Covid Has Caused Thousands of US Deaths: New CDC Data
Medscape Medical News Lisa Rapaport January 03, 2024
While COVID has now claimed more than 1 million lives in the United States alone, these aren't the only fatalities caused at least in part by the virus. A small but growing number of Americans are surviving acute infections only to succumb months later to the lingering health problems caused by long COVID.
Much of the attention on long COVID has centered on the sometimes debilitating symptoms that strike people with the condition, with no formal diagnostic tests or standard treatments available, and the effect it has on quality of life. But new figures from the US Centers for Disease Control and Prevention (CDC) show that long COVID can also be deadly.
More than 5000 Americans have died from long COVID since the start of the pandemic, according to new estimates from the CDC.
This total, based on death certificate data collected by the CDC, includes a preliminary tally of 1491 long COVID deaths in 2023 in addition to 3544 fatalities previously reported from January 2020 through June 2022.
Guidance issued in 2023 on how to formally report long COVID as a cause of death on death certificates should help get a more accurate count of these fatalities going forward, said Robert Anderson, PhD, chief mortality statistician for the CDC.
"We hope that the guidance will help cause of death certifiers be more aware of the impact of long COVID and more likely to report long COVID as a cause of death when appropriate," Anderson said. "That said, we do not expect that this guidance will have a dramatic impact on the trend."
There's no standard definition or diagnostic test for long COVID. It's typically diagnosed when people have symptoms at least 3 months after an acute infection that weren't present before they got sick. As of the end of last year, about 7% of American adults had experienced long COVID at some point, the CDC estimated in September 2023.
The new death tally indicates long COVID remains a significant public health threat and is likely to grow in the years ahead, even though the pandemic may no longer be considered a global health crisis, experts said.
For example, the death certificate figures indicate:
Months and even years after an acute infection, long COVID can contribute to serious and potentially life-threatening conditions that impact nearly every major system in the body, according to the CDC guidelines for identifying the condition on death certificates.
This means long COVID may often be listed as an underlying cause of death when people with this condition die of issues related to their heart, lungs, brain or kidneys, the CDC guidelines noted.
The risk for long COVID fatalities remains elevated for at least 6 months for people with milder acute infections and for at least 2 years in severe cases that require hospitalization, some previous research suggested.
As happens with other acute infections, certain people are more at risk for fatal case of long COVID. Age, race, and ethnicity have all been cited as risk factors by researchers who have been tracking the condition since the start of the pandemic.
Half of long COVID fatalities from July 2021 to June 2022 occurred in people aged 65 years and older, and another 23% were recorded among people aged 50-64 years old, according a report from CDC.
Long COVID death rates also varied by race and ethnicity, from a high of 14.1 cases per million among America Indian and Alaskan natives to a low of 1.5 cases per million among Asian people, the CDC found. Death rates per million were 6.7 for White individuals, 6.4 for Black people, and 4.7 for Hispanic people.
The disproportionate share of Black and Hispanic people who developed and died from severe acute infections may have left fewer survivors to develop long COVID, limiting long COVID fatalities among these groups, the CDC report concluded.
It's also possible that long COVID fatalities were undercounted in these populations because they faced challenges accessing healthcare or seeing providers who could recognize the hallmark symptoms of long COVID.
It's also difficult to distinguish between how many deaths related to the virus ultimately occur as a result of long COVID rather than acute infections. That's because it may depend on a variety of factors, including how consistently medical examiners follow the CDC guidelines, said Ziyad Al-Aly, MD, chief of research at the Veterans Affairs, St. Louis Health Care System and a senior clinical epidemiologist at Washington University in St. Louis.
"Long COVID remains massively underdiagnosed, and death in people with long COVID is misattributed to other things," Al-Aly said.
An accurate test for long COVID could help lead to a more accurate count of these fatalities, Czeisler said. Some preliminary research suggests that it might one day be possible to diagnose long COVID with a blood test.
"The timeline for such a test and the extent to which it would be widely applied is uncertain," Czeisler noted, "though that would certainly be a gamechanger."
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Muscle abnormalities worsen after post-exertional malaise in long COVIDNature Communications volume 15, Article number: 17 (2024
Brent Appelman, · Braeden T. Charlton, · Richie P. Goulding, · Tom J. Kerkhoff, · Ellen A. Breedveld, · Wendy Noort, · Carla Offringa, · Frank W. Bloemers, · Michel van Weeghel, · Bauke V. Schomakers, · Pedro Coelho, · Jelle J. Posthuma, · Eleonora Aronica, · W. Joost Wiersinga, · Michèle van Vugt & · Rob C. I. Wüst
Abstract
A subgroup of patients infected with SARS-CoV-2 remain symptomatic over three months after infection. A distinctive symptom of patients with long COVID is post-exertional malaise, which is associated with a worsening of fatigue- and pain-related symptoms after acute mental or physical exercise, but its underlying pathophysiology is unclear. With this longitudinal case-control study (NCT05225688), we provide new insights into the pathophysiology of post-exertional malaise in patients with long COVID. We show that skeletal muscle structure is associated with a lower exercise capacity in patients, and local and systemic metabolic disturbances, severe exercise-induced myopathy and tissue infiltration of amyloid-containing deposits in skeletal muscles of patients with long COVID worsen after induction of post-exertional malaise. This study highlights novel pathways that help to understand the pathophysiology of post-exertional malaise in patients suffering from long COVID and other post-infectious diseases.
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Exercise Pathophysiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Postacute Sequelae of SARS-CoV-2 - More in Common Than Not?Authors: Joseph P, Singh I, Oliviera R, Capone CA, Mullen MP, Cook DB, … Systrom DM (Harvard Medical School, Boston, USA)
Publication: Chest Journal
Link: https://doi.org/10.1016/j.chest.2023.03.049
The aim of this review was to examine the capacity of invasive and noninvasive cardiopulmonary tests (iCPETs and niCPETs) to assess ME/CFS and post-acute sequelae of COVID-19 (PASC); the commonalities between both conditions, including small fiber neuropathies (SFN), dyspnea, and mitochondrial dysfunction; how symptoms in children differed to adults; and future directions. niCPET studies found that inefficient breathing in ME/CFS patients led to lower peak oxygen uptake (VO2) than in controls. Serial niCPETS (24 hours apart) assessed recovery and PEM, showing further VO2 reduction, lowered levels of exercise tolerance, and earlier anabolic thresholds (AT) in ME/CFS patients. Behavioural and psychological studies found worsened brain function, pain levels, metabolite and immune activity, and further changes to the gut microbiome. Some papers described chronotropic incompetence in both ME/CFS and PASC, but this was not shown in other larger studies.
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Cognitive impairment in post-acute sequelae of COVID-19 and short duration myalgic encephalomyelitis patients is mediated by orthostatic hemodynamic changesAuthors: Day H, Yellman B, Hammer S, Rond C, Bell J, Abbaszadeh S, … Vernon SD (Bateman Horne Centre, United States)
Publication: Frontiers in Neuroscience
Link: https://www.frontiersin.org/articles/10.3389/fnins.2023.1203514/full
Many patients with ME/CFS and post-acute sequelae of COVID-19 (PASC) experience cognitive impairment. This can include trouble with concentration, remembering and decision making. This study sought to determine whether orthostatic haemodynamic changes were associated to cognitive impairment in ME/CFS and PASC.
This study utilised a prospective, observational cohort method, and included 256 participants, in three groups: ME/CFS (140 participants, Institute of Medicine criteria), PASC (34 participants) and healthy controls (82 participants). The ME/CFS group was further divided into two subgroups: illness duration less than four years (71 participants) and illness duration greater than 10 years (69 participants). Participants completed clinical evaluation and assessment, including cognitive efficiency measurements (speed and accuracy of responses). Participants completed a cognitive test before, immediately after, and two and seven days after the orthostatic challenge. The orthostatic challenge was a 10-minute NASA lean test, measuring blood pressure and heart rate, and extrapolating pulse pressure and peripheral perfusion.
The authors found that ME/CFS and PASC participants had significantly lower cognitive efficiency scores immediately after the orthostatic challenge, when compared to healthy controls. In ME/CFS participants with disease duration of greater than 10 years, these scores remained low at two and seven days following the orthostatic challenge. Narrow pulse pressure was observed in PASC and ME/CFS participants, and in PASC participants this was associated with slowed information processing compared to healthy controls. Increased heart rate and decreased procedural reaction was observed during the orthostatic challenge in PASC and some ME/CFS participants with disease duration of less than four years.
PASC participants were seen to experience haemodynamic changes during orthostatic challenge that were associated with slowed reaction time and reduced response accuracy. ME/CFS participants with disease duration of less than 4 years experienced reduced cognitive efficiency associated with elevated heart rate in response to orthostatic challenge. ME/CFS participants with disease duration of greater than 10 years experienced cognitive impairment, but this was not correlated with haemodynamic changes associated with orthostatic challenge. The authors suggest that these findings highlight the necessity of early diagnosis to reduce the impact of haemodynamic and other physiological effects on cognitive impairment symptoms.
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Diagnosis and management of myalgic encephalomyelitis/chronic fatigue syndromeAuthors: Grach SL, Seltzer J, Chon TY, & Ganesh R (Mayo Clinic, United States)
Publication: Mayo Clinic Proceedings
Link: https://www.mayoclinicproceedings.org/article/S0025-6196(23)00402-0/fulltext
There has been an increased interest in ME/CFS as up to 50% of patients with post-COVID syndrome go on to fulfil the criteria for ME/CFS. This review sought to describe a generalist approach to the diagnosis and management of ME/CFS.
Epidemiology/Etiology
· ME/CFS affects all ages, genders, races and socioeconomic backgrounds. Presentation may differ in men compared to women, potentially resulting in underdiagnosis in men.
· Up to 80% of ME/CFS cases are preceded by an infection, most commonly viral, or by multiple smaller events followed by a final trigger causing clear onset.
Diagnosis
· ME/CFS is a diagnosis based on the presence of particular signs and symptoms, not a diagnosis of exclusion. The US Centres for Disease Control and Prevention recommend the 2015 Institute of Medicine ME/CFS diagnostic criteria.
