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Metformin appears to play a role in preventing long COVID when taken early during a COVID-19 infection, according to preprints with The Lancet on SSRN. The preprint hasn’t yet been peer-reviewed or published in a journal.

In particular, metformin led to a 42% drop in long COVID among people who had a mild to moderate COVID-19 infection. 

“Long COVID affects millions of people, and preventing long COVID through a treatment like metformin could prevent significant disruptions in people’s lives,” said lead author Carolyn Bramante, MD, assistant professor of internal medicine and pediatrics at the University of Minnesota, Minneapolis.

Between January 2021 and February 2022, Dr. Bramante and colleagues tested three oral medications – metformin (typically used to treat type 2 diabetes), ivermectin (an antiparasitic), and fluvoxamine (an antidepressant) – in a clinical trial across the United States called COVID-OUT. The people being studied, investigators, care providers, and others involved in the study were blinded to the randomized treatments. The trial was decentralized, with no in-person contact with participants.

The researchers included patients who were aged 30-85 with overweight or obesity, had documentation of a confirmed COVID-19 infection, had fewer than 7 days of symptoms, had no known prior infection, and joined the study within 3 days of their positive test. The study included monthly follow-up for 300 days, and participants indicated whether they received a long COVID diagnosis from a medical doctor, which the researchers confirmed in medical records after participants gave consent.

The medications were prepackaged into pill boxes for fast delivery to participants and to ensure they took the correct number of each type of pill. The packages were sent via same-day courier or overnight shipping.

The metformin doses were doled out over 14 days, with 500 milligrams on the first day, 500 milligrams twice a day for the next 4 days, and then 500 milligrams in the morning and 1,000 milligrams in the evening for the remaining 9 days.

Among the 1,323 people studied, 1,125 agreed to do long-term follow-up for long COVID: 564 in the metformin group and 561 in the blinded placebo group. The average age was 45, and 56% were women, including 7% who were pregnant. 

The average time from the start of symptoms to starting medication was 5 days, and 47% began taking the drug within 4 days or less. About 55% had received the primary COVID-19 vaccination series, including 5.1% who received an initial booster, before enrolling in the study.

Overall, 8.4% of participants reported that a medical provider diagnosed them with long COVID. Of those who took metformin, 6.3% developed long COVID, compared to 10.6% among those who took the identical-matched placebo.

The risk reduction for metformin was 42% versus the placebo, which was consistent across subgroups, including vaccination status and different COVID-19 variants.

When metformin was started less than 4 days after COVID-19 symptoms started, the effect was potentially even greater, with a 64% reduction, as compared with a 36% reduction among those who started metformin after 4 or more days after symptoms.

Neither ivermectin nor fluvoxamine showed any benefits for preventing long COVID.

At the same time, the study authors caution that more research is needed. 

“The COVID-OUT trial does not indicate whether or not metformin would be effective at preventing long COVID if started at the time of emergency department visit or hospitalization for COVID-19, nor whether metformin would be effective as treatment in persons who already have long COVID,” they wrote. “With the burden of long COVID on society, confirmation is urgently needed in a trial that addresses our study’s limitations in order to translate these results into practice and policy.”

Several risk factors for long COVID emerged in the analysis. About 11.1% of the women had a long COVID diagnosis, compared with 4.9% of the men. Also, those who had received at least the primary vaccine series had a lower risk of developing long COVID, at 6.6%, as compared with 10.5% among the unvaccinated. Only 1 of the 57 people who received a booster shot developed long COVID.

Notably, pregnant and lactating people were included in this study, which is important given that pregnant people face higher risks for poor COVID-19 outcomes and are excluded from most nonobstetric clinical trials, the study authors wrote. In this study, they were randomized to metformin or placebo but not ivermectin or fluvoxamine due to limited research about the safety of those drugs during pregnancy and lactation.

The results are now under journal review but show findings consistent with those from other recent studies. Also, in August 2022, the authors published results from COVID-OUT that showed metformin led to a 42% reduction in hospital visits, emergency department visits, and deaths related to severe COVID-19.

“Given the lack of side effects and cost for a 2-week course, I think these data support use of metformin now,” said Eric Topol, MD, founder and director of the Scripps Research Translational Institute and editor-in-chief of Medscape, WebMD’s sister site for health care professionals. 

Dr. Topol, who wasn’t involved with this study, has been a leading voice on COVID-19 research throughout the pandemic. He noted the need for more studies, including a factorial design trial to test metformin and Paxlovid, which has shown promise in preventing long COVID. Dr. Topol also wrote about the preprint in Ground Truths, his online newsletter.

“As I’ve written in the past, I don’t use the term ‘breakthrough’ lightly,” he wrote. “But to see such a pronounced benefit in the current randomized trial of metformin, in the context of its being so safe and low cost, I’d give it a breakthrough categorization.”

Another way to put it, Dr. Topol wrote, is that based on this study, he would take metformin if he became infected with COVID-19. 

Jeremy Faust, MD, an emergency medicine doctor at Brigham and Women’s Hospital in Boston, also wrote about the study in his newsletter, Inside Medicine. He noted that the 42% reduction in long COVID means that 23 COVID-19 patients need to be treated with metformin to prevent one long COVID diagnosis, which is an “important reduction.”

“Bottom line: If a person who meets criteria for obesity or overweight status were to ask me if they should take metformin (for 2 weeks) starting as soon as they learn they have COVID-19, I would say yes in many if not most cases, based on this new data,” he wrote. “This is starting to look like a real win.”

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

Metformin appears to play a role in preventing long COVID when taken early during a COVID-19 infection, according to preprints with The Lancet on SSRN. The preprint hasn’t yet been peer-reviewed or published in a journal.

In particular, metformin led to a 42% drop in long COVID among people who had a mild to moderate COVID-19 infection. 

“Long COVID affects millions of people, and preventing long COVID through a treatment like metformin could prevent significant disruptions in people’s lives,” said lead author Carolyn Bramante, MD, assistant professor of internal medicine and pediatrics at the University of Minnesota, Minneapolis.

Between January 2021 and February 2022, Dr. Bramante and colleagues tested three oral medications – metformin (typically used to treat type 2 diabetes), ivermectin (an antiparasitic), and fluvoxamine (an antidepressant) – in a clinical trial across the United States called COVID-OUT. The people being studied, investigators, care providers, and others involved in the study were blinded to the randomized treatments. The trial was decentralized, with no in-person contact with participants.

The researchers included patients who were aged 30-85 with overweight or obesity, had documentation of a confirmed COVID-19 infection, had fewer than 7 days of symptoms, had no known prior infection, and joined the study within 3 days of their positive test. The study included monthly follow-up for 300 days, and participants indicated whether they received a long COVID diagnosis from a medical doctor, which the researchers confirmed in medical records after participants gave consent.

The medications were prepackaged into pill boxes for fast delivery to participants and to ensure they took the correct number of each type of pill. The packages were sent via same-day courier or overnight shipping.

The metformin doses were doled out over 14 days, with 500 milligrams on the first day, 500 milligrams twice a day for the next 4 days, and then 500 milligrams in the morning and 1,000 milligrams in the evening for the remaining 9 days.

Among the 1,323 people studied, 1,125 agreed to do long-term follow-up for long COVID: 564 in the metformin group and 561 in the blinded placebo group. The average age was 45, and 56% were women, including 7% who were pregnant. 

The average time from the start of symptoms to starting medication was 5 days, and 47% began taking the drug within 4 days or less. About 55% had received the primary COVID-19 vaccination series, including 5.1% who received an initial booster, before enrolling in the study.

Overall, 8.4% of participants reported that a medical provider diagnosed them with long COVID. Of those who took metformin, 6.3% developed long COVID, compared to 10.6% among those who took the identical-matched placebo.

The risk reduction for metformin was 42% versus the placebo, which was consistent across subgroups, including vaccination status and different COVID-19 variants.

When metformin was started less than 4 days after COVID-19 symptoms started, the effect was potentially even greater, with a 64% reduction, as compared with a 36% reduction among those who started metformin after 4 or more days after symptoms.

Neither ivermectin nor fluvoxamine showed any benefits for preventing long COVID.

At the same time, the study authors caution that more research is needed. 

“The COVID-OUT trial does not indicate whether or not metformin would be effective at preventing long COVID if started at the time of emergency department visit or hospitalization for COVID-19, nor whether metformin would be effective as treatment in persons who already have long COVID,” they wrote. “With the burden of long COVID on society, confirmation is urgently needed in a trial that addresses our study’s limitations in order to translate these results into practice and policy.”

Several risk factors for long COVID emerged in the analysis. About 11.1% of the women had a long COVID diagnosis, compared with 4.9% of the men. Also, those who had received at least the primary vaccine series had a lower risk of developing long COVID, at 6.6%, as compared with 10.5% among the unvaccinated. Only 1 of the 57 people who received a booster shot developed long COVID.

Notably, pregnant and lactating people were included in this study, which is important given that pregnant people face higher risks for poor COVID-19 outcomes and are excluded from most nonobstetric clinical trials, the study authors wrote. In this study, they were randomized to metformin or placebo but not ivermectin or fluvoxamine due to limited research about the safety of those drugs during pregnancy and lactation.

The results are now under journal review but show findings consistent with those from other recent studies. Also, in August 2022, the authors published results from COVID-OUT that showed metformin led to a 42% reduction in hospital visits, emergency department visits, and deaths related to severe COVID-19.

“Given the lack of side effects and cost for a 2-week course, I think these data support use of metformin now,” said Eric Topol, MD, founder and director of the Scripps Research Translational Institute and editor-in-chief of Medscape, WebMD’s sister site for health care professionals. 

Dr. Topol, who wasn’t involved with this study, has been a leading voice on COVID-19 research throughout the pandemic. He noted the need for more studies, including a factorial design trial to test metformin and Paxlovid, which has shown promise in preventing long COVID. Dr. Topol also wrote about the preprint in Ground Truths, his online newsletter.

“As I’ve written in the past, I don’t use the term ‘breakthrough’ lightly,” he wrote. “But to see such a pronounced benefit in the current randomized trial of metformin, in the context of its being so safe and low cost, I’d give it a breakthrough categorization.”

Another way to put it, Dr. Topol wrote, is that based on this study, he would take metformin if he became infected with COVID-19. 

Jeremy Faust, MD, an emergency medicine doctor at Brigham and Women’s Hospital in Boston, also wrote about the study in his newsletter, Inside Medicine. He noted that the 42% reduction in long COVID means that 23 COVID-19 patients need to be treated with metformin to prevent one long COVID diagnosis, which is an “important reduction.”

“Bottom line: If a person who meets criteria for obesity or overweight status were to ask me if they should take metformin (for 2 weeks) starting as soon as they learn they have COVID-19, I would say yes in many if not most cases, based on this new data,” he wrote. “This is starting to look like a real win.”

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

Metformin appears to play a role in preventing long COVID when taken early during a COVID-19 infection, according to preprints with The Lancet on SSRN. The preprint hasn’t yet been peer-reviewed or published in a journal.

In particular, metformin led to a 42% drop in long COVID among people who had a mild to moderate COVID-19 infection. 

“Long COVID affects millions of people, and preventing long COVID through a treatment like metformin could prevent significant disruptions in people’s lives,” said lead author Carolyn Bramante, MD, assistant professor of internal medicine and pediatrics at the University of Minnesota, Minneapolis.

Between January 2021 and February 2022, Dr. Bramante and colleagues tested three oral medications – metformin (typically used to treat type 2 diabetes), ivermectin (an antiparasitic), and fluvoxamine (an antidepressant) – in a clinical trial across the United States called COVID-OUT. The people being studied, investigators, care providers, and others involved in the study were blinded to the randomized treatments. The trial was decentralized, with no in-person contact with participants.

The researchers included patients who were aged 30-85 with overweight or obesity, had documentation of a confirmed COVID-19 infection, had fewer than 7 days of symptoms, had no known prior infection, and joined the study within 3 days of their positive test. The study included monthly follow-up for 300 days, and participants indicated whether they received a long COVID diagnosis from a medical doctor, which the researchers confirmed in medical records after participants gave consent.

The medications were prepackaged into pill boxes for fast delivery to participants and to ensure they took the correct number of each type of pill. The packages were sent via same-day courier or overnight shipping.

The metformin doses were doled out over 14 days, with 500 milligrams on the first day, 500 milligrams twice a day for the next 4 days, and then 500 milligrams in the morning and 1,000 milligrams in the evening for the remaining 9 days.

Among the 1,323 people studied, 1,125 agreed to do long-term follow-up for long COVID: 564 in the metformin group and 561 in the blinded placebo group. The average age was 45, and 56% were women, including 7% who were pregnant. 

The average time from the start of symptoms to starting medication was 5 days, and 47% began taking the drug within 4 days or less. About 55% had received the primary COVID-19 vaccination series, including 5.1% who received an initial booster, before enrolling in the study.

