Immunology

Postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a distinct, centrally mediated condition, with evidence of autonomic, immune, and metabolic dysfunction, new "deep phenotyping" data suggested.

The study was initiated in 2016 at the US National Institutes of Health. Its aim was to better elucidate the underlying pathophysiology of ME/CFS, a multisystem disorder characterized by persistent and disabling fatigue, post-exertional malaise, cognitive complaints, and other physical symptoms. A total of 17 carefully selected individuals with PI-ME/CFS onset within the prior 5 years were compared with 21 healthy volunteers on a more extensive set of biologic measurements than has been examined in any prior study of the condition.

Overall, the findings suggested that ME/CFS is “a distinct entity characterized by somatic and cognitive complaints that are centrally mediated,” with fatigue that is “defined by effort preferences and central autonomic dysfunction,” Brian T. Walitt, MD, of the National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, Maryland, and colleagues wrote in the paper, published on February 21 in Nature Communications.

In addition, “there are distinct sex signatures of immune and metabolic dysregulation which suggest persistent antigenic stimulation.” Physical deconditioning over time, while not the source of the condition, “is an important consequence,” the authors added.

Asked to comment, Hector Bonilla, MD, director of the ME/CFS Clinic and codirector of the Stanford Post-Acute COVID-19 Syndrome Clinic, Atherton, California, pointed out that the sample was small and the study was cross-sectional and therefore likely missed dynamic changes in the patients.

Nonetheless, Dr. Bonilla told this news organization, “they have shown clear objective changes in patients with ME/CFS not seen in the controls. These are present in the microbiome, in the immune system, and in metabolites, especially in spinal fluid, that lead to a neuroinflammatory condition. And these are linked with autonomic dysfunction that can explain many of the symptoms that patients experience ... The symptoms are not manufactured by them.”

Thus far, the only treatments for ME/CFS are symptomatic. Understanding the pathophysiology is essential to identifying disease-modifying therapy, study lead author Avindra Nath, MD, Senior Investigator and Clinical Director of Intramural Research at NINDS, told this news organization.

“The disease is real. But our medical profession is limited in what they can do to diagnose or impact them ... The first thing we need to do is try to understand the pathophysiology. So that’s why the study was put together,” Dr. Nath said.

Postinfectious syndromes including ME/CFS have been given many names, including post-Lyme disease, Gulf War illness, and more recently, long COVID. With ME/CFS, the Epstein-Barr virus has historically been one of the most commonly associated triggers, although several other viral, bacterial, and environmental toxins have been implicated.

“There are a whole host of these things that have very similar symptoms or overlapping symptoms ... It’s quite possible that the underlying pathophysiology overlaps between all these syndromes,” Dr. Nath noted.

Another ME/CFS expert not involved in the study, researcher Michael VanElzakker, PhD, of the Neurotherapeutics Division at Harvard Medical School and Massachusetts General Hospital, Boston, said that the possibility of antigen persistence of the infectious pathogen arising from the immune system profiling conducted in the study is noteworthy and merits further study.

“To me, the obvious next step would be techniques like tissue-based assays and T-cell sequencing to try and understand what exactly those antigens are and what their source might be. Importantly, it is probably not the same antigen or pathogen source in all patients, but that’s a question that needs an answer,” Dr. VanElzakker said.

Of note, the 17 study participants had been adjudicated by an expert panel from an initial 484 inquiries and 217 who underwent detailed case reviews. They had to meet at least one of three published ME/CFS criteria and to have moderate to severe clinical symptom severity as determined by several fatigue scores. None met the criteria for psychiatric diagnoses.

Yet, even in the cases that met study criteria, underlying causes emerged in 20% of the participants over time, suggesting diagnostic misattribution. “This misclassification bias has important ramifications on the interpretation of the existing ME/CFS research literature,” the authors wrote.

Dr. VanElzakker noted, “The fact that this research study was probably the most detailed workup many of these patients had ever gotten is a serious indictment of our current profit-based healthcare system’s prioritization of 15-minute doctor’s appointments. It is almost certain that other patients would also benefit from an intensive detailed workup.”
 

Multiple Abnormalities Identified

There were no differences between the PI-ME/CFS and control groups in ventilatory function, muscle oxygenation, mechanical efficiency, resting energy expenditure, basal mitochondrial function of immune cells, muscle fiber composition, or body composition, suggesting the absence of a resting low-energy state, the authors said.

In 40-minute head-up tilt-table testing, there were no differences between the ME/CFS and control groups in frequency or orthostatic hypotension or extensive orthostatic tachycardia. However, a 24-hour ambulatory electrocardiogram showed that the patients with PI-ME/CFS had diminished heart rate variability. They also showed increased heart rate throughout the day, suggesting increased sympathetic activity, and a diminished drop in nighttime heart rate, suggesting decreased parasympathetic activity.

“Considered together, these data suggest that there is an alteration in autonomic tone, implying central nervous system regulatory change,” Dr. Walitt and colleagues wrote.

On the “Effort-Expenditure for Rewards Task,” the participants with PI-ME/CFS showed significant differences in “effort preference,” or a tendency to avoid the harder tasks, as well as a slowing of button-pushing over time, compared with the controls, even with easier tasks. This pattern suggests that those with PI-ME/CFS were “pacing to limit exertion and associated feelings of discomfort,” the authors wrote.

Dr. Nath describes this behavior as akin to “if you develop a flu, you feel that you just want to lay down in bed and not hurt yourself. It’s not that you’re not capable of doing [the task], but your body tells you don’t do it. Your body just wants to fight the infection ... these people just never bounce back.”

Compared with the controls, the participants with PI-ME/CFS failed to maintain a moderate grip force even though there was no difference in maximum grip strength or arm muscle mass. This performance difference correlated with decreased activity of the right temporal-parietal junction, a novel observation suggesting that the fatigue in the PI-ME/CFS group “is due to dysfunction of integrative brain regions that drive the motor cortex, the cause of which needs to be further explored,” Dr. Walitt and colleagues wrote.

On cardiopulmonary testing, peak power, peak respiratory rate, peak heart rate, and peak VO₂ were all lower in the PI-ME/CFS group, correlating to a difference of approximately 3.3 metabolic equivalent of task units. The differential cardiorespiratory performance relates to “autonomic function, hypothalamic-pituitary-adrenal axis hyporesponsiveness, and muscular deconditioning from disuse that clinically impacts activities of daily life,” they said.

In the participants with PI-ME/CFS, catechol levels in cerebrospinal fluid correlated with grip strength and effort preference, and several metabolites of the dopamine pathway correlated with several cognitive symptoms.

“This suggests that central nervous system catechol pathways are dysregulated in PI-ME/CFS and may play a role in effort preference and cognitive complaints,” as well as decreased central catecholamine biosynthesis. Similar findings have been seen in patients with long COVID, the authors noted.

There were increased naive B cells and decreased switched memory B cells in blood of participants with PI-ME/CFS. Contrary to prior studies, there was no consistent pattern of autoimmunity across all participants with PI-ME/CFS, and no previously undescribed antibodies were identified.

However, programmed cell death protein 1, a marker of T-cell exhaustion and activation, was elevated in the cerebrospinal fluid of the patients with PI-ME/CFS.

Several sex-based differences were noted, including in immune cell expression in cerebrospinal fluid, peripheral blood mononuclear cell gene expression, and muscle gene expression. Males and females also differed in the cerebrospinal metabolomics that distinguished the participants with PI-ME/CFS from controls.
 

What Do These Findings Suggest About Treatment?

The data point to several treatment implications. For one, the finding of possible immune exhaustion suggests that immune checkpoint inhibitors may be therapeutic by promoting clearance of foreign antigens. Immune dysfunction leads to neurochemical alterations that affect neuronal circuits, which may be another point of intervention, the authors suggested.

On the other hand, “attempting to target downstream mechanisms with exercise, cognitive behavioral therapy, or autonomic directed therapies may have limited impact on symptom burden, as it would not address the root cause of PI-ME/CFS,” they noted.

Combination therapy targeting multiple pathways along with a personalized medicine approach should be considered, they said.

“I think the most important thing is not to discount these patients,” Dr. Nath told this news organization. “They have a real disease, and we need to be empathetic towards them. We also need to make sure that they don’t have something underlying that is treatable, and then treat them symptomatically the best that you can. If not, then refer them to ME/CFS studies or clinics where people specialize in these conditions and work with them.”

The study authors and Dr. VanElzakker reported no relevant financial relationships. Dr. Bonilla consults for United Health and Resverlogix.
 

A version of this article appeared on Medscape.com.

Postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a distinct, centrally mediated condition, with evidence of autonomic, immune, and metabolic dysfunction, new "deep phenotyping" data suggested.

The study was initiated in 2016 at the US National Institutes of Health. Its aim was to better elucidate the underlying pathophysiology of ME/CFS, a multisystem disorder characterized by persistent and disabling fatigue, post-exertional malaise, cognitive complaints, and other physical symptoms. A total of 17 carefully selected individuals with PI-ME/CFS onset within the prior 5 years were compared with 21 healthy volunteers on a more extensive set of biologic measurements than has been examined in any prior study of the condition.

Overall, the findings suggested that ME/CFS is “a distinct entity characterized by somatic and cognitive complaints that are centrally mediated,” with fatigue that is “defined by effort preferences and central autonomic dysfunction,” Brian T. Walitt, MD, of the National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, Maryland, and colleagues wrote in the paper, published on February 21 in Nature Communications.

In addition, “there are distinct sex signatures of immune and metabolic dysregulation which suggest persistent antigenic stimulation.” Physical deconditioning over time, while not the source of the condition, “is an important consequence,” the authors added.

Asked to comment, Hector Bonilla, MD, director of the ME/CFS Clinic and codirector of the Stanford Post-Acute COVID-19 Syndrome Clinic, Atherton, California, pointed out that the sample was small and the study was cross-sectional and therefore likely missed dynamic changes in the patients.

Nonetheless, Dr. Bonilla told this news organization, “they have shown clear objective changes in patients with ME/CFS not seen in the controls. These are present in the microbiome, in the immune system, and in metabolites, especially in spinal fluid, that lead to a neuroinflammatory condition. And these are linked with autonomic dysfunction that can explain many of the symptoms that patients experience ... The symptoms are not manufactured by them.”

Thus far, the only treatments for ME/CFS are symptomatic. Understanding the pathophysiology is essential to identifying disease-modifying therapy, study lead author Avindra Nath, MD, Senior Investigator and Clinical Director of Intramural Research at NINDS, told this news organization.

“The disease is real. But our medical profession is limited in what they can do to diagnose or impact them ... The first thing we need to do is try to understand the pathophysiology. So that’s why the study was put together,” Dr. Nath said.

Postinfectious syndromes including ME/CFS have been given many names, including post-Lyme disease, Gulf War illness, and more recently, long COVID. With ME/CFS, the Epstein-Barr virus has historically been one of the most commonly associated triggers, although several other viral, bacterial, and environmental toxins have been implicated.

“There are a whole host of these things that have very similar symptoms or overlapping symptoms ... It’s quite possible that the underlying pathophysiology overlaps between all these syndromes,” Dr. Nath noted.

Another ME/CFS expert not involved in the study, researcher Michael VanElzakker, PhD, of the Neurotherapeutics Division at Harvard Medical School and Massachusetts General Hospital, Boston, said that the possibility of antigen persistence of the infectious pathogen arising from the immune system profiling conducted in the study is noteworthy and merits further study.

“To me, the obvious next step would be techniques like tissue-based assays and T-cell sequencing to try and understand what exactly those antigens are and what their source might be. Importantly, it is probably not the same antigen or pathogen source in all patients, but that’s a question that needs an answer,” Dr. VanElzakker said.

Of note, the 17 study participants had been adjudicated by an expert panel from an initial 484 inquiries and 217 who underwent detailed case reviews. They had to meet at least one of three published ME/CFS criteria and to have moderate to severe clinical symptom severity as determined by several fatigue scores. None met the criteria for psychiatric diagnoses.

Yet, even in the cases that met study criteria, underlying causes emerged in 20% of the participants over time, suggesting diagnostic misattribution. “This misclassification bias has important ramifications on the interpretation of the existing ME/CFS research literature,” the authors wrote.

Dr. VanElzakker noted, “The fact that this research study was probably the most detailed workup many of these patients had ever gotten is a serious indictment of our current profit-based healthcare system’s prioritization of 15-minute doctor’s appointments. It is almost certain that other patients would also benefit from an intensive detailed workup.”
 

Multiple Abnormalities Identified

There were no differences between the PI-ME/CFS and control groups in ventilatory function, muscle oxygenation, mechanical efficiency, resting energy expenditure, basal mitochondrial function of immune cells, muscle fiber composition, or body composition, suggesting the absence of a resting low-energy state, the authors said.

In 40-minute head-up tilt-table testing, there were no differences between the ME/CFS and control groups in frequency or orthostatic hypotension or extensive orthostatic tachycardia. However, a 24-hour ambulatory electrocardiogram showed that the patients with PI-ME/CFS had diminished heart rate variability. They also showed increased heart rate throughout the day, suggesting increased sympathetic activity, and a diminished drop in nighttime heart rate, suggesting decreased parasympathetic activity.

“Considered together, these data suggest that there is an alteration in autonomic tone, implying central nervous system regulatory change,” Dr. Walitt and colleagues wrote.

On the “Effort-Expenditure for Rewards Task,” the participants with PI-ME/CFS showed significant differences in “effort preference,” or a tendency to avoid the harder tasks, as well as a slowing of button-pushing over time, compared with the controls, even with easier tasks. This pattern suggests that those with PI-ME/CFS were “pacing to limit exertion and associated feelings of discomfort,” the authors wrote.

Dr. Nath describes this behavior as akin to “if you develop a flu, you feel that you just want to lay down in bed and not hurt yourself. It’s not that you’re not capable of doing [the task], but your body tells you don’t do it. Your body just wants to fight the infection ... these people just never bounce back.”

Compared with the controls, the participants with PI-ME/CFS failed to maintain a moderate grip force even though there was no difference in maximum grip strength or arm muscle mass. This performance difference correlated with decreased activity of the right temporal-parietal junction, a novel observation suggesting that the fatigue in the PI-ME/CFS group “is due to dysfunction of integrative brain regions that drive the motor cortex, the cause of which needs to be further explored,” Dr. Walitt and colleagues wrote.

On cardiopulmonary testing, peak power, peak respiratory rate, peak heart rate, and peak VO₂ were all lower in the PI-ME/CFS group, correlating to a difference of approximately 3.3 metabolic equivalent of task units. The differential cardiorespiratory performance relates to “autonomic function, hypothalamic-pituitary-adrenal axis hyporesponsiveness, and muscular deconditioning from disuse that clinically impacts activities of daily life,” they said.

In the participants with PI-ME/CFS, catechol levels in cerebrospinal fluid correlated with grip strength and effort preference, and several metabolites of the dopamine pathway correlated with several cognitive symptoms.

“This suggests that central nervous system catechol pathways are dysregulated in PI-ME/CFS and may play a role in effort preference and cognitive complaints,” as well as decreased central catecholamine biosynthesis. Similar findings have been seen in patients with long COVID, the authors noted.

There were increased naive B cells and decreased switched memory B cells in blood of participants with PI-ME/CFS. Contrary to prior studies, there was no consistent pattern of autoimmunity across all participants with PI-ME/CFS, and no previously undescribed antibodies were identified.

