC?

While allergic rhinitis affects 30 and 60 million Americans annually, or between 10% to 30% of US adults,¹ how many have nonallergic rhinitis has been difficult to determine.

In a study in allergy clinics, 23% of patients with rhinitis had the nonallergic form, 43% had the allergic form, and 34% had both forms (mixed rhinitis).² Other studies have suggested that up to 52% of patients presenting to allergy clinics with rhinitis have nonallergic rhinitis.³

Over time, patients may not stay in the same category. One study found that 24% of patients originally diagnosed with nonallergic rhinitis developed positive allergy tests when retested 3 or more years after their initial evaluation.⁴

Regardless of the type, untreated or uncontrolled symptoms of rhinitis can significantly affect the quality of life.

All forms of rhinitis are characterized by one or more of the following symptoms: nasal congestion, clear rhinorrhea, sneezing, and itching. These symptoms can be episodic or chronic and can range from mild to debilitating. In addition, rhinitis can lead to systemic symptoms of fatigue, headache, sleep disturbance, and cognitive impairment and can be associated with respiratory symptoms such as sinusitis and asthma.¹

Mechanisms are mostly unknown

While allergic rhinitis leads to symptoms when airborne allergens bind with specific immunoglobulin E (IgE) in the nose, the etiology of most forms of nonallergic rhinitis is unknown. However, several mechanisms have been proposed. These include entopy (local nasal IgE synthesis with negative skin tests),⁵ nocioceptive dysfunction (hyperactive sensory receptors),⁶ and autonomic nervous system abnormalities (hypoactive or hyperactive dysfunction of sympathetic or parasympathetic nerves in the nose).⁷

Does this patient have an allergic cause of rhinitis?

When considering a patient with rhinitis, the most important question is, “Does this patient have an allergic cause of rhinitis?” Allergic and nonallergic rhinitis have similar symptoms, making them difficult to distinguish. However, their mechanisms and treatment differ. By categorizing a patient’s type of rhinitis, the physician can make specific recommendations for avoidance and can initiate treatment with the most appropriate therapy. Misclassification can lead to treatment failure, multiple visits, poor adherence, and frustration for patients with uncontrolled symptoms.

Patients for whom an allergic cause cannot be found by allergy skin testing or serum specific IgE immunoassay (Immunocap/RAST) for environmental aeroallergens are classified as having nonallergic rhinitis.

 

CLUES POINTING TO NONALLERGIC VS ALLERGIC RHINITIS

Nonallergic rhinitis encompasses a range of syndromes with overlapping symptoms. While tools such as the Rhinitis Diagnostic Worksheet are available to help differentiate allergic from nonallergic rhinitis, debate continues about whether it is necessary to characterize different forms of rhinitis before initiating treatment.⁸

The diagnosis of nonallergic rhinitis depends on a thorough history and physical examination. Key questions relate to the triggers that bring on the rhinitis, which will assist the clinician in determining which subtype of rhinitis a patient may be experiencing and therefore how to manage it. Clues:

• Patients with nonallergic rhinitis more often report nasal congestion and rhinorrhea, rather than sneezing and itching, which are predominant symptoms of allergic rhinitis.
• Patients with nonallergic rhinitis tend to develop symptoms at a later age.
• Common triggers of nonallergic rhinitis are changes in weather and temperature, food, perfumes, odors, smoke, and fumes. Animal exposure does not lead to symptoms.
• Patients with nonallergic rhinitis have few complaints of concomitant symptoms of allergic conjunctivitis (itching, watering, redness, and swelling).
• Many patients with nonallergic rhinitis find that antihistamines have no benefit. Also, they do not have other atopic diseases such as eczema or food allergies and have no family history of atopy.

PHYSICAL FINDINGS

Some findings on physical examination may help distinguish allergic from nonallergic rhinitis.

• Patients with long-standing allergic rhinitis may have an “allergic crease,” ie, a horizontal wrinkle near the tip of the nose caused by frequent upward wiping. Another sign may be a gothic arch, which is a narrowing of the hard palate occurring as a child.
• In allergic rhinitis, the turbinates are often pale, moist, and boggy with a bluish tinge.
• 
  Findings such as a deviated nasal septum, discolored nasal discharge, atrophic nasal mucosa, or nasal polyps should prompt consideration of the several subtypes of nonallergic rhinitis (Table 1).

CASE CONTINUED

Our patient’s symptoms can be caused by many different factors. Allergic triggers for rhinitis include both indoor and outdoor sources. The most common allergens include cat, dog, dust mite, cockroach, mold, and pollen allergens. The absence of acute sneezing and itching when around her cat and her recent negative skin-prick tests confirm that the rhinitis symptoms are not allergic.

In this patient, who has symptoms throughout the year but no allergic triggers, consideration of the different subtypes of nonallergic rhinitis may help guide further therapy.

SUBTYPES OF NONALLERGIC RHINITIS

Vasomotor rhinitis

Vasomotor rhinitis is thought to be caused by a variety of neural and vascular triggers, often without an inflammatory cause. These triggers lead to symptoms involving nasal congestion and clear rhinorrhea more than sneezing and itching. The symptoms can be sporadic, with acute onset in relation to identifiable nonallergic triggers, or chronic, with no clear trigger.

Gustatory rhinitis, for example, is a form of vasomotor rhinitis in which clear rhinorrhea occurs suddenly while eating or while drinking alcohol. It may be prevented by using nasal ipratropium (Atrovent) before meals.

Irritant-sensitive vasomotor rhinitis. In some patients, acute vasomotor rhinitis symptoms are brought on by strong odors, cigarette smoke, air pollution, or perfume. When asked, most patients easily identify which of these irritant triggers cause symptoms.

Weather- or temperature-sensitive vasomotor rhinitis. In other patients, a change in temperature, humidity, or barometric pressure or exposure to cold or dry air can cause nasal symptoms.⁹ These triggers are often hard to identify. Weather- or temperature-sensitive vasomotor rhinitis is often mistaken for seasonal allergic rhinitis because weather changes occur in close relation to the peak allergy seasons in the spring and fall. However, this subtype does not respond as well to intranasal steroids.⁹

Other nonallergic triggers of vasomotor rhinitis may include exercise, emotion, and sexual arousal (honeymoon rhinitis).¹⁰

Some triggers, such as tobacco smoke and perfume, are easy to avoid. Other triggers, such as weather changes, are unavoidable. If avoidance measures fail or are inadequate, medications (described below) can be used for prophylaxis and symptomatic treatment.

Drug-induced rhinitis

Drugs of various classes are known to cause either acute or chronic rhinitis. Drug-induced rhinitis has been divided into different types based on the mechanism involved.¹¹

The local inflammatory type occurs in aspirin-exacerbated respiratory disease, which is characterized by nasal polyposis with chronic rhinosinusitis, hyposmia, and moderate to severe persistent asthma. Aspirin and other NSAIDs induce an acute local inflammation, leading to severe rhinitis and asthma symptoms. Avoiding all NSAID products is recommended; aspirin desensitization may lead to improvement in rhinosinusitis and asthma control.

The neurogenic type of drug-induced rhinitis can occur with sympatholytic drugs such as alpha receptor agonists (eg, clonidine [Cat-apres]) and antagonists (eg, prazosin [Minipress]).¹¹ Vasodilators, including phosphodiesterase-5 inhibitors such as sildenafil (Viagra), can lead to acute rhinitis symptoms (“anniversary rhinitis”).

Unknown mechanisms. Many other medications can lead to rhinitis by unknown mechanisms, usually with normal findings on physical examination. These include beta-blockers, angiotensin-converting enzyme inhibitors, calcium channel blockers, exogenous estrogens, oral contraceptives, antipsychotics, and gabapentin (Neurontin).

Correlating the initiation of a drug with the onset of rhinitis can help identify offending medications. Stopping the suspected medication, if feasible, is the first-line treatment.

Rhinitis medicamentosa, typically caused by overuse of over-the-counter topical nasal decongestants, is also classified under drug-induced rhinitis. Patients may not think of nasal decongestants as medications, and the physician may need to ask specifically about their use.

On examination, the nasal mucosa appears beefy red without mucous. Once a diagnosis is made, the physician should identify and treat the original etiology of the nasal congestion that led the patient to self-treat.

Patients with rhinitis medicamentosa often have difficulty discontinuing use of topical decongestants. They should be educated that the withdrawal symptoms can be severe and that more than one attempt at quitting may be needed. To break the cycle of rebound congestion, topical intranasal steroids should be used, though 5 to 7 days of oral steroids may be necessary.¹

Cocaine is a potent vasoconstrictor. Its illicit use should be suspected, especially if the patient presents with symptoms of chronic irritation such as frequent nosebleeds, crusting, and scabbing.¹²

Infectious rhinitis

One of the most common causes of acute rhinitis is upper respiratory infection.

Acute viral upper respiratory infection often presents with thick nasal discharge, sneezing, and nasal obstruction that usually clears in 7 to 10 days but can last up to 3 weeks. Acute bacterial sinusitis can follow, typically in fewer than 2% of patients, with symptoms of persistent nasal congestion, discolored mucus, facial pain, cough, and sometimes fever.

Chronic rhinosinusitis is a syndrome with sinus mucosal inflammation with multiple causes. It is clinically defined as persistent nasal and sinus symptoms lasting longer than 12 weeks and confirmed with computed tomography (CT).¹³ The CT findings of chronic rhinosinusitis include thickening of the lining of the sinus cavities or complete opacification of the pneumatized sinuses.

Major symptoms to consider for diagnosis include facial pain, congestion, obstruction, purulent discharge on examination, and changes in olfaction. Minor symptoms are cough, fatigue, headache, halitosis, fever, ear symptoms, and dental pain.

Treatment may involve 3 or more weeks of an oral antibiotic and a short course of an oral steroid, a daily nasal steroid spray, or both oral and nasal steroids. Most patients can be managed in the primary care setting, but they can be referred to an ear, nose, and throat specialist, an allergist, or an immunologist if their symptoms do not respond to initial therapy.

 

 

Nonallergic rhinitis eosinophilic syndrome

Patients with nonallergic rhinitis eosinophilic syndrome (NARES) are typically middle-aged and have perennial symptoms of sneezing, itching, and rhinorrhea with intermittent exacerbations. They occasionally have associated hyposmia (impaired sense of smell).¹ The diagnosis is made when eosinophils account for more than 5% of cells on a nasal smear and allergy testing is negative.

Patients may develop nasal polyposis and aspirin sensitivity.¹ Entopy has been described in some.¹⁴

Because of the eosinophilic inflammation, this form of nonallergic rhinitis responds well to intranasal steroids.

Immunologic causes

Systemic diseases can affect the nose and cause variable nasal symptoms that can be mistaken for rhinitis. Wegener granulomatosis, sarcoidosis, relapsing polychondritis, midline granulomas, Churg-Strauss syndrome, and amyloidosis can all affect the structures in the nose even before manifesting systemic symptoms. Granulomatous infections in the nose may lead to crusting, bleeding, and nasal obstruction.¹

A lack of a response to intranasal steroids or oral antibiotics should lead to consideration of these conditions, and treatment should be tailored to the specific disease.

Occupational rhinitis

Occupational exposure to chemicals, biologic aerosols, flour, and latex can lead to rhinitis, typically through an inflammatory mechanism. Many patients present with associated occupational asthma. The symptoms improve when the patient is away from work and worsen throughout the work week.

Avoiding the triggering agent is necessary to treat these symptoms.

Hormonal rhinitis

Hormonal rhinitis, ie, rhinitis related to metabolic and endocrine conditions, is most commonly associated with high estrogen states. Nasal congestion has been reported with pregnancy, menses, menarche, and the use of oral contraceptives.¹⁵ The mechanism for congestion in these conditions still needs clarification.

When considering drug therapy, only intranasal budesonide (Rhinocort) has a pregnancy category B rating.

While hypothyroidism and acromegaly have been mentioned in reviews of nonallergic rhinitis, evidence that these disorders cause nonallergic rhinitis is not strong.^16,17

Structurally related rhinitis

Anatomic abnormalities that can cause persistent nasal congestion include nasal septal deviation, turbinate hypertrophy, enlarged adenoids, tumors, and foreign bodies. These can be visualized by simple anterior nasal examination, nasal endoscopy, or radiologic studies. If structural causes lead to impaired quality of life or chronic rhinosinusitis, then consider referral to a specialist for possible surgical treatment.

Clear spontaneous rhinorrhea, with or without trauma, can be caused by cerebrospinal fluid leaking into the nasal cavity.¹⁸ A salty, metallic taste in the mouth can be a clue that the fluid is cerebrospinal fluid. A definitive diagnosis of cerebrospinal fluid leak is made by finding beta-2-transferrin in nasal secretions.

Atrophic rhinitis

Atrophic rhinitis is categorized as primary or secondary.

Primary (idiopathic) atrophic rhinitis is characterized by atrophy of the nasal mucosa and mucosal colonization with Klebsiella ozaenae associated with a foul-smelling nasal discharge.^19,20 This disorder has been primarily reported in young people who present with nasal obstruction, dryness, crusting, and epistaxis. They are from areas with warm climates, such as the Middle East, Southeast Asia, India, Africa, and the Mediterranean.

Secondary atrophic rhinitis can be a complication of nasal or sinus surgery, trauma, granulomatous disease, or exposure to radiation.²¹ This disorder is typically diagnosed with nasal endoscopy and treated with daily saline rinses with or without topical antibiotics.²¹

CASE CONTINUED

Questioned further, our patient says her symptoms are worse when her husband smokes, but that she continues to have congestion and rhinorrhea when he is away on business trips. She notes that her symptoms are often worse on airplanes (dry air with an acute change in barometric pressure), with weather changes, and in cold, dry environments. Symptoms are not induced by eating.

We note that she started taking lisinopril 2 years ago and conjugated equine estrogens 8 years ago. Review of systems reveals no history of facial or head trauma, polyps, or hyposmia.

The rhinitis and congestion are bilateral, and she denies headaches, acid reflux, and conjunctivitis. She has a mild throat-clearing cough that she attributes to postnasal drip.

On physical examination, her blood pressure is 118/76 mm Hg and her pulse is 64. Her turbinates are congested with clear rhinorrhea. The rest of the examination is normal.

AVOID TRIGGERS, PRETREAT BEFORE EXPOSURE

While treatment for nonallergic rhinitis varies according to the cause, there are some general guidelines for therapy (Figure 1).

People with known environmental, non-immunologic, and irritant triggers should be reminded to avoid these exposures if possible.

If triggers are unavoidable, patients can pretreat themselves with topical nasal sprays before exposure. For example, if symptoms occur while on airplanes, then intranasal steroids or antihistamine sprays should be used before getting on the plane.

 

 

Many drugs available

Fortunately, many effective drugs are available to treat nonallergic rhinitis. These have few adverse effects or drug interactions.

Intranasal steroid sprays are considered first-line therapy, as there are studies demonstrating effectiveness in nonallergic rhinitis.²² Intranasal fluticasone propionate (Flonase) and beclomethasone dipropionate (Beconase AQ) are approved by the US Food and Drug Administration (FDA) for treating nonallergic rhinitis. Intranasal mometasone (Nasonex) is approved for treating nasal polyps.

Nasal steroid sprays are most effective if the dominant nasal symptom is congestion, but they have also shown benefit for rhinorrhea, sneezing, and itching.

Side effects of nasal steroid sprays include nasal irritation (dryness, burning, and stinging) and epistaxis, the latter occurring in 5% to 10% of patients.²³

Intranasal antihistamines include azelastine (Astelin, Astepro) and olopatadine (Patanase). They are particularly useful for treating sneezing, congestion, and rhinorrhea.²⁴ Astelin is the only intranasal antihistamine with FDA approval for nonallergic rhinitis.

Side effects of this drug class include bitter taste (with Astelin), sweet taste (with Astepro), headache, and somnolence.

Oral antihistamines such as loratadine (Claritin), cetirizine (Zyrtec), and fexofenadine (Allegra) are now available over the counter, and many patients try them before seeking medical care. These drugs may be helpful for those bothered by sneezing. However, no study has demonstrated their effectiveness for nonallergic rhinitis.²⁵ First-generation antihistamines may help with rhinorrhea via their anticholinergic effects.

Ipratropium, an antimuscarinic agent, decreases secretions by inhibiting the nasal parasympathetic mucous glands. Intranasal ipratropium 0.03% (Atrovent 0.03%) should be considered first-line if the dominant symptom is rhinorrhea. Higher-dose ipratropium 0.06% is approved for rhinorrhea related to the common cold or allergic rhinitis. Because it is used topically, little is absorbed. Its major side effect is nasal dryness.

Decongestants, either oral or topical, can relieve the symptoms of congestion and rhinorrhea in nonallergic rhinitis. They should only be used short-term, as there is little evidence to support their chronic use.

Phenylpropanolamine, a decongestant previously found in over-the-counter cough medicines, was withdrawn from the market in 2000 owing to concern that the drug, especially when used for weight suppression, was linked to hemorrhagic stroke in young women.^26,27 Other oral decongestants, ie, pseudoephedrine and phenylephrine, are still available, but there are no definitive guidelines for their use. Their side effects include tachycardia, increase in blood pressure, and insomnia.

Nasal saline irrigation has been used for centuries to treat rhinitis and sinusitis, despite limited evidence of benefit. A Cochrane review concluded that saline irrigation was well tolerated, had minor side effects, and could provide some relief of rhinosinusitis symptoms either as the sole therapeutic measure or as adjunctive treatment.²⁸ Hypertonic saline solutions, while possibly more effective than isotonic saline in improving mucociliary clearance, are not as well tolerated since they can cause nasal burning and irritation. Presumed benefits of saline irrigation are clearance of nasal secretions, improvement of nasociliary function, and removal of irritants and pollen from the nose.

A strategy

Initial therapy (Table 2) should be based on the presentation. If the patient has a limited response to the therapy at follow-up in 2 to 4 weeks, the physician should consider using adjunctive medications, address patient adherence and technique, and reassess the accuracy of the initial diagnosis. At this point, one can consider referral to a specialist such as an allergist or otolaryngologist, especially if there are comorbid conditions such as asthma or polyps.

Imaging the sinuses with CT, which has replaced standard nasal radiography, may help if one is concerned about chronic rhinosinusitis, nasal polyps, or other anatomic condition that could contribute to persistent symptoms. Cost and radiation exposure should enter into the decision to obtain this study because a diagnosis based on the patient’s report of symptoms may be equally accurate.^29,30

CASE CONTINUED

Our patient has a number of potential causes of her symptoms. Exposure to second-hand tobacco smoke at home and to the air in airplanes could be acute triggers. Weather and temperature changes could explain her chronic symptoms in the spring and fall. Use of an angiotensin-converting enzyme inhibitor (in her case, lisinopril) and estrogen replacement therapy may contribute to perennial symptoms, but the onset of her nonallergic rhinitis does not correlate with the use of these drugs. There are no symptoms to suggest chronic rhinosinusitis or anatomic causes of her symptoms.

This case is typical of vasomotor rhinitis of the weather- or temperature-sensitive type. This diagnosis may explain her lack of improvement with intranasal steroids, though adherence and spray technique should be assessed. At this point, we would recommend trying topical antihistamines daily when chronic symptoms are present or as needed for acute symptoms.