· The lack of diagnostic biomarkers, similarity to other diseases, and reduced clinician awareness of ME/CFS contribute to delayed diagnosis – approximately one third of ME/CFS patients waited at least 5 years for their diagnosis.
· Although ME/CFS is present across a spectrum of mild (approximately 25% of ME/CFS patients), moderate (50%) to severe and very severe (25%), the IOM criteria require a 50% decrease in pre-illness capacity in order to be diagnosed.
Practical considerations in diagnosis
· Patient history: patients often report a wide range of symptoms, it is necessary to determine whether symptoms fulfil the ME/CFS diagnostic criteria. Post-exertional malaise (PEM) is a defining characteristic of ME/CFS.
· Risk factors for ME/CFS: female sex, age 10-19 or 30-39, infection (especially viral), preexisting or family history of autoimmune disease, neurologic or other multisystem chronic disease.
Co-morbidities
· 75-80% of ME/CFS patients report at least one other disease. The most commonly seen co-morbid diseases/disorders include hypermobile Ehlers-Danlos Syndrome, postural orthostatic tachycardia syndrome and other autonomic disorders, and mast cell activation syndrome.
General management
· Managing energy expenditure and avoiding PEM through effective pacing may lead to improvements in functional ability over time and improved quality of life. Identifying the heart rate threshold that triggers PEM and staying below this level may assist self-management.
· Pacing does not involve systematic increases in activity, and is not curative.
· Graded exercise therapy has not been proven to be effective for ME/CFS.
· Pharmacological medications or supplements may assist with symptom management. Patients are often sensitive to medications and may need to be started on a low dose, with gradual increase in dose over time.
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PLoS One . 2022 Mar 15;17(3):e0265315. doi: 10.1371/journal.pone.0265315. eCollection 2022.
Cardiopulmonary, metabolic, and perceptual responses during exercise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Multi-site Clinical Assessment of ME/CFS (MCAM) sub-studyDane B Cook 1 2, Stephanie VanRiper 1 2, Ryan J Dougherty 3, Jacob B Lindheimer 1 2 4, Michael J Falvo 5 6, Yang Chen 7, Jin-Mann S Lin 7, Elizabeth R Unger 7; MCAM Study Group
PMID: 35290404 PMCID: PMC8923458 DOI: 10.1371/journal.pone.0265315
AbstractBackground: Cardiopulmonary exercise testing has demonstrated clinical utility in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). However, to what extent exercise responses are independent of, or confounded by, aerobic fitness remains unclear.
Purpose: To characterize and compare exercise responses in ME/CFS and controls with and without matching for aerobic fitness.
Methods: As part of the Multi-site Clinical Assessment of ME/CFS (MCAM) study, 403 participants (n = 214 ME/CFS; n = 189 controls), across six ME/CFS clinics, completed ramped cycle ergometry to volitional exhaustion. Metabolic, heart rate (HR), and ratings of perceived exertion (RPE) were measured. Ventilatory equivalent ([Formula: see text], [Formula: see text]), metrics of ventilatory efficiency, and chronotropic incompetence (CI) were calculated. Exercise variables were compared using Hedges' g effect size with 95% confidence intervals. Differences in cardiopulmonary and perceptual features during exercise were analyzed using linear mixed effects models with repeated measures for relative exercise intensity (20-100% peak [Formula: see text]). Subgroup analyses were conducted for 198 participants (99 ME/CFS; 99 controls) matched for age (±5 years) and peak [Formula: see text] (~1 ml/kg/min-1).
Results: Ninety percent of tests (n = 194 ME/CFS, n = 169 controls) met standard criteria for peak effort. ME/CFS responses during exercise (20-100% peak [Formula: see text]) were significantly lower for ventilation, breathing frequency, HR, measures of efficiency, and CI and significantly higher for [Formula: see text], [Formula: see text] and RPE (p<0.05adjusted). For the fitness-matched subgroup, differences remained for breathing frequency, [Formula: see text], [Formula: see text], and RPE (p<0.05adjusted), and higher tidal volumes were identified for ME/CFS (p<0.05adjusted). Exercise responses at the gas exchange threshold, peak, and for measures of ventilatory efficiency (e.g., [Formula: see text]) were generally reflective of those seen throughout exercise (i.e., 20-100%).
Conclusion: Compared to fitness-matched controls, cardiopulmonary responses to exercise in ME/CFS are characterized by inefficient exercise ventilation and augmented perception of effort. These data highlight the importance of distinguishing confounding fitness effects to identify responses that may be more specifically associated with ME/CFS.
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Long-term symptom severity and clinical biomarkers in post-COVID-19/chronic fatigue syndrome: results from a prospective observational cohortFranziska Legler h https://doi.org/10.1016/j.eclinm.2023.102146
Summary
BackgroundPost-COVID-19 syndrome (PCS) is characterised by a wide range of symptoms, primarily fatigue and exertion intolerance. While disease courses in the early months post-infection have been well-described, the long-term health consequences for patients with PCS with disabling fatigue remain unclear.
MethodsIn this prospective observational cohort study, we evaluated symptom severity and various biomarkers, including hand grip strength (HGS), cardiovascular function, and laboratory parameters, in 106 patients with PCS with moderate to severe fatigue and exertion intolerance at three time points after infection (3–8, 9–16, and 17–20 months). The study was conducted at the Charité’s Fatigue Centre and the Charité’s outpatient clinic for neuroimmunology at Berlin, Germany from July 16, 2020, to February 18, 2022. A subset of patients (PCS-ME/CFS) met the diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome according to the Canadian Consensus Criteria (CCC). The aim was to determine differences in the disease course between the two patient groups (i.e., PCS vs PCS-ME/CFS) and identify correlating biomarkers.
FindingsPatients with PCS-ME/CFS reported persistently high severity of most symptoms up to 20 months after infection, while patients with PCS showed overall health improvement. Although fatigue and post-exertional malaise (PEM), hallmarks of post-infectious fatigue syndromes, were still evident in both groups, they remained more pronounced in PCS-ME/CFS. Inflammatory biomarkers decreased in both groups, but not antinuclear antibodies. Lower HGS at onset correlated with symptom persistence, particularly in patients with PCS-ME/CFS.
InterpretationOur findings suggest that PCS can persist beyond 20 months post-infection and encompass the full scope of post-infectious ME/CFS as defined by the CCC. Sub-classifying patients with PCS based on the CCC can assist in the management and monitoring of patients with PCS-ME/CFS due to their persistently higher symptom severity.
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Distinguishing features of long COVID identified through immune profilingJon Klein, Jamie Wood, Jillian R. Jaycox, Rahul M. Dhodapkar, Peiwen Lu, Jeff R. Gehlhausen, Alexandra Tabachnikova, Kerrie Greene, Laura Tabacof, Amyn A. Malik, Valter Silva Monteiro, Julio Silva, Kathy Kamath, Abhilash Dhal, Isabel Ott, Gabrielee Valle, Mario Peña-Hernández, Tianyang Mao, Takehiro Takahashi, Carolina Lucas, Eric Song, Dayna McCarthy, Akiko Iwasaki
Nature volume 623, pages139–148 Published: 25 September 2023
Abstract
Post-acute infection syndromes may develop after acute viral disease1. Infection with SARS-CoV-2 can result in the development of a post-acute infection syndrome known as long COVID. Individuals with long COVID frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions2,3,4. However, the biological processes that are associated with the development and persistence of these symptoms are unclear. Here 275 individuals with or without long COVID were enrolled in a cross-sectional study that included multidimensional immune phenotyping and unbiased machine learning methods to identify biological features associated with long COVID. Marked differences were noted in circulating myeloid and lymphocyte populations relative to the matched controls, as well as evidence of exaggerated humoral responses directed against SARS-CoV-2 among participants with long COVID. Furthermore, higher antibody responses directed against non-SARS-CoV-2 viral pathogens were observed among individuals with long COVID, particularly Epstein–Barr virus. Levels of soluble immune mediators and hormones varied among groups, with cortisol levels being lower among participants with long COVID. Integration of immune phenotyping data into unbiased machine learning models identified the key features that are most strongly associated with long COVID status. Collectively, these findings may help to guide future studies into the pathobiology of long COVID and help with developing relevant biomarkers.
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The economic burden of myalgic encephalomyelitis/chronic fatigue syndrome in AustraliaTing Zhao A , Ingrid A. Cox A , Hasnat Ahmad A , Julie A. Campbell A , Martin Hensher A , Andrew J Palmer A , Ryan M. Kelly B , Melissa J. Rogerson B , Karen Wills A and Barbara de Graaff A *
* Correspondence to: [email protected]
Australian Health Review 47(6) 707-715 https://doi.org/10.1071/AH23106
Submitted: 13 July 2023 Accepted: 7 November 2023 Published: 28 November 2023
© 2023 The Author(s) (or their employer(s)). Published by CSIRO Publishing on behalf of AHHA.
Abstract
Objective
This study aimed to estimate costs of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) to patients, government and Australian society.
Methods
Australian ME/CFS patients and their carers were recruited using convenience sampling. Patients completed an online retrospective cost diary, providing ME/CFS-related direct medical, non-medical and indirect costs. Informal care costs were collected directly from carers. Data from the Pharmaceutical Benefits Scheme and Medicare Benefits Schedule were linked to participant survey data. Annual per patient and total societal costs were estimated, broken down by category and presented in 2021 AUD. Factors associated with higher costs were investigated using generalised linear models.
Results
One hundred and seventy five patients (mean age 49 years s.d. 14, 79.4% female) completed the cost diary. Estimated total annual societal costs of ME/CFS in Australia ranged between $1.38 and $10.09 billion, with average annual total costs of $63 400/patient. Three-quarters of these costs were due to indirect costs ($46 731). Disability severity was the key factor associated with higher costs, particularly for indirect costs (being 2.27-fold higher for severe disability than no/mild disability).
Conclusions
ME/CFS poses a significant economic burden in Australia, owing mainly to high indirect and informal care costs.
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Why Are Women More Likely to Get Long COVID?