However, programmed cell death protein 1, a marker of T-cell exhaustion and activation, was elevated in the cerebrospinal fluid of the patients with PI-ME/CFS.

Several sex-based differences were noted, including in immune cell expression in cerebrospinal fluid, peripheral blood mononuclear cell gene expression, and muscle gene expression. Males and females also differed in the cerebrospinal metabolomics that distinguished the participants with PI-ME/CFS from controls.
 

What Do These Findings Suggest About Treatment?

The data point to several treatment implications. For one, the finding of possible immune exhaustion suggests that immune checkpoint inhibitors may be therapeutic by promoting clearance of foreign antigens. Immune dysfunction leads to neurochemical alterations that affect neuronal circuits, which may be another point of intervention, the authors suggested.

On the other hand, “attempting to target downstream mechanisms with exercise, cognitive behavioral therapy, or autonomic directed therapies may have limited impact on symptom burden, as it would not address the root cause of PI-ME/CFS,” they noted.

Combination therapy targeting multiple pathways along with a personalized medicine approach should be considered, they said.

“I think the most important thing is not to discount these patients,” Dr. Nath told this news organization. “They have a real disease, and we need to be empathetic towards them. We also need to make sure that they don’t have something underlying that is treatable, and then treat them symptomatically the best that you can. If not, then refer them to ME/CFS studies or clinics where people specialize in these conditions and work with them.”

The study authors and Dr. VanElzakker reported no relevant financial relationships. Dr. Bonilla consults for United Health and Resverlogix.
 

A version of this article appeared on Medscape.com.

Postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a distinct, centrally mediated condition, with evidence of autonomic, immune, and metabolic dysfunction, new "deep phenotyping" data suggested.

The study was initiated in 2016 at the US National Institutes of Health. Its aim was to better elucidate the underlying pathophysiology of ME/CFS, a multisystem disorder characterized by persistent and disabling fatigue, post-exertional malaise, cognitive complaints, and other physical symptoms. A total of 17 carefully selected individuals with PI-ME/CFS onset within the prior 5 years were compared with 21 healthy volunteers on a more extensive set of biologic measurements than has been examined in any prior study of the condition.

Overall, the findings suggested that ME/CFS is “a distinct entity characterized by somatic and cognitive complaints that are centrally mediated,” with fatigue that is “defined by effort preferences and central autonomic dysfunction,” Brian T. Walitt, MD, of the National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, Maryland, and colleagues wrote in the paper, published on February 21 in Nature Communications.

In addition, “there are distinct sex signatures of immune and metabolic dysregulation which suggest persistent antigenic stimulation.” Physical deconditioning over time, while not the source of the condition, “is an important consequence,” the authors added.

Asked to comment, Hector Bonilla, MD, director of the ME/CFS Clinic and codirector of the Stanford Post-Acute COVID-19 Syndrome Clinic, Atherton, California, pointed out that the sample was small and the study was cross-sectional and therefore likely missed dynamic changes in the patients.

Nonetheless, Dr. Bonilla told this news organization, “they have shown clear objective changes in patients with ME/CFS not seen in the controls. These are present in the microbiome, in the immune system, and in metabolites, especially in spinal fluid, that lead to a neuroinflammatory condition. And these are linked with autonomic dysfunction that can explain many of the symptoms that patients experience ... The symptoms are not manufactured by them.”

Thus far, the only treatments for ME/CFS are symptomatic. Understanding the pathophysiology is essential to identifying disease-modifying therapy, study lead author Avindra Nath, MD, Senior Investigator and Clinical Director of Intramural Research at NINDS, told this news organization.

“The disease is real. But our medical profession is limited in what they can do to diagnose or impact them ... The first thing we need to do is try to understand the pathophysiology. So that’s why the study was put together,” Dr. Nath said.

Postinfectious syndromes including ME/CFS have been given many names, including post-Lyme disease, Gulf War illness, and more recently, long COVID. With ME/CFS, the Epstein-Barr virus has historically been one of the most commonly associated triggers, although several other viral, bacterial, and environmental toxins have been implicated.

“There are a whole host of these things that have very similar symptoms or overlapping symptoms ... It’s quite possible that the underlying pathophysiology overlaps between all these syndromes,” Dr. Nath noted.

Another ME/CFS expert not involved in the study, researcher Michael VanElzakker, PhD, of the Neurotherapeutics Division at Harvard Medical School and Massachusetts General Hospital, Boston, said that the possibility of antigen persistence of the infectious pathogen arising from the immune system profiling conducted in the study is noteworthy and merits further study.

“To me, the obvious next step would be techniques like tissue-based assays and T-cell sequencing to try and understand what exactly those antigens are and what their source might be. Importantly, it is probably not the same antigen or pathogen source in all patients, but that’s a question that needs an answer,” Dr. VanElzakker said.

Of note, the 17 study participants had been adjudicated by an expert panel from an initial 484 inquiries and 217 who underwent detailed case reviews. They had to meet at least one of three published ME/CFS criteria and to have moderate to severe clinical symptom severity as determined by several fatigue scores. None met the criteria for psychiatric diagnoses.

Yet, even in the cases that met study criteria, underlying causes emerged in 20% of the participants over time, suggesting diagnostic misattribution. “This misclassification bias has important ramifications on the interpretation of the existing ME/CFS research literature,” the authors wrote.

Dr. VanElzakker noted, “The fact that this research study was probably the most detailed workup many of these patients had ever gotten is a serious indictment of our current profit-based healthcare system’s prioritization of 15-minute doctor’s appointments. It is almost certain that other patients would also benefit from an intensive detailed workup.”
 

Multiple Abnormalities Identified

There were no differences between the PI-ME/CFS and control groups in ventilatory function, muscle oxygenation, mechanical efficiency, resting energy expenditure, basal mitochondrial function of immune cells, muscle fiber composition, or body composition, suggesting the absence of a resting low-energy state, the authors said.

In 40-minute head-up tilt-table testing, there were no differences between the ME/CFS and control groups in frequency or orthostatic hypotension or extensive orthostatic tachycardia. However, a 24-hour ambulatory electrocardiogram showed that the patients with PI-ME/CFS had diminished heart rate variability. They also showed increased heart rate throughout the day, suggesting increased sympathetic activity, and a diminished drop in nighttime heart rate, suggesting decreased parasympathetic activity.

“Considered together, these data suggest that there is an alteration in autonomic tone, implying central nervous system regulatory change,” Dr. Walitt and colleagues wrote.

On the “Effort-Expenditure for Rewards Task,” the participants with PI-ME/CFS showed significant differences in “effort preference,” or a tendency to avoid the harder tasks, as well as a slowing of button-pushing over time, compared with the controls, even with easier tasks. This pattern suggests that those with PI-ME/CFS were “pacing to limit exertion and associated feelings of discomfort,” the authors wrote.

Dr. Nath describes this behavior as akin to “if you develop a flu, you feel that you just want to lay down in bed and not hurt yourself. It’s not that you’re not capable of doing [the task], but your body tells you don’t do it. Your body just wants to fight the infection ... these people just never bounce back.”

Compared with the controls, the participants with PI-ME/CFS failed to maintain a moderate grip force even though there was no difference in maximum grip strength or arm muscle mass. This performance difference correlated with decreased activity of the right temporal-parietal junction, a novel observation suggesting that the fatigue in the PI-ME/CFS group “is due to dysfunction of integrative brain regions that drive the motor cortex, the cause of which needs to be further explored,” Dr. Walitt and colleagues wrote.

On cardiopulmonary testing, peak power, peak respiratory rate, peak heart rate, and peak VO₂ were all lower in the PI-ME/CFS group, correlating to a difference of approximately 3.3 metabolic equivalent of task units. The differential cardiorespiratory performance relates to “autonomic function, hypothalamic-pituitary-adrenal axis hyporesponsiveness, and muscular deconditioning from disuse that clinically impacts activities of daily life,” they said.

In the participants with PI-ME/CFS, catechol levels in cerebrospinal fluid correlated with grip strength and effort preference, and several metabolites of the dopamine pathway correlated with several cognitive symptoms.

“This suggests that central nervous system catechol pathways are dysregulated in PI-ME/CFS and may play a role in effort preference and cognitive complaints,” as well as decreased central catecholamine biosynthesis. Similar findings have been seen in patients with long COVID, the authors noted.

There were increased naive B cells and decreased switched memory B cells in blood of participants with PI-ME/CFS. Contrary to prior studies, there was no consistent pattern of autoimmunity across all participants with PI-ME/CFS, and no previously undescribed antibodies were identified.

However, programmed cell death protein 1, a marker of T-cell exhaustion and activation, was elevated in the cerebrospinal fluid of the patients with PI-ME/CFS.

Several sex-based differences were noted, including in immune cell expression in cerebrospinal fluid, peripheral blood mononuclear cell gene expression, and muscle gene expression. Males and females also differed in the cerebrospinal metabolomics that distinguished the participants with PI-ME/CFS from controls.
 

What Do These Findings Suggest About Treatment?

The data point to several treatment implications. For one, the finding of possible immune exhaustion suggests that immune checkpoint inhibitors may be therapeutic by promoting clearance of foreign antigens. Immune dysfunction leads to neurochemical alterations that affect neuronal circuits, which may be another point of intervention, the authors suggested.

On the other hand, “attempting to target downstream mechanisms with exercise, cognitive behavioral therapy, or autonomic directed therapies may have limited impact on symptom burden, as it would not address the root cause of PI-ME/CFS,” they noted.

Combination therapy targeting multiple pathways along with a personalized medicine approach should be considered, they said.

“I think the most important thing is not to discount these patients,” Dr. Nath told this news organization. “They have a real disease, and we need to be empathetic towards them. We also need to make sure that they don’t have something underlying that is treatable, and then treat them symptomatically the best that you can. If not, then refer them to ME/CFS studies or clinics where people specialize in these conditions and work with them.”

The study authors and Dr. VanElzakker reported no relevant financial relationships. Dr. Bonilla consults for United Health and Resverlogix.
 

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

I want to briefly discuss a critically important topic that cannot be overly emphasized. It is the relevance, the importance, the benefits, and the outcome of HPV vaccination.

The paper I’m referring to was published in Pediatrics in October 2023. It’s titled, “Ten-Year Follow-up of 9-Valent Human Papillomavirus Vaccine: Immunogenicity, Effectiveness, and Safety.”

Let me emphasize that we’re talking about a 10-year follow-up. In this particular paper and analysis, 301 boys — I emphasize boys — were included and 971 girls at 40 different sites in 13 countries, who received the 9-valent vaccine, which includes HPV 16, 18, and seven other types.

These investigators demonstrated that the seropositivity rate 10 years after vaccination remained high for all nine types they looked at. Most importantly, there was not a single case. Not one. Let me repeat this: There was not a single case of high-grade intraepithelial neoplasia, or worse, or condyloma in either males or females. There was not a single case in over 1000 individuals with a follow-up of more than 10 years.

It is difficult to overstate the magnitude of the benefit associated with HPV vaccination for our children and young adults on their risk of developing highly relevant, life-changing, potentially deadly cancers.

For those of you who are interested in this topic — which should include almost all of you, if not all of you — I encourage you to read this very important follow-up paper, again, demonstrating the simple, overwhelming magnitude of the benefit of HPV vaccination. I thank you for your attention.
 

Dr. Markman is a professor in the department of medical oncology and therapeutics research, City of Hope, Duarte, California, and president of medicine and science, City of Hope Atlanta, Chicago, and Phoenix. He disclosed ties with GlaxoSmithKline; AstraZeneca.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

I want to briefly discuss a critically important topic that cannot be overly emphasized. It is the relevance, the importance, the benefits, and the outcome of HPV vaccination.

The paper I’m referring to was published in Pediatrics in October 2023. It’s titled, “Ten-Year Follow-up of 9-Valent Human Papillomavirus Vaccine: Immunogenicity, Effectiveness, and Safety.”

Let me emphasize that we’re talking about a 10-year follow-up. In this particular paper and analysis, 301 boys — I emphasize boys — were included and 971 girls at 40 different sites in 13 countries, who received the 9-valent vaccine, which includes HPV 16, 18, and seven other types.

These investigators demonstrated that the seropositivity rate 10 years after vaccination remained high for all nine types they looked at. Most importantly, there was not a single case. Not one. Let me repeat this: There was not a single case of high-grade intraepithelial neoplasia, or worse, or condyloma in either males or females. There was not a single case in over 1000 individuals with a follow-up of more than 10 years.

It is difficult to overstate the magnitude of the benefit associated with HPV vaccination for our children and young adults on their risk of developing highly relevant, life-changing, potentially deadly cancers.

For those of you who are interested in this topic — which should include almost all of you, if not all of you — I encourage you to read this very important follow-up paper, again, demonstrating the simple, overwhelming magnitude of the benefit of HPV vaccination. I thank you for your attention.
 

Dr. Markman is a professor in the department of medical oncology and therapeutics research, City of Hope, Duarte, California, and president of medicine and science, City of Hope Atlanta, Chicago, and Phoenix. He disclosed ties with GlaxoSmithKline; AstraZeneca.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

I want to briefly discuss a critically important topic that cannot be overly emphasized. It is the relevance, the importance, the benefits, and the outcome of HPV vaccination.

The paper I’m referring to was published in Pediatrics in October 2023. It’s titled, “Ten-Year Follow-up of 9-Valent Human Papillomavirus Vaccine: Immunogenicity, Effectiveness, and Safety.”

Let me emphasize that we’re talking about a 10-year follow-up. In this particular paper and analysis, 301 boys — I emphasize boys — were included and 971 girls at 40 different sites in 13 countries, who received the 9-valent vaccine, which includes HPV 16, 18, and seven other types.

These investigators demonstrated that the seropositivity rate 10 years after vaccination remained high for all nine types they looked at. Most importantly, there was not a single case. Not one. Let me repeat this: There was not a single case of high-grade intraepithelial neoplasia, or worse, or condyloma in either males or females. There was not a single case in over 1000 individuals with a follow-up of more than 10 years.

It is difficult to overstate the magnitude of the benefit associated with HPV vaccination for our children and young adults on their risk of developing highly relevant, life-changing, potentially deadly cancers.

For those of you who are interested in this topic — which should include almost all of you, if not all of you — I encourage you to read this very important follow-up paper, again, demonstrating the simple, overwhelming magnitude of the benefit of HPV vaccination. I thank you for your attention.
 

Dr. Markman is a professor in the department of medical oncology and therapeutics research, City of Hope, Duarte, California, and president of medicine and science, City of Hope Atlanta, Chicago, and Phoenix. He disclosed ties with GlaxoSmithKline; AstraZeneca.

A version of this article appeared on Medscape.com.

New criteria for pediatric sepsis, based on a novel score that predicts mortality in children with suspected or confirmed infection, perform better than existing organ dysfunction scores and criteria and have the potential to improve clinical care globally, researchers say.

Current pediatric-specific criteria for sepsis were published in 2005, based on expert opinion. In 2016, sepsis was redefined for adults as life-threatening organ dysfunction caused by a dysregulated host response to infection, as opposed to an earlier focus on systemic inflammation. But the paradigm-shifting changes were not extended to children (< 18 years, but not newborns), setting the stage for the new initiative.

The new criteria, and their development and validation, were published in JAMA and presented the same day at the Society of Critical Care Medicine’s 2024 Critical Care Congress in Phoenix, Arizona.
 

