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Impaired cognition associated with COVID-19 appears to have a biological versus psychological basis, early research suggests. Investigators found abnormalities in cerebrospinal fluid (CSF) and other risk factors, including diabetes and hypertension, present in individuals with mild COVID-19 experiencing persistent cognitive problems, often referred to as “brain fog.”

“We’re seeing changes to the [CSF] in the brain of most people who report cognitive changes,” said Joanna Hellmuth, MD, assistant professor of neurology, Memory and Aging Center, University of California, San Francisco. “We’re just in the beginning stages, but I hope this study will provide some legitimacy to this being a true neurologic condition.”

The study was published online Jan. 18, 2022, in Annals of Clinical and Translational Neurology.
 

No guidance

There is currently no guidance on how to identify patients with COVID-related cognitive changes, said Dr. Hellmuth. “The term ‘brain fog’ is not based in science or medicine, but that’s the most common term we use to describe this.”

The analysis included adults with confirmed SARS-CoV-2 infection not requiring hospitalization who were enrolled in the Long-term Impact of Infection with Novel Coronavirus study.

Participants underwent a structured interview that covered COVID-19 illness, past medical history, preexisting cognitive risk factors, medications, and cognitive symptoms following onset of COVID-19. They also completed an in-person battery of cognitive tests.

The analysis included 22 participants with at least one new cognitive symptom who had cognitive post-acute sequelae of SARS-CoV-2 infection (PASC). Ten cognitive controls reported no new cognitive symptoms after acute infection.

Participants were a median age of 41 years, had a median of 16 years of education, and were assessed a median of 10.1 months from their first COVID-19 symptom. There were no group differences in terms of age, gender, years of education, or distribution of race/ethnicity (all P > .05).

Among those with cognitive PASC, 43% reported cognitive symptoms starting 1 or more months after the first COVID symptom. About 29% reported cognitive changes started 2 or more months after their first COVID symptom.

“The immune system could be altered in some way after the infection, and perhaps that’s what’s contributing to these delayed onset cognitive changes,” said Dr. Hellmuth.

Compared with controls, participants with cognitive PASC had more preexisting cognitive risk factors (a median of 2.5 vs. 0; P = .03). These included hypertension and diabetes, which increase the risk of stroke, mild cognitive impairment, vascular dementia, traumatic brain injury, (TBI), learning disabilities, anxiety, depression, stimulant use, and ADHD, which may make the brain more vulnerable to executive functioning problems.

Dr. Hellmuth noted that the study wasn’t powered to determine whether any individual risk factor was associated with risk of cognitive changes.

As there are no published neuropsychological testing criteria for cognitive PASC, the researchers applied the equivalent criteria for HIV-associated neurocognitive disorder (HAND), a similar, virally associated cognitive disorder. Only 59% of those with cognitive PASC met equivalent HAND criteria for objective cognitive impairment versus 70% of cognitive controls. This, the investigators noted, highlights “the challenges and incongruities of using subjective, versus objective cognitive assessments for diagnosis.”
 

Is self-report enough?

While there is currently “nothing objective doctors can hang their hats on to say ‘you do’ or ‘you don’t’ have cognitive changes related to COVID,” using the HAND criteria is “not particularly helpful,” said Dr. Hellmuth. “Comparing an individual to a population-based norm in this case is really nuanced, and we shouldn’t rely on this solely to determine whether they do, or don’t, have cognitive changes.”

Perhaps self-reports in this case are “enough” said Dr. Hellmuth. “People know their brains better than anyone else, better than any doctor will.”

A total of 13 in the cognitive PASC group and 4 in the control group consented to a lumbar puncture. Cognitive PASC participants were older than controls (median of 47 vs. 28 years; P = .03) with no other between-group differences.

Overall, 77% of participants with cognitive PASC had a CSF abnormality, compared with 0% of cognitive controls (P = .01). CSF abnormalities included elevated protein levels with no other explainable cause in 2 of the 13 subjects with PASC, which Dr. Hellmuth said is typically a marker of inflammation.

Researchers also noted abnormal oligoclonal banding, a collection of antibodies, in the blood or brain fluid. These were identified in 69% of participants with cognitive PASC, compared with 0% of cognitive controls (P = .03).

“When we find this pattern in both blood and brain, it suggests a systemic inflammatory disorder,” although “we have no idea what these antibodies are targeting,” said Dr. Hellmuth.

The study represents “the very beginning stages” of PASC becoming a medical diagnosis “where doctors know what to call it, how to treat it, and how to do blood and cerebrospinal fluid tests to diagnose it,” said Dr. Hellmuth.

She hopes PASC will receive medical legitimacy just as TBI has. In years past, a player was hit on the head or had their “bell rung,” simply returned to the field. “Now that we understand the science, we call it a mild TBI or concussion, and we have a very different medical approach to it.”

A limitation of the study was the small sample size, which may hinder the results’ validity. In addition, the study demographics may not reflect the broader population of those impacted by PASC.
 

‘A first substantial step’

Commenting on the research, William Schaffner, MD, professor, division of infectious diseases, Vanderbilt University Medical Center, Nashville, Tenn., said the new results represent “a first substantial step on the road to trying to find out what’s going on” with COVID patients dealing with cognitive issues.

Dr. Schaffner noted that elevated protein levels, identified in some study subjects, “is usually a consequence of previous inflammation” and is “a very interesting” finding. “In people who are otherwise normal, if you do a lumbar puncture, you don’t find elevated proteins.”

However, he noted the “diversity of results” from CSF examinations. “A single pattern does not leap out.”

What the researchers are observing “is not just a phenomenon of the mind or just something psychological,” said Dr. Schaffner. “Something physical is going on here.”

The study was funded by grants from the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke. Dr. Hellmuth received grant support from the National Institutes of Health/NIMH supporting this work and personal fees for medical-legal consultation outside of the submitted work. Dr. Schaffner has disclosed not relevant financial relationships.

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

Impaired cognition associated with COVID-19 appears to have a biological versus psychological basis, early research suggests. Investigators found abnormalities in cerebrospinal fluid (CSF) and other risk factors, including diabetes and hypertension, present in individuals with mild COVID-19 experiencing persistent cognitive problems, often referred to as “brain fog.”

“We’re seeing changes to the [CSF] in the brain of most people who report cognitive changes,” said Joanna Hellmuth, MD, assistant professor of neurology, Memory and Aging Center, University of California, San Francisco. “We’re just in the beginning stages, but I hope this study will provide some legitimacy to this being a true neurologic condition.”

The study was published online Jan. 18, 2022, in Annals of Clinical and Translational Neurology.
 

No guidance

There is currently no guidance on how to identify patients with COVID-related cognitive changes, said Dr. Hellmuth. “The term ‘brain fog’ is not based in science or medicine, but that’s the most common term we use to describe this.”

The analysis included adults with confirmed SARS-CoV-2 infection not requiring hospitalization who were enrolled in the Long-term Impact of Infection with Novel Coronavirus study.

Participants underwent a structured interview that covered COVID-19 illness, past medical history, preexisting cognitive risk factors, medications, and cognitive symptoms following onset of COVID-19. They also completed an in-person battery of cognitive tests.

The analysis included 22 participants with at least one new cognitive symptom who had cognitive post-acute sequelae of SARS-CoV-2 infection (PASC). Ten cognitive controls reported no new cognitive symptoms after acute infection.

Participants were a median age of 41 years, had a median of 16 years of education, and were assessed a median of 10.1 months from their first COVID-19 symptom. There were no group differences in terms of age, gender, years of education, or distribution of race/ethnicity (all P > .05).

Among those with cognitive PASC, 43% reported cognitive symptoms starting 1 or more months after the first COVID symptom. About 29% reported cognitive changes started 2 or more months after their first COVID symptom.

“The immune system could be altered in some way after the infection, and perhaps that’s what’s contributing to these delayed onset cognitive changes,” said Dr. Hellmuth.

Compared with controls, participants with cognitive PASC had more preexisting cognitive risk factors (a median of 2.5 vs. 0; P = .03). These included hypertension and diabetes, which increase the risk of stroke, mild cognitive impairment, vascular dementia, traumatic brain injury, (TBI), learning disabilities, anxiety, depression, stimulant use, and ADHD, which may make the brain more vulnerable to executive functioning problems.

Dr. Hellmuth noted that the study wasn’t powered to determine whether any individual risk factor was associated with risk of cognitive changes.

As there are no published neuropsychological testing criteria for cognitive PASC, the researchers applied the equivalent criteria for HIV-associated neurocognitive disorder (HAND), a similar, virally associated cognitive disorder. Only 59% of those with cognitive PASC met equivalent HAND criteria for objective cognitive impairment versus 70% of cognitive controls. This, the investigators noted, highlights “the challenges and incongruities of using subjective, versus objective cognitive assessments for diagnosis.”
 

Is self-report enough?

While there is currently “nothing objective doctors can hang their hats on to say ‘you do’ or ‘you don’t’ have cognitive changes related to COVID,” using the HAND criteria is “not particularly helpful,” said Dr. Hellmuth. “Comparing an individual to a population-based norm in this case is really nuanced, and we shouldn’t rely on this solely to determine whether they do, or don’t, have cognitive changes.”

Perhaps self-reports in this case are “enough” said Dr. Hellmuth. “People know their brains better than anyone else, better than any doctor will.”

A total of 13 in the cognitive PASC group and 4 in the control group consented to a lumbar puncture. Cognitive PASC participants were older than controls (median of 47 vs. 28 years; P = .03) with no other between-group differences.

Overall, 77% of participants with cognitive PASC had a CSF abnormality, compared with 0% of cognitive controls (P = .01). CSF abnormalities included elevated protein levels with no other explainable cause in 2 of the 13 subjects with PASC, which Dr. Hellmuth said is typically a marker of inflammation.

Researchers also noted abnormal oligoclonal banding, a collection of antibodies, in the blood or brain fluid. These were identified in 69% of participants with cognitive PASC, compared with 0% of cognitive controls (P = .03).

“When we find this pattern in both blood and brain, it suggests a systemic inflammatory disorder,” although “we have no idea what these antibodies are targeting,” said Dr. Hellmuth.

The study represents “the very beginning stages” of PASC becoming a medical diagnosis “where doctors know what to call it, how to treat it, and how to do blood and cerebrospinal fluid tests to diagnose it,” said Dr. Hellmuth.

She hopes PASC will receive medical legitimacy just as TBI has. In years past, a player was hit on the head or had their “bell rung,” simply returned to the field. “Now that we understand the science, we call it a mild TBI or concussion, and we have a very different medical approach to it.”

A limitation of the study was the small sample size, which may hinder the results’ validity. In addition, the study demographics may not reflect the broader population of those impacted by PASC.
 

‘A first substantial step’

Commenting on the research, William Schaffner, MD, professor, division of infectious diseases, Vanderbilt University Medical Center, Nashville, Tenn., said the new results represent “a first substantial step on the road to trying to find out what’s going on” with COVID patients dealing with cognitive issues.

Dr. Schaffner noted that elevated protein levels, identified in some study subjects, “is usually a consequence of previous inflammation” and is “a very interesting” finding. “In people who are otherwise normal, if you do a lumbar puncture, you don’t find elevated proteins.”

However, he noted the “diversity of results” from CSF examinations. “A single pattern does not leap out.”

What the researchers are observing “is not just a phenomenon of the mind or just something psychological,” said Dr. Schaffner. “Something physical is going on here.”

The study was funded by grants from the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke. Dr. Hellmuth received grant support from the National Institutes of Health/NIMH supporting this work and personal fees for medical-legal consultation outside of the submitted work. Dr. Schaffner has disclosed not relevant financial relationships.

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

Impaired cognition associated with COVID-19 appears to have a biological versus psychological basis, early research suggests. Investigators found abnormalities in cerebrospinal fluid (CSF) and other risk factors, including diabetes and hypertension, present in individuals with mild COVID-19 experiencing persistent cognitive problems, often referred to as “brain fog.”

“We’re seeing changes to the [CSF] in the brain of most people who report cognitive changes,” said Joanna Hellmuth, MD, assistant professor of neurology, Memory and Aging Center, University of California, San Francisco. “We’re just in the beginning stages, but I hope this study will provide some legitimacy to this being a true neurologic condition.”

The study was published online Jan. 18, 2022, in Annals of Clinical and Translational Neurology.
 

No guidance

There is currently no guidance on how to identify patients with COVID-related cognitive changes, said Dr. Hellmuth. “The term ‘brain fog’ is not based in science or medicine, but that’s the most common term we use to describe this.”

The analysis included adults with confirmed SARS-CoV-2 infection not requiring hospitalization who were enrolled in the Long-term Impact of Infection with Novel Coronavirus study.

Participants underwent a structured interview that covered COVID-19 illness, past medical history, preexisting cognitive risk factors, medications, and cognitive symptoms following onset of COVID-19. They also completed an in-person battery of cognitive tests.

The analysis included 22 participants with at least one new cognitive symptom who had cognitive post-acute sequelae of SARS-CoV-2 infection (PASC). Ten cognitive controls reported no new cognitive symptoms after acute infection.

Participants were a median age of 41 years, had a median of 16 years of education, and were assessed a median of 10.1 months from their first COVID-19 symptom. There were no group differences in terms of age, gender, years of education, or distribution of race/ethnicity (all P > .05).

Among those with cognitive PASC, 43% reported cognitive symptoms starting 1 or more months after the first COVID symptom. About 29% reported cognitive changes started 2 or more months after their first COVID symptom.

“The immune system could be altered in some way after the infection, and perhaps that’s what’s contributing to these delayed onset cognitive changes,” said Dr. Hellmuth.

Compared with controls, participants with cognitive PASC had more preexisting cognitive risk factors (a median of 2.5 vs. 0; P = .03). These included hypertension and diabetes, which increase the risk of stroke, mild cognitive impairment, vascular dementia, traumatic brain injury, (TBI), learning disabilities, anxiety, depression, stimulant use, and ADHD, which may make the brain more vulnerable to executive functioning problems.

Dr. Hellmuth noted that the study wasn’t powered to determine whether any individual risk factor was associated with risk of cognitive changes.

As there are no published neuropsychological testing criteria for cognitive PASC, the researchers applied the equivalent criteria for HIV-associated neurocognitive disorder (HAND), a similar, virally associated cognitive disorder. Only 59% of those with cognitive PASC met equivalent HAND criteria for objective cognitive impairment versus 70% of cognitive controls. This, the investigators noted, highlights “the challenges and incongruities of using subjective, versus objective cognitive assessments for diagnosis.”
 

Is self-report enough?

While there is currently “nothing objective doctors can hang their hats on to say ‘you do’ or ‘you don’t’ have cognitive changes related to COVID,” using the HAND criteria is “not particularly helpful,” said Dr. Hellmuth. “Comparing an individual to a population-based norm in this case is really nuanced, and we shouldn’t rely on this solely to determine whether they do, or don’t, have cognitive changes.”

Perhaps self-reports in this case are “enough” said Dr. Hellmuth. “People know their brains better than anyone else, better than any doctor will.”

A total of 13 in the cognitive PASC group and 4 in the control group consented to a lumbar puncture. Cognitive PASC participants were older than controls (median of 47 vs. 28 years; P = .03) with no other between-group differences.

Overall, 77% of participants with cognitive PASC had a CSF abnormality, compared with 0% of cognitive controls (P = .01). CSF abnormalities included elevated protein levels with no other explainable cause in 2 of the 13 subjects with PASC, which Dr. Hellmuth said is typically a marker of inflammation.

Researchers also noted abnormal oligoclonal banding, a collection of antibodies, in the blood or brain fluid. These were identified in 69% of participants with cognitive PASC, compared with 0% of cognitive controls (P = .03).

“When we find this pattern in both blood and brain, it suggests a systemic inflammatory disorder,” although “we have no idea what these antibodies are targeting,” said Dr. Hellmuth.

The study represents “the very beginning stages” of PASC becoming a medical diagnosis “where doctors know what to call it, how to treat it, and how to do blood and cerebrospinal fluid tests to diagnose it,” said Dr. Hellmuth.

She hopes PASC will receive medical legitimacy just as TBI has. In years past, a player was hit on the head or had their “bell rung,” simply returned to the field. “Now that we understand the science, we call it a mild TBI or concussion, and we have a very different medical approach to it.”

A limitation of the study was the small sample size, which may hinder the results’ validity. In addition, the study demographics may not reflect the broader population of those impacted by PASC.
 

‘A first substantial step’

Commenting on the research, William Schaffner, MD, professor, division of infectious diseases, Vanderbilt University Medical Center, Nashville, Tenn., said the new results represent “a first substantial step on the road to trying to find out what’s going on” with COVID patients dealing with cognitive issues.

Dr. Schaffner noted that elevated protein levels, identified in some study subjects, “is usually a consequence of previous inflammation” and is “a very interesting” finding. “In people who are otherwise normal, if you do a lumbar puncture, you don’t find elevated proteins.”

However, he noted the “diversity of results” from CSF examinations. “A single pattern does not leap out.”

What the researchers are observing “is not just a phenomenon of the mind or just something psychological,” said Dr. Schaffner. “Something physical is going on here.”

The study was funded by grants from the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke. Dr. Hellmuth received grant support from the National Institutes of Health/NIMH supporting this work and personal fees for medical-legal consultation outside of the submitted work. Dr. Schaffner has disclosed not relevant financial relationships.

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

Two new studies from different parts of the world have identified an increase in the incidence of type 1 diabetes in children since the COVID-19 pandemic began, but the reasons still aren’t clear.

The findings from the two studies, in Germany and the United States, align closely, endocrinologist Jane J. Kim, MD, professor of pediatrics and principal investigator of the U.S. study, told this news organization. “I think that the general conclusion based on their data and our data is that there appears to be an increased rate of new type 1 diabetes diagnoses in children since the onset of the pandemic.”

Dr. Kim noted that because her group’s data pertain to just a single center, she is “heartened to see that the [German team’s] general conclusions are the same as ours.” Moreover, she pointed out that other studies examining this question came from Europe early in the pandemic, whereas “now both they [the German group] and we have had the opportunity to look at what’s happening over a longer period of time.”

But the reason for the association remains unclear. Some answers may be forthcoming from a database designed in mid-2020 specifically to examine the relationship between COVID-19 and new-onset diabetes. Called CoviDiab, the registry aims “to establish the extent and characteristics of new-onset, COVID-19–related diabetes and to investigate its pathogenesis, management, and outcomes,” according to the website.

The first new study, a multicenter German diabetes registry study, was published online Jan. 17 in Diabetes Care by Clemens Kamrath, MD, of Justus Liebig University, Giessen, Germany, and colleagues.

The other, from Rady Children’s Hospital of San Diego, was published online Jan. 24 in JAMA Pediatrics by Bethany L. Gottesman, MD, and colleagues, all with the University of California, San Diego.
 

Mechanisms likely to differ for type 1 versus type 2 diabetes

Neither the German nor the U.S. investigators were able to directly correlate current or prior SARS-CoV-2 infection in children with the subsequent development of type 1 diabetes.

Earlier this month, a study from the U.S. Centers for Disease Control and Prevention did examine that issue, but it also included youth with type 2 diabetes and did not separate out the two groups.

Dr. Kim said her institution has also seen an increase in type 2 diabetes among youth since the COVID-19 pandemic began but did not include that in their current article.

“When we started looking at our data, diabetes and COVID-19 in adults had been relatively well established. To see an increase in type 2 [diabetes] was not so surprising to our group. But we had the sense we were seeing more patients with type 1, and when we looked at our hospital that was very much the case. I think that was a surprise to people,” said Dr. Kim.

Although a direct effect of SARS-CoV-2 on pancreatic beta cells has been proposed, in both the German and San Diego datasets the diagnosis of type 1 diabetes was confirmed with autoantibodies that are typically present years prior to the onset of clinical symptoms.

The German group suggests possible other explanations for the link, including the lack of immune system exposure to other common pediatric infections during pandemic-necessitated social distancing – the so-called hygiene hypothesis – as well as the possible role of psychological stress, which several studies have linked to type 1 diabetes.

But as of now, Dr. Kim said, “Nobody really knows.” 
 

Is the effect direct or indirect?

Using data from the multicenter German Diabetes Prospective Follow-up Registry, Dr. Kamrath and colleagues compared the incidence of type 1 diabetes in children and adolescents from Jan. 1, 2020 through June 30, 2021 with the incidence in 2011-2019.

During the pandemic period, a total of 5,162 youth were newly diagnosed with type 1 diabetes at 236 German centers. That incidence, 24.4 per 100,000 patient-years, was significantly higher than the 21.2 per 100,000 patient-years expected based on the prior decade, with an incidence rate ratio of 1.15 (P < .001). The increase was similar in both males and females.

There was a difference by age, however, as the phenomenon appeared to be limited to the preadolescent age groups. The incidence rate ratios (IRRs) for ages below 6 years and 6-11 years were 1.23 and 1.18 (both P < .001), respectively, compared to a nonsignificant IRR of 1.06 (P = .13) in those aged 12-17 years.

Compared with the expected monthly incidence, the observed incidence was significantly higher in June 2020 (IRR, 1.43; P = .003), July 2020 (IRR, 1.48; P < 0.001), March 2021 (IRR, 1.29; P = .028), and June 2021 (IRR, 1.39; P = .01).

Among the 3,851 patients for whom data on type 1 diabetes-associated autoantibodies were available, the adjusted rates of autoantibody negativity did not differ from 2018-2019 during the entire pandemic period or during the year 2020 or the first half of 2021.  

“Therefore, the increase in the incidence of type 1 diabetes in children appears to be due to immune-mediated type 1 diabetes. However, because autoimmunity and progressive beta-cell destruction typically begin long before the clinical diagnosis of type 1 diabetes, we were surprised to see the incidence of type 1 diabetes followed the peak incidence of COVID-19 and also the pandemic containment measures by only approximately 3 months,” Dr. Kamrath and colleagues write.