Tinker Ready January 19, 2024 Medscape
Annette Gillaspie, a nurse in a small Oregon hospital, hoped she would be back working with patients by now. She contracted COVID-19 on the job early in the pandemic and ended up with long COVID.
After recovering a bit, her fatigue and dizziness returned, and today she is still working a desk job. She has also experienced more severe menstrual periods than before she had COVID.
"Being a female with long COVID definitely does add to the roller-coaster effect of symptoms," Gillaspie said.
Long COVID affects nearly twice as many women as men, with 6.6% of women reporting long COVID compared with 4% of men, according to a recent Census Bureau survey reported by the Centers for Disease Control and Prevention (CDC). Researchers are trying to determine why, what causes the gender disparity, and how best to treat it.
Scientists are also starting to look at the impact of long COVID on female reproductive health, including menstruation, pregnancy, and menopause.
Sex differences are common in infection-associated illnesses, said Beth Pollack, a research scientist specializing in long COVID in the Massachusetts Institute of Technology's Department of Biological Engineering, Cambridge, Massachusetts. "It informs research priorities and the lens with which we understand long COVID."
For example, reproductive health issues for women, such as puberty, pregnancy, and menopause, can alter the course of illness in a subset of women in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and postural orthostatic tachycardia syndrome (POTS), a condition that can cause dizziness and worse.
"This suggests that sex hormones may play key roles in immune responses to infections," Pollack said.
ME/CFS and a Possible Link to Long COVID in Women
Some of the research into long COVID is being led by teams studying infection-associated chronic illnesses like ME/CFS.
The problem: Advocates say ME/CFS has been under-researched. Poorly understood for years, the condition is one of a handful of chronic illnesses linked to infections, including Lyme disease and now long COVID. Perhaps not coincidently, they are more likely to affect women.
Many of the research findings about long COVID mirror data that emerged in past ME/CFS research, said Jaime Seltzer, the scientific director at #MEAction, Santa Monica, California, an advocacy group. One point in particular: ME/CFS strikes women about twice as much as men, according to the CDC.
Seltzer said the response to long COVID could be much further ahead if the research community acknowledged the work done over the years on ME/CFS. Many of the potential biomarkers and risk factors emerging for long COVID were also suspected in ME/CFS, but not thoroughly studied, she said.
She also said not enough work has been done to unravel the links between gender and these chronic conditions.
"We're stuck in this Groundhog Day situation," she said. "There isn't any research, so we can't say anything definitively."
Some New Research, Some New Clues
Scientists like Pollack are slowly making inroads. She was lead author on a 2023 review investigating the impact of long COVID on female reproductive health. The paper highlights long COVID links to ME/CFS, POTS, and Ehlers-Danlos syndrome (EDS), as well as a resulting laundry list of female reproductive health issues. The hope is physicians will examine how the menstrual cycle, pregnancy, and menopause affect symptoms and illness progression of long COVID.
The Tal Research group at MIT (where Pollack works) has also added long COVID to the list of infection-associated illnesses it studies. The lab is conducting a large study looking into both Lyme disease and long COVID. The goals are to identify biomarkers that can predict who will not recover and to advance available treatments.
Another MIT program, "SEXX + Immunity" holds seminars and networking sessions for scientists looking into the role of female and male biology in immune responses to infection.
Barriers to Progress Remain
On the clinical side, female patients with long COVID also have to deal with a historical bias that still lurks in medicine when it comes to women's health, said Alba Azola, MD, an assistant professor of physical medicine at Johns Hopkins Medicine, Baltimore, Maryland.
Azola said she has discovered clinical descriptions of ME/CFE in the literature archives that describe it as "neurasthenia" and dismiss it as psychological.
Patients say that it is still happening, and while it may not be so blunt, "you can read between the lines," Azola said.
Azola, who has worked with long-COVID patients and is now seeing people with ME/CFS, said the symptoms of infection-associated chronic illness can mimic menopause, and many of her patients received that misdiagnosis. She recommends that doctors rule out long COVID for women with multiple symptoms before attributing symptoms to menopause.
Seeing that some long-COVID patients were developing ME/CFS, staff at the Bateman Horne Center in Salt Lake City, Utah, set up a program for the condition in 2021. They were already treating patients with ME/CFS and what they call "multi-symptom chronic complex diseases."
Jennifer Bell, a certified nurse practitioner at the center, said she has not seen any patients with ovarian failure but plenty with reproductive health issues.
"There definitely is a hormonal connection, but I don't think there's a good understanding about what is happening," she said.
Most of her patients are female, and the more serious patients tend to go through a worsening of their symptoms in the week prior to getting a period, she said.
One thing Bell said she's noticed in the past year is an increase in patients with EDS, which is also more common in women.
Like long COVID, many of the conditions traditionally treated at the center have no cure. But Bell said the center has developed an expertise in treating post-exertional malaise, a common symptom of long COVID, and keeps up with the literature for treatments to try, like the combination of guanfacine and the antioxidant N-acetyl cysteine to treat brain fog, an approach developed at Yale.
"It's a very challenging illness to treat," Bell said.
Since the emergence of long COVID, researchers have warned that symptoms vary so much from person to person that treatment will need to be targeted.
Pollack of MIT agrees and sees a big role for personalized medicine.
We need to "identify phenotypes within and across these overlapping and co-occurring illnesses so that we can identify the right therapeutics for each person," she said.
As for Annette Gillaspie, she still hopes her long COVID will subside so she can get out from behind the desk and return to her normal nursing duties.
"I just got to a point where I realized I'm likely never going to be able to do my job," she said. "It was incredibly heart breaking, but it's the reality of long COVID, and I know I'm not the only one to have to step away from a job I loved."
Medscape Medical News © 2024 WebMD, LLC
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The effectiveness of COVID-19 vaccines to cohort study of data from the UK, Spain, and EstoniaMartí Català, PhD Núria Mercadé-Besora, BA Raio Kolde, PhD Nhung T H Trinh, PhD Elena Roel, PhDEdward Burn, PhD et al.
Published:January 11, 2024DOI:https://doi.org/10.1016/S2213-2600(23)00414-9
SummaryBackgroundAlthough vaccines have proved effective to prevent severe COVID-19, their effect on preventing long-term symptoms is not yet fully understood. We aimed to evaluate the overall effect of vaccination to prevent long COVID symptoms and assess comparative effectiveness of the most used vaccines (ChAdOx1 and BNT162b2).
MethodsWe conducted a staggered cohort study using primary care records from the UK (Clinical Practice Research Datalink [CPRD] GOLD and AURUM), Catalonia, Spain (Information System for Research in Primary Care [SIDIAP]), and national health insurance claims from Estonia (CORIVA database). All adults who were registered for at least 180 days as of Jan 4, 2021 (the UK), Feb 20, 2021 (Spain), and Jan 28, 2021 (Estonia) comprised the source population. Vaccination status was used as a time-varying exposure, staggered by vaccine rollout period. Vaccinated people were further classified by vaccine brand according to their first dose received. The primary outcome definition of long COVID was defined as having at least one of 25 WHO-listed symptoms between 90 and 365 days after the date of a PCR-positive test or clinical diagnosis of COVID-19, with no history of that symptom 180 days before SARS-Cov-2 infection. Propensity score overlap weighting was applied separately for each cohort to minimise confounding. Sub-distribution hazard ratios (sHRs) were calculated to estimate vaccine effectiveness against long COVID, and empirically calibrated using negative control outcomes. Random effects meta-analyses across staggered cohorts were conducted to pool overall effect estimates.
FindingsA total of 1 618 395 (CPRD GOLD), 5 729 800 (CPRD AURUM), 2 744 821 (SIDIAP), and 77 603 (CORIVA) vaccinated people and 1 640 371 (CPRD GOLD), 5 860 564 (CPRD AURUM), 2 588 518 (SIDIAP), and 302 267 (CORIVA) unvaccinated people were included. Compared with unvaccinated people, overall HRs for long COVID symptoms in people vaccinated with a first dose of any COVID-19 vaccine were 0·54 (95% CI 0·44–0·67) in CPRD GOLD, 0·48 (0·34–0·68) in CPRD AURUM, 0·71 (0·55–0·91) in SIDIAP, and 0·59 (0·40–0·87) in CORIVA. A slightly stronger preventative effect was seen for the first dose of BNT162b2 than for ChAdOx1 (sHR 0·85 [0·60–1·20] in CPRD GOLD and 0·84 [0·74–0·94] in CPRD AURUM).
InterpretationVaccination against COVID-19 consistently reduced the risk of long COVID symptoms, which highlights the importance of vaccination to prevent persistent COVID-19 symptoms, particularly in adults.
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Impact of COVID-19 vaccination on symptoms and immune phenotypes in vaccine-naïve individuals with Long COVID View ORCID ProfileConnor B Grady, Bornali Bhattacharjee, Julio Silva, Jillian Jaycox, Lik Wee Lee, Valter Silva Monteiro, Mitsuaki Sawano, Daisy Massey, César Caraballo, Jeff R. Gehlhausen, Alexandra Tabachnikova, Tianyang Mao, Carolina Lucas, Mario A. Peña-Hernandez, Lan Xu, Tiffany J. Tzeng, Takehiro Takahashi, Jeph Herrin, Diana Berrent Güthe, Athena Akrami, Gina Assaf, Hannah Davis, Karen Harris, Lisa McCorkell, Wade L Schulz, Daniel Grffin, Hannah Wei, Aaron M Ring, Leying Guan, Charles Dela Cruz, Akiko Iwasaki, View ORCID ProfileHarlan M Krumholz
doi: https://doi.org/10.1101/2024.01.11.24300929
This article is a preprint and has not been peer-reviewed It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.
000020126
AbstractBackground Long COVID contributes to the global burden of disease. Proposed root cause hypotheses include the persistence of SARS-CoV-2 viral reservoir, autoimmunity, and reactivation of latent herpesviruses. Patients have reported various changes in Long COVID symptoms after COVID-19 vaccinations, leaving uncertainty about whether vaccine-induced immune responses may alleviate or worsen disease pathology.
