Miriam E. Tucker

Emerging evidence is shedding light on the common underlying mechanisms contributing to the overlapping clinical phenomena of “long COVID,” myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and dysautonomia.

At the virtual annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (IACFSME), speakers presented data showing similar pathophysiologic abnormalities in people with systemic symptoms associated with ME/CFS who had a prior SARS-CoV-2 infection and those who did not, including individuals whose illness preceded the COVID-19 pandemic.

Core clinical diagnostic criteria for ME/CFS established by the Institute of Medicine in 2015 include substantial decrement in functioning for 6 months or longer, postexertional malaise, or a worsening of symptoms following even minor exertion (often described by patients as “crashes”), unrefreshing sleep, and cognitive dysfunction and/or orthostatic intolerance that are frequent and severe.

Long COVID has been defined in several different ways using different terminology. The U.S. Centers for Disease Control and Prevention, for example, defines “post-COVID conditions” as those continuing four or more weeks beyond first symptoms. The World Health Organization’s clinical case definition of “post COVID-19 condition” includes otherwise unexplained symptoms 3 months from COVID-19 onset and lasting longer than 2 months.

Both ME/CFS and long COVID commonly involve numerous symptoms beyond the defining ones, affecting nearly every organ system in the body, including systemic, neurocognitive, endocrine, cardiovascular, pulmonary, musculoskeletal, and gastrointestinal, with wide variation among individuals. Autonomic dysfunction is common to both conditions, particularly postural orthostatic tachycardia syndrome (POTS).

“My way of understanding these illnesses is that they’re not just multisystem illnesses, but all these interactive systems that lean on each other are dysregulated. … I would say that a very common underlying mediator of both ME/CFS and long COVID is autonomic dysfunction, and it presents as POTS,” Nancy Klimas, MD, director of the Institute for Neuro-Immune Medicine at Nova Southeastern University, Fort Lauderdale, Fla., told this news organization.

Dr. Klimas, who is also director of Clinical Immunology Research at the Miami Veterans Affairs Medical Center, added that “if basic bioenergetics are disrupted and in an oxidative-stress state [then] they have downregulated energy production at the cellular level, which seems to be the case in ME/CFS and now in long COVID.”
 

New ICD-10 codes better characterize the syndromes

New ICD-10 codes for 2023, being implemented on Oct. 1, will enable clinicians to better document all of these interrelated conditions.

Under the existing G93.3, Postviral and related fatigue syndromes, there will now be:

• G93.31 – Postviral fatigue syndrome.
• G93.32 – Myalgic encephalomyelitis/chronic fatigue syndrome (and the separate terms).
• G93.39 – Other postinfection and related fatigue syndromes.

The old R53.82, “Chronic fatigue, unspecified” code now excludes all of the above conditions.

The additional code U09.9 for “post COVID-19 condition, unspecified,” may also be used if applicable.

In addition, a new code for POTS, G90.A, which wasn’t previously mentioned in ICD-10, may also be used starting Oct. 1.

Lucinda Bateman, MD, founder and director of the Bateman Horne Center, Salt Lake City, advises using all applicable codes for a given patient. “If a patient came into my office with long COVID and met criteria for ME/CFS, we would code both, and also any other syndrome criteria that they may meet, such as POTS or fibromyalgia.

“If people use the codes appropriately, then you can understand the overlap better. It increases the likelihood of reimbursement, creates a more accurate medical record for the patient, and provides them with a better tool should they require disability benefits.”

Dr. Bateman advises in-office orthostatic evaluation for all patients with this symptom constellation, using a passive standing evaluation such as the 10-minute NASA Lean test.

“Clinicians should take the time to do orthostatic testing in these patients because it provides objective markers and will help lead us to potential interventions to help improve people’s function.”

The Bateman Horne center offers clinician resources on management of ME/CFS and related conditions.
 

How common is ME/CFS after COVID-19?

According to one published meta-analysis, the global prevalence of “post-acute sequelae of SARS-CoV-2,” defined by any symptom, is about 43% of patients overall following infection, and 49% at 120 days. Fatigue was the most commonly reported symptom, followed by memory problems. As of March 22, the World Health Organization estimated that there have been more than 470 million COVID-19 cases, which would give a figure of about 200 million people who are experiencing a wide range of long-COVID symptoms. 

On the final day of the IACFSME conference, Luis Nacul, MD, of the University of British Columbia, Vancouver, presented several sets of data from his group and others aiming to determine the proportion of individuals who develop symptoms suggestive of ME/CFS following a COVID-19 infection.   

Among a cohort of 88 adults hospitalized with confirmed SARS-CoV-2 infections during the first pandemic wave in 2020 and followed up in the respiratory clinic, rates of reported generalized fatigue were 67% at 3 months and 59.5% at 6 months. Substantial fatigue (that is, present most days and affecting activity levels) were reported by 16% at 3 months and 7% at 6 months. “This should represent in principle the maximum prevalence of cases who would meet the criteria for ME/CFS,” Dr. Nacul said.

Baseline age was indirectly associated with fatigue at 3 and 6 months, while the number of comorbidities a patient had was directly associated. Comorbidities also predicted severe fatigue at 3 months, but the numbers were too small for assessment at 6 months.

Studies involving nonhospitalized patients suggested lower rates. One meta-analysis showed 1-year rates of fatigue in 32% and cognitive impairment in 22%. Another showed very similar rates, reporting fatigue in 28% and memory/concentration difficulties in 18%-19%.   

Dr. Nacul cautioned that these figures are likely overestimates since many of the study populations are taken from respiratory or long-COVID clinics. “The evidence on ‘post-COVID fatigue syndrome’ or ME/CFS following COVID is still evolving. There is a huge need for studies looking more closely at cases meeting well-defined ME/CFS criteria. This unfortunately hasn’t been done for most studies.”
 

Immune system dysfunction appears to underlie many cases

In a keynote address during the conference, Akiko Iwasaki, PhD, of Yale University, New Haven, Conn., pointed out that long COVID and ME/CFS are among many unexplained postacute infection syndromes associated with a long list of viral pathogens, including Ebola, the prior SARS viruses, Epstein-Barr virus, and Dengue, as well as nonviral pathogens such as Coxiella burnetii (Q fever syndrome) and Borrelia (posttreatment Lyme disease syndrome).

Dr. Iwasaki cited a recent Nature Medicine review article that she coauthored on this topic with an ME/CFS patient, noting: “We really need to understand why some people are failing to recover from these types of diseases.”

Emerging evidence supports four different hypotheses regarding pathogenesis: viral reservoir/viral pathogen-associated molecular pattern molecules, autoimmunity, dysbiosis/viral reactivation, and tissue damage

“Right now, it’s too early to exclude or make any conclusions about these. We need to have an open mind to dissect these various possibilities,” she said.

Two speakers reported findings of immune dysregulation in both ME/CFS and long COVID. Wakiro Sato, MD, PhD, of the National Center of Neurology and Psychiatry, Tokyo, reported that anti–G-protein coupled receptor antibodies were found in 33 (55%) of 60 patients with long COVID, and more than 40% had peripheral immune cell profile abnormalities. These findings were similar to those found in patients with ME/CFS, published by Sato’s team (Brain Behav Immun. 2021 Mar 29. doi: 10.1016/j.bbi.2021.03.023) and other researchers in Germany.  

Liisa K. Selin, MD, PhD, professor of pathology at the University of Massachusetts, Worcester, presented data for an analysis of peripheral blood mononuclear cells from 26 donors with ME/CFS (8 with long COVID) and 24 healthy controls. In both patient groups, they found altered expression of inflammatory markers and decreases in CD8 T-cell number and function. The patients with long COVID showed evidence of sustained activation of both T-cell populations with increased CD38 and HLA-DR, associated with a compensatory increased frequency of activated CD4+CD8+ T cells.

“These results are consistent with immune dysregulation associated with overactivation and exhaustion of CD8 T cells, as observed in chronic viral infections and tumor environments,” Dr. Selin said.
 

ME/CFS and long COVID ‘frighteningly similar, if not identical’

Data for a different system derangement in long COVID and ME/CFS, the pathophysiology of exercise intolerance, were presented in another keynote talk by David M. Systrom, MD, a pulmonary and critical care medicine specialist at Brigham and Women’s Hospital and director of the Massachusetts General Hospital cardiopulmonary laboratory, both in Boston. He has conducted invasive cardiopulmonary exercise testing in patients with ME/CFS and patients with long COVID.

Previously, Dr. Systrom and his team found that patients with ME/CFS have distinct defects in both ventricular filling pressure and oxygen extraction from the muscles. Neither of those are features of deconditioning, which is often blamed for exercise intolerance in people with ME/CFS. Rather, the major defect in deconditioning is decreased stroke volume and cardiac output. In ME/CFS patients, he found supranormal pulmonary blood flow, compared with VO₂ max, suggesting peripheral left-to-right shunting.

In addition, Dr. Systrom and colleagues found that a large proportion of ME/CFS patients with these peripheral vascular defects also have biopsy-demonstrated small-fiber neuropathy, suggesting that acute exercise intolerance is related to underlying autonomic nervous system dysfunction.

In Dr. Systrom and colleagues’ long COVID study, invasive cardiopulmonary exercise testing in 10 patients who had recovered from COVID-19 at least 6 months prior and did not have cardiopulmonary disease had significantly revealed reduced peak exercise aerobic capacity (VO₂ max), compared with 10 age- and sex-matched controls. The reduction in peak VO₂ was associated with impaired systemic oxygen extraction, compared with the controls, despite a preserved peak cardiac index.

The long-COVID patients also showed greater ventilatory inefficiency, which “is entirely related to hyperventilation, not intrinsic lung disease,” Dr. Systrom said, adding that while there may be subsets of patients with interstitial lung disease after acute respiratory distress syndrome, these patients didn’t have that. “This for all the world looks like ME/CFS. We think they are frighteningly similar, if not identical,” Dr. Systrom said.  

In a third study for which Dr. Systrom was a coauthor, published in Annals of Neurology, multisystem involvement was found in nine patients following mild COVID-19 infection, using standardized autonomic assessments including Valsalva maneuver, sudomotor and tilt tests, and skin biopsies for small-fiber neuropathy. The findings included cerebrovascular dysregulation with persistent cerebral arteriolar vasoconstriction, small-fiber neuropathy and related dysautonomia, respiratory dysregulation, and chronic inflammation.

Dr. Systrom’s conclusion: “Dyspnea and hyperventilation are common in ME/CFS and long COVID and there is significant overlap with POTS.”

Dr. Bateman disclosed that she is conducting research for Terra Biological. Dr. Systrom said he is conducting research for Astellas.

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

Emerging evidence is shedding light on the common underlying mechanisms contributing to the overlapping clinical phenomena of “long COVID,” myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and dysautonomia.

At the virtual annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (IACFSME), speakers presented data showing similar pathophysiologic abnormalities in people with systemic symptoms associated with ME/CFS who had a prior SARS-CoV-2 infection and those who did not, including individuals whose illness preceded the COVID-19 pandemic.

Core clinical diagnostic criteria for ME/CFS established by the Institute of Medicine in 2015 include substantial decrement in functioning for 6 months or longer, postexertional malaise, or a worsening of symptoms following even minor exertion (often described by patients as “crashes”), unrefreshing sleep, and cognitive dysfunction and/or orthostatic intolerance that are frequent and severe.

Long COVID has been defined in several different ways using different terminology. The U.S. Centers for Disease Control and Prevention, for example, defines “post-COVID conditions” as those continuing four or more weeks beyond first symptoms. The World Health Organization’s clinical case definition of “post COVID-19 condition” includes otherwise unexplained symptoms 3 months from COVID-19 onset and lasting longer than 2 months.

Both ME/CFS and long COVID commonly involve numerous symptoms beyond the defining ones, affecting nearly every organ system in the body, including systemic, neurocognitive, endocrine, cardiovascular, pulmonary, musculoskeletal, and gastrointestinal, with wide variation among individuals. Autonomic dysfunction is common to both conditions, particularly postural orthostatic tachycardia syndrome (POTS).

“My way of understanding these illnesses is that they’re not just multisystem illnesses, but all these interactive systems that lean on each other are dysregulated. … I would say that a very common underlying mediator of both ME/CFS and long COVID is autonomic dysfunction, and it presents as POTS,” Nancy Klimas, MD, director of the Institute for Neuro-Immune Medicine at Nova Southeastern University, Fort Lauderdale, Fla., told this news organization.

Dr. Klimas, who is also director of Clinical Immunology Research at the Miami Veterans Affairs Medical Center, added that “if basic bioenergetics are disrupted and in an oxidative-stress state [then] they have downregulated energy production at the cellular level, which seems to be the case in ME/CFS and now in long COVID.”
 

New ICD-10 codes better characterize the syndromes

New ICD-10 codes for 2023, being implemented on Oct. 1, will enable clinicians to better document all of these interrelated conditions.

Under the existing G93.3, Postviral and related fatigue syndromes, there will now be:

• G93.31 – Postviral fatigue syndrome.
• G93.32 – Myalgic encephalomyelitis/chronic fatigue syndrome (and the separate terms).
• G93.39 – Other postinfection and related fatigue syndromes.

The old R53.82, “Chronic fatigue, unspecified” code now excludes all of the above conditions.

The additional code U09.9 for “post COVID-19 condition, unspecified,” may also be used if applicable.

In addition, a new code for POTS, G90.A, which wasn’t previously mentioned in ICD-10, may also be used starting Oct. 1.

Lucinda Bateman, MD, founder and director of the Bateman Horne Center, Salt Lake City, advises using all applicable codes for a given patient. “If a patient came into my office with long COVID and met criteria for ME/CFS, we would code both, and also any other syndrome criteria that they may meet, such as POTS or fibromyalgia.

“If people use the codes appropriately, then you can understand the overlap better. It increases the likelihood of reimbursement, creates a more accurate medical record for the patient, and provides them with a better tool should they require disability benefits.”

Dr. Bateman advises in-office orthostatic evaluation for all patients with this symptom constellation, using a passive standing evaluation such as the 10-minute NASA Lean test.

“Clinicians should take the time to do orthostatic testing in these patients because it provides objective markers and will help lead us to potential interventions to help improve people’s function.”

The Bateman Horne center offers clinician resources on management of ME/CFS and related conditions.
 

How common is ME/CFS after COVID-19?

According to one published meta-analysis, the global prevalence of “post-acute sequelae of SARS-CoV-2,” defined by any symptom, is about 43% of patients overall following infection, and 49% at 120 days. Fatigue was the most commonly reported symptom, followed by memory problems. As of March 22, the World Health Organization estimated that there have been more than 470 million COVID-19 cases, which would give a figure of about 200 million people who are experiencing a wide range of long-COVID symptoms. 

On the final day of the IACFSME conference, Luis Nacul, MD, of the University of British Columbia, Vancouver, presented several sets of data from his group and others aiming to determine the proportion of individuals who develop symptoms suggestive of ME/CFS following a COVID-19 infection.   

Among a cohort of 88 adults hospitalized with confirmed SARS-CoV-2 infections during the first pandemic wave in 2020 and followed up in the respiratory clinic, rates of reported generalized fatigue were 67% at 3 months and 59.5% at 6 months. Substantial fatigue (that is, present most days and affecting activity levels) were reported by 16% at 3 months and 7% at 6 months. “This should represent in principle the maximum prevalence of cases who would meet the criteria for ME/CFS,” Dr. Nacul said.

Baseline age was indirectly associated with fatigue at 3 and 6 months, while the number of comorbidities a patient had was directly associated. Comorbidities also predicted severe fatigue at 3 months, but the numbers were too small for assessment at 6 months.

Studies involving nonhospitalized patients suggested lower rates. One meta-analysis showed 1-year rates of fatigue in 32% and cognitive impairment in 22%. Another showed very similar rates, reporting fatigue in 28% and memory/concentration difficulties in 18%-19%.   

Dr. Nacul cautioned that these figures are likely overestimates since many of the study populations are taken from respiratory or long-COVID clinics. “The evidence on ‘post-COVID fatigue syndrome’ or ME/CFS following COVID is still evolving. There is a huge need for studies looking more closely at cases meeting well-defined ME/CFS criteria. This unfortunately hasn’t been done for most studies.”
 

Immune system dysfunction appears to underlie many cases

In a keynote address during the conference, Akiko Iwasaki, PhD, of Yale University, New Haven, Conn., pointed out that long COVID and ME/CFS are among many unexplained postacute infection syndromes associated with a long list of viral pathogens, including Ebola, the prior SARS viruses, Epstein-Barr virus, and Dengue, as well as nonviral pathogens such as Coxiella burnetii (Q fever syndrome) and Borrelia (posttreatment Lyme disease syndrome).

Dr. Iwasaki cited a recent Nature Medicine review article that she coauthored on this topic with an ME/CFS patient, noting: “We really need to understand why some people are failing to recover from these types of diseases.”

Emerging evidence supports four different hypotheses regarding pathogenesis: viral reservoir/viral pathogen-associated molecular pattern molecules, autoimmunity, dysbiosis/viral reactivation, and tissue damage

“Right now, it’s too early to exclude or make any conclusions about these. We need to have an open mind to dissect these various possibilities,” she said.

Two speakers reported findings of immune dysregulation in both ME/CFS and long COVID. Wakiro Sato, MD, PhD, of the National Center of Neurology and Psychiatry, Tokyo, reported that anti–G-protein coupled receptor antibodies were found in 33 (55%) of 60 patients with long COVID, and more than 40% had peripheral immune cell profile abnormalities. These findings were similar to those found in patients with ME/CFS, published by Sato’s team (Brain Behav Immun. 2021 Mar 29. doi: 10.1016/j.bbi.2021.03.023) and other researchers in Germany.  

Liisa K. Selin, MD, PhD, professor of pathology at the University of Massachusetts, Worcester, presented data for an analysis of peripheral blood mononuclear cells from 26 donors with ME/CFS (8 with long COVID) and 24 healthy controls. In both patient groups, they found altered expression of inflammatory markers and decreases in CD8 T-cell number and function. The patients with long COVID showed evidence of sustained activation of both T-cell populations with increased CD38 and HLA-DR, associated with a compensatory increased frequency of activated CD4+CD8+ T cells.

“These results are consistent with immune dysregulation associated with overactivation and exhaustion of CD8 T cells, as observed in chronic viral infections and tumor environments,” Dr. Selin said.
 

ME/CFS and long COVID ‘frighteningly similar, if not identical’

Data for a different system derangement in long COVID and ME/CFS, the pathophysiology of exercise intolerance, were presented in another keynote talk by David M. Systrom, MD, a pulmonary and critical care medicine specialist at Brigham and Women’s Hospital and director of the Massachusetts General Hospital cardiopulmonary laboratory, both in Boston. He has conducted invasive cardiopulmonary exercise testing in patients with ME/CFS and patients with long COVID.

Previously, Dr. Systrom and his team found that patients with ME/CFS have distinct defects in both ventricular filling pressure and oxygen extraction from the muscles. Neither of those are features of deconditioning, which is often blamed for exercise intolerance in people with ME/CFS. Rather, the major defect in deconditioning is decreased stroke volume and cardiac output. In ME/CFS patients, he found supranormal pulmonary blood flow, compared with VO₂ max, suggesting peripheral left-to-right shunting.

In addition, Dr. Systrom and colleagues found that a large proportion of ME/CFS patients with these peripheral vascular defects also have biopsy-demonstrated small-fiber neuropathy, suggesting that acute exercise intolerance is related to underlying autonomic nervous system dysfunction.

In Dr. Systrom and colleagues’ long COVID study, invasive cardiopulmonary exercise testing in 10 patients who had recovered from COVID-19 at least 6 months prior and did not have cardiopulmonary disease had significantly revealed reduced peak exercise aerobic capacity (VO₂ max), compared with 10 age- and sex-matched controls. The reduction in peak VO₂ was associated with impaired systemic oxygen extraction, compared with the controls, despite a preserved peak cardiac index.

The long-COVID patients also showed greater ventilatory inefficiency, which “is entirely related to hyperventilation, not intrinsic lung disease,” Dr. Systrom said, adding that while there may be subsets of patients with interstitial lung disease after acute respiratory distress syndrome, these patients didn’t have that. “This for all the world looks like ME/CFS. We think they are frighteningly similar, if not identical,” Dr. Systrom said.  

