The Food and Drug Administration on May 10 granted emergency use authorization (EUA) for the Pfizer coronavirus vaccine to be given to children 12-15 years old.  

The much-expected decision increases the likelihood that schools in the United States will fully reopen in the fall – a goal of both the Biden and Trump administrations.

Acting FDA Commissioner Janet Woodcock, MD, called the decision “a significant step” in “returning to a sense of normalcy.”

“Today’s action allows for a younger population to be protected from COVID-19, bringing us closer to returning to a sense of normalcy and to ending the pandemic,” she said in a statement. “Parents and guardians can rest assured that the agency undertook a rigorous and thorough review of all available data, as we have with all of our COVID-19 vaccine emergency use authorizations.”

The Pfizer adolescent vaccine is not yet a done deal, though.

Next, the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices will decide on May 12 whether to recommend use of the vaccine in this age group. After that, CDC Director Rochelle Walensky, MD, will decide whether to give the green light for the vaccine to be administered to that age group.

The FDA action on May 10 amends the Dec. 11, 2020, emergency use authorization that allowed the Pfizer vaccine to be given to people 16 and older. Pfizer was the first company to receive an EUA for its adult vaccine and is the first to receive authorization for its adolescent vaccine. Pfizer is conducting clinical trials on much younger children, too.

The Moderna and Johnson & Johnson vaccines are authorized for people 18 and up. Moderna also has launched clinical trials in children.

Most health experts have said the United States needs to vaccinate children before the COVID-19 pandemic can truly be brought under control. The 12- to 15-year-old group represents 17 million people, about 5% of the population. Thus far, 58% of U.S. adults have had at least one dose of a vaccine and 34.8% of all Americans are fully vaccinated.

American Academy of Pediatrics President Lee Savio Beers, MD, praised the agency’s decision, calling it a “critically important step in bringing life-saving vaccines to children and adolescents. Our youngest generations have shouldered heavy burdens over the past year, and the vaccine is a hopeful sign that they will be able to begin to experience all the activities that are so important for their health and development.”

President Joe Biden recently announced a new strategy for expanding vaccinations in which vaccinating 12- to 15-year-olds was a key component. He said the administration was ready to ship the adolescent vaccine directly to pharmacies and pediatricians to speed up the vaccination rate.

In March, Anthony S. Fauci, MD, told a Senate committee, “We don’t really know what that magical point of herd immunity is, but we do know that if we get the overwhelming population vaccinated, we’re going to be in good shape. … We ultimately would like to get and have to get children into that mix.” 

Pfizer submitted data to the FDA in late March showing its mRNA vaccine was 100% effective at preventing COVID-19 infection in children ages 12-15 in clinical trials.

Though most children have milder symptoms when infected with the coronavirus, about 1.5 million cases in children aged 11-17 were reported to the CDC between March 1, 2020, and April 30 of this year, the FDA news release said.

Albert Bourla, CEO of Pfizer, tweeted that “today brings very encouraging news for families and adolescents across the United States.

“While this is a meaningful step forward, we are still in a critical period of combating #COVID19 around the world. In the coming weeks, we hope to continue to receive authorizations from global regulators to support worldwide vaccination efforts,” he said. 

“It’s essential for children to be vaccinated against COVID-19. According to data compiled by the AAP and Children’s Hospital Association, more than 3.8 million children have tested positive for COVID-19 in the United States since the start of the pandemic,” said Dr. Savio Beers. “While fewer children than adults have suffered the most severe disease, this is not a benign disease in children. Thousands of children have been hospitalized, and hundreds have died. We will soon have a very safe, highly effective vaccine that can prevent so much suffering. I encourage parents to talk with their pediatricians about how to get the vaccine for their adolescents as soon as they are eligible.”

A version of this article first appeared on Medscape.com.

The Food and Drug Administration on May 10 granted emergency use authorization (EUA) for the Pfizer coronavirus vaccine to be given to children 12-15 years old.  

The much-expected decision increases the likelihood that schools in the United States will fully reopen in the fall – a goal of both the Biden and Trump administrations.

Acting FDA Commissioner Janet Woodcock, MD, called the decision “a significant step” in “returning to a sense of normalcy.”

“Today’s action allows for a younger population to be protected from COVID-19, bringing us closer to returning to a sense of normalcy and to ending the pandemic,” she said in a statement. “Parents and guardians can rest assured that the agency undertook a rigorous and thorough review of all available data, as we have with all of our COVID-19 vaccine emergency use authorizations.”

The Pfizer adolescent vaccine is not yet a done deal, though.

Next, the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices will decide on May 12 whether to recommend use of the vaccine in this age group. After that, CDC Director Rochelle Walensky, MD, will decide whether to give the green light for the vaccine to be administered to that age group.

The FDA action on May 10 amends the Dec. 11, 2020, emergency use authorization that allowed the Pfizer vaccine to be given to people 16 and older. Pfizer was the first company to receive an EUA for its adult vaccine and is the first to receive authorization for its adolescent vaccine. Pfizer is conducting clinical trials on much younger children, too.

The Moderna and Johnson & Johnson vaccines are authorized for people 18 and up. Moderna also has launched clinical trials in children.

Most health experts have said the United States needs to vaccinate children before the COVID-19 pandemic can truly be brought under control. The 12- to 15-year-old group represents 17 million people, about 5% of the population. Thus far, 58% of U.S. adults have had at least one dose of a vaccine and 34.8% of all Americans are fully vaccinated.

American Academy of Pediatrics President Lee Savio Beers, MD, praised the agency’s decision, calling it a “critically important step in bringing life-saving vaccines to children and adolescents. Our youngest generations have shouldered heavy burdens over the past year, and the vaccine is a hopeful sign that they will be able to begin to experience all the activities that are so important for their health and development.”

President Joe Biden recently announced a new strategy for expanding vaccinations in which vaccinating 12- to 15-year-olds was a key component. He said the administration was ready to ship the adolescent vaccine directly to pharmacies and pediatricians to speed up the vaccination rate.

In March, Anthony S. Fauci, MD, told a Senate committee, “We don’t really know what that magical point of herd immunity is, but we do know that if we get the overwhelming population vaccinated, we’re going to be in good shape. … We ultimately would like to get and have to get children into that mix.” 

Pfizer submitted data to the FDA in late March showing its mRNA vaccine was 100% effective at preventing COVID-19 infection in children ages 12-15 in clinical trials.

Though most children have milder symptoms when infected with the coronavirus, about 1.5 million cases in children aged 11-17 were reported to the CDC between March 1, 2020, and April 30 of this year, the FDA news release said.

Albert Bourla, CEO of Pfizer, tweeted that “today brings very encouraging news for families and adolescents across the United States.

“While this is a meaningful step forward, we are still in a critical period of combating #COVID19 around the world. In the coming weeks, we hope to continue to receive authorizations from global regulators to support worldwide vaccination efforts,” he said. 

“It’s essential for children to be vaccinated against COVID-19. According to data compiled by the AAP and Children’s Hospital Association, more than 3.8 million children have tested positive for COVID-19 in the United States since the start of the pandemic,” said Dr. Savio Beers. “While fewer children than adults have suffered the most severe disease, this is not a benign disease in children. Thousands of children have been hospitalized, and hundreds have died. We will soon have a very safe, highly effective vaccine that can prevent so much suffering. I encourage parents to talk with their pediatricians about how to get the vaccine for their adolescents as soon as they are eligible.”

A version of this article first appeared on Medscape.com.

The Food and Drug Administration on May 10 granted emergency use authorization (EUA) for the Pfizer coronavirus vaccine to be given to children 12-15 years old.  

The much-expected decision increases the likelihood that schools in the United States will fully reopen in the fall – a goal of both the Biden and Trump administrations.

Acting FDA Commissioner Janet Woodcock, MD, called the decision “a significant step” in “returning to a sense of normalcy.”

“Today’s action allows for a younger population to be protected from COVID-19, bringing us closer to returning to a sense of normalcy and to ending the pandemic,” she said in a statement. “Parents and guardians can rest assured that the agency undertook a rigorous and thorough review of all available data, as we have with all of our COVID-19 vaccine emergency use authorizations.”

The Pfizer adolescent vaccine is not yet a done deal, though.

Next, the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices will decide on May 12 whether to recommend use of the vaccine in this age group. After that, CDC Director Rochelle Walensky, MD, will decide whether to give the green light for the vaccine to be administered to that age group.

The FDA action on May 10 amends the Dec. 11, 2020, emergency use authorization that allowed the Pfizer vaccine to be given to people 16 and older. Pfizer was the first company to receive an EUA for its adult vaccine and is the first to receive authorization for its adolescent vaccine. Pfizer is conducting clinical trials on much younger children, too.

The Moderna and Johnson & Johnson vaccines are authorized for people 18 and up. Moderna also has launched clinical trials in children.

Most health experts have said the United States needs to vaccinate children before the COVID-19 pandemic can truly be brought under control. The 12- to 15-year-old group represents 17 million people, about 5% of the population. Thus far, 58% of U.S. adults have had at least one dose of a vaccine and 34.8% of all Americans are fully vaccinated.

American Academy of Pediatrics President Lee Savio Beers, MD, praised the agency’s decision, calling it a “critically important step in bringing life-saving vaccines to children and adolescents. Our youngest generations have shouldered heavy burdens over the past year, and the vaccine is a hopeful sign that they will be able to begin to experience all the activities that are so important for their health and development.”

President Joe Biden recently announced a new strategy for expanding vaccinations in which vaccinating 12- to 15-year-olds was a key component. He said the administration was ready to ship the adolescent vaccine directly to pharmacies and pediatricians to speed up the vaccination rate.

In March, Anthony S. Fauci, MD, told a Senate committee, “We don’t really know what that magical point of herd immunity is, but we do know that if we get the overwhelming population vaccinated, we’re going to be in good shape. … We ultimately would like to get and have to get children into that mix.” 

Pfizer submitted data to the FDA in late March showing its mRNA vaccine was 100% effective at preventing COVID-19 infection in children ages 12-15 in clinical trials.

Though most children have milder symptoms when infected with the coronavirus, about 1.5 million cases in children aged 11-17 were reported to the CDC between March 1, 2020, and April 30 of this year, the FDA news release said.

Albert Bourla, CEO of Pfizer, tweeted that “today brings very encouraging news for families and adolescents across the United States.

“While this is a meaningful step forward, we are still in a critical period of combating #COVID19 around the world. In the coming weeks, we hope to continue to receive authorizations from global regulators to support worldwide vaccination efforts,” he said. 

“It’s essential for children to be vaccinated against COVID-19. According to data compiled by the AAP and Children’s Hospital Association, more than 3.8 million children have tested positive for COVID-19 in the United States since the start of the pandemic,” said Dr. Savio Beers. “While fewer children than adults have suffered the most severe disease, this is not a benign disease in children. Thousands of children have been hospitalized, and hundreds have died. We will soon have a very safe, highly effective vaccine that can prevent so much suffering. I encourage parents to talk with their pediatricians about how to get the vaccine for their adolescents as soon as they are eligible.”

A version of this article first appeared on Medscape.com.

Operational changes are linked to improvements in smoking and blood pressure outcomes in primary care practice settings, new research indicates.

The qualitative analysis, published in Annals of Family Medicine , included smoking and blood pressure as separate outcome measures.

The outcomes were calculated using Clinical Quality Measure improvements, with targets of at least 10-point absolute improvements in the proportion of patients with smoking screening, if relevant, counseling, and in the proportion of hypertensive patients with adequately controlled BP. The results were obtained from practices participating in Evidence-NOW, a multisite cardiovascular disease prevention initiative. Configurational Comparative Methods were used to evaluate the joint effects of multiple factors on outcomes.

The majority of practices in the analysis were clinician owned, small (fewer than six clinicians), and/or in an urban location. The researchers sampled and interviewed practice staff from a subset of 104 primary care practices across 7 Cooperatives and 12 states, ranging from small to medium in size, having 10 or fewer clinicians. The interview data were analyzed to identify operational changes, then transformed into numeric data.
 

Operational changes led to improvements in specific contexts

In clinician-owned practices, process improvement, documentation, and referral to resources, combined with a moderate level of facilitation support, led to an improvement of at least 10 points in smoking outcomes.

However, the researchers found that these patterns were not observed in system–owned practices or Federally Qualified Health Centers.

In solo practices, training medical assistants to take an accurate blood pressure led to an improvement of at least 10 points in blood pressure outcomes.

Among larger, clinician-owned practices, measurement of blood pressure a second time when the first was elevated, and documentation of this reading in the electronic heath record, also led to a 10-point or greater improvement in BP outcome when combined with a large amount (50 hours or more) of facilitation.

“There was no magic bullet for improving smoking cessation counseling and blood pressure outcomes across the diverse primary care practices studied,” lead author Deborah J. Cohen, PhD, of Oregon Health & Science University, Portland, said in an interview. “Combinations of operational changes among practice sizes and types led to improvements.”
 

Smaller practices more nimble, experts say

Results of the qualitative data analysis suggest that smaller and clinician-owned practices are more likely to have the capacity for change and improvement compared with larger, hospital/health system–owned practices.

Commenting on the study, Noel Deep, MD, regional medical director at Aspirus Clinics, Ironwood, Mich., said solo or small private practices have a distinct advantage over larger hospital or system-owned practices when implementing new operational changes to improve clinical outcomes.

“A smaller independent practice is nimble, with the physician [or physicians] able to make a quick decision at analyzing the scientific data, planning the changes, implementing them quickly, and doing a rapid cycle review of the results and tweaking the program to attain the targets,” said Dr. Deep, a member of the editorial advisory board of Internal Medicine News.

Kate Rowland, MD, MS, assistant professor in the department of family medicine at Rush Medical College, Chicago, also noted that smaller practices have unique advantages over larger health organizations.

“Larger organizations should replicate the benefits of the smaller office, providing as much local decision-making and autonomy as possible to the site where the changes are happening,” Dr. Rowland explained in an interview.

“The clinicians at these sites are mostly likely to know what is going to be successful for achieving measurable change in the patients they care for,” she added.

The study was funded by the Agency for Healthcare Research and Quality. The authors and other experts interviewed for this piece reported having no conflicts of interest.

Operational changes are linked to improvements in smoking and blood pressure outcomes in primary care practice settings, new research indicates.

The qualitative analysis, published in Annals of Family Medicine , included smoking and blood pressure as separate outcome measures.

The outcomes were calculated using Clinical Quality Measure improvements, with targets of at least 10-point absolute improvements in the proportion of patients with smoking screening, if relevant, counseling, and in the proportion of hypertensive patients with adequately controlled BP. The results were obtained from practices participating in Evidence-NOW, a multisite cardiovascular disease prevention initiative. Configurational Comparative Methods were used to evaluate the joint effects of multiple factors on outcomes.

The majority of practices in the analysis were clinician owned, small (fewer than six clinicians), and/or in an urban location. The researchers sampled and interviewed practice staff from a subset of 104 primary care practices across 7 Cooperatives and 12 states, ranging from small to medium in size, having 10 or fewer clinicians. The interview data were analyzed to identify operational changes, then transformed into numeric data.
 

Operational changes led to improvements in specific contexts

In clinician-owned practices, process improvement, documentation, and referral to resources, combined with a moderate level of facilitation support, led to an improvement of at least 10 points in smoking outcomes.

However, the researchers found that these patterns were not observed in system–owned practices or Federally Qualified Health Centers.

In solo practices, training medical assistants to take an accurate blood pressure led to an improvement of at least 10 points in blood pressure outcomes.

Among larger, clinician-owned practices, measurement of blood pressure a second time when the first was elevated, and documentation of this reading in the electronic heath record, also led to a 10-point or greater improvement in BP outcome when combined with a large amount (50 hours or more) of facilitation.

“There was no magic bullet for improving smoking cessation counseling and blood pressure outcomes across the diverse primary care practices studied,” lead author Deborah J. Cohen, PhD, of Oregon Health & Science University, Portland, said in an interview. “Combinations of operational changes among practice sizes and types led to improvements.”
 

Smaller practices more nimble, experts say

Results of the qualitative data analysis suggest that smaller and clinician-owned practices are more likely to have the capacity for change and improvement compared with larger, hospital/health system–owned practices.

Commenting on the study, Noel Deep, MD, regional medical director at Aspirus Clinics, Ironwood, Mich., said solo or small private practices have a distinct advantage over larger hospital or system-owned practices when implementing new operational changes to improve clinical outcomes.

“A smaller independent practice is nimble, with the physician [or physicians] able to make a quick decision at analyzing the scientific data, planning the changes, implementing them quickly, and doing a rapid cycle review of the results and tweaking the program to attain the targets,” said Dr. Deep, a member of the editorial advisory board of Internal Medicine News.

Kate Rowland, MD, MS, assistant professor in the department of family medicine at Rush Medical College, Chicago, also noted that smaller practices have unique advantages over larger health organizations.

“Larger organizations should replicate the benefits of the smaller office, providing as much local decision-making and autonomy as possible to the site where the changes are happening,” Dr. Rowland explained in an interview.

“The clinicians at these sites are mostly likely to know what is going to be successful for achieving measurable change in the patients they care for,” she added.

The study was funded by the Agency for Healthcare Research and Quality. The authors and other experts interviewed for this piece reported having no conflicts of interest.

Operational changes are linked to improvements in smoking and blood pressure outcomes in primary care practice settings, new research indicates.

The qualitative analysis, published in Annals of Family Medicine , included smoking and blood pressure as separate outcome measures.

The outcomes were calculated using Clinical Quality Measure improvements, with targets of at least 10-point absolute improvements in the proportion of patients with smoking screening, if relevant, counseling, and in the proportion of hypertensive patients with adequately controlled BP. The results were obtained from practices participating in Evidence-NOW, a multisite cardiovascular disease prevention initiative. Configurational Comparative Methods were used to evaluate the joint effects of multiple factors on outcomes.

