BOSTON – When pancreatitis symptoms don’t resolve within a month, patients need some sort of surgical intervention, according to Steven Hughes, MD, FACS, professor and chief of surgical oncology at the University of Florida, Gainesville.

Pancreatitis management has been evolving in recent years. Prophylactic antibiotics and total parenteral nutrition are out; tube feeds are in, and there’s compelling evidence to take the gallbladder out, regardless of etiology, he said at the annual clinical congress of the American College of Surgeons.

However, too many patients get drains placed in the first 2 weeks; it’s the wrong move because it consigns to surgery a lot of patients who otherwise would have recovered on their own. “In the first 2 weeks, please do not place drains. Once you place the drain, you have committed the patient to a very different clinical course,” Dr. Hughes said.

Surgery generally comes a month or more after the initial presentation. Infection is inevitable at that point; the delay gives the lesion time to consolidate and wall itself off, making for a cleaner, safer operation.

Transgastric necrosectomy is the go-to when pancreatic lesions are toward the midline. It’s Dr. Hughes’s favored approach when the anatomy is appropriate; he shared his thoughts at the meeting.

Transgastric necrosectomy provides “single-stop shopping. You can get a thorough debridement in a single procedure,” and durable internal drainage. “Most importantly, from a patient’s perspective, it leaves them without external drains. You can transition a patient who’s been percutaneously drained to no external drainage at the time of this operation,” he said.

Additional pluses include cholecystectomy either before or after necrosectomy and the ability to place enteric feeding systems. “I like to use a combination G-J tube that allows drainage of the emptying stomach along with distal tube feeds,” he said.

Laparoscopic and endoscopic approaches are possible, but Dr. Hughes favors an open procedure “because the finger is the best debriding tool I have found.” There’s an anterior and then posterior gastric incision to dig out the necroma. The anterior incision is closed, but the posterior cut is sealed open to the necroma with a running hemostatic suture to allow for a “large cavity between the cavity and the stomach” for ongoing drainage.

“I have ultrasound on the field, but typically finding the necroma is like falling out of a canoe and finding water.” Even so, “I like to bring a 10-mm straight scope for direct viewing onto the field to explore the necrotic cavity and ensure I’ve done an adequate necrosectomy,” he said.

“I do think that this operation can be performed in patients who have some retrocolic extension even over into the pancreatic head and down the right paracolic gutter, but certainly if the collection extends down towards the pelvis, the notion that this is going to be adequate in and of itself requires further investigation,” he said.

In a cohort of 18 patients he and his colleagues followed for at least 2 years, “I was impressed that this operation is rather durable,” with rapid resolution of disease, Dr. Hughes said. Just a couple people needed additional operations. “The majority created persistent fistulas between the pancreatic body tail and the stomach.”

He cautioned that the procedure “is not for the faint of heart. The splenic vein and the splenic artery as well the celiac axis and portal vein are at risk during this procedure, and if you get into them, you have got a wolf by both ears. I would encourage you to consider referral for these patients.”

Dr. Hughes strongly encouraged surgeons to “ make sure your interventional radiologists and advanced endoscopists are on board, whether for the postop pseudoaneurysm bleeding or recurrent sepsis.”

Dr. Hughes had no relevant disclosures to report.

[email protected]

BOSTON – When pancreatitis symptoms don’t resolve within a month, patients need some sort of surgical intervention, according to Steven Hughes, MD, FACS, professor and chief of surgical oncology at the University of Florida, Gainesville.

Pancreatitis management has been evolving in recent years. Prophylactic antibiotics and total parenteral nutrition are out; tube feeds are in, and there’s compelling evidence to take the gallbladder out, regardless of etiology, he said at the annual clinical congress of the American College of Surgeons.

However, too many patients get drains placed in the first 2 weeks; it’s the wrong move because it consigns to surgery a lot of patients who otherwise would have recovered on their own. “In the first 2 weeks, please do not place drains. Once you place the drain, you have committed the patient to a very different clinical course,” Dr. Hughes said.

Surgery generally comes a month or more after the initial presentation. Infection is inevitable at that point; the delay gives the lesion time to consolidate and wall itself off, making for a cleaner, safer operation.

Transgastric necrosectomy is the go-to when pancreatic lesions are toward the midline. It’s Dr. Hughes’s favored approach when the anatomy is appropriate; he shared his thoughts at the meeting.

Transgastric necrosectomy provides “single-stop shopping. You can get a thorough debridement in a single procedure,” and durable internal drainage. “Most importantly, from a patient’s perspective, it leaves them without external drains. You can transition a patient who’s been percutaneously drained to no external drainage at the time of this operation,” he said.

Additional pluses include cholecystectomy either before or after necrosectomy and the ability to place enteric feeding systems. “I like to use a combination G-J tube that allows drainage of the emptying stomach along with distal tube feeds,” he said.

Laparoscopic and endoscopic approaches are possible, but Dr. Hughes favors an open procedure “because the finger is the best debriding tool I have found.” There’s an anterior and then posterior gastric incision to dig out the necroma. The anterior incision is closed, but the posterior cut is sealed open to the necroma with a running hemostatic suture to allow for a “large cavity between the cavity and the stomach” for ongoing drainage.

“I have ultrasound on the field, but typically finding the necroma is like falling out of a canoe and finding water.” Even so, “I like to bring a 10-mm straight scope for direct viewing onto the field to explore the necrotic cavity and ensure I’ve done an adequate necrosectomy,” he said.

“I do think that this operation can be performed in patients who have some retrocolic extension even over into the pancreatic head and down the right paracolic gutter, but certainly if the collection extends down towards the pelvis, the notion that this is going to be adequate in and of itself requires further investigation,” he said.

In a cohort of 18 patients he and his colleagues followed for at least 2 years, “I was impressed that this operation is rather durable,” with rapid resolution of disease, Dr. Hughes said. Just a couple people needed additional operations. “The majority created persistent fistulas between the pancreatic body tail and the stomach.”

He cautioned that the procedure “is not for the faint of heart. The splenic vein and the splenic artery as well the celiac axis and portal vein are at risk during this procedure, and if you get into them, you have got a wolf by both ears. I would encourage you to consider referral for these patients.”

Dr. Hughes strongly encouraged surgeons to “ make sure your interventional radiologists and advanced endoscopists are on board, whether for the postop pseudoaneurysm bleeding or recurrent sepsis.”

Dr. Hughes had no relevant disclosures to report.

[email protected]

BOSTON – When pancreatitis symptoms don’t resolve within a month, patients need some sort of surgical intervention, according to Steven Hughes, MD, FACS, professor and chief of surgical oncology at the University of Florida, Gainesville.

Pancreatitis management has been evolving in recent years. Prophylactic antibiotics and total parenteral nutrition are out; tube feeds are in, and there’s compelling evidence to take the gallbladder out, regardless of etiology, he said at the annual clinical congress of the American College of Surgeons.

However, too many patients get drains placed in the first 2 weeks; it’s the wrong move because it consigns to surgery a lot of patients who otherwise would have recovered on their own. “In the first 2 weeks, please do not place drains. Once you place the drain, you have committed the patient to a very different clinical course,” Dr. Hughes said.

Surgery generally comes a month or more after the initial presentation. Infection is inevitable at that point; the delay gives the lesion time to consolidate and wall itself off, making for a cleaner, safer operation.

Transgastric necrosectomy is the go-to when pancreatic lesions are toward the midline. It’s Dr. Hughes’s favored approach when the anatomy is appropriate; he shared his thoughts at the meeting.

Transgastric necrosectomy provides “single-stop shopping. You can get a thorough debridement in a single procedure,” and durable internal drainage. “Most importantly, from a patient’s perspective, it leaves them without external drains. You can transition a patient who’s been percutaneously drained to no external drainage at the time of this operation,” he said.

Additional pluses include cholecystectomy either before or after necrosectomy and the ability to place enteric feeding systems. “I like to use a combination G-J tube that allows drainage of the emptying stomach along with distal tube feeds,” he said.

Laparoscopic and endoscopic approaches are possible, but Dr. Hughes favors an open procedure “because the finger is the best debriding tool I have found.” There’s an anterior and then posterior gastric incision to dig out the necroma. The anterior incision is closed, but the posterior cut is sealed open to the necroma with a running hemostatic suture to allow for a “large cavity between the cavity and the stomach” for ongoing drainage.

“I have ultrasound on the field, but typically finding the necroma is like falling out of a canoe and finding water.” Even so, “I like to bring a 10-mm straight scope for direct viewing onto the field to explore the necrotic cavity and ensure I’ve done an adequate necrosectomy,” he said.

“I do think that this operation can be performed in patients who have some retrocolic extension even over into the pancreatic head and down the right paracolic gutter, but certainly if the collection extends down towards the pelvis, the notion that this is going to be adequate in and of itself requires further investigation,” he said.

In a cohort of 18 patients he and his colleagues followed for at least 2 years, “I was impressed that this operation is rather durable,” with rapid resolution of disease, Dr. Hughes said. Just a couple people needed additional operations. “The majority created persistent fistulas between the pancreatic body tail and the stomach.”

He cautioned that the procedure “is not for the faint of heart. The splenic vein and the splenic artery as well the celiac axis and portal vein are at risk during this procedure, and if you get into them, you have got a wolf by both ears. I would encourage you to consider referral for these patients.”

Dr. Hughes strongly encouraged surgeons to “ make sure your interventional radiologists and advanced endoscopists are on board, whether for the postop pseudoaneurysm bleeding or recurrent sepsis.”

Dr. Hughes had no relevant disclosures to report.

[email protected]

Neurologists can expect decreased reimbursement under a proposal by the Centers for Medicare & Medicaid Services that would change how the agency pays for evaluation and management services (E/M), according to an analysis published in JAMA Neurology.

Sripfoto/Thinkstock

The CMS recommendation, issued as part of the agency’s 2019 proposed Physician Fee Schedule, would collapse payments for new and established patients for office/outpatient E/M levels 2-5 (currently between $45 and $211) into single payments. The proposed single payments (return visits $93; new patients $135) are between current rates for levels 3-4. In its proposal, CMS officials said the change would improve payment accuracy and simplify documentation.

If approved, neurologists stand to lose the most money under the payment scheme since the majority of their Medicare payments stem from these services, while specialists who use the services less often would benefit from the modification. Specifically, neurologists would lose a median of $3,226 annually under the CMS proposal and cardiologists would lose a median of $3,203 per year, while dermatologists would gain an annual median of $16,655 and orthopedists would gain a median of $6,239, according to the study.

Lead author Brian C. Callaghan, MD, of the University of Michigan, Ann Arbor, and colleagues evaluated the 2013 Medicare Physician and Other Supplier File to determine the distribution of outpatient E/M codes for levels 2-5 used by different specialists and the proportion of total payments for all physician services attributable to these outpatient codes. Investigators estimated the financial impact of collapsed payments by calculating the difference of actual annual payments for outpatient E/M work and the projected annual payments with the proposed policy change.

Results showed that in 2013 the proportion of outpatient E/M codes billed at levels 4-5 varied widely by specialty. Neurologists for example, billed 70% of their outpatient physician E/M codes under levels 4-5, the highest of any specialty. Cardiologists were also high utilizers of the codes with 65% of their outpatient E/M codes falling between levels 4 and 5. The lowest users for levels 4-5 were dermatologists (11%), orthopedists (22%), and otolaryngologists (25%). Taking into account the distribution and volumes of E/M services, the investigators concluded that CMS’ proposed payment change would be most favorable for surgical specialists, neutral for generalists, and most unfavorable for neurologists.

Dr. Callaghan and colleagues wrote that collapsing E/M payments would likely incentivize all physicians to shorten visit times, which could negatively impact doctor-patient relationships and patient care.

“Given that longer visit times are associated with higher patient satisfaction and important elements of care, the CMS proposal would likely have negative consequence,” Dr. Callaghan and his coauthors wrote. “Current E/M payments strongly undervalue the cognitive work of physicians, compared with procedural-based payments. Based on our data, the recent proposal to collapse E/M payment levels would further undervalue these important services, particularly for neurologists.”

The authors reported receiving grants and fees from organizations, companies, and government agencies outside the published study.

SOURCE: Callaghan B et al. JAMA Neurol. 2018 Oct 31. doi: 10.1001/jamaneurol.2018.3794.

Neurologists can expect decreased reimbursement under a proposal by the Centers for Medicare & Medicaid Services that would change how the agency pays for evaluation and management services (E/M), according to an analysis published in JAMA Neurology.

Sripfoto/Thinkstock

The CMS recommendation, issued as part of the agency’s 2019 proposed Physician Fee Schedule, would collapse payments for new and established patients for office/outpatient E/M levels 2-5 (currently between $45 and $211) into single payments. The proposed single payments (return visits $93; new patients $135) are between current rates for levels 3-4. In its proposal, CMS officials said the change would improve payment accuracy and simplify documentation.

If approved, neurologists stand to lose the most money under the payment scheme since the majority of their Medicare payments stem from these services, while specialists who use the services less often would benefit from the modification. Specifically, neurologists would lose a median of $3,226 annually under the CMS proposal and cardiologists would lose a median of $3,203 per year, while dermatologists would gain an annual median of $16,655 and orthopedists would gain a median of $6,239, according to the study.

Lead author Brian C. Callaghan, MD, of the University of Michigan, Ann Arbor, and colleagues evaluated the 2013 Medicare Physician and Other Supplier File to determine the distribution of outpatient E/M codes for levels 2-5 used by different specialists and the proportion of total payments for all physician services attributable to these outpatient codes. Investigators estimated the financial impact of collapsed payments by calculating the difference of actual annual payments for outpatient E/M work and the projected annual payments with the proposed policy change.

Results showed that in 2013 the proportion of outpatient E/M codes billed at levels 4-5 varied widely by specialty. Neurologists for example, billed 70% of their outpatient physician E/M codes under levels 4-5, the highest of any specialty. Cardiologists were also high utilizers of the codes with 65% of their outpatient E/M codes falling between levels 4 and 5. The lowest users for levels 4-5 were dermatologists (11%), orthopedists (22%), and otolaryngologists (25%). Taking into account the distribution and volumes of E/M services, the investigators concluded that CMS’ proposed payment change would be most favorable for surgical specialists, neutral for generalists, and most unfavorable for neurologists.

Dr. Callaghan and colleagues wrote that collapsing E/M payments would likely incentivize all physicians to shorten visit times, which could negatively impact doctor-patient relationships and patient care.

“Given that longer visit times are associated with higher patient satisfaction and important elements of care, the CMS proposal would likely have negative consequence,” Dr. Callaghan and his coauthors wrote. “Current E/M payments strongly undervalue the cognitive work of physicians, compared with procedural-based payments. Based on our data, the recent proposal to collapse E/M payment levels would further undervalue these important services, particularly for neurologists.”

The authors reported receiving grants and fees from organizations, companies, and government agencies outside the published study.

SOURCE: Callaghan B et al. JAMA Neurol. 2018 Oct 31. doi: 10.1001/jamaneurol.2018.3794.

Neurologists can expect decreased reimbursement under a proposal by the Centers for Medicare & Medicaid Services that would change how the agency pays for evaluation and management services (E/M), according to an analysis published in JAMA Neurology.

Sripfoto/Thinkstock

The CMS recommendation, issued as part of the agency’s 2019 proposed Physician Fee Schedule, would collapse payments for new and established patients for office/outpatient E/M levels 2-5 (currently between $45 and $211) into single payments. The proposed single payments (return visits $93; new patients $135) are between current rates for levels 3-4. In its proposal, CMS officials said the change would improve payment accuracy and simplify documentation.

If approved, neurologists stand to lose the most money under the payment scheme since the majority of their Medicare payments stem from these services, while specialists who use the services less often would benefit from the modification. Specifically, neurologists would lose a median of $3,226 annually under the CMS proposal and cardiologists would lose a median of $3,203 per year, while dermatologists would gain an annual median of $16,655 and orthopedists would gain a median of $6,239, according to the study.

Lead author Brian C. Callaghan, MD, of the University of Michigan, Ann Arbor, and colleagues evaluated the 2013 Medicare Physician and Other Supplier File to determine the distribution of outpatient E/M codes for levels 2-5 used by different specialists and the proportion of total payments for all physician services attributable to these outpatient codes. Investigators estimated the financial impact of collapsed payments by calculating the difference of actual annual payments for outpatient E/M work and the projected annual payments with the proposed policy change.

Results showed that in 2013 the proportion of outpatient E/M codes billed at levels 4-5 varied widely by specialty. Neurologists for example, billed 70% of their outpatient physician E/M codes under levels 4-5, the highest of any specialty. Cardiologists were also high utilizers of the codes with 65% of their outpatient E/M codes falling between levels 4 and 5. The lowest users for levels 4-5 were dermatologists (11%), orthopedists (22%), and otolaryngologists (25%). Taking into account the distribution and volumes of E/M services, the investigators concluded that CMS’ proposed payment change would be most favorable for surgical specialists, neutral for generalists, and most unfavorable for neurologists.

Dr. Callaghan and colleagues wrote that collapsing E/M payments would likely incentivize all physicians to shorten visit times, which could negatively impact doctor-patient relationships and patient care.

“Given that longer visit times are associated with higher patient satisfaction and important elements of care, the CMS proposal would likely have negative consequence,” Dr. Callaghan and his coauthors wrote. “Current E/M payments strongly undervalue the cognitive work of physicians, compared with procedural-based payments. Based on our data, the recent proposal to collapse E/M payment levels would further undervalue these important services, particularly for neurologists.”

The authors reported receiving grants and fees from organizations, companies, and government agencies outside the published study.

SOURCE: Callaghan B et al. JAMA Neurol. 2018 Oct 31. doi: 10.1001/jamaneurol.2018.3794.

Hand-foot-and-mouth disease (HFMD) is a viral illness caused by several enteroviruses, most commonly coxsackievirus A16 (CVA16) and enterovirus 71 (EV71). The disease is generally seen in children younger than 5 years, characterized by lesions of the oral mucosa, palms, and soles, usually lasting 7 to 10 days. Other coxsackie type A viruses, including CVA6, CVA9, and CVA10, also are associated with HFMD.^1-5 Although CVA16 has traditionally been the primary strain causing HFMD, CVA6 has become a major cause of HFMD outbreaks in the United States and worldwide in recent years.^6-12 Interestingly, CVA6 also has been found to be associated with adult HFMD, which has increased in incidence. The CVA6 strain was first identified in association with the disease during HFMD outbreaks in Finland and Singapore in 2008,^13,14 with similar strains detected in subsequent outbreaks in Taiwan, Japan, Spain, France, China, India, and the United States.^12,15-25 Most cases took place in warmer months, with one winter outbreak in Massachusetts in 2012.²⁴

Herein, we review the incidence of CVA6, as well as its atypical presentation, diagnosis, and treatment to aid dermatologists. Given the increasing incidence of HFMD caused by CVA6 and its often atypical presentation, it is important for dermatologists to be aware of this increasingly notable disease state and its viral cause.

