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Alcohol-Related Liver Disease Mortality Higher in Women
TOPLINE:
Women with steatotic liver disease (SLD) related to alcohol consumption are at greater risk of mortality than men with the same condition, new research suggested.
METHODOLOGY:
- Researchers analyzed data from the US National Health and Nutrition Examination Survey III (NHANES III, 1988-1994), which included standardized ultrasonographic measures of hepatic steatosis, assessment of cardiometabolic risk traits, and questionnaire data on alcohol intake.
- Among 10,007 participants aged 20 years and older (mean age, 42 years; 50.3% men) who were included and followed for a median of 26.7 years, 1461 had metabolic dysfunction–associated steatotic liver disease (MASLD), 105 alcohol-related liver disease (ALD), 225 metabolic dysfunction-associated and alcohol-related liver disease (MetALD), 180 other types of SLD, and 8036 no SLD.
- Researchers examined SLD-associated risks for all-cause mortality after adjustment for baseline age, smoking status, systolic blood pressure, antihypertensives, type 2 diabetes, diabetic medication use, body mass index, total cholesterol, high-density lipoprotein cholesterol, lipid-lowering therapy, race, and family income.
TAKEAWAY:
- In men, the prevalence of MASLD, MetALD, and ALD was 18.5%, 3.2%, and 1.7%, respectively, whereas the corresponding prevalence among women was 10.3%, 1.2%, and 0.3%, respectively.
- In multivariable-adjusted survival analyses, MASLD was not significantly associated with all-cause mortality for either sex compared with those without SLD.
- In contrast, MetALD was associated with an 83% higher hazard of all-cause mortality in women (hazard ratio [HR], 1.83), but not significantly associated with mortality in men.
- ALD was significantly associated with all-cause mortality in both sexes, with a greater magnitude in women than men (HRs, 3.49 vs 1.89, respectively) — the equivalent of about a 160% higher mortality risk for women.
- With regard to SLD severity, the trend across worsening phenotypes (ie, MASLD, MetALD, or ALD) was significant for sex differences in mortality but not in prevalence.
IN PRACTICE:
“Because alcohol consumption is modifiable, limiting alcohol intake particularly in women at risk for SLD could be critical as part of efforts to mitigate mortality risk in patients with SLD,” the authors wrote.
SOURCE:
The study, led by Hongwei Ji of Qingdao University, Qingdao, Shandong, China, and Susan Cheng, MD, Cedars-Sinai Medical Center, Los Angeles, was published in the February issue of Journal of Hepatology.
LIMITATIONS:
The study data came from NHANES III, which was conducted between 1988 and 1994. This is a potential limitation, as the prevalence of metabolic dysfunction and alcohol use may have changed since then.
DISCLOSURES:
The study was funded in part by the National Natural Science Foundation of China, the Taishan Scholar Program of Shandong Province, the Shandong Provincial Natural Science Foundation, the National Institutes of Health, and the NIH National Center for Advancing Translational Sciences UCLA Clinical and Translational Research Center. The authors declared no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
TOPLINE:
Women with steatotic liver disease (SLD) related to alcohol consumption are at greater risk of mortality than men with the same condition, new research suggested.
METHODOLOGY:
- Researchers analyzed data from the US National Health and Nutrition Examination Survey III (NHANES III, 1988-1994), which included standardized ultrasonographic measures of hepatic steatosis, assessment of cardiometabolic risk traits, and questionnaire data on alcohol intake.
- Among 10,007 participants aged 20 years and older (mean age, 42 years; 50.3% men) who were included and followed for a median of 26.7 years, 1461 had metabolic dysfunction–associated steatotic liver disease (MASLD), 105 alcohol-related liver disease (ALD), 225 metabolic dysfunction-associated and alcohol-related liver disease (MetALD), 180 other types of SLD, and 8036 no SLD.
- Researchers examined SLD-associated risks for all-cause mortality after adjustment for baseline age, smoking status, systolic blood pressure, antihypertensives, type 2 diabetes, diabetic medication use, body mass index, total cholesterol, high-density lipoprotein cholesterol, lipid-lowering therapy, race, and family income.
TAKEAWAY:
- In men, the prevalence of MASLD, MetALD, and ALD was 18.5%, 3.2%, and 1.7%, respectively, whereas the corresponding prevalence among women was 10.3%, 1.2%, and 0.3%, respectively.
- In multivariable-adjusted survival analyses, MASLD was not significantly associated with all-cause mortality for either sex compared with those without SLD.
- In contrast, MetALD was associated with an 83% higher hazard of all-cause mortality in women (hazard ratio [HR], 1.83), but not significantly associated with mortality in men.
- ALD was significantly associated with all-cause mortality in both sexes, with a greater magnitude in women than men (HRs, 3.49 vs 1.89, respectively) — the equivalent of about a 160% higher mortality risk for women.
- With regard to SLD severity, the trend across worsening phenotypes (ie, MASLD, MetALD, or ALD) was significant for sex differences in mortality but not in prevalence.
IN PRACTICE:
“Because alcohol consumption is modifiable, limiting alcohol intake particularly in women at risk for SLD could be critical as part of efforts to mitigate mortality risk in patients with SLD,” the authors wrote.
SOURCE:
The study, led by Hongwei Ji of Qingdao University, Qingdao, Shandong, China, and Susan Cheng, MD, Cedars-Sinai Medical Center, Los Angeles, was published in the February issue of Journal of Hepatology.
LIMITATIONS:
The study data came from NHANES III, which was conducted between 1988 and 1994. This is a potential limitation, as the prevalence of metabolic dysfunction and alcohol use may have changed since then.
DISCLOSURES:
The study was funded in part by the National Natural Science Foundation of China, the Taishan Scholar Program of Shandong Province, the Shandong Provincial Natural Science Foundation, the National Institutes of Health, and the NIH National Center for Advancing Translational Sciences UCLA Clinical and Translational Research Center. The authors declared no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
TOPLINE:
Women with steatotic liver disease (SLD) related to alcohol consumption are at greater risk of mortality than men with the same condition, new research suggested.
METHODOLOGY:
- Researchers analyzed data from the US National Health and Nutrition Examination Survey III (NHANES III, 1988-1994), which included standardized ultrasonographic measures of hepatic steatosis, assessment of cardiometabolic risk traits, and questionnaire data on alcohol intake.
- Among 10,007 participants aged 20 years and older (mean age, 42 years; 50.3% men) who were included and followed for a median of 26.7 years, 1461 had metabolic dysfunction–associated steatotic liver disease (MASLD), 105 alcohol-related liver disease (ALD), 225 metabolic dysfunction-associated and alcohol-related liver disease (MetALD), 180 other types of SLD, and 8036 no SLD.
- Researchers examined SLD-associated risks for all-cause mortality after adjustment for baseline age, smoking status, systolic blood pressure, antihypertensives, type 2 diabetes, diabetic medication use, body mass index, total cholesterol, high-density lipoprotein cholesterol, lipid-lowering therapy, race, and family income.
TAKEAWAY:
- In men, the prevalence of MASLD, MetALD, and ALD was 18.5%, 3.2%, and 1.7%, respectively, whereas the corresponding prevalence among women was 10.3%, 1.2%, and 0.3%, respectively.
- In multivariable-adjusted survival analyses, MASLD was not significantly associated with all-cause mortality for either sex compared with those without SLD.
- In contrast, MetALD was associated with an 83% higher hazard of all-cause mortality in women (hazard ratio [HR], 1.83), but not significantly associated with mortality in men.
- ALD was significantly associated with all-cause mortality in both sexes, with a greater magnitude in women than men (HRs, 3.49 vs 1.89, respectively) — the equivalent of about a 160% higher mortality risk for women.
- With regard to SLD severity, the trend across worsening phenotypes (ie, MASLD, MetALD, or ALD) was significant for sex differences in mortality but not in prevalence.
IN PRACTICE:
“Because alcohol consumption is modifiable, limiting alcohol intake particularly in women at risk for SLD could be critical as part of efforts to mitigate mortality risk in patients with SLD,” the authors wrote.
SOURCE:
The study, led by Hongwei Ji of Qingdao University, Qingdao, Shandong, China, and Susan Cheng, MD, Cedars-Sinai Medical Center, Los Angeles, was published in the February issue of Journal of Hepatology.
LIMITATIONS:
The study data came from NHANES III, which was conducted between 1988 and 1994. This is a potential limitation, as the prevalence of metabolic dysfunction and alcohol use may have changed since then.
DISCLOSURES:
The study was funded in part by the National Natural Science Foundation of China, the Taishan Scholar Program of Shandong Province, the Shandong Provincial Natural Science Foundation, the National Institutes of Health, and the NIH National Center for Advancing Translational Sciences UCLA Clinical and Translational Research Center. The authors declared no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
‘Deep Phenotyping’ Identifies Abnormalities in ME/CFS
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.
Health Gains of Exercise Greater in Women?
Women may gain greater health benefits from regular physical activity at equivalent or lower doses of activity, compared with men, according to data from more than 400,000 US adults.
Over two decades, with any regular physical activity, all-cause mortality risk was reduced by 24% in women vs 15% in men, and cardiovascular mortality risk was reduced by 36% and 14%, respectively, compared with inactivity, researchers found.
Participating in strength training exercises (vs not) was associated with a reduced risk for all-cause death of 19% in women and 11% men and reductions in cardiovascular death of 30% and 11%, respectively.
“Women have historically and statistically lagged behind men in engaging in meaningful exercise,” co–lead author Martha Gulati, MD, with the Smidt Heart Institute at Cedars-Sinai, Los Angeles, said in a statement. “The beauty of this study is learning that women can get more out of each minute of moderate to vigorous activity than men do. It’s an incentivizing notion that we hope women will take to heart.”
The study was published online February 19 in the Journal of the American College of Cardiology.
Sex-Specific Exercise Advice?
The findings are based on leisure-time physical activity data collected over roughly 20 years via the National Health Interview Survey for 412,413 US adults aged 27-61 years. During roughly 4.9 million person-years of follow-up, there were 39,935 all-cause deaths and 11,670 cardiovascular deaths.
Both men and women achieved a peak survival benefit at 300 minutes of weekly moderate to vigorous aerobic physical activity. But the mortality reduction was substantially greater in women than in men for the same amount of regular exercise (24% vs 18%).
Similarly, for any given dose of physical activity leading up to 300 minutes per week, women derived proportionately greater survival benefits than did men, the authors reported.
“Importantly, the greater magnitude of physical activity-related survival benefit in women than men was consistently found across varied measures and types of physical activity including frequency, duration per session, and intensity of aerobic physical activity, as well as frequency of muscle strengthening activities,” they wrote.
They say multiple factors, including variations in anatomy and physiology, may account for the differences in outcomes between men and women. For example, compared with men, women may use more respiratory, metabolic, and strength demands to conduct the same movement and in turn, reap greater health benefits.
The study also showed only 33% of women and 43% of men regularly engaged in aerobic physical activity, whereas only 20% of women and 28% of men completed a weekly strength training session.
“We hope this study will help everyone, especially women, understand they are poised to gain tremendous benefits from exercise,” senior author Susan Cheng, MD, with the Smidt Heart Institute at Cedars-Sinai, Los Angeles, said in a statement.
In an accompanying editorial, Wael A. Jaber, MD, and Erika Hutt, MD, from Cleveland Clinic Ohio, wrote that this analysis “brings us one step farther in gaining insights into the role and influence of physiological responses to exercise with a sex-specific lens.”
The study is “well designed and adds important information to the body of literature that can potentially close the gender gap and optimize sex-specific physical activity recommendations by policy makers and societal guidelines,” they wrote.
“This study emphasizes that there is no singular approach for exercise. A person’s physical activity needs and goals may change based on their age, health status, and schedule — but the value of any type of exercise is irrefutable,” Eric J. Shiroma, ScD, with the National Heart, Lung, and Blood Institute, said in a statement.
The study was supported in part by grants from the National Institutes of Health. The authors and editorial writers have declared no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
Women may gain greater health benefits from regular physical activity at equivalent or lower doses of activity, compared with men, according to data from more than 400,000 US adults.
Over two decades, with any regular physical activity, all-cause mortality risk was reduced by 24% in women vs 15% in men, and cardiovascular mortality risk was reduced by 36% and 14%, respectively, compared with inactivity, researchers found.
Participating in strength training exercises (vs not) was associated with a reduced risk for all-cause death of 19% in women and 11% men and reductions in cardiovascular death of 30% and 11%, respectively.
“Women have historically and statistically lagged behind men in engaging in meaningful exercise,” co–lead author Martha Gulati, MD, with the Smidt Heart Institute at Cedars-Sinai, Los Angeles, said in a statement. “The beauty of this study is learning that women can get more out of each minute of moderate to vigorous activity than men do. It’s an incentivizing notion that we hope women will take to heart.”
The study was published online February 19 in the Journal of the American College of Cardiology.
Sex-Specific Exercise Advice?
The findings are based on leisure-time physical activity data collected over roughly 20 years via the National Health Interview Survey for 412,413 US adults aged 27-61 years. During roughly 4.9 million person-years of follow-up, there were 39,935 all-cause deaths and 11,670 cardiovascular deaths.
Both men and women achieved a peak survival benefit at 300 minutes of weekly moderate to vigorous aerobic physical activity. But the mortality reduction was substantially greater in women than in men for the same amount of regular exercise (24% vs 18%).
Similarly, for any given dose of physical activity leading up to 300 minutes per week, women derived proportionately greater survival benefits than did men, the authors reported.
“Importantly, the greater magnitude of physical activity-related survival benefit in women than men was consistently found across varied measures and types of physical activity including frequency, duration per session, and intensity of aerobic physical activity, as well as frequency of muscle strengthening activities,” they wrote.
They say multiple factors, including variations in anatomy and physiology, may account for the differences in outcomes between men and women. For example, compared with men, women may use more respiratory, metabolic, and strength demands to conduct the same movement and in turn, reap greater health benefits.
The study also showed only 33% of women and 43% of men regularly engaged in aerobic physical activity, whereas only 20% of women and 28% of men completed a weekly strength training session.
“We hope this study will help everyone, especially women, understand they are poised to gain tremendous benefits from exercise,” senior author Susan Cheng, MD, with the Smidt Heart Institute at Cedars-Sinai, Los Angeles, said in a statement.
In an accompanying editorial, Wael A. Jaber, MD, and Erika Hutt, MD, from Cleveland Clinic Ohio, wrote that this analysis “brings us one step farther in gaining insights into the role and influence of physiological responses to exercise with a sex-specific lens.”
The study is “well designed and adds important information to the body of literature that can potentially close the gender gap and optimize sex-specific physical activity recommendations by policy makers and societal guidelines,” they wrote.
“This study emphasizes that there is no singular approach for exercise. A person’s physical activity needs and goals may change based on their age, health status, and schedule — but the value of any type of exercise is irrefutable,” Eric J. Shiroma, ScD, with the National Heart, Lung, and Blood Institute, said in a statement.
The study was supported in part by grants from the National Institutes of Health. The authors and editorial writers have declared no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
Women may gain greater health benefits from regular physical activity at equivalent or lower doses of activity, compared with men, according to data from more than 400,000 US adults.
Over two decades, with any regular physical activity, all-cause mortality risk was reduced by 24% in women vs 15% in men, and cardiovascular mortality risk was reduced by 36% and 14%, respectively, compared with inactivity, researchers found.
Participating in strength training exercises (vs not) was associated with a reduced risk for all-cause death of 19% in women and 11% men and reductions in cardiovascular death of 30% and 11%, respectively.
“Women have historically and statistically lagged behind men in engaging in meaningful exercise,” co–lead author Martha Gulati, MD, with the Smidt Heart Institute at Cedars-Sinai, Los Angeles, said in a statement. “The beauty of this study is learning that women can get more out of each minute of moderate to vigorous activity than men do. It’s an incentivizing notion that we hope women will take to heart.”
The study was published online February 19 in the Journal of the American College of Cardiology.
Sex-Specific Exercise Advice?
The findings are based on leisure-time physical activity data collected over roughly 20 years via the National Health Interview Survey for 412,413 US adults aged 27-61 years. During roughly 4.9 million person-years of follow-up, there were 39,935 all-cause deaths and 11,670 cardiovascular deaths.
Both men and women achieved a peak survival benefit at 300 minutes of weekly moderate to vigorous aerobic physical activity. But the mortality reduction was substantially greater in women than in men for the same amount of regular exercise (24% vs 18%).
Similarly, for any given dose of physical activity leading up to 300 minutes per week, women derived proportionately greater survival benefits than did men, the authors reported.
“Importantly, the greater magnitude of physical activity-related survival benefit in women than men was consistently found across varied measures and types of physical activity including frequency, duration per session, and intensity of aerobic physical activity, as well as frequency of muscle strengthening activities,” they wrote.
They say multiple factors, including variations in anatomy and physiology, may account for the differences in outcomes between men and women. For example, compared with men, women may use more respiratory, metabolic, and strength demands to conduct the same movement and in turn, reap greater health benefits.
The study also showed only 33% of women and 43% of men regularly engaged in aerobic physical activity, whereas only 20% of women and 28% of men completed a weekly strength training session.
“We hope this study will help everyone, especially women, understand they are poised to gain tremendous benefits from exercise,” senior author Susan Cheng, MD, with the Smidt Heart Institute at Cedars-Sinai, Los Angeles, said in a statement.
In an accompanying editorial, Wael A. Jaber, MD, and Erika Hutt, MD, from Cleveland Clinic Ohio, wrote that this analysis “brings us one step farther in gaining insights into the role and influence of physiological responses to exercise with a sex-specific lens.”
The study is “well designed and adds important information to the body of literature that can potentially close the gender gap and optimize sex-specific physical activity recommendations by policy makers and societal guidelines,” they wrote.
“This study emphasizes that there is no singular approach for exercise. A person’s physical activity needs and goals may change based on their age, health status, and schedule — but the value of any type of exercise is irrefutable,” Eric J. Shiroma, ScD, with the National Heart, Lung, and Blood Institute, said in a statement.
The study was supported in part by grants from the National Institutes of Health. The authors and editorial writers have declared no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
Is Mammography Ready for AI? Opinions Mixed on Usage, Cost Methods
Screening mammograms miss close to one in eight breast cancers. But early research suggests artificial intelligence (AI) could close this detection gap and markedly improve early diagnosis of the disease. Still, questions remain regarding how to best incorporate AI into screenings and whether it’s too soon to deploy the technology.
Already, some radiology clinics are offering AI analysis of mammograms through an add-on cost method.
Mammography patients who visit RadNet facilities, for example, have the option of an additional AI screening of their images. RadNet, the largest national owner and operator of fixed-site diagnostic imaging centers in the United States with more than 370 locations, first launched its AI program in the Northeast. The company has now rolled out its product across all regions in the country.
Because the AI is not reimbursed by insurers, patients must pay a $40 out-of-pocket fee if they want the AI analysis.
“RadNet practices have identified more than 400 women whose cancer was found earlier than it would have been had the AI not been present,” said Greg Sorensen MD, chief science officer for RadNet.
How RadNet’s AI Program Works
Patients coming to RadNet facilities for screening mammography undergo 3D high-resolution mammography that includes the use of 70-micron resolution detector technology, said Dr. Sorensen. The mammogram is reviewed by a qualified radiologist with assistance from two Food and Drug Administration–cleared AI programs, Saige-Q and Saige-Density. The radiologist then makes an interpretation.
Saige-Q is an AI tool that helps identify more suspicious mammograms by providing a quick signal to radiologists if the AI considers a given mammogram to be in a suspicious category, according to Dr. Sorensen. Saige-Density provides a density rating for each mammogram using one of the four standard categories:
- A. Almost entirely fatty
- B. Scattered areas of fibroglandular density
- C. Heterogeneously dense
- D. Extremely dense
Starting in September 2024, the FDA will require all mammogram reports to indicate density.
For patients who choose the $40 add-on service, called Enhanced Breast Cancer Detection, two other FDA-registered AI programs are also applied: Saige-Dx and Saige-Assure. These AI programs go a step further by placing marks on areas within the images that they find suspicious. Mammograms flagged as “high-suspicion” by the AI are then reviewed by a second human radiologist. The first and second radiologists confer to agree on a final diagnosis, Dr. Sorensen explained.