Overall, 8.4% of participants reported that a medical provider diagnosed them with long COVID. Of those who took metformin, 6.3% developed long COVID, compared to 10.6% among those who took the identical-matched placebo.

The risk reduction for metformin was 42% versus the placebo, which was consistent across subgroups, including vaccination status and different COVID-19 variants.

When metformin was started less than 4 days after COVID-19 symptoms started, the effect was potentially even greater, with a 64% reduction, as compared with a 36% reduction among those who started metformin after 4 or more days after symptoms.

Neither ivermectin nor fluvoxamine showed any benefits for preventing long COVID.

At the same time, the study authors caution that more research is needed. 

“The COVID-OUT trial does not indicate whether or not metformin would be effective at preventing long COVID if started at the time of emergency department visit or hospitalization for COVID-19, nor whether metformin would be effective as treatment in persons who already have long COVID,” they wrote. “With the burden of long COVID on society, confirmation is urgently needed in a trial that addresses our study’s limitations in order to translate these results into practice and policy.”

Several risk factors for long COVID emerged in the analysis. About 11.1% of the women had a long COVID diagnosis, compared with 4.9% of the men. Also, those who had received at least the primary vaccine series had a lower risk of developing long COVID, at 6.6%, as compared with 10.5% among the unvaccinated. Only 1 of the 57 people who received a booster shot developed long COVID.

Notably, pregnant and lactating people were included in this study, which is important given that pregnant people face higher risks for poor COVID-19 outcomes and are excluded from most nonobstetric clinical trials, the study authors wrote. In this study, they were randomized to metformin or placebo but not ivermectin or fluvoxamine due to limited research about the safety of those drugs during pregnancy and lactation.

The results are now under journal review but show findings consistent with those from other recent studies. Also, in August 2022, the authors published results from COVID-OUT that showed metformin led to a 42% reduction in hospital visits, emergency department visits, and deaths related to severe COVID-19.

“Given the lack of side effects and cost for a 2-week course, I think these data support use of metformin now,” said Eric Topol, MD, founder and director of the Scripps Research Translational Institute and editor-in-chief of Medscape, WebMD’s sister site for health care professionals. 

Dr. Topol, who wasn’t involved with this study, has been a leading voice on COVID-19 research throughout the pandemic. He noted the need for more studies, including a factorial design trial to test metformin and Paxlovid, which has shown promise in preventing long COVID. Dr. Topol also wrote about the preprint in Ground Truths, his online newsletter.

“As I’ve written in the past, I don’t use the term ‘breakthrough’ lightly,” he wrote. “But to see such a pronounced benefit in the current randomized trial of metformin, in the context of its being so safe and low cost, I’d give it a breakthrough categorization.”

Another way to put it, Dr. Topol wrote, is that based on this study, he would take metformin if he became infected with COVID-19. 

Jeremy Faust, MD, an emergency medicine doctor at Brigham and Women’s Hospital in Boston, also wrote about the study in his newsletter, Inside Medicine. He noted that the 42% reduction in long COVID means that 23 COVID-19 patients need to be treated with metformin to prevent one long COVID diagnosis, which is an “important reduction.”

“Bottom line: If a person who meets criteria for obesity or overweight status were to ask me if they should take metformin (for 2 weeks) starting as soon as they learn they have COVID-19, I would say yes in many if not most cases, based on this new data,” he wrote. “This is starting to look like a real win.”

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

Patients with celiac disease who have COVID-19 are twice as likely to be hospitalized as are individuals without the autoimmune condition, a single-center U.S. study shows.

Vaccination against COVID-19 reduced the risk for hospitalization by almost half for both groups, however, the study finds.

“To our knowledge this is the first study that demonstrated a vaccination effect on mitigation of the risk of hospitalization in celiac disease patients with COVID-19 infection,” write Alberto Rubio-Tapia, MD, director, Celiac Disease Program, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, and colleagues.

Despite the increased risk for hospitalization among patients with celiac disease, there were no significant differences between those with and without the condition with respect to intensive care unit requirement, mortality, or thrombosis, the researchers found.

The findings suggest that celiac disease patients with COVID-19 are “not inherently at greater risk for more severe outcomes,” they wrote.

The study was published online in Clinical Gastroenterology and Hepatology.
 

Comparing outcomes

Although it has been shown that patients with celiac disease have increased susceptibility to viral illnesses, research to date has found similar COVID-19 incidence and outcomes, including hospitalization, between patients with celiac disease and the general population, the researchers wrote.

However, the impact of COVID-19 vaccination is less clear, so the researchers set out to compare the frequency of COVID-19–related outcomes between patients with and without celiac disease before and after vaccination.

Through an analysis of patient medical records, researchers found 171,763 patients diagnosed and treated for COVID-19 at their institution between March 1, 2020, and Jan 1, 2022. Of them, 110 adults had biopsy-proven celiac disease.

The median time from biopsy diagnosis of celiac disease to COVID-19 was 217 months, 66.3% of patients were documented to be following a gluten-free diet, and tissue transglutaminase IgA was positive in 46.2% at the time of COVID-19.

The celiac group was matched by age, ethnicity, sex, and date of COVID-19 diagnosis with a control group of 220 adults without a clinical diagnosis of celiac disease. The two cohorts had similar rates of comorbid obesity, type 2 diabetes, preexisting lung disease, and tobacco use.

Patients with celiac disease were significantly more likely to be hospitalized for COVID-19 than were the control participants, at 24% vs. 11% (hazard ratio, 2.1; P = .009), the researchers wrote.

However, hospitalized patients with celiac disease were less likely to require supplementary oxygen than were the control participants, at 63% vs. 84%.

Vaccination rates for COVID-19 were similar between the two groups, at 64.5% among patients with celiac disease and 70% in the control group. Vaccination was associated with a lower risk for hospitalization on multivariate analysis (HR, 0.53; P = .026).

There was no significant difference in hospitalization rates between vaccinated patients with celiac disease and vaccinated patients in the control group (odds ratio, 1.12; P = .79), the team reported.

The secondary outcomes of ICU requirement, mortality, and thrombosis were minimal in both groups, the researchers wrote.
 

Vaccination’s importance

The different findings regarding hospitalization risk among patients with celiac disease between this study and previous research are likely due to earlier studies not accounting for vaccination status, the researchers wrote.

“This study shows significantly different rates of hospitalization among patients with [celiac disease] depending on their vaccination status, with strong evidence for mitigation of hospitalization risk through vaccination,” they added.

“Vaccination against COVID-19 should be strongly recommended in patients with celiac disease,” the researchers concluded.

No funding was declared. Dr. Rubio-Tapia reported a relationship with Takeda. No other financial relationships were declared.

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

Patients with celiac disease who have COVID-19 are twice as likely to be hospitalized as are individuals without the autoimmune condition, a single-center U.S. study shows.

Vaccination against COVID-19 reduced the risk for hospitalization by almost half for both groups, however, the study finds.

“To our knowledge this is the first study that demonstrated a vaccination effect on mitigation of the risk of hospitalization in celiac disease patients with COVID-19 infection,” write Alberto Rubio-Tapia, MD, director, Celiac Disease Program, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, and colleagues.

Despite the increased risk for hospitalization among patients with celiac disease, there were no significant differences between those with and without the condition with respect to intensive care unit requirement, mortality, or thrombosis, the researchers found.

The findings suggest that celiac disease patients with COVID-19 are “not inherently at greater risk for more severe outcomes,” they wrote.

The study was published online in Clinical Gastroenterology and Hepatology.
 

Comparing outcomes

Although it has been shown that patients with celiac disease have increased susceptibility to viral illnesses, research to date has found similar COVID-19 incidence and outcomes, including hospitalization, between patients with celiac disease and the general population, the researchers wrote.

However, the impact of COVID-19 vaccination is less clear, so the researchers set out to compare the frequency of COVID-19–related outcomes between patients with and without celiac disease before and after vaccination.

Through an analysis of patient medical records, researchers found 171,763 patients diagnosed and treated for COVID-19 at their institution between March 1, 2020, and Jan 1, 2022. Of them, 110 adults had biopsy-proven celiac disease.

The median time from biopsy diagnosis of celiac disease to COVID-19 was 217 months, 66.3% of patients were documented to be following a gluten-free diet, and tissue transglutaminase IgA was positive in 46.2% at the time of COVID-19.

The celiac group was matched by age, ethnicity, sex, and date of COVID-19 diagnosis with a control group of 220 adults without a clinical diagnosis of celiac disease. The two cohorts had similar rates of comorbid obesity, type 2 diabetes, preexisting lung disease, and tobacco use.

Patients with celiac disease were significantly more likely to be hospitalized for COVID-19 than were the control participants, at 24% vs. 11% (hazard ratio, 2.1; P = .009), the researchers wrote.

However, hospitalized patients with celiac disease were less likely to require supplementary oxygen than were the control participants, at 63% vs. 84%.

Vaccination rates for COVID-19 were similar between the two groups, at 64.5% among patients with celiac disease and 70% in the control group. Vaccination was associated with a lower risk for hospitalization on multivariate analysis (HR, 0.53; P = .026).

There was no significant difference in hospitalization rates between vaccinated patients with celiac disease and vaccinated patients in the control group (odds ratio, 1.12; P = .79), the team reported.

The secondary outcomes of ICU requirement, mortality, and thrombosis were minimal in both groups, the researchers wrote.
 

Vaccination’s importance

The different findings regarding hospitalization risk among patients with celiac disease between this study and previous research are likely due to earlier studies not accounting for vaccination status, the researchers wrote.

“This study shows significantly different rates of hospitalization among patients with [celiac disease] depending on their vaccination status, with strong evidence for mitigation of hospitalization risk through vaccination,” they added.

“Vaccination against COVID-19 should be strongly recommended in patients with celiac disease,” the researchers concluded.

No funding was declared. Dr. Rubio-Tapia reported a relationship with Takeda. No other financial relationships were declared.

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

Patients with celiac disease who have COVID-19 are twice as likely to be hospitalized as are individuals without the autoimmune condition, a single-center U.S. study shows.

Vaccination against COVID-19 reduced the risk for hospitalization by almost half for both groups, however, the study finds.

“To our knowledge this is the first study that demonstrated a vaccination effect on mitigation of the risk of hospitalization in celiac disease patients with COVID-19 infection,” write Alberto Rubio-Tapia, MD, director, Celiac Disease Program, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, and colleagues.

Despite the increased risk for hospitalization among patients with celiac disease, there were no significant differences between those with and without the condition with respect to intensive care unit requirement, mortality, or thrombosis, the researchers found.

The findings suggest that celiac disease patients with COVID-19 are “not inherently at greater risk for more severe outcomes,” they wrote.

The study was published online in Clinical Gastroenterology and Hepatology.
 

Comparing outcomes

Although it has been shown that patients with celiac disease have increased susceptibility to viral illnesses, research to date has found similar COVID-19 incidence and outcomes, including hospitalization, between patients with celiac disease and the general population, the researchers wrote.

However, the impact of COVID-19 vaccination is less clear, so the researchers set out to compare the frequency of COVID-19–related outcomes between patients with and without celiac disease before and after vaccination.

Through an analysis of patient medical records, researchers found 171,763 patients diagnosed and treated for COVID-19 at their institution between March 1, 2020, and Jan 1, 2022. Of them, 110 adults had biopsy-proven celiac disease.

The median time from biopsy diagnosis of celiac disease to COVID-19 was 217 months, 66.3% of patients were documented to be following a gluten-free diet, and tissue transglutaminase IgA was positive in 46.2% at the time of COVID-19.

The celiac group was matched by age, ethnicity, sex, and date of COVID-19 diagnosis with a control group of 220 adults without a clinical diagnosis of celiac disease. The two cohorts had similar rates of comorbid obesity, type 2 diabetes, preexisting lung disease, and tobacco use.

Patients with celiac disease were significantly more likely to be hospitalized for COVID-19 than were the control participants, at 24% vs. 11% (hazard ratio, 2.1; P = .009), the researchers wrote.

However, hospitalized patients with celiac disease were less likely to require supplementary oxygen than were the control participants, at 63% vs. 84%.

Vaccination rates for COVID-19 were similar between the two groups, at 64.5% among patients with celiac disease and 70% in the control group. Vaccination was associated with a lower risk for hospitalization on multivariate analysis (HR, 0.53; P = .026).

There was no significant difference in hospitalization rates between vaccinated patients with celiac disease and vaccinated patients in the control group (odds ratio, 1.12; P = .79), the team reported.

The secondary outcomes of ICU requirement, mortality, and thrombosis were minimal in both groups, the researchers wrote.
 

Vaccination’s importance

The different findings regarding hospitalization risk among patients with celiac disease between this study and previous research are likely due to earlier studies not accounting for vaccination status, the researchers wrote.

“This study shows significantly different rates of hospitalization among patients with [celiac disease] depending on their vaccination status, with strong evidence for mitigation of hospitalization risk through vaccination,” they added.