The majority of practices in the analysis were clinician owned, small (fewer than six clinicians), and/or in an urban location. The researchers sampled and interviewed practice staff from a subset of 104 primary care practices across 7 Cooperatives and 12 states, ranging from small to medium in size, having 10 or fewer clinicians. The interview data were analyzed to identify operational changes, then transformed into numeric data.
 

Operational changes led to improvements in specific contexts

In clinician-owned practices, process improvement, documentation, and referral to resources, combined with a moderate level of facilitation support, led to an improvement of at least 10 points in smoking outcomes.

However, the researchers found that these patterns were not observed in system–owned practices or Federally Qualified Health Centers.

In solo practices, training medical assistants to take an accurate blood pressure led to an improvement of at least 10 points in blood pressure outcomes.

Among larger, clinician-owned practices, measurement of blood pressure a second time when the first was elevated, and documentation of this reading in the electronic heath record, also led to a 10-point or greater improvement in BP outcome when combined with a large amount (50 hours or more) of facilitation.

“There was no magic bullet for improving smoking cessation counseling and blood pressure outcomes across the diverse primary care practices studied,” lead author Deborah J. Cohen, PhD, of Oregon Health & Science University, Portland, said in an interview. “Combinations of operational changes among practice sizes and types led to improvements.”
 

Smaller practices more nimble, experts say

Results of the qualitative data analysis suggest that smaller and clinician-owned practices are more likely to have the capacity for change and improvement compared with larger, hospital/health system–owned practices.

Commenting on the study, Noel Deep, MD, regional medical director at Aspirus Clinics, Ironwood, Mich., said solo or small private practices have a distinct advantage over larger hospital or system-owned practices when implementing new operational changes to improve clinical outcomes.

“A smaller independent practice is nimble, with the physician [or physicians] able to make a quick decision at analyzing the scientific data, planning the changes, implementing them quickly, and doing a rapid cycle review of the results and tweaking the program to attain the targets,” said Dr. Deep, a member of the editorial advisory board of Internal Medicine News.

Kate Rowland, MD, MS, assistant professor in the department of family medicine at Rush Medical College, Chicago, also noted that smaller practices have unique advantages over larger health organizations.

“Larger organizations should replicate the benefits of the smaller office, providing as much local decision-making and autonomy as possible to the site where the changes are happening,” Dr. Rowland explained in an interview.

“The clinicians at these sites are mostly likely to know what is going to be successful for achieving measurable change in the patients they care for,” she added.

The study was funded by the Agency for Healthcare Research and Quality. The authors and other experts interviewed for this piece reported having no conflicts of interest.

For patients with mild or remitted ulcerative colitis, a catered, low-fat, high-fiber diet improved quality of life and stool markers of dysbiosis and inflammation, according to the findings of a small crossover trial.

Lisovskaya/iStock/Getty Images

Patients with inflammatory bowel disease often ask what they should eat, but few studies have addressed that question, Julia Fritsch, of the University of Miami and her associates wrote in Clinical Gastroenterology and Hepatology. Building on previous findings that a high-fat diet may contribute to inflammatory bowel disease, they randomly assigned 38 adults whose ulcerative colitis was in remission or mild (with a flare within the past 18 months) to receive either a low-fat diet (with 10% of daily calories from fat and high amounts of fruit and vegetables) or an “improved American standard diet” (with 35%-40% of daily calories from fat but more fruit and vegetables than Americans typically eat). Each diet was catered, delivered to patients’ homes, and lasted 4 weeks, followed by a 2-week washout period, after which each participant switched to the other diet.

Of the 38 patients, 17 completed the study. Food recall surveys over 24 hours showed that both diets were healthier than what participants ate at baseline, and daily web-based food diaries (such as www.nutrihand.com/Static/index.html) confirmed that more than 94% of patients adhered to the amount of fat in each diet. Even though participants in both groups ate only about half of the provided fruits and vegetables, the primary outcome of quality of life based on the short inflammatory bowel disease questionnaire (SIBDQ) significantly improved from a median of 4.98 (interquartile range, 4.1-6.0) at baseline to 5.77 (IQR, 5-6.4) with the low-fat diet and 5.55 (IQR, 4.75-6.25) with the improved American standard diet. Both diets also produced significant improvements in quality of life as measured by the 36-Item Short Form Survey and in disease activity as measured by the partial Mayo score.

Notably, however, only the low-fat diet significantly reduced serum amyloid A, which is a marker of mucosal inflammation, and intestinal dysbiosis, which was quantified by 16S RNA ribosomal sequencing. “Of note, there were several variables that were associated with changes in the microbiota composition,” the researchers wrote. These included the SIBDQ, C-reactive protein, interleukin-6, interleukin-1 beta, and 32 dietary components such as protein, potassium, iron, and zinc.

“These data suggest that even patients in remission [from ulcerative colitis] could benefit from a healthier diet,” the investigators concluded. “Just as importantly, neither diet exacerbated symptoms, which is notable given the higher fiber in both catered diets.” They called catering “a feasible way to perform a diet intervention study with high adherence,” noting that “catering a diet for a patient with IBD for a year costs between $19,000 and $21,000 per patient. The cost of a patient on a biologic such as ustekinumab is approximately $130,752 to $261,504.”

The study was supported by the Crohn’s and Colitis Foundation Broad Medical Research Program, Micky and Madeleine Arison Family Foundation Crohn’s and Colitis Discovery Laboratory, and the Martin Kalser Chair. The senior author disclosed ties to Boehringer Ingelheim, Gilead, AbbVie, Seres Therapeutics, Shire, Landos, Pfizer, and several other pharmaceutical companies. The other researchers reported having no conflicts of interest.

For patients with mild or remitted ulcerative colitis, a catered, low-fat, high-fiber diet improved quality of life and stool markers of dysbiosis and inflammation, according to the findings of a small crossover trial.

Lisovskaya/iStock/Getty Images

Patients with inflammatory bowel disease often ask what they should eat, but few studies have addressed that question, Julia Fritsch, of the University of Miami and her associates wrote in Clinical Gastroenterology and Hepatology. Building on previous findings that a high-fat diet may contribute to inflammatory bowel disease, they randomly assigned 38 adults whose ulcerative colitis was in remission or mild (with a flare within the past 18 months) to receive either a low-fat diet (with 10% of daily calories from fat and high amounts of fruit and vegetables) or an “improved American standard diet” (with 35%-40% of daily calories from fat but more fruit and vegetables than Americans typically eat). Each diet was catered, delivered to patients’ homes, and lasted 4 weeks, followed by a 2-week washout period, after which each participant switched to the other diet.

Of the 38 patients, 17 completed the study. Food recall surveys over 24 hours showed that both diets were healthier than what participants ate at baseline, and daily web-based food diaries (such as www.nutrihand.com/Static/index.html) confirmed that more than 94% of patients adhered to the amount of fat in each diet. Even though participants in both groups ate only about half of the provided fruits and vegetables, the primary outcome of quality of life based on the short inflammatory bowel disease questionnaire (SIBDQ) significantly improved from a median of 4.98 (interquartile range, 4.1-6.0) at baseline to 5.77 (IQR, 5-6.4) with the low-fat diet and 5.55 (IQR, 4.75-6.25) with the improved American standard diet. Both diets also produced significant improvements in quality of life as measured by the 36-Item Short Form Survey and in disease activity as measured by the partial Mayo score.

Notably, however, only the low-fat diet significantly reduced serum amyloid A, which is a marker of mucosal inflammation, and intestinal dysbiosis, which was quantified by 16S RNA ribosomal sequencing. “Of note, there were several variables that were associated with changes in the microbiota composition,” the researchers wrote. These included the SIBDQ, C-reactive protein, interleukin-6, interleukin-1 beta, and 32 dietary components such as protein, potassium, iron, and zinc.

“These data suggest that even patients in remission [from ulcerative colitis] could benefit from a healthier diet,” the investigators concluded. “Just as importantly, neither diet exacerbated symptoms, which is notable given the higher fiber in both catered diets.” They called catering “a feasible way to perform a diet intervention study with high adherence,” noting that “catering a diet for a patient with IBD for a year costs between $19,000 and $21,000 per patient. The cost of a patient on a biologic such as ustekinumab is approximately $130,752 to $261,504.”

The study was supported by the Crohn’s and Colitis Foundation Broad Medical Research Program, Micky and Madeleine Arison Family Foundation Crohn’s and Colitis Discovery Laboratory, and the Martin Kalser Chair. The senior author disclosed ties to Boehringer Ingelheim, Gilead, AbbVie, Seres Therapeutics, Shire, Landos, Pfizer, and several other pharmaceutical companies. The other researchers reported having no conflicts of interest.

For patients with mild or remitted ulcerative colitis, a catered, low-fat, high-fiber diet improved quality of life and stool markers of dysbiosis and inflammation, according to the findings of a small crossover trial.

Lisovskaya/iStock/Getty Images

Patients with inflammatory bowel disease often ask what they should eat, but few studies have addressed that question, Julia Fritsch, of the University of Miami and her associates wrote in Clinical Gastroenterology and Hepatology. Building on previous findings that a high-fat diet may contribute to inflammatory bowel disease, they randomly assigned 38 adults whose ulcerative colitis was in remission or mild (with a flare within the past 18 months) to receive either a low-fat diet (with 10% of daily calories from fat and high amounts of fruit and vegetables) or an “improved American standard diet” (with 35%-40% of daily calories from fat but more fruit and vegetables than Americans typically eat). Each diet was catered, delivered to patients’ homes, and lasted 4 weeks, followed by a 2-week washout period, after which each participant switched to the other diet.

Of the 38 patients, 17 completed the study. Food recall surveys over 24 hours showed that both diets were healthier than what participants ate at baseline, and daily web-based food diaries (such as www.nutrihand.com/Static/index.html) confirmed that more than 94% of patients adhered to the amount of fat in each diet. Even though participants in both groups ate only about half of the provided fruits and vegetables, the primary outcome of quality of life based on the short inflammatory bowel disease questionnaire (SIBDQ) significantly improved from a median of 4.98 (interquartile range, 4.1-6.0) at baseline to 5.77 (IQR, 5-6.4) with the low-fat diet and 5.55 (IQR, 4.75-6.25) with the improved American standard diet. Both diets also produced significant improvements in quality of life as measured by the 36-Item Short Form Survey and in disease activity as measured by the partial Mayo score.

Notably, however, only the low-fat diet significantly reduced serum amyloid A, which is a marker of mucosal inflammation, and intestinal dysbiosis, which was quantified by 16S RNA ribosomal sequencing. “Of note, there were several variables that were associated with changes in the microbiota composition,” the researchers wrote. These included the SIBDQ, C-reactive protein, interleukin-6, interleukin-1 beta, and 32 dietary components such as protein, potassium, iron, and zinc.

“These data suggest that even patients in remission [from ulcerative colitis] could benefit from a healthier diet,” the investigators concluded. “Just as importantly, neither diet exacerbated symptoms, which is notable given the higher fiber in both catered diets.” They called catering “a feasible way to perform a diet intervention study with high adherence,” noting that “catering a diet for a patient with IBD for a year costs between $19,000 and $21,000 per patient. The cost of a patient on a biologic such as ustekinumab is approximately $130,752 to $261,504.”

The study was supported by the Crohn’s and Colitis Foundation Broad Medical Research Program, Micky and Madeleine Arison Family Foundation Crohn’s and Colitis Discovery Laboratory, and the Martin Kalser Chair. The senior author disclosed ties to Boehringer Ingelheim, Gilead, AbbVie, Seres Therapeutics, Shire, Landos, Pfizer, and several other pharmaceutical companies. The other researchers reported having no conflicts of interest.

The selective interleukin-6 (IL-6) trans-signaling inhibitor olamkicept was well tolerated and induced clinical remissions in 3 of 16 adults with moderately to severely active inflammatory bowel disease (IBD), and remission was associated with clear alterations in levels of phospho-STAT3 (pSTAT3) in the intestinal mucosa, researchers reported.

In a 12-week, open-label, prospective phase 2a trial, patients received up to seven infusions of 600-mg olamkicept (sgp130Fc) every 2 weeks. Clinical remissions occurred in two of nine patients with ulcerative colitis and one of seven patients with Crohn’s disease. The overall rate of clinical response was 44%, which included five patients with ulcerative colitis and two patients with Crohn’s disease. Transcriptome isolation and high-throughput RNA sequencing of mucosal tissue specimens showed that clinical remitters had a decrease from baseline to week 14 in the expression of TNF, IL-1A, REG1A, IL-8, IL-1B, and LILRA, a known composite molecular surrogate for mucosal inflammation. In addition, exposing whole-blood samples to a recombinant IL-6/IL-6R fusion protein mimicked physiologic IL-6 activity and demonstrated that pSTAT3 levels dropped within 4 hours of the first olamkicept infusion and throughout treatment. “Our overall finding of decreased pSTAT3-positive cells in remission patients indicates that STAT3 is crucially involved in the mechanism of action of olamkicept,” wrote Stefan Schreiber, MD, of University Medical Center Schleswig-Holstein, Campus Kiel (Germany) together with his associates. The study is published in Gastroenterology.

Blocking the IL-6/ILR receptor can induce IBD remissions but causes “profound immunosuppression,” the investigators noted. Building on prior findings that chronic proinflammatory IL-6 activity is primarily mediated by trans-signaling of a complex of IL-6 and soluble IL6R that engages the gp130 receptor, the researchers developed a “decoy protein,” sgp130Fc (now known as olamkicept), which “exclusively blocks” IL-6 proinflammatory trans-signaling. This decoy protein showed promise in preclinical studies, with no evidence of immunosuppression, they wrote. To further evaluate olamkicept, they recruited adults with moderately to severely active ulcerative colitis or Crohn’s disease from two centers in Germany. The primary clinical assessment was remission, defined as a Mayo score under 2, with a bleeding score of 0 and an endoscopy score of less than 1 for patients with ulcerative colitis, and a Crohn’s Disease Activity Index (CDAI) of less than 150 for patients with Crohn’s disease. The primary molecular outcome was change in the composite molecular surrogate score.

Of the 16 patients, 10 completed the trial. At week 14, endoscopic responses were observed in six patients, all of whom also had a clinical response, and all three patients with clinical remissions also had endoscopic remissions. “The drug was well tolerated in all 16 treated individuals, similar to the results of the [two prior] phase 1 trials,” the researchers wrote. Although significant immunosuppression and intestinal perforations were not seen, 13 patients developed adverse events, most commonly seasonal upper respiratory tract infections, recurrence of herpes labialis, and eczema or erythema. There were five serious adverse events, two of which were cardiac in nature. A larger placebo-controlled trial is underway to further evaluate safety. For now, the researchers wrote, it appears that IL-6 trans-signaling inhibition “might open up novel therapeutic avenues for the treatment of IBD.”

University Hospital Schleswig-Holstein sponsored the study. Ferring AG provided funding and donated the olamkicept. Analyses were funded by EU H2020 SYSCID and EU H2020 Innovative Medicines Initiative 2 Joint Undertaking. Dr. Schreiber reported having coinvented IP and having ties to Pfizer, Bristol Myers Squibb, and Roche. Four coinvestigators disclosed ties to Ferring, AbbVie, Chugai, Roche, Regeneron, Pfizer, Sanofi, Conaris, and Genentech Roche. The other researchers reported having no conflicts of interest.

The selective interleukin-6 (IL-6) trans-signaling inhibitor olamkicept was well tolerated and induced clinical remissions in 3 of 16 adults with moderately to severely active inflammatory bowel disease (IBD), and remission was associated with clear alterations in levels of phospho-STAT3 (pSTAT3) in the intestinal mucosa, researchers reported.

In a 12-week, open-label, prospective phase 2a trial, patients received up to seven infusions of 600-mg olamkicept (sgp130Fc) every 2 weeks. Clinical remissions occurred in two of nine patients with ulcerative colitis and one of seven patients with Crohn’s disease. The overall rate of clinical response was 44%, which included five patients with ulcerative colitis and two patients with Crohn’s disease. Transcriptome isolation and high-throughput RNA sequencing of mucosal tissue specimens showed that clinical remitters had a decrease from baseline to week 14 in the expression of TNF, IL-1A, REG1A, IL-8, IL-1B, and LILRA, a known composite molecular surrogate for mucosal inflammation. In addition, exposing whole-blood samples to a recombinant IL-6/IL-6R fusion protein mimicked physiologic IL-6 activity and demonstrated that pSTAT3 levels dropped within 4 hours of the first olamkicept infusion and throughout treatment. “Our overall finding of decreased pSTAT3-positive cells in remission patients indicates that STAT3 is crucially involved in the mechanism of action of olamkicept,” wrote Stefan Schreiber, MD, of University Medical Center Schleswig-Holstein, Campus Kiel (Germany) together with his associates. The study is published in Gastroenterology.

Blocking the IL-6/ILR receptor can induce IBD remissions but causes “profound immunosuppression,” the investigators noted. Building on prior findings that chronic proinflammatory IL-6 activity is primarily mediated by trans-signaling of a complex of IL-6 and soluble IL6R that engages the gp130 receptor, the researchers developed a “decoy protein,” sgp130Fc (now known as olamkicept), which “exclusively blocks” IL-6 proinflammatory trans-signaling. This decoy protein showed promise in preclinical studies, with no evidence of immunosuppression, they wrote. To further evaluate olamkicept, they recruited adults with moderately to severely active ulcerative colitis or Crohn’s disease from two centers in Germany. The primary clinical assessment was remission, defined as a Mayo score under 2, with a bleeding score of 0 and an endoscopy score of less than 1 for patients with ulcerative colitis, and a Crohn’s Disease Activity Index (CDAI) of less than 150 for patients with Crohn’s disease. The primary molecular outcome was change in the composite molecular surrogate score.