Taken together, they say, the data suggest that “the impact on type 1 diabetes incidence is not due to infection with SARS-CoV-2 but rather a consequence of environmental changes resulting from the pandemic itself or pandemic containment measures.”
 

Similar findings at a U.S. children’s hospital

In the cross-sectional study in San Diego, Dr. Gottesman and colleagues looked at the electronic medical records (EMRs) at Rady Children’s Hospital for patients aged younger than 19 years with at least one positive type 1 diabetes antibody titer.

During March 19, 2020 to March 18, 2021, a total of 187 children were admitted for new-onset type 1 diabetes, compared with just 119 the previous year, a 57% increase.

From July 2020 through February 2021, the number of new type 1 diabetes diagnoses significantly exceeded the number expected based on a quarterly moving average of each of the preceding 5 years.

Only four of the 187 patients (2.1%) diagnosed during the pandemic period had a COVID-19 infection at the time of presentation. Antibody testing to assess prior infection wasn’t feasible, and now that children are receiving the vaccine – and therefore most will have antibodies – “we’ve lost our window of opportunity to look at that question,” Dr. Kim noted.   

As has been previously shown, there was an increase in the percentage of patients presenting with diabetic ketoacidosis during the pandemic compared with the prior 5 years (49.7% vs. 40.7% requiring insulin infusion). However, there was no difference in mean age at presentation, body mass index, A1c, or percentage requiring admission to intensive care.

Because these data only go through March 2021, Dr. Kim noted, “We need to see what’s happening with these different variants. We’ll have a chance to look in a month or two to see the effects of Omicron on the rates of diabetes in the hospital.”
 

Will CoviDiab answer the question?

Data from CoviDiab will include diabetes type in adults and children, registry coprincipal investigator Francesco Rubino, MD, of King’s College London, told this news organization.

“We aimed at having as many as possible cases of new-onset diabetes for which we can have also a minimum set of clinical data including type of diabetes and A1c. By looking at this information we can infer whether a role of COVID-19 in triggering diabetes is clinically plausible – or not – and what type of diabetes is most frequently associated with COVID-19 as this also speaks about mechanisms of action.”

Dr. Rubino said that the CoviDiab team is approaching the data with the assumption that, at least in adults diagnosed with type 2 diabetes, the explanation might be that the person already had undiagnosed diabetes or that the hyperglycemia may be stress-induced and temporary.

“We’re looking at this question with a skeptical eye ... Is it just an association, or does the virus have a role in inducing diabetes from scratch, or can the virus advance pathophysiology in a way that it ends up in full-blown diabetes in predisposed individuals?”

While no single study will prove that SARS-CoV-2 causes diabetes, “combining observations from various studies and approaches we may get a higher degree of certainty,” Dr. Rubino said, noting that the CoviDiab team plans to publish data from the first 800 cases “soon.”

Dr. Kim has reported no relevant financial relationships. Dr. Rubino has reported receiving grants from Ethicon and Medtronic, personal fees from GI Dynamic, Keyron, Novo Nordisk, Ethicon, and Medtronic.

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

Two new studies from different parts of the world have identified an increase in the incidence of type 1 diabetes in children since the COVID-19 pandemic began, but the reasons still aren’t clear.

The findings from the two studies, in Germany and the United States, align closely, endocrinologist Jane J. Kim, MD, professor of pediatrics and principal investigator of the U.S. study, told this news organization. “I think that the general conclusion based on their data and our data is that there appears to be an increased rate of new type 1 diabetes diagnoses in children since the onset of the pandemic.”

Dr. Kim noted that because her group’s data pertain to just a single center, she is “heartened to see that the [German team’s] general conclusions are the same as ours.” Moreover, she pointed out that other studies examining this question came from Europe early in the pandemic, whereas “now both they [the German group] and we have had the opportunity to look at what’s happening over a longer period of time.”

But the reason for the association remains unclear. Some answers may be forthcoming from a database designed in mid-2020 specifically to examine the relationship between COVID-19 and new-onset diabetes. Called CoviDiab, the registry aims “to establish the extent and characteristics of new-onset, COVID-19–related diabetes and to investigate its pathogenesis, management, and outcomes,” according to the website.

The first new study, a multicenter German diabetes registry study, was published online Jan. 17 in Diabetes Care by Clemens Kamrath, MD, of Justus Liebig University, Giessen, Germany, and colleagues.

The other, from Rady Children’s Hospital of San Diego, was published online Jan. 24 in JAMA Pediatrics by Bethany L. Gottesman, MD, and colleagues, all with the University of California, San Diego.
 

Mechanisms likely to differ for type 1 versus type 2 diabetes

Neither the German nor the U.S. investigators were able to directly correlate current or prior SARS-CoV-2 infection in children with the subsequent development of type 1 diabetes.

Earlier this month, a study from the U.S. Centers for Disease Control and Prevention did examine that issue, but it also included youth with type 2 diabetes and did not separate out the two groups.

Dr. Kim said her institution has also seen an increase in type 2 diabetes among youth since the COVID-19 pandemic began but did not include that in their current article.

“When we started looking at our data, diabetes and COVID-19 in adults had been relatively well established. To see an increase in type 2 [diabetes] was not so surprising to our group. But we had the sense we were seeing more patients with type 1, and when we looked at our hospital that was very much the case. I think that was a surprise to people,” said Dr. Kim.

Although a direct effect of SARS-CoV-2 on pancreatic beta cells has been proposed, in both the German and San Diego datasets the diagnosis of type 1 diabetes was confirmed with autoantibodies that are typically present years prior to the onset of clinical symptoms.

The German group suggests possible other explanations for the link, including the lack of immune system exposure to other common pediatric infections during pandemic-necessitated social distancing – the so-called hygiene hypothesis – as well as the possible role of psychological stress, which several studies have linked to type 1 diabetes.

But as of now, Dr. Kim said, “Nobody really knows.” 
 

Is the effect direct or indirect?

Using data from the multicenter German Diabetes Prospective Follow-up Registry, Dr. Kamrath and colleagues compared the incidence of type 1 diabetes in children and adolescents from Jan. 1, 2020 through June 30, 2021 with the incidence in 2011-2019.

During the pandemic period, a total of 5,162 youth were newly diagnosed with type 1 diabetes at 236 German centers. That incidence, 24.4 per 100,000 patient-years, was significantly higher than the 21.2 per 100,000 patient-years expected based on the prior decade, with an incidence rate ratio of 1.15 (P < .001). The increase was similar in both males and females.

There was a difference by age, however, as the phenomenon appeared to be limited to the preadolescent age groups. The incidence rate ratios (IRRs) for ages below 6 years and 6-11 years were 1.23 and 1.18 (both P < .001), respectively, compared to a nonsignificant IRR of 1.06 (P = .13) in those aged 12-17 years.

Compared with the expected monthly incidence, the observed incidence was significantly higher in June 2020 (IRR, 1.43; P = .003), July 2020 (IRR, 1.48; P < 0.001), March 2021 (IRR, 1.29; P = .028), and June 2021 (IRR, 1.39; P = .01).

Among the 3,851 patients for whom data on type 1 diabetes-associated autoantibodies were available, the adjusted rates of autoantibody negativity did not differ from 2018-2019 during the entire pandemic period or during the year 2020 or the first half of 2021.  

“Therefore, the increase in the incidence of type 1 diabetes in children appears to be due to immune-mediated type 1 diabetes. However, because autoimmunity and progressive beta-cell destruction typically begin long before the clinical diagnosis of type 1 diabetes, we were surprised to see the incidence of type 1 diabetes followed the peak incidence of COVID-19 and also the pandemic containment measures by only approximately 3 months,” Dr. Kamrath and colleagues write.

Taken together, they say, the data suggest that “the impact on type 1 diabetes incidence is not due to infection with SARS-CoV-2 but rather a consequence of environmental changes resulting from the pandemic itself or pandemic containment measures.”
 

Similar findings at a U.S. children’s hospital

In the cross-sectional study in San Diego, Dr. Gottesman and colleagues looked at the electronic medical records (EMRs) at Rady Children’s Hospital for patients aged younger than 19 years with at least one positive type 1 diabetes antibody titer.

During March 19, 2020 to March 18, 2021, a total of 187 children were admitted for new-onset type 1 diabetes, compared with just 119 the previous year, a 57% increase.

From July 2020 through February 2021, the number of new type 1 diabetes diagnoses significantly exceeded the number expected based on a quarterly moving average of each of the preceding 5 years.

Only four of the 187 patients (2.1%) diagnosed during the pandemic period had a COVID-19 infection at the time of presentation. Antibody testing to assess prior infection wasn’t feasible, and now that children are receiving the vaccine – and therefore most will have antibodies – “we’ve lost our window of opportunity to look at that question,” Dr. Kim noted.   

As has been previously shown, there was an increase in the percentage of patients presenting with diabetic ketoacidosis during the pandemic compared with the prior 5 years (49.7% vs. 40.7% requiring insulin infusion). However, there was no difference in mean age at presentation, body mass index, A1c, or percentage requiring admission to intensive care.

Because these data only go through March 2021, Dr. Kim noted, “We need to see what’s happening with these different variants. We’ll have a chance to look in a month or two to see the effects of Omicron on the rates of diabetes in the hospital.”
 

Will CoviDiab answer the question?

Data from CoviDiab will include diabetes type in adults and children, registry coprincipal investigator Francesco Rubino, MD, of King’s College London, told this news organization.

“We aimed at having as many as possible cases of new-onset diabetes for which we can have also a minimum set of clinical data including type of diabetes and A1c. By looking at this information we can infer whether a role of COVID-19 in triggering diabetes is clinically plausible – or not – and what type of diabetes is most frequently associated with COVID-19 as this also speaks about mechanisms of action.”

Dr. Rubino said that the CoviDiab team is approaching the data with the assumption that, at least in adults diagnosed with type 2 diabetes, the explanation might be that the person already had undiagnosed diabetes or that the hyperglycemia may be stress-induced and temporary.

“We’re looking at this question with a skeptical eye ... Is it just an association, or does the virus have a role in inducing diabetes from scratch, or can the virus advance pathophysiology in a way that it ends up in full-blown diabetes in predisposed individuals?”

While no single study will prove that SARS-CoV-2 causes diabetes, “combining observations from various studies and approaches we may get a higher degree of certainty,” Dr. Rubino said, noting that the CoviDiab team plans to publish data from the first 800 cases “soon.”

Dr. Kim has reported no relevant financial relationships. Dr. Rubino has reported receiving grants from Ethicon and Medtronic, personal fees from GI Dynamic, Keyron, Novo Nordisk, Ethicon, and Medtronic.

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

Two new studies from different parts of the world have identified an increase in the incidence of type 1 diabetes in children since the COVID-19 pandemic began, but the reasons still aren’t clear.

The findings from the two studies, in Germany and the United States, align closely, endocrinologist Jane J. Kim, MD, professor of pediatrics and principal investigator of the U.S. study, told this news organization. “I think that the general conclusion based on their data and our data is that there appears to be an increased rate of new type 1 diabetes diagnoses in children since the onset of the pandemic.”

Dr. Kim noted that because her group’s data pertain to just a single center, she is “heartened to see that the [German team’s] general conclusions are the same as ours.” Moreover, she pointed out that other studies examining this question came from Europe early in the pandemic, whereas “now both they [the German group] and we have had the opportunity to look at what’s happening over a longer period of time.”

But the reason for the association remains unclear. Some answers may be forthcoming from a database designed in mid-2020 specifically to examine the relationship between COVID-19 and new-onset diabetes. Called CoviDiab, the registry aims “to establish the extent and characteristics of new-onset, COVID-19–related diabetes and to investigate its pathogenesis, management, and outcomes,” according to the website.

The first new study, a multicenter German diabetes registry study, was published online Jan. 17 in Diabetes Care by Clemens Kamrath, MD, of Justus Liebig University, Giessen, Germany, and colleagues.

The other, from Rady Children’s Hospital of San Diego, was published online Jan. 24 in JAMA Pediatrics by Bethany L. Gottesman, MD, and colleagues, all with the University of California, San Diego.
 

Mechanisms likely to differ for type 1 versus type 2 diabetes

Neither the German nor the U.S. investigators were able to directly correlate current or prior SARS-CoV-2 infection in children with the subsequent development of type 1 diabetes.

Earlier this month, a study from the U.S. Centers for Disease Control and Prevention did examine that issue, but it also included youth with type 2 diabetes and did not separate out the two groups.

Dr. Kim said her institution has also seen an increase in type 2 diabetes among youth since the COVID-19 pandemic began but did not include that in their current article.

“When we started looking at our data, diabetes and COVID-19 in adults had been relatively well established. To see an increase in type 2 [diabetes] was not so surprising to our group. But we had the sense we were seeing more patients with type 1, and when we looked at our hospital that was very much the case. I think that was a surprise to people,” said Dr. Kim.

Although a direct effect of SARS-CoV-2 on pancreatic beta cells has been proposed, in both the German and San Diego datasets the diagnosis of type 1 diabetes was confirmed with autoantibodies that are typically present years prior to the onset of clinical symptoms.

The German group suggests possible other explanations for the link, including the lack of immune system exposure to other common pediatric infections during pandemic-necessitated social distancing – the so-called hygiene hypothesis – as well as the possible role of psychological stress, which several studies have linked to type 1 diabetes.

But as of now, Dr. Kim said, “Nobody really knows.” 
 

Is the effect direct or indirect?

Using data from the multicenter German Diabetes Prospective Follow-up Registry, Dr. Kamrath and colleagues compared the incidence of type 1 diabetes in children and adolescents from Jan. 1, 2020 through June 30, 2021 with the incidence in 2011-2019.

During the pandemic period, a total of 5,162 youth were newly diagnosed with type 1 diabetes at 236 German centers. That incidence, 24.4 per 100,000 patient-years, was significantly higher than the 21.2 per 100,000 patient-years expected based on the prior decade, with an incidence rate ratio of 1.15 (P < .001). The increase was similar in both males and females.

There was a difference by age, however, as the phenomenon appeared to be limited to the preadolescent age groups. The incidence rate ratios (IRRs) for ages below 6 years and 6-11 years were 1.23 and 1.18 (both P < .001), respectively, compared to a nonsignificant IRR of 1.06 (P = .13) in those aged 12-17 years.

Compared with the expected monthly incidence, the observed incidence was significantly higher in June 2020 (IRR, 1.43; P = .003), July 2020 (IRR, 1.48; P < 0.001), March 2021 (IRR, 1.29; P = .028), and June 2021 (IRR, 1.39; P = .01).

Among the 3,851 patients for whom data on type 1 diabetes-associated autoantibodies were available, the adjusted rates of autoantibody negativity did not differ from 2018-2019 during the entire pandemic period or during the year 2020 or the first half of 2021.  

“Therefore, the increase in the incidence of type 1 diabetes in children appears to be due to immune-mediated type 1 diabetes. However, because autoimmunity and progressive beta-cell destruction typically begin long before the clinical diagnosis of type 1 diabetes, we were surprised to see the incidence of type 1 diabetes followed the peak incidence of COVID-19 and also the pandemic containment measures by only approximately 3 months,” Dr. Kamrath and colleagues write.

Taken together, they say, the data suggest that “the impact on type 1 diabetes incidence is not due to infection with SARS-CoV-2 but rather a consequence of environmental changes resulting from the pandemic itself or pandemic containment measures.”
 

Similar findings at a U.S. children’s hospital

In the cross-sectional study in San Diego, Dr. Gottesman and colleagues looked at the electronic medical records (EMRs) at Rady Children’s Hospital for patients aged younger than 19 years with at least one positive type 1 diabetes antibody titer.

During March 19, 2020 to March 18, 2021, a total of 187 children were admitted for new-onset type 1 diabetes, compared with just 119 the previous year, a 57% increase.

From July 2020 through February 2021, the number of new type 1 diabetes diagnoses significantly exceeded the number expected based on a quarterly moving average of each of the preceding 5 years.

Only four of the 187 patients (2.1%) diagnosed during the pandemic period had a COVID-19 infection at the time of presentation. Antibody testing to assess prior infection wasn’t feasible, and now that children are receiving the vaccine – and therefore most will have antibodies – “we’ve lost our window of opportunity to look at that question,” Dr. Kim noted.   

As has been previously shown, there was an increase in the percentage of patients presenting with diabetic ketoacidosis during the pandemic compared with the prior 5 years (49.7% vs. 40.7% requiring insulin infusion). However, there was no difference in mean age at presentation, body mass index, A1c, or percentage requiring admission to intensive care.

Because these data only go through March 2021, Dr. Kim noted, “We need to see what’s happening with these different variants. We’ll have a chance to look in a month or two to see the effects of Omicron on the rates of diabetes in the hospital.”
 

Will CoviDiab answer the question?

Data from CoviDiab will include diabetes type in adults and children, registry coprincipal investigator Francesco Rubino, MD, of King’s College London, told this news organization.

“We aimed at having as many as possible cases of new-onset diabetes for which we can have also a minimum set of clinical data including type of diabetes and A1c. By looking at this information we can infer whether a role of COVID-19 in triggering diabetes is clinically plausible – or not – and what type of diabetes is most frequently associated with COVID-19 as this also speaks about mechanisms of action.”

Dr. Rubino said that the CoviDiab team is approaching the data with the assumption that, at least in adults diagnosed with type 2 diabetes, the explanation might be that the person already had undiagnosed diabetes or that the hyperglycemia may be stress-induced and temporary.

“We’re looking at this question with a skeptical eye ... Is it just an association, or does the virus have a role in inducing diabetes from scratch, or can the virus advance pathophysiology in a way that it ends up in full-blown diabetes in predisposed individuals?”

While no single study will prove that SARS-CoV-2 causes diabetes, “combining observations from various studies and approaches we may get a higher degree of certainty,” Dr. Rubino said, noting that the CoviDiab team plans to publish data from the first 800 cases “soon.”

Dr. Kim has reported no relevant financial relationships. Dr. Rubino has reported receiving grants from Ethicon and Medtronic, personal fees from GI Dynamic, Keyron, Novo Nordisk, Ethicon, and Medtronic.

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

Two close colleagues at New York’s Memorial Sloan Kettering Cancer Center, world leaders in hematopoietic stem cell transplantation (HSCT) who were both promoted days after COVID-19 locked down the city in 2020, were too busy battling the pandemic’s impact on patients in the summer of 2021 to notice their latest shared career milestone.

On July 29, 2021, Sergio Giralt, MD, deputy division head of the division of hematologic malignancies and Miguel-Angel Perales, MD, chief of the adult bone marrow transplant service at MSKCC, published their 100th peer-reviewed paper as coauthors. Listing hundreds of such articles on a CV is standard for top-tier physicians, but the pair had gone one better: 100 publications written together in 10 years.

Their centenary article hit scientific newsstands almost exactly a decade after their first joint paper, which appeared in September 2011, not long after they met.

Born in Cuba, Dr. Giralt grew up in Venezuela. From the age of 14, he knew that medicine was his path, and in 1984 he earned a medical degree from the Universidad Central de Venezuela, Caracas. Next came a research position at Harvard Medical School, a residency at the Good Samaritan Hospital, Cincinnati, and a fellowship at the University of Texas MD Anderson Cancer Center, Houston. Dr. Giralt arrived at MSKCC in 2010 as the new chief of the adult bone marrow transplant service. There he was introduced to a new colleague, Dr. Perales. They soon learned that in addition to expertise in hematology, they had second language in common: Spanish.

Dr. Giralt said: “We both have a Spanish background and in a certain sense, there was an affinity there. ... We both have shared experiences.”

Dr. Perales was brought up in Belgium, a European nation with three official languages: French, Dutch, and German. He speaks five tongues in all and learned Spanish from his father, who came from Spain.

Courtesy MSKCC

Fluency in Spanish enables both physicians to take care of the many New Yorkers who are more comfortable in that language – especially when navigating cancer treatment. However, both Dr. Giralt and Dr. Perales said that a second language is more than a professional tool. They described the enjoyable change of persona that happens when they switch to Spanish.

“People who are multilingual have different roles [as much as] different languages,” said Dr. Perales. “When I’m in Spanish, part of my brain is [thinking back to] summer vacations and hanging out with my cousins.”

When it comes to clinical science, however, English is the language of choice.
 

Global leaders in HSCT

Dr. Giralt and Dr. Perales are known worldwide in the field of allogeneic HSCT, a potentially curative treatment for an elongating list of both malignant and nonmalignant diseases.

In 1973, MSKCC conducted the first bone-marrow transplant from an unrelated donor. Fifty years on, medical oncologists in the United States conduct approximately 8,500 allogeneic transplants each year, 72% to treat acute leukemias or myelodysplastic syndrome (MDS).

However, stripping the immune system with intensive chemotherapy ‘conditioning,’ then rebuilding it with non-diseased donor hematopoietic cells is a hazardous undertaking. Older patients are less likely to survive the intensive conditioning, so historically have missed out. Also, even with a good human leukocyte antigen (HLA) match, the recipient needs often brutal immunosuppression.

Since Dr. Giralt and Dr. Perales began their partnership in 2010, the goals of their work have not changed: to develop safer, lower-intensity transplantation suitable for older, more vulnerable patients and reduce fearsome posttransplant sequelae such as graft-versus-host disease (GVHD).

Dr. Giralt’s publication list spans more than 600 peer-reviewed papers, articles and book chapters, almost exclusively on HSCT. Dr. Perales has more than 300 publication credits on the topic.

The two paired up on their first paper just months after Dr. Giralt arrived at MSKCC. That article, published in Biology of Blood and Marrow Transplantation, compared umbilical cord blood for HSCT with donor blood in 367 people with a variety of hematologic malignancies, including acute and chronic leukemias, MDS, and lymphoma.

Courtesy MSKCC

The MSKCC team found that transplant-related mortality in the first 180 days was higher for the cord blood (21%), but thereafter mortality and relapse were much lower than for donated blood, with the result that 2-year progression-free survival of 55% was similar. Dr. Perales, Dr. Giralt and their coauthors concluded that the data provided “strong support” for further work on cord blood as an alternative stem-cell source.