Methods In this prospective study, we evaluated changes in symptoms and immune responses after COVID-19 vaccination in 16 vaccine-naïve individuals with Long COVID. Surveys were administered before vaccination and then at 2, 6, and 12 weeks after receiving the first vaccine dose of the primary series. Simultaneously, SARS-CoV-2-reactive TCR enrichment, SARS-CoV-2-specific antibody responses, antibody responses to other viral and self-antigens, and circulating cytokines were quantified before vaccination and at 6 and 12 weeks after vaccination.
Results Self-report at 12 weeks post-vaccination indicated 10 out of 16 participants had improved health, 3 had no change, 1 had worse health, and 2 reported marginal changes. Significant elevation in SARS-CoV-2-specific TCRs and Spike protein-specific IgG were observed 6 and 12 weeks after vaccination. No changes in reactivities were observed against herpes viruses and self-antigens. Within this dataset, higher baseline sIL-6R was associated with symptom improvement, and the two top features associated with non-improvement were high IFN-β and CNTF, among soluble analytes.
Conclusions Our study showed that in this small sample, vaccination improved the health or resulted in no change to the health of most participants, though few experienced worsening. Vaccination was associated with increased SARS-CoV-2 Spike protein-specific IgG and T cell expansion in most individuals with Long COVID. Symptom improvement was observed in those with baseline elevated sIL-6R, while elevated interferon and neuropeptide levels were associated with a lack of improvement.
Plain language summary The impact of the COVID-19 vaccine on vaccine-naïve individuals suffering from Long COVID is uncertain. This study assessed the experience and immune signatures of 16 unvaccinated participants with Long COVID. A total of 10 participants had improved health status after vaccination, and one person reported only worsening health. As expected, vaccination increased immune cells and antibodies against the viral spike protein. Immune signatures may prove to be predictors of health status after vaccination. However, given the small number of participants, these initial findings need further validation.
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Five Bold Predictions for Long COVID in 2024Sara Novak January 25, 2024 Medscape Medical News
With a number of large-scale clinical trials underway and researchers on the hunt for new therapies, long COVID scientists are hopeful that this is the year patients — and doctors who care for them — will finally see improvements in treating their symptoms.
Here are five bold predictions — all based on encouraging research — that could happen in 2024. At the very least, they are promising signs of progress against a debilitating and frustrating disease.
#1: We'll gain a better understanding of each long COVID phenotype
This past year, a wide breadth of research began showing that long COVID can be defined by a number of different disease phenotypes that present a range of symptoms.
Researchers identified four clinical phenotypes: Chronic fatigue-like syndrome, headache, and memory loss; respiratory syndrome, which includes cough and difficulty breathing; chronic pain; and neurosensorial syndrome, which causes an altered sense of taste and smell.
Identifying specific diagnostic criteria for each phenotype would lead to better health outcomes for patients instead of treating them as if it were a "one-size-fits-all disease," said Nisha Viswanathan, MD, director of the long COVID program at UCLA Health, Los Angeles, California.
Ultimately, she hopes that this year her patients will receive treatments based on the type of long COVID they're personally experiencing, and the symptoms they have, leading to improved health outcomes and more rapid relief.
"Many new medications are focused on different pathways of long COVID, and the challenge becomes which drug is the right drug for each treatment," said Viswanathan.
#2: Monoclonal antibodies may change the game
We're starting to have a better understanding that what's been called "viral persistence" as a main cause of long COVID may potentially be treated with monoclonal antibodies. These are antibodies produced by cloning unique white blood cells to target the circulating spike proteins in the blood that hang out in viral reservoirs and cause the immune system to react as if it's still fighting acute COVID-19.
Smaller-scale studies have already shown promising results. A January 2024 study published in The American Journal of Emergency Medicine followed three patients who completely recovered from long COVID after taking monoclonal antibodies. "Remission occurred despite dissimilar past histories, sex, age, and illness duration," wrote the study authors.
Larger clinical trials are underway at the University of California, San Francisco, California, to test targeted monoclonal antibodies. If the results of the larger study show that monoclonal antibodies are beneficial, then it could be a game changer for a large swath of patients around the world, said David F. Putrino, PhD, who runs the long COVID clinic at Mount Sinai Health System in New York City.
"The idea is that the downstream damage caused by viral persistence will resolve itself once you wipe out the virus," said Putrino.
#3: Paxlovid could prove effective for long COVID
The US Food and Drug Administration granted approval for Paxlovid last May for the treatment of mild to moderate COVID-19 in adults at a high risk for severe disease. The medication is made up of two drugs packaged together. The first, nirmatrelvir, works by blocking a key enzyme required for virus replication. The second, ritonavir, is an antiviral that's been used in patients with HIV and helps boost levels of antivirals in the body.
In a large-scale trial headed up by Putrino and his team, the oral antiviral is being studied for use in the post-viral stage in patients who test negative for acute COVID-19 but have persisting symptoms of long COVID.
Similar to monoclonal antibodies, the idea is to quell viral persistence. If patients have long COVID because they can't clear SAR-CoV-2 from their bodies, Paxlovid could help. But unlike monoclonal antibodies that quash the virus, Paxlovid stops the virus from replicating. It's a different mechanism with the same end goal.
It's been a controversial treatment because it's life-changing for some patients and ineffective for others. In addition, it can cause a range of side effects such as diarrhea, nausea, vomiting, and an impaired sense of taste. The goal of the trial is to see which patients with long COVID are most likely to benefit from the treatment.
#4: Anti-inflammatories like metformin could prove useful
Many of the inflammatory markers persistent in patients with long COVID were similarly present in patients with autoimmune diseases like rheumatoid arthritis, according to a July 2023 study published in JAMA.
The hope is that anti-inflammatory medications may be used to reduce inflammation causing long COVID symptoms. But drugs used to treat rheumatoid arthritis like abatacept and infliximabcan also have serious side effects, including increased risk for infection, flu-like symptoms, and burning of the skin.
"Powerful anti-inflammatories can change a number of pathways in the immune system," said Grace McComsey, MD, who leads the long COVID RECOVER study at University Hospitals Health System in Cleveland, Ohio. Anti-inflammatories hold promise but, McComsey said, "some are more toxic with many side effects, so even if they work, there's still a question about who should take them."
Still, other anti-inflammatories that could work don't have as many side effects. For example, a study published in The Lancet Infectious Diseases found that the diabetes drug metformin reduced a patient's risk for long COVID up to 40% when the drug was taken during the acute stage.
Metformin, compared to other anti-inflammatories (also known as immune modulators), is an inexpensive and widely available drug with relatively few side effects compared with other medications.
#5: Serotonin levels — and selective serotonin reuptake inhibitors (SSRIs) — may be keys to unlocking long COVID
One of the most groundbreaking studies of the year came last November. A study published in the journal Cell found lower circulating serotonin levels in patents with long COVID than in those who did not have the condition. The study also found that the SSRI fluoxetine improved cognitive function in rat models infected with the virus.
Researchers found that the reduction in serotonin levels was partially caused by the body's inability to absorb tryptophan, an amino acid that's a precursor to serotonin. Overactivated blood platelets may also have played a role.
Michael Peluso, MD, an assistant research professor of infectious medicine at the UCSF School of Medicine, San Francisco, California, hopes to take the finding a step further, investigating whether increased serotonin levels in patients with long COVID will lead to improvements in symptoms.
"What we need now is a good clinical trial to see whether altering levels of serotonin in people with long COVID will lead to symptom relief," Peluso said last month in an interview with Medscape Medical News.
If patients show an improvement in symptoms, then the next step is looking into whether SSRIs boost serotonin levels in patients and, as a result, reduce their symptoms.
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Nature: A randomized open-label clinical trial on the effect of Amantadine on post Covid 19 fatigueJanuary 17, 2024 A A Harandi et al 2024 Scientific Reports
Abstract
Many COVID-19 survivors experience lingering post-COVID-19 symptoms, notably chronic fatigue persisting for months after the acute phase. Despite its prevalence, limited research has explored effective treatments for post-COVID-19 fatigue. This randomized controlled clinical trial assessed the impact of Amantadine on patients with post-COVID-19 fatigue. The intervention group received Amantadine for two weeks, while the control group received no treatment. Fatigue levels were assessed using the Visual Analog Fatigue Scale (VAFS) and Fatigue Severity Scale (FSS) questionnaires before and after the trial. At the study's onset, VAFS mean scores were 7.90 ± 0.60 in the intervention group and 7.34 ± 0.58 in the control group (P-value = 0.087). After two weeks, intervention group scores dropped to 3.37 ± 0.44, significantly lower than the control group's 5.97 ± 0.29 (P-value < 0.001). Similarly, FSS mean scores at the trial's commencement were 53.10 ± 5.96 in the intervention group and 50.38 ± 4.88 in the control group (P-value = 0.053). At the trial's end, intervention group scores decreased to 28.40 ± 2.42, markedly lower than the control group's 42.59 ± 1.50 (P-value < 0.001). In this study, we report the safety, tolerability, and substantial fatigue-relieving effects of Amantadine in post-COVID-19 fatigue. The intervention demonstrates a statistically significant reduction in fatigue levels, suggesting Amantadine's potential as an effective treatment for this persistent condition.
Discussion
Amantadine's effectiveness in relieving MS-related fatigue has been frequently shown, and its prescription is recommended by the German MS Society as well as in clinical practice guidelines published by NICE. Given the high incidence rate of post-COVID-19 fatigue and lack of treatment options, the satisfactory result obtained in our study with treatment with Amantadine is considerable. However, to our knowledge, there is no study investigating the effect of Amantadine on fatigue in post-COVID-19 patients to compare their results with ours.
Results
Our results showed a significant difference in the improvement of fatigue in patients receiving Amantadine compared to the control group. This improvement was evident in the FSS and the VAFS scores since the average of both reached less than half of the initial value after two weeks of treatment with Amantadine.
In conclusion, our study demonstrated that consuming Amantadine has a favorable effect on relieving post-COVID-19 fatigue. Our results reveal the safety and tolerability of two-weeks treatment with Amantadine in post-COVID-19 patients. We recommend well-designed double-blind, randomized studies with placebo and larger sample sizes to validate our results.