“Vaccination against COVID-19 should be strongly recommended in patients with celiac disease,” the researchers concluded.

No funding was declared. Dr. Rubio-Tapia reported a relationship with Takeda. No other financial relationships were declared.

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

Proinflammatory elements mediated through metabolic pathways related to obesity and increased cellular senescence in CD57 expression in CD8+ T cells are associated with postacute sequelae of COVID-19 (PASC), according to a Mexican study. The researchers followed a Mexican cohort of 102 patients 3 months and 6 months after acute SARS-CoV-2 infection.

The study’s principal investigator was Diana Gómez-Martín, MD, PhD, of the department of immunology and rheumatology at the Salvador Zubirán National Institute of Medical Sciences and Nutrition, Mexico City. She told this news organization that follow-up of the patients began with the objective of understanding the determinative clinical, genetic, metabolic, and immunological factors in the progression of the acute disease. However, clinical aspects associated with PASC developed in the selected cohort. As a result, the study was extended, and the clinical, metabolic, and immunologic conditions in this single-center Mexican cohort were evaluated 3 months 6 months after the onset of infection.

Dr. Gómez-Martín explained that the immune senescence in CD57 of CD8+ T cells is one of the best-known findings of the present study. If it is confirmed in future studies, it could have important implications. “Its main implication is the possibility of better understanding the physiopathology of the clinical aspects associated with postacute sequelae of COVID-19, potentially being used for early detection and to provide follow-up aimed at patients, in addition to eventually developing targeted therapeutic strategies, such as immunometabolism regulation, in certain populations.”
 

Patients with PASC

The study was conducted from August 2020 to August 2021. Investigators recruited 102 patients (median age, 50.5 years; 55% were women) at the Mexico City Temporary Unit with a confirmed diagnosis of SARS-CoV-2. Of the patients, 44% had mild or moderate COVID-19, 30% had severe cases, and 26% of patients had critical cases. The most frequent comorbidities were obesity (44%), hypertension (24%), and type 2 diabetes (24%). The authors used a questionnaire to assess the presence of symptoms during follow-up. They analyzed immunologic variables at the time of recruitment, as well as levels of cytokines, immunoglobulin G against SARS-CoV-2, and neutrophil extracellular traps (NETs) at 1, 3, and 6 months. At 6 months’ follow-up, 12.7% of the cohort had symptoms compatible with PASC, which was defined for the study as the presence and report of three or more symptoms at 6 months’ follow-up.

As in similar studies, the authors found that female gender, remaining in intensive care, and having had more symptoms and greater titers of anti-SARS-CoV-2 antibodies during the acute infection were associated with the development of clinical aspects associated with PASC. Patients who had the disease at 6 months had increased serum levels of interleukin-1 alpha (6.21 pg/mL vs. 2.21 pg/mL), granulocyte colony-stimulating factor (55.08 pg/mL vs. 14.68 pg/mL), and interferon gamma-induced protein 10 (2,309.40 pg/mL vs. 780 pg/mL). Also, there was a trend toward an increase in serum concentration of interleukin-1 beta, interleukin-6, and interferon-gamma.

Patients whose condition met the definition of persistent PASC had increased expression of CD57 in CD8+ T cells (42,714 arbitrary units vs. 28,506) 6 months after the acute infection. The authors reported that there was no association between the persistence of PASC and the baseline amount of NETs, TRIM63, and anticellular antibodies. Nor was there an association between PASC and the titers of anti-SARS-CoV-2 antibodies at baseline and 1 month after COVID-19 diagnosis. Nonetheless, patients with persistent PASC had higher titers of anti-SARS-CoV-2 IgGs 3 months after the onset of COVID-19.

On the basis of previous data, the researchers aimed to construct a preliminary explanatory model to address the clinical and immunologic features associated with persistent PASC 6 months after SARS-CoV-2 infection. In the univariate analysis, the variables associated with the diagnosis of persistent PASC were the serum levels of granulocyte colony-stimulating factor (odds ratio, 1.01), macrophage inflammatory protein-1 alpha (OR, 1.13), interferon gamma-induced protein 10 (OR, 1.00), interleukin-6 (OR, 1.03), the expression of CD57 in CD8+ T cells (OR, 1.00), and the titers of anti-SARS-CoV-2 IgG at 1 month (OR, 1.45).

Patients with a diagnosis of clinical aspects associated with PASC at 6 months were characterized by certain predisposing factors, such as obesity, greater levels of macrophage inflammatory protein-1 alpha and interferon gamma-induced protein 10 in peripheral blood, greater expression of the senescence CD57 marker in CD8+ T lymphocytes, and persistent symptoms at 3 months.

Using these parameters to construct a predictive model after 3 months, the authors found a sensitivity of 97.7%, specificity of 53.8%, positive predictive value of 93.5%, and a negative predictive value of 77.7% for the diagnosis of clinical aspects associated with PASC at 6 months.
 

Interpreting CD57

One of the researchers who participated in the study was Luis Martínez-Juárez, MD, MPH, DrPH. He is on the operative solutions team at the Carlos Slim Foundation. Dr. Martínez-Juárez pointed out that one of the contributions of this study was that it specifically examined the Mexican population. He noted that “according to the findings, obesity is not only a comorbidity associated with more severe progressions during acute COVID-19 disease, but also, through inflammation parameters, such as interleukin-6, interferon gamma-induced protein 10, and macrophage inflammatory protein-1 alpha, it’s involved in the development of clinical aspects related to postacute sequelae of COVID-19.”

Dr. Gómez-Martín added that finding proinflammatory and obesity parameters in the patients could potentially support the hypothesis of the persistence of virus fragments in adipose tissue as possibly involved in clinical aspects associated with PASC, as some groups have reported in the medical literature.

Angélica Cuapio, MD, DrMed, an immunologist and senior investigator at the Karolinska Institute, Stockholm, who did not participate in the study, said in an interview that the authors’ findings on the sustained increase of the CD57 marker in CD8+ lymphocytes are of notable interest. They may be associated with senescence states or cellular aging or with a stage of chronic viral infections. Therefore, Dr. Cuapio argued, it would have been valuable to include cellular markers of the innate system, such as natural killer cells, since in various infections, an increase in CD57 in lymphocytes is accompanied by an almost proportional increase of this marker in natural killer cells.

“This information would help to determine more accurately if we are talking about a cellular senescence or more about a chronic infection in persistent COVID-19.” The finding is important, but future research is needed in this developing field.

Dr. Cuapio pointed out that the authors found an interesting elevation in interleukin-1 alpha in patients with clinical aspects associated with PASC in a clinically well-characterized population in Mexico. “It is possible that this is a specific marker either of a specific population or location, or this could be an association with a humoral response. Despite the fact that this finding is new and unclear, it is worth investigating. This study is of great value for the scientific community because it’s one more piece in the complex puzzle of clinical aspects associated with postacute sequelae of COVID-19.”

Dr. Gómez-Martín noted that the main limitations of the study consist of its single-center design and the small patient sample. Dr. Martínez-Juárez added that the study did not consider reinfections. In future studies, it would be ideal to integrate other molecular assessments associated with various hypotheses of the physiopathology of clinical aspects associated with PASC, such as microbiota alteration, coagulation anomalies, endothelial damage, and dysfunctional neurologic signaling.

The study was supported and funded by the Carlos Slim Foundation. Dr. Gómez-Martín, Dr. Martínez-Juárez, and Dr. Cuapio have disclosed no relevant financial relationships.

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

Proinflammatory elements mediated through metabolic pathways related to obesity and increased cellular senescence in CD57 expression in CD8+ T cells are associated with postacute sequelae of COVID-19 (PASC), according to a Mexican study. The researchers followed a Mexican cohort of 102 patients 3 months and 6 months after acute SARS-CoV-2 infection.

The study’s principal investigator was Diana Gómez-Martín, MD, PhD, of the department of immunology and rheumatology at the Salvador Zubirán National Institute of Medical Sciences and Nutrition, Mexico City. She told this news organization that follow-up of the patients began with the objective of understanding the determinative clinical, genetic, metabolic, and immunological factors in the progression of the acute disease. However, clinical aspects associated with PASC developed in the selected cohort. As a result, the study was extended, and the clinical, metabolic, and immunologic conditions in this single-center Mexican cohort were evaluated 3 months 6 months after the onset of infection.

Dr. Gómez-Martín explained that the immune senescence in CD57 of CD8+ T cells is one of the best-known findings of the present study. If it is confirmed in future studies, it could have important implications. “Its main implication is the possibility of better understanding the physiopathology of the clinical aspects associated with postacute sequelae of COVID-19, potentially being used for early detection and to provide follow-up aimed at patients, in addition to eventually developing targeted therapeutic strategies, such as immunometabolism regulation, in certain populations.”
 

Patients with PASC

The study was conducted from August 2020 to August 2021. Investigators recruited 102 patients (median age, 50.5 years; 55% were women) at the Mexico City Temporary Unit with a confirmed diagnosis of SARS-CoV-2. Of the patients, 44% had mild or moderate COVID-19, 30% had severe cases, and 26% of patients had critical cases. The most frequent comorbidities were obesity (44%), hypertension (24%), and type 2 diabetes (24%). The authors used a questionnaire to assess the presence of symptoms during follow-up. They analyzed immunologic variables at the time of recruitment, as well as levels of cytokines, immunoglobulin G against SARS-CoV-2, and neutrophil extracellular traps (NETs) at 1, 3, and 6 months. At 6 months’ follow-up, 12.7% of the cohort had symptoms compatible with PASC, which was defined for the study as the presence and report of three or more symptoms at 6 months’ follow-up.

As in similar studies, the authors found that female gender, remaining in intensive care, and having had more symptoms and greater titers of anti-SARS-CoV-2 antibodies during the acute infection were associated with the development of clinical aspects associated with PASC. Patients who had the disease at 6 months had increased serum levels of interleukin-1 alpha (6.21 pg/mL vs. 2.21 pg/mL), granulocyte colony-stimulating factor (55.08 pg/mL vs. 14.68 pg/mL), and interferon gamma-induced protein 10 (2,309.40 pg/mL vs. 780 pg/mL). Also, there was a trend toward an increase in serum concentration of interleukin-1 beta, interleukin-6, and interferon-gamma.

Patients whose condition met the definition of persistent PASC had increased expression of CD57 in CD8+ T cells (42,714 arbitrary units vs. 28,506) 6 months after the acute infection. The authors reported that there was no association between the persistence of PASC and the baseline amount of NETs, TRIM63, and anticellular antibodies. Nor was there an association between PASC and the titers of anti-SARS-CoV-2 antibodies at baseline and 1 month after COVID-19 diagnosis. Nonetheless, patients with persistent PASC had higher titers of anti-SARS-CoV-2 IgGs 3 months after the onset of COVID-19.

On the basis of previous data, the researchers aimed to construct a preliminary explanatory model to address the clinical and immunologic features associated with persistent PASC 6 months after SARS-CoV-2 infection. In the univariate analysis, the variables associated with the diagnosis of persistent PASC were the serum levels of granulocyte colony-stimulating factor (odds ratio, 1.01), macrophage inflammatory protein-1 alpha (OR, 1.13), interferon gamma-induced protein 10 (OR, 1.00), interleukin-6 (OR, 1.03), the expression of CD57 in CD8+ T cells (OR, 1.00), and the titers of anti-SARS-CoV-2 IgG at 1 month (OR, 1.45).

Patients with a diagnosis of clinical aspects associated with PASC at 6 months were characterized by certain predisposing factors, such as obesity, greater levels of macrophage inflammatory protein-1 alpha and interferon gamma-induced protein 10 in peripheral blood, greater expression of the senescence CD57 marker in CD8+ T lymphocytes, and persistent symptoms at 3 months.

Using these parameters to construct a predictive model after 3 months, the authors found a sensitivity of 97.7%, specificity of 53.8%, positive predictive value of 93.5%, and a negative predictive value of 77.7% for the diagnosis of clinical aspects associated with PASC at 6 months.
 

Interpreting CD57

One of the researchers who participated in the study was Luis Martínez-Juárez, MD, MPH, DrPH. He is on the operative solutions team at the Carlos Slim Foundation. Dr. Martínez-Juárez pointed out that one of the contributions of this study was that it specifically examined the Mexican population. He noted that “according to the findings, obesity is not only a comorbidity associated with more severe progressions during acute COVID-19 disease, but also, through inflammation parameters, such as interleukin-6, interferon gamma-induced protein 10, and macrophage inflammatory protein-1 alpha, it’s involved in the development of clinical aspects related to postacute sequelae of COVID-19.”

Dr. Gómez-Martín added that finding proinflammatory and obesity parameters in the patients could potentially support the hypothesis of the persistence of virus fragments in adipose tissue as possibly involved in clinical aspects associated with PASC, as some groups have reported in the medical literature.