During their first decade of collaboration, Dr. Giralt and Dr. Perales worked on any promising avenue that could improve outcomes and the experience of HSCT recipients, including reduced-intensity conditioning regimens to allow older adults to benefit from curative HSCT and donor T-cell depletion by CD34 selection, to reduce graft-versus-host disease (GVHD).

The CD34 protein is typically found on the surface of early stage and highly active stem cell types. Selecting these cell types using a range of techniques can eliminate many other potentially interfering or inactive cells. This enriches the transplant population with the most effective cells and can lower the risk of GVHD.

The 100th paper on which Dr. Giralt and Dr. Perales were coauthors was published in Blood Advances on July 27, 2021. The retrospective study examined the fate of 58 MSKCC patients with a rare form of chronic lymphocytic leukemia, CLL with Richter’s transformation (CLL-RT). It was the largest such study to date of this rare disease.
M.D. Anderson Cancer Center had shown in 2006 that, despite chemotherapy, overall survival in patients with CLL-RT was approximately 8 months. HSCT improved survival dramatically (75% at 3 years; n = 7). However, with the advent of novel targeted drugs for CLL such as ibrutinib (Imbruvica), venetoclax (Venclexta), or idelalisib (Zydelig), the MSKCC team asked themselves: What was the role of reduced-intensive conditioning HSCT? Was it even safe? Among other findings, Dr. Giralt and Dr. Perales’ 100th paper showed that reduced-intensity HSCT remained a viable alternative after a CLL-RT patient progressed on a novel agent.

Impact of the pandemic

When COVID-19 hit, the team lost many research staff and developed a huge backlog, said Dr. Giralt. He and Dr. Perales realized that they needed to be “thoughtful and careful” about which studies to continue. “For example, the CD-34 selection trials we did not close because these are our workhorse trials,” Dr. Giralt said. “We have people we need to treat, and some of the patients that we need to treat can only be treated on trial.”

The team was also able to pivot some of their work into COVID 19 itself, and they collected crucial information on HSCT in recovered COVID-19 patients, as an example.

“We were living through a critical time, but that doesn’t mean we [aren’t] obligated to continue our mission, our research mission,” said Dr. Giralt. “It really is team science. The way we look at it ... there’s a common thread: We both like to do allogeneic transplant, and we both believe in trying to make CD-34 selection better. So we’re both very much [working on] how can we improve what we call ‘the Memorial way’ of doing transplants. Where we separate is, Miguel does primarily lymphoma. He doesn’t do myeloma [like me]. So in those two areas, we’re helping develop the junior faculty in a different way.”
 

Something more in common

Right from the start, Dr. Perales and Dr. Giralt also shared a commitment to mentoring. Since 2010, Dr. Perales has mentored 22 up-and-coming junior faculty, including 10 from Europe (8 from Spain) and 2 from Latin America.

“[It makes] the research enterprise much more productive but [these young scientists] really increase the visibility of the program,” said Dr. Giralt.

He cited Dr. Perales’ track record of mentoring as one of the reasons for his promotion to chief of the adult bone marrow transplant service. In March 2020, Dr. Perales seamlessly stepped into Dr. Giralt’s shoes, while Dr. Giralt moved on to his present role as deputy division head of the division of hematologic malignancies.

Dr. Perales said: “The key aspect [of these promotions] is the fantastic working relationship that we’ve had over the years. ... I consider Sergio my mentor, but also a good friend and colleague. And so I think it’s this ability that we’ve had to work together and that relationship of trust, which has been key.”

“Sergio is somebody who lifts people up,” Dr. Perales added. “Many people will tell you that Sergio has helped them in their career. ... And I think that’s a lesson I’ve learned from him: training the next generation. And [that’s] not just in the U.S., but outside. I think that’s a key role that we have. And our responsibility.”

Asked to comment on their 100th-paper milestone, Dr. Perales firmly turned the spotlight from himself and Dr. Giralt to the junior investigators who have passed through the doors of the bone-marrow transplant program: “This body of work represents not just our collaboration but also the many contributions of our team at MSK ... and beyond MSK.”

This article was updated 1/26/22.

Two close colleagues at New York’s Memorial Sloan Kettering Cancer Center, world leaders in hematopoietic stem cell transplantation (HSCT) who were both promoted days after COVID-19 locked down the city in 2020, were too busy battling the pandemic’s impact on patients in the summer of 2021 to notice their latest shared career milestone.

On July 29, 2021, Sergio Giralt, MD, deputy division head of the division of hematologic malignancies and Miguel-Angel Perales, MD, chief of the adult bone marrow transplant service at MSKCC, published their 100th peer-reviewed paper as coauthors. Listing hundreds of such articles on a CV is standard for top-tier physicians, but the pair had gone one better: 100 publications written together in 10 years.

Their centenary article hit scientific newsstands almost exactly a decade after their first joint paper, which appeared in September 2011, not long after they met.

Born in Cuba, Dr. Giralt grew up in Venezuela. From the age of 14, he knew that medicine was his path, and in 1984 he earned a medical degree from the Universidad Central de Venezuela, Caracas. Next came a research position at Harvard Medical School, a residency at the Good Samaritan Hospital, Cincinnati, and a fellowship at the University of Texas MD Anderson Cancer Center, Houston. Dr. Giralt arrived at MSKCC in 2010 as the new chief of the adult bone marrow transplant service. There he was introduced to a new colleague, Dr. Perales. They soon learned that in addition to expertise in hematology, they had second language in common: Spanish.

Dr. Giralt said: “We both have a Spanish background and in a certain sense, there was an affinity there. ... We both have shared experiences.”

Dr. Perales was brought up in Belgium, a European nation with three official languages: French, Dutch, and German. He speaks five tongues in all and learned Spanish from his father, who came from Spain.

Courtesy MSKCC

Fluency in Spanish enables both physicians to take care of the many New Yorkers who are more comfortable in that language – especially when navigating cancer treatment. However, both Dr. Giralt and Dr. Perales said that a second language is more than a professional tool. They described the enjoyable change of persona that happens when they switch to Spanish.

“People who are multilingual have different roles [as much as] different languages,” said Dr. Perales. “When I’m in Spanish, part of my brain is [thinking back to] summer vacations and hanging out with my cousins.”

When it comes to clinical science, however, English is the language of choice.
 

Global leaders in HSCT

Dr. Giralt and Dr. Perales are known worldwide in the field of allogeneic HSCT, a potentially curative treatment for an elongating list of both malignant and nonmalignant diseases.

In 1973, MSKCC conducted the first bone-marrow transplant from an unrelated donor. Fifty years on, medical oncologists in the United States conduct approximately 8,500 allogeneic transplants each year, 72% to treat acute leukemias or myelodysplastic syndrome (MDS).

However, stripping the immune system with intensive chemotherapy ‘conditioning,’ then rebuilding it with non-diseased donor hematopoietic cells is a hazardous undertaking. Older patients are less likely to survive the intensive conditioning, so historically have missed out. Also, even with a good human leukocyte antigen (HLA) match, the recipient needs often brutal immunosuppression.

Since Dr. Giralt and Dr. Perales began their partnership in 2010, the goals of their work have not changed: to develop safer, lower-intensity transplantation suitable for older, more vulnerable patients and reduce fearsome posttransplant sequelae such as graft-versus-host disease (GVHD).

Dr. Giralt’s publication list spans more than 600 peer-reviewed papers, articles and book chapters, almost exclusively on HSCT. Dr. Perales has more than 300 publication credits on the topic.

The two paired up on their first paper just months after Dr. Giralt arrived at MSKCC. That article, published in Biology of Blood and Marrow Transplantation, compared umbilical cord blood for HSCT with donor blood in 367 people with a variety of hematologic malignancies, including acute and chronic leukemias, MDS, and lymphoma.

Courtesy MSKCC

The MSKCC team found that transplant-related mortality in the first 180 days was higher for the cord blood (21%), but thereafter mortality and relapse were much lower than for donated blood, with the result that 2-year progression-free survival of 55% was similar. Dr. Perales, Dr. Giralt and their coauthors concluded that the data provided “strong support” for further work on cord blood as an alternative stem-cell source.

During their first decade of collaboration, Dr. Giralt and Dr. Perales worked on any promising avenue that could improve outcomes and the experience of HSCT recipients, including reduced-intensity conditioning regimens to allow older adults to benefit from curative HSCT and donor T-cell depletion by CD34 selection, to reduce graft-versus-host disease (GVHD).

The CD34 protein is typically found on the surface of early stage and highly active stem cell types. Selecting these cell types using a range of techniques can eliminate many other potentially interfering or inactive cells. This enriches the transplant population with the most effective cells and can lower the risk of GVHD.

The 100th paper on which Dr. Giralt and Dr. Perales were coauthors was published in Blood Advances on July 27, 2021. The retrospective study examined the fate of 58 MSKCC patients with a rare form of chronic lymphocytic leukemia, CLL with Richter’s transformation (CLL-RT). It was the largest such study to date of this rare disease.
M.D. Anderson Cancer Center had shown in 2006 that, despite chemotherapy, overall survival in patients with CLL-RT was approximately 8 months. HSCT improved survival dramatically (75% at 3 years; n = 7). However, with the advent of novel targeted drugs for CLL such as ibrutinib (Imbruvica), venetoclax (Venclexta), or idelalisib (Zydelig), the MSKCC team asked themselves: What was the role of reduced-intensive conditioning HSCT? Was it even safe? Among other findings, Dr. Giralt and Dr. Perales’ 100th paper showed that reduced-intensity HSCT remained a viable alternative after a CLL-RT patient progressed on a novel agent.

Impact of the pandemic

When COVID-19 hit, the team lost many research staff and developed a huge backlog, said Dr. Giralt. He and Dr. Perales realized that they needed to be “thoughtful and careful” about which studies to continue. “For example, the CD-34 selection trials we did not close because these are our workhorse trials,” Dr. Giralt said. “We have people we need to treat, and some of the patients that we need to treat can only be treated on trial.”

The team was also able to pivot some of their work into COVID 19 itself, and they collected crucial information on HSCT in recovered COVID-19 patients, as an example.

“We were living through a critical time, but that doesn’t mean we [aren’t] obligated to continue our mission, our research mission,” said Dr. Giralt. “It really is team science. The way we look at it ... there’s a common thread: We both like to do allogeneic transplant, and we both believe in trying to make CD-34 selection better. So we’re both very much [working on] how can we improve what we call ‘the Memorial way’ of doing transplants. Where we separate is, Miguel does primarily lymphoma. He doesn’t do myeloma [like me]. So in those two areas, we’re helping develop the junior faculty in a different way.”
 

Something more in common

Right from the start, Dr. Perales and Dr. Giralt also shared a commitment to mentoring. Since 2010, Dr. Perales has mentored 22 up-and-coming junior faculty, including 10 from Europe (8 from Spain) and 2 from Latin America.

“[It makes] the research enterprise much more productive but [these young scientists] really increase the visibility of the program,” said Dr. Giralt.

He cited Dr. Perales’ track record of mentoring as one of the reasons for his promotion to chief of the adult bone marrow transplant service. In March 2020, Dr. Perales seamlessly stepped into Dr. Giralt’s shoes, while Dr. Giralt moved on to his present role as deputy division head of the division of hematologic malignancies.

Dr. Perales said: “The key aspect [of these promotions] is the fantastic working relationship that we’ve had over the years. ... I consider Sergio my mentor, but also a good friend and colleague. And so I think it’s this ability that we’ve had to work together and that relationship of trust, which has been key.”

“Sergio is somebody who lifts people up,” Dr. Perales added. “Many people will tell you that Sergio has helped them in their career. ... And I think that’s a lesson I’ve learned from him: training the next generation. And [that’s] not just in the U.S., but outside. I think that’s a key role that we have. And our responsibility.”

Asked to comment on their 100th-paper milestone, Dr. Perales firmly turned the spotlight from himself and Dr. Giralt to the junior investigators who have passed through the doors of the bone-marrow transplant program: “This body of work represents not just our collaboration but also the many contributions of our team at MSK ... and beyond MSK.”

This article was updated 1/26/22.

Two close colleagues at New York’s Memorial Sloan Kettering Cancer Center, world leaders in hematopoietic stem cell transplantation (HSCT) who were both promoted days after COVID-19 locked down the city in 2020, were too busy battling the pandemic’s impact on patients in the summer of 2021 to notice their latest shared career milestone.

On July 29, 2021, Sergio Giralt, MD, deputy division head of the division of hematologic malignancies and Miguel-Angel Perales, MD, chief of the adult bone marrow transplant service at MSKCC, published their 100th peer-reviewed paper as coauthors. Listing hundreds of such articles on a CV is standard for top-tier physicians, but the pair had gone one better: 100 publications written together in 10 years.

Their centenary article hit scientific newsstands almost exactly a decade after their first joint paper, which appeared in September 2011, not long after they met.

Born in Cuba, Dr. Giralt grew up in Venezuela. From the age of 14, he knew that medicine was his path, and in 1984 he earned a medical degree from the Universidad Central de Venezuela, Caracas. Next came a research position at Harvard Medical School, a residency at the Good Samaritan Hospital, Cincinnati, and a fellowship at the University of Texas MD Anderson Cancer Center, Houston. Dr. Giralt arrived at MSKCC in 2010 as the new chief of the adult bone marrow transplant service. There he was introduced to a new colleague, Dr. Perales. They soon learned that in addition to expertise in hematology, they had second language in common: Spanish.

Dr. Giralt said: “We both have a Spanish background and in a certain sense, there was an affinity there. ... We both have shared experiences.”

Dr. Perales was brought up in Belgium, a European nation with three official languages: French, Dutch, and German. He speaks five tongues in all and learned Spanish from his father, who came from Spain.

Courtesy MSKCC

Fluency in Spanish enables both physicians to take care of the many New Yorkers who are more comfortable in that language – especially when navigating cancer treatment. However, both Dr. Giralt and Dr. Perales said that a second language is more than a professional tool. They described the enjoyable change of persona that happens when they switch to Spanish.

“People who are multilingual have different roles [as much as] different languages,” said Dr. Perales. “When I’m in Spanish, part of my brain is [thinking back to] summer vacations and hanging out with my cousins.”

When it comes to clinical science, however, English is the language of choice.
 

Global leaders in HSCT

Dr. Giralt and Dr. Perales are known worldwide in the field of allogeneic HSCT, a potentially curative treatment for an elongating list of both malignant and nonmalignant diseases.

In 1973, MSKCC conducted the first bone-marrow transplant from an unrelated donor. Fifty years on, medical oncologists in the United States conduct approximately 8,500 allogeneic transplants each year, 72% to treat acute leukemias or myelodysplastic syndrome (MDS).

However, stripping the immune system with intensive chemotherapy ‘conditioning,’ then rebuilding it with non-diseased donor hematopoietic cells is a hazardous undertaking. Older patients are less likely to survive the intensive conditioning, so historically have missed out. Also, even with a good human leukocyte antigen (HLA) match, the recipient needs often brutal immunosuppression.

Since Dr. Giralt and Dr. Perales began their partnership in 2010, the goals of their work have not changed: to develop safer, lower-intensity transplantation suitable for older, more vulnerable patients and reduce fearsome posttransplant sequelae such as graft-versus-host disease (GVHD).

Dr. Giralt’s publication list spans more than 600 peer-reviewed papers, articles and book chapters, almost exclusively on HSCT. Dr. Perales has more than 300 publication credits on the topic.

The two paired up on their first paper just months after Dr. Giralt arrived at MSKCC. That article, published in Biology of Blood and Marrow Transplantation, compared umbilical cord blood for HSCT with donor blood in 367 people with a variety of hematologic malignancies, including acute and chronic leukemias, MDS, and lymphoma.

Courtesy MSKCC

The MSKCC team found that transplant-related mortality in the first 180 days was higher for the cord blood (21%), but thereafter mortality and relapse were much lower than for donated blood, with the result that 2-year progression-free survival of 55% was similar. Dr. Perales, Dr. Giralt and their coauthors concluded that the data provided “strong support” for further work on cord blood as an alternative stem-cell source.

During their first decade of collaboration, Dr. Giralt and Dr. Perales worked on any promising avenue that could improve outcomes and the experience of HSCT recipients, including reduced-intensity conditioning regimens to allow older adults to benefit from curative HSCT and donor T-cell depletion by CD34 selection, to reduce graft-versus-host disease (GVHD).

The CD34 protein is typically found on the surface of early stage and highly active stem cell types. Selecting these cell types using a range of techniques can eliminate many other potentially interfering or inactive cells. This enriches the transplant population with the most effective cells and can lower the risk of GVHD.

The 100th paper on which Dr. Giralt and Dr. Perales were coauthors was published in Blood Advances on July 27, 2021. The retrospective study examined the fate of 58 MSKCC patients with a rare form of chronic lymphocytic leukemia, CLL with Richter’s transformation (CLL-RT). It was the largest such study to date of this rare disease.
M.D. Anderson Cancer Center had shown in 2006 that, despite chemotherapy, overall survival in patients with CLL-RT was approximately 8 months. HSCT improved survival dramatically (75% at 3 years; n = 7). However, with the advent of novel targeted drugs for CLL such as ibrutinib (Imbruvica), venetoclax (Venclexta), or idelalisib (Zydelig), the MSKCC team asked themselves: What was the role of reduced-intensive conditioning HSCT? Was it even safe? Among other findings, Dr. Giralt and Dr. Perales’ 100th paper showed that reduced-intensity HSCT remained a viable alternative after a CLL-RT patient progressed on a novel agent.

Impact of the pandemic

When COVID-19 hit, the team lost many research staff and developed a huge backlog, said Dr. Giralt. He and Dr. Perales realized that they needed to be “thoughtful and careful” about which studies to continue. “For example, the CD-34 selection trials we did not close because these are our workhorse trials,” Dr. Giralt said. “We have people we need to treat, and some of the patients that we need to treat can only be treated on trial.”

The team was also able to pivot some of their work into COVID 19 itself, and they collected crucial information on HSCT in recovered COVID-19 patients, as an example.

“We were living through a critical time, but that doesn’t mean we [aren’t] obligated to continue our mission, our research mission,” said Dr. Giralt. “It really is team science. The way we look at it ... there’s a common thread: We both like to do allogeneic transplant, and we both believe in trying to make CD-34 selection better. So we’re both very much [working on] how can we improve what we call ‘the Memorial way’ of doing transplants. Where we separate is, Miguel does primarily lymphoma. He doesn’t do myeloma [like me]. So in those two areas, we’re helping develop the junior faculty in a different way.”
 

Something more in common

Right from the start, Dr. Perales and Dr. Giralt also shared a commitment to mentoring. Since 2010, Dr. Perales has mentored 22 up-and-coming junior faculty, including 10 from Europe (8 from Spain) and 2 from Latin America.

“[It makes] the research enterprise much more productive but [these young scientists] really increase the visibility of the program,” said Dr. Giralt.

He cited Dr. Perales’ track record of mentoring as one of the reasons for his promotion to chief of the adult bone marrow transplant service. In March 2020, Dr. Perales seamlessly stepped into Dr. Giralt’s shoes, while Dr. Giralt moved on to his present role as deputy division head of the division of hematologic malignancies.

Dr. Perales said: “The key aspect [of these promotions] is the fantastic working relationship that we’ve had over the years. ... I consider Sergio my mentor, but also a good friend and colleague. And so I think it’s this ability that we’ve had to work together and that relationship of trust, which has been key.”

“Sergio is somebody who lifts people up,” Dr. Perales added. “Many people will tell you that Sergio has helped them in their career. ... And I think that’s a lesson I’ve learned from him: training the next generation. And [that’s] not just in the U.S., but outside. I think that’s a key role that we have. And our responsibility.”

Asked to comment on their 100th-paper milestone, Dr. Perales firmly turned the spotlight from himself and Dr. Giralt to the junior investigators who have passed through the doors of the bone-marrow transplant program: “This body of work represents not just our collaboration but also the many contributions of our team at MSK ... and beyond MSK.”

This article was updated 1/26/22.

Rituximab has presented something of a conundrum for patients taking the monoclonal antibody during the COVID-19 pandemic.

Used to manage a variety of autoimmune diseases and cancers, rituximab acts against CD20 proteins expressed on the surface of B cells, causing B-cell depletion. However, it is this B-cell depletion that may put these patients at greater risk of COVID-19 development, progression to more severe disease, and in-hospital mortality. Evidence for this appears to be mixed, with studies showing both that patients using rituximab to manage various diseases are and are not at increased risk for SARS-CoV-2 infection, COVID-19 progression, and mortality.

peterschreiber_media/iStock/Getty Images

As COVID-19 vaccine rollouts take place across the world, more questions have been raised about the relationship between B-cell depletion from anti-CD20 therapies and COVID-19 vaccines. Do rituximab and other anti-CD20 therapies affect a patient’s response to COVID-19 vaccines? If this is the case, does the timing of anti-CD20 treatment matter to maximize B-cell levels and improve the vaccine’s effectiveness? And how do COVID-19 vaccine booster doses factor into the equation?

This article aims to summarize the latest research on how rituximab affects humoral and cell-mediated response following a COVID-19 vaccine primary series, and whether the addition of a COVID-19 vaccine booster dose changes patient response.
 

Humoral and cell-mediated responses following COVID-19 vaccination

First, the bad news: The vaccine is unquestionably safe to administer in patients taking rituximab, but one thing that has been well established is that antibody response to COVID-19 vaccination in these individuals does is reduced. This isn’t entirely unprecedented, as previous studies have shown a weakened immune response to pneumococcal polysaccharide and keyhole limpet hemocyanin vaccines among patients taking rituximab.

“Compromised immunogenicity to the SARS-CoV-2 vaccines has been demonstrated in rituximab-treated patients, which is of particular concern given the observation that B-cell–depleting therapies may be associated with worse COVID outcomes,” Robert F. Spiera, MD, director of the Scleroderma, Vasculitis, and Myositis Center at the Hospital for Special Surgery in New York, said in an interview.

