Infectious Diseases

Respiratory syncytial virus (RSV) and influenza cases are surging to record numbers this winter in the wake of the COVID-19 pandemic when children were sheltering in the home, receiving virtual education, masking, and hand sanitizing, and when other precautionary health measures were in place.

RSV and flu illness in children now have hospital emergency rooms and pediatric ICUs and wards over capacity. As these respiratory infections increase and variants of SARS-CoV-2 come to dominate, we may expect the full impact of a tripledemic (RSV + flu + SARS-CoV-2).

It has been estimated that RSV causes 33 million lower respiratory infections and 3.6 million hospitalizations annually worldwide in children younger than 5 years old (Lancet. 2022 May 19. doi: 10.1016/S0140-6736(22)00478-0). RSV is typically a seasonal respiratory infection occurring in late fall through early winter, when it gives way to dominance by flu. Thus, we have experienced an out-of-season surge in RSV since it began in early fall 2022, and it persists. A likely explanation for the early and persisting surge in RSV is immunity debt (Infect Dis Now. 2021 Aug. doi: 10.1016/j.idnow.2021.05.004).

Immunity debt is an unintended consequence of prevention of infections that occurred because of public health measures to prevent spread of SARS-CoV-2 infections. The COVID-19 lockdown undoubtedly saved many lives. However, while we were sheltering from SARS-CoV-2 infections, we also were avoiding other infections, especially other respiratory infections such as RSV and flu.

Our group studied this in community-based pediatric practices in Rochester, N.Y. Physician-diagnosed, medically attended infectious disease illness visits were assessed in two child cohorts, age 6-36 months from March 15 to Dec. 31, 2020 (the pandemic period), compared with the same months in 2019 (prepandemic). One hundred forty-four children were included in the pandemic cohort and 215 in the prepandemic cohort. Visits for bronchiolitis were 7.4-fold lower (P = .04), acute otitis media 3.7-fold lower (P < .0001), viral upper respiratory infections (URI) 3.8-fold lower (P < .0001), and croup 27.5-fold lower (P < .0001) in the pandemic than the prepandemic cohort (Front Pediatr. 2021 Sep 13. doi: 10.3389/fped.2021.72248).

The significant reduction in respiratory illness during the COVID-19 epidemic we and others observed resulted in a large pool of children who did not experience RSV or flu infections for an entire year or more. Herd immunity dropped. The susceptible child population increased, including children older than typically seen. We had an immunity debt that had to be repaid, and the repayment is occurring now.

As a consequence of the surge in RSV, interest in prevention has gained more attention. In 1966, tragically, two infant deaths and hospitalization of 80% of the participating infants occurred during a clinical trial of an experimental candidate RSV vaccine, which contained an inactivated version of the entire virus. The severe side effect was later found to be caused by both an antibody and a T-cell problem. The antibody produced in response to the inactivated whole virus didn’t have very good functional activity at blocking or neutralizing the virus. That led to deposition of immune complexes and activation of complement that damaged the airways. The vaccine also triggered a T-cell response with inflammatory cytokine release that added to airway obstruction and lack of clearance of the virus. RSV vaccine development was halted and the bar for further studies was raised very high to ensure safety of any future RSV vaccines. Now, 55 years later, two RSV vaccines and a new preventive monoclonal antibody are nearing licensure.

GlaxoSmithKline (GSK) and Pfizer are in phase 3 clinical trials of a safer RSV vaccine that contains only the RSV surface protein known as protein F. Protein F changes its structure when the virus infects and fuses with human respiratory epithelial cells. The GSK and Pfizer vaccines use a molecular strategy developed at the National Institutes of Health to lock protein F into its original, prefusion configuration. A similar strategy was used by Pfizer/BioNTech and Moderna in their design of mRNA vaccines to the SARS-CoV-2 spike surface protein.

A vaccine with the F protein in its prefusion form takes care of the antibody problem that caused the severe side-effects from the 1966 version of inactivated whole virus vaccine because it induces very high-efficiency, high-potency antibodies that neutralize the RSV. The T-cell response is not as well understood and that is why studies are being done in adults first and then moving to young infants.

The new RSV vaccines are being developed for use in adults over age 60, adults with comorbidities, maternal immunization, and infants. Encouraging results were recently reported by GSK and Pfizer from adult trials. In an interim analysis, Pfizer also recently reported that maternal immunization in the late second or third trimester with their vaccine had an efficacy of 82% within a newborn’s first 90 days of life against severe lower respiratory tract illness. At age 6 months, the efficacy was sustained at 69%. So far, both the GSK and Pfizer RSV vaccines have shown a favorable safety profile.

Another strategy in the RSV prevention field has been a monoclonal antibody. Palivizumab (Synagis, AstraZeneca) is used to prevent severe RSV infections in prematurely born and other infants who are at higher risk of mortality and severe morbidity. Soon there will likely be another monoclonal antibody, called nirsevimab (Beyfortus, AstraZeneca and Sanofi). It is approved in Europe but not yet approved in the United States as I prepare this column. Nirsevimab may be even better than palivizumab – based on phase 3 trial data – and a single injection lasts through an entire normal RSV season while palivizumab requires monthly injections.

Similar to the situation with RSV, the flu season started earlier than usual in fall 2022 and has been picking up steam, likely also because of immunity debt. The WHO estimates that annual epidemics of influenza cause 1 billion infections, 3 million to 5 million severe cases, and 300,000-500,000 deaths. Seasonal flu vaccines provide modest protection. Current flu vaccine formulations consist of the hemagglutinin (H) and neuraminidase (N) proteins but those proteins change sufficiently (called antigenic drift) such that production of the vaccines based on a best guess each year often is not correct for the influenza A or influenza B strains that circulate in a given year (antigenic mismatch).

Public health authorities have long worried about a major change in the composition of the H and N proteins of the influenza virus (called antigenic shift). Preparedness and response to the COVID-19 pandemic was based on preparedness and response to an anticipated influenza pandemic similar to the 1918 flu pandemic. For flu, new “universal” vaccines are in development. Among the candidate vaccines are mRNA vaccines, building on the success of the SARS-CoV-2 mRNA vaccines (Science. 2022 Nov 24. doi: 10.1126/science.abm0271).
 

Dr. Pichichero is a specialist in pediatric infectious diseases, Center for Infectious Diseases and Immunology, and director of the Research Institute, at Rochester (N.Y.) General Hospital. He has no conflicts of interest to declare.

Respiratory syncytial virus (RSV) and influenza cases are surging to record numbers this winter in the wake of the COVID-19 pandemic when children were sheltering in the home, receiving virtual education, masking, and hand sanitizing, and when other precautionary health measures were in place.

RSV and flu illness in children now have hospital emergency rooms and pediatric ICUs and wards over capacity. As these respiratory infections increase and variants of SARS-CoV-2 come to dominate, we may expect the full impact of a tripledemic (RSV + flu + SARS-CoV-2).

It has been estimated that RSV causes 33 million lower respiratory infections and 3.6 million hospitalizations annually worldwide in children younger than 5 years old (Lancet. 2022 May 19. doi: 10.1016/S0140-6736(22)00478-0). RSV is typically a seasonal respiratory infection occurring in late fall through early winter, when it gives way to dominance by flu. Thus, we have experienced an out-of-season surge in RSV since it began in early fall 2022, and it persists. A likely explanation for the early and persisting surge in RSV is immunity debt (Infect Dis Now. 2021 Aug. doi: 10.1016/j.idnow.2021.05.004).

Immunity debt is an unintended consequence of prevention of infections that occurred because of public health measures to prevent spread of SARS-CoV-2 infections. The COVID-19 lockdown undoubtedly saved many lives. However, while we were sheltering from SARS-CoV-2 infections, we also were avoiding other infections, especially other respiratory infections such as RSV and flu.

Our group studied this in community-based pediatric practices in Rochester, N.Y. Physician-diagnosed, medically attended infectious disease illness visits were assessed in two child cohorts, age 6-36 months from March 15 to Dec. 31, 2020 (the pandemic period), compared with the same months in 2019 (prepandemic). One hundred forty-four children were included in the pandemic cohort and 215 in the prepandemic cohort. Visits for bronchiolitis were 7.4-fold lower (P = .04), acute otitis media 3.7-fold lower (P < .0001), viral upper respiratory infections (URI) 3.8-fold lower (P < .0001), and croup 27.5-fold lower (P < .0001) in the pandemic than the prepandemic cohort (Front Pediatr. 2021 Sep 13. doi: 10.3389/fped.2021.72248).

The significant reduction in respiratory illness during the COVID-19 epidemic we and others observed resulted in a large pool of children who did not experience RSV or flu infections for an entire year or more. Herd immunity dropped. The susceptible child population increased, including children older than typically seen. We had an immunity debt that had to be repaid, and the repayment is occurring now.

As a consequence of the surge in RSV, interest in prevention has gained more attention. In 1966, tragically, two infant deaths and hospitalization of 80% of the participating infants occurred during a clinical trial of an experimental candidate RSV vaccine, which contained an inactivated version of the entire virus. The severe side effect was later found to be caused by both an antibody and a T-cell problem. The antibody produced in response to the inactivated whole virus didn’t have very good functional activity at blocking or neutralizing the virus. That led to deposition of immune complexes and activation of complement that damaged the airways. The vaccine also triggered a T-cell response with inflammatory cytokine release that added to airway obstruction and lack of clearance of the virus. RSV vaccine development was halted and the bar for further studies was raised very high to ensure safety of any future RSV vaccines. Now, 55 years later, two RSV vaccines and a new preventive monoclonal antibody are nearing licensure.

GlaxoSmithKline (GSK) and Pfizer are in phase 3 clinical trials of a safer RSV vaccine that contains only the RSV surface protein known as protein F. Protein F changes its structure when the virus infects and fuses with human respiratory epithelial cells. The GSK and Pfizer vaccines use a molecular strategy developed at the National Institutes of Health to lock protein F into its original, prefusion configuration. A similar strategy was used by Pfizer/BioNTech and Moderna in their design of mRNA vaccines to the SARS-CoV-2 spike surface protein.

A vaccine with the F protein in its prefusion form takes care of the antibody problem that caused the severe side-effects from the 1966 version of inactivated whole virus vaccine because it induces very high-efficiency, high-potency antibodies that neutralize the RSV. The T-cell response is not as well understood and that is why studies are being done in adults first and then moving to young infants.

The new RSV vaccines are being developed for use in adults over age 60, adults with comorbidities, maternal immunization, and infants. Encouraging results were recently reported by GSK and Pfizer from adult trials. In an interim analysis, Pfizer also recently reported that maternal immunization in the late second or third trimester with their vaccine had an efficacy of 82% within a newborn’s first 90 days of life against severe lower respiratory tract illness. At age 6 months, the efficacy was sustained at 69%. So far, both the GSK and Pfizer RSV vaccines have shown a favorable safety profile.

Another strategy in the RSV prevention field has been a monoclonal antibody. Palivizumab (Synagis, AstraZeneca) is used to prevent severe RSV infections in prematurely born and other infants who are at higher risk of mortality and severe morbidity. Soon there will likely be another monoclonal antibody, called nirsevimab (Beyfortus, AstraZeneca and Sanofi). It is approved in Europe but not yet approved in the United States as I prepare this column. Nirsevimab may be even better than palivizumab – based on phase 3 trial data – and a single injection lasts through an entire normal RSV season while palivizumab requires monthly injections.

Similar to the situation with RSV, the flu season started earlier than usual in fall 2022 and has been picking up steam, likely also because of immunity debt. The WHO estimates that annual epidemics of influenza cause 1 billion infections, 3 million to 5 million severe cases, and 300,000-500,000 deaths. Seasonal flu vaccines provide modest protection. Current flu vaccine formulations consist of the hemagglutinin (H) and neuraminidase (N) proteins but those proteins change sufficiently (called antigenic drift) such that production of the vaccines based on a best guess each year often is not correct for the influenza A or influenza B strains that circulate in a given year (antigenic mismatch).

Public health authorities have long worried about a major change in the composition of the H and N proteins of the influenza virus (called antigenic shift). Preparedness and response to the COVID-19 pandemic was based on preparedness and response to an anticipated influenza pandemic similar to the 1918 flu pandemic. For flu, new “universal” vaccines are in development. Among the candidate vaccines are mRNA vaccines, building on the success of the SARS-CoV-2 mRNA vaccines (Science. 2022 Nov 24. doi: 10.1126/science.abm0271).
 

Dr. Pichichero is a specialist in pediatric infectious diseases, Center for Infectious Diseases and Immunology, and director of the Research Institute, at Rochester (N.Y.) General Hospital. He has no conflicts of interest to declare.

Respiratory syncytial virus (RSV) and influenza cases are surging to record numbers this winter in the wake of the COVID-19 pandemic when children were sheltering in the home, receiving virtual education, masking, and hand sanitizing, and when other precautionary health measures were in place.

RSV and flu illness in children now have hospital emergency rooms and pediatric ICUs and wards over capacity. As these respiratory infections increase and variants of SARS-CoV-2 come to dominate, we may expect the full impact of a tripledemic (RSV + flu + SARS-CoV-2).

It has been estimated that RSV causes 33 million lower respiratory infections and 3.6 million hospitalizations annually worldwide in children younger than 5 years old (Lancet. 2022 May 19. doi: 10.1016/S0140-6736(22)00478-0). RSV is typically a seasonal respiratory infection occurring in late fall through early winter, when it gives way to dominance by flu. Thus, we have experienced an out-of-season surge in RSV since it began in early fall 2022, and it persists. A likely explanation for the early and persisting surge in RSV is immunity debt (Infect Dis Now. 2021 Aug. doi: 10.1016/j.idnow.2021.05.004).

Immunity debt is an unintended consequence of prevention of infections that occurred because of public health measures to prevent spread of SARS-CoV-2 infections. The COVID-19 lockdown undoubtedly saved many lives. However, while we were sheltering from SARS-CoV-2 infections, we also were avoiding other infections, especially other respiratory infections such as RSV and flu.

Our group studied this in community-based pediatric practices in Rochester, N.Y. Physician-diagnosed, medically attended infectious disease illness visits were assessed in two child cohorts, age 6-36 months from March 15 to Dec. 31, 2020 (the pandemic period), compared with the same months in 2019 (prepandemic). One hundred forty-four children were included in the pandemic cohort and 215 in the prepandemic cohort. Visits for bronchiolitis were 7.4-fold lower (P = .04), acute otitis media 3.7-fold lower (P < .0001), viral upper respiratory infections (URI) 3.8-fold lower (P < .0001), and croup 27.5-fold lower (P < .0001) in the pandemic than the prepandemic cohort (Front Pediatr. 2021 Sep 13. doi: 10.3389/fped.2021.72248).

The significant reduction in respiratory illness during the COVID-19 epidemic we and others observed resulted in a large pool of children who did not experience RSV or flu infections for an entire year or more. Herd immunity dropped. The susceptible child population increased, including children older than typically seen. We had an immunity debt that had to be repaid, and the repayment is occurring now.

As a consequence of the surge in RSV, interest in prevention has gained more attention. In 1966, tragically, two infant deaths and hospitalization of 80% of the participating infants occurred during a clinical trial of an experimental candidate RSV vaccine, which contained an inactivated version of the entire virus. The severe side effect was later found to be caused by both an antibody and a T-cell problem. The antibody produced in response to the inactivated whole virus didn’t have very good functional activity at blocking or neutralizing the virus. That led to deposition of immune complexes and activation of complement that damaged the airways. The vaccine also triggered a T-cell response with inflammatory cytokine release that added to airway obstruction and lack of clearance of the virus. RSV vaccine development was halted and the bar for further studies was raised very high to ensure safety of any future RSV vaccines. Now, 55 years later, two RSV vaccines and a new preventive monoclonal antibody are nearing licensure.