Angélica Cuapio, MD, DrMed, an immunologist and senior investigator at the Karolinska Institute, Stockholm, who did not participate in the study, said in an interview that the authors’ findings on the sustained increase of the CD57 marker in CD8+ lymphocytes are of notable interest. They may be associated with senescence states or cellular aging or with a stage of chronic viral infections. Therefore, Dr. Cuapio argued, it would have been valuable to include cellular markers of the innate system, such as natural killer cells, since in various infections, an increase in CD57 in lymphocytes is accompanied by an almost proportional increase of this marker in natural killer cells.

“This information would help to determine more accurately if we are talking about a cellular senescence or more about a chronic infection in persistent COVID-19.” The finding is important, but future research is needed in this developing field.

Dr. Cuapio pointed out that the authors found an interesting elevation in interleukin-1 alpha in patients with clinical aspects associated with PASC in a clinically well-characterized population in Mexico. “It is possible that this is a specific marker either of a specific population or location, or this could be an association with a humoral response. Despite the fact that this finding is new and unclear, it is worth investigating. This study is of great value for the scientific community because it’s one more piece in the complex puzzle of clinical aspects associated with postacute sequelae of COVID-19.”

Dr. Gómez-Martín noted that the main limitations of the study consist of its single-center design and the small patient sample. Dr. Martínez-Juárez added that the study did not consider reinfections. In future studies, it would be ideal to integrate other molecular assessments associated with various hypotheses of the physiopathology of clinical aspects associated with PASC, such as microbiota alteration, coagulation anomalies, endothelial damage, and dysfunctional neurologic signaling.

The study was supported and funded by the Carlos Slim Foundation. Dr. Gómez-Martín, Dr. Martínez-Juárez, and Dr. Cuapio have disclosed no relevant financial relationships.

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

Proinflammatory elements mediated through metabolic pathways related to obesity and increased cellular senescence in CD57 expression in CD8+ T cells are associated with postacute sequelae of COVID-19 (PASC), according to a Mexican study. The researchers followed a Mexican cohort of 102 patients 3 months and 6 months after acute SARS-CoV-2 infection.

The study’s principal investigator was Diana Gómez-Martín, MD, PhD, of the department of immunology and rheumatology at the Salvador Zubirán National Institute of Medical Sciences and Nutrition, Mexico City. She told this news organization that follow-up of the patients began with the objective of understanding the determinative clinical, genetic, metabolic, and immunological factors in the progression of the acute disease. However, clinical aspects associated with PASC developed in the selected cohort. As a result, the study was extended, and the clinical, metabolic, and immunologic conditions in this single-center Mexican cohort were evaluated 3 months 6 months after the onset of infection.

Dr. Gómez-Martín explained that the immune senescence in CD57 of CD8+ T cells is one of the best-known findings of the present study. If it is confirmed in future studies, it could have important implications. “Its main implication is the possibility of better understanding the physiopathology of the clinical aspects associated with postacute sequelae of COVID-19, potentially being used for early detection and to provide follow-up aimed at patients, in addition to eventually developing targeted therapeutic strategies, such as immunometabolism regulation, in certain populations.”
 

Patients with PASC

The study was conducted from August 2020 to August 2021. Investigators recruited 102 patients (median age, 50.5 years; 55% were women) at the Mexico City Temporary Unit with a confirmed diagnosis of SARS-CoV-2. Of the patients, 44% had mild or moderate COVID-19, 30% had severe cases, and 26% of patients had critical cases. The most frequent comorbidities were obesity (44%), hypertension (24%), and type 2 diabetes (24%). The authors used a questionnaire to assess the presence of symptoms during follow-up. They analyzed immunologic variables at the time of recruitment, as well as levels of cytokines, immunoglobulin G against SARS-CoV-2, and neutrophil extracellular traps (NETs) at 1, 3, and 6 months. At 6 months’ follow-up, 12.7% of the cohort had symptoms compatible with PASC, which was defined for the study as the presence and report of three or more symptoms at 6 months’ follow-up.

As in similar studies, the authors found that female gender, remaining in intensive care, and having had more symptoms and greater titers of anti-SARS-CoV-2 antibodies during the acute infection were associated with the development of clinical aspects associated with PASC. Patients who had the disease at 6 months had increased serum levels of interleukin-1 alpha (6.21 pg/mL vs. 2.21 pg/mL), granulocyte colony-stimulating factor (55.08 pg/mL vs. 14.68 pg/mL), and interferon gamma-induced protein 10 (2,309.40 pg/mL vs. 780 pg/mL). Also, there was a trend toward an increase in serum concentration of interleukin-1 beta, interleukin-6, and interferon-gamma.

Patients whose condition met the definition of persistent PASC had increased expression of CD57 in CD8+ T cells (42,714 arbitrary units vs. 28,506) 6 months after the acute infection. The authors reported that there was no association between the persistence of PASC and the baseline amount of NETs, TRIM63, and anticellular antibodies. Nor was there an association between PASC and the titers of anti-SARS-CoV-2 antibodies at baseline and 1 month after COVID-19 diagnosis. Nonetheless, patients with persistent PASC had higher titers of anti-SARS-CoV-2 IgGs 3 months after the onset of COVID-19.

On the basis of previous data, the researchers aimed to construct a preliminary explanatory model to address the clinical and immunologic features associated with persistent PASC 6 months after SARS-CoV-2 infection. In the univariate analysis, the variables associated with the diagnosis of persistent PASC were the serum levels of granulocyte colony-stimulating factor (odds ratio, 1.01), macrophage inflammatory protein-1 alpha (OR, 1.13), interferon gamma-induced protein 10 (OR, 1.00), interleukin-6 (OR, 1.03), the expression of CD57 in CD8+ T cells (OR, 1.00), and the titers of anti-SARS-CoV-2 IgG at 1 month (OR, 1.45).

Patients with a diagnosis of clinical aspects associated with PASC at 6 months were characterized by certain predisposing factors, such as obesity, greater levels of macrophage inflammatory protein-1 alpha and interferon gamma-induced protein 10 in peripheral blood, greater expression of the senescence CD57 marker in CD8+ T lymphocytes, and persistent symptoms at 3 months.

Using these parameters to construct a predictive model after 3 months, the authors found a sensitivity of 97.7%, specificity of 53.8%, positive predictive value of 93.5%, and a negative predictive value of 77.7% for the diagnosis of clinical aspects associated with PASC at 6 months.
 

Interpreting CD57

One of the researchers who participated in the study was Luis Martínez-Juárez, MD, MPH, DrPH. He is on the operative solutions team at the Carlos Slim Foundation. Dr. Martínez-Juárez pointed out that one of the contributions of this study was that it specifically examined the Mexican population. He noted that “according to the findings, obesity is not only a comorbidity associated with more severe progressions during acute COVID-19 disease, but also, through inflammation parameters, such as interleukin-6, interferon gamma-induced protein 10, and macrophage inflammatory protein-1 alpha, it’s involved in the development of clinical aspects related to postacute sequelae of COVID-19.”

Dr. Gómez-Martín added that finding proinflammatory and obesity parameters in the patients could potentially support the hypothesis of the persistence of virus fragments in adipose tissue as possibly involved in clinical aspects associated with PASC, as some groups have reported in the medical literature.

Angélica Cuapio, MD, DrMed, an immunologist and senior investigator at the Karolinska Institute, Stockholm, who did not participate in the study, said in an interview that the authors’ findings on the sustained increase of the CD57 marker in CD8+ lymphocytes are of notable interest. They may be associated with senescence states or cellular aging or with a stage of chronic viral infections. Therefore, Dr. Cuapio argued, it would have been valuable to include cellular markers of the innate system, such as natural killer cells, since in various infections, an increase in CD57 in lymphocytes is accompanied by an almost proportional increase of this marker in natural killer cells.

“This information would help to determine more accurately if we are talking about a cellular senescence or more about a chronic infection in persistent COVID-19.” The finding is important, but future research is needed in this developing field.

Dr. Cuapio pointed out that the authors found an interesting elevation in interleukin-1 alpha in patients with clinical aspects associated with PASC in a clinically well-characterized population in Mexico. “It is possible that this is a specific marker either of a specific population or location, or this could be an association with a humoral response. Despite the fact that this finding is new and unclear, it is worth investigating. This study is of great value for the scientific community because it’s one more piece in the complex puzzle of clinical aspects associated with postacute sequelae of COVID-19.”

Dr. Gómez-Martín noted that the main limitations of the study consist of its single-center design and the small patient sample. Dr. Martínez-Juárez added that the study did not consider reinfections. In future studies, it would be ideal to integrate other molecular assessments associated with various hypotheses of the physiopathology of clinical aspects associated with PASC, such as microbiota alteration, coagulation anomalies, endothelial damage, and dysfunctional neurologic signaling.

The study was supported and funded by the Carlos Slim Foundation. Dr. Gómez-Martín, Dr. Martínez-Juárez, and Dr. Cuapio have disclosed no relevant financial relationships.

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

Prone positioning significantly reduced the need for intubation among nonintubated adults with COVID-19, as indicated by data from a new meta-analysis of more than 2,000 individuals.

The use of prone positioning for nonintubated patients (so-called “awake prone positioning”) has been common since the early days of the COVID-19 pandemic. Prone positioning is more comfortable for patients, and it entails no additional cost. Also, awake prone positioning is less labor intensive than prone positioning for intubated patients, said Jie Li, PhD, in a presentation at the Critical Care Congress sponsored by the Society of Critical Care Medicine.

However, data on the specific benefits of prone positioning are lacking and contradictory, said Dr. Li, a respiratory care specialist at Rush University, Chicago.

Dr. Li and colleagues from a multinational research group found that outcomes were improved for patients who were treated with awake prone positioning – notably, fewer treatment failures at day 28 – but a pair of subsequent studies by other researchers showed contradictory outcomes.

For more definitive evidence, Dr. Li and colleagues conducted a systematic review and meta-analysis of 11 randomized, controlled trials and one unpublished study of awake prone positioning for patients with COVID-19. The studies were published between Jan. 1, 2020, and July 1, 2022, and included a total of 2,886 adult patients.

The primary outcome was the reported cumulative risk of intubation among nonintubated COVID-19 patients. Secondary outcomes included mortality, the need for escalating respiratory support, length of hospital length of stay, ICU admission, and adverse events.

Overall, awake prone positioning significantly reduced the intubation risk among nonintubated patients compared to standard care (risk ratio, 0.85).

A further subgroup analysis showed a significant reduction in risk for intubation among patients supported by high-flow nasal cannula or noninvasive ventilation (RR, 0.83).

However, no additional reduction in intubation risk occurred among patients who received conventional oxygen therapy (RR, 1.02).

Mortality rates were similar for patients who underwent awake prone positioning and those who underwent supine positioning (RR, 0.96), as was the need for additional respiratory support (RR, 1.03). The length of hospital stay, ICU admission, and adverse events were similar between the patients who underwent prone positioning and those who underwent supine positioning.

The findings were limited by several factors. There was a potential for confounding by disease severity, which may have increased the use of respiratory support devices, Li said in her presentation.

“Another factor we should not ignore is the daily duration of prone positioning,” said Dr. Li. More research is needed to identify which factors play the greatest roles in treatment success.

The current study was important in that it evaluated the current evidence of awake prone positioning, “particularly to identify the patients who benefit most from this treatment, in order to guide clinical practice,” Dr. Li said in an interview.

“Since early in the pandemic, awake prone positioning has been broadly utilized to treat patients with COVID-19,” she said. “In 2021, we published a multinational randomized controlled trial with over 1,100 patients enrolled and reported lower treatment failure. However, no significant differences of treatment failure were reported in several subsequent multicenter randomized, controlled trials published after our study.”

Dr. Li said she was not surprised by the findings, which reflect those of her team’s previously published meta-analysis. “The increased number of patients helps confirm our previous finding, even with the inclusion of several recently published randomized controlled trials,” she said.

For clinicians, “the current evidence supports the use of awake prone positioning for patients with COVID-19, particularly those who require advanced respiratory support from high-flow nasal cannula or noninvasive ventilation,” Dr. Li said.

The study received no outside funding. Dr. Li has relationships with AARC, Heyer, Aeorgen, the Rice Foundation, and Fisher & Paykel Healthcare.

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

Prone positioning significantly reduced the need for intubation among nonintubated adults with COVID-19, as indicated by data from a new meta-analysis of more than 2,000 individuals.

The use of prone positioning for nonintubated patients (so-called “awake prone positioning”) has been common since the early days of the COVID-19 pandemic. Prone positioning is more comfortable for patients, and it entails no additional cost. Also, awake prone positioning is less labor intensive than prone positioning for intubated patients, said Jie Li, PhD, in a presentation at the Critical Care Congress sponsored by the Society of Critical Care Medicine.

However, data on the specific benefits of prone positioning are lacking and contradictory, said Dr. Li, a respiratory care specialist at Rush University, Chicago.

