Infants with type 1 spinal muscular atrophy (SMA) showed promising signs, including an increased expression of functional survival motor neuron (SMN) protein in the blood, after 1 year of treatment with oral risdiplam (Evrysdi, Genentech), according to results of part 1 of the FIREFISH study.

A boost in SMN expression has been linked to improvements in survival and motor function, which was also observed in exploratory efficacy outcomes in the 2-part, phase 2-3, open-label study.

“No surviving infant was receiving permanent ventilation at month 12, and 7 of the 21 infants were able to sit without support, which is not expected in patients with type 1 spinal muscular atrophy, according to historical experience,” reported the FIREFISH Working Group led by Giovanni Baranello, MD, PhD, from the Dubowitz Neuromuscular Centre, National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health University College London, and Great Ormond Street Hospital Trust, London.

However, “it cannot be stated with confidence that there was clinical benefit of the agent because the exploratory clinical endpoints were analyzed post hoc and can only be qualitatively compared with historical cohorts,” they added.

The findings were published online Feb. 24 in the New England Journal of Medicine.
 

A phase 2-3 open-label study

The study enrolled 21 infants with type 1 SMA, between the ages of 1 and 7 months. The majority (n = 17) were treated for 1 year with high-dose risdiplam, reaching 0.2 mg/kg of body weight per day by the twelfth month. Four infants in a low-dose cohort were treated with 0.08 mg/kg by the twelfth month. The medication was administered once daily orally in infants who were able to swallow, or by feeding tube for those who could not.

The primary outcomes of this first part of the study were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included event-free survival, defined as being alive without tracheostomy or the use of permanent ventilation for 16 or more hours per day, and the ability to sit without support for at least 5 seconds.

In terms of safety, the study recorded 24 serious adverse events. “The most common serious adverse events were infections of the respiratory tract, and four infants died of respiratory complications; these findings are consistent with the neuromuscular respiratory failure that characterizes spinal muscular atrophy,” the authors reported. “The risdiplam-associated retinal toxic effects that had been previously observed in monkeys were not observed in the current study,” they added.

Regarding SMN protein levels, a median level of 2.1 times the baseline level was observed within 4 weeks after the initiation of treatment in the high-dose cohort, they reported. By 12 months, these median values had increased to 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively.

Looking at exploratory efficacy outcomes, 90% of infants survived without ventilatory support, and seven infants in the high-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg/kg per day) was selected for part 2 of the study.
 

The first oral treatment option

Risdiplam is the third SMA treatment approved by the Food and Drug Administration, “and has the potential to expand access to treatment for people with SMA,” commented Mary Schroth, MD, chief medical officer of Cure SMA, who was not involved in the research. She added that the exploratory outcomes of the FIREFISH study represent “a significant milestone for symptomatic infants with SMA type 1.”

While the other two approved SMA therapies – nusinersen and onasemnogene abeparvovec – have led to improvements in survival and motor function, they are administered either intrathecally or intravenously respectively, while risdiplam is an oral therapy.

Dr. Schroth says there are currently no studies comparing the different SMA treatments. “Cure SMA is actively collecting real-world experience with risdiplam and other SMA treatments through multiple pathways,” she said. “Every individual and family, in collaboration with their health care provider, should discuss SMA treatments and make the decision that is best for them.”

Writing in Neuroscience Insights, a few months after risdiplam’s FDA approval last summer, Ravindra N. Singh MD, from the department of biomedical sciences, Iowa State University, Ames, wrote that, as an orally deliverable small molecule, risdiplam “is a major advancement for the treatment of SMA.”

Now, the FIREFISH study is “welcome news,” he said in an interview. “The results look promising so far,” he added. “I am cautiously optimistic that risdiplam would prove to be a viable alternative to the currently available invasive approaches. However, long-term studies (with appropriate age and sex-matched cohorts) would be needed to fully rule out the potential side effects of the repeated administrations.”

The therapy “is particularly great news for a group of SMA patients that might have tolerability and/or immune response concerns when it comes to nusinersen and gene therapy,” he noted in his article, adding that the ability to store and ship the drug at ambient temperatures, as well as its comparatively low cost are added benefits.

The study was supported by F. Hoffmann–La Roche. Dr. Baranello disclosed that he serves as a consultant for AveXis, F. Hoffmann-La Roche, and Sarepta Therapeutics, as well as PTC Therapeutics, from whom he also receives speaker honoraria. Dr. Schroth disclosed no personal conflicts and is an employee of Cure SMA. Cure SMA works to develop strategic relationships with corporate partners with the goal of working together to lead the way to a world without SMA. In advancement of that mission, Cure SMA has received funding from multiple corporate sources including Aetna, Biogen, Blue Cross Blue Shield, Genentech, Kaiser Permanente, Novartis Gene Therapies, Scholar Rock, and United HealthCare. Cure SMA has no financial stake in any treatment and does not advocate for one treatment over another. Dr. Singh disclosed that Spinraza (Nusinersen), the first FDA-approved SMA drug, is based on the target (US patent # 7,838,657) that was discovered in his former laboratory at UMASS Medical School, Worcester, Mass.

Infants with type 1 spinal muscular atrophy (SMA) showed promising signs, including an increased expression of functional survival motor neuron (SMN) protein in the blood, after 1 year of treatment with oral risdiplam (Evrysdi, Genentech), according to results of part 1 of the FIREFISH study.

A boost in SMN expression has been linked to improvements in survival and motor function, which was also observed in exploratory efficacy outcomes in the 2-part, phase 2-3, open-label study.

“No surviving infant was receiving permanent ventilation at month 12, and 7 of the 21 infants were able to sit without support, which is not expected in patients with type 1 spinal muscular atrophy, according to historical experience,” reported the FIREFISH Working Group led by Giovanni Baranello, MD, PhD, from the Dubowitz Neuromuscular Centre, National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health University College London, and Great Ormond Street Hospital Trust, London.

However, “it cannot be stated with confidence that there was clinical benefit of the agent because the exploratory clinical endpoints were analyzed post hoc and can only be qualitatively compared with historical cohorts,” they added.

The findings were published online Feb. 24 in the New England Journal of Medicine.
 

A phase 2-3 open-label study

The study enrolled 21 infants with type 1 SMA, between the ages of 1 and 7 months. The majority (n = 17) were treated for 1 year with high-dose risdiplam, reaching 0.2 mg/kg of body weight per day by the twelfth month. Four infants in a low-dose cohort were treated with 0.08 mg/kg by the twelfth month. The medication was administered once daily orally in infants who were able to swallow, or by feeding tube for those who could not.

The primary outcomes of this first part of the study were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included event-free survival, defined as being alive without tracheostomy or the use of permanent ventilation for 16 or more hours per day, and the ability to sit without support for at least 5 seconds.

In terms of safety, the study recorded 24 serious adverse events. “The most common serious adverse events were infections of the respiratory tract, and four infants died of respiratory complications; these findings are consistent with the neuromuscular respiratory failure that characterizes spinal muscular atrophy,” the authors reported. “The risdiplam-associated retinal toxic effects that had been previously observed in monkeys were not observed in the current study,” they added.

Regarding SMN protein levels, a median level of 2.1 times the baseline level was observed within 4 weeks after the initiation of treatment in the high-dose cohort, they reported. By 12 months, these median values had increased to 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively.

Looking at exploratory efficacy outcomes, 90% of infants survived without ventilatory support, and seven infants in the high-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg/kg per day) was selected for part 2 of the study.
 

The first oral treatment option

Risdiplam is the third SMA treatment approved by the Food and Drug Administration, “and has the potential to expand access to treatment for people with SMA,” commented Mary Schroth, MD, chief medical officer of Cure SMA, who was not involved in the research. She added that the exploratory outcomes of the FIREFISH study represent “a significant milestone for symptomatic infants with SMA type 1.”

While the other two approved SMA therapies – nusinersen and onasemnogene abeparvovec – have led to improvements in survival and motor function, they are administered either intrathecally or intravenously respectively, while risdiplam is an oral therapy.

Dr. Schroth says there are currently no studies comparing the different SMA treatments. “Cure SMA is actively collecting real-world experience with risdiplam and other SMA treatments through multiple pathways,” she said. “Every individual and family, in collaboration with their health care provider, should discuss SMA treatments and make the decision that is best for them.”

Writing in Neuroscience Insights, a few months after risdiplam’s FDA approval last summer, Ravindra N. Singh MD, from the department of biomedical sciences, Iowa State University, Ames, wrote that, as an orally deliverable small molecule, risdiplam “is a major advancement for the treatment of SMA.”

Now, the FIREFISH study is “welcome news,” he said in an interview. “The results look promising so far,” he added. “I am cautiously optimistic that risdiplam would prove to be a viable alternative to the currently available invasive approaches. However, long-term studies (with appropriate age and sex-matched cohorts) would be needed to fully rule out the potential side effects of the repeated administrations.”

The therapy “is particularly great news for a group of SMA patients that might have tolerability and/or immune response concerns when it comes to nusinersen and gene therapy,” he noted in his article, adding that the ability to store and ship the drug at ambient temperatures, as well as its comparatively low cost are added benefits.

The study was supported by F. Hoffmann–La Roche. Dr. Baranello disclosed that he serves as a consultant for AveXis, F. Hoffmann-La Roche, and Sarepta Therapeutics, as well as PTC Therapeutics, from whom he also receives speaker honoraria. Dr. Schroth disclosed no personal conflicts and is an employee of Cure SMA. Cure SMA works to develop strategic relationships with corporate partners with the goal of working together to lead the way to a world without SMA. In advancement of that mission, Cure SMA has received funding from multiple corporate sources including Aetna, Biogen, Blue Cross Blue Shield, Genentech, Kaiser Permanente, Novartis Gene Therapies, Scholar Rock, and United HealthCare. Cure SMA has no financial stake in any treatment and does not advocate for one treatment over another. Dr. Singh disclosed that Spinraza (Nusinersen), the first FDA-approved SMA drug, is based on the target (US patent # 7,838,657) that was discovered in his former laboratory at UMASS Medical School, Worcester, Mass.

Infants with type 1 spinal muscular atrophy (SMA) showed promising signs, including an increased expression of functional survival motor neuron (SMN) protein in the blood, after 1 year of treatment with oral risdiplam (Evrysdi, Genentech), according to results of part 1 of the FIREFISH study.

A boost in SMN expression has been linked to improvements in survival and motor function, which was also observed in exploratory efficacy outcomes in the 2-part, phase 2-3, open-label study.

“No surviving infant was receiving permanent ventilation at month 12, and 7 of the 21 infants were able to sit without support, which is not expected in patients with type 1 spinal muscular atrophy, according to historical experience,” reported the FIREFISH Working Group led by Giovanni Baranello, MD, PhD, from the Dubowitz Neuromuscular Centre, National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health University College London, and Great Ormond Street Hospital Trust, London.

However, “it cannot be stated with confidence that there was clinical benefit of the agent because the exploratory clinical endpoints were analyzed post hoc and can only be qualitatively compared with historical cohorts,” they added.

The findings were published online Feb. 24 in the New England Journal of Medicine.
 

A phase 2-3 open-label study

The study enrolled 21 infants with type 1 SMA, between the ages of 1 and 7 months. The majority (n = 17) were treated for 1 year with high-dose risdiplam, reaching 0.2 mg/kg of body weight per day by the twelfth month. Four infants in a low-dose cohort were treated with 0.08 mg/kg by the twelfth month. The medication was administered once daily orally in infants who were able to swallow, or by feeding tube for those who could not.

The primary outcomes of this first part of the study were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included event-free survival, defined as being alive without tracheostomy or the use of permanent ventilation for 16 or more hours per day, and the ability to sit without support for at least 5 seconds.

In terms of safety, the study recorded 24 serious adverse events. “The most common serious adverse events were infections of the respiratory tract, and four infants died of respiratory complications; these findings are consistent with the neuromuscular respiratory failure that characterizes spinal muscular atrophy,” the authors reported. “The risdiplam-associated retinal toxic effects that had been previously observed in monkeys were not observed in the current study,” they added.

Regarding SMN protein levels, a median level of 2.1 times the baseline level was observed within 4 weeks after the initiation of treatment in the high-dose cohort, they reported. By 12 months, these median values had increased to 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively.

Looking at exploratory efficacy outcomes, 90% of infants survived without ventilatory support, and seven infants in the high-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg/kg per day) was selected for part 2 of the study.
 

The first oral treatment option

Risdiplam is the third SMA treatment approved by the Food and Drug Administration, “and has the potential to expand access to treatment for people with SMA,” commented Mary Schroth, MD, chief medical officer of Cure SMA, who was not involved in the research. She added that the exploratory outcomes of the FIREFISH study represent “a significant milestone for symptomatic infants with SMA type 1.”

While the other two approved SMA therapies – nusinersen and onasemnogene abeparvovec – have led to improvements in survival and motor function, they are administered either intrathecally or intravenously respectively, while risdiplam is an oral therapy.

Dr. Schroth says there are currently no studies comparing the different SMA treatments. “Cure SMA is actively collecting real-world experience with risdiplam and other SMA treatments through multiple pathways,” she said. “Every individual and family, in collaboration with their health care provider, should discuss SMA treatments and make the decision that is best for them.”

Writing in Neuroscience Insights, a few months after risdiplam’s FDA approval last summer, Ravindra N. Singh MD, from the department of biomedical sciences, Iowa State University, Ames, wrote that, as an orally deliverable small molecule, risdiplam “is a major advancement for the treatment of SMA.”

Now, the FIREFISH study is “welcome news,” he said in an interview. “The results look promising so far,” he added. “I am cautiously optimistic that risdiplam would prove to be a viable alternative to the currently available invasive approaches. However, long-term studies (with appropriate age and sex-matched cohorts) would be needed to fully rule out the potential side effects of the repeated administrations.”

The therapy “is particularly great news for a group of SMA patients that might have tolerability and/or immune response concerns when it comes to nusinersen and gene therapy,” he noted in his article, adding that the ability to store and ship the drug at ambient temperatures, as well as its comparatively low cost are added benefits.

The study was supported by F. Hoffmann–La Roche. Dr. Baranello disclosed that he serves as a consultant for AveXis, F. Hoffmann-La Roche, and Sarepta Therapeutics, as well as PTC Therapeutics, from whom he also receives speaker honoraria. Dr. Schroth disclosed no personal conflicts and is an employee of Cure SMA. Cure SMA works to develop strategic relationships with corporate partners with the goal of working together to lead the way to a world without SMA. In advancement of that mission, Cure SMA has received funding from multiple corporate sources including Aetna, Biogen, Blue Cross Blue Shield, Genentech, Kaiser Permanente, Novartis Gene Therapies, Scholar Rock, and United HealthCare. Cure SMA has no financial stake in any treatment and does not advocate for one treatment over another. Dr. Singh disclosed that Spinraza (Nusinersen), the first FDA-approved SMA drug, is based on the target (US patent # 7,838,657) that was discovered in his former laboratory at UMASS Medical School, Worcester, Mass.

The Biden Administration launched the first phase of the Federally Qualified Health Center (FQHC) Program for COVID-19 Vaccination. Beginning February 15, FQHCs (including centers in the Urban Indian Health Program) began directly receiving vaccines.

                The announcement coincided with a boost in vaccine supply for states, Tribes, and territories. In early February, the Biden Administration announced it would expand vaccine supply to 11 million doses nationwide, a 28% increase since January 20, when President Biden took office. According to a White House fact sheet, “The Administration is committing to maintaining this as the minimum supply level for the next three weeks, and we will continue to work with manufacturers in their efforts to ramp up supply.”

                In February, President Biden and Vice President Harris travelled to Arizona and toured a vaccination site at State Farm Stadium in Glendale. Arizona, one of the first states to reach out for federal help from the new administration, has 15 counties and 22 Tribes with sovereign lands in the state. Those 37 entities work collaboratively with the Federal Emergency Management Agency (FEMA), said Major General Michael McGuire, head of the Arizona National Guard.