International Consensus

“The new criteria we derived are based on data from electronic health records and analysis of more than 3 million pediatric healthcare encounters from 10 hospitals around the world, including in low-resource settings,” L. Nelson Sanchez-Pinto, MD, MBI, a critical care physician at the Ann and Robert H. Lurie Children’s Hospital of Chicago, told this news organization.

Dr. Sanchez-Pinto co-led the data group of the international expert task force convened by the Society of Critical Care Medicine (SCCM) to develop and validate the criteria, which are based on evidence from an international survey, systematic review and meta-analysis, a newly created organ dysfunction score (Phoenix Sepsis Score), and sites on four continents.

Based on the findings, the task force now suggests that pediatric sepsis be defined by a Phoenix Sepsis Score of at least 2 points in children with suspected infection, which indicates potentially life-threatening dysfunction of the respiratory, cardiovascular, coagulation, and/or neurological systems. Septic shock is defined as sepsis with at least 1 cardiovascular point in the score.
 

Disparities Across Settings

To derive and validate the new criteria across differently resourced settings, the researchers conducted a multicenter, international, retrospective cohort study involving 10 health systems in the United States, Colombia, Bangladesh, China, and Kenya, 3 of which were used as external validation sites.

Data were collected from pediatric emergency and inpatient encounters from 2010 to 2019. The development set comprised 3,049,699 children, and the external validation set included 581,317.

Stacked regression models to predict mortality in children with suspected infection were derived and validated using the best-performing organ dysfunction subscores from eight existing scores.

The final model was then translated into the integer-based Phoenix Sepsis Score and used to establish binary criteria for sepsis and septic shock.

Among 172,984 children with suspected infection in the first 24 hours (development set; 1.2% mortality), a four-organ-system model performed best. The Phoenix Sepsis Score — the integer version of the model — had areas under the precision recall curve of 0.23 to 0.38, and areas under the receiver operating characteristic curve of 0.71 to 0.92 to predict mortality in the validation sets.

A Phoenix Sepsis Score of 2 points or higher in children with suspected infection as criteria for sepsis, plus 1 or more cardiovascular points as criteria for septic shock, resulted in a higher positive predictive value and higher or similar sensitivity compared with the 2005 International Pediatric Sepsis Consensus Conference criteria across differently resourced settings.

Specifically, children with a Phoenix Sepsis Score of at least 2 points had in-hospital mortality of 7.1% in higher-resource settings and 28.5% in lower-resource settings — more than 8 times that of children with suspected infection not meeting these criteria.

Mortality also was higher in children who had organ dysfunction in at least one of four organ systems — respiratory, cardiovascular, coagulation, and/or neurological — that was not the primary site of infection.

Children with septic shock, indicated by at least 1 cardiovascular point in the Phoenix Sepsis Score, had severe hypotension for age, blood lactate exceeding 5 mmol/L, or need for vasoactive medication. These children had an in-hospital mortality rate of 10.8% in higher-resource settings and 33.5% in lower-resource settings.
 

A Better Score

Given the findings, the task force recommends that “the former criteria based on systemic inflammatory response syndrome should not be used to diagnose sepsis in children [and] the former term severe sepsis should no longer be used because sepsis is life-threatening organ dysfunction associated with infection and is thus indicative of a severe disease state.”

The task force cautions that although the four organs in the Phoenix Sepsis Score are most commonly involved in sepsis, “this does not diminish the crucial importance of the assessment and management of other organ dysfunction.”

Furthermore, they emphasize that the Phoenix score was designed to identify sepsis in children, not to screen children at risk for developing sepsis or early identification of children with suspected sepsis.
 

Additional Considerations

In related editorials, commentators noted some caveats and concerns with regard to the study design and the new criteria.

Roberto Jabornisky, MD, PhD, of National University of the Northeast, Corrientes, Argentina, and colleagues pointed out that “all the low-resource validation sites were institutions with electronic health records and most had PICUs [pediatric intensive care units], which does not adequately reflect conditions in most low-resource settings. These factors introduce a distinct bias favoring a ‘PICU-based consensus,’ potentially limiting the generalizability and adoption of the new criteria by health care practitioners in non-PICU and nonhospital settings responsible for recognizing and managing children with sepsis.” The editorialists called for additional prospective validation in differently resourced settings, especially those with the highest disease burdens.

“Until then,” they wrote, “it is essential to refrain from considering these criteria as an inflexible directive governing medical interventions for pediatric sepsis. No definition can fully substitute for the clinical judgment of an experienced, vigilant clinician caring for an unwell child.”

Erin F. Carlton, MD, MSc of the University of Michigan, Ann Arbor, and colleagues added in a separate editorial, “The Phoenix criteria identify a sicker subset of patients than prior SIRS [systemic inflammatory response syndrome]-based criteria. Some may worry this higher threshold could delay management of patients not meeting sepsis criteria. Just as patients with chest pain and a troponin leak warrant monitoring and treatment (but are not prioritized for immediate heart catheterization), patients with infection need monitoring and treatment. Improvements in care should thus be judged not only by improved outcomes among patients with sepsis but also by decreased progression to sepsis among patients with infection.”

The International Consensus Criteria paper was supported by the Society of Critical Care Medicine and a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development to Tellen C. Bennett, MD, MS, and Nelson Sanchez-Pinto, MD. Data for the Kenya site were collected with support of the Wellcome Trust to the Kenya Major Overseas Programme. Dr. Jabornisky reported no conflicts of interest. Dr. Carlton reported serving on the Pediatric Surviving Sepsis Campaign Guideline committee and receiving grant support from the NIH.

New criteria for pediatric sepsis, based on a novel score that predicts mortality in children with suspected or confirmed infection, perform better than existing organ dysfunction scores and criteria and have the potential to improve clinical care globally, researchers say.

Current pediatric-specific criteria for sepsis were published in 2005, based on expert opinion. In 2016, sepsis was redefined for adults as life-threatening organ dysfunction caused by a dysregulated host response to infection, as opposed to an earlier focus on systemic inflammation. But the paradigm-shifting changes were not extended to children (< 18 years, but not newborns), setting the stage for the new initiative.

The new criteria, and their development and validation, were published in JAMA and presented the same day at the Society of Critical Care Medicine’s 2024 Critical Care Congress in Phoenix, Arizona.
 

International Consensus

“The new criteria we derived are based on data from electronic health records and analysis of more than 3 million pediatric healthcare encounters from 10 hospitals around the world, including in low-resource settings,” L. Nelson Sanchez-Pinto, MD, MBI, a critical care physician at the Ann and Robert H. Lurie Children’s Hospital of Chicago, told this news organization.

Dr. Sanchez-Pinto co-led the data group of the international expert task force convened by the Society of Critical Care Medicine (SCCM) to develop and validate the criteria, which are based on evidence from an international survey, systematic review and meta-analysis, a newly created organ dysfunction score (Phoenix Sepsis Score), and sites on four continents.

Based on the findings, the task force now suggests that pediatric sepsis be defined by a Phoenix Sepsis Score of at least 2 points in children with suspected infection, which indicates potentially life-threatening dysfunction of the respiratory, cardiovascular, coagulation, and/or neurological systems. Septic shock is defined as sepsis with at least 1 cardiovascular point in the score.
 

Disparities Across Settings

To derive and validate the new criteria across differently resourced settings, the researchers conducted a multicenter, international, retrospective cohort study involving 10 health systems in the United States, Colombia, Bangladesh, China, and Kenya, 3 of which were used as external validation sites.

Data were collected from pediatric emergency and inpatient encounters from 2010 to 2019. The development set comprised 3,049,699 children, and the external validation set included 581,317.

Stacked regression models to predict mortality in children with suspected infection were derived and validated using the best-performing organ dysfunction subscores from eight existing scores.

The final model was then translated into the integer-based Phoenix Sepsis Score and used to establish binary criteria for sepsis and septic shock.

Among 172,984 children with suspected infection in the first 24 hours (development set; 1.2% mortality), a four-organ-system model performed best. The Phoenix Sepsis Score — the integer version of the model — had areas under the precision recall curve of 0.23 to 0.38, and areas under the receiver operating characteristic curve of 0.71 to 0.92 to predict mortality in the validation sets.

A Phoenix Sepsis Score of 2 points or higher in children with suspected infection as criteria for sepsis, plus 1 or more cardiovascular points as criteria for septic shock, resulted in a higher positive predictive value and higher or similar sensitivity compared with the 2005 International Pediatric Sepsis Consensus Conference criteria across differently resourced settings.

Specifically, children with a Phoenix Sepsis Score of at least 2 points had in-hospital mortality of 7.1% in higher-resource settings and 28.5% in lower-resource settings — more than 8 times that of children with suspected infection not meeting these criteria.

Mortality also was higher in children who had organ dysfunction in at least one of four organ systems — respiratory, cardiovascular, coagulation, and/or neurological — that was not the primary site of infection.

Children with septic shock, indicated by at least 1 cardiovascular point in the Phoenix Sepsis Score, had severe hypotension for age, blood lactate exceeding 5 mmol/L, or need for vasoactive medication. These children had an in-hospital mortality rate of 10.8% in higher-resource settings and 33.5% in lower-resource settings.
 

A Better Score

Given the findings, the task force recommends that “the former criteria based on systemic inflammatory response syndrome should not be used to diagnose sepsis in children [and] the former term severe sepsis should no longer be used because sepsis is life-threatening organ dysfunction associated with infection and is thus indicative of a severe disease state.”

The task force cautions that although the four organs in the Phoenix Sepsis Score are most commonly involved in sepsis, “this does not diminish the crucial importance of the assessment and management of other organ dysfunction.”

Furthermore, they emphasize that the Phoenix score was designed to identify sepsis in children, not to screen children at risk for developing sepsis or early identification of children with suspected sepsis.
 

Additional Considerations

In related editorials, commentators noted some caveats and concerns with regard to the study design and the new criteria.

Roberto Jabornisky, MD, PhD, of National University of the Northeast, Corrientes, Argentina, and colleagues pointed out that “all the low-resource validation sites were institutions with electronic health records and most had PICUs [pediatric intensive care units], which does not adequately reflect conditions in most low-resource settings. These factors introduce a distinct bias favoring a ‘PICU-based consensus,’ potentially limiting the generalizability and adoption of the new criteria by health care practitioners in non-PICU and nonhospital settings responsible for recognizing and managing children with sepsis.” The editorialists called for additional prospective validation in differently resourced settings, especially those with the highest disease burdens.

“Until then,” they wrote, “it is essential to refrain from considering these criteria as an inflexible directive governing medical interventions for pediatric sepsis. No definition can fully substitute for the clinical judgment of an experienced, vigilant clinician caring for an unwell child.”

Erin F. Carlton, MD, MSc of the University of Michigan, Ann Arbor, and colleagues added in a separate editorial, “The Phoenix criteria identify a sicker subset of patients than prior SIRS [systemic inflammatory response syndrome]-based criteria. Some may worry this higher threshold could delay management of patients not meeting sepsis criteria. Just as patients with chest pain and a troponin leak warrant monitoring and treatment (but are not prioritized for immediate heart catheterization), patients with infection need monitoring and treatment. Improvements in care should thus be judged not only by improved outcomes among patients with sepsis but also by decreased progression to sepsis among patients with infection.”

The International Consensus Criteria paper was supported by the Society of Critical Care Medicine and a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development to Tellen C. Bennett, MD, MS, and Nelson Sanchez-Pinto, MD. Data for the Kenya site were collected with support of the Wellcome Trust to the Kenya Major Overseas Programme. Dr. Jabornisky reported no conflicts of interest. Dr. Carlton reported serving on the Pediatric Surviving Sepsis Campaign Guideline committee and receiving grant support from the NIH.

New criteria for pediatric sepsis, based on a novel score that predicts mortality in children with suspected or confirmed infection, perform better than existing organ dysfunction scores and criteria and have the potential to improve clinical care globally, researchers say.

Current pediatric-specific criteria for sepsis were published in 2005, based on expert opinion. In 2016, sepsis was redefined for adults as life-threatening organ dysfunction caused by a dysregulated host response to infection, as opposed to an earlier focus on systemic inflammation. But the paradigm-shifting changes were not extended to children (< 18 years, but not newborns), setting the stage for the new initiative.

The new criteria, and their development and validation, were published in JAMA and presented the same day at the Society of Critical Care Medicine’s 2024 Critical Care Congress in Phoenix, Arizona.
 

International Consensus

“The new criteria we derived are based on data from electronic health records and analysis of more than 3 million pediatric healthcare encounters from 10 hospitals around the world, including in low-resource settings,” L. Nelson Sanchez-Pinto, MD, MBI, a critical care physician at the Ann and Robert H. Lurie Children’s Hospital of Chicago, told this news organization.

Dr. Sanchez-Pinto co-led the data group of the international expert task force convened by the Society of Critical Care Medicine (SCCM) to develop and validate the criteria, which are based on evidence from an international survey, systematic review and meta-analysis, a newly created organ dysfunction score (Phoenix Sepsis Score), and sites on four continents.

Based on the findings, the task force now suggests that pediatric sepsis be defined by a Phoenix Sepsis Score of at least 2 points in children with suspected infection, which indicates potentially life-threatening dysfunction of the respiratory, cardiovascular, coagulation, and/or neurological systems. Septic shock is defined as sepsis with at least 1 cardiovascular point in the score.
 

Disparities Across Settings

To derive and validate the new criteria across differently resourced settings, the researchers conducted a multicenter, international, retrospective cohort study involving 10 health systems in the United States, Colombia, Bangladesh, China, and Kenya, 3 of which were used as external validation sites.

Data were collected from pediatric emergency and inpatient encounters from 2010 to 2019. The development set comprised 3,049,699 children, and the external validation set included 581,317.

Stacked regression models to predict mortality in children with suspected infection were derived and validated using the best-performing organ dysfunction subscores from eight existing scores.

The final model was then translated into the integer-based Phoenix Sepsis Score and used to establish binary criteria for sepsis and septic shock.

Among 172,984 children with suspected infection in the first 24 hours (development set; 1.2% mortality), a four-organ-system model performed best. The Phoenix Sepsis Score — the integer version of the model — had areas under the precision recall curve of 0.23 to 0.38, and areas under the receiver operating characteristic curve of 0.71 to 0.92 to predict mortality in the validation sets.

A Phoenix Sepsis Score of 2 points or higher in children with suspected infection as criteria for sepsis, plus 1 or more cardiovascular points as criteria for septic shock, resulted in a higher positive predictive value and higher or similar sensitivity compared with the 2005 International Pediatric Sepsis Consensus Conference criteria across differently resourced settings.

Specifically, children with a Phoenix Sepsis Score of at least 2 points had in-hospital mortality of 7.1% in higher-resource settings and 28.5% in lower-resource settings — more than 8 times that of children with suspected infection not meeting these criteria.

Mortality also was higher in children who had organ dysfunction in at least one of four organ systems — respiratory, cardiovascular, coagulation, and/or neurological — that was not the primary site of infection.

Children with septic shock, indicated by at least 1 cardiovascular point in the Phoenix Sepsis Score, had severe hypotension for age, blood lactate exceeding 5 mmol/L, or need for vasoactive medication. These children had an in-hospital mortality rate of 10.8% in higher-resource settings and 33.5% in lower-resource settings.
 

