Infectious Diseases

Regardless of the severity of their initial illness, 89% of people who were hospitalized with COVID-19 had returned to their original work 2 years later, a new study shows.

The burden of persistent COVID-19 symptoms appeared to improve over time, but a higher percentage of former patients reported poor health, compared with the general population. This suggests that some patients need more time to completely recover from COVID-19, wrote the authors of the new study, which was published in The Lancet Respiratory Medicine. Previous research has shown that the health effects of COVID-19 last for up to a year, but data from longer-term studies are limited, said Lixue Huang, MD, of Capital Medical University, Beijing, one of the study authors, and colleagues.

Methods and results

In the new study, the researchers reviewed data from 1,192 adult patients who were discharged from the hospital after surviving COVID-19 between Jan. 7, 2020, and May 29, 2020. The researchers measured the participants’ health outcomes at 6 months, 12 months, and 2 years after their onset of symptoms. A community-based dataset of 3,383 adults with no history of COVID-19 served as controls to measure the recovery of the COVID-19 patients. The median age of the patients at the time of hospital discharge was 57 years, and 46% were women. The median follow-up time after the onset of symptoms was 185 days, 349 days, and 685 days for the 6-month, 12-month, and 2-year visits, respectively. The researchers measured health outcomes using a 6-min walking distance (6MWD) test, laboratory tests, and questionnaires about symptoms, mental health, health-related quality of life, returning to work, and health care use since leaving the hospital.

Overall, the proportion of COVID-19 survivors with at least one symptom decreased from 68% at 6 months to 55% at 2 years (P < .0001). The most frequent symptoms were fatigue and muscle weakness, reported by approximately one-third of the patients (31%); sleep problems also were reported by 31% of the patients.

The proportion of individuals with poor results on the 6MWD decreased continuously over time, not only in COVID-19 survivors overall, but also in three subgroups of varying initial disease severity. Of the 494 survivors who reported working before becoming ill, 438 (89%) had returned to their original jobs 2 years later. The most common reasons for not returning to work were decreased physical function, unwillingness to return, and unemployment, the researchers noted.

However, at 2 years, COVID-19 survivors reported more pain and discomfort, as well as more anxiety and depression, compared with the controls (23% vs. 5% and 12% vs. 5%, respectively).

In addition, significantly more survivors who needed high levels of respiratory support while hospitalized had lung diffusion impairment (65%), reduced residual volume (62%), and total lung capacity (39%), compared with matched controls (36%, 20%, and 6%, respectively) at 2 years.

Long-COVID concerns

Approximately half of the survivors had symptoms of long COVID at 2 years. These individuals were more likely to report pain or discomfort or anxiety or depression, as well as mobility problems, compared to survivors without long COVID. Participants with long-COVID symptoms were more than twice as likely to have an outpatient clinic visit (odds ratio, 2.82), and not quite twice as likely to be rehospitalized (OR, 1.64).

“We found that [health-related quality of life], exercise capacity, and mental health continued to improve throughout the 2 years regardless of initial disease severity, but about half still had symptomatic sequelae at 2 years,” the researchers wrote in their paper.

Findings can inform doctor-patient discussions

“We are increasingly recognizing that the health effects of COVID-19 may persist beyond acute illness, therefore this is a timely study to assess the long-term impact of COVID-19 with a long follow-up period,” said Suman Pal, MD, an internal medicine physician at the University of New Mexico, Albuquerque, in an interview.

The findings are consistent with the existing literature, said Dr. Pal, who was not involved in the study.  The data from the study “can help clinicians have discussions regarding expected recovery and long-term prognosis for patients with COVID-19,” he noted.

What patients should know is that “studies such as this can help COVID-19 survivors understand and monitor persistent symptoms they may experience, and bring them to the attention of their clinicians,” said Dr. Pal.

However, “As a single-center study with high attrition of subjects during the study period, the findings may not be generalizable,” Dr. Pal emphasized. “Larger-scale studies and patient registries distributed over different geographical areas and time periods will help obtain a better understanding of the nature and prevalence of long COVID,” he said.

The study findings were limited by several factors, including the lack of formerly hospitalized controls with respiratory infections other than COVID-19 to determine which outcomes are COVID-19 specific, the researchers noted. Other limitations included the use of data from only patients at a single center, and from the early stages of the pandemic, as well as the use of self-reports for comorbidities and health outcomes, they said.

However, the results represent the longest-known published longitudinal follow-up of patients who recovered from acute COVID-19, the researchers emphasized. Study strengths included the large sample size, longitudinal design, and long-term follow-up with non-COVID controls to determine outcomes. The researchers noted their plans to conduct annual follow-ups in the current study population. They added that more research is needed to explore rehabilitation programs to promote recovery for COVID-19 survivors and to reduce the effects of long COVID.

The study was supported by the Chinese Academy of Medical Sciences, National Natural Science Foundation of China, National Key Research and Development Program of China, National Administration of Traditional Chinese Medicine, Major Projects of National Science and Technology on New Drug Creation and Development of Pulmonary Tuberculosis, China Evergrande Group, Jack Ma Foundation, Sino Biopharmaceutical, Ping An Insurance (Group), and New Sunshine Charity Foundation. The researchers and Dr. Pal had no financial conflicts to disclose.

This article was updated on 5/16/2022.

Regardless of the severity of their initial illness, 89% of people who were hospitalized with COVID-19 had returned to their original work 2 years later, a new study shows.

The burden of persistent COVID-19 symptoms appeared to improve over time, but a higher percentage of former patients reported poor health, compared with the general population. This suggests that some patients need more time to completely recover from COVID-19, wrote the authors of the new study, which was published in The Lancet Respiratory Medicine. Previous research has shown that the health effects of COVID-19 last for up to a year, but data from longer-term studies are limited, said Lixue Huang, MD, of Capital Medical University, Beijing, one of the study authors, and colleagues.

Methods and results

In the new study, the researchers reviewed data from 1,192 adult patients who were discharged from the hospital after surviving COVID-19 between Jan. 7, 2020, and May 29, 2020. The researchers measured the participants’ health outcomes at 6 months, 12 months, and 2 years after their onset of symptoms. A community-based dataset of 3,383 adults with no history of COVID-19 served as controls to measure the recovery of the COVID-19 patients. The median age of the patients at the time of hospital discharge was 57 years, and 46% were women. The median follow-up time after the onset of symptoms was 185 days, 349 days, and 685 days for the 6-month, 12-month, and 2-year visits, respectively. The researchers measured health outcomes using a 6-min walking distance (6MWD) test, laboratory tests, and questionnaires about symptoms, mental health, health-related quality of life, returning to work, and health care use since leaving the hospital.

Overall, the proportion of COVID-19 survivors with at least one symptom decreased from 68% at 6 months to 55% at 2 years (P < .0001). The most frequent symptoms were fatigue and muscle weakness, reported by approximately one-third of the patients (31%); sleep problems also were reported by 31% of the patients.

The proportion of individuals with poor results on the 6MWD decreased continuously over time, not only in COVID-19 survivors overall, but also in three subgroups of varying initial disease severity. Of the 494 survivors who reported working before becoming ill, 438 (89%) had returned to their original jobs 2 years later. The most common reasons for not returning to work were decreased physical function, unwillingness to return, and unemployment, the researchers noted.

However, at 2 years, COVID-19 survivors reported more pain and discomfort, as well as more anxiety and depression, compared with the controls (23% vs. 5% and 12% vs. 5%, respectively).

In addition, significantly more survivors who needed high levels of respiratory support while hospitalized had lung diffusion impairment (65%), reduced residual volume (62%), and total lung capacity (39%), compared with matched controls (36%, 20%, and 6%, respectively) at 2 years.

Long-COVID concerns

Approximately half of the survivors had symptoms of long COVID at 2 years. These individuals were more likely to report pain or discomfort or anxiety or depression, as well as mobility problems, compared to survivors without long COVID. Participants with long-COVID symptoms were more than twice as likely to have an outpatient clinic visit (odds ratio, 2.82), and not quite twice as likely to be rehospitalized (OR, 1.64).

“We found that [health-related quality of life], exercise capacity, and mental health continued to improve throughout the 2 years regardless of initial disease severity, but about half still had symptomatic sequelae at 2 years,” the researchers wrote in their paper.

Findings can inform doctor-patient discussions

“We are increasingly recognizing that the health effects of COVID-19 may persist beyond acute illness, therefore this is a timely study to assess the long-term impact of COVID-19 with a long follow-up period,” said Suman Pal, MD, an internal medicine physician at the University of New Mexico, Albuquerque, in an interview.

The findings are consistent with the existing literature, said Dr. Pal, who was not involved in the study.  The data from the study “can help clinicians have discussions regarding expected recovery and long-term prognosis for patients with COVID-19,” he noted.

What patients should know is that “studies such as this can help COVID-19 survivors understand and monitor persistent symptoms they may experience, and bring them to the attention of their clinicians,” said Dr. Pal.

However, “As a single-center study with high attrition of subjects during the study period, the findings may not be generalizable,” Dr. Pal emphasized. “Larger-scale studies and patient registries distributed over different geographical areas and time periods will help obtain a better understanding of the nature and prevalence of long COVID,” he said.

The study findings were limited by several factors, including the lack of formerly hospitalized controls with respiratory infections other than COVID-19 to determine which outcomes are COVID-19 specific, the researchers noted. Other limitations included the use of data from only patients at a single center, and from the early stages of the pandemic, as well as the use of self-reports for comorbidities and health outcomes, they said.

However, the results represent the longest-known published longitudinal follow-up of patients who recovered from acute COVID-19, the researchers emphasized. Study strengths included the large sample size, longitudinal design, and long-term follow-up with non-COVID controls to determine outcomes. The researchers noted their plans to conduct annual follow-ups in the current study population. They added that more research is needed to explore rehabilitation programs to promote recovery for COVID-19 survivors and to reduce the effects of long COVID.

The study was supported by the Chinese Academy of Medical Sciences, National Natural Science Foundation of China, National Key Research and Development Program of China, National Administration of Traditional Chinese Medicine, Major Projects of National Science and Technology on New Drug Creation and Development of Pulmonary Tuberculosis, China Evergrande Group, Jack Ma Foundation, Sino Biopharmaceutical, Ping An Insurance (Group), and New Sunshine Charity Foundation. The researchers and Dr. Pal had no financial conflicts to disclose.

This article was updated on 5/16/2022.

Regardless of the severity of their initial illness, 89% of people who were hospitalized with COVID-19 had returned to their original work 2 years later, a new study shows.

The burden of persistent COVID-19 symptoms appeared to improve over time, but a higher percentage of former patients reported poor health, compared with the general population. This suggests that some patients need more time to completely recover from COVID-19, wrote the authors of the new study, which was published in The Lancet Respiratory Medicine. Previous research has shown that the health effects of COVID-19 last for up to a year, but data from longer-term studies are limited, said Lixue Huang, MD, of Capital Medical University, Beijing, one of the study authors, and colleagues.

Methods and results

In the new study, the researchers reviewed data from 1,192 adult patients who were discharged from the hospital after surviving COVID-19 between Jan. 7, 2020, and May 29, 2020. The researchers measured the participants’ health outcomes at 6 months, 12 months, and 2 years after their onset of symptoms. A community-based dataset of 3,383 adults with no history of COVID-19 served as controls to measure the recovery of the COVID-19 patients. The median age of the patients at the time of hospital discharge was 57 years, and 46% were women. The median follow-up time after the onset of symptoms was 185 days, 349 days, and 685 days for the 6-month, 12-month, and 2-year visits, respectively. The researchers measured health outcomes using a 6-min walking distance (6MWD) test, laboratory tests, and questionnaires about symptoms, mental health, health-related quality of life, returning to work, and health care use since leaving the hospital.

Overall, the proportion of COVID-19 survivors with at least one symptom decreased from 68% at 6 months to 55% at 2 years (P < .0001). The most frequent symptoms were fatigue and muscle weakness, reported by approximately one-third of the patients (31%); sleep problems also were reported by 31% of the patients.

The proportion of individuals with poor results on the 6MWD decreased continuously over time, not only in COVID-19 survivors overall, but also in three subgroups of varying initial disease severity. Of the 494 survivors who reported working before becoming ill, 438 (89%) had returned to their original jobs 2 years later. The most common reasons for not returning to work were decreased physical function, unwillingness to return, and unemployment, the researchers noted.

However, at 2 years, COVID-19 survivors reported more pain and discomfort, as well as more anxiety and depression, compared with the controls (23% vs. 5% and 12% vs. 5%, respectively).

In addition, significantly more survivors who needed high levels of respiratory support while hospitalized had lung diffusion impairment (65%), reduced residual volume (62%), and total lung capacity (39%), compared with matched controls (36%, 20%, and 6%, respectively) at 2 years.

Long-COVID concerns

Approximately half of the survivors had symptoms of long COVID at 2 years. These individuals were more likely to report pain or discomfort or anxiety or depression, as well as mobility problems, compared to survivors without long COVID. Participants with long-COVID symptoms were more than twice as likely to have an outpatient clinic visit (odds ratio, 2.82), and not quite twice as likely to be rehospitalized (OR, 1.64).

“We found that [health-related quality of life], exercise capacity, and mental health continued to improve throughout the 2 years regardless of initial disease severity, but about half still had symptomatic sequelae at 2 years,” the researchers wrote in their paper.

Findings can inform doctor-patient discussions

“We are increasingly recognizing that the health effects of COVID-19 may persist beyond acute illness, therefore this is a timely study to assess the long-term impact of COVID-19 with a long follow-up period,” said Suman Pal, MD, an internal medicine physician at the University of New Mexico, Albuquerque, in an interview.

The findings are consistent with the existing literature, said Dr. Pal, who was not involved in the study.  The data from the study “can help clinicians have discussions regarding expected recovery and long-term prognosis for patients with COVID-19,” he noted.

What patients should know is that “studies such as this can help COVID-19 survivors understand and monitor persistent symptoms they may experience, and bring them to the attention of their clinicians,” said Dr. Pal.

However, “As a single-center study with high attrition of subjects during the study period, the findings may not be generalizable,” Dr. Pal emphasized. “Larger-scale studies and patient registries distributed over different geographical areas and time periods will help obtain a better understanding of the nature and prevalence of long COVID,” he said.

The study findings were limited by several factors, including the lack of formerly hospitalized controls with respiratory infections other than COVID-19 to determine which outcomes are COVID-19 specific, the researchers noted. Other limitations included the use of data from only patients at a single center, and from the early stages of the pandemic, as well as the use of self-reports for comorbidities and health outcomes, they said.

However, the results represent the longest-known published longitudinal follow-up of patients who recovered from acute COVID-19, the researchers emphasized. Study strengths included the large sample size, longitudinal design, and long-term follow-up with non-COVID controls to determine outcomes. The researchers noted their plans to conduct annual follow-ups in the current study population. They added that more research is needed to explore rehabilitation programs to promote recovery for COVID-19 survivors and to reduce the effects of long COVID.

The study was supported by the Chinese Academy of Medical Sciences, National Natural Science Foundation of China, National Key Research and Development Program of China, National Administration of Traditional Chinese Medicine, Major Projects of National Science and Technology on New Drug Creation and Development of Pulmonary Tuberculosis, China Evergrande Group, Jack Ma Foundation, Sino Biopharmaceutical, Ping An Insurance (Group), and New Sunshine Charity Foundation. The researchers and Dr. Pal had no financial conflicts to disclose.

This article was updated on 5/16/2022.

Good solutions have great road maps. 

For HIV preexposure prophylaxis (PrEP), the road map might just be that of contraceptive care. Once an onerous process, over time contraceptive care exploded into a range of options across a broad landscape in terms of approach and accessibility.

How then do organizations help vulnerable patients navigate their PrEP journeys using the contraceptive road map as a guide?

That’s what researchers at the University of Washington were intent on demonstrating, according to Julie Dombrowski, MD, MPH, an infectious disease specialist at the University of Washington, Seattle, and deputy director of the HIV/STD Program, Public Health for the city of Seattle and King County, Wash.

“The same sorts of things that happened with oral contraceptive pills – which initially required you to see a gynecologist and get a Pap smear – over time, became much more available,” said Dr. Dombrowski, coauthor of a new study published online in the Journal of Acquired Immune Deficiency Syndrome.

“The basic idea is that PrEP is not medically complicated; it can be easily protocolized,” she told this news organization.
 

