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‘Profound human toll’ in excess deaths from COVID-19 calculated in two studies
However, additional deaths could be indirectly related because people avoided emergency care during the pandemic, new research shows.
Deaths linked to COVID-19 varied by state and phase of the pandemic, as reported in a study from researchers at Virginia Commonwealth University and Yale University that was published online October 12 in JAMA.
Another study published online simultaneously in JAMA took more of an international perspective. Investigators from the University of Pennsylvania and Harvard University found that in America there were more excess deaths and there was higher all-cause mortality during the pandemic than in 18 other countries.
Although the ongoing number of deaths attributable to COVID-19 continues to garner attention, there can be a lag of weeks or months in how long it takes some public health agencies to update their figures.
“For the public at large, the take-home message is twofold: that the number of deaths caused by the pandemic exceeds publicly reported COVID-19 death counts by 20% and that states that reopened or lifted restrictions early suffered a protracted surge in excess deaths that extended into the summer,” lead author of the US-focused study, Steven H. Woolf, MD, MPH, told Medscape Medical News.
The take-away for physicians is in the bigger picture – it is likely that the COVID-19 pandemic is responsible for deaths from other conditions as well. “Surges in COVID-19 were accompanied by an increase in deaths attributed to other causes, such as heart disease and Alzheimer’s disease and dementia,” said Woolf, director emeritus and senior adviser at the Center on Society and Health and professor in the Department of Family Medicine and Population Health at the Virginia Commonwealth University School of Medicine in Richmond, Virginia.
The investigators identified 225,530 excess US deaths in the 5 months from March to July. They report that 67% were directly attributable to COVID-19.
Deaths linked to COVID-19 included those in which the disease was listed as an underlying or contributing cause. US total death rates are “remarkably consistent” year after year, and the investigators calculated a 20% overall jump in mortality.
The study included data from the National Center for Health Statistics and the US Census Bureau for 48 states and the District of Columbia. Connecticut and North Carolina were excluded because of missing data.
Woolf and colleagues also found statistically higher rates of deaths from two other causes, heart disease and Alzheimer’s disease/dementia.
Altered states
New York, New Jersey, Massachusetts, Louisiana, Arizona, Mississippi, Maryland, Delaware, Rhode Island, and Michigan had the highest per capita excess death rates. Three states experienced the shortest epidemics during the study period: New York, New Jersey, and Massachusetts.
Some lessons could be learned by looking at how individual states managed large numbers of people with COVID-19. “Although we suspected that states that reopened early might have put themselves at risk of a pandemic surge, the consistency with which that occurred and the devastating numbers of deaths they suffered was a surprise,” Woolf said.
“The goal of our study is not to look in the rearview mirror and lament what happened months ago but to learn the lesson going forward: Our country will be unable to take control of this pandemic without more robust efforts to control community spread,” Woolf said. “Our study found that states that did this well, such as New York and New Jersey, experienced large surges but bent the curve and were back to baseline in less than 10 weeks.
“If we could do this as a country, countless lives could be saved.”
A global perspective
The United States experienced high mortality linked to COVID-19, as well as high all-cause mortality, compared with 18 other countries, as reported in the study by University of Pennsylvania and Harvard University researchers.
The United States ranked third, with 72 deaths per 100,000 people, among countries with moderate or high mortality. Although perhaps not surprising given the state of SARS-CoV-2 infection across the United States, a question remains as to what extent the relatively high mortality rate is linked to early outbreaks vs “poor long-term response,” the researchers note.
Alyssa Bilinski, MSc, and lead author Ezekiel J. Emanuel, MD, PhD, chair of the Department of Medical Ethics and Health Policy at the University of Pennsylvania Perelman School of Medicine in Philadelphia, calculated the difference in COVID-19 deaths among countries through Sept. 19, 2020. On this date, the United States reported a total 198,589 COVID-19 deaths.
They calculated that, if the US death rates were similar to those in Australia, the United States would have experienced 187,661 fewer COVID-19 deaths. If similar to those of Canada, there would have been 117,622 fewer deaths in the United States.
The US death rate was lower than six other countries with high COVID-19 mortality in the early spring, including Belgium, Spain, and the United Kingdom. However, after May 10, the per capita mortality rate in the United States exceeded the others.
Between May 10 and Sept. 19, the death rate in Italy was 9.1 per 100,000, vs 36.9 per 100,000.
“After the first peak in early spring, US death rates from COVID-19 and from all causes remained higher than even countries with high COVID-19 mortality,” the researchers note. “This may have been a result of several factors, including weak public health infrastructure and a decentralized, inconsistent US response to the pandemic.”
“Mortifying and motivating”
Woolf and colleagues estimate that more than 225,000 excess deaths occurred in recent months; this represents a 20% increase over expected deaths, note Harvey V. Fineberg, MD, PhD, of the Gordon and Betty Moore Foundation, in an accompanying editorial in JAMA.
“Importantly, a condition such as COVID-19 can contribute both directly and indirectly to excess mortality,” he writes.
Although the direct contribution to the mortality rates by those infected is straightforward, “the indirect contribution may relate to circumstances or choices due to the COVID-19 pandemic: for example, a patient who develops symptoms of a stroke is too concerned about COVID-19 to go to the emergency department, and a potentially reversible condition becomes fatal.”
Fineberg notes that “a general indication of the death toll from COVID-19 and the excess deaths related to the pandemic, as presented by Woolf et al, are sufficiently mortifying and motivating.”
“Profound human toll”
“The importance of the estimate by Woolf et al – which suggests that for the entirety of 2020, more than 400,000 excess deaths will occur – cannot be overstated, because it accounts for what could be declines in some causes of death, like motor vehicle crashes, but increases in others, like myocardial infarction,” write Howard Bauchner, MD, editor in chief of JAMA, and Phil B. Fontanarosa, MD, MBA, executive editor of JAMA, in another accompanying editorial.
“These deaths reflect a true measure of the human cost of the Great Pandemic of 2020,” they add.
The study from Emanuel and Bilinski was notable for calculating the excess COVID-19 and all-cause mortality to Sept. 2020, they note. “After the initial peak in early spring, US death rates from COVID-19 and from all causes remained higher than rates in countries with high COVID-19 mortality.”
“Few people will forget the Great Pandemic of 2020, where and how they lived, how it substantially changed their lives, and for many, the profound human toll it has taken,” Bauchner and Fontanarosa write.
The study by Woolf and colleagues was supported by National Center for Advancing Translational Sciences, the National Institute on Aging, and the National Institute of Allergy and Infectious Diseases. The study by Bilinski and Emanuel was partially funded by the Colton Foundation. Woolf, Emanuel, Fineberg, Bauchner, and Fontanarosa have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
However, additional deaths could be indirectly related because people avoided emergency care during the pandemic, new research shows.
Deaths linked to COVID-19 varied by state and phase of the pandemic, as reported in a study from researchers at Virginia Commonwealth University and Yale University that was published online October 12 in JAMA.
Another study published online simultaneously in JAMA took more of an international perspective. Investigators from the University of Pennsylvania and Harvard University found that in America there were more excess deaths and there was higher all-cause mortality during the pandemic than in 18 other countries.
Although the ongoing number of deaths attributable to COVID-19 continues to garner attention, there can be a lag of weeks or months in how long it takes some public health agencies to update their figures.
“For the public at large, the take-home message is twofold: that the number of deaths caused by the pandemic exceeds publicly reported COVID-19 death counts by 20% and that states that reopened or lifted restrictions early suffered a protracted surge in excess deaths that extended into the summer,” lead author of the US-focused study, Steven H. Woolf, MD, MPH, told Medscape Medical News.
The take-away for physicians is in the bigger picture – it is likely that the COVID-19 pandemic is responsible for deaths from other conditions as well. “Surges in COVID-19 were accompanied by an increase in deaths attributed to other causes, such as heart disease and Alzheimer’s disease and dementia,” said Woolf, director emeritus and senior adviser at the Center on Society and Health and professor in the Department of Family Medicine and Population Health at the Virginia Commonwealth University School of Medicine in Richmond, Virginia.
The investigators identified 225,530 excess US deaths in the 5 months from March to July. They report that 67% were directly attributable to COVID-19.
Deaths linked to COVID-19 included those in which the disease was listed as an underlying or contributing cause. US total death rates are “remarkably consistent” year after year, and the investigators calculated a 20% overall jump in mortality.
The study included data from the National Center for Health Statistics and the US Census Bureau for 48 states and the District of Columbia. Connecticut and North Carolina were excluded because of missing data.
Woolf and colleagues also found statistically higher rates of deaths from two other causes, heart disease and Alzheimer’s disease/dementia.
Altered states
New York, New Jersey, Massachusetts, Louisiana, Arizona, Mississippi, Maryland, Delaware, Rhode Island, and Michigan had the highest per capita excess death rates. Three states experienced the shortest epidemics during the study period: New York, New Jersey, and Massachusetts.
Some lessons could be learned by looking at how individual states managed large numbers of people with COVID-19. “Although we suspected that states that reopened early might have put themselves at risk of a pandemic surge, the consistency with which that occurred and the devastating numbers of deaths they suffered was a surprise,” Woolf said.
“The goal of our study is not to look in the rearview mirror and lament what happened months ago but to learn the lesson going forward: Our country will be unable to take control of this pandemic without more robust efforts to control community spread,” Woolf said. “Our study found that states that did this well, such as New York and New Jersey, experienced large surges but bent the curve and were back to baseline in less than 10 weeks.
“If we could do this as a country, countless lives could be saved.”
A global perspective
The United States experienced high mortality linked to COVID-19, as well as high all-cause mortality, compared with 18 other countries, as reported in the study by University of Pennsylvania and Harvard University researchers.
The United States ranked third, with 72 deaths per 100,000 people, among countries with moderate or high mortality. Although perhaps not surprising given the state of SARS-CoV-2 infection across the United States, a question remains as to what extent the relatively high mortality rate is linked to early outbreaks vs “poor long-term response,” the researchers note.
Alyssa Bilinski, MSc, and lead author Ezekiel J. Emanuel, MD, PhD, chair of the Department of Medical Ethics and Health Policy at the University of Pennsylvania Perelman School of Medicine in Philadelphia, calculated the difference in COVID-19 deaths among countries through Sept. 19, 2020. On this date, the United States reported a total 198,589 COVID-19 deaths.
They calculated that, if the US death rates were similar to those in Australia, the United States would have experienced 187,661 fewer COVID-19 deaths. If similar to those of Canada, there would have been 117,622 fewer deaths in the United States.
The US death rate was lower than six other countries with high COVID-19 mortality in the early spring, including Belgium, Spain, and the United Kingdom. However, after May 10, the per capita mortality rate in the United States exceeded the others.
Between May 10 and Sept. 19, the death rate in Italy was 9.1 per 100,000, vs 36.9 per 100,000.
“After the first peak in early spring, US death rates from COVID-19 and from all causes remained higher than even countries with high COVID-19 mortality,” the researchers note. “This may have been a result of several factors, including weak public health infrastructure and a decentralized, inconsistent US response to the pandemic.”
“Mortifying and motivating”
Woolf and colleagues estimate that more than 225,000 excess deaths occurred in recent months; this represents a 20% increase over expected deaths, note Harvey V. Fineberg, MD, PhD, of the Gordon and Betty Moore Foundation, in an accompanying editorial in JAMA.
“Importantly, a condition such as COVID-19 can contribute both directly and indirectly to excess mortality,” he writes.
Although the direct contribution to the mortality rates by those infected is straightforward, “the indirect contribution may relate to circumstances or choices due to the COVID-19 pandemic: for example, a patient who develops symptoms of a stroke is too concerned about COVID-19 to go to the emergency department, and a potentially reversible condition becomes fatal.”
Fineberg notes that “a general indication of the death toll from COVID-19 and the excess deaths related to the pandemic, as presented by Woolf et al, are sufficiently mortifying and motivating.”
“Profound human toll”
“The importance of the estimate by Woolf et al – which suggests that for the entirety of 2020, more than 400,000 excess deaths will occur – cannot be overstated, because it accounts for what could be declines in some causes of death, like motor vehicle crashes, but increases in others, like myocardial infarction,” write Howard Bauchner, MD, editor in chief of JAMA, and Phil B. Fontanarosa, MD, MBA, executive editor of JAMA, in another accompanying editorial.
“These deaths reflect a true measure of the human cost of the Great Pandemic of 2020,” they add.
The study from Emanuel and Bilinski was notable for calculating the excess COVID-19 and all-cause mortality to Sept. 2020, they note. “After the initial peak in early spring, US death rates from COVID-19 and from all causes remained higher than rates in countries with high COVID-19 mortality.”
“Few people will forget the Great Pandemic of 2020, where and how they lived, how it substantially changed their lives, and for many, the profound human toll it has taken,” Bauchner and Fontanarosa write.
The study by Woolf and colleagues was supported by National Center for Advancing Translational Sciences, the National Institute on Aging, and the National Institute of Allergy and Infectious Diseases. The study by Bilinski and Emanuel was partially funded by the Colton Foundation. Woolf, Emanuel, Fineberg, Bauchner, and Fontanarosa have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
However, additional deaths could be indirectly related because people avoided emergency care during the pandemic, new research shows.
Deaths linked to COVID-19 varied by state and phase of the pandemic, as reported in a study from researchers at Virginia Commonwealth University and Yale University that was published online October 12 in JAMA.
Another study published online simultaneously in JAMA took more of an international perspective. Investigators from the University of Pennsylvania and Harvard University found that in America there were more excess deaths and there was higher all-cause mortality during the pandemic than in 18 other countries.
Although the ongoing number of deaths attributable to COVID-19 continues to garner attention, there can be a lag of weeks or months in how long it takes some public health agencies to update their figures.
“For the public at large, the take-home message is twofold: that the number of deaths caused by the pandemic exceeds publicly reported COVID-19 death counts by 20% and that states that reopened or lifted restrictions early suffered a protracted surge in excess deaths that extended into the summer,” lead author of the US-focused study, Steven H. Woolf, MD, MPH, told Medscape Medical News.
The take-away for physicians is in the bigger picture – it is likely that the COVID-19 pandemic is responsible for deaths from other conditions as well. “Surges in COVID-19 were accompanied by an increase in deaths attributed to other causes, such as heart disease and Alzheimer’s disease and dementia,” said Woolf, director emeritus and senior adviser at the Center on Society and Health and professor in the Department of Family Medicine and Population Health at the Virginia Commonwealth University School of Medicine in Richmond, Virginia.
The investigators identified 225,530 excess US deaths in the 5 months from March to July. They report that 67% were directly attributable to COVID-19.
Deaths linked to COVID-19 included those in which the disease was listed as an underlying or contributing cause. US total death rates are “remarkably consistent” year after year, and the investigators calculated a 20% overall jump in mortality.
The study included data from the National Center for Health Statistics and the US Census Bureau for 48 states and the District of Columbia. Connecticut and North Carolina were excluded because of missing data.
Woolf and colleagues also found statistically higher rates of deaths from two other causes, heart disease and Alzheimer’s disease/dementia.
Altered states
New York, New Jersey, Massachusetts, Louisiana, Arizona, Mississippi, Maryland, Delaware, Rhode Island, and Michigan had the highest per capita excess death rates. Three states experienced the shortest epidemics during the study period: New York, New Jersey, and Massachusetts.
Some lessons could be learned by looking at how individual states managed large numbers of people with COVID-19. “Although we suspected that states that reopened early might have put themselves at risk of a pandemic surge, the consistency with which that occurred and the devastating numbers of deaths they suffered was a surprise,” Woolf said.
“The goal of our study is not to look in the rearview mirror and lament what happened months ago but to learn the lesson going forward: Our country will be unable to take control of this pandemic without more robust efforts to control community spread,” Woolf said. “Our study found that states that did this well, such as New York and New Jersey, experienced large surges but bent the curve and were back to baseline in less than 10 weeks.
“If we could do this as a country, countless lives could be saved.”
A global perspective
The United States experienced high mortality linked to COVID-19, as well as high all-cause mortality, compared with 18 other countries, as reported in the study by University of Pennsylvania and Harvard University researchers.
The United States ranked third, with 72 deaths per 100,000 people, among countries with moderate or high mortality. Although perhaps not surprising given the state of SARS-CoV-2 infection across the United States, a question remains as to what extent the relatively high mortality rate is linked to early outbreaks vs “poor long-term response,” the researchers note.
Alyssa Bilinski, MSc, and lead author Ezekiel J. Emanuel, MD, PhD, chair of the Department of Medical Ethics and Health Policy at the University of Pennsylvania Perelman School of Medicine in Philadelphia, calculated the difference in COVID-19 deaths among countries through Sept. 19, 2020. On this date, the United States reported a total 198,589 COVID-19 deaths.
They calculated that, if the US death rates were similar to those in Australia, the United States would have experienced 187,661 fewer COVID-19 deaths. If similar to those of Canada, there would have been 117,622 fewer deaths in the United States.
The US death rate was lower than six other countries with high COVID-19 mortality in the early spring, including Belgium, Spain, and the United Kingdom. However, after May 10, the per capita mortality rate in the United States exceeded the others.
Between May 10 and Sept. 19, the death rate in Italy was 9.1 per 100,000, vs 36.9 per 100,000.
“After the first peak in early spring, US death rates from COVID-19 and from all causes remained higher than even countries with high COVID-19 mortality,” the researchers note. “This may have been a result of several factors, including weak public health infrastructure and a decentralized, inconsistent US response to the pandemic.”
“Mortifying and motivating”
Woolf and colleagues estimate that more than 225,000 excess deaths occurred in recent months; this represents a 20% increase over expected deaths, note Harvey V. Fineberg, MD, PhD, of the Gordon and Betty Moore Foundation, in an accompanying editorial in JAMA.
“Importantly, a condition such as COVID-19 can contribute both directly and indirectly to excess mortality,” he writes.
Although the direct contribution to the mortality rates by those infected is straightforward, “the indirect contribution may relate to circumstances or choices due to the COVID-19 pandemic: for example, a patient who develops symptoms of a stroke is too concerned about COVID-19 to go to the emergency department, and a potentially reversible condition becomes fatal.”
Fineberg notes that “a general indication of the death toll from COVID-19 and the excess deaths related to the pandemic, as presented by Woolf et al, are sufficiently mortifying and motivating.”
“Profound human toll”
“The importance of the estimate by Woolf et al – which suggests that for the entirety of 2020, more than 400,000 excess deaths will occur – cannot be overstated, because it accounts for what could be declines in some causes of death, like motor vehicle crashes, but increases in others, like myocardial infarction,” write Howard Bauchner, MD, editor in chief of JAMA, and Phil B. Fontanarosa, MD, MBA, executive editor of JAMA, in another accompanying editorial.
“These deaths reflect a true measure of the human cost of the Great Pandemic of 2020,” they add.
The study from Emanuel and Bilinski was notable for calculating the excess COVID-19 and all-cause mortality to Sept. 2020, they note. “After the initial peak in early spring, US death rates from COVID-19 and from all causes remained higher than rates in countries with high COVID-19 mortality.”
“Few people will forget the Great Pandemic of 2020, where and how they lived, how it substantially changed their lives, and for many, the profound human toll it has taken,” Bauchner and Fontanarosa write.
The study by Woolf and colleagues was supported by National Center for Advancing Translational Sciences, the National Institute on Aging, and the National Institute of Allergy and Infectious Diseases. The study by Bilinski and Emanuel was partially funded by the Colton Foundation. Woolf, Emanuel, Fineberg, Bauchner, and Fontanarosa have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Human Papillomavirus Vaccination in LGBTQ Patients: The Need for Dermatologists on the Front Lines
Human papillomavirus (HPV) is one of the most common sexually transmitted infections in the United States. It is the causative agent of genital warts, as well as cervical, anal, penile, vulvar, vaginal, and some head and neck cancers.1 Development of the HPV vaccine and its introduction into the scheduled vaccine series recommended by the Centers for Disease Control and Prevention (CDC) represented a major public health milestone. The CDC recommends the HPV vaccine for all children beginning at 11 or 12 years of age, even as early as 9 years, regardless of gender identity or sexuality. As of late 2016, the 9-valent formulation (Gardasil 9 [Merck]) is the only HPV vaccine distributed in the United States, and the vaccination schedule depends specifically on age. The Advisory Committee on Immunization Practices (ACIP) of the CDC revised its recommendations in 2019 to include “shared clinical decision-making regarding HPV vaccination . . . for some adults aged 27 through 45 years.”2 This change in policy has notable implications for sexual and gender minority populations, such as lesbian, gay, bisexual, transgender, and queer or questioning (LGBTQ) patients, especially in the context of dermatologic care. Herein, we discuss HPV-related conditions for LGBTQ patients, barriers to vaccine administration, and the role of dermatologists in promoting an increased vaccination rate in the LGBTQ community.
HPV-Related Conditions
A 2019 review of dermatologic care for LGBTQ patients identified many specific health disparities of HPV.3 Specifically, men who have sex with men (MSM) are more likely than heterosexual men to have oral, anal, and penile HPV infections, including high-risk HPV types.3 From 2011 to 2014, 18% and 13% of MSM had oral HPV infection and high-risk oral HPV infection, respectively, compared to only 11% and 7%, respectively, of men who reported never having had a same-sex sexual partner.4
Similarly, despite the CDC’s position that patients with perianal warts might benefit from digital anal examination or referral for standard or high-resolution anoscopy to detect intra-anal warts, improvements in morbidity have not yet been realized. In 2017, anal cancer incidence was 45.9 cases for every 100,000 person-years among human immunodeficiency (HIV)–positive MSM and 5.1 cases for every 100,000 person-years among HIV-negative MSM vs only 1.5 cases for every 100,000 person-years among men in the United States overall.3 Yet the CDC states that there is insufficient evidence to recommend routine anal cancer screening among MSM, even when a patient is HIV positive. Therefore, current screening practices and treatments are insufficient as MSM continue to have a disproportionately higher rate of HPV-associated disease compared to other populations.
Barriers to HPV Vaccine Administration
The HPV vaccination rate among MSM in adolescent populations varies across reports.5-7 Interestingly, a 2016 survey study found that MSM had approximately 2-times greater odds of initiating the HPV vaccine than heterosexual men.8 However, a study specifically sampling young gay and bisexual men (N=428) found that only 13% had received any doses of the HPV vaccine.6
Regardless, HPV vaccination is much less common among all males than it is among all females, and the low rate of vaccination among sexual minority men has a disproportionate impact, given their higher risk for HPV infection.4 Although the HPV vaccination rate increased from 2014 to 2017, the HPV vaccination rate in MSM overall is less than half of the Healthy People 2020 goal of 80%.9 A 2018 review determined that HPV vaccination is a cost-effective strategy for preventing anal cancer in MSM10; yet male patients might still view the HPV vaccine as a “women’s issue” and are less likely to be vaccinated if they are not prompted by health care providers. Additionally, HPV vaccination is remarkably less likely in MSM when patients are older, uninsured, of lower socioeconomic status, or have not disclosed their sexual identity to their health care provider.9 Dermatologists should be mindful of these barriers to promote HPV vaccination in MSM before, or soon after, sexual debut.
Other members of the LGBTQ community, such as women who have sex with women, face notable HPV-related health disparities and would benefit from increased vaccination efforts by dermatologists. Adolescent and young adult women who have sex with women are less likely than heterosexual adolescent and young adult women to receive routine Papanicolaou tests and initiate HPV vaccination, despite having a higher number of lifetime sexual partners and a higher risk for HPV exposure.11 A 2015 survey study (N=3253) found that after adjusting for covariates, only 8.5% of lesbians and 33.2% of bisexual women and girls who had heard of the HPV vaccine had initiated vaccination compared to 28.4% of their heterosexual counterparts.11 The HPV vaccine is an effective public health tool for the prevention of cervical cancer in these populations. A study of women aged 15 to 19 years in the HPV vaccination era (2007-2014) found significant (P<.05) observed population-level decreases in cervical intraepithelial neoplasia incidence across all grades.12
Transgender women also face a high rate of HPV infection, HIV infection, and other structural and financial disparities, such as low insurance coverage, that can limit their access to vaccination. Transgender men have a higher rate of HPV infection than cisgender men, and those with female internal reproductive organs are less likely to receive routine Papanicolaou tests. A 2018 survey study found that approximately one-third of transgender men and women reported initiating the HPV vaccination series,13 but further investigation is required to make balanced comparisons to cisgender patients.
The Role of the Dermatologist
Collectively, these disparities emphasize the need for increased involvement by dermatologists in HPV vaccination efforts for all LGBTQ patients. Adult patients may have concerns about ties of the HPV vaccine to drug manufacturers and the general safety of vaccination. For pediatric patients, parents/guardians also may be concerned about an assumed but not evidence-based increase in sexual promiscuity following HPV vaccination.14 These topics can be challenging to discuss, but dermatologists have the duty to be proactive and initiate conversation about HPV vaccination, as opposed to waiting for patients to express interest. Dermatologists should stress the safety of the vaccine as well as its potential to protect against multiple, even life-threatening diseases. Providers also can explain that the ACIP recommends catch-up vaccination for all individuals through 26 years of age, regardless of sexual orientation or gender identity.
With the ACIP having recently expanded the appropriate age range for HPV vaccination, we encourage dermatologists to engage in education and shared decision-making to ensure that adult patients with specific risk factors receive the HPV vaccine. Because the expanded ACIP recommendations are aimed at vaccination before HPV exposure, vaccination might not be appropriate for all LGBTQ patients. However, eliciting a sexual history with routine patient intake forms or during the clinical encounter ensures equal access to the HPV vaccine.
Greater awareness of HPV-related disparities and barriers to vaccination in LGBTQ populations has the potential to notably decrease HPV-associated mortality and morbidity. Increased involvement by dermatologists contributes to the efforts of other specialties in universal HPV vaccination, regardless of sexual orientation or gender identity—ideally in younger age groups, such that patients receive the vaccine prior to coitarche.
There are many ways that dermatologists can advocate for HPV vaccination. Those in a multispecialty or academic practice can readily refer patients to an associated internist, primary care physician, or vaccination clinic in the same building or institution. Dermatologists in private practice might be able to administer the HPV vaccine themselves or can advocate for patients to receive the vaccine at a local facility of the Department of Health or at a nonprofit organization, such as a Planned Parenthood center. Although pediatricians and family physicians remain front-line providers of these services, dermatologists represent an additional member of a patient’s care team, capable of advocating for this important intervention.
- Brianti P, De Flammineis E, Mercuri SR. Review of HPV-related diseases and cancers. New Microbiol. 2017;40:80-85.
- Meites E, Szilagyi PG, Chesson HW, et al. Human papillomavirus vaccination for adults: updated recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2019;68:698-702.
- Yeung H, Luk KM, Chen SC, et al. Dermatologic care for lesbian, gay, bisexual, and transgender persons: epidemiology, screening, and disease prevention. J Am Acad Dermatol. 2019;80:591-602.
- Sonawane K, Suk R, Chiao EY, et al. Oral human papillomavirus infection: differences in prevalence between sexes and concordance with genital human papillomavirus infection, NHANES 2011 to 2014. Ann Intern Med. 2017;167:714-724.
- Kosche C, Mansh M, Luskus M, et al. Dermatologic care of sexual and gender minority/LGBTQIA youth, part 2: recognition and management of the unique dermatologic needs of SGM adolescents. Pediatr Dermatol. 2019;35:587-593.
- Reiter PL, McRee A-L, Katz ML, et al. Human papillomavirus vaccination among young adult gay and bisexual men in the United States. Am J Public Health. 2015;105:96-102.
- Charlton BM, Reisner SL, Ag
énor M, et al. Sexual orientation disparities in human papillomavirus vaccination in a longitudinal cohort of U.S. males and females. LGBT Health. 2017;4:202-209. - Agénor M, Peitzmeier SM, Gordon AR, et al. Sexual orientation identity disparities in human papillomavirus vaccination initiation and completion among young adult US women and men. Cancer Causes Control. 2016;27:1187-1196.
- Loretan C, Chamberlain AT, Sanchez T, et al. Trends and characteristics associated with human papillomavirus vaccination uptake among men who have sex with men in the United States, 2014-2017. Sex Transm Dis. 2019;46:465-473.
- Setiawan D, Wondimu A, Ong K, et al. Cost effectiveness of human papillomavirus vaccination for men who have sex with men; reviewing the available evidence. Pharmacoeconomics. 2018;36:929-939.
- Agénor M, Peitzmeier S, Gordon AR, et al. Sexual orientation identity disparities in awareness and initiation of the human papillomavirus vaccine among U.S. women and girls: a national survey. Ann Intern Med. 2015;163:99-106.
- Benard VB, Castle PE, Jenison SA, et al. Population-based incidence rates of cervical intraepithelial neoplasia in the human papillomavirus vaccine era. JAMA Oncol. 2017;3:833-837.
- McRee A-L, Gower AL, Reiter PL. Preventive healthcare services use among transgender young adults. Int J Transgend. 2018;19:417-423.
- Trinidad J. Policy focus: promoting human papilloma virus vaccine to prevent genital warts and cancer. Boston, MA: The Fenway Institute; 2012. https://fenwayhealth.org/documents/the-fenway-institute/policy-briefs/PolicyFocus_HPV_v4_10.09.12.pdf. Accessed September 15, 2020.
Human papillomavirus (HPV) is one of the most common sexually transmitted infections in the United States. It is the causative agent of genital warts, as well as cervical, anal, penile, vulvar, vaginal, and some head and neck cancers.1 Development of the HPV vaccine and its introduction into the scheduled vaccine series recommended by the Centers for Disease Control and Prevention (CDC) represented a major public health milestone. The CDC recommends the HPV vaccine for all children beginning at 11 or 12 years of age, even as early as 9 years, regardless of gender identity or sexuality. As of late 2016, the 9-valent formulation (Gardasil 9 [Merck]) is the only HPV vaccine distributed in the United States, and the vaccination schedule depends specifically on age. The Advisory Committee on Immunization Practices (ACIP) of the CDC revised its recommendations in 2019 to include “shared clinical decision-making regarding HPV vaccination . . . for some adults aged 27 through 45 years.”2 This change in policy has notable implications for sexual and gender minority populations, such as lesbian, gay, bisexual, transgender, and queer or questioning (LGBTQ) patients, especially in the context of dermatologic care. Herein, we discuss HPV-related conditions for LGBTQ patients, barriers to vaccine administration, and the role of dermatologists in promoting an increased vaccination rate in the LGBTQ community.
HPV-Related Conditions
A 2019 review of dermatologic care for LGBTQ patients identified many specific health disparities of HPV.3 Specifically, men who have sex with men (MSM) are more likely than heterosexual men to have oral, anal, and penile HPV infections, including high-risk HPV types.3 From 2011 to 2014, 18% and 13% of MSM had oral HPV infection and high-risk oral HPV infection, respectively, compared to only 11% and 7%, respectively, of men who reported never having had a same-sex sexual partner.4
Similarly, despite the CDC’s position that patients with perianal warts might benefit from digital anal examination or referral for standard or high-resolution anoscopy to detect intra-anal warts, improvements in morbidity have not yet been realized. In 2017, anal cancer incidence was 45.9 cases for every 100,000 person-years among human immunodeficiency (HIV)–positive MSM and 5.1 cases for every 100,000 person-years among HIV-negative MSM vs only 1.5 cases for every 100,000 person-years among men in the United States overall.3 Yet the CDC states that there is insufficient evidence to recommend routine anal cancer screening among MSM, even when a patient is HIV positive. Therefore, current screening practices and treatments are insufficient as MSM continue to have a disproportionately higher rate of HPV-associated disease compared to other populations.
Barriers to HPV Vaccine Administration
The HPV vaccination rate among MSM in adolescent populations varies across reports.5-7 Interestingly, a 2016 survey study found that MSM had approximately 2-times greater odds of initiating the HPV vaccine than heterosexual men.8 However, a study specifically sampling young gay and bisexual men (N=428) found that only 13% had received any doses of the HPV vaccine.6
Regardless, HPV vaccination is much less common among all males than it is among all females, and the low rate of vaccination among sexual minority men has a disproportionate impact, given their higher risk for HPV infection.4 Although the HPV vaccination rate increased from 2014 to 2017, the HPV vaccination rate in MSM overall is less than half of the Healthy People 2020 goal of 80%.9 A 2018 review determined that HPV vaccination is a cost-effective strategy for preventing anal cancer in MSM10; yet male patients might still view the HPV vaccine as a “women’s issue” and are less likely to be vaccinated if they are not prompted by health care providers. Additionally, HPV vaccination is remarkably less likely in MSM when patients are older, uninsured, of lower socioeconomic status, or have not disclosed their sexual identity to their health care provider.9 Dermatologists should be mindful of these barriers to promote HPV vaccination in MSM before, or soon after, sexual debut.
Other members of the LGBTQ community, such as women who have sex with women, face notable HPV-related health disparities and would benefit from increased vaccination efforts by dermatologists. Adolescent and young adult women who have sex with women are less likely than heterosexual adolescent and young adult women to receive routine Papanicolaou tests and initiate HPV vaccination, despite having a higher number of lifetime sexual partners and a higher risk for HPV exposure.11 A 2015 survey study (N=3253) found that after adjusting for covariates, only 8.5% of lesbians and 33.2% of bisexual women and girls who had heard of the HPV vaccine had initiated vaccination compared to 28.4% of their heterosexual counterparts.11 The HPV vaccine is an effective public health tool for the prevention of cervical cancer in these populations. A study of women aged 15 to 19 years in the HPV vaccination era (2007-2014) found significant (P<.05) observed population-level decreases in cervical intraepithelial neoplasia incidence across all grades.12
Transgender women also face a high rate of HPV infection, HIV infection, and other structural and financial disparities, such as low insurance coverage, that can limit their access to vaccination. Transgender men have a higher rate of HPV infection than cisgender men, and those with female internal reproductive organs are less likely to receive routine Papanicolaou tests. A 2018 survey study found that approximately one-third of transgender men and women reported initiating the HPV vaccination series,13 but further investigation is required to make balanced comparisons to cisgender patients.
The Role of the Dermatologist
Collectively, these disparities emphasize the need for increased involvement by dermatologists in HPV vaccination efforts for all LGBTQ patients. Adult patients may have concerns about ties of the HPV vaccine to drug manufacturers and the general safety of vaccination. For pediatric patients, parents/guardians also may be concerned about an assumed but not evidence-based increase in sexual promiscuity following HPV vaccination.14 These topics can be challenging to discuss, but dermatologists have the duty to be proactive and initiate conversation about HPV vaccination, as opposed to waiting for patients to express interest. Dermatologists should stress the safety of the vaccine as well as its potential to protect against multiple, even life-threatening diseases. Providers also can explain that the ACIP recommends catch-up vaccination for all individuals through 26 years of age, regardless of sexual orientation or gender identity.
With the ACIP having recently expanded the appropriate age range for HPV vaccination, we encourage dermatologists to engage in education and shared decision-making to ensure that adult patients with specific risk factors receive the HPV vaccine. Because the expanded ACIP recommendations are aimed at vaccination before HPV exposure, vaccination might not be appropriate for all LGBTQ patients. However, eliciting a sexual history with routine patient intake forms or during the clinical encounter ensures equal access to the HPV vaccine.
Greater awareness of HPV-related disparities and barriers to vaccination in LGBTQ populations has the potential to notably decrease HPV-associated mortality and morbidity. Increased involvement by dermatologists contributes to the efforts of other specialties in universal HPV vaccination, regardless of sexual orientation or gender identity—ideally in younger age groups, such that patients receive the vaccine prior to coitarche.
There are many ways that dermatologists can advocate for HPV vaccination. Those in a multispecialty or academic practice can readily refer patients to an associated internist, primary care physician, or vaccination clinic in the same building or institution. Dermatologists in private practice might be able to administer the HPV vaccine themselves or can advocate for patients to receive the vaccine at a local facility of the Department of Health or at a nonprofit organization, such as a Planned Parenthood center. Although pediatricians and family physicians remain front-line providers of these services, dermatologists represent an additional member of a patient’s care team, capable of advocating for this important intervention.
Human papillomavirus (HPV) is one of the most common sexually transmitted infections in the United States. It is the causative agent of genital warts, as well as cervical, anal, penile, vulvar, vaginal, and some head and neck cancers.1 Development of the HPV vaccine and its introduction into the scheduled vaccine series recommended by the Centers for Disease Control and Prevention (CDC) represented a major public health milestone. The CDC recommends the HPV vaccine for all children beginning at 11 or 12 years of age, even as early as 9 years, regardless of gender identity or sexuality. As of late 2016, the 9-valent formulation (Gardasil 9 [Merck]) is the only HPV vaccine distributed in the United States, and the vaccination schedule depends specifically on age. The Advisory Committee on Immunization Practices (ACIP) of the CDC revised its recommendations in 2019 to include “shared clinical decision-making regarding HPV vaccination . . . for some adults aged 27 through 45 years.”2 This change in policy has notable implications for sexual and gender minority populations, such as lesbian, gay, bisexual, transgender, and queer or questioning (LGBTQ) patients, especially in the context of dermatologic care. Herein, we discuss HPV-related conditions for LGBTQ patients, barriers to vaccine administration, and the role of dermatologists in promoting an increased vaccination rate in the LGBTQ community.
HPV-Related Conditions
A 2019 review of dermatologic care for LGBTQ patients identified many specific health disparities of HPV.3 Specifically, men who have sex with men (MSM) are more likely than heterosexual men to have oral, anal, and penile HPV infections, including high-risk HPV types.3 From 2011 to 2014, 18% and 13% of MSM had oral HPV infection and high-risk oral HPV infection, respectively, compared to only 11% and 7%, respectively, of men who reported never having had a same-sex sexual partner.4
Similarly, despite the CDC’s position that patients with perianal warts might benefit from digital anal examination or referral for standard or high-resolution anoscopy to detect intra-anal warts, improvements in morbidity have not yet been realized. In 2017, anal cancer incidence was 45.9 cases for every 100,000 person-years among human immunodeficiency (HIV)–positive MSM and 5.1 cases for every 100,000 person-years among HIV-negative MSM vs only 1.5 cases for every 100,000 person-years among men in the United States overall.3 Yet the CDC states that there is insufficient evidence to recommend routine anal cancer screening among MSM, even when a patient is HIV positive. Therefore, current screening practices and treatments are insufficient as MSM continue to have a disproportionately higher rate of HPV-associated disease compared to other populations.
Barriers to HPV Vaccine Administration
The HPV vaccination rate among MSM in adolescent populations varies across reports.5-7 Interestingly, a 2016 survey study found that MSM had approximately 2-times greater odds of initiating the HPV vaccine than heterosexual men.8 However, a study specifically sampling young gay and bisexual men (N=428) found that only 13% had received any doses of the HPV vaccine.6
Regardless, HPV vaccination is much less common among all males than it is among all females, and the low rate of vaccination among sexual minority men has a disproportionate impact, given their higher risk for HPV infection.4 Although the HPV vaccination rate increased from 2014 to 2017, the HPV vaccination rate in MSM overall is less than half of the Healthy People 2020 goal of 80%.9 A 2018 review determined that HPV vaccination is a cost-effective strategy for preventing anal cancer in MSM10; yet male patients might still view the HPV vaccine as a “women’s issue” and are less likely to be vaccinated if they are not prompted by health care providers. Additionally, HPV vaccination is remarkably less likely in MSM when patients are older, uninsured, of lower socioeconomic status, or have not disclosed their sexual identity to their health care provider.9 Dermatologists should be mindful of these barriers to promote HPV vaccination in MSM before, or soon after, sexual debut.
