Infectious Disease Practitioner

An international team of researchers studying COVID-19 has made a startling and pivotal discovery: The virus appears to cause the body to make weapons to attack its own tissues.

The finding could unlock a number of COVID-19’s clinical mysteries. They include the puzzling collection of symptoms that can come with the infection; the persistence of symptoms in some people for months after they clear the virus, a phenomenon dubbed long COVID-19; and why some children and adults have a serious inflammatory syndrome, called multisystem inflammatory syndrome in children (MIS-C) or MIS in adults (MIS-A), after their infections.

“It suggests that the virus might be directly causing autoimmunity, which would be fascinating,” says lead study author Paul Utz, MD, who studies immunology and autoimmunity at Stanford (Calif.) University.

The study also deepens the question of whether other respiratory viruses might also break the body’s tolerance to itself, setting people up for autoimmune diseases like multiple sclerosis, rheumatoid arthritis, and lupus later in life.

Dr. Utz said he and his team are next going to study flu patients to see if that virus might also cause this phenomenon.

“My prediction is that it isn’t going to be specific just to SARS-CoV-2. I’m willing to bet that we will find this with other respiratory viruses,” he said.

The study comes on the heels of a handful of smaller, detailed investigations that have come to similar conclusions.

The study included data from more than 300 patients from four hospitals: two in California, one in Pennsylvania, and another in Germany.

Researchers used blood tests to study their immune responses as their infections progressed. Researchers looked for autoantibodies – weapons of the immune system that go rogue and launch an attack against the body’s own tissues. They compared these autoantibodies with those found in people who were not infected with the virus that causes COVID.

As previous studies have found, autoantibodies were more common after COVID – 50% of people hospitalized for their infections had autoantibodies, compared with less than 15% of those who were healthy and uninfected.

Some people with autoantibodies had little change in them as their infections progressed. That suggests the autoantibodies were there to begin with, possibly allowing the infection to burn out of control in the body.

“Their body is set up to get bad COVID, and it’s probably caused by the autoantibodies,” Dr. Utz said.

But in others, about 20% of people who had them, the autoantibodies became more common as the infection progressed, suggesting they were directly related to the viral infection, instead of being a preexisting condition.

Some of these were antibodies that attack key components of the immune system’s weapons against the virus, like interferon. Interferons are proteins that help infected cells call for reinforcements and can also interfere with a virus’s ability to copy itself. Taking them out is a powerful evasive tactic, and previous studies have shown that people who are born with genes that cause them to have lower interferon function, or who make autoantibodies against these proteins, appear to be at higher risk for life-threatening COVID infections.

“It seems to give the virus a powerful advantage,” said study author, John Wherry, PhD, who directs the Institute for Immunology at the University of Pennsylvania, Philadelphia. “Now your immune system, instead of having a tiny little hill to climb, is staring at Mount Everest. That really is devious.”

In addition to those that sabotage the immune system, some people in the study had autoantibodies against muscles and connective tissues that are seen in some rare disorders.

Dr. Utz said they started the study after seeing COVID patients with strange collections of symptoms that looked more like autoimmune diseases than viral infections – skin rashes, joint pain, fatigue, aching muscles, brain swelling, dry eyes, blood that clots easily, and inflamed blood vessels.

“One thing that’s very important to note is that we don’t know if these patients are going to go on to develop autoimmune disease,” Dr. Utz said. “I think we’ll be able to answer that question in the next 6-12 months as we follow the long haulers and study their samples.”

Dr. Utz said it will be important to study autoantibodies in long haulers to see if they can identify exactly which ones seem to be at work in the condition. If you can catch them early, it might be possible to treat those at risk for enduring symptoms with drugs that suppress the immune system.

What this means, he said, is that COVID will be with us for a long, long time.

“We have to realize that there’s going to be long-term damage from this virus for the survivors. Not just the long haulers, but all the people who have lung damage and heart damage and everything else. We’re going to be studying this virus and it’s badness for decades,” Dr. Utz said.

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

An international team of researchers studying COVID-19 has made a startling and pivotal discovery: The virus appears to cause the body to make weapons to attack its own tissues.

The finding could unlock a number of COVID-19’s clinical mysteries. They include the puzzling collection of symptoms that can come with the infection; the persistence of symptoms in some people for months after they clear the virus, a phenomenon dubbed long COVID-19; and why some children and adults have a serious inflammatory syndrome, called multisystem inflammatory syndrome in children (MIS-C) or MIS in adults (MIS-A), after their infections.

“It suggests that the virus might be directly causing autoimmunity, which would be fascinating,” says lead study author Paul Utz, MD, who studies immunology and autoimmunity at Stanford (Calif.) University.

The study also deepens the question of whether other respiratory viruses might also break the body’s tolerance to itself, setting people up for autoimmune diseases like multiple sclerosis, rheumatoid arthritis, and lupus later in life.

Dr. Utz said he and his team are next going to study flu patients to see if that virus might also cause this phenomenon.

“My prediction is that it isn’t going to be specific just to SARS-CoV-2. I’m willing to bet that we will find this with other respiratory viruses,” he said.

The study comes on the heels of a handful of smaller, detailed investigations that have come to similar conclusions.

The study included data from more than 300 patients from four hospitals: two in California, one in Pennsylvania, and another in Germany.

Researchers used blood tests to study their immune responses as their infections progressed. Researchers looked for autoantibodies – weapons of the immune system that go rogue and launch an attack against the body’s own tissues. They compared these autoantibodies with those found in people who were not infected with the virus that causes COVID.

As previous studies have found, autoantibodies were more common after COVID – 50% of people hospitalized for their infections had autoantibodies, compared with less than 15% of those who were healthy and uninfected.

Some people with autoantibodies had little change in them as their infections progressed. That suggests the autoantibodies were there to begin with, possibly allowing the infection to burn out of control in the body.

“Their body is set up to get bad COVID, and it’s probably caused by the autoantibodies,” Dr. Utz said.

But in others, about 20% of people who had them, the autoantibodies became more common as the infection progressed, suggesting they were directly related to the viral infection, instead of being a preexisting condition.

Some of these were antibodies that attack key components of the immune system’s weapons against the virus, like interferon. Interferons are proteins that help infected cells call for reinforcements and can also interfere with a virus’s ability to copy itself. Taking them out is a powerful evasive tactic, and previous studies have shown that people who are born with genes that cause them to have lower interferon function, or who make autoantibodies against these proteins, appear to be at higher risk for life-threatening COVID infections.

“It seems to give the virus a powerful advantage,” said study author, John Wherry, PhD, who directs the Institute for Immunology at the University of Pennsylvania, Philadelphia. “Now your immune system, instead of having a tiny little hill to climb, is staring at Mount Everest. That really is devious.”

In addition to those that sabotage the immune system, some people in the study had autoantibodies against muscles and connective tissues that are seen in some rare disorders.

Dr. Utz said they started the study after seeing COVID patients with strange collections of symptoms that looked more like autoimmune diseases than viral infections – skin rashes, joint pain, fatigue, aching muscles, brain swelling, dry eyes, blood that clots easily, and inflamed blood vessels.

“One thing that’s very important to note is that we don’t know if these patients are going to go on to develop autoimmune disease,” Dr. Utz said. “I think we’ll be able to answer that question in the next 6-12 months as we follow the long haulers and study their samples.”

Dr. Utz said it will be important to study autoantibodies in long haulers to see if they can identify exactly which ones seem to be at work in the condition. If you can catch them early, it might be possible to treat those at risk for enduring symptoms with drugs that suppress the immune system.

What this means, he said, is that COVID will be with us for a long, long time.

“We have to realize that there’s going to be long-term damage from this virus for the survivors. Not just the long haulers, but all the people who have lung damage and heart damage and everything else. We’re going to be studying this virus and it’s badness for decades,” Dr. Utz said.

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

An international team of researchers studying COVID-19 has made a startling and pivotal discovery: The virus appears to cause the body to make weapons to attack its own tissues.

The finding could unlock a number of COVID-19’s clinical mysteries. They include the puzzling collection of symptoms that can come with the infection; the persistence of symptoms in some people for months after they clear the virus, a phenomenon dubbed long COVID-19; and why some children and adults have a serious inflammatory syndrome, called multisystem inflammatory syndrome in children (MIS-C) or MIS in adults (MIS-A), after their infections.

“It suggests that the virus might be directly causing autoimmunity, which would be fascinating,” says lead study author Paul Utz, MD, who studies immunology and autoimmunity at Stanford (Calif.) University.

The study also deepens the question of whether other respiratory viruses might also break the body’s tolerance to itself, setting people up for autoimmune diseases like multiple sclerosis, rheumatoid arthritis, and lupus later in life.

Dr. Utz said he and his team are next going to study flu patients to see if that virus might also cause this phenomenon.

“My prediction is that it isn’t going to be specific just to SARS-CoV-2. I’m willing to bet that we will find this with other respiratory viruses,” he said.

The study comes on the heels of a handful of smaller, detailed investigations that have come to similar conclusions.

The study included data from more than 300 patients from four hospitals: two in California, one in Pennsylvania, and another in Germany.

Researchers used blood tests to study their immune responses as their infections progressed. Researchers looked for autoantibodies – weapons of the immune system that go rogue and launch an attack against the body’s own tissues. They compared these autoantibodies with those found in people who were not infected with the virus that causes COVID.

As previous studies have found, autoantibodies were more common after COVID – 50% of people hospitalized for their infections had autoantibodies, compared with less than 15% of those who were healthy and uninfected.

Some people with autoantibodies had little change in them as their infections progressed. That suggests the autoantibodies were there to begin with, possibly allowing the infection to burn out of control in the body.

“Their body is set up to get bad COVID, and it’s probably caused by the autoantibodies,” Dr. Utz said.

But in others, about 20% of people who had them, the autoantibodies became more common as the infection progressed, suggesting they were directly related to the viral infection, instead of being a preexisting condition.

Some of these were antibodies that attack key components of the immune system’s weapons against the virus, like interferon. Interferons are proteins that help infected cells call for reinforcements and can also interfere with a virus’s ability to copy itself. Taking them out is a powerful evasive tactic, and previous studies have shown that people who are born with genes that cause them to have lower interferon function, or who make autoantibodies against these proteins, appear to be at higher risk for life-threatening COVID infections.

“It seems to give the virus a powerful advantage,” said study author, John Wherry, PhD, who directs the Institute for Immunology at the University of Pennsylvania, Philadelphia. “Now your immune system, instead of having a tiny little hill to climb, is staring at Mount Everest. That really is devious.”

In addition to those that sabotage the immune system, some people in the study had autoantibodies against muscles and connective tissues that are seen in some rare disorders.

Dr. Utz said they started the study after seeing COVID patients with strange collections of symptoms that looked more like autoimmune diseases than viral infections – skin rashes, joint pain, fatigue, aching muscles, brain swelling, dry eyes, blood that clots easily, and inflamed blood vessels.

“One thing that’s very important to note is that we don’t know if these patients are going to go on to develop autoimmune disease,” Dr. Utz said. “I think we’ll be able to answer that question in the next 6-12 months as we follow the long haulers and study their samples.”

Dr. Utz said it will be important to study autoantibodies in long haulers to see if they can identify exactly which ones seem to be at work in the condition. If you can catch them early, it might be possible to treat those at risk for enduring symptoms with drugs that suppress the immune system.

What this means, he said, is that COVID will be with us for a long, long time.

“We have to realize that there’s going to be long-term damage from this virus for the survivors. Not just the long haulers, but all the people who have lung damage and heart damage and everything else. We’re going to be studying this virus and it’s badness for decades,” Dr. Utz said.

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

Ceftolozane-tazobactam (C/T) was found effective for treating pneumonia, intra-abdominal, and urinary tract infections caused by Pseudomonas aeruginosa, according to the results of a retrospective, observational study conducted in critically ill patients.

The multicenter, observational study assessed 95 patients who received C/T for P. aeruginosa serious infections, according to a report published online in the International Journal of Antimicrobial Agents.

C/T is a novel beta-lactam/ beta-lactamase inhibitor combination active against gram-negative bacteria including P. aeruginosa, “This paper presents the largest real-life experience published on C/T therapy for treating serious P. aeruginosa infections according to researchers Barbara Balandin, MD, of the Hospital Universitario Puerta de Hierro, Majadahonda, Spain, and colleagues.

The main infections treated were nosocomial pneumonia (56.2%), intra-abdominal infection (10.5%), tracheobronchitis (8.4%), and urinary tract infection (6.3%). Most infections were complicated with sepsis (49.5%) or septic shock (45.3%), and bacteremia (10.5%).

A total of 46 episodes were treated with high-dose C/T (3 g every 8 hours), and 38 episodes were treated with standard dosage (1.5 g every 8 hours). Almost half (44.2%) of the patients were treated with C/T monotherapy, and the remaining group received combination therapy with other antibiotics, according to the researchers.

The primary outcome of the study was to assess the efficacy and toxicity of C/T therapy. The secondary outcome was to evaluate the risk factors for all-cause 30-day mortality from the first day of therapy.

Favorable results

Most of the infections (93.7%) were severe and included the presence of sepsis (49.5%) or septic shock (45.3%). Bacteremia was observed in 15 (15.7%) patients. Bacteremia was secondary to nosocomial pneumonia in eight cases, catheter infection in five, urinary tract infection in one, and soft tissue infection in one. According to their susceptibility profiles, 46 (48.4%) of the strains were classified as extensively drug-resistant (XDR) P. aeruginosa and 35 (36.5%) were multidrug-resistant (MDR) P. aeruginosa.

Sixty-eight (71.6%) patients presented a favorable clinical response, which was defined as a resolution of presenting symptoms and signs of the infection by the end of therapy. An unfavorable clinical response was considered as persistence or worsening of the presenting symptoms and signs or death occurring during treatment with no other cause identified. Death associated with infection was defined as persistence of signs and symptoms of P. aeruginosa infection during C/T therapy with no other cause identified.

Microbiological eradication was documented in 42.1% (40/95) of the episodes. However, the global ICU mortality was still high, at 36.5%, with mortality mainly related to the severity of the infection.

Mortality was found to be significantly correlated with the Charlson Comorbidity Index (5.7 vs. 4.3; P = .04) and the need for life-supporting therapies such as vasopressors (66.6% vs. 46.9%; P = .03) and renal replacement therapy (46.6% vs. 18.1%; P = .002). In addition, mortality was significantly associated with a higher sequential organ failure assessment (SOFA) score during C/T therapy (SOFA1, SOFA 3, and SOFA 7; P < .001).

No significant differences in outcomes were correlated with demographic features, type and severity of infection, and dose of C/T. Also, there were no differences seen in outcomes between patients treated with C/T monotherapy and combined therapy (30.9% vs. 30.1%; P = .55).

“The lack of a positive effect from combined therapy suggests that C/T monotherapy may be sufficient for treating P. aeruginosa isolates that are susceptible to that agent,” the researchers suggested. “This study shows that C/T appears to be a suitable, effective, and safe drug for treating severe infections due to P. aeruginosa, highlighting nosocomial pneumonia caused by MDR/XDR P. aeruginosa in ICU patients with multiple comorbidities, such as immunosuppression, and needing life-sustaining therapies,” they concluded.

The authors reported that they had no outside funding source and had no conflicts of interest.

[email protected]

Ceftolozane-tazobactam (C/T) was found effective for treating pneumonia, intra-abdominal, and urinary tract infections caused by Pseudomonas aeruginosa, according to the results of a retrospective, observational study conducted in critically ill patients.

The multicenter, observational study assessed 95 patients who received C/T for P. aeruginosa serious infections, according to a report published online in the International Journal of Antimicrobial Agents.

C/T is a novel beta-lactam/ beta-lactamase inhibitor combination active against gram-negative bacteria including P. aeruginosa, “This paper presents the largest real-life experience published on C/T therapy for treating serious P. aeruginosa infections according to researchers Barbara Balandin, MD, of the Hospital Universitario Puerta de Hierro, Majadahonda, Spain, and colleagues.

The main infections treated were nosocomial pneumonia (56.2%), intra-abdominal infection (10.5%), tracheobronchitis (8.4%), and urinary tract infection (6.3%). Most infections were complicated with sepsis (49.5%) or septic shock (45.3%), and bacteremia (10.5%).

A total of 46 episodes were treated with high-dose C/T (3 g every 8 hours), and 38 episodes were treated with standard dosage (1.5 g every 8 hours). Almost half (44.2%) of the patients were treated with C/T monotherapy, and the remaining group received combination therapy with other antibiotics, according to the researchers.

The primary outcome of the study was to assess the efficacy and toxicity of C/T therapy. The secondary outcome was to evaluate the risk factors for all-cause 30-day mortality from the first day of therapy.

Favorable results

Most of the infections (93.7%) were severe and included the presence of sepsis (49.5%) or septic shock (45.3%). Bacteremia was observed in 15 (15.7%) patients. Bacteremia was secondary to nosocomial pneumonia in eight cases, catheter infection in five, urinary tract infection in one, and soft tissue infection in one. According to their susceptibility profiles, 46 (48.4%) of the strains were classified as extensively drug-resistant (XDR) P. aeruginosa and 35 (36.5%) were multidrug-resistant (MDR) P. aeruginosa.

Sixty-eight (71.6%) patients presented a favorable clinical response, which was defined as a resolution of presenting symptoms and signs of the infection by the end of therapy. An unfavorable clinical response was considered as persistence or worsening of the presenting symptoms and signs or death occurring during treatment with no other cause identified. Death associated with infection was defined as persistence of signs and symptoms of P. aeruginosa infection during C/T therapy with no other cause identified.

Microbiological eradication was documented in 42.1% (40/95) of the episodes. However, the global ICU mortality was still high, at 36.5%, with mortality mainly related to the severity of the infection.

Mortality was found to be significantly correlated with the Charlson Comorbidity Index (5.7 vs. 4.3; P = .04) and the need for life-supporting therapies such as vasopressors (66.6% vs. 46.9%; P = .03) and renal replacement therapy (46.6% vs. 18.1%; P = .002). In addition, mortality was significantly associated with a higher sequential organ failure assessment (SOFA) score during C/T therapy (SOFA1, SOFA 3, and SOFA 7; P < .001).

No significant differences in outcomes were correlated with demographic features, type and severity of infection, and dose of C/T. Also, there were no differences seen in outcomes between patients treated with C/T monotherapy and combined therapy (30.9% vs. 30.1%; P = .55).

“The lack of a positive effect from combined therapy suggests that C/T monotherapy may be sufficient for treating P. aeruginosa isolates that are susceptible to that agent,” the researchers suggested. “This study shows that C/T appears to be a suitable, effective, and safe drug for treating severe infections due to P. aeruginosa, highlighting nosocomial pneumonia caused by MDR/XDR P. aeruginosa in ICU patients with multiple comorbidities, such as immunosuppression, and needing life-sustaining therapies,” they concluded.

The authors reported that they had no outside funding source and had no conflicts of interest.

[email protected]

Ceftolozane-tazobactam (C/T) was found effective for treating pneumonia, intra-abdominal, and urinary tract infections caused by Pseudomonas aeruginosa, according to the results of a retrospective, observational study conducted in critically ill patients.

The multicenter, observational study assessed 95 patients who received C/T for P. aeruginosa serious infections, according to a report published online in the International Journal of Antimicrobial Agents.

C/T is a novel beta-lactam/ beta-lactamase inhibitor combination active against gram-negative bacteria including P. aeruginosa, “This paper presents the largest real-life experience published on C/T therapy for treating serious P. aeruginosa infections according to researchers Barbara Balandin, MD, of the Hospital Universitario Puerta de Hierro, Majadahonda, Spain, and colleagues.

The main infections treated were nosocomial pneumonia (56.2%), intra-abdominal infection (10.5%), tracheobronchitis (8.4%), and urinary tract infection (6.3%). Most infections were complicated with sepsis (49.5%) or septic shock (45.3%), and bacteremia (10.5%).