Of the 16 patients, 10 completed the trial. At week 14, endoscopic responses were observed in six patients, all of whom also had a clinical response, and all three patients with clinical remissions also had endoscopic remissions. “The drug was well tolerated in all 16 treated individuals, similar to the results of the [two prior] phase 1 trials,” the researchers wrote. Although significant immunosuppression and intestinal perforations were not seen, 13 patients developed adverse events, most commonly seasonal upper respiratory tract infections, recurrence of herpes labialis, and eczema or erythema. There were five serious adverse events, two of which were cardiac in nature. A larger placebo-controlled trial is underway to further evaluate safety. For now, the researchers wrote, it appears that IL-6 trans-signaling inhibition “might open up novel therapeutic avenues for the treatment of IBD.”

University Hospital Schleswig-Holstein sponsored the study. Ferring AG provided funding and donated the olamkicept. Analyses were funded by EU H2020 SYSCID and EU H2020 Innovative Medicines Initiative 2 Joint Undertaking. Dr. Schreiber reported having coinvented IP and having ties to Pfizer, Bristol Myers Squibb, and Roche. Four coinvestigators disclosed ties to Ferring, AbbVie, Chugai, Roche, Regeneron, Pfizer, Sanofi, Conaris, and Genentech Roche. The other researchers reported having no conflicts of interest.

The selective interleukin-6 (IL-6) trans-signaling inhibitor olamkicept was well tolerated and induced clinical remissions in 3 of 16 adults with moderately to severely active inflammatory bowel disease (IBD), and remission was associated with clear alterations in levels of phospho-STAT3 (pSTAT3) in the intestinal mucosa, researchers reported.

In a 12-week, open-label, prospective phase 2a trial, patients received up to seven infusions of 600-mg olamkicept (sgp130Fc) every 2 weeks. Clinical remissions occurred in two of nine patients with ulcerative colitis and one of seven patients with Crohn’s disease. The overall rate of clinical response was 44%, which included five patients with ulcerative colitis and two patients with Crohn’s disease. Transcriptome isolation and high-throughput RNA sequencing of mucosal tissue specimens showed that clinical remitters had a decrease from baseline to week 14 in the expression of TNF, IL-1A, REG1A, IL-8, IL-1B, and LILRA, a known composite molecular surrogate for mucosal inflammation. In addition, exposing whole-blood samples to a recombinant IL-6/IL-6R fusion protein mimicked physiologic IL-6 activity and demonstrated that pSTAT3 levels dropped within 4 hours of the first olamkicept infusion and throughout treatment. “Our overall finding of decreased pSTAT3-positive cells in remission patients indicates that STAT3 is crucially involved in the mechanism of action of olamkicept,” wrote Stefan Schreiber, MD, of University Medical Center Schleswig-Holstein, Campus Kiel (Germany) together with his associates. The study is published in Gastroenterology.

Blocking the IL-6/ILR receptor can induce IBD remissions but causes “profound immunosuppression,” the investigators noted. Building on prior findings that chronic proinflammatory IL-6 activity is primarily mediated by trans-signaling of a complex of IL-6 and soluble IL6R that engages the gp130 receptor, the researchers developed a “decoy protein,” sgp130Fc (now known as olamkicept), which “exclusively blocks” IL-6 proinflammatory trans-signaling. This decoy protein showed promise in preclinical studies, with no evidence of immunosuppression, they wrote. To further evaluate olamkicept, they recruited adults with moderately to severely active ulcerative colitis or Crohn’s disease from two centers in Germany. The primary clinical assessment was remission, defined as a Mayo score under 2, with a bleeding score of 0 and an endoscopy score of less than 1 for patients with ulcerative colitis, and a Crohn’s Disease Activity Index (CDAI) of less than 150 for patients with Crohn’s disease. The primary molecular outcome was change in the composite molecular surrogate score.

Of the 16 patients, 10 completed the trial. At week 14, endoscopic responses were observed in six patients, all of whom also had a clinical response, and all three patients with clinical remissions also had endoscopic remissions. “The drug was well tolerated in all 16 treated individuals, similar to the results of the [two prior] phase 1 trials,” the researchers wrote. Although significant immunosuppression and intestinal perforations were not seen, 13 patients developed adverse events, most commonly seasonal upper respiratory tract infections, recurrence of herpes labialis, and eczema or erythema. There were five serious adverse events, two of which were cardiac in nature. A larger placebo-controlled trial is underway to further evaluate safety. For now, the researchers wrote, it appears that IL-6 trans-signaling inhibition “might open up novel therapeutic avenues for the treatment of IBD.”

University Hospital Schleswig-Holstein sponsored the study. Ferring AG provided funding and donated the olamkicept. Analyses were funded by EU H2020 SYSCID and EU H2020 Innovative Medicines Initiative 2 Joint Undertaking. Dr. Schreiber reported having coinvented IP and having ties to Pfizer, Bristol Myers Squibb, and Roche. Four coinvestigators disclosed ties to Ferring, AbbVie, Chugai, Roche, Regeneron, Pfizer, Sanofi, Conaris, and Genentech Roche. The other researchers reported having no conflicts of interest.

As the burden of hemophilia B in patients increases from mild to severe forms of the disease, the already high economic cost of treatment rises significantly, according to a large retrospective database study.

Researchers developed four profile categories (mild, moderate, moderate-severe, and severe) for men with hemophilia B on the basis of the frequency of hemorrhage events and factor IX replacement claims as identified from the IBM MarketScan database (June 2011–February 2019). The mean annual health care resource use (HRU) and costs were compared between 5,454 patients with hemophilia B and 1:1 demographically matched controls.
 

Economic burden

Total health care costs rose with increasingly severe clinical profiles, with hemophilia-related treatments being the primary cost driver, researchers led by Tyler W. Buckner, MD, of the University of Colorado at Denver, Aurora, wrote in Blood Advances.

This was particularly true among patients with more severe clinical profiles, who were more likely to be on prophylaxis with all of its associated costs.

The mean overall total costs incurred by patients with hemophilia B over the study period were $201,635 versus $7,879 for matched controls, a more than 25-fold difference (P < .001). In addition, across all four clinical profiles categories, all-cause total costs, medical costs, and pharmacy costs were significantly higher among patients with hemophilia B than matched controls (P < .001 for all), the researchers added.

Annual total health care costs also increased with increasing severity of hemophilia B clinical profiles, ranging from $80,811 and $137,455 in the mild and moderate groups to $251,619 and $632,088 in the moderate-severe and severe groups, respectively.

“Hemophilia-related treatments represented the primary cost driver. HRU was uniformly higher among patients with hemophilia B across clinical profiles, medical service types examined, and with respect to opioid use. The significant burden highlights that unmet needs remain in hemophilia B,” the researchers concluded.

This study was supported by uniQure. Dr. Buckner has received honoraria or fees for serving on advisory boards or as a consultant for uniQure. Several of the coauthors are employees of Analysis Group, which received consulting fees from uniQure to conduct this study, and two of the authors are employees of and own stock in uniQure.

mlesney@mdedge.com

As the burden of hemophilia B in patients increases from mild to severe forms of the disease, the already high economic cost of treatment rises significantly, according to a large retrospective database study.

Researchers developed four profile categories (mild, moderate, moderate-severe, and severe) for men with hemophilia B on the basis of the frequency of hemorrhage events and factor IX replacement claims as identified from the IBM MarketScan database (June 2011–February 2019). The mean annual health care resource use (HRU) and costs were compared between 5,454 patients with hemophilia B and 1:1 demographically matched controls.
 

Economic burden

Total health care costs rose with increasingly severe clinical profiles, with hemophilia-related treatments being the primary cost driver, researchers led by Tyler W. Buckner, MD, of the University of Colorado at Denver, Aurora, wrote in Blood Advances.

This was particularly true among patients with more severe clinical profiles, who were more likely to be on prophylaxis with all of its associated costs.

The mean overall total costs incurred by patients with hemophilia B over the study period were $201,635 versus $7,879 for matched controls, a more than 25-fold difference (P < .001). In addition, across all four clinical profiles categories, all-cause total costs, medical costs, and pharmacy costs were significantly higher among patients with hemophilia B than matched controls (P < .001 for all), the researchers added.

Annual total health care costs also increased with increasing severity of hemophilia B clinical profiles, ranging from $80,811 and $137,455 in the mild and moderate groups to $251,619 and $632,088 in the moderate-severe and severe groups, respectively.

“Hemophilia-related treatments represented the primary cost driver. HRU was uniformly higher among patients with hemophilia B across clinical profiles, medical service types examined, and with respect to opioid use. The significant burden highlights that unmet needs remain in hemophilia B,” the researchers concluded.

This study was supported by uniQure. Dr. Buckner has received honoraria or fees for serving on advisory boards or as a consultant for uniQure. Several of the coauthors are employees of Analysis Group, which received consulting fees from uniQure to conduct this study, and two of the authors are employees of and own stock in uniQure.

mlesney@mdedge.com

As the burden of hemophilia B in patients increases from mild to severe forms of the disease, the already high economic cost of treatment rises significantly, according to a large retrospective database study.

Researchers developed four profile categories (mild, moderate, moderate-severe, and severe) for men with hemophilia B on the basis of the frequency of hemorrhage events and factor IX replacement claims as identified from the IBM MarketScan database (June 2011–February 2019). The mean annual health care resource use (HRU) and costs were compared between 5,454 patients with hemophilia B and 1:1 demographically matched controls.
 

Economic burden

Total health care costs rose with increasingly severe clinical profiles, with hemophilia-related treatments being the primary cost driver, researchers led by Tyler W. Buckner, MD, of the University of Colorado at Denver, Aurora, wrote in Blood Advances.

This was particularly true among patients with more severe clinical profiles, who were more likely to be on prophylaxis with all of its associated costs.

The mean overall total costs incurred by patients with hemophilia B over the study period were $201,635 versus $7,879 for matched controls, a more than 25-fold difference (P < .001). In addition, across all four clinical profiles categories, all-cause total costs, medical costs, and pharmacy costs were significantly higher among patients with hemophilia B than matched controls (P < .001 for all), the researchers added.

Annual total health care costs also increased with increasing severity of hemophilia B clinical profiles, ranging from $80,811 and $137,455 in the mild and moderate groups to $251,619 and $632,088 in the moderate-severe and severe groups, respectively.

“Hemophilia-related treatments represented the primary cost driver. HRU was uniformly higher among patients with hemophilia B across clinical profiles, medical service types examined, and with respect to opioid use. The significant burden highlights that unmet needs remain in hemophilia B,” the researchers concluded.

This study was supported by uniQure. Dr. Buckner has received honoraria or fees for serving on advisory boards or as a consultant for uniQure. Several of the coauthors are employees of Analysis Group, which received consulting fees from uniQure to conduct this study, and two of the authors are employees of and own stock in uniQure.

mlesney@mdedge.com

NSAIDs don’t boost the risk of more severe disease or death in hospitalized patients with COVID-19, a new study finds.

Denise Fulton/MDedge News

“To our knowledge, our prospective study includes the largest number of patients admitted to hospital with COVID-19 to date, and adds to the literature on the safety of NSAIDs and in-hospital outcomes. NSAIDs do not appear to increase the risk of worse in-hospital outcomes ...” the study authors wrote. “NSAIDs are an important analgesic modality and have a vital opioid-sparing role in pain management. Patients and clinicians should be reassured by these findings that NSAIDs are safe in the context of the pandemic.”

The report was published online May 7 in The Lancet Rheumatology and led by clinical research fellow Thomas M. Drake, MBChB, of the University of Edinburgh’s Usher Institute.

For more than a year, researchers worldwide have debated about whether NSAIDs spell trouble for people at risk of COVID-19. In March 2020, French health officials announced that use of the painkillers such as NSAIDs may increase the severity of the disease, and they recommended that patients take acetaminophen instead. The National Health Service in the United Kingdom made a similar recommendation. But other agencies didn’t believe there was enough evidence to support ditching NSAIDs, and recent research studies published in Annals of the Rheumatic Diseases and PLoS Medicine suggested they may be right.

For the new study, researchers identified 72,179 patients who were treated for COVID-19 in British hospitals during January-August 2020. About 56% were men, 74% were White, and 6% took NSAIDs on a regular basis before they entered the hospital. The average age was 70.

The researchers examined whether the patients in either group were more or less likely to die in the hospital, be admitted into a critical care unit, need oxygen treatment, need a ventilator, or suffer kidney injury.

In terms of outcomes, there weren’t any major gaps between the groups overall. The differences in most comparisons were statistically insignificant. For example, 31% of those who didn’t take NSAIDs died vs. 30% of those who did (P = .227). In both groups, 14% required critical care admission (P = .476).

The researchers then focused on two matched groups of 4,205 patients: One group used NSAIDs regularly, and the other group didn’t. The difference in risk of death in those who took NSAIDs vs. those who didn’t was statistically insignificant (odds ratio, 0.95; 95% confidence interval, 0.84-1.07; P = .35). Other comparisons were also statistically insignificant.

The findings offer insight into whether the use of NSAIDs might actually be helpful for patients who develop COVID-19. Scientists believe that COVID-19 is linked to inflammation in the body, and NSAIDs, of course, reduce inflammation. But the researchers didn’t turn up any sign of a benefit.

The new study has some weaknesses: It doesn’t say anything about whether NSAIDs have an impact on whether people get COVID-19 in the first place. Researchers don’t know if high use of NSAIDs may affect the severity of the disease. And it doesn’t examine the potential effect of acetaminophen, although other research suggests the drug also may not cause harm in patients with COVID-19.

Still, the researchers say the study is the largest of its kind to look at the use of NSAIDs by patients who are admitted to the hospital with COVID-19. “Considering all the evidence, if there was an extreme effect of NSAIDs on COVID-19 outcomes or severity, this would have been observed in one or more of the studies that have been done, including the present study,” they wrote.

In a commentary that accompanied the study, three physicians from hospitals in Denmark, led by Kristian Kragholm, MD, of Aalborg University Hospital, praised the research and wrote that it adds to “a growing body of evidence” that NSAIDs don’t make things worse for patients with COVID-19.

The study was funded by the U.K. National Institute for Health Research and the U.K. Medical Research Council. The study and commentary authors reported no relevant disclosures.

NSAIDs don’t boost the risk of more severe disease or death in hospitalized patients with COVID-19, a new study finds.

Denise Fulton/MDedge News

“To our knowledge, our prospective study includes the largest number of patients admitted to hospital with COVID-19 to date, and adds to the literature on the safety of NSAIDs and in-hospital outcomes. NSAIDs do not appear to increase the risk of worse in-hospital outcomes ...” the study authors wrote. “NSAIDs are an important analgesic modality and have a vital opioid-sparing role in pain management. Patients and clinicians should be reassured by these findings that NSAIDs are safe in the context of the pandemic.”

The report was published online May 7 in The Lancet Rheumatology and led by clinical research fellow Thomas M. Drake, MBChB, of the University of Edinburgh’s Usher Institute.

For more than a year, researchers worldwide have debated about whether NSAIDs spell trouble for people at risk of COVID-19. In March 2020, French health officials announced that use of the painkillers such as NSAIDs may increase the severity of the disease, and they recommended that patients take acetaminophen instead. The National Health Service in the United Kingdom made a similar recommendation. But other agencies didn’t believe there was enough evidence to support ditching NSAIDs, and recent research studies published in Annals of the Rheumatic Diseases and PLoS Medicine suggested they may be right.

For the new study, researchers identified 72,179 patients who were treated for COVID-19 in British hospitals during January-August 2020. About 56% were men, 74% were White, and 6% took NSAIDs on a regular basis before they entered the hospital. The average age was 70.

The researchers examined whether the patients in either group were more or less likely to die in the hospital, be admitted into a critical care unit, need oxygen treatment, need a ventilator, or suffer kidney injury.

In terms of outcomes, there weren’t any major gaps between the groups overall. The differences in most comparisons were statistically insignificant. For example, 31% of those who didn’t take NSAIDs died vs. 30% of those who did (P = .227). In both groups, 14% required critical care admission (P = .476).

The researchers then focused on two matched groups of 4,205 patients: One group used NSAIDs regularly, and the other group didn’t. The difference in risk of death in those who took NSAIDs vs. those who didn’t was statistically insignificant (odds ratio, 0.95; 95% confidence interval, 0.84-1.07; P = .35). Other comparisons were also statistically insignificant.

The findings offer insight into whether the use of NSAIDs might actually be helpful for patients who develop COVID-19. Scientists believe that COVID-19 is linked to inflammation in the body, and NSAIDs, of course, reduce inflammation. But the researchers didn’t turn up any sign of a benefit.

The new study has some weaknesses: It doesn’t say anything about whether NSAIDs have an impact on whether people get COVID-19 in the first place. Researchers don’t know if high use of NSAIDs may affect the severity of the disease. And it doesn’t examine the potential effect of acetaminophen, although other research suggests the drug also may not cause harm in patients with COVID-19.

Still, the researchers say the study is the largest of its kind to look at the use of NSAIDs by patients who are admitted to the hospital with COVID-19. “Considering all the evidence, if there was an extreme effect of NSAIDs on COVID-19 outcomes or severity, this would have been observed in one or more of the studies that have been done, including the present study,” they wrote.

In a commentary that accompanied the study, three physicians from hospitals in Denmark, led by Kristian Kragholm, MD, of Aalborg University Hospital, praised the research and wrote that it adds to “a growing body of evidence” that NSAIDs don’t make things worse for patients with COVID-19.

The study was funded by the U.K. National Institute for Health Research and the U.K. Medical Research Council. The study and commentary authors reported no relevant disclosures.

NSAIDs don’t boost the risk of more severe disease or death in hospitalized patients with COVID-19, a new study finds.