Decentralizing HIV PrEP

In addition to her responsibilities at University of Washington, Dr. Dombrowski provides clinical services at the Public Health Sexual Health Clinic (PHSKC) at Seattle’s Harborview Medical Center – a dual-county center that provides confidential STI and HIV evaluation, screening, testing, and treatment on a walk-in basis for a sliding fee.

Sexual health clinics are ideal environments for reaching large numbers of patients, but strategies for integrating PrEP successfully into what are commonly one-time appointments have not been well-described or broadly adopted. 

“Sexual health clinics in general are STD specialty clinics with walk-in access to care; often, patients come into a clinic, get seen, diagnosed, and treated, and they don’t necessarily come back,” said Dr. Dombrowski. 

She said that, because most operations have been set up around same-day treatment, to offer PrEP and successfully change outcomes, there needs to be a shift in the current model toward one that promotes an ongoing relationship with the patients.

So, she and her colleagues decided to see what would happen if they implemented a decentralized PrEP model in their clinic over a 6-year period. They established a protocol that moves from an initial consultation with a clinician to review risk behaviors, ascertain HIV status, and acquire a PrEP prescription, to ongoing interactions with an STI and PrEP-trained disease intervention specialist (DIS).

As the clinic’s PrEP program coordinators, these specialists enroll patients in PrEP drug assistance programs, verify prescription fills, provide follow-up visits and adherence and adverse events assessments, and collect specimens.

“[Disease intervention specialists] are frontline public health workers who ensure that people diagnosed with HIV or an STI – or who’ve been exposed – get necessary testing and treatment,” explained Dr. Dombrowski. “They’re very similar to patient navigators.”

At the same time, clinicians remain the key providers for annual appointments, new symptoms, STI diagnoses, adverse drug reactions, and missed doses. Licensed medical providers review all labs.
 

Shifting responsibilities, better PrEP initiation, retention rates

After establishing the PrEP services protocol, the University of Washington team then assessed retention rates among PrEP patients who attended an initial visit (1,387) from October 2014 to December 2019. Follow-up continued through February 2020. (For study purposes, PrEP discontinuation was defined as either stopping PrEP after initiation or as lost to follow-up, i.e., either not attending a follow-up visit or not responding to more than three DIS calls or text messages).

Just over half of the participants were aged 20-29 years, and a third were aged 30-39. More than 9 out of 10 (93%) were men who sleep with men (MSM), 55% White, 26% Hispanic/Latinx, and 10% Black. 

Over the course of the study, 6,887 PrEP visits were recorded. Quarterly visits increased concurrently with the program expansion, from 31 visits in 2014 to 623 in the fourth quarter (Q4) of 2019. Likewise, while 57% of visits overall were with a clinician, DIS visits increased from 3% in Q4 of 2014 to 45% in Q4 of 2019, an increase of 1,400% in 5 years.

Significant numbers of patients also initiated PrEP in the clinic, especially when prescribing practices were expanded to be part of routine, walk-in visits.

Retention rates also improved, with 43% (510/1,190) of patients still on PrEP at the end of the analysis period. Forty-one percent (490) discontinued PrEP, 21% within 3 months of initiation, and 72% within a year; another 16% moved, transferred care, or tested positive, and were considered “censored.” However, as of July 31, 2021, 54% (265) of the 490 patients who had discontinued PrEP returned to the clinic for a restart visit, 93% of whom refilled their restart prescription.

“This is really basic preventative care and is actually quite easy to do,” noted Sarah Schmalzle, MD, assistant professor of medicine and medical director of the Thrive Program at the Institute of Human Virology at the University of Maryland, Baltimore. Dr. Schmalzle was not involved in the study. 

Dr. Schmalzle practices in inner-city Baltimore, so she and her colleagues have been thorough in terms of setting up PrEP (and postexposure prophylaxis, PEP) programs to ensure that patients access PrEP wherever they want to. But she also said that PrEP is only a part of the sexual wellness and prevention toolbox, and ideally, part of a whole prevention program. 

“Focusing on how to get the prescription out is great but the rest is having ongoing and accurate sexual health conversations, healthy conversations about sex and prevention, to have [an] algorithm in place that says, ‘Here’s your PrEP, this is the next time that you need an appointment, the next time you need labs, I’m going to check your adherence, etc.’ ”

Both Dr. Dombrowski and Dr. Schmalzle emphasized that decentralization is not a one-size model; flexibility is key, especially when it comes to who is providing PrEP 

“People overcomplicate PrEP and clinicians do this too,” said Dr. Dombrowski. “If we are going to successfully increase PrEP and improve the patient experience, we need to decrease the requirement for clinician involvement.”

Dr. Dombrowski has disclosed no relevant financial relationships. Dr. Schmalzle receives grant funding from Gilead Sciences.

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

Good solutions have great road maps. 

For HIV preexposure prophylaxis (PrEP), the road map might just be that of contraceptive care. Once an onerous process, over time contraceptive care exploded into a range of options across a broad landscape in terms of approach and accessibility.

How then do organizations help vulnerable patients navigate their PrEP journeys using the contraceptive road map as a guide?

That’s what researchers at the University of Washington were intent on demonstrating, according to Julie Dombrowski, MD, MPH, an infectious disease specialist at the University of Washington, Seattle, and deputy director of the HIV/STD Program, Public Health for the city of Seattle and King County, Wash.

“The same sorts of things that happened with oral contraceptive pills – which initially required you to see a gynecologist and get a Pap smear – over time, became much more available,” said Dr. Dombrowski, coauthor of a new study published online in the Journal of Acquired Immune Deficiency Syndrome.

“The basic idea is that PrEP is not medically complicated; it can be easily protocolized,” she told this news organization.
 

Decentralizing HIV PrEP

In addition to her responsibilities at University of Washington, Dr. Dombrowski provides clinical services at the Public Health Sexual Health Clinic (PHSKC) at Seattle’s Harborview Medical Center – a dual-county center that provides confidential STI and HIV evaluation, screening, testing, and treatment on a walk-in basis for a sliding fee.

Sexual health clinics are ideal environments for reaching large numbers of patients, but strategies for integrating PrEP successfully into what are commonly one-time appointments have not been well-described or broadly adopted. 

“Sexual health clinics in general are STD specialty clinics with walk-in access to care; often, patients come into a clinic, get seen, diagnosed, and treated, and they don’t necessarily come back,” said Dr. Dombrowski. 

She said that, because most operations have been set up around same-day treatment, to offer PrEP and successfully change outcomes, there needs to be a shift in the current model toward one that promotes an ongoing relationship with the patients.

So, she and her colleagues decided to see what would happen if they implemented a decentralized PrEP model in their clinic over a 6-year period. They established a protocol that moves from an initial consultation with a clinician to review risk behaviors, ascertain HIV status, and acquire a PrEP prescription, to ongoing interactions with an STI and PrEP-trained disease intervention specialist (DIS).

As the clinic’s PrEP program coordinators, these specialists enroll patients in PrEP drug assistance programs, verify prescription fills, provide follow-up visits and adherence and adverse events assessments, and collect specimens.

“[Disease intervention specialists] are frontline public health workers who ensure that people diagnosed with HIV or an STI – or who’ve been exposed – get necessary testing and treatment,” explained Dr. Dombrowski. “They’re very similar to patient navigators.”

At the same time, clinicians remain the key providers for annual appointments, new symptoms, STI diagnoses, adverse drug reactions, and missed doses. Licensed medical providers review all labs.
 

Shifting responsibilities, better PrEP initiation, retention rates

After establishing the PrEP services protocol, the University of Washington team then assessed retention rates among PrEP patients who attended an initial visit (1,387) from October 2014 to December 2019. Follow-up continued through February 2020. (For study purposes, PrEP discontinuation was defined as either stopping PrEP after initiation or as lost to follow-up, i.e., either not attending a follow-up visit or not responding to more than three DIS calls or text messages).

Just over half of the participants were aged 20-29 years, and a third were aged 30-39. More than 9 out of 10 (93%) were men who sleep with men (MSM), 55% White, 26% Hispanic/Latinx, and 10% Black. 

Over the course of the study, 6,887 PrEP visits were recorded. Quarterly visits increased concurrently with the program expansion, from 31 visits in 2014 to 623 in the fourth quarter (Q4) of 2019. Likewise, while 57% of visits overall were with a clinician, DIS visits increased from 3% in Q4 of 2014 to 45% in Q4 of 2019, an increase of 1,400% in 5 years.

Significant numbers of patients also initiated PrEP in the clinic, especially when prescribing practices were expanded to be part of routine, walk-in visits.

Retention rates also improved, with 43% (510/1,190) of patients still on PrEP at the end of the analysis period. Forty-one percent (490) discontinued PrEP, 21% within 3 months of initiation, and 72% within a year; another 16% moved, transferred care, or tested positive, and were considered “censored.” However, as of July 31, 2021, 54% (265) of the 490 patients who had discontinued PrEP returned to the clinic for a restart visit, 93% of whom refilled their restart prescription.

“This is really basic preventative care and is actually quite easy to do,” noted Sarah Schmalzle, MD, assistant professor of medicine and medical director of the Thrive Program at the Institute of Human Virology at the University of Maryland, Baltimore. Dr. Schmalzle was not involved in the study. 

Dr. Schmalzle practices in inner-city Baltimore, so she and her colleagues have been thorough in terms of setting up PrEP (and postexposure prophylaxis, PEP) programs to ensure that patients access PrEP wherever they want to. But she also said that PrEP is only a part of the sexual wellness and prevention toolbox, and ideally, part of a whole prevention program. 

“Focusing on how to get the prescription out is great but the rest is having ongoing and accurate sexual health conversations, healthy conversations about sex and prevention, to have [an] algorithm in place that says, ‘Here’s your PrEP, this is the next time that you need an appointment, the next time you need labs, I’m going to check your adherence, etc.’ ”

Both Dr. Dombrowski and Dr. Schmalzle emphasized that decentralization is not a one-size model; flexibility is key, especially when it comes to who is providing PrEP 

“People overcomplicate PrEP and clinicians do this too,” said Dr. Dombrowski. “If we are going to successfully increase PrEP and improve the patient experience, we need to decrease the requirement for clinician involvement.”

Dr. Dombrowski has disclosed no relevant financial relationships. Dr. Schmalzle receives grant funding from Gilead Sciences.

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

Good solutions have great road maps. 

For HIV preexposure prophylaxis (PrEP), the road map might just be that of contraceptive care. Once an onerous process, over time contraceptive care exploded into a range of options across a broad landscape in terms of approach and accessibility.

How then do organizations help vulnerable patients navigate their PrEP journeys using the contraceptive road map as a guide?

That’s what researchers at the University of Washington were intent on demonstrating, according to Julie Dombrowski, MD, MPH, an infectious disease specialist at the University of Washington, Seattle, and deputy director of the HIV/STD Program, Public Health for the city of Seattle and King County, Wash.

“The same sorts of things that happened with oral contraceptive pills – which initially required you to see a gynecologist and get a Pap smear – over time, became much more available,” said Dr. Dombrowski, coauthor of a new study published online in the Journal of Acquired Immune Deficiency Syndrome.

“The basic idea is that PrEP is not medically complicated; it can be easily protocolized,” she told this news organization.
 

Decentralizing HIV PrEP

In addition to her responsibilities at University of Washington, Dr. Dombrowski provides clinical services at the Public Health Sexual Health Clinic (PHSKC) at Seattle’s Harborview Medical Center – a dual-county center that provides confidential STI and HIV evaluation, screening, testing, and treatment on a walk-in basis for a sliding fee.

Sexual health clinics are ideal environments for reaching large numbers of patients, but strategies for integrating PrEP successfully into what are commonly one-time appointments have not been well-described or broadly adopted. 

“Sexual health clinics in general are STD specialty clinics with walk-in access to care; often, patients come into a clinic, get seen, diagnosed, and treated, and they don’t necessarily come back,” said Dr. Dombrowski. 

She said that, because most operations have been set up around same-day treatment, to offer PrEP and successfully change outcomes, there needs to be a shift in the current model toward one that promotes an ongoing relationship with the patients.

So, she and her colleagues decided to see what would happen if they implemented a decentralized PrEP model in their clinic over a 6-year period. They established a protocol that moves from an initial consultation with a clinician to review risk behaviors, ascertain HIV status, and acquire a PrEP prescription, to ongoing interactions with an STI and PrEP-trained disease intervention specialist (DIS).

As the clinic’s PrEP program coordinators, these specialists enroll patients in PrEP drug assistance programs, verify prescription fills, provide follow-up visits and adherence and adverse events assessments, and collect specimens.

“[Disease intervention specialists] are frontline public health workers who ensure that people diagnosed with HIV or an STI – or who’ve been exposed – get necessary testing and treatment,” explained Dr. Dombrowski. “They’re very similar to patient navigators.”

At the same time, clinicians remain the key providers for annual appointments, new symptoms, STI diagnoses, adverse drug reactions, and missed doses. Licensed medical providers review all labs.
 

Shifting responsibilities, better PrEP initiation, retention rates

After establishing the PrEP services protocol, the University of Washington team then assessed retention rates among PrEP patients who attended an initial visit (1,387) from October 2014 to December 2019. Follow-up continued through February 2020. (For study purposes, PrEP discontinuation was defined as either stopping PrEP after initiation or as lost to follow-up, i.e., either not attending a follow-up visit or not responding to more than three DIS calls or text messages).

Just over half of the participants were aged 20-29 years, and a third were aged 30-39. More than 9 out of 10 (93%) were men who sleep with men (MSM), 55% White, 26% Hispanic/Latinx, and 10% Black. 

Over the course of the study, 6,887 PrEP visits were recorded. Quarterly visits increased concurrently with the program expansion, from 31 visits in 2014 to 623 in the fourth quarter (Q4) of 2019. Likewise, while 57% of visits overall were with a clinician, DIS visits increased from 3% in Q4 of 2014 to 45% in Q4 of 2019, an increase of 1,400% in 5 years.

Significant numbers of patients also initiated PrEP in the clinic, especially when prescribing practices were expanded to be part of routine, walk-in visits.

Retention rates also improved, with 43% (510/1,190) of patients still on PrEP at the end of the analysis period. Forty-one percent (490) discontinued PrEP, 21% within 3 months of initiation, and 72% within a year; another 16% moved, transferred care, or tested positive, and were considered “censored.” However, as of July 31, 2021, 54% (265) of the 490 patients who had discontinued PrEP returned to the clinic for a restart visit, 93% of whom refilled their restart prescription.

“This is really basic preventative care and is actually quite easy to do,” noted Sarah Schmalzle, MD, assistant professor of medicine and medical director of the Thrive Program at the Institute of Human Virology at the University of Maryland, Baltimore. Dr. Schmalzle was not involved in the study. 

Dr. Schmalzle practices in inner-city Baltimore, so she and her colleagues have been thorough in terms of setting up PrEP (and postexposure prophylaxis, PEP) programs to ensure that patients access PrEP wherever they want to. But she also said that PrEP is only a part of the sexual wellness and prevention toolbox, and ideally, part of a whole prevention program. 

“Focusing on how to get the prescription out is great but the rest is having ongoing and accurate sexual health conversations, healthy conversations about sex and prevention, to have [an] algorithm in place that says, ‘Here’s your PrEP, this is the next time that you need an appointment, the next time you need labs, I’m going to check your adherence, etc.’ ”

Both Dr. Dombrowski and Dr. Schmalzle emphasized that decentralization is not a one-size model; flexibility is key, especially when it comes to who is providing PrEP 

“People overcomplicate PrEP and clinicians do this too,” said Dr. Dombrowski. “If we are going to successfully increase PrEP and improve the patient experience, we need to decrease the requirement for clinician involvement.”

Dr. Dombrowski has disclosed no relevant financial relationships. Dr. Schmalzle receives grant funding from Gilead Sciences.

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

The current sustained increase in COVID-19 has brought the total number of cases in children to over 13 million since the start of the pandemic, according to the American Academy of Pediatrics and the Children’s Hospital Association.

The latest weekly count – 62,467 reported for the week ending May 5 – was 17.4% higher than the previous week and marks four consecutive increases since early April, when cases dropped to their lowest point since last summer. The cumulative number of cases in children is 13,052,988, which accounts for 19.0% of all cases reported in the United States, the AAP and CHA said in their weekly COVID-19 report.

Other measures of incidence show the same steady rise. The rate of new admissions of children aged 0-17 with confirmed COVID-19, which had dipped as low as 0.13 per 100,000 population on April 11, was up to 0.19 per 100,000 on May 6, and the 7-day average for total admissions was 136 per day for May 1-7, compared with 118 for the last week of April, according to the Centers for Disease Control and Prevention.