A total of 46 episodes were treated with high-dose C/T (3 g every 8 hours), and 38 episodes were treated with standard dosage (1.5 g every 8 hours). Almost half (44.2%) of the patients were treated with C/T monotherapy, and the remaining group received combination therapy with other antibiotics, according to the researchers.

The primary outcome of the study was to assess the efficacy and toxicity of C/T therapy. The secondary outcome was to evaluate the risk factors for all-cause 30-day mortality from the first day of therapy.

Favorable results

Most of the infections (93.7%) were severe and included the presence of sepsis (49.5%) or septic shock (45.3%). Bacteremia was observed in 15 (15.7%) patients. Bacteremia was secondary to nosocomial pneumonia in eight cases, catheter infection in five, urinary tract infection in one, and soft tissue infection in one. According to their susceptibility profiles, 46 (48.4%) of the strains were classified as extensively drug-resistant (XDR) P. aeruginosa and 35 (36.5%) were multidrug-resistant (MDR) P. aeruginosa.

Sixty-eight (71.6%) patients presented a favorable clinical response, which was defined as a resolution of presenting symptoms and signs of the infection by the end of therapy. An unfavorable clinical response was considered as persistence or worsening of the presenting symptoms and signs or death occurring during treatment with no other cause identified. Death associated with infection was defined as persistence of signs and symptoms of P. aeruginosa infection during C/T therapy with no other cause identified.

Microbiological eradication was documented in 42.1% (40/95) of the episodes. However, the global ICU mortality was still high, at 36.5%, with mortality mainly related to the severity of the infection.

Mortality was found to be significantly correlated with the Charlson Comorbidity Index (5.7 vs. 4.3; P = .04) and the need for life-supporting therapies such as vasopressors (66.6% vs. 46.9%; P = .03) and renal replacement therapy (46.6% vs. 18.1%; P = .002). In addition, mortality was significantly associated with a higher sequential organ failure assessment (SOFA) score during C/T therapy (SOFA1, SOFA 3, and SOFA 7; P < .001).

No significant differences in outcomes were correlated with demographic features, type and severity of infection, and dose of C/T. Also, there were no differences seen in outcomes between patients treated with C/T monotherapy and combined therapy (30.9% vs. 30.1%; P = .55).

“The lack of a positive effect from combined therapy suggests that C/T monotherapy may be sufficient for treating P. aeruginosa isolates that are susceptible to that agent,” the researchers suggested. “This study shows that C/T appears to be a suitable, effective, and safe drug for treating severe infections due to P. aeruginosa, highlighting nosocomial pneumonia caused by MDR/XDR P. aeruginosa in ICU patients with multiple comorbidities, such as immunosuppression, and needing life-sustaining therapies,” they concluded.

The authors reported that they had no outside funding source and had no conflicts of interest.

[email protected]

COVID-19 infection altered the gut microbiota of adult patients and caused depletion of several types of bacteria with known immunomodulatory properties, based on data from a cohort study of 100 patients with confirmed COVID-19 infections from two hospitals.

“As the GI tract is the largest immunological organ in the body and its resident microbiota are known to modulate host immune responses, we hypothesized that the gut microbiota is associated with host inflammatory immune responses in COVID19,” wrote Yun Kit Yeoh, PhD, of the Chinese University of Hong Kong, and colleagues.

In a study published in Gut, the researchers investigated patient microbiota by collecting blood, stool, and patient records between February and May 2020 from 100 confirmed SARS-CoV-2–infected patients in Hong Kong during hospitalization, as well as follow-up stool samples from 27 patients up to 30 days after they cleared the COVID-19 virus; these observations were compared with 78 non–COVID-19 controls.

Overall, 274 stool samples were sequenced. Samples collected from patients during hospitalization for COVID-19 were compared with non–COVID-19 controls. The presence of phylum Bacteroidetes was significantly higher in COVID-19 patients compared with controls (23.9% vs. 12.8%; P < .001), as were Actinobacteria (26.1% vs. 19.0%; P < .001).

After controlling for antibiotics, the investigators found that “differences between cohorts were primarily linked to enrichment of taxa such as Parabacteroides, Sutterella wadsworthensis, and Bacteroides caccae and depletion of Adlercreutzia equolifaciens, Dorea formicigenerans, and Clostridium leptum in COVID-19 relative to non-COVID-19” (P < .05). In addition, Faecalibacterium prausnitzii and Bifidobacterium bifidum were negatively correlated with COVID-19 severity after investigators controlled for patient age and antibiotic use (P < .05).

The researchers also examined bacteria in COVID-19 patients and controls in the context of cytokines and other inflammatory markers. “We hypothesized that these compositional changes play a role in exacerbating disease by contributing to dysregulation of the immune response,” they said.

In fact, species depleted in COVID-19 patients including included B. adolescentis, E. rectale, and F. prausnitzii were negatively correlated with inflammatory markers including CXCL10, IL-10, TNF-alpha, and CCL2.

In addition, 42 stool samples from 27 patients showed significantly distinct gut microbiota from controls up to 30 days (median, 6 days) after virus clearance, regardless of antibiotics use (P < .05), the researchers said.
 

Long-term data needed

The study findings were limited by several factors, including the potential confounding of microbial signatures associated with COVID-19 because of heterogeneous patient management in the clinical setting and the potential that gut microbiota reflects a patient’s health with no impact on disease severity, as well as lack of data on the role of antibiotics for severe and critical patients, the researchers noted. In addition, “gut microbiota composition is highly heterogeneous across human populations and changes in compositions reported here may not necessarily be reflected in patients with COVID-19 from other biogeographies,” they wrote.

The “longer follow-up of patients with COVID-19 (e.g., 3 months to 1 year after clearing the virus) is needed to address questions related to the duration of gut microbiota dysbiosis post recovery, link between microbiota dysbiosis and long-term persistent symptoms, and whether the dysbiosis or enrichment/depletion of specific gut microorganisms predisposes recovered individuals to future health problems,” they wrote.

However, the results suggest a likely role for gut microorganisms in host inflammatory responses to COVID-19 infection, and “underscore an urgent need to understand the specific roles of gut microorganisms in human immune function and systemic inflammation,” they concluded.
 

More than infectious

“A growing body of evidence suggests that severity of illness from COVID-19 is largely determined by the patient’s aberrant immune response to the virus,” Jatin Roper, MD, of Duke University, Durham, N.C., said in an interview. “Therefore, a critical question is: What patient factors determine this immune response? The gut microbiota closely interact with the host immune system and are altered in many immunological diseases,” he said. “Furthermore, the SARS-CoV-2 virus infects enterocytes in the intestine and causes symptomatic gastrointestinal disease in a subset of patients. Therefore, understanding a possible association between gut microbiota and COVID-19 may reveal microbial species involved in disease pathogenesis,” he emphasized.   

In the current study, “I was surprised to find that COVID-19 infection is associated with depletion of immunomodulatory gut bacteria,” said Dr. Roper. “An open question is whether these changes are caused by the SARS-CoV-2 virus and then result in altered immune response. Alternatively, the changes in gut microbiota may be a result of the immune response or other changes associated with the disease,” he said.

“COVID-19 is an immunological disease, not just an infectious disease,” explained Dr. Roper. “The gut microbiota may play an important role in the pathogenesis of the disease. Thus, specific gut microbes could one day be analyzed to risk stratify patients, or even modified to treat the disease,” he noted.
 

Beyond COVID-19

“Given the impact of the gut microbiota on health and disease, as well as the impact of diseases on the microbiota, I am not at all surprised to find that there were significant changes in the microbiota of COVID-19 patients and that these changes are associated with inflammatory cytokines, chemokines, and blood markers of tissue damage,” said Anthony Sung, MD, also of Duke University.

According to Dr. Sung, researchers have already been investigating possible connections between gut microbiota and other conditions such as Alzheimer’s disease, and it’s been hypothesized that these connections are mediated by interactions between the gut microbiota and the immune system.

“While this is an important paper in our understanding of COVID-19, and highlights the microbiome as a potential therapeutic target, we need to conduct clinical trials of microbiota-based interventions before we can fully realize the clinical implications of these findings,” he said.

The study was supported by the Health and Medical Research Fund, the Food and Health Bureau, The Government of the Hong Kong Special Administrative Region, and donations from Hui Hoy & Chow Sin Lan Charity Fund Limited, Pine and Crane Company Limited, Mr. Hui Ming, and The D.H. Chen Foundation. The researchers had no financial conflicts to disclose. Dr. Roper and Dr. Sung had no financial conflicts to disclose.

COVID-19 infection altered the gut microbiota of adult patients and caused depletion of several types of bacteria with known immunomodulatory properties, based on data from a cohort study of 100 patients with confirmed COVID-19 infections from two hospitals.

“As the GI tract is the largest immunological organ in the body and its resident microbiota are known to modulate host immune responses, we hypothesized that the gut microbiota is associated with host inflammatory immune responses in COVID19,” wrote Yun Kit Yeoh, PhD, of the Chinese University of Hong Kong, and colleagues.

In a study published in Gut, the researchers investigated patient microbiota by collecting blood, stool, and patient records between February and May 2020 from 100 confirmed SARS-CoV-2–infected patients in Hong Kong during hospitalization, as well as follow-up stool samples from 27 patients up to 30 days after they cleared the COVID-19 virus; these observations were compared with 78 non–COVID-19 controls.

Overall, 274 stool samples were sequenced. Samples collected from patients during hospitalization for COVID-19 were compared with non–COVID-19 controls. The presence of phylum Bacteroidetes was significantly higher in COVID-19 patients compared with controls (23.9% vs. 12.8%; P < .001), as were Actinobacteria (26.1% vs. 19.0%; P < .001).

After controlling for antibiotics, the investigators found that “differences between cohorts were primarily linked to enrichment of taxa such as Parabacteroides, Sutterella wadsworthensis, and Bacteroides caccae and depletion of Adlercreutzia equolifaciens, Dorea formicigenerans, and Clostridium leptum in COVID-19 relative to non-COVID-19” (P < .05). In addition, Faecalibacterium prausnitzii and Bifidobacterium bifidum were negatively correlated with COVID-19 severity after investigators controlled for patient age and antibiotic use (P < .05).

The researchers also examined bacteria in COVID-19 patients and controls in the context of cytokines and other inflammatory markers. “We hypothesized that these compositional changes play a role in exacerbating disease by contributing to dysregulation of the immune response,” they said.

In fact, species depleted in COVID-19 patients including included B. adolescentis, E. rectale, and F. prausnitzii were negatively correlated with inflammatory markers including CXCL10, IL-10, TNF-alpha, and CCL2.

In addition, 42 stool samples from 27 patients showed significantly distinct gut microbiota from controls up to 30 days (median, 6 days) after virus clearance, regardless of antibiotics use (P < .05), the researchers said.
 

Long-term data needed

The study findings were limited by several factors, including the potential confounding of microbial signatures associated with COVID-19 because of heterogeneous patient management in the clinical setting and the potential that gut microbiota reflects a patient’s health with no impact on disease severity, as well as lack of data on the role of antibiotics for severe and critical patients, the researchers noted. In addition, “gut microbiota composition is highly heterogeneous across human populations and changes in compositions reported here may not necessarily be reflected in patients with COVID-19 from other biogeographies,” they wrote.

The “longer follow-up of patients with COVID-19 (e.g., 3 months to 1 year after clearing the virus) is needed to address questions related to the duration of gut microbiota dysbiosis post recovery, link between microbiota dysbiosis and long-term persistent symptoms, and whether the dysbiosis or enrichment/depletion of specific gut microorganisms predisposes recovered individuals to future health problems,” they wrote.

However, the results suggest a likely role for gut microorganisms in host inflammatory responses to COVID-19 infection, and “underscore an urgent need to understand the specific roles of gut microorganisms in human immune function and systemic inflammation,” they concluded.
 

More than infectious

“A growing body of evidence suggests that severity of illness from COVID-19 is largely determined by the patient’s aberrant immune response to the virus,” Jatin Roper, MD, of Duke University, Durham, N.C., said in an interview. “Therefore, a critical question is: What patient factors determine this immune response? The gut microbiota closely interact with the host immune system and are altered in many immunological diseases,” he said. “Furthermore, the SARS-CoV-2 virus infects enterocytes in the intestine and causes symptomatic gastrointestinal disease in a subset of patients. Therefore, understanding a possible association between gut microbiota and COVID-19 may reveal microbial species involved in disease pathogenesis,” he emphasized.   

In the current study, “I was surprised to find that COVID-19 infection is associated with depletion of immunomodulatory gut bacteria,” said Dr. Roper. “An open question is whether these changes are caused by the SARS-CoV-2 virus and then result in altered immune response. Alternatively, the changes in gut microbiota may be a result of the immune response or other changes associated with the disease,” he said.

“COVID-19 is an immunological disease, not just an infectious disease,” explained Dr. Roper. “The gut microbiota may play an important role in the pathogenesis of the disease. Thus, specific gut microbes could one day be analyzed to risk stratify patients, or even modified to treat the disease,” he noted.
 

Beyond COVID-19

“Given the impact of the gut microbiota on health and disease, as well as the impact of diseases on the microbiota, I am not at all surprised to find that there were significant changes in the microbiota of COVID-19 patients and that these changes are associated with inflammatory cytokines, chemokines, and blood markers of tissue damage,” said Anthony Sung, MD, also of Duke University.

According to Dr. Sung, researchers have already been investigating possible connections between gut microbiota and other conditions such as Alzheimer’s disease, and it’s been hypothesized that these connections are mediated by interactions between the gut microbiota and the immune system.

“While this is an important paper in our understanding of COVID-19, and highlights the microbiome as a potential therapeutic target, we need to conduct clinical trials of microbiota-based interventions before we can fully realize the clinical implications of these findings,” he said.

The study was supported by the Health and Medical Research Fund, the Food and Health Bureau, The Government of the Hong Kong Special Administrative Region, and donations from Hui Hoy & Chow Sin Lan Charity Fund Limited, Pine and Crane Company Limited, Mr. Hui Ming, and The D.H. Chen Foundation. The researchers had no financial conflicts to disclose. Dr. Roper and Dr. Sung had no financial conflicts to disclose.

COVID-19 infection altered the gut microbiota of adult patients and caused depletion of several types of bacteria with known immunomodulatory properties, based on data from a cohort study of 100 patients with confirmed COVID-19 infections from two hospitals.

“As the GI tract is the largest immunological organ in the body and its resident microbiota are known to modulate host immune responses, we hypothesized that the gut microbiota is associated with host inflammatory immune responses in COVID19,” wrote Yun Kit Yeoh, PhD, of the Chinese University of Hong Kong, and colleagues.

In a study published in Gut, the researchers investigated patient microbiota by collecting blood, stool, and patient records between February and May 2020 from 100 confirmed SARS-CoV-2–infected patients in Hong Kong during hospitalization, as well as follow-up stool samples from 27 patients up to 30 days after they cleared the COVID-19 virus; these observations were compared with 78 non–COVID-19 controls.

Overall, 274 stool samples were sequenced. Samples collected from patients during hospitalization for COVID-19 were compared with non–COVID-19 controls. The presence of phylum Bacteroidetes was significantly higher in COVID-19 patients compared with controls (23.9% vs. 12.8%; P < .001), as were Actinobacteria (26.1% vs. 19.0%; P < .001).

After controlling for antibiotics, the investigators found that “differences between cohorts were primarily linked to enrichment of taxa such as Parabacteroides, Sutterella wadsworthensis, and Bacteroides caccae and depletion of Adlercreutzia equolifaciens, Dorea formicigenerans, and Clostridium leptum in COVID-19 relative to non-COVID-19” (P < .05). In addition, Faecalibacterium prausnitzii and Bifidobacterium bifidum were negatively correlated with COVID-19 severity after investigators controlled for patient age and antibiotic use (P < .05).

The researchers also examined bacteria in COVID-19 patients and controls in the context of cytokines and other inflammatory markers. “We hypothesized that these compositional changes play a role in exacerbating disease by contributing to dysregulation of the immune response,” they said.

In fact, species depleted in COVID-19 patients including included B. adolescentis, E. rectale, and F. prausnitzii were negatively correlated with inflammatory markers including CXCL10, IL-10, TNF-alpha, and CCL2.

In addition, 42 stool samples from 27 patients showed significantly distinct gut microbiota from controls up to 30 days (median, 6 days) after virus clearance, regardless of antibiotics use (P < .05), the researchers said.
 

Long-term data needed

The study findings were limited by several factors, including the potential confounding of microbial signatures associated with COVID-19 because of heterogeneous patient management in the clinical setting and the potential that gut microbiota reflects a patient’s health with no impact on disease severity, as well as lack of data on the role of antibiotics for severe and critical patients, the researchers noted. In addition, “gut microbiota composition is highly heterogeneous across human populations and changes in compositions reported here may not necessarily be reflected in patients with COVID-19 from other biogeographies,” they wrote.

The “longer follow-up of patients with COVID-19 (e.g., 3 months to 1 year after clearing the virus) is needed to address questions related to the duration of gut microbiota dysbiosis post recovery, link between microbiota dysbiosis and long-term persistent symptoms, and whether the dysbiosis or enrichment/depletion of specific gut microorganisms predisposes recovered individuals to future health problems,” they wrote.

However, the results suggest a likely role for gut microorganisms in host inflammatory responses to COVID-19 infection, and “underscore an urgent need to understand the specific roles of gut microorganisms in human immune function and systemic inflammation,” they concluded.
 

More than infectious

“A growing body of evidence suggests that severity of illness from COVID-19 is largely determined by the patient’s aberrant immune response to the virus,” Jatin Roper, MD, of Duke University, Durham, N.C., said in an interview. “Therefore, a critical question is: What patient factors determine this immune response? The gut microbiota closely interact with the host immune system and are altered in many immunological diseases,” he said. “Furthermore, the SARS-CoV-2 virus infects enterocytes in the intestine and causes symptomatic gastrointestinal disease in a subset of patients. Therefore, understanding a possible association between gut microbiota and COVID-19 may reveal microbial species involved in disease pathogenesis,” he emphasized.   

In the current study, “I was surprised to find that COVID-19 infection is associated with depletion of immunomodulatory gut bacteria,” said Dr. Roper. “An open question is whether these changes are caused by the SARS-CoV-2 virus and then result in altered immune response. Alternatively, the changes in gut microbiota may be a result of the immune response or other changes associated with the disease,” he said.

“COVID-19 is an immunological disease, not just an infectious disease,” explained Dr. Roper. “The gut microbiota may play an important role in the pathogenesis of the disease. Thus, specific gut microbes could one day be analyzed to risk stratify patients, or even modified to treat the disease,” he noted.
 

Beyond COVID-19

“Given the impact of the gut microbiota on health and disease, as well as the impact of diseases on the microbiota, I am not at all surprised to find that there were significant changes in the microbiota of COVID-19 patients and that these changes are associated with inflammatory cytokines, chemokines, and blood markers of tissue damage,” said Anthony Sung, MD, also of Duke University.

According to Dr. Sung, researchers have already been investigating possible connections between gut microbiota and other conditions such as Alzheimer’s disease, and it’s been hypothesized that these connections are mediated by interactions between the gut microbiota and the immune system.

“While this is an important paper in our understanding of COVID-19, and highlights the microbiome as a potential therapeutic target, we need to conduct clinical trials of microbiota-based interventions before we can fully realize the clinical implications of these findings,” he said.

The study was supported by the Health and Medical Research Fund, the Food and Health Bureau, The Government of the Hong Kong Special Administrative Region, and donations from Hui Hoy & Chow Sin Lan Charity Fund Limited, Pine and Crane Company Limited, Mr. Hui Ming, and The D.H. Chen Foundation. The researchers had no financial conflicts to disclose. Dr. Roper and Dr. Sung had no financial conflicts to disclose.