In a third study for which Dr. Systrom was a coauthor, published in Annals of Neurology, multisystem involvement was found in nine patients following mild COVID-19 infection, using standardized autonomic assessments including Valsalva maneuver, sudomotor and tilt tests, and skin biopsies for small-fiber neuropathy. The findings included cerebrovascular dysregulation with persistent cerebral arteriolar vasoconstriction, small-fiber neuropathy and related dysautonomia, respiratory dysregulation, and chronic inflammation.

Dr. Systrom’s conclusion: “Dyspnea and hyperventilation are common in ME/CFS and long COVID and there is significant overlap with POTS.”

Dr. Bateman disclosed that she is conducting research for Terra Biological. Dr. Systrom said he is conducting research for Astellas.

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

Emerging evidence is shedding light on the common underlying mechanisms contributing to the overlapping clinical phenomena of “long COVID,” myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and dysautonomia.

At the virtual annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (IACFSME), speakers presented data showing similar pathophysiologic abnormalities in people with systemic symptoms associated with ME/CFS who had a prior SARS-CoV-2 infection and those who did not, including individuals whose illness preceded the COVID-19 pandemic.

Core clinical diagnostic criteria for ME/CFS established by the Institute of Medicine in 2015 include substantial decrement in functioning for 6 months or longer, postexertional malaise, or a worsening of symptoms following even minor exertion (often described by patients as “crashes”), unrefreshing sleep, and cognitive dysfunction and/or orthostatic intolerance that are frequent and severe.

Long COVID has been defined in several different ways using different terminology. The U.S. Centers for Disease Control and Prevention, for example, defines “post-COVID conditions” as those continuing four or more weeks beyond first symptoms. The World Health Organization’s clinical case definition of “post COVID-19 condition” includes otherwise unexplained symptoms 3 months from COVID-19 onset and lasting longer than 2 months.

Both ME/CFS and long COVID commonly involve numerous symptoms beyond the defining ones, affecting nearly every organ system in the body, including systemic, neurocognitive, endocrine, cardiovascular, pulmonary, musculoskeletal, and gastrointestinal, with wide variation among individuals. Autonomic dysfunction is common to both conditions, particularly postural orthostatic tachycardia syndrome (POTS).

“My way of understanding these illnesses is that they’re not just multisystem illnesses, but all these interactive systems that lean on each other are dysregulated. … I would say that a very common underlying mediator of both ME/CFS and long COVID is autonomic dysfunction, and it presents as POTS,” Nancy Klimas, MD, director of the Institute for Neuro-Immune Medicine at Nova Southeastern University, Fort Lauderdale, Fla., told this news organization.

Dr. Klimas, who is also director of Clinical Immunology Research at the Miami Veterans Affairs Medical Center, added that “if basic bioenergetics are disrupted and in an oxidative-stress state [then] they have downregulated energy production at the cellular level, which seems to be the case in ME/CFS and now in long COVID.”
 

New ICD-10 codes better characterize the syndromes

New ICD-10 codes for 2023, being implemented on Oct. 1, will enable clinicians to better document all of these interrelated conditions.

Under the existing G93.3, Postviral and related fatigue syndromes, there will now be:

• G93.31 – Postviral fatigue syndrome.
• G93.32 – Myalgic encephalomyelitis/chronic fatigue syndrome (and the separate terms).
• G93.39 – Other postinfection and related fatigue syndromes.

The old R53.82, “Chronic fatigue, unspecified” code now excludes all of the above conditions.

The additional code U09.9 for “post COVID-19 condition, unspecified,” may also be used if applicable.

In addition, a new code for POTS, G90.A, which wasn’t previously mentioned in ICD-10, may also be used starting Oct. 1.

Lucinda Bateman, MD, founder and director of the Bateman Horne Center, Salt Lake City, advises using all applicable codes for a given patient. “If a patient came into my office with long COVID and met criteria for ME/CFS, we would code both, and also any other syndrome criteria that they may meet, such as POTS or fibromyalgia.

“If people use the codes appropriately, then you can understand the overlap better. It increases the likelihood of reimbursement, creates a more accurate medical record for the patient, and provides them with a better tool should they require disability benefits.”

Dr. Bateman advises in-office orthostatic evaluation for all patients with this symptom constellation, using a passive standing evaluation such as the 10-minute NASA Lean test.

“Clinicians should take the time to do orthostatic testing in these patients because it provides objective markers and will help lead us to potential interventions to help improve people’s function.”

The Bateman Horne center offers clinician resources on management of ME/CFS and related conditions.
 

How common is ME/CFS after COVID-19?

According to one published meta-analysis, the global prevalence of “post-acute sequelae of SARS-CoV-2,” defined by any symptom, is about 43% of patients overall following infection, and 49% at 120 days. Fatigue was the most commonly reported symptom, followed by memory problems. As of March 22, the World Health Organization estimated that there have been more than 470 million COVID-19 cases, which would give a figure of about 200 million people who are experiencing a wide range of long-COVID symptoms. 

On the final day of the IACFSME conference, Luis Nacul, MD, of the University of British Columbia, Vancouver, presented several sets of data from his group and others aiming to determine the proportion of individuals who develop symptoms suggestive of ME/CFS following a COVID-19 infection.   

Among a cohort of 88 adults hospitalized with confirmed SARS-CoV-2 infections during the first pandemic wave in 2020 and followed up in the respiratory clinic, rates of reported generalized fatigue were 67% at 3 months and 59.5% at 6 months. Substantial fatigue (that is, present most days and affecting activity levels) were reported by 16% at 3 months and 7% at 6 months. “This should represent in principle the maximum prevalence of cases who would meet the criteria for ME/CFS,” Dr. Nacul said.

Baseline age was indirectly associated with fatigue at 3 and 6 months, while the number of comorbidities a patient had was directly associated. Comorbidities also predicted severe fatigue at 3 months, but the numbers were too small for assessment at 6 months.

Studies involving nonhospitalized patients suggested lower rates. One meta-analysis showed 1-year rates of fatigue in 32% and cognitive impairment in 22%. Another showed very similar rates, reporting fatigue in 28% and memory/concentration difficulties in 18%-19%.   

Dr. Nacul cautioned that these figures are likely overestimates since many of the study populations are taken from respiratory or long-COVID clinics. “The evidence on ‘post-COVID fatigue syndrome’ or ME/CFS following COVID is still evolving. There is a huge need for studies looking more closely at cases meeting well-defined ME/CFS criteria. This unfortunately hasn’t been done for most studies.”
 

Immune system dysfunction appears to underlie many cases

In a keynote address during the conference, Akiko Iwasaki, PhD, of Yale University, New Haven, Conn., pointed out that long COVID and ME/CFS are among many unexplained postacute infection syndromes associated with a long list of viral pathogens, including Ebola, the prior SARS viruses, Epstein-Barr virus, and Dengue, as well as nonviral pathogens such as Coxiella burnetii (Q fever syndrome) and Borrelia (posttreatment Lyme disease syndrome).

Dr. Iwasaki cited a recent Nature Medicine review article that she coauthored on this topic with an ME/CFS patient, noting: “We really need to understand why some people are failing to recover from these types of diseases.”

Emerging evidence supports four different hypotheses regarding pathogenesis: viral reservoir/viral pathogen-associated molecular pattern molecules, autoimmunity, dysbiosis/viral reactivation, and tissue damage

“Right now, it’s too early to exclude or make any conclusions about these. We need to have an open mind to dissect these various possibilities,” she said.

Two speakers reported findings of immune dysregulation in both ME/CFS and long COVID. Wakiro Sato, MD, PhD, of the National Center of Neurology and Psychiatry, Tokyo, reported that anti–G-protein coupled receptor antibodies were found in 33 (55%) of 60 patients with long COVID, and more than 40% had peripheral immune cell profile abnormalities. These findings were similar to those found in patients with ME/CFS, published by Sato’s team (Brain Behav Immun. 2021 Mar 29. doi: 10.1016/j.bbi.2021.03.023) and other researchers in Germany.  

Liisa K. Selin, MD, PhD, professor of pathology at the University of Massachusetts, Worcester, presented data for an analysis of peripheral blood mononuclear cells from 26 donors with ME/CFS (8 with long COVID) and 24 healthy controls. In both patient groups, they found altered expression of inflammatory markers and decreases in CD8 T-cell number and function. The patients with long COVID showed evidence of sustained activation of both T-cell populations with increased CD38 and HLA-DR, associated with a compensatory increased frequency of activated CD4+CD8+ T cells.

“These results are consistent with immune dysregulation associated with overactivation and exhaustion of CD8 T cells, as observed in chronic viral infections and tumor environments,” Dr. Selin said.
 

ME/CFS and long COVID ‘frighteningly similar, if not identical’

Data for a different system derangement in long COVID and ME/CFS, the pathophysiology of exercise intolerance, were presented in another keynote talk by David M. Systrom, MD, a pulmonary and critical care medicine specialist at Brigham and Women’s Hospital and director of the Massachusetts General Hospital cardiopulmonary laboratory, both in Boston. He has conducted invasive cardiopulmonary exercise testing in patients with ME/CFS and patients with long COVID.

Previously, Dr. Systrom and his team found that patients with ME/CFS have distinct defects in both ventricular filling pressure and oxygen extraction from the muscles. Neither of those are features of deconditioning, which is often blamed for exercise intolerance in people with ME/CFS. Rather, the major defect in deconditioning is decreased stroke volume and cardiac output. In ME/CFS patients, he found supranormal pulmonary blood flow, compared with VO₂ max, suggesting peripheral left-to-right shunting.

In addition, Dr. Systrom and colleagues found that a large proportion of ME/CFS patients with these peripheral vascular defects also have biopsy-demonstrated small-fiber neuropathy, suggesting that acute exercise intolerance is related to underlying autonomic nervous system dysfunction.

In Dr. Systrom and colleagues’ long COVID study, invasive cardiopulmonary exercise testing in 10 patients who had recovered from COVID-19 at least 6 months prior and did not have cardiopulmonary disease had significantly revealed reduced peak exercise aerobic capacity (VO₂ max), compared with 10 age- and sex-matched controls. The reduction in peak VO₂ was associated with impaired systemic oxygen extraction, compared with the controls, despite a preserved peak cardiac index.

The long-COVID patients also showed greater ventilatory inefficiency, which “is entirely related to hyperventilation, not intrinsic lung disease,” Dr. Systrom said, adding that while there may be subsets of patients with interstitial lung disease after acute respiratory distress syndrome, these patients didn’t have that. “This for all the world looks like ME/CFS. We think they are frighteningly similar, if not identical,” Dr. Systrom said.  

In a third study for which Dr. Systrom was a coauthor, published in Annals of Neurology, multisystem involvement was found in nine patients following mild COVID-19 infection, using standardized autonomic assessments including Valsalva maneuver, sudomotor and tilt tests, and skin biopsies for small-fiber neuropathy. The findings included cerebrovascular dysregulation with persistent cerebral arteriolar vasoconstriction, small-fiber neuropathy and related dysautonomia, respiratory dysregulation, and chronic inflammation.

Dr. Systrom’s conclusion: “Dyspnea and hyperventilation are common in ME/CFS and long COVID and there is significant overlap with POTS.”

Dr. Bateman disclosed that she is conducting research for Terra Biological. Dr. Systrom said he is conducting research for Astellas.

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

A variety of treatments, most already commercially available, are under investigation for treating the constellation of overlapping symptoms associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), “long COVID,” and dysautonomia.

At the virtual annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis, speakers presented data for a variety of approaches to ease symptoms common across postviral conditions, such as extreme fatigue, postexertional malaise (“crash”), cognitive dysfunction (“brain fog”), orthostatic intolerance including postural orthostatic tachycardia syndrome (POTS), and chronic pain. Most of the modalities are already commercially available for other indications, although some are costly and not covered by payers for these conditions.

“Both post–acute COVID-19 syndrome and ME/CFS are forms of postinfectious viral syndromes and they have overlapping symptoms. ... In the past, patients were told ‘you have chronic fatigue syndrome but there’s nothing we can do for it.’ That certainly is not the case. There aren’t cures, but there are many management techniques to improve symptoms,” Charles W. Lapp, MD, medical director of the Hunter-Hopkins Center, Charlotte, N.C., said in an interview.

A current mainstay of treatment for ME/CFS – including that triggered by COVID-19 – is activity pacing, in which patients learn to stay within their “energy envelopes” in order to avoid postexertional malaise, a worsening of all symptoms with exertion. The use of “graded exercise” is no longer recommended, per U.K. and U.S. guidelines.

Data for the following approaches were presented at the IACFS/ME conference:
 

Pyridostigmine (mestinon, others)

Pyridostigmine, an acetylcholinesterase inhibitor, is approved for the treatment of muscle weakness resulting from myasthenia gravis and is available in generic form. It has previously been shown to produce significant improvement in both symptom burden and heart rate response in POTS.

At the IACFS/ME conference, David M. Systrom, MD, a pulmonary and critical care medicine specialist at Brigham and Women’s Hospital and director of the Massachusetts General Hospital Cardiopulmonary laboratory, both in Boston, summarized his group’s study in patients with ME/CFS using pyridostigmine as both a potential treatment for improving exercise capacity and a proof-of-concept that neurovascular dysregulation underlies exertional intolerance in the condition.

A total of 45 patients were randomized to 60 mg oral pyridostigmine or placebo after an invasive cardiopulmonary exercise test, and a second test performed 50 minutes later. Peak VO₂ increased after pyridostigmine but decreased after placebo (+13.3 mL/min vs. –40.2 mL/min, P < .05). Cardiac output and right atrial pressure were also significantly improved with pyridostigmine and worse with placebo.

“We suggest that treatable neurovascular dysregulation underlies acute exercise intolerance in ME/CFS. ... Pyridostigmine may be a useful repurposed off-label treatment [for] a subset of patients with exercise intolerance,” Dr. Systrom said.

Asked to comment, Dr. Lapp said: “We’ve used Mestinon for years because it helps with POTS and also with neurally mediated hypotension. Systrom is taking it to a new level because he’s shown that it increases preload to the heart.” However, he noted that it’s unclear whether the drug will help patients who don’t have POTS specifically. On the other hand, patients rarely experience side effects from the drug.

Since the generic tablets come only in 60-mg doses, and the starting dose is 30 mg three times a day, he advised cutting the tablets in half during titration up to 60 mg three times a day.
 

Oxaloacetate (benaGene)

David Lyons Kaufman, MD, of the Center for Complex Diseases, Mountain View, Calif., summarized data from his group’s recently published open-label, nonrandomized, “proof-of-concept” study on use of the commercially available nutritional supplement anhydrous enol-oxaloacetate for treating mental and physical fatigue in 76 patients with longstanding ME/CFS and 43 with long-COVID fatigue.

Oxaloacetate is a major step in the Krebs cycle within the mitochondria that are depleted in patients with ME/CFS. It is also an energy metabolite that has multiple effects in cells and mitochondria, Dr. Kaufman explained.

Doses ranging from 500 mg twice daily up to 1,000 mg three times a day were given for 6 weeks. Up to 33% of the patients with ME/CFS and up to 46.8% of the long-COVID group achieved clinical efficacy as measured by physical and mental fatigue scores, compared with just 5.9% of historical ME/CFS controls. All doses showed highly significant improvements.

The only adverse effects were occasional dyspepsia, which was avoided by taking the supplement with food, and insomnia, resolved by having them dose at breakfast and lunch, Dr. Kaufman said.

Following those preliminary data, there is now an ongoing 90-day, randomized, placebo-controlled clinical trial of 80 patients with ME/CFS using 2,000 mg anhydrous enol-oxaloacetate per day. Endpoints include multiple objective measures.

“We have a health care crisis with long COVID, and we’ve had this smoldering crisis with ME/CFS for decades that’s never been addressed. ME/CFS and long COVID, if not identical, are certainly overlapping. ... We have to pursue these translational medicine pilot studies as rapidly as possible,” Dr. Kaufman remarked.

Dr. Lapp told this news organization that it makes sense to use constituents of the Krebs cycle to improve mitochondrial function, but the problem with oxaloacetate is its cost. Dr. Kaufman mentioned that based on the preliminary trial, the therapeutic “sweet spot” appeared to be 1,000 mg twice daily. The manufacturer’s website lists the price for a single bottle of 30 250-mg capsules at $49, or $42 if purchased via a monthly subscription.

“It’s a benign drug, and it’s over the counter. I would give it to any patient who’s got a big wallet,” Dr. Lapp quipped, adding: “If they’ve got the money, they can order it tonight.”
 

Inspiritol

Inspiritol is an investigational “nebulized, inhaled, multimechanism medication designed to treat the major symptoms of respiratory distress with antioxidant, anti-inflammatory, and broad-spectrum antiviral and antibacterial properties. Inspiritol is composed of both endogenously produced and naturally occurring, well-tolerated biochemicals,” according to the company website.

The hypothesis, Liisa K. Selin, MD, PhD, professor of pathology at the University of Massachusetts, Worcester, said at the meeting, is that “ME/CFS and long COVID-19 result from an aberrant response to an immunological trigger like infection, which results in a permanently dysregulated immune system as a result of overactivation of CD8 T cells and subsequent exhaustion.”

Inspiritol, containing five antioxidants, acts as an immune modulator to reverse the CD8 T cell exhaustion and improve symptoms. Administration by inhaler delivers it directly to the brain from the lung. It was originally designed for use in chronic obstructive pulmonary disease and asthma and has shown efficacy for acute COVID-19, Dr. Selin said.

In a preliminary study, four patients with ME/CFS and five with long COVID have been treated with Inspiritol for 2-15 months, and all have self-reported improved symptoms. Cough has been the only reported side effect.

The company is pursuing an Investigational New Drug Application for the product with the Food and Drug Administration and has several patents pending. Dr. Lapp called Inspiritol “very interesting,” and said that reversal of CD8 “exhaustion” also would appear to be a promising approach. However, he noted, “the problem is that we don’t know what’s in it.”
 

Stellate ganglion block

Injection of local anesthetic near the stellate ganglion to block activity of the entire cervical sympathetic chain has been used for nearly a century to treat a variety of sympathetically mediated conditions, including complex regional pain syndrome (CRPS), shingles, and phantom-limb pain. More recently, it has been used in a variety of other conditions, including PTSD, Raynaud’s disease, menopausal hot flashes, and hyperhidrosis.

Insurance companies typically cover it for CRPS, neuropathic upper-extremity pain, hyperhidrosis, and Raynaud’s, said Luke Liu, MD, an anesthesiologist who is founder and chief executive officer of Alaska-based pain management company Neuroversion.

Deborah Duricka, PhD, also with Neuroversion, presented results from a now-published case series of 11 patients with long COVID who underwent stellate ganglion block by a board-certified anesthesiologist, first on one side at the level of C6, then on the contralateral side the following day.

Clinically meaningful benefits were seen in at least five of the patients in fatigue, memory problems, problems concentrating, rapid heartbeat, orthostatic intolerance, sleep problems, postexertional malaise, anxiety, and depression.

The hypothetical mechanism, she said, is that “sympathetic block prevents sympathetically driven vasoconstriction in carotid and vertebral arteries.”

Dr. Liu presented another case series of five patients with ME/CFS who underwent the procedure with ultrasound guidance, again on one side and the other side the next day. All had upper-limb autonomic issues such as Raynaud’s and/or neuropathic pain that had been refractory to more conventional treatments.

All five patients reported improvements in symptoms of ME/CFS, including energy level, cognition, pain, and postexertional malaise. One patient reported “feeling well for the first time in decades.” However, that patient relapsed after a mild viral illness 3.5 months after treatment. Some of the patients have required further treatments.

Dr. Lapp commented that, although the procedure is generally safe when performed by an experienced clinician, “Any time you do an injection like that, there’s a high risk that you could nick an artery or a vein or hit an essential nerve in the neck. That’s why it has to be done under fluoroscopy or ultrasound.”

