COVID-19

Primary care physicians who served marginalized communities had the highest proportion of patients who were unvaccinated against COVID-19, Canadian data suggested.

A study of more than 9000 family physicians in Ontario also found that the physicians with the largest proportion of unvaccinated patients were more likely to be male, to have trained outside Canada, to be older, and to work in an enhanced fee-for-service model than their counterparts who had lower proportions of unvaccinated patients.

“The family physicians with the most unvaccinated patients were also more likely to be solo practitioners and less likely to practice in team-based models, meaning they may have fewer support staff in their clinics,” lead author Jennifer Shuldiner, PhD, a scientist at Women’s College Hospital in Toronto, Ontario, Canada, told this news organization.

The findings were published in CMAJ.
 

Need vs Resources

Dr. Shuldiner and her team had been working on a project to provide additional support to family physicians with large numbers of patients who had not received their COVID-19 vaccinations. Their goal was to encourage family physicians to support these patients in getting vaccinated.

“As we were designing this project, we wondered how these physicians and their patients might differ. What characteristics might they have that would enable us to design and implement an intervention with high uptake and impact?” she said.

The researchers conducted a cross-sectional, population-based cohort study using linked administrative datasets in Ontario. They calculated the percentage of patients unvaccinated against SARS-CoV-2 who were enrolled with each comprehensive care family physician, ranked physicians according to the proportion of unvaccinated patients, and identified 906 physicians in the top 10% of unvaccinated patients. These physicians were compared with the remaining 90% of family physicians.

The physicians with the highest proportion of unvaccinated patients cared for 259,130 unvaccinated patients as of November 1, 2021. The proportion of patients who received two or more doses of the SARS-CoV-2 vaccine in this group was 74.2%. In comparison, the proportion of patients who received two or more doses of the vaccine was 87.0% in the remaining 90% of physicians.

Physicians with the largest proportion of unvaccinated patients were more likely to be male (64.6% vs 48.1%), to have trained outside Canada (46.9% vs 29.3%), to be older (mean age, 56 years vs 49 years), and to work in an enhanced fee-for-service model (49% vs 28%).

The study also found that patients enrolled with physicians in the most unvaccinated group tended to live in places with more ethnic diversity, higher material deprivation, and lower incomes. The proportion of recent immigrants was higher in this group.

“Clinics or practices with a large number of unvaccinated patients could be viable targets for efforts to coordinate public health and primary care,” said Dr. Shuldiner.

The findings indicate “the ongoing inverse relationship between the need for care and its accessibility and utilization. In other words, the practices with the highest need receive the fewest resources,” she noted.

“We know that relationships with trusted family physicians can positively influence patients’ decisions. Our study highlights the need to create equitable systems and processes that create opportunities for primary care teams to play a crucial role in influencing general and COVID-19-specific vaccine-related decision-making.”
 

Helping Primary Care Physicians

Commenting on the study for this news organization, Sabrina Wong, RN, PhD, professor of nursing at the University of British Columbia in Vancouver, British Columbia, Canada, said, “They did quite a nice analysis to show this using administrative data, and I think the information they’ve uncovered will be helpful in trying to fill the gaps and provide these practitioners with more support.”

Dr. Wong did not participate in the study. “The information they provide will be useful in helping us to move forward working with underserved, underresourced communities and also hopefully provide the clinicians, family physicians, and nurse practitioners working in these areas with more resources,” she said.

“The authors also point out that there needs to be more collaboration between public health and primary care to support these communities in their efforts to get the vaccines to the people in these communities who need them.”

The study was supported by a Canadian Institutes of Health Research grant. Dr. Shuldiner and Dr. Wong reported no relevant financial relationships.

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

Primary care physicians who served marginalized communities had the highest proportion of patients who were unvaccinated against COVID-19, Canadian data suggested.

A study of more than 9000 family physicians in Ontario also found that the physicians with the largest proportion of unvaccinated patients were more likely to be male, to have trained outside Canada, to be older, and to work in an enhanced fee-for-service model than their counterparts who had lower proportions of unvaccinated patients.

“The family physicians with the most unvaccinated patients were also more likely to be solo practitioners and less likely to practice in team-based models, meaning they may have fewer support staff in their clinics,” lead author Jennifer Shuldiner, PhD, a scientist at Women’s College Hospital in Toronto, Ontario, Canada, told this news organization.

The findings were published in CMAJ.
 

Need vs Resources

Dr. Shuldiner and her team had been working on a project to provide additional support to family physicians with large numbers of patients who had not received their COVID-19 vaccinations. Their goal was to encourage family physicians to support these patients in getting vaccinated.

“As we were designing this project, we wondered how these physicians and their patients might differ. What characteristics might they have that would enable us to design and implement an intervention with high uptake and impact?” she said.

The researchers conducted a cross-sectional, population-based cohort study using linked administrative datasets in Ontario. They calculated the percentage of patients unvaccinated against SARS-CoV-2 who were enrolled with each comprehensive care family physician, ranked physicians according to the proportion of unvaccinated patients, and identified 906 physicians in the top 10% of unvaccinated patients. These physicians were compared with the remaining 90% of family physicians.

The physicians with the highest proportion of unvaccinated patients cared for 259,130 unvaccinated patients as of November 1, 2021. The proportion of patients who received two or more doses of the SARS-CoV-2 vaccine in this group was 74.2%. In comparison, the proportion of patients who received two or more doses of the vaccine was 87.0% in the remaining 90% of physicians.

Physicians with the largest proportion of unvaccinated patients were more likely to be male (64.6% vs 48.1%), to have trained outside Canada (46.9% vs 29.3%), to be older (mean age, 56 years vs 49 years), and to work in an enhanced fee-for-service model (49% vs 28%).

The study also found that patients enrolled with physicians in the most unvaccinated group tended to live in places with more ethnic diversity, higher material deprivation, and lower incomes. The proportion of recent immigrants was higher in this group.

“Clinics or practices with a large number of unvaccinated patients could be viable targets for efforts to coordinate public health and primary care,” said Dr. Shuldiner.

The findings indicate “the ongoing inverse relationship between the need for care and its accessibility and utilization. In other words, the practices with the highest need receive the fewest resources,” she noted.

“We know that relationships with trusted family physicians can positively influence patients’ decisions. Our study highlights the need to create equitable systems and processes that create opportunities for primary care teams to play a crucial role in influencing general and COVID-19-specific vaccine-related decision-making.”
 

Helping Primary Care Physicians

Commenting on the study for this news organization, Sabrina Wong, RN, PhD, professor of nursing at the University of British Columbia in Vancouver, British Columbia, Canada, said, “They did quite a nice analysis to show this using administrative data, and I think the information they’ve uncovered will be helpful in trying to fill the gaps and provide these practitioners with more support.”

Dr. Wong did not participate in the study. “The information they provide will be useful in helping us to move forward working with underserved, underresourced communities and also hopefully provide the clinicians, family physicians, and nurse practitioners working in these areas with more resources,” she said.

“The authors also point out that there needs to be more collaboration between public health and primary care to support these communities in their efforts to get the vaccines to the people in these communities who need them.”

The study was supported by a Canadian Institutes of Health Research grant. Dr. Shuldiner and Dr. Wong reported no relevant financial relationships.

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

Primary care physicians who served marginalized communities had the highest proportion of patients who were unvaccinated against COVID-19, Canadian data suggested.

A study of more than 9000 family physicians in Ontario also found that the physicians with the largest proportion of unvaccinated patients were more likely to be male, to have trained outside Canada, to be older, and to work in an enhanced fee-for-service model than their counterparts who had lower proportions of unvaccinated patients.

“The family physicians with the most unvaccinated patients were also more likely to be solo practitioners and less likely to practice in team-based models, meaning they may have fewer support staff in their clinics,” lead author Jennifer Shuldiner, PhD, a scientist at Women’s College Hospital in Toronto, Ontario, Canada, told this news organization.

The findings were published in CMAJ.
 

Need vs Resources

Dr. Shuldiner and her team had been working on a project to provide additional support to family physicians with large numbers of patients who had not received their COVID-19 vaccinations. Their goal was to encourage family physicians to support these patients in getting vaccinated.

“As we were designing this project, we wondered how these physicians and their patients might differ. What characteristics might they have that would enable us to design and implement an intervention with high uptake and impact?” she said.

The researchers conducted a cross-sectional, population-based cohort study using linked administrative datasets in Ontario. They calculated the percentage of patients unvaccinated against SARS-CoV-2 who were enrolled with each comprehensive care family physician, ranked physicians according to the proportion of unvaccinated patients, and identified 906 physicians in the top 10% of unvaccinated patients. These physicians were compared with the remaining 90% of family physicians.

The physicians with the highest proportion of unvaccinated patients cared for 259,130 unvaccinated patients as of November 1, 2021. The proportion of patients who received two or more doses of the SARS-CoV-2 vaccine in this group was 74.2%. In comparison, the proportion of patients who received two or more doses of the vaccine was 87.0% in the remaining 90% of physicians.

Physicians with the largest proportion of unvaccinated patients were more likely to be male (64.6% vs 48.1%), to have trained outside Canada (46.9% vs 29.3%), to be older (mean age, 56 years vs 49 years), and to work in an enhanced fee-for-service model (49% vs 28%).

The study also found that patients enrolled with physicians in the most unvaccinated group tended to live in places with more ethnic diversity, higher material deprivation, and lower incomes. The proportion of recent immigrants was higher in this group.

“Clinics or practices with a large number of unvaccinated patients could be viable targets for efforts to coordinate public health and primary care,” said Dr. Shuldiner.

The findings indicate “the ongoing inverse relationship between the need for care and its accessibility and utilization. In other words, the practices with the highest need receive the fewest resources,” she noted.

“We know that relationships with trusted family physicians can positively influence patients’ decisions. Our study highlights the need to create equitable systems and processes that create opportunities for primary care teams to play a crucial role in influencing general and COVID-19-specific vaccine-related decision-making.”
 

Helping Primary Care Physicians

Commenting on the study for this news organization, Sabrina Wong, RN, PhD, professor of nursing at the University of British Columbia in Vancouver, British Columbia, Canada, said, “They did quite a nice analysis to show this using administrative data, and I think the information they’ve uncovered will be helpful in trying to fill the gaps and provide these practitioners with more support.”

Dr. Wong did not participate in the study. “The information they provide will be useful in helping us to move forward working with underserved, underresourced communities and also hopefully provide the clinicians, family physicians, and nurse practitioners working in these areas with more resources,” she said.

“The authors also point out that there needs to be more collaboration between public health and primary care to support these communities in their efforts to get the vaccines to the people in these communities who need them.”

The study was supported by a Canadian Institutes of Health Research grant. Dr. Shuldiner and Dr. Wong reported no relevant financial relationships.

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

TOPLINE: 

There were few cases of SARS-CoV-2 infections among emergency department (ED) healthcare personnel and no substantial changes in the delivery of emergency medical care during the initial phase of the COVID-19 pandemic.

METHODOLOGY:

• This multicenter prospective cohort study of US ED healthcare personnel called Project COVERED was conducted from May to December 2020 to evaluate the following outcomes:
• The possibility of infected ED personnel reporting to work
• The burden of COVID-19 symptoms on an ED personnel’s work status
• The association between SARS-CoV-2 infection levels and ED staffing
• Project COVERED enrolled 1673 ED healthcare personnel with 29,825 person weeks of observational data from 25 geographically diverse EDs.
• The presence of any SARS-CoV-2 infection was determined using reverse transcription polymerase chain reaction or IgG antibody testing at baseline, week 2, week 4, and every four subsequent weeks through week 20.
• Investigators also collected weekly data on ED staffing and the incidence of SARS-CoV-2 infections in healthcare facilities.

TAKEAWAY:

• Despite the absence of widespread natural immunity or COVID-19 vaccine availability during the time of this study, only 4.5% of ED healthcare personnel tested positive for SARS-CoV-2 infections, with more than half (57.3%) not experiencing any symptoms.
• Most personnel (83%) who experienced symptoms associated with COVID-19 reported working at least one shift in the ED and nearly all of them continued to work until they received laboratory confirmation of their infection.
• The working time lost as a result of COVID-19 and related concerns was minimal, as 89 healthcare personnel reported 90 person weeks of missed work (0.3% of all weeks).
• During this study, physician-staffing levels ranged from 98.7% to 102.0% of normal staffing, with similar values noted for nursing and nonclinical staffs. Reduced staffing was rare, even during COVID-19 surges.

IN PRACTICE:

“Our findings suggest that the cumulative interaction between infected healthcare personnel and others resulted in a negligible risk of transmission on the scale of public health emergencies,” the authors wrote.

SOURCE:

This study was led by Kurt D. Weber, MD, Department of Emergency Medicine, Orlando Health, Orlando, Florida, and published online in Annals of Emergency Medicine.

LIMITATIONS:

Data regarding the Delta variant surges that occurred toward the end of December and the ED status after the advent of the COVID-19 vaccine were not recorded. There may also have been a selection bias risk in this study because the volunteer participants may have exhibited behaviors like social distancing and use of protective equipment, which may have decreased their risk for infections.

DISCLOSURES:

This study was funded by a cooperative agreement from the Centers for Disease Control and Prevention and the Institute for Clinical and Translational Science at the University of Iowa through a grant from the National Center for Advancing Translational Sciences at the National Institutes of Health. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE: 

There were few cases of SARS-CoV-2 infections among emergency department (ED) healthcare personnel and no substantial changes in the delivery of emergency medical care during the initial phase of the COVID-19 pandemic.

METHODOLOGY:

• This multicenter prospective cohort study of US ED healthcare personnel called Project COVERED was conducted from May to December 2020 to evaluate the following outcomes:
• The possibility of infected ED personnel reporting to work
• The burden of COVID-19 symptoms on an ED personnel’s work status
• The association between SARS-CoV-2 infection levels and ED staffing
• Project COVERED enrolled 1673 ED healthcare personnel with 29,825 person weeks of observational data from 25 geographically diverse EDs.
• The presence of any SARS-CoV-2 infection was determined using reverse transcription polymerase chain reaction or IgG antibody testing at baseline, week 2, week 4, and every four subsequent weeks through week 20.
• Investigators also collected weekly data on ED staffing and the incidence of SARS-CoV-2 infections in healthcare facilities.

TAKEAWAY:

• Despite the absence of widespread natural immunity or COVID-19 vaccine availability during the time of this study, only 4.5% of ED healthcare personnel tested positive for SARS-CoV-2 infections, with more than half (57.3%) not experiencing any symptoms.
• Most personnel (83%) who experienced symptoms associated with COVID-19 reported working at least one shift in the ED and nearly all of them continued to work until they received laboratory confirmation of their infection.
• The working time lost as a result of COVID-19 and related concerns was minimal, as 89 healthcare personnel reported 90 person weeks of missed work (0.3% of all weeks).
• During this study, physician-staffing levels ranged from 98.7% to 102.0% of normal staffing, with similar values noted for nursing and nonclinical staffs. Reduced staffing was rare, even during COVID-19 surges.

IN PRACTICE:

“Our findings suggest that the cumulative interaction between infected healthcare personnel and others resulted in a negligible risk of transmission on the scale of public health emergencies,” the authors wrote.

SOURCE:

This study was led by Kurt D. Weber, MD, Department of Emergency Medicine, Orlando Health, Orlando, Florida, and published online in Annals of Emergency Medicine.

LIMITATIONS:

Data regarding the Delta variant surges that occurred toward the end of December and the ED status after the advent of the COVID-19 vaccine were not recorded. There may also have been a selection bias risk in this study because the volunteer participants may have exhibited behaviors like social distancing and use of protective equipment, which may have decreased their risk for infections.

DISCLOSURES:

This study was funded by a cooperative agreement from the Centers for Disease Control and Prevention and the Institute for Clinical and Translational Science at the University of Iowa through a grant from the National Center for Advancing Translational Sciences at the National Institutes of Health. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE: 

There were few cases of SARS-CoV-2 infections among emergency department (ED) healthcare personnel and no substantial changes in the delivery of emergency medical care during the initial phase of the COVID-19 pandemic.

METHODOLOGY:

• This multicenter prospective cohort study of US ED healthcare personnel called Project COVERED was conducted from May to December 2020 to evaluate the following outcomes:
• The possibility of infected ED personnel reporting to work
• The burden of COVID-19 symptoms on an ED personnel’s work status
• The association between SARS-CoV-2 infection levels and ED staffing
• Project COVERED enrolled 1673 ED healthcare personnel with 29,825 person weeks of observational data from 25 geographically diverse EDs.
• The presence of any SARS-CoV-2 infection was determined using reverse transcription polymerase chain reaction or IgG antibody testing at baseline, week 2, week 4, and every four subsequent weeks through week 20.
• Investigators also collected weekly data on ED staffing and the incidence of SARS-CoV-2 infections in healthcare facilities.

TAKEAWAY:

• Despite the absence of widespread natural immunity or COVID-19 vaccine availability during the time of this study, only 4.5% of ED healthcare personnel tested positive for SARS-CoV-2 infections, with more than half (57.3%) not experiencing any symptoms.
• Most personnel (83%) who experienced symptoms associated with COVID-19 reported working at least one shift in the ED and nearly all of them continued to work until they received laboratory confirmation of their infection.
• The working time lost as a result of COVID-19 and related concerns was minimal, as 89 healthcare personnel reported 90 person weeks of missed work (0.3% of all weeks).
• During this study, physician-staffing levels ranged from 98.7% to 102.0% of normal staffing, with similar values noted for nursing and nonclinical staffs. Reduced staffing was rare, even during COVID-19 surges.

IN PRACTICE:

“Our findings suggest that the cumulative interaction between infected healthcare personnel and others resulted in a negligible risk of transmission on the scale of public health emergencies,” the authors wrote.

SOURCE:

This study was led by Kurt D. Weber, MD, Department of Emergency Medicine, Orlando Health, Orlando, Florida, and published online in Annals of Emergency Medicine.

LIMITATIONS:

Data regarding the Delta variant surges that occurred toward the end of December and the ED status after the advent of the COVID-19 vaccine were not recorded. There may also have been a selection bias risk in this study because the volunteer participants may have exhibited behaviors like social distancing and use of protective equipment, which may have decreased their risk for infections.

DISCLOSURES:

This study was funded by a cooperative agreement from the Centers for Disease Control and Prevention and the Institute for Clinical and Translational Science at the University of Iowa through a grant from the National Center for Advancing Translational Sciences at the National Institutes of Health. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

Amid the current wave of winter respiratory virus cases, influenza (types A and B) leads the way with the highest number of emergency room visits, followed closely by COVID-19, thanks to the JN.1 variant, and respiratory syncytial virus (RSV). With various similarities and differences in disease presentations, how challenging is it for physician’s to distinguish between, diagnose, and treat COVID-19 vs RSV and influenza? 

While these three respiratory viruses often have similar presentations, you may often find that patients with COVID-19 experience more fever, dry cough, and labored breathing, according to Cyrus Munguti, MD, assistant professor of medicine at KU Medical Center and hospitalist at Wesley Medical Center, Wichita, Kansas. 

“COVID-19 patients tend to have trouble breathing because the alveoli are affected and get inflammation and fluid accumulating in the lungs, and they end up having little to no oxygen,” said Dr. Munguti. “When we check their vital signs, patients with COVID tend to have hypoxemia [meaning saturations are less than 88% or 90% depending on the guidelines you follow].”

Patients with RSV and influenza tend to have more upper respiratory symptoms, like runny nose, sternutation — which later can progress to a cough in the upper airways, Dr. Munguti said. Unlike with COVID-19, patients with RSV and influenza — generally until they are very sick — often do not experience hypoxemia.

Inflammation in the airways can form as a result of all three viruses. Furthermore, bacteria that live in these airways could lead to a secondary bacterial infection in the upper respiratory and lower respiratory tracts — which could then cause pneumonia, Dr. Munguti said.

Another note: Changes in COVID-19 variants over the years have made it increasingly difficult to differentiate COVID-19 symptoms from those of RSV and influenza, according to Panagis Galiatsatos, MD, pulmonologist and associate professor at Johns Hopkins Medicine. “The Alpha through Delta variants really were a lot more lung tissue invading,” Dr. Galiatsatos said. “With the COVID-19 Omicron family — its capabilities are similar to what flu and RSV have done over the years. It’s more airway-invading.”

It’s critical to understand that diagnosing these diseases based on symptoms alone can be quite fickle, according to Dr. Galiatsatos. Objective tests, either at home or in a laboratory, are preferred. This is largely because disease presentation can depend on the host factor that the virus enters into, said Dr. Galiatsatos. For example, virus symptoms may look different for a patient with asthma and for someone with heart disease.

With children being among the most vulnerable for severe respiratory illness, testing and treatment are paramount and can be quite accurate in seasons where respiratory viruses thrive, according to Stan Spinner, MD, chief medical officer at Texas Children’s Pediatrics and Urgent Care. “When individuals are tested for either of these conditions when the prevalence in the community is low, we tend to see false positive results.” 

Texas Children’s Pediatrics and Urgent Care’s 12 sites offer COVID-19 and influenza antigen tests that have results ready in around 10 minutes. RSV testing, on the other hand, is limited to around half of the Texas Children’s Pediatrics and none of the urgent care locations, as the test can only be administered through a nasal swab conducted by a physician. As there is no specific treatment or therapy for RSV, the benefits of RSV testing can actually be quite low — often leading to frustrated parents regarding next steps after diagnosis.

“There are a number of respiratory viruses that may present with similar symptoms as RSV, and some of these viruses may even lead to much of the same adverse outcomes as the RSV virus,” Dr. Galiatsatos said. “Consequently, our physicians need to help parents understand this and give them guidance as to when to seek medical attention for worsening symptoms.”

There are two new RSV immunizations to treat certain demographics of patients, Dr. Spinner added. One is an RSV vaccine for infants under 8 months old, though there is limited supply. There is also an RSV vaccine available for pregnant women (between 32 and 36 weeks gestation) that has proved to be effective in fending off RSV infections in newborns up to 6 months old. 

Physicians should remain diligent in stressing to patients that vaccinations against COVID-19 and influenza play a key role in keeping their families safe during seasons of staggering respiratory infections.

“These vaccines are extremely safe, and while they may not always prevent infection, these vaccines are extremely effective in preventing more serious consequences, such as hospitalization or death,” Dr. Galiatsatos said.
 

A version of this article appeared on Medscape.com.