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News Medical: Long COVID and ME/CFS patients could benefit from a coordinated treatment strategyJanuary 23, 2024 News Medical Life Sciences
“Given the important clinical and pathological overlaps between ME/CFS and Long Covid co-ordinated research is something that the MEA has been calling for since May 2020 – when it became clear that Covid-19 was also triggering a post viral disease with symptoms that were identical to those found in ME/CFS
Sadly, it has taken over three years for many of the researchers involved in Long Covid research to accept that these overlaps occur
However the message is now getting through
Hopefully, this will lead to a better understanding of what causes post viral disease and the development of effective forms of treatment aimed at the underlying disease process in both Long Covid and ME/CFS“
Dr Charles Shepherd,
Trustee and Hon. Medical Adviser to the ME Association.
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Published: 12 December 2023
A pilot study on the immune cell proteome of long COVID patients shows changes to physiological pathways similar to those in myalgic encephalomyelitis/chronic fatigue syndromeKatie Peppercorn, Christina D. Edgar, Torsten Kleffmann & Warren P. Tate
Scientific Reports volume 13, Article number: 22068 (2023)
Abstract
Of those infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), ~ 10% develop the chronic post-viral debilitating condition, long COVID (LC). Although LC is a heterogeneous condition, about half of cases have typical post-viral fatigue with onset and symptoms that are very similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). A key question is whether these conditions are closely related. ME/CFS is a post-stressor fatigue condition that arises from multiple triggers. To investigate the pathophysiology of LC, a pilot study of patients (n = 6) and healthy controls (n = 5) has used quantitative proteomics to discover changes in peripheral blood mononuclear cell (PBMC) proteins. A principal component analysis separated all long COVID patients from healthy controls. Analysis of 3131 proteins identified 162 proteins differentially regulated, of which 37 were related to immune functions, and 21 to mitochondrial functions. Markov cluster analysis identified clusters involved in immune system processes, and two aspects of gene expression-spliceosome and transcription. These results were compared with an earlier dataset of 346 differentially regulated proteins in PBMC’s from ME/CFS patients (n = 9) analysed by the same methodology. There were overlapping protein clusters and enriched molecular pathways particularly in immune functions, suggesting the two conditions have similar immune pathophysiology as a prominent feature, and mitochondrial functions involved in energy production were affected in both conditions.
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Sci.Rep. 2024; 14: 1343.
Published online 2024 Jan 16. doi: 10.1038/s41598-024-51904-z
PMCID: PMC10792128nnnnPMID: 38228731
A randomized open-label clinical trial on the effect of Amantadine on post Covid 19 fatigue
Ali Amini Harandi, 1 Hossein Pakdaman,1 Aida Medghalchi,1 Negin Kimia,1 Alireza Kazemian,1 Fatemeh Siavoshi,1 Siavash Shirzadeh Barough,1 Akram Esfandani,1 Mohammad Hossein Hosseini,1 and Seyed Ali Sobhanian2
Author information Article notes Copyright and License information PMC Disclaimer
Abstract
Many COVID-19 survivors experience lingering post-COVID-19 symptoms, notably chronic fatigue persisting for months after the acute phase. Despite its prevalence, limited research has explored effective treatments for post-COVID-19 fatigue. This randomized controlled clinical trial assessed the impact of Amantadine on patients with post-COVID-19 fatigue. The intervention group received Amantadine for two weeks, while the control group received no treatment. Fatigue levels were assessed using the Visual Analog Fatigue Scale (VAFS) and Fatigue Severity Scale (FSS) questionnaires before and after the trial. At the study's onset, VAFS mean scores were 7.90 ± 0.60 in the intervention group and 7.34 ± 0.58 in the control group (P-value = 0.087). After two weeks, intervention group scores dropped to 3.37 ± 0.44, significantly lower than the control group's 5.97 ± 0.29 (P-value < 0.001). Similarly, FSS mean scores at the trial's commencement were 53.10 ± 5.96 in the intervention group and 50.38 ± 4.88 in the control group (P-value = 0.053). At the trial's end, intervention group scores decreased to 28.40 ± 2.42, markedly lower than the control group's 42.59 ± 1.50 (P-value < 0.001). In this study, we report the safety, tolerability, and substantial fatigue-relieving effects of Amantadine in post-COVID-19 fatigue. The intervention demonstrates a statistically significant reduction in fatigue levels, suggesting Amantadine's potential as an effective treatment for this persistent condition.
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New Tests May Finally Diagnose Long COVIDSara Novak November 29, 2023 Medscape Medical News
One of the biggest challenges facing clinicians who treat long COVID is a lack of consensus when it comes to recognizing and diagnosing the condition. But a new study suggests testing for certain biomarkers may identify long COVID with accuracy approaching 80%.
Effective diagnostic testing would be a game-changer in the long COVID fight, for it’s not just the fatigue, brain fog, heart palpitations, and other persistent symptoms that affect patients. Two out of three people with long COVID also suffer mental health challenges like depression and anxiety. Some patients say their symptoms are not taken seriously by their doctors. And as many as 12% of long COVID patients are unemployed because of the severity of their illness and their employers may be skeptical of their condition.
Quick, accurate diagnosis would eliminate all that. Now a new preprint study suggests that the elevation of certain immune system proteins are a commonality in long COVID patients and identifying them may be an accurate way to diagnose the condition.
Researchers at Cardiff University School of Medicine in Cardiff, Wales, United Kingdom, tracked 166 patients, 79 of whom had been diagnosed with long COVID and 87 who had not. All participants had recovered from a severe bout of acute COVID-19.
In an analysis of the blood plasma of the study participants, researchers found elevated levels of certain components. Four proteins in particular — Ba, iC3b, C5a, and TCC — predicted the presence of long COVID with 78.5% accuracy.
"I was gobsmacked by the results. We’re seeing a massive dysregulation in those four biomarkers," says study author Wioleta Zelek, PhD, a research fellow at Cardiff University. "It’s a combination that we showed was predictive of long COVID."
The study revealed that long COVID was associated with inflammation of the immune system causing these complement proteins to remain dysregulated. Proteins like C3, C4, and C5 are important parts of the immune system because they recruit phagocytes, cells that attack and engulf bacteria and viruses at the site of infection to destroy pathogens like SARS-coV-2.
In the case of long COVID, these proteins remain chronically elevated. While the symptoms of long COVID have seemed largely unrelated to one another, researchers point to elevated inflammation as a connecting factor that causes various systems in the body to go haywire.
"Anything that could help to better diagnose patients with long COVID is research we’re greatly appreciative of within the clinical community," said Nisha Viswanathan, MD, director of the University of California Los Angeles Long COVID program at UCLA Health in Los Angeles.
Testing for biomarkers highlighted in the study, as well as others like serotonin and cortisol, may help doctors separate patients who have long COVID from patients who have similar symptoms caused by other conditions, said Viswanathan. For example, a recent study published in the journal Cell found lower serotonin levels in long COVID patients compared with patients who were diagnosed with acute COVID-19 but recovered from the condition.
Viswanathan cautions that the biomarker test does not answer all the questions about diagnosing long COVID. For example, Viswanathan said scientists don’t know whether complement dysregulation is caused by long COVID and not another underlying medical issue that patients had prior to infection, because "we don’t know where patients’ levels were prior to developing long COVID." For example, those with autoimmune issues are more likely to develop long COVID, which means their levels could have been elevated prior to a COVID infection.
It is increasingly likely, said Viswanathan, that long COVID is an umbrella term for a host of conditions that could be caused by different impacts of the virus. Other research has pointed to the different phenotypes of long COVID. For example, some are focused on cardiopulmonary issues and others on fatigue and gastrointestinal problems.
"It looks like these different phenotypes have a different mechanism for disease," she said. This means that it’s less likely to be a one-size-fits-all condition and the next step in the research should be identifying which biomarker is aligned with which phenotype of the disease.
Better diagnostics will open the door to better treatments, Zelek said. The more doctors understand about the mechanism causing immune dysregulation in long COVID patients, the more they can treat it with existing medications. Zelek’s lab has been studying certain medications like pegcetacoplan (C3 blocker), danicopan (anti-factor D), and iptacopan (anti-factor B) that can be used to break the body’s cycle of inflammation and reduce symptoms experienced in those with long COVID.
These drugs are approved by the US Food and Drug Administration for the treatment of a rare blood disease called paroxysmal nocturnal hemoglobinuria. The C5 inhibitor zilucoplan has also been used in patients hospitalized with COVID-19 and researchers have found that the drug lowered serum C5 and interleukin-8 concentration in the blood, seeming to reduce certain aspects of the immune system’s inflammatory response to the virus.
The Cardiff University research is one of the most detailed studies to highlight long COVID biomarkers to date, said infectious disease specialist Grace McComsey, MD, who leads the long COVID RECOVER study at University Hospitals Health System in Cleveland, Ohio. The research needs to be duplicated in a larger study population that might include the other biomarkers like serotonin and cortisol to see if they’re related, she said.
Researchers are learning more everyday about the various biomarkers that may be linked to long COVID, she added. This Cardiff study showed that a huge percentage of those patients had elevated levels of certain complements. The next step, said McComsey, "is to put all these puzzle pieces together" so that clinicians have a common diagnostic tool or tools that provide patients with some peace of mind in starting their road to recovery.
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Why Are Women More Likely to Get Long COVID?Tinker Ready Medscape medical news January 19, 2024
Annette Gillaspie, a nurse in a small Oregon hospital, hoped she would be back working with patients by now. She contracted COVID-19 on the job early in the pandemic and ended up with long COVID. After recovering a bit, her fatigue and dizziness returned, and today she is still working a desk job. She has also experienced more severe menstrual periods than before she had COVID. "Being a female with long COVID definitely does add to the roller-coaster effect of symptoms," Gillaspie said.
Long COVID affects nearly twice as many women as men, with 6.6% of women reporting long COVID compared with 4% of men, according to a recent Census Bureau survey reported by the Centers for Disease Control and Prevention (CDC). Researchers are trying to determine why, what causes the gender disparity, and how best to treat it.Scientists are also starting to look at the impact of long COVID on female reproductive health, including menstruation, pregnancy, and menopause.