                In his remarks during the tour, President Biden addressed equity, saying, “[I]t really does matter that we have access to the people who are most in need [and are] most affected by the COVID crisis, dying at faster rates, getting sick at faster rates, …but not being able to get into the mix. …Equity is a big thing.”

                To that end, one of the programs under way is to stand up four vaccination centers for the Navajo Nation. Tammy Littrell, Acting Regional Administrator for FEMA, said the centers will help increase tribal members’ access to vaccination, as well as take the burden off from having to drive in “austere winter conditions.”

                In addition to more vaccines, Indian Health Services (IHS) is allocating $1 billion it received to help with COVID-19 response. Of the $1 billion, $790 million will go to testing, contact tracing, containment, and mitigation, among other things. Another $210 million will support IHS, tribal, and urban Indian health programs for vaccine-related activities to ensure broad-based distribution, access, and vaccine coverage. The money is part of the fifth round of supplemental COVID-19 funding from the Coronavirus Response and Relief Supplemental Appropriations Act. The funds transferred so far amount to nearly $3 billion.

                According to IHS, the money can be used to scale up testing by public health, academic, commercial, and hospital laboratories, as well as community-based testing sites, mobile testing units, healthcare facilities, and other entities engaged in COVID-19 testing. The funds are also legally available to lease or purchase non-federally owned facilities to improve COVID-19 preparedness and response capability.

The Biden Administration launched the first phase of the Federally Qualified Health Center (FQHC) Program for COVID-19 Vaccination. Beginning February 15, FQHCs (including centers in the Urban Indian Health Program) began directly receiving vaccines.

                The announcement coincided with a boost in vaccine supply for states, Tribes, and territories. In early February, the Biden Administration announced it would expand vaccine supply to 11 million doses nationwide, a 28% increase since January 20, when President Biden took office. According to a White House fact sheet, “The Administration is committing to maintaining this as the minimum supply level for the next three weeks, and we will continue to work with manufacturers in their efforts to ramp up supply.”

                In February, President Biden and Vice President Harris travelled to Arizona and toured a vaccination site at State Farm Stadium in Glendale. Arizona, one of the first states to reach out for federal help from the new administration, has 15 counties and 22 Tribes with sovereign lands in the state. Those 37 entities work collaboratively with the Federal Emergency Management Agency (FEMA), said Major General Michael McGuire, head of the Arizona National Guard.

                In his remarks during the tour, President Biden addressed equity, saying, “[I]t really does matter that we have access to the people who are most in need [and are] most affected by the COVID crisis, dying at faster rates, getting sick at faster rates, …but not being able to get into the mix. …Equity is a big thing.”

                To that end, one of the programs under way is to stand up four vaccination centers for the Navajo Nation. Tammy Littrell, Acting Regional Administrator for FEMA, said the centers will help increase tribal members’ access to vaccination, as well as take the burden off from having to drive in “austere winter conditions.”

                In addition to more vaccines, Indian Health Services (IHS) is allocating $1 billion it received to help with COVID-19 response. Of the $1 billion, $790 million will go to testing, contact tracing, containment, and mitigation, among other things. Another $210 million will support IHS, tribal, and urban Indian health programs for vaccine-related activities to ensure broad-based distribution, access, and vaccine coverage. The money is part of the fifth round of supplemental COVID-19 funding from the Coronavirus Response and Relief Supplemental Appropriations Act. The funds transferred so far amount to nearly $3 billion.

                According to IHS, the money can be used to scale up testing by public health, academic, commercial, and hospital laboratories, as well as community-based testing sites, mobile testing units, healthcare facilities, and other entities engaged in COVID-19 testing. The funds are also legally available to lease or purchase non-federally owned facilities to improve COVID-19 preparedness and response capability.

The Biden Administration launched the first phase of the Federally Qualified Health Center (FQHC) Program for COVID-19 Vaccination. Beginning February 15, FQHCs (including centers in the Urban Indian Health Program) began directly receiving vaccines.

                The announcement coincided with a boost in vaccine supply for states, Tribes, and territories. In early February, the Biden Administration announced it would expand vaccine supply to 11 million doses nationwide, a 28% increase since January 20, when President Biden took office. According to a White House fact sheet, “The Administration is committing to maintaining this as the minimum supply level for the next three weeks, and we will continue to work with manufacturers in their efforts to ramp up supply.”

                In February, President Biden and Vice President Harris travelled to Arizona and toured a vaccination site at State Farm Stadium in Glendale. Arizona, one of the first states to reach out for federal help from the new administration, has 15 counties and 22 Tribes with sovereign lands in the state. Those 37 entities work collaboratively with the Federal Emergency Management Agency (FEMA), said Major General Michael McGuire, head of the Arizona National Guard.

                In his remarks during the tour, President Biden addressed equity, saying, “[I]t really does matter that we have access to the people who are most in need [and are] most affected by the COVID crisis, dying at faster rates, getting sick at faster rates, …but not being able to get into the mix. …Equity is a big thing.”

                To that end, one of the programs under way is to stand up four vaccination centers for the Navajo Nation. Tammy Littrell, Acting Regional Administrator for FEMA, said the centers will help increase tribal members’ access to vaccination, as well as take the burden off from having to drive in “austere winter conditions.”

                In addition to more vaccines, Indian Health Services (IHS) is allocating $1 billion it received to help with COVID-19 response. Of the $1 billion, $790 million will go to testing, contact tracing, containment, and mitigation, among other things. Another $210 million will support IHS, tribal, and urban Indian health programs for vaccine-related activities to ensure broad-based distribution, access, and vaccine coverage. The money is part of the fifth round of supplemental COVID-19 funding from the Coronavirus Response and Relief Supplemental Appropriations Act. The funds transferred so far amount to nearly $3 billion.

                According to IHS, the money can be used to scale up testing by public health, academic, commercial, and hospital laboratories, as well as community-based testing sites, mobile testing units, healthcare facilities, and other entities engaged in COVID-19 testing. The funds are also legally available to lease or purchase non-federally owned facilities to improve COVID-19 preparedness and response capability.

Despite recent advances in the diagnosis, treatment, and prevention of pediatric tuberculosis in children living with HIV (CLHIV) and HIV-exposed uninfected children (HEU), several unmet needs remain, including studies evaluating the feasibility of shortened TB treatment regimens.

“Children living with HIV contribute disproportionately to pediatric TB mortality rates, accounting for 16% of child TB deaths, and many cases are underdiagnosed and underreported,” said Nicole Salazar-Austin, MD, of Johns Hopkins University in Baltimore. She provided an update on pediatric TB prevention and treatment during an educational symposium at this year’s virtual Conference on Retroviruses & Opportunistic Infections.

Dr. Salazar-Austin summarized current diagnostics for pediatric TB and reviewed options for the prevention and treatment of TB in CLHIV and HEU.
 

TB and CLHIV

Presently, TB is the most common opportunistic infection among CLHIV, and those with severe immune suppression have a fivefold greater risk of TB disease. While antiretroviral therapy (ART) is highly protective against TB disease in CLHIV, only about 50% of eligible children receive ART.

Dr. Salazar-Austin explained that many individuals with TB/HIV coinfection are unaware of their coinfection and not receiving treatment. Despite recommendations, TB preventive therapy is poorly implemented in CLHIV, especially in high-burden settings.
 

Pediatric TB diagnosis

Smear microscopy, culture, and Xpert MTB/RIF Ultra are the main diagnostic modalities for pediatric TB. The Xpert MTB/RIF test is an automated PCR-based assay that simultaneously and rapidly detects Mycobacterium tuberculosis complex and resistance to rifampin. The test is currently recommended by the World Health Organization as the initial diagnostic method for presumptive TB cases in both adults and children.

However, under optimal conditions, only 40% of TB cases will be detected. This is in part due to limited implementation of sputum collection procedures, but recent evidence has shown that collection of multiple specimens improves sensitivity for both culture and Xpert MTB/RIF Ultra across all specimen types, Dr. Salazar-Austin explained.

In 2020, the WHO endorsed the use of stool samples for the diagnosis of pediatric pulmonary TB. Stool Xpert is an emerging alternative, noninvasive method for ruling in pediatric TB disease, and has shown sensitivity and specificity similar to that of Xpert MTB/RIF Ultra.

“TB diagnostics have limited sensitivity in children, and efforts are ongoing to maximize current diagnostics, but new diagnostics are needed,” said Dr. Salazar-Austin.
 

Pediatric TB treatment

Despite the high frequency of TB as an opportunistic infection in CLHIV, current data on co-treatment strategies are limited.

Dolutegravir-based regimens are the preferred first-line regimen for CLHIV. In June 2020, the Food and Drug Administration approved the dispersible dolutegravir tablet, and it is expected to become widely available in 2021.

In children with TB/HIV coinfection who receive dolutegravir and rifampicin, dolutegravir is typically dosed twice daily because of a known drug interaction, based on data from the ODYSSEY study. The WHO recommendations for treatment of pediatric TB/HIV coinfection were recently updated to reflect twice-daily dosing of dolutegravir.

Despite these new recommendations, data are currently limited, and observational pharmacokinetic studies evaluating twice daily dolutegravir with TB treatment in young children are needed.

“More work is needed to evaluate the drug-drug interactions and proper dosing of rifamycins with dolutegravir for the treatment and prevention of TB in CLHIV,” Dr. Salazar-Austin said.

Based on data from TBTC Study 31/ACTG A5349, high-dose rifapentine (a rifamycin) with moxifloxacin (a fluoroquinolone) was noninferior to rifapentine alone in newly diagnosed, culture positive, drug-susceptible TB in children 12 years and older.

Whether rifapentine and moxifloxacin (RPT-Mox) can be used in children under 12 years remains unknown, but future studies may help answer this question, Dr. Salazar-Austin noted. The FDA has restricted the use of fluoroquinolones in children because of a possible effect on cartilage development, she explained.

Furthermore, recent data from the SHINE trial suggested that shortened treatment regimens may hold promise for children with TB.

“While shortened TB treatment regimens hold promise, much work needs to be done in children to implement RPT-Mox, but the results from SHINE can be implemented rapidly,” Dr. Salazar-Austin said.

Dr. Salazar-Austin disclosed no conflicts of interest. The presentation was funded by NICHD, UNITAID, Fogarty Institute, and the IMPAACT network.

Despite recent advances in the diagnosis, treatment, and prevention of pediatric tuberculosis in children living with HIV (CLHIV) and HIV-exposed uninfected children (HEU), several unmet needs remain, including studies evaluating the feasibility of shortened TB treatment regimens.

“Children living with HIV contribute disproportionately to pediatric TB mortality rates, accounting for 16% of child TB deaths, and many cases are underdiagnosed and underreported,” said Nicole Salazar-Austin, MD, of Johns Hopkins University in Baltimore. She provided an update on pediatric TB prevention and treatment during an educational symposium at this year’s virtual Conference on Retroviruses & Opportunistic Infections.

Dr. Salazar-Austin summarized current diagnostics for pediatric TB and reviewed options for the prevention and treatment of TB in CLHIV and HEU.
 

TB and CLHIV

Presently, TB is the most common opportunistic infection among CLHIV, and those with severe immune suppression have a fivefold greater risk of TB disease. While antiretroviral therapy (ART) is highly protective against TB disease in CLHIV, only about 50% of eligible children receive ART.

Dr. Salazar-Austin explained that many individuals with TB/HIV coinfection are unaware of their coinfection and not receiving treatment. Despite recommendations, TB preventive therapy is poorly implemented in CLHIV, especially in high-burden settings.
 

Pediatric TB diagnosis

Smear microscopy, culture, and Xpert MTB/RIF Ultra are the main diagnostic modalities for pediatric TB. The Xpert MTB/RIF test is an automated PCR-based assay that simultaneously and rapidly detects Mycobacterium tuberculosis complex and resistance to rifampin. The test is currently recommended by the World Health Organization as the initial diagnostic method for presumptive TB cases in both adults and children.

However, under optimal conditions, only 40% of TB cases will be detected. This is in part due to limited implementation of sputum collection procedures, but recent evidence has shown that collection of multiple specimens improves sensitivity for both culture and Xpert MTB/RIF Ultra across all specimen types, Dr. Salazar-Austin explained.

In 2020, the WHO endorsed the use of stool samples for the diagnosis of pediatric pulmonary TB. Stool Xpert is an emerging alternative, noninvasive method for ruling in pediatric TB disease, and has shown sensitivity and specificity similar to that of Xpert MTB/RIF Ultra.

“TB diagnostics have limited sensitivity in children, and efforts are ongoing to maximize current diagnostics, but new diagnostics are needed,” said Dr. Salazar-Austin.
 

Pediatric TB treatment

Despite the high frequency of TB as an opportunistic infection in CLHIV, current data on co-treatment strategies are limited.

Dolutegravir-based regimens are the preferred first-line regimen for CLHIV. In June 2020, the Food and Drug Administration approved the dispersible dolutegravir tablet, and it is expected to become widely available in 2021.

In children with TB/HIV coinfection who receive dolutegravir and rifampicin, dolutegravir is typically dosed twice daily because of a known drug interaction, based on data from the ODYSSEY study. The WHO recommendations for treatment of pediatric TB/HIV coinfection were recently updated to reflect twice-daily dosing of dolutegravir.

Despite these new recommendations, data are currently limited, and observational pharmacokinetic studies evaluating twice daily dolutegravir with TB treatment in young children are needed.

“More work is needed to evaluate the drug-drug interactions and proper dosing of rifamycins with dolutegravir for the treatment and prevention of TB in CLHIV,” Dr. Salazar-Austin said.

Based on data from TBTC Study 31/ACTG A5349, high-dose rifapentine (a rifamycin) with moxifloxacin (a fluoroquinolone) was noninferior to rifapentine alone in newly diagnosed, culture positive, drug-susceptible TB in children 12 years and older.

Whether rifapentine and moxifloxacin (RPT-Mox) can be used in children under 12 years remains unknown, but future studies may help answer this question, Dr. Salazar-Austin noted. The FDA has restricted the use of fluoroquinolones in children because of a possible effect on cartilage development, she explained.

Furthermore, recent data from the SHINE trial suggested that shortened treatment regimens may hold promise for children with TB.

“While shortened TB treatment regimens hold promise, much work needs to be done in children to implement RPT-Mox, but the results from SHINE can be implemented rapidly,” Dr. Salazar-Austin said.

Dr. Salazar-Austin disclosed no conflicts of interest. The presentation was funded by NICHD, UNITAID, Fogarty Institute, and the IMPAACT network.

Despite recent advances in the diagnosis, treatment, and prevention of pediatric tuberculosis in children living with HIV (CLHIV) and HIV-exposed uninfected children (HEU), several unmet needs remain, including studies evaluating the feasibility of shortened TB treatment regimens.

“Children living with HIV contribute disproportionately to pediatric TB mortality rates, accounting for 16% of child TB deaths, and many cases are underdiagnosed and underreported,” said Nicole Salazar-Austin, MD, of Johns Hopkins University in Baltimore. She provided an update on pediatric TB prevention and treatment during an educational symposium at this year’s virtual Conference on Retroviruses & Opportunistic Infections.

Dr. Salazar-Austin summarized current diagnostics for pediatric TB and reviewed options for the prevention and treatment of TB in CLHIV and HEU.
 

TB and CLHIV

Presently, TB is the most common opportunistic infection among CLHIV, and those with severe immune suppression have a fivefold greater risk of TB disease. While antiretroviral therapy (ART) is highly protective against TB disease in CLHIV, only about 50% of eligible children receive ART.

Dr. Salazar-Austin explained that many individuals with TB/HIV coinfection are unaware of their coinfection and not receiving treatment. Despite recommendations, TB preventive therapy is poorly implemented in CLHIV, especially in high-burden settings.
 

Pediatric TB diagnosis

Smear microscopy, culture, and Xpert MTB/RIF Ultra are the main diagnostic modalities for pediatric TB. The Xpert MTB/RIF test is an automated PCR-based assay that simultaneously and rapidly detects Mycobacterium tuberculosis complex and resistance to rifampin. The test is currently recommended by the World Health Organization as the initial diagnostic method for presumptive TB cases in both adults and children.