Other members of the LGBTQ community, such as women who have sex with women, face notable HPV-related health disparities and would benefit from increased vaccination efforts by dermatologists. Adolescent and young adult women who have sex with women are less likely than heterosexual adolescent and young adult women to receive routine Papanicolaou tests and initiate HPV vaccination, despite having a higher number of lifetime sexual partners and a higher risk for HPV exposure.11 A 2015 survey study (N=3253) found that after adjusting for covariates, only 8.5% of lesbians and 33.2% of bisexual women and girls who had heard of the HPV vaccine had initiated vaccination compared to 28.4% of their heterosexual counterparts.11 The HPV vaccine is an effective public health tool for the prevention of cervical cancer in these populations. A study of women aged 15 to 19 years in the HPV vaccination era (2007-2014) found significant (P<.05) observed population-level decreases in cervical intraepithelial neoplasia incidence across all grades.12
Transgender women also face a high rate of HPV infection, HIV infection, and other structural and financial disparities, such as low insurance coverage, that can limit their access to vaccination. Transgender men have a higher rate of HPV infection than cisgender men, and those with female internal reproductive organs are less likely to receive routine Papanicolaou tests. A 2018 survey study found that approximately one-third of transgender men and women reported initiating the HPV vaccination series,13 but further investigation is required to make balanced comparisons to cisgender patients.
The Role of the Dermatologist
Collectively, these disparities emphasize the need for increased involvement by dermatologists in HPV vaccination efforts for all LGBTQ patients. Adult patients may have concerns about ties of the HPV vaccine to drug manufacturers and the general safety of vaccination. For pediatric patients, parents/guardians also may be concerned about an assumed but not evidence-based increase in sexual promiscuity following HPV vaccination.14 These topics can be challenging to discuss, but dermatologists have the duty to be proactive and initiate conversation about HPV vaccination, as opposed to waiting for patients to express interest. Dermatologists should stress the safety of the vaccine as well as its potential to protect against multiple, even life-threatening diseases. Providers also can explain that the ACIP recommends catch-up vaccination for all individuals through 26 years of age, regardless of sexual orientation or gender identity.
With the ACIP having recently expanded the appropriate age range for HPV vaccination, we encourage dermatologists to engage in education and shared decision-making to ensure that adult patients with specific risk factors receive the HPV vaccine. Because the expanded ACIP recommendations are aimed at vaccination before HPV exposure, vaccination might not be appropriate for all LGBTQ patients. However, eliciting a sexual history with routine patient intake forms or during the clinical encounter ensures equal access to the HPV vaccine.
Greater awareness of HPV-related disparities and barriers to vaccination in LGBTQ populations has the potential to notably decrease HPV-associated mortality and morbidity. Increased involvement by dermatologists contributes to the efforts of other specialties in universal HPV vaccination, regardless of sexual orientation or gender identity—ideally in younger age groups, such that patients receive the vaccine prior to coitarche.
There are many ways that dermatologists can advocate for HPV vaccination. Those in a multispecialty or academic practice can readily refer patients to an associated internist, primary care physician, or vaccination clinic in the same building or institution. Dermatologists in private practice might be able to administer the HPV vaccine themselves or can advocate for patients to receive the vaccine at a local facility of the Department of Health or at a nonprofit organization, such as a Planned Parenthood center. Although pediatricians and family physicians remain front-line providers of these services, dermatologists represent an additional member of a patient’s care team, capable of advocating for this important intervention.
- Brianti P, De Flammineis E, Mercuri SR. Review of HPV-related diseases and cancers. New Microbiol. 2017;40:80-85.
- Meites E, Szilagyi PG, Chesson HW, et al. Human papillomavirus vaccination for adults: updated recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2019;68:698-702.
- Yeung H, Luk KM, Chen SC, et al. Dermatologic care for lesbian, gay, bisexual, and transgender persons: epidemiology, screening, and disease prevention. J Am Acad Dermatol. 2019;80:591-602.
- Sonawane K, Suk R, Chiao EY, et al. Oral human papillomavirus infection: differences in prevalence between sexes and concordance with genital human papillomavirus infection, NHANES 2011 to 2014. Ann Intern Med. 2017;167:714-724.
- Kosche C, Mansh M, Luskus M, et al. Dermatologic care of sexual and gender minority/LGBTQIA youth, part 2: recognition and management of the unique dermatologic needs of SGM adolescents. Pediatr Dermatol. 2019;35:587-593.
- Reiter PL, McRee A-L, Katz ML, et al. Human papillomavirus vaccination among young adult gay and bisexual men in the United States. Am J Public Health. 2015;105:96-102.
- Charlton BM, Reisner SL, Ag
énor M, et al. Sexual orientation disparities in human papillomavirus vaccination in a longitudinal cohort of U.S. males and females. LGBT Health. 2017;4:202-209. - Agénor M, Peitzmeier SM, Gordon AR, et al. Sexual orientation identity disparities in human papillomavirus vaccination initiation and completion among young adult US women and men. Cancer Causes Control. 2016;27:1187-1196.
- Loretan C, Chamberlain AT, Sanchez T, et al. Trends and characteristics associated with human papillomavirus vaccination uptake among men who have sex with men in the United States, 2014-2017. Sex Transm Dis. 2019;46:465-473.
- Setiawan D, Wondimu A, Ong K, et al. Cost effectiveness of human papillomavirus vaccination for men who have sex with men; reviewing the available evidence. Pharmacoeconomics. 2018;36:929-939.
- Agénor M, Peitzmeier S, Gordon AR, et al. Sexual orientation identity disparities in awareness and initiation of the human papillomavirus vaccine among U.S. women and girls: a national survey. Ann Intern Med. 2015;163:99-106.
- Benard VB, Castle PE, Jenison SA, et al. Population-based incidence rates of cervical intraepithelial neoplasia in the human papillomavirus vaccine era. JAMA Oncol. 2017;3:833-837.
- McRee A-L, Gower AL, Reiter PL. Preventive healthcare services use among transgender young adults. Int J Transgend. 2018;19:417-423.
- Trinidad J. Policy focus: promoting human papilloma virus vaccine to prevent genital warts and cancer. Boston, MA: The Fenway Institute; 2012. https://fenwayhealth.org/documents/the-fenway-institute/policy-briefs/PolicyFocus_HPV_v4_10.09.12.pdf. Accessed September 15, 2020.
- Brianti P, De Flammineis E, Mercuri SR. Review of HPV-related diseases and cancers. New Microbiol. 2017;40:80-85.
- Meites E, Szilagyi PG, Chesson HW, et al. Human papillomavirus vaccination for adults: updated recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2019;68:698-702.
- Yeung H, Luk KM, Chen SC, et al. Dermatologic care for lesbian, gay, bisexual, and transgender persons: epidemiology, screening, and disease prevention. J Am Acad Dermatol. 2019;80:591-602.
- Sonawane K, Suk R, Chiao EY, et al. Oral human papillomavirus infection: differences in prevalence between sexes and concordance with genital human papillomavirus infection, NHANES 2011 to 2014. Ann Intern Med. 2017;167:714-724.
- Kosche C, Mansh M, Luskus M, et al. Dermatologic care of sexual and gender minority/LGBTQIA youth, part 2: recognition and management of the unique dermatologic needs of SGM adolescents. Pediatr Dermatol. 2019;35:587-593.
- Reiter PL, McRee A-L, Katz ML, et al. Human papillomavirus vaccination among young adult gay and bisexual men in the United States. Am J Public Health. 2015;105:96-102.
- Charlton BM, Reisner SL, Ag
énor M, et al. Sexual orientation disparities in human papillomavirus vaccination in a longitudinal cohort of U.S. males and females. LGBT Health. 2017;4:202-209. - Agénor M, Peitzmeier SM, Gordon AR, et al. Sexual orientation identity disparities in human papillomavirus vaccination initiation and completion among young adult US women and men. Cancer Causes Control. 2016;27:1187-1196.
- Loretan C, Chamberlain AT, Sanchez T, et al. Trends and characteristics associated with human papillomavirus vaccination uptake among men who have sex with men in the United States, 2014-2017. Sex Transm Dis. 2019;46:465-473.
- Setiawan D, Wondimu A, Ong K, et al. Cost effectiveness of human papillomavirus vaccination for men who have sex with men; reviewing the available evidence. Pharmacoeconomics. 2018;36:929-939.
- Agénor M, Peitzmeier S, Gordon AR, et al. Sexual orientation identity disparities in awareness and initiation of the human papillomavirus vaccine among U.S. women and girls: a national survey. Ann Intern Med. 2015;163:99-106.
- Benard VB, Castle PE, Jenison SA, et al. Population-based incidence rates of cervical intraepithelial neoplasia in the human papillomavirus vaccine era. JAMA Oncol. 2017;3:833-837.
- McRee A-L, Gower AL, Reiter PL. Preventive healthcare services use among transgender young adults. Int J Transgend. 2018;19:417-423.
- Trinidad J. Policy focus: promoting human papilloma virus vaccine to prevent genital warts and cancer. Boston, MA: The Fenway Institute; 2012. https://fenwayhealth.org/documents/the-fenway-institute/policy-briefs/PolicyFocus_HPV_v4_10.09.12.pdf. Accessed September 15, 2020.
An Unusual Skin Infection With Achromobacter xylosoxidans
Case Report
A 50-year-old woman presented with a sore, tender, red lump on the right superior buttock of 5 months’ duration. Five months prior to presentation the patient used this area to attach the infusion set for an insulin pump, which was left in place for 7 days as opposed to the 2 or 3 days recommended by the device manufacturer. A firm, slightly tender lump formed, similar to prior scars that had developed from use of the insulin pump. However, the lump began to grow and get softer. It was intermittently warm and red. Although the area was sore and tender, she never had any major pain. She also denied any fever, malaise, or other systemic symptoms.
The patient indicated a medical history of type 1 diabetes mellitus diagnosed at 9 years of age; hypertension; asthma; gastroesophageal reflux disease; allergic rhinitis; migraine headaches; depression; hidradenitis suppurativa that resolved after surgical excision; and recurrent vaginal yeast infections, especially when taking antibiotics. She had a surgical history of hidradenitis suppurativa excision at the inguinal folds, bilateral carpal tunnel release, tubal ligation, abdominoplasty, and cholecystectomy. The patient’s current medications included insulin aspart, mometasone furoate, inhaled fluticasone, pantoprazole, cetirizine, spironolactone, duloxetine, sumatriptan, fluconazole, topiramate, and enalapril.
Physical examination revealed normal vital signs and the patient was afebrile. She had no swollen or tender lymph nodes. There was a 5.5×7.0-cm, soft, tender, erythematous subcutaneous mass with no visible punctum or overlying epidermal change on the right superior buttock (Figure 1). Based on the history and physical examination, the differential diagnosis included subcutaneous fat necrosis, epidermal inclusion cyst, and an abscess.
The patient was scheduled for excision of the mass the day after presenting to the clinic. During excision, 10 mL of thick purulent liquid was drained. A sample of the liquid was sent for Gram stain, aerobic and anaerobic culture, and antibiotic sensitivities. Necrotic-appearing adipose and fibrotic tissues were dissected and extirpated through an elliptical incision and submitted for pathologic evaluation.
Histopathology showed a subcutaneous defect with palisaded granulomatous inflammation and sclerosis (Figure 2). There was no detection of microorganisms with Grocott-Gomori methenamine-silver, tissue Gram, or acid-fast stains. There was a focus of acellular material embedded within the inflammation (Figure 3). The Gram stain of the purulent material showed few white blood cells and rare gram-negative bacilli. Culture grew moderate Achromobacter xylosoxidans resistant to cefepime, cefotaxime, and gentamicin. The culture was susceptible to ceftazidime, imipenem, levofloxacin, piperacillin, and trimethoprim-sulfamethoxazole (TMP-SMX).
The patient was prescribed oral TMP-SMX (160 mg of TMP and 800 mg of SMX) twice daily for 10 days. The patient tolerated the procedure and the subsequent antibiotics well. The patient had normal levels of IgA, IgG, and IgM, as well as a negative screening test for human immunodeficiency virus. She healed well from the surgical procedure and has had no recurrence of symptoms.
Comment
Achromobacter xylosoxidans is a nonfermentative, non–spore-forming, motile, gram-negative, aerobic, catalase-positive and oxidase-positive flagellate bacterium. It is an emerging pathogen that was first isolated in 1971 from patients with chronic otitis media.1 Since its recognition, it has been documented to cause a variety of infections, including pneumonia, meningitis, osteomyelitis, endocarditis, and bacteremia, as well as abdominal, urinary tract, ocular, and skin and soft tissue infections.2,3 Those affected usually are immunocompromised, have hematologic disorders, or have indwelling catheters.4 Strains of A xylosoxidans have shown resistance to multiple antibiotics including penicillins, cephalosporins, carbapenems, aminoglycosides, macrolides, fluoroquinolones, and TMP-SMX. Achromobacter xylosoxidans has been documented to form biofilms on plastics, including on contact lenses, urinary and intravenous catheters, and reusable tissue dispensers treated with disinfectant solution.4-6 One study demonstrated that A xylosoxidans is even capable of biodegradation of plastic, using the plastic as its sole source of carbon.7
Our case illustrates an indolent infection with A xylosoxidans forming a granulomatous abscess at the site of an insulin pump that was left in place for 7 days in an immunocompetent patient. Although infections with A xylosoxidans in patients with urinary or intravenous catheters have been reported,4 our case is unique, as the insulin pump was the source of such an infection. It is possible that the subcutaneous focus of acellular material described on the pathology report represented a partially biodegraded piece of the insulin pump catheter that broke off and was serving as a nidus of infection for A xylosoxidans. Although multidrug resistance is common, the culture grown from our patient was susceptible to TMP-SMX, among other antibiotics. Our patient was treated successfully with surgical excision, drainage, and a 10-day course of TMP-SMX.
Conclusion
Health care providers should recognize A xylosoxidans as an emerging pathogen that is capable of forming biofilms on “disinfected” surfaces and medical products, especially plastics. Achromobacter xylosoxidans may be resistant to multiple antibiotics and can cause infections with various presentations.
- Yabuuchi E, Oyama A. Achromobacter xylosoxidans n. sp. from human ear discharge. Jpn J Microbiol. 1971;15:477-481.
- Rodrigues CG, Rays J, Kanegae MY. Native-valve endocarditis caused by Achromobacter xylosoxidans: a case report and review of literature. Autops Case Rep. 2017;7:50-55.
- Tena D, Martínez NM, Losa C, et al. Skin and soft tissue infection caused by Achromobacter xylosoxidans: report of 14 cases. Scand J Infect Dis. 2014;46:130-135.
- Pérez Barragán E, Sandino Pérez J, Corbella L, et al. Achromobacter xylosoxidans bacteremia: clinical and microbiological features in a 10-year case series. Rev Esp Quimioter. 2018;31:268-273.
- Konstantinović N, Ćirković I, Đukić S, et al. Biofilm formation of Achromobacter xylosoxidans on contact lens. Acta Microbiol Immunol Hung. 2017;64:293-300.
- Günther F, Merle U, Frank U, et al. Pseudobacteremia outbreak of biofilm-forming Achromobacter xylosoxidans—environmental transmission. BMC Infect Dis. 2016;16:584.
- Kowalczyk A, Chyc M, Ryszka P, et al. Achromobacter xylosoxidans as a new microorganism strain colonizing high-density polyethylene as a key step to its biodegradation. Environ Sci Pollut Res Int. 2016;23:11349-11356.
Case Report
A 50-year-old woman presented with a sore, tender, red lump on the right superior buttock of 5 months’ duration. Five months prior to presentation the patient used this area to attach the infusion set for an insulin pump, which was left in place for 7 days as opposed to the 2 or 3 days recommended by the device manufacturer. A firm, slightly tender lump formed, similar to prior scars that had developed from use of the insulin pump. However, the lump began to grow and get softer. It was intermittently warm and red. Although the area was sore and tender, she never had any major pain. She also denied any fever, malaise, or other systemic symptoms.
The patient indicated a medical history of type 1 diabetes mellitus diagnosed at 9 years of age; hypertension; asthma; gastroesophageal reflux disease; allergic rhinitis; migraine headaches; depression; hidradenitis suppurativa that resolved after surgical excision; and recurrent vaginal yeast infections, especially when taking antibiotics. She had a surgical history of hidradenitis suppurativa excision at the inguinal folds, bilateral carpal tunnel release, tubal ligation, abdominoplasty, and cholecystectomy. The patient’s current medications included insulin aspart, mometasone furoate, inhaled fluticasone, pantoprazole, cetirizine, spironolactone, duloxetine, sumatriptan, fluconazole, topiramate, and enalapril.
Physical examination revealed normal vital signs and the patient was afebrile. She had no swollen or tender lymph nodes. There was a 5.5×7.0-cm, soft, tender, erythematous subcutaneous mass with no visible punctum or overlying epidermal change on the right superior buttock (Figure 1). Based on the history and physical examination, the differential diagnosis included subcutaneous fat necrosis, epidermal inclusion cyst, and an abscess.
The patient was scheduled for excision of the mass the day after presenting to the clinic. During excision, 10 mL of thick purulent liquid was drained. A sample of the liquid was sent for Gram stain, aerobic and anaerobic culture, and antibiotic sensitivities. Necrotic-appearing adipose and fibrotic tissues were dissected and extirpated through an elliptical incision and submitted for pathologic evaluation.
Histopathology showed a subcutaneous defect with palisaded granulomatous inflammation and sclerosis (Figure 2). There was no detection of microorganisms with Grocott-Gomori methenamine-silver, tissue Gram, or acid-fast stains. There was a focus of acellular material embedded within the inflammation (Figure 3). The Gram stain of the purulent material showed few white blood cells and rare gram-negative bacilli. Culture grew moderate Achromobacter xylosoxidans resistant to cefepime, cefotaxime, and gentamicin. The culture was susceptible to ceftazidime, imipenem, levofloxacin, piperacillin, and trimethoprim-sulfamethoxazole (TMP-SMX).
The patient was prescribed oral TMP-SMX (160 mg of TMP and 800 mg of SMX) twice daily for 10 days. The patient tolerated the procedure and the subsequent antibiotics well. The patient had normal levels of IgA, IgG, and IgM, as well as a negative screening test for human immunodeficiency virus. She healed well from the surgical procedure and has had no recurrence of symptoms.
Comment
Achromobacter xylosoxidans is a nonfermentative, non–spore-forming, motile, gram-negative, aerobic, catalase-positive and oxidase-positive flagellate bacterium. It is an emerging pathogen that was first isolated in 1971 from patients with chronic otitis media.1 Since its recognition, it has been documented to cause a variety of infections, including pneumonia, meningitis, osteomyelitis, endocarditis, and bacteremia, as well as abdominal, urinary tract, ocular, and skin and soft tissue infections.2,3 Those affected usually are immunocompromised, have hematologic disorders, or have indwelling catheters.4 Strains of A xylosoxidans have shown resistance to multiple antibiotics including penicillins, cephalosporins, carbapenems, aminoglycosides, macrolides, fluoroquinolones, and TMP-SMX. Achromobacter xylosoxidans has been documented to form biofilms on plastics, including on contact lenses, urinary and intravenous catheters, and reusable tissue dispensers treated with disinfectant solution.4-6 One study demonstrated that A xylosoxidans is even capable of biodegradation of plastic, using the plastic as its sole source of carbon.7
Our case illustrates an indolent infection with A xylosoxidans forming a granulomatous abscess at the site of an insulin pump that was left in place for 7 days in an immunocompetent patient. Although infections with A xylosoxidans in patients with urinary or intravenous catheters have been reported,4 our case is unique, as the insulin pump was the source of such an infection. It is possible that the subcutaneous focus of acellular material described on the pathology report represented a partially biodegraded piece of the insulin pump catheter that broke off and was serving as a nidus of infection for A xylosoxidans. Although multidrug resistance is common, the culture grown from our patient was susceptible to TMP-SMX, among other antibiotics. Our patient was treated successfully with surgical excision, drainage, and a 10-day course of TMP-SMX.
Conclusion
Health care providers should recognize A xylosoxidans as an emerging pathogen that is capable of forming biofilms on “disinfected” surfaces and medical products, especially plastics. Achromobacter xylosoxidans may be resistant to multiple antibiotics and can cause infections with various presentations.
Case Report
A 50-year-old woman presented with a sore, tender, red lump on the right superior buttock of 5 months’ duration. Five months prior to presentation the patient used this area to attach the infusion set for an insulin pump, which was left in place for 7 days as opposed to the 2 or 3 days recommended by the device manufacturer. A firm, slightly tender lump formed, similar to prior scars that had developed from use of the insulin pump. However, the lump began to grow and get softer. It was intermittently warm and red. Although the area was sore and tender, she never had any major pain. She also denied any fever, malaise, or other systemic symptoms.
The patient indicated a medical history of type 1 diabetes mellitus diagnosed at 9 years of age; hypertension; asthma; gastroesophageal reflux disease; allergic rhinitis; migraine headaches; depression; hidradenitis suppurativa that resolved after surgical excision; and recurrent vaginal yeast infections, especially when taking antibiotics. She had a surgical history of hidradenitis suppurativa excision at the inguinal folds, bilateral carpal tunnel release, tubal ligation, abdominoplasty, and cholecystectomy. The patient’s current medications included insulin aspart, mometasone furoate, inhaled fluticasone, pantoprazole, cetirizine, spironolactone, duloxetine, sumatriptan, fluconazole, topiramate, and enalapril.
Physical examination revealed normal vital signs and the patient was afebrile. She had no swollen or tender lymph nodes. There was a 5.5×7.0-cm, soft, tender, erythematous subcutaneous mass with no visible punctum or overlying epidermal change on the right superior buttock (Figure 1). Based on the history and physical examination, the differential diagnosis included subcutaneous fat necrosis, epidermal inclusion cyst, and an abscess.
The patient was scheduled for excision of the mass the day after presenting to the clinic. During excision, 10 mL of thick purulent liquid was drained. A sample of the liquid was sent for Gram stain, aerobic and anaerobic culture, and antibiotic sensitivities. Necrotic-appearing adipose and fibrotic tissues were dissected and extirpated through an elliptical incision and submitted for pathologic evaluation.
Histopathology showed a subcutaneous defect with palisaded granulomatous inflammation and sclerosis (Figure 2). There was no detection of microorganisms with Grocott-Gomori methenamine-silver, tissue Gram, or acid-fast stains. There was a focus of acellular material embedded within the inflammation (Figure 3). The Gram stain of the purulent material showed few white blood cells and rare gram-negative bacilli. Culture grew moderate Achromobacter xylosoxidans resistant to cefepime, cefotaxime, and gentamicin. The culture was susceptible to ceftazidime, imipenem, levofloxacin, piperacillin, and trimethoprim-sulfamethoxazole (TMP-SMX).
The patient was prescribed oral TMP-SMX (160 mg of TMP and 800 mg of SMX) twice daily for 10 days. The patient tolerated the procedure and the subsequent antibiotics well. The patient had normal levels of IgA, IgG, and IgM, as well as a negative screening test for human immunodeficiency virus. She healed well from the surgical procedure and has had no recurrence of symptoms.
Comment
Achromobacter xylosoxidans is a nonfermentative, non–spore-forming, motile, gram-negative, aerobic, catalase-positive and oxidase-positive flagellate bacterium. It is an emerging pathogen that was first isolated in 1971 from patients with chronic otitis media.1 Since its recognition, it has been documented to cause a variety of infections, including pneumonia, meningitis, osteomyelitis, endocarditis, and bacteremia, as well as abdominal, urinary tract, ocular, and skin and soft tissue infections.2,3 Those affected usually are immunocompromised, have hematologic disorders, or have indwelling catheters.4 Strains of A xylosoxidans have shown resistance to multiple antibiotics including penicillins, cephalosporins, carbapenems, aminoglycosides, macrolides, fluoroquinolones, and TMP-SMX. Achromobacter xylosoxidans has been documented to form biofilms on plastics, including on contact lenses, urinary and intravenous catheters, and reusable tissue dispensers treated with disinfectant solution.4-6 One study demonstrated that A xylosoxidans is even capable of biodegradation of plastic, using the plastic as its sole source of carbon.7
Our case illustrates an indolent infection with A xylosoxidans forming a granulomatous abscess at the site of an insulin pump that was left in place for 7 days in an immunocompetent patient. Although infections with A xylosoxidans in patients with urinary or intravenous catheters have been reported,4 our case is unique, as the insulin pump was the source of such an infection. It is possible that the subcutaneous focus of acellular material described on the pathology report represented a partially biodegraded piece of the insulin pump catheter that broke off and was serving as a nidus of infection for A xylosoxidans. Although multidrug resistance is common, the culture grown from our patient was susceptible to TMP-SMX, among other antibiotics. Our patient was treated successfully with surgical excision, drainage, and a 10-day course of TMP-SMX.
Conclusion
Health care providers should recognize A xylosoxidans as an emerging pathogen that is capable of forming biofilms on “disinfected” surfaces and medical products, especially plastics. Achromobacter xylosoxidans may be resistant to multiple antibiotics and can cause infections with various presentations.
- Yabuuchi E, Oyama A. Achromobacter xylosoxidans n. sp. from human ear discharge. Jpn J Microbiol. 1971;15:477-481.
- Rodrigues CG, Rays J, Kanegae MY. Native-valve endocarditis caused by Achromobacter xylosoxidans: a case report and review of literature. Autops Case Rep. 2017;7:50-55.
- Tena D, Martínez NM, Losa C, et al. Skin and soft tissue infection caused by Achromobacter xylosoxidans: report of 14 cases. Scand J Infect Dis. 2014;46:130-135.
- Pérez Barragán E, Sandino Pérez J, Corbella L, et al. Achromobacter xylosoxidans bacteremia: clinical and microbiological features in a 10-year case series. Rev Esp Quimioter. 2018;31:268-273.
- Konstantinović N, Ćirković I, Đukić S, et al. Biofilm formation of Achromobacter xylosoxidans on contact lens. Acta Microbiol Immunol Hung. 2017;64:293-300.
- Günther F, Merle U, Frank U, et al. Pseudobacteremia outbreak of biofilm-forming Achromobacter xylosoxidans—environmental transmission. BMC Infect Dis. 2016;16:584.
- Kowalczyk A, Chyc M, Ryszka P, et al. Achromobacter xylosoxidans as a new microorganism strain colonizing high-density polyethylene as a key step to its biodegradation. Environ Sci Pollut Res Int. 2016;23:11349-11356.
- Yabuuchi E, Oyama A. Achromobacter xylosoxidans n. sp. from human ear discharge. Jpn J Microbiol. 1971;15:477-481.
- Rodrigues CG, Rays J, Kanegae MY. Native-valve endocarditis caused by Achromobacter xylosoxidans: a case report and review of literature. Autops Case Rep. 2017;7:50-55.
- Tena D, Martínez NM, Losa C, et al. Skin and soft tissue infection caused by Achromobacter xylosoxidans: report of 14 cases. Scand J Infect Dis. 2014;46:130-135.
- Pérez Barragán E, Sandino Pérez J, Corbella L, et al. Achromobacter xylosoxidans bacteremia: clinical and microbiological features in a 10-year case series. Rev Esp Quimioter. 2018;31:268-273.
- Konstantinović N, Ćirković I, Đukić S, et al. Biofilm formation of Achromobacter xylosoxidans on contact lens. Acta Microbiol Immunol Hung. 2017;64:293-300.
- Günther F, Merle U, Frank U, et al. Pseudobacteremia outbreak of biofilm-forming Achromobacter xylosoxidans—environmental transmission. BMC Infect Dis. 2016;16:584.
- Kowalczyk A, Chyc M, Ryszka P, et al. Achromobacter xylosoxidans as a new microorganism strain colonizing high-density polyethylene as a key step to its biodegradation. Environ Sci Pollut Res Int. 2016;23:11349-11356.
Practice Points
- Achromobacter xylosoxidans is an emerging pathogen primarily in the immunocompromised patient.
- Achromobacter xylosoxidans can form biofilms on plastics treated with disinfectant solution, including medical products.
- Strains of A xylosoxidans have shown multiantibiotic resistance.
Cutaneous Leishmaniasis Successfully Treated With Miltefosine
Leishmaniasis is a neglected parasitic disease with an estimated annual incidence of 1.3 million cases, the majority of which manifest as cutaneous leishmaniasis.1 The cutaneous and mucosal forms demonstrate substantial global burden with morbidity and socioeconomic repercussions, while the visceral form is responsible for up to 30,000 deaths annually.2 Despite increasing prevalence in the United States, awareness and diagnosis remain relatively low.3 We describe 2 cases of cutaneous leishmaniasis in New England, United States, in travelers returning from Central America, both successfully treated with miltefosine. We also review prevention, diagnosis, and treatment options.
Case Reports
Patient 1
A 47-year-old woman presented with an enlarging, 2-cm, erythematous, ulcerated nodule on the right dorsal hand of 2 weeks’ duration with accompanying right epitrochlear lymphadenopathy (Figure 1A). She noticed the lesion 10 weeks after returning from Panama, where she had been photographing the jungle. Prior to the initial presentation to dermatology, salicylic acid wart remover, intramuscular ceftriaxone, and oral trimethoprim had failed to alleviate the lesion. Her laboratory results were notable for an elevated C-reactive protein level of 5.4 mg/L (reference range, ≤4.9 mg/L). A punch biopsy demonstrated pseudoepitheliomatous hyperplasia with diffuse dermal lymphohistiocytic inflammation and small intracytoplasmic structures within histiocytes consistent with leishmaniasis (Figure 2). Immunohistochemistry was consistent with leishmaniasis (Figure 3), and polymerase chain reaction performed by the Centers for Disease Control and Prevention (CDC) identified the pathogen as Leishmania braziliensis.
Patient 2
An 18-year-old man presented with an enlarging, well-delineated, tender ulcer of 6 weeks’ duration measuring 2.5×2 cm with an erythematous and edematous border on the right medial forearm with associated epitrochlear lymphadenopathy (Figure 4). Nine weeks prior to initial presentation, he had returned from a 3-month outdoor adventure trip to the Florida Keys, Costa Rica, and Panama. He had used bug repellent intermittently, slept under a bug net, and did not recall any trauma or bite at the ulcer site. Biopsy and tissue culture were obtained, and histopathology demonstrated an ulcer with a dense dermal lymphogranulomatous infiltrate and intracytoplasmic organisms consistent with leishmaniasis. Polymerase chain reaction by the CDC identified the pathogen as Leishmania panamensis.
Treatment
Both patients were prescribed oral miltefosine 50 mg twice daily for 28 days. Patient 1 initiated treatment 1 month after lesion onset, and patient 2 initiated treatment 2.5 months after initial presentation. Both patients had noticeable clinical improvement within 21 days of starting treatment, with lesions diminishing in size and lymphadenopathy resolving. Within 2 months of treatment, patient 1’s ulcer completely resolved with only postinflammatory hyperpigmentation (Figure 1B), while patient 2’s ulcer was noticeably smaller and shallower compared with its peak size of 4.2×2.4 cm (Figure 4B). Miltefosine was well tolerated by both patients; emesis resolved with ondansetron in patient 1 and spontaneously in patient 2, who had asymptomatic temporary hyperkalemia of 5.2 mmol/L (reference range, 3.5–5.0 mmol/L).
Comment
Epidemiology and Prevention
Risk factors for leishmaniasis include weak immunity, poverty, poor housing, poor sanitation, malnutrition, urbanization, climate change, and human migration.4 Our patients were most directly affected by travel to locations where leishmaniasis is endemic. Despite an increasing prevalence of endemic leishmaniasis and new animal hosts in the southern United States, most patients diagnosed in the United States are infected abroad by Leishmania mexicana and L braziliensis, both cutaneous New World species.3 Our patients were infected by species within the New World subgenus Viannia that have potential for mucocutaneous spread.4
Because there is no chemoprophylaxis or acquired active immunity such as vaccines that can mitigate the risk for leishmaniasis, public health efforts focus on preventive measures. Although difficult to achieve, avoidance of the phlebotomine sand fly species that transmit the obligate intracellular Leishmania parasite is a most effective measure.4 Travelers entering geographic regions with higher risk for leishmaniasis should be aware of the inherent risk and determine which methods of prevention, such as N,N-diethyl-meta-toluamide (DEET) insecticides or permethrin-treated protective clothing, are most feasible. Although higher concentrations of DEET provide longer protection, the effectiveness tends to plateau at approximately 50%.5
Presentation and Prognosis
For patients who develop leishmaniasis, the disease course and prognosis depend greatly on the species and manifestation. The most common form of leishmaniasis is localized cutaneous leishmaniasis, which has an annual incidence of up to 1 million cases. It initially presents as macules, usually at the site of inoculation within several months to years of infection.6 The macules expand into papules and plaques that reach maximum size over at least 1 week4 and then progress into crusted ulcers up to 5 cm in diameter with raised edges. Although usually painless and self-limited, these lesions can take years to spontaneously heal, with the risk for atrophic scarring and altered pigmentation. Lymphatic involvement manifests as lymphadenitis or regional lymphadenopathy and is common with lesions caused by the subgenus Viannia.6
Leishmania braziliensis and L panamensis, the species that infected our patients, can uniquely cause cutaneous leishmaniasis that metastasizes into mucocutaneous leishmaniasis, which always affects the nasal mucosa. Risk factors for transformation include a primary lesion site above the waist, multiple or large primary lesions, and delayed healing of primary cutaneous leishmaniasis. Mucocutaneous leishmaniasis can result in notable morbidity and even mortality from invasion and destruction of nasal and oropharyngeal mucosa, as well as intercurrent pneumonia, especially if treatment is insufficient or delayed.4
Diagnosis
Prompt treatment relies on accurate and timely diagnosis, which is complicated by the relative unfamiliarity with leishmaniasis in the United States. The differential diagnosis for cutaneous leishmaniasis is broad, including deep fungal infection, Mycobacterium infection, cutaneous granulomatous conditions, nonmelanoma cutaneous neoplasms, and trauma. Taking a thorough patient history, including potential exposures and travels; having high clinical suspicion; and being aware of classic presentation allows for identification of leishmaniasis and subsequent stratification by manifestation.7
Diagnosis is made by detecting Leishmania organisms or DNA using light microscopy and staining to visualize the kinetoplast in an amastigote, molecular methods, or specialized culturing.7 The CDC is a valuable diagnostic partner for confirmation and speciation. Specific instructions for specimen collection and transportation can be found by contacting the CDC or reading their guide.8 To provide prompt care and reassurance to patients, it is important to be aware of the coordination effort that may be needed to send samples, receive results, and otherwise correspond with a separate institution.
Treatment
Treatment of cutaneous leishmaniasis is indicated to decrease the risk for mucosal dissemination and clinical reactivation of lesions, accelerate healing of lesions, decrease local morbidity caused by large or persistent lesions, and decrease the reservoir of infection in places where infected humans serve as reservoir hosts. Oral treatments include ketoconazole, itraconazole, and fluconazole, recommended at doses ranging from 200 to 600 mg daily for at least 28 days. For severe, refractory, or visceral leishmaniasis, parenteral choices include
Miltefosine is becoming a more common treatment of leishmaniasis because of its oral route, tolerability in nonpregnant patients, and commercial availability. It was approved by the US Food and Drug Administration in 2014 for cutaneous leishmaniasis due to L braziliensis, L panamensis, and Leishmania guyanensis; mucosal leishmaniasis due to L braziliensis; and visceral leishmaniasis due to Leishmania donovani in patients at least 12 years of age. For cutaneous leishmaniasis, the standard dosage of 50 mg twice daily (for patients weighing 30–44 kg) or 3 times daily (for patients weighing 45 kg or more) for 28 consecutive days has cure rates of 48% to 85% by 6 months after therapy ends. Cure is defined as epithelialization of lesions, no enlargement greater than 50% in lesions, no appearance of new lesions, and/or negative parasitology. The antileishmanial mechanism of action is unknown and likely involves interaction with lipids, inhibition of cytochrome c oxidase, and apoptosislike cell death. Miltefosine is contraindicated in pregnancy. The most common adverse reactions in patients include nausea (35.9%–41.7%), motion sickness (29.2%), headache (28.1%), and emesis (4.5%–27.5%). With the exception of headache, these adverse reactions can decrease with administration of food, fluids, and antiemetics. Potentially more serious but rarer adverse reactions include elevated serum creatinine (5%–25%) and transaminases (5%). Although our patients had mild hyperkalemia, it is not an established adverse reaction. However, renal injury has been reported.10
Conclusion
Cutaneous leishmaniasis is increasing in prevalence in the United States due to increased foreign travel. Providers should be familiar with the cutaneous presentation of leishmaniasis, even in areas of low prevalence, to limit the risk for mucocutaneous dissemination from infection with the subgenus Viannia. Prompt treatment is vital to ensuring the best prognosis, and first-line treatment with miltefosine should be strongly considered given its efficacy and tolerability.
- Babuadze G, Alvar J, Argaw D, et al. Epidemiology of visceral leishmaniasis in Georgia. PLoS Negl Trop Dis. 2014;8:e2725.
- Leishmaniasis. World Health Organization website. https://www.afro.who.int/health-topics/Leishmaniasis. Accessed September 15, 2020.
- McIlwee BE, Weis SE, Hosler GA. Incidence of endemic human cutaneous leishmaniasis in the United States. JAMA Dermatol. 2018;154:1032-1039.
- Leishmaniasis. World Health Organization website. https://www.who.int/news-room/fact-sheets/detail/leishmaniasis. Update March 2, 2020. Accessed September 15, 2020.
- Centers for Disease Control and Prevention. Guidelines for DEET insect repellent use. https://www.cdc.gov/malaria/toolkit/DEET.pdf. Accessed September 20, 2020.
- Buescher MD, Rutledge LC, Wirtz RA, et al. The dose-persistence relationship of DEET against Aedes aegypti. Mosq News. 1983;43:364-366.
- Aronson N, Herwaldt BL, Libman M, et al. Diagnosis and treatment of leishmaniasis: clinical practice guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH). Clin Infect Dis. 2016;63:e202-e264.
- US Department of Health and Human Services. Practical guide for specimen collection and reference diagnosis of leishmaniasis. Centers for Disease Control and Prevention website. https://www.cdc.gov/parasites/leishmaniasis/resources/pdf/cdc_diagnosis_guide_leishmaniasis_2016.pdf. Accessed September 15, 2020.
- Visceral leishmaniasis. Drugs for Neglected Diseases Initiative website. https://www.dndi.org/diseases-projects/leishmaniasis/. Accessed September 15, 2020.
- Impavido Medication Guide. Food and Drug Administration Web site. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204684s000lbl.pdf. Revised March 2014. Accessed May 18, 2020.
Leishmaniasis is a neglected parasitic disease with an estimated annual incidence of 1.3 million cases, the majority of which manifest as cutaneous leishmaniasis.1 The cutaneous and mucosal forms demonstrate substantial global burden with morbidity and socioeconomic repercussions, while the visceral form is responsible for up to 30,000 deaths annually.2 Despite increasing prevalence in the United States, awareness and diagnosis remain relatively low.3 We describe 2 cases of cutaneous leishmaniasis in New England, United States, in travelers returning from Central America, both successfully treated with miltefosine. We also review prevention, diagnosis, and treatment options.
Case Reports
Patient 1
A 47-year-old woman presented with an enlarging, 2-cm, erythematous, ulcerated nodule on the right dorsal hand of 2 weeks’ duration with accompanying right epitrochlear lymphadenopathy (Figure 1A). She noticed the lesion 10 weeks after returning from Panama, where she had been photographing the jungle. Prior to the initial presentation to dermatology, salicylic acid wart remover, intramuscular ceftriaxone, and oral trimethoprim had failed to alleviate the lesion. Her laboratory results were notable for an elevated C-reactive protein level of 5.4 mg/L (reference range, ≤4.9 mg/L). A punch biopsy demonstrated pseudoepitheliomatous hyperplasia with diffuse dermal lymphohistiocytic inflammation and small intracytoplasmic structures within histiocytes consistent with leishmaniasis (Figure 2). Immunohistochemistry was consistent with leishmaniasis (Figure 3), and polymerase chain reaction performed by the Centers for Disease Control and Prevention (CDC) identified the pathogen as Leishmania braziliensis.
Patient 2
An 18-year-old man presented with an enlarging, well-delineated, tender ulcer of 6 weeks’ duration measuring 2.5×2 cm with an erythematous and edematous border on the right medial forearm with associated epitrochlear lymphadenopathy (Figure 4). Nine weeks prior to initial presentation, he had returned from a 3-month outdoor adventure trip to the Florida Keys, Costa Rica, and Panama. He had used bug repellent intermittently, slept under a bug net, and did not recall any trauma or bite at the ulcer site. Biopsy and tissue culture were obtained, and histopathology demonstrated an ulcer with a dense dermal lymphogranulomatous infiltrate and intracytoplasmic organisms consistent with leishmaniasis. Polymerase chain reaction by the CDC identified the pathogen as Leishmania panamensis.