Sex differences are common in infection-associated illnesses, said Beth Pollack, a research scientist specializing in long COVID in the Massachusetts Institute of Technology's Department of Biological Engineering, Cambridge, Massachusetts. "It informs research priorities and the lens with which we understand long COVID." For example, reproductive health issues for women, such as puberty, pregnancy, and menopause, can alter the course of illness in a subset of women in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and postural orthostatic tachycardia syndrome (POTS), a condition that can cause dizziness and worse. "This suggests that sex hormones may play key roles in immune responses to infections," Pollack said.
ME/CFS and a Possible Link to Long COVID in Women
Some of the research into long COVID is being led by teams studying infection-associated chronic illnesses like ME/CFS.
The problem: Advocates say ME/CFS has been under-researched. Poorly understood for years, the condition is one of a handful of chronic illnesses linked to infections, including Lyme disease and now long COVID. Perhaps not coincidently, they are more likely to affect women. Many of the research findings about long COVID mirror data that emerged in past ME/CFS research, said Jaime Seltzer, the scientific director at #MEAction, Santa Monica, California, an advocacy group. One point in particular: ME/CFS strikes women about twice as much as men, according to the CDC.
Seltzer said the response to long COVID could be much further ahead if the research community acknowledged the work done over the years on ME/CFS. Many of the potential biomarkers and risk factors emerging for long COVID were also suspected in ME/CFS, but not thoroughly studied, she said. She also said not enough work has been done to unravel the links between gender and these chronic conditions. "We're stuck in this Groundhog Day situation," she said. "There isn't any research, so we can't say anything definitively."
Some New Research, Some New Clues
Scientists like Pollack are slowly making inroads. She was lead author on a 2023 review investigating the impact of long COVID on female reproductive health. The paper highlights long COVID links to ME/CFS, POTS, and Ehlers-Danlos syndrome (EDS), as well as a resulting laundry list of female reproductive health issues. The hope is physicians will examine how the menstrual cycle, pregnancy, and menopause affect symptoms and illness progression of long COVID.
The Tal Research group at MIT (where Pollack works) has also added long COVID to the list of infection-associated illnesses it studies. The lab is conducting a large study looking into both Lyme disease and long COVID. The goals are to identify biomarkers that can predict who will not recover and to advance available treatments. Another MIT program, "SEXX + Immunity" holds seminars and networking sessions for scientists looking into the role of female and male biology in immune responses to infection.
Barriers to Progress Remain
On the clinical side, female patients with long COVID also have to deal with a historical bias that still lurks in medicine when it comes to women's health, said Alba Azola, MD, an assistant professor of physical medicine at Johns Hopkins Medicine, Baltimore, Maryland. Azola said she has discovered clinical descriptions of ME/CFE in the literature archives that describe it as "neurasthenia" and dismiss it as psychological. Patients say that it is still happening, and while it may not be so blunt, "you can read between the lines," Azola said. Azola, who has worked with long-COVID patients and is now seeing people with ME/CFS, said the symptoms of infection-associated chronic illness can mimic menopause, and many of her patients received that misdiagnosis. She recommends that doctors rule out long COVID for women with multiple symptoms before attributing symptoms to menopause.
Seeing that some long-COVID patients were developing ME/CFS, staff at the Bateman Horne Center in Salt Lake City, Utah, set up a program for the condition in 2021. They were already treating patients with ME/CFS and what they call "multi-symptom chronic complex diseases." Jennifer Bell, a certified nurse practitioner at the center, said she has not seen any patients with ovarian failure but plenty with reproductive health issues. "There definitely is a hormonal connection, but I don't think there's a good understanding about what is happening," she said. Most of her patients are female, and the more serious patients tend to go through a worsening of their symptoms in the week prior to getting a period, she said. One thing Bell said she's noticed in the past year is an increase in patients with EDS, which is also more common in women.
Like long COVID, many of the conditions traditionally treated at the center have no cure. But Bell said the center has developed an expertise in treating post-exertional malaise, a common symptom of long COVID, and keeps up with the literature for treatments to try, like the combination of guanfacine and the antioxidant N-acetyl cysteine to treat brain fog, an approach developed at Yale. "It's a very challenging illness to treat," Bell said.
Since the emergence of long COVID, researchers have warned that symptoms vary so much from person to person that treatment will need to be targeted. Pollack of MIT agrees and sees a big role for personalized medicine. We need to "identify phenotypes within and across these overlapping and co-occurring illnesses so that we can identify the right therapeutics for each person," she said.
As for Annette Gillaspie, she still hopes her long COVID will subside so she can get out from behind the desk and return to her normal nursing duties. "I just got to a point where I realized I'm likely never going to be able to do my job," she said. "It was incredibly heart breaking, but it's the reality of long COVID, and I know I'm not the only one to have to step away from a job I loved."
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Medicina (Kaunas). 2023 May; 59(5): 978.
Published online 2023 May 18. doi: 10.3390/medicina59050978PMCID: PMC10224216
PMID: 37241210
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Comorbidities: Linked by Vascular Pathomechanisms and Vasoactive Mediators?
Klaus J. Wirth and Matthias Löhn* Modra Murovska, Academic Editor
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is often associated with various other syndromes or conditions including mast cell activation (MCA), dysmenorrhea and endometriosis, postural tachycardia (POTS) and small fiber neuropathy (SFN). The causes of these syndromes and the reason for their frequent association are not yet fully understood. We previously published a comprehensive hypothesis of the ME/CFS pathophysiology that explains the majority of symptoms, findings and chronicity of the disease. We wondered whether some of the identified key pathomechanisms in ME/CFS are also operative in MCA, endometriosis and dysmenorrhea, POTS, decreased cerebral blood flow and SFN, and possibly may provide clues on their causes and frequent co-occurrence. Our analysis indeed provides strong arguments in favor of this assumption, and we conclude that the main pathomechanisms responsible for this association are excessive generation and spillover into the systemic circulation of inflammatory and vasoactive tissue mediators, dysfunctional β2AdR, and the mutual triggering of symptomatology and disease initiation. Overall, vascular dysfunction appears to be a strong common denominator in these linkages.
Keywords: ME/CFS, long COVID, MCA, endometriosis, dysmenorrhea, orthostatic intolerance, small fiber neuropathy, cerebral blood flow, brain fog, β2-adrenergic receptors
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New Evidence Suggests Long COVID Could Be a Brain InjurySara Novak February 08, 2024 Medscape Medical News
Brain fog is one of the most common, persistent complaints in patients with long COVID. It affects as many as 46% of patients who also deal with other cognitive concerns like memory loss and difficulty concentrating.
Now, researchers believe they know why. A new study has found that these symptoms may be the result of a viral-borne brain injury that may cause cognitive and mental health issues that persist for years.
Researchers found that 351 patients hospitalized with severe COVID-19 had evidence of a long-term brain injury a year after contracting the SARS-CoV-2 virus. The findings were based on a series of cognitive tests, self-reported symptoms, brain scans, and biomarkers.
Brain Deficits Equal to 20 Years of Brain AgingAs part of the preprint study, participants took a cognition test with their scores age-matched to those who had not suffered a serious bout of COVID-19. Then a blood sample was taken to look for specific biomarkers, showing that elevated levels of certain biomarkers were consistent with a brain injury. Using brain scans, researchers also found that certain regions of the brain associated with attention were reduced in volume.
Patients who participated in the study were "less accurate and slower" in their cognition, and suffered from at least one mental health condition, such as depression, anxiety, or posttraumatic stress disorder, according to researchers.
The brain deficits found in COVID-19 patients were equivalent to 20 years of brain aging and provided proof of what doctors have feared: that this virus can damage the brain and result in ongoing mental health issues.
"We found global deficits across cognition," said lead study author Benedict Michael, PhD, director of the Infection Neuroscience Lab at the University of Liverpool in Liverpool, England. "The cognitive and memory problems that patients complained of were associated with neuroanatomical changes to the brain."
Proof That Symptoms Aren't 'Figment' of Patients' ImaginationsCognitive deficits were common among all patients, but the researchers said they don't yet know whether the brain damage causes permanent cognitive decline. But the research provides patients who have been overlooked by some clinicians with proof that their conditions aren't a figment of their imaginations, said Karla L. Thompson, PhD, lead neuropsychologist at the University of North Carolina School of Medicine's COVID Recovery Clinic.
"Even though we're several years into this pandemic, there are still a lot of providers who don't believe that their patients are experiencing these residual symptoms," said Thompson, "That's why the use of biomarkers is important, because it provides an objective indication that the brain has been compromised in some way."
Some patients with long COVID have said that getting their doctors to believe they have a physical ailment has been a persistent problem throughout the pandemic and especially as it relates to the sometimes-vague collection of symptoms associated with brain fog. One study found that as many as 79% of study respondents reported negative interactions with their healthcare providers when they sought treatment for their long-COVID symptoms.
How Do COVID-Related Brain Injuries Happen?Researchers are unsure what's causing these brain injuries, though they have identified some clues. Previous research has suggested that such injuries might be the result of a lack of oxygen to the brain, especially in patients who were hospitalized, like those in this study, and were put on ventilators.
Brain scans have previously shown atrophy to the brain's gray matter in COVID-19 patients, likely caused by inflammation from a heightened immune response rather than the virus itself. This inflammatory response seems to affect the central nervous system. As part of the new study, researchers found some neuroprotective effects of using steroids during hospitalization to reduce brain inflammation.
The results suggest that clinicians should overcome their skepticism and consider the possibility that their patients have suffered a brain injury and should be treated appropriately, said James C. Jackson, PsyD, a neuropsychiatrist at Vanderbilt University School of Medicine. "The old saying is that if it walks like a duck and talks like a duck, it's a duck," said Jackson.
He contends that treatments used for patients who have brain injuries have also been shown to be effective in treating long COVID–related brain fog symptoms. These may include speech, cognitive, and occupational therapy as well as meeting with a neuropsychiatrist for the treatment of related mental health concerns.