A 55-year-old woman has come to the clinic because of clear rhinorrhea and nasal congestion, which occur year-round but are worse in the winter. She reports that at times her nose runs continuously. Nasal symptoms have been present for 4 to 5 years but are worsening. The clear discharge is not associated with sneezing or itching. Though she lives with a cat, her symptoms are not exacerbated by close contact with it.

One year ago, an allergist performed skin testing but found no evidence of allergies as a cause of her rhinitis. A short course of intranasal steroids did not seem to improve her nasal symptoms.

The patient also has hypertension, hypothyroidism, and hot flashes due to menopause; these conditions are well controlled with lisinopril (Zestril), levothyroxine (Synthroid), and estrogen replacement. She has no history of asthma and has had no allergies to drugs, including nonsteroidal anti-inflammatory drugs (NSAIDs.)

How should this patient be evaluated and treated?

COMMON, OFTEN OVERLOOKED

Many patients suffer from rhinitis, but this problem can be overshadowed by other chronic diseases seen in a medical clinic, especially during a brief office visit. When a patient presents with rhinitis, a key question is whether it is allergic or nonallergic.

This review will discuss the different forms of nonallergic rhinitis and their causes, and give recommendations about therapy.

RHINITIS: ALLERGIC OR NONALLERGIC?

While allergic rhinitis affects 30 and 60 million Americans annually, or between 10% to 30% of US adults,¹ how many have nonallergic rhinitis has been difficult to determine.

In a study in allergy clinics, 23% of patients with rhinitis had the nonallergic form, 43% had the allergic form, and 34% had both forms (mixed rhinitis).² Other studies have suggested that up to 52% of patients presenting to allergy clinics with rhinitis have nonallergic rhinitis.³

Over time, patients may not stay in the same category. One study found that 24% of patients originally diagnosed with nonallergic rhinitis developed positive allergy tests when retested 3 or more years after their initial evaluation.⁴

Regardless of the type, untreated or uncontrolled symptoms of rhinitis can significantly affect the quality of life.

All forms of rhinitis are characterized by one or more of the following symptoms: nasal congestion, clear rhinorrhea, sneezing, and itching. These symptoms can be episodic or chronic and can range from mild to debilitating. In addition, rhinitis can lead to systemic symptoms of fatigue, headache, sleep disturbance, and cognitive impairment and can be associated with respiratory symptoms such as sinusitis and asthma.¹

Mechanisms are mostly unknown

While allergic rhinitis leads to symptoms when airborne allergens bind with specific immunoglobulin E (IgE) in the nose, the etiology of most forms of nonallergic rhinitis is unknown. However, several mechanisms have been proposed. These include entopy (local nasal IgE synthesis with negative skin tests),⁵ nocioceptive dysfunction (hyperactive sensory receptors),⁶ and autonomic nervous system abnormalities (hypoactive or hyperactive dysfunction of sympathetic or parasympathetic nerves in the nose).⁷

Does this patient have an allergic cause of rhinitis?

When considering a patient with rhinitis, the most important question is, “Does this patient have an allergic cause of rhinitis?” Allergic and nonallergic rhinitis have similar symptoms, making them difficult to distinguish. However, their mechanisms and treatment differ. By categorizing a patient’s type of rhinitis, the physician can make specific recommendations for avoidance and can initiate treatment with the most appropriate therapy. Misclassification can lead to treatment failure, multiple visits, poor adherence, and frustration for patients with uncontrolled symptoms.

Patients for whom an allergic cause cannot be found by allergy skin testing or serum specific IgE immunoassay (Immunocap/RAST) for environmental aeroallergens are classified as having nonallergic rhinitis.

 

CLUES POINTING TO NONALLERGIC VS ALLERGIC RHINITIS

Nonallergic rhinitis encompasses a range of syndromes with overlapping symptoms. While tools such as the Rhinitis Diagnostic Worksheet are available to help differentiate allergic from nonallergic rhinitis, debate continues about whether it is necessary to characterize different forms of rhinitis before initiating treatment.⁸

The diagnosis of nonallergic rhinitis depends on a thorough history and physical examination. Key questions relate to the triggers that bring on the rhinitis, which will assist the clinician in determining which subtype of rhinitis a patient may be experiencing and therefore how to manage it. Clues:

• Patients with nonallergic rhinitis more often report nasal congestion and rhinorrhea, rather than sneezing and itching, which are predominant symptoms of allergic rhinitis.
• Patients with nonallergic rhinitis tend to develop symptoms at a later age.
• Common triggers of nonallergic rhinitis are changes in weather and temperature, food, perfumes, odors, smoke, and fumes. Animal exposure does not lead to symptoms.
• Patients with nonallergic rhinitis have few complaints of concomitant symptoms of allergic conjunctivitis (itching, watering, redness, and swelling).
• Many patients with nonallergic rhinitis find that antihistamines have no benefit. Also, they do not have other atopic diseases such as eczema or food allergies and have no family history of atopy.

PHYSICAL FINDINGS

Some findings on physical examination may help distinguish allergic from nonallergic rhinitis.

• Patients with long-standing allergic rhinitis may have an “allergic crease,” ie, a horizontal wrinkle near the tip of the nose caused by frequent upward wiping. Another sign may be a gothic arch, which is a narrowing of the hard palate occurring as a child.
• In allergic rhinitis, the turbinates are often pale, moist, and boggy with a bluish tinge.
• 
  Findings such as a deviated nasal septum, discolored nasal discharge, atrophic nasal mucosa, or nasal polyps should prompt consideration of the several subtypes of nonallergic rhinitis (Table 1).

CASE CONTINUED

Our patient’s symptoms can be caused by many different factors. Allergic triggers for rhinitis include both indoor and outdoor sources. The most common allergens include cat, dog, dust mite, cockroach, mold, and pollen allergens. The absence of acute sneezing and itching when around her cat and her recent negative skin-prick tests confirm that the rhinitis symptoms are not allergic.

In this patient, who has symptoms throughout the year but no allergic triggers, consideration of the different subtypes of nonallergic rhinitis may help guide further therapy.

SUBTYPES OF NONALLERGIC RHINITIS

Vasomotor rhinitis

Vasomotor rhinitis is thought to be caused by a variety of neural and vascular triggers, often without an inflammatory cause. These triggers lead to symptoms involving nasal congestion and clear rhinorrhea more than sneezing and itching. The symptoms can be sporadic, with acute onset in relation to identifiable nonallergic triggers, or chronic, with no clear trigger.

Gustatory rhinitis, for example, is a form of vasomotor rhinitis in which clear rhinorrhea occurs suddenly while eating or while drinking alcohol. It may be prevented by using nasal ipratropium (Atrovent) before meals.

Irritant-sensitive vasomotor rhinitis. In some patients, acute vasomotor rhinitis symptoms are brought on by strong odors, cigarette smoke, air pollution, or perfume. When asked, most patients easily identify which of these irritant triggers cause symptoms.

Weather- or temperature-sensitive vasomotor rhinitis. In other patients, a change in temperature, humidity, or barometric pressure or exposure to cold or dry air can cause nasal symptoms.⁹ These triggers are often hard to identify. Weather- or temperature-sensitive vasomotor rhinitis is often mistaken for seasonal allergic rhinitis because weather changes occur in close relation to the peak allergy seasons in the spring and fall. However, this subtype does not respond as well to intranasal steroids.⁹

Other nonallergic triggers of vasomotor rhinitis may include exercise, emotion, and sexual arousal (honeymoon rhinitis).¹⁰

Some triggers, such as tobacco smoke and perfume, are easy to avoid. Other triggers, such as weather changes, are unavoidable. If avoidance measures fail or are inadequate, medications (described below) can be used for prophylaxis and symptomatic treatment.

Drug-induced rhinitis

Drugs of various classes are known to cause either acute or chronic rhinitis. Drug-induced rhinitis has been divided into different types based on the mechanism involved.¹¹

The local inflammatory type occurs in aspirin-exacerbated respiratory disease, which is characterized by nasal polyposis with chronic rhinosinusitis, hyposmia, and moderate to severe persistent asthma. Aspirin and other NSAIDs induce an acute local inflammation, leading to severe rhinitis and asthma symptoms. Avoiding all NSAID products is recommended; aspirin desensitization may lead to improvement in rhinosinusitis and asthma control.

The neurogenic type of drug-induced rhinitis can occur with sympatholytic drugs such as alpha receptor agonists (eg, clonidine [Cat-apres]) and antagonists (eg, prazosin [Minipress]).¹¹ Vasodilators, including phosphodiesterase-5 inhibitors such as sildenafil (Viagra), can lead to acute rhinitis symptoms (“anniversary rhinitis”).

Unknown mechanisms. Many other medications can lead to rhinitis by unknown mechanisms, usually with normal findings on physical examination. These include beta-blockers, angiotensin-converting enzyme inhibitors, calcium channel blockers, exogenous estrogens, oral contraceptives, antipsychotics, and gabapentin (Neurontin).

Correlating the initiation of a drug with the onset of rhinitis can help identify offending medications. Stopping the suspected medication, if feasible, is the first-line treatment.

Rhinitis medicamentosa, typically caused by overuse of over-the-counter topical nasal decongestants, is also classified under drug-induced rhinitis. Patients may not think of nasal decongestants as medications, and the physician may need to ask specifically about their use.

On examination, the nasal mucosa appears beefy red without mucous. Once a diagnosis is made, the physician should identify and treat the original etiology of the nasal congestion that led the patient to self-treat.

Patients with rhinitis medicamentosa often have difficulty discontinuing use of topical decongestants. They should be educated that the withdrawal symptoms can be severe and that more than one attempt at quitting may be needed. To break the cycle of rebound congestion, topical intranasal steroids should be used, though 5 to 7 days of oral steroids may be necessary.¹

Cocaine is a potent vasoconstrictor. Its illicit use should be suspected, especially if the patient presents with symptoms of chronic irritation such as frequent nosebleeds, crusting, and scabbing.¹²

Infectious rhinitis

One of the most common causes of acute rhinitis is upper respiratory infection.

Acute viral upper respiratory infection often presents with thick nasal discharge, sneezing, and nasal obstruction that usually clears in 7 to 10 days but can last up to 3 weeks. Acute bacterial sinusitis can follow, typically in fewer than 2% of patients, with symptoms of persistent nasal congestion, discolored mucus, facial pain, cough, and sometimes fever.

Chronic rhinosinusitis is a syndrome with sinus mucosal inflammation with multiple causes. It is clinically defined as persistent nasal and sinus symptoms lasting longer than 12 weeks and confirmed with computed tomography (CT).¹³ The CT findings of chronic rhinosinusitis include thickening of the lining of the sinus cavities or complete opacification of the pneumatized sinuses.

Major symptoms to consider for diagnosis include facial pain, congestion, obstruction, purulent discharge on examination, and changes in olfaction. Minor symptoms are cough, fatigue, headache, halitosis, fever, ear symptoms, and dental pain.

Treatment may involve 3 or more weeks of an oral antibiotic and a short course of an oral steroid, a daily nasal steroid spray, or both oral and nasal steroids. Most patients can be managed in the primary care setting, but they can be referred to an ear, nose, and throat specialist, an allergist, or an immunologist if their symptoms do not respond to initial therapy.

 

 

Nonallergic rhinitis eosinophilic syndrome

Patients with nonallergic rhinitis eosinophilic syndrome (NARES) are typically middle-aged and have perennial symptoms of sneezing, itching, and rhinorrhea with intermittent exacerbations. They occasionally have associated hyposmia (impaired sense of smell).¹ The diagnosis is made when eosinophils account for more than 5% of cells on a nasal smear and allergy testing is negative.

Patients may develop nasal polyposis and aspirin sensitivity.¹ Entopy has been described in some.¹⁴

Because of the eosinophilic inflammation, this form of nonallergic rhinitis responds well to intranasal steroids.

Immunologic causes

Systemic diseases can affect the nose and cause variable nasal symptoms that can be mistaken for rhinitis. Wegener granulomatosis, sarcoidosis, relapsing polychondritis, midline granulomas, Churg-Strauss syndrome, and amyloidosis can all affect the structures in the nose even before manifesting systemic symptoms. Granulomatous infections in the nose may lead to crusting, bleeding, and nasal obstruction.¹

A lack of a response to intranasal steroids or oral antibiotics should lead to consideration of these conditions, and treatment should be tailored to the specific disease.

Occupational rhinitis

Occupational exposure to chemicals, biologic aerosols, flour, and latex can lead to rhinitis, typically through an inflammatory mechanism. Many patients present with associated occupational asthma. The symptoms improve when the patient is away from work and worsen throughout the work week.

Avoiding the triggering agent is necessary to treat these symptoms.

Hormonal rhinitis

Hormonal rhinitis, ie, rhinitis related to metabolic and endocrine conditions, is most commonly associated with high estrogen states. Nasal congestion has been reported with pregnancy, menses, menarche, and the use of oral contraceptives.¹⁵ The mechanism for congestion in these conditions still needs clarification.

When considering drug therapy, only intranasal budesonide (Rhinocort) has a pregnancy category B rating.

While hypothyroidism and acromegaly have been mentioned in reviews of nonallergic rhinitis, evidence that these disorders cause nonallergic rhinitis is not strong.^16,17

Structurally related rhinitis

Anatomic abnormalities that can cause persistent nasal congestion include nasal septal deviation, turbinate hypertrophy, enlarged adenoids, tumors, and foreign bodies. These can be visualized by simple anterior nasal examination, nasal endoscopy, or radiologic studies. If structural causes lead to impaired quality of life or chronic rhinosinusitis, then consider referral to a specialist for possible surgical treatment.

Clear spontaneous rhinorrhea, with or without trauma, can be caused by cerebrospinal fluid leaking into the nasal cavity.¹⁸ A salty, metallic taste in the mouth can be a clue that the fluid is cerebrospinal fluid. A definitive diagnosis of cerebrospinal fluid leak is made by finding beta-2-transferrin in nasal secretions.

Atrophic rhinitis

Atrophic rhinitis is categorized as primary or secondary.

Primary (idiopathic) atrophic rhinitis is characterized by atrophy of the nasal mucosa and mucosal colonization with Klebsiella ozaenae associated with a foul-smelling nasal discharge.^19,20 This disorder has been primarily reported in young people who present with nasal obstruction, dryness, crusting, and epistaxis. They are from areas with warm climates, such as the Middle East, Southeast Asia, India, Africa, and the Mediterranean.

Secondary atrophic rhinitis can be a complication of nasal or sinus surgery, trauma, granulomatous disease, or exposure to radiation.²¹ This disorder is typically diagnosed with nasal endoscopy and treated with daily saline rinses with or without topical antibiotics.²¹

CASE CONTINUED

Questioned further, our patient says her symptoms are worse when her husband smokes, but that she continues to have congestion and rhinorrhea when he is away on business trips. She notes that her symptoms are often worse on airplanes (dry air with an acute change in barometric pressure), with weather changes, and in cold, dry environments. Symptoms are not induced by eating.

We note that she started taking lisinopril 2 years ago and conjugated equine estrogens 8 years ago. Review of systems reveals no history of facial or head trauma, polyps, or hyposmia.

The rhinitis and congestion are bilateral, and she denies headaches, acid reflux, and conjunctivitis. She has a mild throat-clearing cough that she attributes to postnasal drip.

On physical examination, her blood pressure is 118/76 mm Hg and her pulse is 64. Her turbinates are congested with clear rhinorrhea. The rest of the examination is normal.

AVOID TRIGGERS, PRETREAT BEFORE EXPOSURE

While treatment for nonallergic rhinitis varies according to the cause, there are some general guidelines for therapy (Figure 1).

People with known environmental, non-immunologic, and irritant triggers should be reminded to avoid these exposures if possible.

If triggers are unavoidable, patients can pretreat themselves with topical nasal sprays before exposure. For example, if symptoms occur while on airplanes, then intranasal steroids or antihistamine sprays should be used before getting on the plane.

 

 

Many drugs available

Fortunately, many effective drugs are available to treat nonallergic rhinitis. These have few adverse effects or drug interactions.

Intranasal steroid sprays are considered first-line therapy, as there are studies demonstrating effectiveness in nonallergic rhinitis.²² Intranasal fluticasone propionate (Flonase) and beclomethasone dipropionate (Beconase AQ) are approved by the US Food and Drug Administration (FDA) for treating nonallergic rhinitis. Intranasal mometasone (Nasonex) is approved for treating nasal polyps.

Nasal steroid sprays are most effective if the dominant nasal symptom is congestion, but they have also shown benefit for rhinorrhea, sneezing, and itching.

Side effects of nasal steroid sprays include nasal irritation (dryness, burning, and stinging) and epistaxis, the latter occurring in 5% to 10% of patients.²³

Intranasal antihistamines include azelastine (Astelin, Astepro) and olopatadine (Patanase). They are particularly useful for treating sneezing, congestion, and rhinorrhea.²⁴ Astelin is the only intranasal antihistamine with FDA approval for nonallergic rhinitis.

Side effects of this drug class include bitter taste (with Astelin), sweet taste (with Astepro), headache, and somnolence.

Oral antihistamines such as loratadine (Claritin), cetirizine (Zyrtec), and fexofenadine (Allegra) are now available over the counter, and many patients try them before seeking medical care. These drugs may be helpful for those bothered by sneezing. However, no study has demonstrated their effectiveness for nonallergic rhinitis.²⁵ First-generation antihistamines may help with rhinorrhea via their anticholinergic effects.

Ipratropium, an antimuscarinic agent, decreases secretions by inhibiting the nasal parasympathetic mucous glands. Intranasal ipratropium 0.03% (Atrovent 0.03%) should be considered first-line if the dominant symptom is rhinorrhea. Higher-dose ipratropium 0.06% is approved for rhinorrhea related to the common cold or allergic rhinitis. Because it is used topically, little is absorbed. Its major side effect is nasal dryness.

Decongestants, either oral or topical, can relieve the symptoms of congestion and rhinorrhea in nonallergic rhinitis. They should only be used short-term, as there is little evidence to support their chronic use.

Phenylpropanolamine, a decongestant previously found in over-the-counter cough medicines, was withdrawn from the market in 2000 owing to concern that the drug, especially when used for weight suppression, was linked to hemorrhagic stroke in young women.^26,27 Other oral decongestants, ie, pseudoephedrine and phenylephrine, are still available, but there are no definitive guidelines for their use. Their side effects include tachycardia, increase in blood pressure, and insomnia.

Nasal saline irrigation has been used for centuries to treat rhinitis and sinusitis, despite limited evidence of benefit. A Cochrane review concluded that saline irrigation was well tolerated, had minor side effects, and could provide some relief of rhinosinusitis symptoms either as the sole therapeutic measure or as adjunctive treatment.²⁸ Hypertonic saline solutions, while possibly more effective than isotonic saline in improving mucociliary clearance, are not as well tolerated since they can cause nasal burning and irritation. Presumed benefits of saline irrigation are clearance of nasal secretions, improvement of nasociliary function, and removal of irritants and pollen from the nose.

A strategy

Initial therapy (Table 2) should be based on the presentation. If the patient has a limited response to the therapy at follow-up in 2 to 4 weeks, the physician should consider using adjunctive medications, address patient adherence and technique, and reassess the accuracy of the initial diagnosis. At this point, one can consider referral to a specialist such as an allergist or otolaryngologist, especially if there are comorbid conditions such as asthma or polyps.