The COVID-19 variants that have emerged in the United Kingdom, Brazil, South Africa and now Southern California are eliciting two notably distinct responses from U.S. public health officials.

janiecbros/iStock/Getty Images Plus

First, broad concern. A variant that wreaked havoc in the United Kingdom, leading to a spike in cases and hospitalizations, is surfacing in a growing number of places in the United States. During the week of Jan. 24, another worrisome variant seen in Brazil surfaced in Minnesota. If these or other strains significantly change the way the virus transmits and attacks the body, as scientists fear they might, they could cause yet another prolonged surge in illness and death in the U.S., even as cases have begun to plateau and vaccines are rolling out.

On the other hand, variants aren’t novel or even uncommon in viral illnesses. The viruses that trigger common colds and flus regularly evolve. Even if a mutated strain of SARS-CoV-2, the virus that causes COVID-19, makes it more contagious or makes people sicker, the basic public health response stays the same: Monitor the virus, and any mutations, as it moves across communities. Use masking, testing, physical distancing, and quarantine to contain the spread.

The problem is that the U.S. has struggled with every step of its public health response in its first year of battle against COVID-19. And that raises the question of whether the nation will devote the attention and resources needed to outflank the virus as it evolves.

Researchers are quick to stress that a coronavirus mutation in itself is no cause for alarm. In the course of making millions and billions of copies as part of the infection process, small changes to a virus’s genome happen all the time as a function of evolutionary biology.

“The word ‘variant’ and the word ‘mutation’ have these scary connotations, and they aren’t necessarily scary,” said Kelly Wroblewski, director of infectious disease programs for the Association of Public Health Laboratories.

When a mutation rings public health alarms, it’s typically because it has combined with other mutations and, collectively, changed how the virus behaves. At that point, it may be named a variant. A variant can make a virus spread faster, or more easily jump between species. It can make a virus more successful at making people sicker, or change how our immune systems respond.

SARS-CoV-2 has been mutating for as long as we’ve known about it; mutations were identified by scientists throughout 2020. Though relevant scientifically – mutations can actually be helpful, acting like a fingerprint that allows scientists to track a virus’s spread – the identified strains mostly carried little concern for public health.

Then came the end of the year, when several variants began drawing scrutiny. One of the most concerning, first detected in the United Kingdom, appears to make the virus more transmissible. Emerging evidence suggests it also could be deadlier, though scientists are still debating that.

We know more about the U.K. variant than others not because it’s necessarily worse, but because the British have one of the best virus surveillance programs in the world, said William Hanage, PhD, an epidemiologist and a professor at Harvard University.

By contrast, the U.S. has one of the weakest genomic surveillance programs of any rich country, Dr. Hanage said. “As it is, people like me cobble together partnerships with places and try and beg them” for samples, he said on a recent call with reporters.

Other variant strains were identified in South Africa and Brazil, and they share some mutations with the U.K. variant. That those changes evolved independently in several parts of the world suggests they might present an evolutionary advantage for the virus. Yet another strain was recently identified in Southern California and flagged due to its increasing presence in hard-hit cities like Los Angeles.

The Southern California strain was detected because a team of researchers at Cedars-Sinai, a hospital and research center in Los Angeles, has unfettered access to patient samples. They were able to see that the strain made up a growing share of cases at the hospital in recent weeks, as well as among the limited number of other samples haphazardly collected at a network of labs in the region.

Not only does the U.S. do less genomic sequencing than most wealthy countries, but it also does its surveillance by happenstance. That means it takes longer to detect new strains and draw conclusions about them. It’s not yet clear, for example, whether that Southern California strain was truly worthy of a press release.

Vast swaths of America’s privatized and decentralized system of health care aren’t set up to send samples to public health or academic labs. “I’m more concerned about the systems to detect variants than I am these particular variants,” said Mark Pandori, PhD, director of Nevada’s public health laboratory and associate professor at the University of Nevada-Reno School of Medicine.

Limited genomic surveillance of viruses is yet another side effect of a fragmented and underfunded public health system that’s struggled to test, track contacts and get COVID-19 under control throughout the pandemic, Ms. Wroblewski said.

The nation’s public health infrastructure, generally funded on a disease-by-disease basis, has decent systems set up to sequence flu, foodborne illnesses and tuberculosis, but there has been no national strategy on COVID-19. “To look for variants, it needs to be a national picture if it’s going to be done well,” Ms. Wroblewski said.

The Biden administration has outlined a strategy for a national response to COVID-19, which includes expanded surveillance for variants.

So far, vaccines for COVID-19 appear to protect against the known variants. Moderna has said its vaccine is effective against the U.K. and South African strains, though it yields fewer antibodies in the face of the latter. The company is working to develop a revised dose of the vaccine that could be added to the current two-shot regimen as a precaution.

But a lot of damage can be done in the time it will take to roll out the current vaccine, let alone an update.

Even with limited sampling, the U.K. variant has been detected in more than two dozen U.S. states, and the Centers for Disease Control and Prevention has warned it could be the predominant strain in the U.S. by March. When it took off in the United Kingdom at the end of last year, it caused a swell in cases, overwhelmed hospitals, and led to a holiday lockdown. Whether the U.S. faces the same fate could depend on which strains it is competing against, and how the public behaves in the weeks ahead.

Already risky interactions among people could, on average, get a little riskier. Many researchers are calling for better masks and better indoor ventilation. But any updates on recommendations likely would play at the margins. Even if variants spread more easily, the same recommendations public health experts have been espousing for months – masking, physical distancing, and limiting time indoors with others – will be the best way to ward them off, said Kirsten Bibbins-Domingo, MD, a physician and professor at the University of California, San Francisco.

“It’s very unsexy what the solutions are,” Dr. Bibbins-Domingo said. “But we need everyone to do them.”

That doesn’t make the task simple. Masking remains controversial in many states, and the public’s patience for maintaining physical distance has worn thin.

Adding to the concerns: Though case numbers stabilized in many parts of the U.S. in January, they have stabilized at rates many times what they were during previous periods in the pandemic or in other parts of the world. Having all that virus in so many bodies creates more opportunities for new mutations and new variants to emerge.

“If we keep letting this thing sneak around, it’s going to get around all the measures we take against it, and that’s the worst possible thing,” said Nevada’s Dr. Pandori.

Compared with less virulent strains, a more contagious variant likely will require that more people be vaccinated before a community can see the benefits of widespread immunity. It’s a bleak outlook for a nation already falling behind in the race to vaccinate enough people to bring the pandemic under control.

“When your best solution is to ask people to do the things that they don’t like to do anyway, that’s very scary,” said Dr. Bibbins-Domingo.
 

This story was produced by KHN, which publishes California Healthline, an editorially independent service of the California Health Care Foundation.

The COVID-19 variants that have emerged in the United Kingdom, Brazil, South Africa and now Southern California are eliciting two notably distinct responses from U.S. public health officials.

janiecbros/iStock/Getty Images Plus

First, broad concern. A variant that wreaked havoc in the United Kingdom, leading to a spike in cases and hospitalizations, is surfacing in a growing number of places in the United States. During the week of Jan. 24, another worrisome variant seen in Brazil surfaced in Minnesota. If these or other strains significantly change the way the virus transmits and attacks the body, as scientists fear they might, they could cause yet another prolonged surge in illness and death in the U.S., even as cases have begun to plateau and vaccines are rolling out.

On the other hand, variants aren’t novel or even uncommon in viral illnesses. The viruses that trigger common colds and flus regularly evolve. Even if a mutated strain of SARS-CoV-2, the virus that causes COVID-19, makes it more contagious or makes people sicker, the basic public health response stays the same: Monitor the virus, and any mutations, as it moves across communities. Use masking, testing, physical distancing, and quarantine to contain the spread.

The problem is that the U.S. has struggled with every step of its public health response in its first year of battle against COVID-19. And that raises the question of whether the nation will devote the attention and resources needed to outflank the virus as it evolves.

Researchers are quick to stress that a coronavirus mutation in itself is no cause for alarm. In the course of making millions and billions of copies as part of the infection process, small changes to a virus’s genome happen all the time as a function of evolutionary biology.

“The word ‘variant’ and the word ‘mutation’ have these scary connotations, and they aren’t necessarily scary,” said Kelly Wroblewski, director of infectious disease programs for the Association of Public Health Laboratories.

When a mutation rings public health alarms, it’s typically because it has combined with other mutations and, collectively, changed how the virus behaves. At that point, it may be named a variant. A variant can make a virus spread faster, or more easily jump between species. It can make a virus more successful at making people sicker, or change how our immune systems respond.

SARS-CoV-2 has been mutating for as long as we’ve known about it; mutations were identified by scientists throughout 2020. Though relevant scientifically – mutations can actually be helpful, acting like a fingerprint that allows scientists to track a virus’s spread – the identified strains mostly carried little concern for public health.

Then came the end of the year, when several variants began drawing scrutiny. One of the most concerning, first detected in the United Kingdom, appears to make the virus more transmissible. Emerging evidence suggests it also could be deadlier, though scientists are still debating that.

We know more about the U.K. variant than others not because it’s necessarily worse, but because the British have one of the best virus surveillance programs in the world, said William Hanage, PhD, an epidemiologist and a professor at Harvard University.

By contrast, the U.S. has one of the weakest genomic surveillance programs of any rich country, Dr. Hanage said. “As it is, people like me cobble together partnerships with places and try and beg them” for samples, he said on a recent call with reporters.

Other variant strains were identified in South Africa and Brazil, and they share some mutations with the U.K. variant. That those changes evolved independently in several parts of the world suggests they might present an evolutionary advantage for the virus. Yet another strain was recently identified in Southern California and flagged due to its increasing presence in hard-hit cities like Los Angeles.

The Southern California strain was detected because a team of researchers at Cedars-Sinai, a hospital and research center in Los Angeles, has unfettered access to patient samples. They were able to see that the strain made up a growing share of cases at the hospital in recent weeks, as well as among the limited number of other samples haphazardly collected at a network of labs in the region.

Not only does the U.S. do less genomic sequencing than most wealthy countries, but it also does its surveillance by happenstance. That means it takes longer to detect new strains and draw conclusions about them. It’s not yet clear, for example, whether that Southern California strain was truly worthy of a press release.

Vast swaths of America’s privatized and decentralized system of health care aren’t set up to send samples to public health or academic labs. “I’m more concerned about the systems to detect variants than I am these particular variants,” said Mark Pandori, PhD, director of Nevada’s public health laboratory and associate professor at the University of Nevada-Reno School of Medicine.

Limited genomic surveillance of viruses is yet another side effect of a fragmented and underfunded public health system that’s struggled to test, track contacts and get COVID-19 under control throughout the pandemic, Ms. Wroblewski said.

The nation’s public health infrastructure, generally funded on a disease-by-disease basis, has decent systems set up to sequence flu, foodborne illnesses and tuberculosis, but there has been no national strategy on COVID-19. “To look for variants, it needs to be a national picture if it’s going to be done well,” Ms. Wroblewski said.

The Biden administration has outlined a strategy for a national response to COVID-19, which includes expanded surveillance for variants.

So far, vaccines for COVID-19 appear to protect against the known variants. Moderna has said its vaccine is effective against the U.K. and South African strains, though it yields fewer antibodies in the face of the latter. The company is working to develop a revised dose of the vaccine that could be added to the current two-shot regimen as a precaution.

But a lot of damage can be done in the time it will take to roll out the current vaccine, let alone an update.

Even with limited sampling, the U.K. variant has been detected in more than two dozen U.S. states, and the Centers for Disease Control and Prevention has warned it could be the predominant strain in the U.S. by March. When it took off in the United Kingdom at the end of last year, it caused a swell in cases, overwhelmed hospitals, and led to a holiday lockdown. Whether the U.S. faces the same fate could depend on which strains it is competing against, and how the public behaves in the weeks ahead.

Already risky interactions among people could, on average, get a little riskier. Many researchers are calling for better masks and better indoor ventilation. But any updates on recommendations likely would play at the margins. Even if variants spread more easily, the same recommendations public health experts have been espousing for months – masking, physical distancing, and limiting time indoors with others – will be the best way to ward them off, said Kirsten Bibbins-Domingo, MD, a physician and professor at the University of California, San Francisco.

“It’s very unsexy what the solutions are,” Dr. Bibbins-Domingo said. “But we need everyone to do them.”

That doesn’t make the task simple. Masking remains controversial in many states, and the public’s patience for maintaining physical distance has worn thin.

Adding to the concerns: Though case numbers stabilized in many parts of the U.S. in January, they have stabilized at rates many times what they were during previous periods in the pandemic or in other parts of the world. Having all that virus in so many bodies creates more opportunities for new mutations and new variants to emerge.

“If we keep letting this thing sneak around, it’s going to get around all the measures we take against it, and that’s the worst possible thing,” said Nevada’s Dr. Pandori.

Compared with less virulent strains, a more contagious variant likely will require that more people be vaccinated before a community can see the benefits of widespread immunity. It’s a bleak outlook for a nation already falling behind in the race to vaccinate enough people to bring the pandemic under control.

“When your best solution is to ask people to do the things that they don’t like to do anyway, that’s very scary,” said Dr. Bibbins-Domingo.
 

This story was produced by KHN, which publishes California Healthline, an editorially independent service of the California Health Care Foundation.

The COVID-19 variants that have emerged in the United Kingdom, Brazil, South Africa and now Southern California are eliciting two notably distinct responses from U.S. public health officials.

janiecbros/iStock/Getty Images Plus

First, broad concern. A variant that wreaked havoc in the United Kingdom, leading to a spike in cases and hospitalizations, is surfacing in a growing number of places in the United States. During the week of Jan. 24, another worrisome variant seen in Brazil surfaced in Minnesota. If these or other strains significantly change the way the virus transmits and attacks the body, as scientists fear they might, they could cause yet another prolonged surge in illness and death in the U.S., even as cases have begun to plateau and vaccines are rolling out.

On the other hand, variants aren’t novel or even uncommon in viral illnesses. The viruses that trigger common colds and flus regularly evolve. Even if a mutated strain of SARS-CoV-2, the virus that causes COVID-19, makes it more contagious or makes people sicker, the basic public health response stays the same: Monitor the virus, and any mutations, as it moves across communities. Use masking, testing, physical distancing, and quarantine to contain the spread.

The problem is that the U.S. has struggled with every step of its public health response in its first year of battle against COVID-19. And that raises the question of whether the nation will devote the attention and resources needed to outflank the virus as it evolves.

Researchers are quick to stress that a coronavirus mutation in itself is no cause for alarm. In the course of making millions and billions of copies as part of the infection process, small changes to a virus’s genome happen all the time as a function of evolutionary biology.

“The word ‘variant’ and the word ‘mutation’ have these scary connotations, and they aren’t necessarily scary,” said Kelly Wroblewski, director of infectious disease programs for the Association of Public Health Laboratories.

When a mutation rings public health alarms, it’s typically because it has combined with other mutations and, collectively, changed how the virus behaves. At that point, it may be named a variant. A variant can make a virus spread faster, or more easily jump between species. It can make a virus more successful at making people sicker, or change how our immune systems respond.

SARS-CoV-2 has been mutating for as long as we’ve known about it; mutations were identified by scientists throughout 2020. Though relevant scientifically – mutations can actually be helpful, acting like a fingerprint that allows scientists to track a virus’s spread – the identified strains mostly carried little concern for public health.

Then came the end of the year, when several variants began drawing scrutiny. One of the most concerning, first detected in the United Kingdom, appears to make the virus more transmissible. Emerging evidence suggests it also could be deadlier, though scientists are still debating that.

We know more about the U.K. variant than others not because it’s necessarily worse, but because the British have one of the best virus surveillance programs in the world, said William Hanage, PhD, an epidemiologist and a professor at Harvard University.

By contrast, the U.S. has one of the weakest genomic surveillance programs of any rich country, Dr. Hanage said. “As it is, people like me cobble together partnerships with places and try and beg them” for samples, he said on a recent call with reporters.

Other variant strains were identified in South Africa and Brazil, and they share some mutations with the U.K. variant. That those changes evolved independently in several parts of the world suggests they might present an evolutionary advantage for the virus. Yet another strain was recently identified in Southern California and flagged due to its increasing presence in hard-hit cities like Los Angeles.

The Southern California strain was detected because a team of researchers at Cedars-Sinai, a hospital and research center in Los Angeles, has unfettered access to patient samples. They were able to see that the strain made up a growing share of cases at the hospital in recent weeks, as well as among the limited number of other samples haphazardly collected at a network of labs in the region.

Not only does the U.S. do less genomic sequencing than most wealthy countries, but it also does its surveillance by happenstance. That means it takes longer to detect new strains and draw conclusions about them. It’s not yet clear, for example, whether that Southern California strain was truly worthy of a press release.

Vast swaths of America’s privatized and decentralized system of health care aren’t set up to send samples to public health or academic labs. “I’m more concerned about the systems to detect variants than I am these particular variants,” said Mark Pandori, PhD, director of Nevada’s public health laboratory and associate professor at the University of Nevada-Reno School of Medicine.

Limited genomic surveillance of viruses is yet another side effect of a fragmented and underfunded public health system that’s struggled to test, track contacts and get COVID-19 under control throughout the pandemic, Ms. Wroblewski said.

The nation’s public health infrastructure, generally funded on a disease-by-disease basis, has decent systems set up to sequence flu, foodborne illnesses and tuberculosis, but there has been no national strategy on COVID-19. “To look for variants, it needs to be a national picture if it’s going to be done well,” Ms. Wroblewski said.

The Biden administration has outlined a strategy for a national response to COVID-19, which includes expanded surveillance for variants.

So far, vaccines for COVID-19 appear to protect against the known variants. Moderna has said its vaccine is effective against the U.K. and South African strains, though it yields fewer antibodies in the face of the latter. The company is working to develop a revised dose of the vaccine that could be added to the current two-shot regimen as a precaution.

But a lot of damage can be done in the time it will take to roll out the current vaccine, let alone an update.

Even with limited sampling, the U.K. variant has been detected in more than two dozen U.S. states, and the Centers for Disease Control and Prevention has warned it could be the predominant strain in the U.S. by March. When it took off in the United Kingdom at the end of last year, it caused a swell in cases, overwhelmed hospitals, and led to a holiday lockdown. Whether the U.S. faces the same fate could depend on which strains it is competing against, and how the public behaves in the weeks ahead.

Already risky interactions among people could, on average, get a little riskier. Many researchers are calling for better masks and better indoor ventilation. But any updates on recommendations likely would play at the margins. Even if variants spread more easily, the same recommendations public health experts have been espousing for months – masking, physical distancing, and limiting time indoors with others – will be the best way to ward them off, said Kirsten Bibbins-Domingo, MD, a physician and professor at the University of California, San Francisco.

“It’s very unsexy what the solutions are,” Dr. Bibbins-Domingo said. “But we need everyone to do them.”

That doesn’t make the task simple. Masking remains controversial in many states, and the public’s patience for maintaining physical distance has worn thin.

Adding to the concerns: Though case numbers stabilized in many parts of the U.S. in January, they have stabilized at rates many times what they were during previous periods in the pandemic or in other parts of the world. Having all that virus in so many bodies creates more opportunities for new mutations and new variants to emerge.

“If we keep letting this thing sneak around, it’s going to get around all the measures we take against it, and that’s the worst possible thing,” said Nevada’s Dr. Pandori.

Compared with less virulent strains, a more contagious variant likely will require that more people be vaccinated before a community can see the benefits of widespread immunity. It’s a bleak outlook for a nation already falling behind in the race to vaccinate enough people to bring the pandemic under control.

“When your best solution is to ask people to do the things that they don’t like to do anyway, that’s very scary,” said Dr. Bibbins-Domingo.
 

This story was produced by KHN, which publishes California Healthline, an editorially independent service of the California Health Care Foundation.

Experts discuss how to best protect people with diabetes from serious COVID-19 outcomes in a newly published article that summarizes in-depth discussions on the topic from a conference held online last year.

Lead author and Diabetes Technology Society founder and director David C. Klonoff, MD, said in an interview: “To my knowledge this is the largest article or learning that has been written anywhere ever about the co-occurrence of COVID-19 and diabetes and how COVID-19 affects diabetes ... There are a lot of different dimensions.” 