A Better Score

Given the findings, the task force recommends that “the former criteria based on systemic inflammatory response syndrome should not be used to diagnose sepsis in children [and] the former term severe sepsis should no longer be used because sepsis is life-threatening organ dysfunction associated with infection and is thus indicative of a severe disease state.”

The task force cautions that although the four organs in the Phoenix Sepsis Score are most commonly involved in sepsis, “this does not diminish the crucial importance of the assessment and management of other organ dysfunction.”

Furthermore, they emphasize that the Phoenix score was designed to identify sepsis in children, not to screen children at risk for developing sepsis or early identification of children with suspected sepsis.
 

Additional Considerations

In related editorials, commentators noted some caveats and concerns with regard to the study design and the new criteria.

Roberto Jabornisky, MD, PhD, of National University of the Northeast, Corrientes, Argentina, and colleagues pointed out that “all the low-resource validation sites were institutions with electronic health records and most had PICUs [pediatric intensive care units], which does not adequately reflect conditions in most low-resource settings. These factors introduce a distinct bias favoring a ‘PICU-based consensus,’ potentially limiting the generalizability and adoption of the new criteria by health care practitioners in non-PICU and nonhospital settings responsible for recognizing and managing children with sepsis.” The editorialists called for additional prospective validation in differently resourced settings, especially those with the highest disease burdens.

“Until then,” they wrote, “it is essential to refrain from considering these criteria as an inflexible directive governing medical interventions for pediatric sepsis. No definition can fully substitute for the clinical judgment of an experienced, vigilant clinician caring for an unwell child.”

Erin F. Carlton, MD, MSc of the University of Michigan, Ann Arbor, and colleagues added in a separate editorial, “The Phoenix criteria identify a sicker subset of patients than prior SIRS [systemic inflammatory response syndrome]-based criteria. Some may worry this higher threshold could delay management of patients not meeting sepsis criteria. Just as patients with chest pain and a troponin leak warrant monitoring and treatment (but are not prioritized for immediate heart catheterization), patients with infection need monitoring and treatment. Improvements in care should thus be judged not only by improved outcomes among patients with sepsis but also by decreased progression to sepsis among patients with infection.”

The International Consensus Criteria paper was supported by the Society of Critical Care Medicine and a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development to Tellen C. Bennett, MD, MS, and Nelson Sanchez-Pinto, MD. Data for the Kenya site were collected with support of the Wellcome Trust to the Kenya Major Overseas Programme. Dr. Jabornisky reported no conflicts of interest. Dr. Carlton reported serving on the Pediatric Surviving Sepsis Campaign Guideline committee and receiving grant support from the NIH.

Two doses of the recombinant zoster vaccine (RZV) are effective against herpes zoster (HZ) for 4 years after vaccination, according to a new study published in Annals of Internal Medicine.

Findings from the prospective cohort study showed that people who received two doses of the vaccine, regardless of when they received their second dose, experienced 79% vaccine effectiveness (VE) during the first year, with effectiveness decreasing to 73% by year 4. By contrast, the rate of effectiveness during the first year was 70% for people who received a single dose, falling to 52% effectiveness by year 4.

The findings also showed that the rate of effectiveness was 65% for those taking corticosteroids.

The study was conducted between 2018 and 2022 using data from the Vaccine Safety Datalink, a collaboration between the US Centers for Disease Control and Prevention (CDC) and nine healthcare systems across the country.

Researchers evaluated the incidence of HZ, as determined by a diagnosis and prescription for antiviral medication within 7 days of diagnosis, and monitored RZV status over time.

The findings may quell fears that waiting too long for the second dose reduces the effectiveness of the herpes vaccine, according to Nicola Klein, MD, PhD, director of the Vaccine Study Center at Kaiser Permanente in Oakland, California, who led the study.

The long-term efficacy of the vaccine is especially important because older adults are now living much longer than in previous years, according to Alexandra Tien, MD, a family physician at Medical Associates of Rhode Island in Providence.

“People live these days into their 80s and even 90s,” Dr. Tien said. “That’s a large number of years to need protection for, so it’s really important to have a long-lasting vaccine.”

The CDC currently recommends two doses of RZV separated by 2-6 months for patients aged 50 years and older. Adults older than 19 years who are immunocompromised should receive two doses of RZV separated by 1-2 months, the agency said.

According to Dr. Klein, research does not show whether VE for RZV wanes after 4 years. But interim findings from another study following people in clinical trials found VE levels remained high after 7 years.

The risk for HZ increases with age, reaching a lifetime risk of 50% among adults aged 85 years. Complications like postherpetic neuralgia (PHN) — characterized by long-term tingling, numbness, and disabling pain at the site of the rash — can interfere with the quality of life and ability to function in older adults. The CDC estimates that up to 18% of people with shingles experience PHN, and the risk increases with age.

Just like with any other vaccine, patients sometimes have concerns about the potential side effects of RZV, said Dr. Tien. But those effects, such as muscle pain, nausea, and fever, are mild compared to shingles.

“I always tell patients, with any vaccine, immunization is one of the biggest bangs for your buck in healthcare because you’re preventing a problem,” Dr. Tien said.

This study was funded by the CDC through contracts with participating sites. Study authors reported no disclosures. Dr. Tien reported no disclosures.

A version of this article appeared on Medscape.com.

Two doses of the recombinant zoster vaccine (RZV) are effective against herpes zoster (HZ) for 4 years after vaccination, according to a new study published in Annals of Internal Medicine.

Findings from the prospective cohort study showed that people who received two doses of the vaccine, regardless of when they received their second dose, experienced 79% vaccine effectiveness (VE) during the first year, with effectiveness decreasing to 73% by year 4. By contrast, the rate of effectiveness during the first year was 70% for people who received a single dose, falling to 52% effectiveness by year 4.

The findings also showed that the rate of effectiveness was 65% for those taking corticosteroids.

The study was conducted between 2018 and 2022 using data from the Vaccine Safety Datalink, a collaboration between the US Centers for Disease Control and Prevention (CDC) and nine healthcare systems across the country.

Researchers evaluated the incidence of HZ, as determined by a diagnosis and prescription for antiviral medication within 7 days of diagnosis, and monitored RZV status over time.

The findings may quell fears that waiting too long for the second dose reduces the effectiveness of the herpes vaccine, according to Nicola Klein, MD, PhD, director of the Vaccine Study Center at Kaiser Permanente in Oakland, California, who led the study.

The long-term efficacy of the vaccine is especially important because older adults are now living much longer than in previous years, according to Alexandra Tien, MD, a family physician at Medical Associates of Rhode Island in Providence.

“People live these days into their 80s and even 90s,” Dr. Tien said. “That’s a large number of years to need protection for, so it’s really important to have a long-lasting vaccine.”

The CDC currently recommends two doses of RZV separated by 2-6 months for patients aged 50 years and older. Adults older than 19 years who are immunocompromised should receive two doses of RZV separated by 1-2 months, the agency said.

According to Dr. Klein, research does not show whether VE for RZV wanes after 4 years. But interim findings from another study following people in clinical trials found VE levels remained high after 7 years.

The risk for HZ increases with age, reaching a lifetime risk of 50% among adults aged 85 years. Complications like postherpetic neuralgia (PHN) — characterized by long-term tingling, numbness, and disabling pain at the site of the rash — can interfere with the quality of life and ability to function in older adults. The CDC estimates that up to 18% of people with shingles experience PHN, and the risk increases with age.

Just like with any other vaccine, patients sometimes have concerns about the potential side effects of RZV, said Dr. Tien. But those effects, such as muscle pain, nausea, and fever, are mild compared to shingles.

“I always tell patients, with any vaccine, immunization is one of the biggest bangs for your buck in healthcare because you’re preventing a problem,” Dr. Tien said.

This study was funded by the CDC through contracts with participating sites. Study authors reported no disclosures. Dr. Tien reported no disclosures.

A version of this article appeared on Medscape.com.

Two doses of the recombinant zoster vaccine (RZV) are effective against herpes zoster (HZ) for 4 years after vaccination, according to a new study published in Annals of Internal Medicine.

Findings from the prospective cohort study showed that people who received two doses of the vaccine, regardless of when they received their second dose, experienced 79% vaccine effectiveness (VE) during the first year, with effectiveness decreasing to 73% by year 4. By contrast, the rate of effectiveness during the first year was 70% for people who received a single dose, falling to 52% effectiveness by year 4.

The findings also showed that the rate of effectiveness was 65% for those taking corticosteroids.

The study was conducted between 2018 and 2022 using data from the Vaccine Safety Datalink, a collaboration between the US Centers for Disease Control and Prevention (CDC) and nine healthcare systems across the country.

Researchers evaluated the incidence of HZ, as determined by a diagnosis and prescription for antiviral medication within 7 days of diagnosis, and monitored RZV status over time.

The findings may quell fears that waiting too long for the second dose reduces the effectiveness of the herpes vaccine, according to Nicola Klein, MD, PhD, director of the Vaccine Study Center at Kaiser Permanente in Oakland, California, who led the study.

The long-term efficacy of the vaccine is especially important because older adults are now living much longer than in previous years, according to Alexandra Tien, MD, a family physician at Medical Associates of Rhode Island in Providence.

“People live these days into their 80s and even 90s,” Dr. Tien said. “That’s a large number of years to need protection for, so it’s really important to have a long-lasting vaccine.”

The CDC currently recommends two doses of RZV separated by 2-6 months for patients aged 50 years and older. Adults older than 19 years who are immunocompromised should receive two doses of RZV separated by 1-2 months, the agency said.

According to Dr. Klein, research does not show whether VE for RZV wanes after 4 years. But interim findings from another study following people in clinical trials found VE levels remained high after 7 years.

The risk for HZ increases with age, reaching a lifetime risk of 50% among adults aged 85 years. Complications like postherpetic neuralgia (PHN) — characterized by long-term tingling, numbness, and disabling pain at the site of the rash — can interfere with the quality of life and ability to function in older adults. The CDC estimates that up to 18% of people with shingles experience PHN, and the risk increases with age.

Just like with any other vaccine, patients sometimes have concerns about the potential side effects of RZV, said Dr. Tien. But those effects, such as muscle pain, nausea, and fever, are mild compared to shingles.

“I always tell patients, with any vaccine, immunization is one of the biggest bangs for your buck in healthcare because you’re preventing a problem,” Dr. Tien said.

This study was funded by the CDC through contracts with participating sites. Study authors reported no disclosures. Dr. Tien reported no disclosures.

A version of this article appeared on Medscape.com.

Non–Lyme disease, tick-borne illnesses — such as spotted fever group rickettsiosis (SFGR), ehrlichiosis, and alpha-gal syndrome (AGS) — are emerging public health threats, but whether prior tick exposures are responsible for long-term complications, such as musculoskeletal symptoms or osteoarthritis, has been unclear.

Many patients attribute their nonspecific long-term symptoms, such as musculoskeletal pain, to previous illnesses from tick bites, note authors of a study published in JAMA Network Open. But the researchers, led by Diana L. Zychowski, MD, MPH, with the Division of Infectious Diseases at the University of North Carolina at Chapel Hill, found that Ehrlichia or Rickettsia seropositivity was not associated with chronic musculoskeletal symptoms, though they write that “further investigation into the pathogenesis of [alpha-gal] syndrome is needed.”
 

Tick-Borne Illness Cases Multiplying

Cases of tick-borne illness (TBD) in the United States have multiplied in recent years. More than 50,000 cases of TBD in the United States were reported in 2019, which doubled the number of cases over the previous 2 decades, the authors note.

Most of the cases are Lyme disease, but others — including SFGR and ehrlichiosis — represent an important public health threat, especially in southeastern states, the authors write. Cases of ehrlichiosis, for example, transmitted by the lone star tick, soared more than 10-fold since 2000.

The goal of this study was to evaluate whether there was an association between prior exposure to TBDs endemic to the southeastern United States and chronic musculoskeletal symptoms and radiographic measures of osteoarthritis.

Researchers analyzed 488 blood samples from the fourth visit (2017-2018) of the Johnston County Osteoarthritis (JoCo OA) project, an ongoing population-based study in Johnston County, North Carolina. JoCo OA participants include noninstitutionalized White and Black Johnston County residents 45 years old or older with osteoarthritis.

They measured seroprevalence of Rickettsia- and Ehrlichia-specific immunoglobulin G (IgG) as well as alpha-gal immunoglobulin E (IgE) in patient samples. Only alpha-gal IgE was linked in the study with knee pain, aching, or stiffness. Antibodies to Rickettsia, Ehrlichia, and alpha-gal were not associated with radiographic, symptomatic knee osteoarthritis.

“To our knowledge,” the authors write, “this study was the first population-based seroprevalence study of SFGR, Ehrlichia, and [alpha]-gal.”

The study also found a high prevalence of TBD exposure in the cohort. More than a third (36.5%) had either an alpha-gal IgE level greater than 0.1 IU/mL, a positive test for SFGR IgG antibodies, or a positive test for Ehrlichia IgG antibodies.

Given that not every tick carries an infectious pathogen, the findings show human-tick interactions are common, they write.

“These findings suggest that substantial investment is required to examine the pathogenesis of these TBDs and interventions to reduce human-tick interactions,” the authors conclude.

This study was funded by a Creativity Hub Award from the University of North Carolina Office of the Vice Chancellor for Research. The JoCo OA project is supported in part by grants from the Association of Schools of Public Health/Centers for Disease Control and Prevention (CDC); and grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Authors reported grants from the National Institutes of Health, the CDC, and several pharmaceutical companies.

Non–Lyme disease, tick-borne illnesses — such as spotted fever group rickettsiosis (SFGR), ehrlichiosis, and alpha-gal syndrome (AGS) — are emerging public health threats, but whether prior tick exposures are responsible for long-term complications, such as musculoskeletal symptoms or osteoarthritis, has been unclear.

Many patients attribute their nonspecific long-term symptoms, such as musculoskeletal pain, to previous illnesses from tick bites, note authors of a study published in JAMA Network Open. But the researchers, led by Diana L. Zychowski, MD, MPH, with the Division of Infectious Diseases at the University of North Carolina at Chapel Hill, found that Ehrlichia or Rickettsia seropositivity was not associated with chronic musculoskeletal symptoms, though they write that “further investigation into the pathogenesis of [alpha-gal] syndrome is needed.”
 

Tick-Borne Illness Cases Multiplying

Cases of tick-borne illness (TBD) in the United States have multiplied in recent years. More than 50,000 cases of TBD in the United States were reported in 2019, which doubled the number of cases over the previous 2 decades, the authors note.

Most of the cases are Lyme disease, but others — including SFGR and ehrlichiosis — represent an important public health threat, especially in southeastern states, the authors write. Cases of ehrlichiosis, for example, transmitted by the lone star tick, soared more than 10-fold since 2000.

The goal of this study was to evaluate whether there was an association between prior exposure to TBDs endemic to the southeastern United States and chronic musculoskeletal symptoms and radiographic measures of osteoarthritis.

Researchers analyzed 488 blood samples from the fourth visit (2017-2018) of the Johnston County Osteoarthritis (JoCo OA) project, an ongoing population-based study in Johnston County, North Carolina. JoCo OA participants include noninstitutionalized White and Black Johnston County residents 45 years old or older with osteoarthritis.