However, under optimal conditions, only 40% of TB cases will be detected. This is in part due to limited implementation of sputum collection procedures, but recent evidence has shown that collection of multiple specimens improves sensitivity for both culture and Xpert MTB/RIF Ultra across all specimen types, Dr. Salazar-Austin explained.

In 2020, the WHO endorsed the use of stool samples for the diagnosis of pediatric pulmonary TB. Stool Xpert is an emerging alternative, noninvasive method for ruling in pediatric TB disease, and has shown sensitivity and specificity similar to that of Xpert MTB/RIF Ultra.

“TB diagnostics have limited sensitivity in children, and efforts are ongoing to maximize current diagnostics, but new diagnostics are needed,” said Dr. Salazar-Austin.
 

Pediatric TB treatment

Despite the high frequency of TB as an opportunistic infection in CLHIV, current data on co-treatment strategies are limited.

Dolutegravir-based regimens are the preferred first-line regimen for CLHIV. In June 2020, the Food and Drug Administration approved the dispersible dolutegravir tablet, and it is expected to become widely available in 2021.

In children with TB/HIV coinfection who receive dolutegravir and rifampicin, dolutegravir is typically dosed twice daily because of a known drug interaction, based on data from the ODYSSEY study. The WHO recommendations for treatment of pediatric TB/HIV coinfection were recently updated to reflect twice-daily dosing of dolutegravir.

Despite these new recommendations, data are currently limited, and observational pharmacokinetic studies evaluating twice daily dolutegravir with TB treatment in young children are needed.

“More work is needed to evaluate the drug-drug interactions and proper dosing of rifamycins with dolutegravir for the treatment and prevention of TB in CLHIV,” Dr. Salazar-Austin said.

Based on data from TBTC Study 31/ACTG A5349, high-dose rifapentine (a rifamycin) with moxifloxacin (a fluoroquinolone) was noninferior to rifapentine alone in newly diagnosed, culture positive, drug-susceptible TB in children 12 years and older.

Whether rifapentine and moxifloxacin (RPT-Mox) can be used in children under 12 years remains unknown, but future studies may help answer this question, Dr. Salazar-Austin noted. The FDA has restricted the use of fluoroquinolones in children because of a possible effect on cartilage development, she explained.

Furthermore, recent data from the SHINE trial suggested that shortened treatment regimens may hold promise for children with TB.

“While shortened TB treatment regimens hold promise, much work needs to be done in children to implement RPT-Mox, but the results from SHINE can be implemented rapidly,” Dr. Salazar-Austin said.

Dr. Salazar-Austin disclosed no conflicts of interest. The presentation was funded by NICHD, UNITAID, Fogarty Institute, and the IMPAACT network.

Long-acting injectable (LAI) drug formulations represent a promising new strategy for the prevention and treatment of tuberculosis in women and children, according to an online presentation at the Conference on Retroviruses & Opportunistic Infections, held virtually.

“As a delivery strategy, LAIs hold the potential to unlock a vast chemical space of lipophilic compounds with very potent anti-TB activity that would otherwise not be developed due to poor predicted oral bioavailability,” explained presenter Eric Nuermberger, MD.

He summarized current preventive treatment options for TB and reviewed the potential impact of LAI formulations on TB therapy. In addition, he identified key challenges for future LAI development and proposed a new development path for clinical implementation.
 

Current TB preventive therapies

Despite widespread availability, the uptake of TB preventive therapy is poor and currently lags behind global targets. One key barrier to widespread uptake is the long duration of treatment, which may hinder patient adherence to therapy.

While shorter preventive regimens, such as 1 month of daily isoniazid plus rifapentine, show similar efficacy and higher completion rates, further shortening of therapy and reducing clinic visits are the most direct methods to increase adherence and treatment completion rates, Dr. Nuermberger said.
 

LAI drugs

LAI drug formulations allow for slow release of suitable drugs from a depot injected subcutaneously or intramuscularly.

The goal of LAI formulations is to free patients from the daily burden of oral administration. Other potential benefits include better adherence and efficacy, drug exposure, and the potential to overcome intrinsic poor oral bioavailability by bypassing the GI tract entirely.

Potential indications for LAIs include treatment of latent tuberculosis infection (LTBI), and as continuous therapy in people living with HIV in high-burden settings. There is also potential for treating younger children, such as household contacts, who have difficulty taking oral medications.

“We’ve already seen LAIs revolutionize other areas, such as psychiatry and contraception, and we appear to have another revolution in HIV prevention and treatment,” Dr. Nuermberger explained.

Not all existing TB drugs are suitable for LAI formulations, but drugs such as rifapentine, rifabutin, delamanid, and bedaquiline, show more promise than isoniazid or rifampin because of their physiochemical composition. Of all, bedaquiline may offer the best profile for LAI formulation, Dr. Nuermberger said.

Early proof-of-concept in vivo studies have shown potential use of LAI bedaquiline for TB prevention in both drug-sensitive and drug-resistant TB contacts. Translational PK modeling and simulation predicted that a 1-g intramuscular injection of LAI bedaquiline could maintain therapeutic plasma concentrations in humans for greater than 1 month.

Dr. Nuermberger noted that novel diarylquinoline-based therapies, currently in phase 1 studies, may be even better candidates for LAI-based TB preventive therapy. Early data suggests these compounds may be 10-20 times more potent and have a lower CV risk profile than that of bedaquiline.
 

Considerations for development and implementation

“Despite the promising potential of long-acting injectables for TB, we are still in the very early stages,” said Dr. Nuermberger.

Ensuring and optimizing acceptance of LAI formulations, especially in at-risk populations, will be very important, he explained. Early involvement of children and pregnant women in studies of who may benefit most from LAI drugs will also be essential.

Other important considerations include cost-effectiveness, particularly in at-risk and vulnerable populations. Furthermore, new dedicated research and development programs are needed to continue to develop more drug candidates suitable for LAI.

“Long-acting formulations hold enormous promise to be transformative for combating TB, through simplification of delivery and overcoming issues of adherence that can compromise success of current interventions,” said Andrew Owen, PhD, of the University of Liverpool (England).

“The ability to deliver an entire course of drug in a single visit promises to ensure missed doses don’t compromise outcomes or place unnecessary selective pressure in favor of drug resistance,” Dr. Owen said.

“Recent studies showing the value of one-month oral treatment regimens for LTBI make long-acting formulations seem more realistic and drugs such as long-acting bedaquiline put a one-shot regimen within reach,” Charles W. Flexner, MD, of Johns Hopkins University, Baltimore, said in an interview.

While no LAIs have been approved for TB, Dr. Nuermberger was optimistic that the recent success of LAI formulations for HIV treatment and prevention will catalyze further efforts in the TB landscape.

Dr. Nuermberger disclosed research support from Janssen Pharmaceuticals, TB Alliance, and the Gates Medical Research Institute. The presentation was sponsored by Janssen Pharmaceuticals, Johns Hopkins CFAR, NIH, Unitaid, and the TB Alliance.

Long-acting injectable (LAI) drug formulations represent a promising new strategy for the prevention and treatment of tuberculosis in women and children, according to an online presentation at the Conference on Retroviruses & Opportunistic Infections, held virtually.

“As a delivery strategy, LAIs hold the potential to unlock a vast chemical space of lipophilic compounds with very potent anti-TB activity that would otherwise not be developed due to poor predicted oral bioavailability,” explained presenter Eric Nuermberger, MD.

He summarized current preventive treatment options for TB and reviewed the potential impact of LAI formulations on TB therapy. In addition, he identified key challenges for future LAI development and proposed a new development path for clinical implementation.
 

Current TB preventive therapies

Despite widespread availability, the uptake of TB preventive therapy is poor and currently lags behind global targets. One key barrier to widespread uptake is the long duration of treatment, which may hinder patient adherence to therapy.

While shorter preventive regimens, such as 1 month of daily isoniazid plus rifapentine, show similar efficacy and higher completion rates, further shortening of therapy and reducing clinic visits are the most direct methods to increase adherence and treatment completion rates, Dr. Nuermberger said.
 

LAI drugs

LAI drug formulations allow for slow release of suitable drugs from a depot injected subcutaneously or intramuscularly.

The goal of LAI formulations is to free patients from the daily burden of oral administration. Other potential benefits include better adherence and efficacy, drug exposure, and the potential to overcome intrinsic poor oral bioavailability by bypassing the GI tract entirely.

Potential indications for LAIs include treatment of latent tuberculosis infection (LTBI), and as continuous therapy in people living with HIV in high-burden settings. There is also potential for treating younger children, such as household contacts, who have difficulty taking oral medications.

“We’ve already seen LAIs revolutionize other areas, such as psychiatry and contraception, and we appear to have another revolution in HIV prevention and treatment,” Dr. Nuermberger explained.

Not all existing TB drugs are suitable for LAI formulations, but drugs such as rifapentine, rifabutin, delamanid, and bedaquiline, show more promise than isoniazid or rifampin because of their physiochemical composition. Of all, bedaquiline may offer the best profile for LAI formulation, Dr. Nuermberger said.

Early proof-of-concept in vivo studies have shown potential use of LAI bedaquiline for TB prevention in both drug-sensitive and drug-resistant TB contacts. Translational PK modeling and simulation predicted that a 1-g intramuscular injection of LAI bedaquiline could maintain therapeutic plasma concentrations in humans for greater than 1 month.

Dr. Nuermberger noted that novel diarylquinoline-based therapies, currently in phase 1 studies, may be even better candidates for LAI-based TB preventive therapy. Early data suggests these compounds may be 10-20 times more potent and have a lower CV risk profile than that of bedaquiline.
 

Considerations for development and implementation

“Despite the promising potential of long-acting injectables for TB, we are still in the very early stages,” said Dr. Nuermberger.

Ensuring and optimizing acceptance of LAI formulations, especially in at-risk populations, will be very important, he explained. Early involvement of children and pregnant women in studies of who may benefit most from LAI drugs will also be essential.

Other important considerations include cost-effectiveness, particularly in at-risk and vulnerable populations. Furthermore, new dedicated research and development programs are needed to continue to develop more drug candidates suitable for LAI.

“Long-acting formulations hold enormous promise to be transformative for combating TB, through simplification of delivery and overcoming issues of adherence that can compromise success of current interventions,” said Andrew Owen, PhD, of the University of Liverpool (England).

“The ability to deliver an entire course of drug in a single visit promises to ensure missed doses don’t compromise outcomes or place unnecessary selective pressure in favor of drug resistance,” Dr. Owen said.

“Recent studies showing the value of one-month oral treatment regimens for LTBI make long-acting formulations seem more realistic and drugs such as long-acting bedaquiline put a one-shot regimen within reach,” Charles W. Flexner, MD, of Johns Hopkins University, Baltimore, said in an interview.

While no LAIs have been approved for TB, Dr. Nuermberger was optimistic that the recent success of LAI formulations for HIV treatment and prevention will catalyze further efforts in the TB landscape.

Dr. Nuermberger disclosed research support from Janssen Pharmaceuticals, TB Alliance, and the Gates Medical Research Institute. The presentation was sponsored by Janssen Pharmaceuticals, Johns Hopkins CFAR, NIH, Unitaid, and the TB Alliance.

Long-acting injectable (LAI) drug formulations represent a promising new strategy for the prevention and treatment of tuberculosis in women and children, according to an online presentation at the Conference on Retroviruses & Opportunistic Infections, held virtually.

“As a delivery strategy, LAIs hold the potential to unlock a vast chemical space of lipophilic compounds with very potent anti-TB activity that would otherwise not be developed due to poor predicted oral bioavailability,” explained presenter Eric Nuermberger, MD.

He summarized current preventive treatment options for TB and reviewed the potential impact of LAI formulations on TB therapy. In addition, he identified key challenges for future LAI development and proposed a new development path for clinical implementation.
 

Current TB preventive therapies

Despite widespread availability, the uptake of TB preventive therapy is poor and currently lags behind global targets. One key barrier to widespread uptake is the long duration of treatment, which may hinder patient adherence to therapy.

While shorter preventive regimens, such as 1 month of daily isoniazid plus rifapentine, show similar efficacy and higher completion rates, further shortening of therapy and reducing clinic visits are the most direct methods to increase adherence and treatment completion rates, Dr. Nuermberger said.
 

LAI drugs

LAI drug formulations allow for slow release of suitable drugs from a depot injected subcutaneously or intramuscularly.

The goal of LAI formulations is to free patients from the daily burden of oral administration. Other potential benefits include better adherence and efficacy, drug exposure, and the potential to overcome intrinsic poor oral bioavailability by bypassing the GI tract entirely.

Potential indications for LAIs include treatment of latent tuberculosis infection (LTBI), and as continuous therapy in people living with HIV in high-burden settings. There is also potential for treating younger children, such as household contacts, who have difficulty taking oral medications.

“We’ve already seen LAIs revolutionize other areas, such as psychiatry and contraception, and we appear to have another revolution in HIV prevention and treatment,” Dr. Nuermberger explained.

Not all existing TB drugs are suitable for LAI formulations, but drugs such as rifapentine, rifabutin, delamanid, and bedaquiline, show more promise than isoniazid or rifampin because of their physiochemical composition. Of all, bedaquiline may offer the best profile for LAI formulation, Dr. Nuermberger said.

Early proof-of-concept in vivo studies have shown potential use of LAI bedaquiline for TB prevention in both drug-sensitive and drug-resistant TB contacts. Translational PK modeling and simulation predicted that a 1-g intramuscular injection of LAI bedaquiline could maintain therapeutic plasma concentrations in humans for greater than 1 month.

Dr. Nuermberger noted that novel diarylquinoline-based therapies, currently in phase 1 studies, may be even better candidates for LAI-based TB preventive therapy. Early data suggests these compounds may be 10-20 times more potent and have a lower CV risk profile than that of bedaquiline.
 

Considerations for development and implementation

“Despite the promising potential of long-acting injectables for TB, we are still in the very early stages,” said Dr. Nuermberger.

Ensuring and optimizing acceptance of LAI formulations, especially in at-risk populations, will be very important, he explained. Early involvement of children and pregnant women in studies of who may benefit most from LAI drugs will also be essential.

Other important considerations include cost-effectiveness, particularly in at-risk and vulnerable populations. Furthermore, new dedicated research and development programs are needed to continue to develop more drug candidates suitable for LAI.

“Long-acting formulations hold enormous promise to be transformative for combating TB, through simplification of delivery and overcoming issues of adherence that can compromise success of current interventions,” said Andrew Owen, PhD, of the University of Liverpool (England).

“The ability to deliver an entire course of drug in a single visit promises to ensure missed doses don’t compromise outcomes or place unnecessary selective pressure in favor of drug resistance,” Dr. Owen said.

“Recent studies showing the value of one-month oral treatment regimens for LTBI make long-acting formulations seem more realistic and drugs such as long-acting bedaquiline put a one-shot regimen within reach,” Charles W. Flexner, MD, of Johns Hopkins University, Baltimore, said in an interview.

While no LAIs have been approved for TB, Dr. Nuermberger was optimistic that the recent success of LAI formulations for HIV treatment and prevention will catalyze further efforts in the TB landscape.

Dr. Nuermberger disclosed research support from Janssen Pharmaceuticals, TB Alliance, and the Gates Medical Research Institute. The presentation was sponsored by Janssen Pharmaceuticals, Johns Hopkins CFAR, NIH, Unitaid, and the TB Alliance.

I swear by Apollo Physician and Asclepius and Hygeia and Panacea and all the gods and goddesses, making them my witnesses, that I will fulfill according to my ability and judgment this oath and this covenant.

On my desk sits a bust of Hygeia, a mask from Venice, next to a small sculpture and a figurine of the plague doctor. Nearby, there is a Klimt closeup of Hygeia, a postcard portraying Asclepius, St. Sebastian paintings, and quotes from Maimonides. They whisper secrets and nod to the challenges of the past. These medical specters, ancient voices of the past, keep me grounded. They speak, listen, and elevate me, too. They bring life into my otherwise quiet room.