The 37-page report covers all sessions from the Virtual International COVID-19 and Diabetes Summit, held Aug. 26-27, 2020, which had 800 attendees from six continents, on topics including pathophysiology and COVID-19 risk factors, the impact of social determinants of health on diabetes and COVID-19, and psychological aspects of the COVID-19 pandemic for people with diabetes.

The freely available report was published online Jan. 21 in the Journal of Diabetes Science and Technology by Jennifer Y. Zhang of the Diabetes Technology Society, Burlingame, Calif., and colleagues.

Other topics include medications and vaccines, outpatient diabetes management during the COVID-19 pandemic and the growth of telehealth, inpatient management of diabetes in patients with or without COVID-19, ethical considerations, children, pregnancy, economics of care for COVID-19, government policy, regulation of tests and treatments, patient surveillance/privacy, and research gaps and opportunities.

“A comprehensive report like this is so important because it covers such a wide range of topics that are all relevant when it comes to protecting patients with diabetes during a pandemic. Our report aims to bring together all these different aspects of policy during the pandemic, patient physiology, and patient psychology, so I hope it will be widely read and widely appreciated,” Ms. Zhang said in an interview.

Two important clinical trends arising as a result of the pandemic – the advent of telehealth in diabetes management and the use of continuous glucose monitoring (CGM) in hospital – are expected to continue even after COVID-19 abates, said Dr. Klonoff, medical director of the Diabetes Research Institute at Mills-Peninsula Medical Center, San Mateo, Calif.


 

Telehealth in diabetes here to stay, in U.S. at least  

Dr. Klonoff noted that with diabetes telehealth, or “telediabetes” as it’s been dubbed, by using downloaded device data patients don’t have to travel, pay for parking, or take as much time off work. “There are advantages ... patients really like it,” he said.

And for health care providers, an advantage of remote visits is that the clinician can look at the patient while reviewing the patient’s data. “With telehealth for diabetes, the patient’s face and the software data are right next to each other on the same screen. Even as I’m typing I’m looking at the patient ... I consider that a huge advantage,” Dr. Klonoff said.

Rule changes early in the pandemic made the shift to telehealth in the United States possible, he said.

“Fortunately, Medicare and other payers are covering telehealth. It used to be there was no coverage, so that was a damper. Now that it’s covered I don’t think that’s going to go back. Everybody likes it,” he said. 
 

CGM in hospitals helps detect hypoglycemia on wards

Regarding the increase of inpatient CGM (continuous glucose monitoring) prompted by the need to minimize patient exposure of nursing staff during the pandemic and the relaxing of Food and Drug Administration rules about its use, Dr. Klonoff said this phenomenon has led to two other positive developments.

“For FDA, it’s actually an opportunity to see some data collected. To do a clinical trial [prior to] March 2020 you had to go through a lot of processes to do a study. Once it becomes part of clinical care, then you can collect a lot of data,” he noted.   

Moreover, Dr. Klonoff said there’s an important new area where hospital use of CGM is emerging: detection of hypoglycemia on wards.

“When a patient is in the ICU, if they become hypoglycemic or hyperglycemic it will likely be detected. But on the wards, they simply don’t get the same attention. Just about every doctor has had a case where somebody drifted into hypoglycemia that wasn’t recognized and maybe even died,” he explained.

If, however, “patients treated with insulin could all have CGMs that would be so useful. It would send out an alarm. A lot of times people don’t eat when you think they will. Suddenly the insulin dose is inappropriate and the nurse didn’t realize. Or, if IV nutrition stops and the insulin is given [it can be harmful].”

Another example, he said, is a common scenario when insulin is used in patients who are treated with steroids. “They need insulin, but then the steroid is decreased and the insulin dose isn’t decreased fast enough. All those situations can be helped with CGM.”

Overall, he concluded, COVID-19 has provided many lessons, which are “expanding our horizons.”

Ms. Zhang has reported no relevant financial relationships. Dr. Klonoff has reported being a consultant for Dexcom, EOFlow, Fractyl, Lifecare, Novo Nordisk, Roche Diagnostics, Samsung, and Thirdwayv.

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

Experts discuss how to best protect people with diabetes from serious COVID-19 outcomes in a newly published article that summarizes in-depth discussions on the topic from a conference held online last year.

Lead author and Diabetes Technology Society founder and director David C. Klonoff, MD, said in an interview: “To my knowledge this is the largest article or learning that has been written anywhere ever about the co-occurrence of COVID-19 and diabetes and how COVID-19 affects diabetes ... There are a lot of different dimensions.” 

The 37-page report covers all sessions from the Virtual International COVID-19 and Diabetes Summit, held Aug. 26-27, 2020, which had 800 attendees from six continents, on topics including pathophysiology and COVID-19 risk factors, the impact of social determinants of health on diabetes and COVID-19, and psychological aspects of the COVID-19 pandemic for people with diabetes.

The freely available report was published online Jan. 21 in the Journal of Diabetes Science and Technology by Jennifer Y. Zhang of the Diabetes Technology Society, Burlingame, Calif., and colleagues.

Other topics include medications and vaccines, outpatient diabetes management during the COVID-19 pandemic and the growth of telehealth, inpatient management of diabetes in patients with or without COVID-19, ethical considerations, children, pregnancy, economics of care for COVID-19, government policy, regulation of tests and treatments, patient surveillance/privacy, and research gaps and opportunities.

“A comprehensive report like this is so important because it covers such a wide range of topics that are all relevant when it comes to protecting patients with diabetes during a pandemic. Our report aims to bring together all these different aspects of policy during the pandemic, patient physiology, and patient psychology, so I hope it will be widely read and widely appreciated,” Ms. Zhang said in an interview.

Two important clinical trends arising as a result of the pandemic – the advent of telehealth in diabetes management and the use of continuous glucose monitoring (CGM) in hospital – are expected to continue even after COVID-19 abates, said Dr. Klonoff, medical director of the Diabetes Research Institute at Mills-Peninsula Medical Center, San Mateo, Calif.


 

Telehealth in diabetes here to stay, in U.S. at least  

Dr. Klonoff noted that with diabetes telehealth, or “telediabetes” as it’s been dubbed, by using downloaded device data patients don’t have to travel, pay for parking, or take as much time off work. “There are advantages ... patients really like it,” he said.

And for health care providers, an advantage of remote visits is that the clinician can look at the patient while reviewing the patient’s data. “With telehealth for diabetes, the patient’s face and the software data are right next to each other on the same screen. Even as I’m typing I’m looking at the patient ... I consider that a huge advantage,” Dr. Klonoff said.

Rule changes early in the pandemic made the shift to telehealth in the United States possible, he said.

“Fortunately, Medicare and other payers are covering telehealth. It used to be there was no coverage, so that was a damper. Now that it’s covered I don’t think that’s going to go back. Everybody likes it,” he said. 
 

CGM in hospitals helps detect hypoglycemia on wards

Regarding the increase of inpatient CGM (continuous glucose monitoring) prompted by the need to minimize patient exposure of nursing staff during the pandemic and the relaxing of Food and Drug Administration rules about its use, Dr. Klonoff said this phenomenon has led to two other positive developments.

“For FDA, it’s actually an opportunity to see some data collected. To do a clinical trial [prior to] March 2020 you had to go through a lot of processes to do a study. Once it becomes part of clinical care, then you can collect a lot of data,” he noted.   

Moreover, Dr. Klonoff said there’s an important new area where hospital use of CGM is emerging: detection of hypoglycemia on wards.

“When a patient is in the ICU, if they become hypoglycemic or hyperglycemic it will likely be detected. But on the wards, they simply don’t get the same attention. Just about every doctor has had a case where somebody drifted into hypoglycemia that wasn’t recognized and maybe even died,” he explained.

If, however, “patients treated with insulin could all have CGMs that would be so useful. It would send out an alarm. A lot of times people don’t eat when you think they will. Suddenly the insulin dose is inappropriate and the nurse didn’t realize. Or, if IV nutrition stops and the insulin is given [it can be harmful].”

Another example, he said, is a common scenario when insulin is used in patients who are treated with steroids. “They need insulin, but then the steroid is decreased and the insulin dose isn’t decreased fast enough. All those situations can be helped with CGM.”

Overall, he concluded, COVID-19 has provided many lessons, which are “expanding our horizons.”

Ms. Zhang has reported no relevant financial relationships. Dr. Klonoff has reported being a consultant for Dexcom, EOFlow, Fractyl, Lifecare, Novo Nordisk, Roche Diagnostics, Samsung, and Thirdwayv.

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

Experts discuss how to best protect people with diabetes from serious COVID-19 outcomes in a newly published article that summarizes in-depth discussions on the topic from a conference held online last year.

Lead author and Diabetes Technology Society founder and director David C. Klonoff, MD, said in an interview: “To my knowledge this is the largest article or learning that has been written anywhere ever about the co-occurrence of COVID-19 and diabetes and how COVID-19 affects diabetes ... There are a lot of different dimensions.” 

The 37-page report covers all sessions from the Virtual International COVID-19 and Diabetes Summit, held Aug. 26-27, 2020, which had 800 attendees from six continents, on topics including pathophysiology and COVID-19 risk factors, the impact of social determinants of health on diabetes and COVID-19, and psychological aspects of the COVID-19 pandemic for people with diabetes.

The freely available report was published online Jan. 21 in the Journal of Diabetes Science and Technology by Jennifer Y. Zhang of the Diabetes Technology Society, Burlingame, Calif., and colleagues.

Other topics include medications and vaccines, outpatient diabetes management during the COVID-19 pandemic and the growth of telehealth, inpatient management of diabetes in patients with or without COVID-19, ethical considerations, children, pregnancy, economics of care for COVID-19, government policy, regulation of tests and treatments, patient surveillance/privacy, and research gaps and opportunities.

“A comprehensive report like this is so important because it covers such a wide range of topics that are all relevant when it comes to protecting patients with diabetes during a pandemic. Our report aims to bring together all these different aspects of policy during the pandemic, patient physiology, and patient psychology, so I hope it will be widely read and widely appreciated,” Ms. Zhang said in an interview.

Two important clinical trends arising as a result of the pandemic – the advent of telehealth in diabetes management and the use of continuous glucose monitoring (CGM) in hospital – are expected to continue even after COVID-19 abates, said Dr. Klonoff, medical director of the Diabetes Research Institute at Mills-Peninsula Medical Center, San Mateo, Calif.


 

Telehealth in diabetes here to stay, in U.S. at least  

Dr. Klonoff noted that with diabetes telehealth, or “telediabetes” as it’s been dubbed, by using downloaded device data patients don’t have to travel, pay for parking, or take as much time off work. “There are advantages ... patients really like it,” he said.

And for health care providers, an advantage of remote visits is that the clinician can look at the patient while reviewing the patient’s data. “With telehealth for diabetes, the patient’s face and the software data are right next to each other on the same screen. Even as I’m typing I’m looking at the patient ... I consider that a huge advantage,” Dr. Klonoff said.

Rule changes early in the pandemic made the shift to telehealth in the United States possible, he said.

“Fortunately, Medicare and other payers are covering telehealth. It used to be there was no coverage, so that was a damper. Now that it’s covered I don’t think that’s going to go back. Everybody likes it,” he said. 
 

CGM in hospitals helps detect hypoglycemia on wards

Regarding the increase of inpatient CGM (continuous glucose monitoring) prompted by the need to minimize patient exposure of nursing staff during the pandemic and the relaxing of Food and Drug Administration rules about its use, Dr. Klonoff said this phenomenon has led to two other positive developments.

“For FDA, it’s actually an opportunity to see some data collected. To do a clinical trial [prior to] March 2020 you had to go through a lot of processes to do a study. Once it becomes part of clinical care, then you can collect a lot of data,” he noted.   

Moreover, Dr. Klonoff said there’s an important new area where hospital use of CGM is emerging: detection of hypoglycemia on wards.

“When a patient is in the ICU, if they become hypoglycemic or hyperglycemic it will likely be detected. But on the wards, they simply don’t get the same attention. Just about every doctor has had a case where somebody drifted into hypoglycemia that wasn’t recognized and maybe even died,” he explained.

If, however, “patients treated with insulin could all have CGMs that would be so useful. It would send out an alarm. A lot of times people don’t eat when you think they will. Suddenly the insulin dose is inappropriate and the nurse didn’t realize. Or, if IV nutrition stops and the insulin is given [it can be harmful].”

Another example, he said, is a common scenario when insulin is used in patients who are treated with steroids. “They need insulin, but then the steroid is decreased and the insulin dose isn’t decreased fast enough. All those situations can be helped with CGM.”

Overall, he concluded, COVID-19 has provided many lessons, which are “expanding our horizons.”

Ms. Zhang has reported no relevant financial relationships. Dr. Klonoff has reported being a consultant for Dexcom, EOFlow, Fractyl, Lifecare, Novo Nordisk, Roche Diagnostics, Samsung, and Thirdwayv.

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

Physician offices, which have been deemphasized in the COVID-19 vaccine rollout, should have a more prominent role in the effort going forward, said the Medical Group Management Association in a letter sent to President Joe Biden on Jan. 26.

“Due to our members’ role as community providers, we ask that the Administration include medical group practices in COVID-19 vaccine distribution strategies moving forward,” Halee Fischer-Wright, MD, president and CEO of MGMA, stated in the letter.

“Current vaccine efforts are haphazard at best and appear to rely on a passive first come first served approach with the public rushing to sign up for vaccines when scant supply becomes available,” MGMA noted. “This favors patients who can advocate for themselves or have family members able to do the same. Yet medical group practices already have patient relationships and experience vaccinating patients for influenza and other conditions.”

Moreover, physician practices have data on patient demographics, preexisting conditions, and risk factors. This is valuable information not available to hospitals, pharmacies, and state health departments, MGMA said.

“Furthermore, in a time of uncertainty and misinformation, patients are looking to their own physicians as a trusted source for information on vaccine safety and efficacy,” the letter stated. “Physician group practices can and should play a significant role in vaccine education.”

Despite these advantages of vaccinating patients in doctors’ offices, MGMA pointed out that “states have largely not leveraged physician practices in vaccine rollout efforts.”

In an MGMA survey conducted last week, 85% of independent practices and 45% of hospital- or health system–owned practices that sought COVID-19 vaccine for their patients were unable to obtain any. Of the practices able to get vaccine supplies, the majority said they had received only enough to vaccinate 1% or less of their patients.

Susan R. Bailey, MD, president of the American Medical Association commented in an interview that, “once enough supplies are available, we encourage the administration to ensure physician practices have an adequate supply of COVID-19 vaccines to vaccinate their patients. Physician practices will be an integral part of the vaccine administration process. Physicians are a trusted source of information for patients and their direct conversations and recommendations for patients to get vaccinated will help address hesitancy and result in more people getting vaccinated.”

Many groups, MGMA said, had been approved by their states to distribute the vaccine but received little or no inventory. Practice phone lines have been “flooded” by patients wanting to know why their physicians can’t vaccinate them.
 

Programs vary by state

In an interview, Dr. Fischer-Wright said that most practices want to vaccinate their patients. But only some states have set up programs that allow them to apply for the COVID-19 vaccines. “Most of our practices that were eligible for vaccination have applied for it,” she added.

The New York State Health Department is taking a different approach, according to Dial Hewlett Jr., MD, medical director for disease control services with the Westchester County Department of Health in White Plains, N.Y.. The state health department has designated specific sites across New York as vaccination hubs; in Westchester County, the hub is the Westchester Medical Center. When the hospital receives a vaccine shipment, it distributes some of it to smaller sites such as the county health department, which includes a vaccination clinic.

“So far, they haven’t gotten to the point where they’re distributing to pharmacies or doctors’ offices,” Dr. Hewlett said in an interview.

Right now, he said, the chief limiting factor is vaccine supply. When that expands, he said, physician offices will likely get more vaccine doses.

Both Dr. Hewlett and Dr. Fischer-Wright pointed out that physician offices are limited because they aren’t able to store the Pfizer vaccine, which requires ultracold freezers. “But now that we have the Moderna vaccine, 50% of the 200 million doses that have been promised can be delivered in a physician office,” said Dr. Fischer-Wright.

So why haven’t practices received more vaccine? Besides the inadequate supply across the nation, Dr. Fischer-Wright said, there have been difficulties in getting the vaccine to physician offices. Some MGMA members, she added, did receive vaccine supplies immediately. “These were independent practices that had over 200 physicians.”

Dr. Hewlett noted that some smaller practices have complained to the county department that they couldn’t obtain vaccine because they lacked the clout to compete with larger groups. “They’re not ordering enough product to make it a priority for whoever is involved with the distribution.”

Another problem – evident in the results of MGMA’s recent poll – is that health care systems that have vaccine supplies are sharing them with their own practices before they make any available to community practices.

“If you’re working for Northwell Health, you probably won’t have the kinds of challenges that the small mom-and-pop practice would have,” Dr. Hewlett said.
 

Overcoming vaccine hesitancy

More than a quarter of the U.S. population has indicated they are hesitant to get the COVID-19 vaccine. This is an area where Dr. Fischer-Wright believes physicians can help immensely.

“The benefit of having that type of activity occur in the physician office is that it’s a place where physicians have already established trust with patients,” she said. “And one of the reasons why some people don’t want a shot is that they don’t trust the vaccine. Having a human being that you have a relationship with provide you with the pros and cons is very compelling to get people to make an alternative choice.”

Physicians and their staff will also need to be educated before they administer the vaccine, Dr. Hewlett noted. “There will have to be education on the handling of the vaccine, but I think that can easily be done. Many practices have physician assistants and nurse practitioners who have been doing a lot of vaccinations in the office setting.”
 

Complex logistics

Based on the experience of his department’s vaccination clinic, which has been giving COVID-19 shots since Jan. 5, Dr. Hewlett said private practices have a lot to consider before they launch their own vaccination efforts.

To begin with, he said, “it’s a tricky situation with these vaccines that require two doses.” Before his clinic makes an appointment to vaccinate a patient, the scheduler has to make sure that the patient can return in 21 or 28 days, depending on whether they’re getting the Pfizer or Moderna vaccine.

“It’s difficult if they can’t show up 28 days after that date because we expect the same number of people to show up 28 days later for their second dose,” he said. “This is quite different from a standard medical practice. There aren’t too many situations where a person has to come back to the office after 28 days or 21 days.”

While the Centers for Disease Control and Prevention recently said the immunization schedule can be more flexible, Dr. Hewlett added, his clinic prefers to get patients back on the recommended schedule to make sure the vaccine will be maximally effective.

The clinic also has to follow state regulations requiring that all vaccines it receives be administered within a week of receipt. Right now, the clinic is open 6 days a week, giving about 300-400 shots a day. Each morning, a clerk records how many doses were administered the previous day, along with the lot numbers – and all data must be reported to the state.

The operation is fairly labor intensive. The clinic has a staff of about 30 people, most of whom are now engaged full time in the COVID-19 vaccination effort.

“We have people who check patients in and who screen to make sure no one has COVID symptoms. Other people escort patients to the vaccination stations. We have about 15 nurse practitioners and public health nurses who give the shots, and we have to make sure they’re accounting for every dose that’s given. And we have to make sure everybody getting a dose meets the eligibility criteria for shots,” he said. “We also have an area where patients are watched for 15 minutes after they’re vaccinated. Then there’s a group of five data entry people who locate appointment slots 28 days from today.”

It’s all still “a work in progress,” Dr. Hewlett said, but the staff who give COVID-19 shots and the patients who receive them are gratified to be making a difference.

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

Physician offices, which have been deemphasized in the COVID-19 vaccine rollout, should have a more prominent role in the effort going forward, said the Medical Group Management Association in a letter sent to President Joe Biden on Jan. 26.

“Due to our members’ role as community providers, we ask that the Administration include medical group practices in COVID-19 vaccine distribution strategies moving forward,” Halee Fischer-Wright, MD, president and CEO of MGMA, stated in the letter.