Denise Fulton/MDedge News

“To our knowledge, our prospective study includes the largest number of patients admitted to hospital with COVID-19 to date, and adds to the literature on the safety of NSAIDs and in-hospital outcomes. NSAIDs do not appear to increase the risk of worse in-hospital outcomes ...” the study authors wrote. “NSAIDs are an important analgesic modality and have a vital opioid-sparing role in pain management. Patients and clinicians should be reassured by these findings that NSAIDs are safe in the context of the pandemic.”

The report was published online May 7 in The Lancet Rheumatology and led by clinical research fellow Thomas M. Drake, MBChB, of the University of Edinburgh’s Usher Institute.

For more than a year, researchers worldwide have debated about whether NSAIDs spell trouble for people at risk of COVID-19. In March 2020, French health officials announced that use of the painkillers such as NSAIDs may increase the severity of the disease, and they recommended that patients take acetaminophen instead. The National Health Service in the United Kingdom made a similar recommendation. But other agencies didn’t believe there was enough evidence to support ditching NSAIDs, and recent research studies published in Annals of the Rheumatic Diseases and PLoS Medicine suggested they may be right.

For the new study, researchers identified 72,179 patients who were treated for COVID-19 in British hospitals during January-August 2020. About 56% were men, 74% were White, and 6% took NSAIDs on a regular basis before they entered the hospital. The average age was 70.

The researchers examined whether the patients in either group were more or less likely to die in the hospital, be admitted into a critical care unit, need oxygen treatment, need a ventilator, or suffer kidney injury.

In terms of outcomes, there weren’t any major gaps between the groups overall. The differences in most comparisons were statistically insignificant. For example, 31% of those who didn’t take NSAIDs died vs. 30% of those who did (P = .227). In both groups, 14% required critical care admission (P = .476).

The researchers then focused on two matched groups of 4,205 patients: One group used NSAIDs regularly, and the other group didn’t. The difference in risk of death in those who took NSAIDs vs. those who didn’t was statistically insignificant (odds ratio, 0.95; 95% confidence interval, 0.84-1.07; P = .35). Other comparisons were also statistically insignificant.

The findings offer insight into whether the use of NSAIDs might actually be helpful for patients who develop COVID-19. Scientists believe that COVID-19 is linked to inflammation in the body, and NSAIDs, of course, reduce inflammation. But the researchers didn’t turn up any sign of a benefit.

The new study has some weaknesses: It doesn’t say anything about whether NSAIDs have an impact on whether people get COVID-19 in the first place. Researchers don’t know if high use of NSAIDs may affect the severity of the disease. And it doesn’t examine the potential effect of acetaminophen, although other research suggests the drug also may not cause harm in patients with COVID-19.

Still, the researchers say the study is the largest of its kind to look at the use of NSAIDs by patients who are admitted to the hospital with COVID-19. “Considering all the evidence, if there was an extreme effect of NSAIDs on COVID-19 outcomes or severity, this would have been observed in one or more of the studies that have been done, including the present study,” they wrote.

In a commentary that accompanied the study, three physicians from hospitals in Denmark, led by Kristian Kragholm, MD, of Aalborg University Hospital, praised the research and wrote that it adds to “a growing body of evidence” that NSAIDs don’t make things worse for patients with COVID-19.

The study was funded by the U.K. National Institute for Health Research and the U.K. Medical Research Council. The study and commentary authors reported no relevant disclosures.

Information is scarce regarding the impact of COVID-19 on pregnant women and newborns; health care workers (HCWs), particularly pregnant women,¹ who are caring for patients during the pandemic might experience concern and uncertainty. The American College of Obstetricians and Gynecologists (ACOG) released recommendations, based on expert consensus, regarding pregnant HCWs on December 14, 2020.² We propose an appropriation of the ACOG recommendations for dermatologists and their teams caring for patients during the COVID-19 pandemic.

Risks to Pregnant HCWs

Worldwide, viral pneumonia is a leading cause of death during pregnancy,³ with higher mortality documented among pregnant patients during the 1918 influenza pandemic and the 2003 severe acute respiratory syndrome–associated coronavirus pandemic,³ and an increased rate of hospital admission documented among these patients compared to the general population during the 2009 H1N1 influenza pandemic.⁴

Data from the Centers for Disease Control and Prevention (CDC) suggest that pregnant women with symptomatic COVID-19 (n=30,415) are at increased risk for the following (compared to nonpregnant women with symptomatic COVID-19 [n=431,410])⁵:

• Admission to the intensive care unit (10.5 of every 1000 cases vs 3.9 of every 1000 cases; adjusted risk ratio [aRR]=3.0; 95% CI, 2.6-3.4)

• Receipt of invasive ventilation (2.9 of every 1000 cases vs 1.1 of every 1000 cases; aRR=2.9; 95% CI, 2.2-3.8)

• Receipt of extracorporeal membrane oxygenation (0.7 of every 1000 cases vs 0.3 of every 1000 cases; aRR=2.4; 95% CI, 1.5-4.0)

• Death (1.5 of every 1000 cases vs 1.2 of every 1000 cases; aRR=1.7; 95% CI, 1.2-2.4).

Although the absolute risk of severe COVID-19–related outcomes is low, the CDC includes pregnant women in its increased risk category for COVID-19. Furthermore, in a systematic review of 61 studies comprising 790 COVID-19–positive pregnant women and 548 newborns, the rates of cesarean delivery, premature birth, low birth weight, and adverse pregnancy events (the latter comprising preterm birth, death or stillbirth, and early termination of pregnancy) were estimated to be 72%, 23%, 7%, and 27%, respectively.⁶ In a systematic review of 39 studies (case series and cohort studies), comprising 936 SARS-CoV-2–tested newborns of mothers with COVID-19, mother-to-fetus transmission of SARS-CoV-2 occurred during the third trimester in approximately 3.2% of infected mothers.⁷

In pregnant women with COVID-19 who develop cytokine storm syndrome, a fetal inflammatory response syndrome can ensue, which has been shown to cause ventricular expansion and bleeding in animal models.⁸ In addition, underlying conditions, such as cardiovascular disease, diabetes mellitus, pre-existing lung disease, and obesity, which are well-established risks factors for severe COVID-19 in nonpregnant patients, can increase the severity of COVID-19 in pregnant women.^5,9-11

Recommendations From ACOG for Pregnant HCWs

The American College of Obstetricians and Gynecologists recommends that health care facilities consider limiting the exposure of pregnant HCWs to patients with confirmed or suspected COVID-19. They also recommend that pregnant women continue to work in patient-facing roles if they want to, if recommended personal protective equipment (PPE) is available for them to wear.² The US Food and Drug Administration issued an Emergency Use Authorization for 2 messenger RNA COVID-19 vaccines. Although these vaccines have not been tested in pregnant women, ACOG recommends that COVID-19 vaccines not be withheld from pregnant women who fulfill the criteria for vaccination; pregnant women who decline vaccination should be supported in their decision.¹² In dermatology, telemedicine is an effective alternative to face-to-face visits, reducing the risk of transmitting SARS-CoV-2 to physicians and patients.

Ideally, pregnant dermatology attending physicians and residents can continue to provide care through teledermatology. They also can continue to provide in-person care, if they choose to; however, higher-risk procedures should be avoided.¹² In dermatology, that might include ablative laser procedures to the face, prolonged surgery, such as hair transplantation, and intraoral or intranasal procedures. Alternatively, pregnant dermatology residents can be allocated to clinical rotations in which face-to-face contact with patients is not required such as dermatopathology and a research rotation. Likewise, telework options can be encouraged for other pregnant members of dermatology teams, including front-desk staff, nurses, medical assistants, and remaining ancillary staff.

Guidance on Face Masks for Pregnant HCWs

Universal masking of HCWs has been shown to reduce the rate of health care–related acquisition of SARS-CoV-2.¹³ However, extended use or reuse of N95 respirators might contribute to SARS-CoV-2 transmission.¹⁴ The American College of Obstetricians and Gynecologists recommends that all HCWs wear a face mask at all times while working in a health care facility, even if patients are wearing a face covering or face mask.² Based on CDC guidelines,¹⁵ HCWs in regions where community transmission is moderate or substantial should wear eye protection in addition to a face mask, and they should wear an N95, N95-equivalent, or higher-level respirator instead of a face mask when performing aerosol-generating procedures and surgical procedures. If working in a patient-facing role caring for patients with suspected or confirmed COVID-19, HCWs should wear an N95, N95-equivalent, or higher-level respirator; gown; gloves; and eye protection (goggles or a disposable face shield).¹⁵

Final Thoughts

COVID-19 has brought about acute and likely permanent changes to the US health care system. Dermatologists are integral members of that system and are essential to the treatment of patients with skin, hair, and nail disorders. Pregnant dermatologists and residents should refrain from patient-facing roles when feasible; however, when all recommended PPE are available, they may continue to work in patient-facing roles until they give birth if they desire to do so. Alternatively, teledermatology and non–face-to-face rotations should be encouraged. Higher-risk and aerosol-generating procedures are of particular concern regarding the risk for transmitting SARS-CoV-2 and should be avoided. Correct and universal use of PPE is paramount; when all recommended PPE is not available, pregnant HCWs should avoid exposure to patients with suspected or confirmed COVID-19. These recommendations will help safeguard pregnant members of dermatology teams during the COVID-19 pandemic while maximizing patient care.

Information is scarce regarding the impact of COVID-19 on pregnant women and newborns; health care workers (HCWs), particularly pregnant women,¹ who are caring for patients during the pandemic might experience concern and uncertainty. The American College of Obstetricians and Gynecologists (ACOG) released recommendations, based on expert consensus, regarding pregnant HCWs on December 14, 2020.² We propose an appropriation of the ACOG recommendations for dermatologists and their teams caring for patients during the COVID-19 pandemic.

Risks to Pregnant HCWs

Worldwide, viral pneumonia is a leading cause of death during pregnancy,³ with higher mortality documented among pregnant patients during the 1918 influenza pandemic and the 2003 severe acute respiratory syndrome–associated coronavirus pandemic,³ and an increased rate of hospital admission documented among these patients compared to the general population during the 2009 H1N1 influenza pandemic.⁴

Data from the Centers for Disease Control and Prevention (CDC) suggest that pregnant women with symptomatic COVID-19 (n=30,415) are at increased risk for the following (compared to nonpregnant women with symptomatic COVID-19 [n=431,410])⁵:

• Admission to the intensive care unit (10.5 of every 1000 cases vs 3.9 of every 1000 cases; adjusted risk ratio [aRR]=3.0; 95% CI, 2.6-3.4)

• Receipt of invasive ventilation (2.9 of every 1000 cases vs 1.1 of every 1000 cases; aRR=2.9; 95% CI, 2.2-3.8)

• Receipt of extracorporeal membrane oxygenation (0.7 of every 1000 cases vs 0.3 of every 1000 cases; aRR=2.4; 95% CI, 1.5-4.0)

• Death (1.5 of every 1000 cases vs 1.2 of every 1000 cases; aRR=1.7; 95% CI, 1.2-2.4).

Although the absolute risk of severe COVID-19–related outcomes is low, the CDC includes pregnant women in its increased risk category for COVID-19. Furthermore, in a systematic review of 61 studies comprising 790 COVID-19–positive pregnant women and 548 newborns, the rates of cesarean delivery, premature birth, low birth weight, and adverse pregnancy events (the latter comprising preterm birth, death or stillbirth, and early termination of pregnancy) were estimated to be 72%, 23%, 7%, and 27%, respectively.⁶ In a systematic review of 39 studies (case series and cohort studies), comprising 936 SARS-CoV-2–tested newborns of mothers with COVID-19, mother-to-fetus transmission of SARS-CoV-2 occurred during the third trimester in approximately 3.2% of infected mothers.⁷

In pregnant women with COVID-19 who develop cytokine storm syndrome, a fetal inflammatory response syndrome can ensue, which has been shown to cause ventricular expansion and bleeding in animal models.⁸ In addition, underlying conditions, such as cardiovascular disease, diabetes mellitus, pre-existing lung disease, and obesity, which are well-established risks factors for severe COVID-19 in nonpregnant patients, can increase the severity of COVID-19 in pregnant women.^5,9-11

Recommendations From ACOG for Pregnant HCWs

The American College of Obstetricians and Gynecologists recommends that health care facilities consider limiting the exposure of pregnant HCWs to patients with confirmed or suspected COVID-19. They also recommend that pregnant women continue to work in patient-facing roles if they want to, if recommended personal protective equipment (PPE) is available for them to wear.² The US Food and Drug Administration issued an Emergency Use Authorization for 2 messenger RNA COVID-19 vaccines. Although these vaccines have not been tested in pregnant women, ACOG recommends that COVID-19 vaccines not be withheld from pregnant women who fulfill the criteria for vaccination; pregnant women who decline vaccination should be supported in their decision.¹² In dermatology, telemedicine is an effective alternative to face-to-face visits, reducing the risk of transmitting SARS-CoV-2 to physicians and patients.

Ideally, pregnant dermatology attending physicians and residents can continue to provide care through teledermatology. They also can continue to provide in-person care, if they choose to; however, higher-risk procedures should be avoided.¹² In dermatology, that might include ablative laser procedures to the face, prolonged surgery, such as hair transplantation, and intraoral or intranasal procedures. Alternatively, pregnant dermatology residents can be allocated to clinical rotations in which face-to-face contact with patients is not required such as dermatopathology and a research rotation. Likewise, telework options can be encouraged for other pregnant members of dermatology teams, including front-desk staff, nurses, medical assistants, and remaining ancillary staff.

Guidance on Face Masks for Pregnant HCWs

Universal masking of HCWs has been shown to reduce the rate of health care–related acquisition of SARS-CoV-2.¹³ However, extended use or reuse of N95 respirators might contribute to SARS-CoV-2 transmission.¹⁴ The American College of Obstetricians and Gynecologists recommends that all HCWs wear a face mask at all times while working in a health care facility, even if patients are wearing a face covering or face mask.² Based on CDC guidelines,¹⁵ HCWs in regions where community transmission is moderate or substantial should wear eye protection in addition to a face mask, and they should wear an N95, N95-equivalent, or higher-level respirator instead of a face mask when performing aerosol-generating procedures and surgical procedures. If working in a patient-facing role caring for patients with suspected or confirmed COVID-19, HCWs should wear an N95, N95-equivalent, or higher-level respirator; gown; gloves; and eye protection (goggles or a disposable face shield).¹⁵

Final Thoughts

COVID-19 has brought about acute and likely permanent changes to the US health care system. Dermatologists are integral members of that system and are essential to the treatment of patients with skin, hair, and nail disorders. Pregnant dermatologists and residents should refrain from patient-facing roles when feasible; however, when all recommended PPE are available, they may continue to work in patient-facing roles until they give birth if they desire to do so. Alternatively, teledermatology and non–face-to-face rotations should be encouraged. Higher-risk and aerosol-generating procedures are of particular concern regarding the risk for transmitting SARS-CoV-2 and should be avoided. Correct and universal use of PPE is paramount; when all recommended PPE is not available, pregnant HCWs should avoid exposure to patients with suspected or confirmed COVID-19. These recommendations will help safeguard pregnant members of dermatology teams during the COVID-19 pandemic while maximizing patient care.

Information is scarce regarding the impact of COVID-19 on pregnant women and newborns; health care workers (HCWs), particularly pregnant women,¹ who are caring for patients during the pandemic might experience concern and uncertainty. The American College of Obstetricians and Gynecologists (ACOG) released recommendations, based on expert consensus, regarding pregnant HCWs on December 14, 2020.² We propose an appropriation of the ACOG recommendations for dermatologists and their teams caring for patients during the COVID-19 pandemic.

Risks to Pregnant HCWs

Worldwide, viral pneumonia is a leading cause of death during pregnancy,³ with higher mortality documented among pregnant patients during the 1918 influenza pandemic and the 2003 severe acute respiratory syndrome–associated coronavirus pandemic,³ and an increased rate of hospital admission documented among these patients compared to the general population during the 2009 H1N1 influenza pandemic.⁴

Data from the Centers for Disease Control and Prevention (CDC) suggest that pregnant women with symptomatic COVID-19 (n=30,415) are at increased risk for the following (compared to nonpregnant women with symptomatic COVID-19 [n=431,410])⁵:

• Admission to the intensive care unit (10.5 of every 1000 cases vs 3.9 of every 1000 cases; adjusted risk ratio [aRR]=3.0; 95% CI, 2.6-3.4)

• Receipt of invasive ventilation (2.9 of every 1000 cases vs 1.1 of every 1000 cases; aRR=2.9; 95% CI, 2.2-3.8)

• Receipt of extracorporeal membrane oxygenation (0.7 of every 1000 cases vs 0.3 of every 1000 cases; aRR=2.4; 95% CI, 1.5-4.0)

• Death (1.5 of every 1000 cases vs 1.2 of every 1000 cases; aRR=1.7; 95% CI, 1.2-2.4).