They measured seroprevalence of Rickettsia- and Ehrlichia-specific immunoglobulin G (IgG) as well as alpha-gal immunoglobulin E (IgE) in patient samples. Only alpha-gal IgE was linked in the study with knee pain, aching, or stiffness. Antibodies to Rickettsia, Ehrlichia, and alpha-gal were not associated with radiographic, symptomatic knee osteoarthritis.

“To our knowledge,” the authors write, “this study was the first population-based seroprevalence study of SFGR, Ehrlichia, and [alpha]-gal.”

The study also found a high prevalence of TBD exposure in the cohort. More than a third (36.5%) had either an alpha-gal IgE level greater than 0.1 IU/mL, a positive test for SFGR IgG antibodies, or a positive test for Ehrlichia IgG antibodies.

Given that not every tick carries an infectious pathogen, the findings show human-tick interactions are common, they write.

“These findings suggest that substantial investment is required to examine the pathogenesis of these TBDs and interventions to reduce human-tick interactions,” the authors conclude.

This study was funded by a Creativity Hub Award from the University of North Carolina Office of the Vice Chancellor for Research. The JoCo OA project is supported in part by grants from the Association of Schools of Public Health/Centers for Disease Control and Prevention (CDC); and grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Authors reported grants from the National Institutes of Health, the CDC, and several pharmaceutical companies.

Non–Lyme disease, tick-borne illnesses — such as spotted fever group rickettsiosis (SFGR), ehrlichiosis, and alpha-gal syndrome (AGS) — are emerging public health threats, but whether prior tick exposures are responsible for long-term complications, such as musculoskeletal symptoms or osteoarthritis, has been unclear.

Many patients attribute their nonspecific long-term symptoms, such as musculoskeletal pain, to previous illnesses from tick bites, note authors of a study published in JAMA Network Open. But the researchers, led by Diana L. Zychowski, MD, MPH, with the Division of Infectious Diseases at the University of North Carolina at Chapel Hill, found that Ehrlichia or Rickettsia seropositivity was not associated with chronic musculoskeletal symptoms, though they write that “further investigation into the pathogenesis of [alpha-gal] syndrome is needed.”
 

Tick-Borne Illness Cases Multiplying

Cases of tick-borne illness (TBD) in the United States have multiplied in recent years. More than 50,000 cases of TBD in the United States were reported in 2019, which doubled the number of cases over the previous 2 decades, the authors note.

Most of the cases are Lyme disease, but others — including SFGR and ehrlichiosis — represent an important public health threat, especially in southeastern states, the authors write. Cases of ehrlichiosis, for example, transmitted by the lone star tick, soared more than 10-fold since 2000.

The goal of this study was to evaluate whether there was an association between prior exposure to TBDs endemic to the southeastern United States and chronic musculoskeletal symptoms and radiographic measures of osteoarthritis.

Researchers analyzed 488 blood samples from the fourth visit (2017-2018) of the Johnston County Osteoarthritis (JoCo OA) project, an ongoing population-based study in Johnston County, North Carolina. JoCo OA participants include noninstitutionalized White and Black Johnston County residents 45 years old or older with osteoarthritis.

They measured seroprevalence of Rickettsia- and Ehrlichia-specific immunoglobulin G (IgG) as well as alpha-gal immunoglobulin E (IgE) in patient samples. Only alpha-gal IgE was linked in the study with knee pain, aching, or stiffness. Antibodies to Rickettsia, Ehrlichia, and alpha-gal were not associated with radiographic, symptomatic knee osteoarthritis.

“To our knowledge,” the authors write, “this study was the first population-based seroprevalence study of SFGR, Ehrlichia, and [alpha]-gal.”

The study also found a high prevalence of TBD exposure in the cohort. More than a third (36.5%) had either an alpha-gal IgE level greater than 0.1 IU/mL, a positive test for SFGR IgG antibodies, or a positive test for Ehrlichia IgG antibodies.

Given that not every tick carries an infectious pathogen, the findings show human-tick interactions are common, they write.

“These findings suggest that substantial investment is required to examine the pathogenesis of these TBDs and interventions to reduce human-tick interactions,” the authors conclude.

This study was funded by a Creativity Hub Award from the University of North Carolina Office of the Vice Chancellor for Research. The JoCo OA project is supported in part by grants from the Association of Schools of Public Health/Centers for Disease Control and Prevention (CDC); and grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Authors reported grants from the National Institutes of Health, the CDC, and several pharmaceutical companies.

A new analysis supports using the smallpox antiviral tecovirimat (TPOXX/ST-246) in HIV patients showing the first symptoms of the human smallpox disease mpox (monkeypox), caused by the variola virus.

In a small prospective matched cohort analysis, people with HIV (PWH) and mpox disease who received tecovirimat within 7 days of symptom onset were 13 times less likely to experience progression, compared with PWH not prescribed tecovirimat within that window. In a matched cohort of 112 PWH, mpox disease progression occurred in 5.4% in an early tecovirimat group and in 26.8% in a late- or no-tecovirimat group, for a paired odds ratio of 13.00 (95% CI, 1.71-99.40; P = .002).

“Results of the present study suggest that tecovirimat treatment should be started early at the time of suspected mpox diagnosis in all PWH, especially in those with nonsuppressed HIV viremia or mucosal site involvement,” wrote a team led by Bruce Aldred, MD, of the Division of Infectious Diseases in the Department of Medicine at Emory University School of Medicine in Atlanta, in JAMA Internal Medicine. Early symptoms of mpox include skin rash and mucosal lesions, along with viral symptoms such as fever, headache, muscle aches, back pain, low energy, and swollen lymph nodes.

As of March 1 of last year, the United States reported more than 30,000 cases, while cases numbered more than 86,000 worldwide.

Despite a lack of effectiveness data in humans, tecovirimat was widely prescribed to PWH with mpox during the 2022 epidemic, which disproportionately affected PWH, particularly those with low CD4+ T-cell counts or severe mpox clinical manifestations who needed urgent therapy. Developed to treat smallpox, tecovirimat has antiviral activity against other orthopoxviruses, and has reduced mpox-related morbidity and mortality in animals.

Based on the animal data, approval was granted by the US Food and Drug Administration (FDA) for human mpox treatment. Dr. Aldred and colleagues undertook this cohort analysis in the absence of human data and with the postoutbreak decline in cases impeding recruitment to a full-scale clinical trial.

Study design

The preponderantly Black cohort included 112 PWH diagnosed with mpox at four Atlanta hospitals from June 1 to October 7, 2022. Patients were grouped in an early cohort receiving tecovirimat within 7 days of symptom onset or a no or late cohort (no tecovirimat or treatment more than 7 days after symptom onset. Multivariate logistic regression models identified factors associated with progression, defined as development of at least one severe CDC mpox criterion after symptom day 7.

The cohorts were then matched 1:1 using propensity scores based on the identified factors, and mpox disease progression was compared.

Of 112 PWH, 56 receive early tecovirimat and 56 received no or late treatment. In the early group, the median (interquartile range [IQR]) age was 35 (30-42) years; 54 individuals (96.4%) were cisgender men, 46 (82.1%) were Black, and 10 (17.9%) were, variously, White, American Indian, Alaska Native, Asian, Native Hawaiian or Other Pacific Islander, or of unknown race.

In the late- or no-tecovirimat group, the median (IQR) age was 36 (32-43) years; 54 (96.4%) were cisgender men, 49 (87.5%) were Black, and 7 (12.5%) were individuals of other or unknown race. Mpox disease progression occurred in 3 PWH in the early-tecovirimat group and 15 PWH (26.8%) in the late- or no-tecovirimat group.

Dr. Aldred and colleagues acknowledged that more research is needed to confirm the findings and cited several study limitations. These included the small sample size, the preponderance of Black participants, and the possibility that unmatched confounding variables could have led to the observation of fewer cases of severe disease in the early-tecovirimat cohort.

This study was supported by a grant from the Emory Center for AIDS Research. Coauthors reported grants from various institutes at the National Institutes of Health as well as from multiple pharmaceutical companies.

A new analysis supports using the smallpox antiviral tecovirimat (TPOXX/ST-246) in HIV patients showing the first symptoms of the human smallpox disease mpox (monkeypox), caused by the variola virus.

In a small prospective matched cohort analysis, people with HIV (PWH) and mpox disease who received tecovirimat within 7 days of symptom onset were 13 times less likely to experience progression, compared with PWH not prescribed tecovirimat within that window. In a matched cohort of 112 PWH, mpox disease progression occurred in 5.4% in an early tecovirimat group and in 26.8% in a late- or no-tecovirimat group, for a paired odds ratio of 13.00 (95% CI, 1.71-99.40; P = .002).

“Results of the present study suggest that tecovirimat treatment should be started early at the time of suspected mpox diagnosis in all PWH, especially in those with nonsuppressed HIV viremia or mucosal site involvement,” wrote a team led by Bruce Aldred, MD, of the Division of Infectious Diseases in the Department of Medicine at Emory University School of Medicine in Atlanta, in JAMA Internal Medicine. Early symptoms of mpox include skin rash and mucosal lesions, along with viral symptoms such as fever, headache, muscle aches, back pain, low energy, and swollen lymph nodes.

As of March 1 of last year, the United States reported more than 30,000 cases, while cases numbered more than 86,000 worldwide.

Despite a lack of effectiveness data in humans, tecovirimat was widely prescribed to PWH with mpox during the 2022 epidemic, which disproportionately affected PWH, particularly those with low CD4+ T-cell counts or severe mpox clinical manifestations who needed urgent therapy. Developed to treat smallpox, tecovirimat has antiviral activity against other orthopoxviruses, and has reduced mpox-related morbidity and mortality in animals.

Based on the animal data, approval was granted by the US Food and Drug Administration (FDA) for human mpox treatment. Dr. Aldred and colleagues undertook this cohort analysis in the absence of human data and with the postoutbreak decline in cases impeding recruitment to a full-scale clinical trial.

Study design

The preponderantly Black cohort included 112 PWH diagnosed with mpox at four Atlanta hospitals from June 1 to October 7, 2022. Patients were grouped in an early cohort receiving tecovirimat within 7 days of symptom onset or a no or late cohort (no tecovirimat or treatment more than 7 days after symptom onset. Multivariate logistic regression models identified factors associated with progression, defined as development of at least one severe CDC mpox criterion after symptom day 7.

The cohorts were then matched 1:1 using propensity scores based on the identified factors, and mpox disease progression was compared.

Of 112 PWH, 56 receive early tecovirimat and 56 received no or late treatment. In the early group, the median (interquartile range [IQR]) age was 35 (30-42) years; 54 individuals (96.4%) were cisgender men, 46 (82.1%) were Black, and 10 (17.9%) were, variously, White, American Indian, Alaska Native, Asian, Native Hawaiian or Other Pacific Islander, or of unknown race.

In the late- or no-tecovirimat group, the median (IQR) age was 36 (32-43) years; 54 (96.4%) were cisgender men, 49 (87.5%) were Black, and 7 (12.5%) were individuals of other or unknown race. Mpox disease progression occurred in 3 PWH in the early-tecovirimat group and 15 PWH (26.8%) in the late- or no-tecovirimat group.

Dr. Aldred and colleagues acknowledged that more research is needed to confirm the findings and cited several study limitations. These included the small sample size, the preponderance of Black participants, and the possibility that unmatched confounding variables could have led to the observation of fewer cases of severe disease in the early-tecovirimat cohort.

This study was supported by a grant from the Emory Center for AIDS Research. Coauthors reported grants from various institutes at the National Institutes of Health as well as from multiple pharmaceutical companies.

A new analysis supports using the smallpox antiviral tecovirimat (TPOXX/ST-246) in HIV patients showing the first symptoms of the human smallpox disease mpox (monkeypox), caused by the variola virus.

In a small prospective matched cohort analysis, people with HIV (PWH) and mpox disease who received tecovirimat within 7 days of symptom onset were 13 times less likely to experience progression, compared with PWH not prescribed tecovirimat within that window. In a matched cohort of 112 PWH, mpox disease progression occurred in 5.4% in an early tecovirimat group and in 26.8% in a late- or no-tecovirimat group, for a paired odds ratio of 13.00 (95% CI, 1.71-99.40; P = .002).

“Results of the present study suggest that tecovirimat treatment should be started early at the time of suspected mpox diagnosis in all PWH, especially in those with nonsuppressed HIV viremia or mucosal site involvement,” wrote a team led by Bruce Aldred, MD, of the Division of Infectious Diseases in the Department of Medicine at Emory University School of Medicine in Atlanta, in JAMA Internal Medicine. Early symptoms of mpox include skin rash and mucosal lesions, along with viral symptoms such as fever, headache, muscle aches, back pain, low energy, and swollen lymph nodes.

As of March 1 of last year, the United States reported more than 30,000 cases, while cases numbered more than 86,000 worldwide.

Despite a lack of effectiveness data in humans, tecovirimat was widely prescribed to PWH with mpox during the 2022 epidemic, which disproportionately affected PWH, particularly those with low CD4+ T-cell counts or severe mpox clinical manifestations who needed urgent therapy. Developed to treat smallpox, tecovirimat has antiviral activity against other orthopoxviruses, and has reduced mpox-related morbidity and mortality in animals.

Based on the animal data, approval was granted by the US Food and Drug Administration (FDA) for human mpox treatment. Dr. Aldred and colleagues undertook this cohort analysis in the absence of human data and with the postoutbreak decline in cases impeding recruitment to a full-scale clinical trial.

Study design

The preponderantly Black cohort included 112 PWH diagnosed with mpox at four Atlanta hospitals from June 1 to October 7, 2022. Patients were grouped in an early cohort receiving tecovirimat within 7 days of symptom onset or a no or late cohort (no tecovirimat or treatment more than 7 days after symptom onset. Multivariate logistic regression models identified factors associated with progression, defined as development of at least one severe CDC mpox criterion after symptom day 7.

The cohorts were then matched 1:1 using propensity scores based on the identified factors, and mpox disease progression was compared.

Of 112 PWH, 56 receive early tecovirimat and 56 received no or late treatment. In the early group, the median (interquartile range [IQR]) age was 35 (30-42) years; 54 individuals (96.4%) were cisgender men, 46 (82.1%) were Black, and 10 (17.9%) were, variously, White, American Indian, Alaska Native, Asian, Native Hawaiian or Other Pacific Islander, or of unknown race.

In the late- or no-tecovirimat group, the median (IQR) age was 36 (32-43) years; 54 (96.4%) were cisgender men, 49 (87.5%) were Black, and 7 (12.5%) were individuals of other or unknown race. Mpox disease progression occurred in 3 PWH in the early-tecovirimat group and 15 PWH (26.8%) in the late- or no-tecovirimat group.

Dr. Aldred and colleagues acknowledged that more research is needed to confirm the findings and cited several study limitations. These included the small sample size, the preponderance of Black participants, and the possibility that unmatched confounding variables could have led to the observation of fewer cases of severe disease in the early-tecovirimat cohort.

This study was supported by a grant from the Emory Center for AIDS Research. Coauthors reported grants from various institutes at the National Institutes of Health as well as from multiple pharmaceutical companies.

Harvard Medical School’s Sharon K. Inouye, MD, MPH, is editor in chief of JAMA Internal Medicine and a leading voice in American gerontology. We asked her to choose five of the influential journal’s most impactful studies from 2023 and highlight important take-home messages for internists and their colleagues.
 