“Our research shows that approximately 20% more cancers are found when the safeguard review process is in place,” Dr. Sorensen said. “We also have seen [30%] decreases in recall rates” — the percentage of screening cases in which further tests are recommended by the radiologist.
Bethesda radiologist Janet Storella, MD, has used the AI program for about 3 years and said the technology has improved her screening performance.
The AI is linked to her practice’s imaging software, and radiologists have the option of turning the AI on at any time during their reading of screening mammograms, Dr. Storella explained. Some radiologists review the mammogram first and then initiate the AI, while others like Dr. Storella turn it on at the start, she said. Once initiated, the AI draws bounding boxes — or outlines — around areas that it deems suspicious.
The AI helps focus Dr. Storella’s attention on suspicious areas and grades the level of suspicion into one of four categories: high, intermediate, low, and minimal, she said.
“I find it especially useful in patients who have dense breast tissue,” said Dr. Storella, medical director of women’s imaging at Community Radiology Associates, a RadNet practice. “In these situations, the tissue on the mammogram is a field of white, and cancers are also white, so you’re looking for that little white golf ball on a sea of snow. The AI really helps hone that down to specific areas.”
About 35% of RadNet’s screening mammography patients have enrolled in the Enhanced Breast Cancer Detection program, according to RadNet data. In a recent study of nine general radiologists and nine breast imaging specialists, all radiologists improved their interpretation performance of DBT screening mammograms when reading with RadNet’s AI versus without it. (An average AUC [area under the receiver operating characteristic curve] of 0.93 versus 0.87, demonstrating a difference in AUC of 0.06 (95% CI, 0.04-0.08; P < .001)
Is Mammography Ready for AI?
RadNet is among a growing number of commercial companies offering AI solutions for mammography. MammoScreen and Hologic, for example, are two other companies that provide AI programs to assist radiologists in reading screening mammograms.
“We are at the start of the AI integration into breast imaging at this point,” said Laura Heacock, MD, a breast imaging radiologist and associate professor of radiology at NYU Langone Health. “There are multiple commercial AI models now available to radiologists to use in their practice [ and] there will likely be more. We’re in the transition stage where people are still deciding: Which is the best model to go with? How do I put it in my system? How do I ensure it works they way it was intended? Every practice and medical system will have a different answer to that question.”
At NYU Langone Health, researchers have been developing and studying optimal AI models for breast imaging for several years, Dr. Heacock said. Researchers thus far, have developed AI models for 2D digital mammography, 3D mammograms, breast ultrasound, and breast MRI. Similar to commercial AI systems, the AI is embedded into the picture archiving and communication (PACS) system used by radiologists to review images. Radiologists press a button to launch the AI, which draws a box around suspicious areas of the image and scores the suspicion.
“I take a look of where it is on the mammogram and decide whether that fits my level of suspicion,” Dr. Heacock said. The AI may not understand things about the mammogram like we do. For example, surgical scars look very suspicious to an AI model. But if I’m looking at a mammogram where [the patient] has had a stable scar that hasn’t changed in 10 years, I’m not concerned that the AI found it suspicious. My clinical judgment is the ultimate decider. This is just an additional piece of information that’s helpful to me.”
Research by New York University (NYU) has shown that when used by an expert radiologist the AI models have improved breast cancer detection in all four modalities, she said.
However, the AI has not yet launched at NYU Langone. More research is needed before deploying the technology, according to Dr. Heacock.
“At NYU, we are still testing the benefits to patients,” she said. “We know it improves cancer detection, but we want to make sure there are no drawbacks. We are still exploring the best ways to put it into effect at our institution.”
Dr. Heacock pointed to recent studies on AI in screening mammography that show promise.
An analysis of more than 80,000 women, for example, published in The Lancet Oncology in August, found that AI-supported screen reading led to a similar cancer detection rate as compared with a two-person reader system. This screening resulted in 244 screen-detected cancers, 861 recalls, and a total of 46,345 screen readings, according to the study. Standard screening resulted in 203 screen-detected cancers, 817 recalls, and a total of 83,231 screen readings.
The AI system also reduced the screen-reading workload for radiologists by 44%, the study found.
Meanwhile, a September 2023 study, published in The Lancet Digital Health, found that replacing one radiologist with AI resulted in more cancer detection without a large increase in false-positive cases. The AI led to a 4% higher, noninferior cancer detection rate, compared with radiologist double reading, the study found.
Dr. Heacock emphasized that both studies were conducted in Europe where the standard is for two radiologists to evaluate mammograms.
“That makes the results exciting, but not directly applicable to US practice just yet,” she said.
What Do the Experts Recommend?
Stamatia V. Destounis, MD, FACR, chair of the American College of Radiology (ACR) Breast Imaging Commission, said the college welcomes ongoing research into the efficacy of AI technologies and that AI may prove to be beneficial as an improved workflow tool.
The ACR has not released any guidance about the use of AI for radiologists and have no recommendation about best practices, Dr. Destounis said.
“The decisions regarding which technologies that various health systems and radiology sites choose to use are made by those facilities,” she said.
Dr. Destounis said more research is needed to demonstrate whether or not AI technologies help radiologists produce better results in identifying disease, injury, and illnesses among the general population or in specific groups — whether based on age, physical characteristics, race, ethnicity or risk status for breast cancer.
“Also, a way to measure each AI product is needed so that we can be certain they are relatively equivalent in their efficacy and accuracy — initially and over a prolonged period of time,” she said.
No consensus or concrete recommendation exists about the use of AI in mammography screening, adds Peter P. Yu, MD, FACP, FASCO, physician-in-chief at the Hartford HealthCare Cancer Institute and a member of the newly-created American Society of Clinical Oncology AI task force.
One of the many discussions concerning AI is to what degree patients should be aware that AI is being used in their healthcare and whether they should be required to give consent to its use, Dr. Yu said.
If AI is used to assist radiologists with mammographic interpretation, radiologists should discuss with patients how it’s being used and explain the ultimate reading is in the hands of their physician radiologist, he said.
“In the unlikely situation where there wasn’t a human in the loop and AI was in effect making a medical decision, the patient needs to be aware,” he said. “I’m not aware that any such situation exists today. AI is more likely to be subtly embedded in the software that operates technology, much like it is embedded in manufacturing and transportation.”
Who Will Pay for AI?
When it comes to payment, Dr. Yu said shifting the cost of AI to patients creates serious risk.
“It has enormous potential to increase health inequities,” he said. “If we believe health care is a fundamental human right, AI should inure to the benefit of all, not just those who can afford it. Healthcare should not be a luxury item; if it works, it works for all.”
In general, the issue of payment for AI is still pretty “thorny,” Dr. Heacock noted. Currently, there’s no way for physicians to request direct reimbursement for AI reads of mammograms.
While Dr. Heacock says she is sympathetic to the companies that spend significant time and effort on their AI technology, she doesn’t think charging patients is the right solution.
“We know that many women already have difficulty in paying for mammography-related services and this is just one more charge to confuse them or that they can’t pay,” she said.
Dr. Sorensen expects that, similar to 3D mammography, payers will eventually cover RadNet’s AI technology and that patients will no longer need to pay out of pocket. One Blue Cross carrier will start covering the AI in April 2024, he said.
Screening mammograms miss close to one in eight breast cancers. But early research suggests artificial intelligence (AI) could close this detection gap and markedly improve early diagnosis of the disease. Still, questions remain regarding how to best incorporate AI into screenings and whether it’s too soon to deploy the technology.
Already, some radiology clinics are offering AI analysis of mammograms through an add-on cost method.
Mammography patients who visit RadNet facilities, for example, have the option of an additional AI screening of their images. RadNet, the largest national owner and operator of fixed-site diagnostic imaging centers in the United States with more than 370 locations, first launched its AI program in the Northeast. The company has now rolled out its product across all regions in the country.
Because the AI is not reimbursed by insurers, patients must pay a $40 out-of-pocket fee if they want the AI analysis.
“RadNet practices have identified more than 400 women whose cancer was found earlier than it would have been had the AI not been present,” said Greg Sorensen MD, chief science officer for RadNet.
How RadNet’s AI Program Works
Patients coming to RadNet facilities for screening mammography undergo 3D high-resolution mammography that includes the use of 70-micron resolution detector technology, said Dr. Sorensen. The mammogram is reviewed by a qualified radiologist with assistance from two Food and Drug Administration–cleared AI programs, Saige-Q and Saige-Density. The radiologist then makes an interpretation.
Saige-Q is an AI tool that helps identify more suspicious mammograms by providing a quick signal to radiologists if the AI considers a given mammogram to be in a suspicious category, according to Dr. Sorensen. Saige-Density provides a density rating for each mammogram using one of the four standard categories:
- A. Almost entirely fatty
- B. Scattered areas of fibroglandular density
- C. Heterogeneously dense
- D. Extremely dense
Starting in September 2024, the FDA will require all mammogram reports to indicate density.
For patients who choose the $40 add-on service, called Enhanced Breast Cancer Detection, two other FDA-registered AI programs are also applied: Saige-Dx and Saige-Assure. These AI programs go a step further by placing marks on areas within the images that they find suspicious. Mammograms flagged as “high-suspicion” by the AI are then reviewed by a second human radiologist. The first and second radiologists confer to agree on a final diagnosis, Dr. Sorensen explained.
“Our research shows that approximately 20% more cancers are found when the safeguard review process is in place,” Dr. Sorensen said. “We also have seen [30%] decreases in recall rates” — the percentage of screening cases in which further tests are recommended by the radiologist.
Bethesda radiologist Janet Storella, MD, has used the AI program for about 3 years and said the technology has improved her screening performance.
The AI is linked to her practice’s imaging software, and radiologists have the option of turning the AI on at any time during their reading of screening mammograms, Dr. Storella explained. Some radiologists review the mammogram first and then initiate the AI, while others like Dr. Storella turn it on at the start, she said. Once initiated, the AI draws bounding boxes — or outlines — around areas that it deems suspicious.
The AI helps focus Dr. Storella’s attention on suspicious areas and grades the level of suspicion into one of four categories: high, intermediate, low, and minimal, she said.
“I find it especially useful in patients who have dense breast tissue,” said Dr. Storella, medical director of women’s imaging at Community Radiology Associates, a RadNet practice. “In these situations, the tissue on the mammogram is a field of white, and cancers are also white, so you’re looking for that little white golf ball on a sea of snow. The AI really helps hone that down to specific areas.”
About 35% of RadNet’s screening mammography patients have enrolled in the Enhanced Breast Cancer Detection program, according to RadNet data. In a recent study of nine general radiologists and nine breast imaging specialists, all radiologists improved their interpretation performance of DBT screening mammograms when reading with RadNet’s AI versus without it. (An average AUC [area under the receiver operating characteristic curve] of 0.93 versus 0.87, demonstrating a difference in AUC of 0.06 (95% CI, 0.04-0.08; P < .001)
Is Mammography Ready for AI?
RadNet is among a growing number of commercial companies offering AI solutions for mammography. MammoScreen and Hologic, for example, are two other companies that provide AI programs to assist radiologists in reading screening mammograms.
“We are at the start of the AI integration into breast imaging at this point,” said Laura Heacock, MD, a breast imaging radiologist and associate professor of radiology at NYU Langone Health. “There are multiple commercial AI models now available to radiologists to use in their practice [ and] there will likely be more. We’re in the transition stage where people are still deciding: Which is the best model to go with? How do I put it in my system? How do I ensure it works they way it was intended? Every practice and medical system will have a different answer to that question.”
At NYU Langone Health, researchers have been developing and studying optimal AI models for breast imaging for several years, Dr. Heacock said. Researchers thus far, have developed AI models for 2D digital mammography, 3D mammograms, breast ultrasound, and breast MRI. Similar to commercial AI systems, the AI is embedded into the picture archiving and communication (PACS) system used by radiologists to review images. Radiologists press a button to launch the AI, which draws a box around suspicious areas of the image and scores the suspicion.
“I take a look of where it is on the mammogram and decide whether that fits my level of suspicion,” Dr. Heacock said. The AI may not understand things about the mammogram like we do. For example, surgical scars look very suspicious to an AI model. But if I’m looking at a mammogram where [the patient] has had a stable scar that hasn’t changed in 10 years, I’m not concerned that the AI found it suspicious. My clinical judgment is the ultimate decider. This is just an additional piece of information that’s helpful to me.”
Research by New York University (NYU) has shown that when used by an expert radiologist the AI models have improved breast cancer detection in all four modalities, she said.
However, the AI has not yet launched at NYU Langone. More research is needed before deploying the technology, according to Dr. Heacock.
“At NYU, we are still testing the benefits to patients,” she said. “We know it improves cancer detection, but we want to make sure there are no drawbacks. We are still exploring the best ways to put it into effect at our institution.”
Dr. Heacock pointed to recent studies on AI in screening mammography that show promise.
An analysis of more than 80,000 women, for example, published in The Lancet Oncology in August, found that AI-supported screen reading led to a similar cancer detection rate as compared with a two-person reader system. This screening resulted in 244 screen-detected cancers, 861 recalls, and a total of 46,345 screen readings, according to the study. Standard screening resulted in 203 screen-detected cancers, 817 recalls, and a total of 83,231 screen readings.
The AI system also reduced the screen-reading workload for radiologists by 44%, the study found.
Meanwhile, a September 2023 study, published in The Lancet Digital Health, found that replacing one radiologist with AI resulted in more cancer detection without a large increase in false-positive cases. The AI led to a 4% higher, noninferior cancer detection rate, compared with radiologist double reading, the study found.
Dr. Heacock emphasized that both studies were conducted in Europe where the standard is for two radiologists to evaluate mammograms.
“That makes the results exciting, but not directly applicable to US practice just yet,” she said.
What Do the Experts Recommend?
Stamatia V. Destounis, MD, FACR, chair of the American College of Radiology (ACR) Breast Imaging Commission, said the college welcomes ongoing research into the efficacy of AI technologies and that AI may prove to be beneficial as an improved workflow tool.
The ACR has not released any guidance about the use of AI for radiologists and have no recommendation about best practices, Dr. Destounis said.
“The decisions regarding which technologies that various health systems and radiology sites choose to use are made by those facilities,” she said.
Dr. Destounis said more research is needed to demonstrate whether or not AI technologies help radiologists produce better results in identifying disease, injury, and illnesses among the general population or in specific groups — whether based on age, physical characteristics, race, ethnicity or risk status for breast cancer.
“Also, a way to measure each AI product is needed so that we can be certain they are relatively equivalent in their efficacy and accuracy — initially and over a prolonged period of time,” she said.
No consensus or concrete recommendation exists about the use of AI in mammography screening, adds Peter P. Yu, MD, FACP, FASCO, physician-in-chief at the Hartford HealthCare Cancer Institute and a member of the newly-created American Society of Clinical Oncology AI task force.
One of the many discussions concerning AI is to what degree patients should be aware that AI is being used in their healthcare and whether they should be required to give consent to its use, Dr. Yu said.
If AI is used to assist radiologists with mammographic interpretation, radiologists should discuss with patients how it’s being used and explain the ultimate reading is in the hands of their physician radiologist, he said.
“In the unlikely situation where there wasn’t a human in the loop and AI was in effect making a medical decision, the patient needs to be aware,” he said. “I’m not aware that any such situation exists today. AI is more likely to be subtly embedded in the software that operates technology, much like it is embedded in manufacturing and transportation.”
Who Will Pay for AI?
When it comes to payment, Dr. Yu said shifting the cost of AI to patients creates serious risk.
“It has enormous potential to increase health inequities,” he said. “If we believe health care is a fundamental human right, AI should inure to the benefit of all, not just those who can afford it. Healthcare should not be a luxury item; if it works, it works for all.”
In general, the issue of payment for AI is still pretty “thorny,” Dr. Heacock noted. Currently, there’s no way for physicians to request direct reimbursement for AI reads of mammograms.
While Dr. Heacock says she is sympathetic to the companies that spend significant time and effort on their AI technology, she doesn’t think charging patients is the right solution.
“We know that many women already have difficulty in paying for mammography-related services and this is just one more charge to confuse them or that they can’t pay,” she said.
Dr. Sorensen expects that, similar to 3D mammography, payers will eventually cover RadNet’s AI technology and that patients will no longer need to pay out of pocket. One Blue Cross carrier will start covering the AI in April 2024, he said.
Screening mammograms miss close to one in eight breast cancers. But early research suggests artificial intelligence (AI) could close this detection gap and markedly improve early diagnosis of the disease. Still, questions remain regarding how to best incorporate AI into screenings and whether it’s too soon to deploy the technology.
Already, some radiology clinics are offering AI analysis of mammograms through an add-on cost method.
Mammography patients who visit RadNet facilities, for example, have the option of an additional AI screening of their images. RadNet, the largest national owner and operator of fixed-site diagnostic imaging centers in the United States with more than 370 locations, first launched its AI program in the Northeast. The company has now rolled out its product across all regions in the country.
Because the AI is not reimbursed by insurers, patients must pay a $40 out-of-pocket fee if they want the AI analysis.
“RadNet practices have identified more than 400 women whose cancer was found earlier than it would have been had the AI not been present,” said Greg Sorensen MD, chief science officer for RadNet.
How RadNet’s AI Program Works
Patients coming to RadNet facilities for screening mammography undergo 3D high-resolution mammography that includes the use of 70-micron resolution detector technology, said Dr. Sorensen. The mammogram is reviewed by a qualified radiologist with assistance from two Food and Drug Administration–cleared AI programs, Saige-Q and Saige-Density. The radiologist then makes an interpretation.
Saige-Q is an AI tool that helps identify more suspicious mammograms by providing a quick signal to radiologists if the AI considers a given mammogram to be in a suspicious category, according to Dr. Sorensen. Saige-Density provides a density rating for each mammogram using one of the four standard categories:
- A. Almost entirely fatty
- B. Scattered areas of fibroglandular density
- C. Heterogeneously dense
- D. Extremely dense
Starting in September 2024, the FDA will require all mammogram reports to indicate density.
For patients who choose the $40 add-on service, called Enhanced Breast Cancer Detection, two other FDA-registered AI programs are also applied: Saige-Dx and Saige-Assure. These AI programs go a step further by placing marks on areas within the images that they find suspicious. Mammograms flagged as “high-suspicion” by the AI are then reviewed by a second human radiologist. The first and second radiologists confer to agree on a final diagnosis, Dr. Sorensen explained.
“Our research shows that approximately 20% more cancers are found when the safeguard review process is in place,” Dr. Sorensen said. “We also have seen [30%] decreases in recall rates” — the percentage of screening cases in which further tests are recommended by the radiologist.
Bethesda radiologist Janet Storella, MD, has used the AI program for about 3 years and said the technology has improved her screening performance.
The AI is linked to her practice’s imaging software, and radiologists have the option of turning the AI on at any time during their reading of screening mammograms, Dr. Storella explained. Some radiologists review the mammogram first and then initiate the AI, while others like Dr. Storella turn it on at the start, she said. Once initiated, the AI draws bounding boxes — or outlines — around areas that it deems suspicious.
The AI helps focus Dr. Storella’s attention on suspicious areas and grades the level of suspicion into one of four categories: high, intermediate, low, and minimal, she said.
“I find it especially useful in patients who have dense breast tissue,” said Dr. Storella, medical director of women’s imaging at Community Radiology Associates, a RadNet practice. “In these situations, the tissue on the mammogram is a field of white, and cancers are also white, so you’re looking for that little white golf ball on a sea of snow. The AI really helps hone that down to specific areas.”
About 35% of RadNet’s screening mammography patients have enrolled in the Enhanced Breast Cancer Detection program, according to RadNet data. In a recent study of nine general radiologists and nine breast imaging specialists, all radiologists improved their interpretation performance of DBT screening mammograms when reading with RadNet’s AI versus without it. (An average AUC [area under the receiver operating characteristic curve] of 0.93 versus 0.87, demonstrating a difference in AUC of 0.06 (95% CI, 0.04-0.08; P < .001)
Is Mammography Ready for AI?
RadNet is among a growing number of commercial companies offering AI solutions for mammography. MammoScreen and Hologic, for example, are two other companies that provide AI programs to assist radiologists in reading screening mammograms.