Incidence of CVA6

Coxsackievirus A6 has been identified as the cause of many reported outbreaks of HFMD since it was first identified in 2008, and it is known to cause both pediatric and adult outbreaks.^7-12 It may even be surpassing other strains in frequency in certain areas. In Tianjin, China, for example, EV71 and CVA16 were the most common serotypes causing HFMD from 2008 to 2012; however, in 2013, CVA6 was the most prevalent strain.²⁶ According to one study, “[n]early every Chinese city showed a sharp rise in [CVA6].”²⁷

The incidence of CVA6 also has been increasing in other areas.²⁸ In Spain, CVA6 overtook CVA16 as the dominant cause of HFMD during 2011 and 2012 outbreaks.²⁹ From 2011 to 2012, there was a CVA6-associated HFMD outbreak in North America, with 63 cases reported to the Centers for Disease Control and Prevention (CDC), including 15 adult cases, with approximately 50% having been exposed to children with HFMD.⁹ In 2014, a Minnesota college with approximately 1000 students reported 9 suspected cases of HFMD to the Minnesota Department of Health. Coxsackievirus A6 was isolated, sequenced, and identified by the CDC in 5 of 9 patients (age range, 19–47 years).⁹

In 2015, an outbreak of HFMD took place at Lackland Air Force Base in Texas during a basic military training. Eight cases were confirmed and 45 cases were suspected. The rate of infection was 0.4% (50/12,270) among trainees and 0.3% (2/602) among instructors.⁷ Eight of 12 nasopharyngeal swabs tested positive for EV by way of local real-time reverse transcription–polymerase chain reaction (RT-PCR). Four nasopharyngeal swabs were sent to the CDC for evaluation and all were positive for CVA6.⁷

Presentation

Because the prevalence of CVA6 has increased, it is important to be able to identify the presentation of HFMD caused by this strain. Coxsackievirus A6 has been found to affect a broader demographic and cause more severe cases of HFMD with its unique constellation of findings compared to other known strains. Patients present with flulike symptoms; higher fever than present in typical HFMD; and a longer duration of disease, typically lasting 2 weeks. Patients also may present with more severe skin disease compared to classic HFMD, not only including vesicles but also large bullae, erosions, and ulcers on the dorsal and plantar feet (Figure 1). Skin lesions often are painful and spread to a wider distribution than typical of HFMD, which can include the face, proximal extremities, lips, perianal and groin skin, scalp, and dorsal feet and hands (Figure 2). These areas are classically spared in the prototypical presentation of HFMD in children.^2,6,24,30-33 Vesicles that are typically football shaped (Figure 3) are a diagnostic clue of the disease. After patients have recovered from the disease, they can have delayed-onset palmar and plantar desquamation that usually presents 1 to 3 weeks after the disease. Additionally, another postsyndrome finding is onychomadesis, or detachment of the nail plate from the nail matrix.^6,34-37 This process likely occurs due to direct cytopathic effect to the nail matrix from the viral infection.^24,37 Blistering may be severe and can form hemorrhagic bullae.²⁴ Although cutaneous findings are more severe, neurologic involvement actually is more rare in the CVA6 strain compared to other viral strains known to cause HFMD, specifically EV71. One study found only 2.4% of 141 patients infected with CVA6 had central nervous system involvement, specifically aseptic meningitis or encephalitis.^21,24

Photograph courtesy of Lauren Snitzer, MD (Houston, Texas).

Photograph courtesy of Lauren Snitzer, MD (Houston, Texas).

Photograph courtesy of Lauren Snitzer, MD (Houston, Texas).

In patients with atopic dermatitis, CVA6 also shows a predilection to appear in areas of skin disease, such as the flexural regions of the arms and legs, and is referred to as eczema coxsackium.^24,38,39 It can mimic eczema herpeticum or varicella superinfection, which are important considerations to include in the differential diagnosis. Additionally, CVA6-induced lesions often show up in previously irritated or traumatized areas such as sunburns, fungal infections, and diaper dermatitis in children. Lesions have been described to sometimes mimic Gianotti-Crosti syndrome, with involvement of the extensor surfaces, buttocks, and cheeks, and sparing of the trunk.²⁴

Clinical Diagnosis

Because HFMD is uncommon and atypical in adults, skin biopsies may be used in the initial workup and evaluation of patients. It is important to understand the histologic features associated with HFMD, including spongiosis with exocytosis of neutrophils as well as keratinocyte necrosis and pallor with associated shadow cells.⁶ In one series, the most extensively involved areas of keratinocyte necrosis were the stratum granulosum and upper half of the stratum spinosum.⁴⁰ In the dermis, vascular involvement may be present on a spectrum with the extravasation of red blood cells and leukocytoclasis or true leukocytoclastic vasculitis.^6,40 Vesicular lesions show severe dermal edema and inflammatory infiltrate.^6,41 CD3⁺ and CD8⁺ lymphocytes predominate. Cytotoxic T lymphocytes are present and express granzyme B and granulysin, both important mediators of apoptosis in virally infected keratinocytes.⁶

Adult HFMD primarily is a clinical diagnosis, and histopathologic analysis can be a useful tool in certain cases. Coxsackievirus A6 does not grow well on culture and is not detected by standard serologic testing laboratories, necessitating the use of quantitative RT-PCR analysis.^41,42 In one study, culture was able to detect only 14% to 16% of samples that tested positive by quantitative RT-PCR.⁴³ This form of PCR identifies viral subtype through amplification of enterovirus viral protein 1 capsid gene sequence.²⁴ Unfortunately, this testing often is not offered in most readily available laboratories and often necessitates being sent out to more well-equipped laboratories.^2,24

Treatment

Hand-foot-and-mouth disease is a self-limited illness and requires only supportive care with a focus on hydration and pain management. Lesions heal without scarring but may leave notable postinflammatory pigment alteration that may last months to years, depending on extent of disease and skin type. Secondarily infected individuals should be treated with appropriate antibiotics or antivirals depending on the infectious agent. Hand hygiene is of great importance, and hospitalized patients should be put on strict contact precautions. It also is important to isolate patients from vulnerable individuals, especially pregnant women, as coxsackievirus has been linked to intrauterine infections and loss of pregnancy.²⁴

Genetic Analysis

Genetic studies of the virus have suggested that nonstructural genes may be playing an interesting role in clinical phenotypes and outcomes of CVA6 infection.⁴⁴ These genetic studies also are being implemented into the understanding of the virus’ evolution as well as the construction of vaccinations.^27,44

Conclusion

With the increasing prevalence of CVA6-associated HFMD, it is important to understand the clinical presentation and histologic findings associated with this atypical presentation of the disease as well as the changing epidemiology of the viral strains causing HFMD.

Hand-foot-and-mouth disease (HFMD) is a viral illness caused by several enteroviruses, most commonly coxsackievirus A16 (CVA16) and enterovirus 71 (EV71). The disease is generally seen in children younger than 5 years, characterized by lesions of the oral mucosa, palms, and soles, usually lasting 7 to 10 days. Other coxsackie type A viruses, including CVA6, CVA9, and CVA10, also are associated with HFMD.^1-5 Although CVA16 has traditionally been the primary strain causing HFMD, CVA6 has become a major cause of HFMD outbreaks in the United States and worldwide in recent years.^6-12 Interestingly, CVA6 also has been found to be associated with adult HFMD, which has increased in incidence. The CVA6 strain was first identified in association with the disease during HFMD outbreaks in Finland and Singapore in 2008,^13,14 with similar strains detected in subsequent outbreaks in Taiwan, Japan, Spain, France, China, India, and the United States.^12,15-25 Most cases took place in warmer months, with one winter outbreak in Massachusetts in 2012.²⁴

Herein, we review the incidence of CVA6, as well as its atypical presentation, diagnosis, and treatment to aid dermatologists. Given the increasing incidence of HFMD caused by CVA6 and its often atypical presentation, it is important for dermatologists to be aware of this increasingly notable disease state and its viral cause.

Incidence of CVA6

Coxsackievirus A6 has been identified as the cause of many reported outbreaks of HFMD since it was first identified in 2008, and it is known to cause both pediatric and adult outbreaks.^7-12 It may even be surpassing other strains in frequency in certain areas. In Tianjin, China, for example, EV71 and CVA16 were the most common serotypes causing HFMD from 2008 to 2012; however, in 2013, CVA6 was the most prevalent strain.²⁶ According to one study, “[n]early every Chinese city showed a sharp rise in [CVA6].”²⁷

The incidence of CVA6 also has been increasing in other areas.²⁸ In Spain, CVA6 overtook CVA16 as the dominant cause of HFMD during 2011 and 2012 outbreaks.²⁹ From 2011 to 2012, there was a CVA6-associated HFMD outbreak in North America, with 63 cases reported to the Centers for Disease Control and Prevention (CDC), including 15 adult cases, with approximately 50% having been exposed to children with HFMD.⁹ In 2014, a Minnesota college with approximately 1000 students reported 9 suspected cases of HFMD to the Minnesota Department of Health. Coxsackievirus A6 was isolated, sequenced, and identified by the CDC in 5 of 9 patients (age range, 19–47 years).⁹

In 2015, an outbreak of HFMD took place at Lackland Air Force Base in Texas during a basic military training. Eight cases were confirmed and 45 cases were suspected. The rate of infection was 0.4% (50/12,270) among trainees and 0.3% (2/602) among instructors.⁷ Eight of 12 nasopharyngeal swabs tested positive for EV by way of local real-time reverse transcription–polymerase chain reaction (RT-PCR). Four nasopharyngeal swabs were sent to the CDC for evaluation and all were positive for CVA6.⁷

Presentation

Because the prevalence of CVA6 has increased, it is important to be able to identify the presentation of HFMD caused by this strain. Coxsackievirus A6 has been found to affect a broader demographic and cause more severe cases of HFMD with its unique constellation of findings compared to other known strains. Patients present with flulike symptoms; higher fever than present in typical HFMD; and a longer duration of disease, typically lasting 2 weeks. Patients also may present with more severe skin disease compared to classic HFMD, not only including vesicles but also large bullae, erosions, and ulcers on the dorsal and plantar feet (Figure 1). Skin lesions often are painful and spread to a wider distribution than typical of HFMD, which can include the face, proximal extremities, lips, perianal and groin skin, scalp, and dorsal feet and hands (Figure 2). These areas are classically spared in the prototypical presentation of HFMD in children.^2,6,24,30-33 Vesicles that are typically football shaped (Figure 3) are a diagnostic clue of the disease. After patients have recovered from the disease, they can have delayed-onset palmar and plantar desquamation that usually presents 1 to 3 weeks after the disease. Additionally, another postsyndrome finding is onychomadesis, or detachment of the nail plate from the nail matrix.^6,34-37 This process likely occurs due to direct cytopathic effect to the nail matrix from the viral infection.^24,37 Blistering may be severe and can form hemorrhagic bullae.²⁴ Although cutaneous findings are more severe, neurologic involvement actually is more rare in the CVA6 strain compared to other viral strains known to cause HFMD, specifically EV71. One study found only 2.4% of 141 patients infected with CVA6 had central nervous system involvement, specifically aseptic meningitis or encephalitis.^21,24

Photograph courtesy of Lauren Snitzer, MD (Houston, Texas).

Photograph courtesy of Lauren Snitzer, MD (Houston, Texas).

Photograph courtesy of Lauren Snitzer, MD (Houston, Texas).

In patients with atopic dermatitis, CVA6 also shows a predilection to appear in areas of skin disease, such as the flexural regions of the arms and legs, and is referred to as eczema coxsackium.^24,38,39 It can mimic eczema herpeticum or varicella superinfection, which are important considerations to include in the differential diagnosis. Additionally, CVA6-induced lesions often show up in previously irritated or traumatized areas such as sunburns, fungal infections, and diaper dermatitis in children. Lesions have been described to sometimes mimic Gianotti-Crosti syndrome, with involvement of the extensor surfaces, buttocks, and cheeks, and sparing of the trunk.²⁴

Clinical Diagnosis

Because HFMD is uncommon and atypical in adults, skin biopsies may be used in the initial workup and evaluation of patients. It is important to understand the histologic features associated with HFMD, including spongiosis with exocytosis of neutrophils as well as keratinocyte necrosis and pallor with associated shadow cells.⁶ In one series, the most extensively involved areas of keratinocyte necrosis were the stratum granulosum and upper half of the stratum spinosum.⁴⁰ In the dermis, vascular involvement may be present on a spectrum with the extravasation of red blood cells and leukocytoclasis or true leukocytoclastic vasculitis.^6,40 Vesicular lesions show severe dermal edema and inflammatory infiltrate.^6,41 CD3⁺ and CD8⁺ lymphocytes predominate. Cytotoxic T lymphocytes are present and express granzyme B and granulysin, both important mediators of apoptosis in virally infected keratinocytes.⁶

Adult HFMD primarily is a clinical diagnosis, and histopathologic analysis can be a useful tool in certain cases. Coxsackievirus A6 does not grow well on culture and is not detected by standard serologic testing laboratories, necessitating the use of quantitative RT-PCR analysis.^41,42 In one study, culture was able to detect only 14% to 16% of samples that tested positive by quantitative RT-PCR.⁴³ This form of PCR identifies viral subtype through amplification of enterovirus viral protein 1 capsid gene sequence.²⁴ Unfortunately, this testing often is not offered in most readily available laboratories and often necessitates being sent out to more well-equipped laboratories.^2,24

Treatment

Hand-foot-and-mouth disease is a self-limited illness and requires only supportive care with a focus on hydration and pain management. Lesions heal without scarring but may leave notable postinflammatory pigment alteration that may last months to years, depending on extent of disease and skin type. Secondarily infected individuals should be treated with appropriate antibiotics or antivirals depending on the infectious agent. Hand hygiene is of great importance, and hospitalized patients should be put on strict contact precautions. It also is important to isolate patients from vulnerable individuals, especially pregnant women, as coxsackievirus has been linked to intrauterine infections and loss of pregnancy.²⁴

Genetic Analysis

Genetic studies of the virus have suggested that nonstructural genes may be playing an interesting role in clinical phenotypes and outcomes of CVA6 infection.⁴⁴ These genetic studies also are being implemented into the understanding of the virus’ evolution as well as the construction of vaccinations.^27,44

Conclusion

With the increasing prevalence of CVA6-associated HFMD, it is important to understand the clinical presentation and histologic findings associated with this atypical presentation of the disease as well as the changing epidemiology of the viral strains causing HFMD.

Hand-foot-and-mouth disease (HFMD) is a viral illness caused by several enteroviruses, most commonly coxsackievirus A16 (CVA16) and enterovirus 71 (EV71). The disease is generally seen in children younger than 5 years, characterized by lesions of the oral mucosa, palms, and soles, usually lasting 7 to 10 days. Other coxsackie type A viruses, including CVA6, CVA9, and CVA10, also are associated with HFMD.^1-5 Although CVA16 has traditionally been the primary strain causing HFMD, CVA6 has become a major cause of HFMD outbreaks in the United States and worldwide in recent years.^6-12 Interestingly, CVA6 also has been found to be associated with adult HFMD, which has increased in incidence. The CVA6 strain was first identified in association with the disease during HFMD outbreaks in Finland and Singapore in 2008,^13,14 with similar strains detected in subsequent outbreaks in Taiwan, Japan, Spain, France, China, India, and the United States.^12,15-25 Most cases took place in warmer months, with one winter outbreak in Massachusetts in 2012.²⁴

Herein, we review the incidence of CVA6, as well as its atypical presentation, diagnosis, and treatment to aid dermatologists. Given the increasing incidence of HFMD caused by CVA6 and its often atypical presentation, it is important for dermatologists to be aware of this increasingly notable disease state and its viral cause.

Incidence of CVA6

Coxsackievirus A6 has been identified as the cause of many reported outbreaks of HFMD since it was first identified in 2008, and it is known to cause both pediatric and adult outbreaks.^7-12 It may even be surpassing other strains in frequency in certain areas. In Tianjin, China, for example, EV71 and CVA16 were the most common serotypes causing HFMD from 2008 to 2012; however, in 2013, CVA6 was the most prevalent strain.²⁶ According to one study, “[n]early every Chinese city showed a sharp rise in [CVA6].”²⁷

The incidence of CVA6 also has been increasing in other areas.²⁸ In Spain, CVA6 overtook CVA16 as the dominant cause of HFMD during 2011 and 2012 outbreaks.²⁹ From 2011 to 2012, there was a CVA6-associated HFMD outbreak in North America, with 63 cases reported to the Centers for Disease Control and Prevention (CDC), including 15 adult cases, with approximately 50% having been exposed to children with HFMD.⁹ In 2014, a Minnesota college with approximately 1000 students reported 9 suspected cases of HFMD to the Minnesota Department of Health. Coxsackievirus A6 was isolated, sequenced, and identified by the CDC in 5 of 9 patients (age range, 19–47 years).⁹

In 2015, an outbreak of HFMD took place at Lackland Air Force Base in Texas during a basic military training. Eight cases were confirmed and 45 cases were suspected. The rate of infection was 0.4% (50/12,270) among trainees and 0.3% (2/602) among instructors.⁷ Eight of 12 nasopharyngeal swabs tested positive for EV by way of local real-time reverse transcription–polymerase chain reaction (RT-PCR). Four nasopharyngeal swabs were sent to the CDC for evaluation and all were positive for CVA6.⁷

Presentation

Because the prevalence of CVA6 has increased, it is important to be able to identify the presentation of HFMD caused by this strain. Coxsackievirus A6 has been found to affect a broader demographic and cause more severe cases of HFMD with its unique constellation of findings compared to other known strains. Patients present with flulike symptoms; higher fever than present in typical HFMD; and a longer duration of disease, typically lasting 2 weeks. Patients also may present with more severe skin disease compared to classic HFMD, not only including vesicles but also large bullae, erosions, and ulcers on the dorsal and plantar feet (Figure 1). Skin lesions often are painful and spread to a wider distribution than typical of HFMD, which can include the face, proximal extremities, lips, perianal and groin skin, scalp, and dorsal feet and hands (Figure 2). These areas are classically spared in the prototypical presentation of HFMD in children.^2,6,24,30-33 Vesicles that are typically football shaped (Figure 3) are a diagnostic clue of the disease. After patients have recovered from the disease, they can have delayed-onset palmar and plantar desquamation that usually presents 1 to 3 weeks after the disease. Additionally, another postsyndrome finding is onychomadesis, or detachment of the nail plate from the nail matrix.^6,34-37 This process likely occurs due to direct cytopathic effect to the nail matrix from the viral infection.^24,37 Blistering may be severe and can form hemorrhagic bullae.²⁴ Although cutaneous findings are more severe, neurologic involvement actually is more rare in the CVA6 strain compared to other viral strains known to cause HFMD, specifically EV71. One study found only 2.4% of 141 patients infected with CVA6 had central nervous system involvement, specifically aseptic meningitis or encephalitis.^21,24

Photograph courtesy of Lauren Snitzer, MD (Houston, Texas).