For example, in a recent study from the Medical University of Vienna, 29 (39%) of 74 patients receiving rituximab (43% as monotherapy, 57% with conventional-synthetic disease-modifying antirheumatic drugs) who were vaccinated with either the Comirnaty (Pfizer-BioNTech) or Spikevax (Moderna) COVID-19 vaccine achieved seroconversion, compared with 100% of patients in a healthy control group, and all but 1 patient without detectable CD19+ peripheral B cells did not develop anti–SARS-CoV-2 receptor-binding domain antibodies.

“There is an increasing number of studies in this field, and they confirm that patients treated with rituximab and other anti-CD20 agents have severely reduced serological responses to COVID-19 vaccines,” Ingrid Jyssum, MD, of the division of rheumatology and research at Diakonhjemmet Hospital in Oslo, said in an interview.

One silver lining is that patients treated with anti-CD20 therapies appear to have a cell-mediated response following vaccination even if they don’t develop SARS-CoV-2 antibodies. “Studies that also investigate T-cell responses are starting to emerge, and so far, they show that, even if the patients do not have antibodies, they may have T-cell responses,” Dr. Jyssum said.

One study of 24 patients with autoimmune diseases taking rituximab that evaluated humoral and T-cell responses following vaccination with the Comirnaty vaccine found that none had a humoral response to the vaccine, but the T-cell response from that group did not significantly differ from 35 patients receiving other immunosuppressants and 26 patients in a healthy control group. In another study of rituximab- or ocrelizumab-treated patients who received mRNA-based COVID-19 vaccines, 69.4% developed SARS-CoV-2–specific antibodies, compared with a control group, but 96.2% of patients taking ocrelizumab and 81.8% of patients taking rituximab mounted a spike-specific CD8+ T-cell response, compared with 66.7% in the control group, and there were comparable rates (85%-90%) of spike-specific CD4+ T cells in all groups. In the study from the Medical University of Vienna, T-cell response was detected in rituximab-treated patients who both did and did not mount an antibody response.

The clinical relevance of how a blunted humoral immune response but a respectable T-cell response to COVID-19 vaccines affects patients treated with anti-CD20 therapies isn’t currently known, Dr. Jyssum said.

While these data are reassuring, they’re also incomplete, Dr. Spiera noted. “The ultimate outcome of relevance to assess vaccine efficacy is protection from COVID and from severe outcomes of COVID infection (i.e., hospitalization, mechanical ventilation, death). That data will require assessment of very large numbers of rituximab-treated vaccinated patients to be compared with rituximab-treated unvaccinated patients, and is unlikely to be forthcoming in the very near future.

“In the meantime, however, achieving serologic positivity, meaning having evidence of serologic as well as cellular immunity following vaccination, is a desired outcome, and likely implies more robust immunity.”
 

Does treatment timing impact COVID-19 vaccine response?

Given enough time, B-cell reconstitution will occur in patients taking rituximab. With that in mind, is it beneficial to wait a certain amount of time after a patient has stopped rituximab therapy or time since their last dose before giving them a COVID-19 vaccine? In their guidance on COVID-19 vaccines for patients with rheumatic and musculoskeletal diseases, the American College of Rheumatology said there is moderate evidence to consider “optimal timing of dosing and vaccination with the rheumatology provider before proceeding.”

“Guidelines and preliminary studies of serologic response to COVID vaccine in rituximab-treated patients have suggested that longer time from last rituximab exposure is associated with a greater likelihood of a serologic response,” Dr. Spiera said.

In a brief report published in Arthritis & Rheumatology, Dr. Spiera and colleagues performed a retrospective chart review of 56 patients with varying levels of last exposure to rituximab who received a COVID-19 vaccine. Their results showed that, when patients were vaccinated 6-12 months after the last rituximab dose, 55% were seronegative, and when this was more than 12 months, only 13% were seronegative, compared with seronegativity in 86% who were vaccinated less than 6 months after their last rituximab dose.

The RituxiVac trial, conducted by researchers in Switzerland, also examined vaccine responses of 96 rituximab-treated patients who received Comirnaty or Spikevax; results recently published in The Lancet Rheumatology showed findings similar to other studies, with reduced humoral and cell-mediated responses. In the RituxiVac trial, the median time to last anti-CD20 treatment was 1.07 years.

“The typical interval between rituximab doses [for treatment of rheumatoid arthritis, as well as for remission maintenance in antineutrophil cytoplasmic antibody–associated vasculitis] is typically 6 months, and this has become widely used as the interval from last rituximab to time of COVID vaccination, with a recommendation to wait 4 weeks (if possible) from time of vaccination until the next rituximab administration,” Dr. Spiera explained. However, this window seems to vary depending on the study.

Recent research published in Arthritis & Rheumatology indicates B-cell levels could be a relevant indicator for humoral and cell-mediated response in patients with rheumatic diseases treated with rituximab, with a level of 10 B cells/mcL (0.4% of lymphocytes) identified as one potential marker for likely seroconversion following COVID-19 vaccination.

“In some smaller case series, it has been further recognized that rituximab-treated patients who were beginning to reconstitute peripheral B cells were most likely to respond serologically. Our present study confirmed those findings, demonstrating that the presence of detectable B cells was strongly associated with vaccine responsiveness, and affords complementary information to time from last [rituximab dose] in informing the likelihood of a vaccine response,” Dr. Spiera said.

However, the literature is limited in this area, and an exact cutoff for B-cell counts in these patients isn’t currently known, Dr. Jyssum said. A better metric is time away from anti-CD20 therapies, with CD19 cell count being highly correlated with last infusion.

Dr. Spiera agreed that there is no consistent B-cell percentage that works as a cutoff. “In our study, we looked at it as a binary variable, although we did find that a higher percentage of B cells in the peripheral lymphocyte population was associated with a higher likelihood of seroconversion. We did not, however, identify a ‘threshold’ for vaccine serologic responsiveness.”

Should clinicians measure antibodies?

The Food and Drug Administration and the Centers for Disease Control and Prevention have recommended that health care providers and the public not use COVID-19 antibody tests as a way to gauge immunity after exposure to SARS-CoV-2 and after receiving a COVID-19 vaccination. The ACR’s guidance on COVID-19 vaccination for patients with rheumatic and musculoskeletal diseases strongly recommends against ordering antibody tests for patients with autoimmune inflammatory rheumatic diseases as a way to measure immunity.

“Generally, such measurements are not recommended as the clinical correlate of various antibody levels are not known,” Dr. Jyssum said. “With regular infusions of rituximab or other anti-CD20 agents, one cannot expect that these patients will develop significant levels of antibodies.”

However, she said there might be situations where it’s useful to know whether a patient has developed antibodies at all. “Assessing the significance of specific antibody levels is difficult, and the subject of scientific studies. Patients lacking a humoral vaccine response are left to rely on their T-cell responses and on infectious control measures to prevent disease.”

Dr. Spiera said he disagreed with guidelines recommending against checking antibody levels after vaccination, “particularly in patients treated with immunosuppressive medications that might be expected to blunt their serologic response to the vaccines.

“Although we cannot be sure what level of measurable antibodies offer what level of protection, most clinicians would agree that patients who demonstrate no detectable antibodies (which is a common finding in rituximab-treated patients) should be considered at higher risk,” he said. “Indeed, recommendations regarding booster vaccine administration in general was initially based on the observation of declining antibody levels with longer time from vaccination.”

Do COVID-19 vaccine boosters help patients on anti-CD20 therapy?

As of January 2022, the FDA and CDC have recommended a third primary series shot of COVID-19 vaccines for some moderately to severely immunocompromised patients as young as 5 years old (for Comirnaty vaccine) or a booster shot of either Comirnaty or Spikevax for everyone aged 12 years and older, including immunocompromised people, while the ACR goes into more detail and recommends clinicians time a patient’s booster shot with temporary treatment interruption.

In The Lancet Rheumatology, Dr. Jyssum and colleagues recently published results from the prospective Nor-vaC study examining the humoral and cell-mediated immune responses of 87 patients with RA being treated with rituximab who received the Comirnaty, Spikevax, or Vaxzevria (AstraZeneca) COVID-19 vaccines; of these, 49 patients received a booster dose at a median of 70 days after completing their primary series. The results showed 19 patients (28.1%) had a serologic response after their primary series, while 8 of 49 patients (16.3%) who received their booster dose had a serologic response.

All patients who received a third dose in the study had a T-cell response, Dr. Jyssum said. “This is reassuring for patients and clinicians. T cells have been found to be important in countering COVID-19 disease, but whether we can rely on the T-cell response alone in the absence of antibodies to protect patients from infection or from serious COVID disease is still not determined,” she said.

When asked if she would recommend COVID-19 vaccine booster doses for patients on rituximab, Dr. Jyssum replied: “Absolutely.”

Another study, recently published in Annals of the Rheumatic Diseases, examined heterologous and homologous booster doses for 60 patients receiving rituximab without seroconversion after their COVID-19 vaccine primary series. The results showed no significant difference in new seroconversion at 4 weeks based on whether the patient received a vector or mRNA vaccine (22% vs. 32%), but all patients who received a booster dose with a vector vaccine had specific T-cell responses, compared with 81% of patients who received an mRNA vaccine booster. There was a new humoral and/or cellular response in 9 of 11 patients (82%), and most patients with peripheral B cells (12 of 18 patients; 67%) achieved seroconversion.

“Our data show that a cellular and/or humoral immune response can be achieved on a third COVID-19 vaccination in most of the patients who initially developed neither a humoral nor a cellular immune response,” the researchers concluded. “The efficacy data together with the safety data seen in our trial provide a favorable risk/benefit ratio and support the implementation of a third vaccination for nonseroconverted high-risk autoimmune disease patients treated with B-cell–depleting agents.”

Dr. Spiera said booster doses are an important part of the equation, and “it is important to consider factors that would be associated with a greater likelihood of achieving a serologic response, particularly in those patients who did not demonstrate a serologic response to the initial vaccines series.

“Preliminary data shows that the beginnings of B-cell reconstitution is also associated with a positive serologic response following a booster of the COVID-19 vaccine,” he said.

The authors of the cited studies reported numerous relevant financial disclosures. Dr. Spiera and Dr. Jyssum reported no relevant financial disclosures.

Rituximab has presented something of a conundrum for patients taking the monoclonal antibody during the COVID-19 pandemic.

Used to manage a variety of autoimmune diseases and cancers, rituximab acts against CD20 proteins expressed on the surface of B cells, causing B-cell depletion. However, it is this B-cell depletion that may put these patients at greater risk of COVID-19 development, progression to more severe disease, and in-hospital mortality. Evidence for this appears to be mixed, with studies showing both that patients using rituximab to manage various diseases are and are not at increased risk for SARS-CoV-2 infection, COVID-19 progression, and mortality.

peterschreiber_media/iStock/Getty Images

As COVID-19 vaccine rollouts take place across the world, more questions have been raised about the relationship between B-cell depletion from anti-CD20 therapies and COVID-19 vaccines. Do rituximab and other anti-CD20 therapies affect a patient’s response to COVID-19 vaccines? If this is the case, does the timing of anti-CD20 treatment matter to maximize B-cell levels and improve the vaccine’s effectiveness? And how do COVID-19 vaccine booster doses factor into the equation?

This article aims to summarize the latest research on how rituximab affects humoral and cell-mediated response following a COVID-19 vaccine primary series, and whether the addition of a COVID-19 vaccine booster dose changes patient response.
 

Humoral and cell-mediated responses following COVID-19 vaccination

First, the bad news: The vaccine is unquestionably safe to administer in patients taking rituximab, but one thing that has been well established is that antibody response to COVID-19 vaccination in these individuals does is reduced. This isn’t entirely unprecedented, as previous studies have shown a weakened immune response to pneumococcal polysaccharide and keyhole limpet hemocyanin vaccines among patients taking rituximab.

“Compromised immunogenicity to the SARS-CoV-2 vaccines has been demonstrated in rituximab-treated patients, which is of particular concern given the observation that B-cell–depleting therapies may be associated with worse COVID outcomes,” Robert F. Spiera, MD, director of the Scleroderma, Vasculitis, and Myositis Center at the Hospital for Special Surgery in New York, said in an interview.

For example, in a recent study from the Medical University of Vienna, 29 (39%) of 74 patients receiving rituximab (43% as monotherapy, 57% with conventional-synthetic disease-modifying antirheumatic drugs) who were vaccinated with either the Comirnaty (Pfizer-BioNTech) or Spikevax (Moderna) COVID-19 vaccine achieved seroconversion, compared with 100% of patients in a healthy control group, and all but 1 patient without detectable CD19+ peripheral B cells did not develop anti–SARS-CoV-2 receptor-binding domain antibodies.

“There is an increasing number of studies in this field, and they confirm that patients treated with rituximab and other anti-CD20 agents have severely reduced serological responses to COVID-19 vaccines,” Ingrid Jyssum, MD, of the division of rheumatology and research at Diakonhjemmet Hospital in Oslo, said in an interview.

One silver lining is that patients treated with anti-CD20 therapies appear to have a cell-mediated response following vaccination even if they don’t develop SARS-CoV-2 antibodies. “Studies that also investigate T-cell responses are starting to emerge, and so far, they show that, even if the patients do not have antibodies, they may have T-cell responses,” Dr. Jyssum said.

One study of 24 patients with autoimmune diseases taking rituximab that evaluated humoral and T-cell responses following vaccination with the Comirnaty vaccine found that none had a humoral response to the vaccine, but the T-cell response from that group did not significantly differ from 35 patients receiving other immunosuppressants and 26 patients in a healthy control group. In another study of rituximab- or ocrelizumab-treated patients who received mRNA-based COVID-19 vaccines, 69.4% developed SARS-CoV-2–specific antibodies, compared with a control group, but 96.2% of patients taking ocrelizumab and 81.8% of patients taking rituximab mounted a spike-specific CD8+ T-cell response, compared with 66.7% in the control group, and there were comparable rates (85%-90%) of spike-specific CD4+ T cells in all groups. In the study from the Medical University of Vienna, T-cell response was detected in rituximab-treated patients who both did and did not mount an antibody response.

The clinical relevance of how a blunted humoral immune response but a respectable T-cell response to COVID-19 vaccines affects patients treated with anti-CD20 therapies isn’t currently known, Dr. Jyssum said.

While these data are reassuring, they’re also incomplete, Dr. Spiera noted. “The ultimate outcome of relevance to assess vaccine efficacy is protection from COVID and from severe outcomes of COVID infection (i.e., hospitalization, mechanical ventilation, death). That data will require assessment of very large numbers of rituximab-treated vaccinated patients to be compared with rituximab-treated unvaccinated patients, and is unlikely to be forthcoming in the very near future.

“In the meantime, however, achieving serologic positivity, meaning having evidence of serologic as well as cellular immunity following vaccination, is a desired outcome, and likely implies more robust immunity.”
 

Does treatment timing impact COVID-19 vaccine response?

Given enough time, B-cell reconstitution will occur in patients taking rituximab. With that in mind, is it beneficial to wait a certain amount of time after a patient has stopped rituximab therapy or time since their last dose before giving them a COVID-19 vaccine? In their guidance on COVID-19 vaccines for patients with rheumatic and musculoskeletal diseases, the American College of Rheumatology said there is moderate evidence to consider “optimal timing of dosing and vaccination with the rheumatology provider before proceeding.”

“Guidelines and preliminary studies of serologic response to COVID vaccine in rituximab-treated patients have suggested that longer time from last rituximab exposure is associated with a greater likelihood of a serologic response,” Dr. Spiera said.

In a brief report published in Arthritis & Rheumatology, Dr. Spiera and colleagues performed a retrospective chart review of 56 patients with varying levels of last exposure to rituximab who received a COVID-19 vaccine. Their results showed that, when patients were vaccinated 6-12 months after the last rituximab dose, 55% were seronegative, and when this was more than 12 months, only 13% were seronegative, compared with seronegativity in 86% who were vaccinated less than 6 months after their last rituximab dose.

The RituxiVac trial, conducted by researchers in Switzerland, also examined vaccine responses of 96 rituximab-treated patients who received Comirnaty or Spikevax; results recently published in The Lancet Rheumatology showed findings similar to other studies, with reduced humoral and cell-mediated responses. In the RituxiVac trial, the median time to last anti-CD20 treatment was 1.07 years.

“The typical interval between rituximab doses [for treatment of rheumatoid arthritis, as well as for remission maintenance in antineutrophil cytoplasmic antibody–associated vasculitis] is typically 6 months, and this has become widely used as the interval from last rituximab to time of COVID vaccination, with a recommendation to wait 4 weeks (if possible) from time of vaccination until the next rituximab administration,” Dr. Spiera explained. However, this window seems to vary depending on the study.

Recent research published in Arthritis & Rheumatology indicates B-cell levels could be a relevant indicator for humoral and cell-mediated response in patients with rheumatic diseases treated with rituximab, with a level of 10 B cells/mcL (0.4% of lymphocytes) identified as one potential marker for likely seroconversion following COVID-19 vaccination.

“In some smaller case series, it has been further recognized that rituximab-treated patients who were beginning to reconstitute peripheral B cells were most likely to respond serologically. Our present study confirmed those findings, demonstrating that the presence of detectable B cells was strongly associated with vaccine responsiveness, and affords complementary information to time from last [rituximab dose] in informing the likelihood of a vaccine response,” Dr. Spiera said.

However, the literature is limited in this area, and an exact cutoff for B-cell counts in these patients isn’t currently known, Dr. Jyssum said. A better metric is time away from anti-CD20 therapies, with CD19 cell count being highly correlated with last infusion.

Dr. Spiera agreed that there is no consistent B-cell percentage that works as a cutoff. “In our study, we looked at it as a binary variable, although we did find that a higher percentage of B cells in the peripheral lymphocyte population was associated with a higher likelihood of seroconversion. We did not, however, identify a ‘threshold’ for vaccine serologic responsiveness.”

Should clinicians measure antibodies?

The Food and Drug Administration and the Centers for Disease Control and Prevention have recommended that health care providers and the public not use COVID-19 antibody tests as a way to gauge immunity after exposure to SARS-CoV-2 and after receiving a COVID-19 vaccination. The ACR’s guidance on COVID-19 vaccination for patients with rheumatic and musculoskeletal diseases strongly recommends against ordering antibody tests for patients with autoimmune inflammatory rheumatic diseases as a way to measure immunity.

“Generally, such measurements are not recommended as the clinical correlate of various antibody levels are not known,” Dr. Jyssum said. “With regular infusions of rituximab or other anti-CD20 agents, one cannot expect that these patients will develop significant levels of antibodies.”

However, she said there might be situations where it’s useful to know whether a patient has developed antibodies at all. “Assessing the significance of specific antibody levels is difficult, and the subject of scientific studies. Patients lacking a humoral vaccine response are left to rely on their T-cell responses and on infectious control measures to prevent disease.”

Dr. Spiera said he disagreed with guidelines recommending against checking antibody levels after vaccination, “particularly in patients treated with immunosuppressive medications that might be expected to blunt their serologic response to the vaccines.

“Although we cannot be sure what level of measurable antibodies offer what level of protection, most clinicians would agree that patients who demonstrate no detectable antibodies (which is a common finding in rituximab-treated patients) should be considered at higher risk,” he said. “Indeed, recommendations regarding booster vaccine administration in general was initially based on the observation of declining antibody levels with longer time from vaccination.”

Do COVID-19 vaccine boosters help patients on anti-CD20 therapy?

As of January 2022, the FDA and CDC have recommended a third primary series shot of COVID-19 vaccines for some moderately to severely immunocompromised patients as young as 5 years old (for Comirnaty vaccine) or a booster shot of either Comirnaty or Spikevax for everyone aged 12 years and older, including immunocompromised people, while the ACR goes into more detail and recommends clinicians time a patient’s booster shot with temporary treatment interruption.

In The Lancet Rheumatology, Dr. Jyssum and colleagues recently published results from the prospective Nor-vaC study examining the humoral and cell-mediated immune responses of 87 patients with RA being treated with rituximab who received the Comirnaty, Spikevax, or Vaxzevria (AstraZeneca) COVID-19 vaccines; of these, 49 patients received a booster dose at a median of 70 days after completing their primary series. The results showed 19 patients (28.1%) had a serologic response after their primary series, while 8 of 49 patients (16.3%) who received their booster dose had a serologic response.

All patients who received a third dose in the study had a T-cell response, Dr. Jyssum said. “This is reassuring for patients and clinicians. T cells have been found to be important in countering COVID-19 disease, but whether we can rely on the T-cell response alone in the absence of antibodies to protect patients from infection or from serious COVID disease is still not determined,” she said.

When asked if she would recommend COVID-19 vaccine booster doses for patients on rituximab, Dr. Jyssum replied: “Absolutely.”

Another study, recently published in Annals of the Rheumatic Diseases, examined heterologous and homologous booster doses for 60 patients receiving rituximab without seroconversion after their COVID-19 vaccine primary series. The results showed no significant difference in new seroconversion at 4 weeks based on whether the patient received a vector or mRNA vaccine (22% vs. 32%), but all patients who received a booster dose with a vector vaccine had specific T-cell responses, compared with 81% of patients who received an mRNA vaccine booster. There was a new humoral and/or cellular response in 9 of 11 patients (82%), and most patients with peripheral B cells (12 of 18 patients; 67%) achieved seroconversion.

“Our data show that a cellular and/or humoral immune response can be achieved on a third COVID-19 vaccination in most of the patients who initially developed neither a humoral nor a cellular immune response,” the researchers concluded. “The efficacy data together with the safety data seen in our trial provide a favorable risk/benefit ratio and support the implementation of a third vaccination for nonseroconverted high-risk autoimmune disease patients treated with B-cell–depleting agents.”

Dr. Spiera said booster doses are an important part of the equation, and “it is important to consider factors that would be associated with a greater likelihood of achieving a serologic response, particularly in those patients who did not demonstrate a serologic response to the initial vaccines series.