Q: One of the studies you chose suggests that the antiviral nirmatrelvir (Paxlovid) can ward off long COVID. Could you recap the findings?

A: Researchers followed a group of more than 280,000 Department of Veterans Affairs patients who were seen in 2022, had a positive COVID test, and had at least one risk factor for severe COVID. They focused on those who survived to 30 days after their COVID infection and compared those who received the drug within the first 5 days of a positive test with an equivalent control group.

They found that 13 long COVID symptoms were all significantly less common (relative risk = 0.74) in those who received nirmatrelvir. This was true no matter whether they’d ever had a COVID vaccination.
 

Q: How should this research affect clinical practice?

A: You can’t generalize from this to everyone because, of course, not everyone was included in this study. But it is highly suggestive that this drug is very effective for preventing long COVID.

Nirmatrelvir was touted as being able to shorten duration of illness and prevent hospitalization. But if you were low risk or you were already well into your COVID course, it wasn’t like rush, rush, rush to the doctor to get it.

This changes that equation because we know long COVID is such a huge issue. The vast majority of doctors who work with COVID patients and know this are now being more aggressive about prescribing it.
 

Q: What about patients whom the CDC considers to be at less risk — people with up-to-date vaccinations who are under 50 with mild-to-moderate COVID and no higher-risk medical conditions? Should they take nirmatrelvir?

A: The evidence is not 100% in yet. A study like this one needs to be repeated and include younger people without any risk factors to see if we see the same thing. So it’s a personal choice, and a personal calculus needs to be done. A lot of people are making that choice [to take the drug], and it can be a rational decision.

Q: You also chose a study that links high thyroid hormone levels to higher rates of dementia. What did it reveal?

A: This study looks at patients who had thyrotoxicosis — a thyroid level that’s too high — from hormone produced endogenously, and exogenously. Researchers tracked almost 66,000 patients aged 65 and older and found that thyrotoxicosis from all causes, whether it was endogenous or exogenous, was linked to an increased risk of dementia in a dose-response relationship (adjusted hazard ratio = 1.39).

Q: Is there a clinical take-home message here?

A: When we start patients on thyroid medication, they don’t always get reassessed on a regular basis. Given this finding, a TSH [thyroid-stimulating hormone] level is indicated during the annual wellness check that patients on Medicare can get every year.

Q: Is TSH measured as part of routine blood tests?

A: No it’s not. It has to be ordered. I think that’s why we’re seeing this problem to begin with — because it’s not something we all have awareness about. I wasn’t aware myself that mildly high levels of thyroid could increase the risk of cognitive impairment. Certainly, I’m going to be much more aware in my practice.

Q: You also picked a study about silicosis in workers who are exposed to dust when they make engineered stone countertops, also known as quartz countertops. What were the findings?

A: Silicosis is a very serious lung condition that develops from exposure to crystalline silica. Essentially, sand gets inhaled into the lungs. Workers can be exposed when they’re making engineered stone countertops, the most popular countertops now in the United States.

This study is based on statewide surveys from 2019 to 2022 that the California Department of Public Health does routinely. They gathered cases of silicosis and found 52 — all men with an average age of 45. All but one were Latino immigrants, and most either had no insurance or very poor insurance.
 

Q: The study found that “diagnosis was delayed in 58%, with 38% presenting with advanced disease (progressive massive fibrosis), and 19% died.” What does that tell you?

A: It’s a very serious condition. Once it gets to the advanced stage, it will just continue to progress, and the person will die. That’s why it’s so important to know that it’s absolutely preventable.

Q: Is there a message here for internists?

A: If you treat a lot of immigrants or work in an area where there are a lot of industrial workers, you’re going to want to have a very high suspicion about it. If you see an atypical pattern on the chest x-ray or via diffusion scoring, have a low threshold for getting a pulmonary function test.

Doctors need to be aware and diagnose this very quickly. When patients present, you can pull them out of that work environment or put mitigation systems into place.
 

Q: California regulators were expected to put emergency rules into place in late December to protect workers. Did this study play a role in focusing attention on the problem?

A: This article, along with a commentary and podcast that we put out, really helped with advocacy to improve health and safety for workers at stone-cutting and fabrication shops.

Q: You were impressed by another study about airborne dangers, this one linking air pollution to dementia. What did researchers discover?

A: [This analysis] of more than 27,000 people in the Health and Retirement Study, a respected and rich database, found that exposure to air pollution was associated with greater rates of dementia — an increase of about 8% a year. Exposure to agricultural emissions and wildfire smoke were most robustly associated with a greater risk of dementia.

Q: How are these findings important, especially in light of the unhealthy air spawned by recent wildfires in the United States and Canada?

A: Studies like this will make it even more compelling that we are better prepared for air quality issues.

I grew up in Los Angeles, where smog and pollution were very big issues. I was constantly hearing about various mitigation strategies that were going into place. But after I moved to the East Coast, I almost never heard about prevention.

Now, I’m hoping we can keep this topic in the national conversation.
 

Q: You also highlighted a systematic review of the use of restraints in the emergency department. Why did you choose this research?

A: At JAMA Internal Medicine, we’re really focused on ways we can address health disparities and raise awareness of potential unconscious bias.

This review looked at 10 studies that included more than 2.5 million patient encounters, including 24,000 incidents of physical restraint use. They found that the overall rate of use of restraints was low at below 1%.

But when they are used, Black patients were 1.3 times more likely to be restrained than White patients.
 

Q: What’s the message here?

A: This is an important start to recognizing these differences and then changing our behavior. Perhaps restraints don’t need to be used as often in light of evidence, for example, of increased rates of misdiagnosis of psychosis in the Black population.

Q: How should physicians change their approach to restraints?

A: Restraints are not to be used to control disruption — wild behavior or verbal outbursts. They’re for when someone is a danger to themselves or others.

Dr. Inouye has no conflicts of interest.

Harvard Medical School’s Sharon K. Inouye, MD, MPH, is editor in chief of JAMA Internal Medicine and a leading voice in American gerontology. We asked her to choose five of the influential journal’s most impactful studies from 2023 and highlight important take-home messages for internists and their colleagues.
 

Q: One of the studies you chose suggests that the antiviral nirmatrelvir (Paxlovid) can ward off long COVID. Could you recap the findings?

A: Researchers followed a group of more than 280,000 Department of Veterans Affairs patients who were seen in 2022, had a positive COVID test, and had at least one risk factor for severe COVID. They focused on those who survived to 30 days after their COVID infection and compared those who received the drug within the first 5 days of a positive test with an equivalent control group.

They found that 13 long COVID symptoms were all significantly less common (relative risk = 0.74) in those who received nirmatrelvir. This was true no matter whether they’d ever had a COVID vaccination.
 

Q: How should this research affect clinical practice?

A: You can’t generalize from this to everyone because, of course, not everyone was included in this study. But it is highly suggestive that this drug is very effective for preventing long COVID.

Nirmatrelvir was touted as being able to shorten duration of illness and prevent hospitalization. But if you were low risk or you were already well into your COVID course, it wasn’t like rush, rush, rush to the doctor to get it.

This changes that equation because we know long COVID is such a huge issue. The vast majority of doctors who work with COVID patients and know this are now being more aggressive about prescribing it.
 

Q: What about patients whom the CDC considers to be at less risk — people with up-to-date vaccinations who are under 50 with mild-to-moderate COVID and no higher-risk medical conditions? Should they take nirmatrelvir?

A: The evidence is not 100% in yet. A study like this one needs to be repeated and include younger people without any risk factors to see if we see the same thing. So it’s a personal choice, and a personal calculus needs to be done. A lot of people are making that choice [to take the drug], and it can be a rational decision.

Q: You also chose a study that links high thyroid hormone levels to higher rates of dementia. What did it reveal?

A: This study looks at patients who had thyrotoxicosis — a thyroid level that’s too high — from hormone produced endogenously, and exogenously. Researchers tracked almost 66,000 patients aged 65 and older and found that thyrotoxicosis from all causes, whether it was endogenous or exogenous, was linked to an increased risk of dementia in a dose-response relationship (adjusted hazard ratio = 1.39).

Q: Is there a clinical take-home message here?

A: When we start patients on thyroid medication, they don’t always get reassessed on a regular basis. Given this finding, a TSH [thyroid-stimulating hormone] level is indicated during the annual wellness check that patients on Medicare can get every year.

Q: Is TSH measured as part of routine blood tests?

A: No it’s not. It has to be ordered. I think that’s why we’re seeing this problem to begin with — because it’s not something we all have awareness about. I wasn’t aware myself that mildly high levels of thyroid could increase the risk of cognitive impairment. Certainly, I’m going to be much more aware in my practice.

Q: You also picked a study about silicosis in workers who are exposed to dust when they make engineered stone countertops, also known as quartz countertops. What were the findings?

A: Silicosis is a very serious lung condition that develops from exposure to crystalline silica. Essentially, sand gets inhaled into the lungs. Workers can be exposed when they’re making engineered stone countertops, the most popular countertops now in the United States.

This study is based on statewide surveys from 2019 to 2022 that the California Department of Public Health does routinely. They gathered cases of silicosis and found 52 — all men with an average age of 45. All but one were Latino immigrants, and most either had no insurance or very poor insurance.
 

Q: The study found that “diagnosis was delayed in 58%, with 38% presenting with advanced disease (progressive massive fibrosis), and 19% died.” What does that tell you?

A: It’s a very serious condition. Once it gets to the advanced stage, it will just continue to progress, and the person will die. That’s why it’s so important to know that it’s absolutely preventable.

Q: Is there a message here for internists?

A: If you treat a lot of immigrants or work in an area where there are a lot of industrial workers, you’re going to want to have a very high suspicion about it. If you see an atypical pattern on the chest x-ray or via diffusion scoring, have a low threshold for getting a pulmonary function test.

Doctors need to be aware and diagnose this very quickly. When patients present, you can pull them out of that work environment or put mitigation systems into place.
 

Q: California regulators were expected to put emergency rules into place in late December to protect workers. Did this study play a role in focusing attention on the problem?

A: This article, along with a commentary and podcast that we put out, really helped with advocacy to improve health and safety for workers at stone-cutting and fabrication shops.

Q: You were impressed by another study about airborne dangers, this one linking air pollution to dementia. What did researchers discover?

A: [This analysis] of more than 27,000 people in the Health and Retirement Study, a respected and rich database, found that exposure to air pollution was associated with greater rates of dementia — an increase of about 8% a year. Exposure to agricultural emissions and wildfire smoke were most robustly associated with a greater risk of dementia.

Q: How are these findings important, especially in light of the unhealthy air spawned by recent wildfires in the United States and Canada?

A: Studies like this will make it even more compelling that we are better prepared for air quality issues.

I grew up in Los Angeles, where smog and pollution were very big issues. I was constantly hearing about various mitigation strategies that were going into place. But after I moved to the East Coast, I almost never heard about prevention.

Now, I’m hoping we can keep this topic in the national conversation.
 

Q: You also highlighted a systematic review of the use of restraints in the emergency department. Why did you choose this research?

A: At JAMA Internal Medicine, we’re really focused on ways we can address health disparities and raise awareness of potential unconscious bias.

This review looked at 10 studies that included more than 2.5 million patient encounters, including 24,000 incidents of physical restraint use. They found that the overall rate of use of restraints was low at below 1%.

But when they are used, Black patients were 1.3 times more likely to be restrained than White patients.
 

Q: What’s the message here?

A: This is an important start to recognizing these differences and then changing our behavior. Perhaps restraints don’t need to be used as often in light of evidence, for example, of increased rates of misdiagnosis of psychosis in the Black population.

Q: How should physicians change their approach to restraints?

A: Restraints are not to be used to control disruption — wild behavior or verbal outbursts. They’re for when someone is a danger to themselves or others.

Dr. Inouye has no conflicts of interest.

Harvard Medical School’s Sharon K. Inouye, MD, MPH, is editor in chief of JAMA Internal Medicine and a leading voice in American gerontology. We asked her to choose five of the influential journal’s most impactful studies from 2023 and highlight important take-home messages for internists and their colleagues.
 

Q: One of the studies you chose suggests that the antiviral nirmatrelvir (Paxlovid) can ward off long COVID. Could you recap the findings?

A: Researchers followed a group of more than 280,000 Department of Veterans Affairs patients who were seen in 2022, had a positive COVID test, and had at least one risk factor for severe COVID. They focused on those who survived to 30 days after their COVID infection and compared those who received the drug within the first 5 days of a positive test with an equivalent control group.

They found that 13 long COVID symptoms were all significantly less common (relative risk = 0.74) in those who received nirmatrelvir. This was true no matter whether they’d ever had a COVID vaccination.
 

Q: How should this research affect clinical practice?

A: You can’t generalize from this to everyone because, of course, not everyone was included in this study. But it is highly suggestive that this drug is very effective for preventing long COVID.

Nirmatrelvir was touted as being able to shorten duration of illness and prevent hospitalization. But if you were low risk or you were already well into your COVID course, it wasn’t like rush, rush, rush to the doctor to get it.

This changes that equation because we know long COVID is such a huge issue. The vast majority of doctors who work with COVID patients and know this are now being more aggressive about prescribing it.
 

Q: What about patients whom the CDC considers to be at less risk — people with up-to-date vaccinations who are under 50 with mild-to-moderate COVID and no higher-risk medical conditions? Should they take nirmatrelvir?

A: The evidence is not 100% in yet. A study like this one needs to be repeated and include younger people without any risk factors to see if we see the same thing. So it’s a personal choice, and a personal calculus needs to be done. A lot of people are making that choice [to take the drug], and it can be a rational decision.

Q: You also chose a study that links high thyroid hormone levels to higher rates of dementia. What did it reveal?

A: This study looks at patients who had thyrotoxicosis — a thyroid level that’s too high — from hormone produced endogenously, and exogenously. Researchers tracked almost 66,000 patients aged 65 and older and found that thyrotoxicosis from all causes, whether it was endogenous or exogenous, was linked to an increased risk of dementia in a dose-response relationship (adjusted hazard ratio = 1.39).

Q: Is there a clinical take-home message here?

A: When we start patients on thyroid medication, they don’t always get reassessed on a regular basis. Given this finding, a TSH [thyroid-stimulating hormone] level is indicated during the annual wellness check that patients on Medicare can get every year.

Q: Is TSH measured as part of routine blood tests?

A: No it’s not. It has to be ordered. I think that’s why we’re seeing this problem to begin with — because it’s not something we all have awareness about. I wasn’t aware myself that mildly high levels of thyroid could increase the risk of cognitive impairment. Certainly, I’m going to be much more aware in my practice.

Q: You also picked a study about silicosis in workers who are exposed to dust when they make engineered stone countertops, also known as quartz countertops. What were the findings?

A: Silicosis is a very serious lung condition that develops from exposure to crystalline silica. Essentially, sand gets inhaled into the lungs. Workers can be exposed when they’re making engineered stone countertops, the most popular countertops now in the United States.

This study is based on statewide surveys from 2019 to 2022 that the California Department of Public Health does routinely. They gathered cases of silicosis and found 52 — all men with an average age of 45. All but one were Latino immigrants, and most either had no insurance or very poor insurance.
 

Q: The study found that “diagnosis was delayed in 58%, with 38% presenting with advanced disease (progressive massive fibrosis), and 19% died.” What does that tell you?

A: It’s a very serious condition. Once it gets to the advanced stage, it will just continue to progress, and the person will die. That’s why it’s so important to know that it’s absolutely preventable.