He said he’s had a few patients undergo the procedure, mostly for CRPS, and they seem to have benefited from it. “It might increase cerebral blood flow and preload to the heart, so it might decrease ME/CFS symptoms and help with POTS as well.”

Nonetheless, Dr. Lapp said he wouldn’t consider stellate ganglion block as first-line treatment for ME/CFS or long COVID. “I think it would be for the treatment-resistant patient, when you’ve gone through all the treatments that we know and addressed all the comorbidities and they’re still not getting better.”

But, he added, it is a standard procedure. “Any pain clinic can do a stellate block.”
 

Transcutaneous auricular vagus nerve stimulation

Nicola Clague-Baker, PhD, a physiotherapist at the University of Liverpool (England), presented findings from an international survey of people with ME/CFS regarding their experience with transcutaneous auricular vagus nerve stimulation (taVNS) to manage their autonomic symptoms. The technique involves stimulation of the autonomic nervous system via the vagus nerve using electrodes applied to part of the ear. The theory is that the technique stimulates the parasympathetic nervous system and improves autonomic balance.

Two small previous trials showing benefit of vagus nerve stimulation for people with ME/CFS used more invasive and less comfortable methods of applying the stimulation rather than to the ear, Dr. Clague-Baker and colleagues noted in a poster. It has also been used successfully in treating POTS, another conference speaker noted.

A total of 131 people with ME/CFS (called simply “ME” in the United Kingdom) responded to a survey advertised on social media and websites. The majority (60%) were from the United Kingdom while the rest were from Europe, Australia, and North America. Most were female, and slightly more than half had lived with ME for 10 or more years.

The majority (72%) were still using taVNS, while 28% had stopped using it. Only 9% had used the modality for longer than a year. Respondents identified more than 30 benefits in symptoms and activities, with improvements in postexertional malaise (39%) and brain fog (37%) being the most common. One reported significant reduction in constipation.

However, respondents also mentioned more than 20 short- and long-term negatives, including headaches (15%) and long-term irritation at the site (9%). One participant reported a “big improvement in neuropathic pain, but not so much for muscles and joints.”

Overall, 80% reported that they would continue using taVNS and 67% said they would recommend it to others with ME, and 56% said that the system was mildly to very beneficial.

Dr. Lapp noted that several types of transcutaneous electrical nerve stimulation units with ear clips are sold online, and he’s seen them work well for migraine treatment. However, he cautioned that some patients have had side effects from the treatment, such as headaches and dizziness. “It’s putting an electrical current through your brain. In my mind, it’s another last-ditch measure.”

Dr. Lapp reported no financial disclosures.

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

A variety of treatments, most already commercially available, are under investigation for treating the constellation of overlapping symptoms associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), “long COVID,” and dysautonomia.

At the virtual annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis, speakers presented data for a variety of approaches to ease symptoms common across postviral conditions, such as extreme fatigue, postexertional malaise (“crash”), cognitive dysfunction (“brain fog”), orthostatic intolerance including postural orthostatic tachycardia syndrome (POTS), and chronic pain. Most of the modalities are already commercially available for other indications, although some are costly and not covered by payers for these conditions.

“Both post–acute COVID-19 syndrome and ME/CFS are forms of postinfectious viral syndromes and they have overlapping symptoms. ... In the past, patients were told ‘you have chronic fatigue syndrome but there’s nothing we can do for it.’ That certainly is not the case. There aren’t cures, but there are many management techniques to improve symptoms,” Charles W. Lapp, MD, medical director of the Hunter-Hopkins Center, Charlotte, N.C., said in an interview.

A current mainstay of treatment for ME/CFS – including that triggered by COVID-19 – is activity pacing, in which patients learn to stay within their “energy envelopes” in order to avoid postexertional malaise, a worsening of all symptoms with exertion. The use of “graded exercise” is no longer recommended, per U.K. and U.S. guidelines.

Data for the following approaches were presented at the IACFS/ME conference:
 

Pyridostigmine (mestinon, others)

Pyridostigmine, an acetylcholinesterase inhibitor, is approved for the treatment of muscle weakness resulting from myasthenia gravis and is available in generic form. It has previously been shown to produce significant improvement in both symptom burden and heart rate response in POTS.

At the IACFS/ME conference, David M. Systrom, MD, a pulmonary and critical care medicine specialist at Brigham and Women’s Hospital and director of the Massachusetts General Hospital Cardiopulmonary laboratory, both in Boston, summarized his group’s study in patients with ME/CFS using pyridostigmine as both a potential treatment for improving exercise capacity and a proof-of-concept that neurovascular dysregulation underlies exertional intolerance in the condition.

A total of 45 patients were randomized to 60 mg oral pyridostigmine or placebo after an invasive cardiopulmonary exercise test, and a second test performed 50 minutes later. Peak VO₂ increased after pyridostigmine but decreased after placebo (+13.3 mL/min vs. –40.2 mL/min, P < .05). Cardiac output and right atrial pressure were also significantly improved with pyridostigmine and worse with placebo.

“We suggest that treatable neurovascular dysregulation underlies acute exercise intolerance in ME/CFS. ... Pyridostigmine may be a useful repurposed off-label treatment [for] a subset of patients with exercise intolerance,” Dr. Systrom said.

Asked to comment, Dr. Lapp said: “We’ve used Mestinon for years because it helps with POTS and also with neurally mediated hypotension. Systrom is taking it to a new level because he’s shown that it increases preload to the heart.” However, he noted that it’s unclear whether the drug will help patients who don’t have POTS specifically. On the other hand, patients rarely experience side effects from the drug.

Since the generic tablets come only in 60-mg doses, and the starting dose is 30 mg three times a day, he advised cutting the tablets in half during titration up to 60 mg three times a day.
 

Oxaloacetate (benaGene)

David Lyons Kaufman, MD, of the Center for Complex Diseases, Mountain View, Calif., summarized data from his group’s recently published open-label, nonrandomized, “proof-of-concept” study on use of the commercially available nutritional supplement anhydrous enol-oxaloacetate for treating mental and physical fatigue in 76 patients with longstanding ME/CFS and 43 with long-COVID fatigue.

Oxaloacetate is a major step in the Krebs cycle within the mitochondria that are depleted in patients with ME/CFS. It is also an energy metabolite that has multiple effects in cells and mitochondria, Dr. Kaufman explained.

Doses ranging from 500 mg twice daily up to 1,000 mg three times a day were given for 6 weeks. Up to 33% of the patients with ME/CFS and up to 46.8% of the long-COVID group achieved clinical efficacy as measured by physical and mental fatigue scores, compared with just 5.9% of historical ME/CFS controls. All doses showed highly significant improvements.

The only adverse effects were occasional dyspepsia, which was avoided by taking the supplement with food, and insomnia, resolved by having them dose at breakfast and lunch, Dr. Kaufman said.

Following those preliminary data, there is now an ongoing 90-day, randomized, placebo-controlled clinical trial of 80 patients with ME/CFS using 2,000 mg anhydrous enol-oxaloacetate per day. Endpoints include multiple objective measures.

“We have a health care crisis with long COVID, and we’ve had this smoldering crisis with ME/CFS for decades that’s never been addressed. ME/CFS and long COVID, if not identical, are certainly overlapping. ... We have to pursue these translational medicine pilot studies as rapidly as possible,” Dr. Kaufman remarked.

Dr. Lapp told this news organization that it makes sense to use constituents of the Krebs cycle to improve mitochondrial function, but the problem with oxaloacetate is its cost. Dr. Kaufman mentioned that based on the preliminary trial, the therapeutic “sweet spot” appeared to be 1,000 mg twice daily. The manufacturer’s website lists the price for a single bottle of 30 250-mg capsules at $49, or $42 if purchased via a monthly subscription.

“It’s a benign drug, and it’s over the counter. I would give it to any patient who’s got a big wallet,” Dr. Lapp quipped, adding: “If they’ve got the money, they can order it tonight.”
 

Inspiritol

Inspiritol is an investigational “nebulized, inhaled, multimechanism medication designed to treat the major symptoms of respiratory distress with antioxidant, anti-inflammatory, and broad-spectrum antiviral and antibacterial properties. Inspiritol is composed of both endogenously produced and naturally occurring, well-tolerated biochemicals,” according to the company website.

The hypothesis, Liisa K. Selin, MD, PhD, professor of pathology at the University of Massachusetts, Worcester, said at the meeting, is that “ME/CFS and long COVID-19 result from an aberrant response to an immunological trigger like infection, which results in a permanently dysregulated immune system as a result of overactivation of CD8 T cells and subsequent exhaustion.”

Inspiritol, containing five antioxidants, acts as an immune modulator to reverse the CD8 T cell exhaustion and improve symptoms. Administration by inhaler delivers it directly to the brain from the lung. It was originally designed for use in chronic obstructive pulmonary disease and asthma and has shown efficacy for acute COVID-19, Dr. Selin said.

In a preliminary study, four patients with ME/CFS and five with long COVID have been treated with Inspiritol for 2-15 months, and all have self-reported improved symptoms. Cough has been the only reported side effect.

The company is pursuing an Investigational New Drug Application for the product with the Food and Drug Administration and has several patents pending. Dr. Lapp called Inspiritol “very interesting,” and said that reversal of CD8 “exhaustion” also would appear to be a promising approach. However, he noted, “the problem is that we don’t know what’s in it.”
 

Stellate ganglion block

Injection of local anesthetic near the stellate ganglion to block activity of the entire cervical sympathetic chain has been used for nearly a century to treat a variety of sympathetically mediated conditions, including complex regional pain syndrome (CRPS), shingles, and phantom-limb pain. More recently, it has been used in a variety of other conditions, including PTSD, Raynaud’s disease, menopausal hot flashes, and hyperhidrosis.

Insurance companies typically cover it for CRPS, neuropathic upper-extremity pain, hyperhidrosis, and Raynaud’s, said Luke Liu, MD, an anesthesiologist who is founder and chief executive officer of Alaska-based pain management company Neuroversion.

Deborah Duricka, PhD, also with Neuroversion, presented results from a now-published case series of 11 patients with long COVID who underwent stellate ganglion block by a board-certified anesthesiologist, first on one side at the level of C6, then on the contralateral side the following day.

Clinically meaningful benefits were seen in at least five of the patients in fatigue, memory problems, problems concentrating, rapid heartbeat, orthostatic intolerance, sleep problems, postexertional malaise, anxiety, and depression.

The hypothetical mechanism, she said, is that “sympathetic block prevents sympathetically driven vasoconstriction in carotid and vertebral arteries.”

Dr. Liu presented another case series of five patients with ME/CFS who underwent the procedure with ultrasound guidance, again on one side and the other side the next day. All had upper-limb autonomic issues such as Raynaud’s and/or neuropathic pain that had been refractory to more conventional treatments.

All five patients reported improvements in symptoms of ME/CFS, including energy level, cognition, pain, and postexertional malaise. One patient reported “feeling well for the first time in decades.” However, that patient relapsed after a mild viral illness 3.5 months after treatment. Some of the patients have required further treatments.

Dr. Lapp commented that, although the procedure is generally safe when performed by an experienced clinician, “Any time you do an injection like that, there’s a high risk that you could nick an artery or a vein or hit an essential nerve in the neck. That’s why it has to be done under fluoroscopy or ultrasound.”

He said he’s had a few patients undergo the procedure, mostly for CRPS, and they seem to have benefited from it. “It might increase cerebral blood flow and preload to the heart, so it might decrease ME/CFS symptoms and help with POTS as well.”

Nonetheless, Dr. Lapp said he wouldn’t consider stellate ganglion block as first-line treatment for ME/CFS or long COVID. “I think it would be for the treatment-resistant patient, when you’ve gone through all the treatments that we know and addressed all the comorbidities and they’re still not getting better.”

But, he added, it is a standard procedure. “Any pain clinic can do a stellate block.”
 

Transcutaneous auricular vagus nerve stimulation

Nicola Clague-Baker, PhD, a physiotherapist at the University of Liverpool (England), presented findings from an international survey of people with ME/CFS regarding their experience with transcutaneous auricular vagus nerve stimulation (taVNS) to manage their autonomic symptoms. The technique involves stimulation of the autonomic nervous system via the vagus nerve using electrodes applied to part of the ear. The theory is that the technique stimulates the parasympathetic nervous system and improves autonomic balance.

Two small previous trials showing benefit of vagus nerve stimulation for people with ME/CFS used more invasive and less comfortable methods of applying the stimulation rather than to the ear, Dr. Clague-Baker and colleagues noted in a poster. It has also been used successfully in treating POTS, another conference speaker noted.

A total of 131 people with ME/CFS (called simply “ME” in the United Kingdom) responded to a survey advertised on social media and websites. The majority (60%) were from the United Kingdom while the rest were from Europe, Australia, and North America. Most were female, and slightly more than half had lived with ME for 10 or more years.

The majority (72%) were still using taVNS, while 28% had stopped using it. Only 9% had used the modality for longer than a year. Respondents identified more than 30 benefits in symptoms and activities, with improvements in postexertional malaise (39%) and brain fog (37%) being the most common. One reported significant reduction in constipation.

However, respondents also mentioned more than 20 short- and long-term negatives, including headaches (15%) and long-term irritation at the site (9%). One participant reported a “big improvement in neuropathic pain, but not so much for muscles and joints.”

Overall, 80% reported that they would continue using taVNS and 67% said they would recommend it to others with ME, and 56% said that the system was mildly to very beneficial.

Dr. Lapp noted that several types of transcutaneous electrical nerve stimulation units with ear clips are sold online, and he’s seen them work well for migraine treatment. However, he cautioned that some patients have had side effects from the treatment, such as headaches and dizziness. “It’s putting an electrical current through your brain. In my mind, it’s another last-ditch measure.”

Dr. Lapp reported no financial disclosures.

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

A variety of treatments, most already commercially available, are under investigation for treating the constellation of overlapping symptoms associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), “long COVID,” and dysautonomia.

At the virtual annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis, speakers presented data for a variety of approaches to ease symptoms common across postviral conditions, such as extreme fatigue, postexertional malaise (“crash”), cognitive dysfunction (“brain fog”), orthostatic intolerance including postural orthostatic tachycardia syndrome (POTS), and chronic pain. Most of the modalities are already commercially available for other indications, although some are costly and not covered by payers for these conditions.

“Both post–acute COVID-19 syndrome and ME/CFS are forms of postinfectious viral syndromes and they have overlapping symptoms. ... In the past, patients were told ‘you have chronic fatigue syndrome but there’s nothing we can do for it.’ That certainly is not the case. There aren’t cures, but there are many management techniques to improve symptoms,” Charles W. Lapp, MD, medical director of the Hunter-Hopkins Center, Charlotte, N.C., said in an interview.

A current mainstay of treatment for ME/CFS – including that triggered by COVID-19 – is activity pacing, in which patients learn to stay within their “energy envelopes” in order to avoid postexertional malaise, a worsening of all symptoms with exertion. The use of “graded exercise” is no longer recommended, per U.K. and U.S. guidelines.

Data for the following approaches were presented at the IACFS/ME conference:
 

Pyridostigmine (mestinon, others)

Pyridostigmine, an acetylcholinesterase inhibitor, is approved for the treatment of muscle weakness resulting from myasthenia gravis and is available in generic form. It has previously been shown to produce significant improvement in both symptom burden and heart rate response in POTS.

At the IACFS/ME conference, David M. Systrom, MD, a pulmonary and critical care medicine specialist at Brigham and Women’s Hospital and director of the Massachusetts General Hospital Cardiopulmonary laboratory, both in Boston, summarized his group’s study in patients with ME/CFS using pyridostigmine as both a potential treatment for improving exercise capacity and a proof-of-concept that neurovascular dysregulation underlies exertional intolerance in the condition.

A total of 45 patients were randomized to 60 mg oral pyridostigmine or placebo after an invasive cardiopulmonary exercise test, and a second test performed 50 minutes later. Peak VO₂ increased after pyridostigmine but decreased after placebo (+13.3 mL/min vs. –40.2 mL/min, P < .05). Cardiac output and right atrial pressure were also significantly improved with pyridostigmine and worse with placebo.

“We suggest that treatable neurovascular dysregulation underlies acute exercise intolerance in ME/CFS. ... Pyridostigmine may be a useful repurposed off-label treatment [for] a subset of patients with exercise intolerance,” Dr. Systrom said.

Asked to comment, Dr. Lapp said: “We’ve used Mestinon for years because it helps with POTS and also with neurally mediated hypotension. Systrom is taking it to a new level because he’s shown that it increases preload to the heart.” However, he noted that it’s unclear whether the drug will help patients who don’t have POTS specifically. On the other hand, patients rarely experience side effects from the drug.

Since the generic tablets come only in 60-mg doses, and the starting dose is 30 mg three times a day, he advised cutting the tablets in half during titration up to 60 mg three times a day.
 

Oxaloacetate (benaGene)

David Lyons Kaufman, MD, of the Center for Complex Diseases, Mountain View, Calif., summarized data from his group’s recently published open-label, nonrandomized, “proof-of-concept” study on use of the commercially available nutritional supplement anhydrous enol-oxaloacetate for treating mental and physical fatigue in 76 patients with longstanding ME/CFS and 43 with long-COVID fatigue.

Oxaloacetate is a major step in the Krebs cycle within the mitochondria that are depleted in patients with ME/CFS. It is also an energy metabolite that has multiple effects in cells and mitochondria, Dr. Kaufman explained.

Doses ranging from 500 mg twice daily up to 1,000 mg three times a day were given for 6 weeks. Up to 33% of the patients with ME/CFS and up to 46.8% of the long-COVID group achieved clinical efficacy as measured by physical and mental fatigue scores, compared with just 5.9% of historical ME/CFS controls. All doses showed highly significant improvements.

The only adverse effects were occasional dyspepsia, which was avoided by taking the supplement with food, and insomnia, resolved by having them dose at breakfast and lunch, Dr. Kaufman said.

Following those preliminary data, there is now an ongoing 90-day, randomized, placebo-controlled clinical trial of 80 patients with ME/CFS using 2,000 mg anhydrous enol-oxaloacetate per day. Endpoints include multiple objective measures.

“We have a health care crisis with long COVID, and we’ve had this smoldering crisis with ME/CFS for decades that’s never been addressed. ME/CFS and long COVID, if not identical, are certainly overlapping. ... We have to pursue these translational medicine pilot studies as rapidly as possible,” Dr. Kaufman remarked.

Dr. Lapp told this news organization that it makes sense to use constituents of the Krebs cycle to improve mitochondrial function, but the problem with oxaloacetate is its cost. Dr. Kaufman mentioned that based on the preliminary trial, the therapeutic “sweet spot” appeared to be 1,000 mg twice daily. The manufacturer’s website lists the price for a single bottle of 30 250-mg capsules at $49, or $42 if purchased via a monthly subscription.

“It’s a benign drug, and it’s over the counter. I would give it to any patient who’s got a big wallet,” Dr. Lapp quipped, adding: “If they’ve got the money, they can order it tonight.”
 

Inspiritol

Inspiritol is an investigational “nebulized, inhaled, multimechanism medication designed to treat the major symptoms of respiratory distress with antioxidant, anti-inflammatory, and broad-spectrum antiviral and antibacterial properties. Inspiritol is composed of both endogenously produced and naturally occurring, well-tolerated biochemicals,” according to the company website.

The hypothesis, Liisa K. Selin, MD, PhD, professor of pathology at the University of Massachusetts, Worcester, said at the meeting, is that “ME/CFS and long COVID-19 result from an aberrant response to an immunological trigger like infection, which results in a permanently dysregulated immune system as a result of overactivation of CD8 T cells and subsequent exhaustion.”

Inspiritol, containing five antioxidants, acts as an immune modulator to reverse the CD8 T cell exhaustion and improve symptoms. Administration by inhaler delivers it directly to the brain from the lung. It was originally designed for use in chronic obstructive pulmonary disease and asthma and has shown efficacy for acute COVID-19, Dr. Selin said.

In a preliminary study, four patients with ME/CFS and five with long COVID have been treated with Inspiritol for 2-15 months, and all have self-reported improved symptoms. Cough has been the only reported side effect.