“Preliminary data shows that the beginnings of B-cell reconstitution is also associated with a positive serologic response following a booster of the COVID-19 vaccine,” he said.

The authors of the cited studies reported numerous relevant financial disclosures. Dr. Spiera and Dr. Jyssum reported no relevant financial disclosures.

Rituximab has presented something of a conundrum for patients taking the monoclonal antibody during the COVID-19 pandemic.

Used to manage a variety of autoimmune diseases and cancers, rituximab acts against CD20 proteins expressed on the surface of B cells, causing B-cell depletion. However, it is this B-cell depletion that may put these patients at greater risk of COVID-19 development, progression to more severe disease, and in-hospital mortality. Evidence for this appears to be mixed, with studies showing both that patients using rituximab to manage various diseases are and are not at increased risk for SARS-CoV-2 infection, COVID-19 progression, and mortality.

peterschreiber_media/iStock/Getty Images

As COVID-19 vaccine rollouts take place across the world, more questions have been raised about the relationship between B-cell depletion from anti-CD20 therapies and COVID-19 vaccines. Do rituximab and other anti-CD20 therapies affect a patient’s response to COVID-19 vaccines? If this is the case, does the timing of anti-CD20 treatment matter to maximize B-cell levels and improve the vaccine’s effectiveness? And how do COVID-19 vaccine booster doses factor into the equation?

This article aims to summarize the latest research on how rituximab affects humoral and cell-mediated response following a COVID-19 vaccine primary series, and whether the addition of a COVID-19 vaccine booster dose changes patient response.
 

Humoral and cell-mediated responses following COVID-19 vaccination

First, the bad news: The vaccine is unquestionably safe to administer in patients taking rituximab, but one thing that has been well established is that antibody response to COVID-19 vaccination in these individuals does is reduced. This isn’t entirely unprecedented, as previous studies have shown a weakened immune response to pneumococcal polysaccharide and keyhole limpet hemocyanin vaccines among patients taking rituximab.

“Compromised immunogenicity to the SARS-CoV-2 vaccines has been demonstrated in rituximab-treated patients, which is of particular concern given the observation that B-cell–depleting therapies may be associated with worse COVID outcomes,” Robert F. Spiera, MD, director of the Scleroderma, Vasculitis, and Myositis Center at the Hospital for Special Surgery in New York, said in an interview.

For example, in a recent study from the Medical University of Vienna, 29 (39%) of 74 patients receiving rituximab (43% as monotherapy, 57% with conventional-synthetic disease-modifying antirheumatic drugs) who were vaccinated with either the Comirnaty (Pfizer-BioNTech) or Spikevax (Moderna) COVID-19 vaccine achieved seroconversion, compared with 100% of patients in a healthy control group, and all but 1 patient without detectable CD19+ peripheral B cells did not develop anti–SARS-CoV-2 receptor-binding domain antibodies.

“There is an increasing number of studies in this field, and they confirm that patients treated with rituximab and other anti-CD20 agents have severely reduced serological responses to COVID-19 vaccines,” Ingrid Jyssum, MD, of the division of rheumatology and research at Diakonhjemmet Hospital in Oslo, said in an interview.

One silver lining is that patients treated with anti-CD20 therapies appear to have a cell-mediated response following vaccination even if they don’t develop SARS-CoV-2 antibodies. “Studies that also investigate T-cell responses are starting to emerge, and so far, they show that, even if the patients do not have antibodies, they may have T-cell responses,” Dr. Jyssum said.

One study of 24 patients with autoimmune diseases taking rituximab that evaluated humoral and T-cell responses following vaccination with the Comirnaty vaccine found that none had a humoral response to the vaccine, but the T-cell response from that group did not significantly differ from 35 patients receiving other immunosuppressants and 26 patients in a healthy control group. In another study of rituximab- or ocrelizumab-treated patients who received mRNA-based COVID-19 vaccines, 69.4% developed SARS-CoV-2–specific antibodies, compared with a control group, but 96.2% of patients taking ocrelizumab and 81.8% of patients taking rituximab mounted a spike-specific CD8+ T-cell response, compared with 66.7% in the control group, and there were comparable rates (85%-90%) of spike-specific CD4+ T cells in all groups. In the study from the Medical University of Vienna, T-cell response was detected in rituximab-treated patients who both did and did not mount an antibody response.

The clinical relevance of how a blunted humoral immune response but a respectable T-cell response to COVID-19 vaccines affects patients treated with anti-CD20 therapies isn’t currently known, Dr. Jyssum said.

While these data are reassuring, they’re also incomplete, Dr. Spiera noted. “The ultimate outcome of relevance to assess vaccine efficacy is protection from COVID and from severe outcomes of COVID infection (i.e., hospitalization, mechanical ventilation, death). That data will require assessment of very large numbers of rituximab-treated vaccinated patients to be compared with rituximab-treated unvaccinated patients, and is unlikely to be forthcoming in the very near future.

“In the meantime, however, achieving serologic positivity, meaning having evidence of serologic as well as cellular immunity following vaccination, is a desired outcome, and likely implies more robust immunity.”
 

Does treatment timing impact COVID-19 vaccine response?

Given enough time, B-cell reconstitution will occur in patients taking rituximab. With that in mind, is it beneficial to wait a certain amount of time after a patient has stopped rituximab therapy or time since their last dose before giving them a COVID-19 vaccine? In their guidance on COVID-19 vaccines for patients with rheumatic and musculoskeletal diseases, the American College of Rheumatology said there is moderate evidence to consider “optimal timing of dosing and vaccination with the rheumatology provider before proceeding.”

“Guidelines and preliminary studies of serologic response to COVID vaccine in rituximab-treated patients have suggested that longer time from last rituximab exposure is associated with a greater likelihood of a serologic response,” Dr. Spiera said.

In a brief report published in Arthritis & Rheumatology, Dr. Spiera and colleagues performed a retrospective chart review of 56 patients with varying levels of last exposure to rituximab who received a COVID-19 vaccine. Their results showed that, when patients were vaccinated 6-12 months after the last rituximab dose, 55% were seronegative, and when this was more than 12 months, only 13% were seronegative, compared with seronegativity in 86% who were vaccinated less than 6 months after their last rituximab dose.

The RituxiVac trial, conducted by researchers in Switzerland, also examined vaccine responses of 96 rituximab-treated patients who received Comirnaty or Spikevax; results recently published in The Lancet Rheumatology showed findings similar to other studies, with reduced humoral and cell-mediated responses. In the RituxiVac trial, the median time to last anti-CD20 treatment was 1.07 years.

“The typical interval between rituximab doses [for treatment of rheumatoid arthritis, as well as for remission maintenance in antineutrophil cytoplasmic antibody–associated vasculitis] is typically 6 months, and this has become widely used as the interval from last rituximab to time of COVID vaccination, with a recommendation to wait 4 weeks (if possible) from time of vaccination until the next rituximab administration,” Dr. Spiera explained. However, this window seems to vary depending on the study.

Recent research published in Arthritis & Rheumatology indicates B-cell levels could be a relevant indicator for humoral and cell-mediated response in patients with rheumatic diseases treated with rituximab, with a level of 10 B cells/mcL (0.4% of lymphocytes) identified as one potential marker for likely seroconversion following COVID-19 vaccination.

“In some smaller case series, it has been further recognized that rituximab-treated patients who were beginning to reconstitute peripheral B cells were most likely to respond serologically. Our present study confirmed those findings, demonstrating that the presence of detectable B cells was strongly associated with vaccine responsiveness, and affords complementary information to time from last [rituximab dose] in informing the likelihood of a vaccine response,” Dr. Spiera said.

However, the literature is limited in this area, and an exact cutoff for B-cell counts in these patients isn’t currently known, Dr. Jyssum said. A better metric is time away from anti-CD20 therapies, with CD19 cell count being highly correlated with last infusion.

Dr. Spiera agreed that there is no consistent B-cell percentage that works as a cutoff. “In our study, we looked at it as a binary variable, although we did find that a higher percentage of B cells in the peripheral lymphocyte population was associated with a higher likelihood of seroconversion. We did not, however, identify a ‘threshold’ for vaccine serologic responsiveness.”

Should clinicians measure antibodies?

The Food and Drug Administration and the Centers for Disease Control and Prevention have recommended that health care providers and the public not use COVID-19 antibody tests as a way to gauge immunity after exposure to SARS-CoV-2 and after receiving a COVID-19 vaccination. The ACR’s guidance on COVID-19 vaccination for patients with rheumatic and musculoskeletal diseases strongly recommends against ordering antibody tests for patients with autoimmune inflammatory rheumatic diseases as a way to measure immunity.

“Generally, such measurements are not recommended as the clinical correlate of various antibody levels are not known,” Dr. Jyssum said. “With regular infusions of rituximab or other anti-CD20 agents, one cannot expect that these patients will develop significant levels of antibodies.”

However, she said there might be situations where it’s useful to know whether a patient has developed antibodies at all. “Assessing the significance of specific antibody levels is difficult, and the subject of scientific studies. Patients lacking a humoral vaccine response are left to rely on their T-cell responses and on infectious control measures to prevent disease.”

Dr. Spiera said he disagreed with guidelines recommending against checking antibody levels after vaccination, “particularly in patients treated with immunosuppressive medications that might be expected to blunt their serologic response to the vaccines.

“Although we cannot be sure what level of measurable antibodies offer what level of protection, most clinicians would agree that patients who demonstrate no detectable antibodies (which is a common finding in rituximab-treated patients) should be considered at higher risk,” he said. “Indeed, recommendations regarding booster vaccine administration in general was initially based on the observation of declining antibody levels with longer time from vaccination.”

Do COVID-19 vaccine boosters help patients on anti-CD20 therapy?

As of January 2022, the FDA and CDC have recommended a third primary series shot of COVID-19 vaccines for some moderately to severely immunocompromised patients as young as 5 years old (for Comirnaty vaccine) or a booster shot of either Comirnaty or Spikevax for everyone aged 12 years and older, including immunocompromised people, while the ACR goes into more detail and recommends clinicians time a patient’s booster shot with temporary treatment interruption.

In The Lancet Rheumatology, Dr. Jyssum and colleagues recently published results from the prospective Nor-vaC study examining the humoral and cell-mediated immune responses of 87 patients with RA being treated with rituximab who received the Comirnaty, Spikevax, or Vaxzevria (AstraZeneca) COVID-19 vaccines; of these, 49 patients received a booster dose at a median of 70 days after completing their primary series. The results showed 19 patients (28.1%) had a serologic response after their primary series, while 8 of 49 patients (16.3%) who received their booster dose had a serologic response.

All patients who received a third dose in the study had a T-cell response, Dr. Jyssum said. “This is reassuring for patients and clinicians. T cells have been found to be important in countering COVID-19 disease, but whether we can rely on the T-cell response alone in the absence of antibodies to protect patients from infection or from serious COVID disease is still not determined,” she said.

When asked if she would recommend COVID-19 vaccine booster doses for patients on rituximab, Dr. Jyssum replied: “Absolutely.”

Another study, recently published in Annals of the Rheumatic Diseases, examined heterologous and homologous booster doses for 60 patients receiving rituximab without seroconversion after their COVID-19 vaccine primary series. The results showed no significant difference in new seroconversion at 4 weeks based on whether the patient received a vector or mRNA vaccine (22% vs. 32%), but all patients who received a booster dose with a vector vaccine had specific T-cell responses, compared with 81% of patients who received an mRNA vaccine booster. There was a new humoral and/or cellular response in 9 of 11 patients (82%), and most patients with peripheral B cells (12 of 18 patients; 67%) achieved seroconversion.

“Our data show that a cellular and/or humoral immune response can be achieved on a third COVID-19 vaccination in most of the patients who initially developed neither a humoral nor a cellular immune response,” the researchers concluded. “The efficacy data together with the safety data seen in our trial provide a favorable risk/benefit ratio and support the implementation of a third vaccination for nonseroconverted high-risk autoimmune disease patients treated with B-cell–depleting agents.”

Dr. Spiera said booster doses are an important part of the equation, and “it is important to consider factors that would be associated with a greater likelihood of achieving a serologic response, particularly in those patients who did not demonstrate a serologic response to the initial vaccines series.

“Preliminary data shows that the beginnings of B-cell reconstitution is also associated with a positive serologic response following a booster of the COVID-19 vaccine,” he said.

The authors of the cited studies reported numerous relevant financial disclosures. Dr. Spiera and Dr. Jyssum reported no relevant financial disclosures.

When Mechtild Harf was diagnosed with acute leukemia in 1990, physicians told her and her husband Peter that a bone marrow transplant was her best hope for survival. Back then, her native Germany had only 3,000 registered donors, and none was a match.

“My dad just went crazy, you know, to save his wife,” recalled Katharina Harf, who was a young teen at the time of her mother’s diagnosis.

Courtesy DKMS.org

In the course of 1 year, the Harfs recruited more than 68,000 potential bone marrow donors, but their heroic efforts couldn’t save Mechtild.

“She unfortunately didn’t make it. She died because of leukemia,” Katharina said.

Although Mechtild Harf did not survive, her legacy lives on in the bone marrow and stem cell donor recruitment organization DKMS (Deutsche Knochenmarkspenderdatei, or German Bone Marrow Donor Center).

In May of 1991, Peter Harf and Gerhard Ehninger, MD, the hematologist who treated Mechtild, founded DKMS with the mission, as its website states, “to provide as many blood cancer patients as possible with a second chance at life.”

From its German roots, the nonprofit organization has extended its mission to the United States (where it was initially known as Delete Blood Cancer DKMS), Poland, the United Kingdom, Chile, and in 2021, to South Africa.

Three decades after her mother’s death, Katharina Harf serves as Executive Chairwoman of DKMS U.S., based in New York.
 

World’s largest registry

“DKMS has the largest number of unrelated donors of any organization in the world,” noted Richard E. Champlin, MD, chair of the department of stem cell transplantation and cellular therapy at the University of Texas MD Anderson Cancer Center in Houston.

“In a large fraction of our donor searches, we find matches that are in the DKMS registry,” he said in an interview,

In 2022, DKMS is the largest global bone marrow donor recruitment organization, with more than 10.6 million potential donors registered. Worldwide, more than 91,000 patients have received bone marrow or stem cell grafts donated by registered volunteers.

Alexander Schmidt, MD, PhD, global chief medical officer for DKMS, said that approximately 25% of all registered donors worldwide were recruited by his organization, and 39% of all unrelated donor transplants are made with peripheral blood stem cell or bone marrow products, donated by volunteers who are recruited by DKMS.

Since its founding, DKMS has registered 7.1 million potential donors in Germany, who made a total of 80,000 stem cell donations. DKMS U.S., which began operations in 2004, has registered 1.1 million donors and enabled 4,700 donations.
 

Global partners

DKMS partners with donor centers and recruitment organizations in each country where it operates. In the United States, DKMS works with the National Marrow Donor Program (NMDP) and its “Be The Match” donor registry.

“DKMS donors, both those from DKMS in Germany and those from DKMS in the United States are also listed in the NMDP registry, to make it easier for US search coordinators to accept these donors,” Dr. Schmidt explained in an interview.

The international cooperation and coordination makes it possible for a donor in the UK, for example, to save a life of a patient in Germany, the U.S., Chile, India, or many other parts of the world – anywhere that can be reached in time for a patient in need to receive a stem cell donation.
 

Pandemic affects donations

But, as with just about every aspect of life, the COVID-19 pandemic has created enormous challenges for recruiters, donor centers, and stem cell transplant centers.

Dr. Schmidt said that decline in donations during the pandemic was less severe than initially feared, with a decrease of just 3.5% in 2020, compared with the prepandemic year of 2019. In contrast, though, the average annual growth rate for donations prior to the pandemic was about 4%.

“Nevertheless, at the beginning of the pandemic in March 2020, for a few days things looked quite terrible, because all the borders were closed and flights were canceled, and about 50% of all stem cell products go abroad, and between 20% and 25% go intercontinental,” Dr. Schmidt said.

However, close cooperation and coordination between donor centers and national health authorities soon resolved the problem and helped insure that the flow of life-saving donations could continue with minimal disruption, he noted.

“I don’t think we had any product that could not be delivered at the end of the day, due to the pandemic,” he told this news organization.
 

Workforce and clinical problems

Although the flow of donations within and between nations has continued, the COVID-19 pandemic has had profound negative effects on transplant centers, particularly during the wave of infections caused by the Omicron variant, according to a transplant expert.

“With this most recent strain and how transmissible it is, what we’re dealing with is mass workforce shortages,” said Yi-Bin Chen, MD, director of the bone marrow transplant program at Massachusetts General Hospital in Boston.

“On top of a short-staffed hospital, you then take a very transmissible variant and deplete it even more due to the need to quarantine,” he said in an interview.

Both Dr. Champlin and Dr. Chen said that on-again, off-again pandemic travel bans and donor illnesses have necessitated first obtaining products and cryopreserving them before starting the recipient on a conditioning regimen for the transplant.

“The problem is that, while you can preserve peripheral blood stem cells pretty reliably, cryopreserving bone marrow is a bit more difficult,” Dr. Chen said.

In addition, evidence from recent studies comparing stem cell sources suggest that outcomes are less good with cryopreserved products than with fresh products, and with peripheral blood stem cells compared with bone marrow.

“But you’ve got to make do. A transplant with a cryopreserved product is better than no transplant,” Dr. Chen said.

To make things even more frustrating, as the pandemic waxed and waned throughout 2020 and 2021, the recommendations from donor centers seesawed between using fresh or cryopreserved product, making it difficult to plan a transplant for an individual patient.

The Omicron wave has also resulted in a much higher rate of donor dropout than anticipated, making it that much harder to schedule a transplant, Dr. Chen noted.
 

‘Every patient saved’

The pandemic will eventually subside, however, while the need for stem cell transplantation to treat hematologic malignancies will continue.

DKMS recently launched special aid programs to improve access to stem cell transplants in developing nations by offering financial support, free HLA typing, and other services.

In addition to its core mission of recruiting donors, DKMS is dedicated to improving the quality and efficiency of stem cell transplants. For example, in 2017 scientists in DKMS’ Life Science Lab created an antibody test for donor cytomegalovirus (CMV) infection, using a simple buccal swab rather than a more invasive blood sample. CMV infections can compromise the integrity of stem cell grafts and could be fatal to immunocompromised transplant recipients.

The last word goes to Mechtild Harf’s daughter Katharina.

“My big dream is that every patient will be saved from blood cancer,” she said in a video posted on the DKMS website. “When they get sick, we have a solution for them, whether it’s because they need a donor, with research, building hospitals, providing them with the best medical care we can. I will just keep fighting and keep spreading the word, recruiting donors, raising money – all the things that it takes for us to delete blood cancer.”

“I have to believe that this dream will come true because otherwise, why dream, right?” she said.

Dr. Champlin was the recipient of a Mechtild Harf Science Award and is a member of the board of DKMS U.S. Dr. Schmidt is employed by DKMS. Dr. Chen reported having no relevant disclosures.

When Mechtild Harf was diagnosed with acute leukemia in 1990, physicians told her and her husband Peter that a bone marrow transplant was her best hope for survival. Back then, her native Germany had only 3,000 registered donors, and none was a match.

“My dad just went crazy, you know, to save his wife,” recalled Katharina Harf, who was a young teen at the time of her mother’s diagnosis.

Courtesy DKMS.org

In the course of 1 year, the Harfs recruited more than 68,000 potential bone marrow donors, but their heroic efforts couldn’t save Mechtild.

“She unfortunately didn’t make it. She died because of leukemia,” Katharina said.

Although Mechtild Harf did not survive, her legacy lives on in the bone marrow and stem cell donor recruitment organization DKMS (Deutsche Knochenmarkspenderdatei, or German Bone Marrow Donor Center).

In May of 1991, Peter Harf and Gerhard Ehninger, MD, the hematologist who treated Mechtild, founded DKMS with the mission, as its website states, “to provide as many blood cancer patients as possible with a second chance at life.”

From its German roots, the nonprofit organization has extended its mission to the United States (where it was initially known as Delete Blood Cancer DKMS), Poland, the United Kingdom, Chile, and in 2021, to South Africa.

Three decades after her mother’s death, Katharina Harf serves as Executive Chairwoman of DKMS U.S., based in New York.
 

World’s largest registry

“DKMS has the largest number of unrelated donors of any organization in the world,” noted Richard E. Champlin, MD, chair of the department of stem cell transplantation and cellular therapy at the University of Texas MD Anderson Cancer Center in Houston.

“In a large fraction of our donor searches, we find matches that are in the DKMS registry,” he said in an interview,

In 2022, DKMS is the largest global bone marrow donor recruitment organization, with more than 10.6 million potential donors registered. Worldwide, more than 91,000 patients have received bone marrow or stem cell grafts donated by registered volunteers.

Alexander Schmidt, MD, PhD, global chief medical officer for DKMS, said that approximately 25% of all registered donors worldwide were recruited by his organization, and 39% of all unrelated donor transplants are made with peripheral blood stem cell or bone marrow products, donated by volunteers who are recruited by DKMS.

Since its founding, DKMS has registered 7.1 million potential donors in Germany, who made a total of 80,000 stem cell donations. DKMS U.S., which began operations in 2004, has registered 1.1 million donors and enabled 4,700 donations.
 

Global partners

DKMS partners with donor centers and recruitment organizations in each country where it operates. In the United States, DKMS works with the National Marrow Donor Program (NMDP) and its “Be The Match” donor registry.

“DKMS donors, both those from DKMS in Germany and those from DKMS in the United States are also listed in the NMDP registry, to make it easier for US search coordinators to accept these donors,” Dr. Schmidt explained in an interview.

The international cooperation and coordination makes it possible for a donor in the UK, for example, to save a life of a patient in Germany, the U.S., Chile, India, or many other parts of the world – anywhere that can be reached in time for a patient in need to receive a stem cell donation.
 