Fast forward to today

These medical specters serve as reminders of what makes the field of medicine so inspiring: the selfless acts, the fortitude of spirit, the healers, the long history, and the shoulders of giants we stand upon. From these stories, we spring the healing waters we bathe in to give us the courage to wake up and care for our patients each day. These specters encourage us to defeat any and all of the scourges that come our way.

I hear and read stories about the frontline heroes, the vaccine makers, the PPE creators, the health care workers, grocery store clerks, and teachers. I’m honored to hear of these stories and your sacrifices. I’m inspired to continue upholding your essence, your fight, and your stories. In keeping with ancient empire metaphors, you are taking the slings of the diseased arrows flying to our brethren as you try to keep yourself and others safe.

The sheathing of this sword will come. These arrows will be silenced. But until then, I lean on these pictures, these stories, and these saints, to give us all the strength to wake up each morning and continue healing.

They serve as reminders of what makes the field of medicine so great: the selfless acts, the fortitude of spirit, the healers, the long history, and the shoulders of giants we stand upon. From these stories spring the healing waters we bathe in to give us the courage to wake up and care for our patients each day and defeat any and all scourges that come our way.

So, who do you call in those late, quiet hours, when all seems lost?

Dr. Messler is the executive director, quality initiatives at Glytec and works as a hospitalist at Morton Plant Hospitalist group in Clearwater, Fla. This essay appeared initially on The Hospital Leader, the official blog of SHM.
 

I swear by Apollo Physician and Asclepius and Hygeia and Panacea and all the gods and goddesses, making them my witnesses, that I will fulfill according to my ability and judgment this oath and this covenant.

On my desk sits a bust of Hygeia, a mask from Venice, next to a small sculpture and a figurine of the plague doctor. Nearby, there is a Klimt closeup of Hygeia, a postcard portraying Asclepius, St. Sebastian paintings, and quotes from Maimonides. They whisper secrets and nod to the challenges of the past. These medical specters, ancient voices of the past, keep me grounded. They speak, listen, and elevate me, too. They bring life into my otherwise quiet room.

Fast forward to today

These medical specters serve as reminders of what makes the field of medicine so inspiring: the selfless acts, the fortitude of spirit, the healers, the long history, and the shoulders of giants we stand upon. From these stories, we spring the healing waters we bathe in to give us the courage to wake up and care for our patients each day. These specters encourage us to defeat any and all of the scourges that come our way.

I hear and read stories about the frontline heroes, the vaccine makers, the PPE creators, the health care workers, grocery store clerks, and teachers. I’m honored to hear of these stories and your sacrifices. I’m inspired to continue upholding your essence, your fight, and your stories. In keeping with ancient empire metaphors, you are taking the slings of the diseased arrows flying to our brethren as you try to keep yourself and others safe.

The sheathing of this sword will come. These arrows will be silenced. But until then, I lean on these pictures, these stories, and these saints, to give us all the strength to wake up each morning and continue healing.

They serve as reminders of what makes the field of medicine so great: the selfless acts, the fortitude of spirit, the healers, the long history, and the shoulders of giants we stand upon. From these stories spring the healing waters we bathe in to give us the courage to wake up and care for our patients each day and defeat any and all scourges that come our way.

So, who do you call in those late, quiet hours, when all seems lost?

Dr. Messler is the executive director, quality initiatives at Glytec and works as a hospitalist at Morton Plant Hospitalist group in Clearwater, Fla. This essay appeared initially on The Hospital Leader, the official blog of SHM.
 

I swear by Apollo Physician and Asclepius and Hygeia and Panacea and all the gods and goddesses, making them my witnesses, that I will fulfill according to my ability and judgment this oath and this covenant.

On my desk sits a bust of Hygeia, a mask from Venice, next to a small sculpture and a figurine of the plague doctor. Nearby, there is a Klimt closeup of Hygeia, a postcard portraying Asclepius, St. Sebastian paintings, and quotes from Maimonides. They whisper secrets and nod to the challenges of the past. These medical specters, ancient voices of the past, keep me grounded. They speak, listen, and elevate me, too. They bring life into my otherwise quiet room.

Fast forward to today

These medical specters serve as reminders of what makes the field of medicine so inspiring: the selfless acts, the fortitude of spirit, the healers, the long history, and the shoulders of giants we stand upon. From these stories, we spring the healing waters we bathe in to give us the courage to wake up and care for our patients each day. These specters encourage us to defeat any and all of the scourges that come our way.

I hear and read stories about the frontline heroes, the vaccine makers, the PPE creators, the health care workers, grocery store clerks, and teachers. I’m honored to hear of these stories and your sacrifices. I’m inspired to continue upholding your essence, your fight, and your stories. In keeping with ancient empire metaphors, you are taking the slings of the diseased arrows flying to our brethren as you try to keep yourself and others safe.

The sheathing of this sword will come. These arrows will be silenced. But until then, I lean on these pictures, these stories, and these saints, to give us all the strength to wake up each morning and continue healing.

They serve as reminders of what makes the field of medicine so great: the selfless acts, the fortitude of spirit, the healers, the long history, and the shoulders of giants we stand upon. From these stories spring the healing waters we bathe in to give us the courage to wake up and care for our patients each day and defeat any and all scourges that come our way.

So, who do you call in those late, quiet hours, when all seems lost?

Dr. Messler is the executive director, quality initiatives at Glytec and works as a hospitalist at Morton Plant Hospitalist group in Clearwater, Fla. This essay appeared initially on The Hospital Leader, the official blog of SHM.
 

Another coronavirus surge may be on the way in the United States as daily COVID-19 cases continue to plateau around 60,000, states begin to lift restrictions, and people embark on spring break trips this week, according to CNN.

Outbreaks will likely stem from the B.1.1.7 variant, which was first identified in the United Kingdom, and gain momentum during the next 6-14 weeks.

“Four weeks ago, the B.1.1.7 variant made up about 1%-4% of the virus that we were seeing in communities across the country. Today it’s up to 30%-40%,” Michael Osterholm, PhD, director of the Center for Infectious Disease Research and Policy at the University of Minnesota, Minneapolis, told NBC’s Meet the Press on March 7.

Dr. Osterholm compared the current situation with the “eye of the hurricane,” where the skies appear clear but more storms are on the way. Across Europe, 27 countries are seeing significant B.1.1.7 case increases, and 10 are getting hit hard, he said.

“What we’ve seen in Europe, when we hit that 50% mark, you see cases surge,” he said. “So right now, we do have to keep America as safe as we can from this virus by not letting up on any of the public health measures we’ve taken.”

In January, the CDC warned that B.1.1.7 variant cases would increase in 2021 and become the dominant variant in the country by this month. The United States has now reported more than 3,000 cases across 46 states, according to the latest CDC tally updated on March 7. More than 600 cases have been found in Florida, followed by more than 400 in Michigan.

The CDC has said the tally doesn’t represent the total number of B.1.1.7 cases in the United States, only the ones that have been identified by analyzing samples through genomic sequencing.

“Where it has hit in the U.K. and now elsewhere in Europe, it has been catastrophic,” Celine Gounder, MD, an infectious disease specialist with New York University Langone Health, told CNN on March 7.

The variant is more transmissible than the original novel coronavirus, and the cases in the United States are “increasing exponentially,” she said.

“It has driven up rates of hospitalizations and deaths and it’s very difficult to control,” Dr. Gounder said.

Vaccination numbers aren’t yet high enough to stop the predicted surge, she added. The United States has shipped more than 116 million vaccine doses, according to the latest CDC update on March 7. Nearly 59 million people have received at least one dose, and 30.6 million people have received two vaccine doses. About 9% of the U.S. population has been fully vaccinated.

States shouldn’t ease restrictions until the vaccination numbers are much higher and daily COVID-19 cases fall below 10,000 – and maybe “considerably less than that,” Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, told CNN on March 4.

Several states have already begun to lift COVID-19 safety protocols, with Texas and Mississippi removing mask mandates last week. Businesses in Texas will be able to reopen at full capacity on March 10. For now, public health officials are urging Americans to continue to wear masks, avoid crowds, and follow social distancing guidelines as vaccines roll out across the country.

“This is sort of like we’ve been running this really long marathon, and we’re 100 yards from the finish line and we sit down and we give up,” Dr. Gounder told CNN on Sunday. ‘We’re almost there, we just need to give ourselves a bit more time to get a larger proportion of the population covered with vaccines.”

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

Another coronavirus surge may be on the way in the United States as daily COVID-19 cases continue to plateau around 60,000, states begin to lift restrictions, and people embark on spring break trips this week, according to CNN.

Outbreaks will likely stem from the B.1.1.7 variant, which was first identified in the United Kingdom, and gain momentum during the next 6-14 weeks.

“Four weeks ago, the B.1.1.7 variant made up about 1%-4% of the virus that we were seeing in communities across the country. Today it’s up to 30%-40%,” Michael Osterholm, PhD, director of the Center for Infectious Disease Research and Policy at the University of Minnesota, Minneapolis, told NBC’s Meet the Press on March 7.

Dr. Osterholm compared the current situation with the “eye of the hurricane,” where the skies appear clear but more storms are on the way. Across Europe, 27 countries are seeing significant B.1.1.7 case increases, and 10 are getting hit hard, he said.

“What we’ve seen in Europe, when we hit that 50% mark, you see cases surge,” he said. “So right now, we do have to keep America as safe as we can from this virus by not letting up on any of the public health measures we’ve taken.”

In January, the CDC warned that B.1.1.7 variant cases would increase in 2021 and become the dominant variant in the country by this month. The United States has now reported more than 3,000 cases across 46 states, according to the latest CDC tally updated on March 7. More than 600 cases have been found in Florida, followed by more than 400 in Michigan.

The CDC has said the tally doesn’t represent the total number of B.1.1.7 cases in the United States, only the ones that have been identified by analyzing samples through genomic sequencing.

“Where it has hit in the U.K. and now elsewhere in Europe, it has been catastrophic,” Celine Gounder, MD, an infectious disease specialist with New York University Langone Health, told CNN on March 7.

The variant is more transmissible than the original novel coronavirus, and the cases in the United States are “increasing exponentially,” she said.

“It has driven up rates of hospitalizations and deaths and it’s very difficult to control,” Dr. Gounder said.

Vaccination numbers aren’t yet high enough to stop the predicted surge, she added. The United States has shipped more than 116 million vaccine doses, according to the latest CDC update on March 7. Nearly 59 million people have received at least one dose, and 30.6 million people have received two vaccine doses. About 9% of the U.S. population has been fully vaccinated.

States shouldn’t ease restrictions until the vaccination numbers are much higher and daily COVID-19 cases fall below 10,000 – and maybe “considerably less than that,” Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, told CNN on March 4.

Several states have already begun to lift COVID-19 safety protocols, with Texas and Mississippi removing mask mandates last week. Businesses in Texas will be able to reopen at full capacity on March 10. For now, public health officials are urging Americans to continue to wear masks, avoid crowds, and follow social distancing guidelines as vaccines roll out across the country.

“This is sort of like we’ve been running this really long marathon, and we’re 100 yards from the finish line and we sit down and we give up,” Dr. Gounder told CNN on Sunday. ‘We’re almost there, we just need to give ourselves a bit more time to get a larger proportion of the population covered with vaccines.”

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

Another coronavirus surge may be on the way in the United States as daily COVID-19 cases continue to plateau around 60,000, states begin to lift restrictions, and people embark on spring break trips this week, according to CNN.

Outbreaks will likely stem from the B.1.1.7 variant, which was first identified in the United Kingdom, and gain momentum during the next 6-14 weeks.

“Four weeks ago, the B.1.1.7 variant made up about 1%-4% of the virus that we were seeing in communities across the country. Today it’s up to 30%-40%,” Michael Osterholm, PhD, director of the Center for Infectious Disease Research and Policy at the University of Minnesota, Minneapolis, told NBC’s Meet the Press on March 7.

Dr. Osterholm compared the current situation with the “eye of the hurricane,” where the skies appear clear but more storms are on the way. Across Europe, 27 countries are seeing significant B.1.1.7 case increases, and 10 are getting hit hard, he said.

“What we’ve seen in Europe, when we hit that 50% mark, you see cases surge,” he said. “So right now, we do have to keep America as safe as we can from this virus by not letting up on any of the public health measures we’ve taken.”

In January, the CDC warned that B.1.1.7 variant cases would increase in 2021 and become the dominant variant in the country by this month. The United States has now reported more than 3,000 cases across 46 states, according to the latest CDC tally updated on March 7. More than 600 cases have been found in Florida, followed by more than 400 in Michigan.

The CDC has said the tally doesn’t represent the total number of B.1.1.7 cases in the United States, only the ones that have been identified by analyzing samples through genomic sequencing.

“Where it has hit in the U.K. and now elsewhere in Europe, it has been catastrophic,” Celine Gounder, MD, an infectious disease specialist with New York University Langone Health, told CNN on March 7.

The variant is more transmissible than the original novel coronavirus, and the cases in the United States are “increasing exponentially,” she said.

“It has driven up rates of hospitalizations and deaths and it’s very difficult to control,” Dr. Gounder said.

Vaccination numbers aren’t yet high enough to stop the predicted surge, she added. The United States has shipped more than 116 million vaccine doses, according to the latest CDC update on March 7. Nearly 59 million people have received at least one dose, and 30.6 million people have received two vaccine doses. About 9% of the U.S. population has been fully vaccinated.

States shouldn’t ease restrictions until the vaccination numbers are much higher and daily COVID-19 cases fall below 10,000 – and maybe “considerably less than that,” Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, told CNN on March 4.

Several states have already begun to lift COVID-19 safety protocols, with Texas and Mississippi removing mask mandates last week. Businesses in Texas will be able to reopen at full capacity on March 10. For now, public health officials are urging Americans to continue to wear masks, avoid crowds, and follow social distancing guidelines as vaccines roll out across the country.

“This is sort of like we’ve been running this really long marathon, and we’re 100 yards from the finish line and we sit down and we give up,” Dr. Gounder told CNN on Sunday. ‘We’re almost there, we just need to give ourselves a bit more time to get a larger proportion of the population covered with vaccines.”

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

Direct oral anticoagulants (DOACs) are used in about 1% of patients undergoing surgical mechanical aortic and mitral valve replacement, but in up to 6% of surgical bioprosthetic valve replacements, according to registry data presented at CRT 2021.

In an analysis of the Society of Thoracic Surgery (STS) registry during 2014-2017, DOAC use increased steadily among those undergoing surgical bioprosthetic valve replacement, reaching a number that is potentially clinically significant, according to Ankur Kalra, MD, an interventional cardiologist at Akron General Hospital who has an academic appointment at the Cleveland Clinic.

There was no increase in the use of DOACs observed among patients undergoing mechanical valve replacement, “but even if the number is 1%, they should probably not be used at all until we accrue more data,” Dr. Kalra said.
 

DOACs discouraged in patients with mechanical or bioprosthetic valves

In Food and Drug Administration labeling, DOACs are contraindicated or not recommended. This can be traced to the randomized RE-ALIGN trial, which was stopped prematurely due to evidence of harm from a DOAC, according to Dr. Kalra.

In RE-ALIGN, which enrolled patients undergoing mechanical aortic or mitral valve replacement, dabigatran was associated not only with more bleeding events than warfarin, but also more thromboembolic events.

There are no randomized data comparing the factor Xa inhibitors rivaroxaban or apixaban to warfarin in heart valve surgery, but Dr. Kalra noted cautionary language is found in the labeling of both, “perhaps due to the RE-ALIGN data.”
 

Registry shows trends in prescribing

In the STS registry data, 193 (1.1%) of the 18,142 patients undergoing mechanical aortic valve surgery, 139 (1.0%) of the 13,942 patients undergoing mechanical mitral valve surgery, 5,625 (4.7%) of the 116,203 patients undergoing aortic bioprosthetic aortic valve surgery, and 2,180 (5.9%) of the 39,243 patients undergoing bioprosthetic mitral valve surgery were on a DOAC at discharge.

Among those receiving a mechanical value and placed on a DOAC, about two-thirds were on a factor Xa inhibitor rather than dabigatran. For those receiving a bioprosthetic value, the proportion was greater than 80%. Dr. Kalra speculated that the RE-ALIGN trial might be the reason factor Xa inhibitors were favored.