The company is pursuing an Investigational New Drug Application for the product with the Food and Drug Administration and has several patents pending. Dr. Lapp called Inspiritol “very interesting,” and said that reversal of CD8 “exhaustion” also would appear to be a promising approach. However, he noted, “the problem is that we don’t know what’s in it.”
 

Stellate ganglion block

Injection of local anesthetic near the stellate ganglion to block activity of the entire cervical sympathetic chain has been used for nearly a century to treat a variety of sympathetically mediated conditions, including complex regional pain syndrome (CRPS), shingles, and phantom-limb pain. More recently, it has been used in a variety of other conditions, including PTSD, Raynaud’s disease, menopausal hot flashes, and hyperhidrosis.

Insurance companies typically cover it for CRPS, neuropathic upper-extremity pain, hyperhidrosis, and Raynaud’s, said Luke Liu, MD, an anesthesiologist who is founder and chief executive officer of Alaska-based pain management company Neuroversion.

Deborah Duricka, PhD, also with Neuroversion, presented results from a now-published case series of 11 patients with long COVID who underwent stellate ganglion block by a board-certified anesthesiologist, first on one side at the level of C6, then on the contralateral side the following day.

Clinically meaningful benefits were seen in at least five of the patients in fatigue, memory problems, problems concentrating, rapid heartbeat, orthostatic intolerance, sleep problems, postexertional malaise, anxiety, and depression.

The hypothetical mechanism, she said, is that “sympathetic block prevents sympathetically driven vasoconstriction in carotid and vertebral arteries.”

Dr. Liu presented another case series of five patients with ME/CFS who underwent the procedure with ultrasound guidance, again on one side and the other side the next day. All had upper-limb autonomic issues such as Raynaud’s and/or neuropathic pain that had been refractory to more conventional treatments.

All five patients reported improvements in symptoms of ME/CFS, including energy level, cognition, pain, and postexertional malaise. One patient reported “feeling well for the first time in decades.” However, that patient relapsed after a mild viral illness 3.5 months after treatment. Some of the patients have required further treatments.

Dr. Lapp commented that, although the procedure is generally safe when performed by an experienced clinician, “Any time you do an injection like that, there’s a high risk that you could nick an artery or a vein or hit an essential nerve in the neck. That’s why it has to be done under fluoroscopy or ultrasound.”

He said he’s had a few patients undergo the procedure, mostly for CRPS, and they seem to have benefited from it. “It might increase cerebral blood flow and preload to the heart, so it might decrease ME/CFS symptoms and help with POTS as well.”

Nonetheless, Dr. Lapp said he wouldn’t consider stellate ganglion block as first-line treatment for ME/CFS or long COVID. “I think it would be for the treatment-resistant patient, when you’ve gone through all the treatments that we know and addressed all the comorbidities and they’re still not getting better.”

But, he added, it is a standard procedure. “Any pain clinic can do a stellate block.”
 

Transcutaneous auricular vagus nerve stimulation

Nicola Clague-Baker, PhD, a physiotherapist at the University of Liverpool (England), presented findings from an international survey of people with ME/CFS regarding their experience with transcutaneous auricular vagus nerve stimulation (taVNS) to manage their autonomic symptoms. The technique involves stimulation of the autonomic nervous system via the vagus nerve using electrodes applied to part of the ear. The theory is that the technique stimulates the parasympathetic nervous system and improves autonomic balance.

Two small previous trials showing benefit of vagus nerve stimulation for people with ME/CFS used more invasive and less comfortable methods of applying the stimulation rather than to the ear, Dr. Clague-Baker and colleagues noted in a poster. It has also been used successfully in treating POTS, another conference speaker noted.

A total of 131 people with ME/CFS (called simply “ME” in the United Kingdom) responded to a survey advertised on social media and websites. The majority (60%) were from the United Kingdom while the rest were from Europe, Australia, and North America. Most were female, and slightly more than half had lived with ME for 10 or more years.

The majority (72%) were still using taVNS, while 28% had stopped using it. Only 9% had used the modality for longer than a year. Respondents identified more than 30 benefits in symptoms and activities, with improvements in postexertional malaise (39%) and brain fog (37%) being the most common. One reported significant reduction in constipation.

However, respondents also mentioned more than 20 short- and long-term negatives, including headaches (15%) and long-term irritation at the site (9%). One participant reported a “big improvement in neuropathic pain, but not so much for muscles and joints.”

Overall, 80% reported that they would continue using taVNS and 67% said they would recommend it to others with ME, and 56% said that the system was mildly to very beneficial.

Dr. Lapp noted that several types of transcutaneous electrical nerve stimulation units with ear clips are sold online, and he’s seen them work well for migraine treatment. However, he cautioned that some patients have had side effects from the treatment, such as headaches and dizziness. “It’s putting an electrical current through your brain. In my mind, it’s another last-ditch measure.”

Dr. Lapp reported no financial disclosures.

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

Researchers published the study covered in this summary on researchsquare.com as a preprint that has not yet been peer reviewed.

Key takeaways

• In Japanese adults with type 1 diabetes insulin-pump treatment (continuous subcutaneous insulin infusion) and higher problem-solving perception appear protective against impaired awareness of hypoglycemia (IAH), while diabetic peripheral neuropathy (DPN) is associated with increased risk.
• Diabetes distress and fear of hypoglycemia are common in people with IAH.

Why this matters

• Adults with type 1 diabetes and IAH have a reduced ability to perceive hypoglycemic symptoms and are at risk of severe hypoglycemic events because they are unable to take immediate corrective action.
• This is the first study to identify protective factors and risk factors of IAH in Japanese adults with type 1 diabetes.
• People with IAH may plan to loosen tight glucose management and intentionally omit insulin injection to prevent severe hypoglycemia.
• The information in this report may help improve the management of people with problematic hypoglycemia, the authors suggested. Treatment with an insulin pump and structured education aimed at improving problem-solving skills may be useful interventions for adults with type 1 diabetes and IAH, they suggested.

Study design

• The study involved a cross-sectional analysis of 288 Japanese adults with type 1 diabetes who averaged 50 years old, had diabetes for an average of about 18 years, had an average hemoglobin A1c at baseline of 7.7%, and included about 37% men and 63% women.
• The cohort included 55 people with IAH (19%) and 233 with no impairment of their hypoglycemia awareness, based on their score on the .

Key results

• DPN was significantly more prevalent in the IAH group than in the control group (12.0% vs. 26.5%). A logistic regression analysis showed that the odds ratio for DPN was 2.63-fold higher among people with IAH, compared with those without IAH, but there were no differences in other complications or by HbA1c levels.
• Treatment with continuous subcutaneous insulin therapy (an insulin pump) was significantly less prevalent in the IAH group, compared with those without IAH (23.6% vs 39.5%), with an adjusted odds ratio of 0.48. The two subgroups showed no differences in use of continuous glucose monitoring, used by 56% of the people in each of the two subgroups.
• The two subgroups showed no differences in their healthy lifestyle score, sleep debt, or rates of excessive drinking.
• Mean autonomic symptom scores for both sweating and shaking were significantly reduced in the IAH group, but no between-group differences appeared for palpations or hunger.
• All mean neuroglycopenic symptom scores were significantly lower in those without IAH, including confusion and speech difficulty.
• Scores for measures of diabetes distress and for the worry component of the fear of hypoglycemia were significantly higher in the IAH group, but there were no differences in other psychological measures.
• Higher were significantly associated with decreased IAH risk with a calculated odds ratio of 0.54, but other aspects of hypoglycemia problem-solving such as detection control, goal setting, and strategy evaluation showed no significant links.

Limitations

• The study used a cross-sectional design, which is not suited to making causal inferences.
• The authors characterized DPN as either present or absent. They did not evaluate or analyze the severity of peripheral neuropathy.
• The authors evaluated diabetic cardiac autonomic neuropathy (DCAN) by a person’s coefficient of variation of R-R intervals, and definitive diagnosis of DCAN required at least two positive results on a cardiac autonomic test. More vigorous evaluation using a more definitive assessment of DCAN is needed to relate DCAN and IAH status.

Disclosures

• The study received no commercial funding.
• The authors have disclosed no relevant financial relationships.

This is a summary of a preprint research study, “Protective and risk factors of impaired awareness of hypoglycemia in patients with type 1 diabetes: a cross- sectional analysis of baseline data from the PR-IAH study,” written by researchers at several hospitals in Japan, all affiliated with the National Hospital Organization, on Research Square. The study has not yet been peer reviewed. The full text of the study can be found on researchsquare.com.

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

Researchers published the study covered in this summary on researchsquare.com as a preprint that has not yet been peer reviewed.

Key takeaways

• In Japanese adults with type 1 diabetes insulin-pump treatment (continuous subcutaneous insulin infusion) and higher problem-solving perception appear protective against impaired awareness of hypoglycemia (IAH), while diabetic peripheral neuropathy (DPN) is associated with increased risk.
• Diabetes distress and fear of hypoglycemia are common in people with IAH.

Why this matters

• Adults with type 1 diabetes and IAH have a reduced ability to perceive hypoglycemic symptoms and are at risk of severe hypoglycemic events because they are unable to take immediate corrective action.
• This is the first study to identify protective factors and risk factors of IAH in Japanese adults with type 1 diabetes.
• People with IAH may plan to loosen tight glucose management and intentionally omit insulin injection to prevent severe hypoglycemia.
• The information in this report may help improve the management of people with problematic hypoglycemia, the authors suggested. Treatment with an insulin pump and structured education aimed at improving problem-solving skills may be useful interventions for adults with type 1 diabetes and IAH, they suggested.

Study design

• The study involved a cross-sectional analysis of 288 Japanese adults with type 1 diabetes who averaged 50 years old, had diabetes for an average of about 18 years, had an average hemoglobin A1c at baseline of 7.7%, and included about 37% men and 63% women.
• The cohort included 55 people with IAH (19%) and 233 with no impairment of their hypoglycemia awareness, based on their score on the .

Key results

• DPN was significantly more prevalent in the IAH group than in the control group (12.0% vs. 26.5%). A logistic regression analysis showed that the odds ratio for DPN was 2.63-fold higher among people with IAH, compared with those without IAH, but there were no differences in other complications or by HbA1c levels.
• Treatment with continuous subcutaneous insulin therapy (an insulin pump) was significantly less prevalent in the IAH group, compared with those without IAH (23.6% vs 39.5%), with an adjusted odds ratio of 0.48. The two subgroups showed no differences in use of continuous glucose monitoring, used by 56% of the people in each of the two subgroups.
• The two subgroups showed no differences in their healthy lifestyle score, sleep debt, or rates of excessive drinking.
• Mean autonomic symptom scores for both sweating and shaking were significantly reduced in the IAH group, but no between-group differences appeared for palpations or hunger.
• All mean neuroglycopenic symptom scores were significantly lower in those without IAH, including confusion and speech difficulty.
• Scores for measures of diabetes distress and for the worry component of the fear of hypoglycemia were significantly higher in the IAH group, but there were no differences in other psychological measures.
• Higher were significantly associated with decreased IAH risk with a calculated odds ratio of 0.54, but other aspects of hypoglycemia problem-solving such as detection control, goal setting, and strategy evaluation showed no significant links.

Limitations

• The study used a cross-sectional design, which is not suited to making causal inferences.
• The authors characterized DPN as either present or absent. They did not evaluate or analyze the severity of peripheral neuropathy.
• The authors evaluated diabetic cardiac autonomic neuropathy (DCAN) by a person’s coefficient of variation of R-R intervals, and definitive diagnosis of DCAN required at least two positive results on a cardiac autonomic test. More vigorous evaluation using a more definitive assessment of DCAN is needed to relate DCAN and IAH status.

Disclosures

• The study received no commercial funding.
• The authors have disclosed no relevant financial relationships.

This is a summary of a preprint research study, “Protective and risk factors of impaired awareness of hypoglycemia in patients with type 1 diabetes: a cross- sectional analysis of baseline data from the PR-IAH study,” written by researchers at several hospitals in Japan, all affiliated with the National Hospital Organization, on Research Square. The study has not yet been peer reviewed. The full text of the study can be found on researchsquare.com.

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

Researchers published the study covered in this summary on researchsquare.com as a preprint that has not yet been peer reviewed.

Key takeaways

• In Japanese adults with type 1 diabetes insulin-pump treatment (continuous subcutaneous insulin infusion) and higher problem-solving perception appear protective against impaired awareness of hypoglycemia (IAH), while diabetic peripheral neuropathy (DPN) is associated with increased risk.
• Diabetes distress and fear of hypoglycemia are common in people with IAH.

Why this matters

• Adults with type 1 diabetes and IAH have a reduced ability to perceive hypoglycemic symptoms and are at risk of severe hypoglycemic events because they are unable to take immediate corrective action.
• This is the first study to identify protective factors and risk factors of IAH in Japanese adults with type 1 diabetes.
• People with IAH may plan to loosen tight glucose management and intentionally omit insulin injection to prevent severe hypoglycemia.
• The information in this report may help improve the management of people with problematic hypoglycemia, the authors suggested. Treatment with an insulin pump and structured education aimed at improving problem-solving skills may be useful interventions for adults with type 1 diabetes and IAH, they suggested.

Study design

• The study involved a cross-sectional analysis of 288 Japanese adults with type 1 diabetes who averaged 50 years old, had diabetes for an average of about 18 years, had an average hemoglobin A1c at baseline of 7.7%, and included about 37% men and 63% women.
• The cohort included 55 people with IAH (19%) and 233 with no impairment of their hypoglycemia awareness, based on their score on the .

Key results

• DPN was significantly more prevalent in the IAH group than in the control group (12.0% vs. 26.5%). A logistic regression analysis showed that the odds ratio for DPN was 2.63-fold higher among people with IAH, compared with those without IAH, but there were no differences in other complications or by HbA1c levels.
• Treatment with continuous subcutaneous insulin therapy (an insulin pump) was significantly less prevalent in the IAH group, compared with those without IAH (23.6% vs 39.5%), with an adjusted odds ratio of 0.48. The two subgroups showed no differences in use of continuous glucose monitoring, used by 56% of the people in each of the two subgroups.
• The two subgroups showed no differences in their healthy lifestyle score, sleep debt, or rates of excessive drinking.
• Mean autonomic symptom scores for both sweating and shaking were significantly reduced in the IAH group, but no between-group differences appeared for palpations or hunger.
• All mean neuroglycopenic symptom scores were significantly lower in those without IAH, including confusion and speech difficulty.
• Scores for measures of diabetes distress and for the worry component of the fear of hypoglycemia were significantly higher in the IAH group, but there were no differences in other psychological measures.
• Higher were significantly associated with decreased IAH risk with a calculated odds ratio of 0.54, but other aspects of hypoglycemia problem-solving such as detection control, goal setting, and strategy evaluation showed no significant links.

Limitations

• The study used a cross-sectional design, which is not suited to making causal inferences.
• The authors characterized DPN as either present or absent. They did not evaluate or analyze the severity of peripheral neuropathy.
• The authors evaluated diabetic cardiac autonomic neuropathy (DCAN) by a person’s coefficient of variation of R-R intervals, and definitive diagnosis of DCAN required at least two positive results on a cardiac autonomic test. More vigorous evaluation using a more definitive assessment of DCAN is needed to relate DCAN and IAH status.

Disclosures

• The study received no commercial funding.
• The authors have disclosed no relevant financial relationships.

This is a summary of a preprint research study, “Protective and risk factors of impaired awareness of hypoglycemia in patients with type 1 diabetes: a cross- sectional analysis of baseline data from the PR-IAH study,” written by researchers at several hospitals in Japan, all affiliated with the National Hospital Organization, on Research Square. The study has not yet been peer reviewed. The full text of the study can be found on researchsquare.com.

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

A new clinical practice update from the American Gastroenterological Association offers practical advice around surveillance and use of new screening technologies for Barrett’s esophagus.

The AGA clinical practice update, published in Clinical Gastroenterology and Hepatology comes from the AGA’s Center for GI Innovation and Technology. It offers 15 best practice advice statements based on expert review of existing literature combined with discussion and expert opinion. The aim is “to provide an update on advances and innovation” but not to replace current guidelines.

“Guidelines operate on rigorous methodology which requires the use of [Grading of Recommendations, Assessment, Development and Evaluation] methodology and a higher level of evidence. In gastroenterology especially, innovation is moving quickly and there’s no way for patients to reap their benefits if clinical practice was dictated by guidelines alone. That said, we do need documents that support and drive innovation in clinical practice,” corresponding author Srinadh Komanduri, MD, professor of medicine and surgery in the division of gastroenterology and hepatology at Northwestern University, Chicago, told this news publication.

Asked to comment, Vivek Kaul, MD, the Segal-Watson Professor of Medicine in the Center for Advanced Therapeutic Endoscopy in the division of gastroenterology and hepatology at the University of Rochester (N.Y.) Medical Center, said that the document is “an important attempt to not only present the available scientific literature in a very concise and understandable manner, but it goes above and beyond that in terms of diving into some novel paradigms and technologies and procedures that are either emerging or will be emerging in the near future.”
 

Improving detection by dropping GERD requirement

The first of the 15 statements may also be the most paradigm shifting: The panel suggests screening via standard upper endoscopy of people with at least three risk factors for Barrett’s esophagus and esophageal adenocarcinoma, including those who are male, are non-Hispanic White, are aged above 50 years, and have a history of smoking, chronic gastroesophageal reflux disease (GERD), obesity, or a family history of Barrett’s esophagus or esophageal adenocarcinoma.

This represents a departure from all current guidelines, which stipulate GERD as a necessary prerequisite for screening. But the reason is simple, according to the authors: A majority of patients diagnosed with esophageal cancer never experience classic GERD symptoms.

“There is growing evidence in high-level publications over the last couple of years that reflux is not the ideal predictor, based on odds, for development of Barrett’s esophagus. So the consensus among the experts was that we need to remove GERD as an absolute prerequisite or we’re never going to make progress. In order to make an impact on the rise of esophageal adenocarcinoma we have to increase the denominator of patients we are seeing,” Dr. Komanduri explained.

While it might be difficult to screen every White male over 50 years of age, the data do suggest screening those who also have obesity and/or are current smokers. “That’s a perfect subset you might want to start with. There are permutations that have greater value that don’t occupy unnecessary resource utilization. Most critical are the family history of esophageal cancer or Barrett’s esophagus,” he noted.

Dr. Kaul said that a one-time Barrett’s esophagus screening of all White males over 50 years old “is not unreasonable, especially given the rising rates of esophageal cancer.”

However, he also noted, “The feasibility, preferred screening modality, incremental costs, and yield of this new strategy will need to be studied further. Access to GI endoscopy in the postpandemic world is already a concern and will need to be factored into execution of this [advice statement] and will likely impact adoption in some way.”

For his part, Dr. Komanduri said that more investigation will be needed to validate which patients most benefit from screening and that the AGA is planning educational programs for clinicians about interpreting this new paradigm.
 

New technology could make screening easier and cheaper

The availability of nonendoscopic cell collection devices, including the swallowable Cytosponge (Medtronic), EsoCheck (Lucid), and EsoCap (Capnostics) could help make screening for Barrett’s esophagus easier and more cost effective. They are designed for in-office use and don’t require sedation. Each one is currently in various stages of development and clinical trials. As of now they’re approved in the United States only for cell collection but not for Barrett’s esophagus screening, but their use is endorsed by some guidelines. The Cytosponge in particular is widely available and has been used extensively in the United Kingdom.

Dr. Kaul commented, “While there is a need for nonendoscopic screening devices, the ideal patient population and practice setting for administration of these devices has not been clearly defined. Also, who will be delivering these tests: Primary care or gastroenterology providers? These devices ... represent a major step forward and a novel paradigm for Barrett’s esophagus screening, and the only platform that non-GI providers could use.”
 

Virtual chromoendoscopy: A must have in 2022

A third best practice advice statement shouldn’t be controversial because it’s in other guidelines already, but data show clinicians aren’t always doing it: Performing screening and surveillance endoscopic examinations using virtual chromoendoscopy in addition to high-definition white light endoscopy, with adequate time spent inspecting the Barrett’s segment. The majority of data supporting this is for narrow-band imaging only.