Pandemic affects donations

But, as with just about every aspect of life, the COVID-19 pandemic has created enormous challenges for recruiters, donor centers, and stem cell transplant centers.

Dr. Schmidt said that decline in donations during the pandemic was less severe than initially feared, with a decrease of just 3.5% in 2020, compared with the prepandemic year of 2019. In contrast, though, the average annual growth rate for donations prior to the pandemic was about 4%.

“Nevertheless, at the beginning of the pandemic in March 2020, for a few days things looked quite terrible, because all the borders were closed and flights were canceled, and about 50% of all stem cell products go abroad, and between 20% and 25% go intercontinental,” Dr. Schmidt said.

However, close cooperation and coordination between donor centers and national health authorities soon resolved the problem and helped insure that the flow of life-saving donations could continue with minimal disruption, he noted.

“I don’t think we had any product that could not be delivered at the end of the day, due to the pandemic,” he told this news organization.
 

Workforce and clinical problems

Although the flow of donations within and between nations has continued, the COVID-19 pandemic has had profound negative effects on transplant centers, particularly during the wave of infections caused by the Omicron variant, according to a transplant expert.

“With this most recent strain and how transmissible it is, what we’re dealing with is mass workforce shortages,” said Yi-Bin Chen, MD, director of the bone marrow transplant program at Massachusetts General Hospital in Boston.

“On top of a short-staffed hospital, you then take a very transmissible variant and deplete it even more due to the need to quarantine,” he said in an interview.

Both Dr. Champlin and Dr. Chen said that on-again, off-again pandemic travel bans and donor illnesses have necessitated first obtaining products and cryopreserving them before starting the recipient on a conditioning regimen for the transplant.

“The problem is that, while you can preserve peripheral blood stem cells pretty reliably, cryopreserving bone marrow is a bit more difficult,” Dr. Chen said.

In addition, evidence from recent studies comparing stem cell sources suggest that outcomes are less good with cryopreserved products than with fresh products, and with peripheral blood stem cells compared with bone marrow.

“But you’ve got to make do. A transplant with a cryopreserved product is better than no transplant,” Dr. Chen said.

To make things even more frustrating, as the pandemic waxed and waned throughout 2020 and 2021, the recommendations from donor centers seesawed between using fresh or cryopreserved product, making it difficult to plan a transplant for an individual patient.

The Omicron wave has also resulted in a much higher rate of donor dropout than anticipated, making it that much harder to schedule a transplant, Dr. Chen noted.
 

‘Every patient saved’

The pandemic will eventually subside, however, while the need for stem cell transplantation to treat hematologic malignancies will continue.

DKMS recently launched special aid programs to improve access to stem cell transplants in developing nations by offering financial support, free HLA typing, and other services.

In addition to its core mission of recruiting donors, DKMS is dedicated to improving the quality and efficiency of stem cell transplants. For example, in 2017 scientists in DKMS’ Life Science Lab created an antibody test for donor cytomegalovirus (CMV) infection, using a simple buccal swab rather than a more invasive blood sample. CMV infections can compromise the integrity of stem cell grafts and could be fatal to immunocompromised transplant recipients.

The last word goes to Mechtild Harf’s daughter Katharina.

“My big dream is that every patient will be saved from blood cancer,” she said in a video posted on the DKMS website. “When they get sick, we have a solution for them, whether it’s because they need a donor, with research, building hospitals, providing them with the best medical care we can. I will just keep fighting and keep spreading the word, recruiting donors, raising money – all the things that it takes for us to delete blood cancer.”

“I have to believe that this dream will come true because otherwise, why dream, right?” she said.

Dr. Champlin was the recipient of a Mechtild Harf Science Award and is a member of the board of DKMS U.S. Dr. Schmidt is employed by DKMS. Dr. Chen reported having no relevant disclosures.

When Mechtild Harf was diagnosed with acute leukemia in 1990, physicians told her and her husband Peter that a bone marrow transplant was her best hope for survival. Back then, her native Germany had only 3,000 registered donors, and none was a match.

“My dad just went crazy, you know, to save his wife,” recalled Katharina Harf, who was a young teen at the time of her mother’s diagnosis.

Courtesy DKMS.org

In the course of 1 year, the Harfs recruited more than 68,000 potential bone marrow donors, but their heroic efforts couldn’t save Mechtild.

“She unfortunately didn’t make it. She died because of leukemia,” Katharina said.

Although Mechtild Harf did not survive, her legacy lives on in the bone marrow and stem cell donor recruitment organization DKMS (Deutsche Knochenmarkspenderdatei, or German Bone Marrow Donor Center).

In May of 1991, Peter Harf and Gerhard Ehninger, MD, the hematologist who treated Mechtild, founded DKMS with the mission, as its website states, “to provide as many blood cancer patients as possible with a second chance at life.”

From its German roots, the nonprofit organization has extended its mission to the United States (where it was initially known as Delete Blood Cancer DKMS), Poland, the United Kingdom, Chile, and in 2021, to South Africa.

Three decades after her mother’s death, Katharina Harf serves as Executive Chairwoman of DKMS U.S., based in New York.
 

World’s largest registry

“DKMS has the largest number of unrelated donors of any organization in the world,” noted Richard E. Champlin, MD, chair of the department of stem cell transplantation and cellular therapy at the University of Texas MD Anderson Cancer Center in Houston.

“In a large fraction of our donor searches, we find matches that are in the DKMS registry,” he said in an interview,

In 2022, DKMS is the largest global bone marrow donor recruitment organization, with more than 10.6 million potential donors registered. Worldwide, more than 91,000 patients have received bone marrow or stem cell grafts donated by registered volunteers.

Alexander Schmidt, MD, PhD, global chief medical officer for DKMS, said that approximately 25% of all registered donors worldwide were recruited by his organization, and 39% of all unrelated donor transplants are made with peripheral blood stem cell or bone marrow products, donated by volunteers who are recruited by DKMS.

Since its founding, DKMS has registered 7.1 million potential donors in Germany, who made a total of 80,000 stem cell donations. DKMS U.S., which began operations in 2004, has registered 1.1 million donors and enabled 4,700 donations.
 

Global partners

DKMS partners with donor centers and recruitment organizations in each country where it operates. In the United States, DKMS works with the National Marrow Donor Program (NMDP) and its “Be The Match” donor registry.

“DKMS donors, both those from DKMS in Germany and those from DKMS in the United States are also listed in the NMDP registry, to make it easier for US search coordinators to accept these donors,” Dr. Schmidt explained in an interview.

The international cooperation and coordination makes it possible for a donor in the UK, for example, to save a life of a patient in Germany, the U.S., Chile, India, or many other parts of the world – anywhere that can be reached in time for a patient in need to receive a stem cell donation.
 

Pandemic affects donations

But, as with just about every aspect of life, the COVID-19 pandemic has created enormous challenges for recruiters, donor centers, and stem cell transplant centers.

Dr. Schmidt said that decline in donations during the pandemic was less severe than initially feared, with a decrease of just 3.5% in 2020, compared with the prepandemic year of 2019. In contrast, though, the average annual growth rate for donations prior to the pandemic was about 4%.

“Nevertheless, at the beginning of the pandemic in March 2020, for a few days things looked quite terrible, because all the borders were closed and flights were canceled, and about 50% of all stem cell products go abroad, and between 20% and 25% go intercontinental,” Dr. Schmidt said.

However, close cooperation and coordination between donor centers and national health authorities soon resolved the problem and helped insure that the flow of life-saving donations could continue with minimal disruption, he noted.

“I don’t think we had any product that could not be delivered at the end of the day, due to the pandemic,” he told this news organization.
 

Workforce and clinical problems

Although the flow of donations within and between nations has continued, the COVID-19 pandemic has had profound negative effects on transplant centers, particularly during the wave of infections caused by the Omicron variant, according to a transplant expert.

“With this most recent strain and how transmissible it is, what we’re dealing with is mass workforce shortages,” said Yi-Bin Chen, MD, director of the bone marrow transplant program at Massachusetts General Hospital in Boston.

“On top of a short-staffed hospital, you then take a very transmissible variant and deplete it even more due to the need to quarantine,” he said in an interview.

Both Dr. Champlin and Dr. Chen said that on-again, off-again pandemic travel bans and donor illnesses have necessitated first obtaining products and cryopreserving them before starting the recipient on a conditioning regimen for the transplant.

“The problem is that, while you can preserve peripheral blood stem cells pretty reliably, cryopreserving bone marrow is a bit more difficult,” Dr. Chen said.

In addition, evidence from recent studies comparing stem cell sources suggest that outcomes are less good with cryopreserved products than with fresh products, and with peripheral blood stem cells compared with bone marrow.

“But you’ve got to make do. A transplant with a cryopreserved product is better than no transplant,” Dr. Chen said.

To make things even more frustrating, as the pandemic waxed and waned throughout 2020 and 2021, the recommendations from donor centers seesawed between using fresh or cryopreserved product, making it difficult to plan a transplant for an individual patient.

The Omicron wave has also resulted in a much higher rate of donor dropout than anticipated, making it that much harder to schedule a transplant, Dr. Chen noted.
 

‘Every patient saved’

The pandemic will eventually subside, however, while the need for stem cell transplantation to treat hematologic malignancies will continue.

DKMS recently launched special aid programs to improve access to stem cell transplants in developing nations by offering financial support, free HLA typing, and other services.

In addition to its core mission of recruiting donors, DKMS is dedicated to improving the quality and efficiency of stem cell transplants. For example, in 2017 scientists in DKMS’ Life Science Lab created an antibody test for donor cytomegalovirus (CMV) infection, using a simple buccal swab rather than a more invasive blood sample. CMV infections can compromise the integrity of stem cell grafts and could be fatal to immunocompromised transplant recipients.

The last word goes to Mechtild Harf’s daughter Katharina.

“My big dream is that every patient will be saved from blood cancer,” she said in a video posted on the DKMS website. “When they get sick, we have a solution for them, whether it’s because they need a donor, with research, building hospitals, providing them with the best medical care we can. I will just keep fighting and keep spreading the word, recruiting donors, raising money – all the things that it takes for us to delete blood cancer.”

“I have to believe that this dream will come true because otherwise, why dream, right?” she said.

Dr. Champlin was the recipient of a Mechtild Harf Science Award and is a member of the board of DKMS U.S. Dr. Schmidt is employed by DKMS. Dr. Chen reported having no relevant disclosures.

Two new studies show how COVID-19 threatens the health of pregnant people and their newborn infants.

A study conducted in Scotland showed that unvaccinated pregnant people who got COVID were much more likely to have a stillborn infant or one that dies in the first 28 days. The study also found that pregnant women infected with COVID died or needed hospitalization at a much higher rate than vaccinated women who got pregnant.

The University of Edinburgh and Public Health Scotland studied national data in 88,000 pregnancies between Dec. 2020 and Oct. 2021, according to the study published in Nature Medicine.

Overall, 77.4% of infections, 90.9% of COVID-related hospitalizations, and 98% of critical care cases occurred in the unvaccinated people, as did all newborn deaths.

The study said 2,364 babies were born to women infected with COVID, with 2,353 live births. Eleven babies were stillborn and eight live-born babies died within 28 days. Of the live births, 241 were premature.

The problems were more likely if the infection occurred 28 days or less before the delivery date, the researchers said.

The authors said the low vaccination rate among pregnant people was a problem. Only 32% of people giving birth in Oct. 2021 were fully vaccinated, while 77% of the Scottish female population aged 18-44 was fully vaccinated.

“Vaccine hesitancy in pregnancy thus requires addressing, especially in light of new recommendations for booster vaccination administration 3 months after the initial vaccination course to help protect against new variants such as Omicron,” the authors wrote. “Addressing low vaccine uptake rates in pregnant women is imperative to protect the health of women and babies in the ongoing pandemic.”

Vaccinated women who were pregnant had complication rates that were about the same for all pregnant women, the study shows.

The second study, published in The Lancet, found that women who got COVID while pregnant in five Western U.S. states were more likely to have premature births, low birth weights, and stillbirths, even when the COVID cases are mild.

The Institute for Systems Biology researchers in Seattle studied data for women who gave birth in Alaska, California, Montana, Oregon, or Washington from March 5, 2020, to July 4, 2021. About 18,000 of them were tested for COVID, with 882 testing positive. Of the positive tests, 85 came in the first trimester, 226 in the second trimester, and 571 in the third semester. None of the pregnant women had been vaccinated at the time they were infected.

Most of the birth problems occurred with first and second trimester infections, the study noted, and problems occurred even if the pregnant person didn’t have respiratory complications, a major COVID symptom.

“Pregnant people are at an increased risk of adverse outcomes following SARS-CoV-2 infection, even when maternal COVID-19 is less severe, and they may benefit from increased monitoring following infection,” Jennifer Hadlock, MD, an author of the paper, said in a news release.

The study also pointed out continuing inequities in health care, with most of the positive cases occurring among young, non-White people with Medicaid and high body mass index.

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

Two new studies show how COVID-19 threatens the health of pregnant people and their newborn infants.

A study conducted in Scotland showed that unvaccinated pregnant people who got COVID were much more likely to have a stillborn infant or one that dies in the first 28 days. The study also found that pregnant women infected with COVID died or needed hospitalization at a much higher rate than vaccinated women who got pregnant.

The University of Edinburgh and Public Health Scotland studied national data in 88,000 pregnancies between Dec. 2020 and Oct. 2021, according to the study published in Nature Medicine.

Overall, 77.4% of infections, 90.9% of COVID-related hospitalizations, and 98% of critical care cases occurred in the unvaccinated people, as did all newborn deaths.

The study said 2,364 babies were born to women infected with COVID, with 2,353 live births. Eleven babies were stillborn and eight live-born babies died within 28 days. Of the live births, 241 were premature.

The problems were more likely if the infection occurred 28 days or less before the delivery date, the researchers said.

The authors said the low vaccination rate among pregnant people was a problem. Only 32% of people giving birth in Oct. 2021 were fully vaccinated, while 77% of the Scottish female population aged 18-44 was fully vaccinated.

“Vaccine hesitancy in pregnancy thus requires addressing, especially in light of new recommendations for booster vaccination administration 3 months after the initial vaccination course to help protect against new variants such as Omicron,” the authors wrote. “Addressing low vaccine uptake rates in pregnant women is imperative to protect the health of women and babies in the ongoing pandemic.”

Vaccinated women who were pregnant had complication rates that were about the same for all pregnant women, the study shows.

The second study, published in The Lancet, found that women who got COVID while pregnant in five Western U.S. states were more likely to have premature births, low birth weights, and stillbirths, even when the COVID cases are mild.

The Institute for Systems Biology researchers in Seattle studied data for women who gave birth in Alaska, California, Montana, Oregon, or Washington from March 5, 2020, to July 4, 2021. About 18,000 of them were tested for COVID, with 882 testing positive. Of the positive tests, 85 came in the first trimester, 226 in the second trimester, and 571 in the third semester. None of the pregnant women had been vaccinated at the time they were infected.

Most of the birth problems occurred with first and second trimester infections, the study noted, and problems occurred even if the pregnant person didn’t have respiratory complications, a major COVID symptom.

“Pregnant people are at an increased risk of adverse outcomes following SARS-CoV-2 infection, even when maternal COVID-19 is less severe, and they may benefit from increased monitoring following infection,” Jennifer Hadlock, MD, an author of the paper, said in a news release.

The study also pointed out continuing inequities in health care, with most of the positive cases occurring among young, non-White people with Medicaid and high body mass index.

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

Two new studies show how COVID-19 threatens the health of pregnant people and their newborn infants.

A study conducted in Scotland showed that unvaccinated pregnant people who got COVID were much more likely to have a stillborn infant or one that dies in the first 28 days. The study also found that pregnant women infected with COVID died or needed hospitalization at a much higher rate than vaccinated women who got pregnant.

The University of Edinburgh and Public Health Scotland studied national data in 88,000 pregnancies between Dec. 2020 and Oct. 2021, according to the study published in Nature Medicine.

Overall, 77.4% of infections, 90.9% of COVID-related hospitalizations, and 98% of critical care cases occurred in the unvaccinated people, as did all newborn deaths.

The study said 2,364 babies were born to women infected with COVID, with 2,353 live births. Eleven babies were stillborn and eight live-born babies died within 28 days. Of the live births, 241 were premature.

The problems were more likely if the infection occurred 28 days or less before the delivery date, the researchers said.

The authors said the low vaccination rate among pregnant people was a problem. Only 32% of people giving birth in Oct. 2021 were fully vaccinated, while 77% of the Scottish female population aged 18-44 was fully vaccinated.

“Vaccine hesitancy in pregnancy thus requires addressing, especially in light of new recommendations for booster vaccination administration 3 months after the initial vaccination course to help protect against new variants such as Omicron,” the authors wrote. “Addressing low vaccine uptake rates in pregnant women is imperative to protect the health of women and babies in the ongoing pandemic.”

Vaccinated women who were pregnant had complication rates that were about the same for all pregnant women, the study shows.

The second study, published in The Lancet, found that women who got COVID while pregnant in five Western U.S. states were more likely to have premature births, low birth weights, and stillbirths, even when the COVID cases are mild.

The Institute for Systems Biology researchers in Seattle studied data for women who gave birth in Alaska, California, Montana, Oregon, or Washington from March 5, 2020, to July 4, 2021. About 18,000 of them were tested for COVID, with 882 testing positive. Of the positive tests, 85 came in the first trimester, 226 in the second trimester, and 571 in the third semester. None of the pregnant women had been vaccinated at the time they were infected.

Most of the birth problems occurred with first and second trimester infections, the study noted, and problems occurred even if the pregnant person didn’t have respiratory complications, a major COVID symptom.

“Pregnant people are at an increased risk of adverse outcomes following SARS-CoV-2 infection, even when maternal COVID-19 is less severe, and they may benefit from increased monitoring following infection,” Jennifer Hadlock, MD, an author of the paper, said in a news release.

The study also pointed out continuing inequities in health care, with most of the positive cases occurring among young, non-White people with Medicaid and high body mass index.

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

Approximately 3% of youth who tested positive for COVID-19 in an emergency department setting had severe outcomes after 2 weeks, but this risk was 0.5% among those not admitted to the hospital, based on data from more than 3,000 individuals aged 18 and younger.

In the early stages of the COVID-19 pandemic, youth younger than 18 years accounted for fewer than 5% of reported cases, but now account for approximately 25% of positive cases, wrote Anna L. Funk, PhD, of the University of Calgary, Alberta, Canada, and colleagues.

However, the risk of severe outcomes of youth with COVID-19 remains poorly understood and data from large studies are lacking, they noted.

In a prospective cohort study published in JAMA Network Open, the researchers reviewed data from 3,221 children and adolescents who were tested for COVID-19 at one of 41 emergency departments in 10 countries including Argentina, Australia, Canada, Costa Rica, Italy, New Zealand, Paraguay, Singapore, Spain, and the United States between March 2020 and June 2021. Positive infections were confirmed by polymerase chain reaction (PCR) testing. At 14 days’ follow-up after a positive test, 735 patients (22.8%), were hospitalized, 107 (3.3%) had severe outcomes, and 4 (0.12%) had died. Severe outcomes were significantly more likely in children aged 5-10 years and 10-18 years vs. less than 1 year (odds ratios, 1.60 and 2.39, respectively), and in children with a self-reported chronic illness (OR, 2.34) or a prior episode of pneumonia (OR, 3.15).

Severe outcomes were more likely in patients who presented with symptoms that started 4-7 days before seeking care, compared with those whose symptoms started 0-3 days before seeking care (OR, 2.22).

The researchers also reviewed data from a subgroup of 2,510 individuals who were discharged home from the ED after initial testing. At 14 days’ follow-up, 50 of these patients (2.0%) were hospitalized and 12 (0.5%) had severe outcomes. In addition, the researchers found that the risk of severe outcomes among hospitalized COVID-19–positive youth was nearly four times higher, compared with hospitalized youth who tested negative for COVID-19 (risk difference, 3.9%).

Previous retrospective studies of severe outcomes in children and adolescents with COVID-19 have yielded varying results, in part because of the variation in study populations, the researchers noted in their discussion of the findings. “Our study population provides a risk estimate for youths brought for ED care.” Therefore, “Our lower estimate of severe disease likely reflects our stringent definition, which required the occurrence of complications or specific invasive interventions,” they said.

The study limitations included the potential overestimation of the risk of severe outcomes because patients were recruited in the ED, the researchers noted. Other limitations included variation in regional case definitions, screening criteria, and testing capacity among different sites and time periods. “Thus, 5% of our SARS-CoV-2–positive participants were asymptomatic – most of whom were tested as they were positive contacts of known cases or as part of routine screening procedures,” they said. The findings also are not generalizable to all community EDs and did not account for variants, they added.

However, the results were strengthened by the ability to compare outcomes for children with positive tests to similar children with negative tests, and add to the literature showing an increased risk of severe outcomes for those hospitalized with positive tests, the researchers concluded.
 

Data may inform clinical decisions

“The data [in the current study] are concerning for severe outcomes for children even prior to the Omicron strain,” said Margaret Thew, DNP, FP-BC, of Children’s Wisconsin-Milwaukee Hospital, in an interview. “Presently, the number of children infected with the Omicron strain is much higher and hospitalizations among children are at their highest since COVID-19 began,” she said. “For medical providers caring for this population, the study sheds light on pediatric patients who may be at higher risk of severe illness when they become infected with COVID-19,” she added.

“I was surprised by how high the number of pediatric patients hospitalized (22%) and the percentage (3%) with severe disease were during this time,” given that the timeline for these data preceded the spread of the Omicron strain, said Ms. Thew. “The risk of prior pneumonia was quite surprising. I do not recall seeing prior pneumonia as a risk factor for more severe COVID-19 with children or adults,” she added.

The take-home messaging for clinicians caring for children and adolescents is the added knowledge of the risk factors for severe outcomes from COVID-19, including the 10-18 age range, chronic illness, prior pneumonia, and longer symptom duration before seeking care in the ED, Ms. Thew emphasized.