In both types of valves, whether mechanical or bioprosthetic, more comorbidities predicted a greater likelihood of receiving a DOAC rather than warfarin. For those receiving mechanical values, the comorbidities with a significant association with greater DOAC use included hypertension (P = .003), dyslipidemia (P = .02), arrhythmia (P < .001), and peripheral arterial disease (P < 0.001).

The same factors were significant for predicting increased likelihood of a DOAC following bioprosthetic valve replacement, but there were additional factors, including atrial fibrillation independent of other types of arrhythmias (P < .001), a factor not significant for mechanical valves, as well as diabetes (P < .001), cerebrovascular disease (P < .001), dialysis (P < .001), and endocarditis (P < .001).

“This is probably intuitive, but patients who were on a factor Xa inhibitor before their valve replacement were also more likely to be discharged on a factor Xa inhibitor,” Dr. Kalra said at the virtual meeting, sponsored by MedStar Heart & Vascular Institute.

The year-to-year increase in DOAC use among those undergoing bioprosthetic valve replacement over the study period, which was a significant trend, was not observed among those undergoing mechanical valve replacement. Rather, the 1% proportion remained stable over the study period.

“We wanted to look at outcomes, but we found that the STS database, which only includes data out to 30 days, is not structured for this type of analysis,” Dr. Kalra said. He was also concerned about the limitations of a comparison in which 1% of the sample was being compared to 99%.
 

Expert: One percent is ‘very small number’

David J. Cohen, MD, commented on the 1% figure, which was so low that a moderator questioned whether it could be due mostly to coding errors.

“This is a very, very small number so at some level it is reassuring that it is so low in the mechanical valves,” Dr. Cohen said. However, he was more circumspect about the larger number in bioprosthetic valves.

“I have always thought it was a bit strange there was a warning against using them in bioprosthetic valves, especially in the aortic position,” he said.

Direct oral anticoagulants (DOACs) are used in about 1% of patients undergoing surgical mechanical aortic and mitral valve replacement, but in up to 6% of surgical bioprosthetic valve replacements, according to registry data presented at CRT 2021.

In an analysis of the Society of Thoracic Surgery (STS) registry during 2014-2017, DOAC use increased steadily among those undergoing surgical bioprosthetic valve replacement, reaching a number that is potentially clinically significant, according to Ankur Kalra, MD, an interventional cardiologist at Akron General Hospital who has an academic appointment at the Cleveland Clinic.

There was no increase in the use of DOACs observed among patients undergoing mechanical valve replacement, “but even if the number is 1%, they should probably not be used at all until we accrue more data,” Dr. Kalra said.
 

DOACs discouraged in patients with mechanical or bioprosthetic valves

In Food and Drug Administration labeling, DOACs are contraindicated or not recommended. This can be traced to the randomized RE-ALIGN trial, which was stopped prematurely due to evidence of harm from a DOAC, according to Dr. Kalra.

In RE-ALIGN, which enrolled patients undergoing mechanical aortic or mitral valve replacement, dabigatran was associated not only with more bleeding events than warfarin, but also more thromboembolic events.

There are no randomized data comparing the factor Xa inhibitors rivaroxaban or apixaban to warfarin in heart valve surgery, but Dr. Kalra noted cautionary language is found in the labeling of both, “perhaps due to the RE-ALIGN data.”
 

Registry shows trends in prescribing

In the STS registry data, 193 (1.1%) of the 18,142 patients undergoing mechanical aortic valve surgery, 139 (1.0%) of the 13,942 patients undergoing mechanical mitral valve surgery, 5,625 (4.7%) of the 116,203 patients undergoing aortic bioprosthetic aortic valve surgery, and 2,180 (5.9%) of the 39,243 patients undergoing bioprosthetic mitral valve surgery were on a DOAC at discharge.

Among those receiving a mechanical value and placed on a DOAC, about two-thirds were on a factor Xa inhibitor rather than dabigatran. For those receiving a bioprosthetic value, the proportion was greater than 80%. Dr. Kalra speculated that the RE-ALIGN trial might be the reason factor Xa inhibitors were favored.

In both types of valves, whether mechanical or bioprosthetic, more comorbidities predicted a greater likelihood of receiving a DOAC rather than warfarin. For those receiving mechanical values, the comorbidities with a significant association with greater DOAC use included hypertension (P = .003), dyslipidemia (P = .02), arrhythmia (P < .001), and peripheral arterial disease (P < 0.001).

The same factors were significant for predicting increased likelihood of a DOAC following bioprosthetic valve replacement, but there were additional factors, including atrial fibrillation independent of other types of arrhythmias (P < .001), a factor not significant for mechanical valves, as well as diabetes (P < .001), cerebrovascular disease (P < .001), dialysis (P < .001), and endocarditis (P < .001).

“This is probably intuitive, but patients who were on a factor Xa inhibitor before their valve replacement were also more likely to be discharged on a factor Xa inhibitor,” Dr. Kalra said at the virtual meeting, sponsored by MedStar Heart & Vascular Institute.

The year-to-year increase in DOAC use among those undergoing bioprosthetic valve replacement over the study period, which was a significant trend, was not observed among those undergoing mechanical valve replacement. Rather, the 1% proportion remained stable over the study period.

“We wanted to look at outcomes, but we found that the STS database, which only includes data out to 30 days, is not structured for this type of analysis,” Dr. Kalra said. He was also concerned about the limitations of a comparison in which 1% of the sample was being compared to 99%.
 

Expert: One percent is ‘very small number’

David J. Cohen, MD, commented on the 1% figure, which was so low that a moderator questioned whether it could be due mostly to coding errors.

“This is a very, very small number so at some level it is reassuring that it is so low in the mechanical valves,” Dr. Cohen said. However, he was more circumspect about the larger number in bioprosthetic valves.

“I have always thought it was a bit strange there was a warning against using them in bioprosthetic valves, especially in the aortic position,” he said.

Direct oral anticoagulants (DOACs) are used in about 1% of patients undergoing surgical mechanical aortic and mitral valve replacement, but in up to 6% of surgical bioprosthetic valve replacements, according to registry data presented at CRT 2021.

In an analysis of the Society of Thoracic Surgery (STS) registry during 2014-2017, DOAC use increased steadily among those undergoing surgical bioprosthetic valve replacement, reaching a number that is potentially clinically significant, according to Ankur Kalra, MD, an interventional cardiologist at Akron General Hospital who has an academic appointment at the Cleveland Clinic.

There was no increase in the use of DOACs observed among patients undergoing mechanical valve replacement, “but even if the number is 1%, they should probably not be used at all until we accrue more data,” Dr. Kalra said.
 

DOACs discouraged in patients with mechanical or bioprosthetic valves

In Food and Drug Administration labeling, DOACs are contraindicated or not recommended. This can be traced to the randomized RE-ALIGN trial, which was stopped prematurely due to evidence of harm from a DOAC, according to Dr. Kalra.

In RE-ALIGN, which enrolled patients undergoing mechanical aortic or mitral valve replacement, dabigatran was associated not only with more bleeding events than warfarin, but also more thromboembolic events.

There are no randomized data comparing the factor Xa inhibitors rivaroxaban or apixaban to warfarin in heart valve surgery, but Dr. Kalra noted cautionary language is found in the labeling of both, “perhaps due to the RE-ALIGN data.”
 

Registry shows trends in prescribing

In the STS registry data, 193 (1.1%) of the 18,142 patients undergoing mechanical aortic valve surgery, 139 (1.0%) of the 13,942 patients undergoing mechanical mitral valve surgery, 5,625 (4.7%) of the 116,203 patients undergoing aortic bioprosthetic aortic valve surgery, and 2,180 (5.9%) of the 39,243 patients undergoing bioprosthetic mitral valve surgery were on a DOAC at discharge.

Among those receiving a mechanical value and placed on a DOAC, about two-thirds were on a factor Xa inhibitor rather than dabigatran. For those receiving a bioprosthetic value, the proportion was greater than 80%. Dr. Kalra speculated that the RE-ALIGN trial might be the reason factor Xa inhibitors were favored.

In both types of valves, whether mechanical or bioprosthetic, more comorbidities predicted a greater likelihood of receiving a DOAC rather than warfarin. For those receiving mechanical values, the comorbidities with a significant association with greater DOAC use included hypertension (P = .003), dyslipidemia (P = .02), arrhythmia (P < .001), and peripheral arterial disease (P < 0.001).

The same factors were significant for predicting increased likelihood of a DOAC following bioprosthetic valve replacement, but there were additional factors, including atrial fibrillation independent of other types of arrhythmias (P < .001), a factor not significant for mechanical valves, as well as diabetes (P < .001), cerebrovascular disease (P < .001), dialysis (P < .001), and endocarditis (P < .001).

“This is probably intuitive, but patients who were on a factor Xa inhibitor before their valve replacement were also more likely to be discharged on a factor Xa inhibitor,” Dr. Kalra said at the virtual meeting, sponsored by MedStar Heart & Vascular Institute.

The year-to-year increase in DOAC use among those undergoing bioprosthetic valve replacement over the study period, which was a significant trend, was not observed among those undergoing mechanical valve replacement. Rather, the 1% proportion remained stable over the study period.

“We wanted to look at outcomes, but we found that the STS database, which only includes data out to 30 days, is not structured for this type of analysis,” Dr. Kalra said. He was also concerned about the limitations of a comparison in which 1% of the sample was being compared to 99%.
 

Expert: One percent is ‘very small number’

David J. Cohen, MD, commented on the 1% figure, which was so low that a moderator questioned whether it could be due mostly to coding errors.

“This is a very, very small number so at some level it is reassuring that it is so low in the mechanical valves,” Dr. Cohen said. However, he was more circumspect about the larger number in bioprosthetic valves.

“I have always thought it was a bit strange there was a warning against using them in bioprosthetic valves, especially in the aortic position,” he said.

A single pill of the investigational drug molnupiravir taken twice a day for 5 days eliminated SARS-CoV-2 from the nasopharynx of 49 participants.

That led Carlos del Rio, MD, distinguished professor of medicine at Emory University, Atlanta, to suggest a future in which a drug like molnupiravir could be taken in the first few days of symptoms to prevent severe disease, similar to Tamiflu for influenza.

“I think it’s critically important,” he said of the data. Emory University was involved in the trial of molnupiravir but Dr. del Rio was not part of that team. “This drug offers the first antiviral oral drug that then could be used in an outpatient setting.”

Still, Dr. del Rio said it’s too soon to call this particular drug the breakthrough clinicians need to keep people out of the ICU. “It has the potential to be practice changing; it’s not practice changing at the moment.”

Wendy Painter, MD, of Ridgeback Biotherapeutics, who presented the data at the Conference on Retroviruses and Opportunistic Infections, agreed. While the data are promising, “We will need to see if people get better from actual illness” to assess the real value of the drug in clinical care.

“That’s a phase 3 objective we’ll need to prove,” she said in an interview.

Phase 2/3 efficacy and safety studies of the drug are now underway in hospitalized and nonhospitalized patients.

In a brief prerecorded presentation of the data, Dr. Painter laid out what researchers know so far: Preclinical studies suggest that molnupiravir is effective against a number of viruses, including coronaviruses and specifically SARS-CoV-2. It prevents a virus from replicating by inducing viral error catastrophe (Proc Natl Acad Sci U S A. 2002 Oct 15;99[21]:13374-6) – essentially overloading the virus with replication and mutation until the virus burns itself out and can’t produce replicable copies.

In this phase 2a, randomized, double-blind, controlled trial, researchers recruited 202 adults who were treated at an outpatient clinic with fever or other symptoms of a respiratory virus and confirmed SARS-CoV-2 infection by day 4. Participants were randomly assigned to three different groups: 200 mg of molnupiravir, 400 mg, or 800 mg. The 200-mg arm was matched 1:1 with a placebo-controlled group, and the other two groups had three participants in the active group for every one control.

Participants took the pills twice daily for 5 days, and then were followed for a total of 28 days to monitor for complications or adverse events. At days 3, 5, 7, 14, and 28, researchers also took nasopharyngeal swabs for polymerase chain reaction tests, to sequence the virus, and to grow cultures of SARS-CoV-2 to see if the virus that’s present is actually capable of infecting others.

Notably, the pills do not have to be refrigerated at any point in the process, alleviating the cold-chain challenges that have plagued vaccines.

“There’s an urgent need for an easily produced, transported, stored, and administered antiviral drug against SARS-CoV-2,” Dr. Painter said.

Of the 202 people recruited, 182 had swabs that could be evaluated, of which 78 showed infection at baseline. The results are based on labs of those 78 participants.

By day 3, 28% of patients in the placebo arm had SARS-CoV-2 in their nasopharynx, compared with 20.4% of patients receiving any dose of molnupiravir. But by day 5, none of the participants receiving the active drug had evidence of SARS-CoV-2 in their nasopharynx. In comparison, 24% of people in the placebo arm still had detectable virus.

Halfway through the treatment course, differences in the presence of infectious virus were already evident. By day 3 of the 5-day course, 36.4% of participants in the 200-mg group had detectable virus in the nasopharynx, compared with 21% in the 400-mg group and just 12.5% in the 800-mg group. And although the reduction in SARS-CoV-2 was noticeable in the 200-mg and the 400-mg arms, it was only statistically significant in the 800-mg arm.

In contrast, by the end of the 5 days in the placebo groups, infectious virus varied from 18.2% in the 200-mg placebo group to 30% in the 800-mg group. This points out the variability of the disease course of SARS-CoV-2.

“You just don’t know” which infections will lead to serious disease, Dr. Painter said in an interview. “And don’t you wish we did?”

Seven participants discontinued treatment, though only four experienced adverse events. Three of those discontinued the trial because of adverse events. The study is still blinded, so it’s unclear what those events were, but Dr. Painter said that they were not thought to be related to the study drug.

The bottom line, said Dr. Painter, was that people treated with molnupiravir had starkly different outcomes in lab measures during the study.

“An average of 10 days after symptom onset, 24% of placebo patients remained culture positive” for SARS-CoV-2 – meaning there wasn’t just virus in the nasopharynx, but it was capable of replicating, Dr. Painter said. “In contrast, no infectious virus could be recovered at study day 5 in any molnupiravir-treated patients.”

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

A single pill of the investigational drug molnupiravir taken twice a day for 5 days eliminated SARS-CoV-2 from the nasopharynx of 49 participants.

That led Carlos del Rio, MD, distinguished professor of medicine at Emory University, Atlanta, to suggest a future in which a drug like molnupiravir could be taken in the first few days of symptoms to prevent severe disease, similar to Tamiflu for influenza.

“I think it’s critically important,” he said of the data. Emory University was involved in the trial of molnupiravir but Dr. del Rio was not part of that team. “This drug offers the first antiviral oral drug that then could be used in an outpatient setting.”

Still, Dr. del Rio said it’s too soon to call this particular drug the breakthrough clinicians need to keep people out of the ICU. “It has the potential to be practice changing; it’s not practice changing at the moment.”

Wendy Painter, MD, of Ridgeback Biotherapeutics, who presented the data at the Conference on Retroviruses and Opportunistic Infections, agreed. While the data are promising, “We will need to see if people get better from actual illness” to assess the real value of the drug in clinical care.

“That’s a phase 3 objective we’ll need to prove,” she said in an interview.

Phase 2/3 efficacy and safety studies of the drug are now underway in hospitalized and nonhospitalized patients.

In a brief prerecorded presentation of the data, Dr. Painter laid out what researchers know so far: Preclinical studies suggest that molnupiravir is effective against a number of viruses, including coronaviruses and specifically SARS-CoV-2. It prevents a virus from replicating by inducing viral error catastrophe (Proc Natl Acad Sci U S A. 2002 Oct 15;99[21]:13374-6) – essentially overloading the virus with replication and mutation until the virus burns itself out and can’t produce replicable copies.