“Current vaccine efforts are haphazard at best and appear to rely on a passive first come first served approach with the public rushing to sign up for vaccines when scant supply becomes available,” MGMA noted. “This favors patients who can advocate for themselves or have family members able to do the same. Yet medical group practices already have patient relationships and experience vaccinating patients for influenza and other conditions.”

Moreover, physician practices have data on patient demographics, preexisting conditions, and risk factors. This is valuable information not available to hospitals, pharmacies, and state health departments, MGMA said.

“Furthermore, in a time of uncertainty and misinformation, patients are looking to their own physicians as a trusted source for information on vaccine safety and efficacy,” the letter stated. “Physician group practices can and should play a significant role in vaccine education.”

Despite these advantages of vaccinating patients in doctors’ offices, MGMA pointed out that “states have largely not leveraged physician practices in vaccine rollout efforts.”

In an MGMA survey conducted last week, 85% of independent practices and 45% of hospital- or health system–owned practices that sought COVID-19 vaccine for their patients were unable to obtain any. Of the practices able to get vaccine supplies, the majority said they had received only enough to vaccinate 1% or less of their patients.

Susan R. Bailey, MD, president of the American Medical Association commented in an interview that, “once enough supplies are available, we encourage the administration to ensure physician practices have an adequate supply of COVID-19 vaccines to vaccinate their patients. Physician practices will be an integral part of the vaccine administration process. Physicians are a trusted source of information for patients and their direct conversations and recommendations for patients to get vaccinated will help address hesitancy and result in more people getting vaccinated.”

Many groups, MGMA said, had been approved by their states to distribute the vaccine but received little or no inventory. Practice phone lines have been “flooded” by patients wanting to know why their physicians can’t vaccinate them.
 

Programs vary by state

In an interview, Dr. Fischer-Wright said that most practices want to vaccinate their patients. But only some states have set up programs that allow them to apply for the COVID-19 vaccines. “Most of our practices that were eligible for vaccination have applied for it,” she added.

The New York State Health Department is taking a different approach, according to Dial Hewlett Jr., MD, medical director for disease control services with the Westchester County Department of Health in White Plains, N.Y.. The state health department has designated specific sites across New York as vaccination hubs; in Westchester County, the hub is the Westchester Medical Center. When the hospital receives a vaccine shipment, it distributes some of it to smaller sites such as the county health department, which includes a vaccination clinic.

“So far, they haven’t gotten to the point where they’re distributing to pharmacies or doctors’ offices,” Dr. Hewlett said in an interview.

Right now, he said, the chief limiting factor is vaccine supply. When that expands, he said, physician offices will likely get more vaccine doses.

Both Dr. Hewlett and Dr. Fischer-Wright pointed out that physician offices are limited because they aren’t able to store the Pfizer vaccine, which requires ultracold freezers. “But now that we have the Moderna vaccine, 50% of the 200 million doses that have been promised can be delivered in a physician office,” said Dr. Fischer-Wright.

So why haven’t practices received more vaccine? Besides the inadequate supply across the nation, Dr. Fischer-Wright said, there have been difficulties in getting the vaccine to physician offices. Some MGMA members, she added, did receive vaccine supplies immediately. “These were independent practices that had over 200 physicians.”

Dr. Hewlett noted that some smaller practices have complained to the county department that they couldn’t obtain vaccine because they lacked the clout to compete with larger groups. “They’re not ordering enough product to make it a priority for whoever is involved with the distribution.”

Another problem – evident in the results of MGMA’s recent poll – is that health care systems that have vaccine supplies are sharing them with their own practices before they make any available to community practices.

“If you’re working for Northwell Health, you probably won’t have the kinds of challenges that the small mom-and-pop practice would have,” Dr. Hewlett said.
 

Overcoming vaccine hesitancy

More than a quarter of the U.S. population has indicated they are hesitant to get the COVID-19 vaccine. This is an area where Dr. Fischer-Wright believes physicians can help immensely.

“The benefit of having that type of activity occur in the physician office is that it’s a place where physicians have already established trust with patients,” she said. “And one of the reasons why some people don’t want a shot is that they don’t trust the vaccine. Having a human being that you have a relationship with provide you with the pros and cons is very compelling to get people to make an alternative choice.”

Physicians and their staff will also need to be educated before they administer the vaccine, Dr. Hewlett noted. “There will have to be education on the handling of the vaccine, but I think that can easily be done. Many practices have physician assistants and nurse practitioners who have been doing a lot of vaccinations in the office setting.”
 

Complex logistics

Based on the experience of his department’s vaccination clinic, which has been giving COVID-19 shots since Jan. 5, Dr. Hewlett said private practices have a lot to consider before they launch their own vaccination efforts.

To begin with, he said, “it’s a tricky situation with these vaccines that require two doses.” Before his clinic makes an appointment to vaccinate a patient, the scheduler has to make sure that the patient can return in 21 or 28 days, depending on whether they’re getting the Pfizer or Moderna vaccine.

“It’s difficult if they can’t show up 28 days after that date because we expect the same number of people to show up 28 days later for their second dose,” he said. “This is quite different from a standard medical practice. There aren’t too many situations where a person has to come back to the office after 28 days or 21 days.”

While the Centers for Disease Control and Prevention recently said the immunization schedule can be more flexible, Dr. Hewlett added, his clinic prefers to get patients back on the recommended schedule to make sure the vaccine will be maximally effective.

The clinic also has to follow state regulations requiring that all vaccines it receives be administered within a week of receipt. Right now, the clinic is open 6 days a week, giving about 300-400 shots a day. Each morning, a clerk records how many doses were administered the previous day, along with the lot numbers – and all data must be reported to the state.

The operation is fairly labor intensive. The clinic has a staff of about 30 people, most of whom are now engaged full time in the COVID-19 vaccination effort.

“We have people who check patients in and who screen to make sure no one has COVID symptoms. Other people escort patients to the vaccination stations. We have about 15 nurse practitioners and public health nurses who give the shots, and we have to make sure they’re accounting for every dose that’s given. And we have to make sure everybody getting a dose meets the eligibility criteria for shots,” he said. “We also have an area where patients are watched for 15 minutes after they’re vaccinated. Then there’s a group of five data entry people who locate appointment slots 28 days from today.”

It’s all still “a work in progress,” Dr. Hewlett said, but the staff who give COVID-19 shots and the patients who receive them are gratified to be making a difference.

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

Physician offices, which have been deemphasized in the COVID-19 vaccine rollout, should have a more prominent role in the effort going forward, said the Medical Group Management Association in a letter sent to President Joe Biden on Jan. 26.

“Due to our members’ role as community providers, we ask that the Administration include medical group practices in COVID-19 vaccine distribution strategies moving forward,” Halee Fischer-Wright, MD, president and CEO of MGMA, stated in the letter.

“Current vaccine efforts are haphazard at best and appear to rely on a passive first come first served approach with the public rushing to sign up for vaccines when scant supply becomes available,” MGMA noted. “This favors patients who can advocate for themselves or have family members able to do the same. Yet medical group practices already have patient relationships and experience vaccinating patients for influenza and other conditions.”

Moreover, physician practices have data on patient demographics, preexisting conditions, and risk factors. This is valuable information not available to hospitals, pharmacies, and state health departments, MGMA said.

“Furthermore, in a time of uncertainty and misinformation, patients are looking to their own physicians as a trusted source for information on vaccine safety and efficacy,” the letter stated. “Physician group practices can and should play a significant role in vaccine education.”

Despite these advantages of vaccinating patients in doctors’ offices, MGMA pointed out that “states have largely not leveraged physician practices in vaccine rollout efforts.”

In an MGMA survey conducted last week, 85% of independent practices and 45% of hospital- or health system–owned practices that sought COVID-19 vaccine for their patients were unable to obtain any. Of the practices able to get vaccine supplies, the majority said they had received only enough to vaccinate 1% or less of their patients.

Susan R. Bailey, MD, president of the American Medical Association commented in an interview that, “once enough supplies are available, we encourage the administration to ensure physician practices have an adequate supply of COVID-19 vaccines to vaccinate their patients. Physician practices will be an integral part of the vaccine administration process. Physicians are a trusted source of information for patients and their direct conversations and recommendations for patients to get vaccinated will help address hesitancy and result in more people getting vaccinated.”

Many groups, MGMA said, had been approved by their states to distribute the vaccine but received little or no inventory. Practice phone lines have been “flooded” by patients wanting to know why their physicians can’t vaccinate them.
 

Programs vary by state

In an interview, Dr. Fischer-Wright said that most practices want to vaccinate their patients. But only some states have set up programs that allow them to apply for the COVID-19 vaccines. “Most of our practices that were eligible for vaccination have applied for it,” she added.

The New York State Health Department is taking a different approach, according to Dial Hewlett Jr., MD, medical director for disease control services with the Westchester County Department of Health in White Plains, N.Y.. The state health department has designated specific sites across New York as vaccination hubs; in Westchester County, the hub is the Westchester Medical Center. When the hospital receives a vaccine shipment, it distributes some of it to smaller sites such as the county health department, which includes a vaccination clinic.

“So far, they haven’t gotten to the point where they’re distributing to pharmacies or doctors’ offices,” Dr. Hewlett said in an interview.

Right now, he said, the chief limiting factor is vaccine supply. When that expands, he said, physician offices will likely get more vaccine doses.

Both Dr. Hewlett and Dr. Fischer-Wright pointed out that physician offices are limited because they aren’t able to store the Pfizer vaccine, which requires ultracold freezers. “But now that we have the Moderna vaccine, 50% of the 200 million doses that have been promised can be delivered in a physician office,” said Dr. Fischer-Wright.

So why haven’t practices received more vaccine? Besides the inadequate supply across the nation, Dr. Fischer-Wright said, there have been difficulties in getting the vaccine to physician offices. Some MGMA members, she added, did receive vaccine supplies immediately. “These were independent practices that had over 200 physicians.”

Dr. Hewlett noted that some smaller practices have complained to the county department that they couldn’t obtain vaccine because they lacked the clout to compete with larger groups. “They’re not ordering enough product to make it a priority for whoever is involved with the distribution.”

Another problem – evident in the results of MGMA’s recent poll – is that health care systems that have vaccine supplies are sharing them with their own practices before they make any available to community practices.

“If you’re working for Northwell Health, you probably won’t have the kinds of challenges that the small mom-and-pop practice would have,” Dr. Hewlett said.
 

Overcoming vaccine hesitancy

More than a quarter of the U.S. population has indicated they are hesitant to get the COVID-19 vaccine. This is an area where Dr. Fischer-Wright believes physicians can help immensely.

“The benefit of having that type of activity occur in the physician office is that it’s a place where physicians have already established trust with patients,” she said. “And one of the reasons why some people don’t want a shot is that they don’t trust the vaccine. Having a human being that you have a relationship with provide you with the pros and cons is very compelling to get people to make an alternative choice.”

Physicians and their staff will also need to be educated before they administer the vaccine, Dr. Hewlett noted. “There will have to be education on the handling of the vaccine, but I think that can easily be done. Many practices have physician assistants and nurse practitioners who have been doing a lot of vaccinations in the office setting.”
 

Complex logistics

Based on the experience of his department’s vaccination clinic, which has been giving COVID-19 shots since Jan. 5, Dr. Hewlett said private practices have a lot to consider before they launch their own vaccination efforts.

To begin with, he said, “it’s a tricky situation with these vaccines that require two doses.” Before his clinic makes an appointment to vaccinate a patient, the scheduler has to make sure that the patient can return in 21 or 28 days, depending on whether they’re getting the Pfizer or Moderna vaccine.

“It’s difficult if they can’t show up 28 days after that date because we expect the same number of people to show up 28 days later for their second dose,” he said. “This is quite different from a standard medical practice. There aren’t too many situations where a person has to come back to the office after 28 days or 21 days.”

While the Centers for Disease Control and Prevention recently said the immunization schedule can be more flexible, Dr. Hewlett added, his clinic prefers to get patients back on the recommended schedule to make sure the vaccine will be maximally effective.

The clinic also has to follow state regulations requiring that all vaccines it receives be administered within a week of receipt. Right now, the clinic is open 6 days a week, giving about 300-400 shots a day. Each morning, a clerk records how many doses were administered the previous day, along with the lot numbers – and all data must be reported to the state.

The operation is fairly labor intensive. The clinic has a staff of about 30 people, most of whom are now engaged full time in the COVID-19 vaccination effort.

“We have people who check patients in and who screen to make sure no one has COVID symptoms. Other people escort patients to the vaccination stations. We have about 15 nurse practitioners and public health nurses who give the shots, and we have to make sure they’re accounting for every dose that’s given. And we have to make sure everybody getting a dose meets the eligibility criteria for shots,” he said. “We also have an area where patients are watched for 15 minutes after they’re vaccinated. Then there’s a group of five data entry people who locate appointment slots 28 days from today.”

It’s all still “a work in progress,” Dr. Hewlett said, but the staff who give COVID-19 shots and the patients who receive them are gratified to be making a difference.

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

Hospitalist Sarah Stone, MD, arrived for her day shift at Sharp Chula Vista one day in late December. The ICU and hospital wards were still overflowing with COVID-19 patients. But over the previous couple of months, she’d also seen more and more recovered patients presenting with a myriad of symptoms: pulmonary emboli, cardiomyopathy, a shocking case of aspergillosis, and those rare cases of “long COVID,” the patients who just can’t get better.

This morning it was a woman in her 30s. She felt fine, but 2 weeks after recovering from COVID-19, she had unexplained bruising on her arm, a petechiae rash on her legs, and her gums were bleeding. Once admitted to the emergency department, her platelet count of 5000/mm³ was a dead giveaway of immune thrombocytopenic purpura (ITP).

In Dr. Stone’s experience, new and otherwise unexplained symptoms so soon post COVID-19 can’t be written off as a coincidence without some additional consideration. But a quick preliminary search of the literature during her rounds came up almost empty. She found one report with three cases of post-COVID-19 ITP. But other online resources made no mention of it. Kenneth Johnson, MD, the hematologist/oncologist consulting on the new case, told Dr. Stone he’d seen one other case of post-COVID-19 ITP only earlier that month. Dr. Stone called a sister hospital. They’d seen one other case just weeks before.

“I was surprised to find just three cases in the literature when we had seen three among us in a matter of weeks,” Dr. Stone said in an interview. Something was missing.
 

A missing link

ITP is caused by an immune reaction against a patient’s own platelets. Platelet numbers drop, causing easy bruising, bleeding gums, and internal bleeding. Acute cases can usually be resolved within 3 months, but for some patients the condition can be extended or even chronic.

“We know that infections like influenza can cause ITP, so in this light, [COVID-19-associated ITP] might not be surprising,” Gerard Jansen, MD, PhD, an internist and hematologist in Rotterdam, the Netherlands, said in an interview.

Dr. Jansen and colleagues recorded three cases of post-COVID-19 ITP in May 2020 – the report Dr. Stone had found during her shift. Two patients developed ITP several weeks after COVID-19 and responded to treatment with corticosteroids and intravenous immunoglobulin G (IVIG). The third patient, however, died of intracerebral bleeding while still battling COVID-19. He was retrospectively diagnosed with COVID-19-associated ITP.

A deeper dive into the literature uncovers additional case reports from India, France, the United Kingdom, Turkey, and one from China as early as January 2020. A September 2020 review of ITP secondary to COVID-19 included 23 papers and a total of 45 patients. The review authors noted that more than 70% of cases occurred in patients who were aged over 50 years and 75% had had moderate to severe COVID-19 infections. However, the sample size of 45 is too small to definitively describe what’s happening in the overall population.

ITP’s link to COVID-19 gained a media spotlight after the Miami obstetrician, Gregory Michael, MD, developed ITP days after getting the Pfizer COVID-19 vaccine. In early January, after 2 weeks in the ICU, Dr. Michael died of a hemorrhagic stroke caused by the low platelet count.

Pfizer said in a statement that the company is “actively investigating” the case, “but we don’t believe at this time that there is any direct connection to the vaccine.” Other experts have said the timing, particularly in a relatively young and healthy man, means a link to the vaccine is possible or even likely, but final results won›t be known until the Centers for Disease Control and Prevention finishes its investigation.

But “it is quite unusual to die from ITP,” San Diego hematologist Dr. Johnson said in an interview. In his more than 20 years of practice, he has never had a patient die from the condition.

For his part, Dr. Jansen, the hematologist in Rotterdam, said that at this point we just don’t know if there’s a link between the vaccine and ITP. Both infection and drugs are well established causes of ITP, so with that general mechanism or pathology in mind it makes sense that COVID-19 and the vaccine could instigate ITP. But it would be very difficult to prove in just one instance, he said. And considering the millions who have thus far received the vaccine without incident, and the known risks and dangers of COVID-19, “we still advise to vaccinate,” he said.
 

The number of cases is underestimated

Since his original case report in May, Dr. Jansen has seen five or so additional cases. But the causal link between the coronavirus and the hematologic symptoms is still undefined. “We don’t know much about platelet counts in COVID-19 at all,” he said. It could be that COVID-19 somehow inhibits platelet production or that it kills existing platelets. Whatever the exact relationship to the virus, Dr. Jansen expects that the true number of COVID-19-related ITP cases is higher than current estimates suggest.

One reason it isn’t coming up more often, Dr. Jansen said, may be that the cause of ITP in COVID-19 patients is hard to pin down. In the case report from May, Dr. Jansen and colleagues wrote: “And there are numerous other factors that can cause thrombocytopenia where COVID is concerned. For instance the coagulation activation by COVID‐19 infection leading to disseminated intravascular coagulation (DIC) and subsequent thrombocytopenia. Also, treatments for COVID‐19, including heparin, azithromycin and hydroxychloroquine, may lead to thrombocytopenia.”

Tracking and understanding COVID-19-associated ITP first requires the extensive process of elimination needed to diagnose it.

In addition, drugs used to treat COVID-19 could be masking COVID-19-related ITP. “Dexamethasone is a mainstay of COVID treatment. And it’s how we treat ITP,” Dr. Johnson said, which means physicians may be treating ITP without even registering it. And that’s one hypothesis for why Dr. Stone and Dr. Johnson didn’t see a case until 9 months into the pandemic.

Treating COVID-19-associated ITP also has its challenges, particularly in patients who develop it during an acute COVID-19 infection and are at risk for both internal bleeding and thrombosis. This was the case for the third patient in Dr. Jansen’s case report. The patient developed a pulmonary embolism and had a falling platelet count. He was given a platelet infusion and then an anticoagulant for the thrombosis. But a retrospective look at the case revealed the transfusion “did not increase numbers at all – which suggests ITP,” Dr. Jansen said. Intracerebral bleeding was the cause of death.

That’s why “it’s important to be aware of this phenomenon,” Dr. Jansen said of COVID-19-associated ITP. If a transfusion is unsuccessful, consider that the patient may have ITP and adjust. Dr. Johnson hasn’t had to treat a patient battling both complications simultaneously but says the ideal course of action would be to raise platelets with steroids and IVIG and then give the anticoagulant once the platelet count is higher. But reality is rarely ideal. Often these two treatments will have to be given concurrently since the patient faces two life-threatening risks, he said. “It’s a very challenging situation,” he said.

The good news is that standard treatments for ITP seem to work for COVID-19-associated ITP. The 30-year-old patient of Dr. Stone and Dr. Johnson responded so well to intravenous steroids that IVIG was unnecessary. She’s now on a slow prednisone taper and maintains platelet counts at 114,000/mm³ at her weekly follow-up appointments with Dr. Johnson.

Meanwhile, Dr. Jansen’s two other patients, now nearly a year out of treatment, require no additional medication. One of the patients is fully recovered and, though the other still has lower than normal platelet counts, she has no bleeding symptoms and her platelet counts remain stable. Still, Dr. Jansen is anxious for more data looking at the platelet counts in every COVID-19 patient and to combine findings from existing COVID-19-associated ITP patients.