GlaxoSmithKline (GSK) and Pfizer are in phase 3 clinical trials of a safer RSV vaccine that contains only the RSV surface protein known as protein F. Protein F changes its structure when the virus infects and fuses with human respiratory epithelial cells. The GSK and Pfizer vaccines use a molecular strategy developed at the National Institutes of Health to lock protein F into its original, prefusion configuration. A similar strategy was used by Pfizer/BioNTech and Moderna in their design of mRNA vaccines to the SARS-CoV-2 spike surface protein.

A vaccine with the F protein in its prefusion form takes care of the antibody problem that caused the severe side-effects from the 1966 version of inactivated whole virus vaccine because it induces very high-efficiency, high-potency antibodies that neutralize the RSV. The T-cell response is not as well understood and that is why studies are being done in adults first and then moving to young infants.

The new RSV vaccines are being developed for use in adults over age 60, adults with comorbidities, maternal immunization, and infants. Encouraging results were recently reported by GSK and Pfizer from adult trials. In an interim analysis, Pfizer also recently reported that maternal immunization in the late second or third trimester with their vaccine had an efficacy of 82% within a newborn’s first 90 days of life against severe lower respiratory tract illness. At age 6 months, the efficacy was sustained at 69%. So far, both the GSK and Pfizer RSV vaccines have shown a favorable safety profile.

Another strategy in the RSV prevention field has been a monoclonal antibody. Palivizumab (Synagis, AstraZeneca) is used to prevent severe RSV infections in prematurely born and other infants who are at higher risk of mortality and severe morbidity. Soon there will likely be another monoclonal antibody, called nirsevimab (Beyfortus, AstraZeneca and Sanofi). It is approved in Europe but not yet approved in the United States as I prepare this column. Nirsevimab may be even better than palivizumab – based on phase 3 trial data – and a single injection lasts through an entire normal RSV season while palivizumab requires monthly injections.

Similar to the situation with RSV, the flu season started earlier than usual in fall 2022 and has been picking up steam, likely also because of immunity debt. The WHO estimates that annual epidemics of influenza cause 1 billion infections, 3 million to 5 million severe cases, and 300,000-500,000 deaths. Seasonal flu vaccines provide modest protection. Current flu vaccine formulations consist of the hemagglutinin (H) and neuraminidase (N) proteins but those proteins change sufficiently (called antigenic drift) such that production of the vaccines based on a best guess each year often is not correct for the influenza A or influenza B strains that circulate in a given year (antigenic mismatch).

Public health authorities have long worried about a major change in the composition of the H and N proteins of the influenza virus (called antigenic shift). Preparedness and response to the COVID-19 pandemic was based on preparedness and response to an anticipated influenza pandemic similar to the 1918 flu pandemic. For flu, new “universal” vaccines are in development. Among the candidate vaccines are mRNA vaccines, building on the success of the SARS-CoV-2 mRNA vaccines (Science. 2022 Nov 24. doi: 10.1126/science.abm0271).
 

Dr. Pichichero is a specialist in pediatric infectious diseases, Center for Infectious Diseases and Immunology, and director of the Research Institute, at Rochester (N.Y.) General Hospital. He has no conflicts of interest to declare.

New cases of COVID-19 in children largely held steady over the Thanksgiving holiday, but hospital admissions are telling a somewhat different story.

New pediatric COVID cases for the week ending on Thanksgiving (11/18-11/24) were up by 5.3% over the previous week, but in the most recent week (11/25-12/1) new cases dropped by 2.6%, according to state data collected by the American Academy of Pediatrics and the Children’s Hospital Association.

In both weeks, though, the total case count stayed below 30,000 – a streak that has now lasted 8 weeks – so the actual number of weekly cases remained fairly low, the AAP/CHA weekly report indicates.

The nation’s emergency departments also experienced a small Thanksgiving bump, as the proportion of visits with diagnosed COVID went from 1.0% of all ED visits for children aged 0-11 years on Nov. 14 to 2.0% on Nov. 27, just 3 days after the official holiday, based on data from the Centers for Disease Control and Prevention. The rate was down to 1.5% on Dec. 1, and similar patterns can be seen for children aged 12-15 and 16-17 years.

New hospital admissions, on the other hand, seem to be following a different path, at least according to the CDC. The hospitalization rate for children aged 0-17 years bottomed out at 0.16 new admissions per 100,000 population back on Oct. 21 and has climbed fairly steadily since then. It was up to 0.20 per 100,000 by Nov. 14, had reached 0.22 per 100,000 on Thanksgiving day (11/24), and then continued to 0.26 per 100,000 by Dec. 2, the latest date for which CDC data are available.

The hospitalization story, however, offers yet another twist. The New York Times, using data from the U.S. Department of Health & Human Services, reports that new COVID-related admissions have held steady at 1.0 per 100,000 since Nov. 18. The rate is much higher than has been reported by the CDC, but no increase can be seen in recent weeks among children, which is not the case for Americans overall, Medscape recently reported.

New cases of COVID-19 in children largely held steady over the Thanksgiving holiday, but hospital admissions are telling a somewhat different story.

New pediatric COVID cases for the week ending on Thanksgiving (11/18-11/24) were up by 5.3% over the previous week, but in the most recent week (11/25-12/1) new cases dropped by 2.6%, according to state data collected by the American Academy of Pediatrics and the Children’s Hospital Association.

In both weeks, though, the total case count stayed below 30,000 – a streak that has now lasted 8 weeks – so the actual number of weekly cases remained fairly low, the AAP/CHA weekly report indicates.

The nation’s emergency departments also experienced a small Thanksgiving bump, as the proportion of visits with diagnosed COVID went from 1.0% of all ED visits for children aged 0-11 years on Nov. 14 to 2.0% on Nov. 27, just 3 days after the official holiday, based on data from the Centers for Disease Control and Prevention. The rate was down to 1.5% on Dec. 1, and similar patterns can be seen for children aged 12-15 and 16-17 years.

New hospital admissions, on the other hand, seem to be following a different path, at least according to the CDC. The hospitalization rate for children aged 0-17 years bottomed out at 0.16 new admissions per 100,000 population back on Oct. 21 and has climbed fairly steadily since then. It was up to 0.20 per 100,000 by Nov. 14, had reached 0.22 per 100,000 on Thanksgiving day (11/24), and then continued to 0.26 per 100,000 by Dec. 2, the latest date for which CDC data are available.

The hospitalization story, however, offers yet another twist. The New York Times, using data from the U.S. Department of Health & Human Services, reports that new COVID-related admissions have held steady at 1.0 per 100,000 since Nov. 18. The rate is much higher than has been reported by the CDC, but no increase can be seen in recent weeks among children, which is not the case for Americans overall, Medscape recently reported.

New cases of COVID-19 in children largely held steady over the Thanksgiving holiday, but hospital admissions are telling a somewhat different story.

New pediatric COVID cases for the week ending on Thanksgiving (11/18-11/24) were up by 5.3% over the previous week, but in the most recent week (11/25-12/1) new cases dropped by 2.6%, according to state data collected by the American Academy of Pediatrics and the Children’s Hospital Association.

In both weeks, though, the total case count stayed below 30,000 – a streak that has now lasted 8 weeks – so the actual number of weekly cases remained fairly low, the AAP/CHA weekly report indicates.

The nation’s emergency departments also experienced a small Thanksgiving bump, as the proportion of visits with diagnosed COVID went from 1.0% of all ED visits for children aged 0-11 years on Nov. 14 to 2.0% on Nov. 27, just 3 days after the official holiday, based on data from the Centers for Disease Control and Prevention. The rate was down to 1.5% on Dec. 1, and similar patterns can be seen for children aged 12-15 and 16-17 years.

New hospital admissions, on the other hand, seem to be following a different path, at least according to the CDC. The hospitalization rate for children aged 0-17 years bottomed out at 0.16 new admissions per 100,000 population back on Oct. 21 and has climbed fairly steadily since then. It was up to 0.20 per 100,000 by Nov. 14, had reached 0.22 per 100,000 on Thanksgiving day (11/24), and then continued to 0.26 per 100,000 by Dec. 2, the latest date for which CDC data are available.

The hospitalization story, however, offers yet another twist. The New York Times, using data from the U.S. Department of Health & Human Services, reports that new COVID-related admissions have held steady at 1.0 per 100,000 since Nov. 18. The rate is much higher than has been reported by the CDC, but no increase can be seen in recent weeks among children, which is not the case for Americans overall, Medscape recently reported.

A randomized trial indicating that surgical masks are not inferior to N95 masks in protecting health care workers against COVID-19 has sparked international criticism.

The study’s senior author is John Conly, MD, an infectious disease specialist and professor at the University of Calgary (Alta.), and Alberta Health Services. The findings are not consistent with those of many other studies on this topic.

Commenting about Dr. Conly’s study, Eric Topol, MD, editor-in-chief of Medscape, wrote: “It’s woefully underpowered but ruled out a doubling of hazard for use of medical masks.”

The study, which was partially funded by the World Health Organization, was published online in Annals of Internal Medicine.

This is not the first time that Dr. Conly, who also advises the WHO, has been the subject of controversy. He previously denied that COVID-19 is airborne – a position that is contradicted by strong evidence. In 2021, Dr. Conly made headlines with his controversial claim that N95 respirators can cause harms, including oxygen depletion and carbon dioxide retention.

A detailed examination by the Center for Infectious Disease Research and Policy (CIDRAP) at the University of Minnesota, Minneapolis, pointed out numerous scientific flaws in the study, including inconsistent use of both types of masks. The study also examined health care workers in four very different countries (Canada, Israel, Egypt, and Pakistan) during different periods of the pandemic, which may have affected the results. Furthermore, the study did not account for vaccination status and lacked a control group. CIDRAP receives funding from 3M, which makes N95 respirators.

In a commentary published alongside the study, Roger Chou, MD, professor of medicine at Oregon Health & Science University, Portland, said that the results were “not definitive,” with “a generous noninferiority threshold” that is actually “consistent with up to a relative 70% increased risk ... which may be unacceptable to many health workers.”

Lead study author Mark Loeb, MD, professor of infectious diseases at McMaster University, Hamilton, Ont., defended the findings. “The confidence intervals around this, that is, what the possible results could be if the trial was repeated many times, range from −2.5% to 4.9%,” he told this news organization. “This means that the risk of a COVID-19 infection in those using the medical masks could have ranged from anywhere from 2.5% reduction in risk to a 4.9% increase in risk. Readers and policy makers can decide for themselves about this.”

“There is no point continuing to run underpowered, poorly designed studies that are designed to confirm existing biases,” Raina MacIntyre, PhD, professor of global biosecurity and head of the Biosecurity Program at the Kirby Institute, Sydney, said in an interview. “The new study in Annals of Internal Medicine is entirely consistent with our finding that to prevent infection, you need an N95, and it needs to be worn throughout the whole shift. A surgical mask and intermittent use of N95 are equally ineffective. This should not surprise anyone, given a surgical mask is not designed as respiratory protection but is designed to prevent splash or spray of liquid on the face. Only a respirator is designed as respiratory protection through both the seal around the face and the filter of the face piece to prevent inhalation of virus laden aerosols, but you need to wear it continually in a high-risk environment like a hospital.”

“It makes zero sense to do a randomized trial on something you can measure directly,” said Kimberly Prather, PhD, an atmospheric chemist, professor, and director of the NSF Center for Aerosol Impacts on Chemistry of the Environment at the University of California, San Diego. “In fact, many studies have shown aerosols leaking out of surgical masks. Surgical masks are designed to block large spray droplets. Aerosols (0.5-3 mcm), which have been shown to contain infectious SARS-CoV-2 virus, travel with the air flow, and escape.”

“This study ... will be used to justify policies of supplying health care workers, and perhaps patients and visitors, too, with inadequate protection,” Trish Greenhalgh, MD, professor of primary care health sciences at the University of Oxford (England), told this news organization.

“These authors have been pushing back against treating COVID as airborne for 3 years,” David Fisman, MD, an epidemiologist and infectious disease specialist at the University of Toronto, said in an interview. “So, you’ll see these folks brandishing this very flawed trial to justify continuing the infection control practices that have been so disastrous throughout the pandemic.”

The study was funded by the World Health Organization, the Canadian Institutes of Health Research, and the Juravinski Research Institute. Dr. Conly reported receiving grants from the Canadian Institutes for Health Research, Pfizer, and the WHO. Dr. Chou disclosed being a methodologist for WHO guidelines on infection prevention and control measures for COVID-19. Dr. Loeb disclosed payment for expert testimony on personal protective equipment from the government of Manitoba and the Peel District School Board. Dr. MacIntyre has led a large body of research on masks and respirators in health workers, including four randomized clinical trials. She is the author of a book, “Dark Winter: An insider’s guide to pandemics and biosecurity” (Syndey: NewSouth Publishing, 2022), which covers the history and politics of the controversies around N95 and masks. Dr. Prather reported no disclosures. Dr. Greenhalgh is a member of Independent SAGE and an unpaid adviser to the philanthropic fund Balvi. Dr. Fisman has served as a paid legal expert for the Ontario Nurses’ Association in their challenge to Directive 5, which restricted access to N95 masks in health care. He also served as a paid legal expert for the Elementary Teachers’ Federation of Ontario in its efforts to make schools safer in Ontario.

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

A randomized trial indicating that surgical masks are not inferior to N95 masks in protecting health care workers against COVID-19 has sparked international criticism.

The study’s senior author is John Conly, MD, an infectious disease specialist and professor at the University of Calgary (Alta.), and Alberta Health Services. The findings are not consistent with those of many other studies on this topic.

Commenting about Dr. Conly’s study, Eric Topol, MD, editor-in-chief of Medscape, wrote: “It’s woefully underpowered but ruled out a doubling of hazard for use of medical masks.”

The study, which was partially funded by the World Health Organization, was published online in Annals of Internal Medicine.

This is not the first time that Dr. Conly, who also advises the WHO, has been the subject of controversy. He previously denied that COVID-19 is airborne – a position that is contradicted by strong evidence. In 2021, Dr. Conly made headlines with his controversial claim that N95 respirators can cause harms, including oxygen depletion and carbon dioxide retention.

A detailed examination by the Center for Infectious Disease Research and Policy (CIDRAP) at the University of Minnesota, Minneapolis, pointed out numerous scientific flaws in the study, including inconsistent use of both types of masks. The study also examined health care workers in four very different countries (Canada, Israel, Egypt, and Pakistan) during different periods of the pandemic, which may have affected the results. Furthermore, the study did not account for vaccination status and lacked a control group. CIDRAP receives funding from 3M, which makes N95 respirators.

In a commentary published alongside the study, Roger Chou, MD, professor of medicine at Oregon Health & Science University, Portland, said that the results were “not definitive,” with “a generous noninferiority threshold” that is actually “consistent with up to a relative 70% increased risk ... which may be unacceptable to many health workers.”

Lead study author Mark Loeb, MD, professor of infectious diseases at McMaster University, Hamilton, Ont., defended the findings. “The confidence intervals around this, that is, what the possible results could be if the trial was repeated many times, range from −2.5% to 4.9%,” he told this news organization. “This means that the risk of a COVID-19 infection in those using the medical masks could have ranged from anywhere from 2.5% reduction in risk to a 4.9% increase in risk. Readers and policy makers can decide for themselves about this.”

“There is no point continuing to run underpowered, poorly designed studies that are designed to confirm existing biases,” Raina MacIntyre, PhD, professor of global biosecurity and head of the Biosecurity Program at the Kirby Institute, Sydney, said in an interview. “The new study in Annals of Internal Medicine is entirely consistent with our finding that to prevent infection, you need an N95, and it needs to be worn throughout the whole shift. A surgical mask and intermittent use of N95 are equally ineffective. This should not surprise anyone, given a surgical mask is not designed as respiratory protection but is designed to prevent splash or spray of liquid on the face. Only a respirator is designed as respiratory protection through both the seal around the face and the filter of the face piece to prevent inhalation of virus laden aerosols, but you need to wear it continually in a high-risk environment like a hospital.”