“We are at the start of the AI integration into breast imaging at this point,” said Laura Heacock, MD, a breast imaging radiologist and associate professor of radiology at NYU Langone Health. “There are multiple commercial AI models now available to radiologists to use in their practice [ and] there will likely be more. We’re in the transition stage where people are still deciding: Which is the best model to go with? How do I put it in my system? How do I ensure it works they way it was intended? Every practice and medical system will have a different answer to that question.”
At NYU Langone Health, researchers have been developing and studying optimal AI models for breast imaging for several years, Dr. Heacock said. Researchers thus far, have developed AI models for 2D digital mammography, 3D mammograms, breast ultrasound, and breast MRI. Similar to commercial AI systems, the AI is embedded into the picture archiving and communication (PACS) system used by radiologists to review images. Radiologists press a button to launch the AI, which draws a box around suspicious areas of the image and scores the suspicion.
“I take a look of where it is on the mammogram and decide whether that fits my level of suspicion,” Dr. Heacock said. The AI may not understand things about the mammogram like we do. For example, surgical scars look very suspicious to an AI model. But if I’m looking at a mammogram where [the patient] has had a stable scar that hasn’t changed in 10 years, I’m not concerned that the AI found it suspicious. My clinical judgment is the ultimate decider. This is just an additional piece of information that’s helpful to me.”
Research by New York University (NYU) has shown that when used by an expert radiologist the AI models have improved breast cancer detection in all four modalities, she said.
However, the AI has not yet launched at NYU Langone. More research is needed before deploying the technology, according to Dr. Heacock.
“At NYU, we are still testing the benefits to patients,” she said. “We know it improves cancer detection, but we want to make sure there are no drawbacks. We are still exploring the best ways to put it into effect at our institution.”
Dr. Heacock pointed to recent studies on AI in screening mammography that show promise.
An analysis of more than 80,000 women, for example, published in The Lancet Oncology in August, found that AI-supported screen reading led to a similar cancer detection rate as compared with a two-person reader system. This screening resulted in 244 screen-detected cancers, 861 recalls, and a total of 46,345 screen readings, according to the study. Standard screening resulted in 203 screen-detected cancers, 817 recalls, and a total of 83,231 screen readings.
The AI system also reduced the screen-reading workload for radiologists by 44%, the study found.
Meanwhile, a September 2023 study, published in The Lancet Digital Health, found that replacing one radiologist with AI resulted in more cancer detection without a large increase in false-positive cases. The AI led to a 4% higher, noninferior cancer detection rate, compared with radiologist double reading, the study found.
Dr. Heacock emphasized that both studies were conducted in Europe where the standard is for two radiologists to evaluate mammograms.
“That makes the results exciting, but not directly applicable to US practice just yet,” she said.
What Do the Experts Recommend?
Stamatia V. Destounis, MD, FACR, chair of the American College of Radiology (ACR) Breast Imaging Commission, said the college welcomes ongoing research into the efficacy of AI technologies and that AI may prove to be beneficial as an improved workflow tool.
The ACR has not released any guidance about the use of AI for radiologists and have no recommendation about best practices, Dr. Destounis said.
“The decisions regarding which technologies that various health systems and radiology sites choose to use are made by those facilities,” she said.
Dr. Destounis said more research is needed to demonstrate whether or not AI technologies help radiologists produce better results in identifying disease, injury, and illnesses among the general population or in specific groups — whether based on age, physical characteristics, race, ethnicity or risk status for breast cancer.
“Also, a way to measure each AI product is needed so that we can be certain they are relatively equivalent in their efficacy and accuracy — initially and over a prolonged period of time,” she said.
No consensus or concrete recommendation exists about the use of AI in mammography screening, adds Peter P. Yu, MD, FACP, FASCO, physician-in-chief at the Hartford HealthCare Cancer Institute and a member of the newly-created American Society of Clinical Oncology AI task force.
One of the many discussions concerning AI is to what degree patients should be aware that AI is being used in their healthcare and whether they should be required to give consent to its use, Dr. Yu said.
If AI is used to assist radiologists with mammographic interpretation, radiologists should discuss with patients how it’s being used and explain the ultimate reading is in the hands of their physician radiologist, he said.
“In the unlikely situation where there wasn’t a human in the loop and AI was in effect making a medical decision, the patient needs to be aware,” he said. “I’m not aware that any such situation exists today. AI is more likely to be subtly embedded in the software that operates technology, much like it is embedded in manufacturing and transportation.”
Who Will Pay for AI?
When it comes to payment, Dr. Yu said shifting the cost of AI to patients creates serious risk.
“It has enormous potential to increase health inequities,” he said. “If we believe health care is a fundamental human right, AI should inure to the benefit of all, not just those who can afford it. Healthcare should not be a luxury item; if it works, it works for all.”
In general, the issue of payment for AI is still pretty “thorny,” Dr. Heacock noted. Currently, there’s no way for physicians to request direct reimbursement for AI reads of mammograms.
While Dr. Heacock says she is sympathetic to the companies that spend significant time and effort on their AI technology, she doesn’t think charging patients is the right solution.
“We know that many women already have difficulty in paying for mammography-related services and this is just one more charge to confuse them or that they can’t pay,” she said.
Dr. Sorensen expects that, similar to 3D mammography, payers will eventually cover RadNet’s AI technology and that patients will no longer need to pay out of pocket. One Blue Cross carrier will start covering the AI in April 2024, he said.
Study Eyes Longer IV Ertapenem for Recalcitrant Hidradenitis Suppurativa
“These findings suggest a course of 12 to 16 weeks of ertapenem may be appropriate as a new standard length of therapy in HS patients, which is at least twice the current recommendation of the North American treatment guidelines,” wrote corresponding author Steven R. Cohen, MD, MPH, of the departments of dermatology at Weill Cornell Medicine and Albert Einstein College of Medicine, New York, and his coauthors. The results were published online February 14, 2024, in JAMA Dermatology.
In an earlier study , some of the same researchers evaluated the efficacy of daily IV ertapenem for 6 weeks in seven patients with HS. The patients experienced “notable remediation of disease that was rapidly lost within 1 month of withdrawal.”
Treatment guidelines published in 2019 recommend ertapenem as a highly effective third-line therapy limited to one 6-week course “as rescue therapy or during surgical planning, given the practical barriers to home infusions and concerns about antibiotic resistance” .
For the current analysis, Dr. Cohen and colleagues explored the effects of a longer duration of treatment with ertapenem in this patient population. They retrospectively reviewed the medical records of 98 patients with HS who received care at Albert Einstein College of Medicine’s Montefiore HS Center between 2018 and 2022. Each patient used an elastomeric pump to self-administer 1 g IV ertapenem daily for 12-16 weeks.
Key outcome measures of interest were the HS Physician Global Assessment (PGA) score (a 6-point scale ranging from clear to very severe) and a numerical rating scale (NRS) for pain (an 11-point scale in which a score of 0 indicates no pain and a score of 10 indicates the worst possible pain) and markers of inflammation such as leukocytes, erythrocyte sedimentation rate, C-reactive protein (CRP), and interleukin (IL)-6. The researchers measured these outcomes at baseline, the midcourse of IV ertapenem treatment, at the end of the course, and post therapy.
The mean age of the patients was 35.8 years, 62.2% were female, and 60.2% were Black. The mean treatment duration was 13.1 weeks and the mean posttherapy follow-up occurred after a mean of 7.8 weeks.
Between baseline and posttherapy follow-up, the HS PGA scores dropped from a mean of 3.9 to 2.7 and the NRS for pain dropped from 4.2 to 1.8 (P < .001 for both associations). Markers of inflammation also dropped between baseline and post therapy.
Specifically, values for CRP dropped from 5.4 to 2.4 mg/dL; IL-6 dropped from 25.2 to 13.7, and leukocytes dropped from 11.3 to 10.0 (P < .001 for all associations). Among the 76 patients who participated in a follow-up telephone survey, 63 (80.3%) reported medium to high satisfaction with their course of ertapenem, and 69 (90.8%) said they would recommend the treatment to other patients with HS.
The authors noted certain limitations of their study, including its retrospective, single-center design, the lack of a control group, and the fact that the HS-PGA scores at each visit did not meet the threshold of a 2-point decrease that is considered a clinically meaningful in the medical literature.
The definitive mechanism of ertapenem efficacy remains elusive, the authors pointed out. “Although oral antibiotics are generally accepted as a core therapeutic approach to HS, much less is known about the efficacy of IV antibiotics, especially ertapenem, a parenteral carbapenem possessing activity against many gram-positive bacteria, gram-negative bacteria, and anaerobic organisms,” they wrote.
In an accompanying editorial, Haley B. Naik, MD, MHSc, a dermatologist at the University of California, San Francisco, said that adopting prolonged courses of ertapenem treatment “comes with substantial individual and public health considerations”.
“Even though HS is a noninfectious disease, microbes might play a role in inciting HS immune dysregulation, prompting the inclusion of antimicrobial therapy in treatment regimens. However, broad-spectrum antibiotics for HS are associated with high levels of antibiotic resistance,” she wrote. Prolonged use of ertapenem and other carbapenems in HS treatment “will likely increase antimicrobial resistance, thereby limiting management of both HS and comorbid infections.”
Jennifer L. Hsiao, MD, a dermatologist who directs the HS clinic at the University of Southern California, Los Angeles, who was asked to comment on the study, said that, despite significant advances in the management of HS over the past decade, there are still patients who do not respond adequately to standard treatments.
For these patients, IV ertapenem can serve as a valuable bridge to a longer-term therapeutic option, “be it surgery or escalated immunomodulation,” such as dual biologic therapy, she said. “In my personal experience, IV ertapenem, which like the authors I also typically use for a 12-week course, delivers impressive and fast results even in the worst disease cases.
“It can be difficult to maintain the therapeutic benefit of ertapenem after it is discontinued, which is why patients should be on concomitant medications as they were in this study and have a post-ertapenem treatment plan in place,” said Dr. Hsiao, who was not involved with the study. “Hopefully, we will be able to one day understand why ertapenem is so effective for HS and be able to harness that benefit for patients without concern for antimicrobial resistance.”
Dr. Cohen reported receiving personal fees from Verrica Pharmaceuticals and belonging to the Board of Trustees of the American Skin Association outside the submitted work. No other disclosures were reported. Dr. Naik reported having received grants from AbbVie and the National Institutes of Health; personal fees from Novartis, UCB, Boehringer Ingelheim, 23andMe, Aristea Therapeutics, Medscape, Sonoma Biotherapeutics, DAVA Oncology, and Pfizer; and shares from Radera during the conduct of the study. She is a board member of the Hidradenitis Suppurativa Foundation. Dr. Hsiao disclosed that she is a member of the board of directors for the Hidradenitis Suppurativa Foundation. She has served as a consultant for AbbVie, Aclaris, Boehringer Ingelheim, Incyte, Novartis, UCB, as a speaker for AbbVie, Novartis, and UCB, and as an investigator for Amgen, Boehringer Ingelheim, and Incyte.
“These findings suggest a course of 12 to 16 weeks of ertapenem may be appropriate as a new standard length of therapy in HS patients, which is at least twice the current recommendation of the North American treatment guidelines,” wrote corresponding author Steven R. Cohen, MD, MPH, of the departments of dermatology at Weill Cornell Medicine and Albert Einstein College of Medicine, New York, and his coauthors. The results were published online February 14, 2024, in JAMA Dermatology.
In an earlier study , some of the same researchers evaluated the efficacy of daily IV ertapenem for 6 weeks in seven patients with HS. The patients experienced “notable remediation of disease that was rapidly lost within 1 month of withdrawal.”
Treatment guidelines published in 2019 recommend ertapenem as a highly effective third-line therapy limited to one 6-week course “as rescue therapy or during surgical planning, given the practical barriers to home infusions and concerns about antibiotic resistance” .
For the current analysis, Dr. Cohen and colleagues explored the effects of a longer duration of treatment with ertapenem in this patient population. They retrospectively reviewed the medical records of 98 patients with HS who received care at Albert Einstein College of Medicine’s Montefiore HS Center between 2018 and 2022. Each patient used an elastomeric pump to self-administer 1 g IV ertapenem daily for 12-16 weeks.
Key outcome measures of interest were the HS Physician Global Assessment (PGA) score (a 6-point scale ranging from clear to very severe) and a numerical rating scale (NRS) for pain (an 11-point scale in which a score of 0 indicates no pain and a score of 10 indicates the worst possible pain) and markers of inflammation such as leukocytes, erythrocyte sedimentation rate, C-reactive protein (CRP), and interleukin (IL)-6. The researchers measured these outcomes at baseline, the midcourse of IV ertapenem treatment, at the end of the course, and post therapy.
The mean age of the patients was 35.8 years, 62.2% were female, and 60.2% were Black. The mean treatment duration was 13.1 weeks and the mean posttherapy follow-up occurred after a mean of 7.8 weeks.
Between baseline and posttherapy follow-up, the HS PGA scores dropped from a mean of 3.9 to 2.7 and the NRS for pain dropped from 4.2 to 1.8 (P < .001 for both associations). Markers of inflammation also dropped between baseline and post therapy.
Specifically, values for CRP dropped from 5.4 to 2.4 mg/dL; IL-6 dropped from 25.2 to 13.7, and leukocytes dropped from 11.3 to 10.0 (P < .001 for all associations). Among the 76 patients who participated in a follow-up telephone survey, 63 (80.3%) reported medium to high satisfaction with their course of ertapenem, and 69 (90.8%) said they would recommend the treatment to other patients with HS.
The authors noted certain limitations of their study, including its retrospective, single-center design, the lack of a control group, and the fact that the HS-PGA scores at each visit did not meet the threshold of a 2-point decrease that is considered a clinically meaningful in the medical literature.
The definitive mechanism of ertapenem efficacy remains elusive, the authors pointed out. “Although oral antibiotics are generally accepted as a core therapeutic approach to HS, much less is known about the efficacy of IV antibiotics, especially ertapenem, a parenteral carbapenem possessing activity against many gram-positive bacteria, gram-negative bacteria, and anaerobic organisms,” they wrote.
In an accompanying editorial, Haley B. Naik, MD, MHSc, a dermatologist at the University of California, San Francisco, said that adopting prolonged courses of ertapenem treatment “comes with substantial individual and public health considerations”.
“Even though HS is a noninfectious disease, microbes might play a role in inciting HS immune dysregulation, prompting the inclusion of antimicrobial therapy in treatment regimens. However, broad-spectrum antibiotics for HS are associated with high levels of antibiotic resistance,” she wrote. Prolonged use of ertapenem and other carbapenems in HS treatment “will likely increase antimicrobial resistance, thereby limiting management of both HS and comorbid infections.”
Jennifer L. Hsiao, MD, a dermatologist who directs the HS clinic at the University of Southern California, Los Angeles, who was asked to comment on the study, said that, despite significant advances in the management of HS over the past decade, there are still patients who do not respond adequately to standard treatments.
For these patients, IV ertapenem can serve as a valuable bridge to a longer-term therapeutic option, “be it surgery or escalated immunomodulation,” such as dual biologic therapy, she said. “In my personal experience, IV ertapenem, which like the authors I also typically use for a 12-week course, delivers impressive and fast results even in the worst disease cases.
“It can be difficult to maintain the therapeutic benefit of ertapenem after it is discontinued, which is why patients should be on concomitant medications as they were in this study and have a post-ertapenem treatment plan in place,” said Dr. Hsiao, who was not involved with the study. “Hopefully, we will be able to one day understand why ertapenem is so effective for HS and be able to harness that benefit for patients without concern for antimicrobial resistance.”
Dr. Cohen reported receiving personal fees from Verrica Pharmaceuticals and belonging to the Board of Trustees of the American Skin Association outside the submitted work. No other disclosures were reported. Dr. Naik reported having received grants from AbbVie and the National Institutes of Health; personal fees from Novartis, UCB, Boehringer Ingelheim, 23andMe, Aristea Therapeutics, Medscape, Sonoma Biotherapeutics, DAVA Oncology, and Pfizer; and shares from Radera during the conduct of the study. She is a board member of the Hidradenitis Suppurativa Foundation. Dr. Hsiao disclosed that she is a member of the board of directors for the Hidradenitis Suppurativa Foundation. She has served as a consultant for AbbVie, Aclaris, Boehringer Ingelheim, Incyte, Novartis, UCB, as a speaker for AbbVie, Novartis, and UCB, and as an investigator for Amgen, Boehringer Ingelheim, and Incyte.
“These findings suggest a course of 12 to 16 weeks of ertapenem may be appropriate as a new standard length of therapy in HS patients, which is at least twice the current recommendation of the North American treatment guidelines,” wrote corresponding author Steven R. Cohen, MD, MPH, of the departments of dermatology at Weill Cornell Medicine and Albert Einstein College of Medicine, New York, and his coauthors. The results were published online February 14, 2024, in JAMA Dermatology.
In an earlier study , some of the same researchers evaluated the efficacy of daily IV ertapenem for 6 weeks in seven patients with HS. The patients experienced “notable remediation of disease that was rapidly lost within 1 month of withdrawal.”
Treatment guidelines published in 2019 recommend ertapenem as a highly effective third-line therapy limited to one 6-week course “as rescue therapy or during surgical planning, given the practical barriers to home infusions and concerns about antibiotic resistance” .
For the current analysis, Dr. Cohen and colleagues explored the effects of a longer duration of treatment with ertapenem in this patient population. They retrospectively reviewed the medical records of 98 patients with HS who received care at Albert Einstein College of Medicine’s Montefiore HS Center between 2018 and 2022. Each patient used an elastomeric pump to self-administer 1 g IV ertapenem daily for 12-16 weeks.
Key outcome measures of interest were the HS Physician Global Assessment (PGA) score (a 6-point scale ranging from clear to very severe) and a numerical rating scale (NRS) for pain (an 11-point scale in which a score of 0 indicates no pain and a score of 10 indicates the worst possible pain) and markers of inflammation such as leukocytes, erythrocyte sedimentation rate, C-reactive protein (CRP), and interleukin (IL)-6. The researchers measured these outcomes at baseline, the midcourse of IV ertapenem treatment, at the end of the course, and post therapy.
The mean age of the patients was 35.8 years, 62.2% were female, and 60.2% were Black. The mean treatment duration was 13.1 weeks and the mean posttherapy follow-up occurred after a mean of 7.8 weeks.
Between baseline and posttherapy follow-up, the HS PGA scores dropped from a mean of 3.9 to 2.7 and the NRS for pain dropped from 4.2 to 1.8 (P < .001 for both associations). Markers of inflammation also dropped between baseline and post therapy.
Specifically, values for CRP dropped from 5.4 to 2.4 mg/dL; IL-6 dropped from 25.2 to 13.7, and leukocytes dropped from 11.3 to 10.0 (P < .001 for all associations). Among the 76 patients who participated in a follow-up telephone survey, 63 (80.3%) reported medium to high satisfaction with their course of ertapenem, and 69 (90.8%) said they would recommend the treatment to other patients with HS.
The authors noted certain limitations of their study, including its retrospective, single-center design, the lack of a control group, and the fact that the HS-PGA scores at each visit did not meet the threshold of a 2-point decrease that is considered a clinically meaningful in the medical literature.
The definitive mechanism of ertapenem efficacy remains elusive, the authors pointed out. “Although oral antibiotics are generally accepted as a core therapeutic approach to HS, much less is known about the efficacy of IV antibiotics, especially ertapenem, a parenteral carbapenem possessing activity against many gram-positive bacteria, gram-negative bacteria, and anaerobic organisms,” they wrote.
In an accompanying editorial, Haley B. Naik, MD, MHSc, a dermatologist at the University of California, San Francisco, said that adopting prolonged courses of ertapenem treatment “comes with substantial individual and public health considerations”.
“Even though HS is a noninfectious disease, microbes might play a role in inciting HS immune dysregulation, prompting the inclusion of antimicrobial therapy in treatment regimens. However, broad-spectrum antibiotics for HS are associated with high levels of antibiotic resistance,” she wrote. Prolonged use of ertapenem and other carbapenems in HS treatment “will likely increase antimicrobial resistance, thereby limiting management of both HS and comorbid infections.”