For Dr. Stone, she says she’s added one COVID-19-associated complication to her belt. One less aftereffect will catch her off guard. And she wants others to have the same information.

“It’s just a little bit daunting. We don’t know how bad post-COVID will be,” she said. “There’s so many levels to this disease. Some people deal with it for so long and some people just get better and move on – we think ... so far.”
 

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

Hospitalist Sarah Stone, MD, arrived for her day shift at Sharp Chula Vista one day in late December. The ICU and hospital wards were still overflowing with COVID-19 patients. But over the previous couple of months, she’d also seen more and more recovered patients presenting with a myriad of symptoms: pulmonary emboli, cardiomyopathy, a shocking case of aspergillosis, and those rare cases of “long COVID,” the patients who just can’t get better.

This morning it was a woman in her 30s. She felt fine, but 2 weeks after recovering from COVID-19, she had unexplained bruising on her arm, a petechiae rash on her legs, and her gums were bleeding. Once admitted to the emergency department, her platelet count of 5000/mm³ was a dead giveaway of immune thrombocytopenic purpura (ITP).

In Dr. Stone’s experience, new and otherwise unexplained symptoms so soon post COVID-19 can’t be written off as a coincidence without some additional consideration. But a quick preliminary search of the literature during her rounds came up almost empty. She found one report with three cases of post-COVID-19 ITP. But other online resources made no mention of it. Kenneth Johnson, MD, the hematologist/oncologist consulting on the new case, told Dr. Stone he’d seen one other case of post-COVID-19 ITP only earlier that month. Dr. Stone called a sister hospital. They’d seen one other case just weeks before.

“I was surprised to find just three cases in the literature when we had seen three among us in a matter of weeks,” Dr. Stone said in an interview. Something was missing.
 

A missing link

ITP is caused by an immune reaction against a patient’s own platelets. Platelet numbers drop, causing easy bruising, bleeding gums, and internal bleeding. Acute cases can usually be resolved within 3 months, but for some patients the condition can be extended or even chronic.

“We know that infections like influenza can cause ITP, so in this light, [COVID-19-associated ITP] might not be surprising,” Gerard Jansen, MD, PhD, an internist and hematologist in Rotterdam, the Netherlands, said in an interview.

Dr. Jansen and colleagues recorded three cases of post-COVID-19 ITP in May 2020 – the report Dr. Stone had found during her shift. Two patients developed ITP several weeks after COVID-19 and responded to treatment with corticosteroids and intravenous immunoglobulin G (IVIG). The third patient, however, died of intracerebral bleeding while still battling COVID-19. He was retrospectively diagnosed with COVID-19-associated ITP.

A deeper dive into the literature uncovers additional case reports from India, France, the United Kingdom, Turkey, and one from China as early as January 2020. A September 2020 review of ITP secondary to COVID-19 included 23 papers and a total of 45 patients. The review authors noted that more than 70% of cases occurred in patients who were aged over 50 years and 75% had had moderate to severe COVID-19 infections. However, the sample size of 45 is too small to definitively describe what’s happening in the overall population.

ITP’s link to COVID-19 gained a media spotlight after the Miami obstetrician, Gregory Michael, MD, developed ITP days after getting the Pfizer COVID-19 vaccine. In early January, after 2 weeks in the ICU, Dr. Michael died of a hemorrhagic stroke caused by the low platelet count.

Pfizer said in a statement that the company is “actively investigating” the case, “but we don’t believe at this time that there is any direct connection to the vaccine.” Other experts have said the timing, particularly in a relatively young and healthy man, means a link to the vaccine is possible or even likely, but final results won›t be known until the Centers for Disease Control and Prevention finishes its investigation.

But “it is quite unusual to die from ITP,” San Diego hematologist Dr. Johnson said in an interview. In his more than 20 years of practice, he has never had a patient die from the condition.

For his part, Dr. Jansen, the hematologist in Rotterdam, said that at this point we just don’t know if there’s a link between the vaccine and ITP. Both infection and drugs are well established causes of ITP, so with that general mechanism or pathology in mind it makes sense that COVID-19 and the vaccine could instigate ITP. But it would be very difficult to prove in just one instance, he said. And considering the millions who have thus far received the vaccine without incident, and the known risks and dangers of COVID-19, “we still advise to vaccinate,” he said.
 

The number of cases is underestimated

Since his original case report in May, Dr. Jansen has seen five or so additional cases. But the causal link between the coronavirus and the hematologic symptoms is still undefined. “We don’t know much about platelet counts in COVID-19 at all,” he said. It could be that COVID-19 somehow inhibits platelet production or that it kills existing platelets. Whatever the exact relationship to the virus, Dr. Jansen expects that the true number of COVID-19-related ITP cases is higher than current estimates suggest.

One reason it isn’t coming up more often, Dr. Jansen said, may be that the cause of ITP in COVID-19 patients is hard to pin down. In the case report from May, Dr. Jansen and colleagues wrote: “And there are numerous other factors that can cause thrombocytopenia where COVID is concerned. For instance the coagulation activation by COVID‐19 infection leading to disseminated intravascular coagulation (DIC) and subsequent thrombocytopenia. Also, treatments for COVID‐19, including heparin, azithromycin and hydroxychloroquine, may lead to thrombocytopenia.”

Tracking and understanding COVID-19-associated ITP first requires the extensive process of elimination needed to diagnose it.

In addition, drugs used to treat COVID-19 could be masking COVID-19-related ITP. “Dexamethasone is a mainstay of COVID treatment. And it’s how we treat ITP,” Dr. Johnson said, which means physicians may be treating ITP without even registering it. And that’s one hypothesis for why Dr. Stone and Dr. Johnson didn’t see a case until 9 months into the pandemic.

Treating COVID-19-associated ITP also has its challenges, particularly in patients who develop it during an acute COVID-19 infection and are at risk for both internal bleeding and thrombosis. This was the case for the third patient in Dr. Jansen’s case report. The patient developed a pulmonary embolism and had a falling platelet count. He was given a platelet infusion and then an anticoagulant for the thrombosis. But a retrospective look at the case revealed the transfusion “did not increase numbers at all – which suggests ITP,” Dr. Jansen said. Intracerebral bleeding was the cause of death.

That’s why “it’s important to be aware of this phenomenon,” Dr. Jansen said of COVID-19-associated ITP. If a transfusion is unsuccessful, consider that the patient may have ITP and adjust. Dr. Johnson hasn’t had to treat a patient battling both complications simultaneously but says the ideal course of action would be to raise platelets with steroids and IVIG and then give the anticoagulant once the platelet count is higher. But reality is rarely ideal. Often these two treatments will have to be given concurrently since the patient faces two life-threatening risks, he said. “It’s a very challenging situation,” he said.

The good news is that standard treatments for ITP seem to work for COVID-19-associated ITP. The 30-year-old patient of Dr. Stone and Dr. Johnson responded so well to intravenous steroids that IVIG was unnecessary. She’s now on a slow prednisone taper and maintains platelet counts at 114,000/mm³ at her weekly follow-up appointments with Dr. Johnson.

Meanwhile, Dr. Jansen’s two other patients, now nearly a year out of treatment, require no additional medication. One of the patients is fully recovered and, though the other still has lower than normal platelet counts, she has no bleeding symptoms and her platelet counts remain stable. Still, Dr. Jansen is anxious for more data looking at the platelet counts in every COVID-19 patient and to combine findings from existing COVID-19-associated ITP patients.

For Dr. Stone, she says she’s added one COVID-19-associated complication to her belt. One less aftereffect will catch her off guard. And she wants others to have the same information.

“It’s just a little bit daunting. We don’t know how bad post-COVID will be,” she said. “There’s so many levels to this disease. Some people deal with it for so long and some people just get better and move on – we think ... so far.”
 

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

Hospitalist Sarah Stone, MD, arrived for her day shift at Sharp Chula Vista one day in late December. The ICU and hospital wards were still overflowing with COVID-19 patients. But over the previous couple of months, she’d also seen more and more recovered patients presenting with a myriad of symptoms: pulmonary emboli, cardiomyopathy, a shocking case of aspergillosis, and those rare cases of “long COVID,” the patients who just can’t get better.

This morning it was a woman in her 30s. She felt fine, but 2 weeks after recovering from COVID-19, she had unexplained bruising on her arm, a petechiae rash on her legs, and her gums were bleeding. Once admitted to the emergency department, her platelet count of 5000/mm³ was a dead giveaway of immune thrombocytopenic purpura (ITP).

In Dr. Stone’s experience, new and otherwise unexplained symptoms so soon post COVID-19 can’t be written off as a coincidence without some additional consideration. But a quick preliminary search of the literature during her rounds came up almost empty. She found one report with three cases of post-COVID-19 ITP. But other online resources made no mention of it. Kenneth Johnson, MD, the hematologist/oncologist consulting on the new case, told Dr. Stone he’d seen one other case of post-COVID-19 ITP only earlier that month. Dr. Stone called a sister hospital. They’d seen one other case just weeks before.

“I was surprised to find just three cases in the literature when we had seen three among us in a matter of weeks,” Dr. Stone said in an interview. Something was missing.
 

A missing link

ITP is caused by an immune reaction against a patient’s own platelets. Platelet numbers drop, causing easy bruising, bleeding gums, and internal bleeding. Acute cases can usually be resolved within 3 months, but for some patients the condition can be extended or even chronic.

“We know that infections like influenza can cause ITP, so in this light, [COVID-19-associated ITP] might not be surprising,” Gerard Jansen, MD, PhD, an internist and hematologist in Rotterdam, the Netherlands, said in an interview.

Dr. Jansen and colleagues recorded three cases of post-COVID-19 ITP in May 2020 – the report Dr. Stone had found during her shift. Two patients developed ITP several weeks after COVID-19 and responded to treatment with corticosteroids and intravenous immunoglobulin G (IVIG). The third patient, however, died of intracerebral bleeding while still battling COVID-19. He was retrospectively diagnosed with COVID-19-associated ITP.

A deeper dive into the literature uncovers additional case reports from India, France, the United Kingdom, Turkey, and one from China as early as January 2020. A September 2020 review of ITP secondary to COVID-19 included 23 papers and a total of 45 patients. The review authors noted that more than 70% of cases occurred in patients who were aged over 50 years and 75% had had moderate to severe COVID-19 infections. However, the sample size of 45 is too small to definitively describe what’s happening in the overall population.

ITP’s link to COVID-19 gained a media spotlight after the Miami obstetrician, Gregory Michael, MD, developed ITP days after getting the Pfizer COVID-19 vaccine. In early January, after 2 weeks in the ICU, Dr. Michael died of a hemorrhagic stroke caused by the low platelet count.

Pfizer said in a statement that the company is “actively investigating” the case, “but we don’t believe at this time that there is any direct connection to the vaccine.” Other experts have said the timing, particularly in a relatively young and healthy man, means a link to the vaccine is possible or even likely, but final results won›t be known until the Centers for Disease Control and Prevention finishes its investigation.

But “it is quite unusual to die from ITP,” San Diego hematologist Dr. Johnson said in an interview. In his more than 20 years of practice, he has never had a patient die from the condition.

For his part, Dr. Jansen, the hematologist in Rotterdam, said that at this point we just don’t know if there’s a link between the vaccine and ITP. Both infection and drugs are well established causes of ITP, so with that general mechanism or pathology in mind it makes sense that COVID-19 and the vaccine could instigate ITP. But it would be very difficult to prove in just one instance, he said. And considering the millions who have thus far received the vaccine without incident, and the known risks and dangers of COVID-19, “we still advise to vaccinate,” he said.
 

The number of cases is underestimated

Since his original case report in May, Dr. Jansen has seen five or so additional cases. But the causal link between the coronavirus and the hematologic symptoms is still undefined. “We don’t know much about platelet counts in COVID-19 at all,” he said. It could be that COVID-19 somehow inhibits platelet production or that it kills existing platelets. Whatever the exact relationship to the virus, Dr. Jansen expects that the true number of COVID-19-related ITP cases is higher than current estimates suggest.

One reason it isn’t coming up more often, Dr. Jansen said, may be that the cause of ITP in COVID-19 patients is hard to pin down. In the case report from May, Dr. Jansen and colleagues wrote: “And there are numerous other factors that can cause thrombocytopenia where COVID is concerned. For instance the coagulation activation by COVID‐19 infection leading to disseminated intravascular coagulation (DIC) and subsequent thrombocytopenia. Also, treatments for COVID‐19, including heparin, azithromycin and hydroxychloroquine, may lead to thrombocytopenia.”

Tracking and understanding COVID-19-associated ITP first requires the extensive process of elimination needed to diagnose it.

In addition, drugs used to treat COVID-19 could be masking COVID-19-related ITP. “Dexamethasone is a mainstay of COVID treatment. And it’s how we treat ITP,” Dr. Johnson said, which means physicians may be treating ITP without even registering it. And that’s one hypothesis for why Dr. Stone and Dr. Johnson didn’t see a case until 9 months into the pandemic.

Treating COVID-19-associated ITP also has its challenges, particularly in patients who develop it during an acute COVID-19 infection and are at risk for both internal bleeding and thrombosis. This was the case for the third patient in Dr. Jansen’s case report. The patient developed a pulmonary embolism and had a falling platelet count. He was given a platelet infusion and then an anticoagulant for the thrombosis. But a retrospective look at the case revealed the transfusion “did not increase numbers at all – which suggests ITP,” Dr. Jansen said. Intracerebral bleeding was the cause of death.

That’s why “it’s important to be aware of this phenomenon,” Dr. Jansen said of COVID-19-associated ITP. If a transfusion is unsuccessful, consider that the patient may have ITP and adjust. Dr. Johnson hasn’t had to treat a patient battling both complications simultaneously but says the ideal course of action would be to raise platelets with steroids and IVIG and then give the anticoagulant once the platelet count is higher. But reality is rarely ideal. Often these two treatments will have to be given concurrently since the patient faces two life-threatening risks, he said. “It’s a very challenging situation,” he said.

The good news is that standard treatments for ITP seem to work for COVID-19-associated ITP. The 30-year-old patient of Dr. Stone and Dr. Johnson responded so well to intravenous steroids that IVIG was unnecessary. She’s now on a slow prednisone taper and maintains platelet counts at 114,000/mm³ at her weekly follow-up appointments with Dr. Johnson.

Meanwhile, Dr. Jansen’s two other patients, now nearly a year out of treatment, require no additional medication. One of the patients is fully recovered and, though the other still has lower than normal platelet counts, she has no bleeding symptoms and her platelet counts remain stable. Still, Dr. Jansen is anxious for more data looking at the platelet counts in every COVID-19 patient and to combine findings from existing COVID-19-associated ITP patients.

For Dr. Stone, she says she’s added one COVID-19-associated complication to her belt. One less aftereffect will catch her off guard. And she wants others to have the same information.

“It’s just a little bit daunting. We don’t know how bad post-COVID will be,” she said. “There’s so many levels to this disease. Some people deal with it for so long and some people just get better and move on – we think ... so far.”
 

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

Mounting evidence suggests it’s a mistake to reject the diagnosis of drug reaction with eosinophilia and systemic symptoms, or DRESS, simply because the interval between initiating a drug and symptom onset is less than 15 days, Sarah Walsh, MD, said at the virtual annual congress of the European Academy of Dermatology and Venereology.

The standard dictum has been that diagnosis of this severe T-cell-mediated drug reaction requires more than a 2-week delay in symptom onset following initial drug intake. But this can steer physicians in the wrong direction and lead to stopping an innocent drug while the true culprit medication remains on board. This adversely affects patient prognosis, since a longer duration of drug exposure after symptom onset is associated with increased hospital length of stay and greater mortality risk, explained Dr. Walsh, clinical lead for dermatology at King’s College Hospital, London.

In addition to sharing recent data demonstrating that DRESS symptoms often occur within just a week or 2 of drug exposure, she highlighted several recent advances in the ability to predict DRESS severity. These include clues provided by rash morphology and histopathology, HLA testing, and a novel scoring system to assess DRESS severity and the risk of potentially fatal cytomegalovirus reactivation.

Short-delay DRESS onset

In a retrospective study of 41 patients with a first episode of DRESS in three French dermatology departments, 14 (34%) had onset within 15 days or less of initial exposure to the causative drug. In 6 of 14 patients in the rapid-onset group the offending drug was an antibiotic, while in another 5 the culprit was iodinated contrast media. In the delayed-onset DRESS group, the chief sensitizers were allopurinol in 8 patients, lamotrigine in 6, carbamazepine in 4, and sulfasalazine in 2; of note, none of these 4 delayed-onset DRESS drugs were implicated in any cases of rapid-onset DRESS. There were no differences in the clinical manifestations of DRESS between the rapid- and delayed-onset groups.

Similarly, dermatologists at Government Medical College in Kerala, India, reported in a retrospective study of 100 consecutive patients with DRESS, the drug reaction emerged within 2 weeks after starting the culprit medication in 36% of cases. Indeed, 11 patients became symptomatic within 3-7 days after beginning the medication; in 10 of the 11 cases, the offending agent was an antibiotic, and in 1 patient it was terbinafine. In the 25 cases of DRESS that arose on day 8-14 of drug therapy, the culprit was phenytoin in 14, antibiotics in 6, and 1 each for clopidogrel, hydroxychloroquine, sodium valproate, lamotrigine, and vitamin D₃.

Both groups of investigators concluded that a short time lag between starting a drug and development of symptoms of a drug reaction shouldn’t rule out DRESS as a possibility provided other criteria consistent with the diagnosis are present. Hallmarks of DRESS include an acute extensive rash, fever greater than 38 degrees C, enlarged lymph nodes at two or more sites, internal organ involvement, a low platelet count, elevated eosinophils, and abnormal lymphocyte levels.
 

Rash morphology and histology as prognostic indicators

Dr. Walsh was the lead investigator in a study that identified four distinct patterns of skin involvement in patients with DRESS. The most common type of rash in this single-center retrospective study of 27 consecutive patients was an urticated papular exanthem, present in 13 of the 27 patients. An erythema multiforme-like reaction was present in 8, exfoliative erythroderma in 3, and a morbilliform erythema in 3 others. The worst prognosis was in the subgroup with an erythema multiforme-like rash.

All 27 patients had hepatic involvement, which was severe in 9 cases. Six of the 9 with severe liver impairment had an erythema multiforme-like rash, compared with just 2 of the 18 with mild or moderate liver involvement; thus, an erythema multiforme-like skin eruption was associated with a fivefold increased likelihood of severe hepatic involvement.

“It is a clinical sign that we take seriously at presentation if atypical target lesions are present,” the dermatologist said.

Separately, Taiwanese investigators compared clinical and histopathologic features in a study of 32 patients with DRESS and 17 with maculopapular exanthem. Interface vacuolization, which was present in 29 of the 32 patients with DRESS, was far more prominent than in the comparator group. Moreover, severe dyskeratosis was significantly associated with more severe liver impairment in the DRESS group.
 

HLA testing

Testing for HLA haplotypes associated with severe drug reactions has a useful role as a screening tool prior to prescribing selected high-risk drugs, Dr. Walsh said. For example, it’s known that 6.8% of individuals of European ancestry carry HLA-A*32:01, an allele that was strongly associated with an increased rate of vancomycin-associated DRESS in a case-control study at Vanderbilt University, Nashville, Tenn. Indeed, 19 of 23 individuals with vancomycin-associated DRESS were HLA-A*32:01 positive, compared with none of 46 vancomycin-tolerant controls. Nineteen percent of HLA-A*32:01-positive patients developed DRESS during treatment with vancomycin, and the drug reaction occurred within 4 weeks.

The investigators noted that testing for HLA-A*32:01 is also useful in DRESS occurring in patients on vancomycin and multiple other drugs because the test’s high negative predictive value may safely allow continued therapy with this potent antibiotic for Gram-positive infections.
 