“It makes zero sense to do a randomized trial on something you can measure directly,” said Kimberly Prather, PhD, an atmospheric chemist, professor, and director of the NSF Center for Aerosol Impacts on Chemistry of the Environment at the University of California, San Diego. “In fact, many studies have shown aerosols leaking out of surgical masks. Surgical masks are designed to block large spray droplets. Aerosols (0.5-3 mcm), which have been shown to contain infectious SARS-CoV-2 virus, travel with the air flow, and escape.”

“This study ... will be used to justify policies of supplying health care workers, and perhaps patients and visitors, too, with inadequate protection,” Trish Greenhalgh, MD, professor of primary care health sciences at the University of Oxford (England), told this news organization.

“These authors have been pushing back against treating COVID as airborne for 3 years,” David Fisman, MD, an epidemiologist and infectious disease specialist at the University of Toronto, said in an interview. “So, you’ll see these folks brandishing this very flawed trial to justify continuing the infection control practices that have been so disastrous throughout the pandemic.”

The study was funded by the World Health Organization, the Canadian Institutes of Health Research, and the Juravinski Research Institute. Dr. Conly reported receiving grants from the Canadian Institutes for Health Research, Pfizer, and the WHO. Dr. Chou disclosed being a methodologist for WHO guidelines on infection prevention and control measures for COVID-19. Dr. Loeb disclosed payment for expert testimony on personal protective equipment from the government of Manitoba and the Peel District School Board. Dr. MacIntyre has led a large body of research on masks and respirators in health workers, including four randomized clinical trials. She is the author of a book, “Dark Winter: An insider’s guide to pandemics and biosecurity” (Syndey: NewSouth Publishing, 2022), which covers the history and politics of the controversies around N95 and masks. Dr. Prather reported no disclosures. Dr. Greenhalgh is a member of Independent SAGE and an unpaid adviser to the philanthropic fund Balvi. Dr. Fisman has served as a paid legal expert for the Ontario Nurses’ Association in their challenge to Directive 5, which restricted access to N95 masks in health care. He also served as a paid legal expert for the Elementary Teachers’ Federation of Ontario in its efforts to make schools safer in Ontario.

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

A randomized trial indicating that surgical masks are not inferior to N95 masks in protecting health care workers against COVID-19 has sparked international criticism.

The study’s senior author is John Conly, MD, an infectious disease specialist and professor at the University of Calgary (Alta.), and Alberta Health Services. The findings are not consistent with those of many other studies on this topic.

Commenting about Dr. Conly’s study, Eric Topol, MD, editor-in-chief of Medscape, wrote: “It’s woefully underpowered but ruled out a doubling of hazard for use of medical masks.”

The study, which was partially funded by the World Health Organization, was published online in Annals of Internal Medicine.

This is not the first time that Dr. Conly, who also advises the WHO, has been the subject of controversy. He previously denied that COVID-19 is airborne – a position that is contradicted by strong evidence. In 2021, Dr. Conly made headlines with his controversial claim that N95 respirators can cause harms, including oxygen depletion and carbon dioxide retention.

A detailed examination by the Center for Infectious Disease Research and Policy (CIDRAP) at the University of Minnesota, Minneapolis, pointed out numerous scientific flaws in the study, including inconsistent use of both types of masks. The study also examined health care workers in four very different countries (Canada, Israel, Egypt, and Pakistan) during different periods of the pandemic, which may have affected the results. Furthermore, the study did not account for vaccination status and lacked a control group. CIDRAP receives funding from 3M, which makes N95 respirators.

In a commentary published alongside the study, Roger Chou, MD, professor of medicine at Oregon Health & Science University, Portland, said that the results were “not definitive,” with “a generous noninferiority threshold” that is actually “consistent with up to a relative 70% increased risk ... which may be unacceptable to many health workers.”

Lead study author Mark Loeb, MD, professor of infectious diseases at McMaster University, Hamilton, Ont., defended the findings. “The confidence intervals around this, that is, what the possible results could be if the trial was repeated many times, range from −2.5% to 4.9%,” he told this news organization. “This means that the risk of a COVID-19 infection in those using the medical masks could have ranged from anywhere from 2.5% reduction in risk to a 4.9% increase in risk. Readers and policy makers can decide for themselves about this.”

“There is no point continuing to run underpowered, poorly designed studies that are designed to confirm existing biases,” Raina MacIntyre, PhD, professor of global biosecurity and head of the Biosecurity Program at the Kirby Institute, Sydney, said in an interview. “The new study in Annals of Internal Medicine is entirely consistent with our finding that to prevent infection, you need an N95, and it needs to be worn throughout the whole shift. A surgical mask and intermittent use of N95 are equally ineffective. This should not surprise anyone, given a surgical mask is not designed as respiratory protection but is designed to prevent splash or spray of liquid on the face. Only a respirator is designed as respiratory protection through both the seal around the face and the filter of the face piece to prevent inhalation of virus laden aerosols, but you need to wear it continually in a high-risk environment like a hospital.”

“It makes zero sense to do a randomized trial on something you can measure directly,” said Kimberly Prather, PhD, an atmospheric chemist, professor, and director of the NSF Center for Aerosol Impacts on Chemistry of the Environment at the University of California, San Diego. “In fact, many studies have shown aerosols leaking out of surgical masks. Surgical masks are designed to block large spray droplets. Aerosols (0.5-3 mcm), which have been shown to contain infectious SARS-CoV-2 virus, travel with the air flow, and escape.”

“This study ... will be used to justify policies of supplying health care workers, and perhaps patients and visitors, too, with inadequate protection,” Trish Greenhalgh, MD, professor of primary care health sciences at the University of Oxford (England), told this news organization.

“These authors have been pushing back against treating COVID as airborne for 3 years,” David Fisman, MD, an epidemiologist and infectious disease specialist at the University of Toronto, said in an interview. “So, you’ll see these folks brandishing this very flawed trial to justify continuing the infection control practices that have been so disastrous throughout the pandemic.”

The study was funded by the World Health Organization, the Canadian Institutes of Health Research, and the Juravinski Research Institute. Dr. Conly reported receiving grants from the Canadian Institutes for Health Research, Pfizer, and the WHO. Dr. Chou disclosed being a methodologist for WHO guidelines on infection prevention and control measures for COVID-19. Dr. Loeb disclosed payment for expert testimony on personal protective equipment from the government of Manitoba and the Peel District School Board. Dr. MacIntyre has led a large body of research on masks and respirators in health workers, including four randomized clinical trials. She is the author of a book, “Dark Winter: An insider’s guide to pandemics and biosecurity” (Syndey: NewSouth Publishing, 2022), which covers the history and politics of the controversies around N95 and masks. Dr. Prather reported no disclosures. Dr. Greenhalgh is a member of Independent SAGE and an unpaid adviser to the philanthropic fund Balvi. Dr. Fisman has served as a paid legal expert for the Ontario Nurses’ Association in their challenge to Directive 5, which restricted access to N95 masks in health care. He also served as a paid legal expert for the Elementary Teachers’ Federation of Ontario in its efforts to make schools safer in Ontario.

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

Bacillus Calmette-Guérin (BCG) vaccines are given to more than 100 million children every year, but there is considerable debate regarding the effectiveness of BCG vaccination in preventing tuberculosis and death, particularly among older children and adults.

The most extensive study ever conducted on the efficacy of the BCG vaccine for protection against tuberculosis, stratified by age and history of previous tuberculosis, was published in September 2022 in The Lancet Global Health. The study, which comprises a systematic review and meta-analysis, analyzed individual-level data from 26 case-contact cohort studies published over the past 20 years. The studies included data from 70,000 participants. The primary outcome was a composite of prevalent (diagnosed at or within 90 days of baseline) and incident (diagnosed more than 90 days after baseline) tuberculosis in contacts exposed to tuberculosis. Secondary outcomes were pulmonary tuberculosis, extrapulmonary tuberculosis, and mortality.

Participants were characterized as having been exposed to tuberculosis if they were reported to have been a close contact (either living in the same household or having substantial interaction outside the household) of a person with microbiologically or radiologically diagnosed pulmonary tuberculosis. Previous tuberculosis was defined as a positive interferon-gamma (IFN-gamma) release assay or tuberculin skin test, also known as PPD or Mantoux test.

Most studies included in the analysis were conducted in the past 10 years in countries with a high tuberculosis burden. Those countries included India, South Africa, China, Vietnam, Indonesia, Uganda, the Gambia, and Brazil.
 

Primary outcomes

The study’s main findings included the following:

• The overall effectiveness of BCG vaccination against all forms of tuberculosis was 18% (adjusted odds ratio, 0.82; 95% CI, 0.74-0.91).
• Stratified by age, BCG vaccination only significantly protected against all tuberculosis in children younger than 5 years (aOR, 0.63; 95% CI, 0.49-0.81).
• There was no protective effect among those whose previous tests for tuberculosis were negative unless they were younger than 5 years (aOR, 0.54; 95% CI, 0.32-0.90).
• Among contacts who had a positive tuberculin skin test or IFN-gamma release assay, BCG vaccination significantly protected against tuberculosis among all participants (aOR, 0.81; 95% CI, 0.69-0.96), participants younger than 5 years (aOR, 0.68; 95% CI, 0.47-0.97), and participants aged 5-9 years (aOR, 0.62; 95% CI, 0.38-0.99).
• BCG vaccination was protective against pulmonary tuberculosis (19% effectiveness), but this effect was only seen in children younger than 3 years (42% effectiveness) when stratified by age.
• Protection against all tuberculosis and pulmonary tuberculosis was greater among female participants than male participants.

“This is a definitive BCG protection study because it involves a significant number of individuals evaluated using this meta-analysis. Protection is clearly lost with age. From as early as age 5, no protective effect can be observed. Protection, including against pulmonary tuberculosis, can be observed up to 3 years of age,” stated study author Julio Croda, MD, PhD, chair of the Brazilian Society of Tropical Medicine.

Dr. Croda emphasized that the findings from their study indicate that BCG vaccine protects against pulmonary tuberculosis and that those results differ from results of some previous studies.

“Every physician believes the BCG vaccine protects against serious forms of tuberculosis up to age 5. That fact is not surprising at all,” Dr. Croda remarked. “However, the fact that it protects against pulmonary tuberculosis, especially in children younger than 3, was surprising. In medical practice, we did not believe in this protection.”

Currently, 1.2% of new tuberculosis cases in Brazil occur among those younger than 5. Nevertheless, these cases represent 40.1% of new diagnoses recorded among those younger than 15, highlighting the importance of protection for this age group. An increase in extrapulmonary tuberculosis cases was recently observed in patients younger than 5.

Isabella Ballalai, MD, PhD, is deputy chair of the Brazilian Society of Immunizations. Although she did not participate in this study, she commented on its findings. “All publications are welcome; they help us think,” she explained. She emphasized that the BCG vaccine is not optimal. “There are studies indicating 80% efficacy and others indicating 0%. So, what we can look at is decades of effectiveness in practice.”

Dr. Ballalai explained that the BCG vaccine could keep severe forms of tuberculosis, meningitis, and miliary tuberculosis at bay. She shared her experience of caring for several patients with tuberculous meningitis shortly after she had graduated. “Today, thanks to the BCG vaccine, we don’t see it anymore.” However, she pointed out that the vaccine›s efficacy and effectiveness against pulmonary tuberculosis are low and that pulmonary tuberculosis remains the most significant problem among adults.

Dr. Ballalai also emphasized a few shortcomings of the study. “One is the definition of ‘vaccinated’ and ‘unvaccinated,’ which was based on the presence or absence of a mark on the arm. Today, we know that the absence of a mark does not indicate that the child has not been vaccinated, nor that the vaccine has not been effective. Therefore, several vaccinated participants may have been included amongst the unvaccinated participants.”

The authors emphasized that the definition of “vaccinated” and “unvaccinated” was based on a scar and on vaccination records, and they recognized that participants who did not have a scar on their arm could have been misclassified. Regardless, it is still considered a sensitive indicator. “Few vaccinated children from various settings do not show a scar years after vaccine administration,” they stated in their article.
 

Adults unprotected

Dr. Ballalai also shared her concerns regarding the lack of protection for older individuals. “We know those older than 60 are at greater risk for complications of tuberculosis. Individuals in this age group naturally have a lower immunity, and they usually have comorbidities. From this study, I can only conclude what was already expected: that adults who received a BCG vaccine as infants are not clear of pulmonary tuberculosis.”

Dr. Croda agreed that it was already evident that the BCG vaccine administered at birth did not provide protection for adults. “In the past, even with 80%-90% vaccine coverage, there were numerous tuberculosis cases in adults in Brazil.”
 

Are boosters needed?

The authors concluded that immunoprotection needs to be boosted in older populations, as vaccination at birth is ineffective for adolescents and adults. They have also discussed whether children older than 10 years and adults could benefit from a booster shot.

Dr. Croda emphasized that there is no indication for this, because there are no data regarding protection with a booster dose during adulthood. However, he cited a study conducted in South Africa in which the BCG vaccine was compared with another vaccine, and another study, which is being conducted in India, is assessing whether a BCG booster offers protection against pulmonary tuberculosis. “There are few studies. Perhaps the revaccination of more vulnerable groups could be of interest, but additional studies are needed first.”

Dr. Croda intends to assess revaccination in those deprived of liberty, in which the incidence of tuberculosis is very high. From 2015 to 2021, many new cases were recorded in this population in Brazil. The number rose from 5,860 to 6,773 during that period.

“However, BCG revaccination carries a significant risk of patients presenting with serious adverse events,” Dr. Ballalai pointed out. He noted that several years ago, to extend protection, Brazil adopted a booster program for persons aged 10 years or older, but the program was discontinued owing to the numerous adverse events reported and the absence of evidence of benefit from increased protection against tuberculosis.

“The adult groups at greater risk for severe tuberculosis manifestations normally presented with an underlying disease, particularly in immunocompromised patient groups. The [administration of the] BCG [vaccine] is contraindicated for those who are immunocompromised. And, for the older population, we do not have data on [vaccine] safety,” she emphasized.
 

Nonspecific immune protection

One of the study’s secondary outcomes regarded mortality. Four studies in the meta-analysis followed up tuberculosis contacts for death. In these studies, which evaluated 20,000 participants, BCG vaccination was shown to be significantly protective against death for participants younger than 15 years.

However, the authors urged caution in interpreting these data. They emphasized that they were unable to identify specific mechanisms by which BCG vaccination might have reduced mortality, and there are possible study biases that could have led to an overestimation of mortality benefit. Moreover, given the observational nature of the included studies, vaccinated children might have had higher socioeconomic status and greater access to health care, and they may have been more likely to have received other vaccinations, compared with children who did not receive BCG vaccines.

Nevertheless, previous experimental and observational studies have found that BCG vaccination might provide nonspecific or off-target immune protection against an array of other pathogens.

“In small studies conducted in Africa, those younger than 5 were protected not only against tuberculosis but also against other respiratory diseases,” Dr. Croda affirmed. “However, these are small studies, and for now, there is no recommendation for using BCG vaccination to prevent other respiratory infections.”

A long-awaited, critical study on the impact of the BCG vaccine on COVID-19, in which Brazilian researchers participated, will be published in the New England Journal of Medicine.
 

New vaccines needed

The BCG vaccine is one of the oldest vaccines, but there are still several crucial unanswered questions about its use.

Previously published studies that examined the protective effect of BCG vaccination only considered low-burden settings and the historical literature before 1950. These studies need updating, but doing so has not been a simple task. To answer their questions, individual-level participant data for a prespecified list of variables, including the characteristics of the exposed participant (contact), the index case, and the environment, were requested from authors of all eligible studies.

Much of the data used in the published research were found through discussions with authors and experts in the field, as well as through data deposited in data storage repositories, conference abstracts, dissertations, and even direct requests to the authors. “The Pan-American Health Organization helped with this data collection and contacting some authors,” said Dr. Croda.

With the new data, the authors confirmed that infant BCG vaccination, although important to young children who are at high risk for tuberculosis, does not prevent adult-type cavitary tuberculosis and is therefore insufficient to impede the tuberculosis epidemic. “Novel vaccines are urgently needed,” they concluded.