Amid the current wave of winter respiratory virus cases, influenza (types A and B) leads the way with the highest number of emergency room visits, followed closely by COVID-19, thanks to the JN.1 variant, and respiratory syncytial virus (RSV). With various similarities and differences in disease presentations, how challenging is it for physician’s to distinguish between, diagnose, and treat COVID-19 vs RSV and influenza? 

While these three respiratory viruses often have similar presentations, you may often find that patients with COVID-19 experience more fever, dry cough, and labored breathing, according to Cyrus Munguti, MD, assistant professor of medicine at KU Medical Center and hospitalist at Wesley Medical Center, Wichita, Kansas. 

“COVID-19 patients tend to have trouble breathing because the alveoli are affected and get inflammation and fluid accumulating in the lungs, and they end up having little to no oxygen,” said Dr. Munguti. “When we check their vital signs, patients with COVID tend to have hypoxemia [meaning saturations are less than 88% or 90% depending on the guidelines you follow].”

Patients with RSV and influenza tend to have more upper respiratory symptoms, like runny nose, sternutation — which later can progress to a cough in the upper airways, Dr. Munguti said. Unlike with COVID-19, patients with RSV and influenza — generally until they are very sick — often do not experience hypoxemia.

Inflammation in the airways can form as a result of all three viruses. Furthermore, bacteria that live in these airways could lead to a secondary bacterial infection in the upper respiratory and lower respiratory tracts — which could then cause pneumonia, Dr. Munguti said.

Another note: Changes in COVID-19 variants over the years have made it increasingly difficult to differentiate COVID-19 symptoms from those of RSV and influenza, according to Panagis Galiatsatos, MD, pulmonologist and associate professor at Johns Hopkins Medicine. “The Alpha through Delta variants really were a lot more lung tissue invading,” Dr. Galiatsatos said. “With the COVID-19 Omicron family — its capabilities are similar to what flu and RSV have done over the years. It’s more airway-invading.”

It’s critical to understand that diagnosing these diseases based on symptoms alone can be quite fickle, according to Dr. Galiatsatos. Objective tests, either at home or in a laboratory, are preferred. This is largely because disease presentation can depend on the host factor that the virus enters into, said Dr. Galiatsatos. For example, virus symptoms may look different for a patient with asthma and for someone with heart disease.

With children being among the most vulnerable for severe respiratory illness, testing and treatment are paramount and can be quite accurate in seasons where respiratory viruses thrive, according to Stan Spinner, MD, chief medical officer at Texas Children’s Pediatrics and Urgent Care. “When individuals are tested for either of these conditions when the prevalence in the community is low, we tend to see false positive results.” 

Texas Children’s Pediatrics and Urgent Care’s 12 sites offer COVID-19 and influenza antigen tests that have results ready in around 10 minutes. RSV testing, on the other hand, is limited to around half of the Texas Children’s Pediatrics and none of the urgent care locations, as the test can only be administered through a nasal swab conducted by a physician. As there is no specific treatment or therapy for RSV, the benefits of RSV testing can actually be quite low — often leading to frustrated parents regarding next steps after diagnosis.

“There are a number of respiratory viruses that may present with similar symptoms as RSV, and some of these viruses may even lead to much of the same adverse outcomes as the RSV virus,” Dr. Galiatsatos said. “Consequently, our physicians need to help parents understand this and give them guidance as to when to seek medical attention for worsening symptoms.”

There are two new RSV immunizations to treat certain demographics of patients, Dr. Spinner added. One is an RSV vaccine for infants under 8 months old, though there is limited supply. There is also an RSV vaccine available for pregnant women (between 32 and 36 weeks gestation) that has proved to be effective in fending off RSV infections in newborns up to 6 months old. 

Physicians should remain diligent in stressing to patients that vaccinations against COVID-19 and influenza play a key role in keeping their families safe during seasons of staggering respiratory infections.

“These vaccines are extremely safe, and while they may not always prevent infection, these vaccines are extremely effective in preventing more serious consequences, such as hospitalization or death,” Dr. Galiatsatos said.
 

A version of this article appeared on Medscape.com.

Amid the current wave of winter respiratory virus cases, influenza (types A and B) leads the way with the highest number of emergency room visits, followed closely by COVID-19, thanks to the JN.1 variant, and respiratory syncytial virus (RSV). With various similarities and differences in disease presentations, how challenging is it for physician’s to distinguish between, diagnose, and treat COVID-19 vs RSV and influenza? 

While these three respiratory viruses often have similar presentations, you may often find that patients with COVID-19 experience more fever, dry cough, and labored breathing, according to Cyrus Munguti, MD, assistant professor of medicine at KU Medical Center and hospitalist at Wesley Medical Center, Wichita, Kansas. 

“COVID-19 patients tend to have trouble breathing because the alveoli are affected and get inflammation and fluid accumulating in the lungs, and they end up having little to no oxygen,” said Dr. Munguti. “When we check their vital signs, patients with COVID tend to have hypoxemia [meaning saturations are less than 88% or 90% depending on the guidelines you follow].”

Patients with RSV and influenza tend to have more upper respiratory symptoms, like runny nose, sternutation — which later can progress to a cough in the upper airways, Dr. Munguti said. Unlike with COVID-19, patients with RSV and influenza — generally until they are very sick — often do not experience hypoxemia.

Inflammation in the airways can form as a result of all three viruses. Furthermore, bacteria that live in these airways could lead to a secondary bacterial infection in the upper respiratory and lower respiratory tracts — which could then cause pneumonia, Dr. Munguti said.

Another note: Changes in COVID-19 variants over the years have made it increasingly difficult to differentiate COVID-19 symptoms from those of RSV and influenza, according to Panagis Galiatsatos, MD, pulmonologist and associate professor at Johns Hopkins Medicine. “The Alpha through Delta variants really were a lot more lung tissue invading,” Dr. Galiatsatos said. “With the COVID-19 Omicron family — its capabilities are similar to what flu and RSV have done over the years. It’s more airway-invading.”

It’s critical to understand that diagnosing these diseases based on symptoms alone can be quite fickle, according to Dr. Galiatsatos. Objective tests, either at home or in a laboratory, are preferred. This is largely because disease presentation can depend on the host factor that the virus enters into, said Dr. Galiatsatos. For example, virus symptoms may look different for a patient with asthma and for someone with heart disease.

With children being among the most vulnerable for severe respiratory illness, testing and treatment are paramount and can be quite accurate in seasons where respiratory viruses thrive, according to Stan Spinner, MD, chief medical officer at Texas Children’s Pediatrics and Urgent Care. “When individuals are tested for either of these conditions when the prevalence in the community is low, we tend to see false positive results.” 

Texas Children’s Pediatrics and Urgent Care’s 12 sites offer COVID-19 and influenza antigen tests that have results ready in around 10 minutes. RSV testing, on the other hand, is limited to around half of the Texas Children’s Pediatrics and none of the urgent care locations, as the test can only be administered through a nasal swab conducted by a physician. As there is no specific treatment or therapy for RSV, the benefits of RSV testing can actually be quite low — often leading to frustrated parents regarding next steps after diagnosis.

“There are a number of respiratory viruses that may present with similar symptoms as RSV, and some of these viruses may even lead to much of the same adverse outcomes as the RSV virus,” Dr. Galiatsatos said. “Consequently, our physicians need to help parents understand this and give them guidance as to when to seek medical attention for worsening symptoms.”

There are two new RSV immunizations to treat certain demographics of patients, Dr. Spinner added. One is an RSV vaccine for infants under 8 months old, though there is limited supply. There is also an RSV vaccine available for pregnant women (between 32 and 36 weeks gestation) that has proved to be effective in fending off RSV infections in newborns up to 6 months old. 

Physicians should remain diligent in stressing to patients that vaccinations against COVID-19 and influenza play a key role in keeping their families safe during seasons of staggering respiratory infections.

“These vaccines are extremely safe, and while they may not always prevent infection, these vaccines are extremely effective in preventing more serious consequences, such as hospitalization or death,” Dr. Galiatsatos said.
 

A version of this article appeared on Medscape.com.

Question: What doubles every 2 months and takes more than a decade and a half to reach its ultimate destination?

Answer: Medical knowledge. 

In 2011, researchers projected that by 2020, medical knowledge would double every 73 days. Also in 2011, investigators estimated that clinical research takes 17 years to translate from bench to bedside. 

This “fast-slow” paradox became more relevant than ever in 2020, when the coronavirus pandemic brought the world to a near standstill. Stakeholders in undergraduate, postgraduate, and continuing medical education (CME) were suddenly faced with choices that had been discussed theoretically but not yet applied on a wide scale: How do we deliver education if in-person instruction is not an option? 

Organized medicine and the clinical community made choices based on groundwork that had been laid prior to the pandemic. The medical community acted quickly out of necessity, implementing novel learning methods that are now being utilized and that need to be assessed in an ongoing manner. 

The Backdrop

Medical education has long been dominated by an in-person, didactic model anchored in teacher-centered, classroom-based learning. This design has been firmly entrenched for more than 100 years, since the publication of the Flexner report in 1910, which established the standard of 4 years of medical education. Prior to 2020, many experts acknowledged that alternative practices and emerging technologies should play a role in medical education, but indecision abounded, perhaps because there was no real-world catalyst for reform. Thus, despite various attempts, the adoption of alternative forms of teaching moved slowly. 

Pre-pandemic efforts

In 2017, the American Medication Association issued a report calling for “one of the most complete curricular reforms since the Flexner Report.” It urged leaders to “rethink nearly every facet of physician training,” including “greater emphasis on new technology.” The report also suggested a 14-month pre-rotation program focused on the core medical knowledge necessary to practice in a hospital setting, along with work in a primary care setting once every other week. 

Before the pandemic, “blended learning” (digital and live) and “flipped classroom” approaches were assessed. A meta-analysis comparing a blended learning format to traditional classroom model programs found that blended learning resulted in better knowledge outcomes. In the flipped classroom approach, non-classroom individual or group activities replace in-class instruction after pre-class self-preparation with provided resources. A meta-analysis of 28 comparative studies showed that the flipped classroom approach resulted in improved learning compared to traditional methods. Additionally, bite-sized learning approaches have been implemented and evaluated, showing improvement in immediate knowledge recall. 

Barriers to widespread implementation

Despite the need to increase medical knowledge dissemination and implement approaches proven to do so effectively, barriers to adoption are well documented. Obstacles include time limitations, inadequate technical skills, insufficient infrastructure, and a wide variety in and range of expertise of both learners and institutional strategies. There are also differences in effective techniques for teaching various topics based on the content. Some topics require knowledge-based training, whereas others fall more easily into skills-based training. 

Additionally, when it comes to new evidence that needs to be translated to clinical evaluation and delivery, there is ongoing debate about the established peer-review process, which is rigorous but time-consuming vs the open-access publication process, which can disseminate information more quickly but is prone to error. 

Proposed solutions

Proposed solutions to these barriers include improving educator skills, offering incentives for innovative content development, cultivating better institutional strategies, and achieving buy-in from all stakeholders. Also important is thoughtful adaptation of content to various electronic formats, such as audiovisual presentation of educational material, social media content, and gamification of content, as well as ongoing assessment of both education delivery and consumption—followed by rapid pivoting when necessary. 

Despite these clearly identified challenges and thoughtful solutions, change was relatively slow until March 2020. 

The Trigger

With medical knowledge expanding so rapidly, imagine if medical education moved slowly or came to a complete halt when a worldwide pandemic was declared, the effects would have been catastrophic. COVID pushed organized medicine and the healthcare community to accelerate the adoption of novel technological approaches to keep the medical knowledge pipeline flowing at a relatively reasonable— if not ideal—rate. 

Challenges the pandemic produced, along with potential mitigation strategies, are outlined below.      

Economic consequences: The pandemic resulted in lost income for training programs and decreased funding for graduate medical education.

Possible solution: Creating budget allowances to adopt new technologies

Impact on diversity, equity, and inclusion: COVID-19 amplified existing implicit and explicit biases in society, particularly in the field of medicine. Women trainees and individuals from disadvantaged backgrounds were disproportionately impacted.

Possible solution: Creating programs that increase awareness of the subtle nature of implicit bias and the outsized impact it can have on certain segments of the population, and offering resources to mitigate stressors such as childcare and access to technology solutions

Impact on mental health and wellness: Working through the pandemic was challenging professionally, and the pandemic also exposed individuals to stigma, loneliness, and behavioral health issues (eg, mood and sleeping disorders), which created challenges in personal lives as well. These challenges lasted well over 2 years and have a clear ongoing impact.  

Possible solution: Providing accessible behavioral health resources, regularly assessing and addressing burnout, and regularly cycling trainees off of high-intensity rotations

Education delivery challenges: The sudden cancellation of in-person classes and training, from medical school lectures to rotations, created uncertainty. In-person rounds and bedside learning were significantly restricted. Moreover, as the need to perform clinical duties during the pandemic increased, time for teaching decreased. Some areas were more heavily impacted than others (eg, instruction around elective surgeries, outpatient medicine, and non-critical care training). 

Possible solution: Digitizing education delivery and developing other innovative methods to compensate for a lack of face-to-face instruction

Sudden need for rapid information dissemination: The limits of traditional peer review were tested during the pandemic. Managing individuals infected with the novel coronavirus created a situation where the clinical community needed scientific information quickly, increasing the risk of misinformation. 

Possible solution: Disseminating information as quickly as possible by leveraging public-private partnerships and government investment in high-quality science while maintaining peer review integrity to ensure rigorous evaluation

The Evidence

Early evidence is emerging about efforts undertaken during the pandemic to maintain adequate levels of preclinical learning, clinical training, and CME. 

Preclinical learning: Virtual formats are generally accepted, and interactive discussion is preferred. But be aware of potential stressors.

A cross-sectional study involving 173 histology and pathology students at European University Cyprus found that preclinical medical education is possible via virtual learning. The pandemic forced respondents to adapt immediately to emergency remote teaching. Survey results found the concept was generally well accepted, though some stressors (eg, poor internet connection) impacted perception. Most histology and pathology students (58% and 68%, respectively) said they would prefer blended learning in the future, compared with all-live (39% and 28%, respectively), or all-virtual (4% and 5%, respectively) classrooms. 

In a systematic review of 13 studies that compared digital learning with live classroom education for medical and nursing students, investigators from China found that standalone digital models are as effective as conventional modalities for improving knowledge and practice. Moreover, students preferred interactive discussion to a straight lecture format when participating online. 

Clinical training: Virtual clerkships work, but a blended approach seems preferable.

In a study involving 16 third-year medical students in the general surgery clerkship at Cleveland Clinic, respondents reported their experience before and after participating in a case-based virtual surgery clerkship program. Students were significantly more confident that they could independently assess a surgical consult after taking the course. Average scores of curriculum-based surgical knowledge increased as well. 

In an assessment of alternative approaches to clinical clerkships involving 42 students, investigators from China evaluated the impact of using simulated electronic health records (EHRs) for inpatient training and electronic problem-based learning and virtual interviews for outpatient training. Students using simulated EHRs felt it improved their ability to write in and summarize the record. Those who participated in electronic problem-based learning and virtual interviewing said their interviewing and counseling skills improved. However, students also noted traditional clinical clerkships are better for certain types of learning, suggesting that a blended approach is preferred. 

CME: Virtual CME is accepted and improves performance, but barriers remain, including a preference for face-to-face networking.

Researchers reviewed 2,007 post-activity responses from clinicians who participated in online CME at a South Korean hospital. Of the 1332 participants who reported their satisfaction level, 85% reported being satisfied with the format and content. Among all respondents, nearly 9 in 10 said that the content would influence the way they practice. Of the 611 participants who responded to a follow-up survey 3 months later, 78% said they made changes in their clinical practice based on what they learned. 

However, many clinicians prefer in-person CME. A Canadian-based memory clinic held 5 interprofessional education sessions and reported on participant experience; 3 of the sessions occurred live before March 2020 and 2 were held via videoconference once the pandemic was declared. Ratings of satisfaction, relevance, knowledge acquisition, and knowledge application were similar in both groups, but the virtual sessions were rated as less enjoyable and lacking in networking opportunities. In-person learning was preferred. 

Primary care clinicians in Portugal evaluated a CME digital platform and reported several barriers, including time constraints, perceived excessive work, lack of digital competence, lack of motivation, and emotional factors.      

The Future
Although challenges remain, changes due to the pandemic have been implemented in medical training and have shown preliminary success in certain domains. Medical education is rapidly evolving, and as we move further from the pandemic, diligent ongoing evaluation is needed to assess the best use of technology and various innovative teaching modalities. Keeping medical education learner-centered and instituting timely course correction if certain modalities of knowledge/skill delivery are found to be ineffective will be key to ensuring the robustness of training for future generations.   

Question: What doubles every 2 months and takes more than a decade and a half to reach its ultimate destination?

Answer: Medical knowledge. 

In 2011, researchers projected that by 2020, medical knowledge would double every 73 days. Also in 2011, investigators estimated that clinical research takes 17 years to translate from bench to bedside. 

This “fast-slow” paradox became more relevant than ever in 2020, when the coronavirus pandemic brought the world to a near standstill. Stakeholders in undergraduate, postgraduate, and continuing medical education (CME) were suddenly faced with choices that had been discussed theoretically but not yet applied on a wide scale: How do we deliver education if in-person instruction is not an option? 

Organized medicine and the clinical community made choices based on groundwork that had been laid prior to the pandemic. The medical community acted quickly out of necessity, implementing novel learning methods that are now being utilized and that need to be assessed in an ongoing manner. 

The Backdrop

Medical education has long been dominated by an in-person, didactic model anchored in teacher-centered, classroom-based learning. This design has been firmly entrenched for more than 100 years, since the publication of the Flexner report in 1910, which established the standard of 4 years of medical education. Prior to 2020, many experts acknowledged that alternative practices and emerging technologies should play a role in medical education, but indecision abounded, perhaps because there was no real-world catalyst for reform. Thus, despite various attempts, the adoption of alternative forms of teaching moved slowly. 

Pre-pandemic efforts

In 2017, the American Medication Association issued a report calling for “one of the most complete curricular reforms since the Flexner Report.” It urged leaders to “rethink nearly every facet of physician training,” including “greater emphasis on new technology.” The report also suggested a 14-month pre-rotation program focused on the core medical knowledge necessary to practice in a hospital setting, along with work in a primary care setting once every other week. 

Before the pandemic, “blended learning” (digital and live) and “flipped classroom” approaches were assessed. A meta-analysis comparing a blended learning format to traditional classroom model programs found that blended learning resulted in better knowledge outcomes. In the flipped classroom approach, non-classroom individual or group activities replace in-class instruction after pre-class self-preparation with provided resources. A meta-analysis of 28 comparative studies showed that the flipped classroom approach resulted in improved learning compared to traditional methods. Additionally, bite-sized learning approaches have been implemented and evaluated, showing improvement in immediate knowledge recall. 

Barriers to widespread implementation

Despite the need to increase medical knowledge dissemination and implement approaches proven to do so effectively, barriers to adoption are well documented. Obstacles include time limitations, inadequate technical skills, insufficient infrastructure, and a wide variety in and range of expertise of both learners and institutional strategies. There are also differences in effective techniques for teaching various topics based on the content. Some topics require knowledge-based training, whereas others fall more easily into skills-based training. 

Additionally, when it comes to new evidence that needs to be translated to clinical evaluation and delivery, there is ongoing debate about the established peer-review process, which is rigorous but time-consuming vs the open-access publication process, which can disseminate information more quickly but is prone to error. 

Proposed solutions

Proposed solutions to these barriers include improving educator skills, offering incentives for innovative content development, cultivating better institutional strategies, and achieving buy-in from all stakeholders. Also important is thoughtful adaptation of content to various electronic formats, such as audiovisual presentation of educational material, social media content, and gamification of content, as well as ongoing assessment of both education delivery and consumption—followed by rapid pivoting when necessary. 

Despite these clearly identified challenges and thoughtful solutions, change was relatively slow until March 2020. 

The Trigger

With medical knowledge expanding so rapidly, imagine if medical education moved slowly or came to a complete halt when a worldwide pandemic was declared, the effects would have been catastrophic. COVID pushed organized medicine and the healthcare community to accelerate the adoption of novel technological approaches to keep the medical knowledge pipeline flowing at a relatively reasonable— if not ideal—rate. 

Challenges the pandemic produced, along with potential mitigation strategies, are outlined below.      

Economic consequences: The pandemic resulted in lost income for training programs and decreased funding for graduate medical education.

Possible solution: Creating budget allowances to adopt new technologies

Impact on diversity, equity, and inclusion: COVID-19 amplified existing implicit and explicit biases in society, particularly in the field of medicine. Women trainees and individuals from disadvantaged backgrounds were disproportionately impacted.

Possible solution: Creating programs that increase awareness of the subtle nature of implicit bias and the outsized impact it can have on certain segments of the population, and offering resources to mitigate stressors such as childcare and access to technology solutions

Impact on mental health and wellness: Working through the pandemic was challenging professionally, and the pandemic also exposed individuals to stigma, loneliness, and behavioral health issues (eg, mood and sleeping disorders), which created challenges in personal lives as well. These challenges lasted well over 2 years and have a clear ongoing impact.  

Possible solution: Providing accessible behavioral health resources, regularly assessing and addressing burnout, and regularly cycling trainees off of high-intensity rotations

Education delivery challenges: The sudden cancellation of in-person classes and training, from medical school lectures to rotations, created uncertainty. In-person rounds and bedside learning were significantly restricted. Moreover, as the need to perform clinical duties during the pandemic increased, time for teaching decreased. Some areas were more heavily impacted than others (eg, instruction around elective surgeries, outpatient medicine, and non-critical care training). 

Possible solution: Digitizing education delivery and developing other innovative methods to compensate for a lack of face-to-face instruction

Sudden need for rapid information dissemination: The limits of traditional peer review were tested during the pandemic. Managing individuals infected with the novel coronavirus created a situation where the clinical community needed scientific information quickly, increasing the risk of misinformation. 

Possible solution: Disseminating information as quickly as possible by leveraging public-private partnerships and government investment in high-quality science while maintaining peer review integrity to ensure rigorous evaluation

The Evidence

Early evidence is emerging about efforts undertaken during the pandemic to maintain adequate levels of preclinical learning, clinical training, and CME. 