At the state level, new admission rates for May 6 show wide variation, even regionally. Rhode Island came in with a 0.00 per 100,000 on that day, while Vermont recorded 0.88 admissions per 100,000, the highest of any state and lower only than the District of Columbia’s 1.23 per 100,000. Connecticut (0.45) and Massachusetts (0.33) also were in the highest group (see map), while Maine was in the lowest, CDC data show.

Nationally, emergency department visits also have been rising over the last month or so. Children aged 0-11 years, who were down to a 7-day average of 0.5% of ED visits with diagnosed COVID-19 in early April, saw that number rise to 1.4% on May 5. Children aged 12-15 years went from a rate of 0.3% in late March to the current 1.2%, as did 16- to 17-year-olds, the CDC said on its COVID Data Tracker.

The vaccination effort, meanwhile, continues to lose steam, at least among children who are currently eligible. Initial vaccinations in those aged 5-11 slipped to their lowest-ever 1-week total, 47,000 for April 28 to May 4, while children aged 16-17 continued a long-term slide that has the weekly count down to just 29,000, the AAP said in its weekly vaccination report.

Here’s how those latest recipients changed the populations of vaccinated children in the last week: 35.4% of all 5- to 11-year-olds had received at least one dose as of May 4, compared with 35.3% on April 27, with increases from 67.4% to 67.5% for 12- to 15-year-olds and 72.7% to 72.8% among those aged 16-17, the CDC reported.
 

The current sustained increase in COVID-19 has brought the total number of cases in children to over 13 million since the start of the pandemic, according to the American Academy of Pediatrics and the Children’s Hospital Association.

The latest weekly count – 62,467 reported for the week ending May 5 – was 17.4% higher than the previous week and marks four consecutive increases since early April, when cases dropped to their lowest point since last summer. The cumulative number of cases in children is 13,052,988, which accounts for 19.0% of all cases reported in the United States, the AAP and CHA said in their weekly COVID-19 report.

Other measures of incidence show the same steady rise. The rate of new admissions of children aged 0-17 with confirmed COVID-19, which had dipped as low as 0.13 per 100,000 population on April 11, was up to 0.19 per 100,000 on May 6, and the 7-day average for total admissions was 136 per day for May 1-7, compared with 118 for the last week of April, according to the Centers for Disease Control and Prevention.

At the state level, new admission rates for May 6 show wide variation, even regionally. Rhode Island came in with a 0.00 per 100,000 on that day, while Vermont recorded 0.88 admissions per 100,000, the highest of any state and lower only than the District of Columbia’s 1.23 per 100,000. Connecticut (0.45) and Massachusetts (0.33) also were in the highest group (see map), while Maine was in the lowest, CDC data show.

Nationally, emergency department visits also have been rising over the last month or so. Children aged 0-11 years, who were down to a 7-day average of 0.5% of ED visits with diagnosed COVID-19 in early April, saw that number rise to 1.4% on May 5. Children aged 12-15 years went from a rate of 0.3% in late March to the current 1.2%, as did 16- to 17-year-olds, the CDC said on its COVID Data Tracker.

The vaccination effort, meanwhile, continues to lose steam, at least among children who are currently eligible. Initial vaccinations in those aged 5-11 slipped to their lowest-ever 1-week total, 47,000 for April 28 to May 4, while children aged 16-17 continued a long-term slide that has the weekly count down to just 29,000, the AAP said in its weekly vaccination report.

Here’s how those latest recipients changed the populations of vaccinated children in the last week: 35.4% of all 5- to 11-year-olds had received at least one dose as of May 4, compared with 35.3% on April 27, with increases from 67.4% to 67.5% for 12- to 15-year-olds and 72.7% to 72.8% among those aged 16-17, the CDC reported.
 

The current sustained increase in COVID-19 has brought the total number of cases in children to over 13 million since the start of the pandemic, according to the American Academy of Pediatrics and the Children’s Hospital Association.

The latest weekly count – 62,467 reported for the week ending May 5 – was 17.4% higher than the previous week and marks four consecutive increases since early April, when cases dropped to their lowest point since last summer. The cumulative number of cases in children is 13,052,988, which accounts for 19.0% of all cases reported in the United States, the AAP and CHA said in their weekly COVID-19 report.

Other measures of incidence show the same steady rise. The rate of new admissions of children aged 0-17 with confirmed COVID-19, which had dipped as low as 0.13 per 100,000 population on April 11, was up to 0.19 per 100,000 on May 6, and the 7-day average for total admissions was 136 per day for May 1-7, compared with 118 for the last week of April, according to the Centers for Disease Control and Prevention.

At the state level, new admission rates for May 6 show wide variation, even regionally. Rhode Island came in with a 0.00 per 100,000 on that day, while Vermont recorded 0.88 admissions per 100,000, the highest of any state and lower only than the District of Columbia’s 1.23 per 100,000. Connecticut (0.45) and Massachusetts (0.33) also were in the highest group (see map), while Maine was in the lowest, CDC data show.

Nationally, emergency department visits also have been rising over the last month or so. Children aged 0-11 years, who were down to a 7-day average of 0.5% of ED visits with diagnosed COVID-19 in early April, saw that number rise to 1.4% on May 5. Children aged 12-15 years went from a rate of 0.3% in late March to the current 1.2%, as did 16- to 17-year-olds, the CDC said on its COVID Data Tracker.

The vaccination effort, meanwhile, continues to lose steam, at least among children who are currently eligible. Initial vaccinations in those aged 5-11 slipped to their lowest-ever 1-week total, 47,000 for April 28 to May 4, while children aged 16-17 continued a long-term slide that has the weekly count down to just 29,000, the AAP said in its weekly vaccination report.

Here’s how those latest recipients changed the populations of vaccinated children in the last week: 35.4% of all 5- to 11-year-olds had received at least one dose as of May 4, compared with 35.3% on April 27, with increases from 67.4% to 67.5% for 12- to 15-year-olds and 72.7% to 72.8% among those aged 16-17, the CDC reported.
 

The percentage of low-income pregnant mothers who received influenza and Tdap vaccinations fell sharply during the COVID-19 pandemic, especially in Black and Hispanic patients, a new study finds.

The percentage of patients who received the influenza vaccines at two Medicaid clinics in Houston dropped from 78% before the pandemic to 61% during it (adjusted odds ratio, 0.38; 95% CI, 0.26-0.53; P < .01), researchers reported at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists. The percentage receiving the Tdap vaccine dipped from 85% to 76% (aOR, 0.56; 95% CI, 0.40-0.79; P < .01).

New York–Presbyterian/Weill Cornell Medical Center pediatrician Sallie Permar, MD, PhD, who’s familiar with the study findings, called them “alarming” and said in an interview that they should be “a call to action for providers.”

“Continuing the status quo in our routine preventative health care and clinic operations means that we are losing ground in reduction and elimination of vaccine-preventable diseases,” Dr. Permar said in an interview.

According to corresponding author Bani Ratan, MD, an ob.gyn. with the Baylor College of Medicine, Houston, there’s been little if any previous research into routine, non-COVID vaccination in pregnant women during the pandemic.

For the study, researchers retrospectively analyzed the records of 939 pregnant women who entered prenatal care before 20 weeks (462 from May–November 2019, and 477 from May–November 2020) and delivered at full term.

Among ethnic groups, non-Hispanic Blacks saw the largest decline in influenza vaccines. Among them, the percentage who got them fell from 64% (73/114) to 35% (35/101; aOR, 0.30; 95% CI, 0.17-0.52; P < .01). Only Hispanics had a statistically significant decline in Tdap vaccination (OR, 0.52, 95% CI, 0.34-0.80; P < .01, percentages not provided).

Another study presented at ACOG examined vaccination rates during the pandemic and found that Tdap vaccination rates dipped among pregnant women in a Philadelphia-area health care system.

Possible causes for the decline in routine vaccination include hesitancy linked to the COVID-19 vaccines and fewer office visits because of telemedicine, said Dr. Batan in an interview.

Dr. Permar blamed the role of vaccine misinformation during the pandemic and the mistrust caused by the exclusion of pregnant women from early vaccine trials. She added that “challenges in health care staffing and issues of health care provider burnout that worsened during the pandemic likely contributed to a fraying of the focus on preventive health maintenance simply due to bandwidth of health professionals.”

In a separate study presented at ACOG, researchers at the State University of New York, Syracuse, reported on a survey of 157 pregnant women of whom just 38.2% were vaccinated against COVID-19. Among the unvaccinated, who were more likely to have less education, 66% reported that lack of data about vaccination was their primary concern.

No funding or disclosures are reported by study authors. Dr. Permar reported consulting for Merck, Moderna, GlaxoSmithKline, Pfizer, Dynavax, and Hookipa on cytomegalovirus vaccine programs.

*This story was updated on 5/11/2022.

The percentage of low-income pregnant mothers who received influenza and Tdap vaccinations fell sharply during the COVID-19 pandemic, especially in Black and Hispanic patients, a new study finds.

The percentage of patients who received the influenza vaccines at two Medicaid clinics in Houston dropped from 78% before the pandemic to 61% during it (adjusted odds ratio, 0.38; 95% CI, 0.26-0.53; P < .01), researchers reported at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists. The percentage receiving the Tdap vaccine dipped from 85% to 76% (aOR, 0.56; 95% CI, 0.40-0.79; P < .01).

New York–Presbyterian/Weill Cornell Medical Center pediatrician Sallie Permar, MD, PhD, who’s familiar with the study findings, called them “alarming” and said in an interview that they should be “a call to action for providers.”

“Continuing the status quo in our routine preventative health care and clinic operations means that we are losing ground in reduction and elimination of vaccine-preventable diseases,” Dr. Permar said in an interview.

According to corresponding author Bani Ratan, MD, an ob.gyn. with the Baylor College of Medicine, Houston, there’s been little if any previous research into routine, non-COVID vaccination in pregnant women during the pandemic.

For the study, researchers retrospectively analyzed the records of 939 pregnant women who entered prenatal care before 20 weeks (462 from May–November 2019, and 477 from May–November 2020) and delivered at full term.

Among ethnic groups, non-Hispanic Blacks saw the largest decline in influenza vaccines. Among them, the percentage who got them fell from 64% (73/114) to 35% (35/101; aOR, 0.30; 95% CI, 0.17-0.52; P < .01). Only Hispanics had a statistically significant decline in Tdap vaccination (OR, 0.52, 95% CI, 0.34-0.80; P < .01, percentages not provided).

Another study presented at ACOG examined vaccination rates during the pandemic and found that Tdap vaccination rates dipped among pregnant women in a Philadelphia-area health care system.

Possible causes for the decline in routine vaccination include hesitancy linked to the COVID-19 vaccines and fewer office visits because of telemedicine, said Dr. Batan in an interview.

Dr. Permar blamed the role of vaccine misinformation during the pandemic and the mistrust caused by the exclusion of pregnant women from early vaccine trials. She added that “challenges in health care staffing and issues of health care provider burnout that worsened during the pandemic likely contributed to a fraying of the focus on preventive health maintenance simply due to bandwidth of health professionals.”

In a separate study presented at ACOG, researchers at the State University of New York, Syracuse, reported on a survey of 157 pregnant women of whom just 38.2% were vaccinated against COVID-19. Among the unvaccinated, who were more likely to have less education, 66% reported that lack of data about vaccination was their primary concern.

No funding or disclosures are reported by study authors. Dr. Permar reported consulting for Merck, Moderna, GlaxoSmithKline, Pfizer, Dynavax, and Hookipa on cytomegalovirus vaccine programs.

*This story was updated on 5/11/2022.

The percentage of low-income pregnant mothers who received influenza and Tdap vaccinations fell sharply during the COVID-19 pandemic, especially in Black and Hispanic patients, a new study finds.

The percentage of patients who received the influenza vaccines at two Medicaid clinics in Houston dropped from 78% before the pandemic to 61% during it (adjusted odds ratio, 0.38; 95% CI, 0.26-0.53; P < .01), researchers reported at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists. The percentage receiving the Tdap vaccine dipped from 85% to 76% (aOR, 0.56; 95% CI, 0.40-0.79; P < .01).

New York–Presbyterian/Weill Cornell Medical Center pediatrician Sallie Permar, MD, PhD, who’s familiar with the study findings, called them “alarming” and said in an interview that they should be “a call to action for providers.”

“Continuing the status quo in our routine preventative health care and clinic operations means that we are losing ground in reduction and elimination of vaccine-preventable diseases,” Dr. Permar said in an interview.

According to corresponding author Bani Ratan, MD, an ob.gyn. with the Baylor College of Medicine, Houston, there’s been little if any previous research into routine, non-COVID vaccination in pregnant women during the pandemic.

For the study, researchers retrospectively analyzed the records of 939 pregnant women who entered prenatal care before 20 weeks (462 from May–November 2019, and 477 from May–November 2020) and delivered at full term.

Among ethnic groups, non-Hispanic Blacks saw the largest decline in influenza vaccines. Among them, the percentage who got them fell from 64% (73/114) to 35% (35/101; aOR, 0.30; 95% CI, 0.17-0.52; P < .01). Only Hispanics had a statistically significant decline in Tdap vaccination (OR, 0.52, 95% CI, 0.34-0.80; P < .01, percentages not provided).

Another study presented at ACOG examined vaccination rates during the pandemic and found that Tdap vaccination rates dipped among pregnant women in a Philadelphia-area health care system.

Possible causes for the decline in routine vaccination include hesitancy linked to the COVID-19 vaccines and fewer office visits because of telemedicine, said Dr. Batan in an interview.

Dr. Permar blamed the role of vaccine misinformation during the pandemic and the mistrust caused by the exclusion of pregnant women from early vaccine trials. She added that “challenges in health care staffing and issues of health care provider burnout that worsened during the pandemic likely contributed to a fraying of the focus on preventive health maintenance simply due to bandwidth of health professionals.”

In a separate study presented at ACOG, researchers at the State University of New York, Syracuse, reported on a survey of 157 pregnant women of whom just 38.2% were vaccinated against COVID-19. Among the unvaccinated, who were more likely to have less education, 66% reported that lack of data about vaccination was their primary concern.

No funding or disclosures are reported by study authors. Dr. Permar reported consulting for Merck, Moderna, GlaxoSmithKline, Pfizer, Dynavax, and Hookipa on cytomegalovirus vaccine programs.

*This story was updated on 5/11/2022.

In 2021, the US Preventive Services Task Force (USPSTF) considered 13 topics and made a total of 23 recommendations. They reviewed only 1 new topic. The other 12 were updates of topics previously addressed; no changes were made in 9 of them. In 3, the recommended age of screening or the criteria for screening were expanded. This Practice Alert will review the recommendations made and highlight new recommendations and any changes to previous ones. All complete recommendation statements, rationales, clinical considerations, and evidence reports can be found on the USPSTF website at https://uspreventiveservicestaskforce.org/uspstf/home.¹

Dental caries in children

Dental caries affect about 23% of children between the ages of 2 and 5 years and are associated with multiple adverse social outcomes and medical conditions.² The best way to prevent tooth decay, other than regular brushing with fluoride toothpaste, is to drink water with recommended amounts of fluoride (≥ 0.6 parts fluoride per million parts water).² The USPSTF reaffirmed its recommendation from 2014 that stated when a local water supply lacks sufficient fluoride, primary care clinicians should prescribe oral supplementation for infants and children in the form of fluoride drops starting at age 6 months. The dosage of fluoride depends on patient age and fluoride concentration in the local water (TABLE 1³). The USPSTF also recommends applying topical fluoride as 5% sodium fluoride varnish, every 6 months, starting when the primary teeth erupt.²

BREAKING NEWS At press time, the USPSTF issued its final recommendation on the use of aspirin for primary prevention of cardiovascular disease; see https:// bit.ly/3vklQEe for details.

In addition to fluoride supplements and topical varnish, should clinicians perform screening examinations looking for dental caries? The USPSTF feels there is not enough evidence to assess this practice and gives it an “I” rating (insufficient evidence).

Preventive interventions in pregnancy 

In 2021, the USPSTF assessed 3 topics related to pregnancy and prenatal care.

Screening for gestational diabetes. The USPSTF gave a “B” recommendation for screening at 24 weeks of pregnancy or after, but an “I” statement for screening prior to 24 weeks.⁴ Screening can involve a 1-step or 2-step protocol.

The 2-step protocol is most commonly used in the United States. It involves first measuring serum glucose after a nonfasting 50-g oral glucose challenge; if the resulting level is high, the second step is a 75- or 100-g oral glucose tolerance test lasting 3 hours. The 1-step protocol involves measuring a fasting glucose level, followed by a 75-g oral glucose challenge with glucose levels measured at 1 and 2 hours.