A New Path ForwardTreating long-COVID brain fog like a brain injury can help patients get back to some semblance of normalcy, researchers said. "What we're seeing in terms of brain injury biomarkers and differences in brain scans correlates to real-life problems that these patients are dealing with on a daily basis," said Jackson. These include problems at work and in life with multitasking, remembering details, meeting deadlines, synthesizing large amounts of information, and maintaining focus on the task at hand, he said.
There's also a fear that even with treatment, the aging of the brain caused by the virus might have long-term repercussions and that this enduring injury may cause the early onset of dementia and Alzheimer's disease in those who were already vulnerable to it. One study, from the National Institute of Neurological Disorders and Stroke (NINDS), found that in those infected with COVID-19 who already had dementia, the virus "rapidly accelerated structural and functional brain deterioration."
"We already know the role that neuroinflammation plays in the brains of patients with Alzheimer's disease," said Thompson. "If long COVID is involved in prolonged inflammation of the brain, it goes a long way in explaining the mechanism underlying [the study's reported] brain aging."
Still More to LearnIn some ways, this study raises nearly as many questions as it does answers. While it provides concrete evidence around the damage the virus is doing to the brains of patients who contracted severe COVID-19, researchers don't know about the impact on those who had less serious cases of the virus.
For Ziyad Al-Aly, MD, chief of research and development at the Veterans Affairs St. Louis Health Care System, the concern is that some long-COVID patients may be suffering from cognitive deficits that are more subtle but still impacting their daily lives, and that they're not getting the help they need.
What's more, said Al-Aly, it's unclear whether the impacts of the brain damage are permanent or how to stop them from worsening. Researchers and clinicians need a better understanding of the mechanism that allows this virus to enter the brain and do structural damage. If it's inflammation, will anti-inflammatory or antiviral medications work at preventing it? Will steroids help to offset the damage? "It's critical we find some answers," he said.
"SARS-CoV-2 isn't going anywhere. It will continue to infect the population, so if this is indeed a virus that damages the brain in the long term or permanently, we need to figure out what can be done to stop it," said Al-Aly.
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Infectious Diseases February 14, 2024
Cognitive Symptoms of Post–COVID-19 Condition and Daily FunctioningAbhishek Jaywant, PhD1; Faith M. Gunning, PhD1; Lauren E. Oberlin, PhD1; et alMauricio Santillana, PhD2,3; Katherine Ognyanova, PhD4; James N. Druckman, PhD5; Matthew A. Baum, PhD6; David Lazer, PhD7,8,9,10; Roy H. Perlis, MD, MSc11,12
JAMA Netw Open. 2024;7(2):e2356098. doi:10.1001/jamanetworkopen.2023.56098
Key Points
Question How are post–COVID-19 condition self-reported cognitive symptoms associated with employment status, functional outcomes, and mood?
Findings In this survey study including 14 767 individuals with post–COVID-19 condition surveyed in late 2022 to early 2023, 57% reported experiencing cognitive symptoms daily, compared with 27% with prior SARS-CoV-2 infection who did not develop post–COVID-19 condition. In those with post–COVID-19 condition, cognitive symptoms were associated with greater levels of depressive symptoms, greater reported functional impairment, and lesser likelihood of full-time employment.
Meaning The findings of this study suggest that self-reported cognitive symptoms are prevalent in post–COVID-19 condition, often co-occur with depressive symptoms, and are associated with functional impairment.
Abstract
Importance The frequent occurrence of cognitive symptoms in post–COVID-19 condition has been described, but the nature of these symptoms and their demographic and functional factors are not well characterized in generalizable populations.
Objective To investigate the prevalence of self-reported cognitive symptoms in post–COVID-19 condition, in comparison with individuals with prior acute SARS-CoV-2 infection who did not develop post–COVID-19 condition, and their association with other individual features, including depressive symptoms and functional status.
Design, Setting, and Participants Two waves of a 50-state nonprobability population-based internet survey conducted between December 22, 2022, and May 5, 2023. Participants included survey respondents aged 18 years and older.
Exposure Post–COVID-19 condition, defined as self-report of symptoms attributed to COVID-19 beyond 2 months after the initial month of illness.
Main Outcomes and Measures Seven items from the Neuro-QoL cognition battery assessing the frequency of cognitive symptoms in the past week and patient Health Questionnaire-9.
Results The 14 767 individuals reporting test-confirmed COVID-19 illness at least 2 months before the survey had a mean (SD) age of 44.6 (16.3) years; 568 (3.8%) were Asian, 1484 (10.0%) were Black, 1408 (9.5%) were Hispanic, and 10 811 (73.2%) were White. A total of 10 037 respondents (68.0%) were women and 4730 (32.0%) were men. Of the 1683 individuals reporting post–COVID-19 condition, 955 (56.7%) reported at least 1 cognitive symptom experienced daily, compared with 3552 of 13 084 (27.1%) of those who did not report post–COVID-19 condition. More daily cognitive symptoms were associated with a greater likelihood of reporting at least moderate interference with functioning (unadjusted odds ratio [OR], 1.31 [95% CI, 1.25-1.36]; adjusted [AOR], 1.30 [95% CI, 1.25-1.36]), lesser likelihood of full-time employment (unadjusted OR, 0.95 [95% CI, 0.91-0.99]; AOR, 0.92 [95% CI, 0.88-0.96]) and greater severity of depressive symptoms (unadjusted coefficient, 1.40 [95% CI, 1.29-1.51]; adjusted coefficient 1.27 [95% CI, 1.17-1.38). After including depressive symptoms in regression models, associations were also found between cognitive symptoms and at least moderate interference with everyday functioning (AOR, 1.27 [95% CI, 1.21-1.33]) and between cognitive symptoms and lower odds of full-time employment (AOR, 0.92 [95% CI, 0.88-0.97]).
Conclusions and Relevance The findings of this survey study of US adults suggest that cognitive symptoms are common among individuals with post–COVID-19 condition and associated with greater self-reported functional impairment, lesser likelihood of full-time employment, and greater depressive symptom severity. Screening for and addressing cognitive symptoms is an important component of the public health response to post–COVID-19 condition.
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Original Investigation March 23, 2023
Risk Factors Associated With Post−COVID-19 ConditionA Systematic Review and Meta-analysisVasiliki Tsampasian, MD, MSc1,2; Hussein Elghazaly, MBBS3; Rahul Chattopadhyay, MBBS, MSc1,4; et alMaciej Debski, MD, PhD1,2; Thin Kyi Phyu Naing, MBBS1,2; Pankaj Garg, PhD1,2; Allan Clark, PhD2; Eleana Ntatsaki, MD(Res), MA5,6; Vassilios S. Vassiliou, MBBS, PhD1,2
JAMA Intern Med. 2023;183(6):566-580. doi:10.1001/jamainternmed.2023.0750
COVID-19 Resource Center
Key Points
Question Which individuals are at risk of developing post−COVID-19 condition (PCC)?
Findings This systematic review and meta-analysis of 41 studies including 860 783 patients found that female sex, older age, higher body mass index, smoking, preexisting comorbidities, and previous hospitalization or ICU admission were risk factors significantly associated with developing PCC, and that SARS-CoV-2 vaccination with 2 doses was associated with lower risk of PCC.
Meanings The findings of this systematic review and meta-analysis provide a profile of the characteristics associated with increased risk of developing PCC and suggest that vaccination may be protective against PCC.
Abstract
Importance Post−COVID-19 condition (PCC) is a complex heterogeneous disorder that has affected the lives of millions of people globally. Identification of potential risk factors to better understand who is at risk of developing PCC is important because it would allow for early and appropriate clinical support.
Objective To evaluate the demographic characteristics and comorbidities that have been found to be associated with an increased risk of developing PCC.
Data sources Medline and Embase databases were systematically searched from inception to December 5, 2022.
Study Selection The meta-analysis included all published studies that investigated the risk factors and/or predictors of PCC in adult (≥18 years) patients.
Data Extraction and Synthesis Odds ratios (ORs) for each risk factor were pooled from the selected studies. For each potential risk factor, the random-effects model was used to compare the risk of developing PCC between individuals with and without the risk factor. Data analyses were performed from December 5, 2022, to February 10, 2023.
Main Outcomes and Measures The risk factors for PCC included patient age; sex; body mass index, calculated as weight in kilograms divided by height in meters squared; smoking status; comorbidities, including anxiety and/or depression, asthma, chronic kidney disease, chronic obstructive pulmonary disease, diabetes, immunosuppression, and ischemic heart disease; previous hospitalization or ICU (intensive care unit) admission with COVID-19; and previous vaccination against COVID-19.
Results The initial search yielded 5334 records of which 255 articles underwent full-text evaluation, which identified 41 articles and a total of 860 783 patients that were included. The findings of the meta-analysis showed that female sex (OR, 1.56; 95% CI, 1.41-1.73), age (OR, 1.21; 95% CI, 1.11-1.33), high BMI (OR, 1.15; 95% CI, 1.08-1.23), and smoking (OR, 1.10; 95% CI, 1.07-1.13) were associated with an increased risk of developing PCC. In addition, the presence of comorbidities and previous hospitalization or ICU admission were found to be associated with high risk of PCC (OR, 2.48; 95% CI, 1.97-3.13 and OR, 2.37; 95% CI, 2.18-2.56, respectively). Patients who had been vaccinated against COVID-19 with 2 doses had a significantly lower risk of developing PCC compared with patients who were not vaccinated (OR, 0.57; 95% CI, 0.43-0.76).
Conclusions and Relevance This systematic review and meta-analysis demonstrated that certain demographic characteristics (eg, age and sex), comorbidities, and severe COVID-19 were associated with an increased risk of PCC, whereas vaccination had a protective role against developing PCC sequelae. These findings may enable a better understanding of who may develop PCC and provide additional evidence for the benefits of vaccination.
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Opinion: Toward Solving the Long COVID PuzzleEric Topol February 23, 2024 Medscape medical news
The following first appeared in the Substack of Eric Topol, MD, called Ground Truths.
In recent days, there were several important new reports that help explain the pathophysiology of long COVID. By coincidence, we published a Perspective in Science today to summarize the progress that has been made and the vital work that lies ahead.