Dr. Li and colleagues from a multinational research group found that outcomes were improved for patients who were treated with awake prone positioning – notably, fewer treatment failures at day 28 – but a pair of subsequent studies by other researchers showed contradictory outcomes.

For more definitive evidence, Dr. Li and colleagues conducted a systematic review and meta-analysis of 11 randomized, controlled trials and one unpublished study of awake prone positioning for patients with COVID-19. The studies were published between Jan. 1, 2020, and July 1, 2022, and included a total of 2,886 adult patients.

The primary outcome was the reported cumulative risk of intubation among nonintubated COVID-19 patients. Secondary outcomes included mortality, the need for escalating respiratory support, length of hospital length of stay, ICU admission, and adverse events.

Overall, awake prone positioning significantly reduced the intubation risk among nonintubated patients compared to standard care (risk ratio, 0.85).

A further subgroup analysis showed a significant reduction in risk for intubation among patients supported by high-flow nasal cannula or noninvasive ventilation (RR, 0.83).

However, no additional reduction in intubation risk occurred among patients who received conventional oxygen therapy (RR, 1.02).

Mortality rates were similar for patients who underwent awake prone positioning and those who underwent supine positioning (RR, 0.96), as was the need for additional respiratory support (RR, 1.03). The length of hospital stay, ICU admission, and adverse events were similar between the patients who underwent prone positioning and those who underwent supine positioning.

The findings were limited by several factors. There was a potential for confounding by disease severity, which may have increased the use of respiratory support devices, Li said in her presentation.

“Another factor we should not ignore is the daily duration of prone positioning,” said Dr. Li. More research is needed to identify which factors play the greatest roles in treatment success.

The current study was important in that it evaluated the current evidence of awake prone positioning, “particularly to identify the patients who benefit most from this treatment, in order to guide clinical practice,” Dr. Li said in an interview.

“Since early in the pandemic, awake prone positioning has been broadly utilized to treat patients with COVID-19,” she said. “In 2021, we published a multinational randomized controlled trial with over 1,100 patients enrolled and reported lower treatment failure. However, no significant differences of treatment failure were reported in several subsequent multicenter randomized, controlled trials published after our study.”

Dr. Li said she was not surprised by the findings, which reflect those of her team’s previously published meta-analysis. “The increased number of patients helps confirm our previous finding, even with the inclusion of several recently published randomized controlled trials,” she said.

For clinicians, “the current evidence supports the use of awake prone positioning for patients with COVID-19, particularly those who require advanced respiratory support from high-flow nasal cannula or noninvasive ventilation,” Dr. Li said.

The study received no outside funding. Dr. Li has relationships with AARC, Heyer, Aeorgen, the Rice Foundation, and Fisher & Paykel Healthcare.

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

Prone positioning significantly reduced the need for intubation among nonintubated adults with COVID-19, as indicated by data from a new meta-analysis of more than 2,000 individuals.

The use of prone positioning for nonintubated patients (so-called “awake prone positioning”) has been common since the early days of the COVID-19 pandemic. Prone positioning is more comfortable for patients, and it entails no additional cost. Also, awake prone positioning is less labor intensive than prone positioning for intubated patients, said Jie Li, PhD, in a presentation at the Critical Care Congress sponsored by the Society of Critical Care Medicine.

However, data on the specific benefits of prone positioning are lacking and contradictory, said Dr. Li, a respiratory care specialist at Rush University, Chicago.

Dr. Li and colleagues from a multinational research group found that outcomes were improved for patients who were treated with awake prone positioning – notably, fewer treatment failures at day 28 – but a pair of subsequent studies by other researchers showed contradictory outcomes.

For more definitive evidence, Dr. Li and colleagues conducted a systematic review and meta-analysis of 11 randomized, controlled trials and one unpublished study of awake prone positioning for patients with COVID-19. The studies were published between Jan. 1, 2020, and July 1, 2022, and included a total of 2,886 adult patients.

The primary outcome was the reported cumulative risk of intubation among nonintubated COVID-19 patients. Secondary outcomes included mortality, the need for escalating respiratory support, length of hospital length of stay, ICU admission, and adverse events.

Overall, awake prone positioning significantly reduced the intubation risk among nonintubated patients compared to standard care (risk ratio, 0.85).

A further subgroup analysis showed a significant reduction in risk for intubation among patients supported by high-flow nasal cannula or noninvasive ventilation (RR, 0.83).

However, no additional reduction in intubation risk occurred among patients who received conventional oxygen therapy (RR, 1.02).

Mortality rates were similar for patients who underwent awake prone positioning and those who underwent supine positioning (RR, 0.96), as was the need for additional respiratory support (RR, 1.03). The length of hospital stay, ICU admission, and adverse events were similar between the patients who underwent prone positioning and those who underwent supine positioning.

The findings were limited by several factors. There was a potential for confounding by disease severity, which may have increased the use of respiratory support devices, Li said in her presentation.

“Another factor we should not ignore is the daily duration of prone positioning,” said Dr. Li. More research is needed to identify which factors play the greatest roles in treatment success.

The current study was important in that it evaluated the current evidence of awake prone positioning, “particularly to identify the patients who benefit most from this treatment, in order to guide clinical practice,” Dr. Li said in an interview.

“Since early in the pandemic, awake prone positioning has been broadly utilized to treat patients with COVID-19,” she said. “In 2021, we published a multinational randomized controlled trial with over 1,100 patients enrolled and reported lower treatment failure. However, no significant differences of treatment failure were reported in several subsequent multicenter randomized, controlled trials published after our study.”

Dr. Li said she was not surprised by the findings, which reflect those of her team’s previously published meta-analysis. “The increased number of patients helps confirm our previous finding, even with the inclusion of several recently published randomized controlled trials,” she said.

For clinicians, “the current evidence supports the use of awake prone positioning for patients with COVID-19, particularly those who require advanced respiratory support from high-flow nasal cannula or noninvasive ventilation,” Dr. Li said.

The study received no outside funding. Dr. Li has relationships with AARC, Heyer, Aeorgen, the Rice Foundation, and Fisher & Paykel Healthcare.

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

COVID-19 remains deadlier than influenza in severe cases requiring hospitalization, a new study shows.

People who were hospitalized with Omicron COVID-19 infections were 54% more likely to die, compared with people who were hospitalized with the flu, Swiss researchers found.

The results of the study continue to debunk an earlier belief from the start of the pandemic that the flu was the more dangerous of the two respiratory viruses. The researchers noted that the deadliness of COVID-19, compared with flu, persisted “despite virus evolution and improved management strategies.”

The study was published in JAMA Network Open and included 5,212 patients in Switzerland hospitalized with COVID-19 or the flu. All the COVID patients were infected with the Omicron variant and hospitalized between Jan. 15, 2022, and March 15, 2022. Flu data included cases from January 2018 to March 15, 2022. 

Overall, 7% of COVID-19 patients died, compared with 4.4% of flu patients. Researchers noted that the death rate for hospitalized COVID patients had declined since their previous study, which was conducted during the first COVID wave in the first half of 2020. At that time, the death rate of hospitalized COVID patients was 12.8%. 

Since then, 98% of the Swiss population has been vaccinated. “Vaccination still plays a significant role regarding the main outcome,” the authors concluded, since a secondary analysis in this most recent study showed that unvaccinated COVID patients were twice as likely to die, compared with flu patients.

“Our results demonstrate that COVID-19 still cannot simply be compared with influenza,” they wrote.

While the death rate among COVID patients was significantly higher, there was no difference in the rate that COVID or flu patients were admitted to the ICU, which was around 8%.

A limitation of the study was that all the COVID cases did not have laboratory testing to confirm the Omicron variant. However, the study authors noted that Omicron accounted for at least 95% of cases during the time the patients were hospitalized. The authors were confident that their results were not biased by the potential for other variants being included in the data.

Four coauthors reported receiving grants and personal fees from various sources.

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

COVID-19 remains deadlier than influenza in severe cases requiring hospitalization, a new study shows.

People who were hospitalized with Omicron COVID-19 infections were 54% more likely to die, compared with people who were hospitalized with the flu, Swiss researchers found.

The results of the study continue to debunk an earlier belief from the start of the pandemic that the flu was the more dangerous of the two respiratory viruses. The researchers noted that the deadliness of COVID-19, compared with flu, persisted “despite virus evolution and improved management strategies.”

The study was published in JAMA Network Open and included 5,212 patients in Switzerland hospitalized with COVID-19 or the flu. All the COVID patients were infected with the Omicron variant and hospitalized between Jan. 15, 2022, and March 15, 2022. Flu data included cases from January 2018 to March 15, 2022. 

Overall, 7% of COVID-19 patients died, compared with 4.4% of flu patients. Researchers noted that the death rate for hospitalized COVID patients had declined since their previous study, which was conducted during the first COVID wave in the first half of 2020. At that time, the death rate of hospitalized COVID patients was 12.8%. 

Since then, 98% of the Swiss population has been vaccinated. “Vaccination still plays a significant role regarding the main outcome,” the authors concluded, since a secondary analysis in this most recent study showed that unvaccinated COVID patients were twice as likely to die, compared with flu patients.

“Our results demonstrate that COVID-19 still cannot simply be compared with influenza,” they wrote.

While the death rate among COVID patients was significantly higher, there was no difference in the rate that COVID or flu patients were admitted to the ICU, which was around 8%.

A limitation of the study was that all the COVID cases did not have laboratory testing to confirm the Omicron variant. However, the study authors noted that Omicron accounted for at least 95% of cases during the time the patients were hospitalized. The authors were confident that their results were not biased by the potential for other variants being included in the data.

Four coauthors reported receiving grants and personal fees from various sources.

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

COVID-19 remains deadlier than influenza in severe cases requiring hospitalization, a new study shows.

People who were hospitalized with Omicron COVID-19 infections were 54% more likely to die, compared with people who were hospitalized with the flu, Swiss researchers found.

The results of the study continue to debunk an earlier belief from the start of the pandemic that the flu was the more dangerous of the two respiratory viruses. The researchers noted that the deadliness of COVID-19, compared with flu, persisted “despite virus evolution and improved management strategies.”

The study was published in JAMA Network Open and included 5,212 patients in Switzerland hospitalized with COVID-19 or the flu. All the COVID patients were infected with the Omicron variant and hospitalized between Jan. 15, 2022, and March 15, 2022. Flu data included cases from January 2018 to March 15, 2022. 

Overall, 7% of COVID-19 patients died, compared with 4.4% of flu patients. Researchers noted that the death rate for hospitalized COVID patients had declined since their previous study, which was conducted during the first COVID wave in the first half of 2020. At that time, the death rate of hospitalized COVID patients was 12.8%. 

Since then, 98% of the Swiss population has been vaccinated. “Vaccination still plays a significant role regarding the main outcome,” the authors concluded, since a secondary analysis in this most recent study showed that unvaccinated COVID patients were twice as likely to die, compared with flu patients.

“Our results demonstrate that COVID-19 still cannot simply be compared with influenza,” they wrote.

While the death rate among COVID patients was significantly higher, there was no difference in the rate that COVID or flu patients were admitted to the ICU, which was around 8%.

A limitation of the study was that all the COVID cases did not have laboratory testing to confirm the Omicron variant. However, the study authors noted that Omicron accounted for at least 95% of cases during the time the patients were hospitalized. The authors were confident that their results were not biased by the potential for other variants being included in the data.

Four coauthors reported receiving grants and personal fees from various sources.

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

Treatment with the diabetes drug metformin shows a significant, dose-dependent effect in lowering SARS-CoV-2 viral load within days of administration, according to the latest analysis of the phase 3 COVID-OUT trial. These findings add to a multitude of benefits the drug has been shown to have in COVID infection.

COVID-OUT did not meet its primary endpoint, but it did show important secondary outcomes including a 42% reduction in ED visits and in hospitalizations and/or deaths by day 14, and a 58% reduction in hospitalizations/death by day 28. A further subanalysis has shown a 42% reduction in long COVID, compared with placebo.

“In this phase 3 randomized controlled trial, metformin showed prevention of severe COVID, prevention of long COVID, and an antiviral effect, and this is consistent with other data,” said coauthor Carolyn Bramante, MD, University of Minnesota, Minneapolis, in presenting the findings at the Conference on Retroviruses & Opportunistic Infections.
 

Study details

For the new subanalysis, the authors further evaluated the effects of metformin treatment on SARS-CoV-2 viral load.

A total of 1,323 patients in the study, enrolled at six centers, were randomized to treatment either with metformin 1,000 mg per day on days 2-5 and 1,500 mg per day on days 6 to 14 (n = 187), or to ivermectin 390-470 mcg/kg per day for 3 days (n = 187), fluvoxamine 50 mg twice daily for 14 days, and/or an exact-matching placebo in a 2 x 3 factorial trial design.

The subanalysis on viral load included 483 patients from the trial who were treated with metformin versus 462 who received placebo, who were all enrolled within 3 days of a documented SARS-CoV-2 infection and less than 7 days after symptom onset.