Imaging the sinuses with CT, which has replaced standard nasal radiography, may help if one is concerned about chronic rhinosinusitis, nasal polyps, or other anatomic condition that could contribute to persistent symptoms. Cost and radiation exposure should enter into the decision to obtain this study because a diagnosis based on the patient’s report of symptoms may be equally accurate.^29,30

CASE CONTINUED

Our patient has a number of potential causes of her symptoms. Exposure to second-hand tobacco smoke at home and to the air in airplanes could be acute triggers. Weather and temperature changes could explain her chronic symptoms in the spring and fall. Use of an angiotensin-converting enzyme inhibitor (in her case, lisinopril) and estrogen replacement therapy may contribute to perennial symptoms, but the onset of her nonallergic rhinitis does not correlate with the use of these drugs. There are no symptoms to suggest chronic rhinosinusitis or anatomic causes of her symptoms.

This case is typical of vasomotor rhinitis of the weather- or temperature-sensitive type. This diagnosis may explain her lack of improvement with intranasal steroids, though adherence and spray technique should be assessed. At this point, we would recommend trying topical antihistamines daily when chronic symptoms are present or as needed for acute symptoms.

An otherwise healthy 54-year-old woman presented with a 3-month history of an asymptomatic lesion on the face, at the site of a previous mosquito bite. Physical examination revealed a firm, pink nodule 10 mm in diameter (Figure 1). Telangiectasias were visible, more clearly by dermoscopy, but other features of a basal cell carcinoma were absent. No other skin problem was noted, and no lymphadenopathy was detected.

Histologic study of a biopsy specimen noted a dense dermal inflammatory infiltrate consisting of B lymphocytes (CD20+) with a smaller number of T lymphocytes (CD3+) arranged in several germinal centers, with an admixture of plasma cells and eosinophils (Figure 2). No clonal population was identified by gene-rearrangement studies. Borrelia burgdorferi infection was ruled out.

Q: Which is the most likely diagnosis?

• Basal cell carcinoma
• Squamous cell carcinoma
• Lymphocytoma cutis
• Amelanotic melanoma
• Pyogenic granuloma

A: The correct answer is lymphocytoma cutis. The differential diagnosis of a pink papule on the face of a middle-aged person includes nonmelanoma skin cancer, lymphoma, lymphocytoma cutis, metastatic disease, certain infections, Jessner lymphocytic infiltrate, connective tissue disease, and some adnexal tumors. Histologic study is a useful diagnostic aid in this context.

Basal cell carcinoma is the most common cutaneous malignant neoplasm, and although these tumors rarely metastasize, they are capable of gross tissue destruction, particularly those lesions arising on the face. Clinically, this tumor presents as a shiny, pearly nodule with telangiectasias on the surface, as in our patient, but skin biopsy shows large basaloid lobules of varying shape and size forming a relatively circumscribed mass with a “palisade” around the rim of the lobule.

Squamous cell carcinoma manifests as shallow ulcers, often with a keratinous crust and elevated, indurate borders, but also as plaques or nodules. The clinical diagnosis should be confirmed with skin biopsy, which reveals atypical keratinocytes extending from the epidermis to the dermis with dyskeratosis, intercellular bridges, variable central keratinization, and horn pearl formation, depending on the differentiation of the tumor.

Amelanotic melanoma is nonpigmented and appears as a pink nodule mimicking basal cell carcinoma or squamous cell carcinoma. Histologic study is necessary for the diagnosis, and shows an atypical proliferation of melanocytic cells in the epidermis and dermis.

Pyogenic granuloma is a very common benign vascular lesion considered to be a hyperplastic process or a vascular neoplasm. The lesion typically presents as a red or bluish papule or polyp that bleeds easily, and a reddish homogeneous area surrounded by a white “collarette” is found in most cases. Histologic features of an early lesion resemble granulation tissue and include lobules of capillaries and venules that often radiate from larger, more central vessels.

LYMPHOCYTOMA CUTIS: KEY FEATURES

Lymphocytoma cutis (pseudolymphoma) is a benign reactive polyclonal and inflammatory disorder that most frequently includes B lymphocytes, with a smaller population of T lymphocytes. It infiltrates the skin and resembles rudimentary germinal follicles, as in the present case. The lesion usually presents as an asymptomatic red-brown or violet papule or nodule, 3 mm to 5 cm in diameter, most often on the face, chest, or upper extremities.¹ The lesion may be solitary, as in our patient, but lesions may also be grouped or numerous and widespread. It is three times more common in women than in men. It may resolve spontaneously, but it may also recur.

In Europe, lymphocytoma cutis occurs most often in B burgdorferi infection after a tick bite. Lymphocytoma cutis occurs in 1.3% of cases of B burgdorferi infection,² although other infectious, physical, or chemical agents may produce the same reaction pattern. Tattooing (particularly red areas), acupuncture, vaccination, arthropod reactions, hyposensitization antigen reaction, and ingestion of drug have been implicated in this form of lymphoid hyperplasia.^3,4

DIAGNOSTIC CHALLENGES

Lymphocytoma cutis can be challenging to diagnose, and although it can be suspected clinically, incisional biopsy is usually necessary in order to differentiate it from cutaneous B lymphoma.⁵

The infiltrate is predominantly nodular (> 90%) and located in the upper and mid dermis (“top heavy”) in lymphocytoma cutis, whereas it can be nodular or diffuse in cutaneous B lymphoma, with sharply demarcated borders that are convex rather than concave. Lymphoid follicles with germinal centers are sometimes present, and the interfollicular cellular population is polymorphic in lymphocytoma cutis (lymphocytes, plasma cells, histiocytes, eosinophils). In lymphocytoma cutis, cells express the phenotype of mature B lymphocytes (CD20, CD79a) and show regular and sharply demarcated networks of CD21+ follicular dendritic cells, whereas in cutaneous B lymphoma these networks are irregular. Light chains are usually polyclonal, although monoclonal populations of B cell in cases of cutaneous lymphocytoma cutis have been described. Extracutaneous involvement is possible in cutaneous B lymphoma but is usually absent in lymphocytoma cutis.

Lymphocytoma cutis typically involutes over a period of months, even with no treatment, as it did in our patient. Otherwise, there are different therapeutic options, including intralesional and topical corticosteroids, surgery, and cryosurgery.⁶ Photodynamic therapy with delta-aminolevulinic acid is an effective and safe modality for the treatment of lymphocytoma cutis and may be cosmetically beneficial.⁷

An otherwise healthy 54-year-old woman presented with a 3-month history of an asymptomatic lesion on the face, at the site of a previous mosquito bite. Physical examination revealed a firm, pink nodule 10 mm in diameter (Figure 1). Telangiectasias were visible, more clearly by dermoscopy, but other features of a basal cell carcinoma were absent. No other skin problem was noted, and no lymphadenopathy was detected.

Histologic study of a biopsy specimen noted a dense dermal inflammatory infiltrate consisting of B lymphocytes (CD20+) with a smaller number of T lymphocytes (CD3+) arranged in several germinal centers, with an admixture of plasma cells and eosinophils (Figure 2). No clonal population was identified by gene-rearrangement studies. Borrelia burgdorferi infection was ruled out.

Q: Which is the most likely diagnosis?

• Basal cell carcinoma
• Squamous cell carcinoma
• Lymphocytoma cutis
• Amelanotic melanoma
• Pyogenic granuloma

A: The correct answer is lymphocytoma cutis. The differential diagnosis of a pink papule on the face of a middle-aged person includes nonmelanoma skin cancer, lymphoma, lymphocytoma cutis, metastatic disease, certain infections, Jessner lymphocytic infiltrate, connective tissue disease, and some adnexal tumors. Histologic study is a useful diagnostic aid in this context.

Basal cell carcinoma is the most common cutaneous malignant neoplasm, and although these tumors rarely metastasize, they are capable of gross tissue destruction, particularly those lesions arising on the face. Clinically, this tumor presents as a shiny, pearly nodule with telangiectasias on the surface, as in our patient, but skin biopsy shows large basaloid lobules of varying shape and size forming a relatively circumscribed mass with a “palisade” around the rim of the lobule.

Squamous cell carcinoma manifests as shallow ulcers, often with a keratinous crust and elevated, indurate borders, but also as plaques or nodules. The clinical diagnosis should be confirmed with skin biopsy, which reveals atypical keratinocytes extending from the epidermis to the dermis with dyskeratosis, intercellular bridges, variable central keratinization, and horn pearl formation, depending on the differentiation of the tumor.

Amelanotic melanoma is nonpigmented and appears as a pink nodule mimicking basal cell carcinoma or squamous cell carcinoma. Histologic study is necessary for the diagnosis, and shows an atypical proliferation of melanocytic cells in the epidermis and dermis.

Pyogenic granuloma is a very common benign vascular lesion considered to be a hyperplastic process or a vascular neoplasm. The lesion typically presents as a red or bluish papule or polyp that bleeds easily, and a reddish homogeneous area surrounded by a white “collarette” is found in most cases. Histologic features of an early lesion resemble granulation tissue and include lobules of capillaries and venules that often radiate from larger, more central vessels.

LYMPHOCYTOMA CUTIS: KEY FEATURES

Lymphocytoma cutis (pseudolymphoma) is a benign reactive polyclonal and inflammatory disorder that most frequently includes B lymphocytes, with a smaller population of T lymphocytes. It infiltrates the skin and resembles rudimentary germinal follicles, as in the present case. The lesion usually presents as an asymptomatic red-brown or violet papule or nodule, 3 mm to 5 cm in diameter, most often on the face, chest, or upper extremities.¹ The lesion may be solitary, as in our patient, but lesions may also be grouped or numerous and widespread. It is three times more common in women than in men. It may resolve spontaneously, but it may also recur.

In Europe, lymphocytoma cutis occurs most often in B burgdorferi infection after a tick bite. Lymphocytoma cutis occurs in 1.3% of cases of B burgdorferi infection,² although other infectious, physical, or chemical agents may produce the same reaction pattern. Tattooing (particularly red areas), acupuncture, vaccination, arthropod reactions, hyposensitization antigen reaction, and ingestion of drug have been implicated in this form of lymphoid hyperplasia.^3,4

DIAGNOSTIC CHALLENGES

Lymphocytoma cutis can be challenging to diagnose, and although it can be suspected clinically, incisional biopsy is usually necessary in order to differentiate it from cutaneous B lymphoma.⁵

The infiltrate is predominantly nodular (> 90%) and located in the upper and mid dermis (“top heavy”) in lymphocytoma cutis, whereas it can be nodular or diffuse in cutaneous B lymphoma, with sharply demarcated borders that are convex rather than concave. Lymphoid follicles with germinal centers are sometimes present, and the interfollicular cellular population is polymorphic in lymphocytoma cutis (lymphocytes, plasma cells, histiocytes, eosinophils). In lymphocytoma cutis, cells express the phenotype of mature B lymphocytes (CD20, CD79a) and show regular and sharply demarcated networks of CD21+ follicular dendritic cells, whereas in cutaneous B lymphoma these networks are irregular. Light chains are usually polyclonal, although monoclonal populations of B cell in cases of cutaneous lymphocytoma cutis have been described. Extracutaneous involvement is possible in cutaneous B lymphoma but is usually absent in lymphocytoma cutis.

Lymphocytoma cutis typically involutes over a period of months, even with no treatment, as it did in our patient. Otherwise, there are different therapeutic options, including intralesional and topical corticosteroids, surgery, and cryosurgery.⁶ Photodynamic therapy with delta-aminolevulinic acid is an effective and safe modality for the treatment of lymphocytoma cutis and may be cosmetically beneficial.⁷

An otherwise healthy 54-year-old woman presented with a 3-month history of an asymptomatic lesion on the face, at the site of a previous mosquito bite. Physical examination revealed a firm, pink nodule 10 mm in diameter (Figure 1). Telangiectasias were visible, more clearly by dermoscopy, but other features of a basal cell carcinoma were absent. No other skin problem was noted, and no lymphadenopathy was detected.

Histologic study of a biopsy specimen noted a dense dermal inflammatory infiltrate consisting of B lymphocytes (CD20+) with a smaller number of T lymphocytes (CD3+) arranged in several germinal centers, with an admixture of plasma cells and eosinophils (Figure 2). No clonal population was identified by gene-rearrangement studies. Borrelia burgdorferi infection was ruled out.

Q: Which is the most likely diagnosis?

• Basal cell carcinoma
• Squamous cell carcinoma
• Lymphocytoma cutis
• Amelanotic melanoma
• Pyogenic granuloma

A: The correct answer is lymphocytoma cutis. The differential diagnosis of a pink papule on the face of a middle-aged person includes nonmelanoma skin cancer, lymphoma, lymphocytoma cutis, metastatic disease, certain infections, Jessner lymphocytic infiltrate, connective tissue disease, and some adnexal tumors. Histologic study is a useful diagnostic aid in this context.

Basal cell carcinoma is the most common cutaneous malignant neoplasm, and although these tumors rarely metastasize, they are capable of gross tissue destruction, particularly those lesions arising on the face. Clinically, this tumor presents as a shiny, pearly nodule with telangiectasias on the surface, as in our patient, but skin biopsy shows large basaloid lobules of varying shape and size forming a relatively circumscribed mass with a “palisade” around the rim of the lobule.

Squamous cell carcinoma manifests as shallow ulcers, often with a keratinous crust and elevated, indurate borders, but also as plaques or nodules. The clinical diagnosis should be confirmed with skin biopsy, which reveals atypical keratinocytes extending from the epidermis to the dermis with dyskeratosis, intercellular bridges, variable central keratinization, and horn pearl formation, depending on the differentiation of the tumor.

Amelanotic melanoma is nonpigmented and appears as a pink nodule mimicking basal cell carcinoma or squamous cell carcinoma. Histologic study is necessary for the diagnosis, and shows an atypical proliferation of melanocytic cells in the epidermis and dermis.

Pyogenic granuloma is a very common benign vascular lesion considered to be a hyperplastic process or a vascular neoplasm. The lesion typically presents as a red or bluish papule or polyp that bleeds easily, and a reddish homogeneous area surrounded by a white “collarette” is found in most cases. Histologic features of an early lesion resemble granulation tissue and include lobules of capillaries and venules that often radiate from larger, more central vessels.

LYMPHOCYTOMA CUTIS: KEY FEATURES

Lymphocytoma cutis (pseudolymphoma) is a benign reactive polyclonal and inflammatory disorder that most frequently includes B lymphocytes, with a smaller population of T lymphocytes. It infiltrates the skin and resembles rudimentary germinal follicles, as in the present case. The lesion usually presents as an asymptomatic red-brown or violet papule or nodule, 3 mm to 5 cm in diameter, most often on the face, chest, or upper extremities.¹ The lesion may be solitary, as in our patient, but lesions may also be grouped or numerous and widespread. It is three times more common in women than in men. It may resolve spontaneously, but it may also recur.

In Europe, lymphocytoma cutis occurs most often in B burgdorferi infection after a tick bite. Lymphocytoma cutis occurs in 1.3% of cases of B burgdorferi infection,² although other infectious, physical, or chemical agents may produce the same reaction pattern. Tattooing (particularly red areas), acupuncture, vaccination, arthropod reactions, hyposensitization antigen reaction, and ingestion of drug have been implicated in this form of lymphoid hyperplasia.^3,4

DIAGNOSTIC CHALLENGES

Lymphocytoma cutis can be challenging to diagnose, and although it can be suspected clinically, incisional biopsy is usually necessary in order to differentiate it from cutaneous B lymphoma.⁵

The infiltrate is predominantly nodular (> 90%) and located in the upper and mid dermis (“top heavy”) in lymphocytoma cutis, whereas it can be nodular or diffuse in cutaneous B lymphoma, with sharply demarcated borders that are convex rather than concave. Lymphoid follicles with germinal centers are sometimes present, and the interfollicular cellular population is polymorphic in lymphocytoma cutis (lymphocytes, plasma cells, histiocytes, eosinophils). In lymphocytoma cutis, cells express the phenotype of mature B lymphocytes (CD20, CD79a) and show regular and sharply demarcated networks of CD21+ follicular dendritic cells, whereas in cutaneous B lymphoma these networks are irregular. Light chains are usually polyclonal, although monoclonal populations of B cell in cases of cutaneous lymphocytoma cutis have been described. Extracutaneous involvement is possible in cutaneous B lymphoma but is usually absent in lymphocytoma cutis.

Lymphocytoma cutis typically involutes over a period of months, even with no treatment, as it did in our patient. Otherwise, there are different therapeutic options, including intralesional and topical corticosteroids, surgery, and cryosurgery.⁶ Photodynamic therapy with delta-aminolevulinic acid is an effective and safe modality for the treatment of lymphocytoma cutis and may be cosmetically beneficial.⁷

For most patients with gastroesophageal reflux disease (GERD), a proton pump inhibitor (PPI) is the first choice for treatment.¹ But some patients have symptoms that persist despite PPI therapy, some desire surgery despite successful PPI therapy, and some have persistent extraesophageal symptoms or other complications of reflux. For these patients, surgery is an option.²

In this article, we review the management of GERD and clarify the indications for antireflux surgery based on evidence of safety and efficacy.

GERD DEFINED: SYMPTOMS OR COMPLICATIONS

Defining the role of antireflux surgery is difficult, given the variety of presentations and the absence of a gold standard for diagnosing GERD. Most adults experience several episodes of physiologic reflux daily without symptoms.³ But a broad array of symptoms have been attributed to GERD, including chest pain, cough, and sore throat, and some conditions caused by acid reflux (eg, Barrett esophagus) can be asymptomatic.^4,5

Given these challenges, in 2006 the Montreal Consensus Group defined GERD as “a condition which develops when the reflux of stomach contents causes troublesome symptoms or complications.” ⁴ Critical to the Montreal definition is the distinction between “troublesome symptoms” and “complications” or bodily injury (Table 1).

HEARTBURN ISN’T ALWAYS GERD

Typical GERD presents with the classic symptoms of pyrosis (heartburn) or acid regurgitation, or both.

Although these symptoms are often thought to be specific for GERD, other causes of esophageal injury— eg, eosinophilic esophagitis, infection (Candida, cytomegalovirus, herpes simplex virus), pill-induced esophagitis, or radiation therapy—can produce similar symptoms. Other causes, including coronary artery disease, biliary colic, foregut malignancy, or peptic ulcer disease, should also be considered in patients with supposedly typical GERD. Life-threatening mimics of GERD, such as unstable angina, should be excluded if they are likely, before proceeding with evaluating for possible GERD. Therefore, the initial history and examination should focus on appropriate diagnosis, with careful delineation of symptom quality.

Alarm features for advanced pathology^6–8 include involuntary weight loss, dysphagia, vomiting, evidence of gastrointestinal blood loss, anemia, chest pain, and an epigastric mass.⁷ Admittedly, these features are only mediocre for detecting or excluding gastric or esophageal cancer, with a sensitivity of 67% and a specificity 66%.⁹ Nevertheless, they should prompt an endoscopic examination. In patients who have alarm features but have not yet been treated for GERD, upper endoscopy can identify an abnormality in about 60% of patients.^10–12

PPIs HAVE REPLACED ANTACIDS AND HISTAMINE-2 RECEPTOR ANTAGONISTS

When the symptoms suggest GERD and no alarm features are present, an initial trial of the following lifestyle changes is reasonable:

• Avoiding acidic or refluxogenic foods (coffee, alcohol, chocolate, peppermint, fatty foods, citrus foods)
• Avoiding certain medications (anticholinergics, estrogens, calcium-channel blockers, nitroglycerine, benzodiazepines)
• Losing weight
• Quitting smoking
• Raising the head of the bed
• Staying upright for 2 to 3 hours after meals.