Healthy weight gain in pregnancy. This was the only new topic the USPSTF assessed last year. The resulting recommendation is to offer pregnant women behavioral counseling to promote healthy weight gain and to prevent excessive weight gain in pregnancy. The recommended weight gain depends on the mother’s prepregnancy weight status: 28 to 40 lbs if the mother is underweight; 25 to 35 lbs if she is not under- or overweight; 15 to 25 lbs if she is overweight; and 11 to 20 lbs if she is obese.⁵ Healthy weight gain contributes to preventing gestational diabetes, emergency cesarean sections, and infant macrosomia.

Continue to: Low-dose aspirin

Low-dose aspirin. Reaffirming a recommendation from 2014, the USPSTF advises low-dose aspirin (81 mg/d) starting after 12 weeks’ gestation for all pregnant women who are at high risk for preeclampsia. TABLE 2⁶ lists high- and moderate-risk conditions for preeclampsia and the recommendation for the use of low-dose aspirin.

Sexually transmitted infections

Screening for both chlamydia and gonorrhea in sexually active females through age 24 years was given a “B” recommendation, reaffirming the 2014 recommendation.⁷ Screening for these 2 sexually transmitted infections (STIs) is also recommended for women 25 years and older who are at increased risk of STIs. Risk is defined as having a new sex partner, more than 1 sex partner, a sex partner who has other sex partners, or a sex partner who has an STI; not using condoms consistently; having a previous STI; exchanging sex for money or drugs; or having a history of incarceration.

Screen for both infections simultaneously using a nucleic acid amplification test, testing all sites of sexual exposure. Urine testing can replace cervical, vaginal, and urethral testing. Those found to be positive for either STI should be treated according to the most recent treatment guidelines from the Centers for Disease Control and Prevention (CDC). And sexual partners should be advised to undergo testing.^8,9

The USPSTF could not find evidence for the benefits and harms of screening for STIs in men. Remember that screening applies to those who are asymptomatic. Male sex partners of those found to be infected should be tested, as should those who show any signs or symptoms of an STI. A recent Practice Alert described the most current CDC guidance for diagnosing and treating STIs.⁹

Type 2 diabetes and prediabetes

Screening for type 2 diabetes (T2D) and prediabetes is now recommended for adults ages 35 to 70 years who are overweight or obese.¹⁰ The age to start screening has been lowered to 35 years from the previous recommendation in 2015, which recommended starting at age 40. In addition, the recommendation states that patients with prediabetes should be referred for preventive interventions. It is important that referral is included in the statement because the Affordable Care Act mandates that USPSTF “A” and “B” recommendations must be covered by commercial health insurance with no copay or deductible.

Continue to: Screening can be conducted...

Screening can be conducted using a fasting plasma glucose or A1C level, or with an oral glucose tolerance test. Interventions that can prevent or delay the onset of T2D in those with prediabetes include lifestyle interventions that focus on diet and physical activity, and the use of metformin (although metformin has not been approved for this by the US Food and Drug Administration).

Changes to cancer screening recommendations

In 2021, the USPSTF reviewed and modified its recommendations on screening for 2 types of cancer: colorectal and lung.

For colorectal cancer, the age at which to start screening was lowered from 50 years to 45 years.¹¹ Screening at this earlier age is a “B” recommendation, because, while there is benefit from screening, it is less than for older age groups. Screening individuals ages 50 to 75 years remains an “A” recommendation, and for those ages 76 to 85 years it remains a “C” recommendation. A “C” recommendation means that the overall benefits are small but some individuals might benefit based on their overall health and prior screening results. In its clinical considerations, the USPSTF recommends against screening in those ages 85 and older but, curiously, does not list it as a “D” recommendation. The screening methods and recommended screening intervals for each appear in TABLE 3.¹¹

For lung cancer, annual screening using low-dose computed tomography (CT) was first recommended by the USPSTF in 2013 for adults ages 55 to 80 years with a 30-pack-year smoking history. Screening could stop once 15 years had passed since smoking cessation. In 2021, the USPSTF lowered the age to initiate screening to 50 years, and the smoking history threshold to 20 pack-years.¹² If these recommendations are followed, a current smoker who does not quit smoking could possibly receive 30 annual CT scans. The recommendation does state that screening should stop once a person develops a health condition that significantly affects life expectancy or ability to have lung surgery.

For primary prevention of lung cancer and other chronic diseases through smoking cessation, the USPSTF also reassessed its 2015 recommendations. It reaffirmed the “A” recommendation to ask adults about tobacco use and, for tobacco users, to recommend cessation and provide behavioral therapy and approved pharmacotherapy.¹³ The recommendation differed for pregnant adults in that the USPSTF is unsure about the potential harms of pharmacotherapy in pregnancy and gives that an “I” statement.¹³ An additional “I” statement was made about the use of electronic cigarettes for smoking cessation; the USPSTF recommends using behavioral and pharmacotherapy interventions with proven effectiveness and safety instead.

Continue to: 4 additional recommendation updates with no changes

4 additional recommendation updates with no changes

Screening for high blood pressure in adults ages 18 years and older continues to receive an “A” recommendation.¹⁴ Importantly, the recommendation states that confirmation of high blood pressure should be made in an out-of-­office setting before initiating treatment. Screening for vitamin D deficiency in adults and hearing loss in older adults both continue with “I” statements,^15,16 and screening for asymptomatic carotid artery stenosis continues to receive a “D” recommendation.¹⁷ The implications of the vitamin D “I” statement were discussed in a previous Practice Alert.¹⁸

Continuing value of the USPSTF

The USPSTF continues to set the gold standard for assessment of preventive interventions, and its decisions affect first-dollar coverage by commercial health insurance. The reaffirmation of past recommendations demonstrates the value of adhering to rigorous evidence-based methods (if they are done correctly, they rarely must be markedly changed). And the updating of screening criteria shows the need to constantly review the evolving evidence for current recommendations. Once again, however, funding and staffing limitations allowed the USPSTF to assess only 1 new topic. A listing of all the 2021 recommendations is in TABLE 4.¹

In 2021, the US Preventive Services Task Force (USPSTF) considered 13 topics and made a total of 23 recommendations. They reviewed only 1 new topic. The other 12 were updates of topics previously addressed; no changes were made in 9 of them. In 3, the recommended age of screening or the criteria for screening were expanded. This Practice Alert will review the recommendations made and highlight new recommendations and any changes to previous ones. All complete recommendation statements, rationales, clinical considerations, and evidence reports can be found on the USPSTF website at https://uspreventiveservicestaskforce.org/uspstf/home.¹

Dental caries in children

Dental caries affect about 23% of children between the ages of 2 and 5 years and are associated with multiple adverse social outcomes and medical conditions.² The best way to prevent tooth decay, other than regular brushing with fluoride toothpaste, is to drink water with recommended amounts of fluoride (≥ 0.6 parts fluoride per million parts water).² The USPSTF reaffirmed its recommendation from 2014 that stated when a local water supply lacks sufficient fluoride, primary care clinicians should prescribe oral supplementation for infants and children in the form of fluoride drops starting at age 6 months. The dosage of fluoride depends on patient age and fluoride concentration in the local water (TABLE 1³). The USPSTF also recommends applying topical fluoride as 5% sodium fluoride varnish, every 6 months, starting when the primary teeth erupt.²

BREAKING NEWS At press time, the USPSTF issued its final recommendation on the use of aspirin for primary prevention of cardiovascular disease; see https:// bit.ly/3vklQEe for details.

In addition to fluoride supplements and topical varnish, should clinicians perform screening examinations looking for dental caries? The USPSTF feels there is not enough evidence to assess this practice and gives it an “I” rating (insufficient evidence).

Preventive interventions in pregnancy 

In 2021, the USPSTF assessed 3 topics related to pregnancy and prenatal care.

Screening for gestational diabetes. The USPSTF gave a “B” recommendation for screening at 24 weeks of pregnancy or after, but an “I” statement for screening prior to 24 weeks.⁴ Screening can involve a 1-step or 2-step protocol.

The 2-step protocol is most commonly used in the United States. It involves first measuring serum glucose after a nonfasting 50-g oral glucose challenge; if the resulting level is high, the second step is a 75- or 100-g oral glucose tolerance test lasting 3 hours. The 1-step protocol involves measuring a fasting glucose level, followed by a 75-g oral glucose challenge with glucose levels measured at 1 and 2 hours.

Healthy weight gain in pregnancy. This was the only new topic the USPSTF assessed last year. The resulting recommendation is to offer pregnant women behavioral counseling to promote healthy weight gain and to prevent excessive weight gain in pregnancy. The recommended weight gain depends on the mother’s prepregnancy weight status: 28 to 40 lbs if the mother is underweight; 25 to 35 lbs if she is not under- or overweight; 15 to 25 lbs if she is overweight; and 11 to 20 lbs if she is obese.⁵ Healthy weight gain contributes to preventing gestational diabetes, emergency cesarean sections, and infant macrosomia.

Continue to: Low-dose aspirin

Low-dose aspirin. Reaffirming a recommendation from 2014, the USPSTF advises low-dose aspirin (81 mg/d) starting after 12 weeks’ gestation for all pregnant women who are at high risk for preeclampsia. TABLE 2⁶ lists high- and moderate-risk conditions for preeclampsia and the recommendation for the use of low-dose aspirin.

Sexually transmitted infections

Screening for both chlamydia and gonorrhea in sexually active females through age 24 years was given a “B” recommendation, reaffirming the 2014 recommendation.⁷ Screening for these 2 sexually transmitted infections (STIs) is also recommended for women 25 years and older who are at increased risk of STIs. Risk is defined as having a new sex partner, more than 1 sex partner, a sex partner who has other sex partners, or a sex partner who has an STI; not using condoms consistently; having a previous STI; exchanging sex for money or drugs; or having a history of incarceration.

Screen for both infections simultaneously using a nucleic acid amplification test, testing all sites of sexual exposure. Urine testing can replace cervical, vaginal, and urethral testing. Those found to be positive for either STI should be treated according to the most recent treatment guidelines from the Centers for Disease Control and Prevention (CDC). And sexual partners should be advised to undergo testing.^8,9

The USPSTF could not find evidence for the benefits and harms of screening for STIs in men. Remember that screening applies to those who are asymptomatic. Male sex partners of those found to be infected should be tested, as should those who show any signs or symptoms of an STI. A recent Practice Alert described the most current CDC guidance for diagnosing and treating STIs.⁹

Type 2 diabetes and prediabetes

Screening for type 2 diabetes (T2D) and prediabetes is now recommended for adults ages 35 to 70 years who are overweight or obese.¹⁰ The age to start screening has been lowered to 35 years from the previous recommendation in 2015, which recommended starting at age 40. In addition, the recommendation states that patients with prediabetes should be referred for preventive interventions. It is important that referral is included in the statement because the Affordable Care Act mandates that USPSTF “A” and “B” recommendations must be covered by commercial health insurance with no copay or deductible.

Continue to: Screening can be conducted...

Screening can be conducted using a fasting plasma glucose or A1C level, or with an oral glucose tolerance test. Interventions that can prevent or delay the onset of T2D in those with prediabetes include lifestyle interventions that focus on diet and physical activity, and the use of metformin (although metformin has not been approved for this by the US Food and Drug Administration).

Changes to cancer screening recommendations

In 2021, the USPSTF reviewed and modified its recommendations on screening for 2 types of cancer: colorectal and lung.

For colorectal cancer, the age at which to start screening was lowered from 50 years to 45 years.¹¹ Screening at this earlier age is a “B” recommendation, because, while there is benefit from screening, it is less than for older age groups. Screening individuals ages 50 to 75 years remains an “A” recommendation, and for those ages 76 to 85 years it remains a “C” recommendation. A “C” recommendation means that the overall benefits are small but some individuals might benefit based on their overall health and prior screening results. In its clinical considerations, the USPSTF recommends against screening in those ages 85 and older but, curiously, does not list it as a “D” recommendation. The screening methods and recommended screening intervals for each appear in TABLE 3.¹¹

For lung cancer, annual screening using low-dose computed tomography (CT) was first recommended by the USPSTF in 2013 for adults ages 55 to 80 years with a 30-pack-year smoking history. Screening could stop once 15 years had passed since smoking cessation. In 2021, the USPSTF lowered the age to initiate screening to 50 years, and the smoking history threshold to 20 pack-years.¹² If these recommendations are followed, a current smoker who does not quit smoking could possibly receive 30 annual CT scans. The recommendation does state that screening should stop once a person develops a health condition that significantly affects life expectancy or ability to have lung surgery.

For primary prevention of lung cancer and other chronic diseases through smoking cessation, the USPSTF also reassessed its 2015 recommendations. It reaffirmed the “A” recommendation to ask adults about tobacco use and, for tobacco users, to recommend cessation and provide behavioral therapy and approved pharmacotherapy.¹³ The recommendation differed for pregnant adults in that the USPSTF is unsure about the potential harms of pharmacotherapy in pregnancy and gives that an “I” statement.¹³ An additional “I” statement was made about the use of electronic cigarettes for smoking cessation; the USPSTF recommends using behavioral and pharmacotherapy interventions with proven effectiveness and safety instead.

Continue to: 4 additional recommendation updates with no changes

4 additional recommendation updates with no changes

Screening for high blood pressure in adults ages 18 years and older continues to receive an “A” recommendation.¹⁴ Importantly, the recommendation states that confirmation of high blood pressure should be made in an out-of-­office setting before initiating treatment. Screening for vitamin D deficiency in adults and hearing loss in older adults both continue with “I” statements,^15,16 and screening for asymptomatic carotid artery stenosis continues to receive a “D” recommendation.¹⁷ The implications of the vitamin D “I” statement were discussed in a previous Practice Alert.¹⁸

Continuing value of the USPSTF

The USPSTF continues to set the gold standard for assessment of preventive interventions, and its decisions affect first-dollar coverage by commercial health insurance. The reaffirmation of past recommendations demonstrates the value of adhering to rigorous evidence-based methods (if they are done correctly, they rarely must be markedly changed). And the updating of screening criteria shows the need to constantly review the evolving evidence for current recommendations. Once again, however, funding and staffing limitations allowed the USPSTF to assess only 1 new topic. A listing of all the 2021 recommendations is in TABLE 4.¹

In 2021, the US Preventive Services Task Force (USPSTF) considered 13 topics and made a total of 23 recommendations. They reviewed only 1 new topic. The other 12 were updates of topics previously addressed; no changes were made in 9 of them. In 3, the recommended age of screening or the criteria for screening were expanded. This Practice Alert will review the recommendations made and highlight new recommendations and any changes to previous ones. All complete recommendation statements, rationales, clinical considerations, and evidence reports can be found on the USPSTF website at https://uspreventiveservicestaskforce.org/uspstf/home.¹

Dental caries in children

Dental caries affect about 23% of children between the ages of 2 and 5 years and are associated with multiple adverse social outcomes and medical conditions.² The best way to prevent tooth decay, other than regular brushing with fluoride toothpaste, is to drink water with recommended amounts of fluoride (≥ 0.6 parts fluoride per million parts water).² The USPSTF reaffirmed its recommendation from 2014 that stated when a local water supply lacks sufficient fluoride, primary care clinicians should prescribe oral supplementation for infants and children in the form of fluoride drops starting at age 6 months. The dosage of fluoride depends on patient age and fluoride concentration in the local water (TABLE 1³). The USPSTF also recommends applying topical fluoride as 5% sodium fluoride varnish, every 6 months, starting when the primary teeth erupt.²

BREAKING NEWS At press time, the USPSTF issued its final recommendation on the use of aspirin for primary prevention of cardiovascular disease; see https:// bit.ly/3vklQEe for details.

In addition to fluoride supplements and topical varnish, should clinicians perform screening examinations looking for dental caries? The USPSTF feels there is not enough evidence to assess this practice and gives it an “I” rating (insufficient evidence).

Preventive interventions in pregnancy 

In 2021, the USPSTF assessed 3 topics related to pregnancy and prenatal care.

Screening for gestational diabetes. The USPSTF gave a “B” recommendation for screening at 24 weeks of pregnancy or after, but an “I” statement for screening prior to 24 weeks.⁴ Screening can involve a 1-step or 2-step protocol.

The 2-step protocol is most commonly used in the United States. It involves first measuring serum glucose after a nonfasting 50-g oral glucose challenge; if the resulting level is high, the second step is a 75- or 100-g oral glucose tolerance test lasting 3 hours. The 1-step protocol involves measuring a fasting glucose level, followed by a 75-g oral glucose challenge with glucose levels measured at 1 and 2 hours.