In this phase 2a, randomized, double-blind, controlled trial, researchers recruited 202 adults who were treated at an outpatient clinic with fever or other symptoms of a respiratory virus and confirmed SARS-CoV-2 infection by day 4. Participants were randomly assigned to three different groups: 200 mg of molnupiravir, 400 mg, or 800 mg. The 200-mg arm was matched 1:1 with a placebo-controlled group, and the other two groups had three participants in the active group for every one control.

Participants took the pills twice daily for 5 days, and then were followed for a total of 28 days to monitor for complications or adverse events. At days 3, 5, 7, 14, and 28, researchers also took nasopharyngeal swabs for polymerase chain reaction tests, to sequence the virus, and to grow cultures of SARS-CoV-2 to see if the virus that’s present is actually capable of infecting others.

Notably, the pills do not have to be refrigerated at any point in the process, alleviating the cold-chain challenges that have plagued vaccines.

“There’s an urgent need for an easily produced, transported, stored, and administered antiviral drug against SARS-CoV-2,” Dr. Painter said.

Of the 202 people recruited, 182 had swabs that could be evaluated, of which 78 showed infection at baseline. The results are based on labs of those 78 participants.

By day 3, 28% of patients in the placebo arm had SARS-CoV-2 in their nasopharynx, compared with 20.4% of patients receiving any dose of molnupiravir. But by day 5, none of the participants receiving the active drug had evidence of SARS-CoV-2 in their nasopharynx. In comparison, 24% of people in the placebo arm still had detectable virus.

Halfway through the treatment course, differences in the presence of infectious virus were already evident. By day 3 of the 5-day course, 36.4% of participants in the 200-mg group had detectable virus in the nasopharynx, compared with 21% in the 400-mg group and just 12.5% in the 800-mg group. And although the reduction in SARS-CoV-2 was noticeable in the 200-mg and the 400-mg arms, it was only statistically significant in the 800-mg arm.

In contrast, by the end of the 5 days in the placebo groups, infectious virus varied from 18.2% in the 200-mg placebo group to 30% in the 800-mg group. This points out the variability of the disease course of SARS-CoV-2.

“You just don’t know” which infections will lead to serious disease, Dr. Painter said in an interview. “And don’t you wish we did?”

Seven participants discontinued treatment, though only four experienced adverse events. Three of those discontinued the trial because of adverse events. The study is still blinded, so it’s unclear what those events were, but Dr. Painter said that they were not thought to be related to the study drug.

The bottom line, said Dr. Painter, was that people treated with molnupiravir had starkly different outcomes in lab measures during the study.

“An average of 10 days after symptom onset, 24% of placebo patients remained culture positive” for SARS-CoV-2 – meaning there wasn’t just virus in the nasopharynx, but it was capable of replicating, Dr. Painter said. “In contrast, no infectious virus could be recovered at study day 5 in any molnupiravir-treated patients.”

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

A single pill of the investigational drug molnupiravir taken twice a day for 5 days eliminated SARS-CoV-2 from the nasopharynx of 49 participants.

That led Carlos del Rio, MD, distinguished professor of medicine at Emory University, Atlanta, to suggest a future in which a drug like molnupiravir could be taken in the first few days of symptoms to prevent severe disease, similar to Tamiflu for influenza.

“I think it’s critically important,” he said of the data. Emory University was involved in the trial of molnupiravir but Dr. del Rio was not part of that team. “This drug offers the first antiviral oral drug that then could be used in an outpatient setting.”

Still, Dr. del Rio said it’s too soon to call this particular drug the breakthrough clinicians need to keep people out of the ICU. “It has the potential to be practice changing; it’s not practice changing at the moment.”

Wendy Painter, MD, of Ridgeback Biotherapeutics, who presented the data at the Conference on Retroviruses and Opportunistic Infections, agreed. While the data are promising, “We will need to see if people get better from actual illness” to assess the real value of the drug in clinical care.

“That’s a phase 3 objective we’ll need to prove,” she said in an interview.

Phase 2/3 efficacy and safety studies of the drug are now underway in hospitalized and nonhospitalized patients.

In a brief prerecorded presentation of the data, Dr. Painter laid out what researchers know so far: Preclinical studies suggest that molnupiravir is effective against a number of viruses, including coronaviruses and specifically SARS-CoV-2. It prevents a virus from replicating by inducing viral error catastrophe (Proc Natl Acad Sci U S A. 2002 Oct 15;99[21]:13374-6) – essentially overloading the virus with replication and mutation until the virus burns itself out and can’t produce replicable copies.

In this phase 2a, randomized, double-blind, controlled trial, researchers recruited 202 adults who were treated at an outpatient clinic with fever or other symptoms of a respiratory virus and confirmed SARS-CoV-2 infection by day 4. Participants were randomly assigned to three different groups: 200 mg of molnupiravir, 400 mg, or 800 mg. The 200-mg arm was matched 1:1 with a placebo-controlled group, and the other two groups had three participants in the active group for every one control.

Participants took the pills twice daily for 5 days, and then were followed for a total of 28 days to monitor for complications or adverse events. At days 3, 5, 7, 14, and 28, researchers also took nasopharyngeal swabs for polymerase chain reaction tests, to sequence the virus, and to grow cultures of SARS-CoV-2 to see if the virus that’s present is actually capable of infecting others.

Notably, the pills do not have to be refrigerated at any point in the process, alleviating the cold-chain challenges that have plagued vaccines.

“There’s an urgent need for an easily produced, transported, stored, and administered antiviral drug against SARS-CoV-2,” Dr. Painter said.

Of the 202 people recruited, 182 had swabs that could be evaluated, of which 78 showed infection at baseline. The results are based on labs of those 78 participants.

By day 3, 28% of patients in the placebo arm had SARS-CoV-2 in their nasopharynx, compared with 20.4% of patients receiving any dose of molnupiravir. But by day 5, none of the participants receiving the active drug had evidence of SARS-CoV-2 in their nasopharynx. In comparison, 24% of people in the placebo arm still had detectable virus.

Halfway through the treatment course, differences in the presence of infectious virus were already evident. By day 3 of the 5-day course, 36.4% of participants in the 200-mg group had detectable virus in the nasopharynx, compared with 21% in the 400-mg group and just 12.5% in the 800-mg group. And although the reduction in SARS-CoV-2 was noticeable in the 200-mg and the 400-mg arms, it was only statistically significant in the 800-mg arm.

In contrast, by the end of the 5 days in the placebo groups, infectious virus varied from 18.2% in the 200-mg placebo group to 30% in the 800-mg group. This points out the variability of the disease course of SARS-CoV-2.

“You just don’t know” which infections will lead to serious disease, Dr. Painter said in an interview. “And don’t you wish we did?”

Seven participants discontinued treatment, though only four experienced adverse events. Three of those discontinued the trial because of adverse events. The study is still blinded, so it’s unclear what those events were, but Dr. Painter said that they were not thought to be related to the study drug.

The bottom line, said Dr. Painter, was that people treated with molnupiravir had starkly different outcomes in lab measures during the study.

“An average of 10 days after symptom onset, 24% of placebo patients remained culture positive” for SARS-CoV-2 – meaning there wasn’t just virus in the nasopharynx, but it was capable of replicating, Dr. Painter said. “In contrast, no infectious virus could be recovered at study day 5 in any molnupiravir-treated patients.”

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

Each year, roughly 1 in 60 adult patients with multiple sclerosis (MS) aged 65 years and under is hospitalized with urinary or kidney infections, a new study suggests. That’s more than quadruple the rate in a control cohort. Other types of infections affected patients with MS at a higher rate too.

“The relative risk of all types of inpatient infections and most types of outpatient infections was significantly elevated among the patients with MS. While we expected there to be increased relative risk of urinary or kidney and respiratory infections, we also found higher relative risk of viral, fungal, skin, and opportunistic infections,” said study lead author Riley Bove, MD, an assistant professor at the Weill Institute for Neurosciences at the University of California, San Francisco, who presented the findings at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. She answered follow-up questions in an interview.

A common and treatable condition

“Bladder dysfunction may be present in over 80% of persons in MS and can be a significant source of decreased function and quality of life in addition to increased health care costs and morbidity,” neurologist Barbara Giesser, MD, of the University of California, Los Angeles, said in an interview. “It is common among persons with MS to have bladders that do not empty urine completely. This can predispose them to bladder and kidney infections. Also, some patients may try to self-manage bladder symptoms by restricting fluids, and this can predispose them to infection as well.”

Dr. Giesser, who was asked to comment on the present research, advised neurologists to bring up urinary disorders themselves instead of waiting for patients to mention them. “Patients are often embarrassed to start a discussion about genitourinary dysfunction with their neurologists but will be very appreciative of the opportunity for it to be investigated and treated,” she said. “Neurologists should make sure that this area of neurologic function is addressed in the routine management of their patients with MS because bladder dysfunction, morbidity, and complications associated with it are treatable and preventable.”

For her part, Dr. Bove recommended “early and effective identification of risk, appropriate referral to first-line interventions such as pelvic floor physical therapy and patient education, and early referral to urologists skilled in treating neurogenic bladder. Further, it is important to monitor side effects of medications to ensure there are no unrecognized immune deficits.”

She also cautioned that “common symptoms of [urinary tract infections] in people with MS include symptoms that are also prevalent in neurogenic bladder: urgency, incontinence, and frequency. It is possible that having baseline lower urinary tract symptoms could mask the recognition of a urinary infection, resulting in delayed recognition and treatment of the infections.”

EMD Serono funded the study. Dr. Bove is funded by the National MS Society’s Harry Weaver Award. She has received research support from Biogen and Roche Genentech and consulting/advisory board fees from Alexion, Biogen, EMD Serono, Roche Genentech, Sanofi Genzyme, and Novartis. Dr. Giesser reported no disclosures.

Each year, roughly 1 in 60 adult patients with multiple sclerosis (MS) aged 65 years and under is hospitalized with urinary or kidney infections, a new study suggests. That’s more than quadruple the rate in a control cohort. Other types of infections affected patients with MS at a higher rate too.

“The relative risk of all types of inpatient infections and most types of outpatient infections was significantly elevated among the patients with MS. While we expected there to be increased relative risk of urinary or kidney and respiratory infections, we also found higher relative risk of viral, fungal, skin, and opportunistic infections,” said study lead author Riley Bove, MD, an assistant professor at the Weill Institute for Neurosciences at the University of California, San Francisco, who presented the findings at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. She answered follow-up questions in an interview.

A common and treatable condition

“Bladder dysfunction may be present in over 80% of persons in MS and can be a significant source of decreased function and quality of life in addition to increased health care costs and morbidity,” neurologist Barbara Giesser, MD, of the University of California, Los Angeles, said in an interview. “It is common among persons with MS to have bladders that do not empty urine completely. This can predispose them to bladder and kidney infections. Also, some patients may try to self-manage bladder symptoms by restricting fluids, and this can predispose them to infection as well.”

Dr. Giesser, who was asked to comment on the present research, advised neurologists to bring up urinary disorders themselves instead of waiting for patients to mention them. “Patients are often embarrassed to start a discussion about genitourinary dysfunction with their neurologists but will be very appreciative of the opportunity for it to be investigated and treated,” she said. “Neurologists should make sure that this area of neurologic function is addressed in the routine management of their patients with MS because bladder dysfunction, morbidity, and complications associated with it are treatable and preventable.”

For her part, Dr. Bove recommended “early and effective identification of risk, appropriate referral to first-line interventions such as pelvic floor physical therapy and patient education, and early referral to urologists skilled in treating neurogenic bladder. Further, it is important to monitor side effects of medications to ensure there are no unrecognized immune deficits.”

She also cautioned that “common symptoms of [urinary tract infections] in people with MS include symptoms that are also prevalent in neurogenic bladder: urgency, incontinence, and frequency. It is possible that having baseline lower urinary tract symptoms could mask the recognition of a urinary infection, resulting in delayed recognition and treatment of the infections.”

EMD Serono funded the study. Dr. Bove is funded by the National MS Society’s Harry Weaver Award. She has received research support from Biogen and Roche Genentech and consulting/advisory board fees from Alexion, Biogen, EMD Serono, Roche Genentech, Sanofi Genzyme, and Novartis. Dr. Giesser reported no disclosures.

Each year, roughly 1 in 60 adult patients with multiple sclerosis (MS) aged 65 years and under is hospitalized with urinary or kidney infections, a new study suggests. That’s more than quadruple the rate in a control cohort. Other types of infections affected patients with MS at a higher rate too.

“The relative risk of all types of inpatient infections and most types of outpatient infections was significantly elevated among the patients with MS. While we expected there to be increased relative risk of urinary or kidney and respiratory infections, we also found higher relative risk of viral, fungal, skin, and opportunistic infections,” said study lead author Riley Bove, MD, an assistant professor at the Weill Institute for Neurosciences at the University of California, San Francisco, who presented the findings at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. She answered follow-up questions in an interview.

A common and treatable condition

“Bladder dysfunction may be present in over 80% of persons in MS and can be a significant source of decreased function and quality of life in addition to increased health care costs and morbidity,” neurologist Barbara Giesser, MD, of the University of California, Los Angeles, said in an interview. “It is common among persons with MS to have bladders that do not empty urine completely. This can predispose them to bladder and kidney infections. Also, some patients may try to self-manage bladder symptoms by restricting fluids, and this can predispose them to infection as well.”

Dr. Giesser, who was asked to comment on the present research, advised neurologists to bring up urinary disorders themselves instead of waiting for patients to mention them. “Patients are often embarrassed to start a discussion about genitourinary dysfunction with their neurologists but will be very appreciative of the opportunity for it to be investigated and treated,” she said. “Neurologists should make sure that this area of neurologic function is addressed in the routine management of their patients with MS because bladder dysfunction, morbidity, and complications associated with it are treatable and preventable.”

For her part, Dr. Bove recommended “early and effective identification of risk, appropriate referral to first-line interventions such as pelvic floor physical therapy and patient education, and early referral to urologists skilled in treating neurogenic bladder. Further, it is important to monitor side effects of medications to ensure there are no unrecognized immune deficits.”

She also cautioned that “common symptoms of [urinary tract infections] in people with MS include symptoms that are also prevalent in neurogenic bladder: urgency, incontinence, and frequency. It is possible that having baseline lower urinary tract symptoms could mask the recognition of a urinary infection, resulting in delayed recognition and treatment of the infections.”

EMD Serono funded the study. Dr. Bove is funded by the National MS Society’s Harry Weaver Award. She has received research support from Biogen and Roche Genentech and consulting/advisory board fees from Alexion, Biogen, EMD Serono, Roche Genentech, Sanofi Genzyme, and Novartis. Dr. Giesser reported no disclosures.

There has been a rise in the prevalence of perniolike lesions—erythematous to violaceous, edematous papules or nodules on the fingers or toes—during the coronavirus disease 2019 (COVID-19) pandemic. These lesions are referred to as “COVID toes.” Although several studies have suggested an association with these lesions and COVID-19, and coronavirus particles have been identified in endothelial cells of biopsies of pernio lesions, questions remain on the management, pathophysiology, and implications of these lesions.¹ We provide a practical review for primary care clinicians and dermatologists on the current management, recommendations, and remaining questions, with particular attention to the distinctions for children vs adults presenting with pernio lesions.

Hypothetical Case of a Child Presenting With Acral Lesions

A 7-year-old boy presents with acute-onset, violaceous, mildly painful and pruritic macules on the distal toes that began 3 days earlier and have progressed to involve more toes and appear more purpuric. A review of symptoms reveals no fever, cough, fatigue, or viral symptoms. He has been staying at home for the last few weeks with his brother, mother, and father. His father is working in delivery services and is social distancing at work but not at home. His mother is concerned about the lesions, if they could be COVID toes, and if testing is needed for the patient or family. In your assessment and management of this patient, you consider the following questions.