Jennifer L. Hsiao, MD, a dermatologist who directs the HS clinic at the University of Southern California, Los Angeles, who was asked to comment on the study, said that, despite significant advances in the management of HS over the past decade, there are still patients who do not respond adequately to standard treatments.
For these patients, IV ertapenem can serve as a valuable bridge to a longer-term therapeutic option, “be it surgery or escalated immunomodulation,” such as dual biologic therapy, she said. “In my personal experience, IV ertapenem, which like the authors I also typically use for a 12-week course, delivers impressive and fast results even in the worst disease cases.
“It can be difficult to maintain the therapeutic benefit of ertapenem after it is discontinued, which is why patients should be on concomitant medications as they were in this study and have a post-ertapenem treatment plan in place,” said Dr. Hsiao, who was not involved with the study. “Hopefully, we will be able to one day understand why ertapenem is so effective for HS and be able to harness that benefit for patients without concern for antimicrobial resistance.”
Dr. Cohen reported receiving personal fees from Verrica Pharmaceuticals and belonging to the Board of Trustees of the American Skin Association outside the submitted work. No other disclosures were reported. Dr. Naik reported having received grants from AbbVie and the National Institutes of Health; personal fees from Novartis, UCB, Boehringer Ingelheim, 23andMe, Aristea Therapeutics, Medscape, Sonoma Biotherapeutics, DAVA Oncology, and Pfizer; and shares from Radera during the conduct of the study. She is a board member of the Hidradenitis Suppurativa Foundation. Dr. Hsiao disclosed that she is a member of the board of directors for the Hidradenitis Suppurativa Foundation. She has served as a consultant for AbbVie, Aclaris, Boehringer Ingelheim, Incyte, Novartis, UCB, as a speaker for AbbVie, Novartis, and UCB, and as an investigator for Amgen, Boehringer Ingelheim, and Incyte.
FROM JAMA DERMATOLOGY
Herpes Zoster and Varicella Encephalitis Following the Recombinant Zoster Vaccine
To the Editor:
Reported adverse effects following the recombinant zoster vaccine (RZV) include pyrexia, myalgia, and fatigue.1 We report the case of a patient who developed herpes zoster and subsequent varicella encephalitis within 8 days of receiving the second dose of the RZV.
A 75-year-old man presented to the emergency department with burning pain and pruritus involving the left hip and calf 2 days after receiving the second dose of the RZV. He had a history of chronic lymphocytic leukemia (CLL) and was being clinically monitored. He received the first dose of the RZV without complication 3 months prior. In the emergency department, he was diagnosed with “nerve pain,” given acetaminophen, and discharged home; however, he continued to have worsening pain 8 days later followed by a vesicular eruption that wrapped around the left leg and was concentrated on the inner thigh/groin area in a dermatomal distribution. His primary care physician diagnosed him with herpes zoster and prescribed valacyclovir 1000 mg every 8 hours for 7 days. Two days later, the patient developed weakness and confusion and returned to the emergency department. Upon admission, computed tomography and magnetic resonance imaging/magnetic resonance angiography of the brain was normal. A lumbar puncture confirmed varicella encephalitis via a polymerase chain reaction assay. He was treated with intravenous acyclovir and discharged to a rehabilitation facility. His course was further complicated by a subarachnoid hemorrhage and normal pressure hydrocephalus. He did not require a shunt but continues to have memory impairment, weakness, and cognitive impairment. He is steadily improving with rehabilitative services.
The RZV is an inactivated vaccine composed of the varicella-zoster virus (VZV) glycoprotein E antigen and an adjuvant, AS01B, that boosts both innate and adaptive immunity.2 It was approved by the US Food and Drug Administration in 2017 for prevention of herpes zoster in adults aged 50 years or older. It requires 2 separate injections administered 2 to 6 months apart. Its efficacy for the prevention of cutaneous herpes zoster and postherpetic neuralgia is 97% and 80% to 91%, respectively. It was developed to improve on the existing zoster vaccine live, which contains a live attenuated virus, with efficacy ranging from 38% to 70%.3
The Centers for Disease Control and Prevention initially recommended the RZV for immunocompetent individuals or those taking low-dose immunosuppressant medications as well those who have recovered from an immunocompromising illness. In immunocompetent patients, reported adverse effects include injection site pain and redness, headache, myalgia, fatigue, shivering, fever, and gastrointestinal tract symptoms; however, when the vaccine first came out, many of the studies excluded patients with CLL.4 Our patient’s herpes zoster and varicella encephalitis occurred following administration of the second dose of the RZV. Herpes zoster occurs from declining VZV-specific cell-mediated immunity. Given that the vaccine contains inactive virus, it is unlikely that our patient’s infection was the direct result of dissemination of the virus contained within the vaccine. The RZV specifically generates T-cell responses to the glycoprotein E subunit of VZV, which is thought to be responsible for the high levels of VZV-specific memory T cells with the RZV compared to the zoster vaccine live.5 However, this response does not occur until after the second dose of RZV. Although our patient already had 1 dose of RZV, it was unlikely that he had a substantial number of glycoprotein E and VZV-specific memory T cells to combat virus reactivation. Additionally, his CLL, though mild, may have resulted in an aberrant T-cell response in the presence of already low VZV-specific lymphocytes, allowing for reactivation and dissemination of the virus. Since then, there has been more of an emphasis on looking at the immunogenicity elicited by the vaccine in patients with CLL—both those who are treatment naive and those treated with Bruton tyrosine kinase inhibitors. Both groups of patients have demonstrated reduced immunogenicity in response to RZV, leaving the opportunity for viral reactivation in this patient population.6,7
The safety of the RZV has now been demonstrated in patients with CLL.7 However, even after RZV vaccination, patients with CLL are still at risk for herpes zoster reactivation and may have an aberrant response due to immune cell dysregulation. Our case demonstrates the need to increase monitoring of CLL patients for signs of viral reactivation and shift our focus to providing antiviral therapy quickly after symptom occurrence.
- Centers for Disease Control and Prevention. Shingles: about the vaccine. Updated January 24, 2022. Accessed February 7, 2024. https://www.cdc.gov/vaccines/vpd/shingles/hcp/shingrix/about-vaccine.html
- Dooling KL, Guo A, Patel M, et al. Recommendations of the advisory committee on immunization practices for use of herpes zoster vaccines. MMWR Morb Mortal Wkly Rep. 2018;67:103-108. doi:10.15585/mmwr.mm6703a5external icon
- Hunter P, Fryhofer SA, Szilagyi PG. Vaccination of adults in general medical practice. Mayo Clin Proc. 2020;95:169-183. doi:10.1016/j.mayocp.2019.02.024
- Dagnew AF, Ilhan O, Lee WS, et al. Immunogenicity and safety of the adjuvanted recombinant zoster vaccine in adults with haematological malignancies: a phase 3, randomised, clinical trial and post-hoc efficacy analysis [published correction appears in Lancet Infect Dis. 2020;20:E1]. Lancet Infect Dis. 2019;19:988-1000. doi:10.1016/S1473-3099(19)30163-X
- Levin MJ, Kroehl ME, Johnson MJ, et al. Th1 memory differentiates recombinant from live herpes zoster vaccines. J Clin Invest. 2018;128:4429-4440.
- Pleyer C, Laing KJ, Ali MA, et al. BTK inhibitors impair humoral and cellular responses to recombinant zoster vaccine in CLL. Blood Adv. 2022;6:1732-1740. doi:10.1182/bloodadvances.2021006574
- Pleyer C, Cohen J, Soto S, et al. Response to the Shingrix varicella zoster virus (VZV) vaccine in patients with chronic lymphocytic leukemia (CLL) that are treatment naive or treated with a Bruton’s tyrosine kinase inhibitor (BTK-I). Blood. 2019;134(suppl 1):3053. doi:10.1182/blood-2019-121675
To the Editor:
Reported adverse effects following the recombinant zoster vaccine (RZV) include pyrexia, myalgia, and fatigue.1 We report the case of a patient who developed herpes zoster and subsequent varicella encephalitis within 8 days of receiving the second dose of the RZV.
A 75-year-old man presented to the emergency department with burning pain and pruritus involving the left hip and calf 2 days after receiving the second dose of the RZV. He had a history of chronic lymphocytic leukemia (CLL) and was being clinically monitored. He received the first dose of the RZV without complication 3 months prior. In the emergency department, he was diagnosed with “nerve pain,” given acetaminophen, and discharged home; however, he continued to have worsening pain 8 days later followed by a vesicular eruption that wrapped around the left leg and was concentrated on the inner thigh/groin area in a dermatomal distribution. His primary care physician diagnosed him with herpes zoster and prescribed valacyclovir 1000 mg every 8 hours for 7 days. Two days later, the patient developed weakness and confusion and returned to the emergency department. Upon admission, computed tomography and magnetic resonance imaging/magnetic resonance angiography of the brain was normal. A lumbar puncture confirmed varicella encephalitis via a polymerase chain reaction assay. He was treated with intravenous acyclovir and discharged to a rehabilitation facility. His course was further complicated by a subarachnoid hemorrhage and normal pressure hydrocephalus. He did not require a shunt but continues to have memory impairment, weakness, and cognitive impairment. He is steadily improving with rehabilitative services.
The RZV is an inactivated vaccine composed of the varicella-zoster virus (VZV) glycoprotein E antigen and an adjuvant, AS01B, that boosts both innate and adaptive immunity.2 It was approved by the US Food and Drug Administration in 2017 for prevention of herpes zoster in adults aged 50 years or older. It requires 2 separate injections administered 2 to 6 months apart. Its efficacy for the prevention of cutaneous herpes zoster and postherpetic neuralgia is 97% and 80% to 91%, respectively. It was developed to improve on the existing zoster vaccine live, which contains a live attenuated virus, with efficacy ranging from 38% to 70%.3
The Centers for Disease Control and Prevention initially recommended the RZV for immunocompetent individuals or those taking low-dose immunosuppressant medications as well those who have recovered from an immunocompromising illness. In immunocompetent patients, reported adverse effects include injection site pain and redness, headache, myalgia, fatigue, shivering, fever, and gastrointestinal tract symptoms; however, when the vaccine first came out, many of the studies excluded patients with CLL.4 Our patient’s herpes zoster and varicella encephalitis occurred following administration of the second dose of the RZV. Herpes zoster occurs from declining VZV-specific cell-mediated immunity. Given that the vaccine contains inactive virus, it is unlikely that our patient’s infection was the direct result of dissemination of the virus contained within the vaccine. The RZV specifically generates T-cell responses to the glycoprotein E subunit of VZV, which is thought to be responsible for the high levels of VZV-specific memory T cells with the RZV compared to the zoster vaccine live.5 However, this response does not occur until after the second dose of RZV. Although our patient already had 1 dose of RZV, it was unlikely that he had a substantial number of glycoprotein E and VZV-specific memory T cells to combat virus reactivation. Additionally, his CLL, though mild, may have resulted in an aberrant T-cell response in the presence of already low VZV-specific lymphocytes, allowing for reactivation and dissemination of the virus. Since then, there has been more of an emphasis on looking at the immunogenicity elicited by the vaccine in patients with CLL—both those who are treatment naive and those treated with Bruton tyrosine kinase inhibitors. Both groups of patients have demonstrated reduced immunogenicity in response to RZV, leaving the opportunity for viral reactivation in this patient population.6,7
The safety of the RZV has now been demonstrated in patients with CLL.7 However, even after RZV vaccination, patients with CLL are still at risk for herpes zoster reactivation and may have an aberrant response due to immune cell dysregulation. Our case demonstrates the need to increase monitoring of CLL patients for signs of viral reactivation and shift our focus to providing antiviral therapy quickly after symptom occurrence.
To the Editor:
Reported adverse effects following the recombinant zoster vaccine (RZV) include pyrexia, myalgia, and fatigue.1 We report the case of a patient who developed herpes zoster and subsequent varicella encephalitis within 8 days of receiving the second dose of the RZV.
A 75-year-old man presented to the emergency department with burning pain and pruritus involving the left hip and calf 2 days after receiving the second dose of the RZV. He had a history of chronic lymphocytic leukemia (CLL) and was being clinically monitored. He received the first dose of the RZV without complication 3 months prior. In the emergency department, he was diagnosed with “nerve pain,” given acetaminophen, and discharged home; however, he continued to have worsening pain 8 days later followed by a vesicular eruption that wrapped around the left leg and was concentrated on the inner thigh/groin area in a dermatomal distribution. His primary care physician diagnosed him with herpes zoster and prescribed valacyclovir 1000 mg every 8 hours for 7 days. Two days later, the patient developed weakness and confusion and returned to the emergency department. Upon admission, computed tomography and magnetic resonance imaging/magnetic resonance angiography of the brain was normal. A lumbar puncture confirmed varicella encephalitis via a polymerase chain reaction assay. He was treated with intravenous acyclovir and discharged to a rehabilitation facility. His course was further complicated by a subarachnoid hemorrhage and normal pressure hydrocephalus. He did not require a shunt but continues to have memory impairment, weakness, and cognitive impairment. He is steadily improving with rehabilitative services.
The RZV is an inactivated vaccine composed of the varicella-zoster virus (VZV) glycoprotein E antigen and an adjuvant, AS01B, that boosts both innate and adaptive immunity.2 It was approved by the US Food and Drug Administration in 2017 for prevention of herpes zoster in adults aged 50 years or older. It requires 2 separate injections administered 2 to 6 months apart. Its efficacy for the prevention of cutaneous herpes zoster and postherpetic neuralgia is 97% and 80% to 91%, respectively. It was developed to improve on the existing zoster vaccine live, which contains a live attenuated virus, with efficacy ranging from 38% to 70%.3
The Centers for Disease Control and Prevention initially recommended the RZV for immunocompetent individuals or those taking low-dose immunosuppressant medications as well those who have recovered from an immunocompromising illness. In immunocompetent patients, reported adverse effects include injection site pain and redness, headache, myalgia, fatigue, shivering, fever, and gastrointestinal tract symptoms; however, when the vaccine first came out, many of the studies excluded patients with CLL.4 Our patient’s herpes zoster and varicella encephalitis occurred following administration of the second dose of the RZV. Herpes zoster occurs from declining VZV-specific cell-mediated immunity. Given that the vaccine contains inactive virus, it is unlikely that our patient’s infection was the direct result of dissemination of the virus contained within the vaccine. The RZV specifically generates T-cell responses to the glycoprotein E subunit of VZV, which is thought to be responsible for the high levels of VZV-specific memory T cells with the RZV compared to the zoster vaccine live.5 However, this response does not occur until after the second dose of RZV. Although our patient already had 1 dose of RZV, it was unlikely that he had a substantial number of glycoprotein E and VZV-specific memory T cells to combat virus reactivation. Additionally, his CLL, though mild, may have resulted in an aberrant T-cell response in the presence of already low VZV-specific lymphocytes, allowing for reactivation and dissemination of the virus. Since then, there has been more of an emphasis on looking at the immunogenicity elicited by the vaccine in patients with CLL—both those who are treatment naive and those treated with Bruton tyrosine kinase inhibitors. Both groups of patients have demonstrated reduced immunogenicity in response to RZV, leaving the opportunity for viral reactivation in this patient population.6,7
The safety of the RZV has now been demonstrated in patients with CLL.7 However, even after RZV vaccination, patients with CLL are still at risk for herpes zoster reactivation and may have an aberrant response due to immune cell dysregulation. Our case demonstrates the need to increase monitoring of CLL patients for signs of viral reactivation and shift our focus to providing antiviral therapy quickly after symptom occurrence.
- Centers for Disease Control and Prevention. Shingles: about the vaccine. Updated January 24, 2022. Accessed February 7, 2024. https://www.cdc.gov/vaccines/vpd/shingles/hcp/shingrix/about-vaccine.html
- Dooling KL, Guo A, Patel M, et al. Recommendations of the advisory committee on immunization practices for use of herpes zoster vaccines. MMWR Morb Mortal Wkly Rep. 2018;67:103-108. doi:10.15585/mmwr.mm6703a5external icon
- Hunter P, Fryhofer SA, Szilagyi PG. Vaccination of adults in general medical practice. Mayo Clin Proc. 2020;95:169-183. doi:10.1016/j.mayocp.2019.02.024
- Dagnew AF, Ilhan O, Lee WS, et al. Immunogenicity and safety of the adjuvanted recombinant zoster vaccine in adults with haematological malignancies: a phase 3, randomised, clinical trial and post-hoc efficacy analysis [published correction appears in Lancet Infect Dis. 2020;20:E1]. Lancet Infect Dis. 2019;19:988-1000. doi:10.1016/S1473-3099(19)30163-X
- Levin MJ, Kroehl ME, Johnson MJ, et al. Th1 memory differentiates recombinant from live herpes zoster vaccines. J Clin Invest. 2018;128:4429-4440.
- Pleyer C, Laing KJ, Ali MA, et al. BTK inhibitors impair humoral and cellular responses to recombinant zoster vaccine in CLL. Blood Adv. 2022;6:1732-1740. doi:10.1182/bloodadvances.2021006574
- Pleyer C, Cohen J, Soto S, et al. Response to the Shingrix varicella zoster virus (VZV) vaccine in patients with chronic lymphocytic leukemia (CLL) that are treatment naive or treated with a Bruton’s tyrosine kinase inhibitor (BTK-I). Blood. 2019;134(suppl 1):3053. doi:10.1182/blood-2019-121675
- Centers for Disease Control and Prevention. Shingles: about the vaccine. Updated January 24, 2022. Accessed February 7, 2024. https://www.cdc.gov/vaccines/vpd/shingles/hcp/shingrix/about-vaccine.html
- Dooling KL, Guo A, Patel M, et al. Recommendations of the advisory committee on immunization practices for use of herpes zoster vaccines. MMWR Morb Mortal Wkly Rep. 2018;67:103-108. doi:10.15585/mmwr.mm6703a5external icon
- Hunter P, Fryhofer SA, Szilagyi PG. Vaccination of adults in general medical practice. Mayo Clin Proc. 2020;95:169-183. doi:10.1016/j.mayocp.2019.02.024
- Dagnew AF, Ilhan O, Lee WS, et al. Immunogenicity and safety of the adjuvanted recombinant zoster vaccine in adults with haematological malignancies: a phase 3, randomised, clinical trial and post-hoc efficacy analysis [published correction appears in Lancet Infect Dis. 2020;20:E1]. Lancet Infect Dis. 2019;19:988-1000. doi:10.1016/S1473-3099(19)30163-X
- Levin MJ, Kroehl ME, Johnson MJ, et al. Th1 memory differentiates recombinant from live herpes zoster vaccines. J Clin Invest. 2018;128:4429-4440.
- Pleyer C, Laing KJ, Ali MA, et al. BTK inhibitors impair humoral and cellular responses to recombinant zoster vaccine in CLL. Blood Adv. 2022;6:1732-1740. doi:10.1182/bloodadvances.2021006574
- Pleyer C, Cohen J, Soto S, et al. Response to the Shingrix varicella zoster virus (VZV) vaccine in patients with chronic lymphocytic leukemia (CLL) that are treatment naive or treated with a Bruton’s tyrosine kinase inhibitor (BTK-I). Blood. 2019;134(suppl 1):3053. doi:10.1182/blood-2019-121675
Practice Points
- Patients with chronic lymphocytic leukemia (CLL) are at risk for herpes zoster reactivation even with vaccination due to a decreased immune response. These patients may have an aberrant response due to immune cell dysregulation.
- It is important to increase monitoring of CLL patients for signs of viral reactivation and shift the focus to providing antiviral therapy quickly if herpes zoster symptoms occur.
Rapidly Progressive Necrotizing Myositis Mimicking Pyoderma Gangrenosum
To the Editor:
Necrotizing myositis (NM) is an exceedingly rare necrotizing soft-tissue infection (NSTI) that is characterized by skeletal muscle involvement. β -Hemolytic streptococci, such as Streptococcus pyogenes , are the most common causative organisms. The overall prevalence and incidence of NM is unknown. A review of the literature by Adams et al 2 identified only 21 cases between 1900 and 1985.