Preclinical learning: Virtual formats are generally accepted, and interactive discussion is preferred. But be aware of potential stressors.

A cross-sectional study involving 173 histology and pathology students at European University Cyprus found that preclinical medical education is possible via virtual learning. The pandemic forced respondents to adapt immediately to emergency remote teaching. Survey results found the concept was generally well accepted, though some stressors (eg, poor internet connection) impacted perception. Most histology and pathology students (58% and 68%, respectively) said they would prefer blended learning in the future, compared with all-live (39% and 28%, respectively), or all-virtual (4% and 5%, respectively) classrooms. 

In a systematic review of 13 studies that compared digital learning with live classroom education for medical and nursing students, investigators from China found that standalone digital models are as effective as conventional modalities for improving knowledge and practice. Moreover, students preferred interactive discussion to a straight lecture format when participating online. 

Clinical training: Virtual clerkships work, but a blended approach seems preferable.

In a study involving 16 third-year medical students in the general surgery clerkship at Cleveland Clinic, respondents reported their experience before and after participating in a case-based virtual surgery clerkship program. Students were significantly more confident that they could independently assess a surgical consult after taking the course. Average scores of curriculum-based surgical knowledge increased as well. 

In an assessment of alternative approaches to clinical clerkships involving 42 students, investigators from China evaluated the impact of using simulated electronic health records (EHRs) for inpatient training and electronic problem-based learning and virtual interviews for outpatient training. Students using simulated EHRs felt it improved their ability to write in and summarize the record. Those who participated in electronic problem-based learning and virtual interviewing said their interviewing and counseling skills improved. However, students also noted traditional clinical clerkships are better for certain types of learning, suggesting that a blended approach is preferred. 

CME: Virtual CME is accepted and improves performance, but barriers remain, including a preference for face-to-face networking.

Researchers reviewed 2,007 post-activity responses from clinicians who participated in online CME at a South Korean hospital. Of the 1332 participants who reported their satisfaction level, 85% reported being satisfied with the format and content. Among all respondents, nearly 9 in 10 said that the content would influence the way they practice. Of the 611 participants who responded to a follow-up survey 3 months later, 78% said they made changes in their clinical practice based on what they learned. 

However, many clinicians prefer in-person CME. A Canadian-based memory clinic held 5 interprofessional education sessions and reported on participant experience; 3 of the sessions occurred live before March 2020 and 2 were held via videoconference once the pandemic was declared. Ratings of satisfaction, relevance, knowledge acquisition, and knowledge application were similar in both groups, but the virtual sessions were rated as less enjoyable and lacking in networking opportunities. In-person learning was preferred. 

Primary care clinicians in Portugal evaluated a CME digital platform and reported several barriers, including time constraints, perceived excessive work, lack of digital competence, lack of motivation, and emotional factors.      

The Future
Although challenges remain, changes due to the pandemic have been implemented in medical training and have shown preliminary success in certain domains. Medical education is rapidly evolving, and as we move further from the pandemic, diligent ongoing evaluation is needed to assess the best use of technology and various innovative teaching modalities. Keeping medical education learner-centered and instituting timely course correction if certain modalities of knowledge/skill delivery are found to be ineffective will be key to ensuring the robustness of training for future generations.   

Question: What doubles every 2 months and takes more than a decade and a half to reach its ultimate destination?

Answer: Medical knowledge. 

In 2011, researchers projected that by 2020, medical knowledge would double every 73 days. Also in 2011, investigators estimated that clinical research takes 17 years to translate from bench to bedside. 

This “fast-slow” paradox became more relevant than ever in 2020, when the coronavirus pandemic brought the world to a near standstill. Stakeholders in undergraduate, postgraduate, and continuing medical education (CME) were suddenly faced with choices that had been discussed theoretically but not yet applied on a wide scale: How do we deliver education if in-person instruction is not an option? 

Organized medicine and the clinical community made choices based on groundwork that had been laid prior to the pandemic. The medical community acted quickly out of necessity, implementing novel learning methods that are now being utilized and that need to be assessed in an ongoing manner. 

The Backdrop

Medical education has long been dominated by an in-person, didactic model anchored in teacher-centered, classroom-based learning. This design has been firmly entrenched for more than 100 years, since the publication of the Flexner report in 1910, which established the standard of 4 years of medical education. Prior to 2020, many experts acknowledged that alternative practices and emerging technologies should play a role in medical education, but indecision abounded, perhaps because there was no real-world catalyst for reform. Thus, despite various attempts, the adoption of alternative forms of teaching moved slowly. 

Pre-pandemic efforts

In 2017, the American Medication Association issued a report calling for “one of the most complete curricular reforms since the Flexner Report.” It urged leaders to “rethink nearly every facet of physician training,” including “greater emphasis on new technology.” The report also suggested a 14-month pre-rotation program focused on the core medical knowledge necessary to practice in a hospital setting, along with work in a primary care setting once every other week. 

Before the pandemic, “blended learning” (digital and live) and “flipped classroom” approaches were assessed. A meta-analysis comparing a blended learning format to traditional classroom model programs found that blended learning resulted in better knowledge outcomes. In the flipped classroom approach, non-classroom individual or group activities replace in-class instruction after pre-class self-preparation with provided resources. A meta-analysis of 28 comparative studies showed that the flipped classroom approach resulted in improved learning compared to traditional methods. Additionally, bite-sized learning approaches have been implemented and evaluated, showing improvement in immediate knowledge recall. 

Barriers to widespread implementation

Despite the need to increase medical knowledge dissemination and implement approaches proven to do so effectively, barriers to adoption are well documented. Obstacles include time limitations, inadequate technical skills, insufficient infrastructure, and a wide variety in and range of expertise of both learners and institutional strategies. There are also differences in effective techniques for teaching various topics based on the content. Some topics require knowledge-based training, whereas others fall more easily into skills-based training. 

Additionally, when it comes to new evidence that needs to be translated to clinical evaluation and delivery, there is ongoing debate about the established peer-review process, which is rigorous but time-consuming vs the open-access publication process, which can disseminate information more quickly but is prone to error. 

Proposed solutions

Proposed solutions to these barriers include improving educator skills, offering incentives for innovative content development, cultivating better institutional strategies, and achieving buy-in from all stakeholders. Also important is thoughtful adaptation of content to various electronic formats, such as audiovisual presentation of educational material, social media content, and gamification of content, as well as ongoing assessment of both education delivery and consumption—followed by rapid pivoting when necessary. 

Despite these clearly identified challenges and thoughtful solutions, change was relatively slow until March 2020. 

The Trigger

With medical knowledge expanding so rapidly, imagine if medical education moved slowly or came to a complete halt when a worldwide pandemic was declared, the effects would have been catastrophic. COVID pushed organized medicine and the healthcare community to accelerate the adoption of novel technological approaches to keep the medical knowledge pipeline flowing at a relatively reasonable— if not ideal—rate. 

Challenges the pandemic produced, along with potential mitigation strategies, are outlined below.      

Economic consequences: The pandemic resulted in lost income for training programs and decreased funding for graduate medical education.

Possible solution: Creating budget allowances to adopt new technologies

Impact on diversity, equity, and inclusion: COVID-19 amplified existing implicit and explicit biases in society, particularly in the field of medicine. Women trainees and individuals from disadvantaged backgrounds were disproportionately impacted.

Possible solution: Creating programs that increase awareness of the subtle nature of implicit bias and the outsized impact it can have on certain segments of the population, and offering resources to mitigate stressors such as childcare and access to technology solutions

Impact on mental health and wellness: Working through the pandemic was challenging professionally, and the pandemic also exposed individuals to stigma, loneliness, and behavioral health issues (eg, mood and sleeping disorders), which created challenges in personal lives as well. These challenges lasted well over 2 years and have a clear ongoing impact.  

Possible solution: Providing accessible behavioral health resources, regularly assessing and addressing burnout, and regularly cycling trainees off of high-intensity rotations

Education delivery challenges: The sudden cancellation of in-person classes and training, from medical school lectures to rotations, created uncertainty. In-person rounds and bedside learning were significantly restricted. Moreover, as the need to perform clinical duties during the pandemic increased, time for teaching decreased. Some areas were more heavily impacted than others (eg, instruction around elective surgeries, outpatient medicine, and non-critical care training). 

Possible solution: Digitizing education delivery and developing other innovative methods to compensate for a lack of face-to-face instruction

Sudden need for rapid information dissemination: The limits of traditional peer review were tested during the pandemic. Managing individuals infected with the novel coronavirus created a situation where the clinical community needed scientific information quickly, increasing the risk of misinformation. 

Possible solution: Disseminating information as quickly as possible by leveraging public-private partnerships and government investment in high-quality science while maintaining peer review integrity to ensure rigorous evaluation

The Evidence

Early evidence is emerging about efforts undertaken during the pandemic to maintain adequate levels of preclinical learning, clinical training, and CME. 

Preclinical learning: Virtual formats are generally accepted, and interactive discussion is preferred. But be aware of potential stressors.

A cross-sectional study involving 173 histology and pathology students at European University Cyprus found that preclinical medical education is possible via virtual learning. The pandemic forced respondents to adapt immediately to emergency remote teaching. Survey results found the concept was generally well accepted, though some stressors (eg, poor internet connection) impacted perception. Most histology and pathology students (58% and 68%, respectively) said they would prefer blended learning in the future, compared with all-live (39% and 28%, respectively), or all-virtual (4% and 5%, respectively) classrooms. 

In a systematic review of 13 studies that compared digital learning with live classroom education for medical and nursing students, investigators from China found that standalone digital models are as effective as conventional modalities for improving knowledge and practice. Moreover, students preferred interactive discussion to a straight lecture format when participating online. 

Clinical training: Virtual clerkships work, but a blended approach seems preferable.

In a study involving 16 third-year medical students in the general surgery clerkship at Cleveland Clinic, respondents reported their experience before and after participating in a case-based virtual surgery clerkship program. Students were significantly more confident that they could independently assess a surgical consult after taking the course. Average scores of curriculum-based surgical knowledge increased as well. 

In an assessment of alternative approaches to clinical clerkships involving 42 students, investigators from China evaluated the impact of using simulated electronic health records (EHRs) for inpatient training and electronic problem-based learning and virtual interviews for outpatient training. Students using simulated EHRs felt it improved their ability to write in and summarize the record. Those who participated in electronic problem-based learning and virtual interviewing said their interviewing and counseling skills improved. However, students also noted traditional clinical clerkships are better for certain types of learning, suggesting that a blended approach is preferred. 

CME: Virtual CME is accepted and improves performance, but barriers remain, including a preference for face-to-face networking.

Researchers reviewed 2,007 post-activity responses from clinicians who participated in online CME at a South Korean hospital. Of the 1332 participants who reported their satisfaction level, 85% reported being satisfied with the format and content. Among all respondents, nearly 9 in 10 said that the content would influence the way they practice. Of the 611 participants who responded to a follow-up survey 3 months later, 78% said they made changes in their clinical practice based on what they learned. 

However, many clinicians prefer in-person CME. A Canadian-based memory clinic held 5 interprofessional education sessions and reported on participant experience; 3 of the sessions occurred live before March 2020 and 2 were held via videoconference once the pandemic was declared. Ratings of satisfaction, relevance, knowledge acquisition, and knowledge application were similar in both groups, but the virtual sessions were rated as less enjoyable and lacking in networking opportunities. In-person learning was preferred. 

Primary care clinicians in Portugal evaluated a CME digital platform and reported several barriers, including time constraints, perceived excessive work, lack of digital competence, lack of motivation, and emotional factors.      

The Future
Although challenges remain, changes due to the pandemic have been implemented in medical training and have shown preliminary success in certain domains. Medical education is rapidly evolving, and as we move further from the pandemic, diligent ongoing evaluation is needed to assess the best use of technology and various innovative teaching modalities. Keeping medical education learner-centered and instituting timely course correction if certain modalities of knowledge/skill delivery are found to be ineffective will be key to ensuring the robustness of training for future generations.   

COVID vaccines will have a new formulation in 2023, according to a decision announced by the U.S. Food and Drug Administration, that will focus efforts on circulating variants. The move pushes last year’s bivalent vaccines out of circulation because they will no longer be authorized for use in the United States.

The updated mRNA vaccines for 2023-2024 are being revised to include a single component that corresponds to the Omicron variant XBB.1.5. Like the bivalents offered before, the new monovalents are being manufactured by Moderna and Pfizer.

The new vaccines are authorized for use in individuals age 6 months and older.  And the new options are being developed using a similar process as previous formulations, according to the FDA.
 

Targeting circulating variants

In recent studies, regulators point out the extent of neutralization observed by the updated vaccines against currently circulating viral variants causing COVID-19, including EG.5, BA.2.86, appears to be of a similar magnitude to the extent of neutralization observed with previous versions of the vaccines against corresponding prior variants.

“This suggests that the vaccines are a good match for protecting against the currently circulating COVID-19 variants,” according to the report.

Hundreds of millions of people in the United States have already received previously approved mRNA COVID vaccines, according to regulators who say the benefit-to-risk profile is well understood as they move forward with new formulations.

“Vaccination remains critical to public health and continued protection against serious consequences of COVID-19, including hospitalization and death,” Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, said in a statement. “The public can be assured that these updated vaccines have met the agency’s rigorous scientific standards for safety, effectiveness, and manufacturing quality. We very much encourage those who are eligible to consider getting vaccinated.”
 

Timing the effort

On Sept. 12 the U.S. Centers for Disease Control and Prevention recommended that everyone 6 months and older get an updated COVID-19 vaccine. Updated vaccines from Pfizer-BioNTech and Moderna will be available later this week, according to the agency.

This article was updated 9/14/23.

A version of this article appeared on Medscape.com.

COVID vaccines will have a new formulation in 2023, according to a decision announced by the U.S. Food and Drug Administration, that will focus efforts on circulating variants. The move pushes last year’s bivalent vaccines out of circulation because they will no longer be authorized for use in the United States.

The updated mRNA vaccines for 2023-2024 are being revised to include a single component that corresponds to the Omicron variant XBB.1.5. Like the bivalents offered before, the new monovalents are being manufactured by Moderna and Pfizer.

The new vaccines are authorized for use in individuals age 6 months and older.  And the new options are being developed using a similar process as previous formulations, according to the FDA.
 

Targeting circulating variants

In recent studies, regulators point out the extent of neutralization observed by the updated vaccines against currently circulating viral variants causing COVID-19, including EG.5, BA.2.86, appears to be of a similar magnitude to the extent of neutralization observed with previous versions of the vaccines against corresponding prior variants.

“This suggests that the vaccines are a good match for protecting against the currently circulating COVID-19 variants,” according to the report.

Hundreds of millions of people in the United States have already received previously approved mRNA COVID vaccines, according to regulators who say the benefit-to-risk profile is well understood as they move forward with new formulations.

“Vaccination remains critical to public health and continued protection against serious consequences of COVID-19, including hospitalization and death,” Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, said in a statement. “The public can be assured that these updated vaccines have met the agency’s rigorous scientific standards for safety, effectiveness, and manufacturing quality. We very much encourage those who are eligible to consider getting vaccinated.”
 

Timing the effort

On Sept. 12 the U.S. Centers for Disease Control and Prevention recommended that everyone 6 months and older get an updated COVID-19 vaccine. Updated vaccines from Pfizer-BioNTech and Moderna will be available later this week, according to the agency.

This article was updated 9/14/23.

A version of this article appeared on Medscape.com.

COVID vaccines will have a new formulation in 2023, according to a decision announced by the U.S. Food and Drug Administration, that will focus efforts on circulating variants. The move pushes last year’s bivalent vaccines out of circulation because they will no longer be authorized for use in the United States.

The updated mRNA vaccines for 2023-2024 are being revised to include a single component that corresponds to the Omicron variant XBB.1.5. Like the bivalents offered before, the new monovalents are being manufactured by Moderna and Pfizer.

The new vaccines are authorized for use in individuals age 6 months and older.  And the new options are being developed using a similar process as previous formulations, according to the FDA.
 

Targeting circulating variants

In recent studies, regulators point out the extent of neutralization observed by the updated vaccines against currently circulating viral variants causing COVID-19, including EG.5, BA.2.86, appears to be of a similar magnitude to the extent of neutralization observed with previous versions of the vaccines against corresponding prior variants.

“This suggests that the vaccines are a good match for protecting against the currently circulating COVID-19 variants,” according to the report.

Hundreds of millions of people in the United States have already received previously approved mRNA COVID vaccines, according to regulators who say the benefit-to-risk profile is well understood as they move forward with new formulations.

“Vaccination remains critical to public health and continued protection against serious consequences of COVID-19, including hospitalization and death,” Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, said in a statement. “The public can be assured that these updated vaccines have met the agency’s rigorous scientific standards for safety, effectiveness, and manufacturing quality. We very much encourage those who are eligible to consider getting vaccinated.”
 

Timing the effort

On Sept. 12 the U.S. Centers for Disease Control and Prevention recommended that everyone 6 months and older get an updated COVID-19 vaccine. Updated vaccines from Pfizer-BioNTech and Moderna will be available later this week, according to the agency.

This article was updated 9/14/23.

A version of this article appeared on Medscape.com.

The Centers for Disease Control and Prevention and the World Health Organization have dubbed the BA 2.86 variant of COVID-19 as a variant to watch. 

So far, only 26 cases of “Pirola,” as the new variant is being called, have been identified: 10 in Denmark, four each in Sweden and the United States, three in South Africa, two in Portugal, and one each the United Kingdom, Israel, and Canada. BA 2.86 is a subvariant of Omicron, but according to reports from the CDC, the strain has many more mutations than the ones that came before it. 

With so many facts still unknown about this new variant, this news organization asked experts what people need to be aware of as it continues to spread.
 

What is unique about the BA 2.86 variant? 

“It is unique in that it has more than three mutations on the spike protein,” said Purvi S. Parikh, MD, an infectious disease expert at New York University’s Langone Health. The virus uses the spike proteins to enter our cells. 

This “may mean it will be more transmissible, cause more severe disease, and/or our vaccines and treatments may not work as well, as compared to other variants,” she said.
 

What do we need to watch with BA 2.86 going forward? 

“We don’t know if this variant will be associated with a change in the disease severity. We currently see increased numbers of cases in general, even though we don’t yet see the BA.2.86 in our system,” said Heba Mostafa, PhD, director of the molecular virology laboratory at Johns Hopkins Hospital in Baltimore. 

“It is important to monitor BA.2.86 (and other variants) and understand how its evolution impacts the number of cases and disease outcomes,” she said. “We should all be aware of the current increase in cases, though, and try to get tested and be treated as soon as possible, as antivirals should be effective against the circulating variants.” 
 

What should doctors know?

Dr. Parikh said doctors should generally expect more COVID cases in their clinics and make sure to screen patients even if their symptoms are mild.

“We have tools that can be used – antivirals like Paxlovid are still efficacious with current dominant strains such as EG.5,” she said. “And encourage your patients to get their boosters, mask, wash hands, and social distance.”
 

How well can our vaccines fight BA 2.86?

“Vaccine coverage for the BA.2.86 is an area of uncertainty right now,” said Dr. Mostafa. 

In its report, the CDC said scientists are still figuring out how well the updated COVID vaccine works. It’s expected to be available in the fall, and for now, they believe the new shot will still make infections less severe, new variants and all. 

Prior vaccinations and infections have created antibodies in many people, and that will likely provide some protection, Dr. Mostafa said. “When we experienced the Omicron wave in December 2021, even though the variant was distant from what circulated before its emergence and was associated with a very large increase in the number of cases, vaccinations were still protective against severe disease.” 
 

What is the most important thing to keep track of when it comes to this variant?

According to Dr. Parikh, “it’s most important to monitor how transmissible [BA 2.86] is, how severe it is, and if our current treatments and vaccines work.” 

Dr. Mostafa said how well the new variants escape existing antibody protection should also be studied and watched closely. 
 

What does this stage of the virus mutation tell us about where we are in the pandemic?

The history of the coronavirus over the past few years shows that variants with many changes evolve and can spread very quickly, Dr. Mostafa said. “Now that the virus is endemic, it is essential to monitor, update vaccinations if necessary, diagnose, treat, and implement infection control measures when necessary.”

With the limited data we have so far, experts seem to agree that while the variant’s makeup raises some red flags, it is too soon to jump to any conclusions about how easy it is to catch it and the ways it may change how the virus impacts those who contract it.
 

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

The Centers for Disease Control and Prevention and the World Health Organization have dubbed the BA 2.86 variant of COVID-19 as a variant to watch. 

So far, only 26 cases of “Pirola,” as the new variant is being called, have been identified: 10 in Denmark, four each in Sweden and the United States, three in South Africa, two in Portugal, and one each the United Kingdom, Israel, and Canada. BA 2.86 is a subvariant of Omicron, but according to reports from the CDC, the strain has many more mutations than the ones that came before it. 

With so many facts still unknown about this new variant, this news organization asked experts what people need to be aware of as it continues to spread.
 

What is unique about the BA 2.86 variant? 

“It is unique in that it has more than three mutations on the spike protein,” said Purvi S. Parikh, MD, an infectious disease expert at New York University’s Langone Health. The virus uses the spike proteins to enter our cells. 

This “may mean it will be more transmissible, cause more severe disease, and/or our vaccines and treatments may not work as well, as compared to other variants,” she said.
 

What do we need to watch with BA 2.86 going forward? 

“We don’t know if this variant will be associated with a change in the disease severity. We currently see increased numbers of cases in general, even though we don’t yet see the BA.2.86 in our system,” said Heba Mostafa, PhD, director of the molecular virology laboratory at Johns Hopkins Hospital in Baltimore. 

“It is important to monitor BA.2.86 (and other variants) and understand how its evolution impacts the number of cases and disease outcomes,” she said. “We should all be aware of the current increase in cases, though, and try to get tested and be treated as soon as possible, as antivirals should be effective against the circulating variants.” 
 

What should doctors know?

Dr. Parikh said doctors should generally expect more COVID cases in their clinics and make sure to screen patients even if their symptoms are mild.

“We have tools that can be used – antivirals like Paxlovid are still efficacious with current dominant strains such as EG.5,” she said. “And encourage your patients to get their boosters, mask, wash hands, and social distance.”
 

How well can our vaccines fight BA 2.86?

“Vaccine coverage for the BA.2.86 is an area of uncertainty right now,” said Dr. Mostafa. 