The patients had a median age of 46 years, and all had either overweight or obesity. Only about 2% had diabetes, and only patients considered low-risk were excluded from the trial, including those under age 30 and those with a body mass index under 25.

About half of patients had received a primary vaccine and about 5% had received a vaccine booster. SARS-CoV-2 variants that were prominent during the study included Alpha, Delta, and Omicron.

The viral samples available on days 1, 5, and 10 showed a mean change in viral load from baseline to follow-up; the viral load was significantly lower with metformin versus placebo (–0.64 log10 copies/mL), representing a 4.4-fold greater decrease in viral load with metformin.

The mean rate of undetectable SARS-CoV-2 viral load at day 5 was 49.9% in the metformin group versus 54.6% in the placebo group (odds ratio, 1.235), and the undetectable rate at day 10 was 14.3% in the metformin group and 22.6% in the placebo group (OR, 1.663; P = .003).

An increased antiviral effect corresponded with increases in metformin dosing on days 6 through 14. Furthermore, the antiviral effect became stronger when metformin was started earlier in the course of infection.

Of note, the antiviral effect was more pronounced among those who were not vaccinated (mean, –0.95 log copies/mL), compared with the vaccinated (mean, –0.39 log copies/mL).

The antiviral effect with metformin was similar to that seen with nirmatrelvir at day 5 and was greater than nirmatrelvir at day 10.

No similar relationships in SARS-CoV-2 viral load were observed between ivermectin or fluvoxamine and placebo.

The findings are consistent with results of other recent observational studies, including research showing metformin to be associated with reductions in COVID-19 severity in patients with prediabetes, Dr. Bramante noted.

The authors’ previous analysis looking at long COVID in the COVID-OUT study showed that metformin treatment during acute COVID significantly reduced the risk for a diagnosis of long COVID versus placebo at 300 days following randomization, with a hazard ratio of 0.59 after adjustment for the study drug and vaccination at baseline.

Dr. Bramante noted that metformin’s potential antiviral properties have long been speculated, with some of the earliest research on the drug suggesting less severe outcomes in influenza, and more recently, RNA assays suggesting effects against other RNA viruses, including the Zika virus.

In terms of COVID, Dr. Bramante noted that the drug has plenty of potentially favorable benefits.

“Metformin is very safe and is known to have very few contraindications, so the next steps could be to consider looking at this in terms of a combination therapy,” she said.
 

‘Data from other studies are conflicting’

Commenting on the study, Diane V. Havlir, MD, cautioned that “metformin is currently not recommended in treatment guidelines, [and] data from other studies are conflicting; side effects can be an issue, and the study presented here was in a select population,” she said in an interview.

However, “what is both new and interesting in this presentation is the reduction of viral load, which [was observed] in the samples collected not only on days 1-5, but also days 6-14,” said Dr. Havlir, who is professor and associate chair of clinical research, department of medicine, and chief of the division of HIV, infectious diseases and global medicine and director of the AIDS Research Institute at the University of California, San Francisco.

Key questions the findings raise include whether the results correlate with clinical outcomes or transmission, and whether the findings are generalizable to other populations and settings, Dr. Havlir said.

Ultimately, “we need to continue to pursue all aspects of outpatient treatments for COVID to address questions like these for new and existing agents,” she added.

The trial received funding from the Parsemus Foundation, the Rainwater Charitable Foundation, Fast Grants, and the United Health Group. The authors and Dr. Havlir disclosed no relevant financial relationships.

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

Treatment with the diabetes drug metformin shows a significant, dose-dependent effect in lowering SARS-CoV-2 viral load within days of administration, according to the latest analysis of the phase 3 COVID-OUT trial. These findings add to a multitude of benefits the drug has been shown to have in COVID infection.

COVID-OUT did not meet its primary endpoint, but it did show important secondary outcomes including a 42% reduction in ED visits and in hospitalizations and/or deaths by day 14, and a 58% reduction in hospitalizations/death by day 28. A further subanalysis has shown a 42% reduction in long COVID, compared with placebo.

“In this phase 3 randomized controlled trial, metformin showed prevention of severe COVID, prevention of long COVID, and an antiviral effect, and this is consistent with other data,” said coauthor Carolyn Bramante, MD, University of Minnesota, Minneapolis, in presenting the findings at the Conference on Retroviruses & Opportunistic Infections.
 

Study details

For the new subanalysis, the authors further evaluated the effects of metformin treatment on SARS-CoV-2 viral load.

A total of 1,323 patients in the study, enrolled at six centers, were randomized to treatment either with metformin 1,000 mg per day on days 2-5 and 1,500 mg per day on days 6 to 14 (n = 187), or to ivermectin 390-470 mcg/kg per day for 3 days (n = 187), fluvoxamine 50 mg twice daily for 14 days, and/or an exact-matching placebo in a 2 x 3 factorial trial design.

The subanalysis on viral load included 483 patients from the trial who were treated with metformin versus 462 who received placebo, who were all enrolled within 3 days of a documented SARS-CoV-2 infection and less than 7 days after symptom onset.

The patients had a median age of 46 years, and all had either overweight or obesity. Only about 2% had diabetes, and only patients considered low-risk were excluded from the trial, including those under age 30 and those with a body mass index under 25.

About half of patients had received a primary vaccine and about 5% had received a vaccine booster. SARS-CoV-2 variants that were prominent during the study included Alpha, Delta, and Omicron.

The viral samples available on days 1, 5, and 10 showed a mean change in viral load from baseline to follow-up; the viral load was significantly lower with metformin versus placebo (–0.64 log10 copies/mL), representing a 4.4-fold greater decrease in viral load with metformin.

The mean rate of undetectable SARS-CoV-2 viral load at day 5 was 49.9% in the metformin group versus 54.6% in the placebo group (odds ratio, 1.235), and the undetectable rate at day 10 was 14.3% in the metformin group and 22.6% in the placebo group (OR, 1.663; P = .003).

An increased antiviral effect corresponded with increases in metformin dosing on days 6 through 14. Furthermore, the antiviral effect became stronger when metformin was started earlier in the course of infection.

Of note, the antiviral effect was more pronounced among those who were not vaccinated (mean, –0.95 log copies/mL), compared with the vaccinated (mean, –0.39 log copies/mL).

The antiviral effect with metformin was similar to that seen with nirmatrelvir at day 5 and was greater than nirmatrelvir at day 10.

No similar relationships in SARS-CoV-2 viral load were observed between ivermectin or fluvoxamine and placebo.

The findings are consistent with results of other recent observational studies, including research showing metformin to be associated with reductions in COVID-19 severity in patients with prediabetes, Dr. Bramante noted.

The authors’ previous analysis looking at long COVID in the COVID-OUT study showed that metformin treatment during acute COVID significantly reduced the risk for a diagnosis of long COVID versus placebo at 300 days following randomization, with a hazard ratio of 0.59 after adjustment for the study drug and vaccination at baseline.

Dr. Bramante noted that metformin’s potential antiviral properties have long been speculated, with some of the earliest research on the drug suggesting less severe outcomes in influenza, and more recently, RNA assays suggesting effects against other RNA viruses, including the Zika virus.

In terms of COVID, Dr. Bramante noted that the drug has plenty of potentially favorable benefits.

“Metformin is very safe and is known to have very few contraindications, so the next steps could be to consider looking at this in terms of a combination therapy,” she said.
 

‘Data from other studies are conflicting’

Commenting on the study, Diane V. Havlir, MD, cautioned that “metformin is currently not recommended in treatment guidelines, [and] data from other studies are conflicting; side effects can be an issue, and the study presented here was in a select population,” she said in an interview.

However, “what is both new and interesting in this presentation is the reduction of viral load, which [was observed] in the samples collected not only on days 1-5, but also days 6-14,” said Dr. Havlir, who is professor and associate chair of clinical research, department of medicine, and chief of the division of HIV, infectious diseases and global medicine and director of the AIDS Research Institute at the University of California, San Francisco.

Key questions the findings raise include whether the results correlate with clinical outcomes or transmission, and whether the findings are generalizable to other populations and settings, Dr. Havlir said.

Ultimately, “we need to continue to pursue all aspects of outpatient treatments for COVID to address questions like these for new and existing agents,” she added.

The trial received funding from the Parsemus Foundation, the Rainwater Charitable Foundation, Fast Grants, and the United Health Group. The authors and Dr. Havlir disclosed no relevant financial relationships.

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

Treatment with the diabetes drug metformin shows a significant, dose-dependent effect in lowering SARS-CoV-2 viral load within days of administration, according to the latest analysis of the phase 3 COVID-OUT trial. These findings add to a multitude of benefits the drug has been shown to have in COVID infection.

COVID-OUT did not meet its primary endpoint, but it did show important secondary outcomes including a 42% reduction in ED visits and in hospitalizations and/or deaths by day 14, and a 58% reduction in hospitalizations/death by day 28. A further subanalysis has shown a 42% reduction in long COVID, compared with placebo.

“In this phase 3 randomized controlled trial, metformin showed prevention of severe COVID, prevention of long COVID, and an antiviral effect, and this is consistent with other data,” said coauthor Carolyn Bramante, MD, University of Minnesota, Minneapolis, in presenting the findings at the Conference on Retroviruses & Opportunistic Infections.
 

Study details

For the new subanalysis, the authors further evaluated the effects of metformin treatment on SARS-CoV-2 viral load.

A total of 1,323 patients in the study, enrolled at six centers, were randomized to treatment either with metformin 1,000 mg per day on days 2-5 and 1,500 mg per day on days 6 to 14 (n = 187), or to ivermectin 390-470 mcg/kg per day for 3 days (n = 187), fluvoxamine 50 mg twice daily for 14 days, and/or an exact-matching placebo in a 2 x 3 factorial trial design.

The subanalysis on viral load included 483 patients from the trial who were treated with metformin versus 462 who received placebo, who were all enrolled within 3 days of a documented SARS-CoV-2 infection and less than 7 days after symptom onset.

The patients had a median age of 46 years, and all had either overweight or obesity. Only about 2% had diabetes, and only patients considered low-risk were excluded from the trial, including those under age 30 and those with a body mass index under 25.

About half of patients had received a primary vaccine and about 5% had received a vaccine booster. SARS-CoV-2 variants that were prominent during the study included Alpha, Delta, and Omicron.

The viral samples available on days 1, 5, and 10 showed a mean change in viral load from baseline to follow-up; the viral load was significantly lower with metformin versus placebo (–0.64 log10 copies/mL), representing a 4.4-fold greater decrease in viral load with metformin.

The mean rate of undetectable SARS-CoV-2 viral load at day 5 was 49.9% in the metformin group versus 54.6% in the placebo group (odds ratio, 1.235), and the undetectable rate at day 10 was 14.3% in the metformin group and 22.6% in the placebo group (OR, 1.663; P = .003).

An increased antiviral effect corresponded with increases in metformin dosing on days 6 through 14. Furthermore, the antiviral effect became stronger when metformin was started earlier in the course of infection.

Of note, the antiviral effect was more pronounced among those who were not vaccinated (mean, –0.95 log copies/mL), compared with the vaccinated (mean, –0.39 log copies/mL).

The antiviral effect with metformin was similar to that seen with nirmatrelvir at day 5 and was greater than nirmatrelvir at day 10.

No similar relationships in SARS-CoV-2 viral load were observed between ivermectin or fluvoxamine and placebo.

The findings are consistent with results of other recent observational studies, including research showing metformin to be associated with reductions in COVID-19 severity in patients with prediabetes, Dr. Bramante noted.

The authors’ previous analysis looking at long COVID in the COVID-OUT study showed that metformin treatment during acute COVID significantly reduced the risk for a diagnosis of long COVID versus placebo at 300 days following randomization, with a hazard ratio of 0.59 after adjustment for the study drug and vaccination at baseline.

Dr. Bramante noted that metformin’s potential antiviral properties have long been speculated, with some of the earliest research on the drug suggesting less severe outcomes in influenza, and more recently, RNA assays suggesting effects against other RNA viruses, including the Zika virus.

In terms of COVID, Dr. Bramante noted that the drug has plenty of potentially favorable benefits.

“Metformin is very safe and is known to have very few contraindications, so the next steps could be to consider looking at this in terms of a combination therapy,” she said.
 

‘Data from other studies are conflicting’

Commenting on the study, Diane V. Havlir, MD, cautioned that “metformin is currently not recommended in treatment guidelines, [and] data from other studies are conflicting; side effects can be an issue, and the study presented here was in a select population,” she said in an interview.

However, “what is both new and interesting in this presentation is the reduction of viral load, which [was observed] in the samples collected not only on days 1-5, but also days 6-14,” said Dr. Havlir, who is professor and associate chair of clinical research, department of medicine, and chief of the division of HIV, infectious diseases and global medicine and director of the AIDS Research Institute at the University of California, San Francisco.