Although the absolute risk of severe COVID-19–related outcomes is low, the CDC includes pregnant women in its increased risk category for COVID-19. Furthermore, in a systematic review of 61 studies comprising 790 COVID-19–positive pregnant women and 548 newborns, the rates of cesarean delivery, premature birth, low birth weight, and adverse pregnancy events (the latter comprising preterm birth, death or stillbirth, and early termination of pregnancy) were estimated to be 72%, 23%, 7%, and 27%, respectively.⁶ In a systematic review of 39 studies (case series and cohort studies), comprising 936 SARS-CoV-2–tested newborns of mothers with COVID-19, mother-to-fetus transmission of SARS-CoV-2 occurred during the third trimester in approximately 3.2% of infected mothers.⁷

In pregnant women with COVID-19 who develop cytokine storm syndrome, a fetal inflammatory response syndrome can ensue, which has been shown to cause ventricular expansion and bleeding in animal models.⁸ In addition, underlying conditions, such as cardiovascular disease, diabetes mellitus, pre-existing lung disease, and obesity, which are well-established risks factors for severe COVID-19 in nonpregnant patients, can increase the severity of COVID-19 in pregnant women.^5,9-11

Recommendations From ACOG for Pregnant HCWs

The American College of Obstetricians and Gynecologists recommends that health care facilities consider limiting the exposure of pregnant HCWs to patients with confirmed or suspected COVID-19. They also recommend that pregnant women continue to work in patient-facing roles if they want to, if recommended personal protective equipment (PPE) is available for them to wear.² The US Food and Drug Administration issued an Emergency Use Authorization for 2 messenger RNA COVID-19 vaccines. Although these vaccines have not been tested in pregnant women, ACOG recommends that COVID-19 vaccines not be withheld from pregnant women who fulfill the criteria for vaccination; pregnant women who decline vaccination should be supported in their decision.¹² In dermatology, telemedicine is an effective alternative to face-to-face visits, reducing the risk of transmitting SARS-CoV-2 to physicians and patients.

Ideally, pregnant dermatology attending physicians and residents can continue to provide care through teledermatology. They also can continue to provide in-person care, if they choose to; however, higher-risk procedures should be avoided.¹² In dermatology, that might include ablative laser procedures to the face, prolonged surgery, such as hair transplantation, and intraoral or intranasal procedures. Alternatively, pregnant dermatology residents can be allocated to clinical rotations in which face-to-face contact with patients is not required such as dermatopathology and a research rotation. Likewise, telework options can be encouraged for other pregnant members of dermatology teams, including front-desk staff, nurses, medical assistants, and remaining ancillary staff.

Guidance on Face Masks for Pregnant HCWs

Universal masking of HCWs has been shown to reduce the rate of health care–related acquisition of SARS-CoV-2.¹³ However, extended use or reuse of N95 respirators might contribute to SARS-CoV-2 transmission.¹⁴ The American College of Obstetricians and Gynecologists recommends that all HCWs wear a face mask at all times while working in a health care facility, even if patients are wearing a face covering or face mask.² Based on CDC guidelines,¹⁵ HCWs in regions where community transmission is moderate or substantial should wear eye protection in addition to a face mask, and they should wear an N95, N95-equivalent, or higher-level respirator instead of a face mask when performing aerosol-generating procedures and surgical procedures. If working in a patient-facing role caring for patients with suspected or confirmed COVID-19, HCWs should wear an N95, N95-equivalent, or higher-level respirator; gown; gloves; and eye protection (goggles or a disposable face shield).¹⁵

Final Thoughts

COVID-19 has brought about acute and likely permanent changes to the US health care system. Dermatologists are integral members of that system and are essential to the treatment of patients with skin, hair, and nail disorders. Pregnant dermatologists and residents should refrain from patient-facing roles when feasible; however, when all recommended PPE are available, they may continue to work in patient-facing roles until they give birth if they desire to do so. Alternatively, teledermatology and non–face-to-face rotations should be encouraged. Higher-risk and aerosol-generating procedures are of particular concern regarding the risk for transmitting SARS-CoV-2 and should be avoided. Correct and universal use of PPE is paramount; when all recommended PPE is not available, pregnant HCWs should avoid exposure to patients with suspected or confirmed COVID-19. These recommendations will help safeguard pregnant members of dermatology teams during the COVID-19 pandemic while maximizing patient care.

It’s time for the American Contact Dermatitis Society (ACDS) Allergen of the Year! For 2021, the esteemed award goes to acetophenone azine (AA). If you have never heard of this chemical, you are not alone. Acetophenone azine has been identified in foam materials made of the copolymer ethyl-vinyl acetate (EVA). Contact allergy to AA initially was reported in 2016.¹ There are only a few European and Canadian case reports and one case series of AA contact allergy in the literature, all of which are associated with foam shin pads or shin guards, shoe insoles, and/or flip-flops.^2-6 Acetophenone azine is an important emerging allergen, and in this column, we will introduce you to AA and the sneaky places it can lurk and cause allergic contact dermatitis (ACD). We also highlight diagnosis, management, and patch testing for AA contact allergy.

AA Contact Allergy in the Literature

The first case of AA contact allergy was reported in Europe in 2016 when a 13-year-old male soccer player developed severe lower leg dermatitis and later generalized dermatitis associated with wearing foam shin guards.¹ Patch testing to standard and supplemental trays was negative or not relevant; however, the patient exhibited strong reactions when patch tested directly to a piece of the shin guard soaked in acetone, water, and ethanol. Additional testing with AA diluted in acetone, water, and petrolatum resulted in positive patch test reactions to acetone dilutions of 1%, 0.1%, 0.01%, and 0.001% and aqueous solutions of 1% and 0.1%. Chromatographic analyses with high-performance liquid chromatography (HPLC) of shin guard extracts confirmed the culprit allergen to be AA.¹

In the following months, the same clinic saw 2 more cases of AA contact allergy.² An 11-year-old male soccer player developed lower leg dermatitis and later generalized dermatitis from wearing shin guards. Months later, he also developed dermatitis on the soles of the feet, which was attributed to wearing flip-flops. Patch tests to pieces of the shin guards and flip-flops were positive; AA in acetone 0.1% and 0.01% also was positive. As you might expect, HPLC again confirmed the presence of AA in the shin guards and flip-flops. The third patient was a 12-year-old boy with dermatitis on the soles of both feet; later he also developed a generalized dermatitis. Patch testing to pieces of the insoles of his sneakers and AA in acetone 0.1% and 0.01% was positive. Again, HPLC was positive for the presence of AA in the insoles of his sneakers.²

Several more cases of AA contact allergy have been reported in the literature. A 29-year-old European male hockey player demonstrated contact allergy to the gray foam of his shin pads as well as localized leg dermatitis followed by generalized dermatitis (are you noticing a trend yet?), and later dermatitis on the soles of the feet with positive patch-test reactions to pieces of his shin pads and shoe insoles as well as AA 0.1% and 0.01% in acetone.³ A 6-year-old Canadian male soccer player presented with leg dermatitis and later generalized dermatitis and dermatitis on the soles of the feet with positive reactions to pieces of his shin pads and shoe insoles as well as to AA 1% and 0.1% in petrolatum.⁴ A 17-year-old British male (another trend, all males so far!) hockey player developed dermatitis localized to the legs and positive patch tests to the worn foam inner lining of his shin pads as well as to AA 0.1%, 0.01%, and 0.001% in acetone.⁵Finally, Darrigade et al⁶ published a case series of 6 European children with AA contact allergy associated with shin pads and shoes; all had localized leg dermatitis, and some had generalized dermatitis. Patch testing to pieces of shin pads and shoe parts as well as to AA 0.1% in petrolatum and/or acetone showed with positive reactions to the foam pieces and AA in all 6 patients.

What’s the Deal With AA?

Acetophenone azine (also known as methylphenylketazine or bis[1-phenylethylidene]hydrazine) is composed of 2 acetophenone structures and a hydrazine moiety. It has been identified in EVA foam, which can be found in sports equipment such as shin pads or shin guards, shoes, and flip-flops. Raison-Peyron et al¹ confirmed the presence of AA in EVA foam but reported that they did not know the exact reason for its presence. The authors theorized that AA might be a catalyst during EVA polymerization and also noted that it has antimicrobial and antihelminthic activity.¹ Several authors noted that AA could be a by-product of EVA synthesis and that sports equipment manufacturers might not be aware of its presence in EVA.^2,4-6 Some noted that AA concentration was higher in shin guards than in shoe insoles; they thought this explained why patients reacted first to their shin guards and were perhaps even initially sensitized to the shin guards, as well as why shoe insole contact allergy commonly was reported later or only after allergy to shin guards had already developed.^4,6

Differential Diagnosis of Shin Pad or Shin Guard Dermatitis

We would be remiss if we did not mention the appropriate differential diagnosis when shin pad or shin guard dermatitis is identified. In fact, in most cases, shin guard dermatitis results from irritant contact dermatitis from friction, heat, and/or perspiration. Acetophenone azine contact allergy is not the most likely diagnosis when your sports-savvy, shin guard–wearing patient presents with anterior lower leg dermatitis. However, when conservative therapy (eg, barrier between the shin guard and the skin, control or management of perspiration, topical corticosteroid therapy) fails, patch testing to evaluate for ACD is indicated.

Management of AA Contact Allergy

As astute readers of this column are already aware, treatment of ACD requires strict allergen avoidance. You will find that we have the same recommendations for AA contact allergy. Given that there are only a handful of cases in the literature, there are limited recommendations on practical allergen avoidance other than “don’t wear the problem shin guards, shoe insoles, or flip-flops.” However, Darrigade et al⁶ recommended wearing polyurethane shin guards and leather insoles as alternatives when AA contact allergy is suspected or confirmed. They also made it clear that thick socks worn between shin guards and the skin often are not good enough to avoid ACD because the relevant allergens may achieve skin contact despite the barrier.⁶

Patch Testing for AA Contact Allergy

Historically, ACD to shin guards or shin pads, insoles of shoes, and even flip-flops has been associated with rubber-related chemicals such as mercapto mix, thiuram mix, N-isopropyl-N’-phenyl-p-phenylenediamine, thioureas, and carbamates, as well as dyes, benzoyl peroxide, and urea formaldehyde or phenol formaldehyde resins.¹ Most of these chemicals can be tested with standard screening series or supplemental series. Patients with contact allergy to AA may have negative patch testing to screening series and/or supplemental series and may have strong positive reactions to pieces of suspected foam shin pads or shin guards, shoes, and/or flip-flops. Although Koumaki et al⁵ recommended patch testing for AA contact allergy with AA 0.1% in acetone, Besner Morin et al⁴ mentioned that petrolatum may be a more desirable vehicle because it could maintain stability for a longer period of time. In fact, a 2021 article highlighting the American Contact Dermatitis Society Allergen of the Year recommends testing with either AA 0.1% in acetone or AA 0.1% in petrolatum.⁷ Unfortunately, AA is not commercially available for purchase at the time of publication. We are hopeful that this will change in the near future.

Final Interpretation

Acetophenone azine is an emerging allergen commonly identified in EVA foam and attributed to contact allergy to shin guards or pads, soles of shoes, and flip-flops. Most cases have been reported in Europe and Canada and have been identified in young male athletes. In addition to standard patch testing, athletes with lower leg dermatitis and/or dermatitis of the soles of the feet should undergo patch testing with AA 0.1% in acetone or petrolatum and pieces of the equipment and/or footwear.

It’s time for the American Contact Dermatitis Society (ACDS) Allergen of the Year! For 2021, the esteemed award goes to acetophenone azine (AA). If you have never heard of this chemical, you are not alone. Acetophenone azine has been identified in foam materials made of the copolymer ethyl-vinyl acetate (EVA). Contact allergy to AA initially was reported in 2016.¹ There are only a few European and Canadian case reports and one case series of AA contact allergy in the literature, all of which are associated with foam shin pads or shin guards, shoe insoles, and/or flip-flops.^2-6 Acetophenone azine is an important emerging allergen, and in this column, we will introduce you to AA and the sneaky places it can lurk and cause allergic contact dermatitis (ACD). We also highlight diagnosis, management, and patch testing for AA contact allergy.

AA Contact Allergy in the Literature

The first case of AA contact allergy was reported in Europe in 2016 when a 13-year-old male soccer player developed severe lower leg dermatitis and later generalized dermatitis associated with wearing foam shin guards.¹ Patch testing to standard and supplemental trays was negative or not relevant; however, the patient exhibited strong reactions when patch tested directly to a piece of the shin guard soaked in acetone, water, and ethanol. Additional testing with AA diluted in acetone, water, and petrolatum resulted in positive patch test reactions to acetone dilutions of 1%, 0.1%, 0.01%, and 0.001% and aqueous solutions of 1% and 0.1%. Chromatographic analyses with high-performance liquid chromatography (HPLC) of shin guard extracts confirmed the culprit allergen to be AA.¹

In the following months, the same clinic saw 2 more cases of AA contact allergy.² An 11-year-old male soccer player developed lower leg dermatitis and later generalized dermatitis from wearing shin guards. Months later, he also developed dermatitis on the soles of the feet, which was attributed to wearing flip-flops. Patch tests to pieces of the shin guards and flip-flops were positive; AA in acetone 0.1% and 0.01% also was positive. As you might expect, HPLC again confirmed the presence of AA in the shin guards and flip-flops. The third patient was a 12-year-old boy with dermatitis on the soles of both feet; later he also developed a generalized dermatitis. Patch testing to pieces of the insoles of his sneakers and AA in acetone 0.1% and 0.01% was positive. Again, HPLC was positive for the presence of AA in the insoles of his sneakers.²

Several more cases of AA contact allergy have been reported in the literature. A 29-year-old European male hockey player demonstrated contact allergy to the gray foam of his shin pads as well as localized leg dermatitis followed by generalized dermatitis (are you noticing a trend yet?), and later dermatitis on the soles of the feet with positive patch-test reactions to pieces of his shin pads and shoe insoles as well as AA 0.1% and 0.01% in acetone.³ A 6-year-old Canadian male soccer player presented with leg dermatitis and later generalized dermatitis and dermatitis on the soles of the feet with positive reactions to pieces of his shin pads and shoe insoles as well as to AA 1% and 0.1% in petrolatum.⁴ A 17-year-old British male (another trend, all males so far!) hockey player developed dermatitis localized to the legs and positive patch tests to the worn foam inner lining of his shin pads as well as to AA 0.1%, 0.01%, and 0.001% in acetone.⁵Finally, Darrigade et al⁶ published a case series of 6 European children with AA contact allergy associated with shin pads and shoes; all had localized leg dermatitis, and some had generalized dermatitis. Patch testing to pieces of shin pads and shoe parts as well as to AA 0.1% in petrolatum and/or acetone showed with positive reactions to the foam pieces and AA in all 6 patients.

What’s the Deal With AA?

Acetophenone azine (also known as methylphenylketazine or bis[1-phenylethylidene]hydrazine) is composed of 2 acetophenone structures and a hydrazine moiety. It has been identified in EVA foam, which can be found in sports equipment such as shin pads or shin guards, shoes, and flip-flops. Raison-Peyron et al¹ confirmed the presence of AA in EVA foam but reported that they did not know the exact reason for its presence. The authors theorized that AA might be a catalyst during EVA polymerization and also noted that it has antimicrobial and antihelminthic activity.¹ Several authors noted that AA could be a by-product of EVA synthesis and that sports equipment manufacturers might not be aware of its presence in EVA.^2,4-6 Some noted that AA concentration was higher in shin guards than in shoe insoles; they thought this explained why patients reacted first to their shin guards and were perhaps even initially sensitized to the shin guards, as well as why shoe insole contact allergy commonly was reported later or only after allergy to shin guards had already developed.^4,6

Differential Diagnosis of Shin Pad or Shin Guard Dermatitis

We would be remiss if we did not mention the appropriate differential diagnosis when shin pad or shin guard dermatitis is identified. In fact, in most cases, shin guard dermatitis results from irritant contact dermatitis from friction, heat, and/or perspiration. Acetophenone azine contact allergy is not the most likely diagnosis when your sports-savvy, shin guard–wearing patient presents with anterior lower leg dermatitis. However, when conservative therapy (eg, barrier between the shin guard and the skin, control or management of perspiration, topical corticosteroid therapy) fails, patch testing to evaluate for ACD is indicated.

Management of AA Contact Allergy

As astute readers of this column are already aware, treatment of ACD requires strict allergen avoidance. You will find that we have the same recommendations for AA contact allergy. Given that there are only a handful of cases in the literature, there are limited recommendations on practical allergen avoidance other than “don’t wear the problem shin guards, shoe insoles, or flip-flops.” However, Darrigade et al⁶ recommended wearing polyurethane shin guards and leather insoles as alternatives when AA contact allergy is suspected or confirmed. They also made it clear that thick socks worn between shin guards and the skin often are not good enough to avoid ACD because the relevant allergens may achieve skin contact despite the barrier.⁶

Patch Testing for AA Contact Allergy

Historically, ACD to shin guards or shin pads, insoles of shoes, and even flip-flops has been associated with rubber-related chemicals such as mercapto mix, thiuram mix, N-isopropyl-N’-phenyl-p-phenylenediamine, thioureas, and carbamates, as well as dyes, benzoyl peroxide, and urea formaldehyde or phenol formaldehyde resins.¹ Most of these chemicals can be tested with standard screening series or supplemental series. Patients with contact allergy to AA may have negative patch testing to screening series and/or supplemental series and may have strong positive reactions to pieces of suspected foam shin pads or shin guards, shoes, and/or flip-flops. Although Koumaki et al⁵ recommended patch testing for AA contact allergy with AA 0.1% in acetone, Besner Morin et al⁴ mentioned that petrolatum may be a more desirable vehicle because it could maintain stability for a longer period of time. In fact, a 2021 article highlighting the American Contact Dermatitis Society Allergen of the Year recommends testing with either AA 0.1% in acetone or AA 0.1% in petrolatum.⁷ Unfortunately, AA is not commercially available for purchase at the time of publication. We are hopeful that this will change in the near future.

Final Interpretation

Acetophenone azine is an emerging allergen commonly identified in EVA foam and attributed to contact allergy to shin guards or pads, soles of shoes, and flip-flops. Most cases have been reported in Europe and Canada and have been identified in young male athletes. In addition to standard patch testing, athletes with lower leg dermatitis and/or dermatitis of the soles of the feet should undergo patch testing with AA 0.1% in acetone or petrolatum and pieces of the equipment and/or footwear.