Timely treatment of this infection leads to improved outcomes, but diagnosis can be challenging due to the ambiguous presentation of NM and lack of specific cutaneous changes.3 Clinical manifestations including bullae, blisters, vesicles, and petechiae become more prominent as infection progresses.4 If NM is suspected due to cutaneous manifestations, it is imperative that the underlying cause be identified; for example, NM must be distinguished from the overlapping presentation of pyoderma gangrenosum (PG). Because NM has nearly 100% mortality without prompt surgical intervention, early identification is critical.5 Herein, we report a case of NM that illustrates the correlation of clinical, histological, and imaging findings required to diagnose this potentially fatal infection.
An 80-year-old man presented to the emergency department with worsening pain, edema, and spreading redness of the right wrist over the last 5 weeks. He had a history of atopic dermatitis that was refractory to topical steroids and methotrexate; he was dependent on an oral steroid (prednisone 30 mg/d) for symptom control. The patient reported minor trauma to the area after performing home renovations. He received numerous rounds of oral antibiotics as an outpatient for presumed cellulitis and reported he was “getting better” but that the signs and symptoms of the condition grew worse after outpatient arthrocentesis. Dermatology was consulted to evaluate for a necrotizing neutrophilic dermatosis such as PG.
At the current presentation, the patient was tachycardic and afebrile (temperature, 98.2 °F [36.8 °C]). Physical examination revealed large, exquisitely tender, ill-defined necrotic ulceration of the right wrist with purulent debris and diffuse edema (Figure 1). Sequential evaluation at 6-hour intervals revealed notably increasing purulence, edema, and tenderness. Interconnected sinus tracts that extended to the fascial plane were observed.
Laboratory workup was notable for a markedly elevated C-reactive protein level of 18.9 mg/dL (reference range, 0–0.8 mg/dL) and an elevated white blood cell count of 19.92×109/L (reference range, 4.5–11.0×109/L). Blood and tissue cultures were positive for methicillin-sensitive Staphylococcus aureus. Computed tomography and magnetic resonance imaging (MRI) prior to biopsy demonstrated findings consistent with extensive subcutaneous and intramuscular areas of loculation and foci of gas (Figure 2). These findings were consistent with intramuscular involvement. A punch biopsy revealed a necrotic epidermis filled with neutrophilic pustules and a dense dermal infiltrate of neutrophilic inflammation consistent with infection (Figure 3).
Emergency surgery was performed with debridement of necrotic tissue and muscle. Postoperatively, he became more clinically stable after being placed on cefazolin through a peripherally inserted central catheter. He underwent 4 additional washouts over the ensuing month, as well as tendon reconstructions, a radial forearm flap, and reverse radial forearm flap reconstruction of the forearm. At the time of publication, there has been no recurrence. The patient’s atopic dermatitis is well controlled on dupilumab and topical fluocinonide alone, with a recent IgA level of 1 g/L and a body surface area measurement of 2%. Dupilumab was started 3 months after surgery.
Necrotizing myositis is a rare, rapidly progressive infection involving muscle that can manifest as superficial cutaneous involvement. The clinical manifestation of NM is harder to recognize than other NSTIs such as necrotizing fasciitis, likely due to the initial prodromal phase of NM, which consists of nonspecific constitutional symptoms.3 Systemic findings such as tachycardia, fever, hypotension, and shock occur in only 10% to 40% of NM patients.4,5
In our patient, clues of NM included fulfillment of criteria for systemic inflammatory response syndrome at admission and a presumed source of infection; taken together, these findings should lead to a diagnosis of sepsis until otherwise proven. The patient also reported pain that was not proportional to the skin findings, which suggested an NSTI. His lack of constitutional symptoms may have been due to the effects of prednisone, which was changed to dupilumab during hospitalization.
The clinical and histological findings of NM are nonspecific. Clinical findings include skin discoloration with bullae, blisters, vesicles, or petechiae.4 Our case adds to the descriptive morphology by including marked edema with ulceration, progressive purulence, and interconnected sinuses tracking to the fascial plane. Histologic findings can include confluent necrosis extending from the epidermis to the underlying muscle with dense neutrophilic inflammation. Notably, these findings can mirror necrotizing neutrophilic dermatoses in the absence of an infectious cause. Failure to recognize simple systemic inflammatory response syndrome criteria in NM patients due to slow treatment response or incorrect treatment can can lead to loss of a limb or death.
Workup reveals overlap with necrotizing neutrophilic dermatoses including PG, which is the prototypical neutrophilic dermatosis. Morphologically, PG presents as an ulcer with a purple and undermined border, often having developed from an initial papule, vesicle, or pustule. A neutrophilic infiltrate of the ulcer edge is the major criterion required to diagnose PG6; minor criteria include a positive pathergy test, history of inflammatory arthritis or inflammatory bowel disease, and exclusion of infection.6 When compared directly to an NSTI such as NM, the most important variable that sets PG apart is the absence of bacterial growth on blood and tissue cultures.7
Imaging studies can aid in the clinical diagnosis of NM and help distinguish the disease from PG. Computed tomography and MRI may demonstrate hallmarks of extensive necrotizing infection, such as gas formation and consequent fascial swelling, thickening and edema of involved muscle, and subfascial fluid collection.3,4 Distinct from NM, imaging findings in PG are more subtle, suggesting cellulitic inflammation with edema.8 A defining radiographic feature of NM can be foci of gas within muscle or fascia, though absence of this finding does not exclude NM.1,4
In conclusion, NM is a rare intramuscular infection that can be difficult to diagnose due to its nonspecific presentation and lack of constitutional symptoms. Dermatologists should maintain a high level of suspicion for NM in the setting of rapidly progressive clinical findings; accurate diagnosis requires a multimodal approach with complete correlation of clinical, histological, and imaging findings. Computed tomography and MRI can heighten the approach, even when necrotizing neutrophilic dermatoses and NM have similar clinical and histological appearances. Once a diagnosis of NM is established, prompt surgical and medical intervention improves the prognosis.
- Stevens DL, Baddour LM. Necrotizing soft tissue infections. UpToDate. Updated October 7, 2022. Accessed February 13, 2024. https://www.uptodate.com/contents/necrotizing-soft-tissue-infections?search=Necrotizing%20soft%20tissue%20infections&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1
- Adams EM, Gudmundsson S, Yocum DE, et al. Streptococcal myositis. Arch Intern Med . 1985;145:1020-1023.
- Khanna A, Gurusinghe D, Taylor D. Necrotizing myositis: highlighting the hidden depths—case series and review of the literature. ANZ J Surg . 2020;90:130-134. doi:10.1111/ans.15429
- Boinpally H, Howell RS, Ram B, et al. Necrotizing myositis: a rare necrotizing soft tissue infection involving muscle. Wounds . 2018;30:E116-E120.
- Anaya DA, Dellinger EP. Necrotizing soft-tissue infection: diagnosis and management. Clin Infect Dis . 2007;44:705-710. doi:10.1086/511638
- Maverakis E, Ma C, Shinkai K, et al. Diagnostic criteria of ulcerative pyoderma gangrenosum: a Delphi consensus of international experts. JAMA Dermatol . 2018;154:461-466. doi:10.1001/jamadermatol.2017.5980
- Sanchez IM, Lowenstein S, Johnson KA, et al. Clinical features of neutrophilic dermatosis variants resembling necrotizing fasciitis. JAMA Dermatol . 2019;155:79-84. doi:10.1001/jamadermatol.2018.3890
- Demirdover C, Geyik A, Vayvada H. Necrotising fasciitis or pyoderma gangrenosum: a fatal dilemma. Int Wound J . 2019;16:1347-1353. doi:10.1111/iwj.13196
To the Editor:
Necrotizing myositis (NM) is an exceedingly rare necrotizing soft-tissue infection (NSTI) that is characterized by skeletal muscle involvement. β -Hemolytic streptococci, such as Streptococcus pyogenes , are the most common causative organisms. The overall prevalence and incidence of NM is unknown. A review of the literature by Adams et al 2 identified only 21 cases between 1900 and 1985.
Timely treatment of this infection leads to improved outcomes, but diagnosis can be challenging due to the ambiguous presentation of NM and lack of specific cutaneous changes.3 Clinical manifestations including bullae, blisters, vesicles, and petechiae become more prominent as infection progresses.4 If NM is suspected due to cutaneous manifestations, it is imperative that the underlying cause be identified; for example, NM must be distinguished from the overlapping presentation of pyoderma gangrenosum (PG). Because NM has nearly 100% mortality without prompt surgical intervention, early identification is critical.5 Herein, we report a case of NM that illustrates the correlation of clinical, histological, and imaging findings required to diagnose this potentially fatal infection.
An 80-year-old man presented to the emergency department with worsening pain, edema, and spreading redness of the right wrist over the last 5 weeks. He had a history of atopic dermatitis that was refractory to topical steroids and methotrexate; he was dependent on an oral steroid (prednisone 30 mg/d) for symptom control. The patient reported minor trauma to the area after performing home renovations. He received numerous rounds of oral antibiotics as an outpatient for presumed cellulitis and reported he was “getting better” but that the signs and symptoms of the condition grew worse after outpatient arthrocentesis. Dermatology was consulted to evaluate for a necrotizing neutrophilic dermatosis such as PG.
At the current presentation, the patient was tachycardic and afebrile (temperature, 98.2 °F [36.8 °C]). Physical examination revealed large, exquisitely tender, ill-defined necrotic ulceration of the right wrist with purulent debris and diffuse edema (Figure 1). Sequential evaluation at 6-hour intervals revealed notably increasing purulence, edema, and tenderness. Interconnected sinus tracts that extended to the fascial plane were observed.
Laboratory workup was notable for a markedly elevated C-reactive protein level of 18.9 mg/dL (reference range, 0–0.8 mg/dL) and an elevated white blood cell count of 19.92×109/L (reference range, 4.5–11.0×109/L). Blood and tissue cultures were positive for methicillin-sensitive Staphylococcus aureus. Computed tomography and magnetic resonance imaging (MRI) prior to biopsy demonstrated findings consistent with extensive subcutaneous and intramuscular areas of loculation and foci of gas (Figure 2). These findings were consistent with intramuscular involvement. A punch biopsy revealed a necrotic epidermis filled with neutrophilic pustules and a dense dermal infiltrate of neutrophilic inflammation consistent with infection (Figure 3).
Emergency surgery was performed with debridement of necrotic tissue and muscle. Postoperatively, he became more clinically stable after being placed on cefazolin through a peripherally inserted central catheter. He underwent 4 additional washouts over the ensuing month, as well as tendon reconstructions, a radial forearm flap, and reverse radial forearm flap reconstruction of the forearm. At the time of publication, there has been no recurrence. The patient’s atopic dermatitis is well controlled on dupilumab and topical fluocinonide alone, with a recent IgA level of 1 g/L and a body surface area measurement of 2%. Dupilumab was started 3 months after surgery.
Necrotizing myositis is a rare, rapidly progressive infection involving muscle that can manifest as superficial cutaneous involvement. The clinical manifestation of NM is harder to recognize than other NSTIs such as necrotizing fasciitis, likely due to the initial prodromal phase of NM, which consists of nonspecific constitutional symptoms.3 Systemic findings such as tachycardia, fever, hypotension, and shock occur in only 10% to 40% of NM patients.4,5
In our patient, clues of NM included fulfillment of criteria for systemic inflammatory response syndrome at admission and a presumed source of infection; taken together, these findings should lead to a diagnosis of sepsis until otherwise proven. The patient also reported pain that was not proportional to the skin findings, which suggested an NSTI. His lack of constitutional symptoms may have been due to the effects of prednisone, which was changed to dupilumab during hospitalization.
The clinical and histological findings of NM are nonspecific. Clinical findings include skin discoloration with bullae, blisters, vesicles, or petechiae.4 Our case adds to the descriptive morphology by including marked edema with ulceration, progressive purulence, and interconnected sinuses tracking to the fascial plane. Histologic findings can include confluent necrosis extending from the epidermis to the underlying muscle with dense neutrophilic inflammation. Notably, these findings can mirror necrotizing neutrophilic dermatoses in the absence of an infectious cause. Failure to recognize simple systemic inflammatory response syndrome criteria in NM patients due to slow treatment response or incorrect treatment can can lead to loss of a limb or death.
Workup reveals overlap with necrotizing neutrophilic dermatoses including PG, which is the prototypical neutrophilic dermatosis. Morphologically, PG presents as an ulcer with a purple and undermined border, often having developed from an initial papule, vesicle, or pustule. A neutrophilic infiltrate of the ulcer edge is the major criterion required to diagnose PG6; minor criteria include a positive pathergy test, history of inflammatory arthritis or inflammatory bowel disease, and exclusion of infection.6 When compared directly to an NSTI such as NM, the most important variable that sets PG apart is the absence of bacterial growth on blood and tissue cultures.7
Imaging studies can aid in the clinical diagnosis of NM and help distinguish the disease from PG. Computed tomography and MRI may demonstrate hallmarks of extensive necrotizing infection, such as gas formation and consequent fascial swelling, thickening and edema of involved muscle, and subfascial fluid collection.3,4 Distinct from NM, imaging findings in PG are more subtle, suggesting cellulitic inflammation with edema.8 A defining radiographic feature of NM can be foci of gas within muscle or fascia, though absence of this finding does not exclude NM.1,4
In conclusion, NM is a rare intramuscular infection that can be difficult to diagnose due to its nonspecific presentation and lack of constitutional symptoms. Dermatologists should maintain a high level of suspicion for NM in the setting of rapidly progressive clinical findings; accurate diagnosis requires a multimodal approach with complete correlation of clinical, histological, and imaging findings. Computed tomography and MRI can heighten the approach, even when necrotizing neutrophilic dermatoses and NM have similar clinical and histological appearances. Once a diagnosis of NM is established, prompt surgical and medical intervention improves the prognosis.
To the Editor:
Necrotizing myositis (NM) is an exceedingly rare necrotizing soft-tissue infection (NSTI) that is characterized by skeletal muscle involvement. β -Hemolytic streptococci, such as Streptococcus pyogenes , are the most common causative organisms. The overall prevalence and incidence of NM is unknown. A review of the literature by Adams et al 2 identified only 21 cases between 1900 and 1985.
Timely treatment of this infection leads to improved outcomes, but diagnosis can be challenging due to the ambiguous presentation of NM and lack of specific cutaneous changes.3 Clinical manifestations including bullae, blisters, vesicles, and petechiae become more prominent as infection progresses.4 If NM is suspected due to cutaneous manifestations, it is imperative that the underlying cause be identified; for example, NM must be distinguished from the overlapping presentation of pyoderma gangrenosum (PG). Because NM has nearly 100% mortality without prompt surgical intervention, early identification is critical.5 Herein, we report a case of NM that illustrates the correlation of clinical, histological, and imaging findings required to diagnose this potentially fatal infection.
An 80-year-old man presented to the emergency department with worsening pain, edema, and spreading redness of the right wrist over the last 5 weeks. He had a history of atopic dermatitis that was refractory to topical steroids and methotrexate; he was dependent on an oral steroid (prednisone 30 mg/d) for symptom control. The patient reported minor trauma to the area after performing home renovations. He received numerous rounds of oral antibiotics as an outpatient for presumed cellulitis and reported he was “getting better” but that the signs and symptoms of the condition grew worse after outpatient arthrocentesis. Dermatology was consulted to evaluate for a necrotizing neutrophilic dermatosis such as PG.
At the current presentation, the patient was tachycardic and afebrile (temperature, 98.2 °F [36.8 °C]). Physical examination revealed large, exquisitely tender, ill-defined necrotic ulceration of the right wrist with purulent debris and diffuse edema (Figure 1). Sequential evaluation at 6-hour intervals revealed notably increasing purulence, edema, and tenderness. Interconnected sinus tracts that extended to the fascial plane were observed.
Laboratory workup was notable for a markedly elevated C-reactive protein level of 18.9 mg/dL (reference range, 0–0.8 mg/dL) and an elevated white blood cell count of 19.92×109/L (reference range, 4.5–11.0×109/L). Blood and tissue cultures were positive for methicillin-sensitive Staphylococcus aureus. Computed tomography and magnetic resonance imaging (MRI) prior to biopsy demonstrated findings consistent with extensive subcutaneous and intramuscular areas of loculation and foci of gas (Figure 2). These findings were consistent with intramuscular involvement. A punch biopsy revealed a necrotic epidermis filled with neutrophilic pustules and a dense dermal infiltrate of neutrophilic inflammation consistent with infection (Figure 3).
Emergency surgery was performed with debridement of necrotic tissue and muscle. Postoperatively, he became more clinically stable after being placed on cefazolin through a peripherally inserted central catheter. He underwent 4 additional washouts over the ensuing month, as well as tendon reconstructions, a radial forearm flap, and reverse radial forearm flap reconstruction of the forearm. At the time of publication, there has been no recurrence. The patient’s atopic dermatitis is well controlled on dupilumab and topical fluocinonide alone, with a recent IgA level of 1 g/L and a body surface area measurement of 2%. Dupilumab was started 3 months after surgery.
Necrotizing myositis is a rare, rapidly progressive infection involving muscle that can manifest as superficial cutaneous involvement. The clinical manifestation of NM is harder to recognize than other NSTIs such as necrotizing fasciitis, likely due to the initial prodromal phase of NM, which consists of nonspecific constitutional symptoms.3 Systemic findings such as tachycardia, fever, hypotension, and shock occur in only 10% to 40% of NM patients.4,5
In our patient, clues of NM included fulfillment of criteria for systemic inflammatory response syndrome at admission and a presumed source of infection; taken together, these findings should lead to a diagnosis of sepsis until otherwise proven. The patient also reported pain that was not proportional to the skin findings, which suggested an NSTI. His lack of constitutional symptoms may have been due to the effects of prednisone, which was changed to dupilumab during hospitalization.
The clinical and histological findings of NM are nonspecific. Clinical findings include skin discoloration with bullae, blisters, vesicles, or petechiae.4 Our case adds to the descriptive morphology by including marked edema with ulceration, progressive purulence, and interconnected sinuses tracking to the fascial plane. Histologic findings can include confluent necrosis extending from the epidermis to the underlying muscle with dense neutrophilic inflammation. Notably, these findings can mirror necrotizing neutrophilic dermatoses in the absence of an infectious cause. Failure to recognize simple systemic inflammatory response syndrome criteria in NM patients due to slow treatment response or incorrect treatment can can lead to loss of a limb or death.
Workup reveals overlap with necrotizing neutrophilic dermatoses including PG, which is the prototypical neutrophilic dermatosis. Morphologically, PG presents as an ulcer with a purple and undermined border, often having developed from an initial papule, vesicle, or pustule. A neutrophilic infiltrate of the ulcer edge is the major criterion required to diagnose PG6; minor criteria include a positive pathergy test, history of inflammatory arthritis or inflammatory bowel disease, and exclusion of infection.6 When compared directly to an NSTI such as NM, the most important variable that sets PG apart is the absence of bacterial growth on blood and tissue cultures.7
Imaging studies can aid in the clinical diagnosis of NM and help distinguish the disease from PG. Computed tomography and MRI may demonstrate hallmarks of extensive necrotizing infection, such as gas formation and consequent fascial swelling, thickening and edema of involved muscle, and subfascial fluid collection.3,4 Distinct from NM, imaging findings in PG are more subtle, suggesting cellulitic inflammation with edema.8 A defining radiographic feature of NM can be foci of gas within muscle or fascia, though absence of this finding does not exclude NM.1,4
In conclusion, NM is a rare intramuscular infection that can be difficult to diagnose due to its nonspecific presentation and lack of constitutional symptoms. Dermatologists should maintain a high level of suspicion for NM in the setting of rapidly progressive clinical findings; accurate diagnosis requires a multimodal approach with complete correlation of clinical, histological, and imaging findings. Computed tomography and MRI can heighten the approach, even when necrotizing neutrophilic dermatoses and NM have similar clinical and histological appearances. Once a diagnosis of NM is established, prompt surgical and medical intervention improves the prognosis.
- Stevens DL, Baddour LM. Necrotizing soft tissue infections. UpToDate. Updated October 7, 2022. Accessed February 13, 2024. https://www.uptodate.com/contents/necrotizing-soft-tissue-infections?search=Necrotizing%20soft%20tissue%20infections&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1
- Adams EM, Gudmundsson S, Yocum DE, et al. Streptococcal myositis. Arch Intern Med . 1985;145:1020-1023.