Photograph courtesy of Lauren Snitzer, MD (Houston, Texas).

Photograph courtesy of Lauren Snitzer, MD (Houston, Texas).

In patients with atopic dermatitis, CVA6 also shows a predilection to appear in areas of skin disease, such as the flexural regions of the arms and legs, and is referred to as eczema coxsackium.^24,38,39 It can mimic eczema herpeticum or varicella superinfection, which are important considerations to include in the differential diagnosis. Additionally, CVA6-induced lesions often show up in previously irritated or traumatized areas such as sunburns, fungal infections, and diaper dermatitis in children. Lesions have been described to sometimes mimic Gianotti-Crosti syndrome, with involvement of the extensor surfaces, buttocks, and cheeks, and sparing of the trunk.²⁴

Clinical Diagnosis

Because HFMD is uncommon and atypical in adults, skin biopsies may be used in the initial workup and evaluation of patients. It is important to understand the histologic features associated with HFMD, including spongiosis with exocytosis of neutrophils as well as keratinocyte necrosis and pallor with associated shadow cells.⁶ In one series, the most extensively involved areas of keratinocyte necrosis were the stratum granulosum and upper half of the stratum spinosum.⁴⁰ In the dermis, vascular involvement may be present on a spectrum with the extravasation of red blood cells and leukocytoclasis or true leukocytoclastic vasculitis.^6,40 Vesicular lesions show severe dermal edema and inflammatory infiltrate.^6,41 CD3⁺ and CD8⁺ lymphocytes predominate. Cytotoxic T lymphocytes are present and express granzyme B and granulysin, both important mediators of apoptosis in virally infected keratinocytes.⁶

Adult HFMD primarily is a clinical diagnosis, and histopathologic analysis can be a useful tool in certain cases. Coxsackievirus A6 does not grow well on culture and is not detected by standard serologic testing laboratories, necessitating the use of quantitative RT-PCR analysis.^41,42 In one study, culture was able to detect only 14% to 16% of samples that tested positive by quantitative RT-PCR.⁴³ This form of PCR identifies viral subtype through amplification of enterovirus viral protein 1 capsid gene sequence.²⁴ Unfortunately, this testing often is not offered in most readily available laboratories and often necessitates being sent out to more well-equipped laboratories.^2,24

Treatment

Hand-foot-and-mouth disease is a self-limited illness and requires only supportive care with a focus on hydration and pain management. Lesions heal without scarring but may leave notable postinflammatory pigment alteration that may last months to years, depending on extent of disease and skin type. Secondarily infected individuals should be treated with appropriate antibiotics or antivirals depending on the infectious agent. Hand hygiene is of great importance, and hospitalized patients should be put on strict contact precautions. It also is important to isolate patients from vulnerable individuals, especially pregnant women, as coxsackievirus has been linked to intrauterine infections and loss of pregnancy.²⁴

Genetic Analysis

Genetic studies of the virus have suggested that nonstructural genes may be playing an interesting role in clinical phenotypes and outcomes of CVA6 infection.⁴⁴ These genetic studies also are being implemented into the understanding of the virus’ evolution as well as the construction of vaccinations.^27,44

Conclusion

With the increasing prevalence of CVA6-associated HFMD, it is important to understand the clinical presentation and histologic findings associated with this atypical presentation of the disease as well as the changing epidemiology of the viral strains causing HFMD.

I have written previously about Current Procedural Terminology (CPT) procedure codes submitted on the same date of service as evaluation and management (E/M) services in the context of modifier -25.¹ Billing same-day procedures and E/M services is under close scrutiny by insurers, and accurate and complete documentation is a must.² An understanding of what aspects of evaluation are included in the global surgical package is critical in deciding whether a separate and distinct same-day evaluation was performed. In general, the decision to perform a procedure is included in the payment for the procedure itself, as is the examination of the body site in question, diagnosis of the medical condition, discussion of treatment options, and postoperative services related to the procedure. This is true for CPT codes that contain physician work, which constitute the majority of CPT codes reported by dermatologists.³

However, there is one set of codes where these principles do not apply: the practice expense (PE)–only codes, or no physician work codes. These codes are defined by CPT and the Relative Value Scale Update Committee (RUC) of the American Medical Association as containing no physician work. Their valuations are based only on staff/nursing time and the other aspects of direct and indirect practice costs included in providing the service, such as gauze, sutures, equipment, office rent, and utilities.⁴ Examples of PE-only codes include the nonphysician-performed photodynamic therapy code 96567; phototherapy codes 96900, 96910, and 96912; and patch testing and photopatch testing codes 95044, 95052, and 95056.

For PE-only codes, only the provision of the service by staff is included in the code reimbursement; there is no physician time or work built into these codes. Thus, neither the initial evaluation of the patient by the physician, the decision to perform the procedure, nor the evaluation of therapy effectiveness or side effects or interpretation of the results is included. Understanding that there is no physician involvement in PE-only codes is critical in deciding whether an E/M service should be billed on the same day as a PE-only code. To that end, although a physician does not actually have to personally evaluate the patient on the day of service to bill PE-only codes, the Centers for Medicare & Medicaid Services has indicated that a physician or qualified medical provider must be on premises.⁵ Billing for PE-only services when no provider is present will be interpreted as a false claim or fraudulent billing practice.

Because PE-only codes do not include physician work, an E/M service will be billed in addition to the treatment almost any time a same-day physician evaluation is performed. For example, if a patient presents with a changing mole that is evaluated on the same date of service as phototherapy for the treatment of psoriasis, that service is clearly reportable with an E/M code because the mole check is separate and distinct from the phototherapy treatment. A more common scenario is for the physician to see a patient with a rash consistent with an allergic contact dermatitis and the decision to perform same-day patch testing is made. In this circumstance, the E/M service is still reportable because the evaluation of the rash and the decision to perform patch testing are not included in this PE-only code.

Phototherapy typically is provided as a prolonged course of multiple treatments, and reporting of same-day E/M services during the course of therapy is common. Phototherapy must be monitored by the physician for clinical effectiveness, dose changes, and side effects, as well as to determine whether to continue therapy. A standard operating procedure should be created to document that the physician typically evaluates the patient’s progress at set intervals or as dictated by patient or staff concerns. Reporting an E/M service with every phototherapy session is not considered medically necessary. Moreover, a nurse evaluation of the patient prior to each phototherapy treatment, including questions on disease severity, how the patient did with the last treatment, and whether medications have changed, is included in the payment for the phototherapy codes. Only formal and medically necessary physician E/M services should be billed, not drive-by visits in which the physician pops in just to see how the patient is doing.

Final Thoughts

Practice expense–only codes include no payment for physician time or work but require the presence of a qualified health care provider on premises to bill. Medically necessary physician evaluations on the same day as PE-only services will typically result in both an E/M service and the procedure being reported. Understanding performance and documentation requirements of PE-only codes is critical for proper reimbursement for a dermatology practice.

I have written previously about Current Procedural Terminology (CPT) procedure codes submitted on the same date of service as evaluation and management (E/M) services in the context of modifier -25.¹ Billing same-day procedures and E/M services is under close scrutiny by insurers, and accurate and complete documentation is a must.² An understanding of what aspects of evaluation are included in the global surgical package is critical in deciding whether a separate and distinct same-day evaluation was performed. In general, the decision to perform a procedure is included in the payment for the procedure itself, as is the examination of the body site in question, diagnosis of the medical condition, discussion of treatment options, and postoperative services related to the procedure. This is true for CPT codes that contain physician work, which constitute the majority of CPT codes reported by dermatologists.³

However, there is one set of codes where these principles do not apply: the practice expense (PE)–only codes, or no physician work codes. These codes are defined by CPT and the Relative Value Scale Update Committee (RUC) of the American Medical Association as containing no physician work. Their valuations are based only on staff/nursing time and the other aspects of direct and indirect practice costs included in providing the service, such as gauze, sutures, equipment, office rent, and utilities.⁴ Examples of PE-only codes include the nonphysician-performed photodynamic therapy code 96567; phototherapy codes 96900, 96910, and 96912; and patch testing and photopatch testing codes 95044, 95052, and 95056.

For PE-only codes, only the provision of the service by staff is included in the code reimbursement; there is no physician time or work built into these codes. Thus, neither the initial evaluation of the patient by the physician, the decision to perform the procedure, nor the evaluation of therapy effectiveness or side effects or interpretation of the results is included. Understanding that there is no physician involvement in PE-only codes is critical in deciding whether an E/M service should be billed on the same day as a PE-only code. To that end, although a physician does not actually have to personally evaluate the patient on the day of service to bill PE-only codes, the Centers for Medicare & Medicaid Services has indicated that a physician or qualified medical provider must be on premises.⁵ Billing for PE-only services when no provider is present will be interpreted as a false claim or fraudulent billing practice.

Because PE-only codes do not include physician work, an E/M service will be billed in addition to the treatment almost any time a same-day physician evaluation is performed. For example, if a patient presents with a changing mole that is evaluated on the same date of service as phototherapy for the treatment of psoriasis, that service is clearly reportable with an E/M code because the mole check is separate and distinct from the phototherapy treatment. A more common scenario is for the physician to see a patient with a rash consistent with an allergic contact dermatitis and the decision to perform same-day patch testing is made. In this circumstance, the E/M service is still reportable because the evaluation of the rash and the decision to perform patch testing are not included in this PE-only code.

Phototherapy typically is provided as a prolonged course of multiple treatments, and reporting of same-day E/M services during the course of therapy is common. Phototherapy must be monitored by the physician for clinical effectiveness, dose changes, and side effects, as well as to determine whether to continue therapy. A standard operating procedure should be created to document that the physician typically evaluates the patient’s progress at set intervals or as dictated by patient or staff concerns. Reporting an E/M service with every phototherapy session is not considered medically necessary. Moreover, a nurse evaluation of the patient prior to each phototherapy treatment, including questions on disease severity, how the patient did with the last treatment, and whether medications have changed, is included in the payment for the phototherapy codes. Only formal and medically necessary physician E/M services should be billed, not drive-by visits in which the physician pops in just to see how the patient is doing.

Final Thoughts

Practice expense–only codes include no payment for physician time or work but require the presence of a qualified health care provider on premises to bill. Medically necessary physician evaluations on the same day as PE-only services will typically result in both an E/M service and the procedure being reported. Understanding performance and documentation requirements of PE-only codes is critical for proper reimbursement for a dermatology practice.

I have written previously about Current Procedural Terminology (CPT) procedure codes submitted on the same date of service as evaluation and management (E/M) services in the context of modifier -25.¹ Billing same-day procedures and E/M services is under close scrutiny by insurers, and accurate and complete documentation is a must.² An understanding of what aspects of evaluation are included in the global surgical package is critical in deciding whether a separate and distinct same-day evaluation was performed. In general, the decision to perform a procedure is included in the payment for the procedure itself, as is the examination of the body site in question, diagnosis of the medical condition, discussion of treatment options, and postoperative services related to the procedure. This is true for CPT codes that contain physician work, which constitute the majority of CPT codes reported by dermatologists.³

However, there is one set of codes where these principles do not apply: the practice expense (PE)–only codes, or no physician work codes. These codes are defined by CPT and the Relative Value Scale Update Committee (RUC) of the American Medical Association as containing no physician work. Their valuations are based only on staff/nursing time and the other aspects of direct and indirect practice costs included in providing the service, such as gauze, sutures, equipment, office rent, and utilities.⁴ Examples of PE-only codes include the nonphysician-performed photodynamic therapy code 96567; phototherapy codes 96900, 96910, and 96912; and patch testing and photopatch testing codes 95044, 95052, and 95056.

For PE-only codes, only the provision of the service by staff is included in the code reimbursement; there is no physician time or work built into these codes. Thus, neither the initial evaluation of the patient by the physician, the decision to perform the procedure, nor the evaluation of therapy effectiveness or side effects or interpretation of the results is included. Understanding that there is no physician involvement in PE-only codes is critical in deciding whether an E/M service should be billed on the same day as a PE-only code. To that end, although a physician does not actually have to personally evaluate the patient on the day of service to bill PE-only codes, the Centers for Medicare & Medicaid Services has indicated that a physician or qualified medical provider must be on premises.⁵ Billing for PE-only services when no provider is present will be interpreted as a false claim or fraudulent billing practice.

Because PE-only codes do not include physician work, an E/M service will be billed in addition to the treatment almost any time a same-day physician evaluation is performed. For example, if a patient presents with a changing mole that is evaluated on the same date of service as phototherapy for the treatment of psoriasis, that service is clearly reportable with an E/M code because the mole check is separate and distinct from the phototherapy treatment. A more common scenario is for the physician to see a patient with a rash consistent with an allergic contact dermatitis and the decision to perform same-day patch testing is made. In this circumstance, the E/M service is still reportable because the evaluation of the rash and the decision to perform patch testing are not included in this PE-only code.

Phototherapy typically is provided as a prolonged course of multiple treatments, and reporting of same-day E/M services during the course of therapy is common. Phototherapy must be monitored by the physician for clinical effectiveness, dose changes, and side effects, as well as to determine whether to continue therapy. A standard operating procedure should be created to document that the physician typically evaluates the patient’s progress at set intervals or as dictated by patient or staff concerns. Reporting an E/M service with every phototherapy session is not considered medically necessary. Moreover, a nurse evaluation of the patient prior to each phototherapy treatment, including questions on disease severity, how the patient did with the last treatment, and whether medications have changed, is included in the payment for the phototherapy codes. Only formal and medically necessary physician E/M services should be billed, not drive-by visits in which the physician pops in just to see how the patient is doing.

Final Thoughts

Practice expense–only codes include no payment for physician time or work but require the presence of a qualified health care provider on premises to bill. Medically necessary physician evaluations on the same day as PE-only services will typically result in both an E/M service and the procedure being reported. Understanding performance and documentation requirements of PE-only codes is critical for proper reimbursement for a dermatology practice.

Case Report

An 11-year-old boy presented with atraumatic thickening of the skin on the bilateral distal and proximal interphalangeal joints of 1 year’s duration. The patient also noted small bumps of unknown duration across the bilateral palms and soles with prominence on the lateral aspects. The patient previously used over-the-counter topical wart removal treatment and topical salicylic acid with minimal improvement. The patient reported no pertinent medical or surgical history, although there was a family history of Alport syndrome, predominantly in male relatives. The patient’s father and paternal grandfather were noted to have similar lesions on the palms.

On physical examination, multiple pink to flesh-colored hyperkeratotic plaques were noted over the proximal and distal interphalangeal joints of the bilateral hands (Figure 1A). Upon close inspection, there were small flesh-colored and slightly translucent papules in a linear distribution on the palmar surfaces of the hands (Figure 2A) with predominance on the thenar and hypothenar eminences. The flexural creases of the bilateral wrists also revealed linear flesh-colored papules. The same small flesh-colored and translucent papules also were noted on the plantar surfaces of the bilateral feet (Figure 2B).

A biopsy was obtained from one of the small translucent papules on the left palm. Hematoxylin and eosin–stained sections revealed elevated compact orthokeratosis with an underlying central epidermal dell (Figure 3). A diagnosis of marginal papular keratoderma was made and further elastin staining was completed. Elastin stains showed marked thinning of the elastin fibers throughout the reticular dermis. Many elastin fibers in the reticular dermis demonstrated a fine arborizing pattern that normally is only evident in the papillary dermis (Figure 4). Acrokeratoelastoidosis (AKE) was diagnosed histopathologically, and knuckle pads were diagnosed clinically.

Because the patient was asymptomatic, he did not want treatment of AKE. He had marked improvement of the knuckle pads after 1 month with daily application of urea cream 10% (Figure 1B), and intermittent use was required for maintenance.

Comment

Etiology
Acrokeratoelastoidosis was first described in 1953 and is considered a type of palmoplantar marginal papular keratoderma.¹ There is overlap within the marginal papular keratodermas that makes precise diagnosis difficult within this group. The marginal papular keratodermas on the palms and soles are a group of disorders that include AKE, focal acral hyperkeratosis (FAH), mosaic acral keratosis, degenerative collagenous plaques on the hands, and digital papular calcific elastosis. These diseases are similar in clinical and histopathological features; some argue these diseases are the same entity.²

Acrokeratoelastoidosis has been hypothesized to originate from altered elastic fiber synthesis from fibroblasts.³ Because AKE is rare, most cases of common knuckle pads do not coexist with AKE; therefore, it is unknown if the underlying etiology remains the same for both entities. Unlike AKE, knuckle pads are often associated with Dupuytren contractures, repetitive trauma, or friction to the area.^1,2

Presentation
Acrokeratoelastoidosis is a rare disease with onset in childhood or young adulthood. Childhood cases are inherited in an autosomal-dominant fashion.¹ Adulthood onset suggests a sporadic form of inheritance. Acrokeratoelastoidosis has no gender or racial predilection.⁴ It presents over the thenar and hypothenar eminences, as well as the lateral digits, calcaneal tendon, and dorsal digits.¹ Most often, AKE occurs symmetrically along the border separating the ventral and dorsal aspects on the palms and soles. These lesions present as small, firm, translucent papules that align linearly on the ventral-dorsal palmoplantar junction in a pattern resembling paving stones.¹ Coalescence of papules into plaques has been reported. Extension of lesions to the dorsal and palmar surfaces can occur. Small circumscribed callosities may develop over the metacarpophalangeal and interphalangeal joints resembling knuckle pads.²

Histopathology
Histopathologically, AKE is distinguished by elastorrhexis—thinning, fragmenting, and rarefaction of elastin fibers—in the epidermis and reticular dermis layers.³ Acrokeratoelastoidosis also presents with orthokeratosis overlying a cuplike epithelial depression and possible epithelial acanthosis.^2,5 Many cases exhibit hypergranulosis at the base of the epidermal dell. Dense basophilic granules may be seen in the peripheral cytoplasm of fibroblast cells coming from the hypothesized defect in elastin secretion.^1,3,4

Differential Diagnosis
The main differential diagnosis of AKE is FAH. Clinically and histopathologically they appear identical; both diseases have cuplike epidermal depressions with overlying orthohyperkeratosis and prominent hypergranulosis.⁵ The elastin stains, Verhoeff-van Gieson or acid orcein stain, are imperative for distinguishing these two diseases. Although AKE demonstrates elastorrhexis and reduced elastic fibers, FAH reveals no alteration of elastic fibers. It has been suggested that FAH is a clinical variant of AKE and should be titled AKE without elastorrhexis.¹

Treatment
Acrokeratoelastoidosis is asymptomatic except for mild palmoplantar hyperhidrosis and typically does not require treatment⁴; however, the condition can be of cosmetic concern for patients. Lesions can be treated topically with keratolytics such as tretinoin and salicylic acid. A wide variety of systemic treatments including methotrexate, prednisolone, dapsone, and acitretin have been reported with variable clinical response.^2-4 Copresenting knuckle pads can be treated with urea cream, salicylic acid cream, or intralesional corticosteroids.¹

Case Report

An 11-year-old boy presented with atraumatic thickening of the skin on the bilateral distal and proximal interphalangeal joints of 1 year’s duration. The patient also noted small bumps of unknown duration across the bilateral palms and soles with prominence on the lateral aspects. The patient previously used over-the-counter topical wart removal treatment and topical salicylic acid with minimal improvement. The patient reported no pertinent medical or surgical history, although there was a family history of Alport syndrome, predominantly in male relatives. The patient’s father and paternal grandfather were noted to have similar lesions on the palms.