For someone with mild symptoms, these changes pose minimal risk. Unfortunately, they are unlikely to provide adequate symptom control for most patients.^13–17

Before PPIs were invented, drug therapy for GERD symptoms that did not resolve with lifestyle changes consisted of antacids and, later, histamine-2 receptor antagonists. When maximal therapy failed to control symptoms, fundoplication surgery was considered an appropriate next step.

PPIs substantially changed the management of GERD, suppressing acid secretion much better than histamine-2 receptor antagonists. Taken 30 minutes before breakfast, a single daily dose of a PPI normalizes esophageal acid exposure in 67% of patients.¹⁸ Adding a second dose 30 minutes before dinner raises the number to more than 90%.¹⁹

PPIs have consistently outperformed histamine-2 blockers in the healing of esophagitis and in improving heartburn symptoms and are now the first-line medical therapy for uncomplicated GERD.^6,8,20–25

WHEN PPIs WORK, SURGERY OFFERS NO ADVANTAGE

Patients may not want to take a PPI for the rest of their life, for a number of reasons: cost, the need to take one or more pills daily, and potential adverse effects.²⁶ In these cases, the physician can counsel the patient on the relative merits of long-term medical therapy vs surgery (Table 2).^2,26

The LOTUS trial (Long-Term Usage of Esomeprazole vs Surgery for Treatment of Chronic GERD) compared long-term drug therapy with surgery to maintain remission of symptoms in GERD.²⁷ In this trial, 554 patients whose symptoms initially responded to the PPI esomeprazole (Nexium) were randomized to continue to receive esomeprazole (n = 266) or to undergo laparoscopic antireflux surgery (288 were randomly assigned, and 248 had the operation). Dose adjustment of the esomeprazole was allowed (20–40 mg/day). A total of 372 patients completed 5 years of follow-up (192 esomeprazole, 180 surgery).

Symptoms stayed in remission in 92% of the esomeprazole group and 85% of the surgery group (P = .048). However, the difference was no longer statistically significant after modeling the effects of study dropout. The rate of severe adverse events was similar in both groups: 24.1% with esomeprazole and 28.6% with surgery.

These findings indicate that if symptoms fully abate with medical therapy, surgery offers no advantage. In addition, patients who desire surgery in the hope of avoiding lifelong drug therapy should be made aware that drug therapy and reoperation are often necessary after surgery.²⁸ In most cases, antireflux surgery is unnecessary for patients whose GERD fully responds to PPI therapy.

 

IF PPIs FAIL, FURTHER TESTING NEEDED

But many patients who take PPIs still have symptoms, even though these drugs suppress acid secretion and heal esophagitis. In fact, symptoms completely resolve in only about one-half of patients with erosive disease and one-third of those without erosive disease.²¹

Reasons for an incomplete symptomatic response to PPIs are various. Acid reflux can persist, but this accounts for only 10% of cases.²⁹ About one-third of patients have persistent reflux that is weakly acidic, with a pH higher than 4.29. However, most patients with persistent typical GERD symptoms do not have significant, persistent reflux, or their symptoms are not related to reflux events. In these cases, an alternative cause of the refractory symptoms should be sought.

Further diagnostic testing is indicated when symptoms persist despite PPI therapy. Upper endoscopy will reveal an abnormality such as persistent erosive esophagitis, eosinophilic esophagitis, esophageal stricture, Barrett esophagus, or esophageal cancer in roughly 10% of patients in whom empiric therapy fails.¹⁰

Although patients with persistent symptoms have not been enrolled in many randomized controlled trials, a multivariate analysis showed that failure of medical therapy heralds a poor response to surgery.³⁰ Data such as these have led most experts to discourage fundoplication for such patients now, unlike in the pre-PPI era.

pH and intraluminal impedance testing

However, this recommendation against surgery is not a hard-and-fast rule.

When symptoms of GERD do not respond to twice-daily PPI therapy and the results of upper endoscopy are negative, then an esophageal pH study combined with multichannel intraluminal impedance (MII-pH) testing may help identify patients who will respond to an intensification of medical therapy or to surgery, particularly if symptoms correlate with documented reflux events^31–33 (Figure 1). Most experts believe that esophageal MII-pH testing should be performed while the patient is taking a PPI to best identify patients whose refractory symptoms are most likely to be related to ongoing reflux.

In patients with esophageal regurgitation, most will not achieve adequate relief of symptoms with PPI therapy alone.³⁴ The therapeutic gain of PPI therapy vs placebo averaged just 17% in seven randomized, controlled trials, more than 20% less than the response rate for heartburn.³⁴ This is likely because of structural abnormalities such as reduced lower esophageal sphincter pressure, hiatal hernia, or delayed gastric emptying. Antireflux surgery can correct these structural abnormalities or prevent them from causing so much trouble; however, the presence of true regurgitation should first be confirmed by MII testing. If regurgitation is confirmed, antireflux surgery is warranted, particularly in patients with nocturnal symptoms who may be at high risk of aspiration. With careful patient selection, regurgitation symptoms improve in about 90% after surgery.²

In patients with heartburn, if esophageal acid exposure continues to be abnormal on MII-pH testing, then an escalation of therapy may improve symptoms, particularly if symptoms occur during reflux or if they partially responded to PPI therapy. Options in this scenario include alteration or intensification of acid-suppressive therapy, treatment with baclofen (Lioresal), and antireflux surgery.^18,35,36 In randomized controlled trials of patients whose symptoms partially responded to PPIs, antireflux surgery has performed similarly to PPIs in terms of improving typical GERD symptoms, particularly regurgitation.^27,37–41 Although this scenario is a reasonable indication for antireflux surgery, recommendations should be made with appropriate restraint since it is not easily reversible, some patients experience complications, and up to one-third will have no therapeutic benefit.³⁰

Nonacid reflux. In some cases, MII-pH testing during PPI therapy will reveal reflux of weakly acidic (pH > 4) or alkaline stomach contents, often called “nonacid reflux.”²⁹ Nonacid reflux is often present in patients with esophagitis that persists despite PPI therapy, indicating that even weakly acidic stomach contents can injure the mucosa.⁴² Since intensifying the acid-suppressive therapy is unlikely to improve these symptoms, antireflux surgery may have a role.

In one study,⁴³ nonacid reflux was well controlled by laparoscopic Nissen fundoplication, although 15 (48%) of 31 patients had persistent symptoms of GERD after surgery. No patient had a strong symptom correlation with postoperative reflux events, suggesting an alternative cause of the persistent symptoms. Therefore, antireflux surgery for nonacid reflux should be limited exclusively to patients with strong symptom correlation, and even then it should be considered with restraint, given the limited evidence for benefit and the potential for harm.

If testing is negative. In studies investigating the diagnostic yield of MII-pH testing, more than 50% of patients who had refractory symptoms had a negative MII-pH test.²⁹ In such situations, when the symptoms are strongly correlated with reflux events, the patient is said to have “esophageal hypersensitivity.” A few small studies have suggested that such patients may benefit from surgery, but these data have not been replicated in randomized controlled trials.³²

When the testing is negative and there is no correlation between the patient’s symptoms and reflux events, the patient is unlikely to benefit from antireflux surgery. Care of these patients is beyond the scope of this review.

SURGERY RARELY IMPROVES COUGH, ASTHMA, OR LARYNGITIS

GERD has been implicated as a cause of chronic cough, asthma, and laryngitis, although each of these has many potential causes.^44–46 Despite these associations, the evidence for therapeutic benefit from antireflux therapy is weak.

PPI therapy shows no benefit over placebo for chronic cough of uncertain etiology, but some benefit if GERD is objectively demonstrated.⁴⁷ Laryngitis resolved in just 15% of patients on esomeprazole vs 16% of patients on placebo after excluding patients with moderate to severe heartburn.⁴⁸

In a large randomized controlled trial in patients with asthma, there was no overall improvement in peak flow for the PPI group vs the placebo group, although significant improvement occurred in patients with heartburn and nocturnal respiratory symptoms.⁴⁶

Potent antisecretory therapy seems to improve extraesophageal symptoms when typical GERD symptoms are also present, but it otherwise has shown little evidence of benefit.

The evidence for a benefit from antireflux surgery in patients with extraesophageal GERD syndromes is even more limited. Although one systematic review⁴⁹ found that cough and other laryngeal symptoms improved in 60% to 100% of patients with objective evidence of GERD who underwent fundoplication, virtually all of the studies were uncontrolled case series.⁴⁹

The lone randomized controlled trial in the systematic review compared Nissen fundoplication with ranitidine (Zantac) or antacids only for patients with asthma and GERD, and found no significant difference in peak expiratory flow among the three groups after 2 years. However, asthma symptom scores improved in 75% of the surgical group, 9% of the medical group, and 4% of the control group.⁵⁰

In a study that was not included in the prior systematic review, patients with laryngopharyngeal reflux unresponsive to aggressive acid suppression who subsequently underwent fundoplication fared no better than those who did not.⁵¹

Thus, based on the available data, antireflux surgery is only rarely indicated for extraesophageal symptoms, especially in patients who have no typical GERD symptoms or in patients whose symptoms are refractory to medical therapy.

 

SURGERY FOR EROSIVE ESOPHAGITIS OR BARRETT ESOPHAGUS IF PPI FAILS

Lifelong antireflux therapy is indicated for patients with severe erosive esophagitis or Barrett esophagus. Erosive esophagitis recurs in more than 80% within 12 months of discontinuing antisecretory therapy.⁵² Both Barrett esophagus and esophageal adenocarcinoma are strongly associated with GERD, and nearly 10% of patients with chronic reflux have Barrett esophagus.^53,54 It is suspected that suppressing reflux reduces the rate of progression of Barrett esophagus to esophageal adenocarcinoma, but this remains to be proven.

Perhaps the strongest indication for surgery in the PPI era is for patients who have persistent symptoms and severe erosive esophagitis (Los Angeles grade C or D) despite high-dose PPI therapy. If other causes of persistent esophagitis have been ruled out, fundoplication can induce healing and improve symptoms.^55,56 In these cases, surgery is done to induce remission of the disease when maximal medical therapy has been truly unsuccessful.

Randomized controlled trials suggest that medical and surgical therapies are equally effective for preventing the recurrence of erosive esophagitis or the progression of Barrett esophagus. In a study of 225 patients, at 7 years of follow-up, esophagitis had recurred in 10.4% of patients on omeprazole vs 11.8% of those who had undergone antireflux surgery.⁴⁰ Similarly, open Nissen fundoplication was no different from drug therapy (histamine-2 receptor antagonist or PPI) for progression of Barrett esophagus over a median of 5 years.⁵⁷ A meta-analysis with nearly 5,000 person-years each in the medical and surgical groups also found no significant difference in rates of cancer progression.⁵⁸

Notably, symptoms such as dysphagia, flatulence, and the inability to burp occurred significantly more often in the surgical groups in these studies.

In view of these data, antireflux surgery has no significant advantage over medical therapy for maintaining healing of erosive esophagitis or preventing progression of Barrett esophagus. Thus, it should be reserved for patients who do not desire lifelong drug therapy, provided they understand that there is no therapeutic advantage for their esophagitis or for Barrett esophagus.

SPECIFIC INDICATIONS FOR ANTIREFLUX SURGERY

Now that we have PPIs, several situations remain in which surgery for GERD is either indicated or worth considering.

Antireflux surgery is clearly indicated for:

• Patients with erosive esophagitis that does not heal with maximal drug therapy
• Patients with volume regurgitation, particularly if it occurs at night or if there is evidence of aspiration
• Patients who require lifelong treatment for reflux but who have had a serious adverse event related to PPI therapy, such as refractory Clostridium difficile infection.

Antireflux surgery is also worth considering in patients who for personal reasons wish to avoid long-term or lifelong drug therapy.

Patients should be informed, however, that antireflux surgery has not been shown to be better than medical therapy for maintaining remission of symptoms, for preventing progression of Barrett esophagus, or for maintaining healing of erosive esophagitis. Medical therapy is still the first option for these patients.

Surgery may also be considered in patients with persistent symptoms who have a partial response to medical therapy, who show persistent acidic or weakly acidic reflux on MII-pH testing, and whose symptoms have been correlated with reflux events. Although surgery is not sure to improve their symptoms, benefit is more likely in this patient population compared with those without these characteristics.

Extraesophageal GERD

In patients suspected of having extraesophageal GERD, surgery should be considered if typical GERD symptoms are present and improve with PPI therapy, if the extraesophageal syndrome partially responds to PPI therapy, and if MII-pH testing demonstrates a correlation between symptoms and reflux. Surgery may have a stronger indication in this setting if the patient has nocturnal reflux or extraesophageal symptoms.

When is surgery not an option?

In general, surgery should not be considered in patients who do not have a partial response to PPI therapy or who do not have a strong symptom-reflux correlation on MII-pH testing. In all cases of failed medical therapy without persistent severe erosive disease, the threshold for opting for surgery should be high, given the uncertain response of these patients to surgery.

Peristaltic dysfunction is a relative but not an absolute contraindication to surgery.⁵⁹

RISKS, BENEFITS OF SURGERY FOR GERD

The patient’s preference for surgery over drug therapy should always be balanced against the risks of surgery, including both short-term and long-term adverse events, to allow the patient to make an adequately informed decision (Table 2).^2,26

Adverse events associated with PPI therapy are rare and in many cases the association is debatable.²⁶ Nonetheless, long-term PPI therapy has been most strongly associated with an increased risk of C difficile infection and other enteric infections, although the absolute risk of these events remains low.

Complication rates after antireflux surgery depend on the surgeon’s experience and technique. Death is exceedingly rare. In most high-volume centers, the need to convert from laparoscopic to open fundoplication occurs in fewer than 2.4% of patients.²

Potential perioperative complications include perforation (4%), wound infection (3%), and pneumothorax (2%).²

Antireflux surgery is also associated with a significant risk of dysphagia, bloating, an inability to burp, and excessive flatulence, all of which can markedly impair the quality of life.

A major consideration is that fundoplication is generally irreversible. Reoperation rates have been reported to range from 0% to 15%.² Furthermore, up to 50% of patients still need medical therapy after surgery.^60,61 Of note, only about 25% of patients on medical therapy after surgery will actually have an abnormal pH study.⁶¹

MORE STUDY NEEDED

Future studies directly comparing medical and surgical therapy for carefully selected patients with extraesophageal manifestations of GERD and refractory symptoms should help further delineate outcome in this difficult group of patients.

Under development are new drugs that may inhibit transient relaxation of the lower esophageal sphincter, as well as minimally invasive procedures, which may alter the indications for surgery in coming years.³⁶
 

---

Acknowledgment: The research for this article was supported in part by a grant from the National Institutes of Health (T32 DK07634).

For most patients with gastroesophageal reflux disease (GERD), a proton pump inhibitor (PPI) is the first choice for treatment.¹ But some patients have symptoms that persist despite PPI therapy, some desire surgery despite successful PPI therapy, and some have persistent extraesophageal symptoms or other complications of reflux. For these patients, surgery is an option.²

In this article, we review the management of GERD and clarify the indications for antireflux surgery based on evidence of safety and efficacy.

GERD DEFINED: SYMPTOMS OR COMPLICATIONS

Defining the role of antireflux surgery is difficult, given the variety of presentations and the absence of a gold standard for diagnosing GERD. Most adults experience several episodes of physiologic reflux daily without symptoms.³ But a broad array of symptoms have been attributed to GERD, including chest pain, cough, and sore throat, and some conditions caused by acid reflux (eg, Barrett esophagus) can be asymptomatic.^4,5

Given these challenges, in 2006 the Montreal Consensus Group defined GERD as “a condition which develops when the reflux of stomach contents causes troublesome symptoms or complications.” ⁴ Critical to the Montreal definition is the distinction between “troublesome symptoms” and “complications” or bodily injury (Table 1).

HEARTBURN ISN’T ALWAYS GERD

Typical GERD presents with the classic symptoms of pyrosis (heartburn) or acid regurgitation, or both.

Although these symptoms are often thought to be specific for GERD, other causes of esophageal injury— eg, eosinophilic esophagitis, infection (Candida, cytomegalovirus, herpes simplex virus), pill-induced esophagitis, or radiation therapy—can produce similar symptoms. Other causes, including coronary artery disease, biliary colic, foregut malignancy, or peptic ulcer disease, should also be considered in patients with supposedly typical GERD. Life-threatening mimics of GERD, such as unstable angina, should be excluded if they are likely, before proceeding with evaluating for possible GERD. Therefore, the initial history and examination should focus on appropriate diagnosis, with careful delineation of symptom quality.

Alarm features for advanced pathology^6–8 include involuntary weight loss, dysphagia, vomiting, evidence of gastrointestinal blood loss, anemia, chest pain, and an epigastric mass.⁷ Admittedly, these features are only mediocre for detecting or excluding gastric or esophageal cancer, with a sensitivity of 67% and a specificity 66%.⁹ Nevertheless, they should prompt an endoscopic examination. In patients who have alarm features but have not yet been treated for GERD, upper endoscopy can identify an abnormality in about 60% of patients.^10–12

PPIs HAVE REPLACED ANTACIDS AND HISTAMINE-2 RECEPTOR ANTAGONISTS

When the symptoms suggest GERD and no alarm features are present, an initial trial of the following lifestyle changes is reasonable:

• Avoiding acidic or refluxogenic foods (coffee, alcohol, chocolate, peppermint, fatty foods, citrus foods)
• Avoiding certain medications (anticholinergics, estrogens, calcium-channel blockers, nitroglycerine, benzodiazepines)
• Losing weight
• Quitting smoking
• Raising the head of the bed
• Staying upright for 2 to 3 hours after meals.

For someone with mild symptoms, these changes pose minimal risk. Unfortunately, they are unlikely to provide adequate symptom control for most patients.^13–17

Before PPIs were invented, drug therapy for GERD symptoms that did not resolve with lifestyle changes consisted of antacids and, later, histamine-2 receptor antagonists. When maximal therapy failed to control symptoms, fundoplication surgery was considered an appropriate next step.

PPIs substantially changed the management of GERD, suppressing acid secretion much better than histamine-2 receptor antagonists. Taken 30 minutes before breakfast, a single daily dose of a PPI normalizes esophageal acid exposure in 67% of patients.¹⁸ Adding a second dose 30 minutes before dinner raises the number to more than 90%.¹⁹

PPIs have consistently outperformed histamine-2 blockers in the healing of esophagitis and in improving heartburn symptoms and are now the first-line medical therapy for uncomplicated GERD.^6,8,20–25

WHEN PPIs WORK, SURGERY OFFERS NO ADVANTAGE

Patients may not want to take a PPI for the rest of their life, for a number of reasons: cost, the need to take one or more pills daily, and potential adverse effects.²⁶ In these cases, the physician can counsel the patient on the relative merits of long-term medical therapy vs surgery (Table 2).^2,26

The LOTUS trial (Long-Term Usage of Esomeprazole vs Surgery for Treatment of Chronic GERD) compared long-term drug therapy with surgery to maintain remission of symptoms in GERD.²⁷ In this trial, 554 patients whose symptoms initially responded to the PPI esomeprazole (Nexium) were randomized to continue to receive esomeprazole (n = 266) or to undergo laparoscopic antireflux surgery (288 were randomly assigned, and 248 had the operation). Dose adjustment of the esomeprazole was allowed (20–40 mg/day). A total of 372 patients completed 5 years of follow-up (192 esomeprazole, 180 surgery).