“The blue light lets you pick up early mucosal and vascular changes which might represent dysplastic lesions. It’s not a question of should. It’s a medicolegal slam dunk; you must do it. It’s been a guideline recommendation in the last few years, and it’s just a switch on the scope. It doesn’t require separate equipment, yet people are often still skipping it,” Dr. Komanduri said.

Indeed, Dr. Kaul concurred, “The importance of a high quality, meticulous endoscopic examination for screening and surveillance in Barrett’s esophagus cannot be overemphasized.”
 

‘Finally pushing the needle in the right direction’

The overall goals, Dr. Komanduri said, are “increasing the denominator, using less invasive screening, but finding more patients. If we find more patients we’ll need to stratify their risk. We hope that all these things eventually tie together in a nice story, all with the aim of preventing an invasive cancer that can’t be treated.”

He believes the new update “is a pivotal document in this field that’s going to be a paradigm changer. A lot of aspects need further validation. It’s by no means the end. But I think we’re finally pushing the needle in the right direction as things move forward with innovation.”

Dr. Kaul agrees. “It’s highlighting the principles that may become established paradigms in the future.”

Dr. Komanduri and the other authors of the update reported relationships, including consulting and research support, with companies like Boston Scientific, Medtronic, Virgo Video Solutions, and Castle Biosciences. Dr. Kaul serves as a consultant and advisory board member for CDx Diagnostics, an advisory board member for Castle Biosciences, and an investigator for Lucid Diagnostics.

A new clinical practice update from the American Gastroenterological Association offers practical advice around surveillance and use of new screening technologies for Barrett’s esophagus.

The AGA clinical practice update, published in Clinical Gastroenterology and Hepatology comes from the AGA’s Center for GI Innovation and Technology. It offers 15 best practice advice statements based on expert review of existing literature combined with discussion and expert opinion. The aim is “to provide an update on advances and innovation” but not to replace current guidelines.

“Guidelines operate on rigorous methodology which requires the use of [Grading of Recommendations, Assessment, Development and Evaluation] methodology and a higher level of evidence. In gastroenterology especially, innovation is moving quickly and there’s no way for patients to reap their benefits if clinical practice was dictated by guidelines alone. That said, we do need documents that support and drive innovation in clinical practice,” corresponding author Srinadh Komanduri, MD, professor of medicine and surgery in the division of gastroenterology and hepatology at Northwestern University, Chicago, told this news publication.

Asked to comment, Vivek Kaul, MD, the Segal-Watson Professor of Medicine in the Center for Advanced Therapeutic Endoscopy in the division of gastroenterology and hepatology at the University of Rochester (N.Y.) Medical Center, said that the document is “an important attempt to not only present the available scientific literature in a very concise and understandable manner, but it goes above and beyond that in terms of diving into some novel paradigms and technologies and procedures that are either emerging or will be emerging in the near future.”
 

Improving detection by dropping GERD requirement

The first of the 15 statements may also be the most paradigm shifting: The panel suggests screening via standard upper endoscopy of people with at least three risk factors for Barrett’s esophagus and esophageal adenocarcinoma, including those who are male, are non-Hispanic White, are aged above 50 years, and have a history of smoking, chronic gastroesophageal reflux disease (GERD), obesity, or a family history of Barrett’s esophagus or esophageal adenocarcinoma.

This represents a departure from all current guidelines, which stipulate GERD as a necessary prerequisite for screening. But the reason is simple, according to the authors: A majority of patients diagnosed with esophageal cancer never experience classic GERD symptoms.

“There is growing evidence in high-level publications over the last couple of years that reflux is not the ideal predictor, based on odds, for development of Barrett’s esophagus. So the consensus among the experts was that we need to remove GERD as an absolute prerequisite or we’re never going to make progress. In order to make an impact on the rise of esophageal adenocarcinoma we have to increase the denominator of patients we are seeing,” Dr. Komanduri explained.

While it might be difficult to screen every White male over 50 years of age, the data do suggest screening those who also have obesity and/or are current smokers. “That’s a perfect subset you might want to start with. There are permutations that have greater value that don’t occupy unnecessary resource utilization. Most critical are the family history of esophageal cancer or Barrett’s esophagus,” he noted.

Dr. Kaul said that a one-time Barrett’s esophagus screening of all White males over 50 years old “is not unreasonable, especially given the rising rates of esophageal cancer.”

However, he also noted, “The feasibility, preferred screening modality, incremental costs, and yield of this new strategy will need to be studied further. Access to GI endoscopy in the postpandemic world is already a concern and will need to be factored into execution of this [advice statement] and will likely impact adoption in some way.”

For his part, Dr. Komanduri said that more investigation will be needed to validate which patients most benefit from screening and that the AGA is planning educational programs for clinicians about interpreting this new paradigm.
 

New technology could make screening easier and cheaper

The availability of nonendoscopic cell collection devices, including the swallowable Cytosponge (Medtronic), EsoCheck (Lucid), and EsoCap (Capnostics) could help make screening for Barrett’s esophagus easier and more cost effective. They are designed for in-office use and don’t require sedation. Each one is currently in various stages of development and clinical trials. As of now they’re approved in the United States only for cell collection but not for Barrett’s esophagus screening, but their use is endorsed by some guidelines. The Cytosponge in particular is widely available and has been used extensively in the United Kingdom.

Dr. Kaul commented, “While there is a need for nonendoscopic screening devices, the ideal patient population and practice setting for administration of these devices has not been clearly defined. Also, who will be delivering these tests: Primary care or gastroenterology providers? These devices ... represent a major step forward and a novel paradigm for Barrett’s esophagus screening, and the only platform that non-GI providers could use.”
 

Virtual chromoendoscopy: A must have in 2022

A third best practice advice statement shouldn’t be controversial because it’s in other guidelines already, but data show clinicians aren’t always doing it: Performing screening and surveillance endoscopic examinations using virtual chromoendoscopy in addition to high-definition white light endoscopy, with adequate time spent inspecting the Barrett’s segment. The majority of data supporting this is for narrow-band imaging only.

“The blue light lets you pick up early mucosal and vascular changes which might represent dysplastic lesions. It’s not a question of should. It’s a medicolegal slam dunk; you must do it. It’s been a guideline recommendation in the last few years, and it’s just a switch on the scope. It doesn’t require separate equipment, yet people are often still skipping it,” Dr. Komanduri said.

Indeed, Dr. Kaul concurred, “The importance of a high quality, meticulous endoscopic examination for screening and surveillance in Barrett’s esophagus cannot be overemphasized.”
 

‘Finally pushing the needle in the right direction’

The overall goals, Dr. Komanduri said, are “increasing the denominator, using less invasive screening, but finding more patients. If we find more patients we’ll need to stratify their risk. We hope that all these things eventually tie together in a nice story, all with the aim of preventing an invasive cancer that can’t be treated.”

He believes the new update “is a pivotal document in this field that’s going to be a paradigm changer. A lot of aspects need further validation. It’s by no means the end. But I think we’re finally pushing the needle in the right direction as things move forward with innovation.”

Dr. Kaul agrees. “It’s highlighting the principles that may become established paradigms in the future.”

Dr. Komanduri and the other authors of the update reported relationships, including consulting and research support, with companies like Boston Scientific, Medtronic, Virgo Video Solutions, and Castle Biosciences. Dr. Kaul serves as a consultant and advisory board member for CDx Diagnostics, an advisory board member for Castle Biosciences, and an investigator for Lucid Diagnostics.

A new clinical practice update from the American Gastroenterological Association offers practical advice around surveillance and use of new screening technologies for Barrett’s esophagus.

The AGA clinical practice update, published in Clinical Gastroenterology and Hepatology comes from the AGA’s Center for GI Innovation and Technology. It offers 15 best practice advice statements based on expert review of existing literature combined with discussion and expert opinion. The aim is “to provide an update on advances and innovation” but not to replace current guidelines.

“Guidelines operate on rigorous methodology which requires the use of [Grading of Recommendations, Assessment, Development and Evaluation] methodology and a higher level of evidence. In gastroenterology especially, innovation is moving quickly and there’s no way for patients to reap their benefits if clinical practice was dictated by guidelines alone. That said, we do need documents that support and drive innovation in clinical practice,” corresponding author Srinadh Komanduri, MD, professor of medicine and surgery in the division of gastroenterology and hepatology at Northwestern University, Chicago, told this news publication.

Asked to comment, Vivek Kaul, MD, the Segal-Watson Professor of Medicine in the Center for Advanced Therapeutic Endoscopy in the division of gastroenterology and hepatology at the University of Rochester (N.Y.) Medical Center, said that the document is “an important attempt to not only present the available scientific literature in a very concise and understandable manner, but it goes above and beyond that in terms of diving into some novel paradigms and technologies and procedures that are either emerging or will be emerging in the near future.”
 

Improving detection by dropping GERD requirement

The first of the 15 statements may also be the most paradigm shifting: The panel suggests screening via standard upper endoscopy of people with at least three risk factors for Barrett’s esophagus and esophageal adenocarcinoma, including those who are male, are non-Hispanic White, are aged above 50 years, and have a history of smoking, chronic gastroesophageal reflux disease (GERD), obesity, or a family history of Barrett’s esophagus or esophageal adenocarcinoma.

This represents a departure from all current guidelines, which stipulate GERD as a necessary prerequisite for screening. But the reason is simple, according to the authors: A majority of patients diagnosed with esophageal cancer never experience classic GERD symptoms.

“There is growing evidence in high-level publications over the last couple of years that reflux is not the ideal predictor, based on odds, for development of Barrett’s esophagus. So the consensus among the experts was that we need to remove GERD as an absolute prerequisite or we’re never going to make progress. In order to make an impact on the rise of esophageal adenocarcinoma we have to increase the denominator of patients we are seeing,” Dr. Komanduri explained.

While it might be difficult to screen every White male over 50 years of age, the data do suggest screening those who also have obesity and/or are current smokers. “That’s a perfect subset you might want to start with. There are permutations that have greater value that don’t occupy unnecessary resource utilization. Most critical are the family history of esophageal cancer or Barrett’s esophagus,” he noted.

Dr. Kaul said that a one-time Barrett’s esophagus screening of all White males over 50 years old “is not unreasonable, especially given the rising rates of esophageal cancer.”

However, he also noted, “The feasibility, preferred screening modality, incremental costs, and yield of this new strategy will need to be studied further. Access to GI endoscopy in the postpandemic world is already a concern and will need to be factored into execution of this [advice statement] and will likely impact adoption in some way.”

For his part, Dr. Komanduri said that more investigation will be needed to validate which patients most benefit from screening and that the AGA is planning educational programs for clinicians about interpreting this new paradigm.
 

New technology could make screening easier and cheaper

The availability of nonendoscopic cell collection devices, including the swallowable Cytosponge (Medtronic), EsoCheck (Lucid), and EsoCap (Capnostics) could help make screening for Barrett’s esophagus easier and more cost effective. They are designed for in-office use and don’t require sedation. Each one is currently in various stages of development and clinical trials. As of now they’re approved in the United States only for cell collection but not for Barrett’s esophagus screening, but their use is endorsed by some guidelines. The Cytosponge in particular is widely available and has been used extensively in the United Kingdom.

Dr. Kaul commented, “While there is a need for nonendoscopic screening devices, the ideal patient population and practice setting for administration of these devices has not been clearly defined. Also, who will be delivering these tests: Primary care or gastroenterology providers? These devices ... represent a major step forward and a novel paradigm for Barrett’s esophagus screening, and the only platform that non-GI providers could use.”
 

Virtual chromoendoscopy: A must have in 2022

A third best practice advice statement shouldn’t be controversial because it’s in other guidelines already, but data show clinicians aren’t always doing it: Performing screening and surveillance endoscopic examinations using virtual chromoendoscopy in addition to high-definition white light endoscopy, with adequate time spent inspecting the Barrett’s segment. The majority of data supporting this is for narrow-band imaging only.

“The blue light lets you pick up early mucosal and vascular changes which might represent dysplastic lesions. It’s not a question of should. It’s a medicolegal slam dunk; you must do it. It’s been a guideline recommendation in the last few years, and it’s just a switch on the scope. It doesn’t require separate equipment, yet people are often still skipping it,” Dr. Komanduri said.

Indeed, Dr. Kaul concurred, “The importance of a high quality, meticulous endoscopic examination for screening and surveillance in Barrett’s esophagus cannot be overemphasized.”
 

‘Finally pushing the needle in the right direction’

The overall goals, Dr. Komanduri said, are “increasing the denominator, using less invasive screening, but finding more patients. If we find more patients we’ll need to stratify their risk. We hope that all these things eventually tie together in a nice story, all with the aim of preventing an invasive cancer that can’t be treated.”

He believes the new update “is a pivotal document in this field that’s going to be a paradigm changer. A lot of aspects need further validation. It’s by no means the end. But I think we’re finally pushing the needle in the right direction as things move forward with innovation.”

Dr. Kaul agrees. “It’s highlighting the principles that may become established paradigms in the future.”

Dr. Komanduri and the other authors of the update reported relationships, including consulting and research support, with companies like Boston Scientific, Medtronic, Virgo Video Solutions, and Castle Biosciences. Dr. Kaul serves as a consultant and advisory board member for CDx Diagnostics, an advisory board member for Castle Biosciences, and an investigator for Lucid Diagnostics.

Hormone therapy did not increase mortality in postmenopausal women treated for early-stage estrogen receptor–positive breast cancer, but, in longitudinal data from Denmark, there was a recurrence risk with vaginal estrogen therapy among those treated with aromatase inhibitors.

Genitourinary syndrome of menopause (GSM) – including vaginal dryness, burning, and urinary incontinence – is common in women treated for breast cancer. Adjuvant endocrine therapy, particularly aromatase inhibitors, can aggravate these symptoms. Both local and systemic estrogen therapy are recommended for alleviating GSM symptoms in healthy women, but concerns have been raised about their use in women with breast cancer. Previous studies examining this have suggested possible risks for breast cancer recurrence, but those studies have had several limitations including small samples and short follow-up, particularly for vaginal estrogen therapy.

In the new study, from a national Danish cohort of 8,461 postmenopausal women diagnosed between 1997 and 2004 and treated for early-stage invasive estrogen receptor–positive nonmetastatic breast cancer, neither systemic menopausal hormone therapy (MHT) nor local vaginal estrogen therapy (VET) were associated with an overall increased risk for either breast cancer recurrence or mortality. However, in the subset who had received an aromatase inhibitor – with or without tamoxifen – there was a statistically significant increased risk for breast cancer recurrence, but not mortality.

The results were published in the Journal of the National Cancer Institute.

“The data are reassuring for the majority of women with no adjuvant therapy or tamoxifen. But for those using adjuvant aromatase inhibitors, there might be a small risk,” study lead author Søren Cold, MD, PhD, senior oncologist in the department of oncology at Odense (Denmark) University Hospital, Odense, said in an interview.

Moreover, Dr. Cold noted, while this study didn’t find an increased recurrence risk with MHT for women taking aromatase inhibitors, other studies have. One in particular was stopped because of harm. The reason for the difference here is likely that the previous sample was small – just 133 women.

“Our study is mainly focusing on the use of vaginal estrogen. We had so few patients using systemic menopausal hormone therapy, those data don’t mean much. ... The risk with systemic therapy has been established. The vaginal use hasn’t been thoroughly studied before,” he noted.
 

Breast cancer recurrence elevated with VET and aromatase inhibitors

The study pool was 9,710 women who underwent complete resection for estrogen-positive breast cancer and were all allocated to 5 years of adjuvant endocrine treatment or no adjuvant treatment, according to guidelines. Overall, 3,112 received no adjuvant endocrine treatment, 2,007 were treated with tamoxifen only, 403 with an aromatase inhibitor, and 2,939 with a sequence of tamoxifen and an aromatase inhibitor.

After exclusion of 1,249 who had received VET or MHT prior to breast cancer diagnosis, there were 6,391 not prescribed any estrogen hormonal treatment, 1,957 prescribed VET, and 133 prescribed MHT with or without VET.

During an estimated median 9.8 years’ follow-up, 1,333 women (16%) had a breast cancer recurrence. Of those, 111 had received VET, 16 MHT, and 1,206 neither. Compared with those receiving no hormonal treatment, the adjusted risk of recurrence was similar for the VET users (hazard ratio, 1.08; 95% confidence interval, 0.89-1.32).

However, there was an increased risk for recurrence associated with initiating VET during aromatase inhibitor treatment (HR, 1.39, 95% CI, 1.04-1.85). For women receiving MHT, the adjusted relative risk of recurrence with aromatase inhibitors wasn’t significant (HR, 1.05; 95% CI, 0.62-1.78).

Overall, compared with women who never used hormonal treatment, the absolute 10-year breast cancer recurrence risk was 19.2% for never-users of VET or MHT, 15.4% in VET users, and 17.1% in MHT users.
 

No differences found for mortality

Of the 8,461 women in the study, 40% (3,370) died during an estimated median follow-up of 15.2 years. Of those, 497 had received VET, 47 MHT, and 2,826 neither. Compared with the never-users of estrogen therapy, the adjusted HR for overall survival in VET users was 0.78 (95% CI, 0.71-0.87). The analysis stratified by adjuvant endocrine therapy didn’t show an increase in VET users by use of aromatase inhibitors (aHR, 0.94, 95% CI, 0.70-1.26). The same was found for women prescribed MHT, compared with never-users (aHR, 0.94; 95% CI, 0.70-1.26).

Never-users of VET or MHT had an absolute 10-year overall survival of 73.8% versus 79.5% and 80.5% among the women who used VET or MHT, respectively.

Asked to comment, Nanette Santoro, MD, professor and E. Stewart Taylor Chair of Obstetrics & Gynecology at the University of Colorado at Denver, Aurora, said in an interview: “It is important to look at this issue. These findings raise but don’t answer the question that vaginal estradiol may not be as safe as we hope it is for women with breast cancer using an aromatase inhibitor.”

However, she also pointed out that “the overall increase in risk is not enormous; mortality risk was not increased. Women need to consider that there may be some risk associated with this option in their decision making about taking it. Having a satisfying sex life is also important for many women! It is really compassionate use for quality of life, so there is always that unknown element of risk in the discussion. That unknown risk has to be balanced against the benefit that the estrogen provides.”

And, Dr. Santoro also noted that the use of prescription data poses limitations. “It cannot tell us what was going on in the minds of the patient and the prescriber. There may be differences in the prescriber’s impression of the patient’s risk of recurrence that influenced the decision to provide a prescription. ... Women using AIs [aromatase inhibitors] often get pretty severe vaginal dryness symptoms and may need more estrogen to be comfortable with intercourse, but we really cannot tell this from what is in this paper.”

Indeed, Dr. Cold said: “We admit it’s not a randomized study, but we’ve done what was possible to take [confounding] factors into account, including age, tumor size, nodal status, histology, and comorbidities.”

He suggested that a potential therapeutic approach to reducing the recurrence risk might be to switch VET-treated women to tamoxifen after 2-3 years of aromatase inhibitors.

This work was supported by Breast Friends, a part of the Danish Cancer Society. Dr. Cold received support from Breast Friends for the current study. Some of the other coauthors have pharmaceutical company disclosures. Dr. Santoro is a member of the scientific advisory boards for Astellas, Menogenix, Que Oncology, and Amazon Ember, and is a consultant for Ansh Labs.

Hormone therapy did not increase mortality in postmenopausal women treated for early-stage estrogen receptor–positive breast cancer, but, in longitudinal data from Denmark, there was a recurrence risk with vaginal estrogen therapy among those treated with aromatase inhibitors.

Genitourinary syndrome of menopause (GSM) – including vaginal dryness, burning, and urinary incontinence – is common in women treated for breast cancer. Adjuvant endocrine therapy, particularly aromatase inhibitors, can aggravate these symptoms. Both local and systemic estrogen therapy are recommended for alleviating GSM symptoms in healthy women, but concerns have been raised about their use in women with breast cancer. Previous studies examining this have suggested possible risks for breast cancer recurrence, but those studies have had several limitations including small samples and short follow-up, particularly for vaginal estrogen therapy.