On physical examination, multiple pink to flesh-colored hyperkeratotic plaques were noted over the proximal and distal interphalangeal joints of the bilateral hands (Figure 1A). Upon close inspection, there were small flesh-colored and slightly translucent papules in a linear distribution on the palmar surfaces of the hands (Figure 2A) with predominance on the thenar and hypothenar eminences. The flexural creases of the bilateral wrists also revealed linear flesh-colored papules. The same small flesh-colored and translucent papules also were noted on the plantar surfaces of the bilateral feet (Figure 2B).

A biopsy was obtained from one of the small translucent papules on the left palm. Hematoxylin and eosin–stained sections revealed elevated compact orthokeratosis with an underlying central epidermal dell (Figure 3). A diagnosis of marginal papular keratoderma was made and further elastin staining was completed. Elastin stains showed marked thinning of the elastin fibers throughout the reticular dermis. Many elastin fibers in the reticular dermis demonstrated a fine arborizing pattern that normally is only evident in the papillary dermis (Figure 4). Acrokeratoelastoidosis (AKE) was diagnosed histopathologically, and knuckle pads were diagnosed clinically.

Because the patient was asymptomatic, he did not want treatment of AKE. He had marked improvement of the knuckle pads after 1 month with daily application of urea cream 10% (Figure 1B), and intermittent use was required for maintenance.

Comment

Etiology
Acrokeratoelastoidosis was first described in 1953 and is considered a type of palmoplantar marginal papular keratoderma.¹ There is overlap within the marginal papular keratodermas that makes precise diagnosis difficult within this group. The marginal papular keratodermas on the palms and soles are a group of disorders that include AKE, focal acral hyperkeratosis (FAH), mosaic acral keratosis, degenerative collagenous plaques on the hands, and digital papular calcific elastosis. These diseases are similar in clinical and histopathological features; some argue these diseases are the same entity.²

Acrokeratoelastoidosis has been hypothesized to originate from altered elastic fiber synthesis from fibroblasts.³ Because AKE is rare, most cases of common knuckle pads do not coexist with AKE; therefore, it is unknown if the underlying etiology remains the same for both entities. Unlike AKE, knuckle pads are often associated with Dupuytren contractures, repetitive trauma, or friction to the area.^1,2

Presentation
Acrokeratoelastoidosis is a rare disease with onset in childhood or young adulthood. Childhood cases are inherited in an autosomal-dominant fashion.¹ Adulthood onset suggests a sporadic form of inheritance. Acrokeratoelastoidosis has no gender or racial predilection.⁴ It presents over the thenar and hypothenar eminences, as well as the lateral digits, calcaneal tendon, and dorsal digits.¹ Most often, AKE occurs symmetrically along the border separating the ventral and dorsal aspects on the palms and soles. These lesions present as small, firm, translucent papules that align linearly on the ventral-dorsal palmoplantar junction in a pattern resembling paving stones.¹ Coalescence of papules into plaques has been reported. Extension of lesions to the dorsal and palmar surfaces can occur. Small circumscribed callosities may develop over the metacarpophalangeal and interphalangeal joints resembling knuckle pads.²

Histopathology
Histopathologically, AKE is distinguished by elastorrhexis—thinning, fragmenting, and rarefaction of elastin fibers—in the epidermis and reticular dermis layers.³ Acrokeratoelastoidosis also presents with orthokeratosis overlying a cuplike epithelial depression and possible epithelial acanthosis.^2,5 Many cases exhibit hypergranulosis at the base of the epidermal dell. Dense basophilic granules may be seen in the peripheral cytoplasm of fibroblast cells coming from the hypothesized defect in elastin secretion.^1,3,4

Differential Diagnosis
The main differential diagnosis of AKE is FAH. Clinically and histopathologically they appear identical; both diseases have cuplike epidermal depressions with overlying orthohyperkeratosis and prominent hypergranulosis.⁵ The elastin stains, Verhoeff-van Gieson or acid orcein stain, are imperative for distinguishing these two diseases. Although AKE demonstrates elastorrhexis and reduced elastic fibers, FAH reveals no alteration of elastic fibers. It has been suggested that FAH is a clinical variant of AKE and should be titled AKE without elastorrhexis.¹

Treatment
Acrokeratoelastoidosis is asymptomatic except for mild palmoplantar hyperhidrosis and typically does not require treatment⁴; however, the condition can be of cosmetic concern for patients. Lesions can be treated topically with keratolytics such as tretinoin and salicylic acid. A wide variety of systemic treatments including methotrexate, prednisolone, dapsone, and acitretin have been reported with variable clinical response.^2-4 Copresenting knuckle pads can be treated with urea cream, salicylic acid cream, or intralesional corticosteroids.¹

Case Report

An 11-year-old boy presented with atraumatic thickening of the skin on the bilateral distal and proximal interphalangeal joints of 1 year’s duration. The patient also noted small bumps of unknown duration across the bilateral palms and soles with prominence on the lateral aspects. The patient previously used over-the-counter topical wart removal treatment and topical salicylic acid with minimal improvement. The patient reported no pertinent medical or surgical history, although there was a family history of Alport syndrome, predominantly in male relatives. The patient’s father and paternal grandfather were noted to have similar lesions on the palms.

On physical examination, multiple pink to flesh-colored hyperkeratotic plaques were noted over the proximal and distal interphalangeal joints of the bilateral hands (Figure 1A). Upon close inspection, there were small flesh-colored and slightly translucent papules in a linear distribution on the palmar surfaces of the hands (Figure 2A) with predominance on the thenar and hypothenar eminences. The flexural creases of the bilateral wrists also revealed linear flesh-colored papules. The same small flesh-colored and translucent papules also were noted on the plantar surfaces of the bilateral feet (Figure 2B).

A biopsy was obtained from one of the small translucent papules on the left palm. Hematoxylin and eosin–stained sections revealed elevated compact orthokeratosis with an underlying central epidermal dell (Figure 3). A diagnosis of marginal papular keratoderma was made and further elastin staining was completed. Elastin stains showed marked thinning of the elastin fibers throughout the reticular dermis. Many elastin fibers in the reticular dermis demonstrated a fine arborizing pattern that normally is only evident in the papillary dermis (Figure 4). Acrokeratoelastoidosis (AKE) was diagnosed histopathologically, and knuckle pads were diagnosed clinically.

Because the patient was asymptomatic, he did not want treatment of AKE. He had marked improvement of the knuckle pads after 1 month with daily application of urea cream 10% (Figure 1B), and intermittent use was required for maintenance.

Comment

Etiology
Acrokeratoelastoidosis was first described in 1953 and is considered a type of palmoplantar marginal papular keratoderma.¹ There is overlap within the marginal papular keratodermas that makes precise diagnosis difficult within this group. The marginal papular keratodermas on the palms and soles are a group of disorders that include AKE, focal acral hyperkeratosis (FAH), mosaic acral keratosis, degenerative collagenous plaques on the hands, and digital papular calcific elastosis. These diseases are similar in clinical and histopathological features; some argue these diseases are the same entity.²

Acrokeratoelastoidosis has been hypothesized to originate from altered elastic fiber synthesis from fibroblasts.³ Because AKE is rare, most cases of common knuckle pads do not coexist with AKE; therefore, it is unknown if the underlying etiology remains the same for both entities. Unlike AKE, knuckle pads are often associated with Dupuytren contractures, repetitive trauma, or friction to the area.^1,2

Presentation
Acrokeratoelastoidosis is a rare disease with onset in childhood or young adulthood. Childhood cases are inherited in an autosomal-dominant fashion.¹ Adulthood onset suggests a sporadic form of inheritance. Acrokeratoelastoidosis has no gender or racial predilection.⁴ It presents over the thenar and hypothenar eminences, as well as the lateral digits, calcaneal tendon, and dorsal digits.¹ Most often, AKE occurs symmetrically along the border separating the ventral and dorsal aspects on the palms and soles. These lesions present as small, firm, translucent papules that align linearly on the ventral-dorsal palmoplantar junction in a pattern resembling paving stones.¹ Coalescence of papules into plaques has been reported. Extension of lesions to the dorsal and palmar surfaces can occur. Small circumscribed callosities may develop over the metacarpophalangeal and interphalangeal joints resembling knuckle pads.²

Histopathology
Histopathologically, AKE is distinguished by elastorrhexis—thinning, fragmenting, and rarefaction of elastin fibers—in the epidermis and reticular dermis layers.³ Acrokeratoelastoidosis also presents with orthokeratosis overlying a cuplike epithelial depression and possible epithelial acanthosis.^2,5 Many cases exhibit hypergranulosis at the base of the epidermal dell. Dense basophilic granules may be seen in the peripheral cytoplasm of fibroblast cells coming from the hypothesized defect in elastin secretion.^1,3,4

Differential Diagnosis
The main differential diagnosis of AKE is FAH. Clinically and histopathologically they appear identical; both diseases have cuplike epidermal depressions with overlying orthohyperkeratosis and prominent hypergranulosis.⁵ The elastin stains, Verhoeff-van Gieson or acid orcein stain, are imperative for distinguishing these two diseases. Although AKE demonstrates elastorrhexis and reduced elastic fibers, FAH reveals no alteration of elastic fibers. It has been suggested that FAH is a clinical variant of AKE and should be titled AKE without elastorrhexis.¹

Treatment
Acrokeratoelastoidosis is asymptomatic except for mild palmoplantar hyperhidrosis and typically does not require treatment⁴; however, the condition can be of cosmetic concern for patients. Lesions can be treated topically with keratolytics such as tretinoin and salicylic acid. A wide variety of systemic treatments including methotrexate, prednisolone, dapsone, and acitretin have been reported with variable clinical response.^2-4 Copresenting knuckle pads can be treated with urea cream, salicylic acid cream, or intralesional corticosteroids.¹

This centennial year update focuses primarily on immunization, but also reviews epidemiology, transmission, and treatment.

EPIDEMIOLOGY

2017–2018 was a bad season

The 2017–2018 influenza epidemic was memorable, dominated by influenza A(H3N2) viruses with morbidity and mortality rates approaching pandemic numbers. It lasted 19 weeks, killed more people than any other epidemic since 2010, particularly children, and was associated with 30,453 hospitalizations—almost twice the previous season high in some parts of the United States.²

Regrettably, 171 unvaccinated children died during 2017–2018, accounting for almost 80% of deaths.² The mean age of the children who died was 7.1 years; 51% had at least 1 underlying medical condition placing them at risk for influenza-related complications, and 57% died after hospitalization.²

Recent estimates of the incidence of symptomatic influenza among all ages ranged from 3% to 11%, which is slightly lower than historical estimates. The rates were higher for children under age 18 than for adults.³ Interestingly, influenza A(H3N2) accounted for 50% of cases of non-mumps viral parotitis during the 2014–2015 influenza season in the United States.⁴

Influenza C exists but is rare

Influenza A and B account for almost all influenza-related outpatient visits and hospitalizations. Surveillance data from May 2013 through December 2016 showed that influenza C accounts for 0.5% of influenza-related outpatient visits and hospitalizations, particularly affecting children ages 6 to 24 months. Medical comorbidities and copathogens were seen in all patients requiring intensive care and in most hospitalizations.⁵ Diagnostic tests for influenza C are not widely available.

Dogs and cats: Factories for new flu strains?

While pigs and birds are the major reservoirs of influenza viral genetic diversity from which infection is transmitted to humans, dogs and cats have recently emerged as possible sources of novel reassortant influenza A.⁶ With their frequent close contact with humans, our pets may prove to pose a significant threat.

Obesity a risk factor for influenza

Obesity emerged as a risk factor for severe influenza in the 2009 pandemic. Recent data also showed that obesity increases the duration of influenza A virus shedding, thus increasing duration of contagiousness.⁷

Influenza a cardiovascular risk factor

Previous data showed that influenza was a risk factor for cardiovascular events. Two recent epi­demiologic studies from the United Kingdom showed that laboratory-confirmed influenza was associated with higher rates of myocardial infarction and stroke for up to 4 weeks.^8,9

Which strain is the biggest threat?

Predicting which emerging influenza serotype may cause the next pandemic is difficult, but influenza A(H7N9), which had not infected humans until 2013 but has since infected about 1,600 people in China and killed 37% of them, appears to have the greatest potential.¹⁰

National influenza surveillance programs and influenza-related social media applications have been developed and may get a boost from technology. A smartphone equipped with a temperature sensor can instantly detect one’s temperature with great precision. A 2018 study suggested that a smartphone-driven thermometry application correlated well with national influenza-like illness activity and improved its forecast in real time and up to 3 weeks in advance.¹¹

TRANSMISSION

Humidity may not block transmission

Animal studies have suggested that humidity in the air interferes with transmission of airborne influenza virus, partially from biologic inactivation. But when a recent study used humidity-controlled chambers to investigate the stability of the 2009 influenza A(H1N1) virus in suspended aerosols and stationary droplets, the virus remained infectious in aerosols across a wide range of relative humidities, challenging the common belief that humidity destabilizes respiratory viruses in aerosols.¹²

One sick passenger may not infect the whole plane

Transmission of respiratory viruses on airplane flights has long been considered a potential avenue for spreading influenza. However, a recent study that monitored movements of individuals on 10 transcontinental US flights and simulated inflight transmission based on these data showed a low probability of direct transmission, except for passengers seated in close proximity to an infectious passenger.¹³

WHAT’S IN THE NEW FLU SHOT?

The 2018–2019 quadrivalent vaccine for the Northern Hemisphere¹⁴ contains the following strains:

• A/Michigan/45/2015 A(H1N1)pdm09-like virus
• A/Singapore/INFIMH-16-0019/2016 (H3N2)-like virus
• B/Colorado/06/2017-like virus (Victoria lineage)
• B/Phuket/3073/2013-like virus (Yamagata lineage).

The A(H3N2) (Singapore) and B/Victoria lineage components are new this year. The A(H3N2) strain was the main cause of the 2018 influenza epidemic in the Southern Hemisphere.

The quadrivalent live-attenuated vaccine, which was not recommended during the 2016–2017 and 2017–2018 influenza seasons, has made a comeback and is recommended for the 2018–2019 season in people for whom it is appropriate based on age and comorbidities.¹⁵ Although it was effective against influenza B and A(H3N2) viruses, it was less effective against the influenza A(H1N1)pdm09-like viruses during the 2013–2014 and 2015–2016 seasons.

A/Slovenia/2903/2015, the new A(H1N1)pdm09-like virus included in the 2018–2019 quadrivalent live-attenuated vaccine, is significantly more immunogenic than its predecessor, A/Bolivia/559/2013, but its clinical effectiveness remains to be seen.

How effective is it?

Influenza vaccine effectiveness in the 2017–2018 influenza season was 36% overall, 67% against A(H1N1), 42% against influenza B, and 25% against A(H3N2).¹⁶ It is estimated that influenza vaccine prevents 300 to 4,000 deaths annually in the United States alone.¹⁷

A 2018 Cochrane review¹⁷ concluded that vaccination reduced the incidence of influenza by about half, with 2.3% of the population contracting the flu without vaccination compared with 0.9% with vaccination (risk ratio 0.41, 95% confidence interval 0.36–0.47). The same review found that 71 healthy adults need to be vaccinated to prevent 1 from experiencing influenza, and 29 to prevent 1 influenza-like illness.

Several recent studies showed that influenza vaccine effectiveness varied based on age and influenza serotype, with higher effectiveness in people ages 5 to 17 and ages 18 to 64 than in those age 65 and older.^18–20 A mathematical model of influenza transmission and vaccination in the United States determined that even relatively low-efficacy influenza vaccines can be very useful if optimally distributed across age groups.²¹

Vaccination rates are low, and ‘antivaxxers’ are on the rise

Although the influenza vaccine is recommended in the United States for all people age 6 months and older regardless of the state of their health, vaccination rates remain low. In 2016, only 37% of employed adults were vaccinated. The highest rate was for government employees (45%), followed by private employees (36%), followed by the self-employed (30%).²²

A national goal is to immunize 80% of all Americans and 90% of at-risk populations (which include children and the elderly).²³ The number of US hospitals that require their employees to be vaccinated increased from 37.1% in 2013 to 61.4% in 2017.²⁴ Regrettably, as of March 2018, 14 lawsuits addressing religious objections to hospital influenza vaccination mandates have been filed.²⁵

Despite hundreds of studies demonstrating the efficacy, safety, and cost savings of influenza vaccination, the antivaccine movement has been growing in the United States and worldwide.²⁶ All US states except West Virginia, Mississippi, and California allow nonmedical exemptions from vaccination based on religious or personal belief.²⁷ Several US metropolitan areas represent “hot spots” for these exemptions.²⁸ This may render such areas vulnerable to vaccine-preventable diseases, including influenza.

Herd immunity: We’re all in this together

Some argue that the potential adverse effects and the cost of vaccination outweigh the benefits, but the protective benefits of herd immunity are significant for those with comorbidities or compromised immunity.

Educating the public about herd immunity and local influenza vaccination uptake increases people’s willingness to be vaccinated.²⁹ A key educational point is that at least 70% of a community needs to be vaccinated to prevent community outbreaks; this protects everyone, including those who do not mount a protective antibody response to influenza vaccination and those who are not vaccinated.

DOES ANNUAL VACCINATION BLUNT ITS EFFECTIVENESS?

Some studies from the 1970s and 1980s raised concern over a possible negative effect of annual influenza vaccination on vaccine effectiveness. The “antigenic distance hypothesis” holds that vaccine effectiveness is influenced by antigenic similarity between the previous season’s vaccine serotypes and the epidemic serotypes, as well as the antigenic similarity between the serotypes of the current and previous seasons.