In its report, the CDC said scientists are still figuring out how well the updated COVID vaccine works. It’s expected to be available in the fall, and for now, they believe the new shot will still make infections less severe, new variants and all. 

Prior vaccinations and infections have created antibodies in many people, and that will likely provide some protection, Dr. Mostafa said. “When we experienced the Omicron wave in December 2021, even though the variant was distant from what circulated before its emergence and was associated with a very large increase in the number of cases, vaccinations were still protective against severe disease.” 
 

What is the most important thing to keep track of when it comes to this variant?

According to Dr. Parikh, “it’s most important to monitor how transmissible [BA 2.86] is, how severe it is, and if our current treatments and vaccines work.” 

Dr. Mostafa said how well the new variants escape existing antibody protection should also be studied and watched closely. 
 

What does this stage of the virus mutation tell us about where we are in the pandemic?

The history of the coronavirus over the past few years shows that variants with many changes evolve and can spread very quickly, Dr. Mostafa said. “Now that the virus is endemic, it is essential to monitor, update vaccinations if necessary, diagnose, treat, and implement infection control measures when necessary.”

With the limited data we have so far, experts seem to agree that while the variant’s makeup raises some red flags, it is too soon to jump to any conclusions about how easy it is to catch it and the ways it may change how the virus impacts those who contract it.
 

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

The Centers for Disease Control and Prevention and the World Health Organization have dubbed the BA 2.86 variant of COVID-19 as a variant to watch. 

So far, only 26 cases of “Pirola,” as the new variant is being called, have been identified: 10 in Denmark, four each in Sweden and the United States, three in South Africa, two in Portugal, and one each the United Kingdom, Israel, and Canada. BA 2.86 is a subvariant of Omicron, but according to reports from the CDC, the strain has many more mutations than the ones that came before it. 

With so many facts still unknown about this new variant, this news organization asked experts what people need to be aware of as it continues to spread.
 

What is unique about the BA 2.86 variant? 

“It is unique in that it has more than three mutations on the spike protein,” said Purvi S. Parikh, MD, an infectious disease expert at New York University’s Langone Health. The virus uses the spike proteins to enter our cells. 

This “may mean it will be more transmissible, cause more severe disease, and/or our vaccines and treatments may not work as well, as compared to other variants,” she said.
 

What do we need to watch with BA 2.86 going forward? 

“We don’t know if this variant will be associated with a change in the disease severity. We currently see increased numbers of cases in general, even though we don’t yet see the BA.2.86 in our system,” said Heba Mostafa, PhD, director of the molecular virology laboratory at Johns Hopkins Hospital in Baltimore. 

“It is important to monitor BA.2.86 (and other variants) and understand how its evolution impacts the number of cases and disease outcomes,” she said. “We should all be aware of the current increase in cases, though, and try to get tested and be treated as soon as possible, as antivirals should be effective against the circulating variants.” 
 

What should doctors know?

Dr. Parikh said doctors should generally expect more COVID cases in their clinics and make sure to screen patients even if their symptoms are mild.

“We have tools that can be used – antivirals like Paxlovid are still efficacious with current dominant strains such as EG.5,” she said. “And encourage your patients to get their boosters, mask, wash hands, and social distance.”
 

How well can our vaccines fight BA 2.86?

“Vaccine coverage for the BA.2.86 is an area of uncertainty right now,” said Dr. Mostafa. 

In its report, the CDC said scientists are still figuring out how well the updated COVID vaccine works. It’s expected to be available in the fall, and for now, they believe the new shot will still make infections less severe, new variants and all. 

Prior vaccinations and infections have created antibodies in many people, and that will likely provide some protection, Dr. Mostafa said. “When we experienced the Omicron wave in December 2021, even though the variant was distant from what circulated before its emergence and was associated with a very large increase in the number of cases, vaccinations were still protective against severe disease.” 
 

What is the most important thing to keep track of when it comes to this variant?

According to Dr. Parikh, “it’s most important to monitor how transmissible [BA 2.86] is, how severe it is, and if our current treatments and vaccines work.” 

Dr. Mostafa said how well the new variants escape existing antibody protection should also be studied and watched closely. 
 

What does this stage of the virus mutation tell us about where we are in the pandemic?

The history of the coronavirus over the past few years shows that variants with many changes evolve and can spread very quickly, Dr. Mostafa said. “Now that the virus is endemic, it is essential to monitor, update vaccinations if necessary, diagnose, treat, and implement infection control measures when necessary.”

With the limited data we have so far, experts seem to agree that while the variant’s makeup raises some red flags, it is too soon to jump to any conclusions about how easy it is to catch it and the ways it may change how the virus impacts those who contract it.
 

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

The Department of Health & Human Services has issued an advisory to help medical professionals better recognize the mental health symptoms that may come with long COVID.

The nine mental health symptoms highlighted in the advisory are fatigue; cognitive impairment, including brain fog; anxiety; depression; obsessive-compulsive disorder; sleep disorders; PTSD; psychotic disorder; and start of a substance use disorder.

The advisory noted that social factors can contribute to the mental health problems for racial and ethnic minorities; people with limited access to health care; people who already have behavioral health conditions and physical disabilities; and people who are lesbian, gay, bisexual, transgender, queer, or intersex.

“Long COVID has a range of burdensome physical symptoms and can take a toll on a person’s mental health. It can be very challenging for a person, whether they are impacted themselves, or they are a caregiver for someone who is affected,” Health and Human Services Secretary Xavier Becerra said in a statement. “This advisory helps to raise awareness, especially among primary care practitioners and clinicians who are often the ones treating patients with long COVID.”

The department says about 10% of people infected with COVID have at least one long COVID symptom. Physical symptoms include dizziness, stomach upset, heart palpitations, issues with sexual desire or capacity, loss of smell or taste, thirst, chronic coughing, chest pain, and abnormal movements. 

“We know that people living with long COVID need help today, and providers need help understanding what long COVID is and how to treat it,” Admiral Rachel Levine, MD, assistant secretary for health, said in the statement. “This advisory helps bridge that gap for the behavioral health impacts of long COVID.”

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

The Department of Health & Human Services has issued an advisory to help medical professionals better recognize the mental health symptoms that may come with long COVID.

The nine mental health symptoms highlighted in the advisory are fatigue; cognitive impairment, including brain fog; anxiety; depression; obsessive-compulsive disorder; sleep disorders; PTSD; psychotic disorder; and start of a substance use disorder.

The advisory noted that social factors can contribute to the mental health problems for racial and ethnic minorities; people with limited access to health care; people who already have behavioral health conditions and physical disabilities; and people who are lesbian, gay, bisexual, transgender, queer, or intersex.

“Long COVID has a range of burdensome physical symptoms and can take a toll on a person’s mental health. It can be very challenging for a person, whether they are impacted themselves, or they are a caregiver for someone who is affected,” Health and Human Services Secretary Xavier Becerra said in a statement. “This advisory helps to raise awareness, especially among primary care practitioners and clinicians who are often the ones treating patients with long COVID.”

The department says about 10% of people infected with COVID have at least one long COVID symptom. Physical symptoms include dizziness, stomach upset, heart palpitations, issues with sexual desire or capacity, loss of smell or taste, thirst, chronic coughing, chest pain, and abnormal movements. 

“We know that people living with long COVID need help today, and providers need help understanding what long COVID is and how to treat it,” Admiral Rachel Levine, MD, assistant secretary for health, said in the statement. “This advisory helps bridge that gap for the behavioral health impacts of long COVID.”

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

The Department of Health & Human Services has issued an advisory to help medical professionals better recognize the mental health symptoms that may come with long COVID.

The nine mental health symptoms highlighted in the advisory are fatigue; cognitive impairment, including brain fog; anxiety; depression; obsessive-compulsive disorder; sleep disorders; PTSD; psychotic disorder; and start of a substance use disorder.

The advisory noted that social factors can contribute to the mental health problems for racial and ethnic minorities; people with limited access to health care; people who already have behavioral health conditions and physical disabilities; and people who are lesbian, gay, bisexual, transgender, queer, or intersex.

“Long COVID has a range of burdensome physical symptoms and can take a toll on a person’s mental health. It can be very challenging for a person, whether they are impacted themselves, or they are a caregiver for someone who is affected,” Health and Human Services Secretary Xavier Becerra said in a statement. “This advisory helps to raise awareness, especially among primary care practitioners and clinicians who are often the ones treating patients with long COVID.”

The department says about 10% of people infected with COVID have at least one long COVID symptom. Physical symptoms include dizziness, stomach upset, heart palpitations, issues with sexual desire or capacity, loss of smell or taste, thirst, chronic coughing, chest pain, and abnormal movements. 

“We know that people living with long COVID need help today, and providers need help understanding what long COVID is and how to treat it,” Admiral Rachel Levine, MD, assistant secretary for health, said in the statement. “This advisory helps bridge that gap for the behavioral health impacts of long COVID.”

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

SAN DIEGO – A COVID-19 combination antiviral is the most important new drug primary care physicians have prescribed in recent years – plus it has helped keep many patients out of the hospital, according to a presenter at the annual meeting of the American College of Physicians.

Nirmatrelvir-ritonavir was granted emergency use authorization by the FDA late in 2021 to prevent progression to severe disease when COVID-19 cases and deaths were surging, and the Delta and Omicron variants started to spread.

Gerald Smetana, MD, an internist at Beth Israel Deaconess Medical Center in Boston, discussed nirmatrelvir-ritonavir as an example of how new drugs relevant to primary care can have a profound impact on public health.
 

Understanding the mechanism of action

Nirmatrelvir is the active agent of this combination and inhibits the SARS-CoV-2 main protease (Mpro), which is required for viral replication. In contrast to the SARS-CoV-2 spike protein, Mpro is highly conserved in coronaviruses and rarely acquires mutations. Therefore, unlike monoclonal antibodies targeting the spike protein, nirmatrelvir is active against known Omicron variants and is predicted to remain active against new variants that may emerge. The HIV1 protease inhibitor ritonavir has no activity against SARS-CoV-2. It can help increase the serum concentration of nirmatrelvir by inhibiting its metabolization.

“Although the details are not important for prescribing internists, having a basic understanding of the mechanism of action can help [doctors] better understand for which patients the drugs are indicated,” said Dr. Smetana, also a professor of medicine at Harvard Medical School, Boston. This is particularly important for newly approved drugs with a lot of new information to digest.

“Knowing the mechanisms of action of new drugs can help us predict their efficacy and potential side effects,” said Hubertus Kiefl, MD, an internist at Beth Israel Deaconess Medical Center and a lecturer at Harvard Medical School, during an interview after the session.

Understanding how drugs work also can help clinicians make better decisions, such as avoiding the use of a monoclonal antibody during a surge of a new variant with mutations in surface proteins or carefully managing the use of nirmatrelvir-ritonavir in patients who take certain medications that would cause potentially serious drug-drug interactions, Dr. Kiefl added.

Nirmatrelvir-ritonavir reduces the risk of hospitalization – but only in high-risk patients.

Dr. Smetana presented published data from the EPIC-HR study, a pivotal phase 2-3 clinical trial in 2,246 adult patients with COVID-19, all of whom were unvaccinated. Additionally, all patients had at least one risk factor for progression to severe disease.

When initiated 5 days after symptom onset or earlier, treatment with 300 mg nirmatrelvir plus 100 mg ritonavir twice a day for 5 days led to an 89% relative risk reduction in COVID-19–related hospitalization or death through day 28, compared with placebo.

Subgroup analyses showed that some patients benefited more than others. The highest risk reduction after treatment with nirmatrelvir-ritonavir was observed in patients at least 65 years old.

“It is important to remember that all the patients of this study were unvaccinated and [had] not had prior SARS-CoV-2 infection. This study population isn’t representative of most patients we are seeing today,” said Dr. Smetana.

Unpublished data from a study of standard-risk patients showed a nonsignificant reduction in the risk of hospitalization or death, he said. The study was stopped because of the low rates of hospitalization and death.
 

Effective in real world, but less so than in clinical trials

The fact that the patient cohort in the EPIC-HR trial was different from the patients internists see today makes real-world data critical for determining the usefulness of nirmatrelvir-ritonavir in everyday practice, Dr. Smetana said.

A real-world study from Israel conducted during the first Omicron wave (January to March 2022) showed that treatment with nirmatrelvir alone substantially reduced the relative risk of hospitalization in adults older than 65, with no evidence of benefit in adults aged 40-65. Dr. Smetana highlighted that, unlike the EPIC-HR cohort, most patients in the Israeli study had prior immunity due to vaccination or prior SARS-CoV-2 infection.
 

Many drug-drug interactions, but they can be managed

Nirmatrelvir-ritonavir interacts with many drugs, some of which are commonly used by primary care patients.

To help internists identify drug-drug interactions, Dr. Smetana proposed the use of the Liverpool COVID-19 Drug Interactions Checker, an intuitive tool that can help prescribers identify potential drug-drug interactions, categorize them based on severity, and identify management strategies.

This tool is specific to COVID-19 drugs. The Liverpool group also offers online drug interaction checkers for HIV, hepatitis, and cancer. “We need more tools like this to help improve the safe use of new drugs,” Dr. Smetana said.

To manage drug interactions, according to Dr. Smetana, U.S. treatment guidelines offer the following three options:

• Prescribe an alternative COVID therapy.
• Temporarily withhold concomitant medication if clinically appropriate.
• Adjust the dose of concomitant medication and monitor for adverse effects.

Medication doses that are withheld or modified should be continued through 3 days after completing nirmatrelvir-ritonavir, he added.
 

Important considerations

Commenting on things to consider for patients with COVID-19, Dr. Smetana said that there is a short window after symptom onset when nirmatrelvir-ritonavir can be prescribed, and safety in pregnancy is not known. There is also uncertainty regarding funding of nirmatrelvir-ritonavir prescriptions after the state of emergency is lifted. He reminded attendees that, although nirmatrelvir-ritonavir is the preferred first-line treatment for high-risk patients, another antiviral agent, molnupiravir, is also available and might be more appropriate for some patients.

He also cautioned about prescribing new drugs off label for indications that are not yet FDA-approved. “We are often stewards of limited resources when new drugs first become available but are not yet in sufficient supply to meet demand. Limiting our prescribing to FDA-approved indications helps to ensure equitable access,” he said.

Dr. Smetana and Dr. Kiefl reported no disclosures.

SAN DIEGO – A COVID-19 combination antiviral is the most important new drug primary care physicians have prescribed in recent years – plus it has helped keep many patients out of the hospital, according to a presenter at the annual meeting of the American College of Physicians.

Nirmatrelvir-ritonavir was granted emergency use authorization by the FDA late in 2021 to prevent progression to severe disease when COVID-19 cases and deaths were surging, and the Delta and Omicron variants started to spread.

Gerald Smetana, MD, an internist at Beth Israel Deaconess Medical Center in Boston, discussed nirmatrelvir-ritonavir as an example of how new drugs relevant to primary care can have a profound impact on public health.
 

Understanding the mechanism of action

Nirmatrelvir is the active agent of this combination and inhibits the SARS-CoV-2 main protease (Mpro), which is required for viral replication. In contrast to the SARS-CoV-2 spike protein, Mpro is highly conserved in coronaviruses and rarely acquires mutations. Therefore, unlike monoclonal antibodies targeting the spike protein, nirmatrelvir is active against known Omicron variants and is predicted to remain active against new variants that may emerge. The HIV1 protease inhibitor ritonavir has no activity against SARS-CoV-2. It can help increase the serum concentration of nirmatrelvir by inhibiting its metabolization.

“Although the details are not important for prescribing internists, having a basic understanding of the mechanism of action can help [doctors] better understand for which patients the drugs are indicated,” said Dr. Smetana, also a professor of medicine at Harvard Medical School, Boston. This is particularly important for newly approved drugs with a lot of new information to digest.

“Knowing the mechanisms of action of new drugs can help us predict their efficacy and potential side effects,” said Hubertus Kiefl, MD, an internist at Beth Israel Deaconess Medical Center and a lecturer at Harvard Medical School, during an interview after the session.

Understanding how drugs work also can help clinicians make better decisions, such as avoiding the use of a monoclonal antibody during a surge of a new variant with mutations in surface proteins or carefully managing the use of nirmatrelvir-ritonavir in patients who take certain medications that would cause potentially serious drug-drug interactions, Dr. Kiefl added.

Nirmatrelvir-ritonavir reduces the risk of hospitalization – but only in high-risk patients.

Dr. Smetana presented published data from the EPIC-HR study, a pivotal phase 2-3 clinical trial in 2,246 adult patients with COVID-19, all of whom were unvaccinated. Additionally, all patients had at least one risk factor for progression to severe disease.

When initiated 5 days after symptom onset or earlier, treatment with 300 mg nirmatrelvir plus 100 mg ritonavir twice a day for 5 days led to an 89% relative risk reduction in COVID-19–related hospitalization or death through day 28, compared with placebo.

Subgroup analyses showed that some patients benefited more than others. The highest risk reduction after treatment with nirmatrelvir-ritonavir was observed in patients at least 65 years old.

“It is important to remember that all the patients of this study were unvaccinated and [had] not had prior SARS-CoV-2 infection. This study population isn’t representative of most patients we are seeing today,” said Dr. Smetana.

Unpublished data from a study of standard-risk patients showed a nonsignificant reduction in the risk of hospitalization or death, he said. The study was stopped because of the low rates of hospitalization and death.
 

Effective in real world, but less so than in clinical trials

The fact that the patient cohort in the EPIC-HR trial was different from the patients internists see today makes real-world data critical for determining the usefulness of nirmatrelvir-ritonavir in everyday practice, Dr. Smetana said.

A real-world study from Israel conducted during the first Omicron wave (January to March 2022) showed that treatment with nirmatrelvir alone substantially reduced the relative risk of hospitalization in adults older than 65, with no evidence of benefit in adults aged 40-65. Dr. Smetana highlighted that, unlike the EPIC-HR cohort, most patients in the Israeli study had prior immunity due to vaccination or prior SARS-CoV-2 infection.
 

Many drug-drug interactions, but they can be managed

Nirmatrelvir-ritonavir interacts with many drugs, some of which are commonly used by primary care patients.

To help internists identify drug-drug interactions, Dr. Smetana proposed the use of the Liverpool COVID-19 Drug Interactions Checker, an intuitive tool that can help prescribers identify potential drug-drug interactions, categorize them based on severity, and identify management strategies.

This tool is specific to COVID-19 drugs. The Liverpool group also offers online drug interaction checkers for HIV, hepatitis, and cancer. “We need more tools like this to help improve the safe use of new drugs,” Dr. Smetana said.

To manage drug interactions, according to Dr. Smetana, U.S. treatment guidelines offer the following three options:

• Prescribe an alternative COVID therapy.
• Temporarily withhold concomitant medication if clinically appropriate.
• Adjust the dose of concomitant medication and monitor for adverse effects.

Medication doses that are withheld or modified should be continued through 3 days after completing nirmatrelvir-ritonavir, he added.
 

Important considerations

Commenting on things to consider for patients with COVID-19, Dr. Smetana said that there is a short window after symptom onset when nirmatrelvir-ritonavir can be prescribed, and safety in pregnancy is not known. There is also uncertainty regarding funding of nirmatrelvir-ritonavir prescriptions after the state of emergency is lifted. He reminded attendees that, although nirmatrelvir-ritonavir is the preferred first-line treatment for high-risk patients, another antiviral agent, molnupiravir, is also available and might be more appropriate for some patients.

He also cautioned about prescribing new drugs off label for indications that are not yet FDA-approved. “We are often stewards of limited resources when new drugs first become available but are not yet in sufficient supply to meet demand. Limiting our prescribing to FDA-approved indications helps to ensure equitable access,” he said.

Dr. Smetana and Dr. Kiefl reported no disclosures.

SAN DIEGO – A COVID-19 combination antiviral is the most important new drug primary care physicians have prescribed in recent years – plus it has helped keep many patients out of the hospital, according to a presenter at the annual meeting of the American College of Physicians.

Nirmatrelvir-ritonavir was granted emergency use authorization by the FDA late in 2021 to prevent progression to severe disease when COVID-19 cases and deaths were surging, and the Delta and Omicron variants started to spread.

Gerald Smetana, MD, an internist at Beth Israel Deaconess Medical Center in Boston, discussed nirmatrelvir-ritonavir as an example of how new drugs relevant to primary care can have a profound impact on public health.
 

Understanding the mechanism of action

Nirmatrelvir is the active agent of this combination and inhibits the SARS-CoV-2 main protease (Mpro), which is required for viral replication. In contrast to the SARS-CoV-2 spike protein, Mpro is highly conserved in coronaviruses and rarely acquires mutations. Therefore, unlike monoclonal antibodies targeting the spike protein, nirmatrelvir is active against known Omicron variants and is predicted to remain active against new variants that may emerge. The HIV1 protease inhibitor ritonavir has no activity against SARS-CoV-2. It can help increase the serum concentration of nirmatrelvir by inhibiting its metabolization.

“Although the details are not important for prescribing internists, having a basic understanding of the mechanism of action can help [doctors] better understand for which patients the drugs are indicated,” said Dr. Smetana, also a professor of medicine at Harvard Medical School, Boston. This is particularly important for newly approved drugs with a lot of new information to digest.

“Knowing the mechanisms of action of new drugs can help us predict their efficacy and potential side effects,” said Hubertus Kiefl, MD, an internist at Beth Israel Deaconess Medical Center and a lecturer at Harvard Medical School, during an interview after the session.

Understanding how drugs work also can help clinicians make better decisions, such as avoiding the use of a monoclonal antibody during a surge of a new variant with mutations in surface proteins or carefully managing the use of nirmatrelvir-ritonavir in patients who take certain medications that would cause potentially serious drug-drug interactions, Dr. Kiefl added.

Nirmatrelvir-ritonavir reduces the risk of hospitalization – but only in high-risk patients.

Dr. Smetana presented published data from the EPIC-HR study, a pivotal phase 2-3 clinical trial in 2,246 adult patients with COVID-19, all of whom were unvaccinated. Additionally, all patients had at least one risk factor for progression to severe disease.

When initiated 5 days after symptom onset or earlier, treatment with 300 mg nirmatrelvir plus 100 mg ritonavir twice a day for 5 days led to an 89% relative risk reduction in COVID-19–related hospitalization or death through day 28, compared with placebo.

Subgroup analyses showed that some patients benefited more than others. The highest risk reduction after treatment with nirmatrelvir-ritonavir was observed in patients at least 65 years old.