Treatment
Both patients were prescribed oral miltefosine 50 mg twice daily for 28 days. Patient 1 initiated treatment 1 month after lesion onset, and patient 2 initiated treatment 2.5 months after initial presentation. Both patients had noticeable clinical improvement within 21 days of starting treatment, with lesions diminishing in size and lymphadenopathy resolving. Within 2 months of treatment, patient 1’s ulcer completely resolved with only postinflammatory hyperpigmentation (Figure 1B), while patient 2’s ulcer was noticeably smaller and shallower compared with its peak size of 4.2×2.4 cm (Figure 4B). Miltefosine was well tolerated by both patients; emesis resolved with ondansetron in patient 1 and spontaneously in patient 2, who had asymptomatic temporary hyperkalemia of 5.2 mmol/L (reference range, 3.5–5.0 mmol/L).
Comment
Epidemiology and Prevention
Risk factors for leishmaniasis include weak immunity, poverty, poor housing, poor sanitation, malnutrition, urbanization, climate change, and human migration.4 Our patients were most directly affected by travel to locations where leishmaniasis is endemic. Despite an increasing prevalence of endemic leishmaniasis and new animal hosts in the southern United States, most patients diagnosed in the United States are infected abroad by Leishmania mexicana and L braziliensis, both cutaneous New World species.3 Our patients were infected by species within the New World subgenus Viannia that have potential for mucocutaneous spread.4
Because there is no chemoprophylaxis or acquired active immunity such as vaccines that can mitigate the risk for leishmaniasis, public health efforts focus on preventive measures. Although difficult to achieve, avoidance of the phlebotomine sand fly species that transmit the obligate intracellular Leishmania parasite is a most effective measure.4 Travelers entering geographic regions with higher risk for leishmaniasis should be aware of the inherent risk and determine which methods of prevention, such as N,N-diethyl-meta-toluamide (DEET) insecticides or permethrin-treated protective clothing, are most feasible. Although higher concentrations of DEET provide longer protection, the effectiveness tends to plateau at approximately 50%.5
Presentation and Prognosis
For patients who develop leishmaniasis, the disease course and prognosis depend greatly on the species and manifestation. The most common form of leishmaniasis is localized cutaneous leishmaniasis, which has an annual incidence of up to 1 million cases. It initially presents as macules, usually at the site of inoculation within several months to years of infection.6 The macules expand into papules and plaques that reach maximum size over at least 1 week4 and then progress into crusted ulcers up to 5 cm in diameter with raised edges. Although usually painless and self-limited, these lesions can take years to spontaneously heal, with the risk for atrophic scarring and altered pigmentation. Lymphatic involvement manifests as lymphadenitis or regional lymphadenopathy and is common with lesions caused by the subgenus Viannia.6
Leishmania braziliensis and L panamensis, the species that infected our patients, can uniquely cause cutaneous leishmaniasis that metastasizes into mucocutaneous leishmaniasis, which always affects the nasal mucosa. Risk factors for transformation include a primary lesion site above the waist, multiple or large primary lesions, and delayed healing of primary cutaneous leishmaniasis. Mucocutaneous leishmaniasis can result in notable morbidity and even mortality from invasion and destruction of nasal and oropharyngeal mucosa, as well as intercurrent pneumonia, especially if treatment is insufficient or delayed.4
Diagnosis
Prompt treatment relies on accurate and timely diagnosis, which is complicated by the relative unfamiliarity with leishmaniasis in the United States. The differential diagnosis for cutaneous leishmaniasis is broad, including deep fungal infection, Mycobacterium infection, cutaneous granulomatous conditions, nonmelanoma cutaneous neoplasms, and trauma. Taking a thorough patient history, including potential exposures and travels; having high clinical suspicion; and being aware of classic presentation allows for identification of leishmaniasis and subsequent stratification by manifestation.7
Diagnosis is made by detecting Leishmania organisms or DNA using light microscopy and staining to visualize the kinetoplast in an amastigote, molecular methods, or specialized culturing.7 The CDC is a valuable diagnostic partner for confirmation and speciation. Specific instructions for specimen collection and transportation can be found by contacting the CDC or reading their guide.8 To provide prompt care and reassurance to patients, it is important to be aware of the coordination effort that may be needed to send samples, receive results, and otherwise correspond with a separate institution.
Treatment
Treatment of cutaneous leishmaniasis is indicated to decrease the risk for mucosal dissemination and clinical reactivation of lesions, accelerate healing of lesions, decrease local morbidity caused by large or persistent lesions, and decrease the reservoir of infection in places where infected humans serve as reservoir hosts. Oral treatments include ketoconazole, itraconazole, and fluconazole, recommended at doses ranging from 200 to 600 mg daily for at least 28 days. For severe, refractory, or visceral leishmaniasis, parenteral choices include
Miltefosine is becoming a more common treatment of leishmaniasis because of its oral route, tolerability in nonpregnant patients, and commercial availability. It was approved by the US Food and Drug Administration in 2014 for cutaneous leishmaniasis due to L braziliensis, L panamensis, and Leishmania guyanensis; mucosal leishmaniasis due to L braziliensis; and visceral leishmaniasis due to Leishmania donovani in patients at least 12 years of age. For cutaneous leishmaniasis, the standard dosage of 50 mg twice daily (for patients weighing 30–44 kg) or 3 times daily (for patients weighing 45 kg or more) for 28 consecutive days has cure rates of 48% to 85% by 6 months after therapy ends. Cure is defined as epithelialization of lesions, no enlargement greater than 50% in lesions, no appearance of new lesions, and/or negative parasitology. The antileishmanial mechanism of action is unknown and likely involves interaction with lipids, inhibition of cytochrome c oxidase, and apoptosislike cell death. Miltefosine is contraindicated in pregnancy. The most common adverse reactions in patients include nausea (35.9%–41.7%), motion sickness (29.2%), headache (28.1%), and emesis (4.5%–27.5%). With the exception of headache, these adverse reactions can decrease with administration of food, fluids, and antiemetics. Potentially more serious but rarer adverse reactions include elevated serum creatinine (5%–25%) and transaminases (5%). Although our patients had mild hyperkalemia, it is not an established adverse reaction. However, renal injury has been reported.10
Conclusion
Cutaneous leishmaniasis is increasing in prevalence in the United States due to increased foreign travel. Providers should be familiar with the cutaneous presentation of leishmaniasis, even in areas of low prevalence, to limit the risk for mucocutaneous dissemination from infection with the subgenus Viannia. Prompt treatment is vital to ensuring the best prognosis, and first-line treatment with miltefosine should be strongly considered given its efficacy and tolerability.
Leishmaniasis is a neglected parasitic disease with an estimated annual incidence of 1.3 million cases, the majority of which manifest as cutaneous leishmaniasis.1 The cutaneous and mucosal forms demonstrate substantial global burden with morbidity and socioeconomic repercussions, while the visceral form is responsible for up to 30,000 deaths annually.2 Despite increasing prevalence in the United States, awareness and diagnosis remain relatively low.3 We describe 2 cases of cutaneous leishmaniasis in New England, United States, in travelers returning from Central America, both successfully treated with miltefosine. We also review prevention, diagnosis, and treatment options.
Case Reports
Patient 1
A 47-year-old woman presented with an enlarging, 2-cm, erythematous, ulcerated nodule on the right dorsal hand of 2 weeks’ duration with accompanying right epitrochlear lymphadenopathy (Figure 1A). She noticed the lesion 10 weeks after returning from Panama, where she had been photographing the jungle. Prior to the initial presentation to dermatology, salicylic acid wart remover, intramuscular ceftriaxone, and oral trimethoprim had failed to alleviate the lesion. Her laboratory results were notable for an elevated C-reactive protein level of 5.4 mg/L (reference range, ≤4.9 mg/L). A punch biopsy demonstrated pseudoepitheliomatous hyperplasia with diffuse dermal lymphohistiocytic inflammation and small intracytoplasmic structures within histiocytes consistent with leishmaniasis (Figure 2). Immunohistochemistry was consistent with leishmaniasis (Figure 3), and polymerase chain reaction performed by the Centers for Disease Control and Prevention (CDC) identified the pathogen as Leishmania braziliensis.
Patient 2
An 18-year-old man presented with an enlarging, well-delineated, tender ulcer of 6 weeks’ duration measuring 2.5×2 cm with an erythematous and edematous border on the right medial forearm with associated epitrochlear lymphadenopathy (Figure 4). Nine weeks prior to initial presentation, he had returned from a 3-month outdoor adventure trip to the Florida Keys, Costa Rica, and Panama. He had used bug repellent intermittently, slept under a bug net, and did not recall any trauma or bite at the ulcer site. Biopsy and tissue culture were obtained, and histopathology demonstrated an ulcer with a dense dermal lymphogranulomatous infiltrate and intracytoplasmic organisms consistent with leishmaniasis. Polymerase chain reaction by the CDC identified the pathogen as Leishmania panamensis.
Treatment
Both patients were prescribed oral miltefosine 50 mg twice daily for 28 days. Patient 1 initiated treatment 1 month after lesion onset, and patient 2 initiated treatment 2.5 months after initial presentation. Both patients had noticeable clinical improvement within 21 days of starting treatment, with lesions diminishing in size and lymphadenopathy resolving. Within 2 months of treatment, patient 1’s ulcer completely resolved with only postinflammatory hyperpigmentation (Figure 1B), while patient 2’s ulcer was noticeably smaller and shallower compared with its peak size of 4.2×2.4 cm (Figure 4B). Miltefosine was well tolerated by both patients; emesis resolved with ondansetron in patient 1 and spontaneously in patient 2, who had asymptomatic temporary hyperkalemia of 5.2 mmol/L (reference range, 3.5–5.0 mmol/L).
Comment
Epidemiology and Prevention
Risk factors for leishmaniasis include weak immunity, poverty, poor housing, poor sanitation, malnutrition, urbanization, climate change, and human migration.4 Our patients were most directly affected by travel to locations where leishmaniasis is endemic. Despite an increasing prevalence of endemic leishmaniasis and new animal hosts in the southern United States, most patients diagnosed in the United States are infected abroad by Leishmania mexicana and L braziliensis, both cutaneous New World species.3 Our patients were infected by species within the New World subgenus Viannia that have potential for mucocutaneous spread.4
Because there is no chemoprophylaxis or acquired active immunity such as vaccines that can mitigate the risk for leishmaniasis, public health efforts focus on preventive measures. Although difficult to achieve, avoidance of the phlebotomine sand fly species that transmit the obligate intracellular Leishmania parasite is a most effective measure.4 Travelers entering geographic regions with higher risk for leishmaniasis should be aware of the inherent risk and determine which methods of prevention, such as N,N-diethyl-meta-toluamide (DEET) insecticides or permethrin-treated protective clothing, are most feasible. Although higher concentrations of DEET provide longer protection, the effectiveness tends to plateau at approximately 50%.5
Presentation and Prognosis
For patients who develop leishmaniasis, the disease course and prognosis depend greatly on the species and manifestation. The most common form of leishmaniasis is localized cutaneous leishmaniasis, which has an annual incidence of up to 1 million cases. It initially presents as macules, usually at the site of inoculation within several months to years of infection.6 The macules expand into papules and plaques that reach maximum size over at least 1 week4 and then progress into crusted ulcers up to 5 cm in diameter with raised edges. Although usually painless and self-limited, these lesions can take years to spontaneously heal, with the risk for atrophic scarring and altered pigmentation. Lymphatic involvement manifests as lymphadenitis or regional lymphadenopathy and is common with lesions caused by the subgenus Viannia.6
Leishmania braziliensis and L panamensis, the species that infected our patients, can uniquely cause cutaneous leishmaniasis that metastasizes into mucocutaneous leishmaniasis, which always affects the nasal mucosa. Risk factors for transformation include a primary lesion site above the waist, multiple or large primary lesions, and delayed healing of primary cutaneous leishmaniasis. Mucocutaneous leishmaniasis can result in notable morbidity and even mortality from invasion and destruction of nasal and oropharyngeal mucosa, as well as intercurrent pneumonia, especially if treatment is insufficient or delayed.4
Diagnosis
Prompt treatment relies on accurate and timely diagnosis, which is complicated by the relative unfamiliarity with leishmaniasis in the United States. The differential diagnosis for cutaneous leishmaniasis is broad, including deep fungal infection, Mycobacterium infection, cutaneous granulomatous conditions, nonmelanoma cutaneous neoplasms, and trauma. Taking a thorough patient history, including potential exposures and travels; having high clinical suspicion; and being aware of classic presentation allows for identification of leishmaniasis and subsequent stratification by manifestation.7
Diagnosis is made by detecting Leishmania organisms or DNA using light microscopy and staining to visualize the kinetoplast in an amastigote, molecular methods, or specialized culturing.7 The CDC is a valuable diagnostic partner for confirmation and speciation. Specific instructions for specimen collection and transportation can be found by contacting the CDC or reading their guide.8 To provide prompt care and reassurance to patients, it is important to be aware of the coordination effort that may be needed to send samples, receive results, and otherwise correspond with a separate institution.
Treatment
Treatment of cutaneous leishmaniasis is indicated to decrease the risk for mucosal dissemination and clinical reactivation of lesions, accelerate healing of lesions, decrease local morbidity caused by large or persistent lesions, and decrease the reservoir of infection in places where infected humans serve as reservoir hosts. Oral treatments include ketoconazole, itraconazole, and fluconazole, recommended at doses ranging from 200 to 600 mg daily for at least 28 days. For severe, refractory, or visceral leishmaniasis, parenteral choices include
Miltefosine is becoming a more common treatment of leishmaniasis because of its oral route, tolerability in nonpregnant patients, and commercial availability. It was approved by the US Food and Drug Administration in 2014 for cutaneous leishmaniasis due to L braziliensis, L panamensis, and Leishmania guyanensis; mucosal leishmaniasis due to L braziliensis; and visceral leishmaniasis due to Leishmania donovani in patients at least 12 years of age. For cutaneous leishmaniasis, the standard dosage of 50 mg twice daily (for patients weighing 30–44 kg) or 3 times daily (for patients weighing 45 kg or more) for 28 consecutive days has cure rates of 48% to 85% by 6 months after therapy ends. Cure is defined as epithelialization of lesions, no enlargement greater than 50% in lesions, no appearance of new lesions, and/or negative parasitology. The antileishmanial mechanism of action is unknown and likely involves interaction with lipids, inhibition of cytochrome c oxidase, and apoptosislike cell death. Miltefosine is contraindicated in pregnancy. The most common adverse reactions in patients include nausea (35.9%–41.7%), motion sickness (29.2%), headache (28.1%), and emesis (4.5%–27.5%). With the exception of headache, these adverse reactions can decrease with administration of food, fluids, and antiemetics. Potentially more serious but rarer adverse reactions include elevated serum creatinine (5%–25%) and transaminases (5%). Although our patients had mild hyperkalemia, it is not an established adverse reaction. However, renal injury has been reported.10
Conclusion
Cutaneous leishmaniasis is increasing in prevalence in the United States due to increased foreign travel. Providers should be familiar with the cutaneous presentation of leishmaniasis, even in areas of low prevalence, to limit the risk for mucocutaneous dissemination from infection with the subgenus Viannia. Prompt treatment is vital to ensuring the best prognosis, and first-line treatment with miltefosine should be strongly considered given its efficacy and tolerability.
- Babuadze G, Alvar J, Argaw D, et al. Epidemiology of visceral leishmaniasis in Georgia. PLoS Negl Trop Dis. 2014;8:e2725.
- Leishmaniasis. World Health Organization website. https://www.afro.who.int/health-topics/Leishmaniasis. Accessed September 15, 2020.
- McIlwee BE, Weis SE, Hosler GA. Incidence of endemic human cutaneous leishmaniasis in the United States. JAMA Dermatol. 2018;154:1032-1039.
- Leishmaniasis. World Health Organization website. https://www.who.int/news-room/fact-sheets/detail/leishmaniasis. Update March 2, 2020. Accessed September 15, 2020.
- Centers for Disease Control and Prevention. Guidelines for DEET insect repellent use. https://www.cdc.gov/malaria/toolkit/DEET.pdf. Accessed September 20, 2020.
- Buescher MD, Rutledge LC, Wirtz RA, et al. The dose-persistence relationship of DEET against Aedes aegypti. Mosq News. 1983;43:364-366.
- Aronson N, Herwaldt BL, Libman M, et al. Diagnosis and treatment of leishmaniasis: clinical practice guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH). Clin Infect Dis. 2016;63:e202-e264.
- US Department of Health and Human Services. Practical guide for specimen collection and reference diagnosis of leishmaniasis. Centers for Disease Control and Prevention website. https://www.cdc.gov/parasites/leishmaniasis/resources/pdf/cdc_diagnosis_guide_leishmaniasis_2016.pdf. Accessed September 15, 2020.
- Visceral leishmaniasis. Drugs for Neglected Diseases Initiative website. https://www.dndi.org/diseases-projects/leishmaniasis/. Accessed September 15, 2020.
- Impavido Medication Guide. Food and Drug Administration Web site. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204684s000lbl.pdf. Revised March 2014. Accessed May 18, 2020.
- Babuadze G, Alvar J, Argaw D, et al. Epidemiology of visceral leishmaniasis in Georgia. PLoS Negl Trop Dis. 2014;8:e2725.
- Leishmaniasis. World Health Organization website. https://www.afro.who.int/health-topics/Leishmaniasis. Accessed September 15, 2020.
- McIlwee BE, Weis SE, Hosler GA. Incidence of endemic human cutaneous leishmaniasis in the United States. JAMA Dermatol. 2018;154:1032-1039.
- Leishmaniasis. World Health Organization website. https://www.who.int/news-room/fact-sheets/detail/leishmaniasis. Update March 2, 2020. Accessed September 15, 2020.
- Centers for Disease Control and Prevention. Guidelines for DEET insect repellent use. https://www.cdc.gov/malaria/toolkit/DEET.pdf. Accessed September 20, 2020.
- Buescher MD, Rutledge LC, Wirtz RA, et al. The dose-persistence relationship of DEET against Aedes aegypti. Mosq News. 1983;43:364-366.
- Aronson N, Herwaldt BL, Libman M, et al. Diagnosis and treatment of leishmaniasis: clinical practice guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH). Clin Infect Dis. 2016;63:e202-e264.
- US Department of Health and Human Services. Practical guide for specimen collection and reference diagnosis of leishmaniasis. Centers for Disease Control and Prevention website. https://www.cdc.gov/parasites/leishmaniasis/resources/pdf/cdc_diagnosis_guide_leishmaniasis_2016.pdf. Accessed September 15, 2020.
- Visceral leishmaniasis. Drugs for Neglected Diseases Initiative website. https://www.dndi.org/diseases-projects/leishmaniasis/. Accessed September 15, 2020.
- Impavido Medication Guide. Food and Drug Administration Web site. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204684s000lbl.pdf. Revised March 2014. Accessed May 18, 2020.
Practice Points
- Avoiding phlebotomine sand fly vector bites is the most effective way to prevent leishmaniasis.
- Prompt diagnosis and treatment of cutaneous leishmaniasis caused by Leishmania species that have potential for mucocutaneous spread are key to limiting morbidity and mortality.
- Partnering with the Centers for Disease Control and Prevention is critical for timely diagnosis.
- Miltefosine should be considered as a first-line agent for cutaneous leishmaniasis given its efficacy, tolerability, and ease of administration.
Risk for Deep Fungal Infections During IL-17 and IL-23 Inhibitor Therapy for Psoriasis
Psoriasis is a common chronic, multisystem, inflammatory disease with predominantly skin and joint manifestations that affects approximately 2% of the world’s population.1 It occurs in a variety of clinical forms, from a few well-demarcated, erythematous plaques with a silvery scale to involvement of almost the entire body surface area. Beyond the debilitating physical ailments of the disease, psoriasis also may have psychosocial effects on quality of life.2 The pathogenesis of psoriasis is not fully understood but represents a complex multifactorial disease with both immune-mediated and genetic components. Characterized by hyperplasia of epidermal keratinocytes, psoriasis is shown to be mediated by infiltration of T-cell lymphocytes with an increase of various inflammatory cytokines, including
With the growing understanding of the pathophysiology of psoriasis, focused biologics have been developed to target specific cytokines implicated in the disease process and have been increasingly utilized. Tumor necrosis factor α inhibitors, including adalimumab, infliximab, and etanercept, along with the IL-12/IL-23 inhibitor ustekinumab, have been revolutionary in psoriasis treatment by providing safe and effective long-term therapy; however, there is concern of life-threatening infections with biologics because of the immunosuppressive effects and mechanisms of action.6 Specifically, there have been reported cases of deep fungal infections associated with TNF-α inhibitor use.7
Recently, the advent of IL-17 and IL-23 inhibitors has garnered notable interest in these biologics as promising treatments for psoriasis. With IL-17 and IL-23 supported to have a major role in the pathogenesis of psoriasis, targeting the cytokine is not only logical but also has proven to be effacacious.8-10 Secukinumab, ixekizumab, and brodalumab are IL-17 inhibitors that have been approved by the US Food and Drug Administration (FDA) for the treatment of psoriasis. Secukinumab and ixekizumab are anti–IL-17A monoclonal antibodies, whereas brodalumab is an anti–IL-17 receptor antibody. Risankizumab, guselkumab, and tildrakizumab are IL-23 inhibitors that also have been approved by the FDA for the treatment of psoriasis. As with older biologics, there is concern over the safety of these inhibitors because of the central role of IL-17 and IL-23 in both innate and adaptive immune responses, particularly against fungi.11 Therefore, use of biologics targeting IL-17 and IL-23 may increase susceptibility to deep fungal infections.
Safety data and discussion of the risk for deep fungal infections from IL-17, IL-12/IL-23, and IL-23 inhibitor use for psoriasis treatment currently are lacking. Given the knowledge gap, we sought to synthesize and review the current evidence on risks for deep fungal infections during biologic therapy in patients with psoriasis, with a focus on IL-17 inhibitor therapies.
METHODS
A PubMed search of articles indexed for MEDLINE from database inception to 2019 (1946-2019) was performed to find randomized controlled trials (RCTs), including extended trials and clinical trials, for IL-17, IL-12/IL-23, and IL-23 inhibitors approved by the FDA for psoriasis treatment. The following keywords were used: psoriasis or inflammatory disease and secukinumab, ixekizumab, brodalumab, ustekinumab, risankizumab, guselkumab, or tildrakizumab. Studies were restricted to the English-language literature, and those that did not provide adequate safety data on the specific types of infections that occurred were excluded.
RESULTSIL-17 Inhibitors
Our search yielded RCTs, some including extension trials, and clinical trials of IL-17 inhibitors used for psoriatic disease and other nonpsoriatic conditions (Table).
Risk for Deep Fungal Infection With Secukinumab
The queried studies included 20 RCTs or clinical trials along with extension trials of 3746 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 52 weeks. In a 3-year extension study of SCULPTURE, Bissonnette et al12 reported no new safety concerns for the 340 patients with moderate to severe psoriasis treated with secukinumab. Common adverse events (AEs) included nasopharyngitis, upper respiratory tract infections, and headache, but there were no reports of deep fungal infections.12 In a subsequent 5-year analysis of 168 patients that focused on the 300-mg fixed interval treatment with secukinumab, the safety profile remained favorable, with 0 reports of invasive fungal infections.13 A study (FEATURE) of 118 patients with psoriasis treated with a prefilled syringe of 300 or 150 mg of secukinumab also described an acceptable safety profile and reported no deep fungal infections.14 JUNCTURE, another study utilizing autoinjectors, also found that treatment with 300 or 150 mg of secukinumab was well tolerated in 121 patients, with no deep fungal infections.15 Common AEs for both studies included nasopharyngitis and headache.14,15 A 24-week phase 3 study for scalp psoriasis treated with secukinumab also reported 0 deep fungal infections in 51 patients.16 In an RCT comparing secukinumab and ustekinumab for moderate to severe plaque psoriasis, Blauvelt et al17 demonstrated that the incidence of serious AEs was comparable between the 2 groups, with no reports of invasive fungal infections in the 334 patients exposed to secukinumab. The CLEAR study, which compared secukinumab and ustekinumab, also found no reported deep fungal disease in the 335 patients exposed to secukinumab.18 Secukinumab exhibited a similar safety profile to ustekinumab in both studies, with common AEs being headache and nasopharyngitis.17,18 The GESTURE study investigated the efficacy of secukinumab in 137 patients with palmoplantar psoriasis and reported a favorable profile with no reports of deep fungal disease.19 In a subanalysis of the phase 3 study ERASURE, secukinumab was shown to have a robust and sustainable efficacy in 58 Japanese patients with moderate to severe plaque psoriasis, and there were no reports of invasive fungal infections.20 Another subanalysis of 36 Taiwanese patients from the ERASURE study also had similar findings, with no dose relationship observed for AEs.21 In a phase 2 study of 103 patients with psoriasis, Papp et al22 demonstrated AE rates that were similar across different doses of secukinumab—3×150 mg, 3×75 mg, 3×25 mg, and 1×25 mg—and described no incidences of invasive fungal disease. In a phase 2 regimen-finding study of 337 patients conducted by Rich et al,23 the most commonly reported AEs included nasopharyngitis, worsening psoriasis, and upper respiratory tract infections, but there were no reported deep fungal infections.
Our search also resulted in studies specific to the treatment of psoriatic arthritis (PsA) with secukinumab. McInnes et al9 conducted a phase 2 proof-of-concept trial for patients with PsA and reported no deep fungal infections in 28 patients exposed to 10 mg/kg of secukinumab. A 2-year follow-up with the cohort from FUTURE 1, a phase 3 clinical trial, also showed no new or unexpected safety signals in 404 patients exposed to 150 or 75 mg of secukinumab, including no reports of invasive fungal disease.24 FUTURE 2, a phase 3 clinical trial, demonstrated that the most common AE was upper respiratory tract infection in the 299 patients treatedwith secukinumab, but there were no recorded invasive fungal infections.25 In FUTURE 3, 277 patients were treated with secukinumab, with 14 nonserious candida infections but no observed deep fungal infections.26 A study comparing secukinumab to fumaric acid esters reported that 6 of 105 patients treated with secukinumab also experienced superficial candidiasis, but there were no reports of deep fungal disease.27
Secukinumab also has been used in the treatment of ankylosing spondylitis in a phase 3 RCT (MEASURE 1) in which 4 cases of superficial candidiasis were reported (0.7 cases per 100 patient-years of secukinumab) that were all resolved with standard antifungal therapy.28 In MEASURE 2, a 5-year phase 3 RCT, 145 patients were treated with secukinumab for ankylosing spondylitis, with common AEs including nasopharyngitis, diarrhea, and upper respiratory tract infection, but there were no reports of any invasive fungal infections.29 MEASURE 3 also demonstrated similar results in which no invasive fungal infections were observed.30
Risk for Deep Fungal Infection With Ixekizumab
The queried studies included 7 RCTs or clinical trials of 3523 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 52 weeks. In UNCOVER-A, a phase 3 RCT of the pharmacokinetics and safety of ixekizumab, 204 patients were randomized to a prefilled syringe or autoinjector; 48% of patients experienced AEs, but no invasive fungal infections were observed.31 In an analysis of 3 phase 3 trials of ixekizumab including a total 2334 patients treated with ixekizumab from UNCOVER-1, UNCOVER-2, and UNCOVER-3, oral candidiasis frequently was reported, but no candidal infections met criteria for serious invasive infection.32 In UNCOVER-J, a 52-week phase 3 open-label trial of Japanese patients, 91 patients were treated for plaque psoriasis, erythrodermic psoriasis, or generalized pustular psoriasis using ixekizumab; the most common AEs included allergic reactions and injection-site reactions. One case of oral candidiasis was reported, but there were no reported cases of invasive fungal infections.33 A comparison of ixekizumab vs ustekinumab from the IXORA-S trial demonstrated no substantial differences in AEs between the two, and no cases of deep fungal infections were reported. The most common AE between the 2 groups was nasopharyngitis.34 An open-label extension over 4 years of a phase 2 RCT treated 211 patients with either 120 or 80 mg of ixekizumab; 87% of patients had experienced at least 1 AE, and all AEs were considered mild or moderate in severity, with no invasive fungal disease.35
Our search also resulted in 1 study specific to the treatment of PsA with ixekizumab. A phase 3, 52-week study of patients treated with ixekizumab for PsA observed 2 incidences of oral candidiasis and nail candida infections, but no invasive fungal infections were reported.36
We also found 1 study of ixekizumab used in the treatment of ankylosing spondylitis. COAST-V was a phase 3 RCT of patients treated for ankylosing spondylitis in which 164 patients were treated with ixekizumab; no serious AEs were recorded, including 0 deep fungal infections. The most common AEs observed were nasopharyngitis and upper respiratory tract infections.37
Risk for Deep Fungal Infection With Brodalumab
The queried studies included 9 RCTs and 3 clinical trials along with extension trials of 1599 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 120 weeks. In a phase 2 RCT of Japanese patients with moderate to severe plaque psoriasis, 113 patients were treated with 70, 140, or 210 mg of brodalumab, and the most common AEs were nasopharyngitis, diarrhea, and upper respiratory tract inflammation. There were no reported cases of fungal infections in the study.38 In an open-label extension study of Japanese patients that evaluated the long-term clinical safety of brodalumab, 145 patients were enrolled and observed similar AEs to the RCT, with 7 patients experiencing oral candidiasis and 1 patient having skin candidiasis, but there were no observed deep fungal infections.39 In AMG 827, which evaluated the efficacy and safety of brodalumab, 320 patients were treated, and only 2 serious AEs were reported, neither of which were deep fungal disease.10 A phase 3 RCT conducted by Papp et al40 (AMAGINE-1) also treated 441 patients with moderate to severe plaque psoriasis with brodalumab and observed candida infections in 9 patients that were mild to moderate and responsive to treatment, with no patients discontinuing the study. In a 120-week open-label extension study of 181 patients, Papp et al41 reported 8% of patients experienced serious AEs, with 1 case of latent tuberculosis that led to withdrawal of treatment. A study also investigated the efficacy and safety of brodalumab in 30 patients with generalized pustular psoriasis or psoriatic erythroderma and observed 2 cases of mild candida infections that resolved with treatment. There were no reports of invasive fungal disease.42
Our search also resulted in studies of brodalumab used in the treatment of PsA and nonpsoriatic diseases. In one phase 2 RCT, 113 patients with PsA were treated with 140 mg, 280 mg, or combined doses of brodalumab, with the most common AEs being nasopharyngitis, upper respiratory tract infection, and diarrhea, but there were no reports of deep fungal infection.43 In a phase 1b trial of patients with methotrexate-resistant rheumatoid arthritis treated with brodalumab, common AEs reported included headache, cough, and abdominal pain, with only 1 case of oral candidiasis that was determined not to be drug related.44 Finally, an RCT of patients with moderate to severe asthma treated 226 patients with brodalumab and reported a greater incidence of oral candidiasis in treatment groups compared with placebo (3.5% vs 0%) but saw no instances of invasive fungal infection.45
IL-12/IL-23 Inhibitor
Risk for Deep Fungal Infection With Ustekinumab
The queried studies included 4 RCTs of 954 patients with psoriasis treated with ustekinumab (eTable).46-49 Within these trials, there were no reported cases of serious infections involving deep fungal organisms during the stated follow-up period. The literature search also found long-term safety data from the ACCEPT and PHOENIX trials that included 5437 patients with psoriasis treated with ustekinumab.66,67 There also were no demonstrated incidences of invasive fungal disease in these studies, with most cases of infection being common bacterial or viral infections.
IL-23 Inhibitors
Risk for Deep Fungal Infection With Risankizumab, Guselkumab, and Tildrakizumab
The queried studies included 16 RCTs or clinical trials for psoriatic patients treated with IL-23 inhibitors, including 5 with risankizumab,50-54 9 with guselkumab,55-63 and 2 with tildrakizumab.64,65 Within these trials there were no observed cases of serious infections with deep fungal disease.
COMMENT
Our literature review has demonstrated that there does not appear to be an increased incidence of deep fungal infections for patients treated with IL-17, IL-12/IL-23, or IL-23 inhibitors for psoriatic disease. All of the reviewed studies found no cases of invasive fungal infections for patients with psoriasis treated with secukinumab, ixekizumab, brodalumab, ustekinumab, risankizumab, guselkumab, or tildrakizumab. Patients with other inflammatory conditions, such as ankylosing spondylitis, rheumatoid arthritis, and asthma, also did not appear to show an increased incidence of deep fungal disease.
Although these results show promising safety data for the use of these biologic therapies in treating inflammatory conditions, caution still is warranted, as these medications still are relatively new, with FDA approvals within the last 5 years. Safety data among different study populations also cannot be derived without further investigation, and much of the available literature is limited in long-term data. More extended trials or registry data from a large, broadly representative cohort are necessary to establish the long-term safety and risk for deep fungal infections with IL-17 and especially the newer IL-23 inhibitors.
A small percentage of patients from the reviewed literature did develop superficial candidiasis. This outcome can be expected, as the central role of IL-17 and IL-23 has been recognized in immunologic protection against infections, specifically against fungi.11 Because all of the fungal infections reported for patients on IL-17 inhibitors were superficial candidiasis, guides for practical management and treatment should be implemented to standardize future research and care. A proposed screening algorithm for patients on these biologic therapies involves safety monitoring, including inspection of the oral cavity, folds, and genitals, along with inquiring about symptoms such as burning, dysgeusia, and dysuria.68 If infection is suspected, confirmation by culture, molecular method, or optimally with esophagoscopy can be performed, and appropriate treatment may be initiated.68 Patients with candida infections of the oral cavity, folds, or genitals can be placed on topical therapy such as nystatin, amphotericin B, ciclopirox, or other azoles, while those with infections of the esophagus can be started on oral fluconazole.68
Although there were no reported cases of deep fungal infections, the theoretical risk for developing one while on IL-17 and IL-23 inhibitors may warrant further screening prior to beginning therapy. The TNF inhibitors approved for the treatment of psoriasis currently contain a black box warning for risk for disseminated and extrapulmonary histoplasmosis, coccidioidomycosis, blastomycosis, and other invasive fungal infections, which may highlight the importance of thorough evaluation and awareness of endemic areas for patients on biologics. Prior to initiating treatment with TNF inhibitors, current suggestions involve performing a thorough examination along with keeping a high index of suspicion for invasive fungal infections in patients who live in or have traveled to endemic regions.69
Screening for invasive fungal infections for patients on TNF inhibitors involves questioning about potential exposures, such as demolition of old buildings, bird roosts, or spelunking.70 Serologies or antigen testing can be used routinely, but as these tests are insensitive, empiric antifungal therapy should be initiated if there is high enough clinical suspicion.71 Currently, there are no clinical guidelines regarding fungal screening and initiation of IL-17 and IL-23 inhibitors for treatment of psoriasis and other inflammatory conditions, but careful stewardship over using these effective medications should still be practiced.
Upon review of the available safety data on the use of IL-17 and IL-23 inhibitors for the treatment of psoriasis and other inflammatory conditions, there does not appear to be an increased incidence of deep fungal infections. Physicians, however, should still be cautiously optimistic in prescribing these medications, as there is a theoretical risk for infection for all patients on biologics. A high index of suspicion for patients presenting with symptoms of fungal infections should be maintained, and appropriate diagnosis and management should be initiated if they do occur.
- Parisi R, Symmons DP, Griffiths CE, et al. Global epidemiology of psoriasis: a systematic review of incidence and prevalence. J Invest Dermatol. 2013;133:377-385.
- Koo J, Marangell LB, Nakamura M, et al. Depression and suicidality in psoriasis: review of the literature including the cytokine theory of depression. J Eur Acad Dermatol Venereol. 2017;31:1999-2009.
- Krueger JG, Bowcock A. Psoriasis pathophysiology: current concepts of pathogenesis. Ann Rheum Dis. 2005;64 (suppl 2):ii30-36.
- Lee E, Trepicchio WL, Oestreicher JL, et al. Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J Exp Med. 2004;199:125-130.
- Lowes MA, Kikuchi T, Fuentes-Duculan J, et al. Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells. J Invest Dermatol. 2008;128:1207-1211.
- Shear NH. Fulfilling an unmet need in psoriasis: do biologicals hold the key to improved tolerability? Drug Saf. 2006;29:49-66.
- Lee JH, Slifman NR, Gershon SK, et al. Life-threatening histoplasmosis complicating immunotherapy with tumor necrosis factor alpha antagonists infliximab and etanercept. Arthritis Rheum. 2002;46:2565-2570.
- Leonardi C, Matheson R, Zachariae C, et al. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med. 2012;366:1190-1199.
- McInnes IB, Sieper J, Braun J, et al. Efficacy and safety of secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe psoriatic arthritis: a 24-week, randomised, double-blind, placebo-controlled, phase II proof-of-concept trial. Ann Rheum Dis. 2014;73:349-356.
- Papp KA, Leonardi C, Menter A, et al. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N Engl J Med. 2012;366:1181-1189.
- Isailovic N, Daigo K, Mantovani A, et al. Interleukin-17 and innate immunity in infections and chronic inflammation. J Autoimmun. 2015;60:1-11.
- Bissonnette R, Luger T, Thaci D, et al. Secukinumab sustains good efficacy and favourable safety in moderate-to-severe psoriasis after up to 3 years of treatment: results from a double-blind extension study. Br J Dermatol. 2017;177:1033-1042.
- Bissonnette R, Luger T, Thaci D, et al. Secukinumab demonstrates high sustained efficacy and a favourable safety profile in patients with moderate-to-severe psoriasis through 5 years of treatment (SCULPTURE Extension Study). J Eur Acad Dermatol Venereol. 2018;32:1507-1514.
- Blauvelt A, Prinz JC, Gottlieb AB, et al. Secukinumab administration by pre-filled syringe: efficacy, safety and usability results from a randomized controlled trial in psoriasis (FEATURE). Br J Dermatol. 2015;172:484-493.
- Paul C, Lacour JP, Tedremets L, et al. Efficacy, safety and usability of secukinumab administration by autoinjector/pen in psoriasis: a randomized, controlled trial (JUNCTURE). J Eur Acad Dermatol Venereol. 2015;29:1082-1090.
- Bagel J, Duffin KC, Moore A, et al. The effect of secukinumab on moderate-to-severe scalp psoriasis: Results of a 24-week, randomized, double-blind, placebo-controlled phase 3b study. J Am Acad Dermatol. 2017;77:667-674.
- Blauvelt A, Reich K, Tsai TF, et al. Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate-to-severe plaque psoriasis up to 1 year: results from the CLEAR study. J Am Acad Dermatol. 2017;76:60.e9-69.e9.
- Thaci D, Blauvelt A, Reich K, et al. Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate to severe plaque psoriasis: CLEAR, a randomized controlled trial. J Am Acad Dermatol. 2015;73:400-409.
- Gottlieb A, Sullivan J, van Doorn M, et al. Secukinumab shows significant efficacy in palmoplantar psoriasis: results from GESTURE, a randomized controlled trial. J Am Acad Dermatol. 2017;76:70-80.
- Ohtsuki M, Morita A, Abe M, et al. Secukinumab efficacy and safety in Japanese patients with moderate-to-severe plaque psoriasis: subanalysis from ERASURE, a randomized, placebo-controlled, phase 3 study. J Dermatol. 2014;41:1039-1046.
- Wu NL, Hsu CJ, Sun FJ, et al. Efficacy and safety of secukinumab in Taiwanese patients with moderate to severe plaque psoriasis: subanalysis from ERASURE phase III study. J Dermatol. 2017;44:1129-1137.
- Papp KA, Langley RG, Sigurgeirsson B, et al. Efficacy and safety of secukinumab in the treatment of moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled phase II dose-ranging study. Br J Dermatol. 2013;168:412-421.