Key questions the findings raise include whether the results correlate with clinical outcomes or transmission, and whether the findings are generalizable to other populations and settings, Dr. Havlir said.

Ultimately, “we need to continue to pursue all aspects of outpatient treatments for COVID to address questions like these for new and existing agents,” she added.

The trial received funding from the Parsemus Foundation, the Rainwater Charitable Foundation, Fast Grants, and the United Health Group. The authors and Dr. Havlir disclosed no relevant financial relationships.

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

A new study shows the Pfizer vaccine is safe and highly effective against COVID-19 in children as young as 6 months old.

A three-dose series of the Pfizer COVID-19 vaccine was 73% effective at preventing symptomatic COVID-19 in children aged 6 months to 4 years, the researchers found. They also found that an examination of reactions and safety results “did not suggest any concerns.”

The study, published in the New England Journal of Medicine, included 1,776 children aged 6 months to 2 years old, and 2,750 children aged 2-4 years. Children were randomly assigned to receive either the three-shot series of the Pfizer vaccine or placebo shots. Participants received the first dose of the vaccine by March 31, 2022, and lived in Brazil, Finland, Poland, Spain, or the United States.

The authors wrote that having safe and effective COVID vaccines for young children is important to protect them from hospitalization or death and because young children play a role in spreading highly transmissible variants of the virus. COVID hospitalizations for children under 5 years old peaked at a rate of 14.5 per 100,000 in January 2022, the authors wrote, noting that the Omicron virus variant appeared to affect young children more severely than the previous variant, Delta.

When the researchers evaluated vaccine effectiveness by age group, they found that it prevented symptomatic COVID in 75.8% of children aged 6 months to 2 years, and in 71.8% of children aged 2-4 years.

Less than 0.5% of participants reported severe reactions to the vaccine. The most common reactions reported were tenderness or pain. Reactions typically appeared within the first couple days following vaccine administration and resolved within 2 days. No cases of inflammation of the heart muscle or its lining were reported among participants.

Uptake of COVID vaccines for young children has been lower than other age groups in the United States. The Centers for Disease Control and Prevention says 10% of children younger than 5 have received at least one dose of a COVID-19 vaccine, and 5% have completed a primary vaccine series.

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

A new study shows the Pfizer vaccine is safe and highly effective against COVID-19 in children as young as 6 months old.

A three-dose series of the Pfizer COVID-19 vaccine was 73% effective at preventing symptomatic COVID-19 in children aged 6 months to 4 years, the researchers found. They also found that an examination of reactions and safety results “did not suggest any concerns.”

The study, published in the New England Journal of Medicine, included 1,776 children aged 6 months to 2 years old, and 2,750 children aged 2-4 years. Children were randomly assigned to receive either the three-shot series of the Pfizer vaccine or placebo shots. Participants received the first dose of the vaccine by March 31, 2022, and lived in Brazil, Finland, Poland, Spain, or the United States.

The authors wrote that having safe and effective COVID vaccines for young children is important to protect them from hospitalization or death and because young children play a role in spreading highly transmissible variants of the virus. COVID hospitalizations for children under 5 years old peaked at a rate of 14.5 per 100,000 in January 2022, the authors wrote, noting that the Omicron virus variant appeared to affect young children more severely than the previous variant, Delta.

When the researchers evaluated vaccine effectiveness by age group, they found that it prevented symptomatic COVID in 75.8% of children aged 6 months to 2 years, and in 71.8% of children aged 2-4 years.

Less than 0.5% of participants reported severe reactions to the vaccine. The most common reactions reported were tenderness or pain. Reactions typically appeared within the first couple days following vaccine administration and resolved within 2 days. No cases of inflammation of the heart muscle or its lining were reported among participants.

Uptake of COVID vaccines for young children has been lower than other age groups in the United States. The Centers for Disease Control and Prevention says 10% of children younger than 5 have received at least one dose of a COVID-19 vaccine, and 5% have completed a primary vaccine series.

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

A new study shows the Pfizer vaccine is safe and highly effective against COVID-19 in children as young as 6 months old.

A three-dose series of the Pfizer COVID-19 vaccine was 73% effective at preventing symptomatic COVID-19 in children aged 6 months to 4 years, the researchers found. They also found that an examination of reactions and safety results “did not suggest any concerns.”

The study, published in the New England Journal of Medicine, included 1,776 children aged 6 months to 2 years old, and 2,750 children aged 2-4 years. Children were randomly assigned to receive either the three-shot series of the Pfizer vaccine or placebo shots. Participants received the first dose of the vaccine by March 31, 2022, and lived in Brazil, Finland, Poland, Spain, or the United States.

The authors wrote that having safe and effective COVID vaccines for young children is important to protect them from hospitalization or death and because young children play a role in spreading highly transmissible variants of the virus. COVID hospitalizations for children under 5 years old peaked at a rate of 14.5 per 100,000 in January 2022, the authors wrote, noting that the Omicron virus variant appeared to affect young children more severely than the previous variant, Delta.

When the researchers evaluated vaccine effectiveness by age group, they found that it prevented symptomatic COVID in 75.8% of children aged 6 months to 2 years, and in 71.8% of children aged 2-4 years.

Less than 0.5% of participants reported severe reactions to the vaccine. The most common reactions reported were tenderness or pain. Reactions typically appeared within the first couple days following vaccine administration and resolved within 2 days. No cases of inflammation of the heart muscle or its lining were reported among participants.

Uptake of COVID vaccines for young children has been lower than other age groups in the United States. The Centers for Disease Control and Prevention says 10% of children younger than 5 have received at least one dose of a COVID-19 vaccine, and 5% have completed a primary vaccine series.

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

The natural immunity provided by a COVID infection protects a person against severe illness on a par with two doses of mRNA vaccine, a new study says. 

People who’ve been infected with COVID reduced their chances of hospitalization and death by 88% over 10 months compared to somebody who hasn’t been infected, according to the study, published in The Lancet. 

The natural immunity provided by infection was “at least as high, if not higher” than the immunity provided by two doses of Moderna or Pfizer mRNA vaccines against the ancestral, Alpha, Delta, and Omicron BA.1 variants, the researchers reported. 

But protection against the BA.1 subvariant of Omicron was not as high – 36% at 10 months after infection, wrote the research team from the Institute for Health Metrics and Evaluation at the University of Washington.

They examined 65 studies from 19 countries through Sept. 31, 2022. They did not study data about infection from Omicron XBB and its sub-lineages. People who had immunity from both infection and vaccination, known as hybrid immunity, were not studied. 

The findings don’t mean people should skip the vaccines and get COVID on purpose, one of the researchers told NBC News. 

“The problem of saying ‘I’m gonna get infected to get immunity’ is you might be one of those people that end up in the hospital or die,” said Christopher Murray, MD, DPhil, director of the IHME. “Why would you take the risk when you can get immunity through vaccination quite safely?”

The findings could help people figure out the most effective time to get vaccinated or boosted and guide officials in setting policies on workplace vaccine mandates and rules for high-occupancy indoor settings, the researchers concluded.

This was the largest meta-analysis of immunity following infection to date, NBC News reports.

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

The natural immunity provided by a COVID infection protects a person against severe illness on a par with two doses of mRNA vaccine, a new study says. 

People who’ve been infected with COVID reduced their chances of hospitalization and death by 88% over 10 months compared to somebody who hasn’t been infected, according to the study, published in The Lancet. 

The natural immunity provided by infection was “at least as high, if not higher” than the immunity provided by two doses of Moderna or Pfizer mRNA vaccines against the ancestral, Alpha, Delta, and Omicron BA.1 variants, the researchers reported. 

But protection against the BA.1 subvariant of Omicron was not as high – 36% at 10 months after infection, wrote the research team from the Institute for Health Metrics and Evaluation at the University of Washington.

They examined 65 studies from 19 countries through Sept. 31, 2022. They did not study data about infection from Omicron XBB and its sub-lineages. People who had immunity from both infection and vaccination, known as hybrid immunity, were not studied. 

The findings don’t mean people should skip the vaccines and get COVID on purpose, one of the researchers told NBC News. 

“The problem of saying ‘I’m gonna get infected to get immunity’ is you might be one of those people that end up in the hospital or die,” said Christopher Murray, MD, DPhil, director of the IHME. “Why would you take the risk when you can get immunity through vaccination quite safely?”

The findings could help people figure out the most effective time to get vaccinated or boosted and guide officials in setting policies on workplace vaccine mandates and rules for high-occupancy indoor settings, the researchers concluded.

This was the largest meta-analysis of immunity following infection to date, NBC News reports.

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

The natural immunity provided by a COVID infection protects a person against severe illness on a par with two doses of mRNA vaccine, a new study says. 

People who’ve been infected with COVID reduced their chances of hospitalization and death by 88% over 10 months compared to somebody who hasn’t been infected, according to the study, published in The Lancet. 

The natural immunity provided by infection was “at least as high, if not higher” than the immunity provided by two doses of Moderna or Pfizer mRNA vaccines against the ancestral, Alpha, Delta, and Omicron BA.1 variants, the researchers reported. 

But protection against the BA.1 subvariant of Omicron was not as high – 36% at 10 months after infection, wrote the research team from the Institute for Health Metrics and Evaluation at the University of Washington.

They examined 65 studies from 19 countries through Sept. 31, 2022. They did not study data about infection from Omicron XBB and its sub-lineages. People who had immunity from both infection and vaccination, known as hybrid immunity, were not studied. 

The findings don’t mean people should skip the vaccines and get COVID on purpose, one of the researchers told NBC News. 

“The problem of saying ‘I’m gonna get infected to get immunity’ is you might be one of those people that end up in the hospital or die,” said Christopher Murray, MD, DPhil, director of the IHME. “Why would you take the risk when you can get immunity through vaccination quite safely?”

The findings could help people figure out the most effective time to get vaccinated or boosted and guide officials in setting policies on workplace vaccine mandates and rules for high-occupancy indoor settings, the researchers concluded.

This was the largest meta-analysis of immunity following infection to date, NBC News reports.

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

Approximately one in four patients with untreated COVID-19 experience symptom relapse, while almost one in three exhibits relapse of viral load, a recent study finds.

These findings offer a natural history of COVID-19 that will inform discussions and research concerning antiviral therapy, lead author Jonathan Z. Li, MD, associate professor of infectious disease at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, and colleagues reported in Annals of Internal Medicine.

“There are increasing reports that high-risk patients are avoiding nirmatrelvir-ritonavir due to concerns about post-Paxlovid rebound, but there remains a gap in our knowledge of the frequency of symptom and viral relapse during untreated natural infection,” Dr. Li said in a written comment.

To address this gap, Dr. Li and colleagues analyzed data from 563 participants from the placebo group of the Adaptive Platform Treatment Trial for Outpatients with COVID-19 (ACTIV-2/A5401).

From days 0-28, patients recorded severity of 13 symptoms, with scores ranging from absent to severe (absent = 0, mild = 1, moderate = 2, severe = 3). RNA testing was performed on samples from nasal swabs on days 0–14, 21, and 28.

“The symptom rebound definition was determined by consensus of the study team, which comprises more than 10 infectious disease, pulmonary, and critical care physicians, as likely representing a clinically meaningful change in symptoms,” Dr. Li said.

Symptom scores needed to increase by at least 4 points to reach the threshold. For instance, a patient would qualify for relapse if they had worsening of four symptoms from mild to moderate, emergence of two new moderate symptoms, or emergence of one new moderate and two new mild symptoms.

The threshold for viral relapse was defined by an increase of at least 0.5 log10 RNA copies/mL from one nasal swab to the next, while high-level viral relapse was defined by an increase of at least 5.0 log10 RNA copies/mL. The former threshold was chosen based on previous analysis of viral rebound after nirmatrelvir treatment in the EPIC-HR phase 3 trial, whereas the high-level relapse point was based on Dr. Li and colleagues’ previous work linking this cutoff with the presence of infectious virus.

Their present analysis revealed that 26% of patients had symptom relapse at a median of 11 days after first symptom onset. Viral relapse occurred in 31% of patients, while high-level viral relapse occurred in 13% of participants. In about 9 out 10 cases, these relapses were detected at only one time point, suggesting they were transient. Of note, symptom relapse and high-level viral relapse occurred simultaneously in only 3% of patients.

This lack of correlation was “surprising” and “highlights that recovery from any infection is not always a linear process,” Dr. Li said.

This finding also suggests that untreated patients with recurring symptoms probably pose a low risk of contagion, according to David Wohl, MD, coauthor of the paper and professor of medicine in the division of infectious diseases at the University of North Carolina at Chapel Hill.
 

Paxlovid may not be to blame for COVID-19 rebound

“These results provide important context for the reports of Paxlovid rebound and show that baseline rates of symptom and viral relapse should be accounted for when studying the risk of rebound after antiviral therapy,” Dr. Li said.