Symptoms stayed in remission in 92% of the esomeprazole group and 85% of the surgery group (P = .048). However, the difference was no longer statistically significant after modeling the effects of study dropout. The rate of severe adverse events was similar in both groups: 24.1% with esomeprazole and 28.6% with surgery.

These findings indicate that if symptoms fully abate with medical therapy, surgery offers no advantage. In addition, patients who desire surgery in the hope of avoiding lifelong drug therapy should be made aware that drug therapy and reoperation are often necessary after surgery.²⁸ In most cases, antireflux surgery is unnecessary for patients whose GERD fully responds to PPI therapy.

 

IF PPIs FAIL, FURTHER TESTING NEEDED

But many patients who take PPIs still have symptoms, even though these drugs suppress acid secretion and heal esophagitis. In fact, symptoms completely resolve in only about one-half of patients with erosive disease and one-third of those without erosive disease.²¹

Reasons for an incomplete symptomatic response to PPIs are various. Acid reflux can persist, but this accounts for only 10% of cases.²⁹ About one-third of patients have persistent reflux that is weakly acidic, with a pH higher than 4.29. However, most patients with persistent typical GERD symptoms do not have significant, persistent reflux, or their symptoms are not related to reflux events. In these cases, an alternative cause of the refractory symptoms should be sought.

Further diagnostic testing is indicated when symptoms persist despite PPI therapy. Upper endoscopy will reveal an abnormality such as persistent erosive esophagitis, eosinophilic esophagitis, esophageal stricture, Barrett esophagus, or esophageal cancer in roughly 10% of patients in whom empiric therapy fails.¹⁰

Although patients with persistent symptoms have not been enrolled in many randomized controlled trials, a multivariate analysis showed that failure of medical therapy heralds a poor response to surgery.³⁰ Data such as these have led most experts to discourage fundoplication for such patients now, unlike in the pre-PPI era.

pH and intraluminal impedance testing

However, this recommendation against surgery is not a hard-and-fast rule.

When symptoms of GERD do not respond to twice-daily PPI therapy and the results of upper endoscopy are negative, then an esophageal pH study combined with multichannel intraluminal impedance (MII-pH) testing may help identify patients who will respond to an intensification of medical therapy or to surgery, particularly if symptoms correlate with documented reflux events^31–33 (Figure 1). Most experts believe that esophageal MII-pH testing should be performed while the patient is taking a PPI to best identify patients whose refractory symptoms are most likely to be related to ongoing reflux.

In patients with esophageal regurgitation, most will not achieve adequate relief of symptoms with PPI therapy alone.³⁴ The therapeutic gain of PPI therapy vs placebo averaged just 17% in seven randomized, controlled trials, more than 20% less than the response rate for heartburn.³⁴ This is likely because of structural abnormalities such as reduced lower esophageal sphincter pressure, hiatal hernia, or delayed gastric emptying. Antireflux surgery can correct these structural abnormalities or prevent them from causing so much trouble; however, the presence of true regurgitation should first be confirmed by MII testing. If regurgitation is confirmed, antireflux surgery is warranted, particularly in patients with nocturnal symptoms who may be at high risk of aspiration. With careful patient selection, regurgitation symptoms improve in about 90% after surgery.²

In patients with heartburn, if esophageal acid exposure continues to be abnormal on MII-pH testing, then an escalation of therapy may improve symptoms, particularly if symptoms occur during reflux or if they partially responded to PPI therapy. Options in this scenario include alteration or intensification of acid-suppressive therapy, treatment with baclofen (Lioresal), and antireflux surgery.^18,35,36 In randomized controlled trials of patients whose symptoms partially responded to PPIs, antireflux surgery has performed similarly to PPIs in terms of improving typical GERD symptoms, particularly regurgitation.^27,37–41 Although this scenario is a reasonable indication for antireflux surgery, recommendations should be made with appropriate restraint since it is not easily reversible, some patients experience complications, and up to one-third will have no therapeutic benefit.³⁰

Nonacid reflux. In some cases, MII-pH testing during PPI therapy will reveal reflux of weakly acidic (pH > 4) or alkaline stomach contents, often called “nonacid reflux.”²⁹ Nonacid reflux is often present in patients with esophagitis that persists despite PPI therapy, indicating that even weakly acidic stomach contents can injure the mucosa.⁴² Since intensifying the acid-suppressive therapy is unlikely to improve these symptoms, antireflux surgery may have a role.

In one study,⁴³ nonacid reflux was well controlled by laparoscopic Nissen fundoplication, although 15 (48%) of 31 patients had persistent symptoms of GERD after surgery. No patient had a strong symptom correlation with postoperative reflux events, suggesting an alternative cause of the persistent symptoms. Therefore, antireflux surgery for nonacid reflux should be limited exclusively to patients with strong symptom correlation, and even then it should be considered with restraint, given the limited evidence for benefit and the potential for harm.

If testing is negative. In studies investigating the diagnostic yield of MII-pH testing, more than 50% of patients who had refractory symptoms had a negative MII-pH test.²⁹ In such situations, when the symptoms are strongly correlated with reflux events, the patient is said to have “esophageal hypersensitivity.” A few small studies have suggested that such patients may benefit from surgery, but these data have not been replicated in randomized controlled trials.³²

When the testing is negative and there is no correlation between the patient’s symptoms and reflux events, the patient is unlikely to benefit from antireflux surgery. Care of these patients is beyond the scope of this review.

SURGERY RARELY IMPROVES COUGH, ASTHMA, OR LARYNGITIS

GERD has been implicated as a cause of chronic cough, asthma, and laryngitis, although each of these has many potential causes.^44–46 Despite these associations, the evidence for therapeutic benefit from antireflux therapy is weak.

PPI therapy shows no benefit over placebo for chronic cough of uncertain etiology, but some benefit if GERD is objectively demonstrated.⁴⁷ Laryngitis resolved in just 15% of patients on esomeprazole vs 16% of patients on placebo after excluding patients with moderate to severe heartburn.⁴⁸

In a large randomized controlled trial in patients with asthma, there was no overall improvement in peak flow for the PPI group vs the placebo group, although significant improvement occurred in patients with heartburn and nocturnal respiratory symptoms.⁴⁶

Potent antisecretory therapy seems to improve extraesophageal symptoms when typical GERD symptoms are also present, but it otherwise has shown little evidence of benefit.

The evidence for a benefit from antireflux surgery in patients with extraesophageal GERD syndromes is even more limited. Although one systematic review⁴⁹ found that cough and other laryngeal symptoms improved in 60% to 100% of patients with objective evidence of GERD who underwent fundoplication, virtually all of the studies were uncontrolled case series.⁴⁹

The lone randomized controlled trial in the systematic review compared Nissen fundoplication with ranitidine (Zantac) or antacids only for patients with asthma and GERD, and found no significant difference in peak expiratory flow among the three groups after 2 years. However, asthma symptom scores improved in 75% of the surgical group, 9% of the medical group, and 4% of the control group.⁵⁰

In a study that was not included in the prior systematic review, patients with laryngopharyngeal reflux unresponsive to aggressive acid suppression who subsequently underwent fundoplication fared no better than those who did not.⁵¹

Thus, based on the available data, antireflux surgery is only rarely indicated for extraesophageal symptoms, especially in patients who have no typical GERD symptoms or in patients whose symptoms are refractory to medical therapy.

 

SURGERY FOR EROSIVE ESOPHAGITIS OR BARRETT ESOPHAGUS IF PPI FAILS

Lifelong antireflux therapy is indicated for patients with severe erosive esophagitis or Barrett esophagus. Erosive esophagitis recurs in more than 80% within 12 months of discontinuing antisecretory therapy.⁵² Both Barrett esophagus and esophageal adenocarcinoma are strongly associated with GERD, and nearly 10% of patients with chronic reflux have Barrett esophagus.^53,54 It is suspected that suppressing reflux reduces the rate of progression of Barrett esophagus to esophageal adenocarcinoma, but this remains to be proven.

Perhaps the strongest indication for surgery in the PPI era is for patients who have persistent symptoms and severe erosive esophagitis (Los Angeles grade C or D) despite high-dose PPI therapy. If other causes of persistent esophagitis have been ruled out, fundoplication can induce healing and improve symptoms.^55,56 In these cases, surgery is done to induce remission of the disease when maximal medical therapy has been truly unsuccessful.

Randomized controlled trials suggest that medical and surgical therapies are equally effective for preventing the recurrence of erosive esophagitis or the progression of Barrett esophagus. In a study of 225 patients, at 7 years of follow-up, esophagitis had recurred in 10.4% of patients on omeprazole vs 11.8% of those who had undergone antireflux surgery.⁴⁰ Similarly, open Nissen fundoplication was no different from drug therapy (histamine-2 receptor antagonist or PPI) for progression of Barrett esophagus over a median of 5 years.⁵⁷ A meta-analysis with nearly 5,000 person-years each in the medical and surgical groups also found no significant difference in rates of cancer progression.⁵⁸

Notably, symptoms such as dysphagia, flatulence, and the inability to burp occurred significantly more often in the surgical groups in these studies.

In view of these data, antireflux surgery has no significant advantage over medical therapy for maintaining healing of erosive esophagitis or preventing progression of Barrett esophagus. Thus, it should be reserved for patients who do not desire lifelong drug therapy, provided they understand that there is no therapeutic advantage for their esophagitis or for Barrett esophagus.

SPECIFIC INDICATIONS FOR ANTIREFLUX SURGERY

Now that we have PPIs, several situations remain in which surgery for GERD is either indicated or worth considering.

Antireflux surgery is clearly indicated for:

• Patients with erosive esophagitis that does not heal with maximal drug therapy
• Patients with volume regurgitation, particularly if it occurs at night or if there is evidence of aspiration
• Patients who require lifelong treatment for reflux but who have had a serious adverse event related to PPI therapy, such as refractory Clostridium difficile infection.

Antireflux surgery is also worth considering in patients who for personal reasons wish to avoid long-term or lifelong drug therapy.

Patients should be informed, however, that antireflux surgery has not been shown to be better than medical therapy for maintaining remission of symptoms, for preventing progression of Barrett esophagus, or for maintaining healing of erosive esophagitis. Medical therapy is still the first option for these patients.

Surgery may also be considered in patients with persistent symptoms who have a partial response to medical therapy, who show persistent acidic or weakly acidic reflux on MII-pH testing, and whose symptoms have been correlated with reflux events. Although surgery is not sure to improve their symptoms, benefit is more likely in this patient population compared with those without these characteristics.

Extraesophageal GERD

In patients suspected of having extraesophageal GERD, surgery should be considered if typical GERD symptoms are present and improve with PPI therapy, if the extraesophageal syndrome partially responds to PPI therapy, and if MII-pH testing demonstrates a correlation between symptoms and reflux. Surgery may have a stronger indication in this setting if the patient has nocturnal reflux or extraesophageal symptoms.

When is surgery not an option?

In general, surgery should not be considered in patients who do not have a partial response to PPI therapy or who do not have a strong symptom-reflux correlation on MII-pH testing. In all cases of failed medical therapy without persistent severe erosive disease, the threshold for opting for surgery should be high, given the uncertain response of these patients to surgery.

Peristaltic dysfunction is a relative but not an absolute contraindication to surgery.⁵⁹

RISKS, BENEFITS OF SURGERY FOR GERD

The patient’s preference for surgery over drug therapy should always be balanced against the risks of surgery, including both short-term and long-term adverse events, to allow the patient to make an adequately informed decision (Table 2).^2,26

Adverse events associated with PPI therapy are rare and in many cases the association is debatable.²⁶ Nonetheless, long-term PPI therapy has been most strongly associated with an increased risk of C difficile infection and other enteric infections, although the absolute risk of these events remains low.

Complication rates after antireflux surgery depend on the surgeon’s experience and technique. Death is exceedingly rare. In most high-volume centers, the need to convert from laparoscopic to open fundoplication occurs in fewer than 2.4% of patients.²

Potential perioperative complications include perforation (4%), wound infection (3%), and pneumothorax (2%).²

Antireflux surgery is also associated with a significant risk of dysphagia, bloating, an inability to burp, and excessive flatulence, all of which can markedly impair the quality of life.

A major consideration is that fundoplication is generally irreversible. Reoperation rates have been reported to range from 0% to 15%.² Furthermore, up to 50% of patients still need medical therapy after surgery.^60,61 Of note, only about 25% of patients on medical therapy after surgery will actually have an abnormal pH study.⁶¹

MORE STUDY NEEDED

Future studies directly comparing medical and surgical therapy for carefully selected patients with extraesophageal manifestations of GERD and refractory symptoms should help further delineate outcome in this difficult group of patients.

Under development are new drugs that may inhibit transient relaxation of the lower esophageal sphincter, as well as minimally invasive procedures, which may alter the indications for surgery in coming years.³⁶
 

---

Acknowledgment: The research for this article was supported in part by a grant from the National Institutes of Health (T32 DK07634).

For most patients with gastroesophageal reflux disease (GERD), a proton pump inhibitor (PPI) is the first choice for treatment.¹ But some patients have symptoms that persist despite PPI therapy, some desire surgery despite successful PPI therapy, and some have persistent extraesophageal symptoms or other complications of reflux. For these patients, surgery is an option.²

In this article, we review the management of GERD and clarify the indications for antireflux surgery based on evidence of safety and efficacy.

GERD DEFINED: SYMPTOMS OR COMPLICATIONS

Defining the role of antireflux surgery is difficult, given the variety of presentations and the absence of a gold standard for diagnosing GERD. Most adults experience several episodes of physiologic reflux daily without symptoms.³ But a broad array of symptoms have been attributed to GERD, including chest pain, cough, and sore throat, and some conditions caused by acid reflux (eg, Barrett esophagus) can be asymptomatic.^4,5

Given these challenges, in 2006 the Montreal Consensus Group defined GERD as “a condition which develops when the reflux of stomach contents causes troublesome symptoms or complications.” ⁴ Critical to the Montreal definition is the distinction between “troublesome symptoms” and “complications” or bodily injury (Table 1).

HEARTBURN ISN’T ALWAYS GERD

Typical GERD presents with the classic symptoms of pyrosis (heartburn) or acid regurgitation, or both.

Although these symptoms are often thought to be specific for GERD, other causes of esophageal injury— eg, eosinophilic esophagitis, infection (Candida, cytomegalovirus, herpes simplex virus), pill-induced esophagitis, or radiation therapy—can produce similar symptoms. Other causes, including coronary artery disease, biliary colic, foregut malignancy, or peptic ulcer disease, should also be considered in patients with supposedly typical GERD. Life-threatening mimics of GERD, such as unstable angina, should be excluded if they are likely, before proceeding with evaluating for possible GERD. Therefore, the initial history and examination should focus on appropriate diagnosis, with careful delineation of symptom quality.

Alarm features for advanced pathology^6–8 include involuntary weight loss, dysphagia, vomiting, evidence of gastrointestinal blood loss, anemia, chest pain, and an epigastric mass.⁷ Admittedly, these features are only mediocre for detecting or excluding gastric or esophageal cancer, with a sensitivity of 67% and a specificity 66%.⁹ Nevertheless, they should prompt an endoscopic examination. In patients who have alarm features but have not yet been treated for GERD, upper endoscopy can identify an abnormality in about 60% of patients.^10–12

PPIs HAVE REPLACED ANTACIDS AND HISTAMINE-2 RECEPTOR ANTAGONISTS

When the symptoms suggest GERD and no alarm features are present, an initial trial of the following lifestyle changes is reasonable:

• Avoiding acidic or refluxogenic foods (coffee, alcohol, chocolate, peppermint, fatty foods, citrus foods)
• Avoiding certain medications (anticholinergics, estrogens, calcium-channel blockers, nitroglycerine, benzodiazepines)
• Losing weight
• Quitting smoking
• Raising the head of the bed
• Staying upright for 2 to 3 hours after meals.

For someone with mild symptoms, these changes pose minimal risk. Unfortunately, they are unlikely to provide adequate symptom control for most patients.^13–17

Before PPIs were invented, drug therapy for GERD symptoms that did not resolve with lifestyle changes consisted of antacids and, later, histamine-2 receptor antagonists. When maximal therapy failed to control symptoms, fundoplication surgery was considered an appropriate next step.

PPIs substantially changed the management of GERD, suppressing acid secretion much better than histamine-2 receptor antagonists. Taken 30 minutes before breakfast, a single daily dose of a PPI normalizes esophageal acid exposure in 67% of patients.¹⁸ Adding a second dose 30 minutes before dinner raises the number to more than 90%.¹⁹

PPIs have consistently outperformed histamine-2 blockers in the healing of esophagitis and in improving heartburn symptoms and are now the first-line medical therapy for uncomplicated GERD.^6,8,20–25

WHEN PPIs WORK, SURGERY OFFERS NO ADVANTAGE

Patients may not want to take a PPI for the rest of their life, for a number of reasons: cost, the need to take one or more pills daily, and potential adverse effects.²⁶ In these cases, the physician can counsel the patient on the relative merits of long-term medical therapy vs surgery (Table 2).^2,26

The LOTUS trial (Long-Term Usage of Esomeprazole vs Surgery for Treatment of Chronic GERD) compared long-term drug therapy with surgery to maintain remission of symptoms in GERD.²⁷ In this trial, 554 patients whose symptoms initially responded to the PPI esomeprazole (Nexium) were randomized to continue to receive esomeprazole (n = 266) or to undergo laparoscopic antireflux surgery (288 were randomly assigned, and 248 had the operation). Dose adjustment of the esomeprazole was allowed (20–40 mg/day). A total of 372 patients completed 5 years of follow-up (192 esomeprazole, 180 surgery).

Symptoms stayed in remission in 92% of the esomeprazole group and 85% of the surgery group (P = .048). However, the difference was no longer statistically significant after modeling the effects of study dropout. The rate of severe adverse events was similar in both groups: 24.1% with esomeprazole and 28.6% with surgery.

These findings indicate that if symptoms fully abate with medical therapy, surgery offers no advantage. In addition, patients who desire surgery in the hope of avoiding lifelong drug therapy should be made aware that drug therapy and reoperation are often necessary after surgery.²⁸ In most cases, antireflux surgery is unnecessary for patients whose GERD fully responds to PPI therapy.

 

IF PPIs FAIL, FURTHER TESTING NEEDED

But many patients who take PPIs still have symptoms, even though these drugs suppress acid secretion and heal esophagitis. In fact, symptoms completely resolve in only about one-half of patients with erosive disease and one-third of those without erosive disease.²¹

Reasons for an incomplete symptomatic response to PPIs are various. Acid reflux can persist, but this accounts for only 10% of cases.²⁹ About one-third of patients have persistent reflux that is weakly acidic, with a pH higher than 4.29. However, most patients with persistent typical GERD symptoms do not have significant, persistent reflux, or their symptoms are not related to reflux events. In these cases, an alternative cause of the refractory symptoms should be sought.