“We need to develop novel, more effective vaccines, which, when administered during infancy, would ensure lifelong protection,” Dr. Croda added.

Dr. Croda and Dr. Ballalai reported no relevant financial relationships.

This article was translated from the Medscape Portuguese edition. A version of this article appeared on Medscape.com.

Bacillus Calmette-Guérin (BCG) vaccines are given to more than 100 million children every year, but there is considerable debate regarding the effectiveness of BCG vaccination in preventing tuberculosis and death, particularly among older children and adults.

The most extensive study ever conducted on the efficacy of the BCG vaccine for protection against tuberculosis, stratified by age and history of previous tuberculosis, was published in September 2022 in The Lancet Global Health. The study, which comprises a systematic review and meta-analysis, analyzed individual-level data from 26 case-contact cohort studies published over the past 20 years. The studies included data from 70,000 participants. The primary outcome was a composite of prevalent (diagnosed at or within 90 days of baseline) and incident (diagnosed more than 90 days after baseline) tuberculosis in contacts exposed to tuberculosis. Secondary outcomes were pulmonary tuberculosis, extrapulmonary tuberculosis, and mortality.

Participants were characterized as having been exposed to tuberculosis if they were reported to have been a close contact (either living in the same household or having substantial interaction outside the household) of a person with microbiologically or radiologically diagnosed pulmonary tuberculosis. Previous tuberculosis was defined as a positive interferon-gamma (IFN-gamma) release assay or tuberculin skin test, also known as PPD or Mantoux test.

Most studies included in the analysis were conducted in the past 10 years in countries with a high tuberculosis burden. Those countries included India, South Africa, China, Vietnam, Indonesia, Uganda, the Gambia, and Brazil.
 

Primary outcomes

The study’s main findings included the following:

• The overall effectiveness of BCG vaccination against all forms of tuberculosis was 18% (adjusted odds ratio, 0.82; 95% CI, 0.74-0.91).
• Stratified by age, BCG vaccination only significantly protected against all tuberculosis in children younger than 5 years (aOR, 0.63; 95% CI, 0.49-0.81).
• There was no protective effect among those whose previous tests for tuberculosis were negative unless they were younger than 5 years (aOR, 0.54; 95% CI, 0.32-0.90).
• Among contacts who had a positive tuberculin skin test or IFN-gamma release assay, BCG vaccination significantly protected against tuberculosis among all participants (aOR, 0.81; 95% CI, 0.69-0.96), participants younger than 5 years (aOR, 0.68; 95% CI, 0.47-0.97), and participants aged 5-9 years (aOR, 0.62; 95% CI, 0.38-0.99).
• BCG vaccination was protective against pulmonary tuberculosis (19% effectiveness), but this effect was only seen in children younger than 3 years (42% effectiveness) when stratified by age.
• Protection against all tuberculosis and pulmonary tuberculosis was greater among female participants than male participants.

“This is a definitive BCG protection study because it involves a significant number of individuals evaluated using this meta-analysis. Protection is clearly lost with age. From as early as age 5, no protective effect can be observed. Protection, including against pulmonary tuberculosis, can be observed up to 3 years of age,” stated study author Julio Croda, MD, PhD, chair of the Brazilian Society of Tropical Medicine.

Dr. Croda emphasized that the findings from their study indicate that BCG vaccine protects against pulmonary tuberculosis and that those results differ from results of some previous studies.

“Every physician believes the BCG vaccine protects against serious forms of tuberculosis up to age 5. That fact is not surprising at all,” Dr. Croda remarked. “However, the fact that it protects against pulmonary tuberculosis, especially in children younger than 3, was surprising. In medical practice, we did not believe in this protection.”

Currently, 1.2% of new tuberculosis cases in Brazil occur among those younger than 5. Nevertheless, these cases represent 40.1% of new diagnoses recorded among those younger than 15, highlighting the importance of protection for this age group. An increase in extrapulmonary tuberculosis cases was recently observed in patients younger than 5.

Isabella Ballalai, MD, PhD, is deputy chair of the Brazilian Society of Immunizations. Although she did not participate in this study, she commented on its findings. “All publications are welcome; they help us think,” she explained. She emphasized that the BCG vaccine is not optimal. “There are studies indicating 80% efficacy and others indicating 0%. So, what we can look at is decades of effectiveness in practice.”

Dr. Ballalai explained that the BCG vaccine could keep severe forms of tuberculosis, meningitis, and miliary tuberculosis at bay. She shared her experience of caring for several patients with tuberculous meningitis shortly after she had graduated. “Today, thanks to the BCG vaccine, we don’t see it anymore.” However, she pointed out that the vaccine›s efficacy and effectiveness against pulmonary tuberculosis are low and that pulmonary tuberculosis remains the most significant problem among adults.

Dr. Ballalai also emphasized a few shortcomings of the study. “One is the definition of ‘vaccinated’ and ‘unvaccinated,’ which was based on the presence or absence of a mark on the arm. Today, we know that the absence of a mark does not indicate that the child has not been vaccinated, nor that the vaccine has not been effective. Therefore, several vaccinated participants may have been included amongst the unvaccinated participants.”

The authors emphasized that the definition of “vaccinated” and “unvaccinated” was based on a scar and on vaccination records, and they recognized that participants who did not have a scar on their arm could have been misclassified. Regardless, it is still considered a sensitive indicator. “Few vaccinated children from various settings do not show a scar years after vaccine administration,” they stated in their article.
 

Adults unprotected

Dr. Ballalai also shared her concerns regarding the lack of protection for older individuals. “We know those older than 60 are at greater risk for complications of tuberculosis. Individuals in this age group naturally have a lower immunity, and they usually have comorbidities. From this study, I can only conclude what was already expected: that adults who received a BCG vaccine as infants are not clear of pulmonary tuberculosis.”

Dr. Croda agreed that it was already evident that the BCG vaccine administered at birth did not provide protection for adults. “In the past, even with 80%-90% vaccine coverage, there were numerous tuberculosis cases in adults in Brazil.”
 

Are boosters needed?

The authors concluded that immunoprotection needs to be boosted in older populations, as vaccination at birth is ineffective for adolescents and adults. They have also discussed whether children older than 10 years and adults could benefit from a booster shot.

Dr. Croda emphasized that there is no indication for this, because there are no data regarding protection with a booster dose during adulthood. However, he cited a study conducted in South Africa in which the BCG vaccine was compared with another vaccine, and another study, which is being conducted in India, is assessing whether a BCG booster offers protection against pulmonary tuberculosis. “There are few studies. Perhaps the revaccination of more vulnerable groups could be of interest, but additional studies are needed first.”

Dr. Croda intends to assess revaccination in those deprived of liberty, in which the incidence of tuberculosis is very high. From 2015 to 2021, many new cases were recorded in this population in Brazil. The number rose from 5,860 to 6,773 during that period.

“However, BCG revaccination carries a significant risk of patients presenting with serious adverse events,” Dr. Ballalai pointed out. He noted that several years ago, to extend protection, Brazil adopted a booster program for persons aged 10 years or older, but the program was discontinued owing to the numerous adverse events reported and the absence of evidence of benefit from increased protection against tuberculosis.

“The adult groups at greater risk for severe tuberculosis manifestations normally presented with an underlying disease, particularly in immunocompromised patient groups. The [administration of the] BCG [vaccine] is contraindicated for those who are immunocompromised. And, for the older population, we do not have data on [vaccine] safety,” she emphasized.
 

Nonspecific immune protection

One of the study’s secondary outcomes regarded mortality. Four studies in the meta-analysis followed up tuberculosis contacts for death. In these studies, which evaluated 20,000 participants, BCG vaccination was shown to be significantly protective against death for participants younger than 15 years.

However, the authors urged caution in interpreting these data. They emphasized that they were unable to identify specific mechanisms by which BCG vaccination might have reduced mortality, and there are possible study biases that could have led to an overestimation of mortality benefit. Moreover, given the observational nature of the included studies, vaccinated children might have had higher socioeconomic status and greater access to health care, and they may have been more likely to have received other vaccinations, compared with children who did not receive BCG vaccines.

Nevertheless, previous experimental and observational studies have found that BCG vaccination might provide nonspecific or off-target immune protection against an array of other pathogens.

“In small studies conducted in Africa, those younger than 5 were protected not only against tuberculosis but also against other respiratory diseases,” Dr. Croda affirmed. “However, these are small studies, and for now, there is no recommendation for using BCG vaccination to prevent other respiratory infections.”

A long-awaited, critical study on the impact of the BCG vaccine on COVID-19, in which Brazilian researchers participated, will be published in the New England Journal of Medicine.
 

New vaccines needed

The BCG vaccine is one of the oldest vaccines, but there are still several crucial unanswered questions about its use.

Previously published studies that examined the protective effect of BCG vaccination only considered low-burden settings and the historical literature before 1950. These studies need updating, but doing so has not been a simple task. To answer their questions, individual-level participant data for a prespecified list of variables, including the characteristics of the exposed participant (contact), the index case, and the environment, were requested from authors of all eligible studies.

Much of the data used in the published research were found through discussions with authors and experts in the field, as well as through data deposited in data storage repositories, conference abstracts, dissertations, and even direct requests to the authors. “The Pan-American Health Organization helped with this data collection and contacting some authors,” said Dr. Croda.

With the new data, the authors confirmed that infant BCG vaccination, although important to young children who are at high risk for tuberculosis, does not prevent adult-type cavitary tuberculosis and is therefore insufficient to impede the tuberculosis epidemic. “Novel vaccines are urgently needed,” they concluded.

“We need to develop novel, more effective vaccines, which, when administered during infancy, would ensure lifelong protection,” Dr. Croda added.

Dr. Croda and Dr. Ballalai reported no relevant financial relationships.

This article was translated from the Medscape Portuguese edition. A version of this article appeared on Medscape.com.

Bacillus Calmette-Guérin (BCG) vaccines are given to more than 100 million children every year, but there is considerable debate regarding the effectiveness of BCG vaccination in preventing tuberculosis and death, particularly among older children and adults.

The most extensive study ever conducted on the efficacy of the BCG vaccine for protection against tuberculosis, stratified by age and history of previous tuberculosis, was published in September 2022 in The Lancet Global Health. The study, which comprises a systematic review and meta-analysis, analyzed individual-level data from 26 case-contact cohort studies published over the past 20 years. The studies included data from 70,000 participants. The primary outcome was a composite of prevalent (diagnosed at or within 90 days of baseline) and incident (diagnosed more than 90 days after baseline) tuberculosis in contacts exposed to tuberculosis. Secondary outcomes were pulmonary tuberculosis, extrapulmonary tuberculosis, and mortality.

Participants were characterized as having been exposed to tuberculosis if they were reported to have been a close contact (either living in the same household or having substantial interaction outside the household) of a person with microbiologically or radiologically diagnosed pulmonary tuberculosis. Previous tuberculosis was defined as a positive interferon-gamma (IFN-gamma) release assay or tuberculin skin test, also known as PPD or Mantoux test.

Most studies included in the analysis were conducted in the past 10 years in countries with a high tuberculosis burden. Those countries included India, South Africa, China, Vietnam, Indonesia, Uganda, the Gambia, and Brazil.
 

Primary outcomes

The study’s main findings included the following:

• The overall effectiveness of BCG vaccination against all forms of tuberculosis was 18% (adjusted odds ratio, 0.82; 95% CI, 0.74-0.91).
• Stratified by age, BCG vaccination only significantly protected against all tuberculosis in children younger than 5 years (aOR, 0.63; 95% CI, 0.49-0.81).
• There was no protective effect among those whose previous tests for tuberculosis were negative unless they were younger than 5 years (aOR, 0.54; 95% CI, 0.32-0.90).
• Among contacts who had a positive tuberculin skin test or IFN-gamma release assay, BCG vaccination significantly protected against tuberculosis among all participants (aOR, 0.81; 95% CI, 0.69-0.96), participants younger than 5 years (aOR, 0.68; 95% CI, 0.47-0.97), and participants aged 5-9 years (aOR, 0.62; 95% CI, 0.38-0.99).
• BCG vaccination was protective against pulmonary tuberculosis (19% effectiveness), but this effect was only seen in children younger than 3 years (42% effectiveness) when stratified by age.
• Protection against all tuberculosis and pulmonary tuberculosis was greater among female participants than male participants.

“This is a definitive BCG protection study because it involves a significant number of individuals evaluated using this meta-analysis. Protection is clearly lost with age. From as early as age 5, no protective effect can be observed. Protection, including against pulmonary tuberculosis, can be observed up to 3 years of age,” stated study author Julio Croda, MD, PhD, chair of the Brazilian Society of Tropical Medicine.

Dr. Croda emphasized that the findings from their study indicate that BCG vaccine protects against pulmonary tuberculosis and that those results differ from results of some previous studies.

“Every physician believes the BCG vaccine protects against serious forms of tuberculosis up to age 5. That fact is not surprising at all,” Dr. Croda remarked. “However, the fact that it protects against pulmonary tuberculosis, especially in children younger than 3, was surprising. In medical practice, we did not believe in this protection.”

Currently, 1.2% of new tuberculosis cases in Brazil occur among those younger than 5. Nevertheless, these cases represent 40.1% of new diagnoses recorded among those younger than 15, highlighting the importance of protection for this age group. An increase in extrapulmonary tuberculosis cases was recently observed in patients younger than 5.

Isabella Ballalai, MD, PhD, is deputy chair of the Brazilian Society of Immunizations. Although she did not participate in this study, she commented on its findings. “All publications are welcome; they help us think,” she explained. She emphasized that the BCG vaccine is not optimal. “There are studies indicating 80% efficacy and others indicating 0%. So, what we can look at is decades of effectiveness in practice.”

Dr. Ballalai explained that the BCG vaccine could keep severe forms of tuberculosis, meningitis, and miliary tuberculosis at bay. She shared her experience of caring for several patients with tuberculous meningitis shortly after she had graduated. “Today, thanks to the BCG vaccine, we don’t see it anymore.” However, she pointed out that the vaccine›s efficacy and effectiveness against pulmonary tuberculosis are low and that pulmonary tuberculosis remains the most significant problem among adults.

Dr. Ballalai also emphasized a few shortcomings of the study. “One is the definition of ‘vaccinated’ and ‘unvaccinated,’ which was based on the presence or absence of a mark on the arm. Today, we know that the absence of a mark does not indicate that the child has not been vaccinated, nor that the vaccine has not been effective. Therefore, several vaccinated participants may have been included amongst the unvaccinated participants.”

The authors emphasized that the definition of “vaccinated” and “unvaccinated” was based on a scar and on vaccination records, and they recognized that participants who did not have a scar on their arm could have been misclassified. Regardless, it is still considered a sensitive indicator. “Few vaccinated children from various settings do not show a scar years after vaccine administration,” they stated in their article.
 

Adults unprotected

Dr. Ballalai also shared her concerns regarding the lack of protection for older individuals. “We know those older than 60 are at greater risk for complications of tuberculosis. Individuals in this age group naturally have a lower immunity, and they usually have comorbidities. From this study, I can only conclude what was already expected: that adults who received a BCG vaccine as infants are not clear of pulmonary tuberculosis.”

Dr. Croda agreed that it was already evident that the BCG vaccine administered at birth did not provide protection for adults. “In the past, even with 80%-90% vaccine coverage, there were numerous tuberculosis cases in adults in Brazil.”
 

Are boosters needed?

The authors concluded that immunoprotection needs to be boosted in older populations, as vaccination at birth is ineffective for adolescents and adults. They have also discussed whether children older than 10 years and adults could benefit from a booster shot.

Dr. Croda emphasized that there is no indication for this, because there are no data regarding protection with a booster dose during adulthood. However, he cited a study conducted in South Africa in which the BCG vaccine was compared with another vaccine, and another study, which is being conducted in India, is assessing whether a BCG booster offers protection against pulmonary tuberculosis. “There are few studies. Perhaps the revaccination of more vulnerable groups could be of interest, but additional studies are needed first.”