- Rich P, Sigurgeirsson B, Thaci D, et al. Secukinumab induction and maintenance therapy in moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled, phase II regimen-finding study. Br J Dermatol. 2013;168:402-411.
- Kavanaugh A, Mease PJ, Reimold AM, et al. Secukinumab for long-term treatment of psoriatic arthritis: a two-year followup from a phase III, randomized, double-blind placebo-controlled study. Arthritis Care Res (Hoboken). 2017;69:347-355.
- McInnes IB, Mease PJ, Kirkham B, et al. Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015;386:1137-1146.
- Nash P, Mease PJ, McInnes IB, et al. Efficacy and safety of secukinumab administration by autoinjector in patients with psoriatic arthritis: results from a randomized, placebo-controlled trial (FUTURE 3). Arthritis Res Ther. 2018;20:47.
- Sticherling M, Mrowietz U, Augustin M, et al. Secukinumab is superior to fumaric acid esters in treating patients with moderate-to-severe plaque psoriasis who are naive to systemic treatments: results from the randomized controlled PRIME trial. Br J Dermatol. 2017;177:1024-1032.
- Braun J, Baraliakos X, Deodhar A, et al. Effect of secukinumab on clinical and radiographic outcomes in ankylosing spondylitis: 2-year results from the randomised phase III MEASURE 1 study. Ann Rheum Dis. 2017;76:1070-1077.
- Marzo-Ortega H, Sieper J, Kivitz A, et al. Secukinumab provides sustained improvements in the signs and symptoms of active ankylosing spondylitis with high retention rate: 3-year results from the phase III trial, MEASURE 2. RMD Open. 2017;3:e000592.
- Pavelka K, Kivitz A, Dokoupilova E, et al. Efficacy, safety, and tolerability of secukinumab in patients with active ankylosing spondylitis: a randomized, double-blind phase 3 study, MEASURE 3. Arthritis Res Ther. 2017;19:285.
- Callis Duffin K, Bagel J, Bukhalo M, et al. Phase 3, open-label, randomized study of the pharmacokinetics, efficacy and safety of ixekizumab following subcutaneous administration using a prefilled syringe or an autoinjector in patients with moderate-to-severe plaque psoriasis (UNCOVER-A). J Eur Acad Dermatol Venereol. 2017;31:107-113.
- Gordon KB, Colombel JF, Hardin DS. Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis. N Engl J Med. 2016;375:2102.
- Saeki H, Nakagawa H, Nakajo K, et al. Efficacy and safety of ixekizumab treatment for Japanese patients with moderate to severe plaque psoriasis, erythrodermic psoriasis and generalized pustular psoriasis: results from a 52-week, open-label, phase 3 study (UNCOVER-J). J Dermatol. 2017;44:355-362.
- Reich K, Pinter A, Lacour JP, et al. Comparison of ixekizumab with ustekinumab in moderate-to-severe psoriasis: 24-week results from IXORA-S, a phase III study. Br J Dermatol. 2017;177:1014-1023.
- Zachariae C, Gordon K, Kimball AB, et al. Efficacy and safety of ixekizumab over 4 years of open-label treatment in a phase 2 study in chronic plaque psoriasis. J Am Acad Dermatol. 2018;79:294.e6-301.e6.
- van der Heijde D, Gladman DD, Kishimoto M, et al. Efficacy and safety of ixekizumab in patients with active psoriatic arthritis: 52-week results from a phase III study (SPIRIT-P1). J Rheumatol. 2018;45:367-377.
- van der Heijde D, Cheng-Chung Wei J, Dougados M, et al. Ixekizumab, an interleukin-17A antagonist in the treatment of ankylosing spondylitis or radiographic axial spondyloarthritis in patients previously untreated with biological disease-modifying anti-rheumatic drugs (COAST-V): 16 week results of a phase 3 randomised, double-blind, active-controlled and placebo-controlled trial. Lancet. 2018;392:2441-2451.
- Nakagawa H, Niiro H, Ootaki K, et al. Brodalumab, a human anti-interleukin-17-receptor antibody in the treatment of Japanese patients with moderate-to-severe plaque psoriasis: efficacy and safety results from a phase II randomized controlled study. J Dermatol Sci. 2016;81:44-52.
- Umezawa Y, Nakagawa H, Niiro H, et al. Long-term clinical safety and efficacy of brodalumab in the treatment of Japanese patients with moderate-to-severe plaque psoriasis. J Eur Acad Dermatol Venereol. 2016;30:1957-1960.
- Papp KA, Reich K, Paul C, et al. A prospective phase III, randomized, double-blind, placebo-controlled study of brodalumab in patients with moderate-to-severe plaque psoriasis. Br J Dermatol. 2016;175:273-286.
- Papp K, Leonardi C, Menter A, et al. Safety and efficacy of brodalumab for psoriasis after 120 weeks of treatment. J Am Acad Dermatol. 2014;71:1183.e3-1190.e3.
- Yamasaki K, Nakagawa H, Kubo Y, et al. Efficacy and safety of brodalumab in patients with generalized pustular psoriasis and psoriatic erythroderma: results from a 52-week, open-label study. Br J Dermatol. 2017;176:741-751.
- Mease PJ, Genovese MC, Greenwald MW, et al. Brodalumab, an anti-IL17RA monoclonal antibody, in psoriatic arthritis. N Engl J Med. 2014;370:2295-2306.
- Martin DA, Churchill M, Flores-Suarez L, et al. A phase Ib multiple ascending dose study evaluating safety, pharmacokinetics, and early clinical response of brodalumab, a human anti-IL-17R antibody, in methotrexate-resistant rheumatoid arthritis. Arthritis Res Ther. 2013;15:R164.
- Busse WW, Holgate S, Kerwin E, et al. Randomized, double-blind, placebo-controlled study of brodalumab, a human anti-IL-17 receptor monoclonal antibody, in moderate to severe asthma. Am J Respir Crit Care Med. 2013;188:1294-1302.
- Igarashi A, Kato T, Kato M, et al. Efficacy and safety of ustekinumab in Japanese patients with moderate-to-severe plaque-type psoriasis: long-term results from a phase 2/3 clinical trial. J Dermatol. 2012;39:242-252.
- Krueger GG, Langley RG, Leonardi C, et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med. 2007;356:580-592.
- Leonardi CL, Kimball AB, Papp KA, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet. 2008;371:1665-1674.
- Tsai TF, Ho JC, Song M, et al. Efficacy and safety of ustekinumab for the treatment of moderate-to-severe psoriasis: a phase III, randomized, placebo-controlled trial in Taiwanese and Korean patients (PEARL). J Dermatol Sci. 2011;63:154-163.
- Gordon KB, Strober B, Lebwohl M, et al. Efficacy and safety of risankizumab in moderate-to-severe plaque psoriasis (UltIMMa-1 and UltIMMa-2): results from two double-blind, randomised, placebo-controlled and ustekinumab-controlled phase 3 trials. Lancet. 2018;392:650-661.
- Krueger JG, Ferris LK, Menter A, et al. Anti-IL-23A mAb BI 655066 for treatment of moderate-to-severe psoriasis: safety, efficacy, pharmacokinetics, and biomarker results of a single-rising-dose, randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol. 2015;136:116.e7-124.e7.
- Ohtsuki M, Fujita H, Watanabe M, et al. Efficacy and safety of risankizumab in Japanese patients with moderate to severe plaque psoriasis: results from the SustaIMM phase 2/3 trial. J Dermatol. 2019;46:686-694.
- Papp KA, Blauvelt A, Bukhalo M, et al. Risankizumab versus ustekinumab for moderate-to-severe plaque psoriasis. N Engl J Med. 2017;376:1551-1560.
- Reich K, Gooderham M, Thaci D, et al. Risankizumab compared with adalimumab in patients with moderate-to-severe plaque psoriasis (IMMvent): a randomised, double-blind, active-comparator-controlled phase 3 trial. Lancet. 2019;394:576-586.
- Blauvelt A, Papp KA, Griffiths CE, et al. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: results from the phase III, double-blinded, placebo- and active comparator-controlled VOYAGE 1 trial. J Am Acad Dermatol. 2017;76:405-417.
- Deodhar A, Gottlieb AB, Boehncke WH, et al. Efficacy and safety of guselkumab in patients with active psoriatic arthritis: a randomised, double-blind, placebo-controlled, phase 2 study. Lancet. 2018;391:2213-2224.
- Gordon KB, Duffin KC, Bissonnette R, et al. A phase 2 trial of guselkumab versus adalimumab for plaque psoriasis. N Engl J Med. 2015;373:136-144.
- Langley RG, Tsai TF, Flavin S, et al. Efficacy and safety of guselkumab in patients with psoriasis who have an inadequate response to ustekinumab: results of the randomized, double-blind, phase III NAVIGATE trial. Br J Dermatol. 2018;178:114-123.
- Nemoto O, Hirose K, Shibata S, et al. Safety and efficacy of guselkumab in Japanese patients with moderate-to-severe plaque psoriasis: a randomized, placebo-controlled, ascending-dose study. Br J Dermatol. 2018;178:689-696.
- Ohtsuki M, Kubo H, Morishima H, et al. Guselkumab, an anti-interleukin-23 monoclonal antibody, for the treatment of moderate to severe plaque-type psoriasis in Japanese patients: Efficacy and safety results from a phase 3, randomized, double-blind, placebo-controlled study. J Dermatol. 2018;45:1053-1062.
- Reich K, Armstrong AW, Foley P, et al. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: results from the phase III, double-blind, placebo- and active comparator-controlled VOYAGE 2 trial. J Am Acad Dermatol. 2017;76:418-431.
- Reich K, Armstrong AW, Langley RG, et al. Guselkumab versus secukinumab for the treatment of moderate-to-severe psoriasis (ECLIPSE): results from a phase 3, randomised controlled trial. Lancet. 2019;394:831-839.
- Terui T, Kobayashi S, Okubo Y, et al. Efficacy and safety of guselkumab, an anti-interleukin 23 monoclonal antibody, for palmoplantar pustulosis: a randomized clinical trial. JAMA Dermatol. 2018;154:309-316.
- Papp K, Thaci D, Reich K, et al. Tildrakizumab (MK-3222), an anti-interleukin-23p19 monoclonal antibody, improves psoriasis in a phase IIb randomized placebo-controlled trial. Br J Dermatol. 2015;173:930-939.
- Reich K, Papp KA, Blauvelt A, et al. Tildrakizumab versus placebo or etanercept for chronic plaque psoriasis (reSURFACE 1 and reSURFACE 2): results from two randomised controlled, phase 3 trials. Lancet. 2017;390:276-288.
- Gordon KB, Papp KA, Langley RG, et al. Long-term safety experience of ustekinumab in patients with moderate to severe psoriasis (part II of II): results from analyses of infections and malignancy from pooled phase II and III clinical trials. J Am Acad Dermatol. 2012;66:742-751.
- Papp KA, Griffiths CE, Gordon K, et al. Long-term safety of ustekinumab in patients with moderate-to-severe psoriasis: final results from 5 years of follow-up. Br J Dermatol. 2013;168:844-854.
- Saunte DM, Mrowietz U, Puig L, et al. Candida infections in patients with psoriasis and psoriatic arthritis treated with interleukin-17 inhibitors and their practical management. Br J Dermatol. 2017;177:47-62.
- Lis K, Kuzawinska O, Balkowiec-Iskra E. Tumor necrosis factor inhibitors—state of knowledge. Arch Med Sci. 2014;10:1175-1185.
- Hage CA, Bowyer S, Tarvin SE, et al. Recognition, diagnosis, and treatment of histoplasmosis complicating tumor necrosis factor blocker therapy. Clin Infect Dis. 2010;50:85-92
- Hage CA, Ribes JA, Wengenack NL, et al. A multicenter evaluation of tests for diagnosis of histoplasmosis. Clin Infect Dis. 2011;53:448-454.
Psoriasis is a common chronic, multisystem, inflammatory disease with predominantly skin and joint manifestations that affects approximately 2% of the world’s population.1 It occurs in a variety of clinical forms, from a few well-demarcated, erythematous plaques with a silvery scale to involvement of almost the entire body surface area. Beyond the debilitating physical ailments of the disease, psoriasis also may have psychosocial effects on quality of life.2 The pathogenesis of psoriasis is not fully understood but represents a complex multifactorial disease with both immune-mediated and genetic components. Characterized by hyperplasia of epidermal keratinocytes, psoriasis is shown to be mediated by infiltration of T-cell lymphocytes with an increase of various inflammatory cytokines, including
With the growing understanding of the pathophysiology of psoriasis, focused biologics have been developed to target specific cytokines implicated in the disease process and have been increasingly utilized. Tumor necrosis factor α inhibitors, including adalimumab, infliximab, and etanercept, along with the IL-12/IL-23 inhibitor ustekinumab, have been revolutionary in psoriasis treatment by providing safe and effective long-term therapy; however, there is concern of life-threatening infections with biologics because of the immunosuppressive effects and mechanisms of action.6 Specifically, there have been reported cases of deep fungal infections associated with TNF-α inhibitor use.7
Recently, the advent of IL-17 and IL-23 inhibitors has garnered notable interest in these biologics as promising treatments for psoriasis. With IL-17 and IL-23 supported to have a major role in the pathogenesis of psoriasis, targeting the cytokine is not only logical but also has proven to be effacacious.8-10 Secukinumab, ixekizumab, and brodalumab are IL-17 inhibitors that have been approved by the US Food and Drug Administration (FDA) for the treatment of psoriasis. Secukinumab and ixekizumab are anti–IL-17A monoclonal antibodies, whereas brodalumab is an anti–IL-17 receptor antibody. Risankizumab, guselkumab, and tildrakizumab are IL-23 inhibitors that also have been approved by the FDA for the treatment of psoriasis. As with older biologics, there is concern over the safety of these inhibitors because of the central role of IL-17 and IL-23 in both innate and adaptive immune responses, particularly against fungi.11 Therefore, use of biologics targeting IL-17 and IL-23 may increase susceptibility to deep fungal infections.
Safety data and discussion of the risk for deep fungal infections from IL-17, IL-12/IL-23, and IL-23 inhibitor use for psoriasis treatment currently are lacking. Given the knowledge gap, we sought to synthesize and review the current evidence on risks for deep fungal infections during biologic therapy in patients with psoriasis, with a focus on IL-17 inhibitor therapies.
METHODS
A PubMed search of articles indexed for MEDLINE from database inception to 2019 (1946-2019) was performed to find randomized controlled trials (RCTs), including extended trials and clinical trials, for IL-17, IL-12/IL-23, and IL-23 inhibitors approved by the FDA for psoriasis treatment. The following keywords were used: psoriasis or inflammatory disease and secukinumab, ixekizumab, brodalumab, ustekinumab, risankizumab, guselkumab, or tildrakizumab. Studies were restricted to the English-language literature, and those that did not provide adequate safety data on the specific types of infections that occurred were excluded.
RESULTSIL-17 Inhibitors
Our search yielded RCTs, some including extension trials, and clinical trials of IL-17 inhibitors used for psoriatic disease and other nonpsoriatic conditions (Table).
Risk for Deep Fungal Infection With Secukinumab
The queried studies included 20 RCTs or clinical trials along with extension trials of 3746 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 52 weeks. In a 3-year extension study of SCULPTURE, Bissonnette et al12 reported no new safety concerns for the 340 patients with moderate to severe psoriasis treated with secukinumab. Common adverse events (AEs) included nasopharyngitis, upper respiratory tract infections, and headache, but there were no reports of deep fungal infections.12 In a subsequent 5-year analysis of 168 patients that focused on the 300-mg fixed interval treatment with secukinumab, the safety profile remained favorable, with 0 reports of invasive fungal infections.13 A study (FEATURE) of 118 patients with psoriasis treated with a prefilled syringe of 300 or 150 mg of secukinumab also described an acceptable safety profile and reported no deep fungal infections.14 JUNCTURE, another study utilizing autoinjectors, also found that treatment with 300 or 150 mg of secukinumab was well tolerated in 121 patients, with no deep fungal infections.15 Common AEs for both studies included nasopharyngitis and headache.14,15 A 24-week phase 3 study for scalp psoriasis treated with secukinumab also reported 0 deep fungal infections in 51 patients.16 In an RCT comparing secukinumab and ustekinumab for moderate to severe plaque psoriasis, Blauvelt et al17 demonstrated that the incidence of serious AEs was comparable between the 2 groups, with no reports of invasive fungal infections in the 334 patients exposed to secukinumab. The CLEAR study, which compared secukinumab and ustekinumab, also found no reported deep fungal disease in the 335 patients exposed to secukinumab.18 Secukinumab exhibited a similar safety profile to ustekinumab in both studies, with common AEs being headache and nasopharyngitis.17,18 The GESTURE study investigated the efficacy of secukinumab in 137 patients with palmoplantar psoriasis and reported a favorable profile with no reports of deep fungal disease.19 In a subanalysis of the phase 3 study ERASURE, secukinumab was shown to have a robust and sustainable efficacy in 58 Japanese patients with moderate to severe plaque psoriasis, and there were no reports of invasive fungal infections.20 Another subanalysis of 36 Taiwanese patients from the ERASURE study also had similar findings, with no dose relationship observed for AEs.21 In a phase 2 study of 103 patients with psoriasis, Papp et al22 demonstrated AE rates that were similar across different doses of secukinumab—3×150 mg, 3×75 mg, 3×25 mg, and 1×25 mg—and described no incidences of invasive fungal disease. In a phase 2 regimen-finding study of 337 patients conducted by Rich et al,23 the most commonly reported AEs included nasopharyngitis, worsening psoriasis, and upper respiratory tract infections, but there were no reported deep fungal infections.
Our search also resulted in studies specific to the treatment of psoriatic arthritis (PsA) with secukinumab. McInnes et al9 conducted a phase 2 proof-of-concept trial for patients with PsA and reported no deep fungal infections in 28 patients exposed to 10 mg/kg of secukinumab. A 2-year follow-up with the cohort from FUTURE 1, a phase 3 clinical trial, also showed no new or unexpected safety signals in 404 patients exposed to 150 or 75 mg of secukinumab, including no reports of invasive fungal disease.24 FUTURE 2, a phase 3 clinical trial, demonstrated that the most common AE was upper respiratory tract infection in the 299 patients treatedwith secukinumab, but there were no recorded invasive fungal infections.25 In FUTURE 3, 277 patients were treated with secukinumab, with 14 nonserious candida infections but no observed deep fungal infections.26 A study comparing secukinumab to fumaric acid esters reported that 6 of 105 patients treated with secukinumab also experienced superficial candidiasis, but there were no reports of deep fungal disease.27
Secukinumab also has been used in the treatment of ankylosing spondylitis in a phase 3 RCT (MEASURE 1) in which 4 cases of superficial candidiasis were reported (0.7 cases per 100 patient-years of secukinumab) that were all resolved with standard antifungal therapy.28 In MEASURE 2, a 5-year phase 3 RCT, 145 patients were treated with secukinumab for ankylosing spondylitis, with common AEs including nasopharyngitis, diarrhea, and upper respiratory tract infection, but there were no reports of any invasive fungal infections.29 MEASURE 3 also demonstrated similar results in which no invasive fungal infections were observed.30
Risk for Deep Fungal Infection With Ixekizumab
The queried studies included 7 RCTs or clinical trials of 3523 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 52 weeks. In UNCOVER-A, a phase 3 RCT of the pharmacokinetics and safety of ixekizumab, 204 patients were randomized to a prefilled syringe or autoinjector; 48% of patients experienced AEs, but no invasive fungal infections were observed.31 In an analysis of 3 phase 3 trials of ixekizumab including a total 2334 patients treated with ixekizumab from UNCOVER-1, UNCOVER-2, and UNCOVER-3, oral candidiasis frequently was reported, but no candidal infections met criteria for serious invasive infection.32 In UNCOVER-J, a 52-week phase 3 open-label trial of Japanese patients, 91 patients were treated for plaque psoriasis, erythrodermic psoriasis, or generalized pustular psoriasis using ixekizumab; the most common AEs included allergic reactions and injection-site reactions. One case of oral candidiasis was reported, but there were no reported cases of invasive fungal infections.33 A comparison of ixekizumab vs ustekinumab from the IXORA-S trial demonstrated no substantial differences in AEs between the two, and no cases of deep fungal infections were reported. The most common AE between the 2 groups was nasopharyngitis.34 An open-label extension over 4 years of a phase 2 RCT treated 211 patients with either 120 or 80 mg of ixekizumab; 87% of patients had experienced at least 1 AE, and all AEs were considered mild or moderate in severity, with no invasive fungal disease.35
Our search also resulted in 1 study specific to the treatment of PsA with ixekizumab. A phase 3, 52-week study of patients treated with ixekizumab for PsA observed 2 incidences of oral candidiasis and nail candida infections, but no invasive fungal infections were reported.36
We also found 1 study of ixekizumab used in the treatment of ankylosing spondylitis. COAST-V was a phase 3 RCT of patients treated for ankylosing spondylitis in which 164 patients were treated with ixekizumab; no serious AEs were recorded, including 0 deep fungal infections. The most common AEs observed were nasopharyngitis and upper respiratory tract infections.37
Risk for Deep Fungal Infection With Brodalumab
The queried studies included 9 RCTs and 3 clinical trials along with extension trials of 1599 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 120 weeks. In a phase 2 RCT of Japanese patients with moderate to severe plaque psoriasis, 113 patients were treated with 70, 140, or 210 mg of brodalumab, and the most common AEs were nasopharyngitis, diarrhea, and upper respiratory tract inflammation. There were no reported cases of fungal infections in the study.38 In an open-label extension study of Japanese patients that evaluated the long-term clinical safety of brodalumab, 145 patients were enrolled and observed similar AEs to the RCT, with 7 patients experiencing oral candidiasis and 1 patient having skin candidiasis, but there were no observed deep fungal infections.39 In AMG 827, which evaluated the efficacy and safety of brodalumab, 320 patients were treated, and only 2 serious AEs were reported, neither of which were deep fungal disease.10 A phase 3 RCT conducted by Papp et al40 (AMAGINE-1) also treated 441 patients with moderate to severe plaque psoriasis with brodalumab and observed candida infections in 9 patients that were mild to moderate and responsive to treatment, with no patients discontinuing the study. In a 120-week open-label extension study of 181 patients, Papp et al41 reported 8% of patients experienced serious AEs, with 1 case of latent tuberculosis that led to withdrawal of treatment. A study also investigated the efficacy and safety of brodalumab in 30 patients with generalized pustular psoriasis or psoriatic erythroderma and observed 2 cases of mild candida infections that resolved with treatment. There were no reports of invasive fungal disease.42
Our search also resulted in studies of brodalumab used in the treatment of PsA and nonpsoriatic diseases. In one phase 2 RCT, 113 patients with PsA were treated with 140 mg, 280 mg, or combined doses of brodalumab, with the most common AEs being nasopharyngitis, upper respiratory tract infection, and diarrhea, but there were no reports of deep fungal infection.43 In a phase 1b trial of patients with methotrexate-resistant rheumatoid arthritis treated with brodalumab, common AEs reported included headache, cough, and abdominal pain, with only 1 case of oral candidiasis that was determined not to be drug related.44 Finally, an RCT of patients with moderate to severe asthma treated 226 patients with brodalumab and reported a greater incidence of oral candidiasis in treatment groups compared with placebo (3.5% vs 0%) but saw no instances of invasive fungal infection.45
IL-12/IL-23 Inhibitor
Risk for Deep Fungal Infection With Ustekinumab
The queried studies included 4 RCTs of 954 patients with psoriasis treated with ustekinumab (eTable).46-49 Within these trials, there were no reported cases of serious infections involving deep fungal organisms during the stated follow-up period. The literature search also found long-term safety data from the ACCEPT and PHOENIX trials that included 5437 patients with psoriasis treated with ustekinumab.66,67 There also were no demonstrated incidences of invasive fungal disease in these studies, with most cases of infection being common bacterial or viral infections.
IL-23 Inhibitors
Risk for Deep Fungal Infection With Risankizumab, Guselkumab, and Tildrakizumab
The queried studies included 16 RCTs or clinical trials for psoriatic patients treated with IL-23 inhibitors, including 5 with risankizumab,50-54 9 with guselkumab,55-63 and 2 with tildrakizumab.64,65 Within these trials there were no observed cases of serious infections with deep fungal disease.
COMMENT
Our literature review has demonstrated that there does not appear to be an increased incidence of deep fungal infections for patients treated with IL-17, IL-12/IL-23, or IL-23 inhibitors for psoriatic disease. All of the reviewed studies found no cases of invasive fungal infections for patients with psoriasis treated with secukinumab, ixekizumab, brodalumab, ustekinumab, risankizumab, guselkumab, or tildrakizumab. Patients with other inflammatory conditions, such as ankylosing spondylitis, rheumatoid arthritis, and asthma, also did not appear to show an increased incidence of deep fungal disease.
Although these results show promising safety data for the use of these biologic therapies in treating inflammatory conditions, caution still is warranted, as these medications still are relatively new, with FDA approvals within the last 5 years. Safety data among different study populations also cannot be derived without further investigation, and much of the available literature is limited in long-term data. More extended trials or registry data from a large, broadly representative cohort are necessary to establish the long-term safety and risk for deep fungal infections with IL-17 and especially the newer IL-23 inhibitors.
A small percentage of patients from the reviewed literature did develop superficial candidiasis. This outcome can be expected, as the central role of IL-17 and IL-23 has been recognized in immunologic protection against infections, specifically against fungi.11 Because all of the fungal infections reported for patients on IL-17 inhibitors were superficial candidiasis, guides for practical management and treatment should be implemented to standardize future research and care. A proposed screening algorithm for patients on these biologic therapies involves safety monitoring, including inspection of the oral cavity, folds, and genitals, along with inquiring about symptoms such as burning, dysgeusia, and dysuria.68 If infection is suspected, confirmation by culture, molecular method, or optimally with esophagoscopy can be performed, and appropriate treatment may be initiated.68 Patients with candida infections of the oral cavity, folds, or genitals can be placed on topical therapy such as nystatin, amphotericin B, ciclopirox, or other azoles, while those with infections of the esophagus can be started on oral fluconazole.68
Although there were no reported cases of deep fungal infections, the theoretical risk for developing one while on IL-17 and IL-23 inhibitors may warrant further screening prior to beginning therapy. The TNF inhibitors approved for the treatment of psoriasis currently contain a black box warning for risk for disseminated and extrapulmonary histoplasmosis, coccidioidomycosis, blastomycosis, and other invasive fungal infections, which may highlight the importance of thorough evaluation and awareness of endemic areas for patients on biologics. Prior to initiating treatment with TNF inhibitors, current suggestions involve performing a thorough examination along with keeping a high index of suspicion for invasive fungal infections in patients who live in or have traveled to endemic regions.69
Screening for invasive fungal infections for patients on TNF inhibitors involves questioning about potential exposures, such as demolition of old buildings, bird roosts, or spelunking.70 Serologies or antigen testing can be used routinely, but as these tests are insensitive, empiric antifungal therapy should be initiated if there is high enough clinical suspicion.71 Currently, there are no clinical guidelines regarding fungal screening and initiation of IL-17 and IL-23 inhibitors for treatment of psoriasis and other inflammatory conditions, but careful stewardship over using these effective medications should still be practiced.
Upon review of the available safety data on the use of IL-17 and IL-23 inhibitors for the treatment of psoriasis and other inflammatory conditions, there does not appear to be an increased incidence of deep fungal infections. Physicians, however, should still be cautiously optimistic in prescribing these medications, as there is a theoretical risk for infection for all patients on biologics. A high index of suspicion for patients presenting with symptoms of fungal infections should be maintained, and appropriate diagnosis and management should be initiated if they do occur.
Psoriasis is a common chronic, multisystem, inflammatory disease with predominantly skin and joint manifestations that affects approximately 2% of the world’s population.1 It occurs in a variety of clinical forms, from a few well-demarcated, erythematous plaques with a silvery scale to involvement of almost the entire body surface area. Beyond the debilitating physical ailments of the disease, psoriasis also may have psychosocial effects on quality of life.2 The pathogenesis of psoriasis is not fully understood but represents a complex multifactorial disease with both immune-mediated and genetic components. Characterized by hyperplasia of epidermal keratinocytes, psoriasis is shown to be mediated by infiltration of T-cell lymphocytes with an increase of various inflammatory cytokines, including
With the growing understanding of the pathophysiology of psoriasis, focused biologics have been developed to target specific cytokines implicated in the disease process and have been increasingly utilized. Tumor necrosis factor α inhibitors, including adalimumab, infliximab, and etanercept, along with the IL-12/IL-23 inhibitor ustekinumab, have been revolutionary in psoriasis treatment by providing safe and effective long-term therapy; however, there is concern of life-threatening infections with biologics because of the immunosuppressive effects and mechanisms of action.6 Specifically, there have been reported cases of deep fungal infections associated with TNF-α inhibitor use.7
Recently, the advent of IL-17 and IL-23 inhibitors has garnered notable interest in these biologics as promising treatments for psoriasis. With IL-17 and IL-23 supported to have a major role in the pathogenesis of psoriasis, targeting the cytokine is not only logical but also has proven to be effacacious.8-10 Secukinumab, ixekizumab, and brodalumab are IL-17 inhibitors that have been approved by the US Food and Drug Administration (FDA) for the treatment of psoriasis. Secukinumab and ixekizumab are anti–IL-17A monoclonal antibodies, whereas brodalumab is an anti–IL-17 receptor antibody. Risankizumab, guselkumab, and tildrakizumab are IL-23 inhibitors that also have been approved by the FDA for the treatment of psoriasis. As with older biologics, there is concern over the safety of these inhibitors because of the central role of IL-17 and IL-23 in both innate and adaptive immune responses, particularly against fungi.11 Therefore, use of biologics targeting IL-17 and IL-23 may increase susceptibility to deep fungal infections.
Safety data and discussion of the risk for deep fungal infections from IL-17, IL-12/IL-23, and IL-23 inhibitor use for psoriasis treatment currently are lacking. Given the knowledge gap, we sought to synthesize and review the current evidence on risks for deep fungal infections during biologic therapy in patients with psoriasis, with a focus on IL-17 inhibitor therapies.
METHODS
A PubMed search of articles indexed for MEDLINE from database inception to 2019 (1946-2019) was performed to find randomized controlled trials (RCTs), including extended trials and clinical trials, for IL-17, IL-12/IL-23, and IL-23 inhibitors approved by the FDA for psoriasis treatment. The following keywords were used: psoriasis or inflammatory disease and secukinumab, ixekizumab, brodalumab, ustekinumab, risankizumab, guselkumab, or tildrakizumab. Studies were restricted to the English-language literature, and those that did not provide adequate safety data on the specific types of infections that occurred were excluded.
RESULTSIL-17 Inhibitors
Our search yielded RCTs, some including extension trials, and clinical trials of IL-17 inhibitors used for psoriatic disease and other nonpsoriatic conditions (Table).
Risk for Deep Fungal Infection With Secukinumab
The queried studies included 20 RCTs or clinical trials along with extension trials of 3746 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 52 weeks. In a 3-year extension study of SCULPTURE, Bissonnette et al12 reported no new safety concerns for the 340 patients with moderate to severe psoriasis treated with secukinumab. Common adverse events (AEs) included nasopharyngitis, upper respiratory tract infections, and headache, but there were no reports of deep fungal infections.12 In a subsequent 5-year analysis of 168 patients that focused on the 300-mg fixed interval treatment with secukinumab, the safety profile remained favorable, with 0 reports of invasive fungal infections.13 A study (FEATURE) of 118 patients with psoriasis treated with a prefilled syringe of 300 or 150 mg of secukinumab also described an acceptable safety profile and reported no deep fungal infections.14 JUNCTURE, another study utilizing autoinjectors, also found that treatment with 300 or 150 mg of secukinumab was well tolerated in 121 patients, with no deep fungal infections.15 Common AEs for both studies included nasopharyngitis and headache.14,15 A 24-week phase 3 study for scalp psoriasis treated with secukinumab also reported 0 deep fungal infections in 51 patients.16 In an RCT comparing secukinumab and ustekinumab for moderate to severe plaque psoriasis, Blauvelt et al17 demonstrated that the incidence of serious AEs was comparable between the 2 groups, with no reports of invasive fungal infections in the 334 patients exposed to secukinumab. The CLEAR study, which compared secukinumab and ustekinumab, also found no reported deep fungal disease in the 335 patients exposed to secukinumab.18 Secukinumab exhibited a similar safety profile to ustekinumab in both studies, with common AEs being headache and nasopharyngitis.17,18 The GESTURE study investigated the efficacy of secukinumab in 137 patients with palmoplantar psoriasis and reported a favorable profile with no reports of deep fungal disease.19 In a subanalysis of the phase 3 study ERASURE, secukinumab was shown to have a robust and sustainable efficacy in 58 Japanese patients with moderate to severe plaque psoriasis, and there were no reports of invasive fungal infections.20 Another subanalysis of 36 Taiwanese patients from the ERASURE study also had similar findings, with no dose relationship observed for AEs.21 In a phase 2 study of 103 patients with psoriasis, Papp et al22 demonstrated AE rates that were similar across different doses of secukinumab—3×150 mg, 3×75 mg, 3×25 mg, and 1×25 mg—and described no incidences of invasive fungal disease. In a phase 2 regimen-finding study of 337 patients conducted by Rich et al,23 the most commonly reported AEs included nasopharyngitis, worsening psoriasis, and upper respiratory tract infections, but there were no reported deep fungal infections.
Our search also resulted in studies specific to the treatment of psoriatic arthritis (PsA) with secukinumab. McInnes et al9 conducted a phase 2 proof-of-concept trial for patients with PsA and reported no deep fungal infections in 28 patients exposed to 10 mg/kg of secukinumab. A 2-year follow-up with the cohort from FUTURE 1, a phase 3 clinical trial, also showed no new or unexpected safety signals in 404 patients exposed to 150 or 75 mg of secukinumab, including no reports of invasive fungal disease.24 FUTURE 2, a phase 3 clinical trial, demonstrated that the most common AE was upper respiratory tract infection in the 299 patients treatedwith secukinumab, but there were no recorded invasive fungal infections.25 In FUTURE 3, 277 patients were treated with secukinumab, with 14 nonserious candida infections but no observed deep fungal infections.26 A study comparing secukinumab to fumaric acid esters reported that 6 of 105 patients treated with secukinumab also experienced superficial candidiasis, but there were no reports of deep fungal disease.27
Secukinumab also has been used in the treatment of ankylosing spondylitis in a phase 3 RCT (MEASURE 1) in which 4 cases of superficial candidiasis were reported (0.7 cases per 100 patient-years of secukinumab) that were all resolved with standard antifungal therapy.28 In MEASURE 2, a 5-year phase 3 RCT, 145 patients were treated with secukinumab for ankylosing spondylitis, with common AEs including nasopharyngitis, diarrhea, and upper respiratory tract infection, but there were no reports of any invasive fungal infections.29 MEASURE 3 also demonstrated similar results in which no invasive fungal infections were observed.30
Risk for Deep Fungal Infection With Ixekizumab
The queried studies included 7 RCTs or clinical trials of 3523 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 52 weeks. In UNCOVER-A, a phase 3 RCT of the pharmacokinetics and safety of ixekizumab, 204 patients were randomized to a prefilled syringe or autoinjector; 48% of patients experienced AEs, but no invasive fungal infections were observed.31 In an analysis of 3 phase 3 trials of ixekizumab including a total 2334 patients treated with ixekizumab from UNCOVER-1, UNCOVER-2, and UNCOVER-3, oral candidiasis frequently was reported, but no candidal infections met criteria for serious invasive infection.32 In UNCOVER-J, a 52-week phase 3 open-label trial of Japanese patients, 91 patients were treated for plaque psoriasis, erythrodermic psoriasis, or generalized pustular psoriasis using ixekizumab; the most common AEs included allergic reactions and injection-site reactions. One case of oral candidiasis was reported, but there were no reported cases of invasive fungal infections.33 A comparison of ixekizumab vs ustekinumab from the IXORA-S trial demonstrated no substantial differences in AEs between the two, and no cases of deep fungal infections were reported. The most common AE between the 2 groups was nasopharyngitis.34 An open-label extension over 4 years of a phase 2 RCT treated 211 patients with either 120 or 80 mg of ixekizumab; 87% of patients had experienced at least 1 AE, and all AEs were considered mild or moderate in severity, with no invasive fungal disease.35
Our search also resulted in 1 study specific to the treatment of PsA with ixekizumab. A phase 3, 52-week study of patients treated with ixekizumab for PsA observed 2 incidences of oral candidiasis and nail candida infections, but no invasive fungal infections were reported.36
We also found 1 study of ixekizumab used in the treatment of ankylosing spondylitis. COAST-V was a phase 3 RCT of patients treated for ankylosing spondylitis in which 164 patients were treated with ixekizumab; no serious AEs were recorded, including 0 deep fungal infections. The most common AEs observed were nasopharyngitis and upper respiratory tract infections.37
Risk for Deep Fungal Infection With Brodalumab
The queried studies included 9 RCTs and 3 clinical trials along with extension trials of 1599 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 120 weeks. In a phase 2 RCT of Japanese patients with moderate to severe plaque psoriasis, 113 patients were treated with 70, 140, or 210 mg of brodalumab, and the most common AEs were nasopharyngitis, diarrhea, and upper respiratory tract inflammation. There were no reported cases of fungal infections in the study.38 In an open-label extension study of Japanese patients that evaluated the long-term clinical safety of brodalumab, 145 patients were enrolled and observed similar AEs to the RCT, with 7 patients experiencing oral candidiasis and 1 patient having skin candidiasis, but there were no observed deep fungal infections.39 In AMG 827, which evaluated the efficacy and safety of brodalumab, 320 patients were treated, and only 2 serious AEs were reported, neither of which were deep fungal disease.10 A phase 3 RCT conducted by Papp et al40 (AMAGINE-1) also treated 441 patients with moderate to severe plaque psoriasis with brodalumab and observed candida infections in 9 patients that were mild to moderate and responsive to treatment, with no patients discontinuing the study. In a 120-week open-label extension study of 181 patients, Papp et al41 reported 8% of patients experienced serious AEs, with 1 case of latent tuberculosis that led to withdrawal of treatment. A study also investigated the efficacy and safety of brodalumab in 30 patients with generalized pustular psoriasis or psoriatic erythroderma and observed 2 cases of mild candida infections that resolved with treatment. There were no reports of invasive fungal disease.42
Our search also resulted in studies of brodalumab used in the treatment of PsA and nonpsoriatic diseases. In one phase 2 RCT, 113 patients with PsA were treated with 140 mg, 280 mg, or combined doses of brodalumab, with the most common AEs being nasopharyngitis, upper respiratory tract infection, and diarrhea, but there were no reports of deep fungal infection.43 In a phase 1b trial of patients with methotrexate-resistant rheumatoid arthritis treated with brodalumab, common AEs reported included headache, cough, and abdominal pain, with only 1 case of oral candidiasis that was determined not to be drug related.44 Finally, an RCT of patients with moderate to severe asthma treated 226 patients with brodalumab and reported a greater incidence of oral candidiasis in treatment groups compared with placebo (3.5% vs 0%) but saw no instances of invasive fungal infection.45
IL-12/IL-23 Inhibitor
Risk for Deep Fungal Infection With Ustekinumab
The queried studies included 4 RCTs of 954 patients with psoriasis treated with ustekinumab (eTable).46-49 Within these trials, there were no reported cases of serious infections involving deep fungal organisms during the stated follow-up period. The literature search also found long-term safety data from the ACCEPT and PHOENIX trials that included 5437 patients with psoriasis treated with ustekinumab.66,67 There also were no demonstrated incidences of invasive fungal disease in these studies, with most cases of infection being common bacterial or viral infections.
IL-23 Inhibitors
Risk for Deep Fungal Infection With Risankizumab, Guselkumab, and Tildrakizumab
The queried studies included 16 RCTs or clinical trials for psoriatic patients treated with IL-23 inhibitors, including 5 with risankizumab,50-54 9 with guselkumab,55-63 and 2 with tildrakizumab.64,65 Within these trials there were no observed cases of serious infections with deep fungal disease.