A meta-analysis of studies from 2010 through 2015 showed significant inconsistencies in repeat vaccination effects within and between seasons and serotypes. It also showed that vaccine effectiveness may be influenced by more than 1 previous season, particularly for influenza A(H3N2), in which repeated vaccination can blunt the hemagglutinin antibody response.³⁰

A study from Japan showed that people who needed medical attention for influenza in the previous season were at lower risk of a similar event in the current season.³¹ Prior-season influenza vaccination reduced current-season vaccine effectiveness only in those who did not have medically attended influenza in the prior season. This suggests that infection is more immunogenic than vaccination, but only against the serotype causing the infection and not the other serotypes included in the vaccine.

An Australian study showed that annual influenza vaccination did not decrease vaccine effectiveness against influenza-associated hospitalization. Rather, effectiveness increased by about 15% in those vaccinated in both current and previous seasons compared with those vaccinated in either season alone.³²

European investigators showed that repeated seasonal influenza vaccination in the elderly prevented the need for hospitalization due to influenza A(H3N2) and B, but not A(H1N1)pdm09.³³

High-dose vaccine for older adults

The high-dose influenza vaccine has been licensed since 2009 for use in the United States for people ages 65 and older.

Recent studies confirmed that high-dose vaccine is more effective than standard-dose vaccine in veterans³⁴ and US Medicare beneficiaries.³⁵

The high-dose vaccine is rapidly becoming the primary vaccine given to people ages 65 and older in retail pharmacies, where vaccination begins earlier in the season than in providers’ offices.³⁶ Some studies have shown that the standard-dose vaccine wanes in effectiveness toward the end of the influenza season (particularly if the season is long) if it is given very early. It remains to be seen whether the same applies to the high-dose influenza vaccine.

Some advocate twice-annual influenza vaccination, particularly for older adults living in tropical and subtropical areas, where influenza seasons are more prolonged. However, a recently published study observed reductions in influenza-specific hemagglutination inhibition and cell-mediated immunity after twice-annual vaccination.³⁷

Vaccination is beneficial during pregnancy

Many studies have shown the value of influenza vaccination during pregnancy for both mothers and their infants.

One recently published study showed that 18% of infants who developed influenza required hospitalization.³⁸ In that study, prenatal and postpartum maternal influenza vaccination decreased the odds of influenza in infants by 61% and 53%, respectively.

Another study showed that vaccine effectiveness did not vary by gestational age at vaccination.³⁹

Some studies have shown that influenza virus infection can increase susceptibility to certain bacterial infections. A post hoc analysis of an influenza vaccination study in pregnant women suggested that the vaccine was also associated with decreased rates of pertussis in these women.⁴⁰

Factors that make vaccination less effective

Several factors including age-related frailty and iatrogenic and disease-related immunosuppression can affect vaccine effectiveness.

Frailty. A recent study showed that vaccine effectiveness was 77.6% in nonfrail older adults but only 58.7% in frail older adults.⁴¹

Immunosuppression. Temporary discontinuation of methotrexate for 2 weeks after influenza vaccination in patients with rheumatoid arthritis improves vaccine immunogenicity without precipitating disease flare.⁴² Solid-organ and hematopoietic stem cell transplant recipients who received influenza vaccine were less likely to develop pneumonia and require intensive care unit admission.⁴³

The high-dose influenza vaccine is more immunogenic than the standard-dose vaccine in solid-organ transplant recipients.⁴⁴

Statins are widely prescribed and have recently been associated with reduced influenza vaccine effectiveness against medically attended acute respiratory illness, but their benefits in preventing cardiovascular events outweigh this risk.⁴⁵

FUTURE VACCINE CONSIDERATIONS

Moving away from eggs

During the annual egg-based production process, which takes several months, the influenza vaccine acquires antigenic changes that allow replication in eggs, particularly in the hemagglutinin protein, which mediates receptor binding. This process of egg adaptation may cause antigenic changes that decrease vaccine effectiveness against circulating viruses.

The cell-based baculovirus influenza vaccine grown in dog kidney cells has higher antigenic content and is not subject to the limitations of egg-based vaccine, although it still requires annual updates. A recombinant influenza vaccine reduces the probability of influenza-like illness by 30% compared with the egg-based influenza vaccine, but also still requires annual updates.⁴⁶ The market share of these non-egg-based vaccines is small, and thus their effectiveness has yet to be demonstrated.

The US Department of Defense administered the cell-based influenza vaccine to about one-third of Armed Forces personnel, their families, and retirees in the 2017–2018 influenza seasons, and data on its effectiveness are expected in the near future.⁴⁷

A universal vaccine would be ideal

The quest continues for a universal influenza vaccine, one that remains protective for several years and does not require annual updates.⁴⁸ Such a vaccine would protect against seasonal epidemic influenza drift variants and pandemic strains. More people could likely be persuaded to be vaccinated once rather than every year.

David Schumick, medical illustrator; adapted from reference 49; illustration of the influenza hemagglutinin created in part with data from reference 50.

An ideal universal vaccine would be suitable for all age groups, at least 75% effective against symptomatic influenza virus infection, protective against all influenza A viruses (influenza A, not B, causes pandemics and seasonal epidemics), and durable through multiple influenza seasons.⁵¹

Research and production of such a vaccine are expected to require funding of about $1 billion over the next 5 years.

Boosting effectiveness

Estimates of influenza vaccine effectiveness range from 40% to 60% in years when the vaccine viruses closely match the circulating viruses, and variably lower when they do not match. The efficacy of most other vaccines given to prevent other infections is much higher.

New technologies to improve influenza vaccine effectiveness are needed, particularly for influenza A(H3N2) viruses, which are rapidly evolving and are highly susceptible to egg-adaptive mutations in the manufacturing process.

In one study, a nanoparticle vaccine formulated with a saponin-based adjuvant induced hemagglutination inhibition responses that were even greater than those induced by the high-dose vaccine.⁵²

Immunoglobulin A (IgA) may be a more effective vaccine target than traditional influenza vaccines that target IgG, since different parts of IgA may engage the influenza virus simultaneously.⁵³

Vaccines can be developed more quickly than in the past. The timeline from viral sequencing to human studies with deoxyribonucleic acid plasmid vaccines decreased from 20 months in 2003 for the severe acquired respiratory syndrome coronavirus to 11 months in 2006 for influenza A/Indonesia/2006 (H5), to 4 months in 2009 for influenza A/California/2009 (H1), to 3.5 months in 2016 for Zika virus.⁵⁴ This is because it is possible today to sequence a virus and insert the genetic material into a vaccine platform without ever having to grow the virus.

Numerous studies have found anti-influenza medications to be effective. Nevertheless, in an analysis of the 2011–2016 influenza seasons, only 15% of high-risk patients were prescribed anti-influenza medications within 2 days of symptom onset, including 37% in those with laboratory-confirmed influenza.⁵⁵ Fever was associated with an increased rate of antiviral treatment, but 25% of high-risk outpatients were afebrile. Empiric treatment of 4 high-risk outpatients with acute respiratory illness was needed to treat 1 patient with influenza.⁵⁵

Treatment with a neuraminidase inhibitor within 2 days of illness has recently been shown to improve survival and shorten duration of viral shedding in patients with avian influenza A(H7N9) infection.⁵⁶ Antiviral treatment within 2 days of illness is associated with improved outcomes in transplant recipients⁵⁷ and with a lower risk of otitis media in children.⁵⁸

Appropriate anti-influenza treatment is as important as avoiding unnecessary antibiotics. Regrettably, as many as one-third of patients with laboratory-confirmed influenza are prescribed antibiotics.⁵⁹

The US Food and Drug Administration warns against fraudulent unapproved over-the-counter influenza products.⁶⁰

Baloxavir marboxil

Baloxavir marboxil is a new anti-influenza medication approved in Japan in February 2018 and anticipated to be available in the United States sometime in 2019.

This prodrug is hydrolyzed in vivo to the active metabolite, which selectively inhibits cap-dependent endonuclease enzyme, a key enzyme in initiation of messenger ribonucleic acid synthesis required for influenza viral replication.⁶¹

In a double-blind phase 3 trial, the median time to alleviation of influenza symptoms is 26.5 hours shorter with baloxavir marboxil than with placebo. One tablet was as effective as 5 days of the neuraminidase inhibitor oseltamivir and was associated with greater reduction in viral load 1 day after initiation, and similar side effects.⁶² Of concern is the emergence of nucleic acid substitutions conferring resistance to baloxavir; this occurred in 2.2% and 9.7% of baloxavir recipients in the phase 2 and 3 trials, respectively.

CLOSING THE GAPS

Several gaps in the management of influenza persist since the 1918 pandemic.¹ These include gaps in epidemiology, prevention, diagnosis, treatment, and prognosis.

• Global networks wider than current ones are needed to address this global disease and to prioritize coordination efforts.
• Establishing and strengthening clinical capacity is needed in limited resource settings. New technologies are needed to expedite vaccine development and to achieve progress toward a universal vaccine.
• Current diagnostic tests do not distinguish between seasonal and novel influenza A viruses of zoonotic origin, which are expected to cause the next pandemic.
• Current antivirals have been shown to shorten duration of illness in outpatients with uncomplicated influenza, but the benefit in hospitalized patients has been less well established.
• In 2007, resistance of seasonal influenza A(H1N1) to oseltamivir became widespread. In 2009, pandemic influenza A(H1N1), which is highly susceptible to oseltamivir, replaced the seasonal virus and remains the predominantly circulating A(H1N1) strain.
• A small-molecule fragment, N-cyclohexyaltaurine, binds to the conserved hemagglutinin receptor-binding site in a manner that mimics the binding mode of the natural receptor sialic acid. This can serve as a template to guide the development of novel broad-spectrum small-molecule anti-influenza drugs.⁶³
• Biomarkers that can accurately predict development of severe disease in patients with influenza are needed.

This centennial year update focuses primarily on immunization, but also reviews epidemiology, transmission, and treatment.

EPIDEMIOLOGY

2017–2018 was a bad season

The 2017–2018 influenza epidemic was memorable, dominated by influenza A(H3N2) viruses with morbidity and mortality rates approaching pandemic numbers. It lasted 19 weeks, killed more people than any other epidemic since 2010, particularly children, and was associated with 30,453 hospitalizations—almost twice the previous season high in some parts of the United States.²

Regrettably, 171 unvaccinated children died during 2017–2018, accounting for almost 80% of deaths.² The mean age of the children who died was 7.1 years; 51% had at least 1 underlying medical condition placing them at risk for influenza-related complications, and 57% died after hospitalization.²

Recent estimates of the incidence of symptomatic influenza among all ages ranged from 3% to 11%, which is slightly lower than historical estimates. The rates were higher for children under age 18 than for adults.³ Interestingly, influenza A(H3N2) accounted for 50% of cases of non-mumps viral parotitis during the 2014–2015 influenza season in the United States.⁴

Influenza C exists but is rare

Influenza A and B account for almost all influenza-related outpatient visits and hospitalizations. Surveillance data from May 2013 through December 2016 showed that influenza C accounts for 0.5% of influenza-related outpatient visits and hospitalizations, particularly affecting children ages 6 to 24 months. Medical comorbidities and copathogens were seen in all patients requiring intensive care and in most hospitalizations.⁵ Diagnostic tests for influenza C are not widely available.

Dogs and cats: Factories for new flu strains?

While pigs and birds are the major reservoirs of influenza viral genetic diversity from which infection is transmitted to humans, dogs and cats have recently emerged as possible sources of novel reassortant influenza A.⁶ With their frequent close contact with humans, our pets may prove to pose a significant threat.

Obesity a risk factor for influenza

Obesity emerged as a risk factor for severe influenza in the 2009 pandemic. Recent data also showed that obesity increases the duration of influenza A virus shedding, thus increasing duration of contagiousness.⁷

Influenza a cardiovascular risk factor

Previous data showed that influenza was a risk factor for cardiovascular events. Two recent epi­demiologic studies from the United Kingdom showed that laboratory-confirmed influenza was associated with higher rates of myocardial infarction and stroke for up to 4 weeks.^8,9

Which strain is the biggest threat?

Predicting which emerging influenza serotype may cause the next pandemic is difficult, but influenza A(H7N9), which had not infected humans until 2013 but has since infected about 1,600 people in China and killed 37% of them, appears to have the greatest potential.¹⁰

National influenza surveillance programs and influenza-related social media applications have been developed and may get a boost from technology. A smartphone equipped with a temperature sensor can instantly detect one’s temperature with great precision. A 2018 study suggested that a smartphone-driven thermometry application correlated well with national influenza-like illness activity and improved its forecast in real time and up to 3 weeks in advance.¹¹

TRANSMISSION

Humidity may not block transmission

Animal studies have suggested that humidity in the air interferes with transmission of airborne influenza virus, partially from biologic inactivation. But when a recent study used humidity-controlled chambers to investigate the stability of the 2009 influenza A(H1N1) virus in suspended aerosols and stationary droplets, the virus remained infectious in aerosols across a wide range of relative humidities, challenging the common belief that humidity destabilizes respiratory viruses in aerosols.¹²

One sick passenger may not infect the whole plane

Transmission of respiratory viruses on airplane flights has long been considered a potential avenue for spreading influenza. However, a recent study that monitored movements of individuals on 10 transcontinental US flights and simulated inflight transmission based on these data showed a low probability of direct transmission, except for passengers seated in close proximity to an infectious passenger.¹³

WHAT’S IN THE NEW FLU SHOT?

The 2018–2019 quadrivalent vaccine for the Northern Hemisphere¹⁴ contains the following strains:

• A/Michigan/45/2015 A(H1N1)pdm09-like virus
• A/Singapore/INFIMH-16-0019/2016 (H3N2)-like virus
• B/Colorado/06/2017-like virus (Victoria lineage)
• B/Phuket/3073/2013-like virus (Yamagata lineage).

The A(H3N2) (Singapore) and B/Victoria lineage components are new this year. The A(H3N2) strain was the main cause of the 2018 influenza epidemic in the Southern Hemisphere.

The quadrivalent live-attenuated vaccine, which was not recommended during the 2016–2017 and 2017–2018 influenza seasons, has made a comeback and is recommended for the 2018–2019 season in people for whom it is appropriate based on age and comorbidities.¹⁵ Although it was effective against influenza B and A(H3N2) viruses, it was less effective against the influenza A(H1N1)pdm09-like viruses during the 2013–2014 and 2015–2016 seasons.

A/Slovenia/2903/2015, the new A(H1N1)pdm09-like virus included in the 2018–2019 quadrivalent live-attenuated vaccine, is significantly more immunogenic than its predecessor, A/Bolivia/559/2013, but its clinical effectiveness remains to be seen.

How effective is it?

Influenza vaccine effectiveness in the 2017–2018 influenza season was 36% overall, 67% against A(H1N1), 42% against influenza B, and 25% against A(H3N2).¹⁶ It is estimated that influenza vaccine prevents 300 to 4,000 deaths annually in the United States alone.¹⁷

A 2018 Cochrane review¹⁷ concluded that vaccination reduced the incidence of influenza by about half, with 2.3% of the population contracting the flu without vaccination compared with 0.9% with vaccination (risk ratio 0.41, 95% confidence interval 0.36–0.47). The same review found that 71 healthy adults need to be vaccinated to prevent 1 from experiencing influenza, and 29 to prevent 1 influenza-like illness.

Several recent studies showed that influenza vaccine effectiveness varied based on age and influenza serotype, with higher effectiveness in people ages 5 to 17 and ages 18 to 64 than in those age 65 and older.^18–20 A mathematical model of influenza transmission and vaccination in the United States determined that even relatively low-efficacy influenza vaccines can be very useful if optimally distributed across age groups.²¹

Vaccination rates are low, and ‘antivaxxers’ are on the rise

Although the influenza vaccine is recommended in the United States for all people age 6 months and older regardless of the state of their health, vaccination rates remain low. In 2016, only 37% of employed adults were vaccinated. The highest rate was for government employees (45%), followed by private employees (36%), followed by the self-employed (30%).²²

A national goal is to immunize 80% of all Americans and 90% of at-risk populations (which include children and the elderly).²³ The number of US hospitals that require their employees to be vaccinated increased from 37.1% in 2013 to 61.4% in 2017.²⁴ Regrettably, as of March 2018, 14 lawsuits addressing religious objections to hospital influenza vaccination mandates have been filed.²⁵

Despite hundreds of studies demonstrating the efficacy, safety, and cost savings of influenza vaccination, the antivaccine movement has been growing in the United States and worldwide.²⁶ All US states except West Virginia, Mississippi, and California allow nonmedical exemptions from vaccination based on religious or personal belief.²⁷ Several US metropolitan areas represent “hot spots” for these exemptions.²⁸ This may render such areas vulnerable to vaccine-preventable diseases, including influenza.

Herd immunity: We’re all in this together

Some argue that the potential adverse effects and the cost of vaccination outweigh the benefits, but the protective benefits of herd immunity are significant for those with comorbidities or compromised immunity.

Educating the public about herd immunity and local influenza vaccination uptake increases people’s willingness to be vaccinated.²⁹ A key educational point is that at least 70% of a community needs to be vaccinated to prevent community outbreaks; this protects everyone, including those who do not mount a protective antibody response to influenza vaccination and those who are not vaccinated.

DOES ANNUAL VACCINATION BLUNT ITS EFFECTIVENESS?

Some studies from the 1970s and 1980s raised concern over a possible negative effect of annual influenza vaccination on vaccine effectiveness. The “antigenic distance hypothesis” holds that vaccine effectiveness is influenced by antigenic similarity between the previous season’s vaccine serotypes and the epidemic serotypes, as well as the antigenic similarity between the serotypes of the current and previous seasons.

A meta-analysis of studies from 2010 through 2015 showed significant inconsistencies in repeat vaccination effects within and between seasons and serotypes. It also showed that vaccine effectiveness may be influenced by more than 1 previous season, particularly for influenza A(H3N2), in which repeated vaccination can blunt the hemagglutinin antibody response.³⁰

A study from Japan showed that people who needed medical attention for influenza in the previous season were at lower risk of a similar event in the current season.³¹ Prior-season influenza vaccination reduced current-season vaccine effectiveness only in those who did not have medically attended influenza in the prior season. This suggests that infection is more immunogenic than vaccination, but only against the serotype causing the infection and not the other serotypes included in the vaccine.

An Australian study showed that annual influenza vaccination did not decrease vaccine effectiveness against influenza-associated hospitalization. Rather, effectiveness increased by about 15% in those vaccinated in both current and previous seasons compared with those vaccinated in either season alone.³²

European investigators showed that repeated seasonal influenza vaccination in the elderly prevented the need for hospitalization due to influenza A(H3N2) and B, but not A(H1N1)pdm09.³³

High-dose vaccine for older adults

The high-dose influenza vaccine has been licensed since 2009 for use in the United States for people ages 65 and older.