What Is the Relationship Between These Clinical Findings and COVID-19?
Despite negative polymerase chain reaction (PCR) tests reported in cases of chilblains during the COVID-19 pandemic as well as the possibility that these lesions are an indirect result of environmental factors or behavioral changes during quarantine, the majority of studies favor an association between these chilblains lesions and COVID-19 infection.^2,3 Most compellingly, COVID-19 viral particles have been identified by immunohistochemistry and electron microscopy in the endothelial cells of biopsies of these lesions.¹ Additionally, there is evidence for possible associations of other viruses, including Epstein-Barr virus and parvovirus B19, with chilblains lesions.^4,5 In sum, with the lack of any large prospective study, the weight of current evidence suggests that these perniolike skin lesions are not specific markers of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).⁶

Published studies differ in reporting the coincidence of perniolike lesions with typical COVID-19 symptoms, including fever, dyspnea, cough, fatigue, myalgia, headache, and anosmia, among others. Some studies have reported that up to 63% of patients with reported perniolike lesions developed typical COVID-19 symptoms, but other studies found that no patients with these lesions developed symptoms.^6-11 Studies with younger cohorts tended to report lower prevalence of COVID-19 symptoms, and within cohorts, younger patients tended to have less severe symptoms. For example, 78.8% of patients in a cohort (n=58) with an average age of 14 years did not experience COVID-19–related symptoms.⁶ Based on these data, it has been hypothesized that patients with chilblainslike lesions may represent a subpopulation who will have a robust interferon response that is protective from more symptomatic and severe COVID-19.^12-14

Current evidence suggests that these lesions are most likely to occur between 9 days and 2 months after the onset of COVID-19 symptoms.^4,9,10 Most cases have been only mildly symptomatic, with an overall favorable prognosis of both lesions and any viral symptoms.^8,10 The lesions typically resolve without treatment within a few days of initial onset.^15,16

What Should Be the Workup and Management of These Lesions?
Given the currently available information and favorable prognosis, usually no further workup specific to the perniolike lesions is required in the case of an asymptomatic child presenting with acral lesions, and the majority of management will center around patient and parent/guardian education and reassurance. When asked by the patient’s parent, “What does it mean that my child has these lesions?”, clinicians can provide information on the possible association with COVID-19 and the excellent, self-resolving prognosis. An example of honest and reasonable phrasing with current understanding might be, “We are currently not certain if COVID-19 causes these lesions, although there are data to suggest that they are associated. There are a lot of data showing that children with these lesions either do not have any symptoms or have very mild symptoms that resolve without treatment.”

For management, important considerations include how painful the lesions are to the individual patient and how they affect quality of life. If less severe, clinicians can reassure patients and parents/guardians that the lesions will likely self-resolve without treatment. If worsening or symptomatic, clinicians can try typical treatments for chilblains, such as topical steroids, whole-body warming, and nifedipine.^17-19 Obtaining a review of symptoms, including COVID-19 symptoms and general viral symptoms, is important given the rare cases of children with severe COVID-19.^20,21

The question of COVID-19 testing as related to these lesions remains controversial, and currently there are still differing perspectives on the need for biopsy, PCR for COVID-19, or serologies for COVID-19 in patients presenting with these lesions. Some experts report that additional testing is not needed in the pediatric population because of the high frequency of negative testing reported to date.^22,23 However, these children may be silent carriers, and until more is known about their potential to transmit the virus, testing may be considered if resources allow, particularly if the patient has a known exposure.^10,12,16,24 The ultimate decision to pursue biopsy or serologic workup for COVID-19 remains up to clinical discretion with consideration of symptoms, severity, and immunocompromised household contacts. If lesions developed after infection, PCR likely will result negative, whereas serologic testing may reveal antibodies.

Hypothetical Case of an Adult Presenting With Acral Lesions and COVID-19 Symptoms

A 50-year-old man presents with acute-onset, violaceous, painful, edematous plaques on the distal toes that began 3 days earlier and have progressed to include the soles. A review of symptoms reveals fever (temperature, 38.4 °C [101 °F]), cough, dyspnea, diarrhea, and severe asthenia. He has had interactions with a coworker who recently tested positive for COVID-19.

How Should You Consider These Lesions in the Context of the Other Symptoms Concerning for COVID-19?
In contrast to the asymptomatic child above, this adult has chilblainslike lesions and viral symptoms. In adults, chilblainslike lesions have been associated with relatively mild COVID-19, and patients with these lesions who are otherwise asymptomatic have largely tested negative for COVID-19 by PCR and serologic antibody testing.^11,25,26

True acral ischemia, which is more severe and should be differentiated from chilblains, has been reported in critically ill patients.⁹ Additionally, studies have found that retiform purpura is the most common cutaneous finding in patients with severe COVID-19.²⁷ For this patient, who has an examination consistent with progressive and severe chilblainslike lesions and suspicion for COVID-19 infection, it is important to observe and monitor these lesions, as clinical progression suggestive of acral ischemia or retiform purpura should be taken seriously and may indicate worsening of the underlying disease. Early intervention with anticoagulation might be considered, though there currently is no evidence of successful treatment.²⁸

What Causes These Lesions in a Patient With COVID-19?
The underlying pathophysiology has been proposed to be a monocytic-macrophage–induced hyperinflammatory systemic state that damages the lungs, as well as the gastrointestinal, renal, and endothelial systems. The activation of the innate immune system triggers a cytokine storm that creates a hypercoagulable state that ultimately can manifest as superficial thromboses, leading to gangrene of the extremities. Additionally, interferon response and resulting hypercytokinemia may cause direct cytopathic damage to the endothelium of arterioles and capillaries, causing the development of papulovesicular lesions that resemble the chilblainslike lesions observed in children.²⁹ In contrast to children, who typically have no or mild COVID-19 symptoms, adults may have a delayed interferon response, which has been proposed to allow for more severe manifestations of infection.^12,30

How Should an Adult With Perniolike Lesions Be Managed?
Adults with chilblainslike lesions and no other signs or symptoms of COVID-19 infection do not necessarily need be tested for COVID-19, given the reports demonstrating most patients in this clinical situation will have negative PCRs and serologies for antibodies. However, there have been several reports of adults with acro-ischemic skin findings who also had severe COVID-19, with an observed incidence of 23% in intensive care unit patients with COVID-19.^27,28,31,32 If there is suspicion of infection with COVID-19, it is advisable to first obtain workup for COVID-19 and other viruses that can cause acral lesions, including Epstein-Barr virus and parvovirus. Other pertinent laboratory tests may include D-dimer, fibrinogen, prothrombin time, activated partial thromboplastin time, antithrombin activity, platelet count, neutrophil count, procalcitonin, triglycerides, ferritin, C-reactive protein, and hemoglobin. For patients with evidence of worsening acro-ischemia, regular monitoring of these values up to several times per week can allow for initiation of vascular intervention, including angiontensin-converting enzyme inhibitors, statins, or antiplatelet drugs.³² The presence of antiphospholipid antibodies also has been associated with critically ill patients who develop digit ischemia as part of the sequelae of COVID-19 infection and therefore may act as an important marker for the potential to develop disseminated intravascular coagulation in this patient.³³ Even if COVID-19 infection is not suspected, a thorough review of systems is important to look for an underlying connective tissue disease, such as systemic lupus erythematosus, which is associated with pernio. Associated symptoms may warrant workup with antinuclear antibodies and other appropriate autoimmune serologies.

If there is any doubt of the diagnosis, the patient is experiencing symptoms from the lesion, or the patient is experiencing other viral symptoms, it is appropriate to biopsy immediately to confirm the diagnosis. Prior studies have identified fibrin clots, angiocentric and eccrinotropic lymphocytic infiltrates, lymphocytic vasculopathy, and papillary dermal edema as the most common features in chilblainslike lesions during the COVID-19 pandemic.⁹

For COVID-19 testing, many studies have revealed adult patients with an acute hypercoagulable state testing positive by SARS-CoV-2 PCR. These same patients also experienced thromboembolic events shortly after testing positive for COVID-19, which suggests that patients with elevated D-dimer and fibrinogen likely will have a viral load that is sufficient to test positive for COVID-19.^32,34-36 It is appropriate to test all patients with suspected COVID-19, especially adults who are more likely to experience adverse complications secondary to infection.

This patient experiencing COVID-19 symptoms with signs of acral ischemia is likely to test positive by PCR, and additional testing for serologic antibodies is unlikely to be clinically meaningful in this patient’s state. Furthermore, there is little evidence that serology is reliable because of the markedly high levels of both false-negative and false-positive results when using the available antibody testing kits.³⁷ The latter evidence makes serology testing of little value for the general population, but particularly for patients with acute COVID-19.

Conclusion and Outstanding Questions

There is evidence suggesting an association between chilblainslike lesions and COVID-19.^11,22,38,39 Children presenting with these lesions have an excellent prognosis and only need a workup or treatment if there are other symptoms, as the lesions self-resolve in the majority of reported cases.^7-9 Adults presenting with these lesions and without symptoms likewise are unlikely to test positive for COVID-19, and the lesions typically resolve spontaneously or with first-line treatment. However, adults presenting with these lesions and COVID-19 symptoms should raise clinical concern for evolving skin manifestations of acro-ischemia. If the diagnosis is uncertain or systemic symptoms are concerning, biopsy, COVID-19 PCR, and other appropriate laboratory workup should be obtained.

There remains controversy and uncertainty over the relationship between these skin findings and SARS-CoV-2 infection, with clinical evidence to support both a direct relationship representing convalescent-phase cutaneous reaction as well as an indirect epiphenomenon. If there was a direct relationship, we would have expected to see a rise in the incidence of acral lesions proportionate to the rising caseload of COVID-19 after the reopening of many states in the summer of 2020. Similarly, because young adults represent the largest demographic of increasing cases and as some schools have remained open for in-person instruction during the current academic year, we also would have expected the incidence of chilblains-like lesions presenting to dermatologists and pediatricians to increase alongside these cases. Continued evaluation of emerging literature and ongoing efforts to understand the cause of this observed phenomenon will hopefully help us arrive at a future understanding of the pathophysiology of this puzzling skin manifestation.⁴⁰

There has been a rise in the prevalence of perniolike lesions—erythematous to violaceous, edematous papules or nodules on the fingers or toes—during the coronavirus disease 2019 (COVID-19) pandemic. These lesions are referred to as “COVID toes.” Although several studies have suggested an association with these lesions and COVID-19, and coronavirus particles have been identified in endothelial cells of biopsies of pernio lesions, questions remain on the management, pathophysiology, and implications of these lesions.¹ We provide a practical review for primary care clinicians and dermatologists on the current management, recommendations, and remaining questions, with particular attention to the distinctions for children vs adults presenting with pernio lesions.

Hypothetical Case of a Child Presenting With Acral Lesions

A 7-year-old boy presents with acute-onset, violaceous, mildly painful and pruritic macules on the distal toes that began 3 days earlier and have progressed to involve more toes and appear more purpuric. A review of symptoms reveals no fever, cough, fatigue, or viral symptoms. He has been staying at home for the last few weeks with his brother, mother, and father. His father is working in delivery services and is social distancing at work but not at home. His mother is concerned about the lesions, if they could be COVID toes, and if testing is needed for the patient or family. In your assessment and management of this patient, you consider the following questions.

What Is the Relationship Between These Clinical Findings and COVID-19?
Despite negative polymerase chain reaction (PCR) tests reported in cases of chilblains during the COVID-19 pandemic as well as the possibility that these lesions are an indirect result of environmental factors or behavioral changes during quarantine, the majority of studies favor an association between these chilblains lesions and COVID-19 infection.^2,3 Most compellingly, COVID-19 viral particles have been identified by immunohistochemistry and electron microscopy in the endothelial cells of biopsies of these lesions.¹ Additionally, there is evidence for possible associations of other viruses, including Epstein-Barr virus and parvovirus B19, with chilblains lesions.^4,5 In sum, with the lack of any large prospective study, the weight of current evidence suggests that these perniolike skin lesions are not specific markers of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).⁶

Published studies differ in reporting the coincidence of perniolike lesions with typical COVID-19 symptoms, including fever, dyspnea, cough, fatigue, myalgia, headache, and anosmia, among others. Some studies have reported that up to 63% of patients with reported perniolike lesions developed typical COVID-19 symptoms, but other studies found that no patients with these lesions developed symptoms.^6-11 Studies with younger cohorts tended to report lower prevalence of COVID-19 symptoms, and within cohorts, younger patients tended to have less severe symptoms. For example, 78.8% of patients in a cohort (n=58) with an average age of 14 years did not experience COVID-19–related symptoms.⁶ Based on these data, it has been hypothesized that patients with chilblainslike lesions may represent a subpopulation who will have a robust interferon response that is protective from more symptomatic and severe COVID-19.^12-14

Current evidence suggests that these lesions are most likely to occur between 9 days and 2 months after the onset of COVID-19 symptoms.^4,9,10 Most cases have been only mildly symptomatic, with an overall favorable prognosis of both lesions and any viral symptoms.^8,10 The lesions typically resolve without treatment within a few days of initial onset.^15,16

What Should Be the Workup and Management of These Lesions?
Given the currently available information and favorable prognosis, usually no further workup specific to the perniolike lesions is required in the case of an asymptomatic child presenting with acral lesions, and the majority of management will center around patient and parent/guardian education and reassurance. When asked by the patient’s parent, “What does it mean that my child has these lesions?”, clinicians can provide information on the possible association with COVID-19 and the excellent, self-resolving prognosis. An example of honest and reasonable phrasing with current understanding might be, “We are currently not certain if COVID-19 causes these lesions, although there are data to suggest that they are associated. There are a lot of data showing that children with these lesions either do not have any symptoms or have very mild symptoms that resolve without treatment.”

For management, important considerations include how painful the lesions are to the individual patient and how they affect quality of life. If less severe, clinicians can reassure patients and parents/guardians that the lesions will likely self-resolve without treatment. If worsening or symptomatic, clinicians can try typical treatments for chilblains, such as topical steroids, whole-body warming, and nifedipine.^17-19 Obtaining a review of symptoms, including COVID-19 symptoms and general viral symptoms, is important given the rare cases of children with severe COVID-19.^20,21

The question of COVID-19 testing as related to these lesions remains controversial, and currently there are still differing perspectives on the need for biopsy, PCR for COVID-19, or serologies for COVID-19 in patients presenting with these lesions. Some experts report that additional testing is not needed in the pediatric population because of the high frequency of negative testing reported to date.^22,23 However, these children may be silent carriers, and until more is known about their potential to transmit the virus, testing may be considered if resources allow, particularly if the patient has a known exposure.^10,12,16,24 The ultimate decision to pursue biopsy or serologic workup for COVID-19 remains up to clinical discretion with consideration of symptoms, severity, and immunocompromised household contacts. If lesions developed after infection, PCR likely will result negative, whereas serologic testing may reveal antibodies.

Hypothetical Case of an Adult Presenting With Acral Lesions and COVID-19 Symptoms

A 50-year-old man presents with acute-onset, violaceous, painful, edematous plaques on the distal toes that began 3 days earlier and have progressed to include the soles. A review of symptoms reveals fever (temperature, 38.4 °C [101 °F]), cough, dyspnea, diarrhea, and severe asthenia. He has had interactions with a coworker who recently tested positive for COVID-19.