COMMENT
Our literature review has demonstrated that there does not appear to be an increased incidence of deep fungal infections for patients treated with IL-17, IL-12/IL-23, or IL-23 inhibitors for psoriatic disease. All of the reviewed studies found no cases of invasive fungal infections for patients with psoriasis treated with secukinumab, ixekizumab, brodalumab, ustekinumab, risankizumab, guselkumab, or tildrakizumab. Patients with other inflammatory conditions, such as ankylosing spondylitis, rheumatoid arthritis, and asthma, also did not appear to show an increased incidence of deep fungal disease.
Although these results show promising safety data for the use of these biologic therapies in treating inflammatory conditions, caution still is warranted, as these medications still are relatively new, with FDA approvals within the last 5 years. Safety data among different study populations also cannot be derived without further investigation, and much of the available literature is limited in long-term data. More extended trials or registry data from a large, broadly representative cohort are necessary to establish the long-term safety and risk for deep fungal infections with IL-17 and especially the newer IL-23 inhibitors.
A small percentage of patients from the reviewed literature did develop superficial candidiasis. This outcome can be expected, as the central role of IL-17 and IL-23 has been recognized in immunologic protection against infections, specifically against fungi.11 Because all of the fungal infections reported for patients on IL-17 inhibitors were superficial candidiasis, guides for practical management and treatment should be implemented to standardize future research and care. A proposed screening algorithm for patients on these biologic therapies involves safety monitoring, including inspection of the oral cavity, folds, and genitals, along with inquiring about symptoms such as burning, dysgeusia, and dysuria.68 If infection is suspected, confirmation by culture, molecular method, or optimally with esophagoscopy can be performed, and appropriate treatment may be initiated.68 Patients with candida infections of the oral cavity, folds, or genitals can be placed on topical therapy such as nystatin, amphotericin B, ciclopirox, or other azoles, while those with infections of the esophagus can be started on oral fluconazole.68
Although there were no reported cases of deep fungal infections, the theoretical risk for developing one while on IL-17 and IL-23 inhibitors may warrant further screening prior to beginning therapy. The TNF inhibitors approved for the treatment of psoriasis currently contain a black box warning for risk for disseminated and extrapulmonary histoplasmosis, coccidioidomycosis, blastomycosis, and other invasive fungal infections, which may highlight the importance of thorough evaluation and awareness of endemic areas for patients on biologics. Prior to initiating treatment with TNF inhibitors, current suggestions involve performing a thorough examination along with keeping a high index of suspicion for invasive fungal infections in patients who live in or have traveled to endemic regions.69
Screening for invasive fungal infections for patients on TNF inhibitors involves questioning about potential exposures, such as demolition of old buildings, bird roosts, or spelunking.70 Serologies or antigen testing can be used routinely, but as these tests are insensitive, empiric antifungal therapy should be initiated if there is high enough clinical suspicion.71 Currently, there are no clinical guidelines regarding fungal screening and initiation of IL-17 and IL-23 inhibitors for treatment of psoriasis and other inflammatory conditions, but careful stewardship over using these effective medications should still be practiced.
Upon review of the available safety data on the use of IL-17 and IL-23 inhibitors for the treatment of psoriasis and other inflammatory conditions, there does not appear to be an increased incidence of deep fungal infections. Physicians, however, should still be cautiously optimistic in prescribing these medications, as there is a theoretical risk for infection for all patients on biologics. A high index of suspicion for patients presenting with symptoms of fungal infections should be maintained, and appropriate diagnosis and management should be initiated if they do occur.
- Parisi R, Symmons DP, Griffiths CE, et al. Global epidemiology of psoriasis: a systematic review of incidence and prevalence. J Invest Dermatol. 2013;133:377-385.
- Koo J, Marangell LB, Nakamura M, et al. Depression and suicidality in psoriasis: review of the literature including the cytokine theory of depression. J Eur Acad Dermatol Venereol. 2017;31:1999-2009.
- Krueger JG, Bowcock A. Psoriasis pathophysiology: current concepts of pathogenesis. Ann Rheum Dis. 2005;64 (suppl 2):ii30-36.
- Lee E, Trepicchio WL, Oestreicher JL, et al. Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J Exp Med. 2004;199:125-130.
- Lowes MA, Kikuchi T, Fuentes-Duculan J, et al. Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells. J Invest Dermatol. 2008;128:1207-1211.
- Shear NH. Fulfilling an unmet need in psoriasis: do biologicals hold the key to improved tolerability? Drug Saf. 2006;29:49-66.
- Lee JH, Slifman NR, Gershon SK, et al. Life-threatening histoplasmosis complicating immunotherapy with tumor necrosis factor alpha antagonists infliximab and etanercept. Arthritis Rheum. 2002;46:2565-2570.
- Leonardi C, Matheson R, Zachariae C, et al. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med. 2012;366:1190-1199.
- McInnes IB, Sieper J, Braun J, et al. Efficacy and safety of secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe psoriatic arthritis: a 24-week, randomised, double-blind, placebo-controlled, phase II proof-of-concept trial. Ann Rheum Dis. 2014;73:349-356.
- Papp KA, Leonardi C, Menter A, et al. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N Engl J Med. 2012;366:1181-1189.
- Isailovic N, Daigo K, Mantovani A, et al. Interleukin-17 and innate immunity in infections and chronic inflammation. J Autoimmun. 2015;60:1-11.
- Bissonnette R, Luger T, Thaci D, et al. Secukinumab sustains good efficacy and favourable safety in moderate-to-severe psoriasis after up to 3 years of treatment: results from a double-blind extension study. Br J Dermatol. 2017;177:1033-1042.
- Bissonnette R, Luger T, Thaci D, et al. Secukinumab demonstrates high sustained efficacy and a favourable safety profile in patients with moderate-to-severe psoriasis through 5 years of treatment (SCULPTURE Extension Study). J Eur Acad Dermatol Venereol. 2018;32:1507-1514.
- Blauvelt A, Prinz JC, Gottlieb AB, et al. Secukinumab administration by pre-filled syringe: efficacy, safety and usability results from a randomized controlled trial in psoriasis (FEATURE). Br J Dermatol. 2015;172:484-493.
- Paul C, Lacour JP, Tedremets L, et al. Efficacy, safety and usability of secukinumab administration by autoinjector/pen in psoriasis: a randomized, controlled trial (JUNCTURE). J Eur Acad Dermatol Venereol. 2015;29:1082-1090.
- Bagel J, Duffin KC, Moore A, et al. The effect of secukinumab on moderate-to-severe scalp psoriasis: Results of a 24-week, randomized, double-blind, placebo-controlled phase 3b study. J Am Acad Dermatol. 2017;77:667-674.
- Blauvelt A, Reich K, Tsai TF, et al. Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate-to-severe plaque psoriasis up to 1 year: results from the CLEAR study. J Am Acad Dermatol. 2017;76:60.e9-69.e9.
- Thaci D, Blauvelt A, Reich K, et al. Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate to severe plaque psoriasis: CLEAR, a randomized controlled trial. J Am Acad Dermatol. 2015;73:400-409.
- Gottlieb A, Sullivan J, van Doorn M, et al. Secukinumab shows significant efficacy in palmoplantar psoriasis: results from GESTURE, a randomized controlled trial. J Am Acad Dermatol. 2017;76:70-80.
- Ohtsuki M, Morita A, Abe M, et al. Secukinumab efficacy and safety in Japanese patients with moderate-to-severe plaque psoriasis: subanalysis from ERASURE, a randomized, placebo-controlled, phase 3 study. J Dermatol. 2014;41:1039-1046.
- Wu NL, Hsu CJ, Sun FJ, et al. Efficacy and safety of secukinumab in Taiwanese patients with moderate to severe plaque psoriasis: subanalysis from ERASURE phase III study. J Dermatol. 2017;44:1129-1137.
- Papp KA, Langley RG, Sigurgeirsson B, et al. Efficacy and safety of secukinumab in the treatment of moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled phase II dose-ranging study. Br J Dermatol. 2013;168:412-421.
- Rich P, Sigurgeirsson B, Thaci D, et al. Secukinumab induction and maintenance therapy in moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled, phase II regimen-finding study. Br J Dermatol. 2013;168:402-411.
- Kavanaugh A, Mease PJ, Reimold AM, et al. Secukinumab for long-term treatment of psoriatic arthritis: a two-year followup from a phase III, randomized, double-blind placebo-controlled study. Arthritis Care Res (Hoboken). 2017;69:347-355.
- McInnes IB, Mease PJ, Kirkham B, et al. Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015;386:1137-1146.
- Nash P, Mease PJ, McInnes IB, et al. Efficacy and safety of secukinumab administration by autoinjector in patients with psoriatic arthritis: results from a randomized, placebo-controlled trial (FUTURE 3). Arthritis Res Ther. 2018;20:47.
- Sticherling M, Mrowietz U, Augustin M, et al. Secukinumab is superior to fumaric acid esters in treating patients with moderate-to-severe plaque psoriasis who are naive to systemic treatments: results from the randomized controlled PRIME trial. Br J Dermatol. 2017;177:1024-1032.
- Braun J, Baraliakos X, Deodhar A, et al. Effect of secukinumab on clinical and radiographic outcomes in ankylosing spondylitis: 2-year results from the randomised phase III MEASURE 1 study. Ann Rheum Dis. 2017;76:1070-1077.
- Marzo-Ortega H, Sieper J, Kivitz A, et al. Secukinumab provides sustained improvements in the signs and symptoms of active ankylosing spondylitis with high retention rate: 3-year results from the phase III trial, MEASURE 2. RMD Open. 2017;3:e000592.
- Pavelka K, Kivitz A, Dokoupilova E, et al. Efficacy, safety, and tolerability of secukinumab in patients with active ankylosing spondylitis: a randomized, double-blind phase 3 study, MEASURE 3. Arthritis Res Ther. 2017;19:285.
- Callis Duffin K, Bagel J, Bukhalo M, et al. Phase 3, open-label, randomized study of the pharmacokinetics, efficacy and safety of ixekizumab following subcutaneous administration using a prefilled syringe or an autoinjector in patients with moderate-to-severe plaque psoriasis (UNCOVER-A). J Eur Acad Dermatol Venereol. 2017;31:107-113.
- Gordon KB, Colombel JF, Hardin DS. Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis. N Engl J Med. 2016;375:2102.
- Saeki H, Nakagawa H, Nakajo K, et al. Efficacy and safety of ixekizumab treatment for Japanese patients with moderate to severe plaque psoriasis, erythrodermic psoriasis and generalized pustular psoriasis: results from a 52-week, open-label, phase 3 study (UNCOVER-J). J Dermatol. 2017;44:355-362.
- Reich K, Pinter A, Lacour JP, et al. Comparison of ixekizumab with ustekinumab in moderate-to-severe psoriasis: 24-week results from IXORA-S, a phase III study. Br J Dermatol. 2017;177:1014-1023.
- Zachariae C, Gordon K, Kimball AB, et al. Efficacy and safety of ixekizumab over 4 years of open-label treatment in a phase 2 study in chronic plaque psoriasis. J Am Acad Dermatol. 2018;79:294.e6-301.e6.
- van der Heijde D, Gladman DD, Kishimoto M, et al. Efficacy and safety of ixekizumab in patients with active psoriatic arthritis: 52-week results from a phase III study (SPIRIT-P1). J Rheumatol. 2018;45:367-377.
- van der Heijde D, Cheng-Chung Wei J, Dougados M, et al. Ixekizumab, an interleukin-17A antagonist in the treatment of ankylosing spondylitis or radiographic axial spondyloarthritis in patients previously untreated with biological disease-modifying anti-rheumatic drugs (COAST-V): 16 week results of a phase 3 randomised, double-blind, active-controlled and placebo-controlled trial. Lancet. 2018;392:2441-2451.
- Nakagawa H, Niiro H, Ootaki K, et al. Brodalumab, a human anti-interleukin-17-receptor antibody in the treatment of Japanese patients with moderate-to-severe plaque psoriasis: efficacy and safety results from a phase II randomized controlled study. J Dermatol Sci. 2016;81:44-52.
- Umezawa Y, Nakagawa H, Niiro H, et al. Long-term clinical safety and efficacy of brodalumab in the treatment of Japanese patients with moderate-to-severe plaque psoriasis. J Eur Acad Dermatol Venereol. 2016;30:1957-1960.
- Papp KA, Reich K, Paul C, et al. A prospective phase III, randomized, double-blind, placebo-controlled study of brodalumab in patients with moderate-to-severe plaque psoriasis. Br J Dermatol. 2016;175:273-286.
- Papp K, Leonardi C, Menter A, et al. Safety and efficacy of brodalumab for psoriasis after 120 weeks of treatment. J Am Acad Dermatol. 2014;71:1183.e3-1190.e3.
- Yamasaki K, Nakagawa H, Kubo Y, et al. Efficacy and safety of brodalumab in patients with generalized pustular psoriasis and psoriatic erythroderma: results from a 52-week, open-label study. Br J Dermatol. 2017;176:741-751.
- Mease PJ, Genovese MC, Greenwald MW, et al. Brodalumab, an anti-IL17RA monoclonal antibody, in psoriatic arthritis. N Engl J Med. 2014;370:2295-2306.
- Martin DA, Churchill M, Flores-Suarez L, et al. A phase Ib multiple ascending dose study evaluating safety, pharmacokinetics, and early clinical response of brodalumab, a human anti-IL-17R antibody, in methotrexate-resistant rheumatoid arthritis. Arthritis Res Ther. 2013;15:R164.
- Busse WW, Holgate S, Kerwin E, et al. Randomized, double-blind, placebo-controlled study of brodalumab, a human anti-IL-17 receptor monoclonal antibody, in moderate to severe asthma. Am J Respir Crit Care Med. 2013;188:1294-1302.
- Igarashi A, Kato T, Kato M, et al. Efficacy and safety of ustekinumab in Japanese patients with moderate-to-severe plaque-type psoriasis: long-term results from a phase 2/3 clinical trial. J Dermatol. 2012;39:242-252.
- Krueger GG, Langley RG, Leonardi C, et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med. 2007;356:580-592.
- Leonardi CL, Kimball AB, Papp KA, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet. 2008;371:1665-1674.
- Tsai TF, Ho JC, Song M, et al. Efficacy and safety of ustekinumab for the treatment of moderate-to-severe psoriasis: a phase III, randomized, placebo-controlled trial in Taiwanese and Korean patients (PEARL). J Dermatol Sci. 2011;63:154-163.
- Gordon KB, Strober B, Lebwohl M, et al. Efficacy and safety of risankizumab in moderate-to-severe plaque psoriasis (UltIMMa-1 and UltIMMa-2): results from two double-blind, randomised, placebo-controlled and ustekinumab-controlled phase 3 trials. Lancet. 2018;392:650-661.
- Krueger JG, Ferris LK, Menter A, et al. Anti-IL-23A mAb BI 655066 for treatment of moderate-to-severe psoriasis: safety, efficacy, pharmacokinetics, and biomarker results of a single-rising-dose, randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol. 2015;136:116.e7-124.e7.
- Ohtsuki M, Fujita H, Watanabe M, et al. Efficacy and safety of risankizumab in Japanese patients with moderate to severe plaque psoriasis: results from the SustaIMM phase 2/3 trial. J Dermatol. 2019;46:686-694.
- Papp KA, Blauvelt A, Bukhalo M, et al. Risankizumab versus ustekinumab for moderate-to-severe plaque psoriasis. N Engl J Med. 2017;376:1551-1560.
- Reich K, Gooderham M, Thaci D, et al. Risankizumab compared with adalimumab in patients with moderate-to-severe plaque psoriasis (IMMvent): a randomised, double-blind, active-comparator-controlled phase 3 trial. Lancet. 2019;394:576-586.
- Blauvelt A, Papp KA, Griffiths CE, et al. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: results from the phase III, double-blinded, placebo- and active comparator-controlled VOYAGE 1 trial. J Am Acad Dermatol. 2017;76:405-417.
- Deodhar A, Gottlieb AB, Boehncke WH, et al. Efficacy and safety of guselkumab in patients with active psoriatic arthritis: a randomised, double-blind, placebo-controlled, phase 2 study. Lancet. 2018;391:2213-2224.
- Gordon KB, Duffin KC, Bissonnette R, et al. A phase 2 trial of guselkumab versus adalimumab for plaque psoriasis. N Engl J Med. 2015;373:136-144.
- Langley RG, Tsai TF, Flavin S, et al. Efficacy and safety of guselkumab in patients with psoriasis who have an inadequate response to ustekinumab: results of the randomized, double-blind, phase III NAVIGATE trial. Br J Dermatol. 2018;178:114-123.
- Nemoto O, Hirose K, Shibata S, et al. Safety and efficacy of guselkumab in Japanese patients with moderate-to-severe plaque psoriasis: a randomized, placebo-controlled, ascending-dose study. Br J Dermatol. 2018;178:689-696.
- Ohtsuki M, Kubo H, Morishima H, et al. Guselkumab, an anti-interleukin-23 monoclonal antibody, for the treatment of moderate to severe plaque-type psoriasis in Japanese patients: Efficacy and safety results from a phase 3, randomized, double-blind, placebo-controlled study. J Dermatol. 2018;45:1053-1062.
- Reich K, Armstrong AW, Foley P, et al. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: results from the phase III, double-blind, placebo- and active comparator-controlled VOYAGE 2 trial. J Am Acad Dermatol. 2017;76:418-431.
- Reich K, Armstrong AW, Langley RG, et al. Guselkumab versus secukinumab for the treatment of moderate-to-severe psoriasis (ECLIPSE): results from a phase 3, randomised controlled trial. Lancet. 2019;394:831-839.
- Terui T, Kobayashi S, Okubo Y, et al. Efficacy and safety of guselkumab, an anti-interleukin 23 monoclonal antibody, for palmoplantar pustulosis: a randomized clinical trial. JAMA Dermatol. 2018;154:309-316.
- Papp K, Thaci D, Reich K, et al. Tildrakizumab (MK-3222), an anti-interleukin-23p19 monoclonal antibody, improves psoriasis in a phase IIb randomized placebo-controlled trial. Br J Dermatol. 2015;173:930-939.
- Reich K, Papp KA, Blauvelt A, et al. Tildrakizumab versus placebo or etanercept for chronic plaque psoriasis (reSURFACE 1 and reSURFACE 2): results from two randomised controlled, phase 3 trials. Lancet. 2017;390:276-288.
- Gordon KB, Papp KA, Langley RG, et al. Long-term safety experience of ustekinumab in patients with moderate to severe psoriasis (part II of II): results from analyses of infections and malignancy from pooled phase II and III clinical trials. J Am Acad Dermatol. 2012;66:742-751.
- Papp KA, Griffiths CE, Gordon K, et al. Long-term safety of ustekinumab in patients with moderate-to-severe psoriasis: final results from 5 years of follow-up. Br J Dermatol. 2013;168:844-854.
- Saunte DM, Mrowietz U, Puig L, et al. Candida infections in patients with psoriasis and psoriatic arthritis treated with interleukin-17 inhibitors and their practical management. Br J Dermatol. 2017;177:47-62.
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- Hage CA, Bowyer S, Tarvin SE, et al. Recognition, diagnosis, and treatment of histoplasmosis complicating tumor necrosis factor blocker therapy. Clin Infect Dis. 2010;50:85-92
- Hage CA, Ribes JA, Wengenack NL, et al. A multicenter evaluation of tests for diagnosis of histoplasmosis. Clin Infect Dis. 2011;53:448-454.
- Parisi R, Symmons DP, Griffiths CE, et al. Global epidemiology of psoriasis: a systematic review of incidence and prevalence. J Invest Dermatol. 2013;133:377-385.
- Koo J, Marangell LB, Nakamura M, et al. Depression and suicidality in psoriasis: review of the literature including the cytokine theory of depression. J Eur Acad Dermatol Venereol. 2017;31:1999-2009.
- Krueger JG, Bowcock A. Psoriasis pathophysiology: current concepts of pathogenesis. Ann Rheum Dis. 2005;64 (suppl 2):ii30-36.
- Lee E, Trepicchio WL, Oestreicher JL, et al. Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J Exp Med. 2004;199:125-130.
- Lowes MA, Kikuchi T, Fuentes-Duculan J, et al. Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells. J Invest Dermatol. 2008;128:1207-1211.
- Shear NH. Fulfilling an unmet need in psoriasis: do biologicals hold the key to improved tolerability? Drug Saf. 2006;29:49-66.
- Lee JH, Slifman NR, Gershon SK, et al. Life-threatening histoplasmosis complicating immunotherapy with tumor necrosis factor alpha antagonists infliximab and etanercept. Arthritis Rheum. 2002;46:2565-2570.
- Leonardi C, Matheson R, Zachariae C, et al. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med. 2012;366:1190-1199.
- McInnes IB, Sieper J, Braun J, et al. Efficacy and safety of secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe psoriatic arthritis: a 24-week, randomised, double-blind, placebo-controlled, phase II proof-of-concept trial. Ann Rheum Dis. 2014;73:349-356.
- Papp KA, Leonardi C, Menter A, et al. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N Engl J Med. 2012;366:1181-1189.
- Isailovic N, Daigo K, Mantovani A, et al. Interleukin-17 and innate immunity in infections and chronic inflammation. J Autoimmun. 2015;60:1-11.
- Bissonnette R, Luger T, Thaci D, et al. Secukinumab sustains good efficacy and favourable safety in moderate-to-severe psoriasis after up to 3 years of treatment: results from a double-blind extension study. Br J Dermatol. 2017;177:1033-1042.
- Bissonnette R, Luger T, Thaci D, et al. Secukinumab demonstrates high sustained efficacy and a favourable safety profile in patients with moderate-to-severe psoriasis through 5 years of treatment (SCULPTURE Extension Study). J Eur Acad Dermatol Venereol. 2018;32:1507-1514.
- Blauvelt A, Prinz JC, Gottlieb AB, et al. Secukinumab administration by pre-filled syringe: efficacy, safety and usability results from a randomized controlled trial in psoriasis (FEATURE). Br J Dermatol. 2015;172:484-493.
- Paul C, Lacour JP, Tedremets L, et al. Efficacy, safety and usability of secukinumab administration by autoinjector/pen in psoriasis: a randomized, controlled trial (JUNCTURE). J Eur Acad Dermatol Venereol. 2015;29:1082-1090.
- Bagel J, Duffin KC, Moore A, et al. The effect of secukinumab on moderate-to-severe scalp psoriasis: Results of a 24-week, randomized, double-blind, placebo-controlled phase 3b study. J Am Acad Dermatol. 2017;77:667-674.
- Blauvelt A, Reich K, Tsai TF, et al. Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate-to-severe plaque psoriasis up to 1 year: results from the CLEAR study. J Am Acad Dermatol. 2017;76:60.e9-69.e9.
- Thaci D, Blauvelt A, Reich K, et al. Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate to severe plaque psoriasis: CLEAR, a randomized controlled trial. J Am Acad Dermatol. 2015;73:400-409.
- Gottlieb A, Sullivan J, van Doorn M, et al. Secukinumab shows significant efficacy in palmoplantar psoriasis: results from GESTURE, a randomized controlled trial. J Am Acad Dermatol. 2017;76:70-80.
- Ohtsuki M, Morita A, Abe M, et al. Secukinumab efficacy and safety in Japanese patients with moderate-to-severe plaque psoriasis: subanalysis from ERASURE, a randomized, placebo-controlled, phase 3 study. J Dermatol. 2014;41:1039-1046.
- Wu NL, Hsu CJ, Sun FJ, et al. Efficacy and safety of secukinumab in Taiwanese patients with moderate to severe plaque psoriasis: subanalysis from ERASURE phase III study. J Dermatol. 2017;44:1129-1137.
- Papp KA, Langley RG, Sigurgeirsson B, et al. Efficacy and safety of secukinumab in the treatment of moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled phase II dose-ranging study. Br J Dermatol. 2013;168:412-421.
- Rich P, Sigurgeirsson B, Thaci D, et al. Secukinumab induction and maintenance therapy in moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled, phase II regimen-finding study. Br J Dermatol. 2013;168:402-411.
- Kavanaugh A, Mease PJ, Reimold AM, et al. Secukinumab for long-term treatment of psoriatic arthritis: a two-year followup from a phase III, randomized, double-blind placebo-controlled study. Arthritis Care Res (Hoboken). 2017;69:347-355.
- McInnes IB, Mease PJ, Kirkham B, et al. Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015;386:1137-1146.
- Nash P, Mease PJ, McInnes IB, et al. Efficacy and safety of secukinumab administration by autoinjector in patients with psoriatic arthritis: results from a randomized, placebo-controlled trial (FUTURE 3). Arthritis Res Ther. 2018;20:47.
- Sticherling M, Mrowietz U, Augustin M, et al. Secukinumab is superior to fumaric acid esters in treating patients with moderate-to-severe plaque psoriasis who are naive to systemic treatments: results from the randomized controlled PRIME trial. Br J Dermatol. 2017;177:1024-1032.
- Braun J, Baraliakos X, Deodhar A, et al. Effect of secukinumab on clinical and radiographic outcomes in ankylosing spondylitis: 2-year results from the randomised phase III MEASURE 1 study. Ann Rheum Dis. 2017;76:1070-1077.
- Marzo-Ortega H, Sieper J, Kivitz A, et al. Secukinumab provides sustained improvements in the signs and symptoms of active ankylosing spondylitis with high retention rate: 3-year results from the phase III trial, MEASURE 2. RMD Open. 2017;3:e000592.
- Pavelka K, Kivitz A, Dokoupilova E, et al. Efficacy, safety, and tolerability of secukinumab in patients with active ankylosing spondylitis: a randomized, double-blind phase 3 study, MEASURE 3. Arthritis Res Ther. 2017;19:285.
- Callis Duffin K, Bagel J, Bukhalo M, et al. Phase 3, open-label, randomized study of the pharmacokinetics, efficacy and safety of ixekizumab following subcutaneous administration using a prefilled syringe or an autoinjector in patients with moderate-to-severe plaque psoriasis (UNCOVER-A). J Eur Acad Dermatol Venereol. 2017;31:107-113.
- Gordon KB, Colombel JF, Hardin DS. Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis. N Engl J Med. 2016;375:2102.
- Saeki H, Nakagawa H, Nakajo K, et al. Efficacy and safety of ixekizumab treatment for Japanese patients with moderate to severe plaque psoriasis, erythrodermic psoriasis and generalized pustular psoriasis: results from a 52-week, open-label, phase 3 study (UNCOVER-J). J Dermatol. 2017;44:355-362.
- Reich K, Pinter A, Lacour JP, et al. Comparison of ixekizumab with ustekinumab in moderate-to-severe psoriasis: 24-week results from IXORA-S, a phase III study. Br J Dermatol. 2017;177:1014-1023.
- Zachariae C, Gordon K, Kimball AB, et al. Efficacy and safety of ixekizumab over 4 years of open-label treatment in a phase 2 study in chronic plaque psoriasis. J Am Acad Dermatol. 2018;79:294.e6-301.e6.
- van der Heijde D, Gladman DD, Kishimoto M, et al. Efficacy and safety of ixekizumab in patients with active psoriatic arthritis: 52-week results from a phase III study (SPIRIT-P1). J Rheumatol. 2018;45:367-377.
- van der Heijde D, Cheng-Chung Wei J, Dougados M, et al. Ixekizumab, an interleukin-17A antagonist in the treatment of ankylosing spondylitis or radiographic axial spondyloarthritis in patients previously untreated with biological disease-modifying anti-rheumatic drugs (COAST-V): 16 week results of a phase 3 randomised, double-blind, active-controlled and placebo-controlled trial. Lancet. 2018;392:2441-2451.
- Nakagawa H, Niiro H, Ootaki K, et al. Brodalumab, a human anti-interleukin-17-receptor antibody in the treatment of Japanese patients with moderate-to-severe plaque psoriasis: efficacy and safety results from a phase II randomized controlled study. J Dermatol Sci. 2016;81:44-52.
- Umezawa Y, Nakagawa H, Niiro H, et al. Long-term clinical safety and efficacy of brodalumab in the treatment of Japanese patients with moderate-to-severe plaque psoriasis. J Eur Acad Dermatol Venereol. 2016;30:1957-1960.
- Papp KA, Reich K, Paul C, et al. A prospective phase III, randomized, double-blind, placebo-controlled study of brodalumab in patients with moderate-to-severe plaque psoriasis. Br J Dermatol. 2016;175:273-286.
- Papp K, Leonardi C, Menter A, et al. Safety and efficacy of brodalumab for psoriasis after 120 weeks of treatment. J Am Acad Dermatol. 2014;71:1183.e3-1190.e3.
- Yamasaki K, Nakagawa H, Kubo Y, et al. Efficacy and safety of brodalumab in patients with generalized pustular psoriasis and psoriatic erythroderma: results from a 52-week, open-label study. Br J Dermatol. 2017;176:741-751.
- Mease PJ, Genovese MC, Greenwald MW, et al. Brodalumab, an anti-IL17RA monoclonal antibody, in psoriatic arthritis. N Engl J Med. 2014;370:2295-2306.
- Martin DA, Churchill M, Flores-Suarez L, et al. A phase Ib multiple ascending dose study evaluating safety, pharmacokinetics, and early clinical response of brodalumab, a human anti-IL-17R antibody, in methotrexate-resistant rheumatoid arthritis. Arthritis Res Ther. 2013;15:R164.
- Busse WW, Holgate S, Kerwin E, et al. Randomized, double-blind, placebo-controlled study of brodalumab, a human anti-IL-17 receptor monoclonal antibody, in moderate to severe asthma. Am J Respir Crit Care Med. 2013;188:1294-1302.
- Igarashi A, Kato T, Kato M, et al. Efficacy and safety of ustekinumab in Japanese patients with moderate-to-severe plaque-type psoriasis: long-term results from a phase 2/3 clinical trial. J Dermatol. 2012;39:242-252.
- Krueger GG, Langley RG, Leonardi C, et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med. 2007;356:580-592.
- Leonardi CL, Kimball AB, Papp KA, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet. 2008;371:1665-1674.
- Tsai TF, Ho JC, Song M, et al. Efficacy and safety of ustekinumab for the treatment of moderate-to-severe psoriasis: a phase III, randomized, placebo-controlled trial in Taiwanese and Korean patients (PEARL). J Dermatol Sci. 2011;63:154-163.
- Gordon KB, Strober B, Lebwohl M, et al. Efficacy and safety of risankizumab in moderate-to-severe plaque psoriasis (UltIMMa-1 and UltIMMa-2): results from two double-blind, randomised, placebo-controlled and ustekinumab-controlled phase 3 trials. Lancet. 2018;392:650-661.
- Krueger JG, Ferris LK, Menter A, et al. Anti-IL-23A mAb BI 655066 for treatment of moderate-to-severe psoriasis: safety, efficacy, pharmacokinetics, and biomarker results of a single-rising-dose, randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol. 2015;136:116.e7-124.e7.
- Ohtsuki M, Fujita H, Watanabe M, et al. Efficacy and safety of risankizumab in Japanese patients with moderate to severe plaque psoriasis: results from the SustaIMM phase 2/3 trial. J Dermatol. 2019;46:686-694.
- Papp KA, Blauvelt A, Bukhalo M, et al. Risankizumab versus ustekinumab for moderate-to-severe plaque psoriasis. N Engl J Med. 2017;376:1551-1560.
- Reich K, Gooderham M, Thaci D, et al. Risankizumab compared with adalimumab in patients with moderate-to-severe plaque psoriasis (IMMvent): a randomised, double-blind, active-comparator-controlled phase 3 trial. Lancet. 2019;394:576-586.
- Blauvelt A, Papp KA, Griffiths CE, et al. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: results from the phase III, double-blinded, placebo- and active comparator-controlled VOYAGE 1 trial. J Am Acad Dermatol. 2017;76:405-417.
- Deodhar A, Gottlieb AB, Boehncke WH, et al. Efficacy and safety of guselkumab in patients with active psoriatic arthritis: a randomised, double-blind, placebo-controlled, phase 2 study. Lancet. 2018;391:2213-2224.
- Gordon KB, Duffin KC, Bissonnette R, et al. A phase 2 trial of guselkumab versus adalimumab for plaque psoriasis. N Engl J Med. 2015;373:136-144.
- Langley RG, Tsai TF, Flavin S, et al. Efficacy and safety of guselkumab in patients with psoriasis who have an inadequate response to ustekinumab: results of the randomized, double-blind, phase III NAVIGATE trial. Br J Dermatol. 2018;178:114-123.
- Nemoto O, Hirose K, Shibata S, et al. Safety and efficacy of guselkumab in Japanese patients with moderate-to-severe plaque psoriasis: a randomized, placebo-controlled, ascending-dose study. Br J Dermatol. 2018;178:689-696.
- Ohtsuki M, Kubo H, Morishima H, et al. Guselkumab, an anti-interleukin-23 monoclonal antibody, for the treatment of moderate to severe plaque-type psoriasis in Japanese patients: Efficacy and safety results from a phase 3, randomized, double-blind, placebo-controlled study. J Dermatol. 2018;45:1053-1062.
- Reich K, Armstrong AW, Foley P, et al. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: results from the phase III, double-blind, placebo- and active comparator-controlled VOYAGE 2 trial. J Am Acad Dermatol. 2017;76:418-431.
- Reich K, Armstrong AW, Langley RG, et al. Guselkumab versus secukinumab for the treatment of moderate-to-severe psoriasis (ECLIPSE): results from a phase 3, randomised controlled trial. Lancet. 2019;394:831-839.
- Terui T, Kobayashi S, Okubo Y, et al. Efficacy and safety of guselkumab, an anti-interleukin 23 monoclonal antibody, for palmoplantar pustulosis: a randomized clinical trial. JAMA Dermatol. 2018;154:309-316.
- Papp K, Thaci D, Reich K, et al. Tildrakizumab (MK-3222), an anti-interleukin-23p19 monoclonal antibody, improves psoriasis in a phase IIb randomized placebo-controlled trial. Br J Dermatol. 2015;173:930-939.
- Reich K, Papp KA, Blauvelt A, et al. Tildrakizumab versus placebo or etanercept for chronic plaque psoriasis (reSURFACE 1 and reSURFACE 2): results from two randomised controlled, phase 3 trials. Lancet. 2017;390:276-288.
- Gordon KB, Papp KA, Langley RG, et al. Long-term safety experience of ustekinumab in patients with moderate to severe psoriasis (part II of II): results from analyses of infections and malignancy from pooled phase II and III clinical trials. J Am Acad Dermatol. 2012;66:742-751.
- Papp KA, Griffiths CE, Gordon K, et al. Long-term safety of ustekinumab in patients with moderate-to-severe psoriasis: final results from 5 years of follow-up. Br J Dermatol. 2013;168:844-854.
- Saunte DM, Mrowietz U, Puig L, et al. Candida infections in patients with psoriasis and psoriatic arthritis treated with interleukin-17 inhibitors and their practical management. Br J Dermatol. 2017;177:47-62.
- Lis K, Kuzawinska O, Balkowiec-Iskra E. Tumor necrosis factor inhibitors—state of knowledge. Arch Med Sci. 2014;10:1175-1185.
- Hage CA, Bowyer S, Tarvin SE, et al. Recognition, diagnosis, and treatment of histoplasmosis complicating tumor necrosis factor blocker therapy. Clin Infect Dis. 2010;50:85-92
- Hage CA, Ribes JA, Wengenack NL, et al. A multicenter evaluation of tests for diagnosis of histoplasmosis. Clin Infect Dis. 2011;53:448-454.
Practice Points
- The use of IL-17, IL-12/IL-23, and IL-23 inhibitors for psoriasis and other inflammatory conditions does not appear to increase the risk for deep fungal infections.
- Physicians should still be cautiously optimistic in prescribing these medications, as IL-17 and IL-23 play a central role in immunologic defenses, particularly against fungi.
- A high index of suspicion should be maintained for patients from endemic areas who are being treated with biologics.
HPV vaccination remains below Healthy People goals despite increases
and vary widely across states based on data from a nested cohort study including more than 7 million children.
“Understanding regional and temporal variations in HPV vaccination coverage may help improve HPV vaccination uptake by informing public health policy,” Szu-Ta Chen, MD, of Harvard University, Boston, and colleagues wrote in Pediatrics.
To identify trends in one-dose and two-dose human papillomavirus (HPV) vaccination coverage, the researchers reviewed data from the MarketScan health care database between January 2003 and December 2017 that included 7,837,480 children and 19,843,737 person-years. The children were followed starting at age 9, when HPV vaccination could begin, and ending at one of the following: the first or second vaccination, insurance disenrollment, December 2017, or the end of the year in which they turned 17.
Overall, the proportion of 15-year-old girls and boys with at least a one-dose HPV vaccination increased from 38% and 5%, respectively, in 2011 to 57% and 51%, respectively, in 2017. The comparable proportions of girls and boys with at least a two-dose vaccination increased from 30% and 2%, respectively, in 2011 to 46% and 39%, respectively, in 2017.
Coverage lacks consistency across states
However, the vaccination coverage varied widely across states; two-dose HPV vaccination coverage ranged from 80% of girls in the District of Columbia to 15% of boys in Mississippi. In general, states with more HPV vaccine interventions had higher levels of vaccination, the researchers noted.
Legislation to improve vaccination education showed the strongest association with coverage; an 8.8% increase in coverage for girls and an 8.7% increase for boys. Pediatrician availability also was a factor associated with a 1.1% increase in coverage estimated for every pediatrician per 10,000 children.
Cumulative HPV vaccinations seen among children continuously enrolled in the study were similar to the primary analysis, the Dr. Chen and associates said. “After the initial HPV vaccination, 87% of girls and 82% of boys received a second dose by age 17 in the most recent cohorts.”
However, the HPV vaccination coverage remains below the Healthy People 2020 goal of 80% of children vaccinated by age 15 years, the researchers said. Barriers to vaccination may include a lack of routine clinical encounters in adolescents aged 11-17 years. HPV vaccination coverage was higher in urban populations, compared with rural, which may be related to a lack of providers in rural areas.
“Thus, measures beyond recommending routine vaccination at annual check-ups might be necessary to attain sufficient HPV vaccine coverage, and the optimal strategy may differ by state characteristics,” they wrote.
The study findings were limited by several factors including the use of data from only commercially-insured children and lack of data on vaccines received outside of insurance, the researchers noted.
However, the results were strengthened by the large, population-based sample, and support the need for increased efforts in HPV vaccination. “Most states will not achieve the Healthy People 2020 goal of 80% coverage with at least two HPV vaccine doses by 2020,” Dr. Chen and associates concluded.
Vaccination goals are possible with effort in the right places
The fact of below-target vaccination for HPV in the United States may be old news, but the current study offers new insights on HPV uptake, Amanda F. Dempsey, MD, PhD, of the University of Colorado at Denver, in Aurora, wrote in an accompanying editorial.
“A unique feature of this study is the ability of its researchers to study individuals over time, particularly at a national scope,” which yielded two key messages, she said.
The longitudinal examination of vaccination levels among birth cohorts showed that similar vaccination levels were achieved more quickly each year.
“For example, among the birth cohort from the year 2000, representing 17-year-olds at the time data were abstracted for the study, 40% vaccination coverage was achieved when this group was 14 years old. In contrast, among the birth cohort from the year 2005, representing 12-year-olds at the time of data abstraction, 40% vaccination coverage was reached at the age of 12,” Dr. Dempsey explained.
In addition, the study design allowed the researchers to model future vaccine coverage based on current trends, said Dr. Dempsey. “The authors estimate that, by the year 2022, the 2012 birth cohort will have reached 80% coverage for the first dose in the HPV vaccine series.”
Dr. Dempsey said she was surprised that the models did not support the hypothesis that school mandates for vaccination would increase coverage; however, there were few states in this category.
Although the findings were limited by the lack of data on uninsured children and those insured by Medicaid, the state-by-state results show that the achievement of national vaccination goals is possible, Dr. Dempsey said. In addition, the findings “warrant close consideration by policy makers and the medical community at large regarding vaccination policies and workforce,” she emphasized.The study received no outside funding. Dr. Chen had no financial conflicts to disclose. Several coauthors reported research grants to their institutions from pharmaceutical companies or being consultants to such companies. Dr. Dempsey disclosed serving on the advisory boards for Merck, Pfizer, and Sanofi Pasteur.