“It is important to remember that all the patients of this study were unvaccinated and [had] not had prior SARS-CoV-2 infection. This study population isn’t representative of most patients we are seeing today,” said Dr. Smetana.

Unpublished data from a study of standard-risk patients showed a nonsignificant reduction in the risk of hospitalization or death, he said. The study was stopped because of the low rates of hospitalization and death.
 

Effective in real world, but less so than in clinical trials

The fact that the patient cohort in the EPIC-HR trial was different from the patients internists see today makes real-world data critical for determining the usefulness of nirmatrelvir-ritonavir in everyday practice, Dr. Smetana said.

A real-world study from Israel conducted during the first Omicron wave (January to March 2022) showed that treatment with nirmatrelvir alone substantially reduced the relative risk of hospitalization in adults older than 65, with no evidence of benefit in adults aged 40-65. Dr. Smetana highlighted that, unlike the EPIC-HR cohort, most patients in the Israeli study had prior immunity due to vaccination or prior SARS-CoV-2 infection.
 

Many drug-drug interactions, but they can be managed

Nirmatrelvir-ritonavir interacts with many drugs, some of which are commonly used by primary care patients.

To help internists identify drug-drug interactions, Dr. Smetana proposed the use of the Liverpool COVID-19 Drug Interactions Checker, an intuitive tool that can help prescribers identify potential drug-drug interactions, categorize them based on severity, and identify management strategies.

This tool is specific to COVID-19 drugs. The Liverpool group also offers online drug interaction checkers for HIV, hepatitis, and cancer. “We need more tools like this to help improve the safe use of new drugs,” Dr. Smetana said.

To manage drug interactions, according to Dr. Smetana, U.S. treatment guidelines offer the following three options:

• Prescribe an alternative COVID therapy.
• Temporarily withhold concomitant medication if clinically appropriate.
• Adjust the dose of concomitant medication and monitor for adverse effects.

Medication doses that are withheld or modified should be continued through 3 days after completing nirmatrelvir-ritonavir, he added.
 

Important considerations

Commenting on things to consider for patients with COVID-19, Dr. Smetana said that there is a short window after symptom onset when nirmatrelvir-ritonavir can be prescribed, and safety in pregnancy is not known. There is also uncertainty regarding funding of nirmatrelvir-ritonavir prescriptions after the state of emergency is lifted. He reminded attendees that, although nirmatrelvir-ritonavir is the preferred first-line treatment for high-risk patients, another antiviral agent, molnupiravir, is also available and might be more appropriate for some patients.

He also cautioned about prescribing new drugs off label for indications that are not yet FDA-approved. “We are often stewards of limited resources when new drugs first become available but are not yet in sufficient supply to meet demand. Limiting our prescribing to FDA-approved indications helps to ensure equitable access,” he said.

Dr. Smetana and Dr. Kiefl reported no disclosures.

COVID-19 is a potentially severe systemic disease caused by SARS-CoV-2. SARS-CoV and Middle East respiratory syndrome (MERS-CoV) caused fatal epidemics in Asia in 2002 to 2003 and in the Arabian Peninsula in 2012, respectively. In 2019, SARS-CoV-2 was detected in patients with severe, sometimes fatal pneumonia of previously unknown origin; it rapidly spread around the world, and the World Health Organization declared the disease a pandemic on March 11, 2020. SARS-CoV-2 is a β-coronavirus that is genetically related to the bat coronavirus and SARS-CoV; it is a single-stranded RNA virus of which several variants and subvariants exist. The SARS-CoV-2 viral particles bind via their surface spike protein (S protein) to the angiotensin-converting enzyme 2 receptor present on the membrane of several cell types, including epidermal and adnexal keratinocytes.^1,2 The α and δ variants, predominant from 2020 to 2021, mainly affected the lower respiratory tract and caused severe, potentially fatal pneumonia, especially in patients older than 65 years and/or with comorbidities, such as obesity, hypertension, diabetes, and (iatrogenic) immunosuppression. The ο variant, which appeared in late 2021, is more contagious than the initial variants, but it causes a less severe disease preferentially affecting the upper respiratory airways.³ As of April 5, 2023, more than 762,000,000 confirmed cases of COVID-19 have been recorded worldwide, causing more than 6,800,000 deaths.⁴

Early studies from China describing the symptoms of COVID-19 reported a low frequency of skin manifestations (0.2%), probably because they were focused on the most severe disease symptoms.⁵ Subsequently, when COVID-19 spread to the rest of the world, an increasing number of skin manifestations were reported in association with the disease. After the first publication from northern Italy in spring 2020, which was specifically devoted to skin manifestations of COVID-19,⁶ an explosive number of publications reported a large number of skin manifestations, and national registries were established in several countries to record these manifestations, such as the American Academy of Dermatology and the International League of Dermatological Societies registry,^7,8 the COVIDSKIN registry of the French Dermatology Society,⁹ and the Italian registry.¹⁰ Highlighting the unprecedented number of scientific articles published on this new disease, a PubMed search of articles indexed for MEDLINE search using the terms SARS-CoV-2 or COVID-19, on April 6, 2023, revealed 351,596 articles; that is more than 300 articles published every day in this database alone, with a large number of them concerning the skin.

SKIN DISEASSES ASSOCIATED WITH COVID-19

There are several types of COVID-19–related skin manifestations, depending on the circumstances of onset and the evolution of the pandemic.

Skin Manifestations Associated With SARS-CoV-2 Infection

The estimated incidence varies greatly according to the published series of patients, possibly depending on the geographic location. The estimated incidence seems lower in Asian countries, such as China (0.2%)⁵ and Japan (0.56%),¹¹ compared with Europe (up to 20%).⁶ Skin manifestations associated with SARS-CoV-2 infection affect individuals of all ages, slightly more females, and are clinically polymorphous; some of them are associated with the severity of the infection.¹² They may precede, accompany, or appear after the symptoms of COVID-19, most often within a month of the infection, of which they rarely are the only manifestation; however, their precise relationship to SARS-CoV-2 is not always well known. They have been classified according to their clinical presentation into several forms.^13-15

Morbilliform Maculopapular Eruption—Representing 16% to 53% of skin manifestations, morbilliform and maculopapular eruptions usually appear within 15 days of infection; they manifest with more or less confluent erythematous macules that may be hemorrhagic/petechial, and usually are asymptomatic and rarely pruritic. The rash mainly affects the trunk and limbs, sparing the face, palmoplantar regions, and mucous membranes; it appears concomitantly with or a few days after the first symptoms of COVID-19 (eg, fever, respiratory symptoms), regresses within a few days, and does not appear to be associated with disease severity. The distinction from maculopapular drug eruptions may be subtle. Histologically, the rash manifests with a spongiform dermatitis (ie, variable parakeratosis; spongiosis; and a mixed dermal perivascular infiltrate of lymphocytes, eosinophils and histiocytes, depending on the lesion age)(Figure 1). The etiopathogenesis is unknown; it may involve immune complexes to SARS-CoV-2 deposited on skin vessels. Treatment is not mandatory; if necessary, local or systemic corticosteroids may be used.

Vesicular (Pseudovaricella) Rash—This rash accounts for 11% to 18% of all skin manifestations and usually appears within 15 days of COVID-19 onset. It manifests with small monomorphous or varicellalike (pseudopolymorphic) vesicles appearing on the trunk, usually in young patients. The vesicles may be herpetiform, hemorrhagic, or pruritic, and appear before or within 3 days of the onset of mild COVID-19 symptoms; they regress within a few days without scarring. Histologically, the lesions show basal cell vacuolization; multinucleated, dyskeratotic/apoptotic or ballooning/acantholytic epidermal keratinocytes; reticular degeneration of the epidermis; intraepidermal vesicles sometimes resembling herpetic vesicular infections or Grover disease; and mild dermal inflammation. There is no specific treatment.

Urticaria—Urticarial rash, or urticaria, represents 5% to 16% of skin manifestations; usually appears within 15 days of disease onset; and manifests with pruritic, migratory, edematous papules appearing mainly on the trunk and occasionally the face and limbs. The urticarial rash tends to be associated with more severe forms of the disease and regresses within a week, responding to antihistamines. Of note, clinically similar rashes can be caused by drugs. Histologically, the lesions show dermal edema and a mild perivascular lymphocytic infiltrate, sometimes admixed with eosinophils.

Chilblainlike Lesions—Chilblainlike lesions (CBLLs) account for 19% of skin manifestations associated with COVID-19¹³ and present as erythematous-purplish, edematous lesions that can be mildly pruritic or painful, appearing on the toes—COVID toes—and more rarely the fingers (Figure 2). They were seen epidemically during the first pandemic wave (2020 lockdown) in several countries, and clinically are very similar to, if not indistinguishable from, idiopathic chilblains, but are not necessarily associated with cold exposure. They appear in young, generally healthy patients or those with mild COVID-19 symptoms 2 to 4 weeks after symptom onset. They regress spontaneously or under local corticosteroid treatment within a few days or weeks. Histologically, CBLLs are indistinguishable from chilblains of other origins, namely idiopathic (seasonal) ones. They manifest with necrosis of epidermal keratinocytes; dermal edema that may be severe, leading to the development of subepidermal pseudobullae; a rather dense perivascular and perieccrine gland lymphocytic infiltrate; and sometimes with vascular lesions (eg, edema of endothelial cells, microthromboses of dermal capillaries and venules, fibrinoid deposits within the wall of dermal venules)(Figure 3).^16-18 Most patients (>80%) with CBLLs have negative serologic or polymerase chain reaction tests for SARS-CoV-2,¹⁹ which generated a lively debate about the role of SARS-CoV-2 in the genesis of CBLLs. According to some authors, SARS-CoV-2 plays no direct role, and CBLLs would occur in young people who sit or walk barefoot on cold floors at home during confinement.^20-23 Remarkably, CBLLs appeared in patients with no history of chilblains during a season that was not particularly cold, namely in France or in southern California, where their incidence was much higher compared to the same time period of prior years. Some reports have supported a direct role for the virus based on questionable observations of the virus within skin lesions (eg, sweat glands, endothelial cells) by immunohistochemistry, electron microscopy, and/or in situ hybridization.^17,24,25 A more satisfactory hypothesis would involve the role of a strong innate immunity leading to elimination of the virus before the development of specific antibodies via the increased production of type 1 interferon (IFN-1); this would affect the vessels, causing CBLLs. This mechanism would be similar to the one observed in some interferonopathies (eg, Aicardi-Goutières syndrome), also characterized by IFN-1 hypersecretion and chilblains.^26-29 According to this hypothesis, CBLLs should be considered a paraviral rash similar to other skin manifestations associated with COVID-19.³⁰

Acro-ischemia—Acro-ischemia livedoid lesions account for 1% to 6% of skin manifestations and comprise lesions of livedo (either reticulated or racemosa); necrotic acral bullae; and gangrenous necrosis of the extremities, especially the toes. The livedoid lesions most often appear within 15 days of COVID-19 symptom onset, and the purpuric lesions somewhat later (2–4 weeks); they mainly affect adult patients, last about 10 days, and are the hallmark of severe infection, presumably related to microthromboses of the cutaneous capillaries (endothelial dysfunction, prothrombotic state, elevated D-dimers). Histologically, they show capillary thrombosis and dermoepidermal necrosis (Figure 4).

Other Reported Polymorphic or Atypical Rashes—Erythema multiforme–like eruptions may appear before other COVID-19 symptoms and manifest as reddish-purple, nearly symmetric, diffuse, occasionally targetoid bullous or necrotic macules. The eruptions mainly affect adults and most often are seen on the palms, elbows, knees, and sometimes the mucous membranes. The rash regresses in 1 to 3 weeks without scarring and represents a delayed cutaneous hypersensitivity reaction. Histologically, the lesions show vacuolization of basal epidermal keratinocytes, keratinocyte necrosis, dermoepidermal detachment, a variably dense dermal T-lymphocytic infiltrate, and red blood cell extravasation (Figure 5).

Leukocytoclastic vasculitis may be generalized or localized. It manifests clinically by petechial/purpuric maculopapules, especially on the legs, mainly in elderly patients with COVID-19. Histologically, the lesions show necrotizing changes of dermal postcapillary venules, neutrophilic perivascular inflammation, red blood cell extravasation, and occasionally vascular IgA deposits by direct immunofluorescence examination. The course usually is benign.

The incidence of pityriasis rosea and of clinically similar rashes (referred to as “pityriasis rosea–like”) increased 5-fold during the COVID-19 pandemic.^31,32 These dermatoses manifest with erythematous, scaly, circinate plaques, typically with an initial herald lesion followed a few days later by smaller erythematous macules. Histologically, the lesions comprise a spongiform dermatitis with intraepidermal exocytosis of red blood cells and a mild to moderate dermal lymphocytic infiltrate.

Erythrodysesthesia, or hand-foot syndrome, manifests with edematous erythema and palmoplantar desquamation accompanied by a burning sensation or pain. This syndrome is known as an adverse effect of some chemotherapies because of the associated drug toxicity and sweat gland inflammation; it was observed in 40% of 666 COVID-19–positive patients with mild to moderate pneumonitis.³³

“COVID nose” is a rare cutaneous manifestation characterized by nasal pigmentation comprising multiple coalescent frecklelike macules on the tip and wings of the nose and sometimes the malar areas. These lesions predominantly appear in women aged 25 to 65 years and show on average 23 days after onset of COVID-19, which is usually mild. This pigmentation is similar to pigmentary changes after infection with chikungunya; it can be treated with depigmenting products such as azelaic acid and hydroquinone cream with sunscreen use, and it regresses in 2 to 4 months.³⁴

Telogen effluvium (excessive and temporary shedding of normal telogen club hairs of the entire scalp due to the disturbance of the hair cycle) is reportedly frequent in patients (48%) 1 month after COVID-19 infection, but it may appear later (after 12 weeks).³⁵ Alopecia also is frequently reported during long (or postacute) COVID-19 (ie, the symptomatic disease phase past the acute 4 weeks’ stage of the infection) and shows a female predominance³⁶; it likely represents the telogen effluvium seen 90 days after a severe illness. Trichodynia (pruritus, burning, pain, or paresthesia of the scalp) also is reportedly common (developing in more than 58% of patients) and is associated with telogen effluvium in 44% of cases. Several cases of alopecia areata (AA) triggered or aggravated by COVID-19 also have been reported^37,38; they could be explained by the “cytokine storm” triggered by the infection, involving T and B lymphocytes; plasmacytoid dendritic cells; natural killer cells with oversecretion of IL-6, IL-4, tumor necrosis factor α, and IFN type I; and a cytotoxic reaction associated with loss of the immune privilege of hair follicles.

Nail Manifestations

The red half-moon nail sign is an asymptomatic purplish-red band around the distal margin of the lunula that affects some adult patients with COVID-19.³⁹ It appears shortly after onset of symptoms, likely the manifestation of vascular inflammation in the nail bed, and regresses slowly after approximately 1 week.⁴⁰ Beau lines are transverse grooves in the nail plate due to the temporary arrest of the proximal nail matrix growth accompanying systemic illnesses; they appear approximately 2 to 3 weeks after the onset of COVID-19.⁴¹ Furthermore, nail alterations can be caused by drugs used to treat COVID-19, such as longitudinal melanonychia due to treatment with hydroxychloroquine or fluorescence of the lunula or nail plate due to treatment with favipiravir.⁴²

Multisystem Inflammatory Syndrome

Multisystem inflammatory syndrome (MIS) is clinically similar to Kawasaki disease; it typically affects children⁴³ and more rarely adults with COVID-19. It manifests with fever, weakness, and biological inflammation and also frequently with skin lesions (72%), which are polymorphous and include morbilliform rash (27%); urticaria (24%); periorbital edema (24%); nonspecific erythema (21.2%); retiform purpura (18%); targetoid lesions (15%); malar rash (15.2%); and periareolar erythema (6%).⁴⁴ Compared to Kawasaki disease, MIS affects slightly older children (mean age, 8.5 vs 3 years) and more frequently includes cardiac and gastrointestinal manifestations; the mortality rate also is slightly higher (2% vs 0.17%).⁴⁵

Confirmed COVID-19 Infection

At the beginning of the pandemic, skin manifestations were reported in patients who were suspected of having COVID-19 but did not always have biological confirmation of SARS-CoV-2 infection due to the unavailability of diagnostic tests or the physical impossibility of testing. However, subsequent studies have confirmed that most of these dermatoses were indeed associated with COVID-19 infection.^9,46 For example, a study of 655 patients with confirmed COVID-19 infection reported maculopapular (38%), vascular (22%), urticarial (15%), and vesicular (15%) rashes; erythema multiforme or Stevens-Johnson–like syndrome (3%, often related to the use of hydroxychloroquine); generalized pruritus (1%); and MIS (0.5%). The study confirmed that CBLLs were mostly seen in young patients with mild disease, whereas livedo (fixed rash) and retiform purpura occurred in older patients with a guarded prognosis.⁴⁶

Remarkably, most dermatoses associated with SARS-CoV-2 infection were reported during the initial waves of the pandemic, which were due to the α and δ viral variants. These manifestations were reported more rarely when the ο variant was predominant, even though most patients (63%) who developed CBLLs in the first wave also developed them during the second pandemic wave.⁴⁷ This decrease in the incidence of COVID-19–associated dermatoses could be because of the lower pathogenicity of the o variant,³ a lower tropism for the skin, and variations in SARS-CoV-2 antigenicity that would induce a different immunologic response, combined with an increasingly stronger herd immunity compared to the first pandemic waves achieved through vaccination and spontaneous infections in the population. Additional reasons may include different baseline characteristics in patients hospitalized with COVID-19 (regarding comorbidities, disease severity, and received treatments), and the possibility that some of the initially reported COVID-19–associated skin manifestations could have been produced by different etiologic agents.⁴⁸ In the last 2 years, COVID-19–related skin manifestations have been reported mainly as adverse events to COVID-19 vaccination.

CUTANEOUS ADVERSE EFFECTS OF DRUGS USED TO TREAT COVID-19

Prior to the advent of vaccines and specific treatments for SARS-CoV-2, various drugs were used—namely hydroxychloroquine, ivermectin, and tocilizumab—that did not prove efficacious and caused diverse adverse effects, including cutaneous eruptions such as urticaria, maculopapular eruptions, erythema multiforme or Stevens-Johnson syndrome, vasculitis, longitudinal melanonychia, and acute generalized exanthematous pustulosis.^49,50 Nirmatrelvir 150 mg–ritonavir 100 mg, which was authorized for emergency use by the US Food and Drug Administration for the treatment of COVID-19, is a viral protease inhibitor blocking the replication of the virus. Ritonavir can induce pruritus, maculopapular rash, acne, Stevens-Johnson syndrome, and toxic epidermal necrolysis; of note, these effects have been observed following administration of ritonavir for treatment of HIV at higher daily doses and for much longer periods of time compared with treatment of COVID-19 (600–1200 mg vs 200 mg/d, respectively). These cutaneous drug side effects are clinically similar to the manifestations caused either directly or indirectly by SARS-CoV-2 infection; therefore, it may be difficult to differentiate them.

DERMATOSES DUE TO PROTECTIVE DEVICES

Dermatoses due to personal protective equipment such as masks or face shields affected the general population and mostly health care professionals⁵¹; 54.4% of 879 health care professionals in one study reported such events.⁵² These dermatoses mainly include contact dermatitis of the face (nose, forehead, and cheeks) of irritant or allergic nature (eg, from preservatives releasing formaldehyde contained in masks and protective goggles). They manifest with skin dryness; desquamation; maceration; fissures; or erosions or ulcerations of the cheeks, forehead, and nose. Cases of pressure urticaria also have been reported. Irritant dermatitis induced by the frequent use of disinfectants (eg, soaps, hydroalcoholic sanitizing gels) also can affect the hands. Allergic hand dermatitis can be caused by medical gloves.

The term maskne (or mask acne) refers to a variety of mechanical acne due to the prolonged use of surgical masks (>4 hours per day for ≥6 weeks); it includes cases of de novo acne and cases of pre-existing acne aggravated by wearing a mask. Maskne is characterized by acne lesions located on the facial area covered by the mask (Figure 6). It is caused by follicular occlusion; increased sebum secretion; mechanical stress (pressure, friction); and dysbiosis of the microbiome induced by changes in heat, pH, and humidity. Preventive measures include application of noncomedogenic moisturizers or gauze before wearing the mask as well as facial cleansing with appropriate nonalcoholic products. Similar to acne, rosacea often is aggravated by prolonged wearing of surgical masks (mask rosacea).^53,54

DERMATOSES REVEALED OR AGGRAVATED BY COVID-19

Exacerbation of various skin diseases has been reported after infection with SARS-CoV-2.⁵⁵ Psoriasis and acrodermatitis continua of Hallopeau,⁵⁶ which may progress into generalized, pustular, or erythrodermic forms,⁵⁷ have been reported; the role of hydroxychloroquine and oral corticosteroids used for the treatment of COVID-19 has been suspected.⁵⁷ Atopic dermatitis patients—26% to 43%—have experienced worsening of their disease after symptomatic COVID-19 infection.⁵⁸ The incidence of herpesvirus infections, including herpes zoster, increased during the pandemic.⁵⁹ Alopecia areata relapses occurred in 42.5% of 392 patients with preexisting disease within 2 months of COVID-19 onset in one study,⁶⁰ possibly favored by the psychological stress; however, some studies have not confirmed the aggravating role of COVID-19 on alopecia areata.⁶¹ Lupus erythematosus, which may relapse in the form of Rowell syndrome,⁶² and livedoid vasculopathy⁶³ also have been reported following COVID-19 infection.