Healthy weight gain in pregnancy. This was the only new topic the USPSTF assessed last year. The resulting recommendation is to offer pregnant women behavioral counseling to promote healthy weight gain and to prevent excessive weight gain in pregnancy. The recommended weight gain depends on the mother’s prepregnancy weight status: 28 to 40 lbs if the mother is underweight; 25 to 35 lbs if she is not under- or overweight; 15 to 25 lbs if she is overweight; and 11 to 20 lbs if she is obese.⁵ Healthy weight gain contributes to preventing gestational diabetes, emergency cesarean sections, and infant macrosomia.

Continue to: Low-dose aspirin

Low-dose aspirin. Reaffirming a recommendation from 2014, the USPSTF advises low-dose aspirin (81 mg/d) starting after 12 weeks’ gestation for all pregnant women who are at high risk for preeclampsia. TABLE 2⁶ lists high- and moderate-risk conditions for preeclampsia and the recommendation for the use of low-dose aspirin.

Sexually transmitted infections

Screening for both chlamydia and gonorrhea in sexually active females through age 24 years was given a “B” recommendation, reaffirming the 2014 recommendation.⁷ Screening for these 2 sexually transmitted infections (STIs) is also recommended for women 25 years and older who are at increased risk of STIs. Risk is defined as having a new sex partner, more than 1 sex partner, a sex partner who has other sex partners, or a sex partner who has an STI; not using condoms consistently; having a previous STI; exchanging sex for money or drugs; or having a history of incarceration.

Screen for both infections simultaneously using a nucleic acid amplification test, testing all sites of sexual exposure. Urine testing can replace cervical, vaginal, and urethral testing. Those found to be positive for either STI should be treated according to the most recent treatment guidelines from the Centers for Disease Control and Prevention (CDC). And sexual partners should be advised to undergo testing.^8,9

The USPSTF could not find evidence for the benefits and harms of screening for STIs in men. Remember that screening applies to those who are asymptomatic. Male sex partners of those found to be infected should be tested, as should those who show any signs or symptoms of an STI. A recent Practice Alert described the most current CDC guidance for diagnosing and treating STIs.⁹

Type 2 diabetes and prediabetes

Screening for type 2 diabetes (T2D) and prediabetes is now recommended for adults ages 35 to 70 years who are overweight or obese.¹⁰ The age to start screening has been lowered to 35 years from the previous recommendation in 2015, which recommended starting at age 40. In addition, the recommendation states that patients with prediabetes should be referred for preventive interventions. It is important that referral is included in the statement because the Affordable Care Act mandates that USPSTF “A” and “B” recommendations must be covered by commercial health insurance with no copay or deductible.

Continue to: Screening can be conducted...

Screening can be conducted using a fasting plasma glucose or A1C level, or with an oral glucose tolerance test. Interventions that can prevent or delay the onset of T2D in those with prediabetes include lifestyle interventions that focus on diet and physical activity, and the use of metformin (although metformin has not been approved for this by the US Food and Drug Administration).

Changes to cancer screening recommendations

In 2021, the USPSTF reviewed and modified its recommendations on screening for 2 types of cancer: colorectal and lung.

For colorectal cancer, the age at which to start screening was lowered from 50 years to 45 years.¹¹ Screening at this earlier age is a “B” recommendation, because, while there is benefit from screening, it is less than for older age groups. Screening individuals ages 50 to 75 years remains an “A” recommendation, and for those ages 76 to 85 years it remains a “C” recommendation. A “C” recommendation means that the overall benefits are small but some individuals might benefit based on their overall health and prior screening results. In its clinical considerations, the USPSTF recommends against screening in those ages 85 and older but, curiously, does not list it as a “D” recommendation. The screening methods and recommended screening intervals for each appear in TABLE 3.¹¹

For lung cancer, annual screening using low-dose computed tomography (CT) was first recommended by the USPSTF in 2013 for adults ages 55 to 80 years with a 30-pack-year smoking history. Screening could stop once 15 years had passed since smoking cessation. In 2021, the USPSTF lowered the age to initiate screening to 50 years, and the smoking history threshold to 20 pack-years.¹² If these recommendations are followed, a current smoker who does not quit smoking could possibly receive 30 annual CT scans. The recommendation does state that screening should stop once a person develops a health condition that significantly affects life expectancy or ability to have lung surgery.

For primary prevention of lung cancer and other chronic diseases through smoking cessation, the USPSTF also reassessed its 2015 recommendations. It reaffirmed the “A” recommendation to ask adults about tobacco use and, for tobacco users, to recommend cessation and provide behavioral therapy and approved pharmacotherapy.¹³ The recommendation differed for pregnant adults in that the USPSTF is unsure about the potential harms of pharmacotherapy in pregnancy and gives that an “I” statement.¹³ An additional “I” statement was made about the use of electronic cigarettes for smoking cessation; the USPSTF recommends using behavioral and pharmacotherapy interventions with proven effectiveness and safety instead.

Continue to: 4 additional recommendation updates with no changes

4 additional recommendation updates with no changes

Screening for high blood pressure in adults ages 18 years and older continues to receive an “A” recommendation.¹⁴ Importantly, the recommendation states that confirmation of high blood pressure should be made in an out-of-­office setting before initiating treatment. Screening for vitamin D deficiency in adults and hearing loss in older adults both continue with “I” statements,^15,16 and screening for asymptomatic carotid artery stenosis continues to receive a “D” recommendation.¹⁷ The implications of the vitamin D “I” statement were discussed in a previous Practice Alert.¹⁸

Continuing value of the USPSTF

The USPSTF continues to set the gold standard for assessment of preventive interventions, and its decisions affect first-dollar coverage by commercial health insurance. The reaffirmation of past recommendations demonstrates the value of adhering to rigorous evidence-based methods (if they are done correctly, they rarely must be markedly changed). And the updating of screening criteria shows the need to constantly review the evolving evidence for current recommendations. Once again, however, funding and staffing limitations allowed the USPSTF to assess only 1 new topic. A listing of all the 2021 recommendations is in TABLE 4.¹

An investigational, novel oral antibiotic with greater selectivity than vancomycin, metronidazole, and even fidaxomicin may offer improved protection of healthy gut bacteria during the treatment of Clostridium difficile infection (CDI), according to ongoing research.

“CDI treatment has historically been dominated by metronidazole and vancomycin,” said Katherine Johnson, DO, from the Western Infectious Disease Consultants, P.C., Denver. However, these broad-spectrum drugs negatively affect healthy bacteria in the gut and increase the risk of CDI recurrence.

This is also a problem for drugs in the CDI antibiotic pipeline: Many candidate drugs have failed because of their broad-spectrum activity, she added during a session at the Peggy Lillis Foundation 2022 National C. diff. Advocacy Summit.

“An ideal CDI therapy would be a very narrow-spectrum antibiotic that has a minimal effect on normal gut bacteria,” she said.

Dr. Johnson is currently working on a phase 2 clinical trial that is evaluating the novel antibiotic, dubbed CRS3123, for the treatment of primary CDI and first-recurrence CDI. The investigational agent targets and inhibits a form of the methionyl tRNA synthetase enzyme, which is strictly required for protein biosynthesis in C. diff. and is therefore an ideal target for treatment of primary and recurrent CDI.

In her session, Dr. Johnson reported that CRS3123 inhibits the damaging toxins produced by C. diff., potentially resulting in more rapid symptom resolution. Additionally, owing to its novel mode of action, no strains are currently resistant to CRS3123.

She presented findings from an animal study that showed that CRS3123 was superior to vancomycin in terms of prolonging survival. She also presented findings from phase 1 clinical trials that showed that most adverse events (AEs) associated with CRS3123 were mild. No serious AEs were reported.
 

A ‘huge infectious burden’

If successful in further research, CRS3123 could offer significant value to patients with C. diff., especially those with recurrent infection, given the sometimes extreme clinical, quality-of-life, and economic burdens associated with CDI.

“CDI is a huge infectious burden to the U.S. health care system and globally has been listed by the Centers for Disease Control and Prevention as an urgent threat,” Byron Vaughn, MD, from the University of Minnesota, told this news organization.

“Despite a number of antibiotic stewardship and infection control and prevention efforts, we haven’t seen much of a change in the incidence of CDI,” he said. He said that the risk of recurrence can be as high as 30%.

While oral vancomycin is effective for treating C. diff., Dr. Vaughn noted that the antibiotic lacks selectivity and destroys healthy gut bacteria, resulting in substantial dysbiosis. “Dysbiosis is really the key to getting recurrent C. diff.,” he explained, “because if you have healthy gut bacteria, you will inherently resist CDI.”

Dr. Vaughn stated that his center is in the startup phase for being a site for a clinical trial of CRS3123. The hope is that CRS3123, because its spectrum is narrower than that of fidaxomicin and vancomycin, doesn’t induce intestinal dysbiosis. “It really just treats the C. diff. and leaves every other bug alone so that your gut bacteria can recover while the C. diff. is being treated,” he said. “And then when you stop CRS3123, you have healthy gut bacteria already present to prevent recurrence.”

If this is confirmed in large-scale trials, there could be a “dramatic decrease” in the rates of recurrent C. diff., said Dr. Vaughn.

Aside from the potential clinical impact, the economic implications of a novel selective antibiotic that preserves healthy gut bacteria could be significant, he added. “Depending on exactly what population you’re looking at, probably about a third of the cost of C. diff. is actually attributable to recurrence. That’s a huge economic burden that could be improved.”

Dr. Johnson is an employee of Crestone, which is developing CRS3123. Dr. Vaughn reports no relevant financial relationships.

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

An investigational, novel oral antibiotic with greater selectivity than vancomycin, metronidazole, and even fidaxomicin may offer improved protection of healthy gut bacteria during the treatment of Clostridium difficile infection (CDI), according to ongoing research.

“CDI treatment has historically been dominated by metronidazole and vancomycin,” said Katherine Johnson, DO, from the Western Infectious Disease Consultants, P.C., Denver. However, these broad-spectrum drugs negatively affect healthy bacteria in the gut and increase the risk of CDI recurrence.

This is also a problem for drugs in the CDI antibiotic pipeline: Many candidate drugs have failed because of their broad-spectrum activity, she added during a session at the Peggy Lillis Foundation 2022 National C. diff. Advocacy Summit.

“An ideal CDI therapy would be a very narrow-spectrum antibiotic that has a minimal effect on normal gut bacteria,” she said.

Dr. Johnson is currently working on a phase 2 clinical trial that is evaluating the novel antibiotic, dubbed CRS3123, for the treatment of primary CDI and first-recurrence CDI. The investigational agent targets and inhibits a form of the methionyl tRNA synthetase enzyme, which is strictly required for protein biosynthesis in C. diff. and is therefore an ideal target for treatment of primary and recurrent CDI.

In her session, Dr. Johnson reported that CRS3123 inhibits the damaging toxins produced by C. diff., potentially resulting in more rapid symptom resolution. Additionally, owing to its novel mode of action, no strains are currently resistant to CRS3123.

She presented findings from an animal study that showed that CRS3123 was superior to vancomycin in terms of prolonging survival. She also presented findings from phase 1 clinical trials that showed that most adverse events (AEs) associated with CRS3123 were mild. No serious AEs were reported.
 

A ‘huge infectious burden’

If successful in further research, CRS3123 could offer significant value to patients with C. diff., especially those with recurrent infection, given the sometimes extreme clinical, quality-of-life, and economic burdens associated with CDI.

“CDI is a huge infectious burden to the U.S. health care system and globally has been listed by the Centers for Disease Control and Prevention as an urgent threat,” Byron Vaughn, MD, from the University of Minnesota, told this news organization.

“Despite a number of antibiotic stewardship and infection control and prevention efforts, we haven’t seen much of a change in the incidence of CDI,” he said. He said that the risk of recurrence can be as high as 30%.

While oral vancomycin is effective for treating C. diff., Dr. Vaughn noted that the antibiotic lacks selectivity and destroys healthy gut bacteria, resulting in substantial dysbiosis. “Dysbiosis is really the key to getting recurrent C. diff.,” he explained, “because if you have healthy gut bacteria, you will inherently resist CDI.”

Dr. Vaughn stated that his center is in the startup phase for being a site for a clinical trial of CRS3123. The hope is that CRS3123, because its spectrum is narrower than that of fidaxomicin and vancomycin, doesn’t induce intestinal dysbiosis. “It really just treats the C. diff. and leaves every other bug alone so that your gut bacteria can recover while the C. diff. is being treated,” he said. “And then when you stop CRS3123, you have healthy gut bacteria already present to prevent recurrence.”

If this is confirmed in large-scale trials, there could be a “dramatic decrease” in the rates of recurrent C. diff., said Dr. Vaughn.

Aside from the potential clinical impact, the economic implications of a novel selective antibiotic that preserves healthy gut bacteria could be significant, he added. “Depending on exactly what population you’re looking at, probably about a third of the cost of C. diff. is actually attributable to recurrence. That’s a huge economic burden that could be improved.”

Dr. Johnson is an employee of Crestone, which is developing CRS3123. Dr. Vaughn reports no relevant financial relationships.

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

An investigational, novel oral antibiotic with greater selectivity than vancomycin, metronidazole, and even fidaxomicin may offer improved protection of healthy gut bacteria during the treatment of Clostridium difficile infection (CDI), according to ongoing research.

“CDI treatment has historically been dominated by metronidazole and vancomycin,” said Katherine Johnson, DO, from the Western Infectious Disease Consultants, P.C., Denver. However, these broad-spectrum drugs negatively affect healthy bacteria in the gut and increase the risk of CDI recurrence.

This is also a problem for drugs in the CDI antibiotic pipeline: Many candidate drugs have failed because of their broad-spectrum activity, she added during a session at the Peggy Lillis Foundation 2022 National C. diff. Advocacy Summit.

“An ideal CDI therapy would be a very narrow-spectrum antibiotic that has a minimal effect on normal gut bacteria,” she said.

Dr. Johnson is currently working on a phase 2 clinical trial that is evaluating the novel antibiotic, dubbed CRS3123, for the treatment of primary CDI and first-recurrence CDI. The investigational agent targets and inhibits a form of the methionyl tRNA synthetase enzyme, which is strictly required for protein biosynthesis in C. diff. and is therefore an ideal target for treatment of primary and recurrent CDI.

In her session, Dr. Johnson reported that CRS3123 inhibits the damaging toxins produced by C. diff., potentially resulting in more rapid symptom resolution. Additionally, owing to its novel mode of action, no strains are currently resistant to CRS3123.

She presented findings from an animal study that showed that CRS3123 was superior to vancomycin in terms of prolonging survival. She also presented findings from phase 1 clinical trials that showed that most adverse events (AEs) associated with CRS3123 were mild. No serious AEs were reported.
 

A ‘huge infectious burden’

If successful in further research, CRS3123 could offer significant value to patients with C. diff., especially those with recurrent infection, given the sometimes extreme clinical, quality-of-life, and economic burdens associated with CDI.

“CDI is a huge infectious burden to the U.S. health care system and globally has been listed by the Centers for Disease Control and Prevention as an urgent threat,” Byron Vaughn, MD, from the University of Minnesota, told this news organization.

“Despite a number of antibiotic stewardship and infection control and prevention efforts, we haven’t seen much of a change in the incidence of CDI,” he said. He said that the risk of recurrence can be as high as 30%.

While oral vancomycin is effective for treating C. diff., Dr. Vaughn noted that the antibiotic lacks selectivity and destroys healthy gut bacteria, resulting in substantial dysbiosis. “Dysbiosis is really the key to getting recurrent C. diff.,” he explained, “because if you have healthy gut bacteria, you will inherently resist CDI.”

Dr. Vaughn stated that his center is in the startup phase for being a site for a clinical trial of CRS3123. The hope is that CRS3123, because its spectrum is narrower than that of fidaxomicin and vancomycin, doesn’t induce intestinal dysbiosis. “It really just treats the C. diff. and leaves every other bug alone so that your gut bacteria can recover while the C. diff. is being treated,” he said. “And then when you stop CRS3123, you have healthy gut bacteria already present to prevent recurrence.”

If this is confirmed in large-scale trials, there could be a “dramatic decrease” in the rates of recurrent C. diff., said Dr. Vaughn.

Aside from the potential clinical impact, the economic implications of a novel selective antibiotic that preserves healthy gut bacteria could be significant, he added. “Depending on exactly what population you’re looking at, probably about a third of the cost of C. diff. is actually attributable to recurrence. That’s a huge economic burden that could be improved.”