How Should You Consider These Lesions in the Context of the Other Symptoms Concerning for COVID-19?
In contrast to the asymptomatic child above, this adult has chilblainslike lesions and viral symptoms. In adults, chilblainslike lesions have been associated with relatively mild COVID-19, and patients with these lesions who are otherwise asymptomatic have largely tested negative for COVID-19 by PCR and serologic antibody testing.^11,25,26

True acral ischemia, which is more severe and should be differentiated from chilblains, has been reported in critically ill patients.⁹ Additionally, studies have found that retiform purpura is the most common cutaneous finding in patients with severe COVID-19.²⁷ For this patient, who has an examination consistent with progressive and severe chilblainslike lesions and suspicion for COVID-19 infection, it is important to observe and monitor these lesions, as clinical progression suggestive of acral ischemia or retiform purpura should be taken seriously and may indicate worsening of the underlying disease. Early intervention with anticoagulation might be considered, though there currently is no evidence of successful treatment.²⁸

What Causes These Lesions in a Patient With COVID-19?
The underlying pathophysiology has been proposed to be a monocytic-macrophage–induced hyperinflammatory systemic state that damages the lungs, as well as the gastrointestinal, renal, and endothelial systems. The activation of the innate immune system triggers a cytokine storm that creates a hypercoagulable state that ultimately can manifest as superficial thromboses, leading to gangrene of the extremities. Additionally, interferon response and resulting hypercytokinemia may cause direct cytopathic damage to the endothelium of arterioles and capillaries, causing the development of papulovesicular lesions that resemble the chilblainslike lesions observed in children.²⁹ In contrast to children, who typically have no or mild COVID-19 symptoms, adults may have a delayed interferon response, which has been proposed to allow for more severe manifestations of infection.^12,30

How Should an Adult With Perniolike Lesions Be Managed?
Adults with chilblainslike lesions and no other signs or symptoms of COVID-19 infection do not necessarily need be tested for COVID-19, given the reports demonstrating most patients in this clinical situation will have negative PCRs and serologies for antibodies. However, there have been several reports of adults with acro-ischemic skin findings who also had severe COVID-19, with an observed incidence of 23% in intensive care unit patients with COVID-19.^27,28,31,32 If there is suspicion of infection with COVID-19, it is advisable to first obtain workup for COVID-19 and other viruses that can cause acral lesions, including Epstein-Barr virus and parvovirus. Other pertinent laboratory tests may include D-dimer, fibrinogen, prothrombin time, activated partial thromboplastin time, antithrombin activity, platelet count, neutrophil count, procalcitonin, triglycerides, ferritin, C-reactive protein, and hemoglobin. For patients with evidence of worsening acro-ischemia, regular monitoring of these values up to several times per week can allow for initiation of vascular intervention, including angiontensin-converting enzyme inhibitors, statins, or antiplatelet drugs.³² The presence of antiphospholipid antibodies also has been associated with critically ill patients who develop digit ischemia as part of the sequelae of COVID-19 infection and therefore may act as an important marker for the potential to develop disseminated intravascular coagulation in this patient.³³ Even if COVID-19 infection is not suspected, a thorough review of systems is important to look for an underlying connective tissue disease, such as systemic lupus erythematosus, which is associated with pernio. Associated symptoms may warrant workup with antinuclear antibodies and other appropriate autoimmune serologies.

If there is any doubt of the diagnosis, the patient is experiencing symptoms from the lesion, or the patient is experiencing other viral symptoms, it is appropriate to biopsy immediately to confirm the diagnosis. Prior studies have identified fibrin clots, angiocentric and eccrinotropic lymphocytic infiltrates, lymphocytic vasculopathy, and papillary dermal edema as the most common features in chilblainslike lesions during the COVID-19 pandemic.⁹

For COVID-19 testing, many studies have revealed adult patients with an acute hypercoagulable state testing positive by SARS-CoV-2 PCR. These same patients also experienced thromboembolic events shortly after testing positive for COVID-19, which suggests that patients with elevated D-dimer and fibrinogen likely will have a viral load that is sufficient to test positive for COVID-19.^32,34-36 It is appropriate to test all patients with suspected COVID-19, especially adults who are more likely to experience adverse complications secondary to infection.

This patient experiencing COVID-19 symptoms with signs of acral ischemia is likely to test positive by PCR, and additional testing for serologic antibodies is unlikely to be clinically meaningful in this patient’s state. Furthermore, there is little evidence that serology is reliable because of the markedly high levels of both false-negative and false-positive results when using the available antibody testing kits.³⁷ The latter evidence makes serology testing of little value for the general population, but particularly for patients with acute COVID-19.

Conclusion and Outstanding Questions

There is evidence suggesting an association between chilblainslike lesions and COVID-19.^11,22,38,39 Children presenting with these lesions have an excellent prognosis and only need a workup or treatment if there are other symptoms, as the lesions self-resolve in the majority of reported cases.^7-9 Adults presenting with these lesions and without symptoms likewise are unlikely to test positive for COVID-19, and the lesions typically resolve spontaneously or with first-line treatment. However, adults presenting with these lesions and COVID-19 symptoms should raise clinical concern for evolving skin manifestations of acro-ischemia. If the diagnosis is uncertain or systemic symptoms are concerning, biopsy, COVID-19 PCR, and other appropriate laboratory workup should be obtained.

There remains controversy and uncertainty over the relationship between these skin findings and SARS-CoV-2 infection, with clinical evidence to support both a direct relationship representing convalescent-phase cutaneous reaction as well as an indirect epiphenomenon. If there was a direct relationship, we would have expected to see a rise in the incidence of acral lesions proportionate to the rising caseload of COVID-19 after the reopening of many states in the summer of 2020. Similarly, because young adults represent the largest demographic of increasing cases and as some schools have remained open for in-person instruction during the current academic year, we also would have expected the incidence of chilblains-like lesions presenting to dermatologists and pediatricians to increase alongside these cases. Continued evaluation of emerging literature and ongoing efforts to understand the cause of this observed phenomenon will hopefully help us arrive at a future understanding of the pathophysiology of this puzzling skin manifestation.⁴⁰

There has been a rise in the prevalence of perniolike lesions—erythematous to violaceous, edematous papules or nodules on the fingers or toes—during the coronavirus disease 2019 (COVID-19) pandemic. These lesions are referred to as “COVID toes.” Although several studies have suggested an association with these lesions and COVID-19, and coronavirus particles have been identified in endothelial cells of biopsies of pernio lesions, questions remain on the management, pathophysiology, and implications of these lesions.¹ We provide a practical review for primary care clinicians and dermatologists on the current management, recommendations, and remaining questions, with particular attention to the distinctions for children vs adults presenting with pernio lesions.

Hypothetical Case of a Child Presenting With Acral Lesions

A 7-year-old boy presents with acute-onset, violaceous, mildly painful and pruritic macules on the distal toes that began 3 days earlier and have progressed to involve more toes and appear more purpuric. A review of symptoms reveals no fever, cough, fatigue, or viral symptoms. He has been staying at home for the last few weeks with his brother, mother, and father. His father is working in delivery services and is social distancing at work but not at home. His mother is concerned about the lesions, if they could be COVID toes, and if testing is needed for the patient or family. In your assessment and management of this patient, you consider the following questions.

What Is the Relationship Between These Clinical Findings and COVID-19?
Despite negative polymerase chain reaction (PCR) tests reported in cases of chilblains during the COVID-19 pandemic as well as the possibility that these lesions are an indirect result of environmental factors or behavioral changes during quarantine, the majority of studies favor an association between these chilblains lesions and COVID-19 infection.^2,3 Most compellingly, COVID-19 viral particles have been identified by immunohistochemistry and electron microscopy in the endothelial cells of biopsies of these lesions.¹ Additionally, there is evidence for possible associations of other viruses, including Epstein-Barr virus and parvovirus B19, with chilblains lesions.^4,5 In sum, with the lack of any large prospective study, the weight of current evidence suggests that these perniolike skin lesions are not specific markers of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).⁶

Published studies differ in reporting the coincidence of perniolike lesions with typical COVID-19 symptoms, including fever, dyspnea, cough, fatigue, myalgia, headache, and anosmia, among others. Some studies have reported that up to 63% of patients with reported perniolike lesions developed typical COVID-19 symptoms, but other studies found that no patients with these lesions developed symptoms.^6-11 Studies with younger cohorts tended to report lower prevalence of COVID-19 symptoms, and within cohorts, younger patients tended to have less severe symptoms. For example, 78.8% of patients in a cohort (n=58) with an average age of 14 years did not experience COVID-19–related symptoms.⁶ Based on these data, it has been hypothesized that patients with chilblainslike lesions may represent a subpopulation who will have a robust interferon response that is protective from more symptomatic and severe COVID-19.^12-14

Current evidence suggests that these lesions are most likely to occur between 9 days and 2 months after the onset of COVID-19 symptoms.^4,9,10 Most cases have been only mildly symptomatic, with an overall favorable prognosis of both lesions and any viral symptoms.^8,10 The lesions typically resolve without treatment within a few days of initial onset.^15,16

What Should Be the Workup and Management of These Lesions?
Given the currently available information and favorable prognosis, usually no further workup specific to the perniolike lesions is required in the case of an asymptomatic child presenting with acral lesions, and the majority of management will center around patient and parent/guardian education and reassurance. When asked by the patient’s parent, “What does it mean that my child has these lesions?”, clinicians can provide information on the possible association with COVID-19 and the excellent, self-resolving prognosis. An example of honest and reasonable phrasing with current understanding might be, “We are currently not certain if COVID-19 causes these lesions, although there are data to suggest that they are associated. There are a lot of data showing that children with these lesions either do not have any symptoms or have very mild symptoms that resolve without treatment.”

For management, important considerations include how painful the lesions are to the individual patient and how they affect quality of life. If less severe, clinicians can reassure patients and parents/guardians that the lesions will likely self-resolve without treatment. If worsening or symptomatic, clinicians can try typical treatments for chilblains, such as topical steroids, whole-body warming, and nifedipine.^17-19 Obtaining a review of symptoms, including COVID-19 symptoms and general viral symptoms, is important given the rare cases of children with severe COVID-19.^20,21

The question of COVID-19 testing as related to these lesions remains controversial, and currently there are still differing perspectives on the need for biopsy, PCR for COVID-19, or serologies for COVID-19 in patients presenting with these lesions. Some experts report that additional testing is not needed in the pediatric population because of the high frequency of negative testing reported to date.^22,23 However, these children may be silent carriers, and until more is known about their potential to transmit the virus, testing may be considered if resources allow, particularly if the patient has a known exposure.^10,12,16,24 The ultimate decision to pursue biopsy or serologic workup for COVID-19 remains up to clinical discretion with consideration of symptoms, severity, and immunocompromised household contacts. If lesions developed after infection, PCR likely will result negative, whereas serologic testing may reveal antibodies.

Hypothetical Case of an Adult Presenting With Acral Lesions and COVID-19 Symptoms

A 50-year-old man presents with acute-onset, violaceous, painful, edematous plaques on the distal toes that began 3 days earlier and have progressed to include the soles. A review of symptoms reveals fever (temperature, 38.4 °C [101 °F]), cough, dyspnea, diarrhea, and severe asthenia. He has had interactions with a coworker who recently tested positive for COVID-19.

How Should You Consider These Lesions in the Context of the Other Symptoms Concerning for COVID-19?
In contrast to the asymptomatic child above, this adult has chilblainslike lesions and viral symptoms. In adults, chilblainslike lesions have been associated with relatively mild COVID-19, and patients with these lesions who are otherwise asymptomatic have largely tested negative for COVID-19 by PCR and serologic antibody testing.^11,25,26

True acral ischemia, which is more severe and should be differentiated from chilblains, has been reported in critically ill patients.⁹ Additionally, studies have found that retiform purpura is the most common cutaneous finding in patients with severe COVID-19.²⁷ For this patient, who has an examination consistent with progressive and severe chilblainslike lesions and suspicion for COVID-19 infection, it is important to observe and monitor these lesions, as clinical progression suggestive of acral ischemia or retiform purpura should be taken seriously and may indicate worsening of the underlying disease. Early intervention with anticoagulation might be considered, though there currently is no evidence of successful treatment.²⁸

What Causes These Lesions in a Patient With COVID-19?
The underlying pathophysiology has been proposed to be a monocytic-macrophage–induced hyperinflammatory systemic state that damages the lungs, as well as the gastrointestinal, renal, and endothelial systems. The activation of the innate immune system triggers a cytokine storm that creates a hypercoagulable state that ultimately can manifest as superficial thromboses, leading to gangrene of the extremities. Additionally, interferon response and resulting hypercytokinemia may cause direct cytopathic damage to the endothelium of arterioles and capillaries, causing the development of papulovesicular lesions that resemble the chilblainslike lesions observed in children.²⁹ In contrast to children, who typically have no or mild COVID-19 symptoms, adults may have a delayed interferon response, which has been proposed to allow for more severe manifestations of infection.^12,30

How Should an Adult With Perniolike Lesions Be Managed?
Adults with chilblainslike lesions and no other signs or symptoms of COVID-19 infection do not necessarily need be tested for COVID-19, given the reports demonstrating most patients in this clinical situation will have negative PCRs and serologies for antibodies. However, there have been several reports of adults with acro-ischemic skin findings who also had severe COVID-19, with an observed incidence of 23% in intensive care unit patients with COVID-19.^27,28,31,32 If there is suspicion of infection with COVID-19, it is advisable to first obtain workup for COVID-19 and other viruses that can cause acral lesions, including Epstein-Barr virus and parvovirus. Other pertinent laboratory tests may include D-dimer, fibrinogen, prothrombin time, activated partial thromboplastin time, antithrombin activity, platelet count, neutrophil count, procalcitonin, triglycerides, ferritin, C-reactive protein, and hemoglobin. For patients with evidence of worsening acro-ischemia, regular monitoring of these values up to several times per week can allow for initiation of vascular intervention, including angiontensin-converting enzyme inhibitors, statins, or antiplatelet drugs.³² The presence of antiphospholipid antibodies also has been associated with critically ill patients who develop digit ischemia as part of the sequelae of COVID-19 infection and therefore may act as an important marker for the potential to develop disseminated intravascular coagulation in this patient.³³ Even if COVID-19 infection is not suspected, a thorough review of systems is important to look for an underlying connective tissue disease, such as systemic lupus erythematosus, which is associated with pernio. Associated symptoms may warrant workup with antinuclear antibodies and other appropriate autoimmune serologies.

If there is any doubt of the diagnosis, the patient is experiencing symptoms from the lesion, or the patient is experiencing other viral symptoms, it is appropriate to biopsy immediately to confirm the diagnosis. Prior studies have identified fibrin clots, angiocentric and eccrinotropic lymphocytic infiltrates, lymphocytic vasculopathy, and papillary dermal edema as the most common features in chilblainslike lesions during the COVID-19 pandemic.⁹

For COVID-19 testing, many studies have revealed adult patients with an acute hypercoagulable state testing positive by SARS-CoV-2 PCR. These same patients also experienced thromboembolic events shortly after testing positive for COVID-19, which suggests that patients with elevated D-dimer and fibrinogen likely will have a viral load that is sufficient to test positive for COVID-19.^32,34-36 It is appropriate to test all patients with suspected COVID-19, especially adults who are more likely to experience adverse complications secondary to infection.

This patient experiencing COVID-19 symptoms with signs of acral ischemia is likely to test positive by PCR, and additional testing for serologic antibodies is unlikely to be clinically meaningful in this patient’s state. Furthermore, there is little evidence that serology is reliable because of the markedly high levels of both false-negative and false-positive results when using the available antibody testing kits.³⁷ The latter evidence makes serology testing of little value for the general population, but particularly for patients with acute COVID-19.

Conclusion and Outstanding Questions

There is evidence suggesting an association between chilblainslike lesions and COVID-19.^11,22,38,39 Children presenting with these lesions have an excellent prognosis and only need a workup or treatment if there are other symptoms, as the lesions self-resolve in the majority of reported cases.^7-9 Adults presenting with these lesions and without symptoms likewise are unlikely to test positive for COVID-19, and the lesions typically resolve spontaneously or with first-line treatment. However, adults presenting with these lesions and COVID-19 symptoms should raise clinical concern for evolving skin manifestations of acro-ischemia. If the diagnosis is uncertain or systemic symptoms are concerning, biopsy, COVID-19 PCR, and other appropriate laboratory workup should be obtained.

There remains controversy and uncertainty over the relationship between these skin findings and SARS-CoV-2 infection, with clinical evidence to support both a direct relationship representing convalescent-phase cutaneous reaction as well as an indirect epiphenomenon. If there was a direct relationship, we would have expected to see a rise in the incidence of acral lesions proportionate to the rising caseload of COVID-19 after the reopening of many states in the summer of 2020. Similarly, because young adults represent the largest demographic of increasing cases and as some schools have remained open for in-person instruction during the current academic year, we also would have expected the incidence of chilblains-like lesions presenting to dermatologists and pediatricians to increase alongside these cases. Continued evaluation of emerging literature and ongoing efforts to understand the cause of this observed phenomenon will hopefully help us arrive at a future understanding of the pathophysiology of this puzzling skin manifestation.⁴⁰