Dr. Croda intends to assess revaccination in those deprived of liberty, in which the incidence of tuberculosis is very high. From 2015 to 2021, many new cases were recorded in this population in Brazil. The number rose from 5,860 to 6,773 during that period.

“However, BCG revaccination carries a significant risk of patients presenting with serious adverse events,” Dr. Ballalai pointed out. He noted that several years ago, to extend protection, Brazil adopted a booster program for persons aged 10 years or older, but the program was discontinued owing to the numerous adverse events reported and the absence of evidence of benefit from increased protection against tuberculosis.

“The adult groups at greater risk for severe tuberculosis manifestations normally presented with an underlying disease, particularly in immunocompromised patient groups. The [administration of the] BCG [vaccine] is contraindicated for those who are immunocompromised. And, for the older population, we do not have data on [vaccine] safety,” she emphasized.
 

Nonspecific immune protection

One of the study’s secondary outcomes regarded mortality. Four studies in the meta-analysis followed up tuberculosis contacts for death. In these studies, which evaluated 20,000 participants, BCG vaccination was shown to be significantly protective against death for participants younger than 15 years.

However, the authors urged caution in interpreting these data. They emphasized that they were unable to identify specific mechanisms by which BCG vaccination might have reduced mortality, and there are possible study biases that could have led to an overestimation of mortality benefit. Moreover, given the observational nature of the included studies, vaccinated children might have had higher socioeconomic status and greater access to health care, and they may have been more likely to have received other vaccinations, compared with children who did not receive BCG vaccines.

Nevertheless, previous experimental and observational studies have found that BCG vaccination might provide nonspecific or off-target immune protection against an array of other pathogens.

“In small studies conducted in Africa, those younger than 5 were protected not only against tuberculosis but also against other respiratory diseases,” Dr. Croda affirmed. “However, these are small studies, and for now, there is no recommendation for using BCG vaccination to prevent other respiratory infections.”

A long-awaited, critical study on the impact of the BCG vaccine on COVID-19, in which Brazilian researchers participated, will be published in the New England Journal of Medicine.
 

New vaccines needed

The BCG vaccine is one of the oldest vaccines, but there are still several crucial unanswered questions about its use.

Previously published studies that examined the protective effect of BCG vaccination only considered low-burden settings and the historical literature before 1950. These studies need updating, but doing so has not been a simple task. To answer their questions, individual-level participant data for a prespecified list of variables, including the characteristics of the exposed participant (contact), the index case, and the environment, were requested from authors of all eligible studies.

Much of the data used in the published research were found through discussions with authors and experts in the field, as well as through data deposited in data storage repositories, conference abstracts, dissertations, and even direct requests to the authors. “The Pan-American Health Organization helped with this data collection and contacting some authors,” said Dr. Croda.

With the new data, the authors confirmed that infant BCG vaccination, although important to young children who are at high risk for tuberculosis, does not prevent adult-type cavitary tuberculosis and is therefore insufficient to impede the tuberculosis epidemic. “Novel vaccines are urgently needed,” they concluded.

“We need to develop novel, more effective vaccines, which, when administered during infancy, would ensure lifelong protection,” Dr. Croda added.

Dr. Croda and Dr. Ballalai reported no relevant financial relationships.

This article was translated from the Medscape Portuguese edition. A version of this article appeared on Medscape.com.

The American Academy of Pediatrics is cautioning physicians and parents to be on the lookout for unnecessary diagnostic testing associated with several common pediatric conditions.

Children seen for these conditions in emergency settings and even in primary care offices could experience avoidable pain, exposure to harmful radiation, and other harms, according to the group.

“The emergency department has the ability to rapidly perform myriad diagnostic tests and receive results quickly,” said Paul Mullan, MD, MPH, chair of the AAP’s Section of Emergency Medicine’s Choosing Wisely task force. “However, this comes with the danger of diagnostic overtesting.”

The five recommendations are as follows:

• Radiographs should not be obtained for children with bronchiolitis, croup, asthma, or first-time wheezing.
• Laboratory tests for screening should not be undertaken in the medical clearance process of children who require inpatient psychiatric admission unless clinically indicated.
• Laboratory testing or a CT scan of the head should not be ordered for a child with an unprovoked, generalized seizure or a simple febrile seizure whose mental status has returned to baseline.
• Abdominal radiographs should not be obtained for suspected constipation.
• Comprehensive viral panel testing should not be undertaken for children who are suspected of having respiratory viral illnesses.

The AAP task force partnered with Choosing Wisely Canada to create the recommendations. The list is the first of its kind to be published jointly by two countries, according to the release.

“We hope this Choosing Wisely list will encourage clinicians to rely on their clinical skills and avoid unnecessary tests,” said Dr. Mullan, who is also a physician at Children’s Hospital of the King’s Daughters and professor of pediatrics at Eastern Virginia Medical School, Norfolk.

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

The American Academy of Pediatrics is cautioning physicians and parents to be on the lookout for unnecessary diagnostic testing associated with several common pediatric conditions.

Children seen for these conditions in emergency settings and even in primary care offices could experience avoidable pain, exposure to harmful radiation, and other harms, according to the group.

“The emergency department has the ability to rapidly perform myriad diagnostic tests and receive results quickly,” said Paul Mullan, MD, MPH, chair of the AAP’s Section of Emergency Medicine’s Choosing Wisely task force. “However, this comes with the danger of diagnostic overtesting.”

The five recommendations are as follows:

• Radiographs should not be obtained for children with bronchiolitis, croup, asthma, or first-time wheezing.
• Laboratory tests for screening should not be undertaken in the medical clearance process of children who require inpatient psychiatric admission unless clinically indicated.
• Laboratory testing or a CT scan of the head should not be ordered for a child with an unprovoked, generalized seizure or a simple febrile seizure whose mental status has returned to baseline.
• Abdominal radiographs should not be obtained for suspected constipation.
• Comprehensive viral panel testing should not be undertaken for children who are suspected of having respiratory viral illnesses.

The AAP task force partnered with Choosing Wisely Canada to create the recommendations. The list is the first of its kind to be published jointly by two countries, according to the release.

“We hope this Choosing Wisely list will encourage clinicians to rely on their clinical skills and avoid unnecessary tests,” said Dr. Mullan, who is also a physician at Children’s Hospital of the King’s Daughters and professor of pediatrics at Eastern Virginia Medical School, Norfolk.

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

The American Academy of Pediatrics is cautioning physicians and parents to be on the lookout for unnecessary diagnostic testing associated with several common pediatric conditions.

Children seen for these conditions in emergency settings and even in primary care offices could experience avoidable pain, exposure to harmful radiation, and other harms, according to the group.

“The emergency department has the ability to rapidly perform myriad diagnostic tests and receive results quickly,” said Paul Mullan, MD, MPH, chair of the AAP’s Section of Emergency Medicine’s Choosing Wisely task force. “However, this comes with the danger of diagnostic overtesting.”

The five recommendations are as follows:

• Radiographs should not be obtained for children with bronchiolitis, croup, asthma, or first-time wheezing.
• Laboratory tests for screening should not be undertaken in the medical clearance process of children who require inpatient psychiatric admission unless clinically indicated.
• Laboratory testing or a CT scan of the head should not be ordered for a child with an unprovoked, generalized seizure or a simple febrile seizure whose mental status has returned to baseline.
• Abdominal radiographs should not be obtained for suspected constipation.
• Comprehensive viral panel testing should not be undertaken for children who are suspected of having respiratory viral illnesses.

The AAP task force partnered with Choosing Wisely Canada to create the recommendations. The list is the first of its kind to be published jointly by two countries, according to the release.

“We hope this Choosing Wisely list will encourage clinicians to rely on their clinical skills and avoid unnecessary tests,” said Dr. Mullan, who is also a physician at Children’s Hospital of the King’s Daughters and professor of pediatrics at Eastern Virginia Medical School, Norfolk.

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

(Reuters) – Eli Lilly’s COVID-19 drug bebtelovimab is not currently authorized for emergency use in the United States, the Food and Drug Administration said, citing it is not expected to neutralize the dominant BQ.1 and BQ.1.1 subvariants of Omicron.

The announcement on Nov. 30 takes away authorization from the last COVID-19 monoclonal antibody treatment, leaving Pfizer’s antiviral drug Paxlovid, Merck’s Lagevrio, and Gilead Sciences’ Veklury as treatments for the disease, besides convalescent plasma for some patients.

AstraZeneca’s monoclonal antibody Evusheld is also authorized for protection against COVID-19 infection in some people.

Eli Lilly and its authorized distributors have paused commercial distribution of the monoclonal antibody until further notice from the agency, while the U.S. government has also paused fulfillment of any pending requests under its scheme to help uninsured and underinsured Americans access the drug.

The drug, which was discovered by Abcellera and commercialized by Eli Lilly, received an authorization from the FDA in February.

BQ.1 and BQ.1.1 have become the dominant strains in the United States after a steady increase in prevalence over the last 2 months, surpassing Omicron’s BA.5 subvariant, which had driven cases earlier in the year.

The subvariants accounted for around 57% of the cases nationally, as per government data last week.

Reuters Health Information © 2022 

(Reuters) – Eli Lilly’s COVID-19 drug bebtelovimab is not currently authorized for emergency use in the United States, the Food and Drug Administration said, citing it is not expected to neutralize the dominant BQ.1 and BQ.1.1 subvariants of Omicron.

The announcement on Nov. 30 takes away authorization from the last COVID-19 monoclonal antibody treatment, leaving Pfizer’s antiviral drug Paxlovid, Merck’s Lagevrio, and Gilead Sciences’ Veklury as treatments for the disease, besides convalescent plasma for some patients.

AstraZeneca’s monoclonal antibody Evusheld is also authorized for protection against COVID-19 infection in some people.

Eli Lilly and its authorized distributors have paused commercial distribution of the monoclonal antibody until further notice from the agency, while the U.S. government has also paused fulfillment of any pending requests under its scheme to help uninsured and underinsured Americans access the drug.

The drug, which was discovered by Abcellera and commercialized by Eli Lilly, received an authorization from the FDA in February.

BQ.1 and BQ.1.1 have become the dominant strains in the United States after a steady increase in prevalence over the last 2 months, surpassing Omicron’s BA.5 subvariant, which had driven cases earlier in the year.

The subvariants accounted for around 57% of the cases nationally, as per government data last week.

Reuters Health Information © 2022 

(Reuters) – Eli Lilly’s COVID-19 drug bebtelovimab is not currently authorized for emergency use in the United States, the Food and Drug Administration said, citing it is not expected to neutralize the dominant BQ.1 and BQ.1.1 subvariants of Omicron.

The announcement on Nov. 30 takes away authorization from the last COVID-19 monoclonal antibody treatment, leaving Pfizer’s antiviral drug Paxlovid, Merck’s Lagevrio, and Gilead Sciences’ Veklury as treatments for the disease, besides convalescent plasma for some patients.

AstraZeneca’s monoclonal antibody Evusheld is also authorized for protection against COVID-19 infection in some people.

Eli Lilly and its authorized distributors have paused commercial distribution of the monoclonal antibody until further notice from the agency, while the U.S. government has also paused fulfillment of any pending requests under its scheme to help uninsured and underinsured Americans access the drug.

The drug, which was discovered by Abcellera and commercialized by Eli Lilly, received an authorization from the FDA in February.

BQ.1 and BQ.1.1 have become the dominant strains in the United States after a steady increase in prevalence over the last 2 months, surpassing Omicron’s BA.5 subvariant, which had driven cases earlier in the year.

The subvariants accounted for around 57% of the cases nationally, as per government data last week.

Reuters Health Information © 2022 

The Diagnosis: Mid-Borderline Multibacillary Leprosy

The biopsies showed a granulomatous dermatitis involving the dermis and subcutaneous adipose tissue (Figure, A). Fite staining also revealed numerous acid-fast bacilli (AFB) throughout the dermis (Figure, B); however, polymerase chain reaction (PCR) for Mycobacterium tuberculosis was negative, and concomitant AFB tissue culture showed no growth after 8 weeks of incubation from the left wrist biopsy (Table). Interestingly, a left inguinal lymph node biopsy performed 6 months prior to presentation that helped to establish the diagnosis of follicular lymphoma also revealed nonnecrotizing granulomas and the presence of rare AFB; this formalin-fixed specimen subsequently tested negative for M tuberculosis and nontuberculous mycobacteria (NTM) by broad-range PCR. Due to a high index of suspicion, another unpreserved skin biopsy of the right knee was sent for NTM testing with PCR. Primers to 16S ribosomal RNA and the beta subunit of RNA polymerase, rpoB, gene detected Mycobacterium leprae DNA, leading to the diagnosis of mid-borderline (or borderline-borderline) multibacillary leprosy. Our patient subsequently reported subtle hypoesthesia of the plaques on the knees. He recalled eating undercooked armadillo meat in the southern United States more than 30 years prior to admission. In addition, he had a history of being incarcerated in the northeastern United States. This case was reported to the National Hansen’s Disease Program, and our patient was started on a 2-year course of daily clarithromycin, daily minocycline, and once-monthly moxifloxacin. His family also was evaluated and did not have any skin lesions concerning for leprosy.

Leprosy is a major global health concern, transmitted via breaks in the skin, respiratory secretions, and contact with armadillos. It continues to be endemic in India, Brazil, and Indonesia.¹ In the United States where leprosy is nonendemic, 159 new cases were detected in 2020; the most notable risk factors in the United States are armadillo exposure and travel history.^2,3 Mycobacterium leprae are intracellular bacilli that preferentially infect macrophages and Schwann cells, resulting in erythematous or hypopigmented skin lesions that often are anesthetic. Mycobacterium leprae has the longest doubling time of all bacteria with unknown in vitro growth requirements and a typical in vivo incubation period of 2 to 10 years.⁴ Therefore, in vitro cultures will yield no growth, as seen in our case. In our patient, Fite stain showed acid-fast organisms in multiple tissue specimens, but AFB cultures demonstrated no growth after 8 weeks of incubation. Although clinicopathologic correlation is most important, PCR analysis can help to assist in the diagnosis of leprosy. Unpreserved tissue should be used when possible, as the fixation process may adversely affect the analytic sensitivity of subsequent PCR-based assays.⁵ In our case, NTM were not detected by PCR in the inguinal lymph node specimen despite demonstrating rare AFB staining. This result likely was multifactorial, including the effect of formalin fixation and paraffin embedding as well as concomitant low biomass.

Leprosy is known as a great imitator, and clinical manifestations (both neurologic and cutaneous) depend on host immune response to the mycobacteria. Although tuberculoid leprosy (associated with T helper type 1 immune response) is distinguished by few asymmetric, well-demarcated, and often hypopigmented plaques, lepromatous leprosy (associated with T helper type 2 response) is characterized by numerous symmetric and poorly defined lesions. Borderline leprosy, as seen in our patient, is the most common type of leprosy and shows features of both tuberculoid and lepromatous leprosy.⁴ It also may be particularly difficult to diagnose.^6,7 Borderline-borderline leprosy involves lesions that mostly are of the lepromatous type and symmetric but also may include raised plaques, as in tuberculoid leprosy.⁴ Plaques in an annular configuration with central clearing, as seen in our patient, are considered suggestive.⁸ Histopathology of borderline-borderline leprosy lesions shows subepidermal clear zones, and granulomas are more diffuse than in tuberculoid leprosy.⁴

Given the noncaseating granulomatous dermatitis seen on histopathology and the relatively higher incidence of sarcoidosis in our region of practice, our initial differential included sarcoidosis and other granulomatous disorders such as granuloma annulare. Interestingly, sarcoidosis has been misdiagnosed as leprosy on multiple occasions in countries where leprosy is endemic.^9,10 Localized cutaneous leishmaniasis typically presents with infiltrated plaques and nodules that may ulcerate; diffuse and disseminated as well as mucocutaneous presentations may occur depending on the species and severity of infection. Parasitized macrophages containing amastigotes may be seen in the dermis highlighted by CD1a immunostaining. Mycosis fungoides presents as papulosquamous patches or plaques, often favoring sunprotected sites; the hypopigmented variant may mimic the central clearing seen in leprosy.