- Khanna A, Gurusinghe D, Taylor D. Necrotizing myositis: highlighting the hidden depths—case series and review of the literature. ANZ J Surg . 2020;90:130-134. doi:10.1111/ans.15429
- Boinpally H, Howell RS, Ram B, et al. Necrotizing myositis: a rare necrotizing soft tissue infection involving muscle. Wounds . 2018;30:E116-E120.
- Anaya DA, Dellinger EP. Necrotizing soft-tissue infection: diagnosis and management. Clin Infect Dis . 2007;44:705-710. doi:10.1086/511638
- Maverakis E, Ma C, Shinkai K, et al. Diagnostic criteria of ulcerative pyoderma gangrenosum: a Delphi consensus of international experts. JAMA Dermatol . 2018;154:461-466. doi:10.1001/jamadermatol.2017.5980
- Sanchez IM, Lowenstein S, Johnson KA, et al. Clinical features of neutrophilic dermatosis variants resembling necrotizing fasciitis. JAMA Dermatol . 2019;155:79-84. doi:10.1001/jamadermatol.2018.3890
- Demirdover C, Geyik A, Vayvada H. Necrotising fasciitis or pyoderma gangrenosum: a fatal dilemma. Int Wound J . 2019;16:1347-1353. doi:10.1111/iwj.13196
- Stevens DL, Baddour LM. Necrotizing soft tissue infections. UpToDate. Updated October 7, 2022. Accessed February 13, 2024. https://www.uptodate.com/contents/necrotizing-soft-tissue-infections?search=Necrotizing%20soft%20tissue%20infections&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1
- Adams EM, Gudmundsson S, Yocum DE, et al. Streptococcal myositis. Arch Intern Med . 1985;145:1020-1023.
- Khanna A, Gurusinghe D, Taylor D. Necrotizing myositis: highlighting the hidden depths—case series and review of the literature. ANZ J Surg . 2020;90:130-134. doi:10.1111/ans.15429
- Boinpally H, Howell RS, Ram B, et al. Necrotizing myositis: a rare necrotizing soft tissue infection involving muscle. Wounds . 2018;30:E116-E120.
- Anaya DA, Dellinger EP. Necrotizing soft-tissue infection: diagnosis and management. Clin Infect Dis . 2007;44:705-710. doi:10.1086/511638
- Maverakis E, Ma C, Shinkai K, et al. Diagnostic criteria of ulcerative pyoderma gangrenosum: a Delphi consensus of international experts. JAMA Dermatol . 2018;154:461-466. doi:10.1001/jamadermatol.2017.5980
- Sanchez IM, Lowenstein S, Johnson KA, et al. Clinical features of neutrophilic dermatosis variants resembling necrotizing fasciitis. JAMA Dermatol . 2019;155:79-84. doi:10.1001/jamadermatol.2018.3890
- Demirdover C, Geyik A, Vayvada H. Necrotising fasciitis or pyoderma gangrenosum: a fatal dilemma. Int Wound J . 2019;16:1347-1353. doi:10.1111/iwj.13196
Practice Points
- The accurate diagnosis of necrotizing myositis (NM) requires a multimodal approach with complete clinical, histological, and radiographic correlation.
- Necrotizing myositis can manifest as violaceous erythematous plaques, bullae, blisters, or vesicles with petechiae, marked edema with ulceration, progressive purulence, and interconnected sinuses tracking to the fascial plane.
- The differential diagnosis of NM includes pyoderma gangrenosum.
Adding Antithrombotic to tPA Does Not Improve Stroke Outcome
PHOENIX — , results of new research show.
“Ultimately, we found no benefit for either medication added to standard-of-care thrombolysis in terms of improving stroke outcomes,” said lead study author Opeolu M. Adeoye, MD, professor of emergency medicine and department chair, Washington University School of Medicine, St. Louis, Missouri.
The results were surprising and disappointing for Dr. Adeoye. “We went into the trial hopeful and thinking we would be able to benefit patients in reducing disability from stroke,” he said.
The Multi-Arm Optimization of Stroke Thrombolysis (MOST) trial was stopped early because of futility following recommendations from the data and safety monitoring board.
The findings were presented at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.
A thrombolytic drug alone doesn’t help all patients, particularly those with larger clots. “Clots can open; they can reform; they can re-occlude, etc.,” said another author, Andrew D. Barreto, MD, associate professor, Department of Neurology, University of Texas Health Science Center, Houston. “The thought was that adding additional medications that thin the blood, like argatroban or eptifibatide, would amplify the effects of the clot-busting drug.”
Indeed, this approach has had success in cardiology in terms of blood vessel opening, said Dr. Adeoye, adding that some preclinical data suggest that antithrombotic drugs may be neuroprotective.
Six phase 2 studies going back over a dozen years suggested that these drugs are safe in stroke patients. Although these studies weren’t powered for efficacy, “we did see a signal that adding them would be better than just the clot-busting drug alone.” These findings prompted the current phase 3 trial, said Dr. Barreto.
The three-arm, single-blind MOST trial included 514 adult patients with acute ischemic stroke and a National Institutes of Health Stroke Scale (NIHSS) score of 6 or greater at 57 US centers. In the study cohort the mean age was about 68 years, 70% White/25% Black, and with about equal numbers of female and male patients.
All received standard stroke care including thrombolysis within 3 hours of symptom onset. Initially, researchers used intravenous alteplase (0.9 mg/kg), but as the standard of care changed over time, they began using tenecteplase (0.25 mg/kg).
Study patients were also randomly assigned to receive placebo or either argatroban (100 mcg/kg bolus followed by 3 mcg/kg per minute for 12 hours) or eptifibatide (135 mcg/kg bolus followed by 0.75 mcg/kg/min infusion for 2 hours). These treatments were initiated within 75 minutes of thrombolysis.
Two Different Mechanisms
The drugs have different mechanisms of action. Argatroban is an anticoagulant, a direct inhibitor of thrombin, while the antiplatelet eptifibatide blocks the glycoprotein IIb/IIIa receptor and was specifically developed to ensure rapid inhibition of platelet aggregation.
Patients could also receive endovascular thrombectomy as part of their usual care. In this study, about 44% of patients received this treatment.
The primary endpoint was 90-day utility weighted modified Rankin Scale (uw-mRS) scores, where the worst outcome is 0 and the best outcome is 10.
The study used a response-adaptive randomization design, where the randomization switches from a drug that doesn’t appear to have a chance of working to the arm more likely to be beneficial.
Of the 514 patients, the analysis included 228 in the placebo, 59 in the argatroban, and 227 in eptifibatide groups. Of the total, 421 completed the study.
The mean 90-day uw-mRS was 6.8 in the placebo group, 5.2 in the argatroban group, and 6.3 in the eptifibatide group.
The probability of argatroban being better than placebo was 0.2%; the probability of eptifibatide being better than placebo was 0.9%. The futility threshold was enrollment of 500 and less than a 20% chance of benefit, thus the decision to stop the trial.
In all subgroup analyses, which looked at age, stroke severity, the two thrombolytic drugs, and use of endovascular therapy, “we didn’t really see much of a signal that would suggest that’s the group we would need to be testing further,” said Dr. Barreto.
No Increased ICH Risk
The primary safety outcome was symptomatic intracranial hemorrhage within 36 hours of randomization. The researchers found no significant increase in rates of this outcome.
The argatroban cohort had significantly lower odds of favorable outcomes compared with placebo, noted Dr. Adeoye. For example, it had more all-cause deaths, although none were related to the study drug.
Speculating on why the intervention didn’t work, Dr. Barreto pointed to changes in standard of care between the earlier trials and the current one, including the incorporation of endovascular therapy and switch to tenecteplase.
Although the results were disappointing, Dr. Adeoye sees a bright side. “What we’re very proud of, and excited about, is the fact that we have a definitive answer on these two drugs, and we did it in one trial as opposed to sequential, separate ongoing trials.”
But he stressed that more work needs to be done, especially given that even with endovascular therapy, half of stroke patients don’t achieve independence.
“In this trial, we established that argatroban and eptifibatide added to thrombolysis did not work, but that doesn’t address the fact that we need to continue to see what we can do to improve the total proportion of stroke patients who, after our treatments, are functionally independent 90 days after the stroke.”
Down the Rabbit Hole
Commenting on the research, Larry B. Goldstein, MD, professor and chair, Department of Neurology, University of Kentucky, Lexington, praised the study’s adaptive design, noted that the hypothesis the study was based on was “reasonable” given the concern about additional thromboses, and found the results useful.
“The goal is not only to see what works but also what doesn’t work so we don’t go down that rabbit hole.”
He also pointed out that because the two blood-thinning drugs studied have very different mechanisms of action, it’s unlikely that another antithrombotic would add benefit to thrombolysis, “but you never say never.”
Dr. Adeoye and Dr. Barreto report research funding from the National Institutes of Health/National Institute of Neurological Disorders and Stroke. Dr. Adeoye also reports an executive role, receiving royalties/being a patent beneficiary, Sense Diagnostics, Inc. Dr. Goldstein has no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
PHOENIX — , results of new research show.
“Ultimately, we found no benefit for either medication added to standard-of-care thrombolysis in terms of improving stroke outcomes,” said lead study author Opeolu M. Adeoye, MD, professor of emergency medicine and department chair, Washington University School of Medicine, St. Louis, Missouri.
The results were surprising and disappointing for Dr. Adeoye. “We went into the trial hopeful and thinking we would be able to benefit patients in reducing disability from stroke,” he said.
The Multi-Arm Optimization of Stroke Thrombolysis (MOST) trial was stopped early because of futility following recommendations from the data and safety monitoring board.
The findings were presented at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.
A thrombolytic drug alone doesn’t help all patients, particularly those with larger clots. “Clots can open; they can reform; they can re-occlude, etc.,” said another author, Andrew D. Barreto, MD, associate professor, Department of Neurology, University of Texas Health Science Center, Houston. “The thought was that adding additional medications that thin the blood, like argatroban or eptifibatide, would amplify the effects of the clot-busting drug.”
Indeed, this approach has had success in cardiology in terms of blood vessel opening, said Dr. Adeoye, adding that some preclinical data suggest that antithrombotic drugs may be neuroprotective.
Six phase 2 studies going back over a dozen years suggested that these drugs are safe in stroke patients. Although these studies weren’t powered for efficacy, “we did see a signal that adding them would be better than just the clot-busting drug alone.” These findings prompted the current phase 3 trial, said Dr. Barreto.
The three-arm, single-blind MOST trial included 514 adult patients with acute ischemic stroke and a National Institutes of Health Stroke Scale (NIHSS) score of 6 or greater at 57 US centers. In the study cohort the mean age was about 68 years, 70% White/25% Black, and with about equal numbers of female and male patients.
All received standard stroke care including thrombolysis within 3 hours of symptom onset. Initially, researchers used intravenous alteplase (0.9 mg/kg), but as the standard of care changed over time, they began using tenecteplase (0.25 mg/kg).
Study patients were also randomly assigned to receive placebo or either argatroban (100 mcg/kg bolus followed by 3 mcg/kg per minute for 12 hours) or eptifibatide (135 mcg/kg bolus followed by 0.75 mcg/kg/min infusion for 2 hours). These treatments were initiated within 75 minutes of thrombolysis.
Two Different Mechanisms
The drugs have different mechanisms of action. Argatroban is an anticoagulant, a direct inhibitor of thrombin, while the antiplatelet eptifibatide blocks the glycoprotein IIb/IIIa receptor and was specifically developed to ensure rapid inhibition of platelet aggregation.
Patients could also receive endovascular thrombectomy as part of their usual care. In this study, about 44% of patients received this treatment.
The primary endpoint was 90-day utility weighted modified Rankin Scale (uw-mRS) scores, where the worst outcome is 0 and the best outcome is 10.
The study used a response-adaptive randomization design, where the randomization switches from a drug that doesn’t appear to have a chance of working to the arm more likely to be beneficial.
Of the 514 patients, the analysis included 228 in the placebo, 59 in the argatroban, and 227 in eptifibatide groups. Of the total, 421 completed the study.
The mean 90-day uw-mRS was 6.8 in the placebo group, 5.2 in the argatroban group, and 6.3 in the eptifibatide group.
The probability of argatroban being better than placebo was 0.2%; the probability of eptifibatide being better than placebo was 0.9%. The futility threshold was enrollment of 500 and less than a 20% chance of benefit, thus the decision to stop the trial.
In all subgroup analyses, which looked at age, stroke severity, the two thrombolytic drugs, and use of endovascular therapy, “we didn’t really see much of a signal that would suggest that’s the group we would need to be testing further,” said Dr. Barreto.
No Increased ICH Risk
The primary safety outcome was symptomatic intracranial hemorrhage within 36 hours of randomization. The researchers found no significant increase in rates of this outcome.
The argatroban cohort had significantly lower odds of favorable outcomes compared with placebo, noted Dr. Adeoye. For example, it had more all-cause deaths, although none were related to the study drug.
Speculating on why the intervention didn’t work, Dr. Barreto pointed to changes in standard of care between the earlier trials and the current one, including the incorporation of endovascular therapy and switch to tenecteplase.
Although the results were disappointing, Dr. Adeoye sees a bright side. “What we’re very proud of, and excited about, is the fact that we have a definitive answer on these two drugs, and we did it in one trial as opposed to sequential, separate ongoing trials.”
But he stressed that more work needs to be done, especially given that even with endovascular therapy, half of stroke patients don’t achieve independence.
“In this trial, we established that argatroban and eptifibatide added to thrombolysis did not work, but that doesn’t address the fact that we need to continue to see what we can do to improve the total proportion of stroke patients who, after our treatments, are functionally independent 90 days after the stroke.”
Down the Rabbit Hole
Commenting on the research, Larry B. Goldstein, MD, professor and chair, Department of Neurology, University of Kentucky, Lexington, praised the study’s adaptive design, noted that the hypothesis the study was based on was “reasonable” given the concern about additional thromboses, and found the results useful.
“The goal is not only to see what works but also what doesn’t work so we don’t go down that rabbit hole.”
He also pointed out that because the two blood-thinning drugs studied have very different mechanisms of action, it’s unlikely that another antithrombotic would add benefit to thrombolysis, “but you never say never.”
Dr. Adeoye and Dr. Barreto report research funding from the National Institutes of Health/National Institute of Neurological Disorders and Stroke. Dr. Adeoye also reports an executive role, receiving royalties/being a patent beneficiary, Sense Diagnostics, Inc. Dr. Goldstein has no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
PHOENIX — , results of new research show.
“Ultimately, we found no benefit for either medication added to standard-of-care thrombolysis in terms of improving stroke outcomes,” said lead study author Opeolu M. Adeoye, MD, professor of emergency medicine and department chair, Washington University School of Medicine, St. Louis, Missouri.
The results were surprising and disappointing for Dr. Adeoye. “We went into the trial hopeful and thinking we would be able to benefit patients in reducing disability from stroke,” he said.
The Multi-Arm Optimization of Stroke Thrombolysis (MOST) trial was stopped early because of futility following recommendations from the data and safety monitoring board.
The findings were presented at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.
A thrombolytic drug alone doesn’t help all patients, particularly those with larger clots. “Clots can open; they can reform; they can re-occlude, etc.,” said another author, Andrew D. Barreto, MD, associate professor, Department of Neurology, University of Texas Health Science Center, Houston. “The thought was that adding additional medications that thin the blood, like argatroban or eptifibatide, would amplify the effects of the clot-busting drug.”
Indeed, this approach has had success in cardiology in terms of blood vessel opening, said Dr. Adeoye, adding that some preclinical data suggest that antithrombotic drugs may be neuroprotective.
Six phase 2 studies going back over a dozen years suggested that these drugs are safe in stroke patients. Although these studies weren’t powered for efficacy, “we did see a signal that adding them would be better than just the clot-busting drug alone.” These findings prompted the current phase 3 trial, said Dr. Barreto.
The three-arm, single-blind MOST trial included 514 adult patients with acute ischemic stroke and a National Institutes of Health Stroke Scale (NIHSS) score of 6 or greater at 57 US centers. In the study cohort the mean age was about 68 years, 70% White/25% Black, and with about equal numbers of female and male patients.
All received standard stroke care including thrombolysis within 3 hours of symptom onset. Initially, researchers used intravenous alteplase (0.9 mg/kg), but as the standard of care changed over time, they began using tenecteplase (0.25 mg/kg).
Study patients were also randomly assigned to receive placebo or either argatroban (100 mcg/kg bolus followed by 3 mcg/kg per minute for 12 hours) or eptifibatide (135 mcg/kg bolus followed by 0.75 mcg/kg/min infusion for 2 hours). These treatments were initiated within 75 minutes of thrombolysis.
Two Different Mechanisms
The drugs have different mechanisms of action. Argatroban is an anticoagulant, a direct inhibitor of thrombin, while the antiplatelet eptifibatide blocks the glycoprotein IIb/IIIa receptor and was specifically developed to ensure rapid inhibition of platelet aggregation.
Patients could also receive endovascular thrombectomy as part of their usual care. In this study, about 44% of patients received this treatment.
The primary endpoint was 90-day utility weighted modified Rankin Scale (uw-mRS) scores, where the worst outcome is 0 and the best outcome is 10.
The study used a response-adaptive randomization design, where the randomization switches from a drug that doesn’t appear to have a chance of working to the arm more likely to be beneficial.
Of the 514 patients, the analysis included 228 in the placebo, 59 in the argatroban, and 227 in eptifibatide groups. Of the total, 421 completed the study.
The mean 90-day uw-mRS was 6.8 in the placebo group, 5.2 in the argatroban group, and 6.3 in the eptifibatide group.
The probability of argatroban being better than placebo was 0.2%; the probability of eptifibatide being better than placebo was 0.9%. The futility threshold was enrollment of 500 and less than a 20% chance of benefit, thus the decision to stop the trial.
In all subgroup analyses, which looked at age, stroke severity, the two thrombolytic drugs, and use of endovascular therapy, “we didn’t really see much of a signal that would suggest that’s the group we would need to be testing further,” said Dr. Barreto.
No Increased ICH Risk
The primary safety outcome was symptomatic intracranial hemorrhage within 36 hours of randomization. The researchers found no significant increase in rates of this outcome.
The argatroban cohort had significantly lower odds of favorable outcomes compared with placebo, noted Dr. Adeoye. For example, it had more all-cause deaths, although none were related to the study drug.
Speculating on why the intervention didn’t work, Dr. Barreto pointed to changes in standard of care between the earlier trials and the current one, including the incorporation of endovascular therapy and switch to tenecteplase.
Although the results were disappointing, Dr. Adeoye sees a bright side. “What we’re very proud of, and excited about, is the fact that we have a definitive answer on these two drugs, and we did it in one trial as opposed to sequential, separate ongoing trials.”
But he stressed that more work needs to be done, especially given that even with endovascular therapy, half of stroke patients don’t achieve independence.
“In this trial, we established that argatroban and eptifibatide added to thrombolysis did not work, but that doesn’t address the fact that we need to continue to see what we can do to improve the total proportion of stroke patients who, after our treatments, are functionally independent 90 days after the stroke.”
Down the Rabbit Hole
Commenting on the research, Larry B. Goldstein, MD, professor and chair, Department of Neurology, University of Kentucky, Lexington, praised the study’s adaptive design, noted that the hypothesis the study was based on was “reasonable” given the concern about additional thromboses, and found the results useful.
“The goal is not only to see what works but also what doesn’t work so we don’t go down that rabbit hole.”
He also pointed out that because the two blood-thinning drugs studied have very different mechanisms of action, it’s unlikely that another antithrombotic would add benefit to thrombolysis, “but you never say never.”