Further diagnostic testing is indicated when symptoms persist despite PPI therapy. Upper endoscopy will reveal an abnormality such as persistent erosive esophagitis, eosinophilic esophagitis, esophageal stricture, Barrett esophagus, or esophageal cancer in roughly 10% of patients in whom empiric therapy fails.¹⁰

Although patients with persistent symptoms have not been enrolled in many randomized controlled trials, a multivariate analysis showed that failure of medical therapy heralds a poor response to surgery.³⁰ Data such as these have led most experts to discourage fundoplication for such patients now, unlike in the pre-PPI era.

pH and intraluminal impedance testing

However, this recommendation against surgery is not a hard-and-fast rule.

When symptoms of GERD do not respond to twice-daily PPI therapy and the results of upper endoscopy are negative, then an esophageal pH study combined with multichannel intraluminal impedance (MII-pH) testing may help identify patients who will respond to an intensification of medical therapy or to surgery, particularly if symptoms correlate with documented reflux events^31–33 (Figure 1). Most experts believe that esophageal MII-pH testing should be performed while the patient is taking a PPI to best identify patients whose refractory symptoms are most likely to be related to ongoing reflux.

In patients with esophageal regurgitation, most will not achieve adequate relief of symptoms with PPI therapy alone.³⁴ The therapeutic gain of PPI therapy vs placebo averaged just 17% in seven randomized, controlled trials, more than 20% less than the response rate for heartburn.³⁴ This is likely because of structural abnormalities such as reduced lower esophageal sphincter pressure, hiatal hernia, or delayed gastric emptying. Antireflux surgery can correct these structural abnormalities or prevent them from causing so much trouble; however, the presence of true regurgitation should first be confirmed by MII testing. If regurgitation is confirmed, antireflux surgery is warranted, particularly in patients with nocturnal symptoms who may be at high risk of aspiration. With careful patient selection, regurgitation symptoms improve in about 90% after surgery.²

In patients with heartburn, if esophageal acid exposure continues to be abnormal on MII-pH testing, then an escalation of therapy may improve symptoms, particularly if symptoms occur during reflux or if they partially responded to PPI therapy. Options in this scenario include alteration or intensification of acid-suppressive therapy, treatment with baclofen (Lioresal), and antireflux surgery.^18,35,36 In randomized controlled trials of patients whose symptoms partially responded to PPIs, antireflux surgery has performed similarly to PPIs in terms of improving typical GERD symptoms, particularly regurgitation.^27,37–41 Although this scenario is a reasonable indication for antireflux surgery, recommendations should be made with appropriate restraint since it is not easily reversible, some patients experience complications, and up to one-third will have no therapeutic benefit.³⁰

Nonacid reflux. In some cases, MII-pH testing during PPI therapy will reveal reflux of weakly acidic (pH > 4) or alkaline stomach contents, often called “nonacid reflux.”²⁹ Nonacid reflux is often present in patients with esophagitis that persists despite PPI therapy, indicating that even weakly acidic stomach contents can injure the mucosa.⁴² Since intensifying the acid-suppressive therapy is unlikely to improve these symptoms, antireflux surgery may have a role.

In one study,⁴³ nonacid reflux was well controlled by laparoscopic Nissen fundoplication, although 15 (48%) of 31 patients had persistent symptoms of GERD after surgery. No patient had a strong symptom correlation with postoperative reflux events, suggesting an alternative cause of the persistent symptoms. Therefore, antireflux surgery for nonacid reflux should be limited exclusively to patients with strong symptom correlation, and even then it should be considered with restraint, given the limited evidence for benefit and the potential for harm.

If testing is negative. In studies investigating the diagnostic yield of MII-pH testing, more than 50% of patients who had refractory symptoms had a negative MII-pH test.²⁹ In such situations, when the symptoms are strongly correlated with reflux events, the patient is said to have “esophageal hypersensitivity.” A few small studies have suggested that such patients may benefit from surgery, but these data have not been replicated in randomized controlled trials.³²

When the testing is negative and there is no correlation between the patient’s symptoms and reflux events, the patient is unlikely to benefit from antireflux surgery. Care of these patients is beyond the scope of this review.

SURGERY RARELY IMPROVES COUGH, ASTHMA, OR LARYNGITIS

GERD has been implicated as a cause of chronic cough, asthma, and laryngitis, although each of these has many potential causes.^44–46 Despite these associations, the evidence for therapeutic benefit from antireflux therapy is weak.

PPI therapy shows no benefit over placebo for chronic cough of uncertain etiology, but some benefit if GERD is objectively demonstrated.⁴⁷ Laryngitis resolved in just 15% of patients on esomeprazole vs 16% of patients on placebo after excluding patients with moderate to severe heartburn.⁴⁸

In a large randomized controlled trial in patients with asthma, there was no overall improvement in peak flow for the PPI group vs the placebo group, although significant improvement occurred in patients with heartburn and nocturnal respiratory symptoms.⁴⁶

Potent antisecretory therapy seems to improve extraesophageal symptoms when typical GERD symptoms are also present, but it otherwise has shown little evidence of benefit.

The evidence for a benefit from antireflux surgery in patients with extraesophageal GERD syndromes is even more limited. Although one systematic review⁴⁹ found that cough and other laryngeal symptoms improved in 60% to 100% of patients with objective evidence of GERD who underwent fundoplication, virtually all of the studies were uncontrolled case series.⁴⁹

The lone randomized controlled trial in the systematic review compared Nissen fundoplication with ranitidine (Zantac) or antacids only for patients with asthma and GERD, and found no significant difference in peak expiratory flow among the three groups after 2 years. However, asthma symptom scores improved in 75% of the surgical group, 9% of the medical group, and 4% of the control group.⁵⁰

In a study that was not included in the prior systematic review, patients with laryngopharyngeal reflux unresponsive to aggressive acid suppression who subsequently underwent fundoplication fared no better than those who did not.⁵¹

Thus, based on the available data, antireflux surgery is only rarely indicated for extraesophageal symptoms, especially in patients who have no typical GERD symptoms or in patients whose symptoms are refractory to medical therapy.

 

SURGERY FOR EROSIVE ESOPHAGITIS OR BARRETT ESOPHAGUS IF PPI FAILS

Lifelong antireflux therapy is indicated for patients with severe erosive esophagitis or Barrett esophagus. Erosive esophagitis recurs in more than 80% within 12 months of discontinuing antisecretory therapy.⁵² Both Barrett esophagus and esophageal adenocarcinoma are strongly associated with GERD, and nearly 10% of patients with chronic reflux have Barrett esophagus.^53,54 It is suspected that suppressing reflux reduces the rate of progression of Barrett esophagus to esophageal adenocarcinoma, but this remains to be proven.

Perhaps the strongest indication for surgery in the PPI era is for patients who have persistent symptoms and severe erosive esophagitis (Los Angeles grade C or D) despite high-dose PPI therapy. If other causes of persistent esophagitis have been ruled out, fundoplication can induce healing and improve symptoms.^55,56 In these cases, surgery is done to induce remission of the disease when maximal medical therapy has been truly unsuccessful.

Randomized controlled trials suggest that medical and surgical therapies are equally effective for preventing the recurrence of erosive esophagitis or the progression of Barrett esophagus. In a study of 225 patients, at 7 years of follow-up, esophagitis had recurred in 10.4% of patients on omeprazole vs 11.8% of those who had undergone antireflux surgery.⁴⁰ Similarly, open Nissen fundoplication was no different from drug therapy (histamine-2 receptor antagonist or PPI) for progression of Barrett esophagus over a median of 5 years.⁵⁷ A meta-analysis with nearly 5,000 person-years each in the medical and surgical groups also found no significant difference in rates of cancer progression.⁵⁸

Notably, symptoms such as dysphagia, flatulence, and the inability to burp occurred significantly more often in the surgical groups in these studies.

In view of these data, antireflux surgery has no significant advantage over medical therapy for maintaining healing of erosive esophagitis or preventing progression of Barrett esophagus. Thus, it should be reserved for patients who do not desire lifelong drug therapy, provided they understand that there is no therapeutic advantage for their esophagitis or for Barrett esophagus.

SPECIFIC INDICATIONS FOR ANTIREFLUX SURGERY

Now that we have PPIs, several situations remain in which surgery for GERD is either indicated or worth considering.

Antireflux surgery is clearly indicated for:

• Patients with erosive esophagitis that does not heal with maximal drug therapy
• Patients with volume regurgitation, particularly if it occurs at night or if there is evidence of aspiration
• Patients who require lifelong treatment for reflux but who have had a serious adverse event related to PPI therapy, such as refractory Clostridium difficile infection.

Antireflux surgery is also worth considering in patients who for personal reasons wish to avoid long-term or lifelong drug therapy.

Patients should be informed, however, that antireflux surgery has not been shown to be better than medical therapy for maintaining remission of symptoms, for preventing progression of Barrett esophagus, or for maintaining healing of erosive esophagitis. Medical therapy is still the first option for these patients.

Surgery may also be considered in patients with persistent symptoms who have a partial response to medical therapy, who show persistent acidic or weakly acidic reflux on MII-pH testing, and whose symptoms have been correlated with reflux events. Although surgery is not sure to improve their symptoms, benefit is more likely in this patient population compared with those without these characteristics.

Extraesophageal GERD

In patients suspected of having extraesophageal GERD, surgery should be considered if typical GERD symptoms are present and improve with PPI therapy, if the extraesophageal syndrome partially responds to PPI therapy, and if MII-pH testing demonstrates a correlation between symptoms and reflux. Surgery may have a stronger indication in this setting if the patient has nocturnal reflux or extraesophageal symptoms.

When is surgery not an option?

In general, surgery should not be considered in patients who do not have a partial response to PPI therapy or who do not have a strong symptom-reflux correlation on MII-pH testing. In all cases of failed medical therapy without persistent severe erosive disease, the threshold for opting for surgery should be high, given the uncertain response of these patients to surgery.

Peristaltic dysfunction is a relative but not an absolute contraindication to surgery.⁵⁹

RISKS, BENEFITS OF SURGERY FOR GERD

The patient’s preference for surgery over drug therapy should always be balanced against the risks of surgery, including both short-term and long-term adverse events, to allow the patient to make an adequately informed decision (Table 2).^2,26

Adverse events associated with PPI therapy are rare and in many cases the association is debatable.²⁶ Nonetheless, long-term PPI therapy has been most strongly associated with an increased risk of C difficile infection and other enteric infections, although the absolute risk of these events remains low.

Complication rates after antireflux surgery depend on the surgeon’s experience and technique. Death is exceedingly rare. In most high-volume centers, the need to convert from laparoscopic to open fundoplication occurs in fewer than 2.4% of patients.²

Potential perioperative complications include perforation (4%), wound infection (3%), and pneumothorax (2%).²

Antireflux surgery is also associated with a significant risk of dysphagia, bloating, an inability to burp, and excessive flatulence, all of which can markedly impair the quality of life.

A major consideration is that fundoplication is generally irreversible. Reoperation rates have been reported to range from 0% to 15%.² Furthermore, up to 50% of patients still need medical therapy after surgery.^60,61 Of note, only about 25% of patients on medical therapy after surgery will actually have an abnormal pH study.⁶¹

MORE STUDY NEEDED

Future studies directly comparing medical and surgical therapy for carefully selected patients with extraesophageal manifestations of GERD and refractory symptoms should help further delineate outcome in this difficult group of patients.

Under development are new drugs that may inhibit transient relaxation of the lower esophageal sphincter, as well as minimally invasive procedures, which may alter the indications for surgery in coming years.³⁶
 

---

Acknowledgment: The research for this article was supported in part by a grant from the National Institutes of Health (T32 DK07634).

A 29-year-old white man with no chronic medical problems presents to the emergency department with shortness of breath, left-sided pleuritic chest pain, cough, and hemoptysis. These symptoms began abruptly 1 day ago and have persisted. He also has mild pain and swelling in both calves. He denies having any fever, night sweats, or chills. On further questioning, he reports having taken a long, nonstop driving trip that lasted 8 hours 1 week ago.

His medical history is negative, and he specifically reports no history of deep venous thrombosis or pulmonary embolism. He underwent appendectomy 10 years ago but has had no other operations. He does not take any medications. His family history is noncontributory and is negative for venous thromboembolism. He smokes and uses alcohol occasionally but not illicit drugs.

Examination. He appears to be in considerable distress because of his chest pain. His temperature is 100.4°F (38.0°C), blood pressure 125/70 mm Hg, heart rate 125 beats per minute, respiratory rate 26 breaths per minute, oxygen saturation 92% on room air, and body mass index 19 kg/m².

Chest examination reveals diminished vesicular breathing in the left base, which is normal to percussion without added sounds. Both calves are swollen and tender to palpation without skin discoloration. The rest of his examination is normal.

Laboratory values:

• White blood cell count 9.3 × 10⁹/L (reference range 4.5–11.0)
• Hemoglobin 15.9 g/dL (14.0–17.5)
• Platelets 205 × 10⁹/L (150–350)
• Sodium 140 mEq/L (136–142)
• Potassium 3.9 mEq/L (3.5–5.0)
• Chloride 108 mEq/L (96–106)
• Bicarbonate 23 mEq/L (21–28)
• Blood urea nitrogen 14 mg/dL (8–23)
• Creatinine 0.9 mg/dL (0.6–1.2)
• Glucose 95 mg/dL (70–110)
• International normalized ratio (INR) 0.90 (0.00–1.2)
• Partial thromboplastin time 27.5 seconds (24.6–31.8)
• Creatine phosphokinase 205 U/L (39–308)
• Troponin T < 0.015 ng/mL (0.01–0.045).

Pulmonary embolism is diagnosed

Electrocardiography shows sinus tachycardia. Chest radiography shows small atelectatic changes at the left lung base (Figure 1). Pulmonary embolism is suspected, and a serum Ddimer level is obtained; it is 4,054 ng/mL (reference range < 500). Computed tomography of the chest confirms bilateral acute pulmonary emboli (Figure 2). Doppler ultrasonography of both legs reveals bilateral deep venous thrombosis. Echocardiography shows mildly elevated right ventricular systolic pressure at 47 mm Hg.

Factor V Leiden is diagnosed, and the patient recovers with treatment

Anticoagulation is started in the emergency department.

Given this patient’s young age and clot burden, a hypercoagulable state is suspected. Thrombophilia screening is performed, with tests for the factor V Leiden mutation, the prothrombin G20210A mutation, and antiphospholipid and lupus anticoagulant antibodies. The rest of the thrombophilia panel, including antithrombin III, factor VIII, protein C, and protein S, is deferred because the levels of these substances would be expected to change during the acute thrombosis.

The direct test for factor V Leiden mutation is positive for the heterozygous type. The test for the prothrombin G20210A mutation is negative, and his antiphospholipid antibody levels, including the lupus anticoagulant titer, are within normal limits.

The patient is kept on a standard regimen of unfractionated heparin, overlapped with warfarin (Coumadin) until his INR is 2.0 to 3.0 on 2 consecutive days. His hospital course is uneventful and his condition gradually improves.

He is discharged home to continue on oral anticoagulation for 6 months with a target INR of 2.0 to 3.0. Two weeks after completing his anticoagulation therapy, his levels of antithrombin III, factor VIII, protein C, and protein S are all within normal limits.

FACTOR V LEIDEN IS COMMON

Factor V Leiden is the most common inherited thrombophilia, with a prevalence of 3% to 7% in the general US population,¹ approximately 5% in whites, 2.2% in Hispanics, and 1.2% in blacks.² Its prevalence in patients with venous thromboembolism, however, is 50%.^1,3 The annual incidence of venous thromboembolism in patients with factor V Leiden is 0.5%.^4,5

 

MORE COAGULATION, LESS ANTICOAGULATION

Factor V has a critical position in both the coagulant and anticoagulant pathways. Factor V Leiden results in a hypercoagulable state by both increasing coagulation and decreasing anticoagulation.

This mutation causes factor V to be resistant to being cleaved and inactivated by activated protein C, a condition known as APC resistance. As a result, more factor Va is available within the prothrombinase complex, increasing coagulation by increased generation of thrombin.^6–8

Furthermore, a cofactor formed by cleavage of factor V at position 506 is thought to support activated protein C in degrading factor VIIIa (in the tenase complex), along with protein S. People with factor V Leiden lack this cleavage product and thus have less anticoagulant activity from activated protein C. The increased coagulation and decreased anticoagulation appear to contribute equally to the hypercoagulable state in factor V Leiden-associated APC resistance.^9–11

Heterozygosity for the factor V Leiden mutation accounts for 90% to 95% of cases of APC resistance. A much smaller number of people are homozygous for it.¹

People who are homozygous for factor V Leiden are at higher risk of venous thromboembolism than those who are heterozygous for it, since the latter group’s blood contains both factor V Leiden and normal factor V. The normal factor V allows anticoagulation via the second pathway of inactivation of factor VIIIa by activated protein C, giving some protection against thrombosis. In people who are homozygous for factor V Leiden, the lack of normal factor V acting as an anticoagulant protein results in a higher thrombotic risk.^9–11

Other factor V mutations may also cause APC resistance

Although factor V Leiden is the only genetic defect for which a causal relationship with APC resistance has been clearly determined, other, rarer hereditary factor V mutations or polymorphisms have been described, such as factor V Cambridge (Arg306Thr)¹² and factor V Hong Kong (Arg306Gly).¹³ These mutations may result in APC resistance, but their clinical association with thrombosis is less clear.¹⁴ Factor V Liverpool (Ile359Thr) is associated with a higher risk of thrombosis, apparently because of reduced APC-mediated inactivation of factor Va and because it is a poor cofactor with activated protein C for the inactivation of factor VIIIa.¹⁵

An R2 haplotype has also been described in association with APC resistance.^16,17 The phenomenon may be due to a reduction in activated protein C cofactor activity.⁹ However, not all studies have been convincing regarding the role of this haplotype in clinical disease.¹⁸ Coinheritance of this haplotype with factor V Leiden may increase the risk of venous thromboembolism above that associated with factor V Leiden alone.¹⁹

Although factor V Leiden is the most common cause of inherited APC resistance, other changes in hemostasis cause acquired APC resistance and may contribute to the thrombotic tendency in these patients.^20–22 The most common causes of acquired APC resistance include elevated factor VIII levels,^23–25 pregnancy,^26–28 use of oral contraceptives,^29,30 and antiphospholipid antibodies.³¹

USUALLY MANIFESTS AS DEEP VEIN THROMBOSIS

Factor V Leiden usually manifests as deep vein thrombosis with or without pulmonary embolism, but thrombosis in unusual locations also occurs.³²

The risk of a first episode of venous thromboembolism is two to five times higher with heterozygous factor V Leiden. However, even though the relative risk is high, the absolute risk is low. Furthermore, despite the higher risk of venous thrombosis, there is no evidence that heterozygosity for factor V Leiden increases the overall mortality rate.^4,33–36

In people with homozygous factor V Leiden or with combined inherited thrombophilias, the risk of venous thromboembolism is increased to a greater degree: it is 20 to 50 times higher.^7,8,37–39 However, whether the risk of death is higher is not clear.

VENOUS THROMBOEMBOLISM IS MULTIFACTORIAL

The pathogenesis of venous thromboembolism is multifactorial and involves an interaction between inherited and acquired factors. Very often, people with factor V Leiden have additional risk factors that contribute to the development of venous clots, and it is very unusual for them to have thrombosis in the absence of these additional factors.