In the new study, from a national Danish cohort of 8,461 postmenopausal women diagnosed between 1997 and 2004 and treated for early-stage invasive estrogen receptor–positive nonmetastatic breast cancer, neither systemic menopausal hormone therapy (MHT) nor local vaginal estrogen therapy (VET) were associated with an overall increased risk for either breast cancer recurrence or mortality. However, in the subset who had received an aromatase inhibitor – with or without tamoxifen – there was a statistically significant increased risk for breast cancer recurrence, but not mortality.

The results were published in the Journal of the National Cancer Institute.

“The data are reassuring for the majority of women with no adjuvant therapy or tamoxifen. But for those using adjuvant aromatase inhibitors, there might be a small risk,” study lead author Søren Cold, MD, PhD, senior oncologist in the department of oncology at Odense (Denmark) University Hospital, Odense, said in an interview.

Moreover, Dr. Cold noted, while this study didn’t find an increased recurrence risk with MHT for women taking aromatase inhibitors, other studies have. One in particular was stopped because of harm. The reason for the difference here is likely that the previous sample was small – just 133 women.

“Our study is mainly focusing on the use of vaginal estrogen. We had so few patients using systemic menopausal hormone therapy, those data don’t mean much. ... The risk with systemic therapy has been established. The vaginal use hasn’t been thoroughly studied before,” he noted.
 

Breast cancer recurrence elevated with VET and aromatase inhibitors

The study pool was 9,710 women who underwent complete resection for estrogen-positive breast cancer and were all allocated to 5 years of adjuvant endocrine treatment or no adjuvant treatment, according to guidelines. Overall, 3,112 received no adjuvant endocrine treatment, 2,007 were treated with tamoxifen only, 403 with an aromatase inhibitor, and 2,939 with a sequence of tamoxifen and an aromatase inhibitor.

After exclusion of 1,249 who had received VET or MHT prior to breast cancer diagnosis, there were 6,391 not prescribed any estrogen hormonal treatment, 1,957 prescribed VET, and 133 prescribed MHT with or without VET.

During an estimated median 9.8 years’ follow-up, 1,333 women (16%) had a breast cancer recurrence. Of those, 111 had received VET, 16 MHT, and 1,206 neither. Compared with those receiving no hormonal treatment, the adjusted risk of recurrence was similar for the VET users (hazard ratio, 1.08; 95% confidence interval, 0.89-1.32).

However, there was an increased risk for recurrence associated with initiating VET during aromatase inhibitor treatment (HR, 1.39, 95% CI, 1.04-1.85). For women receiving MHT, the adjusted relative risk of recurrence with aromatase inhibitors wasn’t significant (HR, 1.05; 95% CI, 0.62-1.78).

Overall, compared with women who never used hormonal treatment, the absolute 10-year breast cancer recurrence risk was 19.2% for never-users of VET or MHT, 15.4% in VET users, and 17.1% in MHT users.
 

No differences found for mortality

Of the 8,461 women in the study, 40% (3,370) died during an estimated median follow-up of 15.2 years. Of those, 497 had received VET, 47 MHT, and 2,826 neither. Compared with the never-users of estrogen therapy, the adjusted HR for overall survival in VET users was 0.78 (95% CI, 0.71-0.87). The analysis stratified by adjuvant endocrine therapy didn’t show an increase in VET users by use of aromatase inhibitors (aHR, 0.94, 95% CI, 0.70-1.26). The same was found for women prescribed MHT, compared with never-users (aHR, 0.94; 95% CI, 0.70-1.26).

Never-users of VET or MHT had an absolute 10-year overall survival of 73.8% versus 79.5% and 80.5% among the women who used VET or MHT, respectively.

Asked to comment, Nanette Santoro, MD, professor and E. Stewart Taylor Chair of Obstetrics & Gynecology at the University of Colorado at Denver, Aurora, said in an interview: “It is important to look at this issue. These findings raise but don’t answer the question that vaginal estradiol may not be as safe as we hope it is for women with breast cancer using an aromatase inhibitor.”

However, she also pointed out that “the overall increase in risk is not enormous; mortality risk was not increased. Women need to consider that there may be some risk associated with this option in their decision making about taking it. Having a satisfying sex life is also important for many women! It is really compassionate use for quality of life, so there is always that unknown element of risk in the discussion. That unknown risk has to be balanced against the benefit that the estrogen provides.”

And, Dr. Santoro also noted that the use of prescription data poses limitations. “It cannot tell us what was going on in the minds of the patient and the prescriber. There may be differences in the prescriber’s impression of the patient’s risk of recurrence that influenced the decision to provide a prescription. ... Women using AIs [aromatase inhibitors] often get pretty severe vaginal dryness symptoms and may need more estrogen to be comfortable with intercourse, but we really cannot tell this from what is in this paper.”

Indeed, Dr. Cold said: “We admit it’s not a randomized study, but we’ve done what was possible to take [confounding] factors into account, including age, tumor size, nodal status, histology, and comorbidities.”

He suggested that a potential therapeutic approach to reducing the recurrence risk might be to switch VET-treated women to tamoxifen after 2-3 years of aromatase inhibitors.

This work was supported by Breast Friends, a part of the Danish Cancer Society. Dr. Cold received support from Breast Friends for the current study. Some of the other coauthors have pharmaceutical company disclosures. Dr. Santoro is a member of the scientific advisory boards for Astellas, Menogenix, Que Oncology, and Amazon Ember, and is a consultant for Ansh Labs.

Hormone therapy did not increase mortality in postmenopausal women treated for early-stage estrogen receptor–positive breast cancer, but, in longitudinal data from Denmark, there was a recurrence risk with vaginal estrogen therapy among those treated with aromatase inhibitors.

Genitourinary syndrome of menopause (GSM) – including vaginal dryness, burning, and urinary incontinence – is common in women treated for breast cancer. Adjuvant endocrine therapy, particularly aromatase inhibitors, can aggravate these symptoms. Both local and systemic estrogen therapy are recommended for alleviating GSM symptoms in healthy women, but concerns have been raised about their use in women with breast cancer. Previous studies examining this have suggested possible risks for breast cancer recurrence, but those studies have had several limitations including small samples and short follow-up, particularly for vaginal estrogen therapy.

In the new study, from a national Danish cohort of 8,461 postmenopausal women diagnosed between 1997 and 2004 and treated for early-stage invasive estrogen receptor–positive nonmetastatic breast cancer, neither systemic menopausal hormone therapy (MHT) nor local vaginal estrogen therapy (VET) were associated with an overall increased risk for either breast cancer recurrence or mortality. However, in the subset who had received an aromatase inhibitor – with or without tamoxifen – there was a statistically significant increased risk for breast cancer recurrence, but not mortality.

The results were published in the Journal of the National Cancer Institute.

“The data are reassuring for the majority of women with no adjuvant therapy or tamoxifen. But for those using adjuvant aromatase inhibitors, there might be a small risk,” study lead author Søren Cold, MD, PhD, senior oncologist in the department of oncology at Odense (Denmark) University Hospital, Odense, said in an interview.

Moreover, Dr. Cold noted, while this study didn’t find an increased recurrence risk with MHT for women taking aromatase inhibitors, other studies have. One in particular was stopped because of harm. The reason for the difference here is likely that the previous sample was small – just 133 women.

“Our study is mainly focusing on the use of vaginal estrogen. We had so few patients using systemic menopausal hormone therapy, those data don’t mean much. ... The risk with systemic therapy has been established. The vaginal use hasn’t been thoroughly studied before,” he noted.
 

Breast cancer recurrence elevated with VET and aromatase inhibitors

The study pool was 9,710 women who underwent complete resection for estrogen-positive breast cancer and were all allocated to 5 years of adjuvant endocrine treatment or no adjuvant treatment, according to guidelines. Overall, 3,112 received no adjuvant endocrine treatment, 2,007 were treated with tamoxifen only, 403 with an aromatase inhibitor, and 2,939 with a sequence of tamoxifen and an aromatase inhibitor.

After exclusion of 1,249 who had received VET or MHT prior to breast cancer diagnosis, there were 6,391 not prescribed any estrogen hormonal treatment, 1,957 prescribed VET, and 133 prescribed MHT with or without VET.

During an estimated median 9.8 years’ follow-up, 1,333 women (16%) had a breast cancer recurrence. Of those, 111 had received VET, 16 MHT, and 1,206 neither. Compared with those receiving no hormonal treatment, the adjusted risk of recurrence was similar for the VET users (hazard ratio, 1.08; 95% confidence interval, 0.89-1.32).

However, there was an increased risk for recurrence associated with initiating VET during aromatase inhibitor treatment (HR, 1.39, 95% CI, 1.04-1.85). For women receiving MHT, the adjusted relative risk of recurrence with aromatase inhibitors wasn’t significant (HR, 1.05; 95% CI, 0.62-1.78).

Overall, compared with women who never used hormonal treatment, the absolute 10-year breast cancer recurrence risk was 19.2% for never-users of VET or MHT, 15.4% in VET users, and 17.1% in MHT users.
 

No differences found for mortality

Of the 8,461 women in the study, 40% (3,370) died during an estimated median follow-up of 15.2 years. Of those, 497 had received VET, 47 MHT, and 2,826 neither. Compared with the never-users of estrogen therapy, the adjusted HR for overall survival in VET users was 0.78 (95% CI, 0.71-0.87). The analysis stratified by adjuvant endocrine therapy didn’t show an increase in VET users by use of aromatase inhibitors (aHR, 0.94, 95% CI, 0.70-1.26). The same was found for women prescribed MHT, compared with never-users (aHR, 0.94; 95% CI, 0.70-1.26).

Never-users of VET or MHT had an absolute 10-year overall survival of 73.8% versus 79.5% and 80.5% among the women who used VET or MHT, respectively.

Asked to comment, Nanette Santoro, MD, professor and E. Stewart Taylor Chair of Obstetrics & Gynecology at the University of Colorado at Denver, Aurora, said in an interview: “It is important to look at this issue. These findings raise but don’t answer the question that vaginal estradiol may not be as safe as we hope it is for women with breast cancer using an aromatase inhibitor.”

However, she also pointed out that “the overall increase in risk is not enormous; mortality risk was not increased. Women need to consider that there may be some risk associated with this option in their decision making about taking it. Having a satisfying sex life is also important for many women! It is really compassionate use for quality of life, so there is always that unknown element of risk in the discussion. That unknown risk has to be balanced against the benefit that the estrogen provides.”

And, Dr. Santoro also noted that the use of prescription data poses limitations. “It cannot tell us what was going on in the minds of the patient and the prescriber. There may be differences in the prescriber’s impression of the patient’s risk of recurrence that influenced the decision to provide a prescription. ... Women using AIs [aromatase inhibitors] often get pretty severe vaginal dryness symptoms and may need more estrogen to be comfortable with intercourse, but we really cannot tell this from what is in this paper.”

Indeed, Dr. Cold said: “We admit it’s not a randomized study, but we’ve done what was possible to take [confounding] factors into account, including age, tumor size, nodal status, histology, and comorbidities.”

He suggested that a potential therapeutic approach to reducing the recurrence risk might be to switch VET-treated women to tamoxifen after 2-3 years of aromatase inhibitors.

This work was supported by Breast Friends, a part of the Danish Cancer Society. Dr. Cold received support from Breast Friends for the current study. Some of the other coauthors have pharmaceutical company disclosures. Dr. Santoro is a member of the scientific advisory boards for Astellas, Menogenix, Que Oncology, and Amazon Ember, and is a consultant for Ansh Labs.

Vertex Pharmaceuticals has acquired ViaCyte, bringing together two of the leading biotechnology companies developing stem cell–derived islet cell replacement therapies for type 1 diabetes.

The $320 million cash purchase “will accelerate our goal of transforming, if not curing, type 1 diabetes by expanding our capabilities and bringing additional tools, technologies, and assets to our current stem cell-based programs,” said Vertex Chief Executive Officer and President Reshma Kewalramani, MD, in a company statement.

Last month, Vertex reported on a phase 1/2 multicenter clinical trial for two patients with type 1 diabetes who experienced improved blood glucose control with half doses of the company’s investigational allogeneic stem cell-derived islets (VX-880).

The first person to receive the product remained completely insulin-independent at 9 months post-transplant. A third patient has received the full targeted dose, but the data for this participant have yet to be reported.

For Viacyte’s part, last week the company announced that a clinical hold placed by the U.S. Food and Drug Administration on the trial has been lifted, allowing it to move forward with a planned total enrollment of 17 patients.

“The FDA requested additional information on the program, which we provided expeditiously. We are pleased that the hold has been lifted and look forward to continuing the Phase 1/2 trial in the U.S.,” a Vertex spokesperson told this news organization.

And a company official for ViaCyte presented results for three patients who received pancreatic precursor (PEC-01) cells derived from the company’s proprietary pluripotent stem cell line at the annual meeting of the Endocrine Society held in June. The cells are housed in an open delivery device implanted into a patient’s forearm. All three participants experienced improved blood glucose levels.

That presentation followed ViaCyte’s announcement in February that the first patient with type 1 diabetes had been dosed in a Phase 1 clinical trial of its investigational allogeneic, gene-edited, stem cell-derived product, VCTX210, developed in collaboration with CRISPR Therapeutics’ gene-editing technology. The aim is to generate islet cells that will produce insulin while avoiding recognition by the immune system, thus rendering immunosuppressive drugs unnecessary.

According to Vertex’s announcement, “The acquisition of ViaCyte provides Vertex with complementary assets, capabilities, and technologies, including additional human stem cell lines, intellectual property around stem cell differentiation, and Good Manufacturing Practice ... facilities for cell-based therapies that could accelerate Vertex’s ongoing type 1 diabetes programs. The acquisition also provides access to novel hypoimmune stem cell assets via the ViaCyte collaboration with CRISPR Therapeutics.”

In response to the announcement, the type 1 diabetes advocacy organization JDRF, which has funded the work of both companies, said in a statement that the acquisition “represents a significant stride in cures research for the type 1 diabetes community.”

“The coming together of two leaders in the cell-derived therapies field will undoubtedly accelerate the development of VX-880 by combining their resources, technologies, intellectual property, and more,” it added.

A third company developing stem cell–derived islet cell therapies, Sernova, said in a statement provided to this news organization: “We are very confident that bringing important game-changing technologies together, as we are seeing across the industry, will result in several viable technologies for the millions of people with type 1 diabetes ... We are thrilled that there are several technologies under development using different approaches that have the potential to provide a ‘functional cure’ for this disease.”

Vertex anticipates the acquisition will close later in 2022.

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

Vertex Pharmaceuticals has acquired ViaCyte, bringing together two of the leading biotechnology companies developing stem cell–derived islet cell replacement therapies for type 1 diabetes.

The $320 million cash purchase “will accelerate our goal of transforming, if not curing, type 1 diabetes by expanding our capabilities and bringing additional tools, technologies, and assets to our current stem cell-based programs,” said Vertex Chief Executive Officer and President Reshma Kewalramani, MD, in a company statement.

Last month, Vertex reported on a phase 1/2 multicenter clinical trial for two patients with type 1 diabetes who experienced improved blood glucose control with half doses of the company’s investigational allogeneic stem cell-derived islets (VX-880).

The first person to receive the product remained completely insulin-independent at 9 months post-transplant. A third patient has received the full targeted dose, but the data for this participant have yet to be reported.

For Viacyte’s part, last week the company announced that a clinical hold placed by the U.S. Food and Drug Administration on the trial has been lifted, allowing it to move forward with a planned total enrollment of 17 patients.

“The FDA requested additional information on the program, which we provided expeditiously. We are pleased that the hold has been lifted and look forward to continuing the Phase 1/2 trial in the U.S.,” a Vertex spokesperson told this news organization.

And a company official for ViaCyte presented results for three patients who received pancreatic precursor (PEC-01) cells derived from the company’s proprietary pluripotent stem cell line at the annual meeting of the Endocrine Society held in June. The cells are housed in an open delivery device implanted into a patient’s forearm. All three participants experienced improved blood glucose levels.

That presentation followed ViaCyte’s announcement in February that the first patient with type 1 diabetes had been dosed in a Phase 1 clinical trial of its investigational allogeneic, gene-edited, stem cell-derived product, VCTX210, developed in collaboration with CRISPR Therapeutics’ gene-editing technology. The aim is to generate islet cells that will produce insulin while avoiding recognition by the immune system, thus rendering immunosuppressive drugs unnecessary.

According to Vertex’s announcement, “The acquisition of ViaCyte provides Vertex with complementary assets, capabilities, and technologies, including additional human stem cell lines, intellectual property around stem cell differentiation, and Good Manufacturing Practice ... facilities for cell-based therapies that could accelerate Vertex’s ongoing type 1 diabetes programs. The acquisition also provides access to novel hypoimmune stem cell assets via the ViaCyte collaboration with CRISPR Therapeutics.”

In response to the announcement, the type 1 diabetes advocacy organization JDRF, which has funded the work of both companies, said in a statement that the acquisition “represents a significant stride in cures research for the type 1 diabetes community.”

“The coming together of two leaders in the cell-derived therapies field will undoubtedly accelerate the development of VX-880 by combining their resources, technologies, intellectual property, and more,” it added.

A third company developing stem cell–derived islet cell therapies, Sernova, said in a statement provided to this news organization: “We are very confident that bringing important game-changing technologies together, as we are seeing across the industry, will result in several viable technologies for the millions of people with type 1 diabetes ... We are thrilled that there are several technologies under development using different approaches that have the potential to provide a ‘functional cure’ for this disease.”

Vertex anticipates the acquisition will close later in 2022.

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

Vertex Pharmaceuticals has acquired ViaCyte, bringing together two of the leading biotechnology companies developing stem cell–derived islet cell replacement therapies for type 1 diabetes.

The $320 million cash purchase “will accelerate our goal of transforming, if not curing, type 1 diabetes by expanding our capabilities and bringing additional tools, technologies, and assets to our current stem cell-based programs,” said Vertex Chief Executive Officer and President Reshma Kewalramani, MD, in a company statement.

Last month, Vertex reported on a phase 1/2 multicenter clinical trial for two patients with type 1 diabetes who experienced improved blood glucose control with half doses of the company’s investigational allogeneic stem cell-derived islets (VX-880).

The first person to receive the product remained completely insulin-independent at 9 months post-transplant. A third patient has received the full targeted dose, but the data for this participant have yet to be reported.

For Viacyte’s part, last week the company announced that a clinical hold placed by the U.S. Food and Drug Administration on the trial has been lifted, allowing it to move forward with a planned total enrollment of 17 patients.

“The FDA requested additional information on the program, which we provided expeditiously. We are pleased that the hold has been lifted and look forward to continuing the Phase 1/2 trial in the U.S.,” a Vertex spokesperson told this news organization.

And a company official for ViaCyte presented results for three patients who received pancreatic precursor (PEC-01) cells derived from the company’s proprietary pluripotent stem cell line at the annual meeting of the Endocrine Society held in June. The cells are housed in an open delivery device implanted into a patient’s forearm. All three participants experienced improved blood glucose levels.

That presentation followed ViaCyte’s announcement in February that the first patient with type 1 diabetes had been dosed in a Phase 1 clinical trial of its investigational allogeneic, gene-edited, stem cell-derived product, VCTX210, developed in collaboration with CRISPR Therapeutics’ gene-editing technology. The aim is to generate islet cells that will produce insulin while avoiding recognition by the immune system, thus rendering immunosuppressive drugs unnecessary.

According to Vertex’s announcement, “The acquisition of ViaCyte provides Vertex with complementary assets, capabilities, and technologies, including additional human stem cell lines, intellectual property around stem cell differentiation, and Good Manufacturing Practice ... facilities for cell-based therapies that could accelerate Vertex’s ongoing type 1 diabetes programs. The acquisition also provides access to novel hypoimmune stem cell assets via the ViaCyte collaboration with CRISPR Therapeutics.”

In response to the announcement, the type 1 diabetes advocacy organization JDRF, which has funded the work of both companies, said in a statement that the acquisition “represents a significant stride in cures research for the type 1 diabetes community.”

“The coming together of two leaders in the cell-derived therapies field will undoubtedly accelerate the development of VX-880 by combining their resources, technologies, intellectual property, and more,” it added.