However, additional research is needed on the impact of the new strains of COVID-19 on pediatric and adolescent hospitalizations, Ms. Thew said. Research also is needed on the other illnesses that have resulted from COVID-19, including illness requiring antibiotic use or medical interventions or treatments, and on the risk of combined COVID-19 and influenza viruses, she noted.

The study was supported by the Canadian Institutes of Health Research, Alberta Innovates, the Alberta Health Services University of Calgary Clinical Research Fund, the Alberta Children’s Hospital Research Institute, the COVID-19 Research Accelerator Funding Track (CRAFT) Program at the University of California, Davis, and the Cincinnati Children’s Hospital Medical Center Division of Emergency Medicine Small Grants Program. Lead author Dr. Funk was supported by the University of Calgary Eyes-High Post-Doctoral Research Fund, but had no financial conflicts to disclose. Ms. Thew had no financial conflicts to disclose and serves on the Editorial Advisory Board of Pediatric News.

Approximately 3% of youth who tested positive for COVID-19 in an emergency department setting had severe outcomes after 2 weeks, but this risk was 0.5% among those not admitted to the hospital, based on data from more than 3,000 individuals aged 18 and younger.

In the early stages of the COVID-19 pandemic, youth younger than 18 years accounted for fewer than 5% of reported cases, but now account for approximately 25% of positive cases, wrote Anna L. Funk, PhD, of the University of Calgary, Alberta, Canada, and colleagues.

However, the risk of severe outcomes of youth with COVID-19 remains poorly understood and data from large studies are lacking, they noted.

In a prospective cohort study published in JAMA Network Open, the researchers reviewed data from 3,221 children and adolescents who were tested for COVID-19 at one of 41 emergency departments in 10 countries including Argentina, Australia, Canada, Costa Rica, Italy, New Zealand, Paraguay, Singapore, Spain, and the United States between March 2020 and June 2021. Positive infections were confirmed by polymerase chain reaction (PCR) testing. At 14 days’ follow-up after a positive test, 735 patients (22.8%), were hospitalized, 107 (3.3%) had severe outcomes, and 4 (0.12%) had died. Severe outcomes were significantly more likely in children aged 5-10 years and 10-18 years vs. less than 1 year (odds ratios, 1.60 and 2.39, respectively), and in children with a self-reported chronic illness (OR, 2.34) or a prior episode of pneumonia (OR, 3.15).

Severe outcomes were more likely in patients who presented with symptoms that started 4-7 days before seeking care, compared with those whose symptoms started 0-3 days before seeking care (OR, 2.22).

The researchers also reviewed data from a subgroup of 2,510 individuals who were discharged home from the ED after initial testing. At 14 days’ follow-up, 50 of these patients (2.0%) were hospitalized and 12 (0.5%) had severe outcomes. In addition, the researchers found that the risk of severe outcomes among hospitalized COVID-19–positive youth was nearly four times higher, compared with hospitalized youth who tested negative for COVID-19 (risk difference, 3.9%).

Previous retrospective studies of severe outcomes in children and adolescents with COVID-19 have yielded varying results, in part because of the variation in study populations, the researchers noted in their discussion of the findings. “Our study population provides a risk estimate for youths brought for ED care.” Therefore, “Our lower estimate of severe disease likely reflects our stringent definition, which required the occurrence of complications or specific invasive interventions,” they said.

The study limitations included the potential overestimation of the risk of severe outcomes because patients were recruited in the ED, the researchers noted. Other limitations included variation in regional case definitions, screening criteria, and testing capacity among different sites and time periods. “Thus, 5% of our SARS-CoV-2–positive participants were asymptomatic – most of whom were tested as they were positive contacts of known cases or as part of routine screening procedures,” they said. The findings also are not generalizable to all community EDs and did not account for variants, they added.

However, the results were strengthened by the ability to compare outcomes for children with positive tests to similar children with negative tests, and add to the literature showing an increased risk of severe outcomes for those hospitalized with positive tests, the researchers concluded.
 

Data may inform clinical decisions

“The data [in the current study] are concerning for severe outcomes for children even prior to the Omicron strain,” said Margaret Thew, DNP, FP-BC, of Children’s Wisconsin-Milwaukee Hospital, in an interview. “Presently, the number of children infected with the Omicron strain is much higher and hospitalizations among children are at their highest since COVID-19 began,” she said. “For medical providers caring for this population, the study sheds light on pediatric patients who may be at higher risk of severe illness when they become infected with COVID-19,” she added.

“I was surprised by how high the number of pediatric patients hospitalized (22%) and the percentage (3%) with severe disease were during this time,” given that the timeline for these data preceded the spread of the Omicron strain, said Ms. Thew. “The risk of prior pneumonia was quite surprising. I do not recall seeing prior pneumonia as a risk factor for more severe COVID-19 with children or adults,” she added.

The take-home messaging for clinicians caring for children and adolescents is the added knowledge of the risk factors for severe outcomes from COVID-19, including the 10-18 age range, chronic illness, prior pneumonia, and longer symptom duration before seeking care in the ED, Ms. Thew emphasized.

However, additional research is needed on the impact of the new strains of COVID-19 on pediatric and adolescent hospitalizations, Ms. Thew said. Research also is needed on the other illnesses that have resulted from COVID-19, including illness requiring antibiotic use or medical interventions or treatments, and on the risk of combined COVID-19 and influenza viruses, she noted.

The study was supported by the Canadian Institutes of Health Research, Alberta Innovates, the Alberta Health Services University of Calgary Clinical Research Fund, the Alberta Children’s Hospital Research Institute, the COVID-19 Research Accelerator Funding Track (CRAFT) Program at the University of California, Davis, and the Cincinnati Children’s Hospital Medical Center Division of Emergency Medicine Small Grants Program. Lead author Dr. Funk was supported by the University of Calgary Eyes-High Post-Doctoral Research Fund, but had no financial conflicts to disclose. Ms. Thew had no financial conflicts to disclose and serves on the Editorial Advisory Board of Pediatric News.

Approximately 3% of youth who tested positive for COVID-19 in an emergency department setting had severe outcomes after 2 weeks, but this risk was 0.5% among those not admitted to the hospital, based on data from more than 3,000 individuals aged 18 and younger.

In the early stages of the COVID-19 pandemic, youth younger than 18 years accounted for fewer than 5% of reported cases, but now account for approximately 25% of positive cases, wrote Anna L. Funk, PhD, of the University of Calgary, Alberta, Canada, and colleagues.

However, the risk of severe outcomes of youth with COVID-19 remains poorly understood and data from large studies are lacking, they noted.

In a prospective cohort study published in JAMA Network Open, the researchers reviewed data from 3,221 children and adolescents who were tested for COVID-19 at one of 41 emergency departments in 10 countries including Argentina, Australia, Canada, Costa Rica, Italy, New Zealand, Paraguay, Singapore, Spain, and the United States between March 2020 and June 2021. Positive infections were confirmed by polymerase chain reaction (PCR) testing. At 14 days’ follow-up after a positive test, 735 patients (22.8%), were hospitalized, 107 (3.3%) had severe outcomes, and 4 (0.12%) had died. Severe outcomes were significantly more likely in children aged 5-10 years and 10-18 years vs. less than 1 year (odds ratios, 1.60 and 2.39, respectively), and in children with a self-reported chronic illness (OR, 2.34) or a prior episode of pneumonia (OR, 3.15).

Severe outcomes were more likely in patients who presented with symptoms that started 4-7 days before seeking care, compared with those whose symptoms started 0-3 days before seeking care (OR, 2.22).

The researchers also reviewed data from a subgroup of 2,510 individuals who were discharged home from the ED after initial testing. At 14 days’ follow-up, 50 of these patients (2.0%) were hospitalized and 12 (0.5%) had severe outcomes. In addition, the researchers found that the risk of severe outcomes among hospitalized COVID-19–positive youth was nearly four times higher, compared with hospitalized youth who tested negative for COVID-19 (risk difference, 3.9%).

Previous retrospective studies of severe outcomes in children and adolescents with COVID-19 have yielded varying results, in part because of the variation in study populations, the researchers noted in their discussion of the findings. “Our study population provides a risk estimate for youths brought for ED care.” Therefore, “Our lower estimate of severe disease likely reflects our stringent definition, which required the occurrence of complications or specific invasive interventions,” they said.

The study limitations included the potential overestimation of the risk of severe outcomes because patients were recruited in the ED, the researchers noted. Other limitations included variation in regional case definitions, screening criteria, and testing capacity among different sites and time periods. “Thus, 5% of our SARS-CoV-2–positive participants were asymptomatic – most of whom were tested as they were positive contacts of known cases or as part of routine screening procedures,” they said. The findings also are not generalizable to all community EDs and did not account for variants, they added.

However, the results were strengthened by the ability to compare outcomes for children with positive tests to similar children with negative tests, and add to the literature showing an increased risk of severe outcomes for those hospitalized with positive tests, the researchers concluded.
 

Data may inform clinical decisions

“The data [in the current study] are concerning for severe outcomes for children even prior to the Omicron strain,” said Margaret Thew, DNP, FP-BC, of Children’s Wisconsin-Milwaukee Hospital, in an interview. “Presently, the number of children infected with the Omicron strain is much higher and hospitalizations among children are at their highest since COVID-19 began,” she said. “For medical providers caring for this population, the study sheds light on pediatric patients who may be at higher risk of severe illness when they become infected with COVID-19,” she added.

“I was surprised by how high the number of pediatric patients hospitalized (22%) and the percentage (3%) with severe disease were during this time,” given that the timeline for these data preceded the spread of the Omicron strain, said Ms. Thew. “The risk of prior pneumonia was quite surprising. I do not recall seeing prior pneumonia as a risk factor for more severe COVID-19 with children or adults,” she added.

The take-home messaging for clinicians caring for children and adolescents is the added knowledge of the risk factors for severe outcomes from COVID-19, including the 10-18 age range, chronic illness, prior pneumonia, and longer symptom duration before seeking care in the ED, Ms. Thew emphasized.

However, additional research is needed on the impact of the new strains of COVID-19 on pediatric and adolescent hospitalizations, Ms. Thew said. Research also is needed on the other illnesses that have resulted from COVID-19, including illness requiring antibiotic use or medical interventions or treatments, and on the risk of combined COVID-19 and influenza viruses, she noted.

The study was supported by the Canadian Institutes of Health Research, Alberta Innovates, the Alberta Health Services University of Calgary Clinical Research Fund, the Alberta Children’s Hospital Research Institute, the COVID-19 Research Accelerator Funding Track (CRAFT) Program at the University of California, Davis, and the Cincinnati Children’s Hospital Medical Center Division of Emergency Medicine Small Grants Program. Lead author Dr. Funk was supported by the University of Calgary Eyes-High Post-Doctoral Research Fund, but had no financial conflicts to disclose. Ms. Thew had no financial conflicts to disclose and serves on the Editorial Advisory Board of Pediatric News.

Intranasal ketamine may be a viable treatment option for acute cluster headache attacks, a pilot study has found, though it did not reduce pain intensity as quickly as initially anticipated.

“In clinical practice, intranasal ketamine might be a valuable tool for severely affected patients with insufficient response or intolerance to current first-line treatment,” wrote Anja S. Petersen, MD, of the Danish Headache Center at Rigshospitalet-Glostrup (Denmark) and her coauthors. The study was published online ahead of print in Headache.

To assess ketamine’s safety and efficacy in treating cluster headache attacks, the researchers launched a single-center, open-label, proof-of-concept study of 23 Danish patients with chronic cluster headache. Their average age was 51, 70% were males, and their mean disease duration was 18 years. Twenty of the participants suffered a spontaneous attack while under in-hospital observation and were treated with 15 mg of intranasal ketamine every 6 minutes to a maximum of five times.

Fifteen minutes after ketamine was administered, mean pain intensity (±SD) was reduced from 7.2 (±1.3) to 6.1 (±3.1) on an 11-point numeric rating scale, equivalent to a 15% reduction and well below the primary endpoint of a 50% or greater reduction. Only 4 of the 20 participants had a reduction of 50% or more, and 4 patients chose rescue medication at 15 minutes. However, at 30 minutes pain intensity was reduced by 59% (mean difference 4.3, 95% confidence interval, 2.4-6.2, P > 0.001), with 11 out of 16 participants scoring a 4 or below.

Eight of the 20 participants reported feeling complete relief from the ketamine nasal spray, while 6 participants reported feeling no effects. Half of the patients said they preferred ketamine to oxygen and/or sumatriptan injection. Seventeen patients (83%) reported side effects, but 12 of them classified their side effects as “few.” No serious adverse events were identified, with the most common adverse events being dizziness, lightheadedness, nausea/vomiting, and paresthesia.
 

Debating ketamine’s potential for cluster headache patients

“I’m not crazy about the prospects,” said Stewart J. Tepper, MD, professor of neurology at the Geisel School of Medicine at Dartmouth, Hanover, N.H., in an interview. “It was an admirable proof-of-concept trial, and well worth doing. These are desperate patients. But if the aim was to decrease pain intensity within 15 minutes for cluster patients without side effects, this clearly did not do that,” Dr. Tepper said.

“In a sense, this study was to evaluate whether glutamate might be a target for chronic cluster headache, to determine if blocking NMDA glutamate receptors by ketamine would be effective,” Dr. Tepper said. “And I must say, I’m not very impressed.”

He noted his concerns about the study – including 30 minutes being an “unacceptable” wait for patients undergoing a cluster attack, the 20% of patients who required a rescue at 15 minutes, and the various side effects that come with ketamine in nasal form – and said the results did not sway him to consider ketamine a practical option for cluster headache patients.

“You add all of that up, and I would say this was an equivocal study,” he said. “There might be enough there to be worth studying in episodic cluster rather than chronic cluster; there might be enough to consider a randomized, placebo-controlled trial. But it’s not something that I would ring the bell at Wall Street about.”

“The acute treatment of a patient with chronic cluster headache is a real problem for us headache specialists,” added Alan Rapoport, MD, professor of neurology at University of California, Los Angeles, and past president of the International Headache Society, in an interview. “Cluster headache is probably the worst pain we deal with; women who’ve gone through childbirth say that cluster headache is worse. So it’s very reasonable to have tried.”

“It’s not an impressive finding,” he said, “but it does indicate that there’s some value here. Maybe they need to change the dose; maybe they need to get it in faster by doing something tricky like combining the drug with another substance that will make it attach to the nasal mucosa better. I urge them to study it again, and I hope that they come up with better results the next time, because what they attempted to study is absolutely vital.”

The authors acknowledged their study’s limitations, including a homogeneous patient population and the lack of placebo-controlled verification of effect after 30 minutes. They added, however, that a pilot study like this provides “critical information and paves the way for subsequent placebo-controlled studies.” They also admitted that “daily usage [of ketamine] seems suboptimal” because of the potential of patients becoming addicted.

The study was funded by CCH Pharmaceuticals. Several authors reported receiving speaker’s fees and being subinvestigators in trials run by various pharmaceutical companies, including CCH Pharmaceuticals.

Intranasal ketamine may be a viable treatment option for acute cluster headache attacks, a pilot study has found, though it did not reduce pain intensity as quickly as initially anticipated.

“In clinical practice, intranasal ketamine might be a valuable tool for severely affected patients with insufficient response or intolerance to current first-line treatment,” wrote Anja S. Petersen, MD, of the Danish Headache Center at Rigshospitalet-Glostrup (Denmark) and her coauthors. The study was published online ahead of print in Headache.

To assess ketamine’s safety and efficacy in treating cluster headache attacks, the researchers launched a single-center, open-label, proof-of-concept study of 23 Danish patients with chronic cluster headache. Their average age was 51, 70% were males, and their mean disease duration was 18 years. Twenty of the participants suffered a spontaneous attack while under in-hospital observation and were treated with 15 mg of intranasal ketamine every 6 minutes to a maximum of five times.

Fifteen minutes after ketamine was administered, mean pain intensity (±SD) was reduced from 7.2 (±1.3) to 6.1 (±3.1) on an 11-point numeric rating scale, equivalent to a 15% reduction and well below the primary endpoint of a 50% or greater reduction. Only 4 of the 20 participants had a reduction of 50% or more, and 4 patients chose rescue medication at 15 minutes. However, at 30 minutes pain intensity was reduced by 59% (mean difference 4.3, 95% confidence interval, 2.4-6.2, P > 0.001), with 11 out of 16 participants scoring a 4 or below.

Eight of the 20 participants reported feeling complete relief from the ketamine nasal spray, while 6 participants reported feeling no effects. Half of the patients said they preferred ketamine to oxygen and/or sumatriptan injection. Seventeen patients (83%) reported side effects, but 12 of them classified their side effects as “few.” No serious adverse events were identified, with the most common adverse events being dizziness, lightheadedness, nausea/vomiting, and paresthesia.
 

Debating ketamine’s potential for cluster headache patients

“I’m not crazy about the prospects,” said Stewart J. Tepper, MD, professor of neurology at the Geisel School of Medicine at Dartmouth, Hanover, N.H., in an interview. “It was an admirable proof-of-concept trial, and well worth doing. These are desperate patients. But if the aim was to decrease pain intensity within 15 minutes for cluster patients without side effects, this clearly did not do that,” Dr. Tepper said.

“In a sense, this study was to evaluate whether glutamate might be a target for chronic cluster headache, to determine if blocking NMDA glutamate receptors by ketamine would be effective,” Dr. Tepper said. “And I must say, I’m not very impressed.”

He noted his concerns about the study – including 30 minutes being an “unacceptable” wait for patients undergoing a cluster attack, the 20% of patients who required a rescue at 15 minutes, and the various side effects that come with ketamine in nasal form – and said the results did not sway him to consider ketamine a practical option for cluster headache patients.

“You add all of that up, and I would say this was an equivocal study,” he said. “There might be enough there to be worth studying in episodic cluster rather than chronic cluster; there might be enough to consider a randomized, placebo-controlled trial. But it’s not something that I would ring the bell at Wall Street about.”

“The acute treatment of a patient with chronic cluster headache is a real problem for us headache specialists,” added Alan Rapoport, MD, professor of neurology at University of California, Los Angeles, and past president of the International Headache Society, in an interview. “Cluster headache is probably the worst pain we deal with; women who’ve gone through childbirth say that cluster headache is worse. So it’s very reasonable to have tried.”

“It’s not an impressive finding,” he said, “but it does indicate that there’s some value here. Maybe they need to change the dose; maybe they need to get it in faster by doing something tricky like combining the drug with another substance that will make it attach to the nasal mucosa better. I urge them to study it again, and I hope that they come up with better results the next time, because what they attempted to study is absolutely vital.”

The authors acknowledged their study’s limitations, including a homogeneous patient population and the lack of placebo-controlled verification of effect after 30 minutes. They added, however, that a pilot study like this provides “critical information and paves the way for subsequent placebo-controlled studies.” They also admitted that “daily usage [of ketamine] seems suboptimal” because of the potential of patients becoming addicted.

The study was funded by CCH Pharmaceuticals. Several authors reported receiving speaker’s fees and being subinvestigators in trials run by various pharmaceutical companies, including CCH Pharmaceuticals.

Intranasal ketamine may be a viable treatment option for acute cluster headache attacks, a pilot study has found, though it did not reduce pain intensity as quickly as initially anticipated.

“In clinical practice, intranasal ketamine might be a valuable tool for severely affected patients with insufficient response or intolerance to current first-line treatment,” wrote Anja S. Petersen, MD, of the Danish Headache Center at Rigshospitalet-Glostrup (Denmark) and her coauthors. The study was published online ahead of print in Headache.

To assess ketamine’s safety and efficacy in treating cluster headache attacks, the researchers launched a single-center, open-label, proof-of-concept study of 23 Danish patients with chronic cluster headache. Their average age was 51, 70% were males, and their mean disease duration was 18 years. Twenty of the participants suffered a spontaneous attack while under in-hospital observation and were treated with 15 mg of intranasal ketamine every 6 minutes to a maximum of five times.

Fifteen minutes after ketamine was administered, mean pain intensity (±SD) was reduced from 7.2 (±1.3) to 6.1 (±3.1) on an 11-point numeric rating scale, equivalent to a 15% reduction and well below the primary endpoint of a 50% or greater reduction. Only 4 of the 20 participants had a reduction of 50% or more, and 4 patients chose rescue medication at 15 minutes. However, at 30 minutes pain intensity was reduced by 59% (mean difference 4.3, 95% confidence interval, 2.4-6.2, P > 0.001), with 11 out of 16 participants scoring a 4 or below.

Eight of the 20 participants reported feeling complete relief from the ketamine nasal spray, while 6 participants reported feeling no effects. Half of the patients said they preferred ketamine to oxygen and/or sumatriptan injection. Seventeen patients (83%) reported side effects, but 12 of them classified their side effects as “few.” No serious adverse events were identified, with the most common adverse events being dizziness, lightheadedness, nausea/vomiting, and paresthesia.
 

Debating ketamine’s potential for cluster headache patients

“I’m not crazy about the prospects,” said Stewart J. Tepper, MD, professor of neurology at the Geisel School of Medicine at Dartmouth, Hanover, N.H., in an interview. “It was an admirable proof-of-concept trial, and well worth doing. These are desperate patients. But if the aim was to decrease pain intensity within 15 minutes for cluster patients without side effects, this clearly did not do that,” Dr. Tepper said.

“In a sense, this study was to evaluate whether glutamate might be a target for chronic cluster headache, to determine if blocking NMDA glutamate receptors by ketamine would be effective,” Dr. Tepper said. “And I must say, I’m not very impressed.”

He noted his concerns about the study – including 30 minutes being an “unacceptable” wait for patients undergoing a cluster attack, the 20% of patients who required a rescue at 15 minutes, and the various side effects that come with ketamine in nasal form – and said the results did not sway him to consider ketamine a practical option for cluster headache patients.