SOURCE: Chen S-T et al. Pediatrics. 2020 Sep 14. doi: 10.1542/peds.2019-3557.
and vary widely across states based on data from a nested cohort study including more than 7 million children.
“Understanding regional and temporal variations in HPV vaccination coverage may help improve HPV vaccination uptake by informing public health policy,” Szu-Ta Chen, MD, of Harvard University, Boston, and colleagues wrote in Pediatrics.
To identify trends in one-dose and two-dose human papillomavirus (HPV) vaccination coverage, the researchers reviewed data from the MarketScan health care database between January 2003 and December 2017 that included 7,837,480 children and 19,843,737 person-years. The children were followed starting at age 9, when HPV vaccination could begin, and ending at one of the following: the first or second vaccination, insurance disenrollment, December 2017, or the end of the year in which they turned 17.
Overall, the proportion of 15-year-old girls and boys with at least a one-dose HPV vaccination increased from 38% and 5%, respectively, in 2011 to 57% and 51%, respectively, in 2017. The comparable proportions of girls and boys with at least a two-dose vaccination increased from 30% and 2%, respectively, in 2011 to 46% and 39%, respectively, in 2017.
Coverage lacks consistency across states
However, the vaccination coverage varied widely across states; two-dose HPV vaccination coverage ranged from 80% of girls in the District of Columbia to 15% of boys in Mississippi. In general, states with more HPV vaccine interventions had higher levels of vaccination, the researchers noted.
Legislation to improve vaccination education showed the strongest association with coverage; an 8.8% increase in coverage for girls and an 8.7% increase for boys. Pediatrician availability also was a factor associated with a 1.1% increase in coverage estimated for every pediatrician per 10,000 children.
Cumulative HPV vaccinations seen among children continuously enrolled in the study were similar to the primary analysis, the Dr. Chen and associates said. “After the initial HPV vaccination, 87% of girls and 82% of boys received a second dose by age 17 in the most recent cohorts.”
However, the HPV vaccination coverage remains below the Healthy People 2020 goal of 80% of children vaccinated by age 15 years, the researchers said. Barriers to vaccination may include a lack of routine clinical encounters in adolescents aged 11-17 years. HPV vaccination coverage was higher in urban populations, compared with rural, which may be related to a lack of providers in rural areas.
“Thus, measures beyond recommending routine vaccination at annual check-ups might be necessary to attain sufficient HPV vaccine coverage, and the optimal strategy may differ by state characteristics,” they wrote.
The study findings were limited by several factors including the use of data from only commercially-insured children and lack of data on vaccines received outside of insurance, the researchers noted.
However, the results were strengthened by the large, population-based sample, and support the need for increased efforts in HPV vaccination. “Most states will not achieve the Healthy People 2020 goal of 80% coverage with at least two HPV vaccine doses by 2020,” Dr. Chen and associates concluded.
Vaccination goals are possible with effort in the right places
The fact of below-target vaccination for HPV in the United States may be old news, but the current study offers new insights on HPV uptake, Amanda F. Dempsey, MD, PhD, of the University of Colorado at Denver, in Aurora, wrote in an accompanying editorial.
“A unique feature of this study is the ability of its researchers to study individuals over time, particularly at a national scope,” which yielded two key messages, she said.
The longitudinal examination of vaccination levels among birth cohorts showed that similar vaccination levels were achieved more quickly each year.
“For example, among the birth cohort from the year 2000, representing 17-year-olds at the time data were abstracted for the study, 40% vaccination coverage was achieved when this group was 14 years old. In contrast, among the birth cohort from the year 2005, representing 12-year-olds at the time of data abstraction, 40% vaccination coverage was reached at the age of 12,” Dr. Dempsey explained.
In addition, the study design allowed the researchers to model future vaccine coverage based on current trends, said Dr. Dempsey. “The authors estimate that, by the year 2022, the 2012 birth cohort will have reached 80% coverage for the first dose in the HPV vaccine series.”
Dr. Dempsey said she was surprised that the models did not support the hypothesis that school mandates for vaccination would increase coverage; however, there were few states in this category.
Although the findings were limited by the lack of data on uninsured children and those insured by Medicaid, the state-by-state results show that the achievement of national vaccination goals is possible, Dr. Dempsey said. In addition, the findings “warrant close consideration by policy makers and the medical community at large regarding vaccination policies and workforce,” she emphasized.The study received no outside funding. Dr. Chen had no financial conflicts to disclose. Several coauthors reported research grants to their institutions from pharmaceutical companies or being consultants to such companies. Dr. Dempsey disclosed serving on the advisory boards for Merck, Pfizer, and Sanofi Pasteur.
SOURCE: Chen S-T et al. Pediatrics. 2020 Sep 14. doi: 10.1542/peds.2019-3557.
and vary widely across states based on data from a nested cohort study including more than 7 million children.
“Understanding regional and temporal variations in HPV vaccination coverage may help improve HPV vaccination uptake by informing public health policy,” Szu-Ta Chen, MD, of Harvard University, Boston, and colleagues wrote in Pediatrics.
To identify trends in one-dose and two-dose human papillomavirus (HPV) vaccination coverage, the researchers reviewed data from the MarketScan health care database between January 2003 and December 2017 that included 7,837,480 children and 19,843,737 person-years. The children were followed starting at age 9, when HPV vaccination could begin, and ending at one of the following: the first or second vaccination, insurance disenrollment, December 2017, or the end of the year in which they turned 17.
Overall, the proportion of 15-year-old girls and boys with at least a one-dose HPV vaccination increased from 38% and 5%, respectively, in 2011 to 57% and 51%, respectively, in 2017. The comparable proportions of girls and boys with at least a two-dose vaccination increased from 30% and 2%, respectively, in 2011 to 46% and 39%, respectively, in 2017.
Coverage lacks consistency across states
However, the vaccination coverage varied widely across states; two-dose HPV vaccination coverage ranged from 80% of girls in the District of Columbia to 15% of boys in Mississippi. In general, states with more HPV vaccine interventions had higher levels of vaccination, the researchers noted.
Legislation to improve vaccination education showed the strongest association with coverage; an 8.8% increase in coverage for girls and an 8.7% increase for boys. Pediatrician availability also was a factor associated with a 1.1% increase in coverage estimated for every pediatrician per 10,000 children.
Cumulative HPV vaccinations seen among children continuously enrolled in the study were similar to the primary analysis, the Dr. Chen and associates said. “After the initial HPV vaccination, 87% of girls and 82% of boys received a second dose by age 17 in the most recent cohorts.”
However, the HPV vaccination coverage remains below the Healthy People 2020 goal of 80% of children vaccinated by age 15 years, the researchers said. Barriers to vaccination may include a lack of routine clinical encounters in adolescents aged 11-17 years. HPV vaccination coverage was higher in urban populations, compared with rural, which may be related to a lack of providers in rural areas.
“Thus, measures beyond recommending routine vaccination at annual check-ups might be necessary to attain sufficient HPV vaccine coverage, and the optimal strategy may differ by state characteristics,” they wrote.
The study findings were limited by several factors including the use of data from only commercially-insured children and lack of data on vaccines received outside of insurance, the researchers noted.
However, the results were strengthened by the large, population-based sample, and support the need for increased efforts in HPV vaccination. “Most states will not achieve the Healthy People 2020 goal of 80% coverage with at least two HPV vaccine doses by 2020,” Dr. Chen and associates concluded.
Vaccination goals are possible with effort in the right places
The fact of below-target vaccination for HPV in the United States may be old news, but the current study offers new insights on HPV uptake, Amanda F. Dempsey, MD, PhD, of the University of Colorado at Denver, in Aurora, wrote in an accompanying editorial.
“A unique feature of this study is the ability of its researchers to study individuals over time, particularly at a national scope,” which yielded two key messages, she said.
The longitudinal examination of vaccination levels among birth cohorts showed that similar vaccination levels were achieved more quickly each year.
“For example, among the birth cohort from the year 2000, representing 17-year-olds at the time data were abstracted for the study, 40% vaccination coverage was achieved when this group was 14 years old. In contrast, among the birth cohort from the year 2005, representing 12-year-olds at the time of data abstraction, 40% vaccination coverage was reached at the age of 12,” Dr. Dempsey explained.
In addition, the study design allowed the researchers to model future vaccine coverage based on current trends, said Dr. Dempsey. “The authors estimate that, by the year 2022, the 2012 birth cohort will have reached 80% coverage for the first dose in the HPV vaccine series.”
Dr. Dempsey said she was surprised that the models did not support the hypothesis that school mandates for vaccination would increase coverage; however, there were few states in this category.
Although the findings were limited by the lack of data on uninsured children and those insured by Medicaid, the state-by-state results show that the achievement of national vaccination goals is possible, Dr. Dempsey said. In addition, the findings “warrant close consideration by policy makers and the medical community at large regarding vaccination policies and workforce,” she emphasized.The study received no outside funding. Dr. Chen had no financial conflicts to disclose. Several coauthors reported research grants to their institutions from pharmaceutical companies or being consultants to such companies. Dr. Dempsey disclosed serving on the advisory boards for Merck, Pfizer, and Sanofi Pasteur.
SOURCE: Chen S-T et al. Pediatrics. 2020 Sep 14. doi: 10.1542/peds.2019-3557.
FROM PEDIATRICS
Prospects and challenges for the upcoming influenza season
The 2020-2021 influenza season is shaping up to be challenging. Its likely concurrence with the ongoing severe acute respiratory syndrome-coronavirus 2 (SARS-coV-2) pandemic (COVID-19) will pose diagnostic and therapeutic dilemmas and could overload the hospital system. But there could also be potential synergies in preventing morbidity and mortality from each disease.
A consistent pattern overthe past few influenza seasons
During the 2019-2020 flu season, there were an estimated 410,000 to 740,000 hospitalizations and 24,000 to 62,000 deaths attributed to influenza.1 As seen in FIGURE 1, office visits for influenza-like illness (ILI) began to increase in late November and early December in each of the last 3 years (2017-2018, 2018-2019, 2019-2020) and stayed elevated above baseline for about 4 months each season.1
The effectiveness of influenza vaccine during the 2019-2020 season is being estimated using the US Flu Vaccine Effectiveness Network, which has close to 9000 enrollees. Overall, it appears the vaccine was 39% effective against medically attended influenza, with a higher effectiveness against influenza B (44%) than against A/H1N1 (31%). Effectiveness against influenza B was similar in all age groups, but effectiveness against A/H1N1 was highest for those ages 50 to 64 years (45%) and lowest for those ages 6 months through 8 years (22%), although 95% confidence intervals overlapped for all age groups (FIGURE 2). These preliminary effectiveness rates were presented at the summer meeting of the Advisory Committee on Immunization Practices (ACIP).1
Influenza vaccine safety data for 2019-2020 were based on the Vaccine Adverse Event Reporting System (VAERS), a passive surveillance system, and on the Vaccine Safety Datalink (VSD) system, an active surveillance system involving close to 6 million doses administered at VSD sites. No safety concerns were identified for any of the different vaccine types. Both the VAERS and VSD surveillance systems have been described in more detail in a previous Practice Alert.2
Recommendations for 2020-2021
The composition of the influenza vaccines for this year’s flu season will be different for 3 of the 4 antigens: A/H1N1, A/H2N2 and B/Victoria.3 The antigens included in the influenza vaccines each year are decided on in the spring, based on surveillance of circulating strains around the world. The effectiveness of the vaccine each year largely depends on how well the strains included in the vaccine match those circulating in the United States during the influenza season.
The main immunization recommendation for preventing morbidity and mortality from influenza has not changed: All individuals ages 6 months and older without a contraindication should receive an influenza vaccine.4 The Centers for Disease Control and Prevention (CDC) recommends that patients receive the vaccine by the end of October.4 This includes the second dose for those children younger than 9 years who need 2 doses—ie, those who have received fewer than 2 doses of influenza vaccine prior to July 2020. Vaccination should continue through the end of the season for anyone who has not received a 2020-2021 influenza vaccine.
Two new influenza vaccine products are available for use in those ages 65 years and older: Fluzone high-dose quadrivalent and Fluad Quadrivalent (adjuvanted).4 Both of these products were available last year as trivalent options. Currently no specific vaccine product is listed as preferred by ACIP for those ages 65 and older.
Continue to: New vaccine contraindications
New vaccine contraindications. Four medical conditions have been added to the list of contraindications for quadrivalent live, attenuated influenza vaccine (LAIV4): cochlear implant, cerebrospinal fluid leak, asplenia (anatomic and functional), and sickle cell anemia.4 In addition, those who receive LAIV4 should not be prescribed an influenza antiviral until 2 weeks after receiving the vaccine. And the vaccine should not be administered for 48 hours after receipt of oseltamivir or zanamivir, 5 days after peramivir, and 17 days after baloxavir marboxil.4 This is to prevent possible antiviral inactivation of the live attenuated influenza viruses in the vaccine.
For those who have a history of severe allergic reaction to eggs, there are now 2 egg-free options: cell-culture-based inactivated vaccine (ccIIV4) and recombinant influenza vaccine (RIV4).3,4 Urticaria alone is not considered a severe reaction. If neither of these egg-free options is available, a vaccine may still be administered in a medical setting supervised by a provider who is able to manage a severe allergic reaction (which rarely occurs).
All vaccine products available for the upcoming influenza season are listed and described on the CDC Web site, as is a summary of related recommendations.4 Particular attention should be paid to the dose of vaccine administered, as it differs by product for those ages 6 through 35 months of age and those ages 65 years and older.
Use of antiviral medications
Four antiviral medications are now available for treating influenza (3 neuraminidase inhibitors and 1 endonuclease inhibitor), and there are 2 agents for preventing influenza, both neuraminidase inhibitors (TABLE 1).5 The CDC recommends treating with antivirals as soon as possible if individuals with confirmed or suspected influenza require hospitalization; have severe, complicated, or progressive illness; or are at high risk for complications. Use antivirals based on clinical judgment if previously healthy individuals do not have severe complications and are not at increased risk for complications, and only if the medication can be started within 48 hours of symptom onset.
The CDC discourages widespread use of antivirals to prevent influenza, either pre- or postexposure, although it specifies certain situations in which usage would be acceptable (TABLE 2).5 There is some concern that widespread use could lead to the emergence of drug-resistant strains and that using postexposure dosing could lead to suboptimal treatment if influenza infection occurred before the start of prophylaxis. If postexposure antivirals are prescribed, they should be started within 48 hours of exposure and continued for 7 days after the last exposure.
Continue to: A potential perfect storm
A potential perfect storm: Concurrence of influenza and SARS-coV-19
While we have vaccines and antivirals to prevent influenza, and have effective antivirals for treatment, no prevention or treatment options exist for COVID-19, except, possibly, dexamethasone to reduce mortality among those seriously ill.6 The concurrence of influenza and COVID-19 will present unique challenges for the health care system.
Action steps. Keep abreast of the incidences of circulating SARS-coV-19 and influenza viruses in your community. The similar signs and symptoms of these 2 infectious agents will complicate diagnosis. Rapid, or point-of-care, tests for influenza are widely available, but their accuracy varies and not all tests detect both influenza A and B. The CDC lists approved point-of-care tests at www.cdc.gov/flu/professionals/diagnosis/table-ridt.html and advises on how to interpret these test results when influenza is and is not circulating in the community, at www.cdc.gov/flu/professionals/diagnosis/clinician_guidance_ridt.htm.
Clinical practice advice for both conditions should be implemented when any patient presents with ILI:7
- Most patients who are not seriously ill and have no conditions that place them at high risk for adverse outcomes can be treated symptomatically at home.
- Those with ILI should be tested for both influenza virus and SARS-CoV-2 if testing is available. It is possible to be co-infected.
- Sick patients should self-isolate at home for the duration of their symptoms.
- If others live in the house, the sick person should stay in a separate room and wear a mask. Everyone in the house should cover coughs and sneezes (if not wearing a mask), dispose of used tissues in a trash can (rather than leaving them on night stands and countertops), and wash hands frequently.
- All household members should be vaccinated against influenza. Those who are unvaccinated, and those at high risk who have been recently vaccinated, can consider influenza antiviral prophylaxis. If the sick family member is confirmed to have COVID-19, with no co-existing influenza, anti-influenza antiviral prophylaxis may be discontinued.
- Clinical infection control practices should be the same for anyone presenting with ILI.7 Enhanced clinic-based infection control practices to prevent spread of SARS-CoV-2 are listed in TABLE 3.8
Since there currently are no preventive medications proven to work for COVID-19, the main clinical decision physicians will have to make when a patient presents with ILI is whether to use antivirals to treat those who are at risk for complications based on the result of rapid, on-site influenza testing, or clinical presentation, or both. In this situation, knowledge of which viruses are circulating at high rates in the community could be valuable.
Milder season or perfect storm? The society-wide interventions that have been encouraged (although not mandated everywhere) to prevent community spread of SARS-CoV-2 should help prevent the community spread of influenza as well, and, if adhered to, may lead to a milder influenza season than would otherwise have occurred. However, given the uncertainties, the combination of influenza and coronavirus could present a perfect storm for the health care system and result in higher-than-normal morbidity and mortality from ILI and pneumonia overall.
Continue to: The possibility that one or more vaccines...
The possibility that one or more vaccines to prevent COVID-19 may be available in late 2020 or early 2021 offers hope. However, in current testing, the vaccine is not being given simultaneously with the influenza vaccine. If the potential for adverse interaction exists between the vaccines, it is important that influenza vaccine be given by mid- to late-October to avoid such an interaction if and when the new SARS-CoV-2 vaccine becomes available. Individuals who have symptoms of COVID-19 should not be vaccinated with influenza vaccine until they are considered noninfectious.
Encourage influenza vaccination. The COVID-19 pandemic may make it difficult to achieve desired community influenza vaccine levels because of decreased visits to medical facilities for preventive care, possible lower insurance coverage due to loss of employment, and a decrease in worksite mass vaccination programs. This makes it important for family physicians to encourage and offer influenza vaccines at their clinical sites.
Several evidence-based practices have been shown to improve vaccine uptake. Examples of such practices include patient reminder and recall systems that provide feedback to clinicians about rates of vaccination among patients, and establishing standing orders for vaccine administration that allow other health care providers to assess a patient’s immunization status and administer vaccinations according to a protocol.9 Finally, the CDC provides a video on how to recommend influenza vaccine to those who may be resistant (www.cdc.gov/vaccines/howirecommend/adult-vacc-videos.html).
SIDEBAR
CDC influenza resources
Point-of-care tests that detect both influenza A and B viruses approved by the CDC
www.cdc.gov/flu/professionals/diagnosis/table-ridt.html
Advice on how to interpret the test results
www.cdc.gov/flu/professionals/diagnosis/clinician_guidance_ridt.htm
How to recommend influenza vaccine to reluctant patients
www.cdc.gov/vaccines/howirecommend/adult-vacc-videos.html
CDC, Centers for Disease Control and Prevention.
1. Grohskopf L. Influenza work groups: updates, considerations, and proposed recommendations for the 2020-2021 season. Presented at the ACIP meeting June 24, 2020. www.youtube.com/watch?v=W1SV2DSJsaQ&list=PLvrp9iOILTQb6D9e1YZWpbUvzfptNMKx2&index=8&t=0s. [Time stamp: 1:26:48] Accessed Septemeber 29, 2020.
2. Campos-Outcalt D. Facts to help you keep pace with the vaccine conversation. J Fam Pract. 2019;68:341-346.
3. Grohskopf L, Alyanak E, Broder KR, et al. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices—United States, 2020-21 Influenza Season. MMWR Recomm Rep. 2020;69:1-24.
4. Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP)—United States, 2020-21 Summary of Recommendations. www.cdc.gov/flu/pdf/professionals/acip/acip-2020-21-summary-of-recommendations.pdf. Accessed September 29, 2020.
5. CDC. Influenza antiviral medications: summary for clinicians. www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm. Accessed September 29, 2020.
6. NIH. COVID-19 treatment guidelines. Corticosteroids. www.covid19treatmentguidelines.nih.gov/immune-based-therapy/immunomodulators/corticosteroids/. Accessed September 29, 2020.
7. CDC. Infection control. www.cdc.gov/infectioncontrol/. Accessed September 29, 2020.
8. CDC. Interim infection prevention and control recommendations for healthcare personnel during the coronavirus disease 2019 (COVID-19) pandemic. www.cdc.gov/coronavirus/2019-ncov/hcp/infection-control.html. Accessed September 29, 2020.
9. HHS. CPSTF findings for increasing vaccination. www.thecommunityguide.org/content/task-force-findings-increasing-vaccination. Accessed September 29, 2020.
The 2020-2021 influenza season is shaping up to be challenging. Its likely concurrence with the ongoing severe acute respiratory syndrome-coronavirus 2 (SARS-coV-2) pandemic (COVID-19) will pose diagnostic and therapeutic dilemmas and could overload the hospital system. But there could also be potential synergies in preventing morbidity and mortality from each disease.
A consistent pattern overthe past few influenza seasons
During the 2019-2020 flu season, there were an estimated 410,000 to 740,000 hospitalizations and 24,000 to 62,000 deaths attributed to influenza.1 As seen in FIGURE 1, office visits for influenza-like illness (ILI) began to increase in late November and early December in each of the last 3 years (2017-2018, 2018-2019, 2019-2020) and stayed elevated above baseline for about 4 months each season.1
The effectiveness of influenza vaccine during the 2019-2020 season is being estimated using the US Flu Vaccine Effectiveness Network, which has close to 9000 enrollees. Overall, it appears the vaccine was 39% effective against medically attended influenza, with a higher effectiveness against influenza B (44%) than against A/H1N1 (31%). Effectiveness against influenza B was similar in all age groups, but effectiveness against A/H1N1 was highest for those ages 50 to 64 years (45%) and lowest for those ages 6 months through 8 years (22%), although 95% confidence intervals overlapped for all age groups (FIGURE 2). These preliminary effectiveness rates were presented at the summer meeting of the Advisory Committee on Immunization Practices (ACIP).1
Influenza vaccine safety data for 2019-2020 were based on the Vaccine Adverse Event Reporting System (VAERS), a passive surveillance system, and on the Vaccine Safety Datalink (VSD) system, an active surveillance system involving close to 6 million doses administered at VSD sites. No safety concerns were identified for any of the different vaccine types. Both the VAERS and VSD surveillance systems have been described in more detail in a previous Practice Alert.2
Recommendations for 2020-2021
The composition of the influenza vaccines for this year’s flu season will be different for 3 of the 4 antigens: A/H1N1, A/H2N2 and B/Victoria.3 The antigens included in the influenza vaccines each year are decided on in the spring, based on surveillance of circulating strains around the world. The effectiveness of the vaccine each year largely depends on how well the strains included in the vaccine match those circulating in the United States during the influenza season.
The main immunization recommendation for preventing morbidity and mortality from influenza has not changed: All individuals ages 6 months and older without a contraindication should receive an influenza vaccine.4 The Centers for Disease Control and Prevention (CDC) recommends that patients receive the vaccine by the end of October.4 This includes the second dose for those children younger than 9 years who need 2 doses—ie, those who have received fewer than 2 doses of influenza vaccine prior to July 2020. Vaccination should continue through the end of the season for anyone who has not received a 2020-2021 influenza vaccine.
Two new influenza vaccine products are available for use in those ages 65 years and older: Fluzone high-dose quadrivalent and Fluad Quadrivalent (adjuvanted).4 Both of these products were available last year as trivalent options. Currently no specific vaccine product is listed as preferred by ACIP for those ages 65 and older.
Continue to: New vaccine contraindications
New vaccine contraindications. Four medical conditions have been added to the list of contraindications for quadrivalent live, attenuated influenza vaccine (LAIV4): cochlear implant, cerebrospinal fluid leak, asplenia (anatomic and functional), and sickle cell anemia.4 In addition, those who receive LAIV4 should not be prescribed an influenza antiviral until 2 weeks after receiving the vaccine. And the vaccine should not be administered for 48 hours after receipt of oseltamivir or zanamivir, 5 days after peramivir, and 17 days after baloxavir marboxil.4 This is to prevent possible antiviral inactivation of the live attenuated influenza viruses in the vaccine.
For those who have a history of severe allergic reaction to eggs, there are now 2 egg-free options: cell-culture-based inactivated vaccine (ccIIV4) and recombinant influenza vaccine (RIV4).3,4 Urticaria alone is not considered a severe reaction. If neither of these egg-free options is available, a vaccine may still be administered in a medical setting supervised by a provider who is able to manage a severe allergic reaction (which rarely occurs).
All vaccine products available for the upcoming influenza season are listed and described on the CDC Web site, as is a summary of related recommendations.4 Particular attention should be paid to the dose of vaccine administered, as it differs by product for those ages 6 through 35 months of age and those ages 65 years and older.
Use of antiviral medications
Four antiviral medications are now available for treating influenza (3 neuraminidase inhibitors and 1 endonuclease inhibitor), and there are 2 agents for preventing influenza, both neuraminidase inhibitors (TABLE 1).5 The CDC recommends treating with antivirals as soon as possible if individuals with confirmed or suspected influenza require hospitalization; have severe, complicated, or progressive illness; or are at high risk for complications. Use antivirals based on clinical judgment if previously healthy individuals do not have severe complications and are not at increased risk for complications, and only if the medication can be started within 48 hours of symptom onset.
The CDC discourages widespread use of antivirals to prevent influenza, either pre- or postexposure, although it specifies certain situations in which usage would be acceptable (TABLE 2).5 There is some concern that widespread use could lead to the emergence of drug-resistant strains and that using postexposure dosing could lead to suboptimal treatment if influenza infection occurred before the start of prophylaxis. If postexposure antivirals are prescribed, they should be started within 48 hours of exposure and continued for 7 days after the last exposure.
Continue to: A potential perfect storm
A potential perfect storm: Concurrence of influenza and SARS-coV-19
While we have vaccines and antivirals to prevent influenza, and have effective antivirals for treatment, no prevention or treatment options exist for COVID-19, except, possibly, dexamethasone to reduce mortality among those seriously ill.6 The concurrence of influenza and COVID-19 will present unique challenges for the health care system.
Action steps. Keep abreast of the incidences of circulating SARS-coV-19 and influenza viruses in your community. The similar signs and symptoms of these 2 infectious agents will complicate diagnosis. Rapid, or point-of-care, tests for influenza are widely available, but their accuracy varies and not all tests detect both influenza A and B. The CDC lists approved point-of-care tests at www.cdc.gov/flu/professionals/diagnosis/table-ridt.html and advises on how to interpret these test results when influenza is and is not circulating in the community, at www.cdc.gov/flu/professionals/diagnosis/clinician_guidance_ridt.htm.
Clinical practice advice for both conditions should be implemented when any patient presents with ILI:7
- Most patients who are not seriously ill and have no conditions that place them at high risk for adverse outcomes can be treated symptomatically at home.
- Those with ILI should be tested for both influenza virus and SARS-CoV-2 if testing is available. It is possible to be co-infected.
- Sick patients should self-isolate at home for the duration of their symptoms.
- If others live in the house, the sick person should stay in a separate room and wear a mask. Everyone in the house should cover coughs and sneezes (if not wearing a mask), dispose of used tissues in a trash can (rather than leaving them on night stands and countertops), and wash hands frequently.
- All household members should be vaccinated against influenza. Those who are unvaccinated, and those at high risk who have been recently vaccinated, can consider influenza antiviral prophylaxis. If the sick family member is confirmed to have COVID-19, with no co-existing influenza, anti-influenza antiviral prophylaxis may be discontinued.
- Clinical infection control practices should be the same for anyone presenting with ILI.7 Enhanced clinic-based infection control practices to prevent spread of SARS-CoV-2 are listed in TABLE 3.8
Since there currently are no preventive medications proven to work for COVID-19, the main clinical decision physicians will have to make when a patient presents with ILI is whether to use antivirals to treat those who are at risk for complications based on the result of rapid, on-site influenza testing, or clinical presentation, or both. In this situation, knowledge of which viruses are circulating at high rates in the community could be valuable.
Milder season or perfect storm? The society-wide interventions that have been encouraged (although not mandated everywhere) to prevent community spread of SARS-CoV-2 should help prevent the community spread of influenza as well, and, if adhered to, may lead to a milder influenza season than would otherwise have occurred. However, given the uncertainties, the combination of influenza and coronavirus could present a perfect storm for the health care system and result in higher-than-normal morbidity and mortality from ILI and pneumonia overall.
Continue to: The possibility that one or more vaccines...
The possibility that one or more vaccines to prevent COVID-19 may be available in late 2020 or early 2021 offers hope. However, in current testing, the vaccine is not being given simultaneously with the influenza vaccine. If the potential for adverse interaction exists between the vaccines, it is important that influenza vaccine be given by mid- to late-October to avoid such an interaction if and when the new SARS-CoV-2 vaccine becomes available. Individuals who have symptoms of COVID-19 should not be vaccinated with influenza vaccine until they are considered noninfectious.
Encourage influenza vaccination. The COVID-19 pandemic may make it difficult to achieve desired community influenza vaccine levels because of decreased visits to medical facilities for preventive care, possible lower insurance coverage due to loss of employment, and a decrease in worksite mass vaccination programs. This makes it important for family physicians to encourage and offer influenza vaccines at their clinical sites.
Several evidence-based practices have been shown to improve vaccine uptake. Examples of such practices include patient reminder and recall systems that provide feedback to clinicians about rates of vaccination among patients, and establishing standing orders for vaccine administration that allow other health care providers to assess a patient’s immunization status and administer vaccinations according to a protocol.9 Finally, the CDC provides a video on how to recommend influenza vaccine to those who may be resistant (www.cdc.gov/vaccines/howirecommend/adult-vacc-videos.html).
SIDEBAR
CDC influenza resources
Point-of-care tests that detect both influenza A and B viruses approved by the CDC
www.cdc.gov/flu/professionals/diagnosis/table-ridt.html
Advice on how to interpret the test results
www.cdc.gov/flu/professionals/diagnosis/clinician_guidance_ridt.htm
How to recommend influenza vaccine to reluctant patients
www.cdc.gov/vaccines/howirecommend/adult-vacc-videos.html
CDC, Centers for Disease Control and Prevention.
The 2020-2021 influenza season is shaping up to be challenging. Its likely concurrence with the ongoing severe acute respiratory syndrome-coronavirus 2 (SARS-coV-2) pandemic (COVID-19) will pose diagnostic and therapeutic dilemmas and could overload the hospital system. But there could also be potential synergies in preventing morbidity and mortality from each disease.
A consistent pattern overthe past few influenza seasons
During the 2019-2020 flu season, there were an estimated 410,000 to 740,000 hospitalizations and 24,000 to 62,000 deaths attributed to influenza.1 As seen in FIGURE 1, office visits for influenza-like illness (ILI) began to increase in late November and early December in each of the last 3 years (2017-2018, 2018-2019, 2019-2020) and stayed elevated above baseline for about 4 months each season.1
The effectiveness of influenza vaccine during the 2019-2020 season is being estimated using the US Flu Vaccine Effectiveness Network, which has close to 9000 enrollees. Overall, it appears the vaccine was 39% effective against medically attended influenza, with a higher effectiveness against influenza B (44%) than against A/H1N1 (31%). Effectiveness against influenza B was similar in all age groups, but effectiveness against A/H1N1 was highest for those ages 50 to 64 years (45%) and lowest for those ages 6 months through 8 years (22%), although 95% confidence intervals overlapped for all age groups (FIGURE 2). These preliminary effectiveness rates were presented at the summer meeting of the Advisory Committee on Immunization Practices (ACIP).1
Influenza vaccine safety data for 2019-2020 were based on the Vaccine Adverse Event Reporting System (VAERS), a passive surveillance system, and on the Vaccine Safety Datalink (VSD) system, an active surveillance system involving close to 6 million doses administered at VSD sites. No safety concerns were identified for any of the different vaccine types. Both the VAERS and VSD surveillance systems have been described in more detail in a previous Practice Alert.2
Recommendations for 2020-2021
The composition of the influenza vaccines for this year’s flu season will be different for 3 of the 4 antigens: A/H1N1, A/H2N2 and B/Victoria.3 The antigens included in the influenza vaccines each year are decided on in the spring, based on surveillance of circulating strains around the world. The effectiveness of the vaccine each year largely depends on how well the strains included in the vaccine match those circulating in the United States during the influenza season.
The main immunization recommendation for preventing morbidity and mortality from influenza has not changed: All individuals ages 6 months and older without a contraindication should receive an influenza vaccine.4 The Centers for Disease Control and Prevention (CDC) recommends that patients receive the vaccine by the end of October.4 This includes the second dose for those children younger than 9 years who need 2 doses—ie, those who have received fewer than 2 doses of influenza vaccine prior to July 2020. Vaccination should continue through the end of the season for anyone who has not received a 2020-2021 influenza vaccine.
Two new influenza vaccine products are available for use in those ages 65 years and older: Fluzone high-dose quadrivalent and Fluad Quadrivalent (adjuvanted).4 Both of these products were available last year as trivalent options. Currently no specific vaccine product is listed as preferred by ACIP for those ages 65 and older.
Continue to: New vaccine contraindications
New vaccine contraindications. Four medical conditions have been added to the list of contraindications for quadrivalent live, attenuated influenza vaccine (LAIV4): cochlear implant, cerebrospinal fluid leak, asplenia (anatomic and functional), and sickle cell anemia.4 In addition, those who receive LAIV4 should not be prescribed an influenza antiviral until 2 weeks after receiving the vaccine. And the vaccine should not be administered for 48 hours after receipt of oseltamivir or zanamivir, 5 days after peramivir, and 17 days after baloxavir marboxil.4 This is to prevent possible antiviral inactivation of the live attenuated influenza viruses in the vaccine.
For those who have a history of severe allergic reaction to eggs, there are now 2 egg-free options: cell-culture-based inactivated vaccine (ccIIV4) and recombinant influenza vaccine (RIV4).3,4 Urticaria alone is not considered a severe reaction. If neither of these egg-free options is available, a vaccine may still be administered in a medical setting supervised by a provider who is able to manage a severe allergic reaction (which rarely occurs).
All vaccine products available for the upcoming influenza season are listed and described on the CDC Web site, as is a summary of related recommendations.4 Particular attention should be paid to the dose of vaccine administered, as it differs by product for those ages 6 through 35 months of age and those ages 65 years and older.
Use of antiviral medications
Four antiviral medications are now available for treating influenza (3 neuraminidase inhibitors and 1 endonuclease inhibitor), and there are 2 agents for preventing influenza, both neuraminidase inhibitors (TABLE 1).5 The CDC recommends treating with antivirals as soon as possible if individuals with confirmed or suspected influenza require hospitalization; have severe, complicated, or progressive illness; or are at high risk for complications. Use antivirals based on clinical judgment if previously healthy individuals do not have severe complications and are not at increased risk for complications, and only if the medication can be started within 48 hours of symptom onset.
The CDC discourages widespread use of antivirals to prevent influenza, either pre- or postexposure, although it specifies certain situations in which usage would be acceptable (TABLE 2).5 There is some concern that widespread use could lead to the emergence of drug-resistant strains and that using postexposure dosing could lead to suboptimal treatment if influenza infection occurred before the start of prophylaxis. If postexposure antivirals are prescribed, they should be started within 48 hours of exposure and continued for 7 days after the last exposure.
Continue to: A potential perfect storm
A potential perfect storm: Concurrence of influenza and SARS-coV-19
While we have vaccines and antivirals to prevent influenza, and have effective antivirals for treatment, no prevention or treatment options exist for COVID-19, except, possibly, dexamethasone to reduce mortality among those seriously ill.6 The concurrence of influenza and COVID-19 will present unique challenges for the health care system.
Action steps. Keep abreast of the incidences of circulating SARS-coV-19 and influenza viruses in your community. The similar signs and symptoms of these 2 infectious agents will complicate diagnosis. Rapid, or point-of-care, tests for influenza are widely available, but their accuracy varies and not all tests detect both influenza A and B. The CDC lists approved point-of-care tests at www.cdc.gov/flu/professionals/diagnosis/table-ridt.html and advises on how to interpret these test results when influenza is and is not circulating in the community, at www.cdc.gov/flu/professionals/diagnosis/clinician_guidance_ridt.htm.
Clinical practice advice for both conditions should be implemented when any patient presents with ILI:7
- Most patients who are not seriously ill and have no conditions that place them at high risk for adverse outcomes can be treated symptomatically at home.
- Those with ILI should be tested for both influenza virus and SARS-CoV-2 if testing is available. It is possible to be co-infected.
- Sick patients should self-isolate at home for the duration of their symptoms.
- If others live in the house, the sick person should stay in a separate room and wear a mask. Everyone in the house should cover coughs and sneezes (if not wearing a mask), dispose of used tissues in a trash can (rather than leaving them on night stands and countertops), and wash hands frequently.
- All household members should be vaccinated against influenza. Those who are unvaccinated, and those at high risk who have been recently vaccinated, can consider influenza antiviral prophylaxis. If the sick family member is confirmed to have COVID-19, with no co-existing influenza, anti-influenza antiviral prophylaxis may be discontinued.
- Clinical infection control practices should be the same for anyone presenting with ILI.7 Enhanced clinic-based infection control practices to prevent spread of SARS-CoV-2 are listed in TABLE 3.8
Since there currently are no preventive medications proven to work for COVID-19, the main clinical decision physicians will have to make when a patient presents with ILI is whether to use antivirals to treat those who are at risk for complications based on the result of rapid, on-site influenza testing, or clinical presentation, or both. In this situation, knowledge of which viruses are circulating at high rates in the community could be valuable.
Milder season or perfect storm? The society-wide interventions that have been encouraged (although not mandated everywhere) to prevent community spread of SARS-CoV-2 should help prevent the community spread of influenza as well, and, if adhered to, may lead to a milder influenza season than would otherwise have occurred. However, given the uncertainties, the combination of influenza and coronavirus could present a perfect storm for the health care system and result in higher-than-normal morbidity and mortality from ILI and pneumonia overall.
Continue to: The possibility that one or more vaccines...
The possibility that one or more vaccines to prevent COVID-19 may be available in late 2020 or early 2021 offers hope. However, in current testing, the vaccine is not being given simultaneously with the influenza vaccine. If the potential for adverse interaction exists between the vaccines, it is important that influenza vaccine be given by mid- to late-October to avoid such an interaction if and when the new SARS-CoV-2 vaccine becomes available. Individuals who have symptoms of COVID-19 should not be vaccinated with influenza vaccine until they are considered noninfectious.
Encourage influenza vaccination. The COVID-19 pandemic may make it difficult to achieve desired community influenza vaccine levels because of decreased visits to medical facilities for preventive care, possible lower insurance coverage due to loss of employment, and a decrease in worksite mass vaccination programs. This makes it important for family physicians to encourage and offer influenza vaccines at their clinical sites.
Several evidence-based practices have been shown to improve vaccine uptake. Examples of such practices include patient reminder and recall systems that provide feedback to clinicians about rates of vaccination among patients, and establishing standing orders for vaccine administration that allow other health care providers to assess a patient’s immunization status and administer vaccinations according to a protocol.9 Finally, the CDC provides a video on how to recommend influenza vaccine to those who may be resistant (www.cdc.gov/vaccines/howirecommend/adult-vacc-videos.html).
SIDEBAR
CDC influenza resources
Point-of-care tests that detect both influenza A and B viruses approved by the CDC
www.cdc.gov/flu/professionals/diagnosis/table-ridt.html
Advice on how to interpret the test results
www.cdc.gov/flu/professionals/diagnosis/clinician_guidance_ridt.htm
How to recommend influenza vaccine to reluctant patients
www.cdc.gov/vaccines/howirecommend/adult-vacc-videos.html
CDC, Centers for Disease Control and Prevention.