A third company developing stem cell–derived islet cell therapies, Sernova, said in a statement provided to this news organization: “We are very confident that bringing important game-changing technologies together, as we are seeing across the industry, will result in several viable technologies for the millions of people with type 1 diabetes ... We are thrilled that there are several technologies under development using different approaches that have the potential to provide a ‘functional cure’ for this disease.”

Vertex anticipates the acquisition will close later in 2022.

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

Minimizing dietary consumption of simple sugars may help alleviate symptoms of gastroesophageal reflux disease (GERD), new data suggest.

People who consumed lower quantities of simple sugars experienced significant improvement in total acid exposure time, number of reflux episodes, and subjective reports of heartburn and reflux symptoms, compared with those consuming higher amounts of simple sugars, the authors report.

The authors call their study the first randomized controlled diet intervention trial to investigate both the amount and type of carbohydrate on symptomatic GERD and one of only a few to investigate any type of dietary intervention for GERD.

“There’s really almost no rigorous scientific evidence on any of the foods or ingredients or nutrients that are often recommended to avoid if you have GERD,” corresponding author Heidi J. Silver, RD, PhD, told this news organization. Dr. Silver is research professor of medicine at Vanderbilt University School of Medicine and director of the Vanderbilt Diet, Body Composition, and Human Metabolism Core in Nashville, Tenn.

Even the avoidance of fatty foods, which has been long promoted as part of GERD management, has little evidence to support it.

“With fat, there’s some belief that it may slow down gastric emptying. Therefore, if you had slower gastric emptying, you would have a longer time for the food to put pressure on the lower esophageal sphincter and create an environment for reflux. So, it’s kind of conceptually what is thought but not really tested,” she notes.

The findings were published online in the American Journal of Gastroenterology.
 

Greatest symptom reduction with low simple carb intake

To test the role of dietary carbohydrates, Dr. Silver and her colleagues randomly assigned 98 U.S. veterans with symptomatic GERD to intake of one of four diets with varying carbohydrate types and amounts for 9 weeks: high total/high simple (the control group), high total/low simple, low total/high simple, or low total/low simple. The total caloric intake was approximately the same for all groups.

At baseline, the average total carbohydrate consumption was 43.7% of calories, and the average simple sugar intake was 116.5 g/d. The two “low-total” groups averaged about a 10% reduction in carbohydrate calories. The “low-simple” groups reduced simple sugars by about half.

There were no changes in body weight in the control group, whereas all three of the other groups lost some weight, ranging from 1.5-2.0 kg (3.3-4.4 lb) despite calorie totals designed for weight maintenance.

There was a significant effect of diet on the two primary outcomes, total esophageal acid exposure time, and total number of reflux episodes, as measured by 24-hour ambulatory pH monitoring. The change in total acid exposure time was significantly greater for the high total/low simple group, compared with the high total/high simple group.

The participants’ ratings of symptoms assessed by the Gastroesophageal Reflux Disease Questionnaire and the GERD Symptom Assessment Scale, including heartburn frequency and severity, pain in throat/chest, and sleep disturbance, improved in all modified diet groups, compared with the control group. The mean degree of improvement in heartburn and regurgitation was twice as great for the modified diets, compared with the controls, and was greatest for the two “low-simple” carb groups.

Dr. Silver and colleagues hypothesize that the differential effects of the diets may relate to the way that dietary carbohydrates are sensed in the gastrointestinal tract after being enzymatically degraded into monosaccharides, possibly affecting lower esophageal tone via the effects of gut-derived hormones including ghrelin and glucagon-like peptide 1 that are secreted in response to macronutrient intake.

Although more data are needed about the effects of carbohydrates in GERD, Dr. Silver advised, “I do think it would be smart for clinicians, when they’re discussing diet, that they bring up the simple sugars. There’s no potential harm in reducing simple sugars. You’re only benefiting yourself in multiple ways. We know that the consumption of simple sugars is extremely excessive, not just in America but worldwide.”

Asked to comment, Philip O. Katz, MD, professor of medicine and director of the GI Function Laboratories at Weill Cornell Medicine, New York, told this news organization that “this is one of the better-designed studies with a lot of care looking at a lot of endpoints that are intriguing and useful.”

“What it says to me is there is potential for nonpharmacologic interventions for GERD that include diet change for helping patients,” he said. “This shows promise for a diet that doesn’t just concentrate on fat or acidic products and is a possible way of augmenting reflux treatment.”

However, Dr. Katz cautioned, “I don’t think anybody should do more with a 9-week study than look at it as good potential.”

“I would tell patients that this is something that they might try, but I wouldn’t make it a rigid requirement based on these data,” he added. “If I were involved in this study, the next thing I would do is transition it to real life and look at compliance to see if results were sustained at 18 weeks or 6 months.”
 

Diet part of an ‘overall reflux program’

Overall, Dr. Katz, who was the first author of the American College of Gastroenterology’s Clinical Guideline for the Diagnosis and Management of Gastroesophageal Reflux Disease, pointed out that the main nonpharmacologic advice for GERD management includes “Eat smaller meals, don’t eat before bed, don’t lie down after you eat, and reduce any individually known trigger foods.”

Essentially, he views dietary interventions as complementary to medication and other interventions.

“When people really have GERD – not just heartburn – dietary change is an adjunct,” Dr. Katz said. “GERD is a real disease, like diabetes. For some with GERD, maybe this is the only thing they need to do. But, in general, this will be an adjunct to augment an overall reflux program.”

And that program, both Dr. Silver and Dr. Katz said, should include referral to a dietitian or nutritionist.

“If you’re going to invest time in getting your patients to change their diet, it should be done with professional help, a qualified nutritionist who can work with the patient. This should not be a fad,” Dr. Katz said.

Dr. Silver noted, “In contrast to a physician, the dietitian looks at everything the person is eating. If they’re consuming a lot of simple sugars, I certainly would make that recommendation to reduce, along with other recommendations for GERD. It could be easily incorporated. We included examples in the paper of what we did to achieve that reduction and some things clinicians could focus on.”

One obvious approach, she said, is to advise patients to cut the amount of sugared soda they’re drinking, if not eliminate it entirely.

The study was funded by a VA Merit Award. Dr. Silver has no further disclosures. Dr. Katz is a consultant for Phathom Pharmaceuticals and Sebella Pharmaceuticals and serves on an advisory board for AstraZeneca.

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

Minimizing dietary consumption of simple sugars may help alleviate symptoms of gastroesophageal reflux disease (GERD), new data suggest.

People who consumed lower quantities of simple sugars experienced significant improvement in total acid exposure time, number of reflux episodes, and subjective reports of heartburn and reflux symptoms, compared with those consuming higher amounts of simple sugars, the authors report.

The authors call their study the first randomized controlled diet intervention trial to investigate both the amount and type of carbohydrate on symptomatic GERD and one of only a few to investigate any type of dietary intervention for GERD.

“There’s really almost no rigorous scientific evidence on any of the foods or ingredients or nutrients that are often recommended to avoid if you have GERD,” corresponding author Heidi J. Silver, RD, PhD, told this news organization. Dr. Silver is research professor of medicine at Vanderbilt University School of Medicine and director of the Vanderbilt Diet, Body Composition, and Human Metabolism Core in Nashville, Tenn.

Even the avoidance of fatty foods, which has been long promoted as part of GERD management, has little evidence to support it.

“With fat, there’s some belief that it may slow down gastric emptying. Therefore, if you had slower gastric emptying, you would have a longer time for the food to put pressure on the lower esophageal sphincter and create an environment for reflux. So, it’s kind of conceptually what is thought but not really tested,” she notes.

The findings were published online in the American Journal of Gastroenterology.
 

Greatest symptom reduction with low simple carb intake

To test the role of dietary carbohydrates, Dr. Silver and her colleagues randomly assigned 98 U.S. veterans with symptomatic GERD to intake of one of four diets with varying carbohydrate types and amounts for 9 weeks: high total/high simple (the control group), high total/low simple, low total/high simple, or low total/low simple. The total caloric intake was approximately the same for all groups.

At baseline, the average total carbohydrate consumption was 43.7% of calories, and the average simple sugar intake was 116.5 g/d. The two “low-total” groups averaged about a 10% reduction in carbohydrate calories. The “low-simple” groups reduced simple sugars by about half.

There were no changes in body weight in the control group, whereas all three of the other groups lost some weight, ranging from 1.5-2.0 kg (3.3-4.4 lb) despite calorie totals designed for weight maintenance.

There was a significant effect of diet on the two primary outcomes, total esophageal acid exposure time, and total number of reflux episodes, as measured by 24-hour ambulatory pH monitoring. The change in total acid exposure time was significantly greater for the high total/low simple group, compared with the high total/high simple group.

The participants’ ratings of symptoms assessed by the Gastroesophageal Reflux Disease Questionnaire and the GERD Symptom Assessment Scale, including heartburn frequency and severity, pain in throat/chest, and sleep disturbance, improved in all modified diet groups, compared with the control group. The mean degree of improvement in heartburn and regurgitation was twice as great for the modified diets, compared with the controls, and was greatest for the two “low-simple” carb groups.

Dr. Silver and colleagues hypothesize that the differential effects of the diets may relate to the way that dietary carbohydrates are sensed in the gastrointestinal tract after being enzymatically degraded into monosaccharides, possibly affecting lower esophageal tone via the effects of gut-derived hormones including ghrelin and glucagon-like peptide 1 that are secreted in response to macronutrient intake.

Although more data are needed about the effects of carbohydrates in GERD, Dr. Silver advised, “I do think it would be smart for clinicians, when they’re discussing diet, that they bring up the simple sugars. There’s no potential harm in reducing simple sugars. You’re only benefiting yourself in multiple ways. We know that the consumption of simple sugars is extremely excessive, not just in America but worldwide.”

Asked to comment, Philip O. Katz, MD, professor of medicine and director of the GI Function Laboratories at Weill Cornell Medicine, New York, told this news organization that “this is one of the better-designed studies with a lot of care looking at a lot of endpoints that are intriguing and useful.”

“What it says to me is there is potential for nonpharmacologic interventions for GERD that include diet change for helping patients,” he said. “This shows promise for a diet that doesn’t just concentrate on fat or acidic products and is a possible way of augmenting reflux treatment.”

However, Dr. Katz cautioned, “I don’t think anybody should do more with a 9-week study than look at it as good potential.”

“I would tell patients that this is something that they might try, but I wouldn’t make it a rigid requirement based on these data,” he added. “If I were involved in this study, the next thing I would do is transition it to real life and look at compliance to see if results were sustained at 18 weeks or 6 months.”
 

Diet part of an ‘overall reflux program’

Overall, Dr. Katz, who was the first author of the American College of Gastroenterology’s Clinical Guideline for the Diagnosis and Management of Gastroesophageal Reflux Disease, pointed out that the main nonpharmacologic advice for GERD management includes “Eat smaller meals, don’t eat before bed, don’t lie down after you eat, and reduce any individually known trigger foods.”

Essentially, he views dietary interventions as complementary to medication and other interventions.

“When people really have GERD – not just heartburn – dietary change is an adjunct,” Dr. Katz said. “GERD is a real disease, like diabetes. For some with GERD, maybe this is the only thing they need to do. But, in general, this will be an adjunct to augment an overall reflux program.”

And that program, both Dr. Silver and Dr. Katz said, should include referral to a dietitian or nutritionist.

“If you’re going to invest time in getting your patients to change their diet, it should be done with professional help, a qualified nutritionist who can work with the patient. This should not be a fad,” Dr. Katz said.

Dr. Silver noted, “In contrast to a physician, the dietitian looks at everything the person is eating. If they’re consuming a lot of simple sugars, I certainly would make that recommendation to reduce, along with other recommendations for GERD. It could be easily incorporated. We included examples in the paper of what we did to achieve that reduction and some things clinicians could focus on.”

One obvious approach, she said, is to advise patients to cut the amount of sugared soda they’re drinking, if not eliminate it entirely.

The study was funded by a VA Merit Award. Dr. Silver has no further disclosures. Dr. Katz is a consultant for Phathom Pharmaceuticals and Sebella Pharmaceuticals and serves on an advisory board for AstraZeneca.

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

Minimizing dietary consumption of simple sugars may help alleviate symptoms of gastroesophageal reflux disease (GERD), new data suggest.

People who consumed lower quantities of simple sugars experienced significant improvement in total acid exposure time, number of reflux episodes, and subjective reports of heartburn and reflux symptoms, compared with those consuming higher amounts of simple sugars, the authors report.

The authors call their study the first randomized controlled diet intervention trial to investigate both the amount and type of carbohydrate on symptomatic GERD and one of only a few to investigate any type of dietary intervention for GERD.

“There’s really almost no rigorous scientific evidence on any of the foods or ingredients or nutrients that are often recommended to avoid if you have GERD,” corresponding author Heidi J. Silver, RD, PhD, told this news organization. Dr. Silver is research professor of medicine at Vanderbilt University School of Medicine and director of the Vanderbilt Diet, Body Composition, and Human Metabolism Core in Nashville, Tenn.

Even the avoidance of fatty foods, which has been long promoted as part of GERD management, has little evidence to support it.

“With fat, there’s some belief that it may slow down gastric emptying. Therefore, if you had slower gastric emptying, you would have a longer time for the food to put pressure on the lower esophageal sphincter and create an environment for reflux. So, it’s kind of conceptually what is thought but not really tested,” she notes.

The findings were published online in the American Journal of Gastroenterology.
 

Greatest symptom reduction with low simple carb intake

To test the role of dietary carbohydrates, Dr. Silver and her colleagues randomly assigned 98 U.S. veterans with symptomatic GERD to intake of one of four diets with varying carbohydrate types and amounts for 9 weeks: high total/high simple (the control group), high total/low simple, low total/high simple, or low total/low simple. The total caloric intake was approximately the same for all groups.

At baseline, the average total carbohydrate consumption was 43.7% of calories, and the average simple sugar intake was 116.5 g/d. The two “low-total” groups averaged about a 10% reduction in carbohydrate calories. The “low-simple” groups reduced simple sugars by about half.

There were no changes in body weight in the control group, whereas all three of the other groups lost some weight, ranging from 1.5-2.0 kg (3.3-4.4 lb) despite calorie totals designed for weight maintenance.

There was a significant effect of diet on the two primary outcomes, total esophageal acid exposure time, and total number of reflux episodes, as measured by 24-hour ambulatory pH monitoring. The change in total acid exposure time was significantly greater for the high total/low simple group, compared with the high total/high simple group.

The participants’ ratings of symptoms assessed by the Gastroesophageal Reflux Disease Questionnaire and the GERD Symptom Assessment Scale, including heartburn frequency and severity, pain in throat/chest, and sleep disturbance, improved in all modified diet groups, compared with the control group. The mean degree of improvement in heartburn and regurgitation was twice as great for the modified diets, compared with the controls, and was greatest for the two “low-simple” carb groups.

Dr. Silver and colleagues hypothesize that the differential effects of the diets may relate to the way that dietary carbohydrates are sensed in the gastrointestinal tract after being enzymatically degraded into monosaccharides, possibly affecting lower esophageal tone via the effects of gut-derived hormones including ghrelin and glucagon-like peptide 1 that are secreted in response to macronutrient intake.

Although more data are needed about the effects of carbohydrates in GERD, Dr. Silver advised, “I do think it would be smart for clinicians, when they’re discussing diet, that they bring up the simple sugars. There’s no potential harm in reducing simple sugars. You’re only benefiting yourself in multiple ways. We know that the consumption of simple sugars is extremely excessive, not just in America but worldwide.”

Asked to comment, Philip O. Katz, MD, professor of medicine and director of the GI Function Laboratories at Weill Cornell Medicine, New York, told this news organization that “this is one of the better-designed studies with a lot of care looking at a lot of endpoints that are intriguing and useful.”

“What it says to me is there is potential for nonpharmacologic interventions for GERD that include diet change for helping patients,” he said. “This shows promise for a diet that doesn’t just concentrate on fat or acidic products and is a possible way of augmenting reflux treatment.”

However, Dr. Katz cautioned, “I don’t think anybody should do more with a 9-week study than look at it as good potential.”

“I would tell patients that this is something that they might try, but I wouldn’t make it a rigid requirement based on these data,” he added. “If I were involved in this study, the next thing I would do is transition it to real life and look at compliance to see if results were sustained at 18 weeks or 6 months.”
 

Diet part of an ‘overall reflux program’

Overall, Dr. Katz, who was the first author of the American College of Gastroenterology’s Clinical Guideline for the Diagnosis and Management of Gastroesophageal Reflux Disease, pointed out that the main nonpharmacologic advice for GERD management includes “Eat smaller meals, don’t eat before bed, don’t lie down after you eat, and reduce any individually known trigger foods.”

Essentially, he views dietary interventions as complementary to medication and other interventions.

“When people really have GERD – not just heartburn – dietary change is an adjunct,” Dr. Katz said. “GERD is a real disease, like diabetes. For some with GERD, maybe this is the only thing they need to do. But, in general, this will be an adjunct to augment an overall reflux program.”

And that program, both Dr. Silver and Dr. Katz said, should include referral to a dietitian or nutritionist.

“If you’re going to invest time in getting your patients to change their diet, it should be done with professional help, a qualified nutritionist who can work with the patient. This should not be a fad,” Dr. Katz said.

Dr. Silver noted, “In contrast to a physician, the dietitian looks at everything the person is eating. If they’re consuming a lot of simple sugars, I certainly would make that recommendation to reduce, along with other recommendations for GERD. It could be easily incorporated. We included examples in the paper of what we did to achieve that reduction and some things clinicians could focus on.”

One obvious approach, she said, is to advise patients to cut the amount of sugared soda they’re drinking, if not eliminate it entirely.

The study was funded by a VA Merit Award. Dr. Silver has no further disclosures. Dr. Katz is a consultant for Phathom Pharmaceuticals and Sebella Pharmaceuticals and serves on an advisory board for AstraZeneca.

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

Screening children for type 1 diabetes–associated islet autoantibodies at ages 2 years and 6 years would identify most of those who go on to develop the condition by mid-adolescence, new data suggest.

Both genetic screening and islet-cell autoantibody screening for type 1 diabetes risk have become less expensive in recent years. Nonetheless, as of now, most children who receive such screening do so through programs that screen relatives of people who already have the condition, such as the global TrialNet program.

Some in the type 1 diabetes field have urged wider screening, with the rationale that knowledge of increased risk can prepare families to recognize the early signs of hyperglycemia and seek medical help to prevent the onset of diabetic ketoacidosis.

Moreover, potential therapies to prevent or delay type 1 diabetes are currently in development, including the anti-CD3 monoclonal antibody teplizumab (Tzield, Provention Bio).

However, given that the incidence of type 1 diabetes is about 1 in 300 children, any population-wide screening program would need to be implemented in the most efficient and cost-effective way possible with limited numbers of tests, say Mohamed Ghalwash, PhD, of the Center for Computational Health, IBM Research, Yorktown Heights, N.Y., and colleagues.

Results from their analysis of nearly 25,000 children from five prospective cohorts in Europe and the United States were published online  in Lancet Diabetes & Endocrinology.
 

Screening in kids feasible, but may need geographic tweaking

“Our results show that initial screening for islet autoantibodies at two ages (2 years and 6 years) is sensitive and efficient for public health translation but might require adjustment by country on the basis of population-specific disease characteristics,” Dr. Ghalwash and colleagues write.

In an accompanying editorial, pediatric endocrinologist Maria J. Redondo, MD, PhD, writes: “This study is timely because recent successes in preventing type 1 diabetes highlight the need to identify the best candidates for intervention ... This paper constitutes an important contribution to the literature.”

However, Dr. Redondo, of Baylor College of Medicine and Texas Children’s Hospital, Houston, also cautioned: “It remains to be seen whether Dr. Ghalwash and colleagues’ strategy could work in the general population, because all the participants in the combined dataset had genetic risk factors for the disease or a relative with type 1 diabetes, in whom performance is expected to be higher.”

She also noted that most participants were of northern European ancestry and that it is unknown whether the same or a similar screening strategy could be applied to individuals older than 15 years, in whom preclinical type 1 diabetes progresses more slowly.
 