SKIN MANIFESTATIONS ASSOCIATED WITH COVID-19 VACCINES

In parallel with the rapid spread of COVID-19 vaccination,⁴ an increasing number of skin manifestations has been observed following vaccination; these dermatoses now are more frequently reported than those related to natural SARS-CoV-2 infection.^64-70 Vaccine-induced skin manifestations have a reported incidence of approximately 4% and show a female predominance.⁶⁵ Most of them (79%) have been reported in association with messenger RNA (mRNA)–based vaccines, which have been the most widely used; however, the frequency of side effects would be lower after mRNA vaccines than after inactivated virus-based vaccines. Eighteen percent occurred after the adenoviral vector vaccine, and 3% after the inactivated virus vaccine.⁷⁰ Fifty-nine percent were observed after the first dose. They are clinically polymorphous and generally benign, regressing spontaneously after a few days, and they should not constitute a contraindication to vaccination.Interestingly, many skin manifestations are similar to those associated with natural SARS-CoV-2 infection; however, their frequency and severity does not seem to depend on whether the patients had developed skin reactions during prior SARS-CoV-2 infection. These reactions have been classified into several types:

• Immediate local reactions at the injection site: pain, erythema, or edema represent the vast majority (96%) of reactions to vaccines. They appear within 7 days after vaccination (average, 1 day), slightly more frequently (59%) after the first dose. They concern mostly young patients and are benign, regressing in 2 to 3 days.⁷⁰
 

• Delayed local reactions: characterized by pain or pruritus, erythema, and skin induration mimicking cellulitis (COVID arm) and represent 1.7% of postvaccination reactions. They correspond to a delayed hypersensitivity reaction and appear approximately 7 days after vaccination, most often after the first vaccine dose (75% of cases), which is almost invariably mRNA based.⁷⁰

• Urticarial reactions corresponding to an immediate (type 1) hypersensitivity reaction: constitute 1% of postvaccination reactions, probably due to an allergy to vaccine ingredients. They appear on average 1 day after vaccination, almost always with mRNA vaccines.⁷⁰

• Angioedema: characterized by mucosal or subcutaneous edema and constitutes 0.5% of postvaccination reactions. It is a potentially serious reaction that appears on average 12 hours after vaccination, always with an mRNA-based vaccine.⁷⁰

• Morbilliform rash: represents delayed hypersensitivity reactions (0.1% of postvaccination reactions) that appear mostly after the first dose (72%), on average 3 days after vaccination, always with an mRNA-based vaccine.⁷⁰

• Herpes zoster: usually develops after the first vaccine dose in elderly patients (69% of cases) on average 4 days after vaccination and constitutes 0.1% of postvaccination reactions.⁷¹

• Bullous diseases: mainly bullous pemphigoid (90%) and more rarely pemphigus (5%) or bullous erythema pigmentosum (5%). They appear in elderly patients on average 7 days after vaccination and constitute 0.04% of postvaccination reactions.⁷²

• Chilblainlike lesions: several such cases have been reported so far⁷³; they constitute 0.03% of postvaccination reactions.⁷⁰ Clinically, they are similar to those associated with natural COVID-19; they appear mostly after the first dose (64%), on average 5 days after vaccination with the mRNA or adenovirus vaccine, and show a female predominance. The appearance of these lesions in vaccinated patients, who are a priori not carriers of the virus, strongly suggests that CBLLs are due to the immune reaction against SARS-CoV-2 rather than to a direct effect of this virus on the skin, which also is a likely scenario with regards to other skin manifestations seen during the successive COVID-19 epidemic waves.^73-75

• Reactions to hyaluronic acid–containing cosmetic fillers: erythema, edema, and potentially painful induration at the filler injection sites. They constitute 0.04% of postvaccination skin reactions and appear 24 hours after vaccination with mRNA-based vaccines, equally after the first or second dose.⁷⁶

• Pityriasis rosea–like rash: most occur after the second dose of mRNA-based vaccines (0.023% of postvaccination skin reactions).⁷⁰

• Severe reactions: these include acute generalized exanthematous pustulosis⁷⁷ and Stevens-Johnson syndrome.⁷⁸ One case of each has been reported after the adenoviral vector vaccine 3 days after vaccination.

Other more rarely observed manifestations include reactivation/aggravation or de novo appearance of inflammatory dermatoses such as psoriasis,^79,80 leukocytoclastic vasculitis,^81,82 lymphocytic⁸³ or urticarial⁸⁴ vasculitis, Sweet syndrome,⁸⁵ lupus erythematosus, dermatomyositis,^86,87 alopecia,^37,88 infection with Trichophyton rubrum,⁸⁹ Grover disease,⁹⁰ and lymphomatoid reactions (such as recurrences of cutaneous T-cell lymphomas [CD30⁺], and de novo development of lymphomatoid papulosis).⁹¹

FINAL THOUGHTS

COVID-19 is associated with several skin manifestations, even though the causative role of SARS-CoV-2 has remained elusive. These dermatoses are highly polymorphous, mostly benign, and usually spontaneously regressive, but some of them reflect severe infection. They mostly were described during the first pandemic waves, reported in several national and international registries, which allowed for their morphological classification. Currently, cutaneous adverse effects of vaccines are the most frequently reported dermatoses associated with SARS-CoV-2, and it is likely that they will continue to be observed while COVID-19 vaccination lasts. Hopefully the end of the COVID-19 pandemic is near. In January 2023, the International Health Regulations Emergency Committee of the World Health Organization acknowledged that the COVID-19 pandemic may be approaching an inflexion point, and even though the event continues to constitute a public health emergency of international concern, the higher levels of population immunity achieved globally through infection and/or vaccination may limit the impact of SARS-CoV-2 on morbidity and mortality. However, there is little doubt that this virus will remain a permanently established pathogen in humans and animals for the foreseeable future.⁹² Therefore, physicians—especially dermatologists—should be aware of the various skin manifestations associated with COVID-19 so they can more efficiently manage their patients.

COVID-19 is a potentially severe systemic disease caused by SARS-CoV-2. SARS-CoV and Middle East respiratory syndrome (MERS-CoV) caused fatal epidemics in Asia in 2002 to 2003 and in the Arabian Peninsula in 2012, respectively. In 2019, SARS-CoV-2 was detected in patients with severe, sometimes fatal pneumonia of previously unknown origin; it rapidly spread around the world, and the World Health Organization declared the disease a pandemic on March 11, 2020. SARS-CoV-2 is a β-coronavirus that is genetically related to the bat coronavirus and SARS-CoV; it is a single-stranded RNA virus of which several variants and subvariants exist. The SARS-CoV-2 viral particles bind via their surface spike protein (S protein) to the angiotensin-converting enzyme 2 receptor present on the membrane of several cell types, including epidermal and adnexal keratinocytes.^1,2 The α and δ variants, predominant from 2020 to 2021, mainly affected the lower respiratory tract and caused severe, potentially fatal pneumonia, especially in patients older than 65 years and/or with comorbidities, such as obesity, hypertension, diabetes, and (iatrogenic) immunosuppression. The ο variant, which appeared in late 2021, is more contagious than the initial variants, but it causes a less severe disease preferentially affecting the upper respiratory airways.³ As of April 5, 2023, more than 762,000,000 confirmed cases of COVID-19 have been recorded worldwide, causing more than 6,800,000 deaths.⁴

Early studies from China describing the symptoms of COVID-19 reported a low frequency of skin manifestations (0.2%), probably because they were focused on the most severe disease symptoms.⁵ Subsequently, when COVID-19 spread to the rest of the world, an increasing number of skin manifestations were reported in association with the disease. After the first publication from northern Italy in spring 2020, which was specifically devoted to skin manifestations of COVID-19,⁶ an explosive number of publications reported a large number of skin manifestations, and national registries were established in several countries to record these manifestations, such as the American Academy of Dermatology and the International League of Dermatological Societies registry,^7,8 the COVIDSKIN registry of the French Dermatology Society,⁹ and the Italian registry.¹⁰ Highlighting the unprecedented number of scientific articles published on this new disease, a PubMed search of articles indexed for MEDLINE search using the terms SARS-CoV-2 or COVID-19, on April 6, 2023, revealed 351,596 articles; that is more than 300 articles published every day in this database alone, with a large number of them concerning the skin.

SKIN DISEASSES ASSOCIATED WITH COVID-19

There are several types of COVID-19–related skin manifestations, depending on the circumstances of onset and the evolution of the pandemic.

Skin Manifestations Associated With SARS-CoV-2 Infection

The estimated incidence varies greatly according to the published series of patients, possibly depending on the geographic location. The estimated incidence seems lower in Asian countries, such as China (0.2%)⁵ and Japan (0.56%),¹¹ compared with Europe (up to 20%).⁶ Skin manifestations associated with SARS-CoV-2 infection affect individuals of all ages, slightly more females, and are clinically polymorphous; some of them are associated with the severity of the infection.¹² They may precede, accompany, or appear after the symptoms of COVID-19, most often within a month of the infection, of which they rarely are the only manifestation; however, their precise relationship to SARS-CoV-2 is not always well known. They have been classified according to their clinical presentation into several forms.^13-15

Morbilliform Maculopapular Eruption—Representing 16% to 53% of skin manifestations, morbilliform and maculopapular eruptions usually appear within 15 days of infection; they manifest with more or less confluent erythematous macules that may be hemorrhagic/petechial, and usually are asymptomatic and rarely pruritic. The rash mainly affects the trunk and limbs, sparing the face, palmoplantar regions, and mucous membranes; it appears concomitantly with or a few days after the first symptoms of COVID-19 (eg, fever, respiratory symptoms), regresses within a few days, and does not appear to be associated with disease severity. The distinction from maculopapular drug eruptions may be subtle. Histologically, the rash manifests with a spongiform dermatitis (ie, variable parakeratosis; spongiosis; and a mixed dermal perivascular infiltrate of lymphocytes, eosinophils and histiocytes, depending on the lesion age)(Figure 1). The etiopathogenesis is unknown; it may involve immune complexes to SARS-CoV-2 deposited on skin vessels. Treatment is not mandatory; if necessary, local or systemic corticosteroids may be used.

Vesicular (Pseudovaricella) Rash—This rash accounts for 11% to 18% of all skin manifestations and usually appears within 15 days of COVID-19 onset. It manifests with small monomorphous or varicellalike (pseudopolymorphic) vesicles appearing on the trunk, usually in young patients. The vesicles may be herpetiform, hemorrhagic, or pruritic, and appear before or within 3 days of the onset of mild COVID-19 symptoms; they regress within a few days without scarring. Histologically, the lesions show basal cell vacuolization; multinucleated, dyskeratotic/apoptotic or ballooning/acantholytic epidermal keratinocytes; reticular degeneration of the epidermis; intraepidermal vesicles sometimes resembling herpetic vesicular infections or Grover disease; and mild dermal inflammation. There is no specific treatment.

Urticaria—Urticarial rash, or urticaria, represents 5% to 16% of skin manifestations; usually appears within 15 days of disease onset; and manifests with pruritic, migratory, edematous papules appearing mainly on the trunk and occasionally the face and limbs. The urticarial rash tends to be associated with more severe forms of the disease and regresses within a week, responding to antihistamines. Of note, clinically similar rashes can be caused by drugs. Histologically, the lesions show dermal edema and a mild perivascular lymphocytic infiltrate, sometimes admixed with eosinophils.

Chilblainlike Lesions—Chilblainlike lesions (CBLLs) account for 19% of skin manifestations associated with COVID-19¹³ and present as erythematous-purplish, edematous lesions that can be mildly pruritic or painful, appearing on the toes—COVID toes—and more rarely the fingers (Figure 2). They were seen epidemically during the first pandemic wave (2020 lockdown) in several countries, and clinically are very similar to, if not indistinguishable from, idiopathic chilblains, but are not necessarily associated with cold exposure. They appear in young, generally healthy patients or those with mild COVID-19 symptoms 2 to 4 weeks after symptom onset. They regress spontaneously or under local corticosteroid treatment within a few days or weeks. Histologically, CBLLs are indistinguishable from chilblains of other origins, namely idiopathic (seasonal) ones. They manifest with necrosis of epidermal keratinocytes; dermal edema that may be severe, leading to the development of subepidermal pseudobullae; a rather dense perivascular and perieccrine gland lymphocytic infiltrate; and sometimes with vascular lesions (eg, edema of endothelial cells, microthromboses of dermal capillaries and venules, fibrinoid deposits within the wall of dermal venules)(Figure 3).^16-18 Most patients (>80%) with CBLLs have negative serologic or polymerase chain reaction tests for SARS-CoV-2,¹⁹ which generated a lively debate about the role of SARS-CoV-2 in the genesis of CBLLs. According to some authors, SARS-CoV-2 plays no direct role, and CBLLs would occur in young people who sit or walk barefoot on cold floors at home during confinement.^20-23 Remarkably, CBLLs appeared in patients with no history of chilblains during a season that was not particularly cold, namely in France or in southern California, where their incidence was much higher compared to the same time period of prior years. Some reports have supported a direct role for the virus based on questionable observations of the virus within skin lesions (eg, sweat glands, endothelial cells) by immunohistochemistry, electron microscopy, and/or in situ hybridization.^17,24,25 A more satisfactory hypothesis would involve the role of a strong innate immunity leading to elimination of the virus before the development of specific antibodies via the increased production of type 1 interferon (IFN-1); this would affect the vessels, causing CBLLs. This mechanism would be similar to the one observed in some interferonopathies (eg, Aicardi-Goutières syndrome), also characterized by IFN-1 hypersecretion and chilblains.^26-29 According to this hypothesis, CBLLs should be considered a paraviral rash similar to other skin manifestations associated with COVID-19.³⁰

Acro-ischemia—Acro-ischemia livedoid lesions account for 1% to 6% of skin manifestations and comprise lesions of livedo (either reticulated or racemosa); necrotic acral bullae; and gangrenous necrosis of the extremities, especially the toes. The livedoid lesions most often appear within 15 days of COVID-19 symptom onset, and the purpuric lesions somewhat later (2–4 weeks); they mainly affect adult patients, last about 10 days, and are the hallmark of severe infection, presumably related to microthromboses of the cutaneous capillaries (endothelial dysfunction, prothrombotic state, elevated D-dimers). Histologically, they show capillary thrombosis and dermoepidermal necrosis (Figure 4).

Other Reported Polymorphic or Atypical Rashes—Erythema multiforme–like eruptions may appear before other COVID-19 symptoms and manifest as reddish-purple, nearly symmetric, diffuse, occasionally targetoid bullous or necrotic macules. The eruptions mainly affect adults and most often are seen on the palms, elbows, knees, and sometimes the mucous membranes. The rash regresses in 1 to 3 weeks without scarring and represents a delayed cutaneous hypersensitivity reaction. Histologically, the lesions show vacuolization of basal epidermal keratinocytes, keratinocyte necrosis, dermoepidermal detachment, a variably dense dermal T-lymphocytic infiltrate, and red blood cell extravasation (Figure 5).

Leukocytoclastic vasculitis may be generalized or localized. It manifests clinically by petechial/purpuric maculopapules, especially on the legs, mainly in elderly patients with COVID-19. Histologically, the lesions show necrotizing changes of dermal postcapillary venules, neutrophilic perivascular inflammation, red blood cell extravasation, and occasionally vascular IgA deposits by direct immunofluorescence examination. The course usually is benign.

The incidence of pityriasis rosea and of clinically similar rashes (referred to as “pityriasis rosea–like”) increased 5-fold during the COVID-19 pandemic.^31,32 These dermatoses manifest with erythematous, scaly, circinate plaques, typically with an initial herald lesion followed a few days later by smaller erythematous macules. Histologically, the lesions comprise a spongiform dermatitis with intraepidermal exocytosis of red blood cells and a mild to moderate dermal lymphocytic infiltrate.

Erythrodysesthesia, or hand-foot syndrome, manifests with edematous erythema and palmoplantar desquamation accompanied by a burning sensation or pain. This syndrome is known as an adverse effect of some chemotherapies because of the associated drug toxicity and sweat gland inflammation; it was observed in 40% of 666 COVID-19–positive patients with mild to moderate pneumonitis.³³

“COVID nose” is a rare cutaneous manifestation characterized by nasal pigmentation comprising multiple coalescent frecklelike macules on the tip and wings of the nose and sometimes the malar areas. These lesions predominantly appear in women aged 25 to 65 years and show on average 23 days after onset of COVID-19, which is usually mild. This pigmentation is similar to pigmentary changes after infection with chikungunya; it can be treated with depigmenting products such as azelaic acid and hydroquinone cream with sunscreen use, and it regresses in 2 to 4 months.³⁴

Telogen effluvium (excessive and temporary shedding of normal telogen club hairs of the entire scalp due to the disturbance of the hair cycle) is reportedly frequent in patients (48%) 1 month after COVID-19 infection, but it may appear later (after 12 weeks).³⁵ Alopecia also is frequently reported during long (or postacute) COVID-19 (ie, the symptomatic disease phase past the acute 4 weeks’ stage of the infection) and shows a female predominance³⁶; it likely represents the telogen effluvium seen 90 days after a severe illness. Trichodynia (pruritus, burning, pain, or paresthesia of the scalp) also is reportedly common (developing in more than 58% of patients) and is associated with telogen effluvium in 44% of cases. Several cases of alopecia areata (AA) triggered or aggravated by COVID-19 also have been reported^37,38; they could be explained by the “cytokine storm” triggered by the infection, involving T and B lymphocytes; plasmacytoid dendritic cells; natural killer cells with oversecretion of IL-6, IL-4, tumor necrosis factor α, and IFN type I; and a cytotoxic reaction associated with loss of the immune privilege of hair follicles.

Nail Manifestations

The red half-moon nail sign is an asymptomatic purplish-red band around the distal margin of the lunula that affects some adult patients with COVID-19.³⁹ It appears shortly after onset of symptoms, likely the manifestation of vascular inflammation in the nail bed, and regresses slowly after approximately 1 week.⁴⁰ Beau lines are transverse grooves in the nail plate due to the temporary arrest of the proximal nail matrix growth accompanying systemic illnesses; they appear approximately 2 to 3 weeks after the onset of COVID-19.⁴¹ Furthermore, nail alterations can be caused by drugs used to treat COVID-19, such as longitudinal melanonychia due to treatment with hydroxychloroquine or fluorescence of the lunula or nail plate due to treatment with favipiravir.⁴²

Multisystem Inflammatory Syndrome

Multisystem inflammatory syndrome (MIS) is clinically similar to Kawasaki disease; it typically affects children⁴³ and more rarely adults with COVID-19. It manifests with fever, weakness, and biological inflammation and also frequently with skin lesions (72%), which are polymorphous and include morbilliform rash (27%); urticaria (24%); periorbital edema (24%); nonspecific erythema (21.2%); retiform purpura (18%); targetoid lesions (15%); malar rash (15.2%); and periareolar erythema (6%).⁴⁴ Compared to Kawasaki disease, MIS affects slightly older children (mean age, 8.5 vs 3 years) and more frequently includes cardiac and gastrointestinal manifestations; the mortality rate also is slightly higher (2% vs 0.17%).⁴⁵

Confirmed COVID-19 Infection

At the beginning of the pandemic, skin manifestations were reported in patients who were suspected of having COVID-19 but did not always have biological confirmation of SARS-CoV-2 infection due to the unavailability of diagnostic tests or the physical impossibility of testing. However, subsequent studies have confirmed that most of these dermatoses were indeed associated with COVID-19 infection.^9,46 For example, a study of 655 patients with confirmed COVID-19 infection reported maculopapular (38%), vascular (22%), urticarial (15%), and vesicular (15%) rashes; erythema multiforme or Stevens-Johnson–like syndrome (3%, often related to the use of hydroxychloroquine); generalized pruritus (1%); and MIS (0.5%). The study confirmed that CBLLs were mostly seen in young patients with mild disease, whereas livedo (fixed rash) and retiform purpura occurred in older patients with a guarded prognosis.⁴⁶

Remarkably, most dermatoses associated with SARS-CoV-2 infection were reported during the initial waves of the pandemic, which were due to the α and δ viral variants. These manifestations were reported more rarely when the ο variant was predominant, even though most patients (63%) who developed CBLLs in the first wave also developed them during the second pandemic wave.⁴⁷ This decrease in the incidence of COVID-19–associated dermatoses could be because of the lower pathogenicity of the o variant,³ a lower tropism for the skin, and variations in SARS-CoV-2 antigenicity that would induce a different immunologic response, combined with an increasingly stronger herd immunity compared to the first pandemic waves achieved through vaccination and spontaneous infections in the population. Additional reasons may include different baseline characteristics in patients hospitalized with COVID-19 (regarding comorbidities, disease severity, and received treatments), and the possibility that some of the initially reported COVID-19–associated skin manifestations could have been produced by different etiologic agents.⁴⁸ In the last 2 years, COVID-19–related skin manifestations have been reported mainly as adverse events to COVID-19 vaccination.

CUTANEOUS ADVERSE EFFECTS OF DRUGS USED TO TREAT COVID-19

Prior to the advent of vaccines and specific treatments for SARS-CoV-2, various drugs were used—namely hydroxychloroquine, ivermectin, and tocilizumab—that did not prove efficacious and caused diverse adverse effects, including cutaneous eruptions such as urticaria, maculopapular eruptions, erythema multiforme or Stevens-Johnson syndrome, vasculitis, longitudinal melanonychia, and acute generalized exanthematous pustulosis.^49,50 Nirmatrelvir 150 mg–ritonavir 100 mg, which was authorized for emergency use by the US Food and Drug Administration for the treatment of COVID-19, is a viral protease inhibitor blocking the replication of the virus. Ritonavir can induce pruritus, maculopapular rash, acne, Stevens-Johnson syndrome, and toxic epidermal necrolysis; of note, these effects have been observed following administration of ritonavir for treatment of HIV at higher daily doses and for much longer periods of time compared with treatment of COVID-19 (600–1200 mg vs 200 mg/d, respectively). These cutaneous drug side effects are clinically similar to the manifestations caused either directly or indirectly by SARS-CoV-2 infection; therefore, it may be difficult to differentiate them.

DERMATOSES DUE TO PROTECTIVE DEVICES

Dermatoses due to personal protective equipment such as masks or face shields affected the general population and mostly health care professionals⁵¹; 54.4% of 879 health care professionals in one study reported such events.⁵² These dermatoses mainly include contact dermatitis of the face (nose, forehead, and cheeks) of irritant or allergic nature (eg, from preservatives releasing formaldehyde contained in masks and protective goggles). They manifest with skin dryness; desquamation; maceration; fissures; or erosions or ulcerations of the cheeks, forehead, and nose. Cases of pressure urticaria also have been reported. Irritant dermatitis induced by the frequent use of disinfectants (eg, soaps, hydroalcoholic sanitizing gels) also can affect the hands. Allergic hand dermatitis can be caused by medical gloves.