A DRESS prognostic scoring system

Japanese researchers have developed a scoring system for DRESS for use in monitoring severity of the drug reaction, predicting prognosis, and estimating the risk of developing cytomegalovirus disease and its potentially fatal complications. The scoring system incorporates patient factors, including age, duration of drug exposure after symptom onset; rash characteristics, such as percentage of body surface area involved and presence or absence of erythroderma; appetite loss; and laboratory values.

“It yields a prognostic score that can be used to determine treatment choices, such as immediate intervention with anti-CMV agents. It’s a very useful tool,” Dr. Walsh said.

She reported having no financial conflicts regarding her presentation.

[email protected]

Mounting evidence suggests it’s a mistake to reject the diagnosis of drug reaction with eosinophilia and systemic symptoms, or DRESS, simply because the interval between initiating a drug and symptom onset is less than 15 days, Sarah Walsh, MD, said at the virtual annual congress of the European Academy of Dermatology and Venereology.

The standard dictum has been that diagnosis of this severe T-cell-mediated drug reaction requires more than a 2-week delay in symptom onset following initial drug intake. But this can steer physicians in the wrong direction and lead to stopping an innocent drug while the true culprit medication remains on board. This adversely affects patient prognosis, since a longer duration of drug exposure after symptom onset is associated with increased hospital length of stay and greater mortality risk, explained Dr. Walsh, clinical lead for dermatology at King’s College Hospital, London.

In addition to sharing recent data demonstrating that DRESS symptoms often occur within just a week or 2 of drug exposure, she highlighted several recent advances in the ability to predict DRESS severity. These include clues provided by rash morphology and histopathology, HLA testing, and a novel scoring system to assess DRESS severity and the risk of potentially fatal cytomegalovirus reactivation.

Short-delay DRESS onset

In a retrospective study of 41 patients with a first episode of DRESS in three French dermatology departments, 14 (34%) had onset within 15 days or less of initial exposure to the causative drug. In 6 of 14 patients in the rapid-onset group the offending drug was an antibiotic, while in another 5 the culprit was iodinated contrast media. In the delayed-onset DRESS group, the chief sensitizers were allopurinol in 8 patients, lamotrigine in 6, carbamazepine in 4, and sulfasalazine in 2; of note, none of these 4 delayed-onset DRESS drugs were implicated in any cases of rapid-onset DRESS. There were no differences in the clinical manifestations of DRESS between the rapid- and delayed-onset groups.

Similarly, dermatologists at Government Medical College in Kerala, India, reported in a retrospective study of 100 consecutive patients with DRESS, the drug reaction emerged within 2 weeks after starting the culprit medication in 36% of cases. Indeed, 11 patients became symptomatic within 3-7 days after beginning the medication; in 10 of the 11 cases, the offending agent was an antibiotic, and in 1 patient it was terbinafine. In the 25 cases of DRESS that arose on day 8-14 of drug therapy, the culprit was phenytoin in 14, antibiotics in 6, and 1 each for clopidogrel, hydroxychloroquine, sodium valproate, lamotrigine, and vitamin D₃.

Both groups of investigators concluded that a short time lag between starting a drug and development of symptoms of a drug reaction shouldn’t rule out DRESS as a possibility provided other criteria consistent with the diagnosis are present. Hallmarks of DRESS include an acute extensive rash, fever greater than 38 degrees C, enlarged lymph nodes at two or more sites, internal organ involvement, a low platelet count, elevated eosinophils, and abnormal lymphocyte levels.
 

Rash morphology and histology as prognostic indicators

Dr. Walsh was the lead investigator in a study that identified four distinct patterns of skin involvement in patients with DRESS. The most common type of rash in this single-center retrospective study of 27 consecutive patients was an urticated papular exanthem, present in 13 of the 27 patients. An erythema multiforme-like reaction was present in 8, exfoliative erythroderma in 3, and a morbilliform erythema in 3 others. The worst prognosis was in the subgroup with an erythema multiforme-like rash.

All 27 patients had hepatic involvement, which was severe in 9 cases. Six of the 9 with severe liver impairment had an erythema multiforme-like rash, compared with just 2 of the 18 with mild or moderate liver involvement; thus, an erythema multiforme-like skin eruption was associated with a fivefold increased likelihood of severe hepatic involvement.

“It is a clinical sign that we take seriously at presentation if atypical target lesions are present,” the dermatologist said.

Separately, Taiwanese investigators compared clinical and histopathologic features in a study of 32 patients with DRESS and 17 with maculopapular exanthem. Interface vacuolization, which was present in 29 of the 32 patients with DRESS, was far more prominent than in the comparator group. Moreover, severe dyskeratosis was significantly associated with more severe liver impairment in the DRESS group.
 

HLA testing

Testing for HLA haplotypes associated with severe drug reactions has a useful role as a screening tool prior to prescribing selected high-risk drugs, Dr. Walsh said. For example, it’s known that 6.8% of individuals of European ancestry carry HLA-A*32:01, an allele that was strongly associated with an increased rate of vancomycin-associated DRESS in a case-control study at Vanderbilt University, Nashville, Tenn. Indeed, 19 of 23 individuals with vancomycin-associated DRESS were HLA-A*32:01 positive, compared with none of 46 vancomycin-tolerant controls. Nineteen percent of HLA-A*32:01-positive patients developed DRESS during treatment with vancomycin, and the drug reaction occurred within 4 weeks.

The investigators noted that testing for HLA-A*32:01 is also useful in DRESS occurring in patients on vancomycin and multiple other drugs because the test’s high negative predictive value may safely allow continued therapy with this potent antibiotic for Gram-positive infections.
 

A DRESS prognostic scoring system

Japanese researchers have developed a scoring system for DRESS for use in monitoring severity of the drug reaction, predicting prognosis, and estimating the risk of developing cytomegalovirus disease and its potentially fatal complications. The scoring system incorporates patient factors, including age, duration of drug exposure after symptom onset; rash characteristics, such as percentage of body surface area involved and presence or absence of erythroderma; appetite loss; and laboratory values.

“It yields a prognostic score that can be used to determine treatment choices, such as immediate intervention with anti-CMV agents. It’s a very useful tool,” Dr. Walsh said.

She reported having no financial conflicts regarding her presentation.

[email protected]

Mounting evidence suggests it’s a mistake to reject the diagnosis of drug reaction with eosinophilia and systemic symptoms, or DRESS, simply because the interval between initiating a drug and symptom onset is less than 15 days, Sarah Walsh, MD, said at the virtual annual congress of the European Academy of Dermatology and Venereology.

The standard dictum has been that diagnosis of this severe T-cell-mediated drug reaction requires more than a 2-week delay in symptom onset following initial drug intake. But this can steer physicians in the wrong direction and lead to stopping an innocent drug while the true culprit medication remains on board. This adversely affects patient prognosis, since a longer duration of drug exposure after symptom onset is associated with increased hospital length of stay and greater mortality risk, explained Dr. Walsh, clinical lead for dermatology at King’s College Hospital, London.

In addition to sharing recent data demonstrating that DRESS symptoms often occur within just a week or 2 of drug exposure, she highlighted several recent advances in the ability to predict DRESS severity. These include clues provided by rash morphology and histopathology, HLA testing, and a novel scoring system to assess DRESS severity and the risk of potentially fatal cytomegalovirus reactivation.

Short-delay DRESS onset

In a retrospective study of 41 patients with a first episode of DRESS in three French dermatology departments, 14 (34%) had onset within 15 days or less of initial exposure to the causative drug. In 6 of 14 patients in the rapid-onset group the offending drug was an antibiotic, while in another 5 the culprit was iodinated contrast media. In the delayed-onset DRESS group, the chief sensitizers were allopurinol in 8 patients, lamotrigine in 6, carbamazepine in 4, and sulfasalazine in 2; of note, none of these 4 delayed-onset DRESS drugs were implicated in any cases of rapid-onset DRESS. There were no differences in the clinical manifestations of DRESS between the rapid- and delayed-onset groups.

Similarly, dermatologists at Government Medical College in Kerala, India, reported in a retrospective study of 100 consecutive patients with DRESS, the drug reaction emerged within 2 weeks after starting the culprit medication in 36% of cases. Indeed, 11 patients became symptomatic within 3-7 days after beginning the medication; in 10 of the 11 cases, the offending agent was an antibiotic, and in 1 patient it was terbinafine. In the 25 cases of DRESS that arose on day 8-14 of drug therapy, the culprit was phenytoin in 14, antibiotics in 6, and 1 each for clopidogrel, hydroxychloroquine, sodium valproate, lamotrigine, and vitamin D₃.

Both groups of investigators concluded that a short time lag between starting a drug and development of symptoms of a drug reaction shouldn’t rule out DRESS as a possibility provided other criteria consistent with the diagnosis are present. Hallmarks of DRESS include an acute extensive rash, fever greater than 38 degrees C, enlarged lymph nodes at two or more sites, internal organ involvement, a low platelet count, elevated eosinophils, and abnormal lymphocyte levels.
 

Rash morphology and histology as prognostic indicators

Dr. Walsh was the lead investigator in a study that identified four distinct patterns of skin involvement in patients with DRESS. The most common type of rash in this single-center retrospective study of 27 consecutive patients was an urticated papular exanthem, present in 13 of the 27 patients. An erythema multiforme-like reaction was present in 8, exfoliative erythroderma in 3, and a morbilliform erythema in 3 others. The worst prognosis was in the subgroup with an erythema multiforme-like rash.

All 27 patients had hepatic involvement, which was severe in 9 cases. Six of the 9 with severe liver impairment had an erythema multiforme-like rash, compared with just 2 of the 18 with mild or moderate liver involvement; thus, an erythema multiforme-like skin eruption was associated with a fivefold increased likelihood of severe hepatic involvement.

“It is a clinical sign that we take seriously at presentation if atypical target lesions are present,” the dermatologist said.

Separately, Taiwanese investigators compared clinical and histopathologic features in a study of 32 patients with DRESS and 17 with maculopapular exanthem. Interface vacuolization, which was present in 29 of the 32 patients with DRESS, was far more prominent than in the comparator group. Moreover, severe dyskeratosis was significantly associated with more severe liver impairment in the DRESS group.
 

HLA testing

Testing for HLA haplotypes associated with severe drug reactions has a useful role as a screening tool prior to prescribing selected high-risk drugs, Dr. Walsh said. For example, it’s known that 6.8% of individuals of European ancestry carry HLA-A*32:01, an allele that was strongly associated with an increased rate of vancomycin-associated DRESS in a case-control study at Vanderbilt University, Nashville, Tenn. Indeed, 19 of 23 individuals with vancomycin-associated DRESS were HLA-A*32:01 positive, compared with none of 46 vancomycin-tolerant controls. Nineteen percent of HLA-A*32:01-positive patients developed DRESS during treatment with vancomycin, and the drug reaction occurred within 4 weeks.

The investigators noted that testing for HLA-A*32:01 is also useful in DRESS occurring in patients on vancomycin and multiple other drugs because the test’s high negative predictive value may safely allow continued therapy with this potent antibiotic for Gram-positive infections.
 

A DRESS prognostic scoring system

Japanese researchers have developed a scoring system for DRESS for use in monitoring severity of the drug reaction, predicting prognosis, and estimating the risk of developing cytomegalovirus disease and its potentially fatal complications. The scoring system incorporates patient factors, including age, duration of drug exposure after symptom onset; rash characteristics, such as percentage of body surface area involved and presence or absence of erythroderma; appetite loss; and laboratory values.

“It yields a prognostic score that can be used to determine treatment choices, such as immediate intervention with anti-CMV agents. It’s a very useful tool,” Dr. Walsh said.

She reported having no financial conflicts regarding her presentation.

[email protected]

The Biden administration is exploring whether factories can be retrofitted to produce more of the Pfizer/BioNTech and Moderna COVID-19 mRNA vaccines to speed up vaccination of the vast majority of Americans.

The announcement comes as the nation is on track to see 479,000-514,000 deaths by the end of February, said Rochelle Walensky, MD, the director of the Centers for Disease Control and Prevention.

Dr. Walensky, speaking to reporters Wednesday in the first briefing from the White House COVID-19 Response Team, said that 1.6 million COVID-19 shots had been administered each day over the past week and that 3.4 million Americans have been fully vaccinated with two doses.

More than 500 million doses will be needed to vaccinate every American older than 16 years, Andy Slavitt, the senior advisor to the COVID-19 response team, told reporters. Pfizer and Moderna are due to deliver an additional 200 million doses near the end of March, and President Biden is seeking to purchase another 200 million doses from the companies, said Mr. Slavitt.

But it may not be enough. Whether companies can retrofit factories to produce vaccines is “something that’s under active exploration,” Mr. Slavitt said.

“This is a national emergency,” said Jeff Zients, the White House COVID-19 response coordinator. “Everything is on the table across the whole supply chain,” he said. He noted that the administration was also buying low-dead-space syringes to help extract an additional sixth dose from every Pfizer vial.

Mr. Slavitt said the team had identified 12 areas in which Mr. Biden was authorized to use the Defense Production Act to spur the manufacture of items such as masks and COVID-19 diagnostics.
 

More sequencing needed

As new variants emerge, vaccine makers and the CDC are racing to stay a step ahead. “RNA viruses mutate all the time – that’s what they do, that’s their business,” said Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases and Mr. Biden’s chief medical adviser, in the briefing.

Three concerning variants have emerged: the B117, which is circulating widely in the United Kingdom; the B1.351 in South Africa; and the P.1 in Brazil. As of Jan. 26, no cases involving the B1.351 variant have been detected in the United States; one person with the P.1 variant was identified in Minnesota. The CDC has identified 308 cases of the U.K. variant in 26 states, said Dr. Walensky.

The United States is dismally behind in surveillance and sequencing of variants, said Zients. “We are 43rd in the world at genomic sequencing,” which he said was “totally unacceptable.”

Dr. Walensky said the CDC is working on improving data collection and sequencing, but she said more money is needed to “do the amount of sequencing and surveillance that we need in order to be able to detect these when they first start to emerge.”

Both she and Mr. Zients called on Congress to pass Mr. Biden’s proposed American Rescue package, which includes more money for sequencing.

Dr. Fauci said the National Institutes of Health was collaborating with the CDC to determine whether other newly emerging variants pose any threat – such as increased transmissibility or lethality or some other functional characteristic. Scientists will also monitor “in real-time” whether current vaccines continue to make neutralizing antibodies against these mutants.

“With the U.K. variant, what we’re seeing is a very slight, if at all, impact on vaccine-induced antibodies and very little impact on anything else,” he said. With the South African variant, there is “a multifold diminution in the in vitro neutralization by vaccine-induced antibodies,” but “it still is well within the cushion of protection” for the current vaccines.

But, he added, “we have to be concerned looking forward of what the further evolution of this might be.” The anti-COVID monoclonal antibodies – bamlanivimab and the combination of casirivimab and imdevimab – are “more seriously inhibited by this South African strain,” which is spurring development of new monoclonals.

Dr. Fauci also noted that the Johnson & Johnson/Janssen vaccine that is in development – for which phase 3 data may be released within days – was tested in South Africa and Brazil in addition to the United States. The comparative data could help researchers and clinicians make better-informed decisions about what vaccine to use if the South African variant “seeds itself in the U.S.”

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

The Biden administration is exploring whether factories can be retrofitted to produce more of the Pfizer/BioNTech and Moderna COVID-19 mRNA vaccines to speed up vaccination of the vast majority of Americans.

The announcement comes as the nation is on track to see 479,000-514,000 deaths by the end of February, said Rochelle Walensky, MD, the director of the Centers for Disease Control and Prevention.

Dr. Walensky, speaking to reporters Wednesday in the first briefing from the White House COVID-19 Response Team, said that 1.6 million COVID-19 shots had been administered each day over the past week and that 3.4 million Americans have been fully vaccinated with two doses.

More than 500 million doses will be needed to vaccinate every American older than 16 years, Andy Slavitt, the senior advisor to the COVID-19 response team, told reporters. Pfizer and Moderna are due to deliver an additional 200 million doses near the end of March, and President Biden is seeking to purchase another 200 million doses from the companies, said Mr. Slavitt.

But it may not be enough. Whether companies can retrofit factories to produce vaccines is “something that’s under active exploration,” Mr. Slavitt said.

“This is a national emergency,” said Jeff Zients, the White House COVID-19 response coordinator. “Everything is on the table across the whole supply chain,” he said. He noted that the administration was also buying low-dead-space syringes to help extract an additional sixth dose from every Pfizer vial.

Mr. Slavitt said the team had identified 12 areas in which Mr. Biden was authorized to use the Defense Production Act to spur the manufacture of items such as masks and COVID-19 diagnostics.
 

More sequencing needed

As new variants emerge, vaccine makers and the CDC are racing to stay a step ahead. “RNA viruses mutate all the time – that’s what they do, that’s their business,” said Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases and Mr. Biden’s chief medical adviser, in the briefing.

Three concerning variants have emerged: the B117, which is circulating widely in the United Kingdom; the B1.351 in South Africa; and the P.1 in Brazil. As of Jan. 26, no cases involving the B1.351 variant have been detected in the United States; one person with the P.1 variant was identified in Minnesota. The CDC has identified 308 cases of the U.K. variant in 26 states, said Dr. Walensky.

The United States is dismally behind in surveillance and sequencing of variants, said Zients. “We are 43rd in the world at genomic sequencing,” which he said was “totally unacceptable.”

Dr. Walensky said the CDC is working on improving data collection and sequencing, but she said more money is needed to “do the amount of sequencing and surveillance that we need in order to be able to detect these when they first start to emerge.”

Both she and Mr. Zients called on Congress to pass Mr. Biden’s proposed American Rescue package, which includes more money for sequencing.

Dr. Fauci said the National Institutes of Health was collaborating with the CDC to determine whether other newly emerging variants pose any threat – such as increased transmissibility or lethality or some other functional characteristic. Scientists will also monitor “in real-time” whether current vaccines continue to make neutralizing antibodies against these mutants.

“With the U.K. variant, what we’re seeing is a very slight, if at all, impact on vaccine-induced antibodies and very little impact on anything else,” he said. With the South African variant, there is “a multifold diminution in the in vitro neutralization by vaccine-induced antibodies,” but “it still is well within the cushion of protection” for the current vaccines.

But, he added, “we have to be concerned looking forward of what the further evolution of this might be.” The anti-COVID monoclonal antibodies – bamlanivimab and the combination of casirivimab and imdevimab – are “more seriously inhibited by this South African strain,” which is spurring development of new monoclonals.

Dr. Fauci also noted that the Johnson & Johnson/Janssen vaccine that is in development – for which phase 3 data may be released within days – was tested in South Africa and Brazil in addition to the United States. The comparative data could help researchers and clinicians make better-informed decisions about what vaccine to use if the South African variant “seeds itself in the U.S.”

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

The Biden administration is exploring whether factories can be retrofitted to produce more of the Pfizer/BioNTech and Moderna COVID-19 mRNA vaccines to speed up vaccination of the vast majority of Americans.

The announcement comes as the nation is on track to see 479,000-514,000 deaths by the end of February, said Rochelle Walensky, MD, the director of the Centers for Disease Control and Prevention.

Dr. Walensky, speaking to reporters Wednesday in the first briefing from the White House COVID-19 Response Team, said that 1.6 million COVID-19 shots had been administered each day over the past week and that 3.4 million Americans have been fully vaccinated with two doses.

More than 500 million doses will be needed to vaccinate every American older than 16 years, Andy Slavitt, the senior advisor to the COVID-19 response team, told reporters. Pfizer and Moderna are due to deliver an additional 200 million doses near the end of March, and President Biden is seeking to purchase another 200 million doses from the companies, said Mr. Slavitt.

But it may not be enough. Whether companies can retrofit factories to produce vaccines is “something that’s under active exploration,” Mr. Slavitt said.

“This is a national emergency,” said Jeff Zients, the White House COVID-19 response coordinator. “Everything is on the table across the whole supply chain,” he said. He noted that the administration was also buying low-dead-space syringes to help extract an additional sixth dose from every Pfizer vial.