Two-time childhood screening yielded high sensitivity, specificity

The data from a total of 24,662 participants were pooled from five prospective cohorts from Finland (DIPP), Germany (BABYDIAB), Sweden (DiPiS), and the United States (DAISY and DEW-IT).

All were at elevated risk for type 1 diabetes based on human leukocyte antigen (HLA) genotyping, and some had first-degree relatives with the condition. Participants were screened annually for three type 1 diabetes–associated autoantibodies up to age 15 years or the onset of type 1 diabetes.

During follow-up, 672 children developed type 1 diabetes by age 15 years and 6,050 did not. (The rest hadn’t yet reached age 15 years or type 1 diabetes onset.) The median age at first appearance of islet autoantibodies was 4.5 years.

A two-age screening strategy at 2 years and 6 years was more sensitive than screening at just one age, with a sensitivity of 82% and a positive predictive value of 79% for the development of type 1 diabetes by age 15 years.

The predictive value increased with the number of autoantibodies tested. For example, a single islet autoantibody at age 2 years indicated a 4-year risk of developing type 1 diabetes by age 5.99 years of 31%, while multiple antibody positivity at age 2 years carried a 4-year risk of 55%.

By age 6 years, the risk over the next 9 years was 39% if the test had been negative at age 2 years and 70% if the test had been positive at 2 years. But overall, a 6-year-old with multiple autoantibodies had an overall 83% risk of type 1 diabetes regardless of the test result at 2 years.

The predictive performance of sensitivity by age differed by country, suggesting that the optimal ages for autoantibody testing might differ by geographic region, Dr. Ghalwash and colleagues say.

Dr. Redondo commented, “The model might require adaptation to local factors that affect the progression and prevalence of type 1 diabetes.” And, she added, “important aspects, such as screening cost, global access, acceptability, and follow-up support will need to be addressed for this strategy to be a viable public health option.”

The study was funded by JDRF. Dr. Ghalwash and another author are employees of IBM. A third author was a JDRF employee when the research was done and is now an employee of Janssen Research and Development. Dr. Redondo has reported no relevant financial relationships.

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

Screening children for type 1 diabetes–associated islet autoantibodies at ages 2 years and 6 years would identify most of those who go on to develop the condition by mid-adolescence, new data suggest.

Both genetic screening and islet-cell autoantibody screening for type 1 diabetes risk have become less expensive in recent years. Nonetheless, as of now, most children who receive such screening do so through programs that screen relatives of people who already have the condition, such as the global TrialNet program.

Some in the type 1 diabetes field have urged wider screening, with the rationale that knowledge of increased risk can prepare families to recognize the early signs of hyperglycemia and seek medical help to prevent the onset of diabetic ketoacidosis.

Moreover, potential therapies to prevent or delay type 1 diabetes are currently in development, including the anti-CD3 monoclonal antibody teplizumab (Tzield, Provention Bio).

However, given that the incidence of type 1 diabetes is about 1 in 300 children, any population-wide screening program would need to be implemented in the most efficient and cost-effective way possible with limited numbers of tests, say Mohamed Ghalwash, PhD, of the Center for Computational Health, IBM Research, Yorktown Heights, N.Y., and colleagues.

Results from their analysis of nearly 25,000 children from five prospective cohorts in Europe and the United States were published online  in Lancet Diabetes & Endocrinology.
 

Screening in kids feasible, but may need geographic tweaking

“Our results show that initial screening for islet autoantibodies at two ages (2 years and 6 years) is sensitive and efficient for public health translation but might require adjustment by country on the basis of population-specific disease characteristics,” Dr. Ghalwash and colleagues write.

In an accompanying editorial, pediatric endocrinologist Maria J. Redondo, MD, PhD, writes: “This study is timely because recent successes in preventing type 1 diabetes highlight the need to identify the best candidates for intervention ... This paper constitutes an important contribution to the literature.”

However, Dr. Redondo, of Baylor College of Medicine and Texas Children’s Hospital, Houston, also cautioned: “It remains to be seen whether Dr. Ghalwash and colleagues’ strategy could work in the general population, because all the participants in the combined dataset had genetic risk factors for the disease or a relative with type 1 diabetes, in whom performance is expected to be higher.”

She also noted that most participants were of northern European ancestry and that it is unknown whether the same or a similar screening strategy could be applied to individuals older than 15 years, in whom preclinical type 1 diabetes progresses more slowly.
 

Two-time childhood screening yielded high sensitivity, specificity

The data from a total of 24,662 participants were pooled from five prospective cohorts from Finland (DIPP), Germany (BABYDIAB), Sweden (DiPiS), and the United States (DAISY and DEW-IT).

All were at elevated risk for type 1 diabetes based on human leukocyte antigen (HLA) genotyping, and some had first-degree relatives with the condition. Participants were screened annually for three type 1 diabetes–associated autoantibodies up to age 15 years or the onset of type 1 diabetes.

During follow-up, 672 children developed type 1 diabetes by age 15 years and 6,050 did not. (The rest hadn’t yet reached age 15 years or type 1 diabetes onset.) The median age at first appearance of islet autoantibodies was 4.5 years.

A two-age screening strategy at 2 years and 6 years was more sensitive than screening at just one age, with a sensitivity of 82% and a positive predictive value of 79% for the development of type 1 diabetes by age 15 years.

The predictive value increased with the number of autoantibodies tested. For example, a single islet autoantibody at age 2 years indicated a 4-year risk of developing type 1 diabetes by age 5.99 years of 31%, while multiple antibody positivity at age 2 years carried a 4-year risk of 55%.

By age 6 years, the risk over the next 9 years was 39% if the test had been negative at age 2 years and 70% if the test had been positive at 2 years. But overall, a 6-year-old with multiple autoantibodies had an overall 83% risk of type 1 diabetes regardless of the test result at 2 years.

The predictive performance of sensitivity by age differed by country, suggesting that the optimal ages for autoantibody testing might differ by geographic region, Dr. Ghalwash and colleagues say.

Dr. Redondo commented, “The model might require adaptation to local factors that affect the progression and prevalence of type 1 diabetes.” And, she added, “important aspects, such as screening cost, global access, acceptability, and follow-up support will need to be addressed for this strategy to be a viable public health option.”

The study was funded by JDRF. Dr. Ghalwash and another author are employees of IBM. A third author was a JDRF employee when the research was done and is now an employee of Janssen Research and Development. Dr. Redondo has reported no relevant financial relationships.

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

Screening children for type 1 diabetes–associated islet autoantibodies at ages 2 years and 6 years would identify most of those who go on to develop the condition by mid-adolescence, new data suggest.

Both genetic screening and islet-cell autoantibody screening for type 1 diabetes risk have become less expensive in recent years. Nonetheless, as of now, most children who receive such screening do so through programs that screen relatives of people who already have the condition, such as the global TrialNet program.

Some in the type 1 diabetes field have urged wider screening, with the rationale that knowledge of increased risk can prepare families to recognize the early signs of hyperglycemia and seek medical help to prevent the onset of diabetic ketoacidosis.

Moreover, potential therapies to prevent or delay type 1 diabetes are currently in development, including the anti-CD3 monoclonal antibody teplizumab (Tzield, Provention Bio).

However, given that the incidence of type 1 diabetes is about 1 in 300 children, any population-wide screening program would need to be implemented in the most efficient and cost-effective way possible with limited numbers of tests, say Mohamed Ghalwash, PhD, of the Center for Computational Health, IBM Research, Yorktown Heights, N.Y., and colleagues.

Results from their analysis of nearly 25,000 children from five prospective cohorts in Europe and the United States were published online  in Lancet Diabetes & Endocrinology.
 

Screening in kids feasible, but may need geographic tweaking

“Our results show that initial screening for islet autoantibodies at two ages (2 years and 6 years) is sensitive and efficient for public health translation but might require adjustment by country on the basis of population-specific disease characteristics,” Dr. Ghalwash and colleagues write.

In an accompanying editorial, pediatric endocrinologist Maria J. Redondo, MD, PhD, writes: “This study is timely because recent successes in preventing type 1 diabetes highlight the need to identify the best candidates for intervention ... This paper constitutes an important contribution to the literature.”

However, Dr. Redondo, of Baylor College of Medicine and Texas Children’s Hospital, Houston, also cautioned: “It remains to be seen whether Dr. Ghalwash and colleagues’ strategy could work in the general population, because all the participants in the combined dataset had genetic risk factors for the disease or a relative with type 1 diabetes, in whom performance is expected to be higher.”

She also noted that most participants were of northern European ancestry and that it is unknown whether the same or a similar screening strategy could be applied to individuals older than 15 years, in whom preclinical type 1 diabetes progresses more slowly.
 

Two-time childhood screening yielded high sensitivity, specificity

The data from a total of 24,662 participants were pooled from five prospective cohorts from Finland (DIPP), Germany (BABYDIAB), Sweden (DiPiS), and the United States (DAISY and DEW-IT).

All were at elevated risk for type 1 diabetes based on human leukocyte antigen (HLA) genotyping, and some had first-degree relatives with the condition. Participants were screened annually for three type 1 diabetes–associated autoantibodies up to age 15 years or the onset of type 1 diabetes.

During follow-up, 672 children developed type 1 diabetes by age 15 years and 6,050 did not. (The rest hadn’t yet reached age 15 years or type 1 diabetes onset.) The median age at first appearance of islet autoantibodies was 4.5 years.

A two-age screening strategy at 2 years and 6 years was more sensitive than screening at just one age, with a sensitivity of 82% and a positive predictive value of 79% for the development of type 1 diabetes by age 15 years.

The predictive value increased with the number of autoantibodies tested. For example, a single islet autoantibody at age 2 years indicated a 4-year risk of developing type 1 diabetes by age 5.99 years of 31%, while multiple antibody positivity at age 2 years carried a 4-year risk of 55%.

By age 6 years, the risk over the next 9 years was 39% if the test had been negative at age 2 years and 70% if the test had been positive at 2 years. But overall, a 6-year-old with multiple autoantibodies had an overall 83% risk of type 1 diabetes regardless of the test result at 2 years.

The predictive performance of sensitivity by age differed by country, suggesting that the optimal ages for autoantibody testing might differ by geographic region, Dr. Ghalwash and colleagues say.

Dr. Redondo commented, “The model might require adaptation to local factors that affect the progression and prevalence of type 1 diabetes.” And, she added, “important aspects, such as screening cost, global access, acceptability, and follow-up support will need to be addressed for this strategy to be a viable public health option.”

The study was funded by JDRF. Dr. Ghalwash and another author are employees of IBM. A third author was a JDRF employee when the research was done and is now an employee of Janssen Research and Development. Dr. Redondo has reported no relevant financial relationships.

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

Researchers published the study covered in this summary on medRxiv.org as a preprint that has not yet been peer reviewed.

Key takeaways

• The study results suggest that obesity may accelerate waning of antibody response to SARS-CoV-2 vaccination and increased breakthrough infections with COVID-19.
• The findings documented evidence of reduced neutralizing antibody capacity 6 months after primary vaccination in people with severe obesity.
• This was a large study involving about more than 3.5 million people who had received at least two doses of COVID-19 vaccine, including more than 650,000 with obesity.

Why this matters

• Obesity is associated with comorbidities that independently increase the risk for severe COVID-19, including type 2 diabetes, chronic kidney disease, and heart failure.
• The authors concluded that additional or more frequent booster doses are likely to be required to maintain protection among people with obesity against COVID-19.

Study design

• Prospective longitudinal study of the incidence and severity of COVID-19 infections and immune responses in a cohort of more than 3.5 million adults from a Scottish healthcare database who received two or three doses of COVID-19 vaccine. The data came from the study, centered at the University of Edinburgh.
• About 16% had obesity with a body mass index of 30-39.9 kg/m², and an additional 3% had severe obesity with a BMI of 40 or greater.
• Although not specified in this preprint, another said that the vaccines administered in Scotland have been the Pfizer-BioNTech and Oxford-AstraZeneca formulations.

Key results

• Between Sept. 14, 2020, and March 19, 2022, 10,983 people (0.3% of the total cohort; 6.0 events per 1,000 person-years) had severe COVID-19, consisting of 9,733 who were hospitalized and 2,207 who died (957 of those hospitalized also died).
• People with obesity or severe obesity were at higher risk of hospitalization or death from COVID-19 after both a second and third (booster) dose of vaccine.
• Compared with those with normal weight, those with severe obesity (BMI higher than 40) were at significantly increased risk for severe COVID-19 after a second vaccine dose, with an adjusted rate ratio 1.76, whereas those with standard obesity (BMI, 30-40) were at a modestly but significantly increased risk with an adjusted rate ratio of 1.11.
• Breakthrough infections after the second dose for those with severe obesity, obesity, and normal weight occurred on average at 10 weeks, 15 weeks, and 20 weeks, respectively.
• Interaction testing showed that vaccine effectiveness significantly diminished over time across BMI groups, and protection waned more rapidly as BMI increased.
• Results from immunophenotyping studies run in a subgroup of several dozen subjects with severe obesity or normal weight showed significant decrements in the robustness of antibody responses in those with severe obesity 6 months after a second or third vaccine dose.

Limitations

• The authors did not specify any limitations.

Disclosures

• The study received no commercial funding.
• One author received funding from Wellcome.

This is a summary of a preprint research study , “Accelerated waning of the humoral response to SARS-CoV-2 vaccines in obesity,” published by researchers primarily at the University of Cambridge (England), on medRxiv. This study has not yet been peer reviewed. The full text of the study can be found on medRxiv.org.



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

Researchers published the study covered in this summary on medRxiv.org as a preprint that has not yet been peer reviewed.

Key takeaways

• The study results suggest that obesity may accelerate waning of antibody response to SARS-CoV-2 vaccination and increased breakthrough infections with COVID-19.
• The findings documented evidence of reduced neutralizing antibody capacity 6 months after primary vaccination in people with severe obesity.
• This was a large study involving about more than 3.5 million people who had received at least two doses of COVID-19 vaccine, including more than 650,000 with obesity.

Why this matters

• Obesity is associated with comorbidities that independently increase the risk for severe COVID-19, including type 2 diabetes, chronic kidney disease, and heart failure.
• The authors concluded that additional or more frequent booster doses are likely to be required to maintain protection among people with obesity against COVID-19.

Study design

• Prospective longitudinal study of the incidence and severity of COVID-19 infections and immune responses in a cohort of more than 3.5 million adults from a Scottish healthcare database who received two or three doses of COVID-19 vaccine. The data came from the study, centered at the University of Edinburgh.
• About 16% had obesity with a body mass index of 30-39.9 kg/m², and an additional 3% had severe obesity with a BMI of 40 or greater.
• Although not specified in this preprint, another said that the vaccines administered in Scotland have been the Pfizer-BioNTech and Oxford-AstraZeneca formulations.

Key results

• Between Sept. 14, 2020, and March 19, 2022, 10,983 people (0.3% of the total cohort; 6.0 events per 1,000 person-years) had severe COVID-19, consisting of 9,733 who were hospitalized and 2,207 who died (957 of those hospitalized also died).
• People with obesity or severe obesity were at higher risk of hospitalization or death from COVID-19 after both a second and third (booster) dose of vaccine.
• Compared with those with normal weight, those with severe obesity (BMI higher than 40) were at significantly increased risk for severe COVID-19 after a second vaccine dose, with an adjusted rate ratio 1.76, whereas those with standard obesity (BMI, 30-40) were at a modestly but significantly increased risk with an adjusted rate ratio of 1.11.
• Breakthrough infections after the second dose for those with severe obesity, obesity, and normal weight occurred on average at 10 weeks, 15 weeks, and 20 weeks, respectively.
• Interaction testing showed that vaccine effectiveness significantly diminished over time across BMI groups, and protection waned more rapidly as BMI increased.
• Results from immunophenotyping studies run in a subgroup of several dozen subjects with severe obesity or normal weight showed significant decrements in the robustness of antibody responses in those with severe obesity 6 months after a second or third vaccine dose.

Limitations

• The authors did not specify any limitations.

Disclosures

• The study received no commercial funding.
• One author received funding from Wellcome.

This is a summary of a preprint research study , “Accelerated waning of the humoral response to SARS-CoV-2 vaccines in obesity,” published by researchers primarily at the University of Cambridge (England), on medRxiv. This study has not yet been peer reviewed. The full text of the study can be found on medRxiv.org.



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

Researchers published the study covered in this summary on medRxiv.org as a preprint that has not yet been peer reviewed.

Key takeaways

• The study results suggest that obesity may accelerate waning of antibody response to SARS-CoV-2 vaccination and increased breakthrough infections with COVID-19.
• The findings documented evidence of reduced neutralizing antibody capacity 6 months after primary vaccination in people with severe obesity.
• This was a large study involving about more than 3.5 million people who had received at least two doses of COVID-19 vaccine, including more than 650,000 with obesity.

Why this matters

• Obesity is associated with comorbidities that independently increase the risk for severe COVID-19, including type 2 diabetes, chronic kidney disease, and heart failure.
• The authors concluded that additional or more frequent booster doses are likely to be required to maintain protection among people with obesity against COVID-19.

Study design

• Prospective longitudinal study of the incidence and severity of COVID-19 infections and immune responses in a cohort of more than 3.5 million adults from a Scottish healthcare database who received two or three doses of COVID-19 vaccine. The data came from the study, centered at the University of Edinburgh.
• About 16% had obesity with a body mass index of 30-39.9 kg/m², and an additional 3% had severe obesity with a BMI of 40 or greater.
• Although not specified in this preprint, another said that the vaccines administered in Scotland have been the Pfizer-BioNTech and Oxford-AstraZeneca formulations.

Key results

• Between Sept. 14, 2020, and March 19, 2022, 10,983 people (0.3% of the total cohort; 6.0 events per 1,000 person-years) had severe COVID-19, consisting of 9,733 who were hospitalized and 2,207 who died (957 of those hospitalized also died).
• People with obesity or severe obesity were at higher risk of hospitalization or death from COVID-19 after both a second and third (booster) dose of vaccine.
• Compared with those with normal weight, those with severe obesity (BMI higher than 40) were at significantly increased risk for severe COVID-19 after a second vaccine dose, with an adjusted rate ratio 1.76, whereas those with standard obesity (BMI, 30-40) were at a modestly but significantly increased risk with an adjusted rate ratio of 1.11.
• Breakthrough infections after the second dose for those with severe obesity, obesity, and normal weight occurred on average at 10 weeks, 15 weeks, and 20 weeks, respectively.
• Interaction testing showed that vaccine effectiveness significantly diminished over time across BMI groups, and protection waned more rapidly as BMI increased.
• Results from immunophenotyping studies run in a subgroup of several dozen subjects with severe obesity or normal weight showed significant decrements in the robustness of antibody responses in those with severe obesity 6 months after a second or third vaccine dose.

Limitations

• The authors did not specify any limitations.

Disclosures

• The study received no commercial funding.
• One author received funding from Wellcome.

This is a summary of a preprint research study , “Accelerated waning of the humoral response to SARS-CoV-2 vaccines in obesity,” published by researchers primarily at the University of Cambridge (England), on medRxiv. This study has not yet been peer reviewed. The full text of the study can be found on medRxiv.org.



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

The U.S. Food and Drug Administration has approved a supplemental indication for the combination phentermine and topiramate extended-release capsules (Qsymia, Vivus) in patients aged 12 years and older with obesity.

The indication is for use as additional therapy along with a reduced-calorie diet and increased physical activity in youth with obesity, defined as a body mass index of the 95th percentile or greater when standardized for age and sex.

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

The U.S. Food and Drug Administration has approved a supplemental indication for the combination phentermine and topiramate extended-release capsules (Qsymia, Vivus) in patients aged 12 years and older with obesity.

The indication is for use as additional therapy along with a reduced-calorie diet and increased physical activity in youth with obesity, defined as a body mass index of the 95th percentile or greater when standardized for age and sex.

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

The U.S. Food and Drug Administration has approved a supplemental indication for the combination phentermine and topiramate extended-release capsules (Qsymia, Vivus) in patients aged 12 years and older with obesity.

The indication is for use as additional therapy along with a reduced-calorie diet and increased physical activity in youth with obesity, defined as a body mass index of the 95th percentile or greater when standardized for age and sex.

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