Recent studies confirmed that high-dose vaccine is more effective than standard-dose vaccine in veterans³⁴ and US Medicare beneficiaries.³⁵

The high-dose vaccine is rapidly becoming the primary vaccine given to people ages 65 and older in retail pharmacies, where vaccination begins earlier in the season than in providers’ offices.³⁶ Some studies have shown that the standard-dose vaccine wanes in effectiveness toward the end of the influenza season (particularly if the season is long) if it is given very early. It remains to be seen whether the same applies to the high-dose influenza vaccine.

Some advocate twice-annual influenza vaccination, particularly for older adults living in tropical and subtropical areas, where influenza seasons are more prolonged. However, a recently published study observed reductions in influenza-specific hemagglutination inhibition and cell-mediated immunity after twice-annual vaccination.³⁷

Vaccination is beneficial during pregnancy

Many studies have shown the value of influenza vaccination during pregnancy for both mothers and their infants.

One recently published study showed that 18% of infants who developed influenza required hospitalization.³⁸ In that study, prenatal and postpartum maternal influenza vaccination decreased the odds of influenza in infants by 61% and 53%, respectively.

Another study showed that vaccine effectiveness did not vary by gestational age at vaccination.³⁹

Some studies have shown that influenza virus infection can increase susceptibility to certain bacterial infections. A post hoc analysis of an influenza vaccination study in pregnant women suggested that the vaccine was also associated with decreased rates of pertussis in these women.⁴⁰

Factors that make vaccination less effective

Several factors including age-related frailty and iatrogenic and disease-related immunosuppression can affect vaccine effectiveness.

Frailty. A recent study showed that vaccine effectiveness was 77.6% in nonfrail older adults but only 58.7% in frail older adults.⁴¹

Immunosuppression. Temporary discontinuation of methotrexate for 2 weeks after influenza vaccination in patients with rheumatoid arthritis improves vaccine immunogenicity without precipitating disease flare.⁴² Solid-organ and hematopoietic stem cell transplant recipients who received influenza vaccine were less likely to develop pneumonia and require intensive care unit admission.⁴³

The high-dose influenza vaccine is more immunogenic than the standard-dose vaccine in solid-organ transplant recipients.⁴⁴

Statins are widely prescribed and have recently been associated with reduced influenza vaccine effectiveness against medically attended acute respiratory illness, but their benefits in preventing cardiovascular events outweigh this risk.⁴⁵

FUTURE VACCINE CONSIDERATIONS

Moving away from eggs

During the annual egg-based production process, which takes several months, the influenza vaccine acquires antigenic changes that allow replication in eggs, particularly in the hemagglutinin protein, which mediates receptor binding. This process of egg adaptation may cause antigenic changes that decrease vaccine effectiveness against circulating viruses.

The cell-based baculovirus influenza vaccine grown in dog kidney cells has higher antigenic content and is not subject to the limitations of egg-based vaccine, although it still requires annual updates. A recombinant influenza vaccine reduces the probability of influenza-like illness by 30% compared with the egg-based influenza vaccine, but also still requires annual updates.⁴⁶ The market share of these non-egg-based vaccines is small, and thus their effectiveness has yet to be demonstrated.

The US Department of Defense administered the cell-based influenza vaccine to about one-third of Armed Forces personnel, their families, and retirees in the 2017–2018 influenza seasons, and data on its effectiveness are expected in the near future.⁴⁷

A universal vaccine would be ideal

The quest continues for a universal influenza vaccine, one that remains protective for several years and does not require annual updates.⁴⁸ Such a vaccine would protect against seasonal epidemic influenza drift variants and pandemic strains. More people could likely be persuaded to be vaccinated once rather than every year.

David Schumick, medical illustrator; adapted from reference 49; illustration of the influenza hemagglutinin created in part with data from reference 50.

An ideal universal vaccine would be suitable for all age groups, at least 75% effective against symptomatic influenza virus infection, protective against all influenza A viruses (influenza A, not B, causes pandemics and seasonal epidemics), and durable through multiple influenza seasons.⁵¹

Research and production of such a vaccine are expected to require funding of about $1 billion over the next 5 years.

Boosting effectiveness

Estimates of influenza vaccine effectiveness range from 40% to 60% in years when the vaccine viruses closely match the circulating viruses, and variably lower when they do not match. The efficacy of most other vaccines given to prevent other infections is much higher.

New technologies to improve influenza vaccine effectiveness are needed, particularly for influenza A(H3N2) viruses, which are rapidly evolving and are highly susceptible to egg-adaptive mutations in the manufacturing process.

In one study, a nanoparticle vaccine formulated with a saponin-based adjuvant induced hemagglutination inhibition responses that were even greater than those induced by the high-dose vaccine.⁵²

Immunoglobulin A (IgA) may be a more effective vaccine target than traditional influenza vaccines that target IgG, since different parts of IgA may engage the influenza virus simultaneously.⁵³

Vaccines can be developed more quickly than in the past. The timeline from viral sequencing to human studies with deoxyribonucleic acid plasmid vaccines decreased from 20 months in 2003 for the severe acquired respiratory syndrome coronavirus to 11 months in 2006 for influenza A/Indonesia/2006 (H5), to 4 months in 2009 for influenza A/California/2009 (H1), to 3.5 months in 2016 for Zika virus.⁵⁴ This is because it is possible today to sequence a virus and insert the genetic material into a vaccine platform without ever having to grow the virus.

Numerous studies have found anti-influenza medications to be effective. Nevertheless, in an analysis of the 2011–2016 influenza seasons, only 15% of high-risk patients were prescribed anti-influenza medications within 2 days of symptom onset, including 37% in those with laboratory-confirmed influenza.⁵⁵ Fever was associated with an increased rate of antiviral treatment, but 25% of high-risk outpatients were afebrile. Empiric treatment of 4 high-risk outpatients with acute respiratory illness was needed to treat 1 patient with influenza.⁵⁵

Treatment with a neuraminidase inhibitor within 2 days of illness has recently been shown to improve survival and shorten duration of viral shedding in patients with avian influenza A(H7N9) infection.⁵⁶ Antiviral treatment within 2 days of illness is associated with improved outcomes in transplant recipients⁵⁷ and with a lower risk of otitis media in children.⁵⁸

Appropriate anti-influenza treatment is as important as avoiding unnecessary antibiotics. Regrettably, as many as one-third of patients with laboratory-confirmed influenza are prescribed antibiotics.⁵⁹

The US Food and Drug Administration warns against fraudulent unapproved over-the-counter influenza products.⁶⁰

Baloxavir marboxil

Baloxavir marboxil is a new anti-influenza medication approved in Japan in February 2018 and anticipated to be available in the United States sometime in 2019.

This prodrug is hydrolyzed in vivo to the active metabolite, which selectively inhibits cap-dependent endonuclease enzyme, a key enzyme in initiation of messenger ribonucleic acid synthesis required for influenza viral replication.⁶¹

In a double-blind phase 3 trial, the median time to alleviation of influenza symptoms is 26.5 hours shorter with baloxavir marboxil than with placebo. One tablet was as effective as 5 days of the neuraminidase inhibitor oseltamivir and was associated with greater reduction in viral load 1 day after initiation, and similar side effects.⁶² Of concern is the emergence of nucleic acid substitutions conferring resistance to baloxavir; this occurred in 2.2% and 9.7% of baloxavir recipients in the phase 2 and 3 trials, respectively.

CLOSING THE GAPS

Several gaps in the management of influenza persist since the 1918 pandemic.¹ These include gaps in epidemiology, prevention, diagnosis, treatment, and prognosis.

• Global networks wider than current ones are needed to address this global disease and to prioritize coordination efforts.
• Establishing and strengthening clinical capacity is needed in limited resource settings. New technologies are needed to expedite vaccine development and to achieve progress toward a universal vaccine.
• Current diagnostic tests do not distinguish between seasonal and novel influenza A viruses of zoonotic origin, which are expected to cause the next pandemic.
• Current antivirals have been shown to shorten duration of illness in outpatients with uncomplicated influenza, but the benefit in hospitalized patients has been less well established.
• In 2007, resistance of seasonal influenza A(H1N1) to oseltamivir became widespread. In 2009, pandemic influenza A(H1N1), which is highly susceptible to oseltamivir, replaced the seasonal virus and remains the predominantly circulating A(H1N1) strain.
• A small-molecule fragment, N-cyclohexyaltaurine, binds to the conserved hemagglutinin receptor-binding site in a manner that mimics the binding mode of the natural receptor sialic acid. This can serve as a template to guide the development of novel broad-spectrum small-molecule anti-influenza drugs.⁶³
• Biomarkers that can accurately predict development of severe disease in patients with influenza are needed.

This centennial year update focuses primarily on immunization, but also reviews epidemiology, transmission, and treatment.

EPIDEMIOLOGY

2017–2018 was a bad season

The 2017–2018 influenza epidemic was memorable, dominated by influenza A(H3N2) viruses with morbidity and mortality rates approaching pandemic numbers. It lasted 19 weeks, killed more people than any other epidemic since 2010, particularly children, and was associated with 30,453 hospitalizations—almost twice the previous season high in some parts of the United States.²

Regrettably, 171 unvaccinated children died during 2017–2018, accounting for almost 80% of deaths.² The mean age of the children who died was 7.1 years; 51% had at least 1 underlying medical condition placing them at risk for influenza-related complications, and 57% died after hospitalization.²

Recent estimates of the incidence of symptomatic influenza among all ages ranged from 3% to 11%, which is slightly lower than historical estimates. The rates were higher for children under age 18 than for adults.³ Interestingly, influenza A(H3N2) accounted for 50% of cases of non-mumps viral parotitis during the 2014–2015 influenza season in the United States.⁴

Influenza C exists but is rare

Influenza A and B account for almost all influenza-related outpatient visits and hospitalizations. Surveillance data from May 2013 through December 2016 showed that influenza C accounts for 0.5% of influenza-related outpatient visits and hospitalizations, particularly affecting children ages 6 to 24 months. Medical comorbidities and copathogens were seen in all patients requiring intensive care and in most hospitalizations.⁵ Diagnostic tests for influenza C are not widely available.

Dogs and cats: Factories for new flu strains?

While pigs and birds are the major reservoirs of influenza viral genetic diversity from which infection is transmitted to humans, dogs and cats have recently emerged as possible sources of novel reassortant influenza A.⁶ With their frequent close contact with humans, our pets may prove to pose a significant threat.

Obesity a risk factor for influenza

Obesity emerged as a risk factor for severe influenza in the 2009 pandemic. Recent data also showed that obesity increases the duration of influenza A virus shedding, thus increasing duration of contagiousness.⁷

Influenza a cardiovascular risk factor

Previous data showed that influenza was a risk factor for cardiovascular events. Two recent epi­demiologic studies from the United Kingdom showed that laboratory-confirmed influenza was associated with higher rates of myocardial infarction and stroke for up to 4 weeks.^8,9

Which strain is the biggest threat?

Predicting which emerging influenza serotype may cause the next pandemic is difficult, but influenza A(H7N9), which had not infected humans until 2013 but has since infected about 1,600 people in China and killed 37% of them, appears to have the greatest potential.¹⁰

National influenza surveillance programs and influenza-related social media applications have been developed and may get a boost from technology. A smartphone equipped with a temperature sensor can instantly detect one’s temperature with great precision. A 2018 study suggested that a smartphone-driven thermometry application correlated well with national influenza-like illness activity and improved its forecast in real time and up to 3 weeks in advance.¹¹

TRANSMISSION

Humidity may not block transmission

Animal studies have suggested that humidity in the air interferes with transmission of airborne influenza virus, partially from biologic inactivation. But when a recent study used humidity-controlled chambers to investigate the stability of the 2009 influenza A(H1N1) virus in suspended aerosols and stationary droplets, the virus remained infectious in aerosols across a wide range of relative humidities, challenging the common belief that humidity destabilizes respiratory viruses in aerosols.¹²

One sick passenger may not infect the whole plane

Transmission of respiratory viruses on airplane flights has long been considered a potential avenue for spreading influenza. However, a recent study that monitored movements of individuals on 10 transcontinental US flights and simulated inflight transmission based on these data showed a low probability of direct transmission, except for passengers seated in close proximity to an infectious passenger.¹³

WHAT’S IN THE NEW FLU SHOT?

The 2018–2019 quadrivalent vaccine for the Northern Hemisphere¹⁴ contains the following strains:

• A/Michigan/45/2015 A(H1N1)pdm09-like virus
• A/Singapore/INFIMH-16-0019/2016 (H3N2)-like virus
• B/Colorado/06/2017-like virus (Victoria lineage)
• B/Phuket/3073/2013-like virus (Yamagata lineage).

The A(H3N2) (Singapore) and B/Victoria lineage components are new this year. The A(H3N2) strain was the main cause of the 2018 influenza epidemic in the Southern Hemisphere.

The quadrivalent live-attenuated vaccine, which was not recommended during the 2016–2017 and 2017–2018 influenza seasons, has made a comeback and is recommended for the 2018–2019 season in people for whom it is appropriate based on age and comorbidities.¹⁵ Although it was effective against influenza B and A(H3N2) viruses, it was less effective against the influenza A(H1N1)pdm09-like viruses during the 2013–2014 and 2015–2016 seasons.

A/Slovenia/2903/2015, the new A(H1N1)pdm09-like virus included in the 2018–2019 quadrivalent live-attenuated vaccine, is significantly more immunogenic than its predecessor, A/Bolivia/559/2013, but its clinical effectiveness remains to be seen.

How effective is it?

Influenza vaccine effectiveness in the 2017–2018 influenza season was 36% overall, 67% against A(H1N1), 42% against influenza B, and 25% against A(H3N2).¹⁶ It is estimated that influenza vaccine prevents 300 to 4,000 deaths annually in the United States alone.¹⁷

A 2018 Cochrane review¹⁷ concluded that vaccination reduced the incidence of influenza by about half, with 2.3% of the population contracting the flu without vaccination compared with 0.9% with vaccination (risk ratio 0.41, 95% confidence interval 0.36–0.47). The same review found that 71 healthy adults need to be vaccinated to prevent 1 from experiencing influenza, and 29 to prevent 1 influenza-like illness.

Several recent studies showed that influenza vaccine effectiveness varied based on age and influenza serotype, with higher effectiveness in people ages 5 to 17 and ages 18 to 64 than in those age 65 and older.^18–20 A mathematical model of influenza transmission and vaccination in the United States determined that even relatively low-efficacy influenza vaccines can be very useful if optimally distributed across age groups.²¹

Vaccination rates are low, and ‘antivaxxers’ are on the rise

Although the influenza vaccine is recommended in the United States for all people age 6 months and older regardless of the state of their health, vaccination rates remain low. In 2016, only 37% of employed adults were vaccinated. The highest rate was for government employees (45%), followed by private employees (36%), followed by the self-employed (30%).²²

A national goal is to immunize 80% of all Americans and 90% of at-risk populations (which include children and the elderly).²³ The number of US hospitals that require their employees to be vaccinated increased from 37.1% in 2013 to 61.4% in 2017.²⁴ Regrettably, as of March 2018, 14 lawsuits addressing religious objections to hospital influenza vaccination mandates have been filed.²⁵

Despite hundreds of studies demonstrating the efficacy, safety, and cost savings of influenza vaccination, the antivaccine movement has been growing in the United States and worldwide.²⁶ All US states except West Virginia, Mississippi, and California allow nonmedical exemptions from vaccination based on religious or personal belief.²⁷ Several US metropolitan areas represent “hot spots” for these exemptions.²⁸ This may render such areas vulnerable to vaccine-preventable diseases, including influenza.

Herd immunity: We’re all in this together

Some argue that the potential adverse effects and the cost of vaccination outweigh the benefits, but the protective benefits of herd immunity are significant for those with comorbidities or compromised immunity.

Educating the public about herd immunity and local influenza vaccination uptake increases people’s willingness to be vaccinated.²⁹ A key educational point is that at least 70% of a community needs to be vaccinated to prevent community outbreaks; this protects everyone, including those who do not mount a protective antibody response to influenza vaccination and those who are not vaccinated.

DOES ANNUAL VACCINATION BLUNT ITS EFFECTIVENESS?

Some studies from the 1970s and 1980s raised concern over a possible negative effect of annual influenza vaccination on vaccine effectiveness. The “antigenic distance hypothesis” holds that vaccine effectiveness is influenced by antigenic similarity between the previous season’s vaccine serotypes and the epidemic serotypes, as well as the antigenic similarity between the serotypes of the current and previous seasons.

A meta-analysis of studies from 2010 through 2015 showed significant inconsistencies in repeat vaccination effects within and between seasons and serotypes. It also showed that vaccine effectiveness may be influenced by more than 1 previous season, particularly for influenza A(H3N2), in which repeated vaccination can blunt the hemagglutinin antibody response.³⁰

A study from Japan showed that people who needed medical attention for influenza in the previous season were at lower risk of a similar event in the current season.³¹ Prior-season influenza vaccination reduced current-season vaccine effectiveness only in those who did not have medically attended influenza in the prior season. This suggests that infection is more immunogenic than vaccination, but only against the serotype causing the infection and not the other serotypes included in the vaccine.

An Australian study showed that annual influenza vaccination did not decrease vaccine effectiveness against influenza-associated hospitalization. Rather, effectiveness increased by about 15% in those vaccinated in both current and previous seasons compared with those vaccinated in either season alone.³²

European investigators showed that repeated seasonal influenza vaccination in the elderly prevented the need for hospitalization due to influenza A(H3N2) and B, but not A(H1N1)pdm09.³³

High-dose vaccine for older adults

The high-dose influenza vaccine has been licensed since 2009 for use in the United States for people ages 65 and older.

Recent studies confirmed that high-dose vaccine is more effective than standard-dose vaccine in veterans³⁴ and US Medicare beneficiaries.³⁵

The high-dose vaccine is rapidly becoming the primary vaccine given to people ages 65 and older in retail pharmacies, where vaccination begins earlier in the season than in providers’ offices.³⁶ Some studies have shown that the standard-dose vaccine wanes in effectiveness toward the end of the influenza season (particularly if the season is long) if it is given very early. It remains to be seen whether the same applies to the high-dose influenza vaccine.

Some advocate twice-annual influenza vaccination, particularly for older adults living in tropical and subtropical areas, where influenza seasons are more prolonged. However, a recently published study observed reductions in influenza-specific hemagglutination inhibition and cell-mediated immunity after twice-annual vaccination.³⁷

Vaccination is beneficial during pregnancy

Many studies have shown the value of influenza vaccination during pregnancy for both mothers and their infants.

One recently published study showed that 18% of infants who developed influenza required hospitalization.³⁸ In that study, prenatal and postpartum maternal influenza vaccination decreased the odds of influenza in infants by 61% and 53%, respectively.

Another study showed that vaccine effectiveness did not vary by gestational age at vaccination.³⁹

Some studies have shown that influenza virus infection can increase susceptibility to certain bacterial infections. A post hoc analysis of an influenza vaccination study in pregnant women suggested that the vaccine was also associated with decreased rates of pertussis in these women.⁴⁰

Factors that make vaccination less effective

Several factors including age-related frailty and iatrogenic and disease-related immunosuppression can affect vaccine effectiveness.