“You add all of that up, and I would say this was an equivocal study,” he said. “There might be enough there to be worth studying in episodic cluster rather than chronic cluster; there might be enough to consider a randomized, placebo-controlled trial. But it’s not something that I would ring the bell at Wall Street about.”

“The acute treatment of a patient with chronic cluster headache is a real problem for us headache specialists,” added Alan Rapoport, MD, professor of neurology at University of California, Los Angeles, and past president of the International Headache Society, in an interview. “Cluster headache is probably the worst pain we deal with; women who’ve gone through childbirth say that cluster headache is worse. So it’s very reasonable to have tried.”

“It’s not an impressive finding,” he said, “but it does indicate that there’s some value here. Maybe they need to change the dose; maybe they need to get it in faster by doing something tricky like combining the drug with another substance that will make it attach to the nasal mucosa better. I urge them to study it again, and I hope that they come up with better results the next time, because what they attempted to study is absolutely vital.”

The authors acknowledged their study’s limitations, including a homogeneous patient population and the lack of placebo-controlled verification of effect after 30 minutes. They added, however, that a pilot study like this provides “critical information and paves the way for subsequent placebo-controlled studies.” They also admitted that “daily usage [of ketamine] seems suboptimal” because of the potential of patients becoming addicted.

The study was funded by CCH Pharmaceuticals. Several authors reported receiving speaker’s fees and being subinvestigators in trials run by various pharmaceutical companies, including CCH Pharmaceuticals.

With the country looking increasingly to rapid testing as an off-ramp from the COVID-19 pandemic, a new study shows that the performance of the tests in children falls below standards set by regulatory agencies in the United States and elsewhere for diagnostic accuracy.

Experts said the findings, from a meta-analysis by researchers in the United Kingdom and Germany, underscore that, while a positive result on a rapid test is almost certainly an indicator of infection, negative results often are unreliable and can lead to a false sense of security.

“Real-life performance of current antigen tests for professional use in pediatric populations is below the minimum performance criteria set by WHO, the United States Food and Drug Administration, or the Medicines and Healthcare products Regulatory Agency (U.K.),” according to Naomi Fujita-Rohwerder, PhD, a research associate at the Cologne-based German Institute for Quality and Efficiency in Health Care (IQWiG), and her colleagues, whose study appears in BMJ Evidence-Based Medicine.

The researchers said that the study suggests that performance of rapid testing in a pediatric population is comparable to that in adults. However, they said they could not identify any studies investigating self-testing in children, which also could affect test performance.

Egon Ozer, MD, PhD, director of the center for pathogen genomics and microbial evolution at Northwestern University in Chicago, said the finding that specificity was high but sensitivity was middling “suggests that we should be very careful about interpreting negative antigen test results in children and recognize that there is a fair amount of uncertainty in the tests in this situation.”

Researchers from IQWiG, which examines the advantages and disadvantages of medical interventions, and the University of Manchester (England), conducted the systematic review and meta-analysis, which they described as the first of its kind to evaluate the diagnostic accuracy of rapid point-of-care tests for current SARS-CoV-2 infections in children.

They compiled information from 17 studies with a total 6,355 participants. They compared all antigen tests to reverse-transcription polymerase chain reaction (PCR). The studies compared eight antigen tests from six different brands. The rapid antigen tests, available from pharmacies and online stores, are widely used for self-testing in schools and testing toddlers before kindergarten.

The pooled diagnostic sensitivity of antigen tests was 64.2% and specificity was 99.1%.

Dr. Ozer noted that the analysis “was not able to address important outstanding questions such as the likelihood of transmitting infection with a false-negative antigen test versus a true-negative antigen test or how much repeated testing can increase the sensitivity.”

“In Europe, we don’t know how most tests perform in real life,” Dr. Fujita-Rohwerder said. “And even in countries like the United States, where market access is more stringent, we don’t know whether self-testing performed by children or sample collection in toddlers by laypersons has a significant impact on the diagnostic accuracy. Also, diagnostic accuracy estimates reported in our study may not apply to the current omicron or future variants of SARS-CoV-2 or vaccinated children. Hopefully, these essential gaps in the evidence will get addressed soon.”

Dr. Ozer said one takeaway from this study is negative antigen tests should not be considered a “free pass” in children, especially if the child is symptomatic, has been recently exposed to COVID-19, or is planning to spend time with individuals with conditions that place them at high risk for complications of COVID-19 infection. “In such cases, consider getting PCR testing or at least performing a repeat antigen test 36-48 hours after the first negative,” he said.

Dr. Fujita-Rohwerder said the low diagnostic sensitivity may affect the use of the tests. The gaps in evidence her group found in their study point to research needed to support evidence-based decision-making. “In particular, evidence is needed on real-life performance of tests in schools, self-testing performed by children, and kindergarten, [particularly] sample collection in toddlers by laypersons,” she said.

However, she stressed, testing is only a single measure. “Effectively reducing the spread of SARS-CoV-2 during the current pandemic requires multilayered mitigation measures,” she said. “Rapid testing represents one single layer. It can have its use at the population level, even though the sensitivity of antigen tests is lower than expected. However, antigen-based rapid testing is not a magic bullet: If your kid tests negative, do not disregard other mitigation measures.”

Edward Campbell, PhD, a virologist at Loyola University of Chicago, who serves on the board of LaGrange Elementary School District 102 outside Chicago, said the findings were unsurprising.

“This study generally looks consistent with what is known for adults. These rapid antigen tests are less sensitive than other tests,” said Dr. Campbell, who also runs a testing company for private schools in the Chicago area using reverse transcription-loop-mediated isothermal amplification technology. Even so, he said, “These tests are still effective at identifying people who are infectious to some degree. Never miss an opportunity to test.”

Dr. Fujita-Rohwerder disclosed no relevant financial conflicts of interest. Dr. Campbell owns Safeguard Surveillance.

With the country looking increasingly to rapid testing as an off-ramp from the COVID-19 pandemic, a new study shows that the performance of the tests in children falls below standards set by regulatory agencies in the United States and elsewhere for diagnostic accuracy.

Experts said the findings, from a meta-analysis by researchers in the United Kingdom and Germany, underscore that, while a positive result on a rapid test is almost certainly an indicator of infection, negative results often are unreliable and can lead to a false sense of security.

“Real-life performance of current antigen tests for professional use in pediatric populations is below the minimum performance criteria set by WHO, the United States Food and Drug Administration, or the Medicines and Healthcare products Regulatory Agency (U.K.),” according to Naomi Fujita-Rohwerder, PhD, a research associate at the Cologne-based German Institute for Quality and Efficiency in Health Care (IQWiG), and her colleagues, whose study appears in BMJ Evidence-Based Medicine.

The researchers said that the study suggests that performance of rapid testing in a pediatric population is comparable to that in adults. However, they said they could not identify any studies investigating self-testing in children, which also could affect test performance.

Egon Ozer, MD, PhD, director of the center for pathogen genomics and microbial evolution at Northwestern University in Chicago, said the finding that specificity was high but sensitivity was middling “suggests that we should be very careful about interpreting negative antigen test results in children and recognize that there is a fair amount of uncertainty in the tests in this situation.”

Researchers from IQWiG, which examines the advantages and disadvantages of medical interventions, and the University of Manchester (England), conducted the systematic review and meta-analysis, which they described as the first of its kind to evaluate the diagnostic accuracy of rapid point-of-care tests for current SARS-CoV-2 infections in children.

They compiled information from 17 studies with a total 6,355 participants. They compared all antigen tests to reverse-transcription polymerase chain reaction (PCR). The studies compared eight antigen tests from six different brands. The rapid antigen tests, available from pharmacies and online stores, are widely used for self-testing in schools and testing toddlers before kindergarten.

The pooled diagnostic sensitivity of antigen tests was 64.2% and specificity was 99.1%.

Dr. Ozer noted that the analysis “was not able to address important outstanding questions such as the likelihood of transmitting infection with a false-negative antigen test versus a true-negative antigen test or how much repeated testing can increase the sensitivity.”

“In Europe, we don’t know how most tests perform in real life,” Dr. Fujita-Rohwerder said. “And even in countries like the United States, where market access is more stringent, we don’t know whether self-testing performed by children or sample collection in toddlers by laypersons has a significant impact on the diagnostic accuracy. Also, diagnostic accuracy estimates reported in our study may not apply to the current omicron or future variants of SARS-CoV-2 or vaccinated children. Hopefully, these essential gaps in the evidence will get addressed soon.”

Dr. Ozer said one takeaway from this study is negative antigen tests should not be considered a “free pass” in children, especially if the child is symptomatic, has been recently exposed to COVID-19, or is planning to spend time with individuals with conditions that place them at high risk for complications of COVID-19 infection. “In such cases, consider getting PCR testing or at least performing a repeat antigen test 36-48 hours after the first negative,” he said.

Dr. Fujita-Rohwerder said the low diagnostic sensitivity may affect the use of the tests. The gaps in evidence her group found in their study point to research needed to support evidence-based decision-making. “In particular, evidence is needed on real-life performance of tests in schools, self-testing performed by children, and kindergarten, [particularly] sample collection in toddlers by laypersons,” she said.

However, she stressed, testing is only a single measure. “Effectively reducing the spread of SARS-CoV-2 during the current pandemic requires multilayered mitigation measures,” she said. “Rapid testing represents one single layer. It can have its use at the population level, even though the sensitivity of antigen tests is lower than expected. However, antigen-based rapid testing is not a magic bullet: If your kid tests negative, do not disregard other mitigation measures.”

Edward Campbell, PhD, a virologist at Loyola University of Chicago, who serves on the board of LaGrange Elementary School District 102 outside Chicago, said the findings were unsurprising.

“This study generally looks consistent with what is known for adults. These rapid antigen tests are less sensitive than other tests,” said Dr. Campbell, who also runs a testing company for private schools in the Chicago area using reverse transcription-loop-mediated isothermal amplification technology. Even so, he said, “These tests are still effective at identifying people who are infectious to some degree. Never miss an opportunity to test.”

Dr. Fujita-Rohwerder disclosed no relevant financial conflicts of interest. Dr. Campbell owns Safeguard Surveillance.

With the country looking increasingly to rapid testing as an off-ramp from the COVID-19 pandemic, a new study shows that the performance of the tests in children falls below standards set by regulatory agencies in the United States and elsewhere for diagnostic accuracy.

Experts said the findings, from a meta-analysis by researchers in the United Kingdom and Germany, underscore that, while a positive result on a rapid test is almost certainly an indicator of infection, negative results often are unreliable and can lead to a false sense of security.

“Real-life performance of current antigen tests for professional use in pediatric populations is below the minimum performance criteria set by WHO, the United States Food and Drug Administration, or the Medicines and Healthcare products Regulatory Agency (U.K.),” according to Naomi Fujita-Rohwerder, PhD, a research associate at the Cologne-based German Institute for Quality and Efficiency in Health Care (IQWiG), and her colleagues, whose study appears in BMJ Evidence-Based Medicine.

The researchers said that the study suggests that performance of rapid testing in a pediatric population is comparable to that in adults. However, they said they could not identify any studies investigating self-testing in children, which also could affect test performance.

Egon Ozer, MD, PhD, director of the center for pathogen genomics and microbial evolution at Northwestern University in Chicago, said the finding that specificity was high but sensitivity was middling “suggests that we should be very careful about interpreting negative antigen test results in children and recognize that there is a fair amount of uncertainty in the tests in this situation.”

Researchers from IQWiG, which examines the advantages and disadvantages of medical interventions, and the University of Manchester (England), conducted the systematic review and meta-analysis, which they described as the first of its kind to evaluate the diagnostic accuracy of rapid point-of-care tests for current SARS-CoV-2 infections in children.

They compiled information from 17 studies with a total 6,355 participants. They compared all antigen tests to reverse-transcription polymerase chain reaction (PCR). The studies compared eight antigen tests from six different brands. The rapid antigen tests, available from pharmacies and online stores, are widely used for self-testing in schools and testing toddlers before kindergarten.

The pooled diagnostic sensitivity of antigen tests was 64.2% and specificity was 99.1%.

Dr. Ozer noted that the analysis “was not able to address important outstanding questions such as the likelihood of transmitting infection with a false-negative antigen test versus a true-negative antigen test or how much repeated testing can increase the sensitivity.”

“In Europe, we don’t know how most tests perform in real life,” Dr. Fujita-Rohwerder said. “And even in countries like the United States, where market access is more stringent, we don’t know whether self-testing performed by children or sample collection in toddlers by laypersons has a significant impact on the diagnostic accuracy. Also, diagnostic accuracy estimates reported in our study may not apply to the current omicron or future variants of SARS-CoV-2 or vaccinated children. Hopefully, these essential gaps in the evidence will get addressed soon.”

Dr. Ozer said one takeaway from this study is negative antigen tests should not be considered a “free pass” in children, especially if the child is symptomatic, has been recently exposed to COVID-19, or is planning to spend time with individuals with conditions that place them at high risk for complications of COVID-19 infection. “In such cases, consider getting PCR testing or at least performing a repeat antigen test 36-48 hours after the first negative,” he said.

Dr. Fujita-Rohwerder said the low diagnostic sensitivity may affect the use of the tests. The gaps in evidence her group found in their study point to research needed to support evidence-based decision-making. “In particular, evidence is needed on real-life performance of tests in schools, self-testing performed by children, and kindergarten, [particularly] sample collection in toddlers by laypersons,” she said.

However, she stressed, testing is only a single measure. “Effectively reducing the spread of SARS-CoV-2 during the current pandemic requires multilayered mitigation measures,” she said. “Rapid testing represents one single layer. It can have its use at the population level, even though the sensitivity of antigen tests is lower than expected. However, antigen-based rapid testing is not a magic bullet: If your kid tests negative, do not disregard other mitigation measures.”

Edward Campbell, PhD, a virologist at Loyola University of Chicago, who serves on the board of LaGrange Elementary School District 102 outside Chicago, said the findings were unsurprising.

“This study generally looks consistent with what is known for adults. These rapid antigen tests are less sensitive than other tests,” said Dr. Campbell, who also runs a testing company for private schools in the Chicago area using reverse transcription-loop-mediated isothermal amplification technology. Even so, he said, “These tests are still effective at identifying people who are infectious to some degree. Never miss an opportunity to test.”

Dr. Fujita-Rohwerder disclosed no relevant financial conflicts of interest. Dr. Campbell owns Safeguard Surveillance.

Fed up with personal attacks on the nation’s top infectious disease expert, scores of leading scientists and physicians have signed an open letter defending Anthony Fauci, MD, for his years of service to the public and his leadership on the pandemic.

“We deplore the personal attacks on Dr. Fauci. The criticism is inaccurate, unscientific, ill-founded in the facts and, increasingly, motivated by partisan politics,” reads the letter of support, initiated by Ezekiel Emanuel, MD, and signed by almost 300 scientists and public health and medical professionals, including Nobel Laureates, a former Republican senator, and leadership of medical societies and institutions.

Dr. Fauci has led the National Institute for Allergy and Infectious Diseases since 1984 and serves as President Biden’s top medical advisor on the pandemic.

“Dr. Anthony Fauci has served the U.S.A. with wisdom and integrity for nearly 40 years. Through HIV, Ebola, and now COVID, he has unswervingly served the United States guiding the country to very successful outcomes. He has our unreserved respect and trust as a scientist and a national leader,” the letter reads.

Dr. Fauci has repeatedly faced harsh criticism from congressional Republicans, especially Sen. Rand Paul (R-Ky.) and Sen. Roger Marshall (R-Kan.).

At a particularly contentious congressional hearing earlier this week on the federal government’s response to Omicron, Dr. Fauci fought back, telling Sen. Marshall, “You’re so misinformed, it’s extraordinary.”

Dr. Fauci, who has received death threats and harassment of his family, told Sen. Rand that his “completely untrue” statements and rhetoric “kindles the crazies out there.”
 

‘Sagacious counsel’

The personal attacks on Dr. Fauci are a “distraction from what should be the national focus – working together to finally overcome a pandemic that is killing about 500,000 people a year. We are grateful for Dr. Fauci’s dedication and tireless efforts to help the country through this pandemic and other health crises,” the letter reads.

“Throughout the COVID-19 pandemic, Dr. Fauci has provided the American political leadership and the public with sagacious counsel in these most difficult of times. His advice has been as well informed as data and the rapidly evolving circumstances allowed,” it states.

“Importantly,” Dr. Fauci has given his advice with “humility, being clear about what we know and what is unknown, but requires judgment. He has consistently emphasized the importance of mask-wearing, social distancing, and vaccination. These are standard and necessary public health measures that we all support,” the letter states.

“We are grateful that Dr. Fauci has consistently stated the science in a way that represents the facts as they emerge, without unwarranted speculation.”

“Sadly, in these politically polarized times where misinformation contaminates the United States’ response to the pandemic, routine public health measures have become unnecessarily controversial, undermining the effectiveness of our country’s response,” the letter reads.

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

Fed up with personal attacks on the nation’s top infectious disease expert, scores of leading scientists and physicians have signed an open letter defending Anthony Fauci, MD, for his years of service to the public and his leadership on the pandemic.

“We deplore the personal attacks on Dr. Fauci. The criticism is inaccurate, unscientific, ill-founded in the facts and, increasingly, motivated by partisan politics,” reads the letter of support, initiated by Ezekiel Emanuel, MD, and signed by almost 300 scientists and public health and medical professionals, including Nobel Laureates, a former Republican senator, and leadership of medical societies and institutions.

Dr. Fauci has led the National Institute for Allergy and Infectious Diseases since 1984 and serves as President Biden’s top medical advisor on the pandemic.

“Dr. Anthony Fauci has served the U.S.A. with wisdom and integrity for nearly 40 years. Through HIV, Ebola, and now COVID, he has unswervingly served the United States guiding the country to very successful outcomes. He has our unreserved respect and trust as a scientist and a national leader,” the letter reads.

Dr. Fauci has repeatedly faced harsh criticism from congressional Republicans, especially Sen. Rand Paul (R-Ky.) and Sen. Roger Marshall (R-Kan.).

At a particularly contentious congressional hearing earlier this week on the federal government’s response to Omicron, Dr. Fauci fought back, telling Sen. Marshall, “You’re so misinformed, it’s extraordinary.”

Dr. Fauci, who has received death threats and harassment of his family, told Sen. Rand that his “completely untrue” statements and rhetoric “kindles the crazies out there.”
 

‘Sagacious counsel’

The personal attacks on Dr. Fauci are a “distraction from what should be the national focus – working together to finally overcome a pandemic that is killing about 500,000 people a year. We are grateful for Dr. Fauci’s dedication and tireless efforts to help the country through this pandemic and other health crises,” the letter reads.

“Throughout the COVID-19 pandemic, Dr. Fauci has provided the American political leadership and the public with sagacious counsel in these most difficult of times. His advice has been as well informed as data and the rapidly evolving circumstances allowed,” it states.

“Importantly,” Dr. Fauci has given his advice with “humility, being clear about what we know and what is unknown, but requires judgment. He has consistently emphasized the importance of mask-wearing, social distancing, and vaccination. These are standard and necessary public health measures that we all support,” the letter states.

“We are grateful that Dr. Fauci has consistently stated the science in a way that represents the facts as they emerge, without unwarranted speculation.”

“Sadly, in these politically polarized times where misinformation contaminates the United States’ response to the pandemic, routine public health measures have become unnecessarily controversial, undermining the effectiveness of our country’s response,” the letter reads.

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

Fed up with personal attacks on the nation’s top infectious disease expert, scores of leading scientists and physicians have signed an open letter defending Anthony Fauci, MD, for his years of service to the public and his leadership on the pandemic.

“We deplore the personal attacks on Dr. Fauci. The criticism is inaccurate, unscientific, ill-founded in the facts and, increasingly, motivated by partisan politics,” reads the letter of support, initiated by Ezekiel Emanuel, MD, and signed by almost 300 scientists and public health and medical professionals, including Nobel Laureates, a former Republican senator, and leadership of medical societies and institutions.

Dr. Fauci has led the National Institute for Allergy and Infectious Diseases since 1984 and serves as President Biden’s top medical advisor on the pandemic.

“Dr. Anthony Fauci has served the U.S.A. with wisdom and integrity for nearly 40 years. Through HIV, Ebola, and now COVID, he has unswervingly served the United States guiding the country to very successful outcomes. He has our unreserved respect and trust as a scientist and a national leader,” the letter reads.

Dr. Fauci has repeatedly faced harsh criticism from congressional Republicans, especially Sen. Rand Paul (R-Ky.) and Sen. Roger Marshall (R-Kan.).

At a particularly contentious congressional hearing earlier this week on the federal government’s response to Omicron, Dr. Fauci fought back, telling Sen. Marshall, “You’re so misinformed, it’s extraordinary.”

Dr. Fauci, who has received death threats and harassment of his family, told Sen. Rand that his “completely untrue” statements and rhetoric “kindles the crazies out there.”
 

‘Sagacious counsel’

The personal attacks on Dr. Fauci are a “distraction from what should be the national focus – working together to finally overcome a pandemic that is killing about 500,000 people a year. We are grateful for Dr. Fauci’s dedication and tireless efforts to help the country through this pandemic and other health crises,” the letter reads.

“Throughout the COVID-19 pandemic, Dr. Fauci has provided the American political leadership and the public with sagacious counsel in these most difficult of times. His advice has been as well informed as data and the rapidly evolving circumstances allowed,” it states.

“Importantly,” Dr. Fauci has given his advice with “humility, being clear about what we know and what is unknown, but requires judgment. He has consistently emphasized the importance of mask-wearing, social distancing, and vaccination. These are standard and necessary public health measures that we all support,” the letter states.

“We are grateful that Dr. Fauci has consistently stated the science in a way that represents the facts as they emerge, without unwarranted speculation.”

“Sadly, in these politically polarized times where misinformation contaminates the United States’ response to the pandemic, routine public health measures have become unnecessarily controversial, undermining the effectiveness of our country’s response,” the letter reads.

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