The term maskne (or mask acne) refers to a variety of mechanical acne due to the prolonged use of surgical masks (>4 hours per day for ≥6 weeks); it includes cases of de novo acne and cases of pre-existing acne aggravated by wearing a mask. Maskne is characterized by acne lesions located on the facial area covered by the mask (Figure 6). It is caused by follicular occlusion; increased sebum secretion; mechanical stress (pressure, friction); and dysbiosis of the microbiome induced by changes in heat, pH, and humidity. Preventive measures include application of noncomedogenic moisturizers or gauze before wearing the mask as well as facial cleansing with appropriate nonalcoholic products. Similar to acne, rosacea often is aggravated by prolonged wearing of surgical masks (mask rosacea).^53,54

DERMATOSES REVEALED OR AGGRAVATED BY COVID-19

Exacerbation of various skin diseases has been reported after infection with SARS-CoV-2.⁵⁵ Psoriasis and acrodermatitis continua of Hallopeau,⁵⁶ which may progress into generalized, pustular, or erythrodermic forms,⁵⁷ have been reported; the role of hydroxychloroquine and oral corticosteroids used for the treatment of COVID-19 has been suspected.⁵⁷ Atopic dermatitis patients—26% to 43%—have experienced worsening of their disease after symptomatic COVID-19 infection.⁵⁸ The incidence of herpesvirus infections, including herpes zoster, increased during the pandemic.⁵⁹ Alopecia areata relapses occurred in 42.5% of 392 patients with preexisting disease within 2 months of COVID-19 onset in one study,⁶⁰ possibly favored by the psychological stress; however, some studies have not confirmed the aggravating role of COVID-19 on alopecia areata.⁶¹ Lupus erythematosus, which may relapse in the form of Rowell syndrome,⁶² and livedoid vasculopathy⁶³ also have been reported following COVID-19 infection.

SKIN MANIFESTATIONS ASSOCIATED WITH COVID-19 VACCINES

In parallel with the rapid spread of COVID-19 vaccination,⁴ an increasing number of skin manifestations has been observed following vaccination; these dermatoses now are more frequently reported than those related to natural SARS-CoV-2 infection.^64-70 Vaccine-induced skin manifestations have a reported incidence of approximately 4% and show a female predominance.⁶⁵ Most of them (79%) have been reported in association with messenger RNA (mRNA)–based vaccines, which have been the most widely used; however, the frequency of side effects would be lower after mRNA vaccines than after inactivated virus-based vaccines. Eighteen percent occurred after the adenoviral vector vaccine, and 3% after the inactivated virus vaccine.⁷⁰ Fifty-nine percent were observed after the first dose. They are clinically polymorphous and generally benign, regressing spontaneously after a few days, and they should not constitute a contraindication to vaccination.Interestingly, many skin manifestations are similar to those associated with natural SARS-CoV-2 infection; however, their frequency and severity does not seem to depend on whether the patients had developed skin reactions during prior SARS-CoV-2 infection. These reactions have been classified into several types:

• Immediate local reactions at the injection site: pain, erythema, or edema represent the vast majority (96%) of reactions to vaccines. They appear within 7 days after vaccination (average, 1 day), slightly more frequently (59%) after the first dose. They concern mostly young patients and are benign, regressing in 2 to 3 days.⁷⁰
 

• Delayed local reactions: characterized by pain or pruritus, erythema, and skin induration mimicking cellulitis (COVID arm) and represent 1.7% of postvaccination reactions. They correspond to a delayed hypersensitivity reaction and appear approximately 7 days after vaccination, most often after the first vaccine dose (75% of cases), which is almost invariably mRNA based.⁷⁰

• Urticarial reactions corresponding to an immediate (type 1) hypersensitivity reaction: constitute 1% of postvaccination reactions, probably due to an allergy to vaccine ingredients. They appear on average 1 day after vaccination, almost always with mRNA vaccines.⁷⁰

• Angioedema: characterized by mucosal or subcutaneous edema and constitutes 0.5% of postvaccination reactions. It is a potentially serious reaction that appears on average 12 hours after vaccination, always with an mRNA-based vaccine.⁷⁰

• Morbilliform rash: represents delayed hypersensitivity reactions (0.1% of postvaccination reactions) that appear mostly after the first dose (72%), on average 3 days after vaccination, always with an mRNA-based vaccine.⁷⁰

• Herpes zoster: usually develops after the first vaccine dose in elderly patients (69% of cases) on average 4 days after vaccination and constitutes 0.1% of postvaccination reactions.⁷¹

• Bullous diseases: mainly bullous pemphigoid (90%) and more rarely pemphigus (5%) or bullous erythema pigmentosum (5%). They appear in elderly patients on average 7 days after vaccination and constitute 0.04% of postvaccination reactions.⁷²

• Chilblainlike lesions: several such cases have been reported so far⁷³; they constitute 0.03% of postvaccination reactions.⁷⁰ Clinically, they are similar to those associated with natural COVID-19; they appear mostly after the first dose (64%), on average 5 days after vaccination with the mRNA or adenovirus vaccine, and show a female predominance. The appearance of these lesions in vaccinated patients, who are a priori not carriers of the virus, strongly suggests that CBLLs are due to the immune reaction against SARS-CoV-2 rather than to a direct effect of this virus on the skin, which also is a likely scenario with regards to other skin manifestations seen during the successive COVID-19 epidemic waves.^73-75

• Reactions to hyaluronic acid–containing cosmetic fillers: erythema, edema, and potentially painful induration at the filler injection sites. They constitute 0.04% of postvaccination skin reactions and appear 24 hours after vaccination with mRNA-based vaccines, equally after the first or second dose.⁷⁶

• Pityriasis rosea–like rash: most occur after the second dose of mRNA-based vaccines (0.023% of postvaccination skin reactions).⁷⁰

• Severe reactions: these include acute generalized exanthematous pustulosis⁷⁷ and Stevens-Johnson syndrome.⁷⁸ One case of each has been reported after the adenoviral vector vaccine 3 days after vaccination.

Other more rarely observed manifestations include reactivation/aggravation or de novo appearance of inflammatory dermatoses such as psoriasis,^79,80 leukocytoclastic vasculitis,^81,82 lymphocytic⁸³ or urticarial⁸⁴ vasculitis, Sweet syndrome,⁸⁵ lupus erythematosus, dermatomyositis,^86,87 alopecia,^37,88 infection with Trichophyton rubrum,⁸⁹ Grover disease,⁹⁰ and lymphomatoid reactions (such as recurrences of cutaneous T-cell lymphomas [CD30⁺], and de novo development of lymphomatoid papulosis).⁹¹

FINAL THOUGHTS

COVID-19 is associated with several skin manifestations, even though the causative role of SARS-CoV-2 has remained elusive. These dermatoses are highly polymorphous, mostly benign, and usually spontaneously regressive, but some of them reflect severe infection. They mostly were described during the first pandemic waves, reported in several national and international registries, which allowed for their morphological classification. Currently, cutaneous adverse effects of vaccines are the most frequently reported dermatoses associated with SARS-CoV-2, and it is likely that they will continue to be observed while COVID-19 vaccination lasts. Hopefully the end of the COVID-19 pandemic is near. In January 2023, the International Health Regulations Emergency Committee of the World Health Organization acknowledged that the COVID-19 pandemic may be approaching an inflexion point, and even though the event continues to constitute a public health emergency of international concern, the higher levels of population immunity achieved globally through infection and/or vaccination may limit the impact of SARS-CoV-2 on morbidity and mortality. However, there is little doubt that this virus will remain a permanently established pathogen in humans and animals for the foreseeable future.⁹² Therefore, physicians—especially dermatologists—should be aware of the various skin manifestations associated with COVID-19 so they can more efficiently manage their patients.

COVID-19 is a potentially severe systemic disease caused by SARS-CoV-2. SARS-CoV and Middle East respiratory syndrome (MERS-CoV) caused fatal epidemics in Asia in 2002 to 2003 and in the Arabian Peninsula in 2012, respectively. In 2019, SARS-CoV-2 was detected in patients with severe, sometimes fatal pneumonia of previously unknown origin; it rapidly spread around the world, and the World Health Organization declared the disease a pandemic on March 11, 2020. SARS-CoV-2 is a β-coronavirus that is genetically related to the bat coronavirus and SARS-CoV; it is a single-stranded RNA virus of which several variants and subvariants exist. The SARS-CoV-2 viral particles bind via their surface spike protein (S protein) to the angiotensin-converting enzyme 2 receptor present on the membrane of several cell types, including epidermal and adnexal keratinocytes.^1,2 The α and δ variants, predominant from 2020 to 2021, mainly affected the lower respiratory tract and caused severe, potentially fatal pneumonia, especially in patients older than 65 years and/or with comorbidities, such as obesity, hypertension, diabetes, and (iatrogenic) immunosuppression. The ο variant, which appeared in late 2021, is more contagious than the initial variants, but it causes a less severe disease preferentially affecting the upper respiratory airways.³ As of April 5, 2023, more than 762,000,000 confirmed cases of COVID-19 have been recorded worldwide, causing more than 6,800,000 deaths.⁴

Early studies from China describing the symptoms of COVID-19 reported a low frequency of skin manifestations (0.2%), probably because they were focused on the most severe disease symptoms.⁵ Subsequently, when COVID-19 spread to the rest of the world, an increasing number of skin manifestations were reported in association with the disease. After the first publication from northern Italy in spring 2020, which was specifically devoted to skin manifestations of COVID-19,⁶ an explosive number of publications reported a large number of skin manifestations, and national registries were established in several countries to record these manifestations, such as the American Academy of Dermatology and the International League of Dermatological Societies registry,^7,8 the COVIDSKIN registry of the French Dermatology Society,⁹ and the Italian registry.¹⁰ Highlighting the unprecedented number of scientific articles published on this new disease, a PubMed search of articles indexed for MEDLINE search using the terms SARS-CoV-2 or COVID-19, on April 6, 2023, revealed 351,596 articles; that is more than 300 articles published every day in this database alone, with a large number of them concerning the skin.

SKIN DISEASSES ASSOCIATED WITH COVID-19

There are several types of COVID-19–related skin manifestations, depending on the circumstances of onset and the evolution of the pandemic.

Skin Manifestations Associated With SARS-CoV-2 Infection

The estimated incidence varies greatly according to the published series of patients, possibly depending on the geographic location. The estimated incidence seems lower in Asian countries, such as China (0.2%)⁵ and Japan (0.56%),¹¹ compared with Europe (up to 20%).⁶ Skin manifestations associated with SARS-CoV-2 infection affect individuals of all ages, slightly more females, and are clinically polymorphous; some of them are associated with the severity of the infection.¹² They may precede, accompany, or appear after the symptoms of COVID-19, most often within a month of the infection, of which they rarely are the only manifestation; however, their precise relationship to SARS-CoV-2 is not always well known. They have been classified according to their clinical presentation into several forms.^13-15

Morbilliform Maculopapular Eruption—Representing 16% to 53% of skin manifestations, morbilliform and maculopapular eruptions usually appear within 15 days of infection; they manifest with more or less confluent erythematous macules that may be hemorrhagic/petechial, and usually are asymptomatic and rarely pruritic. The rash mainly affects the trunk and limbs, sparing the face, palmoplantar regions, and mucous membranes; it appears concomitantly with or a few days after the first symptoms of COVID-19 (eg, fever, respiratory symptoms), regresses within a few days, and does not appear to be associated with disease severity. The distinction from maculopapular drug eruptions may be subtle. Histologically, the rash manifests with a spongiform dermatitis (ie, variable parakeratosis; spongiosis; and a mixed dermal perivascular infiltrate of lymphocytes, eosinophils and histiocytes, depending on the lesion age)(Figure 1). The etiopathogenesis is unknown; it may involve immune complexes to SARS-CoV-2 deposited on skin vessels. Treatment is not mandatory; if necessary, local or systemic corticosteroids may be used.

Vesicular (Pseudovaricella) Rash—This rash accounts for 11% to 18% of all skin manifestations and usually appears within 15 days of COVID-19 onset. It manifests with small monomorphous or varicellalike (pseudopolymorphic) vesicles appearing on the trunk, usually in young patients. The vesicles may be herpetiform, hemorrhagic, or pruritic, and appear before or within 3 days of the onset of mild COVID-19 symptoms; they regress within a few days without scarring. Histologically, the lesions show basal cell vacuolization; multinucleated, dyskeratotic/apoptotic or ballooning/acantholytic epidermal keratinocytes; reticular degeneration of the epidermis; intraepidermal vesicles sometimes resembling herpetic vesicular infections or Grover disease; and mild dermal inflammation. There is no specific treatment.

Urticaria—Urticarial rash, or urticaria, represents 5% to 16% of skin manifestations; usually appears within 15 days of disease onset; and manifests with pruritic, migratory, edematous papules appearing mainly on the trunk and occasionally the face and limbs. The urticarial rash tends to be associated with more severe forms of the disease and regresses within a week, responding to antihistamines. Of note, clinically similar rashes can be caused by drugs. Histologically, the lesions show dermal edema and a mild perivascular lymphocytic infiltrate, sometimes admixed with eosinophils.

Chilblainlike Lesions—Chilblainlike lesions (CBLLs) account for 19% of skin manifestations associated with COVID-19¹³ and present as erythematous-purplish, edematous lesions that can be mildly pruritic or painful, appearing on the toes—COVID toes—and more rarely the fingers (Figure 2). They were seen epidemically during the first pandemic wave (2020 lockdown) in several countries, and clinically are very similar to, if not indistinguishable from, idiopathic chilblains, but are not necessarily associated with cold exposure. They appear in young, generally healthy patients or those with mild COVID-19 symptoms 2 to 4 weeks after symptom onset. They regress spontaneously or under local corticosteroid treatment within a few days or weeks. Histologically, CBLLs are indistinguishable from chilblains of other origins, namely idiopathic (seasonal) ones. They manifest with necrosis of epidermal keratinocytes; dermal edema that may be severe, leading to the development of subepidermal pseudobullae; a rather dense perivascular and perieccrine gland lymphocytic infiltrate; and sometimes with vascular lesions (eg, edema of endothelial cells, microthromboses of dermal capillaries and venules, fibrinoid deposits within the wall of dermal venules)(Figure 3).^16-18 Most patients (>80%) with CBLLs have negative serologic or polymerase chain reaction tests for SARS-CoV-2,¹⁹ which generated a lively debate about the role of SARS-CoV-2 in the genesis of CBLLs. According to some authors, SARS-CoV-2 plays no direct role, and CBLLs would occur in young people who sit or walk barefoot on cold floors at home during confinement.^20-23 Remarkably, CBLLs appeared in patients with no history of chilblains during a season that was not particularly cold, namely in France or in southern California, where their incidence was much higher compared to the same time period of prior years. Some reports have supported a direct role for the virus based on questionable observations of the virus within skin lesions (eg, sweat glands, endothelial cells) by immunohistochemistry, electron microscopy, and/or in situ hybridization.^17,24,25 A more satisfactory hypothesis would involve the role of a strong innate immunity leading to elimination of the virus before the development of specific antibodies via the increased production of type 1 interferon (IFN-1); this would affect the vessels, causing CBLLs. This mechanism would be similar to the one observed in some interferonopathies (eg, Aicardi-Goutières syndrome), also characterized by IFN-1 hypersecretion and chilblains.^26-29 According to this hypothesis, CBLLs should be considered a paraviral rash similar to other skin manifestations associated with COVID-19.³⁰

Acro-ischemia—Acro-ischemia livedoid lesions account for 1% to 6% of skin manifestations and comprise lesions of livedo (either reticulated or racemosa); necrotic acral bullae; and gangrenous necrosis of the extremities, especially the toes. The livedoid lesions most often appear within 15 days of COVID-19 symptom onset, and the purpuric lesions somewhat later (2–4 weeks); they mainly affect adult patients, last about 10 days, and are the hallmark of severe infection, presumably related to microthromboses of the cutaneous capillaries (endothelial dysfunction, prothrombotic state, elevated D-dimers). Histologically, they show capillary thrombosis and dermoepidermal necrosis (Figure 4).

Other Reported Polymorphic or Atypical Rashes—Erythema multiforme–like eruptions may appear before other COVID-19 symptoms and manifest as reddish-purple, nearly symmetric, diffuse, occasionally targetoid bullous or necrotic macules. The eruptions mainly affect adults and most often are seen on the palms, elbows, knees, and sometimes the mucous membranes. The rash regresses in 1 to 3 weeks without scarring and represents a delayed cutaneous hypersensitivity reaction. Histologically, the lesions show vacuolization of basal epidermal keratinocytes, keratinocyte necrosis, dermoepidermal detachment, a variably dense dermal T-lymphocytic infiltrate, and red blood cell extravasation (Figure 5).

Leukocytoclastic vasculitis may be generalized or localized. It manifests clinically by petechial/purpuric maculopapules, especially on the legs, mainly in elderly patients with COVID-19. Histologically, the lesions show necrotizing changes of dermal postcapillary venules, neutrophilic perivascular inflammation, red blood cell extravasation, and occasionally vascular IgA deposits by direct immunofluorescence examination. The course usually is benign.

The incidence of pityriasis rosea and of clinically similar rashes (referred to as “pityriasis rosea–like”) increased 5-fold during the COVID-19 pandemic.^31,32 These dermatoses manifest with erythematous, scaly, circinate plaques, typically with an initial herald lesion followed a few days later by smaller erythematous macules. Histologically, the lesions comprise a spongiform dermatitis with intraepidermal exocytosis of red blood cells and a mild to moderate dermal lymphocytic infiltrate.

Erythrodysesthesia, or hand-foot syndrome, manifests with edematous erythema and palmoplantar desquamation accompanied by a burning sensation or pain. This syndrome is known as an adverse effect of some chemotherapies because of the associated drug toxicity and sweat gland inflammation; it was observed in 40% of 666 COVID-19–positive patients with mild to moderate pneumonitis.³³

“COVID nose” is a rare cutaneous manifestation characterized by nasal pigmentation comprising multiple coalescent frecklelike macules on the tip and wings of the nose and sometimes the malar areas. These lesions predominantly appear in women aged 25 to 65 years and show on average 23 days after onset of COVID-19, which is usually mild. This pigmentation is similar to pigmentary changes after infection with chikungunya; it can be treated with depigmenting products such as azelaic acid and hydroquinone cream with sunscreen use, and it regresses in 2 to 4 months.³⁴

Telogen effluvium (excessive and temporary shedding of normal telogen club hairs of the entire scalp due to the disturbance of the hair cycle) is reportedly frequent in patients (48%) 1 month after COVID-19 infection, but it may appear later (after 12 weeks).³⁵ Alopecia also is frequently reported during long (or postacute) COVID-19 (ie, the symptomatic disease phase past the acute 4 weeks’ stage of the infection) and shows a female predominance³⁶; it likely represents the telogen effluvium seen 90 days after a severe illness. Trichodynia (pruritus, burning, pain, or paresthesia of the scalp) also is reportedly common (developing in more than 58% of patients) and is associated with telogen effluvium in 44% of cases. Several cases of alopecia areata (AA) triggered or aggravated by COVID-19 also have been reported^37,38; they could be explained by the “cytokine storm” triggered by the infection, involving T and B lymphocytes; plasmacytoid dendritic cells; natural killer cells with oversecretion of IL-6, IL-4, tumor necrosis factor α, and IFN type I; and a cytotoxic reaction associated with loss of the immune privilege of hair follicles.

Nail Manifestations

The red half-moon nail sign is an asymptomatic purplish-red band around the distal margin of the lunula that affects some adult patients with COVID-19.³⁹ It appears shortly after onset of symptoms, likely the manifestation of vascular inflammation in the nail bed, and regresses slowly after approximately 1 week.⁴⁰ Beau lines are transverse grooves in the nail plate due to the temporary arrest of the proximal nail matrix growth accompanying systemic illnesses; they appear approximately 2 to 3 weeks after the onset of COVID-19.⁴¹ Furthermore, nail alterations can be caused by drugs used to treat COVID-19, such as longitudinal melanonychia due to treatment with hydroxychloroquine or fluorescence of the lunula or nail plate due to treatment with favipiravir.⁴²

Multisystem Inflammatory Syndrome

Multisystem inflammatory syndrome (MIS) is clinically similar to Kawasaki disease; it typically affects children⁴³ and more rarely adults with COVID-19. It manifests with fever, weakness, and biological inflammation and also frequently with skin lesions (72%), which are polymorphous and include morbilliform rash (27%); urticaria (24%); periorbital edema (24%); nonspecific erythema (21.2%); retiform purpura (18%); targetoid lesions (15%); malar rash (15.2%); and periareolar erythema (6%).⁴⁴ Compared to Kawasaki disease, MIS affects slightly older children (mean age, 8.5 vs 3 years) and more frequently includes cardiac and gastrointestinal manifestations; the mortality rate also is slightly higher (2% vs 0.17%).⁴⁵

Confirmed COVID-19 Infection

At the beginning of the pandemic, skin manifestations were reported in patients who were suspected of having COVID-19 but did not always have biological confirmation of SARS-CoV-2 infection due to the unavailability of diagnostic tests or the physical impossibility of testing. However, subsequent studies have confirmed that most of these dermatoses were indeed associated with COVID-19 infection.^9,46 For example, a study of 655 patients with confirmed COVID-19 infection reported maculopapular (38%), vascular (22%), urticarial (15%), and vesicular (15%) rashes; erythema multiforme or Stevens-Johnson–like syndrome (3%, often related to the use of hydroxychloroquine); generalized pruritus (1%); and MIS (0.5%). The study confirmed that CBLLs were mostly seen in young patients with mild disease, whereas livedo (fixed rash) and retiform purpura occurred in older patients with a guarded prognosis.⁴⁶

Remarkably, most dermatoses associated with SARS-CoV-2 infection were reported during the initial waves of the pandemic, which were due to the α and δ viral variants. These manifestations were reported more rarely when the ο variant was predominant, even though most patients (63%) who developed CBLLs in the first wave also developed them during the second pandemic wave.⁴⁷ This decrease in the incidence of COVID-19–associated dermatoses could be because of the lower pathogenicity of the o variant,³ a lower tropism for the skin, and variations in SARS-CoV-2 antigenicity that would induce a different immunologic response, combined with an increasingly stronger herd immunity compared to the first pandemic waves achieved through vaccination and spontaneous infections in the population. Additional reasons may include different baseline characteristics in patients hospitalized with COVID-19 (regarding comorbidities, disease severity, and received treatments), and the possibility that some of the initially reported COVID-19–associated skin manifestations could have been produced by different etiologic agents.⁴⁸ In the last 2 years, COVID-19–related skin manifestations have been reported mainly as adverse events to COVID-19 vaccination.