Frailty. A recent study showed that vaccine effectiveness was 77.6% in nonfrail older adults but only 58.7% in frail older adults.⁴¹

Immunosuppression. Temporary discontinuation of methotrexate for 2 weeks after influenza vaccination in patients with rheumatoid arthritis improves vaccine immunogenicity without precipitating disease flare.⁴² Solid-organ and hematopoietic stem cell transplant recipients who received influenza vaccine were less likely to develop pneumonia and require intensive care unit admission.⁴³

The high-dose influenza vaccine is more immunogenic than the standard-dose vaccine in solid-organ transplant recipients.⁴⁴

Statins are widely prescribed and have recently been associated with reduced influenza vaccine effectiveness against medically attended acute respiratory illness, but their benefits in preventing cardiovascular events outweigh this risk.⁴⁵

FUTURE VACCINE CONSIDERATIONS

Moving away from eggs

During the annual egg-based production process, which takes several months, the influenza vaccine acquires antigenic changes that allow replication in eggs, particularly in the hemagglutinin protein, which mediates receptor binding. This process of egg adaptation may cause antigenic changes that decrease vaccine effectiveness against circulating viruses.

The cell-based baculovirus influenza vaccine grown in dog kidney cells has higher antigenic content and is not subject to the limitations of egg-based vaccine, although it still requires annual updates. A recombinant influenza vaccine reduces the probability of influenza-like illness by 30% compared with the egg-based influenza vaccine, but also still requires annual updates.⁴⁶ The market share of these non-egg-based vaccines is small, and thus their effectiveness has yet to be demonstrated.

The US Department of Defense administered the cell-based influenza vaccine to about one-third of Armed Forces personnel, their families, and retirees in the 2017–2018 influenza seasons, and data on its effectiveness are expected in the near future.⁴⁷

A universal vaccine would be ideal

The quest continues for a universal influenza vaccine, one that remains protective for several years and does not require annual updates.⁴⁸ Such a vaccine would protect against seasonal epidemic influenza drift variants and pandemic strains. More people could likely be persuaded to be vaccinated once rather than every year.

David Schumick, medical illustrator; adapted from reference 49; illustration of the influenza hemagglutinin created in part with data from reference 50.

An ideal universal vaccine would be suitable for all age groups, at least 75% effective against symptomatic influenza virus infection, protective against all influenza A viruses (influenza A, not B, causes pandemics and seasonal epidemics), and durable through multiple influenza seasons.⁵¹

Research and production of such a vaccine are expected to require funding of about $1 billion over the next 5 years.

Boosting effectiveness

Estimates of influenza vaccine effectiveness range from 40% to 60% in years when the vaccine viruses closely match the circulating viruses, and variably lower when they do not match. The efficacy of most other vaccines given to prevent other infections is much higher.

New technologies to improve influenza vaccine effectiveness are needed, particularly for influenza A(H3N2) viruses, which are rapidly evolving and are highly susceptible to egg-adaptive mutations in the manufacturing process.

In one study, a nanoparticle vaccine formulated with a saponin-based adjuvant induced hemagglutination inhibition responses that were even greater than those induced by the high-dose vaccine.⁵²

Immunoglobulin A (IgA) may be a more effective vaccine target than traditional influenza vaccines that target IgG, since different parts of IgA may engage the influenza virus simultaneously.⁵³

Vaccines can be developed more quickly than in the past. The timeline from viral sequencing to human studies with deoxyribonucleic acid plasmid vaccines decreased from 20 months in 2003 for the severe acquired respiratory syndrome coronavirus to 11 months in 2006 for influenza A/Indonesia/2006 (H5), to 4 months in 2009 for influenza A/California/2009 (H1), to 3.5 months in 2016 for Zika virus.⁵⁴ This is because it is possible today to sequence a virus and insert the genetic material into a vaccine platform without ever having to grow the virus.

Numerous studies have found anti-influenza medications to be effective. Nevertheless, in an analysis of the 2011–2016 influenza seasons, only 15% of high-risk patients were prescribed anti-influenza medications within 2 days of symptom onset, including 37% in those with laboratory-confirmed influenza.⁵⁵ Fever was associated with an increased rate of antiviral treatment, but 25% of high-risk outpatients were afebrile. Empiric treatment of 4 high-risk outpatients with acute respiratory illness was needed to treat 1 patient with influenza.⁵⁵

Treatment with a neuraminidase inhibitor within 2 days of illness has recently been shown to improve survival and shorten duration of viral shedding in patients with avian influenza A(H7N9) infection.⁵⁶ Antiviral treatment within 2 days of illness is associated with improved outcomes in transplant recipients⁵⁷ and with a lower risk of otitis media in children.⁵⁸

Appropriate anti-influenza treatment is as important as avoiding unnecessary antibiotics. Regrettably, as many as one-third of patients with laboratory-confirmed influenza are prescribed antibiotics.⁵⁹

The US Food and Drug Administration warns against fraudulent unapproved over-the-counter influenza products.⁶⁰

Baloxavir marboxil

Baloxavir marboxil is a new anti-influenza medication approved in Japan in February 2018 and anticipated to be available in the United States sometime in 2019.

This prodrug is hydrolyzed in vivo to the active metabolite, which selectively inhibits cap-dependent endonuclease enzyme, a key enzyme in initiation of messenger ribonucleic acid synthesis required for influenza viral replication.⁶¹

In a double-blind phase 3 trial, the median time to alleviation of influenza symptoms is 26.5 hours shorter with baloxavir marboxil than with placebo. One tablet was as effective as 5 days of the neuraminidase inhibitor oseltamivir and was associated with greater reduction in viral load 1 day after initiation, and similar side effects.⁶² Of concern is the emergence of nucleic acid substitutions conferring resistance to baloxavir; this occurred in 2.2% and 9.7% of baloxavir recipients in the phase 2 and 3 trials, respectively.

CLOSING THE GAPS

Several gaps in the management of influenza persist since the 1918 pandemic.¹ These include gaps in epidemiology, prevention, diagnosis, treatment, and prognosis.

• Global networks wider than current ones are needed to address this global disease and to prioritize coordination efforts.
• Establishing and strengthening clinical capacity is needed in limited resource settings. New technologies are needed to expedite vaccine development and to achieve progress toward a universal vaccine.
• Current diagnostic tests do not distinguish between seasonal and novel influenza A viruses of zoonotic origin, which are expected to cause the next pandemic.
• Current antivirals have been shown to shorten duration of illness in outpatients with uncomplicated influenza, but the benefit in hospitalized patients has been less well established.
• In 2007, resistance of seasonal influenza A(H1N1) to oseltamivir became widespread. In 2009, pandemic influenza A(H1N1), which is highly susceptible to oseltamivir, replaced the seasonal virus and remains the predominantly circulating A(H1N1) strain.
• A small-molecule fragment, N-cyclohexyaltaurine, binds to the conserved hemagglutinin receptor-binding site in a manner that mimics the binding mode of the natural receptor sialic acid. This can serve as a template to guide the development of novel broad-spectrum small-molecule anti-influenza drugs.⁶³
• Biomarkers that can accurately predict development of severe disease in patients with influenza are needed.

Two recent studies published in Cell, “Personalized Gut Mucosal Colonization Resistance to Empiric Probiotics Is Associated with Unique Host and Microbiome Features” and “Post-Antibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by Probiotics and Improved by Autologous FMT,” have received significant media coverage and are causing questions and concern among physicians and patients who use probiotic supplements.

The AGA Center for Gut Microbiome Research and Education provides three reminders for talking to your patient about probiotics:

1. Probiotics are generally thought to be safe for healthy individuals, but we don’t know the long-term consequences. For individuals who have a chronic disease, are immunocompromised, or otherwise vulnerable (such as the elderly), patients should seek guidance from physicians on whether probiotics may be appropriate. In general, probiotics should not be used indiscriminately; potential risk and benefit should be considered as for all human interventions.

2. This research does not conclude that probiotics are unsafe or useless for everyone. However, the results suggest that individuals may respond very differently to the same probiotic product depending on their diet, genetics, microbiome, and other aspects of their health. Experts are trying to better understand which bacteria are best for whom, under which conditions as we transition from an era of empiric medicine to precision medicine.

3. Probiotics currently on the market are foods or dietary supplements. To date, no probiotic products have been approved by the FDA to treat, mitigate, cure, or prevent specific diseases.

AGA has recently developed educational materials for patients on probiotics, which can be accessed at www.gastro.org/probiotics in English and Spanish. Share this resource with your patients by printing it out, emailing or uploading to your patient portal.
 

[email protected]

Two recent studies published in Cell, “Personalized Gut Mucosal Colonization Resistance to Empiric Probiotics Is Associated with Unique Host and Microbiome Features” and “Post-Antibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by Probiotics and Improved by Autologous FMT,” have received significant media coverage and are causing questions and concern among physicians and patients who use probiotic supplements.

The AGA Center for Gut Microbiome Research and Education provides three reminders for talking to your patient about probiotics:

1. Probiotics are generally thought to be safe for healthy individuals, but we don’t know the long-term consequences. For individuals who have a chronic disease, are immunocompromised, or otherwise vulnerable (such as the elderly), patients should seek guidance from physicians on whether probiotics may be appropriate. In general, probiotics should not be used indiscriminately; potential risk and benefit should be considered as for all human interventions.

2. This research does not conclude that probiotics are unsafe or useless for everyone. However, the results suggest that individuals may respond very differently to the same probiotic product depending on their diet, genetics, microbiome, and other aspects of their health. Experts are trying to better understand which bacteria are best for whom, under which conditions as we transition from an era of empiric medicine to precision medicine.

3. Probiotics currently on the market are foods or dietary supplements. To date, no probiotic products have been approved by the FDA to treat, mitigate, cure, or prevent specific diseases.

AGA has recently developed educational materials for patients on probiotics, which can be accessed at www.gastro.org/probiotics in English and Spanish. Share this resource with your patients by printing it out, emailing or uploading to your patient portal.
 

[email protected]

Two recent studies published in Cell, “Personalized Gut Mucosal Colonization Resistance to Empiric Probiotics Is Associated with Unique Host and Microbiome Features” and “Post-Antibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by Probiotics and Improved by Autologous FMT,” have received significant media coverage and are causing questions and concern among physicians and patients who use probiotic supplements.

The AGA Center for Gut Microbiome Research and Education provides three reminders for talking to your patient about probiotics:

1. Probiotics are generally thought to be safe for healthy individuals, but we don’t know the long-term consequences. For individuals who have a chronic disease, are immunocompromised, or otherwise vulnerable (such as the elderly), patients should seek guidance from physicians on whether probiotics may be appropriate. In general, probiotics should not be used indiscriminately; potential risk and benefit should be considered as for all human interventions.

2. This research does not conclude that probiotics are unsafe or useless for everyone. However, the results suggest that individuals may respond very differently to the same probiotic product depending on their diet, genetics, microbiome, and other aspects of their health. Experts are trying to better understand which bacteria are best for whom, under which conditions as we transition from an era of empiric medicine to precision medicine.

3. Probiotics currently on the market are foods or dietary supplements. To date, no probiotic products have been approved by the FDA to treat, mitigate, cure, or prevent specific diseases.

AGA has recently developed educational materials for patients on probiotics, which can be accessed at www.gastro.org/probiotics in English and Spanish. Share this resource with your patients by printing it out, emailing or uploading to your patient portal.
 

[email protected]

Each year, we provide more than $2 million in research funding.

What will the practice of gastroenterology look like in 20 years? It is our hope that physicians have an abundance of new tools and treatments to care for their patients suffering from digestive disorders.

How will we get there? New treatments and devices are the result of years of research.

To help make this dream a reality, AGA – through the AGA Research Foundation – has made a commitment to support investigators in GI and hepatology with its Research Awards Program. In the past year, the foundation provided $2.1 million in research funding to 41 highly qualified investigators. These diverse researchers range from young investigators to more seasoned leaders in GI, all embarking on novel research projects that will advance our understanding of digestive conditions and pave the way for future discoveries in the field.

The AGA Research Foundation sincerely thanks all of its donors – without your gifts, this work wouldn’t be possible.

Please join us to help spark the scientific breakthroughs of today so clinicians will have the tools to improve care tomorrow. Donate your tax-deductible gift today at www.gastro.org/donateonline.
 

[email protected]

Each year, we provide more than $2 million in research funding.

What will the practice of gastroenterology look like in 20 years? It is our hope that physicians have an abundance of new tools and treatments to care for their patients suffering from digestive disorders.

How will we get there? New treatments and devices are the result of years of research.

To help make this dream a reality, AGA – through the AGA Research Foundation – has made a commitment to support investigators in GI and hepatology with its Research Awards Program. In the past year, the foundation provided $2.1 million in research funding to 41 highly qualified investigators. These diverse researchers range from young investigators to more seasoned leaders in GI, all embarking on novel research projects that will advance our understanding of digestive conditions and pave the way for future discoveries in the field.

The AGA Research Foundation sincerely thanks all of its donors – without your gifts, this work wouldn’t be possible.

Please join us to help spark the scientific breakthroughs of today so clinicians will have the tools to improve care tomorrow. Donate your tax-deductible gift today at www.gastro.org/donateonline.
 

[email protected]

Each year, we provide more than $2 million in research funding.

What will the practice of gastroenterology look like in 20 years? It is our hope that physicians have an abundance of new tools and treatments to care for their patients suffering from digestive disorders.

How will we get there? New treatments and devices are the result of years of research.

To help make this dream a reality, AGA – through the AGA Research Foundation – has made a commitment to support investigators in GI and hepatology with its Research Awards Program. In the past year, the foundation provided $2.1 million in research funding to 41 highly qualified investigators. These diverse researchers range from young investigators to more seasoned leaders in GI, all embarking on novel research projects that will advance our understanding of digestive conditions and pave the way for future discoveries in the field.

The AGA Research Foundation sincerely thanks all of its donors – without your gifts, this work wouldn’t be possible.

Please join us to help spark the scientific breakthroughs of today so clinicians will have the tools to improve care tomorrow. Donate your tax-deductible gift today at www.gastro.org/donateonline.
 

[email protected]

The evening James Wu (not his real name) learned he had leukemia, he asked his nurse to please get his doctor. There was something important he had to ask her.

“I have this mole. On my back.” He squirmed anxiously. “Doctor, is it dangerous?”

James did have something dangerous – though it had nothing to do with a skin blemish he’d had his whole life. Earlier that day, I had pulled up a chair and told him we had final results from the bone marrow biopsy I had done the day before. It was unfortunately what we suspected. James had cancer. It was a type of cancer called acute lymphoblastic leukemia, a cancer of the blood.

James had said nothing. He looked down, shocked, and crestfallen. Even though we had planted the seeds early that this was likely cancer, the confirmation is always heartbreaking. It closes the door on optimism, shutting out the slim hope that it could be something else. Anything else.

I could have said more. But I waited.

I stopped talking because my experiences have mirrored what the data shows: Once a patient hears “cancer,” they often stop listening. We could go on, spelling out the next steps and treatment options. But patients usually don’t retain it. The details don’t mean anything right now.

Instead, I usually just hint at what’s to come. Most importantly, I reassure them that we are with them now, every step of the way. This will be a road we’ll walk together.

It was silent for a while. Finally, James spoke.

“OK,” he said. “So … it’s not something in my diet?”

“No. It’s a leukemia.”

“It cannot be related to stress?”

“No. You did nothing to cause this.”

For most, it’s a process. After dropping the diagnostic bomb, treatment is another conversation. Prognosis another. If I have the luxury of continuity, I try to carve the information into chunks, giving patients time to process each piece.

This felt especially salient for James, who was in his mid-30s and had never even been in a hospital before, much less dealt with a serious diagnosis. His grandparents had died of “old age,” and no one in his family had been sick. He had never interacted with the health care system in a meaningful way. Even words like chemotherapy seemed beyond him, existing in a different world from the one he lived in. Cancer was abstract.

“Would I be awake during chemotherapy?”

“Yes. Completely.”

James had a wife, a 2-year-old, and a full-time job. Watching his daughter aimlessly wander around the hospital room, I wondered, were they planning on having more children? We could get the fertility specialist to see him before starting chemotherapy.

I looked at his nightstand, where his laptop was open to data-packed spreadsheets, and I wondered what his work meant for him. Would he want to continue working through his treatment? We could have our social worker write a letter to his employer.

There would be time for all of that. Later.

I said that, for tonight, there would be nothing else. Tomorrow, we would do an ultrasound of his heart and arrange for a special IV to administer chemotherapy. Then, I would come back, and we would talk about the treatment, and what it all means, in a lot more detail.

I asked James if he had any questions right now. As expected, he said no. Until a few hours later, when I was called about his very important question.

That day, looking into the terrified face of a previously healthy 30-something-year-old, I could see the future. I could see the month-long hospital stay. The chemotherapy would kill his immune system, he would get fevers, and bacteria would grow in his bloodstream. He’d get short of breath and we’d find fungus growing in his lungs. He’d take an antifungal and it would make him hallucinate. Maybe he’d spend a few days in the ICU, requiring a large catheter in his neck just to maintain his blood pressure. He would bleed; we would transfuse him with blood. He would get so many bone marrow biopsies and lumbar punctures that his skin would be marked, and he would tell each proceduralist where to go. It would be months of treatment. And then miraculously, it would go into remission. He would celebrate; his wife would cry. Maybe he’d get a bone marrow transplant; we’d find out his brother was a match, and he’d fly in from thousands of miles away. He would get graft-versus-host disease, and his skin would harden. And even after all of that, even if his bone marrow was clear of disease, he would not say he was “cured.” He would live in fear of this because he would know how likely it was to relapse. Maybe in a few months, maybe in a few years. Every cough would be a catastrophe. Every ache a fear of the worst. He would become intimately familiar with words like minimal residual disease and neutropenia, frequent the message boards, and always have a bag packed in case he needed to come back to the hospital. Everything else, from that moment on, would come in second place.

There, then, with his toddler playfully tugging at his hospital gown, I said none of that.

Instead, I examined his back. I told him his mole looked fine.

“Wow,” he breathed a long sigh of relief. “Thank you, doctor. That’s good news.”

Certain details of this story were modified slightly to protect privacy.
 

Dr. Yurkiewicz is a fellow in hematology and oncology at Stanford (Calif.) University. Follow her on Twitter @ilanayurkiewicz.

The evening James Wu (not his real name) learned he had leukemia, he asked his nurse to please get his doctor. There was something important he had to ask her.

“I have this mole. On my back.” He squirmed anxiously. “Doctor, is it dangerous?”