It’s time for the American Contact Dermatitis Society (ACDS) Allergen of the Year! For 2021, the esteemed award goes to acetophenone azine (AA). If you have never heard of this chemical, you are not alone. Acetophenone azine has been identified in foam materials made of the copolymer ethyl-vinyl acetate (EVA). Contact allergy to AA initially was reported in 2016.¹ There are only a few European and Canadian case reports and one case series of AA contact allergy in the literature, all of which are associated with foam shin pads or shin guards, shoe insoles, and/or flip-flops.^2-6 Acetophenone azine is an important emerging allergen, and in this column, we will introduce you to AA and the sneaky places it can lurk and cause allergic contact dermatitis (ACD). We also highlight diagnosis, management, and patch testing for AA contact allergy.

AA Contact Allergy in the Literature

The first case of AA contact allergy was reported in Europe in 2016 when a 13-year-old male soccer player developed severe lower leg dermatitis and later generalized dermatitis associated with wearing foam shin guards.¹ Patch testing to standard and supplemental trays was negative or not relevant; however, the patient exhibited strong reactions when patch tested directly to a piece of the shin guard soaked in acetone, water, and ethanol. Additional testing with AA diluted in acetone, water, and petrolatum resulted in positive patch test reactions to acetone dilutions of 1%, 0.1%, 0.01%, and 0.001% and aqueous solutions of 1% and 0.1%. Chromatographic analyses with high-performance liquid chromatography (HPLC) of shin guard extracts confirmed the culprit allergen to be AA.¹

In the following months, the same clinic saw 2 more cases of AA contact allergy.² An 11-year-old male soccer player developed lower leg dermatitis and later generalized dermatitis from wearing shin guards. Months later, he also developed dermatitis on the soles of the feet, which was attributed to wearing flip-flops. Patch tests to pieces of the shin guards and flip-flops were positive; AA in acetone 0.1% and 0.01% also was positive. As you might expect, HPLC again confirmed the presence of AA in the shin guards and flip-flops. The third patient was a 12-year-old boy with dermatitis on the soles of both feet; later he also developed a generalized dermatitis. Patch testing to pieces of the insoles of his sneakers and AA in acetone 0.1% and 0.01% was positive. Again, HPLC was positive for the presence of AA in the insoles of his sneakers.²

Several more cases of AA contact allergy have been reported in the literature. A 29-year-old European male hockey player demonstrated contact allergy to the gray foam of his shin pads as well as localized leg dermatitis followed by generalized dermatitis (are you noticing a trend yet?), and later dermatitis on the soles of the feet with positive patch-test reactions to pieces of his shin pads and shoe insoles as well as AA 0.1% and 0.01% in acetone.³ A 6-year-old Canadian male soccer player presented with leg dermatitis and later generalized dermatitis and dermatitis on the soles of the feet with positive reactions to pieces of his shin pads and shoe insoles as well as to AA 1% and 0.1% in petrolatum.⁴ A 17-year-old British male (another trend, all males so far!) hockey player developed dermatitis localized to the legs and positive patch tests to the worn foam inner lining of his shin pads as well as to AA 0.1%, 0.01%, and 0.001% in acetone.⁵Finally, Darrigade et al⁶ published a case series of 6 European children with AA contact allergy associated with shin pads and shoes; all had localized leg dermatitis, and some had generalized dermatitis. Patch testing to pieces of shin pads and shoe parts as well as to AA 0.1% in petrolatum and/or acetone showed with positive reactions to the foam pieces and AA in all 6 patients.

What’s the Deal With AA?

Acetophenone azine (also known as methylphenylketazine or bis[1-phenylethylidene]hydrazine) is composed of 2 acetophenone structures and a hydrazine moiety. It has been identified in EVA foam, which can be found in sports equipment such as shin pads or shin guards, shoes, and flip-flops. Raison-Peyron et al¹ confirmed the presence of AA in EVA foam but reported that they did not know the exact reason for its presence. The authors theorized that AA might be a catalyst during EVA polymerization and also noted that it has antimicrobial and antihelminthic activity.¹ Several authors noted that AA could be a by-product of EVA synthesis and that sports equipment manufacturers might not be aware of its presence in EVA.^2,4-6 Some noted that AA concentration was higher in shin guards than in shoe insoles; they thought this explained why patients reacted first to their shin guards and were perhaps even initially sensitized to the shin guards, as well as why shoe insole contact allergy commonly was reported later or only after allergy to shin guards had already developed.^4,6

Differential Diagnosis of Shin Pad or Shin Guard Dermatitis

We would be remiss if we did not mention the appropriate differential diagnosis when shin pad or shin guard dermatitis is identified. In fact, in most cases, shin guard dermatitis results from irritant contact dermatitis from friction, heat, and/or perspiration. Acetophenone azine contact allergy is not the most likely diagnosis when your sports-savvy, shin guard–wearing patient presents with anterior lower leg dermatitis. However, when conservative therapy (eg, barrier between the shin guard and the skin, control or management of perspiration, topical corticosteroid therapy) fails, patch testing to evaluate for ACD is indicated.

Management of AA Contact Allergy

As astute readers of this column are already aware, treatment of ACD requires strict allergen avoidance. You will find that we have the same recommendations for AA contact allergy. Given that there are only a handful of cases in the literature, there are limited recommendations on practical allergen avoidance other than “don’t wear the problem shin guards, shoe insoles, or flip-flops.” However, Darrigade et al⁶ recommended wearing polyurethane shin guards and leather insoles as alternatives when AA contact allergy is suspected or confirmed. They also made it clear that thick socks worn between shin guards and the skin often are not good enough to avoid ACD because the relevant allergens may achieve skin contact despite the barrier.⁶

Patch Testing for AA Contact Allergy

Historically, ACD to shin guards or shin pads, insoles of shoes, and even flip-flops has been associated with rubber-related chemicals such as mercapto mix, thiuram mix, N-isopropyl-N’-phenyl-p-phenylenediamine, thioureas, and carbamates, as well as dyes, benzoyl peroxide, and urea formaldehyde or phenol formaldehyde resins.¹ Most of these chemicals can be tested with standard screening series or supplemental series. Patients with contact allergy to AA may have negative patch testing to screening series and/or supplemental series and may have strong positive reactions to pieces of suspected foam shin pads or shin guards, shoes, and/or flip-flops. Although Koumaki et al⁵ recommended patch testing for AA contact allergy with AA 0.1% in acetone, Besner Morin et al⁴ mentioned that petrolatum may be a more desirable vehicle because it could maintain stability for a longer period of time. In fact, a 2021 article highlighting the American Contact Dermatitis Society Allergen of the Year recommends testing with either AA 0.1% in acetone or AA 0.1% in petrolatum.⁷ Unfortunately, AA is not commercially available for purchase at the time of publication. We are hopeful that this will change in the near future.

Final Interpretation

Acetophenone azine is an emerging allergen commonly identified in EVA foam and attributed to contact allergy to shin guards or pads, soles of shoes, and flip-flops. Most cases have been reported in Europe and Canada and have been identified in young male athletes. In addition to standard patch testing, athletes with lower leg dermatitis and/or dermatitis of the soles of the feet should undergo patch testing with AA 0.1% in acetone or petrolatum and pieces of the equipment and/or footwear.

Desmoplastic melanoma (DMM) is a rare variant of melanoma that presents major challenges to both clinicians and pathologists.¹ Clinically, the lesions may appear as subtle bland papules, nodules, or plaques. They can be easily mistaken for benign growths, leading to a delayed diagnosis. Consequently, most DMMs at the time of diagnosis tend to be thick, with a mean Breslow depth ranging from 2.0 to 6.5 mm.² Histopathologic evaluation has its difficulties. At scanning magnification, these tumors may show low cellularity, mimicking a benign proliferation. It is well recognized that S-100 and other tumor markers lack specificity for DMM, which can be positive in a range of neural tumors and other cell types.² In some amelanotic tumors, DMM becomes virtually indistinguishable from benign peripheral sheath tumors such as neurofribroma.³

Desmoplastic melanoma is exceedingly uncommon in the United States, with an estimated annual incidence rate of 2.0 cases per million.² Typical locations of presentation include sun-exposed skin, with the head and neck regions representing more than half of reported cases.² Desmoplastic melanoma largely is a disease of fair-skinned patients, with 95.5% of cases in the United States occurring in white non-Hispanic individuals. Advancing age, male gender, and head and neck location are associated with an increased risk for DMM-specific death.² It is important that new or changing lesions in the correct cohort and location are biopsied promptly. We present this case to highlight the ongoing challenges of diagnosing DMM both clinically and histologically and to review the salient features of this often benign-appearing tumor.

Case Report

A 51-year-old White man with a history of prostate cancer, a personal and family history of melanoma, and benign neurofibromas presented with a 6-mm, pink, well-demarcated, soft papule on the left lateral neck (Figure 1). The lesion had been stable for many years but began growing more rapidly 1 to 2 years prior to presentation. The lesion was asymptomatic, and he denied changes in color or texture. There also was no bleeding or ulceration. A review of systems was unremarkable. A shave biopsy of the lesion revealed a nodular spindle cell tumor in the dermis resembling a neurofibroma on low power (Figure 2). However, overlying the tumor was a confluent proliferation positive for MART-1 and S-100, which was consistent with a diagnosis of melanoma in situ (Figure 3). Higher-power evaluation of the dermal proliferation showed both bland and hyperchromatic spindled and epithelioid cells (Figure 4), with rare mitotic figures highlighted by PHH3, an uncommon finding in neurofibromas (Figure 5). The dermal spindle cells were positive for S-100 and p75 and negative for Melan-A. Epithelial membrane antigen highlighted a faint sheath surrounding the dermal component. Ki-67 revealed a mildly increased proliferative index in the dermal component. The diagnosis of DMM was made after outside dermatopathology consultation was in agreement. However, the possibility of a melanoma in situ growing in association with an underlying neurofibroma remained a diagnostic consideration histologically. The lesion was widely excised.

Comment

Differential for DMM
Early DMMs may not show sufficient cytologic atypia to permit obvious distinction from neurofibromas, which becomes problematic when encountering a spindle cell proliferation within severely sun-damaged skin, or even more so when an intraepidermal population of melanocytes is situated above a dermal population of slender, spindled, S-100–positive cells, as seen in our patient.⁴ For these challenging scenarios, Yeh and McCalmont⁴ have proposed evaluating for a CD34 “fingerprint” pattern. This pattern typically is widespread in neurofibroma but absent or limited in DMM, and it is a useful adjunct in the differential diagnosis when conventional immunohistochemistry has little contribution.

There are several case reports in the literature of DMM mimicking other benign or malignant proliferations. In 2012, Jou et al⁵ described a case of a 62-year-old White man who presented with an oral nodule consistent with fibrous inflammatory hyperplasia clinically. Incisional biopsy later confirmed the diagnosis of amelanotic DMM.⁵ Similar case reports have been described in which the diagnosis of DMM was later found to resemble a sarcoma and malignant peripheral nerve sheath tumor.^6,7

Diagnosis of DMM
The prototypical DMM is an asymmetrical and deeply infiltrative spindle cell lesion in severely sun-damaged skin. By definition, the individual melanocytes are separated by connective tissue components, giving the tumor a paucicellular appearance.¹ Although the low cellularity can give a deceptively bland scanning aspect, on high-power examination there usually are identifiable atypical spindled cells with enlarged, elongated, and hyperchromatic nuclei. S-100 typically is diffusely positive in DMM, though occasional cases show more limited staining.⁸ Other commonly used and more specific markers of melanocytic differentiation, including HMB45 and Melan-A, typically are negative in the paucicellular spindle cell components.⁹ Desmoplastic melanoma can be further categorized by the degree of fibrosis within a particular tumor. If fibrosis is prominent throughout the entire tumor, it is named pure DMM. On the other hand, fibrosis may only represent a portion of an otherwise nondesmoplastic melanoma, which is known as combined DMM.¹⁰

Conclusion

We present this case to highlight the ongoing challenges of diagnosing DMM both clinically and histologically. Although a bland-appearing lesion, key clinical features prompting a biopsy in our patient included recent growth of the lesion, a personal history of melanoma, the patient’s fair skin type, a history of heavy sun exposure, and the location of the lesion. According to Busam,¹¹ an associated melanoma in situ component is identified in 80% to 85% of DMM cases. Detection of a melanoma in situ component associated with a malignant spindle cell tumor can help establish the diagnosis of DMM. In the absence of melanoma in situ, a strong diffuse immunoreactivity for S-100 and lack of epithelial markers support the diagnosis.¹¹ After review of the literature, our case likely represents DMM as opposed to a melanoma in situ developing within a neurofibroma.

Desmoplastic melanoma (DMM) is a rare variant of melanoma that presents major challenges to both clinicians and pathologists.¹ Clinically, the lesions may appear as subtle bland papules, nodules, or plaques. They can be easily mistaken for benign growths, leading to a delayed diagnosis. Consequently, most DMMs at the time of diagnosis tend to be thick, with a mean Breslow depth ranging from 2.0 to 6.5 mm.² Histopathologic evaluation has its difficulties. At scanning magnification, these tumors may show low cellularity, mimicking a benign proliferation. It is well recognized that S-100 and other tumor markers lack specificity for DMM, which can be positive in a range of neural tumors and other cell types.² In some amelanotic tumors, DMM becomes virtually indistinguishable from benign peripheral sheath tumors such as neurofribroma.³

Desmoplastic melanoma is exceedingly uncommon in the United States, with an estimated annual incidence rate of 2.0 cases per million.² Typical locations of presentation include sun-exposed skin, with the head and neck regions representing more than half of reported cases.² Desmoplastic melanoma largely is a disease of fair-skinned patients, with 95.5% of cases in the United States occurring in white non-Hispanic individuals. Advancing age, male gender, and head and neck location are associated with an increased risk for DMM-specific death.² It is important that new or changing lesions in the correct cohort and location are biopsied promptly. We present this case to highlight the ongoing challenges of diagnosing DMM both clinically and histologically and to review the salient features of this often benign-appearing tumor.

Case Report

A 51-year-old White man with a history of prostate cancer, a personal and family history of melanoma, and benign neurofibromas presented with a 6-mm, pink, well-demarcated, soft papule on the left lateral neck (Figure 1). The lesion had been stable for many years but began growing more rapidly 1 to 2 years prior to presentation. The lesion was asymptomatic, and he denied changes in color or texture. There also was no bleeding or ulceration. A review of systems was unremarkable. A shave biopsy of the lesion revealed a nodular spindle cell tumor in the dermis resembling a neurofibroma on low power (Figure 2). However, overlying the tumor was a confluent proliferation positive for MART-1 and S-100, which was consistent with a diagnosis of melanoma in situ (Figure 3). Higher-power evaluation of the dermal proliferation showed both bland and hyperchromatic spindled and epithelioid cells (Figure 4), with rare mitotic figures highlighted by PHH3, an uncommon finding in neurofibromas (Figure 5). The dermal spindle cells were positive for S-100 and p75 and negative for Melan-A. Epithelial membrane antigen highlighted a faint sheath surrounding the dermal component. Ki-67 revealed a mildly increased proliferative index in the dermal component. The diagnosis of DMM was made after outside dermatopathology consultation was in agreement. However, the possibility of a melanoma in situ growing in association with an underlying neurofibroma remained a diagnostic consideration histologically. The lesion was widely excised.

Comment

Differential for DMM
Early DMMs may not show sufficient cytologic atypia to permit obvious distinction from neurofibromas, which becomes problematic when encountering a spindle cell proliferation within severely sun-damaged skin, or even more so when an intraepidermal population of melanocytes is situated above a dermal population of slender, spindled, S-100–positive cells, as seen in our patient.⁴ For these challenging scenarios, Yeh and McCalmont⁴ have proposed evaluating for a CD34 “fingerprint” pattern. This pattern typically is widespread in neurofibroma but absent or limited in DMM, and it is a useful adjunct in the differential diagnosis when conventional immunohistochemistry has little contribution.

There are several case reports in the literature of DMM mimicking other benign or malignant proliferations. In 2012, Jou et al⁵ described a case of a 62-year-old White man who presented with an oral nodule consistent with fibrous inflammatory hyperplasia clinically. Incisional biopsy later confirmed the diagnosis of amelanotic DMM.⁵ Similar case reports have been described in which the diagnosis of DMM was later found to resemble a sarcoma and malignant peripheral nerve sheath tumor.^6,7

Diagnosis of DMM
The prototypical DMM is an asymmetrical and deeply infiltrative spindle cell lesion in severely sun-damaged skin. By definition, the individual melanocytes are separated by connective tissue components, giving the tumor a paucicellular appearance.¹ Although the low cellularity can give a deceptively bland scanning aspect, on high-power examination there usually are identifiable atypical spindled cells with enlarged, elongated, and hyperchromatic nuclei. S-100 typically is diffusely positive in DMM, though occasional cases show more limited staining.⁸ Other commonly used and more specific markers of melanocytic differentiation, including HMB45 and Melan-A, typically are negative in the paucicellular spindle cell components.⁹ Desmoplastic melanoma can be further categorized by the degree of fibrosis within a particular tumor. If fibrosis is prominent throughout the entire tumor, it is named pure DMM. On the other hand, fibrosis may only represent a portion of an otherwise nondesmoplastic melanoma, which is known as combined DMM.¹⁰

Conclusion

We present this case to highlight the ongoing challenges of diagnosing DMM both clinically and histologically. Although a bland-appearing lesion, key clinical features prompting a biopsy in our patient included recent growth of the lesion, a personal history of melanoma, the patient’s fair skin type, a history of heavy sun exposure, and the location of the lesion. According to Busam,¹¹ an associated melanoma in situ component is identified in 80% to 85% of DMM cases. Detection of a melanoma in situ component associated with a malignant spindle cell tumor can help establish the diagnosis of DMM. In the absence of melanoma in situ, a strong diffuse immunoreactivity for S-100 and lack of epithelial markers support the diagnosis.¹¹ After review of the literature, our case likely represents DMM as opposed to a melanoma in situ developing within a neurofibroma.