Dr. Adeoye and Dr. Barreto report research funding from the National Institutes of Health/National Institute of Neurological Disorders and Stroke. Dr. Adeoye also reports an executive role, receiving royalties/being a patent beneficiary, Sense Diagnostics, Inc. Dr. Goldstein has no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
FROM ISC 2024
Dermatologic Reactions Following COVID-19 Vaccination: A Case Series
Cutaneous reactions associated with the Pfizer-BioNTech COVID-19 vaccine have been reported worldwide since December 2020. Local injection site reactions (<1%) such as erythema, swelling, delayed local reactions (1%–10%), morbilliform rash, urticarial reactions, pityriasis rosea, Rowell syndrome, and lichen planus have been reported following the Pfizer-BioNTech COVID-19 vaccine.1 Cutaneous reactions reported in association with the Sinovac-Coronavac COVID-19 vaccine include swelling, redness, itching, discoloration, induration (1%–10%), urticaria, petechial rash, and exacerbation of psoriasis at the local injection site (<1%).2
We describe 7 patients from Turkey who presented with various dermatologic problems 5 to 28 days after COVID-19 vaccination, highlighting the possibility of early and late cutaneous reactions related to the vaccine (Table).
Case Reports
Patient 1—A 44-year-old woman was admitted to the dermatology clinic with painful lesions on the trunk of 3 days’ duration. Dermatologic examination revealed grouped erythematous vesicles showing dermatomal spread in the right thoracolumbar (dermatome T10) region. The patient reported that she had received 2 doses of the Sinovac-Coronavac vaccine (doses 1 and 2) and 2 doses of the BioNTech COVID-19 vaccine (doses 3 and 4); the rash had developed 28 days after she received the 4th dose. Her medical history was unremarkable. The lesions regressed after 1 week of treatment with oral valacyclovir 1000 mg 3 times daily, but she developed postherpetic neuralgia 1 week after starting treatment, which resolved after 8 weeks.
Patient 2—A 68-year-old woman presented to the dermatology clinic for evaluation of painful sores on the upper lip of 1 day’s duration. She had a history of rheumatoid arthritis, hypertension, and atopy and was currently taking prednisone and etanercept. Dermatologic examination revealed grouped vesicles on an erythematous base on the upper lip. A diagnosis of herpes labialis was made. The patient reported that she had received a third dose of the Sinovac-Coronavac vaccine 10 days prior to the appearance of the lesions. Her symptoms resolved completely within 2 weeks of treatment with topical acyclovir.
Patient 3—A 64-year-old woman was admitted to the hospital with pain, redness, and watery sores on and around the left eyelid of 2 days’ duration. Dermatologic evaluation revealed the erythematous surface of the left eyelid and periorbital area showed partial crusts, clustered vesicles, erythema, and edema. Additionally, the conjunctiva was purulent and erythematous. The patient’s medical history was notable for allergic asthma, hypertension, anxiety, and depression. For this reason, the patient was prescribed an angiotensin receptor blocker and a selective serotonin reuptake inhibitor. She noted that a similar rash had developed around the left eye 6 years prior that was diagnosed as herpes zoster (HZ). She also reported that she had received 2 doses of the Sinovac-Coronavac COVID-19 vaccine followed by 1 dose of the BioNTech COVID-19 vaccine, which she had received 2 weeks before the rash developed. The patient was treated at the eye clinic and was found to have ocular involvement. Ophthalmology was consulted and a diagnosis of herpes zoster ophthalmicus (HZO) was made. Systemic valacyclovir treatment was initiated, resulting in clinical improvement within 3 weeks.
Patient 4—A 75-year-old man was admitted to the hospital with chest and back pain and widespread muscle pain of several days’ duration. His medical history was remarkable for diabetes mellitus, hypertension, depression, and coronary artery bypass surgery. A medication history revealed treatment with a β-blocker, acetylsalicylic acid, a calcium channel blocker, a dipeptidyl peptidase 4 inhibitor, and a selective serotonin reuptake inhibitor. Dermatologic examination revealed grouped vesicles on an erythematous background in dermatome T5 on the right chest and back. A diagnosis of HZ was made. The patient reported that he had received 2 doses of the Sinovac-Coronavac vaccine followed by 1 dose of the Pfizer-BioNTech vaccine 2 weeks prior to the current presentation. He was treated with valacyclovir for 1 week, and his symptoms resolved entirely within 3 weeks.
Patient 5—A 50-year-old woman presented to the hospital for evaluation of painful sores on the back, chest, groin, and abdomen of 10 days’ duration. The lesions initially had developed 7 days after receiving the BioNTech COVID-19 vaccine; she previously had received 2 doses of the Sinovac-Coronavac vaccine. The patient had a history of untreated psoriasis. Dermatologic examination revealed grouped vesicles on an erythematous background in the T2–L2 dermatomes on the left side of the trunk. A diagnosis of HZ was made. The lesions resolved after 1 week of treatment with systemic valacyclovir; however, she subsequently developed postherpetic neuralgia, hypoesthesia, and postinflammatory hyperpigmentation in the affected regions.
Patient 6—A 37-year-old woman presented to the hospital with redness, swelling, and itching all over the body of 3 days’ duration. The patient noted that the rash would subside and reappear throughout the day. Her medical history was unremarkable, except for COVID-19 infection 6 months prior. She had received a second dose of the BioNTech vaccine 20 days prior to development of symptoms. Dermatologic examination revealed widespread erythematous urticarial plaques. A diagnosis of acute urticaria was made. The patient recovered completely after 1 week of treatment with a systemic steroid and 3 weeks of antihistamine treatment.
Patient 7—A 63-year-old woman presented to the hospital with widespread itching and rash that appeared 5 days after the first dose of the BioNTech COVID-19 vaccine. The patient reported that the rash resolved spontaneously within a few hours but then reappeared. Her medical history revealed that she was taking tamoxifen for breast cancer and that she previously had received 2 doses of the Sinovac-Coronavac vaccine. Dermatologic examination revealed erythematous urticarial plaques on the trunk and arms. A diagnosis of urticaria was made, and her symptoms resolved after 6 weeks of antihistamine treatment.
Comment
Skin lesions associated with COVID-19 infection have been reported worldwide3,4 as well as dermatologic reactions following COVID-19 vaccination. In one case from Turkey, HZ infection was reported in a 68-year-old man 5 days after he received a second dose of the COVID-19 vaccine.5 In another case, HZ infection developed in a 78-year-old man 5 days after COVID-19 vaccination.6 Numerous cases of HZ infection developing within 1 to 26 days of COVID-19 vaccination have been reported worldwide.7-9
In a study conducted in the United States, 40 skin reactions associated with the COVID-19 vaccine were investigated; of these cases, 87.5% (35/40) were reported as varicella-zoster virus, and 12.5% (5/40) were reported as herpes simplex reactivation; 54% (19/35) and 80% (4/5) of these cases, respectively, were associated with the Pfizer-BioNTech vaccine.10 The average age of patients who developed a skin reaction was 46 years, and 70% (28/40) were women. The time to onset of the reaction was 2 to 13 days after vaccination, and symptoms were reported to improve within 7 days on average.10
Another study from Spain examined 405 vaccine-related skin reactions, 40.2% of which were related to the Pfizer-BioNTech vaccine. Among them, 80.2% occurred in women; 13.8% of cases were diagnosed as varicella-zoster virus or HZ virus reactivation, and 14.6% were urticaria. Eighty reactions (21%) were classified as severe/very severe and 81% required treatment.11 One study reported 414 skin reactions from the COVID-19 vaccine from December 2020 to February 2021; of these cases, 83% occurred after the Moderna vaccine, which is not available in Turkey, and 17% occurred after the Pfizer-BioNTech vaccine.12A systematic review of 91 patients who developed HZ infection after COVID-19 vaccination reported that 10% (9/91) of cases were receiving immunosuppressive therapy and 13% (12/91) had an autoimmune disease.7 In our case series, it is known that at least 2 of the patients (patients 2 and 5), including 1 patient with rheumatoid arthritis (patient 2) who was on immunosuppressive treatment, had autoimmune disorders. However, reports in the literature indicate that most patients with autoimmune inflammatory rheumatic diseases remain stable after vaccination.13
Herpes zoster ophthalmicus is a rare form of HZ caused by involvement of the ophthalmic branch of the trigeminal nerve that manifests as vesicular lesions and retinitis, uveitis, keratitis, conjunctivitis, and pain on an erythematous background. Two cases of women who developed HZO infection after Pfizer-BioNTech vaccination were reported in the literature.14 Although patient 3 in our case series had a history of HZO 6 years prior, the possibility of the Pfizer-BioNTech vaccine triggering HZO should be taken into consideration.
Although cutaneous reactions after the Sinovac-Coronavac vaccine were observed in only 1 of 7 patients in our case series, skin reactions after Sinovac-Coronavac (an inactivated viral vaccine) have been reported in the literature. In one study, after a total of 35,229 injections, the incidence of cutaneous adverse events due to Sinovac-Coronavac was reported to be 0.94% and 0.70% after the first and second doses, respectively.15 Therefore, further study results are needed to directly attribute the reactions to COVID-19 vaccination.
Conclusion
Our case series highlights that clinicians should be vigilant in diagnosing cutaneous reactions following COVID-19 vaccination early to prevent potential complications. Early recognition of reactions is crucial, and the prognosis can be improved with appropriate treatment. Despite the potential dermatologic adverse effects of the COVID-19 vaccine, the most effective way to protect against serious COVID-19 infection is to continue to be vaccinated.
- Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine. N Engl J Med. 2020;383:2603-2615.
- Zhang Y, Zeng G, Pan H, et al. Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18–59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Lancet Infect Dis. 2021;21:181-192.
- Tan SW, Tam YC, Oh CC. Skin manifestations of COVID-19: a worldwide review. JAAD Int. 2021;2:119-133.
- Singh H, Kaur H, Singh K, et al. Cutaneous manifestations of COVID-19: a systematic review. advances in wound care. 2021;10:51-80.
- Aksu SB, Öztürk GZ. A rare case of shingles after COVID-19 vaccine: is it a possible adverse effect? clinical and experimental vaccine research. 2021;10:198-201.
- Bostan E, Yalici-Armagan B. Herpes zoster following inactivated COVID-19 vaccine: a coexistence or coincidence? J Cosmet Dermatol. 2021;20:1566-1567.
- Katsikas Triantafyllidis K, Giannos P, Mian IT, et al. Varicella zoster virus reactivation following COVID-19 vaccination: a systematic review of case reports. Vaccines (Basel). 2021;9:1013. doi:10.3390/vaccines9091013
- Rodríguez-Jiménez P, Chicharro P, Cabrera LM, et al. Varicella-zoster virus reactivation after SARS-CoV-2 BNT162b2 mRNA vaccination: report of 5 cases. JAAD Case Rep. 2021;12:58-59. doi:10.1016/j.jdcr.2021.04.014
- Lee C, Cotter D, Basa J, et al. 20 Post-COVID-19 vaccine-related shingles cases seen at the Las Vegas Dermatology clinic and sent to us via social media. J Cosmet Dermatol. 2021;20:1960-1964.
- Fathy RA, McMahon DE, Lee C, et al. Varicella-zoster and herpes simplex virus reactivation post-COVID-19 vaccination: a review of 40 cases in an International Dermatology Registry. J Eur Acad Dermatol Venerol. 2022;36:E6-E9.
- Català A, Muñoz-Santos C, Galván-Casas C, et al. Cutaneous reactions after SARS-CoV-2 vaccination: a cross-sectional Spanish nationwide study of 405 cases. Br J Dermatol. 2022;186:142-152.
- McMahon DE, Amerson E, Rosenbach M, et al. Cutaneous reactions reported after Moderna and Pfizer COVID-19 vaccination: a registry-based study of 414 cases. J Am Acad Dermatol. 2021;85:46-55.
- Furer V, Eviatar T, Zisman D, et al. Immunogenicity and safety of the BNT162b2 mRNA COVID-19 vaccine in adult patients with autoimmune inflammatory rheumatic diseases and in the general population: a multicentre study. Ann Rheum Dis. 2021;80:1330-1338.
- Bernardini N, Skroza N, Mambrin A, et al. Herpes zoster ophthalmicus in two women after Pfizer-BioNTech (BNT162b2) vaccine. J Med Virol. 2022;94:817-818.
- Rerknimitr P, Puaratanaarunkon T, Wongtada C, et al. Cutaneous adverse reactions from 35,229 doses of Sinovac and AstraZeneca COVID-19 vaccination: a prospective cohort study in healthcare workers. J Eur Acad Dermatol Venereol. 2022;36:E158-E161.
Cutaneous reactions associated with the Pfizer-BioNTech COVID-19 vaccine have been reported worldwide since December 2020. Local injection site reactions (<1%) such as erythema, swelling, delayed local reactions (1%–10%), morbilliform rash, urticarial reactions, pityriasis rosea, Rowell syndrome, and lichen planus have been reported following the Pfizer-BioNTech COVID-19 vaccine.1 Cutaneous reactions reported in association with the Sinovac-Coronavac COVID-19 vaccine include swelling, redness, itching, discoloration, induration (1%–10%), urticaria, petechial rash, and exacerbation of psoriasis at the local injection site (<1%).2
We describe 7 patients from Turkey who presented with various dermatologic problems 5 to 28 days after COVID-19 vaccination, highlighting the possibility of early and late cutaneous reactions related to the vaccine (Table).
Case Reports
Patient 1—A 44-year-old woman was admitted to the dermatology clinic with painful lesions on the trunk of 3 days’ duration. Dermatologic examination revealed grouped erythematous vesicles showing dermatomal spread in the right thoracolumbar (dermatome T10) region. The patient reported that she had received 2 doses of the Sinovac-Coronavac vaccine (doses 1 and 2) and 2 doses of the BioNTech COVID-19 vaccine (doses 3 and 4); the rash had developed 28 days after she received the 4th dose. Her medical history was unremarkable. The lesions regressed after 1 week of treatment with oral valacyclovir 1000 mg 3 times daily, but she developed postherpetic neuralgia 1 week after starting treatment, which resolved after 8 weeks.
Patient 2—A 68-year-old woman presented to the dermatology clinic for evaluation of painful sores on the upper lip of 1 day’s duration. She had a history of rheumatoid arthritis, hypertension, and atopy and was currently taking prednisone and etanercept. Dermatologic examination revealed grouped vesicles on an erythematous base on the upper lip. A diagnosis of herpes labialis was made. The patient reported that she had received a third dose of the Sinovac-Coronavac vaccine 10 days prior to the appearance of the lesions. Her symptoms resolved completely within 2 weeks of treatment with topical acyclovir.
Patient 3—A 64-year-old woman was admitted to the hospital with pain, redness, and watery sores on and around the left eyelid of 2 days’ duration. Dermatologic evaluation revealed the erythematous surface of the left eyelid and periorbital area showed partial crusts, clustered vesicles, erythema, and edema. Additionally, the conjunctiva was purulent and erythematous. The patient’s medical history was notable for allergic asthma, hypertension, anxiety, and depression. For this reason, the patient was prescribed an angiotensin receptor blocker and a selective serotonin reuptake inhibitor. She noted that a similar rash had developed around the left eye 6 years prior that was diagnosed as herpes zoster (HZ). She also reported that she had received 2 doses of the Sinovac-Coronavac COVID-19 vaccine followed by 1 dose of the BioNTech COVID-19 vaccine, which she had received 2 weeks before the rash developed. The patient was treated at the eye clinic and was found to have ocular involvement. Ophthalmology was consulted and a diagnosis of herpes zoster ophthalmicus (HZO) was made. Systemic valacyclovir treatment was initiated, resulting in clinical improvement within 3 weeks.
Patient 4—A 75-year-old man was admitted to the hospital with chest and back pain and widespread muscle pain of several days’ duration. His medical history was remarkable for diabetes mellitus, hypertension, depression, and coronary artery bypass surgery. A medication history revealed treatment with a β-blocker, acetylsalicylic acid, a calcium channel blocker, a dipeptidyl peptidase 4 inhibitor, and a selective serotonin reuptake inhibitor. Dermatologic examination revealed grouped vesicles on an erythematous background in dermatome T5 on the right chest and back. A diagnosis of HZ was made. The patient reported that he had received 2 doses of the Sinovac-Coronavac vaccine followed by 1 dose of the Pfizer-BioNTech vaccine 2 weeks prior to the current presentation. He was treated with valacyclovir for 1 week, and his symptoms resolved entirely within 3 weeks.
Patient 5—A 50-year-old woman presented to the hospital for evaluation of painful sores on the back, chest, groin, and abdomen of 10 days’ duration. The lesions initially had developed 7 days after receiving the BioNTech COVID-19 vaccine; she previously had received 2 doses of the Sinovac-Coronavac vaccine. The patient had a history of untreated psoriasis. Dermatologic examination revealed grouped vesicles on an erythematous background in the T2–L2 dermatomes on the left side of the trunk. A diagnosis of HZ was made. The lesions resolved after 1 week of treatment with systemic valacyclovir; however, she subsequently developed postherpetic neuralgia, hypoesthesia, and postinflammatory hyperpigmentation in the affected regions.
Patient 6—A 37-year-old woman presented to the hospital with redness, swelling, and itching all over the body of 3 days’ duration. The patient noted that the rash would subside and reappear throughout the day. Her medical history was unremarkable, except for COVID-19 infection 6 months prior. She had received a second dose of the BioNTech vaccine 20 days prior to development of symptoms. Dermatologic examination revealed widespread erythematous urticarial plaques. A diagnosis of acute urticaria was made. The patient recovered completely after 1 week of treatment with a systemic steroid and 3 weeks of antihistamine treatment.
Patient 7—A 63-year-old woman presented to the hospital with widespread itching and rash that appeared 5 days after the first dose of the BioNTech COVID-19 vaccine. The patient reported that the rash resolved spontaneously within a few hours but then reappeared. Her medical history revealed that she was taking tamoxifen for breast cancer and that she previously had received 2 doses of the Sinovac-Coronavac vaccine. Dermatologic examination revealed erythematous urticarial plaques on the trunk and arms. A diagnosis of urticaria was made, and her symptoms resolved after 6 weeks of antihistamine treatment.
Comment
Skin lesions associated with COVID-19 infection have been reported worldwide3,4 as well as dermatologic reactions following COVID-19 vaccination. In one case from Turkey, HZ infection was reported in a 68-year-old man 5 days after he received a second dose of the COVID-19 vaccine.5 In another case, HZ infection developed in a 78-year-old man 5 days after COVID-19 vaccination.6 Numerous cases of HZ infection developing within 1 to 26 days of COVID-19 vaccination have been reported worldwide.7-9
In a study conducted in the United States, 40 skin reactions associated with the COVID-19 vaccine were investigated; of these cases, 87.5% (35/40) were reported as varicella-zoster virus, and 12.5% (5/40) were reported as herpes simplex reactivation; 54% (19/35) and 80% (4/5) of these cases, respectively, were associated with the Pfizer-BioNTech vaccine.10 The average age of patients who developed a skin reaction was 46 years, and 70% (28/40) were women. The time to onset of the reaction was 2 to 13 days after vaccination, and symptoms were reported to improve within 7 days on average.10
Another study from Spain examined 405 vaccine-related skin reactions, 40.2% of which were related to the Pfizer-BioNTech vaccine. Among them, 80.2% occurred in women; 13.8% of cases were diagnosed as varicella-zoster virus or HZ virus reactivation, and 14.6% were urticaria. Eighty reactions (21%) were classified as severe/very severe and 81% required treatment.11 One study reported 414 skin reactions from the COVID-19 vaccine from December 2020 to February 2021; of these cases, 83% occurred after the Moderna vaccine, which is not available in Turkey, and 17% occurred after the Pfizer-BioNTech vaccine.12A systematic review of 91 patients who developed HZ infection after COVID-19 vaccination reported that 10% (9/91) of cases were receiving immunosuppressive therapy and 13% (12/91) had an autoimmune disease.7 In our case series, it is known that at least 2 of the patients (patients 2 and 5), including 1 patient with rheumatoid arthritis (patient 2) who was on immunosuppressive treatment, had autoimmune disorders. However, reports in the literature indicate that most patients with autoimmune inflammatory rheumatic diseases remain stable after vaccination.13
Herpes zoster ophthalmicus is a rare form of HZ caused by involvement of the ophthalmic branch of the trigeminal nerve that manifests as vesicular lesions and retinitis, uveitis, keratitis, conjunctivitis, and pain on an erythematous background. Two cases of women who developed HZO infection after Pfizer-BioNTech vaccination were reported in the literature.14 Although patient 3 in our case series had a history of HZO 6 years prior, the possibility of the Pfizer-BioNTech vaccine triggering HZO should be taken into consideration.