Q: Is there a message here for internists?

A: If you treat a lot of immigrants or work in an area where there are a lot of industrial workers, you’re going to want to have a very high suspicion about it. If you see an atypical pattern on the chest x-ray or via diffusion scoring, have a low threshold for getting a pulmonary function test.

Doctors need to be aware and diagnose this very quickly. When patients present, you can pull them out of that work environment or put mitigation systems into place.
 

Q: California regulators were expected to put emergency rules into place in late December to protect workers. Did this study play a role in focusing attention on the problem?

A: This article, along with a commentary and podcast that we put out, really helped with advocacy to improve health and safety for workers at stone-cutting and fabrication shops.

Q: You were impressed by another study about airborne dangers, this one linking air pollution to dementia. What did researchers discover?

A: [This analysis] of more than 27,000 people in the Health and Retirement Study, a respected and rich database, found that exposure to air pollution was associated with greater rates of dementia — an increase of about 8% a year. Exposure to agricultural emissions and wildfire smoke were most robustly associated with a greater risk of dementia.

Q: How are these findings important, especially in light of the unhealthy air spawned by recent wildfires in the United States and Canada?

A: Studies like this will make it even more compelling that we are better prepared for air quality issues.

I grew up in Los Angeles, where smog and pollution were very big issues. I was constantly hearing about various mitigation strategies that were going into place. But after I moved to the East Coast, I almost never heard about prevention.

Now, I’m hoping we can keep this topic in the national conversation.
 

Q: You also highlighted a systematic review of the use of restraints in the emergency department. Why did you choose this research?

A: At JAMA Internal Medicine, we’re really focused on ways we can address health disparities and raise awareness of potential unconscious bias.

This review looked at 10 studies that included more than 2.5 million patient encounters, including 24,000 incidents of physical restraint use. They found that the overall rate of use of restraints was low at below 1%.

But when they are used, Black patients were 1.3 times more likely to be restrained than White patients.
 

Q: What’s the message here?

A: This is an important start to recognizing these differences and then changing our behavior. Perhaps restraints don’t need to be used as often in light of evidence, for example, of increased rates of misdiagnosis of psychosis in the Black population.

Q: How should physicians change their approach to restraints?

A: Restraints are not to be used to control disruption — wild behavior or verbal outbursts. They’re for when someone is a danger to themselves or others.

Dr. Inouye has no conflicts of interest.

One of the biggest challenges facing clinicians who treat long COVID is a lack of consensus when it comes to recognizing and diagnosing the condition. But a new study suggests testing for certain biomarkers may identify long COVID with accuracy approaching 80%.

Effective diagnostic testing would be a game-changer in the long COVID fight, for it’s not just the fatigue, brain fog, heart palpitations, and other persistent symptoms that affect patients. Two out of three people with long COVID also suffer mental health challenges like depression and anxiety. Some patients say their symptoms are not taken seriously by their doctors. And as many as 12% of long COVID patients are unemployed because of the severity of their illness and their employers may be skeptical of their condition.

Quick, accurate diagnosis would eliminate all that. Now a new preprint study suggests that the elevation of certain immune system proteins are a commonality in long COVID patients and identifying them may be an accurate way to diagnose the condition.

Researchers at Cardiff (Wales) University, tracked 166 patients, 79 of whom had been diagnosed with long COVID and 87 who had not. All participants had recovered from a severe bout of acute COVID-19.

In an analysis of the blood plasma of the study participants, researchers found elevated levels of certain components. Four proteins in particular – Ba, iC3b, C5a, and TCC – predicted the presence of long COVID with 78.5% accuracy.

“I was gobsmacked by the results. We’re seeing a massive dysregulation in those four biomarkers,” says study author Wioleta Zelek, PhD, a research fellow at Cardiff University. “It’s a combination that we showed was predictive of long COVID.” 

The study revealed that long COVID was associated with inflammation of the immune system causing these complement proteins to remain dysregulated. Proteins like C3, C4, and C5 are important parts of the immune system because they recruit phagocytes, cells that attack and engulf bacteria and viruses at the site of infection to destroy pathogens like SARS-coV-2. 

In the case of long COVID, these proteins remain chronically elevated. While the symptoms of long COVID have seemed largely unrelated to one another, researchers point to elevated inflammation as a connecting factor that causes various systems in the body to go haywire.

“Anything that could help to better diagnose patients with long COVID is research we’re greatly appreciative of within the clinical community,” said Nisha Viswanathan, MD, director of the University of California, Los Angeles, Long COVID program at UCLA Health. 

Testing for biomarkers highlighted in the study, as well as others like serotonin and cortisol, may help doctors separate patients who have long COVID from patients who have similar symptoms caused by other conditions, said Dr. Viswanathan. For example, a recent study published in the journal Cell found lower serotonin levels in long COVID patients, compared with patients who were diagnosed with acute COVID-19 but recovered from the condition.

Dr. Viswanathan cautions that the biomarker test does not answer all the questions about diagnosing long COVID. For example, Dr. Viswanathan said scientists don’t know whether complement dysregulation is caused by long COVID and not another underlying medical issue that patients had prior to infection, because “we don’t know where patients’ levels were prior to developing long COVID.” For example, those with autoimmune issues are more likely to develop long COVID, which means their levels could have been elevated prior to a COVID infection.

It is increasingly likely, said Dr. Viswanathan, that long COVID is an umbrella term for a host of conditions that could be caused by different impacts of the virus. Other research has pointed to the different phenotypes of long COVID. For example, some are focused on cardiopulmonary issues and others on fatigue and gastrointestinal problems. 

“It looks like these different phenotypes have a different mechanism for disease,” she said. This means that it’s less likely to be a one-size-fits-all condition and the next step in the research should be identifying which biomarker is aligned with which phenotype of the disease. 

Better diagnostics will open the door to better treatments, Dr. Zelek said. The more doctors understand about the mechanism causing immune dysregulation in long COVID patients, the more they can treat it with existing medications. Dr. Zelek’s lab has been studying certain medications like pegcetacoplan (C3 blocker), danicopan (anti-factor D), and iptacopan (anti-factor B) that can be used to break the body’s cycle of inflammation and reduce symptoms experienced in those with long COVID. 

These drugs are approved by the U.S. Food and Drug Administration for the treatment of a rare blood disease called paroxysmal nocturnal hemoglobinuria. The C5 inhibitor zilucoplan has also been used in patients hospitalized with COVID-19 and researchers have found that the drug lowered serum C5 and interleukin-8 concentration in the blood, seeming to reduce certain aspects of the immune system’s inflammatory response to the virus. 

The Cardiff University research is one of the most detailed studies to highlight long COVID biomarkers to date, said infectious disease specialist Grace McComsey, MD, who leads the long COVID RECOVER study at University Hospitals Health System in Cleveland, Ohio. The research needs to be duplicated in a larger study population that might include the other biomarkers like serotonin and cortisol to see if they’re related, she said. 

Researchers are learning more everyday about the various biomarkers that may be linked to long COVID, she added. This Cardiff study showed that a huge percentage of those patients had elevated levels of certain complements. The next step, said Dr. McComsey, “is to put all these puzzle pieces together” so that clinicians have a common diagnostic tool or tools that provide patients with some peace of mind in starting their road to recovery.

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

One of the biggest challenges facing clinicians who treat long COVID is a lack of consensus when it comes to recognizing and diagnosing the condition. But a new study suggests testing for certain biomarkers may identify long COVID with accuracy approaching 80%.

Effective diagnostic testing would be a game-changer in the long COVID fight, for it’s not just the fatigue, brain fog, heart palpitations, and other persistent symptoms that affect patients. Two out of three people with long COVID also suffer mental health challenges like depression and anxiety. Some patients say their symptoms are not taken seriously by their doctors. And as many as 12% of long COVID patients are unemployed because of the severity of their illness and their employers may be skeptical of their condition.

Quick, accurate diagnosis would eliminate all that. Now a new preprint study suggests that the elevation of certain immune system proteins are a commonality in long COVID patients and identifying them may be an accurate way to diagnose the condition.

Researchers at Cardiff (Wales) University, tracked 166 patients, 79 of whom had been diagnosed with long COVID and 87 who had not. All participants had recovered from a severe bout of acute COVID-19.

In an analysis of the blood plasma of the study participants, researchers found elevated levels of certain components. Four proteins in particular – Ba, iC3b, C5a, and TCC – predicted the presence of long COVID with 78.5% accuracy.

“I was gobsmacked by the results. We’re seeing a massive dysregulation in those four biomarkers,” says study author Wioleta Zelek, PhD, a research fellow at Cardiff University. “It’s a combination that we showed was predictive of long COVID.” 

The study revealed that long COVID was associated with inflammation of the immune system causing these complement proteins to remain dysregulated. Proteins like C3, C4, and C5 are important parts of the immune system because they recruit phagocytes, cells that attack and engulf bacteria and viruses at the site of infection to destroy pathogens like SARS-coV-2. 

In the case of long COVID, these proteins remain chronically elevated. While the symptoms of long COVID have seemed largely unrelated to one another, researchers point to elevated inflammation as a connecting factor that causes various systems in the body to go haywire.

“Anything that could help to better diagnose patients with long COVID is research we’re greatly appreciative of within the clinical community,” said Nisha Viswanathan, MD, director of the University of California, Los Angeles, Long COVID program at UCLA Health. 

Testing for biomarkers highlighted in the study, as well as others like serotonin and cortisol, may help doctors separate patients who have long COVID from patients who have similar symptoms caused by other conditions, said Dr. Viswanathan. For example, a recent study published in the journal Cell found lower serotonin levels in long COVID patients, compared with patients who were diagnosed with acute COVID-19 but recovered from the condition.

Dr. Viswanathan cautions that the biomarker test does not answer all the questions about diagnosing long COVID. For example, Dr. Viswanathan said scientists don’t know whether complement dysregulation is caused by long COVID and not another underlying medical issue that patients had prior to infection, because “we don’t know where patients’ levels were prior to developing long COVID.” For example, those with autoimmune issues are more likely to develop long COVID, which means their levels could have been elevated prior to a COVID infection.

It is increasingly likely, said Dr. Viswanathan, that long COVID is an umbrella term for a host of conditions that could be caused by different impacts of the virus. Other research has pointed to the different phenotypes of long COVID. For example, some are focused on cardiopulmonary issues and others on fatigue and gastrointestinal problems. 

“It looks like these different phenotypes have a different mechanism for disease,” she said. This means that it’s less likely to be a one-size-fits-all condition and the next step in the research should be identifying which biomarker is aligned with which phenotype of the disease. 

Better diagnostics will open the door to better treatments, Dr. Zelek said. The more doctors understand about the mechanism causing immune dysregulation in long COVID patients, the more they can treat it with existing medications. Dr. Zelek’s lab has been studying certain medications like pegcetacoplan (C3 blocker), danicopan (anti-factor D), and iptacopan (anti-factor B) that can be used to break the body’s cycle of inflammation and reduce symptoms experienced in those with long COVID. 

These drugs are approved by the U.S. Food and Drug Administration for the treatment of a rare blood disease called paroxysmal nocturnal hemoglobinuria. The C5 inhibitor zilucoplan has also been used in patients hospitalized with COVID-19 and researchers have found that the drug lowered serum C5 and interleukin-8 concentration in the blood, seeming to reduce certain aspects of the immune system’s inflammatory response to the virus. 

The Cardiff University research is one of the most detailed studies to highlight long COVID biomarkers to date, said infectious disease specialist Grace McComsey, MD, who leads the long COVID RECOVER study at University Hospitals Health System in Cleveland, Ohio. The research needs to be duplicated in a larger study population that might include the other biomarkers like serotonin and cortisol to see if they’re related, she said. 

Researchers are learning more everyday about the various biomarkers that may be linked to long COVID, she added. This Cardiff study showed that a huge percentage of those patients had elevated levels of certain complements. The next step, said Dr. McComsey, “is to put all these puzzle pieces together” so that clinicians have a common diagnostic tool or tools that provide patients with some peace of mind in starting their road to recovery.

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

One of the biggest challenges facing clinicians who treat long COVID is a lack of consensus when it comes to recognizing and diagnosing the condition. But a new study suggests testing for certain biomarkers may identify long COVID with accuracy approaching 80%.

Effective diagnostic testing would be a game-changer in the long COVID fight, for it’s not just the fatigue, brain fog, heart palpitations, and other persistent symptoms that affect patients. Two out of three people with long COVID also suffer mental health challenges like depression and anxiety. Some patients say their symptoms are not taken seriously by their doctors. And as many as 12% of long COVID patients are unemployed because of the severity of their illness and their employers may be skeptical of their condition.

Quick, accurate diagnosis would eliminate all that. Now a new preprint study suggests that the elevation of certain immune system proteins are a commonality in long COVID patients and identifying them may be an accurate way to diagnose the condition.

Researchers at Cardiff (Wales) University, tracked 166 patients, 79 of whom had been diagnosed with long COVID and 87 who had not. All participants had recovered from a severe bout of acute COVID-19.

In an analysis of the blood plasma of the study participants, researchers found elevated levels of certain components. Four proteins in particular – Ba, iC3b, C5a, and TCC – predicted the presence of long COVID with 78.5% accuracy.

“I was gobsmacked by the results. We’re seeing a massive dysregulation in those four biomarkers,” says study author Wioleta Zelek, PhD, a research fellow at Cardiff University. “It’s a combination that we showed was predictive of long COVID.” 

The study revealed that long COVID was associated with inflammation of the immune system causing these complement proteins to remain dysregulated. Proteins like C3, C4, and C5 are important parts of the immune system because they recruit phagocytes, cells that attack and engulf bacteria and viruses at the site of infection to destroy pathogens like SARS-coV-2. 

In the case of long COVID, these proteins remain chronically elevated. While the symptoms of long COVID have seemed largely unrelated to one another, researchers point to elevated inflammation as a connecting factor that causes various systems in the body to go haywire.

“Anything that could help to better diagnose patients with long COVID is research we’re greatly appreciative of within the clinical community,” said Nisha Viswanathan, MD, director of the University of California, Los Angeles, Long COVID program at UCLA Health. 

Testing for biomarkers highlighted in the study, as well as others like serotonin and cortisol, may help doctors separate patients who have long COVID from patients who have similar symptoms caused by other conditions, said Dr. Viswanathan. For example, a recent study published in the journal Cell found lower serotonin levels in long COVID patients, compared with patients who were diagnosed with acute COVID-19 but recovered from the condition.

Dr. Viswanathan cautions that the biomarker test does not answer all the questions about diagnosing long COVID. For example, Dr. Viswanathan said scientists don’t know whether complement dysregulation is caused by long COVID and not another underlying medical issue that patients had prior to infection, because “we don’t know where patients’ levels were prior to developing long COVID.” For example, those with autoimmune issues are more likely to develop long COVID, which means their levels could have been elevated prior to a COVID infection.

It is increasingly likely, said Dr. Viswanathan, that long COVID is an umbrella term for a host of conditions that could be caused by different impacts of the virus. Other research has pointed to the different phenotypes of long COVID. For example, some are focused on cardiopulmonary issues and others on fatigue and gastrointestinal problems. 

“It looks like these different phenotypes have a different mechanism for disease,” she said. This means that it’s less likely to be a one-size-fits-all condition and the next step in the research should be identifying which biomarker is aligned with which phenotype of the disease. 