Mr. Slavitt said the team had identified 12 areas in which Mr. Biden was authorized to use the Defense Production Act to spur the manufacture of items such as masks and COVID-19 diagnostics.
 

More sequencing needed

As new variants emerge, vaccine makers and the CDC are racing to stay a step ahead. “RNA viruses mutate all the time – that’s what they do, that’s their business,” said Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases and Mr. Biden’s chief medical adviser, in the briefing.

Three concerning variants have emerged: the B117, which is circulating widely in the United Kingdom; the B1.351 in South Africa; and the P.1 in Brazil. As of Jan. 26, no cases involving the B1.351 variant have been detected in the United States; one person with the P.1 variant was identified in Minnesota. The CDC has identified 308 cases of the U.K. variant in 26 states, said Dr. Walensky.

The United States is dismally behind in surveillance and sequencing of variants, said Zients. “We are 43rd in the world at genomic sequencing,” which he said was “totally unacceptable.”

Dr. Walensky said the CDC is working on improving data collection and sequencing, but she said more money is needed to “do the amount of sequencing and surveillance that we need in order to be able to detect these when they first start to emerge.”

Both she and Mr. Zients called on Congress to pass Mr. Biden’s proposed American Rescue package, which includes more money for sequencing.

Dr. Fauci said the National Institutes of Health was collaborating with the CDC to determine whether other newly emerging variants pose any threat – such as increased transmissibility or lethality or some other functional characteristic. Scientists will also monitor “in real-time” whether current vaccines continue to make neutralizing antibodies against these mutants.

“With the U.K. variant, what we’re seeing is a very slight, if at all, impact on vaccine-induced antibodies and very little impact on anything else,” he said. With the South African variant, there is “a multifold diminution in the in vitro neutralization by vaccine-induced antibodies,” but “it still is well within the cushion of protection” for the current vaccines.

But, he added, “we have to be concerned looking forward of what the further evolution of this might be.” The anti-COVID monoclonal antibodies – bamlanivimab and the combination of casirivimab and imdevimab – are “more seriously inhibited by this South African strain,” which is spurring development of new monoclonals.

Dr. Fauci also noted that the Johnson & Johnson/Janssen vaccine that is in development – for which phase 3 data may be released within days – was tested in South Africa and Brazil in addition to the United States. The comparative data could help researchers and clinicians make better-informed decisions about what vaccine to use if the South African variant “seeds itself in the U.S.”

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

A follow-up look at an international registry suggests that some people may have persistent, long-lasting dermatologic manifestations – especially so-called “COVID toes” – as a result of infection with or exposure to the SARS-CoV-2 virus, but some dermatologists question if the skin signs and symptoms are truly related.

In their commentary in the Lancet Infectious Diseases, Esther P. Freeman, MD, PhD, and colleagues who lead and participate in the American Academy of Dermatology’s international registry said their analysis “revealed a previously unreported subset of patients who experience long-haul symptoms in dermatology-dominant COVID-19.”

Some of the data was presented at the 29th European Academy of Dermatology and Venereology in late October 2020, but has since been updated with more cases.

Dermatologists who spoke with this news organization said it has not been settled that some skin manifestations – such as pernio/chilblains rashes, seen primarily in nonhospitalized patients, and described in the registry – are definitively caused by COVID. They also noted that in some cases, patients who initially test negative for COVID-19 by polymerase chain reaction (PCR) sometimes do not ever develop antibodies, which could mean they were never actually exposed to SARS-CoV-2.

M. Alexander Otto/MDedge News

“I still question whether the perniosis is directly related to infection with SARS-CoV-2 or not,” said Anthony Fernandez, MD, PhD, director of medical and inpatient dermatology and assistant professor of dermatopathology at the Cleveland Clinic. His uncertainty is driven by the lack of seroconversion and that few cases were seen over the summer in the United States – suggesting that it may still be a result of cold temperatures.

“I’m not sure there is a definitive correct answer, definitely not that everyone would agree on,” said Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Conn.

Dr. Freeman, however, believed that pernio and especially persistent lesions are caused by an immune response to COVID.

In an interview, she noted the multiple cases of patients in the registry who did seroconvert and that, while a registry is not a perfect means of getting an answer, it is good for generating questions. Taken collectively, the cases in the registry can “tell a story for further hypotheses,” said Dr. Freeman, who is director of global health dermatology at Massachusetts General Hospital and assistant professor of dermatology at Harvard University, both in Boston.

“We were noticing this signal across the world” that patients “developed these toe lesions and they never got better,” said Dr. Freeman. Generally, people who experience pernio, also described as COVID toes or “COVID fingers,” recover in 4-8 weeks. But in the registry, “we did have this subset of patients who really were experiencing these very longstanding symptoms,” she added.

Two patients with lab-confirmed COVID have had long-lasting pernio of 133 days and 150 days. “I’m caring for a cohort in Boston who have had long COVID of the skin and symptoms for over 10 months,” Dr. Freeman said.
 

Pernio dominates

The registry – a collaboration between the AAD and the International League of Dermatological Societies – was launched in April 2020. Any medical professional can enter case information. From April to October, 1,030 total cases and 331 laboratory-confirmed or suspected COVID-19 cases with dermatological manifestations were entered from 41 countries.

Most of the cases were just recorded at a single time point, which is an acknowledged limitation of the study.

Dr. Freeman and colleagues reached out to registry participants in June and August to get updates on COVID lab test results and sign and symptom duration. Overall, 234 total and 96 lab-confirmed COVID infections had more lengthy data about sign and symptom duration.

Pernio lasted a median of 15 days in patients with suspected disease and 12 days for those with lab-confirmed COVID, compared with a median of 7 days for morbilliform eruptions, 4 days for urticarial eruptions, and 20 days for papulosquamous eruptions – all in patients with lab-confirmed disease.

Of the 103 cases of pernio, 7 had symptoms lasting more than 60 days. Only two of those seven patients had lab-confirmed COVID. Initially, the one patient tested negative with nasopharyngeal PCR, and serum IgM and IgG. Six weeks after pernio onset, the patient – still experiencing fatigue and pernio – seroconverted to anti–SARS-CoV-2 IgM positivity.

The other long-haul patient, after a negative PCR, tested positive for SARS-CoV-2 serum IgG 1 month after pernio onset.

Robust immune response?

Dr. Freeman said these patients might have a very high interferon response initially to the virus, which makes for a mild to nonexistent disease, but could create inflammation elsewhere. “I almost view the toes as an innocent bystander of a robust immune response to SARS-CoV-2.”

Although he has not seen extended pernio or other skin manifestations in his patients, Dr. Fernandez said the interferon hypothesis is “fair,” and “the best that’s out there.” Dr. Fernandez is currently studying cutaneous manifestations of COVID-19 as a principal investigator of a trial sponsored by the Clinical and Translational Science Collaborative of Cleveland.

Dr. Ko said in an interview that she has not observed long-haul skin issues in her patients, but Yale colleagues have.

In a study, she and Yale colleagues published in September, SARS-CoV-2 spike protein was detected in perniotic lesions, but not nuclear protein or viral RNA. The test they used – immunohistochemistry – can be nonspecific, which muddied results.

She does not think there is replicating virus in the skin or the lesions. Instead, said Dr. Ko, “either there is viral spike protein that has somehow become disassociated from actively replicating virus that somehow got deposited in endothelial cells,” or the staining “was spurious,” or some other protein is cross-reacting. “And the people who are unlucky enough to have that protein in their endothelial cells can manifest this COVID-toe, COVID-finger phenomenon.”

To her, it’s an unsolved mystery. “The weird thing is, we’ve never before had this much perniosis,” Dr. Ko said.

Dr. Fernandez is not convinced yet, noting that, in Cleveland, more pernio cases were observed in March and April than in the summer. “If it is a manifestation of the infection then you also need the right environment, the cold weather for this manifestation to present,” he said. “Or, it really isn’t a direct manifestation of COVID-19 but may be more related to other factors,” such as lifestyle changes related to limitations implemented to help mitigate the spread of the disease.

“To me the jury is still out whether or not the perniotic lesions really can tell us something about a patient’s exposure and infection with SARS-CoV-2,” he said.

Dr. Freeman reported receiving a grant from the International League of Dermatological Societies and nonfinancial support from the AAD for the study. Dr. Ko reported no conflicts. Dr. Fernadnez had no disclosures.

A follow-up look at an international registry suggests that some people may have persistent, long-lasting dermatologic manifestations – especially so-called “COVID toes” – as a result of infection with or exposure to the SARS-CoV-2 virus, but some dermatologists question if the skin signs and symptoms are truly related.

In their commentary in the Lancet Infectious Diseases, Esther P. Freeman, MD, PhD, and colleagues who lead and participate in the American Academy of Dermatology’s international registry said their analysis “revealed a previously unreported subset of patients who experience long-haul symptoms in dermatology-dominant COVID-19.”

Some of the data was presented at the 29th European Academy of Dermatology and Venereology in late October 2020, but has since been updated with more cases.

Dermatologists who spoke with this news organization said it has not been settled that some skin manifestations – such as pernio/chilblains rashes, seen primarily in nonhospitalized patients, and described in the registry – are definitively caused by COVID. They also noted that in some cases, patients who initially test negative for COVID-19 by polymerase chain reaction (PCR) sometimes do not ever develop antibodies, which could mean they were never actually exposed to SARS-CoV-2.

M. Alexander Otto/MDedge News

“I still question whether the perniosis is directly related to infection with SARS-CoV-2 or not,” said Anthony Fernandez, MD, PhD, director of medical and inpatient dermatology and assistant professor of dermatopathology at the Cleveland Clinic. His uncertainty is driven by the lack of seroconversion and that few cases were seen over the summer in the United States – suggesting that it may still be a result of cold temperatures.

“I’m not sure there is a definitive correct answer, definitely not that everyone would agree on,” said Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Conn.

Dr. Freeman, however, believed that pernio and especially persistent lesions are caused by an immune response to COVID.

In an interview, she noted the multiple cases of patients in the registry who did seroconvert and that, while a registry is not a perfect means of getting an answer, it is good for generating questions. Taken collectively, the cases in the registry can “tell a story for further hypotheses,” said Dr. Freeman, who is director of global health dermatology at Massachusetts General Hospital and assistant professor of dermatology at Harvard University, both in Boston.

“We were noticing this signal across the world” that patients “developed these toe lesions and they never got better,” said Dr. Freeman. Generally, people who experience pernio, also described as COVID toes or “COVID fingers,” recover in 4-8 weeks. But in the registry, “we did have this subset of patients who really were experiencing these very longstanding symptoms,” she added.

Two patients with lab-confirmed COVID have had long-lasting pernio of 133 days and 150 days. “I’m caring for a cohort in Boston who have had long COVID of the skin and symptoms for over 10 months,” Dr. Freeman said.
 

Pernio dominates

The registry – a collaboration between the AAD and the International League of Dermatological Societies – was launched in April 2020. Any medical professional can enter case information. From April to October, 1,030 total cases and 331 laboratory-confirmed or suspected COVID-19 cases with dermatological manifestations were entered from 41 countries.

Most of the cases were just recorded at a single time point, which is an acknowledged limitation of the study.

Dr. Freeman and colleagues reached out to registry participants in June and August to get updates on COVID lab test results and sign and symptom duration. Overall, 234 total and 96 lab-confirmed COVID infections had more lengthy data about sign and symptom duration.

Pernio lasted a median of 15 days in patients with suspected disease and 12 days for those with lab-confirmed COVID, compared with a median of 7 days for morbilliform eruptions, 4 days for urticarial eruptions, and 20 days for papulosquamous eruptions – all in patients with lab-confirmed disease.

Of the 103 cases of pernio, 7 had symptoms lasting more than 60 days. Only two of those seven patients had lab-confirmed COVID. Initially, the one patient tested negative with nasopharyngeal PCR, and serum IgM and IgG. Six weeks after pernio onset, the patient – still experiencing fatigue and pernio – seroconverted to anti–SARS-CoV-2 IgM positivity.

The other long-haul patient, after a negative PCR, tested positive for SARS-CoV-2 serum IgG 1 month after pernio onset.

Robust immune response?

Dr. Freeman said these patients might have a very high interferon response initially to the virus, which makes for a mild to nonexistent disease, but could create inflammation elsewhere. “I almost view the toes as an innocent bystander of a robust immune response to SARS-CoV-2.”

Although he has not seen extended pernio or other skin manifestations in his patients, Dr. Fernandez said the interferon hypothesis is “fair,” and “the best that’s out there.” Dr. Fernandez is currently studying cutaneous manifestations of COVID-19 as a principal investigator of a trial sponsored by the Clinical and Translational Science Collaborative of Cleveland.

Dr. Ko said in an interview that she has not observed long-haul skin issues in her patients, but Yale colleagues have.

In a study, she and Yale colleagues published in September, SARS-CoV-2 spike protein was detected in perniotic lesions, but not nuclear protein or viral RNA. The test they used – immunohistochemistry – can be nonspecific, which muddied results.

She does not think there is replicating virus in the skin or the lesions. Instead, said Dr. Ko, “either there is viral spike protein that has somehow become disassociated from actively replicating virus that somehow got deposited in endothelial cells,” or the staining “was spurious,” or some other protein is cross-reacting. “And the people who are unlucky enough to have that protein in their endothelial cells can manifest this COVID-toe, COVID-finger phenomenon.”

To her, it’s an unsolved mystery. “The weird thing is, we’ve never before had this much perniosis,” Dr. Ko said.

Dr. Fernandez is not convinced yet, noting that, in Cleveland, more pernio cases were observed in March and April than in the summer. “If it is a manifestation of the infection then you also need the right environment, the cold weather for this manifestation to present,” he said. “Or, it really isn’t a direct manifestation of COVID-19 but may be more related to other factors,” such as lifestyle changes related to limitations implemented to help mitigate the spread of the disease.

“To me the jury is still out whether or not the perniotic lesions really can tell us something about a patient’s exposure and infection with SARS-CoV-2,” he said.

Dr. Freeman reported receiving a grant from the International League of Dermatological Societies and nonfinancial support from the AAD for the study. Dr. Ko reported no conflicts. Dr. Fernadnez had no disclosures.

A follow-up look at an international registry suggests that some people may have persistent, long-lasting dermatologic manifestations – especially so-called “COVID toes” – as a result of infection with or exposure to the SARS-CoV-2 virus, but some dermatologists question if the skin signs and symptoms are truly related.

In their commentary in the Lancet Infectious Diseases, Esther P. Freeman, MD, PhD, and colleagues who lead and participate in the American Academy of Dermatology’s international registry said their analysis “revealed a previously unreported subset of patients who experience long-haul symptoms in dermatology-dominant COVID-19.”

Some of the data was presented at the 29th European Academy of Dermatology and Venereology in late October 2020, but has since been updated with more cases.

Dermatologists who spoke with this news organization said it has not been settled that some skin manifestations – such as pernio/chilblains rashes, seen primarily in nonhospitalized patients, and described in the registry – are definitively caused by COVID. They also noted that in some cases, patients who initially test negative for COVID-19 by polymerase chain reaction (PCR) sometimes do not ever develop antibodies, which could mean they were never actually exposed to SARS-CoV-2.

M. Alexander Otto/MDedge News

“I still question whether the perniosis is directly related to infection with SARS-CoV-2 or not,” said Anthony Fernandez, MD, PhD, director of medical and inpatient dermatology and assistant professor of dermatopathology at the Cleveland Clinic. His uncertainty is driven by the lack of seroconversion and that few cases were seen over the summer in the United States – suggesting that it may still be a result of cold temperatures.

“I’m not sure there is a definitive correct answer, definitely not that everyone would agree on,” said Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Conn.

Dr. Freeman, however, believed that pernio and especially persistent lesions are caused by an immune response to COVID.

In an interview, she noted the multiple cases of patients in the registry who did seroconvert and that, while a registry is not a perfect means of getting an answer, it is good for generating questions. Taken collectively, the cases in the registry can “tell a story for further hypotheses,” said Dr. Freeman, who is director of global health dermatology at Massachusetts General Hospital and assistant professor of dermatology at Harvard University, both in Boston.

“We were noticing this signal across the world” that patients “developed these toe lesions and they never got better,” said Dr. Freeman. Generally, people who experience pernio, also described as COVID toes or “COVID fingers,” recover in 4-8 weeks. But in the registry, “we did have this subset of patients who really were experiencing these very longstanding symptoms,” she added.

Two patients with lab-confirmed COVID have had long-lasting pernio of 133 days and 150 days. “I’m caring for a cohort in Boston who have had long COVID of the skin and symptoms for over 10 months,” Dr. Freeman said.
 

Pernio dominates

The registry – a collaboration between the AAD and the International League of Dermatological Societies – was launched in April 2020. Any medical professional can enter case information. From April to October, 1,030 total cases and 331 laboratory-confirmed or suspected COVID-19 cases with dermatological manifestations were entered from 41 countries.

Most of the cases were just recorded at a single time point, which is an acknowledged limitation of the study.

Dr. Freeman and colleagues reached out to registry participants in June and August to get updates on COVID lab test results and sign and symptom duration. Overall, 234 total and 96 lab-confirmed COVID infections had more lengthy data about sign and symptom duration.

Pernio lasted a median of 15 days in patients with suspected disease and 12 days for those with lab-confirmed COVID, compared with a median of 7 days for morbilliform eruptions, 4 days for urticarial eruptions, and 20 days for papulosquamous eruptions – all in patients with lab-confirmed disease.

Of the 103 cases of pernio, 7 had symptoms lasting more than 60 days. Only two of those seven patients had lab-confirmed COVID. Initially, the one patient tested negative with nasopharyngeal PCR, and serum IgM and IgG. Six weeks after pernio onset, the patient – still experiencing fatigue and pernio – seroconverted to anti–SARS-CoV-2 IgM positivity.

The other long-haul patient, after a negative PCR, tested positive for SARS-CoV-2 serum IgG 1 month after pernio onset.

Robust immune response?

Dr. Freeman said these patients might have a very high interferon response initially to the virus, which makes for a mild to nonexistent disease, but could create inflammation elsewhere. “I almost view the toes as an innocent bystander of a robust immune response to SARS-CoV-2.”

Although he has not seen extended pernio or other skin manifestations in his patients, Dr. Fernandez said the interferon hypothesis is “fair,” and “the best that’s out there.” Dr. Fernandez is currently studying cutaneous manifestations of COVID-19 as a principal investigator of a trial sponsored by the Clinical and Translational Science Collaborative of Cleveland.

Dr. Ko said in an interview that she has not observed long-haul skin issues in her patients, but Yale colleagues have.

In a study, she and Yale colleagues published in September, SARS-CoV-2 spike protein was detected in perniotic lesions, but not nuclear protein or viral RNA. The test they used – immunohistochemistry – can be nonspecific, which muddied results.

She does not think there is replicating virus in the skin or the lesions. Instead, said Dr. Ko, “either there is viral spike protein that has somehow become disassociated from actively replicating virus that somehow got deposited in endothelial cells,” or the staining “was spurious,” or some other protein is cross-reacting. “And the people who are unlucky enough to have that protein in their endothelial cells can manifest this COVID-toe, COVID-finger phenomenon.”

To her, it’s an unsolved mystery. “The weird thing is, we’ve never before had this much perniosis,” Dr. Ko said.

Dr. Fernandez is not convinced yet, noting that, in Cleveland, more pernio cases were observed in March and April than in the summer. “If it is a manifestation of the infection then you also need the right environment, the cold weather for this manifestation to present,” he said. “Or, it really isn’t a direct manifestation of COVID-19 but may be more related to other factors,” such as lifestyle changes related to limitations implemented to help mitigate the spread of the disease.

“To me the jury is still out whether or not the perniotic lesions really can tell us something about a patient’s exposure and infection with SARS-CoV-2,” he said.

Dr. Freeman reported receiving a grant from the International League of Dermatological Societies and nonfinancial support from the AAD for the study. Dr. Ko reported no conflicts. Dr. Fernadnez had no disclosures.