1. Grohskopf L. Influenza work groups: updates, considerations, and proposed recommendations for the 2020-2021 season. Presented at the ACIP meeting June 24, 2020. www.youtube.com/watch?v=W1SV2DSJsaQ&list=PLvrp9iOILTQb6D9e1YZWpbUvzfptNMKx2&index=8&t=0s. [Time stamp: 1:26:48] Accessed Septemeber 29, 2020.
2. Campos-Outcalt D. Facts to help you keep pace with the vaccine conversation. J Fam Pract. 2019;68:341-346.
3. Grohskopf L, Alyanak E, Broder KR, et al. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices—United States, 2020-21 Influenza Season. MMWR Recomm Rep. 2020;69:1-24.
4. Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP)—United States, 2020-21 Summary of Recommendations. www.cdc.gov/flu/pdf/professionals/acip/acip-2020-21-summary-of-recommendations.pdf. Accessed September 29, 2020.
5. CDC. Influenza antiviral medications: summary for clinicians. www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm. Accessed September 29, 2020.
6. NIH. COVID-19 treatment guidelines. Corticosteroids. www.covid19treatmentguidelines.nih.gov/immune-based-therapy/immunomodulators/corticosteroids/. Accessed September 29, 2020.
7. CDC. Infection control. www.cdc.gov/infectioncontrol/. Accessed September 29, 2020.
8. CDC. Interim infection prevention and control recommendations for healthcare personnel during the coronavirus disease 2019 (COVID-19) pandemic. www.cdc.gov/coronavirus/2019-ncov/hcp/infection-control.html. Accessed September 29, 2020.
9. HHS. CPSTF findings for increasing vaccination. www.thecommunityguide.org/content/task-force-findings-increasing-vaccination. Accessed September 29, 2020.
1. Grohskopf L. Influenza work groups: updates, considerations, and proposed recommendations for the 2020-2021 season. Presented at the ACIP meeting June 24, 2020. www.youtube.com/watch?v=W1SV2DSJsaQ&list=PLvrp9iOILTQb6D9e1YZWpbUvzfptNMKx2&index=8&t=0s. [Time stamp: 1:26:48] Accessed Septemeber 29, 2020.
2. Campos-Outcalt D. Facts to help you keep pace with the vaccine conversation. J Fam Pract. 2019;68:341-346.
3. Grohskopf L, Alyanak E, Broder KR, et al. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices—United States, 2020-21 Influenza Season. MMWR Recomm Rep. 2020;69:1-24.
4. Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP)—United States, 2020-21 Summary of Recommendations. www.cdc.gov/flu/pdf/professionals/acip/acip-2020-21-summary-of-recommendations.pdf. Accessed September 29, 2020.
5. CDC. Influenza antiviral medications: summary for clinicians. www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm. Accessed September 29, 2020.
6. NIH. COVID-19 treatment guidelines. Corticosteroids. www.covid19treatmentguidelines.nih.gov/immune-based-therapy/immunomodulators/corticosteroids/. Accessed September 29, 2020.
7. CDC. Infection control. www.cdc.gov/infectioncontrol/. Accessed September 29, 2020.
8. CDC. Interim infection prevention and control recommendations for healthcare personnel during the coronavirus disease 2019 (COVID-19) pandemic. www.cdc.gov/coronavirus/2019-ncov/hcp/infection-control.html. Accessed September 29, 2020.
9. HHS. CPSTF findings for increasing vaccination. www.thecommunityguide.org/content/task-force-findings-increasing-vaccination. Accessed September 29, 2020.
Choosing Wisely: 10 practices to stop—or adopt—to reduce overuse in health care
When medical care is based on consistent, good-quality evidence, most physicians adopt it. However, not all care is well supported by the literature and may, in fact, be overused without offering benefit to patients. Choosing Wisely, at www.choosingwisely.org, is a health care initiative that highlights screening and testing recommendations from specialty societies in an effort to encourage patients and clinicians to talk about how to make high-value, effective health care decisions and avoid overuse. (See “Test and Tx overutilization: A bigger problem than you might think"1-3).
SIDEBAR
Test and Tx overutilization: A bigger problem than you might think
Care that isn’t backed up by the medical literature is adopted by some physicians and not adopted by others, leading to practice variations. Some variation is to be expected, since no 2 patients require exactly the same care, but substantial variations may be a clue to overuse.
A 2006 analysis of inpatient lab studies found that doctors ordered an average of 2.96 studies per patient per day, but only 29% of these tests (0.95 test/patient/day) contributed to management.1 A 2016 systematic review found more than 800 studies on overuse were published in a single year.2 One study of thyroid nodules followed almost 1000 patients with nodules as they underwent routine follow-up imaging. At the end of the study, 7 were found to have cancer, but of those, only 3 had enlarging or changing nodules that would have been detected with the follow-up imaging being studied. Three of the cancers were stable in size and 1 was found incidentally.3
Enabling physician and patient dialogue. The initiative began in 2010 when the American Board of Internal Medicine convened a panel of experts to identify low-value tests and therapies. Their list took the form of a “Top Five Things” that may not be high value in patient care, and it used language tailored to patients and physicians so that they could converse meaningfully. Physicians could use the evidence to make a clinical decision, and patients could feel empowered to ask informed questions about recommendations they received. The initiative has now expanded to include ways that health care systems can reduce low-value interventions.
Scope of participation. Since the first Choosing Wisely recommendations were published in 2013, more than 80 professional associations have contributed lists of their own. Professional societies participate voluntarily. The American Academy of Family Physicians (AAFP), Society of General Internal Medicine, and American Academy of Pediatrics (AAP) have contributed lists relevant to primary care. All Choosing Wisely recommendations can be searched or sorted by specialty organization. Recommendations are reviewed and revised regularly. If the evidence becomes conflicted or contradictory, recommendations are withdrawn.
Making meaningful improvements by Choosing Wisely
Several studies have shown that health care systems can implement Choosing Wisely recommendations to reduce overuse of unnecessary tests. A 2015 study examined the effect of applying a Choosing Wisely recommendation to reduce the use of continuous pulse oximetry in pediatric inpatients with asthma, wheezing, or bronchiolitis. The recommendation, from the Society of Hospital Medicine–Pediatric Hospital Medicine, advises against continuous pulse oximetry in children with acute respiratory illnesses unless the child is using supplemental oxygen.4 This study, done at the Cincinnati Children’s Hospital Medical Center, found that within 3 months of initiating a protocol on all general pediatrics floors, the average time on pulse oximetry after meeting clinical goals decreased from 10.7 hours to 3.1 hours. In addition, the percentage of patients who had their continuous pulse oximetry stopped within 2 hours of clinical stability (a goal time) increased from 25% to 46%.5
Patients are important drivers of health care utilization. A 2003 study showed that physicians are more likely to order referrals, tests, and prescriptions when patients ask for them, and that nearly 1 in 4 patients did so.6 A 2002 study found that physicians granted all but 3% of patient’s requests for orders or tests, and that fulfilling requests correlated with patient satisfaction in the specialty office studied (cardiology) but not in the primary care (internal medicine) office.7
From its inception, Choosing Wisely has considered patients as full partners in conversations about health care utilization. Choosing Wisely partners with Consumer Reports to create and disseminate plain-language summaries of recommendations. Community groups and physician organizations have also participated in implementation efforts. In 2018, Choosing Wisely secured a grant to expand outreach to diverse or underserved communities.
Choosing Wisely recommendations are not guidelines or mandates. They are intended to be evidence-based advice from a specialty society to its members and to patients about care that is often unnecessary. The goal is to create a conversation and not to eliminate these services from ever being offered or used.
Continue to: Improve your practice with these 10 primary care recommendations
Improve your practice with these 10 primary care recommendations
1 Avoid imaging studies in early acute low back pain without red flags.
Both the AAFP and the American Society of Anesthesiologists recommend against routine X-rays, magnetic resonance imaging, and computed tomography (CT) scans in the first 6 weeks of acute low back pain (LBP).8,9 The American College of Emergency Physicians (ACEP) recommends against routine lumbar spine imaging for emergency department (ED) patients.10 In all cases, imaging is indicated if the patient has any signs or symptoms of neurologic deficits or other indications, such as signs of spinal infection or fracture. However, as ACEP notes, diagnostic imaging does not typically help identify the cause of acute LBP, and when it does, it does not reduce the time to symptom improvement.10
2 Prescribe oral contraceptives on the basis of a medical history and a blood pressure measurement. No routine pelvic exam or other physical exam is necessary.
This AAFP recommendation11 is based on clinical practice guidelines from the American College of Obstetricians and Gynecologists (ACOG) and other research.12 The ACOG practice guideline supports provision of hormonal contraception without a pelvic exam, cervical cancer (Pap) testing, urine pregnancy testing, or testing for sexually transmitted infections. ACOG guidelines also support over-the-counter provision of hormonal contraceptives, including combined oral contraceptives.12
3 Stop recommending daily self-glucose monitoring for patients with diabetes who are not using insulin.
Both the AAFP and the Society for General Internal Medicine recommend against daily blood sugar checks for people who do not use insulin.13,14 A Cochrane review of 9 trials (3300 patients) found that after 6 months, hemoglobin A1C was reduced by 0.3% in people who checked their sugar daily compared with those who did not, but this difference was not significant after a year.15 Hypoglycemic episodes were more common in the “checking” group, and there were no differences in quality of life. A qualitative study found that blood sugar results had little impact on patients’ motivation to change behavior.16
4 Don’t screen for herpes simplex virus (HSV) infection in asymptomatic adults, even those who are pregnant.
This AAFP recommendation17 comes from a US Preventive Services Task Force (USPSTF) Grade D recommendation.18 Most people with positive HSV-2 serology have had an outbreak; even those who do not think they have had one will realize that they had the symptoms once they hear them described.18 With available tests, 1 in 2 positive results for HSV-2 among asymptomatic people will be a false-positive.18
There is no known cure, intervention, or reduction in transmission for infected patients who do not have symptoms.18 Also, serologically detected HSV-2 does not reliably predict genital herpes; and HSV-1 has been found to cause an increasing percentage of genital infection cases.18
Continue to: 5 Don't screen for testicular cancer in asymptomatic individuals
5 Don’t screen for testicular cancer in asymptomatic individuals.
This AAFP recommendation19 also comes from a USPSTF Grade D recommendation.20 A 2010 systematic review found no evidence to support screening of asymptomatic people with a physical exam or ultrasound. All available studies involved symptomatic patients.20
6 Stop recommending cough and cold medicines for children younger than 4 years.
The AAP recommends that clinicians discourage the use of any cough or cold medicine for children in this age-group.21 A 2008 study found that more than 7000 children annually presented to EDs for adverse events from cough and cold medicines.22 Previous studies found no benefit in reducing symptoms.23 In children older than 12 months, a Cochrane review found that honey has a modest benefit for cough in single-night trials.24
7 Avoid performing serum allergy panels.
The American Academy of Allergy, Asthma, and Immunology discourages the use of serum panel testing when patients present with allergy symptoms.25 A patient can have a strong positive immunoglobulin E (IgE) serum result to an allergen and have no clinical allergic symptoms or can have a weak positive serum result and a strong clinical reaction. Targeted skin or serum IgE testing—for example, testing for cashew allergy in a patient known to have had a reaction after eating one—is reasonable.26
8 Avoid routine electroencephalography (EEG), head CT, and carotid ultrasound as initial work-up for simple syncope in adults.
These recommendations, from the American Epilepsy Society,27 ACEP,28 American College of Physicians,29 and American Academy of Neurology (AAN),30 emphasize the low yield of routine work-ups for patients with simple syncope. The AAN notes that 40% of people will experience syncope during adulthood and most will not have carotid disease, which generally manifests with stroke-like symptoms rather than syncope. One study found that approximately 1 in 8 patients referred to an epilepsy clinic had neurocardiogenic syncope rather than epilepsy.31
EEGs have high false-negative and false-positive rates, and history-taking is a better tool with which to make a diagnosis. CT scans performed in the ED were found to contribute to the diagnosis of simple syncope in fewer than 2% of cases of syncope, compared with orthostatic blood pressure (25% of cases).32
Continue to: 9 Wait to refer children with umbilical hernias to pediatric surgery until they are 4 to 5 years of age
9 Wait to refer children with umbilical hernias to pediatric surgery until they are 4 to 5 years of age.
The AAP Section on Surgery offers evidence that the risk-benefit analysis strongly favors waiting on intervention.33 About 1 in 4 children will have an umbilical hernia, and about 85% of cases will resolve by age 5. The strangulation rate with umbilical hernias is very low, and although the risk of infection with surgery is likewise low, the risk of recurrence following surgery before the age of 4 is as high as 2.4%.34 The AAP Section on Surgery recommends against strapping or restraining the hernia, as well.
10 Avoid using appetite stimulants, such as megesterol, and high-calorie nutritional supplements to treat anorexia and cachexia in older adults.
Instead, the American Geriatrics Society recommends that physicians encourage caregivers to serve appealing food, provide support with eating, and remove barriers to appetite and nutrition.35 A Cochrane review showed that high-calorie supplements, such as Boost or Ensure, are associated with very modest weight gain—about 2% of weight—but are not associated with an increased life expectancy or improved quality of life.36
Prescription appetite stimulants are associated with adverse effects and yield inconsistent benefits in older adults. Megesterol, for example, was associated with headache, gastrointestinal adverse effects, insomnia, weakness, and fatigue. Mirtazapine is associated with sedation and fatigue.37
CORRESPONDENCE
Kathleen Rowland, MD, MS, Rush Copley Family Medicine Residency, Rush Medical College, 600 South Paulina, Kidston House Room 605, Chicago IL 60612; [email protected].
1. Miyakis S, Karamanof G, Liontos M, et al. Factors contributing to inappropriate ordering of tests in an academic medical department and the effect of an educational feedback strategy. Postgrad Med J. 2006;82:823-829.
2. Morgan DJ, Dhruva SS, Wright SM, et al. Update on medical overuse: a systematic review. JAMA Intern Med. 2016;176:1687-1692.
3. Durante C, Costante G, Lucisano G, et al. The natural history of benign thyroid nodules. JAMA. 2015;313:926-935.
4. Choosing Wisely. Society of Hospital Medicine—Pediatric hospital medicine. Don’t use continuous pulse oximetry routinely in children with acute respiratory illness unless they are on supplemental oxygen. www.choosingwisely.org/clinician-lists/society-hospital-medicine-pediatric-continuous-pulse-oximetry-in-children-with-acute-respiratory-illness/. Accessed September 28, 2020.
5. Schondelmeyer AC, Simmons JM, Statile AM, et al. Using quality improvement to reduce continuous pulse oximetry use in children with wheezing. Pediatrics. 2015;135:e1044-e1051.
6. Kravitz RL, Bell RA, Azari R, et al. Direct observation of requests for clinical services in office practice: what do patients want and do they get it? Arch Intern Med. 2003;163:1673-1681.
7. Kravitz RL, Bell RA, Franz CE, et al. Characterizing patient requests and physician responses in office practice. Health Serv Res. 2002;37:217-238.
8. Choosing Wisely. American Academy of Family Physicians. Don’t do imaging for low back pain within the first six weeks, unless red flags are present. www.choosingwisely.org/clinician-lists/american-academy-family-physicians-imaging-low-back-pain/. Accessed September 28, 2020.
9. Choosing Wisely. American Society of Anesthesiologists–Pain Medicine. Avoid imaging studies (MRI, CT or X-rays) for acute low back pain without specific indications. www.choosingwisely.org/clinician-lists/american-society-anesthesiologists-imaging-studies-for-acute-low-back-pain/. Accessed September 28, 2020.
10. Choosing Wisely. American College of Emergency Physicians. Avoid lumbar spine imaging in the emergency department for adults with non-traumatic back pain unless the patient has severe or progressive neurologic deficits or is suspected of having a serious underlying condition (such as vertebral infection, cauda equina syndrome, or cancer with bony metastasis). www.choosingwisely.org/clinician-lists/acep-lumbar-spine-imaging-in-the-ed/. Accessed September 28, 2020.
11. Choosing Wisely. American Academy of Family Physicians. Don’t require a pelvic exam or other physical exam to prescribe oral contraceptive medications. www.choosingwisely.org/clinician-lists/american-academy-family-physicians-pelvic-or-physical-exams-to-prescribe-oral-contraceptives/. Accessed September 28, 2020.
12. Over-the-counter access to hormonal contraception. ACOG Committee Opinion, Number 788. Obstet Gynecol. 2019;134:e96-e105. https://journals.lww.com/greenjournal/Fulltext/2019/10000/Over_the_Counter_Access_to_Hormonal_Contraception_.46.aspx. Accessed September 28, 2020.
13. Choosing Wisely. American Academy of Family Physicians. Don’t routinely recommend daily home glucose monitoring for patients who have Type 2 diabetes mellitus and are not using insulin. www.choosingwisely.org/clinician-lists/aafp-daily-home-glucose-monitoring-for-patients-with-type-2-diabetes. Accessed September 28, 2020.
14. Choosing Wisely. Society of General Internal Medicine. Don’t recommend daily home finger glucose testing in patients with Type 2 diabetes mellitus not using insulin. www.choosingwisely.org/clinician-lists/society-general-internal-medicine-daily-home-finger-glucose-testing-type-2-diabetes-mellitus/. Accessed September 28, 2020.
15. Malanda UL, Welschen LM, Riphagen II, et al. Self‐monitoring of blood glucose in patients with type 2 diabetes mellitus who are not using insulin. Cochrane Database Syst Rev. 2012(1):CD005060.
16. Peel E, Douglas M, Lawton J. Self monitoring of blood glucose in type 2 diabetes: longitudinal qualitative study of patients’ perspectives. BMJ. 2007;335:493.
17. Choosing Wisely. American Academy of Family Physicians. Don’t screen for genital herpes simplex virus infection (HSV) in asymptomatic adults, including pregnant women. www.choosingwisely.org/clinician-lists/aafp-genital-herpes-screening-in-asymptomatic-adults/. Accessed September 28, 2020.
18. Bibbins-Domingo K, Grossman DC, Curry SJ, et al. Serologic screening for genital herpes infection: US Preventive Services Task Force recommendation statement. JAMA. 2016;316:2525-2530.
19. Choosing Wisely. American Academy of Family Physicians. Don’t screen for testicular cancer in asymptomatic adolescent and adult males. www.choosingwisely.org/clinician-lists/aafp-testicular-cancer-screening-in-asymptomatic-adolescent-and-adult-men/. Accessed September 28, 2020.
20. Lin K, Sharangpani R. Screening for testicular cancer: an evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2010;153:396-399.
21. Choosing Wisely. American Academy of Pediatrics. Cough and cold medicines should not be prescribed, recommended or used for respiratory illnesses in young children. www.choosingwisely.org/clinician-lists/american-academy-pediatrics-cough-and-cold-medicines-for-children-under-four/. Accessed September 28, 2020.
22. Schaefer MK, Shehab N, Cohen AL, et al. Adverse events from cough and cold medications in children. Pediatrics. 2008;121:783-787.
23. Carr BC. Efficacy, abuse, and toxicity of over-the-counter cough and cold medicines in the pediatric population. Curr Opin Pediatr. 2006;18:184-188.
24. Oduwole O, Udoh EE, Oyo‐Ita A, et al. Honey for acute cough in children. Cochrane Database Syst Rev. 2018(4):CD007094.
25. Choosing Wisely. American Academy of Allergy, Asthma & Immunology. Don’t perform unproven diagnostic tests, such as immunoglobulin G(lgG) testing or an indiscriminate battery of immunoglobulin E(lgE) tests, in the evaluation of allergy. www.choosingwisely.org/clinician-lists/american-academy-allergy-asthma-immunology-diagnostic-tests-for-allergy-evaluation/. Accessed September 28, 2020.
26. Cox L, Williams B, Sicherer S, et al. Pearls and pitfalls of allergy diagnostic testing: report from the American College of Allergy, Asthma and Immunology Specific IgE Test Task Force. Ann Allergy Asthma Immunol. 2008;101:580-592.
27. Choosing Wisely. American Epilepsy Society. Do not routinely order electroencephalogram (EEG) as part of initial syncope work-up. www.choosingwisely.org/clinician-lists/aes-eeg-as-part-of-initial-syncope-work-up/. Accessed September 28, 2020.
28. Choosing Wisely. American College of Emergency Physicians. Avoid CT of the head in asymptomatic adult patients in the emergency department with syncope, insignificant trauma and a normal neurological evaluation. www.choosingwisely.org/clinician-lists/acep-avoid-head-ct-for-asymptomatic-adults-with-syncope/. Accessed September 28, 2020.
29. Choosing Wisely. American College of Physicians. In the evaluation of simple syncope and a normal neurological examination, don’t obtain brain imaging studies (CT or MRI). www.choosingwisely.org/clinician-lists/american-college-physicians-brain-imaging-to-evaluate-simple-syncope/. Accessed September 28, 2020.
30. Choosing Wisely. American Academy of Neurology. Don’t perform imaging of the carotid arteries for simple syncope without other neurologic symptoms. www.choosingwisely.org/clinician-lists/american-academy-neurology-carotid-artery-imaging-for-simple-syncope/. Accessed September 28, 2020.
31. Josephson CB, Rahey S, Sadler RM. Neurocardiogenic syncope: frequency and consequences of its misdiagnosis as epilepsy. Can J Neurol Sci. 2007;34:221-224.
32. Mendu ML, McAvay G, Lampert R, et al. Yield of diagnostic tests in evaluating syncopal episodes in older patients. Arch Intern Med. 2009;169:1299-1305.
33. Choosing Wisely. American Academy of Pediatrics–Section on Surgery. Avoid referring most children with umbilical hernias to a pediatric surgeon until around age 4-5 years. www.choosingwisely.org/clinician-lists/aap-sosu-avoid-surgery-referral-for-umbilical-hernias-until-age-4-5/. Accessed September 28, 2020.
34. Antonoff MB, Kreykes NS, Saltzman DA, et al. American Academy of Pediatrics Section on Surgery hernia survey revisited. J Pediatr Surg. 2005;40:1009-1014.
35. Choosing Wisely. American Geriatrics Society. Avoid using prescription appetite stimulants or high-calorie supplements for treatment of anorexia or cachexia in older adults; instead, optimize social supports, discontinue medications that may interfere with eating, provide appealing food and feeding assistance, and clarify patient goals and expectations. www.choosingwisely.org/clinician-lists/american-geriatrics-society-prescription-appetite-stimulants-to-treat-anorexia-cachexia-in-elderly/. Accessed September 28, 2020.
36. Milne AC, Potter J, Vivanti A, et al. Protein and energy supplementation in elderly people at risk from malnutrition. Cochrane Database Sys Rev. 2009(2):CD003288.
37. Fox CB, Treadway AK, Blaszczyk AT, et al. Megestrol acetate and mirtazapine for the treatment of unplanned weight loss in the elderly. Pharmacotherapy. 2009;29:383-397.
When medical care is based on consistent, good-quality evidence, most physicians adopt it. However, not all care is well supported by the literature and may, in fact, be overused without offering benefit to patients. Choosing Wisely, at www.choosingwisely.org, is a health care initiative that highlights screening and testing recommendations from specialty societies in an effort to encourage patients and clinicians to talk about how to make high-value, effective health care decisions and avoid overuse. (See “Test and Tx overutilization: A bigger problem than you might think"1-3).
SIDEBAR
Test and Tx overutilization: A bigger problem than you might think
Care that isn’t backed up by the medical literature is adopted by some physicians and not adopted by others, leading to practice variations. Some variation is to be expected, since no 2 patients require exactly the same care, but substantial variations may be a clue to overuse.
A 2006 analysis of inpatient lab studies found that doctors ordered an average of 2.96 studies per patient per day, but only 29% of these tests (0.95 test/patient/day) contributed to management.1 A 2016 systematic review found more than 800 studies on overuse were published in a single year.2 One study of thyroid nodules followed almost 1000 patients with nodules as they underwent routine follow-up imaging. At the end of the study, 7 were found to have cancer, but of those, only 3 had enlarging or changing nodules that would have been detected with the follow-up imaging being studied. Three of the cancers were stable in size and 1 was found incidentally.3
Enabling physician and patient dialogue. The initiative began in 2010 when the American Board of Internal Medicine convened a panel of experts to identify low-value tests and therapies. Their list took the form of a “Top Five Things” that may not be high value in patient care, and it used language tailored to patients and physicians so that they could converse meaningfully. Physicians could use the evidence to make a clinical decision, and patients could feel empowered to ask informed questions about recommendations they received. The initiative has now expanded to include ways that health care systems can reduce low-value interventions.
Scope of participation. Since the first Choosing Wisely recommendations were published in 2013, more than 80 professional associations have contributed lists of their own. Professional societies participate voluntarily. The American Academy of Family Physicians (AAFP), Society of General Internal Medicine, and American Academy of Pediatrics (AAP) have contributed lists relevant to primary care. All Choosing Wisely recommendations can be searched or sorted by specialty organization. Recommendations are reviewed and revised regularly. If the evidence becomes conflicted or contradictory, recommendations are withdrawn.
Making meaningful improvements by Choosing Wisely
Several studies have shown that health care systems can implement Choosing Wisely recommendations to reduce overuse of unnecessary tests. A 2015 study examined the effect of applying a Choosing Wisely recommendation to reduce the use of continuous pulse oximetry in pediatric inpatients with asthma, wheezing, or bronchiolitis. The recommendation, from the Society of Hospital Medicine–Pediatric Hospital Medicine, advises against continuous pulse oximetry in children with acute respiratory illnesses unless the child is using supplemental oxygen.4 This study, done at the Cincinnati Children’s Hospital Medical Center, found that within 3 months of initiating a protocol on all general pediatrics floors, the average time on pulse oximetry after meeting clinical goals decreased from 10.7 hours to 3.1 hours. In addition, the percentage of patients who had their continuous pulse oximetry stopped within 2 hours of clinical stability (a goal time) increased from 25% to 46%.5
Patients are important drivers of health care utilization. A 2003 study showed that physicians are more likely to order referrals, tests, and prescriptions when patients ask for them, and that nearly 1 in 4 patients did so.6 A 2002 study found that physicians granted all but 3% of patient’s requests for orders or tests, and that fulfilling requests correlated with patient satisfaction in the specialty office studied (cardiology) but not in the primary care (internal medicine) office.7
From its inception, Choosing Wisely has considered patients as full partners in conversations about health care utilization. Choosing Wisely partners with Consumer Reports to create and disseminate plain-language summaries of recommendations. Community groups and physician organizations have also participated in implementation efforts. In 2018, Choosing Wisely secured a grant to expand outreach to diverse or underserved communities.
Choosing Wisely recommendations are not guidelines or mandates. They are intended to be evidence-based advice from a specialty society to its members and to patients about care that is often unnecessary. The goal is to create a conversation and not to eliminate these services from ever being offered or used.
Continue to: Improve your practice with these 10 primary care recommendations
Improve your practice with these 10 primary care recommendations
1 Avoid imaging studies in early acute low back pain without red flags.
Both the AAFP and the American Society of Anesthesiologists recommend against routine X-rays, magnetic resonance imaging, and computed tomography (CT) scans in the first 6 weeks of acute low back pain (LBP).8,9 The American College of Emergency Physicians (ACEP) recommends against routine lumbar spine imaging for emergency department (ED) patients.10 In all cases, imaging is indicated if the patient has any signs or symptoms of neurologic deficits or other indications, such as signs of spinal infection or fracture. However, as ACEP notes, diagnostic imaging does not typically help identify the cause of acute LBP, and when it does, it does not reduce the time to symptom improvement.10
2 Prescribe oral contraceptives on the basis of a medical history and a blood pressure measurement. No routine pelvic exam or other physical exam is necessary.
This AAFP recommendation11 is based on clinical practice guidelines from the American College of Obstetricians and Gynecologists (ACOG) and other research.12 The ACOG practice guideline supports provision of hormonal contraception without a pelvic exam, cervical cancer (Pap) testing, urine pregnancy testing, or testing for sexually transmitted infections. ACOG guidelines also support over-the-counter provision of hormonal contraceptives, including combined oral contraceptives.12
3 Stop recommending daily self-glucose monitoring for patients with diabetes who are not using insulin.
Both the AAFP and the Society for General Internal Medicine recommend against daily blood sugar checks for people who do not use insulin.13,14 A Cochrane review of 9 trials (3300 patients) found that after 6 months, hemoglobin A1C was reduced by 0.3% in people who checked their sugar daily compared with those who did not, but this difference was not significant after a year.15 Hypoglycemic episodes were more common in the “checking” group, and there were no differences in quality of life. A qualitative study found that blood sugar results had little impact on patients’ motivation to change behavior.16
4 Don’t screen for herpes simplex virus (HSV) infection in asymptomatic adults, even those who are pregnant.
This AAFP recommendation17 comes from a US Preventive Services Task Force (USPSTF) Grade D recommendation.18 Most people with positive HSV-2 serology have had an outbreak; even those who do not think they have had one will realize that they had the symptoms once they hear them described.18 With available tests, 1 in 2 positive results for HSV-2 among asymptomatic people will be a false-positive.18
There is no known cure, intervention, or reduction in transmission for infected patients who do not have symptoms.18 Also, serologically detected HSV-2 does not reliably predict genital herpes; and HSV-1 has been found to cause an increasing percentage of genital infection cases.18
Continue to: 5 Don't screen for testicular cancer in asymptomatic individuals
5 Don’t screen for testicular cancer in asymptomatic individuals.
This AAFP recommendation19 also comes from a USPSTF Grade D recommendation.20 A 2010 systematic review found no evidence to support screening of asymptomatic people with a physical exam or ultrasound. All available studies involved symptomatic patients.20
6 Stop recommending cough and cold medicines for children younger than 4 years.
The AAP recommends that clinicians discourage the use of any cough or cold medicine for children in this age-group.21 A 2008 study found that more than 7000 children annually presented to EDs for adverse events from cough and cold medicines.22 Previous studies found no benefit in reducing symptoms.23 In children older than 12 months, a Cochrane review found that honey has a modest benefit for cough in single-night trials.24
7 Avoid performing serum allergy panels.
The American Academy of Allergy, Asthma, and Immunology discourages the use of serum panel testing when patients present with allergy symptoms.25 A patient can have a strong positive immunoglobulin E (IgE) serum result to an allergen and have no clinical allergic symptoms or can have a weak positive serum result and a strong clinical reaction. Targeted skin or serum IgE testing—for example, testing for cashew allergy in a patient known to have had a reaction after eating one—is reasonable.26
8 Avoid routine electroencephalography (EEG), head CT, and carotid ultrasound as initial work-up for simple syncope in adults.
These recommendations, from the American Epilepsy Society,27 ACEP,28 American College of Physicians,29 and American Academy of Neurology (AAN),30 emphasize the low yield of routine work-ups for patients with simple syncope. The AAN notes that 40% of people will experience syncope during adulthood and most will not have carotid disease, which generally manifests with stroke-like symptoms rather than syncope. One study found that approximately 1 in 8 patients referred to an epilepsy clinic had neurocardiogenic syncope rather than epilepsy.31
EEGs have high false-negative and false-positive rates, and history-taking is a better tool with which to make a diagnosis. CT scans performed in the ED were found to contribute to the diagnosis of simple syncope in fewer than 2% of cases of syncope, compared with orthostatic blood pressure (25% of cases).32
Continue to: 9 Wait to refer children with umbilical hernias to pediatric surgery until they are 4 to 5 years of age
9 Wait to refer children with umbilical hernias to pediatric surgery until they are 4 to 5 years of age.
The AAP Section on Surgery offers evidence that the risk-benefit analysis strongly favors waiting on intervention.33 About 1 in 4 children will have an umbilical hernia, and about 85% of cases will resolve by age 5. The strangulation rate with umbilical hernias is very low, and although the risk of infection with surgery is likewise low, the risk of recurrence following surgery before the age of 4 is as high as 2.4%.34 The AAP Section on Surgery recommends against strapping or restraining the hernia, as well.
10 Avoid using appetite stimulants, such as megesterol, and high-calorie nutritional supplements to treat anorexia and cachexia in older adults.
Instead, the American Geriatrics Society recommends that physicians encourage caregivers to serve appealing food, provide support with eating, and remove barriers to appetite and nutrition.35 A Cochrane review showed that high-calorie supplements, such as Boost or Ensure, are associated with very modest weight gain—about 2% of weight—but are not associated with an increased life expectancy or improved quality of life.36
Prescription appetite stimulants are associated with adverse effects and yield inconsistent benefits in older adults. Megesterol, for example, was associated with headache, gastrointestinal adverse effects, insomnia, weakness, and fatigue. Mirtazapine is associated with sedation and fatigue.37
CORRESPONDENCE
Kathleen Rowland, MD, MS, Rush Copley Family Medicine Residency, Rush Medical College, 600 South Paulina, Kidston House Room 605, Chicago IL 60612; [email protected].
When medical care is based on consistent, good-quality evidence, most physicians adopt it. However, not all care is well supported by the literature and may, in fact, be overused without offering benefit to patients. Choosing Wisely, at www.choosingwisely.org, is a health care initiative that highlights screening and testing recommendations from specialty societies in an effort to encourage patients and clinicians to talk about how to make high-value, effective health care decisions and avoid overuse. (See “Test and Tx overutilization: A bigger problem than you might think"1-3).
SIDEBAR
Test and Tx overutilization: A bigger problem than you might think
Care that isn’t backed up by the medical literature is adopted by some physicians and not adopted by others, leading to practice variations. Some variation is to be expected, since no 2 patients require exactly the same care, but substantial variations may be a clue to overuse.
A 2006 analysis of inpatient lab studies found that doctors ordered an average of 2.96 studies per patient per day, but only 29% of these tests (0.95 test/patient/day) contributed to management.1 A 2016 systematic review found more than 800 studies on overuse were published in a single year.2 One study of thyroid nodules followed almost 1000 patients with nodules as they underwent routine follow-up imaging. At the end of the study, 7 were found to have cancer, but of those, only 3 had enlarging or changing nodules that would have been detected with the follow-up imaging being studied. Three of the cancers were stable in size and 1 was found incidentally.3
Enabling physician and patient dialogue. The initiative began in 2010 when the American Board of Internal Medicine convened a panel of experts to identify low-value tests and therapies. Their list took the form of a “Top Five Things” that may not be high value in patient care, and it used language tailored to patients and physicians so that they could converse meaningfully. Physicians could use the evidence to make a clinical decision, and patients could feel empowered to ask informed questions about recommendations they received. The initiative has now expanded to include ways that health care systems can reduce low-value interventions.
Scope of participation. Since the first Choosing Wisely recommendations were published in 2013, more than 80 professional associations have contributed lists of their own. Professional societies participate voluntarily. The American Academy of Family Physicians (AAFP), Society of General Internal Medicine, and American Academy of Pediatrics (AAP) have contributed lists relevant to primary care. All Choosing Wisely recommendations can be searched or sorted by specialty organization. Recommendations are reviewed and revised regularly. If the evidence becomes conflicted or contradictory, recommendations are withdrawn.
Making meaningful improvements by Choosing Wisely
Several studies have shown that health care systems can implement Choosing Wisely recommendations to reduce overuse of unnecessary tests. A 2015 study examined the effect of applying a Choosing Wisely recommendation to reduce the use of continuous pulse oximetry in pediatric inpatients with asthma, wheezing, or bronchiolitis. The recommendation, from the Society of Hospital Medicine–Pediatric Hospital Medicine, advises against continuous pulse oximetry in children with acute respiratory illnesses unless the child is using supplemental oxygen.4 This study, done at the Cincinnati Children’s Hospital Medical Center, found that within 3 months of initiating a protocol on all general pediatrics floors, the average time on pulse oximetry after meeting clinical goals decreased from 10.7 hours to 3.1 hours. In addition, the percentage of patients who had their continuous pulse oximetry stopped within 2 hours of clinical stability (a goal time) increased from 25% to 46%.5
Patients are important drivers of health care utilization. A 2003 study showed that physicians are more likely to order referrals, tests, and prescriptions when patients ask for them, and that nearly 1 in 4 patients did so.6 A 2002 study found that physicians granted all but 3% of patient’s requests for orders or tests, and that fulfilling requests correlated with patient satisfaction in the specialty office studied (cardiology) but not in the primary care (internal medicine) office.7
From its inception, Choosing Wisely has considered patients as full partners in conversations about health care utilization. Choosing Wisely partners with Consumer Reports to create and disseminate plain-language summaries of recommendations. Community groups and physician organizations have also participated in implementation efforts. In 2018, Choosing Wisely secured a grant to expand outreach to diverse or underserved communities.
Choosing Wisely recommendations are not guidelines or mandates. They are intended to be evidence-based advice from a specialty society to its members and to patients about care that is often unnecessary. The goal is to create a conversation and not to eliminate these services from ever being offered or used.
Continue to: Improve your practice with these 10 primary care recommendations
Improve your practice with these 10 primary care recommendations
1 Avoid imaging studies in early acute low back pain without red flags.
Both the AAFP and the American Society of Anesthesiologists recommend against routine X-rays, magnetic resonance imaging, and computed tomography (CT) scans in the first 6 weeks of acute low back pain (LBP).8,9 The American College of Emergency Physicians (ACEP) recommends against routine lumbar spine imaging for emergency department (ED) patients.10 In all cases, imaging is indicated if the patient has any signs or symptoms of neurologic deficits or other indications, such as signs of spinal infection or fracture. However, as ACEP notes, diagnostic imaging does not typically help identify the cause of acute LBP, and when it does, it does not reduce the time to symptom improvement.10
2 Prescribe oral contraceptives on the basis of a medical history and a blood pressure measurement. No routine pelvic exam or other physical exam is necessary.
This AAFP recommendation11 is based on clinical practice guidelines from the American College of Obstetricians and Gynecologists (ACOG) and other research.12 The ACOG practice guideline supports provision of hormonal contraception without a pelvic exam, cervical cancer (Pap) testing, urine pregnancy testing, or testing for sexually transmitted infections. ACOG guidelines also support over-the-counter provision of hormonal contraceptives, including combined oral contraceptives.12
3 Stop recommending daily self-glucose monitoring for patients with diabetes who are not using insulin.
Both the AAFP and the Society for General Internal Medicine recommend against daily blood sugar checks for people who do not use insulin.13,14 A Cochrane review of 9 trials (3300 patients) found that after 6 months, hemoglobin A1C was reduced by 0.3% in people who checked their sugar daily compared with those who did not, but this difference was not significant after a year.15 Hypoglycemic episodes were more common in the “checking” group, and there were no differences in quality of life. A qualitative study found that blood sugar results had little impact on patients’ motivation to change behavior.16
4 Don’t screen for herpes simplex virus (HSV) infection in asymptomatic adults, even those who are pregnant.
This AAFP recommendation17 comes from a US Preventive Services Task Force (USPSTF) Grade D recommendation.18 Most people with positive HSV-2 serology have had an outbreak; even those who do not think they have had one will realize that they had the symptoms once they hear them described.18 With available tests, 1 in 2 positive results for HSV-2 among asymptomatic people will be a false-positive.18
There is no known cure, intervention, or reduction in transmission for infected patients who do not have symptoms.18 Also, serologically detected HSV-2 does not reliably predict genital herpes; and HSV-1 has been found to cause an increasing percentage of genital infection cases.18
Continue to: 5 Don't screen for testicular cancer in asymptomatic individuals
5 Don’t screen for testicular cancer in asymptomatic individuals.
This AAFP recommendation19 also comes from a USPSTF Grade D recommendation.20 A 2010 systematic review found no evidence to support screening of asymptomatic people with a physical exam or ultrasound. All available studies involved symptomatic patients.20
6 Stop recommending cough and cold medicines for children younger than 4 years.
The AAP recommends that clinicians discourage the use of any cough or cold medicine for children in this age-group.21 A 2008 study found that more than 7000 children annually presented to EDs for adverse events from cough and cold medicines.22 Previous studies found no benefit in reducing symptoms.23 In children older than 12 months, a Cochrane review found that honey has a modest benefit for cough in single-night trials.24
7 Avoid performing serum allergy panels.
The American Academy of Allergy, Asthma, and Immunology discourages the use of serum panel testing when patients present with allergy symptoms.25 A patient can have a strong positive immunoglobulin E (IgE) serum result to an allergen and have no clinical allergic symptoms or can have a weak positive serum result and a strong clinical reaction. Targeted skin or serum IgE testing—for example, testing for cashew allergy in a patient known to have had a reaction after eating one—is reasonable.26
8 Avoid routine electroencephalography (EEG), head CT, and carotid ultrasound as initial work-up for simple syncope in adults.