CUTANEOUS ADVERSE EFFECTS OF DRUGS USED TO TREAT COVID-19

Prior to the advent of vaccines and specific treatments for SARS-CoV-2, various drugs were used—namely hydroxychloroquine, ivermectin, and tocilizumab—that did not prove efficacious and caused diverse adverse effects, including cutaneous eruptions such as urticaria, maculopapular eruptions, erythema multiforme or Stevens-Johnson syndrome, vasculitis, longitudinal melanonychia, and acute generalized exanthematous pustulosis.^49,50 Nirmatrelvir 150 mg–ritonavir 100 mg, which was authorized for emergency use by the US Food and Drug Administration for the treatment of COVID-19, is a viral protease inhibitor blocking the replication of the virus. Ritonavir can induce pruritus, maculopapular rash, acne, Stevens-Johnson syndrome, and toxic epidermal necrolysis; of note, these effects have been observed following administration of ritonavir for treatment of HIV at higher daily doses and for much longer periods of time compared with treatment of COVID-19 (600–1200 mg vs 200 mg/d, respectively). These cutaneous drug side effects are clinically similar to the manifestations caused either directly or indirectly by SARS-CoV-2 infection; therefore, it may be difficult to differentiate them.

DERMATOSES DUE TO PROTECTIVE DEVICES

Dermatoses due to personal protective equipment such as masks or face shields affected the general population and mostly health care professionals⁵¹; 54.4% of 879 health care professionals in one study reported such events.⁵² These dermatoses mainly include contact dermatitis of the face (nose, forehead, and cheeks) of irritant or allergic nature (eg, from preservatives releasing formaldehyde contained in masks and protective goggles). They manifest with skin dryness; desquamation; maceration; fissures; or erosions or ulcerations of the cheeks, forehead, and nose. Cases of pressure urticaria also have been reported. Irritant dermatitis induced by the frequent use of disinfectants (eg, soaps, hydroalcoholic sanitizing gels) also can affect the hands. Allergic hand dermatitis can be caused by medical gloves.

The term maskne (or mask acne) refers to a variety of mechanical acne due to the prolonged use of surgical masks (>4 hours per day for ≥6 weeks); it includes cases of de novo acne and cases of pre-existing acne aggravated by wearing a mask. Maskne is characterized by acne lesions located on the facial area covered by the mask (Figure 6). It is caused by follicular occlusion; increased sebum secretion; mechanical stress (pressure, friction); and dysbiosis of the microbiome induced by changes in heat, pH, and humidity. Preventive measures include application of noncomedogenic moisturizers or gauze before wearing the mask as well as facial cleansing with appropriate nonalcoholic products. Similar to acne, rosacea often is aggravated by prolonged wearing of surgical masks (mask rosacea).^53,54

DERMATOSES REVEALED OR AGGRAVATED BY COVID-19

Exacerbation of various skin diseases has been reported after infection with SARS-CoV-2.⁵⁵ Psoriasis and acrodermatitis continua of Hallopeau,⁵⁶ which may progress into generalized, pustular, or erythrodermic forms,⁵⁷ have been reported; the role of hydroxychloroquine and oral corticosteroids used for the treatment of COVID-19 has been suspected.⁵⁷ Atopic dermatitis patients—26% to 43%—have experienced worsening of their disease after symptomatic COVID-19 infection.⁵⁸ The incidence of herpesvirus infections, including herpes zoster, increased during the pandemic.⁵⁹ Alopecia areata relapses occurred in 42.5% of 392 patients with preexisting disease within 2 months of COVID-19 onset in one study,⁶⁰ possibly favored by the psychological stress; however, some studies have not confirmed the aggravating role of COVID-19 on alopecia areata.⁶¹ Lupus erythematosus, which may relapse in the form of Rowell syndrome,⁶² and livedoid vasculopathy⁶³ also have been reported following COVID-19 infection.

SKIN MANIFESTATIONS ASSOCIATED WITH COVID-19 VACCINES

In parallel with the rapid spread of COVID-19 vaccination,⁴ an increasing number of skin manifestations has been observed following vaccination; these dermatoses now are more frequently reported than those related to natural SARS-CoV-2 infection.^64-70 Vaccine-induced skin manifestations have a reported incidence of approximately 4% and show a female predominance.⁶⁵ Most of them (79%) have been reported in association with messenger RNA (mRNA)–based vaccines, which have been the most widely used; however, the frequency of side effects would be lower after mRNA vaccines than after inactivated virus-based vaccines. Eighteen percent occurred after the adenoviral vector vaccine, and 3% after the inactivated virus vaccine.⁷⁰ Fifty-nine percent were observed after the first dose. They are clinically polymorphous and generally benign, regressing spontaneously after a few days, and they should not constitute a contraindication to vaccination.Interestingly, many skin manifestations are similar to those associated with natural SARS-CoV-2 infection; however, their frequency and severity does not seem to depend on whether the patients had developed skin reactions during prior SARS-CoV-2 infection. These reactions have been classified into several types:

• Immediate local reactions at the injection site: pain, erythema, or edema represent the vast majority (96%) of reactions to vaccines. They appear within 7 days after vaccination (average, 1 day), slightly more frequently (59%) after the first dose. They concern mostly young patients and are benign, regressing in 2 to 3 days.⁷⁰
 

• Delayed local reactions: characterized by pain or pruritus, erythema, and skin induration mimicking cellulitis (COVID arm) and represent 1.7% of postvaccination reactions. They correspond to a delayed hypersensitivity reaction and appear approximately 7 days after vaccination, most often after the first vaccine dose (75% of cases), which is almost invariably mRNA based.⁷⁰

• Urticarial reactions corresponding to an immediate (type 1) hypersensitivity reaction: constitute 1% of postvaccination reactions, probably due to an allergy to vaccine ingredients. They appear on average 1 day after vaccination, almost always with mRNA vaccines.⁷⁰

• Angioedema: characterized by mucosal or subcutaneous edema and constitutes 0.5% of postvaccination reactions. It is a potentially serious reaction that appears on average 12 hours after vaccination, always with an mRNA-based vaccine.⁷⁰

• Morbilliform rash: represents delayed hypersensitivity reactions (0.1% of postvaccination reactions) that appear mostly after the first dose (72%), on average 3 days after vaccination, always with an mRNA-based vaccine.⁷⁰

• Herpes zoster: usually develops after the first vaccine dose in elderly patients (69% of cases) on average 4 days after vaccination and constitutes 0.1% of postvaccination reactions.⁷¹

• Bullous diseases: mainly bullous pemphigoid (90%) and more rarely pemphigus (5%) or bullous erythema pigmentosum (5%). They appear in elderly patients on average 7 days after vaccination and constitute 0.04% of postvaccination reactions.⁷²

• Chilblainlike lesions: several such cases have been reported so far⁷³; they constitute 0.03% of postvaccination reactions.⁷⁰ Clinically, they are similar to those associated with natural COVID-19; they appear mostly after the first dose (64%), on average 5 days after vaccination with the mRNA or adenovirus vaccine, and show a female predominance. The appearance of these lesions in vaccinated patients, who are a priori not carriers of the virus, strongly suggests that CBLLs are due to the immune reaction against SARS-CoV-2 rather than to a direct effect of this virus on the skin, which also is a likely scenario with regards to other skin manifestations seen during the successive COVID-19 epidemic waves.^73-75

• Reactions to hyaluronic acid–containing cosmetic fillers: erythema, edema, and potentially painful induration at the filler injection sites. They constitute 0.04% of postvaccination skin reactions and appear 24 hours after vaccination with mRNA-based vaccines, equally after the first or second dose.⁷⁶

• Pityriasis rosea–like rash: most occur after the second dose of mRNA-based vaccines (0.023% of postvaccination skin reactions).⁷⁰

• Severe reactions: these include acute generalized exanthematous pustulosis⁷⁷ and Stevens-Johnson syndrome.⁷⁸ One case of each has been reported after the adenoviral vector vaccine 3 days after vaccination.

Other more rarely observed manifestations include reactivation/aggravation or de novo appearance of inflammatory dermatoses such as psoriasis,^79,80 leukocytoclastic vasculitis,^81,82 lymphocytic⁸³ or urticarial⁸⁴ vasculitis, Sweet syndrome,⁸⁵ lupus erythematosus, dermatomyositis,^86,87 alopecia,^37,88 infection with Trichophyton rubrum,⁸⁹ Grover disease,⁹⁰ and lymphomatoid reactions (such as recurrences of cutaneous T-cell lymphomas [CD30⁺], and de novo development of lymphomatoid papulosis).⁹¹

FINAL THOUGHTS

COVID-19 is associated with several skin manifestations, even though the causative role of SARS-CoV-2 has remained elusive. These dermatoses are highly polymorphous, mostly benign, and usually spontaneously regressive, but some of them reflect severe infection. They mostly were described during the first pandemic waves, reported in several national and international registries, which allowed for their morphological classification. Currently, cutaneous adverse effects of vaccines are the most frequently reported dermatoses associated with SARS-CoV-2, and it is likely that they will continue to be observed while COVID-19 vaccination lasts. Hopefully the end of the COVID-19 pandemic is near. In January 2023, the International Health Regulations Emergency Committee of the World Health Organization acknowledged that the COVID-19 pandemic may be approaching an inflexion point, and even though the event continues to constitute a public health emergency of international concern, the higher levels of population immunity achieved globally through infection and/or vaccination may limit the impact of SARS-CoV-2 on morbidity and mortality. However, there is little doubt that this virus will remain a permanently established pathogen in humans and animals for the foreseeable future.⁹² Therefore, physicians—especially dermatologists—should be aware of the various skin manifestations associated with COVID-19 so they can more efficiently manage their patients.

Researchers have found for the first time that COVID infection has crossed the placenta and caused brain damage in two newborns, according to a study published online today in Pediatrics .

One of the infants died at 13 months and the other remained in hospice care at time of manuscript submission.

Lead author Merline Benny, MD, with the division of neonatology, department of pediatrics at University of Miami, and colleagues briefed reporters today ahead of the release.

Zelda Calvert

“This is a first,” said senior author Shahnaz Duara, MD, medical director of the Neonatal Intensive Care Unit at Holtz Children’s Hospital, Miami, explaining it is the first study to confirm cross-placental SARS-CoV-2 transmission leading to brain injury in a newborn.
 

Both infants negative for the virus at birth

The two infants were admitted in the early days of the pandemic in the Delta wave to the neonatal ICU at Holtz Children’s Hospital at University of Miami/Jackson Memorial Medical Center.

Both infants tested negative for the virus at birth, but had significantly elevated SARS-CoV-2 antibodies in their blood, indicating that either antibodies crossed the placenta, or the virus crossed and the immune response was the baby’s.

Dr. Benny explained that the researchers have seen, to this point, more than 700 mother/infant pairs in whom the mother tested positive for COVID in Jackson hospital.

Most who tested positive for COVID were asymptomatic and most of the mothers and infants left the hospital without complications.

“However, (these) two babies had a very unusual clinical picture,” Dr. Benny said.

Those infants were born to mothers who became COVID positive in the second trimester and delivered a few weeks later.

Seizures started on day 1 of life

The babies began to seize from the first day of life. They had profound low tone (hypotonia) in their clinical exam, Dr. Benny explained.

“We had absolutely no good explanation for the early seizures and the degree of brain injury we saw,” Dr. Duara said.

Dr. Benny said that as their bodies grew, they had very small head circumference. Unlike some babies born with the Zika virus, these babies were not microcephalic at birth. Brain imaging on the two babies indicated significant brain atrophy, and neurodevelopment exams showed significant delay.

Discussions began with the center’s multidisciplinary team including neurologists, pathologists, neuroradiologists, and obstetricians who cared for both the mothers and the babies.

The experts examined the placentas and found some characteristic COVID changes and presence of the COVID virus. This was accompanied by increased markers for inflammation and a severe reduction in a hormone critical for placental health and brain development.

Examining the infant’s autopsy findings further raised suspicions of maternal transmission, something that had not been documented before.

Coauthor Ali G. Saad, MD, pediatric and perinatal pathology director at Miami, said, “I have seen literally thousands of brains in autopsies over the last 14 years, and this was the most dramatic case of leukoencephalopathy or loss of white matter in a patient with no significant reason. That’s what triggered the investigation.”
 

Mothers had very different presentations

Coauthor Michael J. Paidas, MD, with the department of obstetrics, gynecology, and reproductive sciences at Miami, pointed out that the circumstances of the two mothers, who were in their 20s, were very different.

One mother delivered at 32 weeks and had a very severe COVID presentation and spent a month in the intensive care unit. The team decided to deliver the child to save the mother, Dr. Paidas said.

In contrast, the other mother had asymptomatic COVID infection in the second trimester and delivered at full term.

He said one of the early suspicions in the babies’ presentations was hypoxic ischemic encephalopathy. “But it wasn’t lack of blood flow to the placenta that caused this,” he said. “As best we can tell, it was the viral infection.”
 

Instances are rare

The researchers emphasized that these instances are rare and have not been seen before or since the period of this study to their knowledge.

Dr. Duara said, “This is something we want to alert the medical community to more than the general public. We do not want the lay public to be panicked. We’re trying to understand what made these two pregnancies different, so we can direct research towards protecting vulnerable babies.”

Previous data have indicated a relatively benign status in infants who test negative for the COVID virus after birth. Dr. Benny added that COVID vaccination has been found safe in pregnancy and both vaccination and breastfeeding can help passage of antibodies to the infant and help protect the baby. Because these cases happened in the early days of the pandemic, no vaccines were available.

Dr. Paidas received funding from BioIncept to study hypoxic-ischemic encephalopathy with Preimplantation Factor, is a scientific advisory board member, and has stock options. Dr. Paidas and coauthor Dr. Jayakumar are coinventors of SPIKENET, University of Miami, patent pending 2023. The other authors have no conflicts of interest to disclose.

Researchers have found for the first time that COVID infection has crossed the placenta and caused brain damage in two newborns, according to a study published online today in Pediatrics .

One of the infants died at 13 months and the other remained in hospice care at time of manuscript submission.

Lead author Merline Benny, MD, with the division of neonatology, department of pediatrics at University of Miami, and colleagues briefed reporters today ahead of the release.

Zelda Calvert

“This is a first,” said senior author Shahnaz Duara, MD, medical director of the Neonatal Intensive Care Unit at Holtz Children’s Hospital, Miami, explaining it is the first study to confirm cross-placental SARS-CoV-2 transmission leading to brain injury in a newborn.
 

Both infants negative for the virus at birth

The two infants were admitted in the early days of the pandemic in the Delta wave to the neonatal ICU at Holtz Children’s Hospital at University of Miami/Jackson Memorial Medical Center.

Both infants tested negative for the virus at birth, but had significantly elevated SARS-CoV-2 antibodies in their blood, indicating that either antibodies crossed the placenta, or the virus crossed and the immune response was the baby’s.

Dr. Benny explained that the researchers have seen, to this point, more than 700 mother/infant pairs in whom the mother tested positive for COVID in Jackson hospital.

Most who tested positive for COVID were asymptomatic and most of the mothers and infants left the hospital without complications.

“However, (these) two babies had a very unusual clinical picture,” Dr. Benny said.

Those infants were born to mothers who became COVID positive in the second trimester and delivered a few weeks later.

Seizures started on day 1 of life

The babies began to seize from the first day of life. They had profound low tone (hypotonia) in their clinical exam, Dr. Benny explained.

“We had absolutely no good explanation for the early seizures and the degree of brain injury we saw,” Dr. Duara said.

Dr. Benny said that as their bodies grew, they had very small head circumference. Unlike some babies born with the Zika virus, these babies were not microcephalic at birth. Brain imaging on the two babies indicated significant brain atrophy, and neurodevelopment exams showed significant delay.

Discussions began with the center’s multidisciplinary team including neurologists, pathologists, neuroradiologists, and obstetricians who cared for both the mothers and the babies.

The experts examined the placentas and found some characteristic COVID changes and presence of the COVID virus. This was accompanied by increased markers for inflammation and a severe reduction in a hormone critical for placental health and brain development.

Examining the infant’s autopsy findings further raised suspicions of maternal transmission, something that had not been documented before.

Coauthor Ali G. Saad, MD, pediatric and perinatal pathology director at Miami, said, “I have seen literally thousands of brains in autopsies over the last 14 years, and this was the most dramatic case of leukoencephalopathy or loss of white matter in a patient with no significant reason. That’s what triggered the investigation.”
 

Mothers had very different presentations

Coauthor Michael J. Paidas, MD, with the department of obstetrics, gynecology, and reproductive sciences at Miami, pointed out that the circumstances of the two mothers, who were in their 20s, were very different.

One mother delivered at 32 weeks and had a very severe COVID presentation and spent a month in the intensive care unit. The team decided to deliver the child to save the mother, Dr. Paidas said.

In contrast, the other mother had asymptomatic COVID infection in the second trimester and delivered at full term.

He said one of the early suspicions in the babies’ presentations was hypoxic ischemic encephalopathy. “But it wasn’t lack of blood flow to the placenta that caused this,” he said. “As best we can tell, it was the viral infection.”
 

Instances are rare

The researchers emphasized that these instances are rare and have not been seen before or since the period of this study to their knowledge.

Dr. Duara said, “This is something we want to alert the medical community to more than the general public. We do not want the lay public to be panicked. We’re trying to understand what made these two pregnancies different, so we can direct research towards protecting vulnerable babies.”

Previous data have indicated a relatively benign status in infants who test negative for the COVID virus after birth. Dr. Benny added that COVID vaccination has been found safe in pregnancy and both vaccination and breastfeeding can help passage of antibodies to the infant and help protect the baby. Because these cases happened in the early days of the pandemic, no vaccines were available.

Dr. Paidas received funding from BioIncept to study hypoxic-ischemic encephalopathy with Preimplantation Factor, is a scientific advisory board member, and has stock options. Dr. Paidas and coauthor Dr. Jayakumar are coinventors of SPIKENET, University of Miami, patent pending 2023. The other authors have no conflicts of interest to disclose.

Researchers have found for the first time that COVID infection has crossed the placenta and caused brain damage in two newborns, according to a study published online today in Pediatrics .

One of the infants died at 13 months and the other remained in hospice care at time of manuscript submission.

Lead author Merline Benny, MD, with the division of neonatology, department of pediatrics at University of Miami, and colleagues briefed reporters today ahead of the release.

Zelda Calvert

“This is a first,” said senior author Shahnaz Duara, MD, medical director of the Neonatal Intensive Care Unit at Holtz Children’s Hospital, Miami, explaining it is the first study to confirm cross-placental SARS-CoV-2 transmission leading to brain injury in a newborn.
 

Both infants negative for the virus at birth

The two infants were admitted in the early days of the pandemic in the Delta wave to the neonatal ICU at Holtz Children’s Hospital at University of Miami/Jackson Memorial Medical Center.

Both infants tested negative for the virus at birth, but had significantly elevated SARS-CoV-2 antibodies in their blood, indicating that either antibodies crossed the placenta, or the virus crossed and the immune response was the baby’s.

Dr. Benny explained that the researchers have seen, to this point, more than 700 mother/infant pairs in whom the mother tested positive for COVID in Jackson hospital.

Most who tested positive for COVID were asymptomatic and most of the mothers and infants left the hospital without complications.

“However, (these) two babies had a very unusual clinical picture,” Dr. Benny said.

Those infants were born to mothers who became COVID positive in the second trimester and delivered a few weeks later.

Seizures started on day 1 of life

The babies began to seize from the first day of life. They had profound low tone (hypotonia) in their clinical exam, Dr. Benny explained.

“We had absolutely no good explanation for the early seizures and the degree of brain injury we saw,” Dr. Duara said.

Dr. Benny said that as their bodies grew, they had very small head circumference. Unlike some babies born with the Zika virus, these babies were not microcephalic at birth. Brain imaging on the two babies indicated significant brain atrophy, and neurodevelopment exams showed significant delay.

Discussions began with the center’s multidisciplinary team including neurologists, pathologists, neuroradiologists, and obstetricians who cared for both the mothers and the babies.

The experts examined the placentas and found some characteristic COVID changes and presence of the COVID virus. This was accompanied by increased markers for inflammation and a severe reduction in a hormone critical for placental health and brain development.

Examining the infant’s autopsy findings further raised suspicions of maternal transmission, something that had not been documented before.

Coauthor Ali G. Saad, MD, pediatric and perinatal pathology director at Miami, said, “I have seen literally thousands of brains in autopsies over the last 14 years, and this was the most dramatic case of leukoencephalopathy or loss of white matter in a patient with no significant reason. That’s what triggered the investigation.”
 

Mothers had very different presentations

Coauthor Michael J. Paidas, MD, with the department of obstetrics, gynecology, and reproductive sciences at Miami, pointed out that the circumstances of the two mothers, who were in their 20s, were very different.

One mother delivered at 32 weeks and had a very severe COVID presentation and spent a month in the intensive care unit. The team decided to deliver the child to save the mother, Dr. Paidas said.

In contrast, the other mother had asymptomatic COVID infection in the second trimester and delivered at full term.

He said one of the early suspicions in the babies’ presentations was hypoxic ischemic encephalopathy. “But it wasn’t lack of blood flow to the placenta that caused this,” he said. “As best we can tell, it was the viral infection.”
 

Instances are rare

The researchers emphasized that these instances are rare and have not been seen before or since the period of this study to their knowledge.

Dr. Duara said, “This is something we want to alert the medical community to more than the general public. We do not want the lay public to be panicked. We’re trying to understand what made these two pregnancies different, so we can direct research towards protecting vulnerable babies.”

Previous data have indicated a relatively benign status in infants who test negative for the COVID virus after birth. Dr. Benny added that COVID vaccination has been found safe in pregnancy and both vaccination and breastfeeding can help passage of antibodies to the infant and help protect the baby. Because these cases happened in the early days of the pandemic, no vaccines were available.

Dr. Paidas received funding from BioIncept to study hypoxic-ischemic encephalopathy with Preimplantation Factor, is a scientific advisory board member, and has stock options. Dr. Paidas and coauthor Dr. Jayakumar are coinventors of SPIKENET, University of Miami, patent pending 2023. The other authors have no conflicts of interest to disclose.