Dr. Johnson is an employee of Crestone, which is developing CRS3123. Dr. Vaughn reports no relevant financial relationships.

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

Clostridioides difficile infection is often confirmed through toxin testing, yet toxin tests alone may not be sufficient for diagnosing and guiding treatment decisions for patients with CDI.

“The presence of a toxigenic strain does not always equal disease,” said David Lyerly, PhD, during a session on C. difficile toxin testing at the Peggy Lillis Foundation 2022 National C. diff Advocacy Summit.

Dr. Lyerly, the chief science officer at Techlab, explained that exotoxins A and B are produced by specific strains of C. difficile and are involved in infections, but some patients who test positive for these toxins by polymerase chain reaction or other tests do not have CDI or they are not appropriate candidates for CDI treatment.

Several studies conducted during the past decade, however, support the importance of toxin detection. Some research has suggested that toxin-positive patients tend to have more clinically severe disease than those who test negative, he noted.

Although its use is limited when it is used alone, toxin testing is needed to confirm a CDI diagnosis and to ensure antibiotic stewardship, Dr. Lyerly said.

He suggested that, in addition to toxin testing, there is a need for molecular measures and other improved diagnostics to identify candidates most likely to benefit from CDI treatment.

“Because we generally detect toxin genes instead of toxin proteins, you can identify persons colonized with toxigenic C. difficile who do not actually have CDI,” Kevin W. Garey, PharmD, from the University of Houston, said in an interview.

Dr. Garey added that a person could likewise have low levels of toxins that aren’t detected by toxin tests but could still have CDI.

“Given this, better diagnostics that incorporate active toxin production and your body’s response to those toxins are needed,” he said, especially since C. difficile toxins are responsible for disease sequelae, including gastroenteritis, colonic perforation, sepsis, and death.
 

Toxin testing a ‘controversial area’

“C. difficile toxin testing has been a controversial area for almost a decade or more,” Shruti K. Gohil, MD, from University of California, Irvine, Health Epidemiology and Infection Prevention, said in an interview.

Dr. Gohil noted that toxin testing is a better test for clinical C. difficile colitis but by itself can miss C. difficile. “So, we are in this conundrum nationally,” she said.

“Many facilities will use a double- or triple-test strategy to make sure that you have a true C. difficile case mandating the use of antibiotics,” she explained. “The reason we test specifically with the enzyme immunoassay or toxin test is to know whether or not you have real C. difficile that’s actively producing the toxin for colitis.”

A patient with C. difficile who has been treated and is in recovery may still test positive on a C. difficile toxin test, added Dr. Gohil. “It would be great if we had a test that could really judge an active, clinical C. difficile infection. This [test] would help in identifying the right patients who need treatment and would also be able to tell if a patient has been cleared of C. difficile.”

Dr. Lyerly is an employee of Techlab. Dr. Garey and Dr. Gohil reported no relevant financial relationships.

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

Clostridioides difficile infection is often confirmed through toxin testing, yet toxin tests alone may not be sufficient for diagnosing and guiding treatment decisions for patients with CDI.

“The presence of a toxigenic strain does not always equal disease,” said David Lyerly, PhD, during a session on C. difficile toxin testing at the Peggy Lillis Foundation 2022 National C. diff Advocacy Summit.

Dr. Lyerly, the chief science officer at Techlab, explained that exotoxins A and B are produced by specific strains of C. difficile and are involved in infections, but some patients who test positive for these toxins by polymerase chain reaction or other tests do not have CDI or they are not appropriate candidates for CDI treatment.

Several studies conducted during the past decade, however, support the importance of toxin detection. Some research has suggested that toxin-positive patients tend to have more clinically severe disease than those who test negative, he noted.

Although its use is limited when it is used alone, toxin testing is needed to confirm a CDI diagnosis and to ensure antibiotic stewardship, Dr. Lyerly said.

He suggested that, in addition to toxin testing, there is a need for molecular measures and other improved diagnostics to identify candidates most likely to benefit from CDI treatment.

“Because we generally detect toxin genes instead of toxin proteins, you can identify persons colonized with toxigenic C. difficile who do not actually have CDI,” Kevin W. Garey, PharmD, from the University of Houston, said in an interview.

Dr. Garey added that a person could likewise have low levels of toxins that aren’t detected by toxin tests but could still have CDI.

“Given this, better diagnostics that incorporate active toxin production and your body’s response to those toxins are needed,” he said, especially since C. difficile toxins are responsible for disease sequelae, including gastroenteritis, colonic perforation, sepsis, and death.
 

Toxin testing a ‘controversial area’

“C. difficile toxin testing has been a controversial area for almost a decade or more,” Shruti K. Gohil, MD, from University of California, Irvine, Health Epidemiology and Infection Prevention, said in an interview.

Dr. Gohil noted that toxin testing is a better test for clinical C. difficile colitis but by itself can miss C. difficile. “So, we are in this conundrum nationally,” she said.

“Many facilities will use a double- or triple-test strategy to make sure that you have a true C. difficile case mandating the use of antibiotics,” she explained. “The reason we test specifically with the enzyme immunoassay or toxin test is to know whether or not you have real C. difficile that’s actively producing the toxin for colitis.”

A patient with C. difficile who has been treated and is in recovery may still test positive on a C. difficile toxin test, added Dr. Gohil. “It would be great if we had a test that could really judge an active, clinical C. difficile infection. This [test] would help in identifying the right patients who need treatment and would also be able to tell if a patient has been cleared of C. difficile.”

Dr. Lyerly is an employee of Techlab. Dr. Garey and Dr. Gohil reported no relevant financial relationships.

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

Clostridioides difficile infection is often confirmed through toxin testing, yet toxin tests alone may not be sufficient for diagnosing and guiding treatment decisions for patients with CDI.

“The presence of a toxigenic strain does not always equal disease,” said David Lyerly, PhD, during a session on C. difficile toxin testing at the Peggy Lillis Foundation 2022 National C. diff Advocacy Summit.

Dr. Lyerly, the chief science officer at Techlab, explained that exotoxins A and B are produced by specific strains of C. difficile and are involved in infections, but some patients who test positive for these toxins by polymerase chain reaction or other tests do not have CDI or they are not appropriate candidates for CDI treatment.

Several studies conducted during the past decade, however, support the importance of toxin detection. Some research has suggested that toxin-positive patients tend to have more clinically severe disease than those who test negative, he noted.

Although its use is limited when it is used alone, toxin testing is needed to confirm a CDI diagnosis and to ensure antibiotic stewardship, Dr. Lyerly said.

He suggested that, in addition to toxin testing, there is a need for molecular measures and other improved diagnostics to identify candidates most likely to benefit from CDI treatment.

“Because we generally detect toxin genes instead of toxin proteins, you can identify persons colonized with toxigenic C. difficile who do not actually have CDI,” Kevin W. Garey, PharmD, from the University of Houston, said in an interview.

Dr. Garey added that a person could likewise have low levels of toxins that aren’t detected by toxin tests but could still have CDI.

“Given this, better diagnostics that incorporate active toxin production and your body’s response to those toxins are needed,” he said, especially since C. difficile toxins are responsible for disease sequelae, including gastroenteritis, colonic perforation, sepsis, and death.
 

Toxin testing a ‘controversial area’

“C. difficile toxin testing has been a controversial area for almost a decade or more,” Shruti K. Gohil, MD, from University of California, Irvine, Health Epidemiology and Infection Prevention, said in an interview.

Dr. Gohil noted that toxin testing is a better test for clinical C. difficile colitis but by itself can miss C. difficile. “So, we are in this conundrum nationally,” she said.

“Many facilities will use a double- or triple-test strategy to make sure that you have a true C. difficile case mandating the use of antibiotics,” she explained. “The reason we test specifically with the enzyme immunoassay or toxin test is to know whether or not you have real C. difficile that’s actively producing the toxin for colitis.”

A patient with C. difficile who has been treated and is in recovery may still test positive on a C. difficile toxin test, added Dr. Gohil. “It would be great if we had a test that could really judge an active, clinical C. difficile infection. This [test] would help in identifying the right patients who need treatment and would also be able to tell if a patient has been cleared of C. difficile.”

Dr. Lyerly is an employee of Techlab. Dr. Garey and Dr. Gohil reported no relevant financial relationships.

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

This spring, global health advisories have been issued regarding an alarming – and as-yet unexplained – uptick of hepatitis in children. Currently, over 200 cases have been reported worldwide, a relatively small amount that nonetheless belies a considerable toll, including several deaths and the need for liver transplantation in a number of patients. The long-term implications are not yet known. Global health officials are working hard to determine a cause, with many focusing on the underlying cases of adenovirus that several patients have presented with.

To understand more, this news organization reached out to frequent contributor William F. Balistreri, MD, a specialist in pediatric gastroenterology and hepatology at Cincinnati Children’s Hospital Medical Center, where to date they have treated at least six cases of hepatitis in otherwise healthy young children, with one requiring a liver transplant. Dr. Balistreri discussed how the outbreak has developed to date, his advice to hepatologists and pediatricians, and where we stand now in this fast-evolving crisis.
 

Tracing the outbreak in the United States

How has this outbreak played out thus far in the United States, and what have we learned from that?

Sporadic reports of cases in multiple states are appearing. On April 21, 2022, a health alert was issued by the Centers for Disease Control and Prevention, recommending testing for adenovirus in children with acute hepatitis of an unknown etiology.

Baker and colleagues recently described five children with severe hepatitis and adenovirus viremia who were admitted to a children’s hospital in Birmingham, Ala., between October and November 2021. In collaboration with local and state officials, the CDC reviewed clinical records in order to identify patients with hepatitis and concomitant adenovirus infection, confirmed by polymerase chain reaction (PCR).

By February 2022, a total of nine children were identified. There was no epidemiologic linkage among these nine patients; all were well and immunocompetent. The prodromal features were somewhat similar: upper respiratory infection, vomiting, diarrhea, and jaundice. All children had markedly elevated aminotransferase levels and variably elevated total bilirubin levels. Extensive workup for other causes of acute liver injury (for example, other viruses, toxins/drugs, metabolic and autoimmune diseases) was unrevealing.

Specifically, none had documented SARS-CoV-2 infection. However, in all nine children, adenovirus was detected in whole blood samples. In the six children who underwent liver biopsy, there was nonspecific hepatitis, without inclusions or immunohistochemical detection of viral agents, including adenovirus. In three patients, the liver injury progressed, and despite the administration of antiviral agents, two underwent liver transplantation.

Baker and colleagues also suggested that measurement of adenovirus titers in whole blood (rather than plasma) may be more sensitive.

The CDC has recommended monitoring and surveillance in order to more fully understand the nature of the illness.
 

European and global cases

What has been the experience with this in Europe and elsewhere globally?

In mid-to-late 2021, several cases of acute hepatitis of unknown nature in children were identified in Europe. Public health officials in the United Kingdom investigated the high number of cases seen in children from England, Scotland, and Wales. They noted approximately 60 cases in England, mostly in children aged 2-5 years.

Marsh and colleagues reported a cluster of cases of severe hepatitis of unknown origin in Scotland affecting children aged 3-5 years. In Scotland, admitted cases were routinely tested for SARS-CoV-2. Of the 13 cases, five had a recent positive test. They discussed the possibility of increased severity of disease following infection with Omicron BA.2 (the dominant SARS-CoV-2 virus circulating in Scotland at that time) or infection by an uncharacterized SARS-CoV-2 variant. None of the children had been vaccinated for SARS-CoV-2.

On April 15, 2022, the World Health Organization Disease Outbreak News published a report of acute hepatitis of unknown etiology occurring in Great Britain and Northern Ireland. By April 21, 2022, 169 cases of acute hepatitis of unknown origin in children younger than 16 years had been reported from 11 countries in the WHO European region and 1 country in the WHO region of the Americas. Approximately 10% required a liver transplantation and at least one death was reported.

What has been established about the possible connection to the SARS-CoV-2 virus, particularly as it relates to coinfection with adenovirus?

In that WHO report of 169 cases, adenovirus was detected in 74 and SARS-CoV-2 in 20. Of note, 19 cases had a SARS-CoV-2 and adenovirus coinfection.

The report’s authors emphasized that, “while adenovirus is a possible hypothesis, investigations are ongoing for the causative agent.” The authors questioned whether this represents a continuing increase in cases of hepatitis or reflects an increased awareness.

The stated priority of the WHO is to determine the cause and to further refine control and prevention actions.

Given the worldwide nature of this outbreak, have connections between any of the cases been made yet?

Not to my knowledge.
 

What clinicians need to know

What makes this outbreak of hepatitis cases particularly concerning to the health care community, in comparison to other childhood diseases that occur globally? Is it because the cause is unknown or is it for other reasons?

It may be a collective heightened concern following the emergence of COVID.

Whether it represents a new form of acute hepatitis, a continuing increase in cases of hepatitis, or an increased awareness because of the well-publicized alerts remains to be determined. We certainly saw “viral-induced hepatitis” in the past.

Young patients may first be brought to pediatricians. What, if anything, should pediatricians be on the lookout for? Do they need a heightened index of suspicion or are the cases too rare at this point?

An awareness of the “outbreak” may allow the clinician to extend the typical workup of a child presenting with an undefined, presumably viral illness.

In the cases reported, the prodromal and/or presenting symptoms were respiratory and gastrointestinal in nature. They include nausea, vomiting, diarrhea, and abdominal pain.

Specifically, if jaundice and/or scleral icterus is noted, then hepatitis should be suspected.

Should pediatricians consider early referral to a pediatric gastroenterologist or hepatologist?

Yes, because there is the potential for finding a treatable cause (for example, autoimmune hepatitis or a specific metabolic disease) in a patient presenting in this fashion.

In addition, the potential for progression to acute liver failure (with coagulopathy and encephalopathy), albeit rare, exists.

What do hepatologists need to be doing when presented with suspected cases?

The typical clinical picture holds and the workup is standard. The one new key, given the recent data, is to test for adenovirus, using whole blood versus plasma, as the former may be more sensitive.

In addition, it is prudent to check for SARS-CoV-2 by PCR.

What are the major questions that remain and that you’d like to see elucidated going forward?

There are many. Is this a new disease? A new variant of adenovirus? A synergy or susceptibility related to SARS-CoV-2? Is it related to a variant of SARS-CoV-2? Is it triggering an adverse immune response? Are there other epigenetic factors involved? And finally, is this an increase, or is it related to a collective heightened concern following the pandemic?

Dr. Balistreri is the Dorothy M.M. Kersten Professor of Pediatrics, director emeritus of the Pediatric Liver Care Center, medical director emeritus of liver transplantation, and professor at the University of Cincinnati; he is also with the department of pediatrics at Cincinnati Children’s Hospital Medical Center.

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

This spring, global health advisories have been issued regarding an alarming – and as-yet unexplained – uptick of hepatitis in children. Currently, over 200 cases have been reported worldwide, a relatively small amount that nonetheless belies a considerable toll, including several deaths and the need for liver transplantation in a number of patients. The long-term implications are not yet known. Global health officials are working hard to determine a cause, with many focusing on the underlying cases of adenovirus that several patients have presented with.

To understand more, this news organization reached out to frequent contributor William F. Balistreri, MD, a specialist in pediatric gastroenterology and hepatology at Cincinnati Children’s Hospital Medical Center, where to date they have treated at least six cases of hepatitis in otherwise healthy young children, with one requiring a liver transplant. Dr. Balistreri discussed how the outbreak has developed to date, his advice to hepatologists and pediatricians, and where we stand now in this fast-evolving crisis.
 

Tracing the outbreak in the United States

How has this outbreak played out thus far in the United States, and what have we learned from that?

Sporadic reports of cases in multiple states are appearing. On April 21, 2022, a health alert was issued by the Centers for Disease Control and Prevention, recommending testing for adenovirus in children with acute hepatitis of an unknown etiology.

Baker and colleagues recently described five children with severe hepatitis and adenovirus viremia who were admitted to a children’s hospital in Birmingham, Ala., between October and November 2021. In collaboration with local and state officials, the CDC reviewed clinical records in order to identify patients with hepatitis and concomitant adenovirus infection, confirmed by polymerase chain reaction (PCR).

By February 2022, a total of nine children were identified. There was no epidemiologic linkage among these nine patients; all were well and immunocompetent. The prodromal features were somewhat similar: upper respiratory infection, vomiting, diarrhea, and jaundice. All children had markedly elevated aminotransferase levels and variably elevated total bilirubin levels. Extensive workup for other causes of acute liver injury (for example, other viruses, toxins/drugs, metabolic and autoimmune diseases) was unrevealing.