James did have something dangerous – though it had nothing to do with a skin blemish he’d had his whole life. Earlier that day, I had pulled up a chair and told him we had final results from the bone marrow biopsy I had done the day before. It was unfortunately what we suspected. James had cancer. It was a type of cancer called acute lymphoblastic leukemia, a cancer of the blood.

James had said nothing. He looked down, shocked, and crestfallen. Even though we had planted the seeds early that this was likely cancer, the confirmation is always heartbreaking. It closes the door on optimism, shutting out the slim hope that it could be something else. Anything else.

I could have said more. But I waited.

I stopped talking because my experiences have mirrored what the data shows: Once a patient hears “cancer,” they often stop listening. We could go on, spelling out the next steps and treatment options. But patients usually don’t retain it. The details don’t mean anything right now.

Instead, I usually just hint at what’s to come. Most importantly, I reassure them that we are with them now, every step of the way. This will be a road we’ll walk together.

It was silent for a while. Finally, James spoke.

“OK,” he said. “So … it’s not something in my diet?”

“No. It’s a leukemia.”

“It cannot be related to stress?”

“No. You did nothing to cause this.”

For most, it’s a process. After dropping the diagnostic bomb, treatment is another conversation. Prognosis another. If I have the luxury of continuity, I try to carve the information into chunks, giving patients time to process each piece.

This felt especially salient for James, who was in his mid-30s and had never even been in a hospital before, much less dealt with a serious diagnosis. His grandparents had died of “old age,” and no one in his family had been sick. He had never interacted with the health care system in a meaningful way. Even words like chemotherapy seemed beyond him, existing in a different world from the one he lived in. Cancer was abstract.

“Would I be awake during chemotherapy?”

“Yes. Completely.”

James had a wife, a 2-year-old, and a full-time job. Watching his daughter aimlessly wander around the hospital room, I wondered, were they planning on having more children? We could get the fertility specialist to see him before starting chemotherapy.

I looked at his nightstand, where his laptop was open to data-packed spreadsheets, and I wondered what his work meant for him. Would he want to continue working through his treatment? We could have our social worker write a letter to his employer.

There would be time for all of that. Later.

I said that, for tonight, there would be nothing else. Tomorrow, we would do an ultrasound of his heart and arrange for a special IV to administer chemotherapy. Then, I would come back, and we would talk about the treatment, and what it all means, in a lot more detail.

I asked James if he had any questions right now. As expected, he said no. Until a few hours later, when I was called about his very important question.

That day, looking into the terrified face of a previously healthy 30-something-year-old, I could see the future. I could see the month-long hospital stay. The chemotherapy would kill his immune system, he would get fevers, and bacteria would grow in his bloodstream. He’d get short of breath and we’d find fungus growing in his lungs. He’d take an antifungal and it would make him hallucinate. Maybe he’d spend a few days in the ICU, requiring a large catheter in his neck just to maintain his blood pressure. He would bleed; we would transfuse him with blood. He would get so many bone marrow biopsies and lumbar punctures that his skin would be marked, and he would tell each proceduralist where to go. It would be months of treatment. And then miraculously, it would go into remission. He would celebrate; his wife would cry. Maybe he’d get a bone marrow transplant; we’d find out his brother was a match, and he’d fly in from thousands of miles away. He would get graft-versus-host disease, and his skin would harden. And even after all of that, even if his bone marrow was clear of disease, he would not say he was “cured.” He would live in fear of this because he would know how likely it was to relapse. Maybe in a few months, maybe in a few years. Every cough would be a catastrophe. Every ache a fear of the worst. He would become intimately familiar with words like minimal residual disease and neutropenia, frequent the message boards, and always have a bag packed in case he needed to come back to the hospital. Everything else, from that moment on, would come in second place.

There, then, with his toddler playfully tugging at his hospital gown, I said none of that.

Instead, I examined his back. I told him his mole looked fine.

“Wow,” he breathed a long sigh of relief. “Thank you, doctor. That’s good news.”

Certain details of this story were modified slightly to protect privacy.
 

Dr. Yurkiewicz is a fellow in hematology and oncology at Stanford (Calif.) University. Follow her on Twitter @ilanayurkiewicz.

The evening James Wu (not his real name) learned he had leukemia, he asked his nurse to please get his doctor. There was something important he had to ask her.

“I have this mole. On my back.” He squirmed anxiously. “Doctor, is it dangerous?”

James did have something dangerous – though it had nothing to do with a skin blemish he’d had his whole life. Earlier that day, I had pulled up a chair and told him we had final results from the bone marrow biopsy I had done the day before. It was unfortunately what we suspected. James had cancer. It was a type of cancer called acute lymphoblastic leukemia, a cancer of the blood.

James had said nothing. He looked down, shocked, and crestfallen. Even though we had planted the seeds early that this was likely cancer, the confirmation is always heartbreaking. It closes the door on optimism, shutting out the slim hope that it could be something else. Anything else.

I could have said more. But I waited.

I stopped talking because my experiences have mirrored what the data shows: Once a patient hears “cancer,” they often stop listening. We could go on, spelling out the next steps and treatment options. But patients usually don’t retain it. The details don’t mean anything right now.

Instead, I usually just hint at what’s to come. Most importantly, I reassure them that we are with them now, every step of the way. This will be a road we’ll walk together.

It was silent for a while. Finally, James spoke.

“OK,” he said. “So … it’s not something in my diet?”

“No. It’s a leukemia.”

“It cannot be related to stress?”

“No. You did nothing to cause this.”

For most, it’s a process. After dropping the diagnostic bomb, treatment is another conversation. Prognosis another. If I have the luxury of continuity, I try to carve the information into chunks, giving patients time to process each piece.

This felt especially salient for James, who was in his mid-30s and had never even been in a hospital before, much less dealt with a serious diagnosis. His grandparents had died of “old age,” and no one in his family had been sick. He had never interacted with the health care system in a meaningful way. Even words like chemotherapy seemed beyond him, existing in a different world from the one he lived in. Cancer was abstract.

“Would I be awake during chemotherapy?”

“Yes. Completely.”

James had a wife, a 2-year-old, and a full-time job. Watching his daughter aimlessly wander around the hospital room, I wondered, were they planning on having more children? We could get the fertility specialist to see him before starting chemotherapy.

I looked at his nightstand, where his laptop was open to data-packed spreadsheets, and I wondered what his work meant for him. Would he want to continue working through his treatment? We could have our social worker write a letter to his employer.

There would be time for all of that. Later.

I said that, for tonight, there would be nothing else. Tomorrow, we would do an ultrasound of his heart and arrange for a special IV to administer chemotherapy. Then, I would come back, and we would talk about the treatment, and what it all means, in a lot more detail.

I asked James if he had any questions right now. As expected, he said no. Until a few hours later, when I was called about his very important question.

That day, looking into the terrified face of a previously healthy 30-something-year-old, I could see the future. I could see the month-long hospital stay. The chemotherapy would kill his immune system, he would get fevers, and bacteria would grow in his bloodstream. He’d get short of breath and we’d find fungus growing in his lungs. He’d take an antifungal and it would make him hallucinate. Maybe he’d spend a few days in the ICU, requiring a large catheter in his neck just to maintain his blood pressure. He would bleed; we would transfuse him with blood. He would get so many bone marrow biopsies and lumbar punctures that his skin would be marked, and he would tell each proceduralist where to go. It would be months of treatment. And then miraculously, it would go into remission. He would celebrate; his wife would cry. Maybe he’d get a bone marrow transplant; we’d find out his brother was a match, and he’d fly in from thousands of miles away. He would get graft-versus-host disease, and his skin would harden. And even after all of that, even if his bone marrow was clear of disease, he would not say he was “cured.” He would live in fear of this because he would know how likely it was to relapse. Maybe in a few months, maybe in a few years. Every cough would be a catastrophe. Every ache a fear of the worst. He would become intimately familiar with words like minimal residual disease and neutropenia, frequent the message boards, and always have a bag packed in case he needed to come back to the hospital. Everything else, from that moment on, would come in second place.

There, then, with his toddler playfully tugging at his hospital gown, I said none of that.

Instead, I examined his back. I told him his mole looked fine.

“Wow,” he breathed a long sigh of relief. “Thank you, doctor. That’s good news.”

Certain details of this story were modified slightly to protect privacy.
 

Dr. Yurkiewicz is a fellow in hematology and oncology at Stanford (Calif.) University. Follow her on Twitter @ilanayurkiewicz.

Crohn’s disease was significantly associated with anal canal high-risk human papillomavirus (HPV) infection in a prospective, single-center study of patients undergoing colonoscopy for various indications.

xrender/Thinkstock

High-risk HPV and HPV strain 16 were detected in 30% of patients with Crohn’s disease and 18% of patients without Crohn’s disease (P = .005), said Lucine Vuitton, MD, of University Hospital of Besançon (France) and her associates. “Increasing our knowledge of HPV infection of anal tissues could help physicians identify populations at risk and promote prophylaxis with vaccination and adequate screening,” the investigators wrote in the November issue of Clinical Gastroenterology and Hepatology.

Most anal cancers are squamous cell carcinomas, for which infection with high-risk HPV (especially high-risk HPV16) is a driving risk factor. Case studies and literature reviews have linked Crohn’s disease to increased rates of anal canal cancers, but population-based data were lacking, the researchers wrote. Therefore, they prospectively analyzed anal tissue samples from 467 consecutive patients undergoing colonoscopy at a tertiary care center in France. Median age was 54 years (interquartile range, 18-86 years), and 52% of patients were women. No patient had detectable macroscopic neoplastic lesions at the anal margin at baseline.

The researchers used the QIAamp DNA Blood minikit (Qiagen) for DNA extraction and the INNO-LiPA HPV Genotyping Extra kit (Fujirebio Diagnostics) for HPV DNA detection and genotyping. These methods identified HPV DNA in anal tissue samples from 34% of the patients and high-risk HPV DNA in 18% of patients. The most prevalent genotype was HPV16 (detected in 7% of samples), followed by HPV51, HPV52, and HPV39.

A total of 112 patients were receiving at least one immunosuppressive treatment for inflammatory bowel disease or another condition. Seventy patients had Crohn’s disease, and 29 patients had ulcerative colitis. The prevalence of anal canal high-risk HPV and HPV16 infection in patients with ulcerative colitis was similar to that seen in those without inflammatory bowel disease. However, patients with Crohn’s disease were more likely to have anal canal high-risk HPV infection (30%) and HPV16 infection (14%), compared with patients without Crohn’s disease (18% and 7%, respectively). Additionally, among 22 patients with Crohn’s disease and perianal involvement, 11 had HPV DNA in the anal canal versus 30% of other patients with inflammatory bowel disease.

Women were more likely to have anal canal high-risk HPV (23%) infection than were men (13%; P = .004). In a multivariable analysis of self-reported data and medical data, significant risk factors for high-risk HPV infection included female sex, a history of sexually transmitted infections, having more than 10 sexual partners over the life course, having at least one sexual partner during the past year, current smoking, and immunosuppressive therapy. The multivariable analysis also linked Crohn’s disease with anal canal high-risk HPV16 infection (odds ratio, 3.8), but the association did not reach statistical significance (95% confidence interval, 0.9-16.9).

Most patients with Crohn’s disease were on immunosuppressive therapy, “which markedly affected statistical power,” the researchers commented. Nonetheless, their findings support HPV vaccination for patients with Crohn’s disease, as well as efforts to target high-risk patients who could benefit from anal cancer screening, they said.

The work was funded by the APICHU research grant from Besançon (France) University Hospital and by the Région de Franche-Comté. Dr. Vuitton disclosed ties to AbbVie, Ferring, MSD, Hospira, Janssen, and Takeda. Three coinvestigators disclosed relationships with AbbVie, MSD, Hospira, Mayoli, and Roche.

SOURCE: Vuitton L et al. Clin Gastroenterol Hepatol. 2018 Nov. doi: 10.1016/j.cgh.2018.03.008.

Crohn’s disease was significantly associated with anal canal high-risk human papillomavirus (HPV) infection in a prospective, single-center study of patients undergoing colonoscopy for various indications.

xrender/Thinkstock

High-risk HPV and HPV strain 16 were detected in 30% of patients with Crohn’s disease and 18% of patients without Crohn’s disease (P = .005), said Lucine Vuitton, MD, of University Hospital of Besançon (France) and her associates. “Increasing our knowledge of HPV infection of anal tissues could help physicians identify populations at risk and promote prophylaxis with vaccination and adequate screening,” the investigators wrote in the November issue of Clinical Gastroenterology and Hepatology.

Most anal cancers are squamous cell carcinomas, for which infection with high-risk HPV (especially high-risk HPV16) is a driving risk factor. Case studies and literature reviews have linked Crohn’s disease to increased rates of anal canal cancers, but population-based data were lacking, the researchers wrote. Therefore, they prospectively analyzed anal tissue samples from 467 consecutive patients undergoing colonoscopy at a tertiary care center in France. Median age was 54 years (interquartile range, 18-86 years), and 52% of patients were women. No patient had detectable macroscopic neoplastic lesions at the anal margin at baseline.

The researchers used the QIAamp DNA Blood minikit (Qiagen) for DNA extraction and the INNO-LiPA HPV Genotyping Extra kit (Fujirebio Diagnostics) for HPV DNA detection and genotyping. These methods identified HPV DNA in anal tissue samples from 34% of the patients and high-risk HPV DNA in 18% of patients. The most prevalent genotype was HPV16 (detected in 7% of samples), followed by HPV51, HPV52, and HPV39.

A total of 112 patients were receiving at least one immunosuppressive treatment for inflammatory bowel disease or another condition. Seventy patients had Crohn’s disease, and 29 patients had ulcerative colitis. The prevalence of anal canal high-risk HPV and HPV16 infection in patients with ulcerative colitis was similar to that seen in those without inflammatory bowel disease. However, patients with Crohn’s disease were more likely to have anal canal high-risk HPV infection (30%) and HPV16 infection (14%), compared with patients without Crohn’s disease (18% and 7%, respectively). Additionally, among 22 patients with Crohn’s disease and perianal involvement, 11 had HPV DNA in the anal canal versus 30% of other patients with inflammatory bowel disease.

Women were more likely to have anal canal high-risk HPV (23%) infection than were men (13%; P = .004). In a multivariable analysis of self-reported data and medical data, significant risk factors for high-risk HPV infection included female sex, a history of sexually transmitted infections, having more than 10 sexual partners over the life course, having at least one sexual partner during the past year, current smoking, and immunosuppressive therapy. The multivariable analysis also linked Crohn’s disease with anal canal high-risk HPV16 infection (odds ratio, 3.8), but the association did not reach statistical significance (95% confidence interval, 0.9-16.9).

Most patients with Crohn’s disease were on immunosuppressive therapy, “which markedly affected statistical power,” the researchers commented. Nonetheless, their findings support HPV vaccination for patients with Crohn’s disease, as well as efforts to target high-risk patients who could benefit from anal cancer screening, they said.

The work was funded by the APICHU research grant from Besançon (France) University Hospital and by the Région de Franche-Comté. Dr. Vuitton disclosed ties to AbbVie, Ferring, MSD, Hospira, Janssen, and Takeda. Three coinvestigators disclosed relationships with AbbVie, MSD, Hospira, Mayoli, and Roche.

SOURCE: Vuitton L et al. Clin Gastroenterol Hepatol. 2018 Nov. doi: 10.1016/j.cgh.2018.03.008.

Crohn’s disease was significantly associated with anal canal high-risk human papillomavirus (HPV) infection in a prospective, single-center study of patients undergoing colonoscopy for various indications.

xrender/Thinkstock

High-risk HPV and HPV strain 16 were detected in 30% of patients with Crohn’s disease and 18% of patients without Crohn’s disease (P = .005), said Lucine Vuitton, MD, of University Hospital of Besançon (France) and her associates. “Increasing our knowledge of HPV infection of anal tissues could help physicians identify populations at risk and promote prophylaxis with vaccination and adequate screening,” the investigators wrote in the November issue of Clinical Gastroenterology and Hepatology.

Most anal cancers are squamous cell carcinomas, for which infection with high-risk HPV (especially high-risk HPV16) is a driving risk factor. Case studies and literature reviews have linked Crohn’s disease to increased rates of anal canal cancers, but population-based data were lacking, the researchers wrote. Therefore, they prospectively analyzed anal tissue samples from 467 consecutive patients undergoing colonoscopy at a tertiary care center in France. Median age was 54 years (interquartile range, 18-86 years), and 52% of patients were women. No patient had detectable macroscopic neoplastic lesions at the anal margin at baseline.

The researchers used the QIAamp DNA Blood minikit (Qiagen) for DNA extraction and the INNO-LiPA HPV Genotyping Extra kit (Fujirebio Diagnostics) for HPV DNA detection and genotyping. These methods identified HPV DNA in anal tissue samples from 34% of the patients and high-risk HPV DNA in 18% of patients. The most prevalent genotype was HPV16 (detected in 7% of samples), followed by HPV51, HPV52, and HPV39.

A total of 112 patients were receiving at least one immunosuppressive treatment for inflammatory bowel disease or another condition. Seventy patients had Crohn’s disease, and 29 patients had ulcerative colitis. The prevalence of anal canal high-risk HPV and HPV16 infection in patients with ulcerative colitis was similar to that seen in those without inflammatory bowel disease. However, patients with Crohn’s disease were more likely to have anal canal high-risk HPV infection (30%) and HPV16 infection (14%), compared with patients without Crohn’s disease (18% and 7%, respectively). Additionally, among 22 patients with Crohn’s disease and perianal involvement, 11 had HPV DNA in the anal canal versus 30% of other patients with inflammatory bowel disease.

Women were more likely to have anal canal high-risk HPV (23%) infection than were men (13%; P = .004). In a multivariable analysis of self-reported data and medical data, significant risk factors for high-risk HPV infection included female sex, a history of sexually transmitted infections, having more than 10 sexual partners over the life course, having at least one sexual partner during the past year, current smoking, and immunosuppressive therapy. The multivariable analysis also linked Crohn’s disease with anal canal high-risk HPV16 infection (odds ratio, 3.8), but the association did not reach statistical significance (95% confidence interval, 0.9-16.9).

Most patients with Crohn’s disease were on immunosuppressive therapy, “which markedly affected statistical power,” the researchers commented. Nonetheless, their findings support HPV vaccination for patients with Crohn’s disease, as well as efforts to target high-risk patients who could benefit from anal cancer screening, they said.

The work was funded by the APICHU research grant from Besançon (France) University Hospital and by the Région de Franche-Comté. Dr. Vuitton disclosed ties to AbbVie, Ferring, MSD, Hospira, Janssen, and Takeda. Three coinvestigators disclosed relationships with AbbVie, MSD, Hospira, Mayoli, and Roche.

SOURCE: Vuitton L et al. Clin Gastroenterol Hepatol. 2018 Nov. doi: 10.1016/j.cgh.2018.03.008.