Better diagnostics will open the door to better treatments, Dr. Zelek said. The more doctors understand about the mechanism causing immune dysregulation in long COVID patients, the more they can treat it with existing medications. Dr. Zelek’s lab has been studying certain medications like pegcetacoplan (C3 blocker), danicopan (anti-factor D), and iptacopan (anti-factor B) that can be used to break the body’s cycle of inflammation and reduce symptoms experienced in those with long COVID. 

These drugs are approved by the U.S. Food and Drug Administration for the treatment of a rare blood disease called paroxysmal nocturnal hemoglobinuria. The C5 inhibitor zilucoplan has also been used in patients hospitalized with COVID-19 and researchers have found that the drug lowered serum C5 and interleukin-8 concentration in the blood, seeming to reduce certain aspects of the immune system’s inflammatory response to the virus. 

The Cardiff University research is one of the most detailed studies to highlight long COVID biomarkers to date, said infectious disease specialist Grace McComsey, MD, who leads the long COVID RECOVER study at University Hospitals Health System in Cleveland, Ohio. The research needs to be duplicated in a larger study population that might include the other biomarkers like serotonin and cortisol to see if they’re related, she said. 

Researchers are learning more everyday about the various biomarkers that may be linked to long COVID, she added. This Cardiff study showed that a huge percentage of those patients had elevated levels of certain complements. The next step, said Dr. McComsey, “is to put all these puzzle pieces together” so that clinicians have a common diagnostic tool or tools that provide patients with some peace of mind in starting their road to recovery.

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

TOPLINE:

Children with asthma exposed to worsening psychosocial environmental factors during childhood were more likely to have more severe asthma symptoms than those without such exposures.

METHODOLOGY:

• The researchers reviewed data from the Longitudinal Study of Australian Children, a nationally representative cohort that also collects data on the health, psychosocial, and environmental status of parents, and used three multivariate models to assess the impact of psychosocial environmental factors on asthma symptoms at ages 1 year, 4-5 years, and 14-15 years.
• The study population included 3,917 children aged 0-15 years who were sorted into three asthma symptom trajectory groups (low/no asthma, transient high asthma, and persistent high asthma); asthma symptoms were defined as a history of chest wheezing lasting at least a week within the past 12 months.
• The researchers identified several psychosocial environmental factors as exposure variables on the basis of literature reviews; these factors were maternal depression, parents’ financial hardship, parental availability, and parental stressful life events.

TAKEAWAY:

• The mean scores of psychosocial factors for the overall study population remained stable over time, but groups of children exposed to bad trajectories of psychosocial factors were significantly more likely to have transient high and persistent high asthma symptoms.
• In the first year of life, only parents’ stressful life events were significantly associated with the persistent high asthma symptom trajectory group in an adjusted analysis.
• At age 4-5 years, maternal depression, low parental availability, and parents’ stressful life events were significantly associated with persistent high asthma; parents’ financial hardship was significantly associated with transient high asthma symptoms.
• At age 14-15 years, children exposed to “moderate and increasing” maternal depression, “moderate and declining” parents’ financial hardship, and “moderate and increasing” parents’ stressful life events were significantly associated with persistent high asthma versus no or low asthma, with relative risk ratios of 1.55, 1.40, and 1.77, respectively.

IN PRACTICE:

The study findings highlight the need for policy makers to take action to improve asthma control in children by reducing exposure to harmful psychosocial environmental factors, the researchers concluded.

SOURCE:

The lead author of the study was K.M. Shahunja, MBBS, PhD candidate at the University of Queensland, Brisbane, Australia. The study was published online in Pediatric Pulmonology.

LIMITATIONS:

The study is the first known to examine asthma symptom trajectories at different developmental stages, but participant attrition and missing values were limiting factors, as was the inability to account for all potential psychosocial environmental factors that might influence asthma symptoms in childhood.

DISCLOSURES:

The study received no outside funding. The researchers had no financial conflicts to disclose.

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

TOPLINE:

Children with asthma exposed to worsening psychosocial environmental factors during childhood were more likely to have more severe asthma symptoms than those without such exposures.

METHODOLOGY:

• The researchers reviewed data from the Longitudinal Study of Australian Children, a nationally representative cohort that also collects data on the health, psychosocial, and environmental status of parents, and used three multivariate models to assess the impact of psychosocial environmental factors on asthma symptoms at ages 1 year, 4-5 years, and 14-15 years.
• The study population included 3,917 children aged 0-15 years who were sorted into three asthma symptom trajectory groups (low/no asthma, transient high asthma, and persistent high asthma); asthma symptoms were defined as a history of chest wheezing lasting at least a week within the past 12 months.
• The researchers identified several psychosocial environmental factors as exposure variables on the basis of literature reviews; these factors were maternal depression, parents’ financial hardship, parental availability, and parental stressful life events.

TAKEAWAY:

• The mean scores of psychosocial factors for the overall study population remained stable over time, but groups of children exposed to bad trajectories of psychosocial factors were significantly more likely to have transient high and persistent high asthma symptoms.
• In the first year of life, only parents’ stressful life events were significantly associated with the persistent high asthma symptom trajectory group in an adjusted analysis.
• At age 4-5 years, maternal depression, low parental availability, and parents’ stressful life events were significantly associated with persistent high asthma; parents’ financial hardship was significantly associated with transient high asthma symptoms.
• At age 14-15 years, children exposed to “moderate and increasing” maternal depression, “moderate and declining” parents’ financial hardship, and “moderate and increasing” parents’ stressful life events were significantly associated with persistent high asthma versus no or low asthma, with relative risk ratios of 1.55, 1.40, and 1.77, respectively.

IN PRACTICE:

The study findings highlight the need for policy makers to take action to improve asthma control in children by reducing exposure to harmful psychosocial environmental factors, the researchers concluded.

SOURCE:

The lead author of the study was K.M. Shahunja, MBBS, PhD candidate at the University of Queensland, Brisbane, Australia. The study was published online in Pediatric Pulmonology.

LIMITATIONS:

The study is the first known to examine asthma symptom trajectories at different developmental stages, but participant attrition and missing values were limiting factors, as was the inability to account for all potential psychosocial environmental factors that might influence asthma symptoms in childhood.

DISCLOSURES:

The study received no outside funding. The researchers had no financial conflicts to disclose.

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

TOPLINE:

Children with asthma exposed to worsening psychosocial environmental factors during childhood were more likely to have more severe asthma symptoms than those without such exposures.

METHODOLOGY:

• The researchers reviewed data from the Longitudinal Study of Australian Children, a nationally representative cohort that also collects data on the health, psychosocial, and environmental status of parents, and used three multivariate models to assess the impact of psychosocial environmental factors on asthma symptoms at ages 1 year, 4-5 years, and 14-15 years.
• The study population included 3,917 children aged 0-15 years who were sorted into three asthma symptom trajectory groups (low/no asthma, transient high asthma, and persistent high asthma); asthma symptoms were defined as a history of chest wheezing lasting at least a week within the past 12 months.
• The researchers identified several psychosocial environmental factors as exposure variables on the basis of literature reviews; these factors were maternal depression, parents’ financial hardship, parental availability, and parental stressful life events.

TAKEAWAY:

• The mean scores of psychosocial factors for the overall study population remained stable over time, but groups of children exposed to bad trajectories of psychosocial factors were significantly more likely to have transient high and persistent high asthma symptoms.
• In the first year of life, only parents’ stressful life events were significantly associated with the persistent high asthma symptom trajectory group in an adjusted analysis.
• At age 4-5 years, maternal depression, low parental availability, and parents’ stressful life events were significantly associated with persistent high asthma; parents’ financial hardship was significantly associated with transient high asthma symptoms.
• At age 14-15 years, children exposed to “moderate and increasing” maternal depression, “moderate and declining” parents’ financial hardship, and “moderate and increasing” parents’ stressful life events were significantly associated with persistent high asthma versus no or low asthma, with relative risk ratios of 1.55, 1.40, and 1.77, respectively.

IN PRACTICE:

The study findings highlight the need for policy makers to take action to improve asthma control in children by reducing exposure to harmful psychosocial environmental factors, the researchers concluded.

SOURCE:

The lead author of the study was K.M. Shahunja, MBBS, PhD candidate at the University of Queensland, Brisbane, Australia. The study was published online in Pediatric Pulmonology.

LIMITATIONS:

The study is the first known to examine asthma symptom trajectories at different developmental stages, but participant attrition and missing values were limiting factors, as was the inability to account for all potential psychosocial environmental factors that might influence asthma symptoms in childhood.

DISCLOSURES:

The study received no outside funding. The researchers had no financial conflicts to disclose.

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

TOPLINE:

In individuals with low B-cell counts, T cells have enhanced responses to COVID-19 vaccination and may help prevent severe disease after infection.

METHODOLOGY:

• How the immune systems of B cell–deficient patients respond to SARS-CoV-2 infection and vaccination is not fully understood.
• Researchers evaluated anti–SARS-CoV-2 T-cell responses in 33 patients treated with rituximab (RTX), 12 patients with common variable immune deficiency, and 44 controls.
• The study analyzed effector and memory CD4+ and CD8+ T-cell responses to SARS-CoV-2 after infection and vaccination.

TAKEAWAY: 

• All B cell–deficient individuals (those treated with RTX or those with a diagnosis of common variable immune deficiency) had increased effector and memory T-cell responses after SARS-CoV-2 vaccination, compared with controls.
• Patients treated with RTX who were vaccinated against COVID-19 had 4.8-fold reduced odds of moderate or severe disease. (These data were not available for patients with common variable immune deficiency.)
• RTX treatment was associated with a decrease in preexisting T-cell immunity in unvaccinated patients, regardless of prior infection with SARS-CoV-2.
• This association was not found in vaccinated patients treated with RTX.

IN PRACTICE:

“[These findings] provide support for vaccination in this vulnerable population and demonstrate the potential benefit of vaccine-induced CD8+ T-cell responses on reducing disease severity from SARS-CoV-2 infection in the absence of spike protein–specific antibodies,” the authors wrote.

SOURCE:

The study was published online on November 29 in Science Translational Medicine. The first author is Reza Zonozi, MD, who conducted the research while at Massachusetts General Hospital, Boston, and is now in private practice in northern Virginia. 

LIMITATIONS:

Researchers did not obtain specimens from patients with common variable immune deficiency after SARS-CoV-2 infection. Only a small subset of immunophenotyped participants had subsequent SARS-CoV-2 infection.

DISCLOSURES:

The research was supported by grants from the National Institutes of Health, the Centers for Disease Control and Prevention, the Howard Hughes Medical Institute, the Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard Medical School, the Mark and Lisa Schwartz Foundation and E. Schwartz; the Lambertus Family Foundation; and S. Edgerly and P. Edgerly. Four authors reported relationships with pharmaceutical companies including AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead Sciences, Merck, and Pfizer.

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

TOPLINE:

In individuals with low B-cell counts, T cells have enhanced responses to COVID-19 vaccination and may help prevent severe disease after infection.

METHODOLOGY:

• How the immune systems of B cell–deficient patients respond to SARS-CoV-2 infection and vaccination is not fully understood.
• Researchers evaluated anti–SARS-CoV-2 T-cell responses in 33 patients treated with rituximab (RTX), 12 patients with common variable immune deficiency, and 44 controls.
• The study analyzed effector and memory CD4+ and CD8+ T-cell responses to SARS-CoV-2 after infection and vaccination.

TAKEAWAY: 

• All B cell–deficient individuals (those treated with RTX or those with a diagnosis of common variable immune deficiency) had increased effector and memory T-cell responses after SARS-CoV-2 vaccination, compared with controls.
• Patients treated with RTX who were vaccinated against COVID-19 had 4.8-fold reduced odds of moderate or severe disease. (These data were not available for patients with common variable immune deficiency.)
• RTX treatment was associated with a decrease in preexisting T-cell immunity in unvaccinated patients, regardless of prior infection with SARS-CoV-2.
• This association was not found in vaccinated patients treated with RTX.

IN PRACTICE:

“[These findings] provide support for vaccination in this vulnerable population and demonstrate the potential benefit of vaccine-induced CD8+ T-cell responses on reducing disease severity from SARS-CoV-2 infection in the absence of spike protein–specific antibodies,” the authors wrote.

SOURCE:

The study was published online on November 29 in Science Translational Medicine. The first author is Reza Zonozi, MD, who conducted the research while at Massachusetts General Hospital, Boston, and is now in private practice in northern Virginia. 

LIMITATIONS:

Researchers did not obtain specimens from patients with common variable immune deficiency after SARS-CoV-2 infection. Only a small subset of immunophenotyped participants had subsequent SARS-CoV-2 infection.

DISCLOSURES:

The research was supported by grants from the National Institutes of Health, the Centers for Disease Control and Prevention, the Howard Hughes Medical Institute, the Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard Medical School, the Mark and Lisa Schwartz Foundation and E. Schwartz; the Lambertus Family Foundation; and S. Edgerly and P. Edgerly. Four authors reported relationships with pharmaceutical companies including AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead Sciences, Merck, and Pfizer.

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

TOPLINE:

In individuals with low B-cell counts, T cells have enhanced responses to COVID-19 vaccination and may help prevent severe disease after infection.

METHODOLOGY:

• How the immune systems of B cell–deficient patients respond to SARS-CoV-2 infection and vaccination is not fully understood.
• Researchers evaluated anti–SARS-CoV-2 T-cell responses in 33 patients treated with rituximab (RTX), 12 patients with common variable immune deficiency, and 44 controls.
• The study analyzed effector and memory CD4+ and CD8+ T-cell responses to SARS-CoV-2 after infection and vaccination.

TAKEAWAY: 

• All B cell–deficient individuals (those treated with RTX or those with a diagnosis of common variable immune deficiency) had increased effector and memory T-cell responses after SARS-CoV-2 vaccination, compared with controls.
• Patients treated with RTX who were vaccinated against COVID-19 had 4.8-fold reduced odds of moderate or severe disease. (These data were not available for patients with common variable immune deficiency.)
• RTX treatment was associated with a decrease in preexisting T-cell immunity in unvaccinated patients, regardless of prior infection with SARS-CoV-2.
• This association was not found in vaccinated patients treated with RTX.

IN PRACTICE:

“[These findings] provide support for vaccination in this vulnerable population and demonstrate the potential benefit of vaccine-induced CD8+ T-cell responses on reducing disease severity from SARS-CoV-2 infection in the absence of spike protein–specific antibodies,” the authors wrote.

SOURCE:

The study was published online on November 29 in Science Translational Medicine. The first author is Reza Zonozi, MD, who conducted the research while at Massachusetts General Hospital, Boston, and is now in private practice in northern Virginia. 

LIMITATIONS:

Researchers did not obtain specimens from patients with common variable immune deficiency after SARS-CoV-2 infection. Only a small subset of immunophenotyped participants had subsequent SARS-CoV-2 infection.

DISCLOSURES:

The research was supported by grants from the National Institutes of Health, the Centers for Disease Control and Prevention, the Howard Hughes Medical Institute, the Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard Medical School, the Mark and Lisa Schwartz Foundation and E. Schwartz; the Lambertus Family Foundation; and S. Edgerly and P. Edgerly. Four authors reported relationships with pharmaceutical companies including AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead Sciences, Merck, and Pfizer.

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