Specifically, none had documented SARS-CoV-2 infection. However, in all nine children, adenovirus was detected in whole blood samples. In the six children who underwent liver biopsy, there was nonspecific hepatitis, without inclusions or immunohistochemical detection of viral agents, including adenovirus. In three patients, the liver injury progressed, and despite the administration of antiviral agents, two underwent liver transplantation.

Baker and colleagues also suggested that measurement of adenovirus titers in whole blood (rather than plasma) may be more sensitive.

The CDC has recommended monitoring and surveillance in order to more fully understand the nature of the illness.
 

European and global cases

What has been the experience with this in Europe and elsewhere globally?

In mid-to-late 2021, several cases of acute hepatitis of unknown nature in children were identified in Europe. Public health officials in the United Kingdom investigated the high number of cases seen in children from England, Scotland, and Wales. They noted approximately 60 cases in England, mostly in children aged 2-5 years.

Marsh and colleagues reported a cluster of cases of severe hepatitis of unknown origin in Scotland affecting children aged 3-5 years. In Scotland, admitted cases were routinely tested for SARS-CoV-2. Of the 13 cases, five had a recent positive test. They discussed the possibility of increased severity of disease following infection with Omicron BA.2 (the dominant SARS-CoV-2 virus circulating in Scotland at that time) or infection by an uncharacterized SARS-CoV-2 variant. None of the children had been vaccinated for SARS-CoV-2.

On April 15, 2022, the World Health Organization Disease Outbreak News published a report of acute hepatitis of unknown etiology occurring in Great Britain and Northern Ireland. By April 21, 2022, 169 cases of acute hepatitis of unknown origin in children younger than 16 years had been reported from 11 countries in the WHO European region and 1 country in the WHO region of the Americas. Approximately 10% required a liver transplantation and at least one death was reported.

What has been established about the possible connection to the SARS-CoV-2 virus, particularly as it relates to coinfection with adenovirus?

In that WHO report of 169 cases, adenovirus was detected in 74 and SARS-CoV-2 in 20. Of note, 19 cases had a SARS-CoV-2 and adenovirus coinfection.

The report’s authors emphasized that, “while adenovirus is a possible hypothesis, investigations are ongoing for the causative agent.” The authors questioned whether this represents a continuing increase in cases of hepatitis or reflects an increased awareness.

The stated priority of the WHO is to determine the cause and to further refine control and prevention actions.

Given the worldwide nature of this outbreak, have connections between any of the cases been made yet?

Not to my knowledge.
 

What clinicians need to know

What makes this outbreak of hepatitis cases particularly concerning to the health care community, in comparison to other childhood diseases that occur globally? Is it because the cause is unknown or is it for other reasons?

It may be a collective heightened concern following the emergence of COVID.

Whether it represents a new form of acute hepatitis, a continuing increase in cases of hepatitis, or an increased awareness because of the well-publicized alerts remains to be determined. We certainly saw “viral-induced hepatitis” in the past.

Young patients may first be brought to pediatricians. What, if anything, should pediatricians be on the lookout for? Do they need a heightened index of suspicion or are the cases too rare at this point?

An awareness of the “outbreak” may allow the clinician to extend the typical workup of a child presenting with an undefined, presumably viral illness.

In the cases reported, the prodromal and/or presenting symptoms were respiratory and gastrointestinal in nature. They include nausea, vomiting, diarrhea, and abdominal pain.

Specifically, if jaundice and/or scleral icterus is noted, then hepatitis should be suspected.

Should pediatricians consider early referral to a pediatric gastroenterologist or hepatologist?

Yes, because there is the potential for finding a treatable cause (for example, autoimmune hepatitis or a specific metabolic disease) in a patient presenting in this fashion.

In addition, the potential for progression to acute liver failure (with coagulopathy and encephalopathy), albeit rare, exists.

What do hepatologists need to be doing when presented with suspected cases?

The typical clinical picture holds and the workup is standard. The one new key, given the recent data, is to test for adenovirus, using whole blood versus plasma, as the former may be more sensitive.

In addition, it is prudent to check for SARS-CoV-2 by PCR.

What are the major questions that remain and that you’d like to see elucidated going forward?

There are many. Is this a new disease? A new variant of adenovirus? A synergy or susceptibility related to SARS-CoV-2? Is it related to a variant of SARS-CoV-2? Is it triggering an adverse immune response? Are there other epigenetic factors involved? And finally, is this an increase, or is it related to a collective heightened concern following the pandemic?

Dr. Balistreri is the Dorothy M.M. Kersten Professor of Pediatrics, director emeritus of the Pediatric Liver Care Center, medical director emeritus of liver transplantation, and professor at the University of Cincinnati; he is also with the department of pediatrics at Cincinnati Children’s Hospital Medical Center.

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

This spring, global health advisories have been issued regarding an alarming – and as-yet unexplained – uptick of hepatitis in children. Currently, over 200 cases have been reported worldwide, a relatively small amount that nonetheless belies a considerable toll, including several deaths and the need for liver transplantation in a number of patients. The long-term implications are not yet known. Global health officials are working hard to determine a cause, with many focusing on the underlying cases of adenovirus that several patients have presented with.

To understand more, this news organization reached out to frequent contributor William F. Balistreri, MD, a specialist in pediatric gastroenterology and hepatology at Cincinnati Children’s Hospital Medical Center, where to date they have treated at least six cases of hepatitis in otherwise healthy young children, with one requiring a liver transplant. Dr. Balistreri discussed how the outbreak has developed to date, his advice to hepatologists and pediatricians, and where we stand now in this fast-evolving crisis.
 

Tracing the outbreak in the United States

How has this outbreak played out thus far in the United States, and what have we learned from that?

Sporadic reports of cases in multiple states are appearing. On April 21, 2022, a health alert was issued by the Centers for Disease Control and Prevention, recommending testing for adenovirus in children with acute hepatitis of an unknown etiology.

Baker and colleagues recently described five children with severe hepatitis and adenovirus viremia who were admitted to a children’s hospital in Birmingham, Ala., between October and November 2021. In collaboration with local and state officials, the CDC reviewed clinical records in order to identify patients with hepatitis and concomitant adenovirus infection, confirmed by polymerase chain reaction (PCR).

By February 2022, a total of nine children were identified. There was no epidemiologic linkage among these nine patients; all were well and immunocompetent. The prodromal features were somewhat similar: upper respiratory infection, vomiting, diarrhea, and jaundice. All children had markedly elevated aminotransferase levels and variably elevated total bilirubin levels. Extensive workup for other causes of acute liver injury (for example, other viruses, toxins/drugs, metabolic and autoimmune diseases) was unrevealing.

Specifically, none had documented SARS-CoV-2 infection. However, in all nine children, adenovirus was detected in whole blood samples. In the six children who underwent liver biopsy, there was nonspecific hepatitis, without inclusions or immunohistochemical detection of viral agents, including adenovirus. In three patients, the liver injury progressed, and despite the administration of antiviral agents, two underwent liver transplantation.

Baker and colleagues also suggested that measurement of adenovirus titers in whole blood (rather than plasma) may be more sensitive.

The CDC has recommended monitoring and surveillance in order to more fully understand the nature of the illness.
 

European and global cases

What has been the experience with this in Europe and elsewhere globally?

In mid-to-late 2021, several cases of acute hepatitis of unknown nature in children were identified in Europe. Public health officials in the United Kingdom investigated the high number of cases seen in children from England, Scotland, and Wales. They noted approximately 60 cases in England, mostly in children aged 2-5 years.

Marsh and colleagues reported a cluster of cases of severe hepatitis of unknown origin in Scotland affecting children aged 3-5 years. In Scotland, admitted cases were routinely tested for SARS-CoV-2. Of the 13 cases, five had a recent positive test. They discussed the possibility of increased severity of disease following infection with Omicron BA.2 (the dominant SARS-CoV-2 virus circulating in Scotland at that time) or infection by an uncharacterized SARS-CoV-2 variant. None of the children had been vaccinated for SARS-CoV-2.

On April 15, 2022, the World Health Organization Disease Outbreak News published a report of acute hepatitis of unknown etiology occurring in Great Britain and Northern Ireland. By April 21, 2022, 169 cases of acute hepatitis of unknown origin in children younger than 16 years had been reported from 11 countries in the WHO European region and 1 country in the WHO region of the Americas. Approximately 10% required a liver transplantation and at least one death was reported.

What has been established about the possible connection to the SARS-CoV-2 virus, particularly as it relates to coinfection with adenovirus?

In that WHO report of 169 cases, adenovirus was detected in 74 and SARS-CoV-2 in 20. Of note, 19 cases had a SARS-CoV-2 and adenovirus coinfection.

The report’s authors emphasized that, “while adenovirus is a possible hypothesis, investigations are ongoing for the causative agent.” The authors questioned whether this represents a continuing increase in cases of hepatitis or reflects an increased awareness.

The stated priority of the WHO is to determine the cause and to further refine control and prevention actions.

Given the worldwide nature of this outbreak, have connections between any of the cases been made yet?

Not to my knowledge.
 

What clinicians need to know

What makes this outbreak of hepatitis cases particularly concerning to the health care community, in comparison to other childhood diseases that occur globally? Is it because the cause is unknown or is it for other reasons?

It may be a collective heightened concern following the emergence of COVID.

Whether it represents a new form of acute hepatitis, a continuing increase in cases of hepatitis, or an increased awareness because of the well-publicized alerts remains to be determined. We certainly saw “viral-induced hepatitis” in the past.

Young patients may first be brought to pediatricians. What, if anything, should pediatricians be on the lookout for? Do they need a heightened index of suspicion or are the cases too rare at this point?

An awareness of the “outbreak” may allow the clinician to extend the typical workup of a child presenting with an undefined, presumably viral illness.

In the cases reported, the prodromal and/or presenting symptoms were respiratory and gastrointestinal in nature. They include nausea, vomiting, diarrhea, and abdominal pain.

Specifically, if jaundice and/or scleral icterus is noted, then hepatitis should be suspected.

Should pediatricians consider early referral to a pediatric gastroenterologist or hepatologist?

Yes, because there is the potential for finding a treatable cause (for example, autoimmune hepatitis or a specific metabolic disease) in a patient presenting in this fashion.

In addition, the potential for progression to acute liver failure (with coagulopathy and encephalopathy), albeit rare, exists.

What do hepatologists need to be doing when presented with suspected cases?

The typical clinical picture holds and the workup is standard. The one new key, given the recent data, is to test for adenovirus, using whole blood versus plasma, as the former may be more sensitive.

In addition, it is prudent to check for SARS-CoV-2 by PCR.

What are the major questions that remain and that you’d like to see elucidated going forward?

There are many. Is this a new disease? A new variant of adenovirus? A synergy or susceptibility related to SARS-CoV-2? Is it related to a variant of SARS-CoV-2? Is it triggering an adverse immune response? Are there other epigenetic factors involved? And finally, is this an increase, or is it related to a collective heightened concern following the pandemic?

Dr. Balistreri is the Dorothy M.M. Kersten Professor of Pediatrics, director emeritus of the Pediatric Liver Care Center, medical director emeritus of liver transplantation, and professor at the University of Cincinnati; he is also with the department of pediatrics at Cincinnati Children’s Hospital Medical Center.

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

Having had a recent acute febrile illness was associated with an increased risk for ischemic stroke, whereas having received an influenza vaccination was associated with a reduced risk for stroke in a large new case-control study.

“While influenza vaccination is a cost-effective method to prevent influenza, it is also an effective way to reduce the burden of stroke,” said study author Christopher Schwarzbach, MD, of Ludwigshafen (Germany) Hospital.  

“Our results therefore encourage the wider use of influenza vaccination,” he concluded.

Dr. Schwarzbach presented these data from the INTERSTROKE study at the 2022 European Stroke Organisation Conference.

He explained that acute inflammatory disease is thought to increase the risk for cerebrovascular events, and the seasonality of influenza-like illness appears to be associated with the seasonality of cardiovascular and cerebrovascular events. Previous observational studies have also shown a link between influenza vaccination and a reduced risk for stroke.

The current INTERSTROKE study was a large international case-control study conducted between 2007 and 2015 that involved 13,447 cases (patients within 5 days of their first stroke) and a similar number of age- and gender-matched people from 32 countries across the world.

All cases and control subjects were systematically asked whether they had acute febrile illness in the previous 4 weeks and whether they had received an influenza vaccination within the previous year.

Conditional logistical regression was used to quantify the results, with adjustment for 13 different possible confounding factors, including hypertension, activity, smoking, cardiovascular risk factors, and socioeconomic factors.

Results showed that having had an acute febrile illness in the previous 4 weeks was more commonly reported in the patients with an acute ischemic stroke (8.7%) than in control patients (5.6%). After adjustment for confounding factors, this gives an adjusted risk ratio of 1.18, which was of borderline statistical significance (95% confidence limits, 1.01-1.39), Dr. Schwarzbach reported.

The association between recent febrile illness and acute ischemic stroke was stronger when compared with community control subjects (adjusted odds ratio, 2.0), but it was absent when compared with hospital control subjects.

The association was also only apparent in Australia, China, North America, and Western Europe; it was not seen in other parts of the world.

There was no association between acute febrile illness and acute cerebral hemorrhage.
 

Flu vaccine linked to halving of stroke risk

Having received a flu vaccine in the previous year was strongly associated with a lower risk for any type of stroke (aOR, 0.53), ischemic stroke (aOR, 0.57), and hemorrhagic stroke (aOR, 0.34).

Dr. Schwarzbach noted that these results were also consistent in an extended statistical model that included variables that might reflect a willingness to be vaccinated and when compared with both community and hospital-based control subjects.

The strength of the association between influenza vaccination and reduced risk for stroke was similar when compared with either community or hospital control subjects, and was only moderately stronger during than outside the influenza season.

The association was also seen in all regions of the world apart from Africa and South Asia, Dr. Schwarzbach reported, but he noted that vaccination rates in these two regions were extremely low.  

The researchers also found that the magnitude of the associations between flu vaccination and lower risk for stroke were stronger in individuals who had multiple annual vaccinations, with an odds ratio of 0.54 in those who had received a vaccine every year for the previous 5 years, and of 0.79 in those who had received one to four vaccinations in the previous 5 years.
 

Mechanism: Immune stimulation?

Discussing possible mechanisms behind these results, Dr. Schwarzbach noted that the finding that the association with influenza vaccination and reduced stroke risk was independent of seasonality was surprising. “We had expected the protective effect of vaccination to be bigger during the influenza season, but this wasn’t the case.”

He suggested that one explanation might be the inclusion of regions of the world where this seasonality doesn’t exist.

But he pointed out that the finding of a stronger association between flu vaccination and lower stroke risk in those who had received more vaccinations has given rise to another theory: that it is the stimulation of the immune system rather than the protection of infection against influenza that is the key factor.

In an interview with Dr. Schwarzbach, Guillaume Turk, MD, professor of neurology at GHU Paris, pointed out that causal inferences are always difficult in case-control studies and in clinical epidemiology in general.

“What makes you think that this association between influenza vaccination and decreased risk is causal rather than due to unmeasured confounders? For example, patients who received vaccination may have received more medical attention and may have been more aware of the risk factors for stroke,” he asked.  

Dr. Schwarzbach replied: “Yes, this is the issue of healthy user bias, which is always a problem in this type of research and is hard to address.”

“What we tried to do here is to adjust for variables that might influence the willingness of people to get vaccinated,” he added. “These were mainly socioeconomic factors. But, of course, this is something that we can’t rule out.”

Dr. Schwarzbach noted that, for more reliable information on this association, prospective studies are needed.
 

‘A plausible effect’

Discussing the study after the presentation, William Whiteley, BM, PhD, a clinical epidemiologist at the University of Edinburgh and a consultant neurologist in NHS Lothian, said vaccination was a potentially important way to reduce stroke.

“In this study, there was a plausible effect on reducing stroke incidence from vaccination against influenza, and also a plausible increase in the risk of stroke from having a recent febrile illness, which we have seen in other studies,” he commented.

Dr. Whiteley noted that this observation was particularly relevant now because of the COVID-19 pandemic.

“We’ve all been worried about the risk of heart attack and stroke after COVID, where we’ve seen quite early high risks, and we are also optimistic about the effect of vaccination on reducing those incidences. We’ve seen data from the U.K. that there may be around a 20% reduction in risk of stroke from vaccination. So, it’s all quite plausible, but at the moment it’s all based on observational evidence and we really need some randomized evidence,” he said.  