These factors include older age, surgery, obesity, prolonged travel, immobility, hospitalization, oral contraceptive use, hormonal replacement therapy, pregnancy, and malignancy. They increase the risk of venous thrombosis in normal individuals as well, but more so in people with factor V Leiden.^40–43

Testing for other known causes of thrombophilia may also be pursued. These include elevated homocysteine levels, the factor II (prothrombin) G20210A mutation, anticardiolipin antibody, lupus anticoagulant, and deficiencies of antithrombin III, protein C, and protein S.

Factor V Leiden by itself does not appear to increase the risk of arterial thrombosis, ie, heart attack and stroke.^{33,38,44–46}

Family history: A risk indicator for venous thrombosis

Family history is an important indicator of risk for a first venous thromboembolic event, regardless of other risk factors identified. The risk of a first event is two to three times higher in people with a family history of thrombosis in a first-degree relative. The risk is four times higher when multiple family members are affected, at least one of them before age 50.⁴⁷

In people with genetic thrombophilia, the risk of thrombosis (especially unprovoked thrombosis at a young age) is also higher in those with a strong family history than in those without a family history. In those with factor V Leiden, the risk of venous thromboembolism is three to four times higher if there is a positive family history. The risk is five times higher in carriers of factor V Leiden with a family history of venous thromboembolism before age 50, and 13 times higher in those with more than one affected family member.⁴⁷

Possible shared environmental factors or coinheritance of other unidentified genetic factors may also contribute to the higher susceptibility in thrombosis-prone families.

TESTING FOR APC RESISTANCE AND FACTOR V LEIDEN

The factor V Leiden mutation can be detected directly by genetic testing of peripheral blood mononuclear cells. This method is relatively time-consuming and expensive, however.

At present, the most cost-effective approach is to test first for APC resistance using a second-generation coagulation assay—the modified APC sensitivity test. In this clot-based method, the patient’s sample is prediluted with factor V-deficient plasma to eliminate the effect of lupus anticoagulants and factor deficiencies that could prolong the baseline clotting time, and heparin is inactivated by polybrene. Then either an augmented partial-thromboplastin-time-based assay or a tissue-factor-dependent factor V assay is performed.

This test is nearly 100% sensitive and specific for factor V Leiden, in contrast to the first-generation, or classic, APC sensitivity test, which lacked specificity and sensitivity for it.^{9–11,48–60} This modification also permits testing of patients receiving anticoagulants or who have abnormal augmented partial thromboplastin times due to coagulation factor deficiencies.

A positive result on the modified APC sensitivity test should be confirmed by a direct genetic test for the factor V Leiden mutation. An APC resistance assay is unnecessary if a direct genetic test is used initially.

 

HOW LONG TO GIVE ANTICOAGULATION AFTER VENOUS THROMBOEMBOLISM?

Patients who have had an episode of venous thromboembolism have to be treated with anticoagulants.

In general, the initial management of venous thromboembolism in patients with heritable thrombophilias is no different from that in any other patient with a clot. Anticoagulants such as warfarin are given at a target INR of 2.5 (range 2.0–3.0).³² The duration of treatment is based on the risk factors that resulted in the thrombotic event.

After a first event, some authorities recommend anticoagulant therapy for 6 months.³² A shorter period (3 months) is recommended if there is a transient risk factor (eg, surgery, oral contraceptive use, travel, pregnancy, the puerperium) and the thrombosis is confined to distal veins (eg, the calf veins).³²

Factor V Leiden does not necessarily increase the risk of recurrent events in patients who have a transient risk factor. Therefore, people who are heterozygous for this mutation do not usually need to be treated lifelong with anticoagulants if they have had only one episode of deep vein thrombosis or pulmonary embolism, given the risk of bleeding associated with anticoagulation, unless they have additional risk factors.

Conditions in which indefinite anticoagulation may be required after careful consideration of the risks and benefits are:

• Life-threatening events such as near-fatal pulmonary embolism
• Cerebral or visceral vein thrombosis
• Recurrent thrombotic events
• Additional persistent risk factors (eg, active malignant neoplasm, extremity paresis, and antiphospholipid antibodies)
• Combined thrombophilias (eg, combined heterozygosity for factor V Leiden and the prothrombin G20210A mutation)
• Homozygosity for factor V Leiden.^32,46,48

Factor V Leiden by itself or combined with other thrombophilic abnormalities is not associated with a higher risk of recurrent venous thromboembolism during warfarin therapy (a possible exception is the combination of factor V Leiden plus antiphospholipid antibodies).^32,34 Furthermore, current evidence suggests that no thrombophilic defect is a clinically important risk factor for recurrent venous thromboembolism after anticoagulant therapy is stopped. All these facts indicate that clinical factors are probably more important than laboratory abnormalities in determining the duration of anticoagulation therapy.^{32,35,36,61–63}

PRIMARY PROPHYLAXIS IN PATIENTS WITH FACTOR V LEIDEN

Factor V Leiden is only one of many risk factors for deep vein thrombosis or pulmonary embolism. If carriers of factor V Leiden have never had a blood clot, then they are not routinely treated with an anticoagulant. Rather, they should be counseled about reducing or eliminating other factors that may add to their risk of developing a clot in the future.

Usually, the effect of risk factors is additive: the more risk factors present, the higher the risk.^46,50 Sometimes, however, the effect of multiple risk factors is more than additive.

Some risk factors, such as genetics or age, are not alterable, but many can be controlled by medications or lifestyle modifications. Therefore, general measures and precautions are recommended to minimize the risk of thrombosis. For example:

Losing weight (if the patient is overweight) is an important intervention for risk reduction, since obesity is probably the most common modifiable risk factor for developing blood clots.

Avoiding long periods of immobility is recommended. For example, if the patient is taking a long car ride (more than 2 hours), then stopping every few hours and walking around for a few minutes is a good way to keep the blood circulating. If the patient has a desk job, getting up and walking around the office periodically is advised. On long airplane trips, a walk in the aisle every so often and preventing dehydration by drinking plenty of fluids and avoiding alcohol are recommended.

Wearing elastic stockings with a graduated elastic pressure may prevent deep venous thrombosis from developing on long flights.^63–65

Staying active and getting regular exercise through such activities as walking, bicycling, or swimming are helpful.

Avoiding smoking is critical.^50,63

Thromboprophylaxis is recommended for most acutely ill hospitalized patients, especially those confined to bed with additional risk factors. Guidelines for prophylaxis are based on an individualized risk assessment and not on thrombophilia status. Prophylactic anticoagulation is routinely recommended for patients undergoing major high-risk surgery, such as an orthopedic, urologic, gynecologic, or bariatric procedure. Any excess thrombotic risk conferred by thrombophilia is likely small compared with the risk of surgery, and recommendations on the duration and intensity of thromboprophylaxis are not based on thrombophilic status.^46,48

Education. Pain, swelling, redness of a limb, unexplained shortness of breath, and chest pain are the most common symptoms of deep vein thrombosis and pulmonary embolism.^46,50 It is crucial to teach patients with factor V Leiden to recognize these symptoms and to seek early medical attention in case they experience any of them.

SCREENING FAMILY MEMBERS FOR THE FACTOR V LEIDEN MUTATION

Factor V Leiden by itself is a relatively mild thrombophilic defect that does not cause thrombosis in all carriers, and there is no evidence that early diagnosis reduces rates of morbidity or mortality. Therefore, routine screening of all asymptomatic relatives of affected patients with venous thrombosis is not recommended. Rather, the decision to screen should be made on an individual basis.^50,66

Screening may be beneficial in selected cases, especially when patients have a strong family history of recurrent venous thrombosis at a young age (younger than 50 years) and the family member has additional risk factors for venous thromboembolism such as oral contraception or is planning for pregnancy.^32,48,49,66

A 29-year-old white man with no chronic medical problems presents to the emergency department with shortness of breath, left-sided pleuritic chest pain, cough, and hemoptysis. These symptoms began abruptly 1 day ago and have persisted. He also has mild pain and swelling in both calves. He denies having any fever, night sweats, or chills. On further questioning, he reports having taken a long, nonstop driving trip that lasted 8 hours 1 week ago.

His medical history is negative, and he specifically reports no history of deep venous thrombosis or pulmonary embolism. He underwent appendectomy 10 years ago but has had no other operations. He does not take any medications. His family history is noncontributory and is negative for venous thromboembolism. He smokes and uses alcohol occasionally but not illicit drugs.

Examination. He appears to be in considerable distress because of his chest pain. His temperature is 100.4°F (38.0°C), blood pressure 125/70 mm Hg, heart rate 125 beats per minute, respiratory rate 26 breaths per minute, oxygen saturation 92% on room air, and body mass index 19 kg/m².

Chest examination reveals diminished vesicular breathing in the left base, which is normal to percussion without added sounds. Both calves are swollen and tender to palpation without skin discoloration. The rest of his examination is normal.

Laboratory values:

• White blood cell count 9.3 × 10⁹/L (reference range 4.5–11.0)
• Hemoglobin 15.9 g/dL (14.0–17.5)
• Platelets 205 × 10⁹/L (150–350)
• Sodium 140 mEq/L (136–142)
• Potassium 3.9 mEq/L (3.5–5.0)
• Chloride 108 mEq/L (96–106)
• Bicarbonate 23 mEq/L (21–28)
• Blood urea nitrogen 14 mg/dL (8–23)
• Creatinine 0.9 mg/dL (0.6–1.2)
• Glucose 95 mg/dL (70–110)
• International normalized ratio (INR) 0.90 (0.00–1.2)
• Partial thromboplastin time 27.5 seconds (24.6–31.8)
• Creatine phosphokinase 205 U/L (39–308)
• Troponin T < 0.015 ng/mL (0.01–0.045).

Pulmonary embolism is diagnosed

Electrocardiography shows sinus tachycardia. Chest radiography shows small atelectatic changes at the left lung base (Figure 1). Pulmonary embolism is suspected, and a serum Ddimer level is obtained; it is 4,054 ng/mL (reference range < 500). Computed tomography of the chest confirms bilateral acute pulmonary emboli (Figure 2). Doppler ultrasonography of both legs reveals bilateral deep venous thrombosis. Echocardiography shows mildly elevated right ventricular systolic pressure at 47 mm Hg.

Factor V Leiden is diagnosed, and the patient recovers with treatment

Anticoagulation is started in the emergency department.

Given this patient’s young age and clot burden, a hypercoagulable state is suspected. Thrombophilia screening is performed, with tests for the factor V Leiden mutation, the prothrombin G20210A mutation, and antiphospholipid and lupus anticoagulant antibodies. The rest of the thrombophilia panel, including antithrombin III, factor VIII, protein C, and protein S, is deferred because the levels of these substances would be expected to change during the acute thrombosis.

The direct test for factor V Leiden mutation is positive for the heterozygous type. The test for the prothrombin G20210A mutation is negative, and his antiphospholipid antibody levels, including the lupus anticoagulant titer, are within normal limits.

The patient is kept on a standard regimen of unfractionated heparin, overlapped with warfarin (Coumadin) until his INR is 2.0 to 3.0 on 2 consecutive days. His hospital course is uneventful and his condition gradually improves.

He is discharged home to continue on oral anticoagulation for 6 months with a target INR of 2.0 to 3.0. Two weeks after completing his anticoagulation therapy, his levels of antithrombin III, factor VIII, protein C, and protein S are all within normal limits.

FACTOR V LEIDEN IS COMMON

Factor V Leiden is the most common inherited thrombophilia, with a prevalence of 3% to 7% in the general US population,¹ approximately 5% in whites, 2.2% in Hispanics, and 1.2% in blacks.² Its prevalence in patients with venous thromboembolism, however, is 50%.^1,3 The annual incidence of venous thromboembolism in patients with factor V Leiden is 0.5%.^4,5

 

MORE COAGULATION, LESS ANTICOAGULATION

Factor V has a critical position in both the coagulant and anticoagulant pathways. Factor V Leiden results in a hypercoagulable state by both increasing coagulation and decreasing anticoagulation.

This mutation causes factor V to be resistant to being cleaved and inactivated by activated protein C, a condition known as APC resistance. As a result, more factor Va is available within the prothrombinase complex, increasing coagulation by increased generation of thrombin.^6–8

Furthermore, a cofactor formed by cleavage of factor V at position 506 is thought to support activated protein C in degrading factor VIIIa (in the tenase complex), along with protein S. People with factor V Leiden lack this cleavage product and thus have less anticoagulant activity from activated protein C. The increased coagulation and decreased anticoagulation appear to contribute equally to the hypercoagulable state in factor V Leiden-associated APC resistance.^9–11

Heterozygosity for the factor V Leiden mutation accounts for 90% to 95% of cases of APC resistance. A much smaller number of people are homozygous for it.¹

People who are homozygous for factor V Leiden are at higher risk of venous thromboembolism than those who are heterozygous for it, since the latter group’s blood contains both factor V Leiden and normal factor V. The normal factor V allows anticoagulation via the second pathway of inactivation of factor VIIIa by activated protein C, giving some protection against thrombosis. In people who are homozygous for factor V Leiden, the lack of normal factor V acting as an anticoagulant protein results in a higher thrombotic risk.^9–11

Other factor V mutations may also cause APC resistance

Although factor V Leiden is the only genetic defect for which a causal relationship with APC resistance has been clearly determined, other, rarer hereditary factor V mutations or polymorphisms have been described, such as factor V Cambridge (Arg306Thr)¹² and factor V Hong Kong (Arg306Gly).¹³ These mutations may result in APC resistance, but their clinical association with thrombosis is less clear.¹⁴ Factor V Liverpool (Ile359Thr) is associated with a higher risk of thrombosis, apparently because of reduced APC-mediated inactivation of factor Va and because it is a poor cofactor with activated protein C for the inactivation of factor VIIIa.¹⁵

An R2 haplotype has also been described in association with APC resistance.^16,17 The phenomenon may be due to a reduction in activated protein C cofactor activity.⁹ However, not all studies have been convincing regarding the role of this haplotype in clinical disease.¹⁸ Coinheritance of this haplotype with factor V Leiden may increase the risk of venous thromboembolism above that associated with factor V Leiden alone.¹⁹

Although factor V Leiden is the most common cause of inherited APC resistance, other changes in hemostasis cause acquired APC resistance and may contribute to the thrombotic tendency in these patients.^20–22 The most common causes of acquired APC resistance include elevated factor VIII levels,^23–25 pregnancy,^26–28 use of oral contraceptives,^29,30 and antiphospholipid antibodies.³¹

USUALLY MANIFESTS AS DEEP VEIN THROMBOSIS

Factor V Leiden usually manifests as deep vein thrombosis with or without pulmonary embolism, but thrombosis in unusual locations also occurs.³²

The risk of a first episode of venous thromboembolism is two to five times higher with heterozygous factor V Leiden. However, even though the relative risk is high, the absolute risk is low. Furthermore, despite the higher risk of venous thrombosis, there is no evidence that heterozygosity for factor V Leiden increases the overall mortality rate.^4,33–36

In people with homozygous factor V Leiden or with combined inherited thrombophilias, the risk of venous thromboembolism is increased to a greater degree: it is 20 to 50 times higher.^7,8,37–39 However, whether the risk of death is higher is not clear.

VENOUS THROMBOEMBOLISM IS MULTIFACTORIAL

The pathogenesis of venous thromboembolism is multifactorial and involves an interaction between inherited and acquired factors. Very often, people with factor V Leiden have additional risk factors that contribute to the development of venous clots, and it is very unusual for them to have thrombosis in the absence of these additional factors.

These factors include older age, surgery, obesity, prolonged travel, immobility, hospitalization, oral contraceptive use, hormonal replacement therapy, pregnancy, and malignancy. They increase the risk of venous thrombosis in normal individuals as well, but more so in people with factor V Leiden.^40–43

Testing for other known causes of thrombophilia may also be pursued. These include elevated homocysteine levels, the factor II (prothrombin) G20210A mutation, anticardiolipin antibody, lupus anticoagulant, and deficiencies of antithrombin III, protein C, and protein S.

Factor V Leiden by itself does not appear to increase the risk of arterial thrombosis, ie, heart attack and stroke.^{33,38,44–46}

Family history: A risk indicator for venous thrombosis

Family history is an important indicator of risk for a first venous thromboembolic event, regardless of other risk factors identified. The risk of a first event is two to three times higher in people with a family history of thrombosis in a first-degree relative. The risk is four times higher when multiple family members are affected, at least one of them before age 50.⁴⁷

In people with genetic thrombophilia, the risk of thrombosis (especially unprovoked thrombosis at a young age) is also higher in those with a strong family history than in those without a family history. In those with factor V Leiden, the risk of venous thromboembolism is three to four times higher if there is a positive family history. The risk is five times higher in carriers of factor V Leiden with a family history of venous thromboembolism before age 50, and 13 times higher in those with more than one affected family member.⁴⁷

Possible shared environmental factors or coinheritance of other unidentified genetic factors may also contribute to the higher susceptibility in thrombosis-prone families.

TESTING FOR APC RESISTANCE AND FACTOR V LEIDEN

The factor V Leiden mutation can be detected directly by genetic testing of peripheral blood mononuclear cells. This method is relatively time-consuming and expensive, however.

At present, the most cost-effective approach is to test first for APC resistance using a second-generation coagulation assay—the modified APC sensitivity test. In this clot-based method, the patient’s sample is prediluted with factor V-deficient plasma to eliminate the effect of lupus anticoagulants and factor deficiencies that could prolong the baseline clotting time, and heparin is inactivated by polybrene. Then either an augmented partial-thromboplastin-time-based assay or a tissue-factor-dependent factor V assay is performed.

This test is nearly 100% sensitive and specific for factor V Leiden, in contrast to the first-generation, or classic, APC sensitivity test, which lacked specificity and sensitivity for it.^{9–11,48–60} This modification also permits testing of patients receiving anticoagulants or who have abnormal augmented partial thromboplastin times due to coagulation factor deficiencies.

A positive result on the modified APC sensitivity test should be confirmed by a direct genetic test for the factor V Leiden mutation. An APC resistance assay is unnecessary if a direct genetic test is used initially.

 

HOW LONG TO GIVE ANTICOAGULATION AFTER VENOUS THROMBOEMBOLISM?

Patients who have had an episode of venous thromboembolism have to be treated with anticoagulants.

In general, the initial management of venous thromboembolism in patients with heritable thrombophilias is no different from that in any other patient with a clot. Anticoagulants such as warfarin are given at a target INR of 2.5 (range 2.0–3.0).³² The duration of treatment is based on the risk factors that resulted in the thrombotic event.

After a first event, some authorities recommend anticoagulant therapy for 6 months.³² A shorter period (3 months) is recommended if there is a transient risk factor (eg, surgery, oral contraceptive use, travel, pregnancy, the puerperium) and the thrombosis is confined to distal veins (eg, the calf veins).³²

Factor V Leiden does not necessarily increase the risk of recurrent events in patients who have a transient risk factor. Therefore, people who are heterozygous for this mutation do not usually need to be treated lifelong with anticoagulants if they have had only one episode of deep vein thrombosis or pulmonary embolism, given the risk of bleeding associated with anticoagulation, unless they have additional risk factors.