Although cutaneous reactions after the Sinovac-Coronavac vaccine were observed in only 1 of 7 patients in our case series, skin reactions after Sinovac-Coronavac (an inactivated viral vaccine) have been reported in the literature. In one study, after a total of 35,229 injections, the incidence of cutaneous adverse events due to Sinovac-Coronavac was reported to be 0.94% and 0.70% after the first and second doses, respectively.15 Therefore, further study results are needed to directly attribute the reactions to COVID-19 vaccination.
Conclusion
Our case series highlights that clinicians should be vigilant in diagnosing cutaneous reactions following COVID-19 vaccination early to prevent potential complications. Early recognition of reactions is crucial, and the prognosis can be improved with appropriate treatment. Despite the potential dermatologic adverse effects of the COVID-19 vaccine, the most effective way to protect against serious COVID-19 infection is to continue to be vaccinated.
Cutaneous reactions associated with the Pfizer-BioNTech COVID-19 vaccine have been reported worldwide since December 2020. Local injection site reactions (<1%) such as erythema, swelling, delayed local reactions (1%–10%), morbilliform rash, urticarial reactions, pityriasis rosea, Rowell syndrome, and lichen planus have been reported following the Pfizer-BioNTech COVID-19 vaccine.1 Cutaneous reactions reported in association with the Sinovac-Coronavac COVID-19 vaccine include swelling, redness, itching, discoloration, induration (1%–10%), urticaria, petechial rash, and exacerbation of psoriasis at the local injection site (<1%).2
We describe 7 patients from Turkey who presented with various dermatologic problems 5 to 28 days after COVID-19 vaccination, highlighting the possibility of early and late cutaneous reactions related to the vaccine (Table).
Case Reports
Patient 1—A 44-year-old woman was admitted to the dermatology clinic with painful lesions on the trunk of 3 days’ duration. Dermatologic examination revealed grouped erythematous vesicles showing dermatomal spread in the right thoracolumbar (dermatome T10) region. The patient reported that she had received 2 doses of the Sinovac-Coronavac vaccine (doses 1 and 2) and 2 doses of the BioNTech COVID-19 vaccine (doses 3 and 4); the rash had developed 28 days after she received the 4th dose. Her medical history was unremarkable. The lesions regressed after 1 week of treatment with oral valacyclovir 1000 mg 3 times daily, but she developed postherpetic neuralgia 1 week after starting treatment, which resolved after 8 weeks.
Patient 2—A 68-year-old woman presented to the dermatology clinic for evaluation of painful sores on the upper lip of 1 day’s duration. She had a history of rheumatoid arthritis, hypertension, and atopy and was currently taking prednisone and etanercept. Dermatologic examination revealed grouped vesicles on an erythematous base on the upper lip. A diagnosis of herpes labialis was made. The patient reported that she had received a third dose of the Sinovac-Coronavac vaccine 10 days prior to the appearance of the lesions. Her symptoms resolved completely within 2 weeks of treatment with topical acyclovir.
Patient 3—A 64-year-old woman was admitted to the hospital with pain, redness, and watery sores on and around the left eyelid of 2 days’ duration. Dermatologic evaluation revealed the erythematous surface of the left eyelid and periorbital area showed partial crusts, clustered vesicles, erythema, and edema. Additionally, the conjunctiva was purulent and erythematous. The patient’s medical history was notable for allergic asthma, hypertension, anxiety, and depression. For this reason, the patient was prescribed an angiotensin receptor blocker and a selective serotonin reuptake inhibitor. She noted that a similar rash had developed around the left eye 6 years prior that was diagnosed as herpes zoster (HZ). She also reported that she had received 2 doses of the Sinovac-Coronavac COVID-19 vaccine followed by 1 dose of the BioNTech COVID-19 vaccine, which she had received 2 weeks before the rash developed. The patient was treated at the eye clinic and was found to have ocular involvement. Ophthalmology was consulted and a diagnosis of herpes zoster ophthalmicus (HZO) was made. Systemic valacyclovir treatment was initiated, resulting in clinical improvement within 3 weeks.
Patient 4—A 75-year-old man was admitted to the hospital with chest and back pain and widespread muscle pain of several days’ duration. His medical history was remarkable for diabetes mellitus, hypertension, depression, and coronary artery bypass surgery. A medication history revealed treatment with a β-blocker, acetylsalicylic acid, a calcium channel blocker, a dipeptidyl peptidase 4 inhibitor, and a selective serotonin reuptake inhibitor. Dermatologic examination revealed grouped vesicles on an erythematous background in dermatome T5 on the right chest and back. A diagnosis of HZ was made. The patient reported that he had received 2 doses of the Sinovac-Coronavac vaccine followed by 1 dose of the Pfizer-BioNTech vaccine 2 weeks prior to the current presentation. He was treated with valacyclovir for 1 week, and his symptoms resolved entirely within 3 weeks.
Patient 5—A 50-year-old woman presented to the hospital for evaluation of painful sores on the back, chest, groin, and abdomen of 10 days’ duration. The lesions initially had developed 7 days after receiving the BioNTech COVID-19 vaccine; she previously had received 2 doses of the Sinovac-Coronavac vaccine. The patient had a history of untreated psoriasis. Dermatologic examination revealed grouped vesicles on an erythematous background in the T2–L2 dermatomes on the left side of the trunk. A diagnosis of HZ was made. The lesions resolved after 1 week of treatment with systemic valacyclovir; however, she subsequently developed postherpetic neuralgia, hypoesthesia, and postinflammatory hyperpigmentation in the affected regions.
Patient 6—A 37-year-old woman presented to the hospital with redness, swelling, and itching all over the body of 3 days’ duration. The patient noted that the rash would subside and reappear throughout the day. Her medical history was unremarkable, except for COVID-19 infection 6 months prior. She had received a second dose of the BioNTech vaccine 20 days prior to development of symptoms. Dermatologic examination revealed widespread erythematous urticarial plaques. A diagnosis of acute urticaria was made. The patient recovered completely after 1 week of treatment with a systemic steroid and 3 weeks of antihistamine treatment.
Patient 7—A 63-year-old woman presented to the hospital with widespread itching and rash that appeared 5 days after the first dose of the BioNTech COVID-19 vaccine. The patient reported that the rash resolved spontaneously within a few hours but then reappeared. Her medical history revealed that she was taking tamoxifen for breast cancer and that she previously had received 2 doses of the Sinovac-Coronavac vaccine. Dermatologic examination revealed erythematous urticarial plaques on the trunk and arms. A diagnosis of urticaria was made, and her symptoms resolved after 6 weeks of antihistamine treatment.
Comment
Skin lesions associated with COVID-19 infection have been reported worldwide3,4 as well as dermatologic reactions following COVID-19 vaccination. In one case from Turkey, HZ infection was reported in a 68-year-old man 5 days after he received a second dose of the COVID-19 vaccine.5 In another case, HZ infection developed in a 78-year-old man 5 days after COVID-19 vaccination.6 Numerous cases of HZ infection developing within 1 to 26 days of COVID-19 vaccination have been reported worldwide.7-9
In a study conducted in the United States, 40 skin reactions associated with the COVID-19 vaccine were investigated; of these cases, 87.5% (35/40) were reported as varicella-zoster virus, and 12.5% (5/40) were reported as herpes simplex reactivation; 54% (19/35) and 80% (4/5) of these cases, respectively, were associated with the Pfizer-BioNTech vaccine.10 The average age of patients who developed a skin reaction was 46 years, and 70% (28/40) were women. The time to onset of the reaction was 2 to 13 days after vaccination, and symptoms were reported to improve within 7 days on average.10
Another study from Spain examined 405 vaccine-related skin reactions, 40.2% of which were related to the Pfizer-BioNTech vaccine. Among them, 80.2% occurred in women; 13.8% of cases were diagnosed as varicella-zoster virus or HZ virus reactivation, and 14.6% were urticaria. Eighty reactions (21%) were classified as severe/very severe and 81% required treatment.11 One study reported 414 skin reactions from the COVID-19 vaccine from December 2020 to February 2021; of these cases, 83% occurred after the Moderna vaccine, which is not available in Turkey, and 17% occurred after the Pfizer-BioNTech vaccine.12A systematic review of 91 patients who developed HZ infection after COVID-19 vaccination reported that 10% (9/91) of cases were receiving immunosuppressive therapy and 13% (12/91) had an autoimmune disease.7 In our case series, it is known that at least 2 of the patients (patients 2 and 5), including 1 patient with rheumatoid arthritis (patient 2) who was on immunosuppressive treatment, had autoimmune disorders. However, reports in the literature indicate that most patients with autoimmune inflammatory rheumatic diseases remain stable after vaccination.13
Herpes zoster ophthalmicus is a rare form of HZ caused by involvement of the ophthalmic branch of the trigeminal nerve that manifests as vesicular lesions and retinitis, uveitis, keratitis, conjunctivitis, and pain on an erythematous background. Two cases of women who developed HZO infection after Pfizer-BioNTech vaccination were reported in the literature.14 Although patient 3 in our case series had a history of HZO 6 years prior, the possibility of the Pfizer-BioNTech vaccine triggering HZO should be taken into consideration.
Although cutaneous reactions after the Sinovac-Coronavac vaccine were observed in only 1 of 7 patients in our case series, skin reactions after Sinovac-Coronavac (an inactivated viral vaccine) have been reported in the literature. In one study, after a total of 35,229 injections, the incidence of cutaneous adverse events due to Sinovac-Coronavac was reported to be 0.94% and 0.70% after the first and second doses, respectively.15 Therefore, further study results are needed to directly attribute the reactions to COVID-19 vaccination.
Conclusion
Our case series highlights that clinicians should be vigilant in diagnosing cutaneous reactions following COVID-19 vaccination early to prevent potential complications. Early recognition of reactions is crucial, and the prognosis can be improved with appropriate treatment. Despite the potential dermatologic adverse effects of the COVID-19 vaccine, the most effective way to protect against serious COVID-19 infection is to continue to be vaccinated.
- Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine. N Engl J Med. 2020;383:2603-2615.
- Zhang Y, Zeng G, Pan H, et al. Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18–59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Lancet Infect Dis. 2021;21:181-192.
- Tan SW, Tam YC, Oh CC. Skin manifestations of COVID-19: a worldwide review. JAAD Int. 2021;2:119-133.
- Singh H, Kaur H, Singh K, et al. Cutaneous manifestations of COVID-19: a systematic review. advances in wound care. 2021;10:51-80.
- Aksu SB, Öztürk GZ. A rare case of shingles after COVID-19 vaccine: is it a possible adverse effect? clinical and experimental vaccine research. 2021;10:198-201.
- Bostan E, Yalici-Armagan B. Herpes zoster following inactivated COVID-19 vaccine: a coexistence or coincidence? J Cosmet Dermatol. 2021;20:1566-1567.
- Katsikas Triantafyllidis K, Giannos P, Mian IT, et al. Varicella zoster virus reactivation following COVID-19 vaccination: a systematic review of case reports. Vaccines (Basel). 2021;9:1013. doi:10.3390/vaccines9091013
- Rodríguez-Jiménez P, Chicharro P, Cabrera LM, et al. Varicella-zoster virus reactivation after SARS-CoV-2 BNT162b2 mRNA vaccination: report of 5 cases. JAAD Case Rep. 2021;12:58-59. doi:10.1016/j.jdcr.2021.04.014
- Lee C, Cotter D, Basa J, et al. 20 Post-COVID-19 vaccine-related shingles cases seen at the Las Vegas Dermatology clinic and sent to us via social media. J Cosmet Dermatol. 2021;20:1960-1964.
- Fathy RA, McMahon DE, Lee C, et al. Varicella-zoster and herpes simplex virus reactivation post-COVID-19 vaccination: a review of 40 cases in an International Dermatology Registry. J Eur Acad Dermatol Venerol. 2022;36:E6-E9.
- Català A, Muñoz-Santos C, Galván-Casas C, et al. Cutaneous reactions after SARS-CoV-2 vaccination: a cross-sectional Spanish nationwide study of 405 cases. Br J Dermatol. 2022;186:142-152.
- McMahon DE, Amerson E, Rosenbach M, et al. Cutaneous reactions reported after Moderna and Pfizer COVID-19 vaccination: a registry-based study of 414 cases. J Am Acad Dermatol. 2021;85:46-55.
- Furer V, Eviatar T, Zisman D, et al. Immunogenicity and safety of the BNT162b2 mRNA COVID-19 vaccine in adult patients with autoimmune inflammatory rheumatic diseases and in the general population: a multicentre study. Ann Rheum Dis. 2021;80:1330-1338.
- Bernardini N, Skroza N, Mambrin A, et al. Herpes zoster ophthalmicus in two women after Pfizer-BioNTech (BNT162b2) vaccine. J Med Virol. 2022;94:817-818.
- Rerknimitr P, Puaratanaarunkon T, Wongtada C, et al. Cutaneous adverse reactions from 35,229 doses of Sinovac and AstraZeneca COVID-19 vaccination: a prospective cohort study in healthcare workers. J Eur Acad Dermatol Venereol. 2022;36:E158-E161.
- Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine. N Engl J Med. 2020;383:2603-2615.
- Zhang Y, Zeng G, Pan H, et al. Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18–59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Lancet Infect Dis. 2021;21:181-192.
- Tan SW, Tam YC, Oh CC. Skin manifestations of COVID-19: a worldwide review. JAAD Int. 2021;2:119-133.
- Singh H, Kaur H, Singh K, et al. Cutaneous manifestations of COVID-19: a systematic review. advances in wound care. 2021;10:51-80.
- Aksu SB, Öztürk GZ. A rare case of shingles after COVID-19 vaccine: is it a possible adverse effect? clinical and experimental vaccine research. 2021;10:198-201.
- Bostan E, Yalici-Armagan B. Herpes zoster following inactivated COVID-19 vaccine: a coexistence or coincidence? J Cosmet Dermatol. 2021;20:1566-1567.
- Katsikas Triantafyllidis K, Giannos P, Mian IT, et al. Varicella zoster virus reactivation following COVID-19 vaccination: a systematic review of case reports. Vaccines (Basel). 2021;9:1013. doi:10.3390/vaccines9091013
- Rodríguez-Jiménez P, Chicharro P, Cabrera LM, et al. Varicella-zoster virus reactivation after SARS-CoV-2 BNT162b2 mRNA vaccination: report of 5 cases. JAAD Case Rep. 2021;12:58-59. doi:10.1016/j.jdcr.2021.04.014
- Lee C, Cotter D, Basa J, et al. 20 Post-COVID-19 vaccine-related shingles cases seen at the Las Vegas Dermatology clinic and sent to us via social media. J Cosmet Dermatol. 2021;20:1960-1964.
- Fathy RA, McMahon DE, Lee C, et al. Varicella-zoster and herpes simplex virus reactivation post-COVID-19 vaccination: a review of 40 cases in an International Dermatology Registry. J Eur Acad Dermatol Venerol. 2022;36:E6-E9.
- Català A, Muñoz-Santos C, Galván-Casas C, et al. Cutaneous reactions after SARS-CoV-2 vaccination: a cross-sectional Spanish nationwide study of 405 cases. Br J Dermatol. 2022;186:142-152.
- McMahon DE, Amerson E, Rosenbach M, et al. Cutaneous reactions reported after Moderna and Pfizer COVID-19 vaccination: a registry-based study of 414 cases. J Am Acad Dermatol. 2021;85:46-55.
- Furer V, Eviatar T, Zisman D, et al. Immunogenicity and safety of the BNT162b2 mRNA COVID-19 vaccine in adult patients with autoimmune inflammatory rheumatic diseases and in the general population: a multicentre study. Ann Rheum Dis. 2021;80:1330-1338.
- Bernardini N, Skroza N, Mambrin A, et al. Herpes zoster ophthalmicus in two women after Pfizer-BioNTech (BNT162b2) vaccine. J Med Virol. 2022;94:817-818.
- Rerknimitr P, Puaratanaarunkon T, Wongtada C, et al. Cutaneous adverse reactions from 35,229 doses of Sinovac and AstraZeneca COVID-19 vaccination: a prospective cohort study in healthcare workers. J Eur Acad Dermatol Venereol. 2022;36:E158-E161.
Practice Points
- Cutaneous reactions have been reported following COVID-19 vaccination.
- Herpes infections and urticarial reactions can be associated with COVID-19 vaccination, regardless of the delay in onset between the injection and symptom development.
Determinants of Topical Corticosteroid Effectiveness in Eosinophilic Esophagitis in Real‐World Practice
Key clinical point: Reduced symptom severity and use of budesonide orodispersible tablets and high topical corticosteroid (tC) doses (eg, fluticasone propionate metered dose ≥ 1 mg/day from inhalation devices) are all independent predictors of tC effectiveness in patients with eosinophilic esophagitis (EoE) in the real‐world setting.
Major finding: Corticosteroid treatment proved to be the most important determining factor in achieving clinico-histological remission, with budesonide orodispersible tablets presenting the highest efficacy (adjusted odds ratio [aOR], 18.9; P < .001). High tC doses (aOR, 4.3; P = .03) and lower symptom scores (aOR, 0.9; P = .01) were also significant predictors of tC effectiveness.
Study details: This real-world cross‐sectional analysis of the multicenter EoE CONNECT registry assessed the data on 1456 prescriptions of tC monotherapy used in 866 patients with EoE.
Disclosures: This study did not receive any specific funding. The authors declared no conflicts of interest.
Source: Laserna‐Mendieta EJ, Navarro P, Casabona-Francés S, et al. Swallowed topical corticosteroids for eosinophilic esophagitis: Utilization and real‐world efficacy from the EoE CONNECT registry. United European Gastroenterol J. Published online January 29, 2024. Source
Key clinical point: Reduced symptom severity and use of budesonide orodispersible tablets and high topical corticosteroid (tC) doses (eg, fluticasone propionate metered dose ≥ 1 mg/day from inhalation devices) are all independent predictors of tC effectiveness in patients with eosinophilic esophagitis (EoE) in the real‐world setting.
Major finding: Corticosteroid treatment proved to be the most important determining factor in achieving clinico-histological remission, with budesonide orodispersible tablets presenting the highest efficacy (adjusted odds ratio [aOR], 18.9; P < .001). High tC doses (aOR, 4.3; P = .03) and lower symptom scores (aOR, 0.9; P = .01) were also significant predictors of tC effectiveness.
Study details: This real-world cross‐sectional analysis of the multicenter EoE CONNECT registry assessed the data on 1456 prescriptions of tC monotherapy used in 866 patients with EoE.
Disclosures: This study did not receive any specific funding. The authors declared no conflicts of interest.
Source: Laserna‐Mendieta EJ, Navarro P, Casabona-Francés S, et al. Swallowed topical corticosteroids for eosinophilic esophagitis: Utilization and real‐world efficacy from the EoE CONNECT registry. United European Gastroenterol J. Published online January 29, 2024. Source
Key clinical point: Reduced symptom severity and use of budesonide orodispersible tablets and high topical corticosteroid (tC) doses (eg, fluticasone propionate metered dose ≥ 1 mg/day from inhalation devices) are all independent predictors of tC effectiveness in patients with eosinophilic esophagitis (EoE) in the real‐world setting.
Major finding: Corticosteroid treatment proved to be the most important determining factor in achieving clinico-histological remission, with budesonide orodispersible tablets presenting the highest efficacy (adjusted odds ratio [aOR], 18.9; P < .001). High tC doses (aOR, 4.3; P = .03) and lower symptom scores (aOR, 0.9; P = .01) were also significant predictors of tC effectiveness.
Study details: This real-world cross‐sectional analysis of the multicenter EoE CONNECT registry assessed the data on 1456 prescriptions of tC monotherapy used in 866 patients with EoE.
Disclosures: This study did not receive any specific funding. The authors declared no conflicts of interest.
Source: Laserna‐Mendieta EJ, Navarro P, Casabona-Francés S, et al. Swallowed topical corticosteroids for eosinophilic esophagitis: Utilization and real‐world efficacy from the EoE CONNECT registry. United European Gastroenterol J. Published online January 29, 2024. Source