“Vaccination and infections have all sorts of odd confounders,” he added. “People who get vaccines tend to be more healthy than those who don’t get vaccines, so you can start to see quite implausible effects of vaccination on overall mortality, which probably aren’t real, and you probably can’t get rid of that totally with statistical methods.”

Alastair Webb, MD, University of Oxford (England), asked how reliable the current findings were, given that the occurrence of febrile illnesses and receipt of vaccines were all self-reported, and although there was an association for ischemic stroke and febrile illness, this seemed to go in the opposite direction for hemorrhagic stroke. He also noted that the 50% reduction in stroke risk with vaccination in this study seemed “quite a large magnitude of effect.”

Dr. Whiteley replied: “Yes, it is large, but it is promising.” He cited a previous meta-analysis of randomized studies that showed a roughly 25%-35% reduction in vascular events after flu vaccination, but noted that there was a lot of heterogeneity between studies.

“I’m not sure we’re going to see much more randomized evidence, but I think we can probably all agree that having a vaccine against flu or COVID is a good thing for all of us,” Dr. Whiteley concluded.

The INTERSTROKE study was funded by the Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Health Research Board Ireland, Swedish Research Council, Swedish Heart and Lung Foundation, The Health & Medical Care Committee of the Regional Executive Board, Region Vastra Gotaland (Sweden), AstraZeneca, Boehringer Ingelheim, Pfizer, MSD, Chest, Heart and Stroke Scotland, and The Stroke Association, with support from The UK Stroke Research Network. The authors reported no relevant disclosures.

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

Having had a recent acute febrile illness was associated with an increased risk for ischemic stroke, whereas having received an influenza vaccination was associated with a reduced risk for stroke in a large new case-control study.

“While influenza vaccination is a cost-effective method to prevent influenza, it is also an effective way to reduce the burden of stroke,” said study author Christopher Schwarzbach, MD, of Ludwigshafen (Germany) Hospital.  

“Our results therefore encourage the wider use of influenza vaccination,” he concluded.

Dr. Schwarzbach presented these data from the INTERSTROKE study at the 2022 European Stroke Organisation Conference.

He explained that acute inflammatory disease is thought to increase the risk for cerebrovascular events, and the seasonality of influenza-like illness appears to be associated with the seasonality of cardiovascular and cerebrovascular events. Previous observational studies have also shown a link between influenza vaccination and a reduced risk for stroke.

The current INTERSTROKE study was a large international case-control study conducted between 2007 and 2015 that involved 13,447 cases (patients within 5 days of their first stroke) and a similar number of age- and gender-matched people from 32 countries across the world.

All cases and control subjects were systematically asked whether they had acute febrile illness in the previous 4 weeks and whether they had received an influenza vaccination within the previous year.

Conditional logistical regression was used to quantify the results, with adjustment for 13 different possible confounding factors, including hypertension, activity, smoking, cardiovascular risk factors, and socioeconomic factors.

Results showed that having had an acute febrile illness in the previous 4 weeks was more commonly reported in the patients with an acute ischemic stroke (8.7%) than in control patients (5.6%). After adjustment for confounding factors, this gives an adjusted risk ratio of 1.18, which was of borderline statistical significance (95% confidence limits, 1.01-1.39), Dr. Schwarzbach reported.

The association between recent febrile illness and acute ischemic stroke was stronger when compared with community control subjects (adjusted odds ratio, 2.0), but it was absent when compared with hospital control subjects.

The association was also only apparent in Australia, China, North America, and Western Europe; it was not seen in other parts of the world.

There was no association between acute febrile illness and acute cerebral hemorrhage.
 

Flu vaccine linked to halving of stroke risk

Having received a flu vaccine in the previous year was strongly associated with a lower risk for any type of stroke (aOR, 0.53), ischemic stroke (aOR, 0.57), and hemorrhagic stroke (aOR, 0.34).

Dr. Schwarzbach noted that these results were also consistent in an extended statistical model that included variables that might reflect a willingness to be vaccinated and when compared with both community and hospital-based control subjects.

The strength of the association between influenza vaccination and reduced risk for stroke was similar when compared with either community or hospital control subjects, and was only moderately stronger during than outside the influenza season.

The association was also seen in all regions of the world apart from Africa and South Asia, Dr. Schwarzbach reported, but he noted that vaccination rates in these two regions were extremely low.  

The researchers also found that the magnitude of the associations between flu vaccination and lower risk for stroke were stronger in individuals who had multiple annual vaccinations, with an odds ratio of 0.54 in those who had received a vaccine every year for the previous 5 years, and of 0.79 in those who had received one to four vaccinations in the previous 5 years.
 

Mechanism: Immune stimulation?

Discussing possible mechanisms behind these results, Dr. Schwarzbach noted that the finding that the association with influenza vaccination and reduced stroke risk was independent of seasonality was surprising. “We had expected the protective effect of vaccination to be bigger during the influenza season, but this wasn’t the case.”

He suggested that one explanation might be the inclusion of regions of the world where this seasonality doesn’t exist.

But he pointed out that the finding of a stronger association between flu vaccination and lower stroke risk in those who had received more vaccinations has given rise to another theory: that it is the stimulation of the immune system rather than the protection of infection against influenza that is the key factor.

In an interview with Dr. Schwarzbach, Guillaume Turk, MD, professor of neurology at GHU Paris, pointed out that causal inferences are always difficult in case-control studies and in clinical epidemiology in general.

“What makes you think that this association between influenza vaccination and decreased risk is causal rather than due to unmeasured confounders? For example, patients who received vaccination may have received more medical attention and may have been more aware of the risk factors for stroke,” he asked.  

Dr. Schwarzbach replied: “Yes, this is the issue of healthy user bias, which is always a problem in this type of research and is hard to address.”

“What we tried to do here is to adjust for variables that might influence the willingness of people to get vaccinated,” he added. “These were mainly socioeconomic factors. But, of course, this is something that we can’t rule out.”

Dr. Schwarzbach noted that, for more reliable information on this association, prospective studies are needed.
 

‘A plausible effect’

Discussing the study after the presentation, William Whiteley, BM, PhD, a clinical epidemiologist at the University of Edinburgh and a consultant neurologist in NHS Lothian, said vaccination was a potentially important way to reduce stroke.

“In this study, there was a plausible effect on reducing stroke incidence from vaccination against influenza, and also a plausible increase in the risk of stroke from having a recent febrile illness, which we have seen in other studies,” he commented.

Dr. Whiteley noted that this observation was particularly relevant now because of the COVID-19 pandemic.

“We’ve all been worried about the risk of heart attack and stroke after COVID, where we’ve seen quite early high risks, and we are also optimistic about the effect of vaccination on reducing those incidences. We’ve seen data from the U.K. that there may be around a 20% reduction in risk of stroke from vaccination. So, it’s all quite plausible, but at the moment it’s all based on observational evidence and we really need some randomized evidence,” he said.  

“Vaccination and infections have all sorts of odd confounders,” he added. “People who get vaccines tend to be more healthy than those who don’t get vaccines, so you can start to see quite implausible effects of vaccination on overall mortality, which probably aren’t real, and you probably can’t get rid of that totally with statistical methods.”

Alastair Webb, MD, University of Oxford (England), asked how reliable the current findings were, given that the occurrence of febrile illnesses and receipt of vaccines were all self-reported, and although there was an association for ischemic stroke and febrile illness, this seemed to go in the opposite direction for hemorrhagic stroke. He also noted that the 50% reduction in stroke risk with vaccination in this study seemed “quite a large magnitude of effect.”

Dr. Whiteley replied: “Yes, it is large, but it is promising.” He cited a previous meta-analysis of randomized studies that showed a roughly 25%-35% reduction in vascular events after flu vaccination, but noted that there was a lot of heterogeneity between studies.

“I’m not sure we’re going to see much more randomized evidence, but I think we can probably all agree that having a vaccine against flu or COVID is a good thing for all of us,” Dr. Whiteley concluded.

The INTERSTROKE study was funded by the Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Health Research Board Ireland, Swedish Research Council, Swedish Heart and Lung Foundation, The Health & Medical Care Committee of the Regional Executive Board, Region Vastra Gotaland (Sweden), AstraZeneca, Boehringer Ingelheim, Pfizer, MSD, Chest, Heart and Stroke Scotland, and The Stroke Association, with support from The UK Stroke Research Network. The authors reported no relevant disclosures.

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

Having had a recent acute febrile illness was associated with an increased risk for ischemic stroke, whereas having received an influenza vaccination was associated with a reduced risk for stroke in a large new case-control study.

“While influenza vaccination is a cost-effective method to prevent influenza, it is also an effective way to reduce the burden of stroke,” said study author Christopher Schwarzbach, MD, of Ludwigshafen (Germany) Hospital.  

“Our results therefore encourage the wider use of influenza vaccination,” he concluded.

Dr. Schwarzbach presented these data from the INTERSTROKE study at the 2022 European Stroke Organisation Conference.

He explained that acute inflammatory disease is thought to increase the risk for cerebrovascular events, and the seasonality of influenza-like illness appears to be associated with the seasonality of cardiovascular and cerebrovascular events. Previous observational studies have also shown a link between influenza vaccination and a reduced risk for stroke.

The current INTERSTROKE study was a large international case-control study conducted between 2007 and 2015 that involved 13,447 cases (patients within 5 days of their first stroke) and a similar number of age- and gender-matched people from 32 countries across the world.

All cases and control subjects were systematically asked whether they had acute febrile illness in the previous 4 weeks and whether they had received an influenza vaccination within the previous year.

Conditional logistical regression was used to quantify the results, with adjustment for 13 different possible confounding factors, including hypertension, activity, smoking, cardiovascular risk factors, and socioeconomic factors.

Results showed that having had an acute febrile illness in the previous 4 weeks was more commonly reported in the patients with an acute ischemic stroke (8.7%) than in control patients (5.6%). After adjustment for confounding factors, this gives an adjusted risk ratio of 1.18, which was of borderline statistical significance (95% confidence limits, 1.01-1.39), Dr. Schwarzbach reported.

The association between recent febrile illness and acute ischemic stroke was stronger when compared with community control subjects (adjusted odds ratio, 2.0), but it was absent when compared with hospital control subjects.

The association was also only apparent in Australia, China, North America, and Western Europe; it was not seen in other parts of the world.

There was no association between acute febrile illness and acute cerebral hemorrhage.
 

Flu vaccine linked to halving of stroke risk

Having received a flu vaccine in the previous year was strongly associated with a lower risk for any type of stroke (aOR, 0.53), ischemic stroke (aOR, 0.57), and hemorrhagic stroke (aOR, 0.34).

Dr. Schwarzbach noted that these results were also consistent in an extended statistical model that included variables that might reflect a willingness to be vaccinated and when compared with both community and hospital-based control subjects.

The strength of the association between influenza vaccination and reduced risk for stroke was similar when compared with either community or hospital control subjects, and was only moderately stronger during than outside the influenza season.

The association was also seen in all regions of the world apart from Africa and South Asia, Dr. Schwarzbach reported, but he noted that vaccination rates in these two regions were extremely low.  

The researchers also found that the magnitude of the associations between flu vaccination and lower risk for stroke were stronger in individuals who had multiple annual vaccinations, with an odds ratio of 0.54 in those who had received a vaccine every year for the previous 5 years, and of 0.79 in those who had received one to four vaccinations in the previous 5 years.
 

Mechanism: Immune stimulation?

Discussing possible mechanisms behind these results, Dr. Schwarzbach noted that the finding that the association with influenza vaccination and reduced stroke risk was independent of seasonality was surprising. “We had expected the protective effect of vaccination to be bigger during the influenza season, but this wasn’t the case.”

He suggested that one explanation might be the inclusion of regions of the world where this seasonality doesn’t exist.

But he pointed out that the finding of a stronger association between flu vaccination and lower stroke risk in those who had received more vaccinations has given rise to another theory: that it is the stimulation of the immune system rather than the protection of infection against influenza that is the key factor.

In an interview with Dr. Schwarzbach, Guillaume Turk, MD, professor of neurology at GHU Paris, pointed out that causal inferences are always difficult in case-control studies and in clinical epidemiology in general.

“What makes you think that this association between influenza vaccination and decreased risk is causal rather than due to unmeasured confounders? For example, patients who received vaccination may have received more medical attention and may have been more aware of the risk factors for stroke,” he asked.  

Dr. Schwarzbach replied: “Yes, this is the issue of healthy user bias, which is always a problem in this type of research and is hard to address.”

“What we tried to do here is to adjust for variables that might influence the willingness of people to get vaccinated,” he added. “These were mainly socioeconomic factors. But, of course, this is something that we can’t rule out.”

Dr. Schwarzbach noted that, for more reliable information on this association, prospective studies are needed.
 

‘A plausible effect’

Discussing the study after the presentation, William Whiteley, BM, PhD, a clinical epidemiologist at the University of Edinburgh and a consultant neurologist in NHS Lothian, said vaccination was a potentially important way to reduce stroke.

“In this study, there was a plausible effect on reducing stroke incidence from vaccination against influenza, and also a plausible increase in the risk of stroke from having a recent febrile illness, which we have seen in other studies,” he commented.

Dr. Whiteley noted that this observation was particularly relevant now because of the COVID-19 pandemic.

“We’ve all been worried about the risk of heart attack and stroke after COVID, where we’ve seen quite early high risks, and we are also optimistic about the effect of vaccination on reducing those incidences. We’ve seen data from the U.K. that there may be around a 20% reduction in risk of stroke from vaccination. So, it’s all quite plausible, but at the moment it’s all based on observational evidence and we really need some randomized evidence,” he said.  

“Vaccination and infections have all sorts of odd confounders,” he added. “People who get vaccines tend to be more healthy than those who don’t get vaccines, so you can start to see quite implausible effects of vaccination on overall mortality, which probably aren’t real, and you probably can’t get rid of that totally with statistical methods.”

Alastair Webb, MD, University of Oxford (England), asked how reliable the current findings were, given that the occurrence of febrile illnesses and receipt of vaccines were all self-reported, and although there was an association for ischemic stroke and febrile illness, this seemed to go in the opposite direction for hemorrhagic stroke. He also noted that the 50% reduction in stroke risk with vaccination in this study seemed “quite a large magnitude of effect.”

Dr. Whiteley replied: “Yes, it is large, but it is promising.” He cited a previous meta-analysis of randomized studies that showed a roughly 25%-35% reduction in vascular events after flu vaccination, but noted that there was a lot of heterogeneity between studies.

“I’m not sure we’re going to see much more randomized evidence, but I think we can probably all agree that having a vaccine against flu or COVID is a good thing for all of us,” Dr. Whiteley concluded.

The INTERSTROKE study was funded by the Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Health Research Board Ireland, Swedish Research Council, Swedish Heart and Lung Foundation, The Health & Medical Care Committee of the Regional Executive Board, Region Vastra Gotaland (Sweden), AstraZeneca, Boehringer Ingelheim, Pfizer, MSD, Chest, Heart and Stroke Scotland, and The Stroke Association, with support from The UK Stroke Research Network. The authors reported no relevant disclosures.

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

The U.S. Food and Drug Administration has approved two vonoprazan-based treatments for Helicobacter pylori infection: Voquezna Triple Pak (vonoprazan, amoxicillin, clarithromycin) and Voquezna Dual Pak (vonoprazan, amoxicillin), both from Phathom Pharmaceuticals.

Vonoprazan is an oral potassium-competitive acid blocker and “the first innovative acid suppressant from a new drug class approved in the United States in over 30 years,” the company said in a news release announcing the approval.

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

The U.S. Food and Drug Administration has approved two vonoprazan-based treatments for Helicobacter pylori infection: Voquezna Triple Pak (vonoprazan, amoxicillin, clarithromycin) and Voquezna Dual Pak (vonoprazan, amoxicillin), both from Phathom Pharmaceuticals.

Vonoprazan is an oral potassium-competitive acid blocker and “the first innovative acid suppressant from a new drug class approved in the United States in over 30 years,” the company said in a news release announcing the approval.

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

The U.S. Food and Drug Administration has approved two vonoprazan-based treatments for Helicobacter pylori infection: Voquezna Triple Pak (vonoprazan, amoxicillin, clarithromycin) and Voquezna Dual Pak (vonoprazan, amoxicillin), both from Phathom Pharmaceuticals.

Vonoprazan is an oral potassium-competitive acid blocker and “the first innovative acid suppressant from a new drug class approved in the United States in over 30 years,” the company said in a news release announcing the approval.

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