Conditions in which indefinite anticoagulation may be required after careful consideration of the risks and benefits are:

• Life-threatening events such as near-fatal pulmonary embolism
• Cerebral or visceral vein thrombosis
• Recurrent thrombotic events
• Additional persistent risk factors (eg, active malignant neoplasm, extremity paresis, and antiphospholipid antibodies)
• Combined thrombophilias (eg, combined heterozygosity for factor V Leiden and the prothrombin G20210A mutation)
• Homozygosity for factor V Leiden.^32,46,48

Factor V Leiden by itself or combined with other thrombophilic abnormalities is not associated with a higher risk of recurrent venous thromboembolism during warfarin therapy (a possible exception is the combination of factor V Leiden plus antiphospholipid antibodies).^32,34 Furthermore, current evidence suggests that no thrombophilic defect is a clinically important risk factor for recurrent venous thromboembolism after anticoagulant therapy is stopped. All these facts indicate that clinical factors are probably more important than laboratory abnormalities in determining the duration of anticoagulation therapy.^{32,35,36,61–63}

PRIMARY PROPHYLAXIS IN PATIENTS WITH FACTOR V LEIDEN

Factor V Leiden is only one of many risk factors for deep vein thrombosis or pulmonary embolism. If carriers of factor V Leiden have never had a blood clot, then they are not routinely treated with an anticoagulant. Rather, they should be counseled about reducing or eliminating other factors that may add to their risk of developing a clot in the future.

Usually, the effect of risk factors is additive: the more risk factors present, the higher the risk.^46,50 Sometimes, however, the effect of multiple risk factors is more than additive.

Some risk factors, such as genetics or age, are not alterable, but many can be controlled by medications or lifestyle modifications. Therefore, general measures and precautions are recommended to minimize the risk of thrombosis. For example:

Losing weight (if the patient is overweight) is an important intervention for risk reduction, since obesity is probably the most common modifiable risk factor for developing blood clots.

Avoiding long periods of immobility is recommended. For example, if the patient is taking a long car ride (more than 2 hours), then stopping every few hours and walking around for a few minutes is a good way to keep the blood circulating. If the patient has a desk job, getting up and walking around the office periodically is advised. On long airplane trips, a walk in the aisle every so often and preventing dehydration by drinking plenty of fluids and avoiding alcohol are recommended.

Wearing elastic stockings with a graduated elastic pressure may prevent deep venous thrombosis from developing on long flights.^63–65

Staying active and getting regular exercise through such activities as walking, bicycling, or swimming are helpful.

Avoiding smoking is critical.^50,63

Thromboprophylaxis is recommended for most acutely ill hospitalized patients, especially those confined to bed with additional risk factors. Guidelines for prophylaxis are based on an individualized risk assessment and not on thrombophilia status. Prophylactic anticoagulation is routinely recommended for patients undergoing major high-risk surgery, such as an orthopedic, urologic, gynecologic, or bariatric procedure. Any excess thrombotic risk conferred by thrombophilia is likely small compared with the risk of surgery, and recommendations on the duration and intensity of thromboprophylaxis are not based on thrombophilic status.^46,48

Education. Pain, swelling, redness of a limb, unexplained shortness of breath, and chest pain are the most common symptoms of deep vein thrombosis and pulmonary embolism.^46,50 It is crucial to teach patients with factor V Leiden to recognize these symptoms and to seek early medical attention in case they experience any of them.

SCREENING FAMILY MEMBERS FOR THE FACTOR V LEIDEN MUTATION

Factor V Leiden by itself is a relatively mild thrombophilic defect that does not cause thrombosis in all carriers, and there is no evidence that early diagnosis reduces rates of morbidity or mortality. Therefore, routine screening of all asymptomatic relatives of affected patients with venous thrombosis is not recommended. Rather, the decision to screen should be made on an individual basis.^50,66

Screening may be beneficial in selected cases, especially when patients have a strong family history of recurrent venous thrombosis at a young age (younger than 50 years) and the family member has additional risk factors for venous thromboembolism such as oral contraception or is planning for pregnancy.^32,48,49,66

A 29-year-old white man with no chronic medical problems presents to the emergency department with shortness of breath, left-sided pleuritic chest pain, cough, and hemoptysis. These symptoms began abruptly 1 day ago and have persisted. He also has mild pain and swelling in both calves. He denies having any fever, night sweats, or chills. On further questioning, he reports having taken a long, nonstop driving trip that lasted 8 hours 1 week ago.

His medical history is negative, and he specifically reports no history of deep venous thrombosis or pulmonary embolism. He underwent appendectomy 10 years ago but has had no other operations. He does not take any medications. His family history is noncontributory and is negative for venous thromboembolism. He smokes and uses alcohol occasionally but not illicit drugs.

Examination. He appears to be in considerable distress because of his chest pain. His temperature is 100.4°F (38.0°C), blood pressure 125/70 mm Hg, heart rate 125 beats per minute, respiratory rate 26 breaths per minute, oxygen saturation 92% on room air, and body mass index 19 kg/m².

Chest examination reveals diminished vesicular breathing in the left base, which is normal to percussion without added sounds. Both calves are swollen and tender to palpation without skin discoloration. The rest of his examination is normal.

Laboratory values:

• White blood cell count 9.3 × 10⁹/L (reference range 4.5–11.0)
• Hemoglobin 15.9 g/dL (14.0–17.5)
• Platelets 205 × 10⁹/L (150–350)
• Sodium 140 mEq/L (136–142)
• Potassium 3.9 mEq/L (3.5–5.0)
• Chloride 108 mEq/L (96–106)
• Bicarbonate 23 mEq/L (21–28)
• Blood urea nitrogen 14 mg/dL (8–23)
• Creatinine 0.9 mg/dL (0.6–1.2)
• Glucose 95 mg/dL (70–110)
• International normalized ratio (INR) 0.90 (0.00–1.2)
• Partial thromboplastin time 27.5 seconds (24.6–31.8)
• Creatine phosphokinase 205 U/L (39–308)
• Troponin T < 0.015 ng/mL (0.01–0.045).

Pulmonary embolism is diagnosed

Electrocardiography shows sinus tachycardia. Chest radiography shows small atelectatic changes at the left lung base (Figure 1). Pulmonary embolism is suspected, and a serum Ddimer level is obtained; it is 4,054 ng/mL (reference range < 500). Computed tomography of the chest confirms bilateral acute pulmonary emboli (Figure 2). Doppler ultrasonography of both legs reveals bilateral deep venous thrombosis. Echocardiography shows mildly elevated right ventricular systolic pressure at 47 mm Hg.

Factor V Leiden is diagnosed, and the patient recovers with treatment

Anticoagulation is started in the emergency department.

Given this patient’s young age and clot burden, a hypercoagulable state is suspected. Thrombophilia screening is performed, with tests for the factor V Leiden mutation, the prothrombin G20210A mutation, and antiphospholipid and lupus anticoagulant antibodies. The rest of the thrombophilia panel, including antithrombin III, factor VIII, protein C, and protein S, is deferred because the levels of these substances would be expected to change during the acute thrombosis.

The direct test for factor V Leiden mutation is positive for the heterozygous type. The test for the prothrombin G20210A mutation is negative, and his antiphospholipid antibody levels, including the lupus anticoagulant titer, are within normal limits.

The patient is kept on a standard regimen of unfractionated heparin, overlapped with warfarin (Coumadin) until his INR is 2.0 to 3.0 on 2 consecutive days. His hospital course is uneventful and his condition gradually improves.

He is discharged home to continue on oral anticoagulation for 6 months with a target INR of 2.0 to 3.0. Two weeks after completing his anticoagulation therapy, his levels of antithrombin III, factor VIII, protein C, and protein S are all within normal limits.

FACTOR V LEIDEN IS COMMON

Factor V Leiden is the most common inherited thrombophilia, with a prevalence of 3% to 7% in the general US population,¹ approximately 5% in whites, 2.2% in Hispanics, and 1.2% in blacks.² Its prevalence in patients with venous thromboembolism, however, is 50%.^1,3 The annual incidence of venous thromboembolism in patients with factor V Leiden is 0.5%.^4,5

 

MORE COAGULATION, LESS ANTICOAGULATION

Factor V has a critical position in both the coagulant and anticoagulant pathways. Factor V Leiden results in a hypercoagulable state by both increasing coagulation and decreasing anticoagulation.

This mutation causes factor V to be resistant to being cleaved and inactivated by activated protein C, a condition known as APC resistance. As a result, more factor Va is available within the prothrombinase complex, increasing coagulation by increased generation of thrombin.^6–8

Furthermore, a cofactor formed by cleavage of factor V at position 506 is thought to support activated protein C in degrading factor VIIIa (in the tenase complex), along with protein S. People with factor V Leiden lack this cleavage product and thus have less anticoagulant activity from activated protein C. The increased coagulation and decreased anticoagulation appear to contribute equally to the hypercoagulable state in factor V Leiden-associated APC resistance.^9–11

Heterozygosity for the factor V Leiden mutation accounts for 90% to 95% of cases of APC resistance. A much smaller number of people are homozygous for it.¹

People who are homozygous for factor V Leiden are at higher risk of venous thromboembolism than those who are heterozygous for it, since the latter group’s blood contains both factor V Leiden and normal factor V. The normal factor V allows anticoagulation via the second pathway of inactivation of factor VIIIa by activated protein C, giving some protection against thrombosis. In people who are homozygous for factor V Leiden, the lack of normal factor V acting as an anticoagulant protein results in a higher thrombotic risk.^9–11

Other factor V mutations may also cause APC resistance

Although factor V Leiden is the only genetic defect for which a causal relationship with APC resistance has been clearly determined, other, rarer hereditary factor V mutations or polymorphisms have been described, such as factor V Cambridge (Arg306Thr)¹² and factor V Hong Kong (Arg306Gly).¹³ These mutations may result in APC resistance, but their clinical association with thrombosis is less clear.¹⁴ Factor V Liverpool (Ile359Thr) is associated with a higher risk of thrombosis, apparently because of reduced APC-mediated inactivation of factor Va and because it is a poor cofactor with activated protein C for the inactivation of factor VIIIa.¹⁵

An R2 haplotype has also been described in association with APC resistance.^16,17 The phenomenon may be due to a reduction in activated protein C cofactor activity.⁹ However, not all studies have been convincing regarding the role of this haplotype in clinical disease.¹⁸ Coinheritance of this haplotype with factor V Leiden may increase the risk of venous thromboembolism above that associated with factor V Leiden alone.¹⁹

Although factor V Leiden is the most common cause of inherited APC resistance, other changes in hemostasis cause acquired APC resistance and may contribute to the thrombotic tendency in these patients.^20–22 The most common causes of acquired APC resistance include elevated factor VIII levels,^23–25 pregnancy,^26–28 use of oral contraceptives,^29,30 and antiphospholipid antibodies.³¹

USUALLY MANIFESTS AS DEEP VEIN THROMBOSIS

Factor V Leiden usually manifests as deep vein thrombosis with or without pulmonary embolism, but thrombosis in unusual locations also occurs.³²

The risk of a first episode of venous thromboembolism is two to five times higher with heterozygous factor V Leiden. However, even though the relative risk is high, the absolute risk is low. Furthermore, despite the higher risk of venous thrombosis, there is no evidence that heterozygosity for factor V Leiden increases the overall mortality rate.^4,33–36

In people with homozygous factor V Leiden or with combined inherited thrombophilias, the risk of venous thromboembolism is increased to a greater degree: it is 20 to 50 times higher.^7,8,37–39 However, whether the risk of death is higher is not clear.

VENOUS THROMBOEMBOLISM IS MULTIFACTORIAL

The pathogenesis of venous thromboembolism is multifactorial and involves an interaction between inherited and acquired factors. Very often, people with factor V Leiden have additional risk factors that contribute to the development of venous clots, and it is very unusual for them to have thrombosis in the absence of these additional factors.

These factors include older age, surgery, obesity, prolonged travel, immobility, hospitalization, oral contraceptive use, hormonal replacement therapy, pregnancy, and malignancy. They increase the risk of venous thrombosis in normal individuals as well, but more so in people with factor V Leiden.^40–43

Testing for other known causes of thrombophilia may also be pursued. These include elevated homocysteine levels, the factor II (prothrombin) G20210A mutation, anticardiolipin antibody, lupus anticoagulant, and deficiencies of antithrombin III, protein C, and protein S.

Factor V Leiden by itself does not appear to increase the risk of arterial thrombosis, ie, heart attack and stroke.^{33,38,44–46}

Family history: A risk indicator for venous thrombosis

Family history is an important indicator of risk for a first venous thromboembolic event, regardless of other risk factors identified. The risk of a first event is two to three times higher in people with a family history of thrombosis in a first-degree relative. The risk is four times higher when multiple family members are affected, at least one of them before age 50.⁴⁷

In people with genetic thrombophilia, the risk of thrombosis (especially unprovoked thrombosis at a young age) is also higher in those with a strong family history than in those without a family history. In those with factor V Leiden, the risk of venous thromboembolism is three to four times higher if there is a positive family history. The risk is five times higher in carriers of factor V Leiden with a family history of venous thromboembolism before age 50, and 13 times higher in those with more than one affected family member.⁴⁷

Possible shared environmental factors or coinheritance of other unidentified genetic factors may also contribute to the higher susceptibility in thrombosis-prone families.

TESTING FOR APC RESISTANCE AND FACTOR V LEIDEN

The factor V Leiden mutation can be detected directly by genetic testing of peripheral blood mononuclear cells. This method is relatively time-consuming and expensive, however.

At present, the most cost-effective approach is to test first for APC resistance using a second-generation coagulation assay—the modified APC sensitivity test. In this clot-based method, the patient’s sample is prediluted with factor V-deficient plasma to eliminate the effect of lupus anticoagulants and factor deficiencies that could prolong the baseline clotting time, and heparin is inactivated by polybrene. Then either an augmented partial-thromboplastin-time-based assay or a tissue-factor-dependent factor V assay is performed.

This test is nearly 100% sensitive and specific for factor V Leiden, in contrast to the first-generation, or classic, APC sensitivity test, which lacked specificity and sensitivity for it.^{9–11,48–60} This modification also permits testing of patients receiving anticoagulants or who have abnormal augmented partial thromboplastin times due to coagulation factor deficiencies.

A positive result on the modified APC sensitivity test should be confirmed by a direct genetic test for the factor V Leiden mutation. An APC resistance assay is unnecessary if a direct genetic test is used initially.

 

HOW LONG TO GIVE ANTICOAGULATION AFTER VENOUS THROMBOEMBOLISM?

Patients who have had an episode of venous thromboembolism have to be treated with anticoagulants.

In general, the initial management of venous thromboembolism in patients with heritable thrombophilias is no different from that in any other patient with a clot. Anticoagulants such as warfarin are given at a target INR of 2.5 (range 2.0–3.0).³² The duration of treatment is based on the risk factors that resulted in the thrombotic event.

After a first event, some authorities recommend anticoagulant therapy for 6 months.³² A shorter period (3 months) is recommended if there is a transient risk factor (eg, surgery, oral contraceptive use, travel, pregnancy, the puerperium) and the thrombosis is confined to distal veins (eg, the calf veins).³²

Factor V Leiden does not necessarily increase the risk of recurrent events in patients who have a transient risk factor. Therefore, people who are heterozygous for this mutation do not usually need to be treated lifelong with anticoagulants if they have had only one episode of deep vein thrombosis or pulmonary embolism, given the risk of bleeding associated with anticoagulation, unless they have additional risk factors.

Conditions in which indefinite anticoagulation may be required after careful consideration of the risks and benefits are:

• Life-threatening events such as near-fatal pulmonary embolism
• Cerebral or visceral vein thrombosis
• Recurrent thrombotic events
• Additional persistent risk factors (eg, active malignant neoplasm, extremity paresis, and antiphospholipid antibodies)
• Combined thrombophilias (eg, combined heterozygosity for factor V Leiden and the prothrombin G20210A mutation)
• Homozygosity for factor V Leiden.^32,46,48

Factor V Leiden by itself or combined with other thrombophilic abnormalities is not associated with a higher risk of recurrent venous thromboembolism during warfarin therapy (a possible exception is the combination of factor V Leiden plus antiphospholipid antibodies).^32,34 Furthermore, current evidence suggests that no thrombophilic defect is a clinically important risk factor for recurrent venous thromboembolism after anticoagulant therapy is stopped. All these facts indicate that clinical factors are probably more important than laboratory abnormalities in determining the duration of anticoagulation therapy.^{32,35,36,61–63}

PRIMARY PROPHYLAXIS IN PATIENTS WITH FACTOR V LEIDEN

Factor V Leiden is only one of many risk factors for deep vein thrombosis or pulmonary embolism. If carriers of factor V Leiden have never had a blood clot, then they are not routinely treated with an anticoagulant. Rather, they should be counseled about reducing or eliminating other factors that may add to their risk of developing a clot in the future.

Usually, the effect of risk factors is additive: the more risk factors present, the higher the risk.^46,50 Sometimes, however, the effect of multiple risk factors is more than additive.

Some risk factors, such as genetics or age, are not alterable, but many can be controlled by medications or lifestyle modifications. Therefore, general measures and precautions are recommended to minimize the risk of thrombosis. For example:

Losing weight (if the patient is overweight) is an important intervention for risk reduction, since obesity is probably the most common modifiable risk factor for developing blood clots.

Avoiding long periods of immobility is recommended. For example, if the patient is taking a long car ride (more than 2 hours), then stopping every few hours and walking around for a few minutes is a good way to keep the blood circulating. If the patient has a desk job, getting up and walking around the office periodically is advised. On long airplane trips, a walk in the aisle every so often and preventing dehydration by drinking plenty of fluids and avoiding alcohol are recommended.

Wearing elastic stockings with a graduated elastic pressure may prevent deep venous thrombosis from developing on long flights.^63–65

Staying active and getting regular exercise through such activities as walking, bicycling, or swimming are helpful.

Avoiding smoking is critical.^50,63

Thromboprophylaxis is recommended for most acutely ill hospitalized patients, especially those confined to bed with additional risk factors. Guidelines for prophylaxis are based on an individualized risk assessment and not on thrombophilia status. Prophylactic anticoagulation is routinely recommended for patients undergoing major high-risk surgery, such as an orthopedic, urologic, gynecologic, or bariatric procedure. Any excess thrombotic risk conferred by thrombophilia is likely small compared with the risk of surgery, and recommendations on the duration and intensity of thromboprophylaxis are not based on thrombophilic status.^46,48

Education. Pain, swelling, redness of a limb, unexplained shortness of breath, and chest pain are the most common symptoms of deep vein thrombosis and pulmonary embolism.^46,50 It is crucial to teach patients with factor V Leiden to recognize these symptoms and to seek early medical attention in case they experience any of them.

SCREENING FAMILY MEMBERS FOR THE FACTOR V LEIDEN MUTATION

Factor V Leiden by itself is a relatively mild thrombophilic defect that does not cause thrombosis in all carriers, and there is no evidence that early diagnosis reduces rates of morbidity or mortality. Therefore, routine screening of all asymptomatic relatives of affected patients with venous thrombosis is not recommended. Rather, the decision to screen should be made on an individual basis.^50,66

Screening may be beneficial in selected cases, especially when patients have a strong family history of recurrent venous thrombosis at a young age (younger than 50 years) and the family member has additional risk factors for venous thromboembolism such as oral contraception or is planning for pregnancy.^32,48,49,66