Dr. Wohl suggested that these data can also play a role in conversations with patients who experience rebound after taking antiviral therapy.

“Many who have a return of their symptoms after taking Paxlovid blame the drug, and that may be justified, but this study suggests it happens in untreated people too,” Dr. Wohl said in a written comment.
 

Longer antiviral therapy deserves investigation

This is a “very important study” because it offers a baseline for comparing the natural history of COVID-19 with clinical course after antiviral therapy, said Timothy Henrich, MD, associate professor in the division of experimental medicine at University of California, San Francisco.

“Unlike this natural history, where it’s kind of sputtering up and down as it goes down, [after antiviral therapy,] it goes away for several days, and then it comes back up; and when it comes up, people have symptoms again,” Dr. Henrich said in an interview.

This suggests that each type of rebound is a unique phenomenon and, from a clinical perspective, that antiviral therapy may need to be extended.

“We treat for too short a period of time,” Dr. Henrich said. “We’re able to suppress [SARS-CoV-2] to the point where we’re not detecting it in the nasal pharynx, but it’s clearly still there. And it’s clearly still in a place that can replicate without the drug.”

That said, treating for longer may not be a sure-fire solution, especially if antiviral therapy is started early in the clinical course, as this could delay SARS-CoV-2-specific immune responses that are necessary for resolution, Dr. Henrich added,

“We need further study of longer-term therapies,” he said.

An array of research questions need to be addressed, according to Aditya Shah, MBBS, an infectious disease specialist at Mayo Clinic, Rochester, Minn. In a written comment, he probed the significance of rebound in various clinical scenarios.

“What [type of] rebound matters and what doesn’t?” Dr. Shah asked. “Does symptom rebound matter? How many untreated and treated ‘symptom rebounders’ need additional treatment or health care? If rebound does not really matter, but if Paxlovid helps in certain unvaccinated and high-risk patients, then does rebound matter? Future research should also focus on Paxlovid utility in vaccinated but high-risk patients. Is it as beneficial in them as it is in unvaccinated high-risk patients?”

While potentially regimen-altering questions like these remain unanswered, Dr. Henrich advised providers to keep patients focused on what we do know about the benefits of antiviral therapy given the current 5-day course, which is that it reduces the risk of severe disease and hospitalization.

The investigators disclosed relationships with Merck, Gilead, ViiV, and others. Dr. Henrich disclosed grant support from Merck and a consulting role with Roche. Dr. Shah disclosed no conflicts of interest.

Approximately one in four patients with untreated COVID-19 experience symptom relapse, while almost one in three exhibits relapse of viral load, a recent study finds.

These findings offer a natural history of COVID-19 that will inform discussions and research concerning antiviral therapy, lead author Jonathan Z. Li, MD, associate professor of infectious disease at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, and colleagues reported in Annals of Internal Medicine.

“There are increasing reports that high-risk patients are avoiding nirmatrelvir-ritonavir due to concerns about post-Paxlovid rebound, but there remains a gap in our knowledge of the frequency of symptom and viral relapse during untreated natural infection,” Dr. Li said in a written comment.

To address this gap, Dr. Li and colleagues analyzed data from 563 participants from the placebo group of the Adaptive Platform Treatment Trial for Outpatients with COVID-19 (ACTIV-2/A5401).

From days 0-28, patients recorded severity of 13 symptoms, with scores ranging from absent to severe (absent = 0, mild = 1, moderate = 2, severe = 3). RNA testing was performed on samples from nasal swabs on days 0–14, 21, and 28.

“The symptom rebound definition was determined by consensus of the study team, which comprises more than 10 infectious disease, pulmonary, and critical care physicians, as likely representing a clinically meaningful change in symptoms,” Dr. Li said.

Symptom scores needed to increase by at least 4 points to reach the threshold. For instance, a patient would qualify for relapse if they had worsening of four symptoms from mild to moderate, emergence of two new moderate symptoms, or emergence of one new moderate and two new mild symptoms.

The threshold for viral relapse was defined by an increase of at least 0.5 log10 RNA copies/mL from one nasal swab to the next, while high-level viral relapse was defined by an increase of at least 5.0 log10 RNA copies/mL. The former threshold was chosen based on previous analysis of viral rebound after nirmatrelvir treatment in the EPIC-HR phase 3 trial, whereas the high-level relapse point was based on Dr. Li and colleagues’ previous work linking this cutoff with the presence of infectious virus.

Their present analysis revealed that 26% of patients had symptom relapse at a median of 11 days after first symptom onset. Viral relapse occurred in 31% of patients, while high-level viral relapse occurred in 13% of participants. In about 9 out 10 cases, these relapses were detected at only one time point, suggesting they were transient. Of note, symptom relapse and high-level viral relapse occurred simultaneously in only 3% of patients.

This lack of correlation was “surprising” and “highlights that recovery from any infection is not always a linear process,” Dr. Li said.

This finding also suggests that untreated patients with recurring symptoms probably pose a low risk of contagion, according to David Wohl, MD, coauthor of the paper and professor of medicine in the division of infectious diseases at the University of North Carolina at Chapel Hill.
 

Paxlovid may not be to blame for COVID-19 rebound

“These results provide important context for the reports of Paxlovid rebound and show that baseline rates of symptom and viral relapse should be accounted for when studying the risk of rebound after antiviral therapy,” Dr. Li said.

Dr. Wohl suggested that these data can also play a role in conversations with patients who experience rebound after taking antiviral therapy.

“Many who have a return of their symptoms after taking Paxlovid blame the drug, and that may be justified, but this study suggests it happens in untreated people too,” Dr. Wohl said in a written comment.
 

Longer antiviral therapy deserves investigation

This is a “very important study” because it offers a baseline for comparing the natural history of COVID-19 with clinical course after antiviral therapy, said Timothy Henrich, MD, associate professor in the division of experimental medicine at University of California, San Francisco.

“Unlike this natural history, where it’s kind of sputtering up and down as it goes down, [after antiviral therapy,] it goes away for several days, and then it comes back up; and when it comes up, people have symptoms again,” Dr. Henrich said in an interview.

This suggests that each type of rebound is a unique phenomenon and, from a clinical perspective, that antiviral therapy may need to be extended.

“We treat for too short a period of time,” Dr. Henrich said. “We’re able to suppress [SARS-CoV-2] to the point where we’re not detecting it in the nasal pharynx, but it’s clearly still there. And it’s clearly still in a place that can replicate without the drug.”

That said, treating for longer may not be a sure-fire solution, especially if antiviral therapy is started early in the clinical course, as this could delay SARS-CoV-2-specific immune responses that are necessary for resolution, Dr. Henrich added,

“We need further study of longer-term therapies,” he said.

An array of research questions need to be addressed, according to Aditya Shah, MBBS, an infectious disease specialist at Mayo Clinic, Rochester, Minn. In a written comment, he probed the significance of rebound in various clinical scenarios.

“What [type of] rebound matters and what doesn’t?” Dr. Shah asked. “Does symptom rebound matter? How many untreated and treated ‘symptom rebounders’ need additional treatment or health care? If rebound does not really matter, but if Paxlovid helps in certain unvaccinated and high-risk patients, then does rebound matter? Future research should also focus on Paxlovid utility in vaccinated but high-risk patients. Is it as beneficial in them as it is in unvaccinated high-risk patients?”

While potentially regimen-altering questions like these remain unanswered, Dr. Henrich advised providers to keep patients focused on what we do know about the benefits of antiviral therapy given the current 5-day course, which is that it reduces the risk of severe disease and hospitalization.

The investigators disclosed relationships with Merck, Gilead, ViiV, and others. Dr. Henrich disclosed grant support from Merck and a consulting role with Roche. Dr. Shah disclosed no conflicts of interest.

Approximately one in four patients with untreated COVID-19 experience symptom relapse, while almost one in three exhibits relapse of viral load, a recent study finds.

These findings offer a natural history of COVID-19 that will inform discussions and research concerning antiviral therapy, lead author Jonathan Z. Li, MD, associate professor of infectious disease at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, and colleagues reported in Annals of Internal Medicine.

“There are increasing reports that high-risk patients are avoiding nirmatrelvir-ritonavir due to concerns about post-Paxlovid rebound, but there remains a gap in our knowledge of the frequency of symptom and viral relapse during untreated natural infection,” Dr. Li said in a written comment.

To address this gap, Dr. Li and colleagues analyzed data from 563 participants from the placebo group of the Adaptive Platform Treatment Trial for Outpatients with COVID-19 (ACTIV-2/A5401).

From days 0-28, patients recorded severity of 13 symptoms, with scores ranging from absent to severe (absent = 0, mild = 1, moderate = 2, severe = 3). RNA testing was performed on samples from nasal swabs on days 0–14, 21, and 28.

“The symptom rebound definition was determined by consensus of the study team, which comprises more than 10 infectious disease, pulmonary, and critical care physicians, as likely representing a clinically meaningful change in symptoms,” Dr. Li said.

Symptom scores needed to increase by at least 4 points to reach the threshold. For instance, a patient would qualify for relapse if they had worsening of four symptoms from mild to moderate, emergence of two new moderate symptoms, or emergence of one new moderate and two new mild symptoms.

The threshold for viral relapse was defined by an increase of at least 0.5 log10 RNA copies/mL from one nasal swab to the next, while high-level viral relapse was defined by an increase of at least 5.0 log10 RNA copies/mL. The former threshold was chosen based on previous analysis of viral rebound after nirmatrelvir treatment in the EPIC-HR phase 3 trial, whereas the high-level relapse point was based on Dr. Li and colleagues’ previous work linking this cutoff with the presence of infectious virus.

Their present analysis revealed that 26% of patients had symptom relapse at a median of 11 days after first symptom onset. Viral relapse occurred in 31% of patients, while high-level viral relapse occurred in 13% of participants. In about 9 out 10 cases, these relapses were detected at only one time point, suggesting they were transient. Of note, symptom relapse and high-level viral relapse occurred simultaneously in only 3% of patients.

This lack of correlation was “surprising” and “highlights that recovery from any infection is not always a linear process,” Dr. Li said.

This finding also suggests that untreated patients with recurring symptoms probably pose a low risk of contagion, according to David Wohl, MD, coauthor of the paper and professor of medicine in the division of infectious diseases at the University of North Carolina at Chapel Hill.
 

Paxlovid may not be to blame for COVID-19 rebound

“These results provide important context for the reports of Paxlovid rebound and show that baseline rates of symptom and viral relapse should be accounted for when studying the risk of rebound after antiviral therapy,” Dr. Li said.

Dr. Wohl suggested that these data can also play a role in conversations with patients who experience rebound after taking antiviral therapy.

“Many who have a return of their symptoms after taking Paxlovid blame the drug, and that may be justified, but this study suggests it happens in untreated people too,” Dr. Wohl said in a written comment.
 

Longer antiviral therapy deserves investigation

This is a “very important study” because it offers a baseline for comparing the natural history of COVID-19 with clinical course after antiviral therapy, said Timothy Henrich, MD, associate professor in the division of experimental medicine at University of California, San Francisco.

“Unlike this natural history, where it’s kind of sputtering up and down as it goes down, [after antiviral therapy,] it goes away for several days, and then it comes back up; and when it comes up, people have symptoms again,” Dr. Henrich said in an interview.

This suggests that each type of rebound is a unique phenomenon and, from a clinical perspective, that antiviral therapy may need to be extended.

“We treat for too short a period of time,” Dr. Henrich said. “We’re able to suppress [SARS-CoV-2] to the point where we’re not detecting it in the nasal pharynx, but it’s clearly still there. And it’s clearly still in a place that can replicate without the drug.”

That said, treating for longer may not be a sure-fire solution, especially if antiviral therapy is started early in the clinical course, as this could delay SARS-CoV-2-specific immune responses that are necessary for resolution, Dr. Henrich added,

“We need further study of longer-term therapies,” he said.

An array of research questions need to be addressed, according to Aditya Shah, MBBS, an infectious disease specialist at Mayo Clinic, Rochester, Minn. In a written comment, he probed the significance of rebound in various clinical scenarios.

“What [type of] rebound matters and what doesn’t?” Dr. Shah asked. “Does symptom rebound matter? How many untreated and treated ‘symptom rebounders’ need additional treatment or health care? If rebound does not really matter, but if Paxlovid helps in certain unvaccinated and high-risk patients, then does rebound matter? Future research should also focus on Paxlovid utility in vaccinated but high-risk patients. Is it as beneficial in them as it is in unvaccinated high-risk patients?”

While potentially regimen-altering questions like these remain unanswered, Dr. Henrich advised providers to keep patients focused on what we do know about the benefits of antiviral therapy given the current 5-day course, which is that it reduces the risk of severe disease and hospitalization.

The investigators disclosed relationships with Merck, Gilead, ViiV, and others. Dr. Henrich disclosed grant support from Merck and a consulting role with Roche. Dr. Shah disclosed no conflicts of interest.