The diagnosis of leprosy can be challenging due to varying clinical presentation; indolent growth of the causative organism; and indeterminate nature of stains, including the Fite stain. Although leprosy is an uncommon diagnosis, this case underscores the need to keep it in the differential of granulomatous dermatoses in the appropriate clinical setting, particularly in patients with risk factors for exposure.⁸

The Diagnosis: Mid-Borderline Multibacillary Leprosy

The biopsies showed a granulomatous dermatitis involving the dermis and subcutaneous adipose tissue (Figure, A). Fite staining also revealed numerous acid-fast bacilli (AFB) throughout the dermis (Figure, B); however, polymerase chain reaction (PCR) for Mycobacterium tuberculosis was negative, and concomitant AFB tissue culture showed no growth after 8 weeks of incubation from the left wrist biopsy (Table). Interestingly, a left inguinal lymph node biopsy performed 6 months prior to presentation that helped to establish the diagnosis of follicular lymphoma also revealed nonnecrotizing granulomas and the presence of rare AFB; this formalin-fixed specimen subsequently tested negative for M tuberculosis and nontuberculous mycobacteria (NTM) by broad-range PCR. Due to a high index of suspicion, another unpreserved skin biopsy of the right knee was sent for NTM testing with PCR. Primers to 16S ribosomal RNA and the beta subunit of RNA polymerase, rpoB, gene detected Mycobacterium leprae DNA, leading to the diagnosis of mid-borderline (or borderline-borderline) multibacillary leprosy. Our patient subsequently reported subtle hypoesthesia of the plaques on the knees. He recalled eating undercooked armadillo meat in the southern United States more than 30 years prior to admission. In addition, he had a history of being incarcerated in the northeastern United States. This case was reported to the National Hansen’s Disease Program, and our patient was started on a 2-year course of daily clarithromycin, daily minocycline, and once-monthly moxifloxacin. His family also was evaluated and did not have any skin lesions concerning for leprosy.

Leprosy is a major global health concern, transmitted via breaks in the skin, respiratory secretions, and contact with armadillos. It continues to be endemic in India, Brazil, and Indonesia.¹ In the United States where leprosy is nonendemic, 159 new cases were detected in 2020; the most notable risk factors in the United States are armadillo exposure and travel history.^2,3 Mycobacterium leprae are intracellular bacilli that preferentially infect macrophages and Schwann cells, resulting in erythematous or hypopigmented skin lesions that often are anesthetic. Mycobacterium leprae has the longest doubling time of all bacteria with unknown in vitro growth requirements and a typical in vivo incubation period of 2 to 10 years.⁴ Therefore, in vitro cultures will yield no growth, as seen in our case. In our patient, Fite stain showed acid-fast organisms in multiple tissue specimens, but AFB cultures demonstrated no growth after 8 weeks of incubation. Although clinicopathologic correlation is most important, PCR analysis can help to assist in the diagnosis of leprosy. Unpreserved tissue should be used when possible, as the fixation process may adversely affect the analytic sensitivity of subsequent PCR-based assays.⁵ In our case, NTM were not detected by PCR in the inguinal lymph node specimen despite demonstrating rare AFB staining. This result likely was multifactorial, including the effect of formalin fixation and paraffin embedding as well as concomitant low biomass.

Leprosy is known as a great imitator, and clinical manifestations (both neurologic and cutaneous) depend on host immune response to the mycobacteria. Although tuberculoid leprosy (associated with T helper type 1 immune response) is distinguished by few asymmetric, well-demarcated, and often hypopigmented plaques, lepromatous leprosy (associated with T helper type 2 response) is characterized by numerous symmetric and poorly defined lesions. Borderline leprosy, as seen in our patient, is the most common type of leprosy and shows features of both tuberculoid and lepromatous leprosy.⁴ It also may be particularly difficult to diagnose.^6,7 Borderline-borderline leprosy involves lesions that mostly are of the lepromatous type and symmetric but also may include raised plaques, as in tuberculoid leprosy.⁴ Plaques in an annular configuration with central clearing, as seen in our patient, are considered suggestive.⁸ Histopathology of borderline-borderline leprosy lesions shows subepidermal clear zones, and granulomas are more diffuse than in tuberculoid leprosy.⁴

Given the noncaseating granulomatous dermatitis seen on histopathology and the relatively higher incidence of sarcoidosis in our region of practice, our initial differential included sarcoidosis and other granulomatous disorders such as granuloma annulare. Interestingly, sarcoidosis has been misdiagnosed as leprosy on multiple occasions in countries where leprosy is endemic.^9,10 Localized cutaneous leishmaniasis typically presents with infiltrated plaques and nodules that may ulcerate; diffuse and disseminated as well as mucocutaneous presentations may occur depending on the species and severity of infection. Parasitized macrophages containing amastigotes may be seen in the dermis highlighted by CD1a immunostaining. Mycosis fungoides presents as papulosquamous patches or plaques, often favoring sunprotected sites; the hypopigmented variant may mimic the central clearing seen in leprosy.

The diagnosis of leprosy can be challenging due to varying clinical presentation; indolent growth of the causative organism; and indeterminate nature of stains, including the Fite stain. Although leprosy is an uncommon diagnosis, this case underscores the need to keep it in the differential of granulomatous dermatoses in the appropriate clinical setting, particularly in patients with risk factors for exposure.⁸

The Diagnosis: Mid-Borderline Multibacillary Leprosy

The biopsies showed a granulomatous dermatitis involving the dermis and subcutaneous adipose tissue (Figure, A). Fite staining also revealed numerous acid-fast bacilli (AFB) throughout the dermis (Figure, B); however, polymerase chain reaction (PCR) for Mycobacterium tuberculosis was negative, and concomitant AFB tissue culture showed no growth after 8 weeks of incubation from the left wrist biopsy (Table). Interestingly, a left inguinal lymph node biopsy performed 6 months prior to presentation that helped to establish the diagnosis of follicular lymphoma also revealed nonnecrotizing granulomas and the presence of rare AFB; this formalin-fixed specimen subsequently tested negative for M tuberculosis and nontuberculous mycobacteria (NTM) by broad-range PCR. Due to a high index of suspicion, another unpreserved skin biopsy of the right knee was sent for NTM testing with PCR. Primers to 16S ribosomal RNA and the beta subunit of RNA polymerase, rpoB, gene detected Mycobacterium leprae DNA, leading to the diagnosis of mid-borderline (or borderline-borderline) multibacillary leprosy. Our patient subsequently reported subtle hypoesthesia of the plaques on the knees. He recalled eating undercooked armadillo meat in the southern United States more than 30 years prior to admission. In addition, he had a history of being incarcerated in the northeastern United States. This case was reported to the National Hansen’s Disease Program, and our patient was started on a 2-year course of daily clarithromycin, daily minocycline, and once-monthly moxifloxacin. His family also was evaluated and did not have any skin lesions concerning for leprosy.

Leprosy is a major global health concern, transmitted via breaks in the skin, respiratory secretions, and contact with armadillos. It continues to be endemic in India, Brazil, and Indonesia.¹ In the United States where leprosy is nonendemic, 159 new cases were detected in 2020; the most notable risk factors in the United States are armadillo exposure and travel history.^2,3 Mycobacterium leprae are intracellular bacilli that preferentially infect macrophages and Schwann cells, resulting in erythematous or hypopigmented skin lesions that often are anesthetic. Mycobacterium leprae has the longest doubling time of all bacteria with unknown in vitro growth requirements and a typical in vivo incubation period of 2 to 10 years.⁴ Therefore, in vitro cultures will yield no growth, as seen in our case. In our patient, Fite stain showed acid-fast organisms in multiple tissue specimens, but AFB cultures demonstrated no growth after 8 weeks of incubation. Although clinicopathologic correlation is most important, PCR analysis can help to assist in the diagnosis of leprosy. Unpreserved tissue should be used when possible, as the fixation process may adversely affect the analytic sensitivity of subsequent PCR-based assays.⁵ In our case, NTM were not detected by PCR in the inguinal lymph node specimen despite demonstrating rare AFB staining. This result likely was multifactorial, including the effect of formalin fixation and paraffin embedding as well as concomitant low biomass.

Leprosy is known as a great imitator, and clinical manifestations (both neurologic and cutaneous) depend on host immune response to the mycobacteria. Although tuberculoid leprosy (associated with T helper type 1 immune response) is distinguished by few asymmetric, well-demarcated, and often hypopigmented plaques, lepromatous leprosy (associated with T helper type 2 response) is characterized by numerous symmetric and poorly defined lesions. Borderline leprosy, as seen in our patient, is the most common type of leprosy and shows features of both tuberculoid and lepromatous leprosy.⁴ It also may be particularly difficult to diagnose.^6,7 Borderline-borderline leprosy involves lesions that mostly are of the lepromatous type and symmetric but also may include raised plaques, as in tuberculoid leprosy.⁴ Plaques in an annular configuration with central clearing, as seen in our patient, are considered suggestive.⁸ Histopathology of borderline-borderline leprosy lesions shows subepidermal clear zones, and granulomas are more diffuse than in tuberculoid leprosy.⁴

Given the noncaseating granulomatous dermatitis seen on histopathology and the relatively higher incidence of sarcoidosis in our region of practice, our initial differential included sarcoidosis and other granulomatous disorders such as granuloma annulare. Interestingly, sarcoidosis has been misdiagnosed as leprosy on multiple occasions in countries where leprosy is endemic.^9,10 Localized cutaneous leishmaniasis typically presents with infiltrated plaques and nodules that may ulcerate; diffuse and disseminated as well as mucocutaneous presentations may occur depending on the species and severity of infection. Parasitized macrophages containing amastigotes may be seen in the dermis highlighted by CD1a immunostaining. Mycosis fungoides presents as papulosquamous patches or plaques, often favoring sunprotected sites; the hypopigmented variant may mimic the central clearing seen in leprosy.

The diagnosis of leprosy can be challenging due to varying clinical presentation; indolent growth of the causative organism; and indeterminate nature of stains, including the Fite stain. Although leprosy is an uncommon diagnosis, this case underscores the need to keep it in the differential of granulomatous dermatoses in the appropriate clinical setting, particularly in patients with risk factors for exposure.⁸

Doctors suspect the worst respiratory syncytial virus (RSV) season in years just ended, and the story of a child who had a serious respiratory infection provides a glimpse of what health care providers saw in the fall of 2022.

RSV cases peaked in mid-November, according to the latest Centers for Disease Control and Prevention data, with RSV-associated hospitalizations in the United States among patients 0-4 years having maxed out five times higher than they were at the same time in 2021. These surges strained providers and left parents scrambling for care. Fortunately, pediatric hospitalizations appear to be subsiding.

In interviews, the parents of the child who had a severe case of RSV reflected on their son’s bout with the illness, and doctors described challenges to dealing with the surge in RSV cases this season. The physicians also offered advice on how recognize and respond to future cases of the virus.
 

Sebastian Witt’s story

“I didn’t even know what RSV was,” said Malte Witt, whose son, Sebastian, 2, was recently hospitalized for RSV in Denver.

Mr. Witt and his wife, Emily Witt, both 32, thought they were dealing with a typical cold until Sebastian’s condition dramatically deteriorated about 36 hours after symptom onset.

“He basically just slumped over and collapsed, coughing uncontrollably,” Mr. Witt said in an interview. “He couldn’t catch his breath.”

The Witts rushed Sebastian to the ED at Children’s Hospital Colorado, expecting to see a doctor immediately. Instead, they spent the night in an overcrowded waiting room alongside many other families in the same situation.

“There was no room for anyone to sit anywhere,” Mr. Witt said. “There were people sitting on the floor. I counted maybe six children hooked up to oxygen when we walked in.”

After waiting approximately 45 minutes, a nurse checked Sebastian’s oxygen saturation. The readings were 79%-83%. This range is significantly below thresholds for supplemental oxygen described by most pediatric guidelines, which range from 90 to 94%.

The nurse connected Sebastian to bottled oxygen in the waiting room, and a recheck 4 hours later showed that his oxygen saturation had improved.

But the improvement didn’t last.

“At roughly hour 10 in the waiting room – it was 4 in the morning – you could tell that Seb was exhausted, really not acting like himself,” Mr. Witt said. “We thought maybe it’s just late at night, he hasn’t really slept. But then Emily noticed that his oxygen tank had run out.”

Mr. Witt told a nurse, and after another check revealed low oxygen saturation, Sebastian was finally admitted.
 

Early RSV surge strains pediatric providers

With RSV-associated hospitalizations peaking at 48 per 100,000 children, Colorado has been among the states hardest hit by the virus. New Mexico – where hospitalizations peaked at 56.4 per 100,000 children – comes in second. Even in states like California, where hospitalization rates have been almost 10-fold lower than New Mexico, pediatric providers have been stretched to their limits.

“Many hospitals are really being overwhelmed with admissions for RSV, both routine RSV – relatively mild hospitalizations with bronchiolitis – as well as kids in the ICU with more severe cases,” said Dean Blumberg, MD, chief of the division of pediatric infectious diseases at UC Davis Health, Sacramento, said in an interview.

Dr. Blumberg believes the severity of the 2022-2023 RSV season is likely COVID related.

“All community-associated respiratory viral infections are out of whack because of the pandemic, and all the masking and social distancing that was occurring,” he said.

This may also explain why older kids are coming down with more severe cases of RSV.

“Some children are getting RSV for the first time as older children,” Dr. Blumberg said, noting that, historically, most children were infected in the first 2 years of life. “There are reports of children 3 or 4 years of age being admitted with their first episode of RSV because of the [COVID] pandemic.”

This year’s RSV season is also notable for arriving early, potentially catching the community off guard, according to Jennifer D. Kusma, MD, a primary care pediatrician at Ann & Robert H. Lurie Children’s Hospital of Chicago.

“People who should have been protected often weren’t protected yet,” Dr. Kusma said in an interview.
 

Treatments new, old, and unproven

On Nov. 17, in the midst of the RSV surge, the American Academy of Pediatrics issued updated guidance for palivizumab, an RSV-targeting monoclonal antibody labeled for children at risk of severe RSV, including those with pre-existing lung or heart conditions, and infants with a history of premature birth (less than or equal to 35 weeks’ gestational age).

“If RSV disease activity persists at high levels in a given region through the fall and winter, the AAP supports providing more than five consecutive doses of palivizumab to eligible children,” the update stated.

Insurance companies appear to be responding in kind, covering additional doses for children in need.

“[Payers] have agreed that, if [palivizumab] needs to be given for an additional month or 2 or 3, then they’re making a commitment that they’ll reimburse hospitals for providing that,” Dr. Blumberg said.

For ineligible patients, such as Sebastian, who was born prematurely at 36 weeks – 1 week shy of the label requirement – treatment relies upon supportive care with oxygen and IV fluids.

At home, parents are left with simpler options.

Dr. Blumberg and Dr. Kusma recommended keeping children hydrated, maintaining humidified air, and using saline nose drops with bulb suction to clear mucus.

In the Witts’ experience, that last step may be easier said than done.

“Every time a nurse would walk into the room, Sebastian would yell: ‘Go away, doctor! I don’t want snot sucker!’” Mr. Witt said.

“If you over snot-suck, that’s really uncomfortable for the kid, and really hard for you,” Ms. Witt said. “And it doesn’t make much of a difference. It’s just very hard to find a middle ground, where you’re helping and keeping them comfortable.”

Some parents are turning to novel strategies, such as nebulized hypertonic saline, currently marketed on Amazon for children with RSV.

Although the AAP offers a weak recommendation for nebulized hypertonic saline in children hospitalized more than 72 hours, they advise against it in the emergency setting, citing inconsistent findings in clinical trials.

To any parents tempted by thousands of positive Amazon reviews, Dr. Blumberg said, “I wouldn’t waste my money on that.”

Dr. Kusma agreed.