Desmoplastic melanoma (DMM) is a rare variant of melanoma that presents major challenges to both clinicians and pathologists.¹ Clinically, the lesions may appear as subtle bland papules, nodules, or plaques. They can be easily mistaken for benign growths, leading to a delayed diagnosis. Consequently, most DMMs at the time of diagnosis tend to be thick, with a mean Breslow depth ranging from 2.0 to 6.5 mm.² Histopathologic evaluation has its difficulties. At scanning magnification, these tumors may show low cellularity, mimicking a benign proliferation. It is well recognized that S-100 and other tumor markers lack specificity for DMM, which can be positive in a range of neural tumors and other cell types.² In some amelanotic tumors, DMM becomes virtually indistinguishable from benign peripheral sheath tumors such as neurofribroma.³

Desmoplastic melanoma is exceedingly uncommon in the United States, with an estimated annual incidence rate of 2.0 cases per million.² Typical locations of presentation include sun-exposed skin, with the head and neck regions representing more than half of reported cases.² Desmoplastic melanoma largely is a disease of fair-skinned patients, with 95.5% of cases in the United States occurring in white non-Hispanic individuals. Advancing age, male gender, and head and neck location are associated with an increased risk for DMM-specific death.² It is important that new or changing lesions in the correct cohort and location are biopsied promptly. We present this case to highlight the ongoing challenges of diagnosing DMM both clinically and histologically and to review the salient features of this often benign-appearing tumor.

Case Report

A 51-year-old White man with a history of prostate cancer, a personal and family history of melanoma, and benign neurofibromas presented with a 6-mm, pink, well-demarcated, soft papule on the left lateral neck (Figure 1). The lesion had been stable for many years but began growing more rapidly 1 to 2 years prior to presentation. The lesion was asymptomatic, and he denied changes in color or texture. There also was no bleeding or ulceration. A review of systems was unremarkable. A shave biopsy of the lesion revealed a nodular spindle cell tumor in the dermis resembling a neurofibroma on low power (Figure 2). However, overlying the tumor was a confluent proliferation positive for MART-1 and S-100, which was consistent with a diagnosis of melanoma in situ (Figure 3). Higher-power evaluation of the dermal proliferation showed both bland and hyperchromatic spindled and epithelioid cells (Figure 4), with rare mitotic figures highlighted by PHH3, an uncommon finding in neurofibromas (Figure 5). The dermal spindle cells were positive for S-100 and p75 and negative for Melan-A. Epithelial membrane antigen highlighted a faint sheath surrounding the dermal component. Ki-67 revealed a mildly increased proliferative index in the dermal component. The diagnosis of DMM was made after outside dermatopathology consultation was in agreement. However, the possibility of a melanoma in situ growing in association with an underlying neurofibroma remained a diagnostic consideration histologically. The lesion was widely excised.

Comment

Differential for DMM
Early DMMs may not show sufficient cytologic atypia to permit obvious distinction from neurofibromas, which becomes problematic when encountering a spindle cell proliferation within severely sun-damaged skin, or even more so when an intraepidermal population of melanocytes is situated above a dermal population of slender, spindled, S-100–positive cells, as seen in our patient.⁴ For these challenging scenarios, Yeh and McCalmont⁴ have proposed evaluating for a CD34 “fingerprint” pattern. This pattern typically is widespread in neurofibroma but absent or limited in DMM, and it is a useful adjunct in the differential diagnosis when conventional immunohistochemistry has little contribution.

There are several case reports in the literature of DMM mimicking other benign or malignant proliferations. In 2012, Jou et al⁵ described a case of a 62-year-old White man who presented with an oral nodule consistent with fibrous inflammatory hyperplasia clinically. Incisional biopsy later confirmed the diagnosis of amelanotic DMM.⁵ Similar case reports have been described in which the diagnosis of DMM was later found to resemble a sarcoma and malignant peripheral nerve sheath tumor.^6,7

Diagnosis of DMM
The prototypical DMM is an asymmetrical and deeply infiltrative spindle cell lesion in severely sun-damaged skin. By definition, the individual melanocytes are separated by connective tissue components, giving the tumor a paucicellular appearance.¹ Although the low cellularity can give a deceptively bland scanning aspect, on high-power examination there usually are identifiable atypical spindled cells with enlarged, elongated, and hyperchromatic nuclei. S-100 typically is diffusely positive in DMM, though occasional cases show more limited staining.⁸ Other commonly used and more specific markers of melanocytic differentiation, including HMB45 and Melan-A, typically are negative in the paucicellular spindle cell components.⁹ Desmoplastic melanoma can be further categorized by the degree of fibrosis within a particular tumor. If fibrosis is prominent throughout the entire tumor, it is named pure DMM. On the other hand, fibrosis may only represent a portion of an otherwise nondesmoplastic melanoma, which is known as combined DMM.¹⁰

Conclusion

We present this case to highlight the ongoing challenges of diagnosing DMM both clinically and histologically. Although a bland-appearing lesion, key clinical features prompting a biopsy in our patient included recent growth of the lesion, a personal history of melanoma, the patient’s fair skin type, a history of heavy sun exposure, and the location of the lesion. According to Busam,¹¹ an associated melanoma in situ component is identified in 80% to 85% of DMM cases. Detection of a melanoma in situ component associated with a malignant spindle cell tumor can help establish the diagnosis of DMM. In the absence of melanoma in situ, a strong diffuse immunoreactivity for S-100 and lack of epithelial markers support the diagnosis.¹¹ After review of the literature, our case likely represents DMM as opposed to a melanoma in situ developing within a neurofibroma.

What is West Nile virus? How is it contracted, and who can become infected?

West Nile virus (WNV) is a single-stranded RNA virus of the Flaviviridae family and Flavivirus genus, a lineage that also includes the yellow fever, dengue, Zika, Japanese encephalitis, and Saint Louis encephalitis viruses.¹ Birds serve as the reservoir hosts of WNV, and mosquitoes acquire the virus during feeding.² West Nile virus then is transmitted to humans primarily by bites from Culex mosquitoes, which are especially prevalent in wooded areas during peak mosquito season (summer through early fall in North America).¹ Mosquitoes also can infect horses; however, humans and horses are dead-end hosts, meaning they do not pass the virus on to other biting mosquitoes.³ There also have been rare reports of transmission of WNV through blood and donation as well as mother-to-baby transmission.²

What is the epidemiology of WNV in the United States?

Since the introduction of WNV to the United States in 1999, it has become an important public health concern, with 48,183 cases and 2163 deaths reported since 1999.^2,3 In 2018, Nebraska had the highest number of cases of WNV (n=251), followed by California (n=217), North Dakota (n=204), Illinois (n=176), and South Dakota (n=169).³ West Nile virus is endemic to all 48 contiguous states and Canada, though the Great Plains region is especially affected by WNV due to several factors, such as a greater percentage of rural land, forests, and irrigated areas.⁴ The Great Plains region also has been thought to be an ecological niche for a more virulent species (Culex tarsalis) compared to other regions in the United States.⁵

The annual incidence of WNV in the United States peaked in 2003 at 9862 cases (up from 62 cases in 1999), then declined gradually until 2008 to 2011, during which the incidence was stable at 700 to 1100 new cases per year. However, there was a resurgence of cases (n=5674) in 2012 that steadied at around 2200 cases annually in subsequent years.⁶ Although there likely are several factors affecting WNV incidence trends in the United States, interannual changes in temperature and precipitation have been described. An increased mean annual temperature (from September through October, the end of peak mosquito season) and an increased temperature in winter months (from January through March, prior to peak mosquito season) have both been associated with an increased incidence of WNV.⁷ An increased temperature is thought to increase population numbers of mosquitoes both by increasing reproductive rates and creating ideal breeding environments via pooled water areas.⁸ Depending on the region, both above average and below average precipitation levels in the United States can increase WNV incidence the following year.^7,9

What are the signs and symptoms of WNV infection?

Up to 80% of those infected with WNV are asymptomatic.³ After an incubation period of roughly 2 to 14 days, the remaining 20% may develop symptoms of West Nile fever (WNF), typically a self-limited illness that consists of 3 to 10 days of nonspecific symptoms such as fever, headache, fatigue, muscle pain and/or weakness, eye pain, gastrointestinal tract upset, and a macular rash that usually presents on the trunk or extremities.^1,3 Less than 1% of patients affected by WNV develop neuroinvasive disease, including meningitis, encephalitis, and/or acute flaccid paralysis.¹⁰ West Nile virus neuroinvasive disease can cause permanent neurologic sequelae such as muscle weakness, confusion, memory loss, and fatigue; it carries a mortality rate of 10% to 30%, which is mainly dependent on older age and immunosuppression status.^1,10

What is the reported spectrum of cutaneous findings in WNV?

Of the roughly 20% of patients infected with WNV that develop WNF, approximately 25% to 50% will develop an associated rash.¹ It most commonly is described as a morbilliform or maculopapular rash located on the chest, back, and arms, usually sparing the palms and soles, though 1 case report noted involvement with these areas (Figure).^11,12 It typically appears 5 days after symptom onset, can be associated with defervescence, and lasts less than a week.^1,13 Pruritus and dysesthesia are sometimes present.¹³ Other rare presentations that have been reported include an ill-defined pseudovesicular rash with erythematous papules on the palms and pink, scaly, psoriasiform papules on the feet and thighs, as well as neuroinvasive WNV leading to purpura fulminans.^14,15 A diffuse, erythematous, petechial rash on the face, neck, trunk, and extremities was reported in a pediatric patient, but there have been no reports of a petechial rash associated with WNV in adult patients.¹⁶ These findings suggest some potential variability in the presentation of the WNV rash.

What role does the presence of rash play diagnostically and prognostically?

The rash of WNV has been implicated as a potential prognostic factor in predicting more favorable outcomes.¹⁷ Using 2002 data from the Illinois Department of Public Health and 2003 data from the Colorado Department of Public Health, Huhn and Dworkin¹⁷ found the age-adjusted risk of encephalitis and death to be decreased in WNV patients with a rash (relative risk, 0.44; 95% CI, 0.21-0.92). The reasons for this are not definitively known, but we hypothesize that the rash may prompt patients to seek earlier medical attention or indicate a more robust immune response. Additionally, a rash in WNV more commonly is seen in younger patients, whereas WNV neuroinvasive disease is more common in older patients, who also tend to have worse outcomes.¹⁰ One study found rash to be the only symptom that demonstrated a significant association with seropositivity (overall risk=6.35; P<.05; 95% CI, 3.75-10.80) by multivariate analysis.¹⁸

How is WNV diagnosed? What are the downsides to WNV testing?

Given that the presenting symptoms of WNV and WNF are nonspecific, it becomes challenging to arrive at the diagnosis based solely on physical examination. As such, the patient’s clinical and epidemiologic history, such as timing, pattern, and appearance of the rash or recent history of mosquito bites, is key to arriving at the correct diagnosis. With clinical suspicion, possible diagnostic tests include an IgM enzyme-linked immunosorbent assay (ELISA) for WNV, a plaque reduction neutralization test (PNRT), and blood polymerase chain reaction (PCR).

An ELISA is a confirmatory test to detect IgM antibodies to WNV in the serum. Because IgM seroconversion typically occurs between days 4 and 10 of symptom onset, there is a high probability of initial false-negative testing within the first 8 days after symptom onset.^19,20 Clinical understanding of this fact is imperative, as an initial negative ELISA does not rule out WNV, and a retest is warranted if clinical suspicion is high. In addition to a high initial false-negative rate with ELISA, there are several other limitations to note. IgM antibodies remain elevated for 1 to 3 months or possibly up to a year in immunocompromised patients.¹ Due to this, false positives may be present if there was a recent prior infection. Enzyme-linked immunosorbent assay may not distinguish from different flaviviruses, including the yellow fever, dengue, Zika, Japanese encephalitis, and Saint Louis encephalitis viruses. Seropositivity has been estimated in some states, including 1999 data from New York (2.6%), 2003 data from Nebraska (9.5%), and 2012-2014 data from Connecticut (8.5%).^21-23 Regional variance may be expected, as there also were significant differences in WNV seropositivity between different regions in Nebraska (P<.001).²³

Because ELISA testing for WNV has readily apparent flaws, other tests have been utilized in its diagnosis. The PNRT is the most specific test, and it works by measuring neutralizing antibody titers for different flaviviruses. It has the ability to determine cross-reactivity with other flaviviruses; however, it does not discriminate between a current infection and a prior infection or prior flavivirus vaccine (ie, yellow fever vaccine). Despite this, a positive PNRT can lend credibility to a positive ELISA test and determine specificity for WNV for those with no prior flavivirus exposure.²⁴ According to the Centers for Disease Control and Prevention (CDC), this test can be performed by the CDC or in reference laboratories designated by the CDC.³ Additionally, some state health laboratories may perform PRNTs.

Viral detection with PCR currently is used to screen blood donations and may be beneficial for immunocompromised patients that lack the ability to form a robust antibody response or if a patient presents early, as PCR works best within the first week of symptom onset.¹ Tilley et al²⁵ showed that a combination of PCR and ELISA were able to accurately predict 94.2% of patients (180/191) with documented WNV on a first blood sample compared to 45% and 58.1% for only viral detection or ELISA, respectively. Based on costs from a Midwest academic center, antibody detection tests are around $100 while PCR may range from $500 to $1000 and is only performed in reference laboratories. Although these tests remain in the repertoire for WNV diagnosis, financial stewardship is important.

If there are symptoms of photophobia, phonophobia, nuchal rigidity, loss of consciousness, or marked personality changes, a lumbar puncture for WNV IgM in the cerebrospinal fluid can be performed. As with most viral infections, cerebrospinal fluid findings normally include an elevated protein and lymphocyte count, but neutrophils may be predominantly elevated if the infection is early in its course.²⁶

What are the management options?

To date, there is no curative treatment for WNV, and management is largely supportive. For WNF, over-the-counter pain medications may be helpful to reduce fever and pain. If more severe disease develops, hospitalization for further supportive care may be needed.²⁷ If meningitis or encephalitis is suspected, broad-spectrum antibiotics may need to be started until other common etiologies are ruled out.²⁸

How can you prevent WNV infection?

Disease prevention largely consists of educating the public to avoid heavily wooded areas, especially in areas of high prevalence and during peak months, and to use protective clothing and insect repellant that has been approved by the Environmental Protection Agency.³ Insect repellants approved by the Environmental Protection Agency contain ingredients such as DEET (N, N-diethyl-meta-toluamide), picaridin, IR3535 (ethyl butylacetylaminopropionate), and oil of lemon eucalyptus, which have been proven safe and effective.²⁹ Patients also can protect their homes by using window screens and promptly repairing screens with holes.³

What is the differential diagnosis for WNV?

The differential diagnosis for fever with generalized maculopapular rash broadly ranges from viral etiologies (eg, WNV, Zika, measles), to tick bites (eg, Rocky Mountain spotted fever, ehrlichiosis), to drug-induced rashes. A detailed patient history inquiring on recent sick contacts, travel (WNV in the Midwest, ehrlichiosis in the Southeast), environmental exposures (ticks, mosquitoes), and new medications (typically 7–10 days after starting) is imperative to narrow the differential.³⁰ In addition, the distribution, timing, and clinical characteristics of the rash may aid in diagnosis, along with an appropriately correlated clinical picture. West Nile virus likely will present in the summer in mid central geographic locations and often develops on the trunk and extremities as a blanching, generalized, maculopapular rash around 5 days after symptom onset or with defervescence.¹

What is West Nile virus? How is it contracted, and who can become infected?

West Nile virus (WNV) is a single-stranded RNA virus of the Flaviviridae family and Flavivirus genus, a lineage that also includes the yellow fever, dengue, Zika, Japanese encephalitis, and Saint Louis encephalitis viruses.¹ Birds serve as the reservoir hosts of WNV, and mosquitoes acquire the virus during feeding.² West Nile virus then is transmitted to humans primarily by bites from Culex mosquitoes, which are especially prevalent in wooded areas during peak mosquito season (summer through early fall in North America).¹ Mosquitoes also can infect horses; however, humans and horses are dead-end hosts, meaning they do not pass the virus on to other biting mosquitoes.³ There also have been rare reports of transmission of WNV through blood and donation as well as mother-to-baby transmission.²

What is the epidemiology of WNV in the United States?

Since the introduction of WNV to the United States in 1999, it has become an important public health concern, with 48,183 cases and 2163 deaths reported since 1999.^2,3 In 2018, Nebraska had the highest number of cases of WNV (n=251), followed by California (n=217), North Dakota (n=204), Illinois (n=176), and South Dakota (n=169).³ West Nile virus is endemic to all 48 contiguous states and Canada, though the Great Plains region is especially affected by WNV due to several factors, such as a greater percentage of rural land, forests, and irrigated areas.⁴ The Great Plains region also has been thought to be an ecological niche for a more virulent species (Culex tarsalis) compared to other regions in the United States.⁵

The annual incidence of WNV in the United States peaked in 2003 at 9862 cases (up from 62 cases in 1999), then declined gradually until 2008 to 2011, during which the incidence was stable at 700 to 1100 new cases per year. However, there was a resurgence of cases (n=5674) in 2012 that steadied at around 2200 cases annually in subsequent years.⁶ Although there likely are several factors affecting WNV incidence trends in the United States, interannual changes in temperature and precipitation have been described. An increased mean annual temperature (from September through October, the end of peak mosquito season) and an increased temperature in winter months (from January through March, prior to peak mosquito season) have both been associated with an increased incidence of WNV.⁷ An increased temperature is thought to increase population numbers of mosquitoes both by increasing reproductive rates and creating ideal breeding environments via pooled water areas.⁸ Depending on the region, both above average and below average precipitation levels in the United States can increase WNV incidence the following year.^7,9

What are the signs and symptoms of WNV infection?