These recommendations, from the American Epilepsy Society,27 ACEP,28 American College of Physicians,29 and American Academy of Neurology (AAN),30 emphasize the low yield of routine work-ups for patients with simple syncope. The AAN notes that 40% of people will experience syncope during adulthood and most will not have carotid disease, which generally manifests with stroke-like symptoms rather than syncope. One study found that approximately 1 in 8 patients referred to an epilepsy clinic had neurocardiogenic syncope rather than epilepsy.31
EEGs have high false-negative and false-positive rates, and history-taking is a better tool with which to make a diagnosis. CT scans performed in the ED were found to contribute to the diagnosis of simple syncope in fewer than 2% of cases of syncope, compared with orthostatic blood pressure (25% of cases).32
Continue to: 9 Wait to refer children with umbilical hernias to pediatric surgery until they are 4 to 5 years of age
9 Wait to refer children with umbilical hernias to pediatric surgery until they are 4 to 5 years of age.
The AAP Section on Surgery offers evidence that the risk-benefit analysis strongly favors waiting on intervention.33 About 1 in 4 children will have an umbilical hernia, and about 85% of cases will resolve by age 5. The strangulation rate with umbilical hernias is very low, and although the risk of infection with surgery is likewise low, the risk of recurrence following surgery before the age of 4 is as high as 2.4%.34 The AAP Section on Surgery recommends against strapping or restraining the hernia, as well.
10 Avoid using appetite stimulants, such as megesterol, and high-calorie nutritional supplements to treat anorexia and cachexia in older adults.
Instead, the American Geriatrics Society recommends that physicians encourage caregivers to serve appealing food, provide support with eating, and remove barriers to appetite and nutrition.35 A Cochrane review showed that high-calorie supplements, such as Boost or Ensure, are associated with very modest weight gain—about 2% of weight—but are not associated with an increased life expectancy or improved quality of life.36
Prescription appetite stimulants are associated with adverse effects and yield inconsistent benefits in older adults. Megesterol, for example, was associated with headache, gastrointestinal adverse effects, insomnia, weakness, and fatigue. Mirtazapine is associated with sedation and fatigue.37
CORRESPONDENCE
Kathleen Rowland, MD, MS, Rush Copley Family Medicine Residency, Rush Medical College, 600 South Paulina, Kidston House Room 605, Chicago IL 60612; [email protected].
1. Miyakis S, Karamanof G, Liontos M, et al. Factors contributing to inappropriate ordering of tests in an academic medical department and the effect of an educational feedback strategy. Postgrad Med J. 2006;82:823-829.
2. Morgan DJ, Dhruva SS, Wright SM, et al. Update on medical overuse: a systematic review. JAMA Intern Med. 2016;176:1687-1692.
3. Durante C, Costante G, Lucisano G, et al. The natural history of benign thyroid nodules. JAMA. 2015;313:926-935.
4. Choosing Wisely. Society of Hospital Medicine—Pediatric hospital medicine. Don’t use continuous pulse oximetry routinely in children with acute respiratory illness unless they are on supplemental oxygen. www.choosingwisely.org/clinician-lists/society-hospital-medicine-pediatric-continuous-pulse-oximetry-in-children-with-acute-respiratory-illness/. Accessed September 28, 2020.
5. Schondelmeyer AC, Simmons JM, Statile AM, et al. Using quality improvement to reduce continuous pulse oximetry use in children with wheezing. Pediatrics. 2015;135:e1044-e1051.
6. Kravitz RL, Bell RA, Azari R, et al. Direct observation of requests for clinical services in office practice: what do patients want and do they get it? Arch Intern Med. 2003;163:1673-1681.
7. Kravitz RL, Bell RA, Franz CE, et al. Characterizing patient requests and physician responses in office practice. Health Serv Res. 2002;37:217-238.
8. Choosing Wisely. American Academy of Family Physicians. Don’t do imaging for low back pain within the first six weeks, unless red flags are present. www.choosingwisely.org/clinician-lists/american-academy-family-physicians-imaging-low-back-pain/. Accessed September 28, 2020.
9. Choosing Wisely. American Society of Anesthesiologists–Pain Medicine. Avoid imaging studies (MRI, CT or X-rays) for acute low back pain without specific indications. www.choosingwisely.org/clinician-lists/american-society-anesthesiologists-imaging-studies-for-acute-low-back-pain/. Accessed September 28, 2020.
10. Choosing Wisely. American College of Emergency Physicians. Avoid lumbar spine imaging in the emergency department for adults with non-traumatic back pain unless the patient has severe or progressive neurologic deficits or is suspected of having a serious underlying condition (such as vertebral infection, cauda equina syndrome, or cancer with bony metastasis). www.choosingwisely.org/clinician-lists/acep-lumbar-spine-imaging-in-the-ed/. Accessed September 28, 2020.
11. Choosing Wisely. American Academy of Family Physicians. Don’t require a pelvic exam or other physical exam to prescribe oral contraceptive medications. www.choosingwisely.org/clinician-lists/american-academy-family-physicians-pelvic-or-physical-exams-to-prescribe-oral-contraceptives/. Accessed September 28, 2020.
12. Over-the-counter access to hormonal contraception. ACOG Committee Opinion, Number 788. Obstet Gynecol. 2019;134:e96-e105. https://journals.lww.com/greenjournal/Fulltext/2019/10000/Over_the_Counter_Access_to_Hormonal_Contraception_.46.aspx. Accessed September 28, 2020.
13. Choosing Wisely. American Academy of Family Physicians. Don’t routinely recommend daily home glucose monitoring for patients who have Type 2 diabetes mellitus and are not using insulin. www.choosingwisely.org/clinician-lists/aafp-daily-home-glucose-monitoring-for-patients-with-type-2-diabetes. Accessed September 28, 2020.
14. Choosing Wisely. Society of General Internal Medicine. Don’t recommend daily home finger glucose testing in patients with Type 2 diabetes mellitus not using insulin. www.choosingwisely.org/clinician-lists/society-general-internal-medicine-daily-home-finger-glucose-testing-type-2-diabetes-mellitus/. Accessed September 28, 2020.
15. Malanda UL, Welschen LM, Riphagen II, et al. Self‐monitoring of blood glucose in patients with type 2 diabetes mellitus who are not using insulin. Cochrane Database Syst Rev. 2012(1):CD005060.
16. Peel E, Douglas M, Lawton J. Self monitoring of blood glucose in type 2 diabetes: longitudinal qualitative study of patients’ perspectives. BMJ. 2007;335:493.
17. Choosing Wisely. American Academy of Family Physicians. Don’t screen for genital herpes simplex virus infection (HSV) in asymptomatic adults, including pregnant women. www.choosingwisely.org/clinician-lists/aafp-genital-herpes-screening-in-asymptomatic-adults/. Accessed September 28, 2020.
18. Bibbins-Domingo K, Grossman DC, Curry SJ, et al. Serologic screening for genital herpes infection: US Preventive Services Task Force recommendation statement. JAMA. 2016;316:2525-2530.
19. Choosing Wisely. American Academy of Family Physicians. Don’t screen for testicular cancer in asymptomatic adolescent and adult males. www.choosingwisely.org/clinician-lists/aafp-testicular-cancer-screening-in-asymptomatic-adolescent-and-adult-men/. Accessed September 28, 2020.
20. Lin K, Sharangpani R. Screening for testicular cancer: an evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2010;153:396-399.
21. Choosing Wisely. American Academy of Pediatrics. Cough and cold medicines should not be prescribed, recommended or used for respiratory illnesses in young children. www.choosingwisely.org/clinician-lists/american-academy-pediatrics-cough-and-cold-medicines-for-children-under-four/. Accessed September 28, 2020.
22. Schaefer MK, Shehab N, Cohen AL, et al. Adverse events from cough and cold medications in children. Pediatrics. 2008;121:783-787.
23. Carr BC. Efficacy, abuse, and toxicity of over-the-counter cough and cold medicines in the pediatric population. Curr Opin Pediatr. 2006;18:184-188.
24. Oduwole O, Udoh EE, Oyo‐Ita A, et al. Honey for acute cough in children. Cochrane Database Syst Rev. 2018(4):CD007094.
25. Choosing Wisely. American Academy of Allergy, Asthma & Immunology. Don’t perform unproven diagnostic tests, such as immunoglobulin G(lgG) testing or an indiscriminate battery of immunoglobulin E(lgE) tests, in the evaluation of allergy. www.choosingwisely.org/clinician-lists/american-academy-allergy-asthma-immunology-diagnostic-tests-for-allergy-evaluation/. Accessed September 28, 2020.
26. Cox L, Williams B, Sicherer S, et al. Pearls and pitfalls of allergy diagnostic testing: report from the American College of Allergy, Asthma and Immunology Specific IgE Test Task Force. Ann Allergy Asthma Immunol. 2008;101:580-592.
27. Choosing Wisely. American Epilepsy Society. Do not routinely order electroencephalogram (EEG) as part of initial syncope work-up. www.choosingwisely.org/clinician-lists/aes-eeg-as-part-of-initial-syncope-work-up/. Accessed September 28, 2020.
28. Choosing Wisely. American College of Emergency Physicians. Avoid CT of the head in asymptomatic adult patients in the emergency department with syncope, insignificant trauma and a normal neurological evaluation. www.choosingwisely.org/clinician-lists/acep-avoid-head-ct-for-asymptomatic-adults-with-syncope/. Accessed September 28, 2020.
29. Choosing Wisely. American College of Physicians. In the evaluation of simple syncope and a normal neurological examination, don’t obtain brain imaging studies (CT or MRI). www.choosingwisely.org/clinician-lists/american-college-physicians-brain-imaging-to-evaluate-simple-syncope/. Accessed September 28, 2020.
30. Choosing Wisely. American Academy of Neurology. Don’t perform imaging of the carotid arteries for simple syncope without other neurologic symptoms. www.choosingwisely.org/clinician-lists/american-academy-neurology-carotid-artery-imaging-for-simple-syncope/. Accessed September 28, 2020.
31. Josephson CB, Rahey S, Sadler RM. Neurocardiogenic syncope: frequency and consequences of its misdiagnosis as epilepsy. Can J Neurol Sci. 2007;34:221-224.
32. Mendu ML, McAvay G, Lampert R, et al. Yield of diagnostic tests in evaluating syncopal episodes in older patients. Arch Intern Med. 2009;169:1299-1305.
33. Choosing Wisely. American Academy of Pediatrics–Section on Surgery. Avoid referring most children with umbilical hernias to a pediatric surgeon until around age 4-5 years. www.choosingwisely.org/clinician-lists/aap-sosu-avoid-surgery-referral-for-umbilical-hernias-until-age-4-5/. Accessed September 28, 2020.
34. Antonoff MB, Kreykes NS, Saltzman DA, et al. American Academy of Pediatrics Section on Surgery hernia survey revisited. J Pediatr Surg. 2005;40:1009-1014.
35. Choosing Wisely. American Geriatrics Society. Avoid using prescription appetite stimulants or high-calorie supplements for treatment of anorexia or cachexia in older adults; instead, optimize social supports, discontinue medications that may interfere with eating, provide appealing food and feeding assistance, and clarify patient goals and expectations. www.choosingwisely.org/clinician-lists/american-geriatrics-society-prescription-appetite-stimulants-to-treat-anorexia-cachexia-in-elderly/. Accessed September 28, 2020.
36. Milne AC, Potter J, Vivanti A, et al. Protein and energy supplementation in elderly people at risk from malnutrition. Cochrane Database Sys Rev. 2009(2):CD003288.
37. Fox CB, Treadway AK, Blaszczyk AT, et al. Megestrol acetate and mirtazapine for the treatment of unplanned weight loss in the elderly. Pharmacotherapy. 2009;29:383-397.
1. Miyakis S, Karamanof G, Liontos M, et al. Factors contributing to inappropriate ordering of tests in an academic medical department and the effect of an educational feedback strategy. Postgrad Med J. 2006;82:823-829.
2. Morgan DJ, Dhruva SS, Wright SM, et al. Update on medical overuse: a systematic review. JAMA Intern Med. 2016;176:1687-1692.
3. Durante C, Costante G, Lucisano G, et al. The natural history of benign thyroid nodules. JAMA. 2015;313:926-935.
4. Choosing Wisely. Society of Hospital Medicine—Pediatric hospital medicine. Don’t use continuous pulse oximetry routinely in children with acute respiratory illness unless they are on supplemental oxygen. www.choosingwisely.org/clinician-lists/society-hospital-medicine-pediatric-continuous-pulse-oximetry-in-children-with-acute-respiratory-illness/. Accessed September 28, 2020.
5. Schondelmeyer AC, Simmons JM, Statile AM, et al. Using quality improvement to reduce continuous pulse oximetry use in children with wheezing. Pediatrics. 2015;135:e1044-e1051.
6. Kravitz RL, Bell RA, Azari R, et al. Direct observation of requests for clinical services in office practice: what do patients want and do they get it? Arch Intern Med. 2003;163:1673-1681.
7. Kravitz RL, Bell RA, Franz CE, et al. Characterizing patient requests and physician responses in office practice. Health Serv Res. 2002;37:217-238.
8. Choosing Wisely. American Academy of Family Physicians. Don’t do imaging for low back pain within the first six weeks, unless red flags are present. www.choosingwisely.org/clinician-lists/american-academy-family-physicians-imaging-low-back-pain/. Accessed September 28, 2020.
9. Choosing Wisely. American Society of Anesthesiologists–Pain Medicine. Avoid imaging studies (MRI, CT or X-rays) for acute low back pain without specific indications. www.choosingwisely.org/clinician-lists/american-society-anesthesiologists-imaging-studies-for-acute-low-back-pain/. Accessed September 28, 2020.
10. Choosing Wisely. American College of Emergency Physicians. Avoid lumbar spine imaging in the emergency department for adults with non-traumatic back pain unless the patient has severe or progressive neurologic deficits or is suspected of having a serious underlying condition (such as vertebral infection, cauda equina syndrome, or cancer with bony metastasis). www.choosingwisely.org/clinician-lists/acep-lumbar-spine-imaging-in-the-ed/. Accessed September 28, 2020.
11. Choosing Wisely. American Academy of Family Physicians. Don’t require a pelvic exam or other physical exam to prescribe oral contraceptive medications. www.choosingwisely.org/clinician-lists/american-academy-family-physicians-pelvic-or-physical-exams-to-prescribe-oral-contraceptives/. Accessed September 28, 2020.
12. Over-the-counter access to hormonal contraception. ACOG Committee Opinion, Number 788. Obstet Gynecol. 2019;134:e96-e105. https://journals.lww.com/greenjournal/Fulltext/2019/10000/Over_the_Counter_Access_to_Hormonal_Contraception_.46.aspx. Accessed September 28, 2020.
13. Choosing Wisely. American Academy of Family Physicians. Don’t routinely recommend daily home glucose monitoring for patients who have Type 2 diabetes mellitus and are not using insulin. www.choosingwisely.org/clinician-lists/aafp-daily-home-glucose-monitoring-for-patients-with-type-2-diabetes. Accessed September 28, 2020.
14. Choosing Wisely. Society of General Internal Medicine. Don’t recommend daily home finger glucose testing in patients with Type 2 diabetes mellitus not using insulin. www.choosingwisely.org/clinician-lists/society-general-internal-medicine-daily-home-finger-glucose-testing-type-2-diabetes-mellitus/. Accessed September 28, 2020.
15. Malanda UL, Welschen LM, Riphagen II, et al. Self‐monitoring of blood glucose in patients with type 2 diabetes mellitus who are not using insulin. Cochrane Database Syst Rev. 2012(1):CD005060.
16. Peel E, Douglas M, Lawton J. Self monitoring of blood glucose in type 2 diabetes: longitudinal qualitative study of patients’ perspectives. BMJ. 2007;335:493.
17. Choosing Wisely. American Academy of Family Physicians. Don’t screen for genital herpes simplex virus infection (HSV) in asymptomatic adults, including pregnant women. www.choosingwisely.org/clinician-lists/aafp-genital-herpes-screening-in-asymptomatic-adults/. Accessed September 28, 2020.
18. Bibbins-Domingo K, Grossman DC, Curry SJ, et al. Serologic screening for genital herpes infection: US Preventive Services Task Force recommendation statement. JAMA. 2016;316:2525-2530.
19. Choosing Wisely. American Academy of Family Physicians. Don’t screen for testicular cancer in asymptomatic adolescent and adult males. www.choosingwisely.org/clinician-lists/aafp-testicular-cancer-screening-in-asymptomatic-adolescent-and-adult-men/. Accessed September 28, 2020.
20. Lin K, Sharangpani R. Screening for testicular cancer: an evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2010;153:396-399.
21. Choosing Wisely. American Academy of Pediatrics. Cough and cold medicines should not be prescribed, recommended or used for respiratory illnesses in young children. www.choosingwisely.org/clinician-lists/american-academy-pediatrics-cough-and-cold-medicines-for-children-under-four/. Accessed September 28, 2020.
22. Schaefer MK, Shehab N, Cohen AL, et al. Adverse events from cough and cold medications in children. Pediatrics. 2008;121:783-787.
23. Carr BC. Efficacy, abuse, and toxicity of over-the-counter cough and cold medicines in the pediatric population. Curr Opin Pediatr. 2006;18:184-188.
24. Oduwole O, Udoh EE, Oyo‐Ita A, et al. Honey for acute cough in children. Cochrane Database Syst Rev. 2018(4):CD007094.
25. Choosing Wisely. American Academy of Allergy, Asthma & Immunology. Don’t perform unproven diagnostic tests, such as immunoglobulin G(lgG) testing or an indiscriminate battery of immunoglobulin E(lgE) tests, in the evaluation of allergy. www.choosingwisely.org/clinician-lists/american-academy-allergy-asthma-immunology-diagnostic-tests-for-allergy-evaluation/. Accessed September 28, 2020.
26. Cox L, Williams B, Sicherer S, et al. Pearls and pitfalls of allergy diagnostic testing: report from the American College of Allergy, Asthma and Immunology Specific IgE Test Task Force. Ann Allergy Asthma Immunol. 2008;101:580-592.
27. Choosing Wisely. American Epilepsy Society. Do not routinely order electroencephalogram (EEG) as part of initial syncope work-up. www.choosingwisely.org/clinician-lists/aes-eeg-as-part-of-initial-syncope-work-up/. Accessed September 28, 2020.
28. Choosing Wisely. American College of Emergency Physicians. Avoid CT of the head in asymptomatic adult patients in the emergency department with syncope, insignificant trauma and a normal neurological evaluation. www.choosingwisely.org/clinician-lists/acep-avoid-head-ct-for-asymptomatic-adults-with-syncope/. Accessed September 28, 2020.
29. Choosing Wisely. American College of Physicians. In the evaluation of simple syncope and a normal neurological examination, don’t obtain brain imaging studies (CT or MRI). www.choosingwisely.org/clinician-lists/american-college-physicians-brain-imaging-to-evaluate-simple-syncope/. Accessed September 28, 2020.
30. Choosing Wisely. American Academy of Neurology. Don’t perform imaging of the carotid arteries for simple syncope without other neurologic symptoms. www.choosingwisely.org/clinician-lists/american-academy-neurology-carotid-artery-imaging-for-simple-syncope/. Accessed September 28, 2020.
31. Josephson CB, Rahey S, Sadler RM. Neurocardiogenic syncope: frequency and consequences of its misdiagnosis as epilepsy. Can J Neurol Sci. 2007;34:221-224.
32. Mendu ML, McAvay G, Lampert R, et al. Yield of diagnostic tests in evaluating syncopal episodes in older patients. Arch Intern Med. 2009;169:1299-1305.
33. Choosing Wisely. American Academy of Pediatrics–Section on Surgery. Avoid referring most children with umbilical hernias to a pediatric surgeon until around age 4-5 years. www.choosingwisely.org/clinician-lists/aap-sosu-avoid-surgery-referral-for-umbilical-hernias-until-age-4-5/. Accessed September 28, 2020.
34. Antonoff MB, Kreykes NS, Saltzman DA, et al. American Academy of Pediatrics Section on Surgery hernia survey revisited. J Pediatr Surg. 2005;40:1009-1014.
35. Choosing Wisely. American Geriatrics Society. Avoid using prescription appetite stimulants or high-calorie supplements for treatment of anorexia or cachexia in older adults; instead, optimize social supports, discontinue medications that may interfere with eating, provide appealing food and feeding assistance, and clarify patient goals and expectations. www.choosingwisely.org/clinician-lists/american-geriatrics-society-prescription-appetite-stimulants-to-treat-anorexia-cachexia-in-elderly/. Accessed September 28, 2020.
36. Milne AC, Potter J, Vivanti A, et al. Protein and energy supplementation in elderly people at risk from malnutrition. Cochrane Database Sys Rev. 2009(2):CD003288.
37. Fox CB, Treadway AK, Blaszczyk AT, et al. Megestrol acetate and mirtazapine for the treatment of unplanned weight loss in the elderly. Pharmacotherapy. 2009;29:383-397.
Returning to competition
As we continue to stumble around trying to find our way out of the COVID-19 pandemic, it has become clear that the journey has been a never-ending continuum of exercises in risk/benefit assessment. The population always has sorted itself into a bell-shaped curve from those who are risk averse to those who revel in risk taking. And, of course, with a paucity of facts on which we can base our assessment of risk, the discussion often shifts to our gut feelings about the benefits.
When faced with the question of when it is time for children to return to in-person schooling, there seems to be reasonably good agreement about the benefits of face-to-face learning. The level of risk is still to be determined.
When it comes to the issue of when to return to competitive school sports, the risks are equally indeterminate but there is less agreement on the benefits. This lack of uniformity reflects a long-standing dichotomy between those parents and students with a passion for competitive sports and those who see them as nonessential. This existential tug-of-war has gone on in almost every school system I am aware of when the school budget comes up for a vote.
The debate about a return to competitive sports on a collegiate and professional level unfortunately is colored by enormous revenues from media contracts, which means that high school and middle schools can’t look to what are essentially businesses for guidance. The delay created confusion, fluctuating angst and disappointment, but the end product made some sense. Volleyball (indoor) and football were indefinitely delayed. Heavy breathing between competitors separated by a couple of feet and protected only by a flimsy net or helmet cage seems like a risk not worth taking – at least until we have more information.
Other sports were allowed to start with restrictions based on existing social distancing mandates which include no locker rooms and no fans. Some rules such as no throw-ins for soccer didn’t make sense given what we are learning about the virus. But, for the most part, the compromises should result in a chance to reap the benefits of competition for the students whose families are willing to expose them to the yet to be fully determined risks.
There has been some grumbling from parents who see the no-fans mandate as a step too far. Until we know more about the risk of group gatherings outdoors, having no fans, including parents and grandparents, makes sense. In fact, to me it is a step long overdue and a rare sliver of silver lining to the pandemic. Competitive youth sports are for the kids. They are not meant to be entertainment events. Too often children are exposed to parental pressure (voiced and unvoiced) about their “performance” on the field. Neither my younger sister nor I can remember our parents going to any of my away football games in high school or any of my lacrosse games in college. I never felt the loss.
Will I miss watching my grandchildren compete? Of course I will miss it badly. However, giving kids some space to learn and enjoy the competition for itself in an atmosphere free of parental over-involvement will be a breath of fresh air. Something we need badly during this pandemic.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].
As we continue to stumble around trying to find our way out of the COVID-19 pandemic, it has become clear that the journey has been a never-ending continuum of exercises in risk/benefit assessment. The population always has sorted itself into a bell-shaped curve from those who are risk averse to those who revel in risk taking. And, of course, with a paucity of facts on which we can base our assessment of risk, the discussion often shifts to our gut feelings about the benefits.
When faced with the question of when it is time for children to return to in-person schooling, there seems to be reasonably good agreement about the benefits of face-to-face learning. The level of risk is still to be determined.
When it comes to the issue of when to return to competitive school sports, the risks are equally indeterminate but there is less agreement on the benefits. This lack of uniformity reflects a long-standing dichotomy between those parents and students with a passion for competitive sports and those who see them as nonessential. This existential tug-of-war has gone on in almost every school system I am aware of when the school budget comes up for a vote.
The debate about a return to competitive sports on a collegiate and professional level unfortunately is colored by enormous revenues from media contracts, which means that high school and middle schools can’t look to what are essentially businesses for guidance. The delay created confusion, fluctuating angst and disappointment, but the end product made some sense. Volleyball (indoor) and football were indefinitely delayed. Heavy breathing between competitors separated by a couple of feet and protected only by a flimsy net or helmet cage seems like a risk not worth taking – at least until we have more information.
Other sports were allowed to start with restrictions based on existing social distancing mandates which include no locker rooms and no fans. Some rules such as no throw-ins for soccer didn’t make sense given what we are learning about the virus. But, for the most part, the compromises should result in a chance to reap the benefits of competition for the students whose families are willing to expose them to the yet to be fully determined risks.
There has been some grumbling from parents who see the no-fans mandate as a step too far. Until we know more about the risk of group gatherings outdoors, having no fans, including parents and grandparents, makes sense. In fact, to me it is a step long overdue and a rare sliver of silver lining to the pandemic. Competitive youth sports are for the kids. They are not meant to be entertainment events. Too often children are exposed to parental pressure (voiced and unvoiced) about their “performance” on the field. Neither my younger sister nor I can remember our parents going to any of my away football games in high school or any of my lacrosse games in college. I never felt the loss.
Will I miss watching my grandchildren compete? Of course I will miss it badly. However, giving kids some space to learn and enjoy the competition for itself in an atmosphere free of parental over-involvement will be a breath of fresh air. Something we need badly during this pandemic.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].
As we continue to stumble around trying to find our way out of the COVID-19 pandemic, it has become clear that the journey has been a never-ending continuum of exercises in risk/benefit assessment. The population always has sorted itself into a bell-shaped curve from those who are risk averse to those who revel in risk taking. And, of course, with a paucity of facts on which we can base our assessment of risk, the discussion often shifts to our gut feelings about the benefits.
When faced with the question of when it is time for children to return to in-person schooling, there seems to be reasonably good agreement about the benefits of face-to-face learning. The level of risk is still to be determined.
When it comes to the issue of when to return to competitive school sports, the risks are equally indeterminate but there is less agreement on the benefits. This lack of uniformity reflects a long-standing dichotomy between those parents and students with a passion for competitive sports and those who see them as nonessential. This existential tug-of-war has gone on in almost every school system I am aware of when the school budget comes up for a vote.
The debate about a return to competitive sports on a collegiate and professional level unfortunately is colored by enormous revenues from media contracts, which means that high school and middle schools can’t look to what are essentially businesses for guidance. The delay created confusion, fluctuating angst and disappointment, but the end product made some sense. Volleyball (indoor) and football were indefinitely delayed. Heavy breathing between competitors separated by a couple of feet and protected only by a flimsy net or helmet cage seems like a risk not worth taking – at least until we have more information.
Other sports were allowed to start with restrictions based on existing social distancing mandates which include no locker rooms and no fans. Some rules such as no throw-ins for soccer didn’t make sense given what we are learning about the virus. But, for the most part, the compromises should result in a chance to reap the benefits of competition for the students whose families are willing to expose them to the yet to be fully determined risks.
There has been some grumbling from parents who see the no-fans mandate as a step too far. Until we know more about the risk of group gatherings outdoors, having no fans, including parents and grandparents, makes sense. In fact, to me it is a step long overdue and a rare sliver of silver lining to the pandemic. Competitive youth sports are for the kids. They are not meant to be entertainment events. Too often children are exposed to parental pressure (voiced and unvoiced) about their “performance” on the field. Neither my younger sister nor I can remember our parents going to any of my away football games in high school or any of my lacrosse games in college. I never felt the loss.
Will I miss watching my grandchildren compete? Of course I will miss it badly. However, giving kids some space to learn and enjoy the competition for itself in an atmosphere free of parental over-involvement will be a breath of fresh air. Something we need badly during this pandemic.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].
Remdesivir effective, well-tolerated in final trial report
Drug beats placebo across multiple endpoints in COVID-19 patients
In May 2020, remdesivir received Food and Drug Administration approval for emergency treatment of severe COVID-19 on the basis of a preliminary report on this trial. In August 2020, the FDA expanded the indication to include all hospitalized adult and pediatric patients with suspected or laboratory-confirmed COVID-19 infection irrespective of severity.
“Our findings were consistent with the findings of the preliminary report: a 10-day course of remdesivir was superior to placebo in the treatment of hospitalized patients with COVID-19,” reported a team of investigators led by John H. Beigel, MD, of the Division of Microbiology and Infectious Diseases at the National Institute of Allergy and Infectious Diseases, in the New England Journal of Medicine.
The drug’s broadened indication was not based on the ACTT-1 trial, according to Dr. Beigel. “Other data have demonstrated that remdesivir shortens recovery in patients with lower acuity. In our study, evidence of pneumonia was an enrollment requirement,” he explained in an interview.
In the newly published final ACTT-1 data, the median time to recovery was 10 days for those on active therapy versus 15 days for those randomized to placebo. With a rate ratio of 1.29 (P less than .001), this translated to a recovery that was about one third faster.
In this final report, remdesivir’s significant advantage over placebo regarding the trial’s primary endpoint was reinforced by efficacy on multiple secondary endpoints.
This benefits on multiple secondary endpoints included a 50% greater odds ratio (OR, 1.5; 95% CI, 1.2-1.9) of significant clinical improvement by day 15 after adjustment for baseline severity, a shorter initial length of hospital stay (12 vs. 17 days) and fewer days on oxygen supplementation (13 vs. 21 days) for the subgroup of patients on oxygen at enrollment.
Although the numerically lower mortality in the remdesivir arm (6.75 vs. 11.9%) did not reach statistical significance, Dr. Beigel said, “mortality was moving in the same direction as the other key endpoints.”
According to the study investigators, the types of rates of adverse events on remdesivir, which inhibits viral replication, “were generally similar in the remdesivir and placebo groups.”
In ACTT-1, 1,062 patients were randomized to remdesivir (200 mg loading dose followed by 100 mg daily for up to 9 days) or placebo. Patients were enrolled at study sites in North America, Europe, and Asia.
The data of ACTT-1 confirm a benefit from remdesivir in hospitalized COVID-19 patients with severe disease, but Dr. Beigel said he agrees with the current FDA indication that supports treatment in any hospitalized COVID-19 patient.
“We saw bigger benefits in patients with more severe infections. The benefits are not as large in patients with mild disease, but I think remdesivir should be considered in any hospitalized patient,” Dr. Beigel said.
This point of view is shared.
“I would give this drug to anyone in the hospital infected with COVID-19 assuming there was an ample supply and no need for rationing,” said Donna E. Sweet, MD, professor of internal medicine, University of Kansas, Wichita. She noted that this study has implications for hospital and hospital staff, as well as for patients.
“This type of reduction in recovery time means a reduction in potential exposures to hospital staff, a reduced need for PPE [personal protective equipment], and it will free up beds in the ICU [intensive care unit],” said Dr. Sweet, who also serves as an editorial advisory board member for Internal Medicine News.
An infectious disease specialist at the University of Minnesota also considers remdesivir to have an important role for conserving resources that deserves emphasis.
The reduction in time to recovery “is of benefit to the health system by maintaining hospital bed capacity,” said David R. Boulware, MD, professor of medicine at the University of Minnesota, Minneapolis.
According to his reading of the available data, including those from ACTT-1, the benefit appears to be greatest in those with a moderate degree of illness, which he defined as “sick enough to be hospitalized and require oxygen, yet not severely sick [and] requiring a ventilator or [extracorporeal membrane oxygenation].”
This does not preclude a benefit in those with more severe or milder disease, but patients with mild disease “are likely to recover regardless – or despite – whatever therapy they receive,” he said.
Dr. Beigel, the principal investigator of this trial, reports no potential conflicts of interest.
SOURCE: Beigel JH et al. N Engl J Med. 2020 Oct 8. doi: 10.1056/NEJMoa2007764.
Drug beats placebo across multiple endpoints in COVID-19 patients
Drug beats placebo across multiple endpoints in COVID-19 patients
In May 2020, remdesivir received Food and Drug Administration approval for emergency treatment of severe COVID-19 on the basis of a preliminary report on this trial. In August 2020, the FDA expanded the indication to include all hospitalized adult and pediatric patients with suspected or laboratory-confirmed COVID-19 infection irrespective of severity.
“Our findings were consistent with the findings of the preliminary report: a 10-day course of remdesivir was superior to placebo in the treatment of hospitalized patients with COVID-19,” reported a team of investigators led by John H. Beigel, MD, of the Division of Microbiology and Infectious Diseases at the National Institute of Allergy and Infectious Diseases, in the New England Journal of Medicine.
The drug’s broadened indication was not based on the ACTT-1 trial, according to Dr. Beigel. “Other data have demonstrated that remdesivir shortens recovery in patients with lower acuity. In our study, evidence of pneumonia was an enrollment requirement,” he explained in an interview.
In the newly published final ACTT-1 data, the median time to recovery was 10 days for those on active therapy versus 15 days for those randomized to placebo. With a rate ratio of 1.29 (P less than .001), this translated to a recovery that was about one third faster.
In this final report, remdesivir’s significant advantage over placebo regarding the trial’s primary endpoint was reinforced by efficacy on multiple secondary endpoints.
This benefits on multiple secondary endpoints included a 50% greater odds ratio (OR, 1.5; 95% CI, 1.2-1.9) of significant clinical improvement by day 15 after adjustment for baseline severity, a shorter initial length of hospital stay (12 vs. 17 days) and fewer days on oxygen supplementation (13 vs. 21 days) for the subgroup of patients on oxygen at enrollment.
Although the numerically lower mortality in the remdesivir arm (6.75 vs. 11.9%) did not reach statistical significance, Dr. Beigel said, “mortality was moving in the same direction as the other key endpoints.”
According to the study investigators, the types of rates of adverse events on remdesivir, which inhibits viral replication, “were generally similar in the remdesivir and placebo groups.”
In ACTT-1, 1,062 patients were randomized to remdesivir (200 mg loading dose followed by 100 mg daily for up to 9 days) or placebo. Patients were enrolled at study sites in North America, Europe, and Asia.
The data of ACTT-1 confirm a benefit from remdesivir in hospitalized COVID-19 patients with severe disease, but Dr. Beigel said he agrees with the current FDA indication that supports treatment in any hospitalized COVID-19 patient.
“We saw bigger benefits in patients with more severe infections. The benefits are not as large in patients with mild disease, but I think remdesivir should be considered in any hospitalized patient,” Dr. Beigel said.
This point of view is shared.
“I would give this drug to anyone in the hospital infected with COVID-19 assuming there was an ample supply and no need for rationing,” said Donna E. Sweet, MD, professor of internal medicine, University of Kansas, Wichita. She noted that this study has implications for hospital and hospital staff, as well as for patients.
“This type of reduction in recovery time means a reduction in potential exposures to hospital staff, a reduced need for PPE [personal protective equipment], and it will free up beds in the ICU [intensive care unit],” said Dr. Sweet, who also serves as an editorial advisory board member for Internal Medicine News.
An infectious disease specialist at the University of Minnesota also considers remdesivir to have an important role for conserving resources that deserves emphasis.
The reduction in time to recovery “is of benefit to the health system by maintaining hospital bed capacity,” said David R. Boulware, MD, professor of medicine at the University of Minnesota, Minneapolis.
According to his reading of the available data, including those from ACTT-1, the benefit appears to be greatest in those with a moderate degree of illness, which he defined as “sick enough to be hospitalized and require oxygen, yet not severely sick [and] requiring a ventilator or [extracorporeal membrane oxygenation].”
This does not preclude a benefit in those with more severe or milder disease, but patients with mild disease “are likely to recover regardless – or despite – whatever therapy they receive,” he said.
Dr. Beigel, the principal investigator of this trial, reports no potential conflicts of interest.
SOURCE: Beigel JH et al. N Engl J Med. 2020 Oct 8. doi: 10.1056/NEJMoa2007764.
In May 2020, remdesivir received Food and Drug Administration approval for emergency treatment of severe COVID-19 on the basis of a preliminary report on this trial. In August 2020, the FDA expanded the indication to include all hospitalized adult and pediatric patients with suspected or laboratory-confirmed COVID-19 infection irrespective of severity.
“Our findings were consistent with the findings of the preliminary report: a 10-day course of remdesivir was superior to placebo in the treatment of hospitalized patients with COVID-19,” reported a team of investigators led by John H. Beigel, MD, of the Division of Microbiology and Infectious Diseases at the National Institute of Allergy and Infectious Diseases, in the New England Journal of Medicine.
The drug’s broadened indication was not based on the ACTT-1 trial, according to Dr. Beigel. “Other data have demonstrated that remdesivir shortens recovery in patients with lower acuity. In our study, evidence of pneumonia was an enrollment requirement,” he explained in an interview.
In the newly published final ACTT-1 data, the median time to recovery was 10 days for those on active therapy versus 15 days for those randomized to placebo. With a rate ratio of 1.29 (P less than .001), this translated to a recovery that was about one third faster.
In this final report, remdesivir’s significant advantage over placebo regarding the trial’s primary endpoint was reinforced by efficacy on multiple secondary endpoints.
This benefits on multiple secondary endpoints included a 50% greater odds ratio (OR, 1.5; 95% CI, 1.2-1.9) of significant clinical improvement by day 15 after adjustment for baseline severity, a shorter initial length of hospital stay (12 vs. 17 days) and fewer days on oxygen supplementation (13 vs. 21 days) for the subgroup of patients on oxygen at enrollment.
Although the numerically lower mortality in the remdesivir arm (6.75 vs. 11.9%) did not reach statistical significance, Dr. Beigel said, “mortality was moving in the same direction as the other key endpoints.”
According to the study investigators, the types of rates of adverse events on remdesivir, which inhibits viral replication, “were generally similar in the remdesivir and placebo groups.”
In ACTT-1, 1,062 patients were randomized to remdesivir (200 mg loading dose followed by 100 mg daily for up to 9 days) or placebo. Patients were enrolled at study sites in North America, Europe, and Asia.
The data of ACTT-1 confirm a benefit from remdesivir in hospitalized COVID-19 patients with severe disease, but Dr. Beigel said he agrees with the current FDA indication that supports treatment in any hospitalized COVID-19 patient.
“We saw bigger benefits in patients with more severe infections. The benefits are not as large in patients with mild disease, but I think remdesivir should be considered in any hospitalized patient,” Dr. Beigel said.
This point of view is shared.
“I would give this drug to anyone in the hospital infected with COVID-19 assuming there was an ample supply and no need for rationing,” said Donna E. Sweet, MD, professor of internal medicine, University of Kansas, Wichita. She noted that this study has implications for hospital and hospital staff, as well as for patients.
“This type of reduction in recovery time means a reduction in potential exposures to hospital staff, a reduced need for PPE [personal protective equipment], and it will free up beds in the ICU [intensive care unit],” said Dr. Sweet, who also serves as an editorial advisory board member for Internal Medicine News.
An infectious disease specialist at the University of Minnesota also considers remdesivir to have an important role for conserving resources that deserves emphasis.
The reduction in time to recovery “is of benefit to the health system by maintaining hospital bed capacity,” said David R. Boulware, MD, professor of medicine at the University of Minnesota, Minneapolis.
According to his reading of the available data, including those from ACTT-1, the benefit appears to be greatest in those with a moderate degree of illness, which he defined as “sick enough to be hospitalized and require oxygen, yet not severely sick [and] requiring a ventilator or [extracorporeal membrane oxygenation].”
This does not preclude a benefit in those with more severe or milder disease, but patients with mild disease “are likely to recover regardless – or despite – whatever therapy they receive,” he said.
Dr. Beigel, the principal investigator of this trial, reports no potential conflicts of interest.
SOURCE: Beigel JH et al. N Engl J Med. 2020 Oct 8. doi: 10.1056/NEJMoa2007764.