“[Nebulized hypertonic saline] can be irritating,” she said. “It’s saltwater, essentially. If a parent is in the position where they’re worried about their child’s breathing to the point that they think they need to use it, I would err on the side of calling your pediatrician and being seen.”
 

Going in, coming home

Dr. Kusma said parents should seek medical attention if a child is breathing faster and working harder to get air. Increased work of breathing is characterized by pulling of the skin at the notch where the throat meets the chest bone (tracheal tugging), and flattening of the belly that makes the ribcage more prominent.

Mr. Witt saw these signs in Sebastian. He knew they were significant, because a friend who is a nurse had previously shown him some examples of children who exhibited these symptoms online.

“That’s how I knew that things were actually really dangerous,” Mr. Witt said. “Had she not shown me those videos a month and a half before this happened, I don’t know that we would have hit the alarm bell as quickly as we did.”

After spending their second night and the following day in a cramped preoperative room converted to manage overflow from the emergency department, Sebastian’s condition improved, and he was discharged. The Witts are relieved to be home, but frustrations from their ordeal remain, especially considering the estimated $5,000 in out-of-pocket costs they expect to pay.

“How is this our health care system?” Ms. Witt asked. “This is unbelievable.”
 

An optimistic outlook

RSV seasons typically demonstrate a clear peak, followed by a decline through the rest of the season, suggesting better times lie ahead; however, this season has been anything but typical.

“I’m hopeful that it will just go away and stay away,” Dr. Kusma said, citing this trend. “But I can’t know for sure.”

To anxious parents, Dr. Blumberg offered an optimistic view of RSV seasons to come.

“There’s hope,” he said. “There are vaccines that are being developed that are very close to FDA approval. So, it’s possible that this time next year, we might have widespread RSV vaccination available for children so that we don’t have to go through this nightmare again.”

Dr. Blumberg and Dr. Kusma disclosed no relevant conflicts of interest.

Doctors suspect the worst respiratory syncytial virus (RSV) season in years just ended, and the story of a child who had a serious respiratory infection provides a glimpse of what health care providers saw in the fall of 2022.

RSV cases peaked in mid-November, according to the latest Centers for Disease Control and Prevention data, with RSV-associated hospitalizations in the United States among patients 0-4 years having maxed out five times higher than they were at the same time in 2021. These surges strained providers and left parents scrambling for care. Fortunately, pediatric hospitalizations appear to be subsiding.

In interviews, the parents of the child who had a severe case of RSV reflected on their son’s bout with the illness, and doctors described challenges to dealing with the surge in RSV cases this season. The physicians also offered advice on how recognize and respond to future cases of the virus.
 

Sebastian Witt’s story

“I didn’t even know what RSV was,” said Malte Witt, whose son, Sebastian, 2, was recently hospitalized for RSV in Denver.

Mr. Witt and his wife, Emily Witt, both 32, thought they were dealing with a typical cold until Sebastian’s condition dramatically deteriorated about 36 hours after symptom onset.

“He basically just slumped over and collapsed, coughing uncontrollably,” Mr. Witt said in an interview. “He couldn’t catch his breath.”

The Witts rushed Sebastian to the ED at Children’s Hospital Colorado, expecting to see a doctor immediately. Instead, they spent the night in an overcrowded waiting room alongside many other families in the same situation.

“There was no room for anyone to sit anywhere,” Mr. Witt said. “There were people sitting on the floor. I counted maybe six children hooked up to oxygen when we walked in.”

After waiting approximately 45 minutes, a nurse checked Sebastian’s oxygen saturation. The readings were 79%-83%. This range is significantly below thresholds for supplemental oxygen described by most pediatric guidelines, which range from 90 to 94%.

The nurse connected Sebastian to bottled oxygen in the waiting room, and a recheck 4 hours later showed that his oxygen saturation had improved.

But the improvement didn’t last.

“At roughly hour 10 in the waiting room – it was 4 in the morning – you could tell that Seb was exhausted, really not acting like himself,” Mr. Witt said. “We thought maybe it’s just late at night, he hasn’t really slept. But then Emily noticed that his oxygen tank had run out.”

Mr. Witt told a nurse, and after another check revealed low oxygen saturation, Sebastian was finally admitted.
 

Early RSV surge strains pediatric providers

With RSV-associated hospitalizations peaking at 48 per 100,000 children, Colorado has been among the states hardest hit by the virus. New Mexico – where hospitalizations peaked at 56.4 per 100,000 children – comes in second. Even in states like California, where hospitalization rates have been almost 10-fold lower than New Mexico, pediatric providers have been stretched to their limits.

“Many hospitals are really being overwhelmed with admissions for RSV, both routine RSV – relatively mild hospitalizations with bronchiolitis – as well as kids in the ICU with more severe cases,” said Dean Blumberg, MD, chief of the division of pediatric infectious diseases at UC Davis Health, Sacramento, said in an interview.

Dr. Blumberg believes the severity of the 2022-2023 RSV season is likely COVID related.

“All community-associated respiratory viral infections are out of whack because of the pandemic, and all the masking and social distancing that was occurring,” he said.

This may also explain why older kids are coming down with more severe cases of RSV.

“Some children are getting RSV for the first time as older children,” Dr. Blumberg said, noting that, historically, most children were infected in the first 2 years of life. “There are reports of children 3 or 4 years of age being admitted with their first episode of RSV because of the [COVID] pandemic.”

This year’s RSV season is also notable for arriving early, potentially catching the community off guard, according to Jennifer D. Kusma, MD, a primary care pediatrician at Ann & Robert H. Lurie Children’s Hospital of Chicago.

“People who should have been protected often weren’t protected yet,” Dr. Kusma said in an interview.
 

Treatments new, old, and unproven

On Nov. 17, in the midst of the RSV surge, the American Academy of Pediatrics issued updated guidance for palivizumab, an RSV-targeting monoclonal antibody labeled for children at risk of severe RSV, including those with pre-existing lung or heart conditions, and infants with a history of premature birth (less than or equal to 35 weeks’ gestational age).

“If RSV disease activity persists at high levels in a given region through the fall and winter, the AAP supports providing more than five consecutive doses of palivizumab to eligible children,” the update stated.

Insurance companies appear to be responding in kind, covering additional doses for children in need.

“[Payers] have agreed that, if [palivizumab] needs to be given for an additional month or 2 or 3, then they’re making a commitment that they’ll reimburse hospitals for providing that,” Dr. Blumberg said.

For ineligible patients, such as Sebastian, who was born prematurely at 36 weeks – 1 week shy of the label requirement – treatment relies upon supportive care with oxygen and IV fluids.

At home, parents are left with simpler options.

Dr. Blumberg and Dr. Kusma recommended keeping children hydrated, maintaining humidified air, and using saline nose drops with bulb suction to clear mucus.

In the Witts’ experience, that last step may be easier said than done.

“Every time a nurse would walk into the room, Sebastian would yell: ‘Go away, doctor! I don’t want snot sucker!’” Mr. Witt said.

“If you over snot-suck, that’s really uncomfortable for the kid, and really hard for you,” Ms. Witt said. “And it doesn’t make much of a difference. It’s just very hard to find a middle ground, where you’re helping and keeping them comfortable.”

Some parents are turning to novel strategies, such as nebulized hypertonic saline, currently marketed on Amazon for children with RSV.

Although the AAP offers a weak recommendation for nebulized hypertonic saline in children hospitalized more than 72 hours, they advise against it in the emergency setting, citing inconsistent findings in clinical trials.

To any parents tempted by thousands of positive Amazon reviews, Dr. Blumberg said, “I wouldn’t waste my money on that.”

Dr. Kusma agreed.

“[Nebulized hypertonic saline] can be irritating,” she said. “It’s saltwater, essentially. If a parent is in the position where they’re worried about their child’s breathing to the point that they think they need to use it, I would err on the side of calling your pediatrician and being seen.”
 

Going in, coming home

Dr. Kusma said parents should seek medical attention if a child is breathing faster and working harder to get air. Increased work of breathing is characterized by pulling of the skin at the notch where the throat meets the chest bone (tracheal tugging), and flattening of the belly that makes the ribcage more prominent.

Mr. Witt saw these signs in Sebastian. He knew they were significant, because a friend who is a nurse had previously shown him some examples of children who exhibited these symptoms online.

“That’s how I knew that things were actually really dangerous,” Mr. Witt said. “Had she not shown me those videos a month and a half before this happened, I don’t know that we would have hit the alarm bell as quickly as we did.”

After spending their second night and the following day in a cramped preoperative room converted to manage overflow from the emergency department, Sebastian’s condition improved, and he was discharged. The Witts are relieved to be home, but frustrations from their ordeal remain, especially considering the estimated $5,000 in out-of-pocket costs they expect to pay.

“How is this our health care system?” Ms. Witt asked. “This is unbelievable.”
 

An optimistic outlook

RSV seasons typically demonstrate a clear peak, followed by a decline through the rest of the season, suggesting better times lie ahead; however, this season has been anything but typical.

“I’m hopeful that it will just go away and stay away,” Dr. Kusma said, citing this trend. “But I can’t know for sure.”

To anxious parents, Dr. Blumberg offered an optimistic view of RSV seasons to come.

“There’s hope,” he said. “There are vaccines that are being developed that are very close to FDA approval. So, it’s possible that this time next year, we might have widespread RSV vaccination available for children so that we don’t have to go through this nightmare again.”

Dr. Blumberg and Dr. Kusma disclosed no relevant conflicts of interest.

Doctors suspect the worst respiratory syncytial virus (RSV) season in years just ended, and the story of a child who had a serious respiratory infection provides a glimpse of what health care providers saw in the fall of 2022.

RSV cases peaked in mid-November, according to the latest Centers for Disease Control and Prevention data, with RSV-associated hospitalizations in the United States among patients 0-4 years having maxed out five times higher than they were at the same time in 2021. These surges strained providers and left parents scrambling for care. Fortunately, pediatric hospitalizations appear to be subsiding.

In interviews, the parents of the child who had a severe case of RSV reflected on their son’s bout with the illness, and doctors described challenges to dealing with the surge in RSV cases this season. The physicians also offered advice on how recognize and respond to future cases of the virus.
 

Sebastian Witt’s story

“I didn’t even know what RSV was,” said Malte Witt, whose son, Sebastian, 2, was recently hospitalized for RSV in Denver.

Mr. Witt and his wife, Emily Witt, both 32, thought they were dealing with a typical cold until Sebastian’s condition dramatically deteriorated about 36 hours after symptom onset.

“He basically just slumped over and collapsed, coughing uncontrollably,” Mr. Witt said in an interview. “He couldn’t catch his breath.”

The Witts rushed Sebastian to the ED at Children’s Hospital Colorado, expecting to see a doctor immediately. Instead, they spent the night in an overcrowded waiting room alongside many other families in the same situation.

“There was no room for anyone to sit anywhere,” Mr. Witt said. “There were people sitting on the floor. I counted maybe six children hooked up to oxygen when we walked in.”

After waiting approximately 45 minutes, a nurse checked Sebastian’s oxygen saturation. The readings were 79%-83%. This range is significantly below thresholds for supplemental oxygen described by most pediatric guidelines, which range from 90 to 94%.

The nurse connected Sebastian to bottled oxygen in the waiting room, and a recheck 4 hours later showed that his oxygen saturation had improved.

But the improvement didn’t last.

“At roughly hour 10 in the waiting room – it was 4 in the morning – you could tell that Seb was exhausted, really not acting like himself,” Mr. Witt said. “We thought maybe it’s just late at night, he hasn’t really slept. But then Emily noticed that his oxygen tank had run out.”

Mr. Witt told a nurse, and after another check revealed low oxygen saturation, Sebastian was finally admitted.
 

Early RSV surge strains pediatric providers

With RSV-associated hospitalizations peaking at 48 per 100,000 children, Colorado has been among the states hardest hit by the virus. New Mexico – where hospitalizations peaked at 56.4 per 100,000 children – comes in second. Even in states like California, where hospitalization rates have been almost 10-fold lower than New Mexico, pediatric providers have been stretched to their limits.

“Many hospitals are really being overwhelmed with admissions for RSV, both routine RSV – relatively mild hospitalizations with bronchiolitis – as well as kids in the ICU with more severe cases,” said Dean Blumberg, MD, chief of the division of pediatric infectious diseases at UC Davis Health, Sacramento, said in an interview.

Dr. Blumberg believes the severity of the 2022-2023 RSV season is likely COVID related.

“All community-associated respiratory viral infections are out of whack because of the pandemic, and all the masking and social distancing that was occurring,” he said.

This may also explain why older kids are coming down with more severe cases of RSV.

“Some children are getting RSV for the first time as older children,” Dr. Blumberg said, noting that, historically, most children were infected in the first 2 years of life. “There are reports of children 3 or 4 years of age being admitted with their first episode of RSV because of the [COVID] pandemic.”

This year’s RSV season is also notable for arriving early, potentially catching the community off guard, according to Jennifer D. Kusma, MD, a primary care pediatrician at Ann & Robert H. Lurie Children’s Hospital of Chicago.

“People who should have been protected often weren’t protected yet,” Dr. Kusma said in an interview.
 

Treatments new, old, and unproven

On Nov. 17, in the midst of the RSV surge, the American Academy of Pediatrics issued updated guidance for palivizumab, an RSV-targeting monoclonal antibody labeled for children at risk of severe RSV, including those with pre-existing lung or heart conditions, and infants with a history of premature birth (less than or equal to 35 weeks’ gestational age).

“If RSV disease activity persists at high levels in a given region through the fall and winter, the AAP supports providing more than five consecutive doses of palivizumab to eligible children,” the update stated.

Insurance companies appear to be responding in kind, covering additional doses for children in need.

“[Payers] have agreed that, if [palivizumab] needs to be given for an additional month or 2 or 3, then they’re making a commitment that they’ll reimburse hospitals for providing that,” Dr. Blumberg said.

For ineligible patients, such as Sebastian, who was born prematurely at 36 weeks – 1 week shy of the label requirement – treatment relies upon supportive care with oxygen and IV fluids.

At home, parents are left with simpler options.

Dr. Blumberg and Dr. Kusma recommended keeping children hydrated, maintaining humidified air, and using saline nose drops with bulb suction to clear mucus.

In the Witts’ experience, that last step may be easier said than done.

“Every time a nurse would walk into the room, Sebastian would yell: ‘Go away, doctor! I don’t want snot sucker!’” Mr. Witt said.

“If you over snot-suck, that’s really uncomfortable for the kid, and really hard for you,” Ms. Witt said. “And it doesn’t make much of a difference. It’s just very hard to find a middle ground, where you’re helping and keeping them comfortable.”

Some parents are turning to novel strategies, such as nebulized hypertonic saline, currently marketed on Amazon for children with RSV.

Although the AAP offers a weak recommendation for nebulized hypertonic saline in children hospitalized more than 72 hours, they advise against it in the emergency setting, citing inconsistent findings in clinical trials.

To any parents tempted by thousands of positive Amazon reviews, Dr. Blumberg said, “I wouldn’t waste my money on that.”

Dr. Kusma agreed.

“[Nebulized hypertonic saline] can be irritating,” she said. “It’s saltwater, essentially. If a parent is in the position where they’re worried about their child’s breathing to the point that they think they need to use it, I would err on the side of calling your pediatrician and being seen.”
 

Going in, coming home

Dr. Kusma said parents should seek medical attention if a child is breathing faster and working harder to get air. Increased work of breathing is characterized by pulling of the skin at the notch where the throat meets the chest bone (tracheal tugging), and flattening of the belly that makes the ribcage more prominent.

Mr. Witt saw these signs in Sebastian. He knew they were significant, because a friend who is a nurse had previously shown him some examples of children who exhibited these symptoms online.

“That’s how I knew that things were actually really dangerous,” Mr. Witt said. “Had she not shown me those videos a month and a half before this happened, I don’t know that we would have hit the alarm bell as quickly as we did.”

After spending their second night and the following day in a cramped preoperative room converted to manage overflow from the emergency department, Sebastian’s condition improved, and he was discharged. The Witts are relieved to be home, but frustrations from their ordeal remain, especially considering the estimated $5,000 in out-of-pocket costs they expect to pay.