Up to 80% of those infected with WNV are asymptomatic.³ After an incubation period of roughly 2 to 14 days, the remaining 20% may develop symptoms of West Nile fever (WNF), typically a self-limited illness that consists of 3 to 10 days of nonspecific symptoms such as fever, headache, fatigue, muscle pain and/or weakness, eye pain, gastrointestinal tract upset, and a macular rash that usually presents on the trunk or extremities.^1,3 Less than 1% of patients affected by WNV develop neuroinvasive disease, including meningitis, encephalitis, and/or acute flaccid paralysis.¹⁰ West Nile virus neuroinvasive disease can cause permanent neurologic sequelae such as muscle weakness, confusion, memory loss, and fatigue; it carries a mortality rate of 10% to 30%, which is mainly dependent on older age and immunosuppression status.^1,10

What is the reported spectrum of cutaneous findings in WNV?

Of the roughly 20% of patients infected with WNV that develop WNF, approximately 25% to 50% will develop an associated rash.¹ It most commonly is described as a morbilliform or maculopapular rash located on the chest, back, and arms, usually sparing the palms and soles, though 1 case report noted involvement with these areas (Figure).^11,12 It typically appears 5 days after symptom onset, can be associated with defervescence, and lasts less than a week.^1,13 Pruritus and dysesthesia are sometimes present.¹³ Other rare presentations that have been reported include an ill-defined pseudovesicular rash with erythematous papules on the palms and pink, scaly, psoriasiform papules on the feet and thighs, as well as neuroinvasive WNV leading to purpura fulminans.^14,15 A diffuse, erythematous, petechial rash on the face, neck, trunk, and extremities was reported in a pediatric patient, but there have been no reports of a petechial rash associated with WNV in adult patients.¹⁶ These findings suggest some potential variability in the presentation of the WNV rash.

What role does the presence of rash play diagnostically and prognostically?

The rash of WNV has been implicated as a potential prognostic factor in predicting more favorable outcomes.¹⁷ Using 2002 data from the Illinois Department of Public Health and 2003 data from the Colorado Department of Public Health, Huhn and Dworkin¹⁷ found the age-adjusted risk of encephalitis and death to be decreased in WNV patients with a rash (relative risk, 0.44; 95% CI, 0.21-0.92). The reasons for this are not definitively known, but we hypothesize that the rash may prompt patients to seek earlier medical attention or indicate a more robust immune response. Additionally, a rash in WNV more commonly is seen in younger patients, whereas WNV neuroinvasive disease is more common in older patients, who also tend to have worse outcomes.¹⁰ One study found rash to be the only symptom that demonstrated a significant association with seropositivity (overall risk=6.35; P<.05; 95% CI, 3.75-10.80) by multivariate analysis.¹⁸

How is WNV diagnosed? What are the downsides to WNV testing?

Given that the presenting symptoms of WNV and WNF are nonspecific, it becomes challenging to arrive at the diagnosis based solely on physical examination. As such, the patient’s clinical and epidemiologic history, such as timing, pattern, and appearance of the rash or recent history of mosquito bites, is key to arriving at the correct diagnosis. With clinical suspicion, possible diagnostic tests include an IgM enzyme-linked immunosorbent assay (ELISA) for WNV, a plaque reduction neutralization test (PNRT), and blood polymerase chain reaction (PCR).

An ELISA is a confirmatory test to detect IgM antibodies to WNV in the serum. Because IgM seroconversion typically occurs between days 4 and 10 of symptom onset, there is a high probability of initial false-negative testing within the first 8 days after symptom onset.^19,20 Clinical understanding of this fact is imperative, as an initial negative ELISA does not rule out WNV, and a retest is warranted if clinical suspicion is high. In addition to a high initial false-negative rate with ELISA, there are several other limitations to note. IgM antibodies remain elevated for 1 to 3 months or possibly up to a year in immunocompromised patients.¹ Due to this, false positives may be present if there was a recent prior infection. Enzyme-linked immunosorbent assay may not distinguish from different flaviviruses, including the yellow fever, dengue, Zika, Japanese encephalitis, and Saint Louis encephalitis viruses. Seropositivity has been estimated in some states, including 1999 data from New York (2.6%), 2003 data from Nebraska (9.5%), and 2012-2014 data from Connecticut (8.5%).^21-23 Regional variance may be expected, as there also were significant differences in WNV seropositivity between different regions in Nebraska (P<.001).²³

Because ELISA testing for WNV has readily apparent flaws, other tests have been utilized in its diagnosis. The PNRT is the most specific test, and it works by measuring neutralizing antibody titers for different flaviviruses. It has the ability to determine cross-reactivity with other flaviviruses; however, it does not discriminate between a current infection and a prior infection or prior flavivirus vaccine (ie, yellow fever vaccine). Despite this, a positive PNRT can lend credibility to a positive ELISA test and determine specificity for WNV for those with no prior flavivirus exposure.²⁴ According to the Centers for Disease Control and Prevention (CDC), this test can be performed by the CDC or in reference laboratories designated by the CDC.³ Additionally, some state health laboratories may perform PRNTs.

Viral detection with PCR currently is used to screen blood donations and may be beneficial for immunocompromised patients that lack the ability to form a robust antibody response or if a patient presents early, as PCR works best within the first week of symptom onset.¹ Tilley et al²⁵ showed that a combination of PCR and ELISA were able to accurately predict 94.2% of patients (180/191) with documented WNV on a first blood sample compared to 45% and 58.1% for only viral detection or ELISA, respectively. Based on costs from a Midwest academic center, antibody detection tests are around $100 while PCR may range from $500 to $1000 and is only performed in reference laboratories. Although these tests remain in the repertoire for WNV diagnosis, financial stewardship is important.

If there are symptoms of photophobia, phonophobia, nuchal rigidity, loss of consciousness, or marked personality changes, a lumbar puncture for WNV IgM in the cerebrospinal fluid can be performed. As with most viral infections, cerebrospinal fluid findings normally include an elevated protein and lymphocyte count, but neutrophils may be predominantly elevated if the infection is early in its course.²⁶

What are the management options?

To date, there is no curative treatment for WNV, and management is largely supportive. For WNF, over-the-counter pain medications may be helpful to reduce fever and pain. If more severe disease develops, hospitalization for further supportive care may be needed.²⁷ If meningitis or encephalitis is suspected, broad-spectrum antibiotics may need to be started until other common etiologies are ruled out.²⁸

How can you prevent WNV infection?

Disease prevention largely consists of educating the public to avoid heavily wooded areas, especially in areas of high prevalence and during peak months, and to use protective clothing and insect repellant that has been approved by the Environmental Protection Agency.³ Insect repellants approved by the Environmental Protection Agency contain ingredients such as DEET (N, N-diethyl-meta-toluamide), picaridin, IR3535 (ethyl butylacetylaminopropionate), and oil of lemon eucalyptus, which have been proven safe and effective.²⁹ Patients also can protect their homes by using window screens and promptly repairing screens with holes.³

What is the differential diagnosis for WNV?

The differential diagnosis for fever with generalized maculopapular rash broadly ranges from viral etiologies (eg, WNV, Zika, measles), to tick bites (eg, Rocky Mountain spotted fever, ehrlichiosis), to drug-induced rashes. A detailed patient history inquiring on recent sick contacts, travel (WNV in the Midwest, ehrlichiosis in the Southeast), environmental exposures (ticks, mosquitoes), and new medications (typically 7–10 days after starting) is imperative to narrow the differential.³⁰ In addition, the distribution, timing, and clinical characteristics of the rash may aid in diagnosis, along with an appropriately correlated clinical picture. West Nile virus likely will present in the summer in mid central geographic locations and often develops on the trunk and extremities as a blanching, generalized, maculopapular rash around 5 days after symptom onset or with defervescence.¹

What is West Nile virus? How is it contracted, and who can become infected?

West Nile virus (WNV) is a single-stranded RNA virus of the Flaviviridae family and Flavivirus genus, a lineage that also includes the yellow fever, dengue, Zika, Japanese encephalitis, and Saint Louis encephalitis viruses.¹ Birds serve as the reservoir hosts of WNV, and mosquitoes acquire the virus during feeding.² West Nile virus then is transmitted to humans primarily by bites from Culex mosquitoes, which are especially prevalent in wooded areas during peak mosquito season (summer through early fall in North America).¹ Mosquitoes also can infect horses; however, humans and horses are dead-end hosts, meaning they do not pass the virus on to other biting mosquitoes.³ There also have been rare reports of transmission of WNV through blood and donation as well as mother-to-baby transmission.²

What is the epidemiology of WNV in the United States?

Since the introduction of WNV to the United States in 1999, it has become an important public health concern, with 48,183 cases and 2163 deaths reported since 1999.^2,3 In 2018, Nebraska had the highest number of cases of WNV (n=251), followed by California (n=217), North Dakota (n=204), Illinois (n=176), and South Dakota (n=169).³ West Nile virus is endemic to all 48 contiguous states and Canada, though the Great Plains region is especially affected by WNV due to several factors, such as a greater percentage of rural land, forests, and irrigated areas.⁴ The Great Plains region also has been thought to be an ecological niche for a more virulent species (Culex tarsalis) compared to other regions in the United States.⁵

The annual incidence of WNV in the United States peaked in 2003 at 9862 cases (up from 62 cases in 1999), then declined gradually until 2008 to 2011, during which the incidence was stable at 700 to 1100 new cases per year. However, there was a resurgence of cases (n=5674) in 2012 that steadied at around 2200 cases annually in subsequent years.⁶ Although there likely are several factors affecting WNV incidence trends in the United States, interannual changes in temperature and precipitation have been described. An increased mean annual temperature (from September through October, the end of peak mosquito season) and an increased temperature in winter months (from January through March, prior to peak mosquito season) have both been associated with an increased incidence of WNV.⁷ An increased temperature is thought to increase population numbers of mosquitoes both by increasing reproductive rates and creating ideal breeding environments via pooled water areas.⁸ Depending on the region, both above average and below average precipitation levels in the United States can increase WNV incidence the following year.^7,9

What are the signs and symptoms of WNV infection?

Up to 80% of those infected with WNV are asymptomatic.³ After an incubation period of roughly 2 to 14 days, the remaining 20% may develop symptoms of West Nile fever (WNF), typically a self-limited illness that consists of 3 to 10 days of nonspecific symptoms such as fever, headache, fatigue, muscle pain and/or weakness, eye pain, gastrointestinal tract upset, and a macular rash that usually presents on the trunk or extremities.^1,3 Less than 1% of patients affected by WNV develop neuroinvasive disease, including meningitis, encephalitis, and/or acute flaccid paralysis.¹⁰ West Nile virus neuroinvasive disease can cause permanent neurologic sequelae such as muscle weakness, confusion, memory loss, and fatigue; it carries a mortality rate of 10% to 30%, which is mainly dependent on older age and immunosuppression status.^1,10

What is the reported spectrum of cutaneous findings in WNV?

Of the roughly 20% of patients infected with WNV that develop WNF, approximately 25% to 50% will develop an associated rash.¹ It most commonly is described as a morbilliform or maculopapular rash located on the chest, back, and arms, usually sparing the palms and soles, though 1 case report noted involvement with these areas (Figure).^11,12 It typically appears 5 days after symptom onset, can be associated with defervescence, and lasts less than a week.^1,13 Pruritus and dysesthesia are sometimes present.¹³ Other rare presentations that have been reported include an ill-defined pseudovesicular rash with erythematous papules on the palms and pink, scaly, psoriasiform papules on the feet and thighs, as well as neuroinvasive WNV leading to purpura fulminans.^14,15 A diffuse, erythematous, petechial rash on the face, neck, trunk, and extremities was reported in a pediatric patient, but there have been no reports of a petechial rash associated with WNV in adult patients.¹⁶ These findings suggest some potential variability in the presentation of the WNV rash.

What role does the presence of rash play diagnostically and prognostically?

The rash of WNV has been implicated as a potential prognostic factor in predicting more favorable outcomes.¹⁷ Using 2002 data from the Illinois Department of Public Health and 2003 data from the Colorado Department of Public Health, Huhn and Dworkin¹⁷ found the age-adjusted risk of encephalitis and death to be decreased in WNV patients with a rash (relative risk, 0.44; 95% CI, 0.21-0.92). The reasons for this are not definitively known, but we hypothesize that the rash may prompt patients to seek earlier medical attention or indicate a more robust immune response. Additionally, a rash in WNV more commonly is seen in younger patients, whereas WNV neuroinvasive disease is more common in older patients, who also tend to have worse outcomes.¹⁰ One study found rash to be the only symptom that demonstrated a significant association with seropositivity (overall risk=6.35; P<.05; 95% CI, 3.75-10.80) by multivariate analysis.¹⁸

How is WNV diagnosed? What are the downsides to WNV testing?

Given that the presenting symptoms of WNV and WNF are nonspecific, it becomes challenging to arrive at the diagnosis based solely on physical examination. As such, the patient’s clinical and epidemiologic history, such as timing, pattern, and appearance of the rash or recent history of mosquito bites, is key to arriving at the correct diagnosis. With clinical suspicion, possible diagnostic tests include an IgM enzyme-linked immunosorbent assay (ELISA) for WNV, a plaque reduction neutralization test (PNRT), and blood polymerase chain reaction (PCR).

An ELISA is a confirmatory test to detect IgM antibodies to WNV in the serum. Because IgM seroconversion typically occurs between days 4 and 10 of symptom onset, there is a high probability of initial false-negative testing within the first 8 days after symptom onset.^19,20 Clinical understanding of this fact is imperative, as an initial negative ELISA does not rule out WNV, and a retest is warranted if clinical suspicion is high. In addition to a high initial false-negative rate with ELISA, there are several other limitations to note. IgM antibodies remain elevated for 1 to 3 months or possibly up to a year in immunocompromised patients.¹ Due to this, false positives may be present if there was a recent prior infection. Enzyme-linked immunosorbent assay may not distinguish from different flaviviruses, including the yellow fever, dengue, Zika, Japanese encephalitis, and Saint Louis encephalitis viruses. Seropositivity has been estimated in some states, including 1999 data from New York (2.6%), 2003 data from Nebraska (9.5%), and 2012-2014 data from Connecticut (8.5%).^21-23 Regional variance may be expected, as there also were significant differences in WNV seropositivity between different regions in Nebraska (P<.001).²³

Because ELISA testing for WNV has readily apparent flaws, other tests have been utilized in its diagnosis. The PNRT is the most specific test, and it works by measuring neutralizing antibody titers for different flaviviruses. It has the ability to determine cross-reactivity with other flaviviruses; however, it does not discriminate between a current infection and a prior infection or prior flavivirus vaccine (ie, yellow fever vaccine). Despite this, a positive PNRT can lend credibility to a positive ELISA test and determine specificity for WNV for those with no prior flavivirus exposure.²⁴ According to the Centers for Disease Control and Prevention (CDC), this test can be performed by the CDC or in reference laboratories designated by the CDC.³ Additionally, some state health laboratories may perform PRNTs.

Viral detection with PCR currently is used to screen blood donations and may be beneficial for immunocompromised patients that lack the ability to form a robust antibody response or if a patient presents early, as PCR works best within the first week of symptom onset.¹ Tilley et al²⁵ showed that a combination of PCR and ELISA were able to accurately predict 94.2% of patients (180/191) with documented WNV on a first blood sample compared to 45% and 58.1% for only viral detection or ELISA, respectively. Based on costs from a Midwest academic center, antibody detection tests are around $100 while PCR may range from $500 to $1000 and is only performed in reference laboratories. Although these tests remain in the repertoire for WNV diagnosis, financial stewardship is important.

If there are symptoms of photophobia, phonophobia, nuchal rigidity, loss of consciousness, or marked personality changes, a lumbar puncture for WNV IgM in the cerebrospinal fluid can be performed. As with most viral infections, cerebrospinal fluid findings normally include an elevated protein and lymphocyte count, but neutrophils may be predominantly elevated if the infection is early in its course.²⁶

What are the management options?

To date, there is no curative treatment for WNV, and management is largely supportive. For WNF, over-the-counter pain medications may be helpful to reduce fever and pain. If more severe disease develops, hospitalization for further supportive care may be needed.²⁷ If meningitis or encephalitis is suspected, broad-spectrum antibiotics may need to be started until other common etiologies are ruled out.²⁸

How can you prevent WNV infection?

Disease prevention largely consists of educating the public to avoid heavily wooded areas, especially in areas of high prevalence and during peak months, and to use protective clothing and insect repellant that has been approved by the Environmental Protection Agency.³ Insect repellants approved by the Environmental Protection Agency contain ingredients such as DEET (N, N-diethyl-meta-toluamide), picaridin, IR3535 (ethyl butylacetylaminopropionate), and oil of lemon eucalyptus, which have been proven safe and effective.²⁹ Patients also can protect their homes by using window screens and promptly repairing screens with holes.³

What is the differential diagnosis for WNV?

The differential diagnosis for fever with generalized maculopapular rash broadly ranges from viral etiologies (eg, WNV, Zika, measles), to tick bites (eg, Rocky Mountain spotted fever, ehrlichiosis), to drug-induced rashes. A detailed patient history inquiring on recent sick contacts, travel (WNV in the Midwest, ehrlichiosis in the Southeast), environmental exposures (ticks, mosquitoes), and new medications (typically 7–10 days after starting) is imperative to narrow the differential.³⁰ In addition, the distribution, timing, and clinical characteristics of the rash may aid in diagnosis, along with an appropriately correlated clinical picture. West Nile virus likely will present in the summer in mid central geographic locations and often develops on the trunk and extremities as a blanching, generalized, maculopapular rash around 5 days after symptom onset or with defervescence.¹