“How is this our health care system?” Ms. Witt asked. “This is unbelievable.”
 

An optimistic outlook

RSV seasons typically demonstrate a clear peak, followed by a decline through the rest of the season, suggesting better times lie ahead; however, this season has been anything but typical.

“I’m hopeful that it will just go away and stay away,” Dr. Kusma said, citing this trend. “But I can’t know for sure.”

To anxious parents, Dr. Blumberg offered an optimistic view of RSV seasons to come.

“There’s hope,” he said. “There are vaccines that are being developed that are very close to FDA approval. So, it’s possible that this time next year, we might have widespread RSV vaccination available for children so that we don’t have to go through this nightmare again.”

Dr. Blumberg and Dr. Kusma disclosed no relevant conflicts of interest.

There has been no ebb in the flurry of respiratory illnesses infecting America’s youngest children. More pediatric wards across the country are announcing crises as beds reach capacity, the pediatric death toll jumped significantly in the past week, and sometimes children are being infected with more than one virus at a time.

In Oregon, for example, the governor announced an official state of emergency to help hospitals deal with the surge of respiratory viruses. Doernbecher Children’s Hospital in Portland, which houses half of all pediatric ICU beds statewide, moved to “crisis mode” and said every pediatric ICU bed was full, Oregon Public Broadcasting reported.

Last month, pediatricians nationwide called for a similar emergency declaration from the federal government to help them respond to the wave of illnesses, which include influenza and respiratory syncytial virus (RSV).

“What’s concerning to us are not only the number of infections, but the severity of these infections, leading to a high number of emergency room visits and hospitalizations,” pediatric infectious disease expert Oscar G. Gómez-Duarte, MD, PhD, said in a news release.

Five more pediatric deaths due to the flu were logged by the CDC in the past week, bringing the total for pediatric flu deaths this season to 12. Nearly 21 per 100,000 children ages 4 and under are being hospitalized for the flu, which is double the rate for children ages 5-17. Last year at this time, fewer than 1 child under age 4 per 100,000 were being hospitalized for the flu.

RSV rates are also stunningly high.

“If we look at CDC data, the RSV hospitalization rate is 10 times higher than usual for this point in the season,” American Medical Association Vice President Andrea Garcia, JD, said in this week’s AMA podcast. “And 171 out of every 100,000 infants younger than 6 months were hospitalized with RSV for the week ending Nov. 12. That is more than double the RSV hospitalization rate for newborns last year and seven times the rate in 2018, which is the last complete season we saw before the pandemic.”

Dr. Gómez-Duarte said hospitals are admitting children with respiratory illnesses who had otherwise been healthy, and sometimes they are even seeing patients with more than one illness.

“Yes, some children are getting what we call coinfections, where they become infected with more than one virus at a time. In some instances, a child becomes initially infected with flu, begins to recover, and subsequently comes down with rhinovirus (a common cold virus), RSV, or any other respiratory virus,” he said. “These coinfections tend to be more severe than when the child just has one infection.”

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

There has been no ebb in the flurry of respiratory illnesses infecting America’s youngest children. More pediatric wards across the country are announcing crises as beds reach capacity, the pediatric death toll jumped significantly in the past week, and sometimes children are being infected with more than one virus at a time.

In Oregon, for example, the governor announced an official state of emergency to help hospitals deal with the surge of respiratory viruses. Doernbecher Children’s Hospital in Portland, which houses half of all pediatric ICU beds statewide, moved to “crisis mode” and said every pediatric ICU bed was full, Oregon Public Broadcasting reported.

Last month, pediatricians nationwide called for a similar emergency declaration from the federal government to help them respond to the wave of illnesses, which include influenza and respiratory syncytial virus (RSV).

“What’s concerning to us are not only the number of infections, but the severity of these infections, leading to a high number of emergency room visits and hospitalizations,” pediatric infectious disease expert Oscar G. Gómez-Duarte, MD, PhD, said in a news release.

Five more pediatric deaths due to the flu were logged by the CDC in the past week, bringing the total for pediatric flu deaths this season to 12. Nearly 21 per 100,000 children ages 4 and under are being hospitalized for the flu, which is double the rate for children ages 5-17. Last year at this time, fewer than 1 child under age 4 per 100,000 were being hospitalized for the flu.

RSV rates are also stunningly high.

“If we look at CDC data, the RSV hospitalization rate is 10 times higher than usual for this point in the season,” American Medical Association Vice President Andrea Garcia, JD, said in this week’s AMA podcast. “And 171 out of every 100,000 infants younger than 6 months were hospitalized with RSV for the week ending Nov. 12. That is more than double the RSV hospitalization rate for newborns last year and seven times the rate in 2018, which is the last complete season we saw before the pandemic.”

Dr. Gómez-Duarte said hospitals are admitting children with respiratory illnesses who had otherwise been healthy, and sometimes they are even seeing patients with more than one illness.

“Yes, some children are getting what we call coinfections, where they become infected with more than one virus at a time. In some instances, a child becomes initially infected with flu, begins to recover, and subsequently comes down with rhinovirus (a common cold virus), RSV, or any other respiratory virus,” he said. “These coinfections tend to be more severe than when the child just has one infection.”

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

There has been no ebb in the flurry of respiratory illnesses infecting America’s youngest children. More pediatric wards across the country are announcing crises as beds reach capacity, the pediatric death toll jumped significantly in the past week, and sometimes children are being infected with more than one virus at a time.

In Oregon, for example, the governor announced an official state of emergency to help hospitals deal with the surge of respiratory viruses. Doernbecher Children’s Hospital in Portland, which houses half of all pediatric ICU beds statewide, moved to “crisis mode” and said every pediatric ICU bed was full, Oregon Public Broadcasting reported.

Last month, pediatricians nationwide called for a similar emergency declaration from the federal government to help them respond to the wave of illnesses, which include influenza and respiratory syncytial virus (RSV).

“What’s concerning to us are not only the number of infections, but the severity of these infections, leading to a high number of emergency room visits and hospitalizations,” pediatric infectious disease expert Oscar G. Gómez-Duarte, MD, PhD, said in a news release.

Five more pediatric deaths due to the flu were logged by the CDC in the past week, bringing the total for pediatric flu deaths this season to 12. Nearly 21 per 100,000 children ages 4 and under are being hospitalized for the flu, which is double the rate for children ages 5-17. Last year at this time, fewer than 1 child under age 4 per 100,000 were being hospitalized for the flu.

RSV rates are also stunningly high.

“If we look at CDC data, the RSV hospitalization rate is 10 times higher than usual for this point in the season,” American Medical Association Vice President Andrea Garcia, JD, said in this week’s AMA podcast. “And 171 out of every 100,000 infants younger than 6 months were hospitalized with RSV for the week ending Nov. 12. That is more than double the RSV hospitalization rate for newborns last year and seven times the rate in 2018, which is the last complete season we saw before the pandemic.”

Dr. Gómez-Duarte said hospitals are admitting children with respiratory illnesses who had otherwise been healthy, and sometimes they are even seeing patients with more than one illness.

“Yes, some children are getting what we call coinfections, where they become infected with more than one virus at a time. In some instances, a child becomes initially infected with flu, begins to recover, and subsequently comes down with rhinovirus (a common cold virus), RSV, or any other respiratory virus,” he said. “These coinfections tend to be more severe than when the child just has one infection.”

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

An early and influential paper on long COVID that appeared in The Lancet has been flagged with an expression of concern while the journal investigates “data errors” brought to light by a reader.

An editorial that accompanied the paper when it was published in January of last year described it as “the first large cohort study with 6-months’ follow-up” of people hospitalized with COVID-19. The article has received plenty of attention since then.

Titled “6-month consequences of COVID-19 in patients discharged from hospital: a cohort study,” the paper has been cited nearly 1,600 times, according to Clarivate’s Web of Science. Altmetric finds references to it in multiple documents from the World Health Organization.

According to the expression of concern, dated November 24, a reader found inconsistencies between the data in the article and a later paper describing the same cohort of patients after a year of follow-up. That discovery sparked an investigation that is still ongoing:

• On Jan 8, 2021, The Lancet published an Article, 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study, by Chaolin Huang and colleagues. 1 On Aug 28, 2021, The Lancet published an Article, 1-year outcomes in hospital survivors with COVID-19: a longitudinal cohort study, by Lixue Huang and colleagues. 2 We received an inquiry from a researcher on data inconsistencies between these two Articles, and we sought an explanation from the corresponding author of the two papers. On Nov 7, 2022, Lancet editors were informed that inconsistencies between the 6-month and the 1-year data were due to “some variables in the dataset used for the 6-month paper were mistakenly disrupted in order”. In view of the extent of these data errors, we now issue an Expression of Concern about the 6-month paper 1 while we investigate further, including further statistical and clinical review of the corrected data. We will update this notice as soon as we have further information.

The corresponding author of both papers, Bin Cao of China’s National Center for Respiratory Medicine and the China-Japan Friendship Hospital in Beijing, has not responded to our request for comment.

A profile of Cao published in Lancet Infectious Diseases last March described him as “a leading researcher in pneumonia and influenza” who “has been instrumental in increasing knowledge about COVID-19.” In addition to the follow-up study of hospitalized COVID patients:

• Cao’s seminal papers during the COVID-19 pandemic include the first report of the clinical characteristics of COVID-19 patients in Wuhan, the description of the risk factors for mortality for adult inpatients, and the results of trials testing the use of antiviral drugs, including lopinavir-ritonavir, to treat COVID-19 in China.

We reached out to The Lancet’s press office and Richard Horton, the journal’s editor-in-chief, and received this statement:

• The Lancet Group treats all communications between editors and authors or readers as confidential. Investigations are continuing, and the Expression of Concern will be updated as soon as we have further information to share. More information about our policies is available here: 

This year, The Lancet overtook the New England Journal of Medicine as the medical journal with the highest impact factor, in large part due to the papers it published about COVID-19.

We’ve counted retractions for three of those papers, most notably a paper about the use of the drug hydroxychloroquine that claimed to use medical data from a company called Surgisphere. As Retraction Watch readers may remember, the article was retracted after sleuths questioned if the data were real, and the company would not produce it for review.

This article first appeared on Retraction Watch.

An early and influential paper on long COVID that appeared in The Lancet has been flagged with an expression of concern while the journal investigates “data errors” brought to light by a reader.

An editorial that accompanied the paper when it was published in January of last year described it as “the first large cohort study with 6-months’ follow-up” of people hospitalized with COVID-19. The article has received plenty of attention since then.

Titled “6-month consequences of COVID-19 in patients discharged from hospital: a cohort study,” the paper has been cited nearly 1,600 times, according to Clarivate’s Web of Science. Altmetric finds references to it in multiple documents from the World Health Organization.

According to the expression of concern, dated November 24, a reader found inconsistencies between the data in the article and a later paper describing the same cohort of patients after a year of follow-up. That discovery sparked an investigation that is still ongoing:

• On Jan 8, 2021, The Lancet published an Article, 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study, by Chaolin Huang and colleagues. 1 On Aug 28, 2021, The Lancet published an Article, 1-year outcomes in hospital survivors with COVID-19: a longitudinal cohort study, by Lixue Huang and colleagues. 2 We received an inquiry from a researcher on data inconsistencies between these two Articles, and we sought an explanation from the corresponding author of the two papers. On Nov 7, 2022, Lancet editors were informed that inconsistencies between the 6-month and the 1-year data were due to “some variables in the dataset used for the 6-month paper were mistakenly disrupted in order”. In view of the extent of these data errors, we now issue an Expression of Concern about the 6-month paper 1 while we investigate further, including further statistical and clinical review of the corrected data. We will update this notice as soon as we have further information.

The corresponding author of both papers, Bin Cao of China’s National Center for Respiratory Medicine and the China-Japan Friendship Hospital in Beijing, has not responded to our request for comment.

A profile of Cao published in Lancet Infectious Diseases last March described him as “a leading researcher in pneumonia and influenza” who “has been instrumental in increasing knowledge about COVID-19.” In addition to the follow-up study of hospitalized COVID patients:

• Cao’s seminal papers during the COVID-19 pandemic include the first report of the clinical characteristics of COVID-19 patients in Wuhan, the description of the risk factors for mortality for adult inpatients, and the results of trials testing the use of antiviral drugs, including lopinavir-ritonavir, to treat COVID-19 in China.

We reached out to The Lancet’s press office and Richard Horton, the journal’s editor-in-chief, and received this statement:

• The Lancet Group treats all communications between editors and authors or readers as confidential. Investigations are continuing, and the Expression of Concern will be updated as soon as we have further information to share. More information about our policies is available here: 

This year, The Lancet overtook the New England Journal of Medicine as the medical journal with the highest impact factor, in large part due to the papers it published about COVID-19.

We’ve counted retractions for three of those papers, most notably a paper about the use of the drug hydroxychloroquine that claimed to use medical data from a company called Surgisphere. As Retraction Watch readers may remember, the article was retracted after sleuths questioned if the data were real, and the company would not produce it for review.

This article first appeared on Retraction Watch.

An early and influential paper on long COVID that appeared in The Lancet has been flagged with an expression of concern while the journal investigates “data errors” brought to light by a reader.

An editorial that accompanied the paper when it was published in January of last year described it as “the first large cohort study with 6-months’ follow-up” of people hospitalized with COVID-19. The article has received plenty of attention since then.

Titled “6-month consequences of COVID-19 in patients discharged from hospital: a cohort study,” the paper has been cited nearly 1,600 times, according to Clarivate’s Web of Science. Altmetric finds references to it in multiple documents from the World Health Organization.

According to the expression of concern, dated November 24, a reader found inconsistencies between the data in the article and a later paper describing the same cohort of patients after a year of follow-up. That discovery sparked an investigation that is still ongoing:

• On Jan 8, 2021, The Lancet published an Article, 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study, by Chaolin Huang and colleagues. 1 On Aug 28, 2021, The Lancet published an Article, 1-year outcomes in hospital survivors with COVID-19: a longitudinal cohort study, by Lixue Huang and colleagues. 2 We received an inquiry from a researcher on data inconsistencies between these two Articles, and we sought an explanation from the corresponding author of the two papers. On Nov 7, 2022, Lancet editors were informed that inconsistencies between the 6-month and the 1-year data were due to “some variables in the dataset used for the 6-month paper were mistakenly disrupted in order”. In view of the extent of these data errors, we now issue an Expression of Concern about the 6-month paper 1 while we investigate further, including further statistical and clinical review of the corrected data. We will update this notice as soon as we have further information.

The corresponding author of both papers, Bin Cao of China’s National Center for Respiratory Medicine and the China-Japan Friendship Hospital in Beijing, has not responded to our request for comment.

A profile of Cao published in Lancet Infectious Diseases last March described him as “a leading researcher in pneumonia and influenza” who “has been instrumental in increasing knowledge about COVID-19.” In addition to the follow-up study of hospitalized COVID patients:

• Cao’s seminal papers during the COVID-19 pandemic include the first report of the clinical characteristics of COVID-19 patients in Wuhan, the description of the risk factors for mortality for adult inpatients, and the results of trials testing the use of antiviral drugs, including lopinavir-ritonavir, to treat COVID-19 in China.

We reached out to The Lancet’s press office and Richard Horton, the journal’s editor-in-chief, and received this statement:

• The Lancet Group treats all communications between editors and authors or readers as confidential. Investigations are continuing, and the Expression of Concern will be updated as soon as we have further information to share. More information about our policies is available here: 

This year, The Lancet overtook the New England Journal of Medicine as the medical journal with the highest impact factor, in large part due to the papers it published about COVID-19.

We’ve counted retractions for three of those papers, most notably a paper about the use of the drug hydroxychloroquine that claimed to use medical data from a company called Surgisphere. As Retraction Watch readers may remember, the article was retracted after sleuths questioned if the data were real, and the company would not produce it for review.

This article first appeared on Retraction Watch.