Here, we'll summarize the new findings:
The Leaky Blood-Brain BarrierA systematic study of people with long COVID and controls, using MRI, brain-specific S100β protein, RNA-seq of white blood cells, endothelial cell response in culture provided new insights about the disrupted blood-brain barrier (BBB) in individuals with long COVID and symptoms of brain fog. They are well summarized by Prof Katerina Akassoglou from the Gladstone Institutes, who was not involved in the study and is a highly regarded scientist in the field of neurovascular inflammation: "This study is the first report of BBB disruption correlating with brain fog in patients with long COVID by dynamic contrast enhanced MRI. The MRI findings are in line with neuropathology reporting blood protein accumulation in brains from patients with COVID-19, and I expect that it will be the foundation for future studies at the blood–brain and immune interface for the discovery of mechanisms, biomarkers and therapies for neurological manifestations in long COVID."
The numbers of participants in each group was small, but the phenotyping was extraordinarily deep. Beyond the BBB, the notable findings were dysregulation of the clotting system and pro-inflammatory effects of endothelial cells.
Persistent Infections of SARS-CoV-2 as a Risk FactorFrom a large community surveillance project in the UK, 381 participants were found to have evidence of persistent infections of SARS-CoV-2 for 30 days or more. That was considerably higher than anticipated.
One percent to 3% had persistent infections for more than 30 days. In addition, 0.1%-0.5% had persistent infections for more than 60 days.
Serial assessment of viral loads indicated many of the people had rebounding high levels, indicating that there was likely actively replicating virus.
The risk for long COVID was increased by 55% in people with 12 weeks or more of persistent infection and by 24% in those with infection for 26 weeks or more.
Interferon Gamma as a Possible Biomarker for Diagnosis and TreatmentA new report assayed interferon gamma, part of the first line of defense of innate immunity to a SARS-CoV-2 infection. Individuals with long COVID had persistent elevation after the acute phase, and during follow-up serial assessment of this biomarker showed resolution among the participants with symptom resolution. This will need further assessment, but if replicated and extended, it might fulfill a major unmet need for both confirmation of diagnosis and a surrogate measure for treatments that are being assessed in prospective clinical trials, no less an objective metric for correlation with symptoms.
Myalgic Encephalomyelitis (ME/CFS) Deep PhenotypingThe 8-year, long-awaited NIH project results were published in a 70-page manuscript. Like the BBB study above, the number of participants studies was small but compensated by extensive characterization and suitable matched controls. With the considerable overlap of many of the symptoms of ME/CFS and long COVID, the results are notable: signs of persistent chronic antigen stimulation with immune system dysregulation (with T-cell exhaustion) along with multisystem disruption, some of which is central nervous system regulated, with specific regions of the brain implicated.
On a related note, The Economist had an article about postinfectious neurologic syndrome that occurs with COVID, ME/CFS, Lyme disease, and several other viruses. "Michelle Monje, a neuro-oncologist at Stanford School of Medicine, homed in on precisely how COVID-induced neurological damage might occur — particularly focusing on glial cells, as brain cells other than neurons are known."
Prof Monje has just recorded a new Ground Truths podcast on this topic, which will be posted very soon.
Two New Reports of Vaccination Protection vs Long COVIDFrom a study in the Annals of Epidemiology, Michiganders derived an important protective benefit against long COVID: Long COVID prevalence was 40%-60% lower among adults vaccinated (vs unvaccinated) prior to their COVID-19. This level of protection is consistent with many recent reports and has not been emphasized enough regarding an added benefit of booster shots. The data were previously reviewed on Ground Truths here.
And a new preprint report on protection in children and adolescents looked at different variants (Delta and Omicron) and cause and effect relationship for direct benefit of vaccination. More protection was found in teens than children, with the range of 60%-75%.
Our Science PerspectiveAnd finally, our essay in Science, in which we tried to encapsulate a lot of information on what has been learned so far and what is desperately needed to be done now. Ziyad Al-Aly put together a great thread that reviews the key points.
A Brief SummaryWe're making considerable headway on understanding what drives long COVID, along with the possibility of another biomarker candidate, which would be a big help as randomized clinical trials move forward. Clearly finding effective and safe treatments is an urgent matter and not enough is being done to pursue that yet, despite a long list of potential alluring interventions based on mechanistic insights. Hopefully that will get going now — it cannot happen soon enough.
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Study IDs Immune Abnormality Possibly Causing Long COVIDTinker Ready February 22, 2024 - Medscape
Swiss scientists have identified immune system abnormalities in patients with long COVID that might open the door to new diagnostic tests and treatments.
The researchers found that a group of proteins in the blood that are part of the body's immune response called the "complement system" are not working properly in patients with long COVID.
Blood samples turned up important differences between those who recovered from COVID and those who did not. These differences might be used as biomarkers to diagnose long COVID and might even point the way to new treatments for the condition, the researchers said.
By testing for 6500 blood proteins in about 300 patients, the Swiss researchers found that dysfunctional complement system proteins could possibly explain fatigue and "smoldering inflammation," said Onur Boyman, MD, a professor of immunology from University Hospital Zurich in Zurich, Switzerland.
Long COVID has been linked to hundreds of symptoms including brain fog, chronic fatigue, pain, and digestive issues. Various factors drive the condition and likely work with one another other, said David Putrino, PhD, from the Icahn School of Medicine at Mount Sinai in New York City. The Swiss study is useful because "we're trying to best understand how we can explain all of this far-reaching pathobiology," he said.
Testing Across ContinentsBoyman's team collected blood samples from people with COVID in Europe and New York and tracked them. They compared those who developed long COVID with those who did not. One protein that was most unique to patients with long COVID is a blood complement that activates the immune system, Boyman said. But in people with long COVID, the immune response stays activated after the virus is gone. He described the response as "smoldering inflammation" in multiple organs, including the lungs and the gastrointestinal system.
The complement system also plays a role in clearing the body of dead cells. If the cells "lie around too much," they can trigger an immune response, he said.
That may explain exercise intolerance in people with long COVID, Boyman said. Some people with long COVID have inflammation in the epithelium — the inner layer of their blood vessels. This would make it harder for the circulatory systems to recover from exercise, Boyman said.
"We think this regulated complement system is actually quite a central piece of the puzzle," he said.
The Microclot ConnectionThe findings also support past research linking blood clots to long COVID. He suggested that clinicians and researchers consider testing drugs that regulate or inhibit the complementary system as a treatment of long COVID. Boyman said they are currently used for rare immune diseases.
Resia Pretorius, PhD, a professor of physiological sciences at Stellenbosch University in Stellenbosch, South Africa, said scientists studying the role of microclots in patients with long COVID often see complementary proteins inside the clots, so it has already been associated with long COVID. But she likened this clotting process to a garbage can that "just rolls along and collects everything that gets in its way. I think they are actively driving inflammation and disease."
One factor complicating long COVID diagnosis and treatment is that it is a complex condition that involves multiple organ systems. That's why the latest research suggests an underlying driver for the multiple symptoms of long COVID, Putrino said.
"Not every person has every symptom; not every person has every organ system affected," Putrino said. "Whatever is happening is decided across the whole body."
Research Offers New DirectionThe Swiss paper contributes to the effort to identify systemic issues contributing to long COVID. It gives researchers one more thing to test for and link to specific, long COVID symptoms, opening the door to new treatments, Putrino said.
He doesn't think the study supports treating the complement dysfunction if researchers don't know what's driving it. It may be complicated by the body's failure to clear the virus completely, he said.
Pretorius recommended doctors test patients with long COVID for specific symptoms that may be treated using existing therapies. "If you think your patient had vascular pathology, you can test for it," she said.
Some patients have found certain supplements and over-the-counter products helpful, she said. Among them: Coenzyme Q 10 and clot-busters such as streptokinase and Nattokinase (though she noted some doctors may not be comfortable with supplements).
"It's the only thing we have until we've got trials," she said.
Putrino said more research is needed to identify potential root causes and symptoms. A common refrain, but the only thing that will lead to specific treatments.
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Worsening Symptoms Is Associated with Larger Cerebral Blood Flow Abnormalities during Tilt-Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
C. (Linda) M. C. van Campen 1,* , Peter C. Rowe 2 and Frans C. Visser
Abstract:
Background and Objectives: During tilt testing, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients experience an abnormal reduction in cerebral blood flow (CBF). The relationship between this CBF reduction and symptom severity has not been examined in detail. Our hypothesis was that ME/CFS severity is related to the degree of the CBF reduction during tilt testing.
Materials and Methods:
First, from our database, we selected ME/CFS patients who had undergone assessments of ME/CFS symptomatology and tilt tests on the same day, one at the first visit and the second during a follow-up. The change in symptomatology was related to the change in CBF during the tilt test.
Second, we combined the data of two previously published studies (n = 219), where disease severity as defined by the 2011 international consensus criteria (ICC) was available but not published.
Results: 71 patients were retested because of worsening symptoms. The ICC disease severity distribution (mild-moderate-severe) changed from 51/45/4% at visit-1 to 1/72/27% at follow-up (p < 0.0001). The %CBF reduction changed from initially 19% to 31% at followup (p < 0.0001). Of 39 patients with stable disease, the severity distribution was similar at visit-1 (36/51/13%) and at follow-up (33/49/18%), p = ns. The %CBF reduction remained unchanged: both 24%, p = ns. The combined data of the two previously published studies showed that patients with mild, moderate, and severe disease had %CBF reductions of 25, 29, and 33%, respectively (p < 0.0001).
Conclusions: Disease severity and %CBF reduction during tilt testing are highly associated in ME/CFS: a more severe disease is related to a larger %CBF reduction. The data suggest a causal relationship where a larger CBF reduction leads to worsening symptoms.
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Scientific Reports volume 13, Article number: 20230 (2023)
AbstractPost-acute COVID-19 (PACS) are associated with cardiovascular dysfunction, especially postural orthostatic tachycardia syndrome (POTS). Patients with PACS, both in the absence or presence of POTS, exhibit a wide range of persisting symptoms long after the acute infection. Some of these symptoms may stem from alterations in cardiovascular homeostasis, but the exact mechanisms are poorly understood. The aim of this study was to provide a broad molecular characterization of patients with PACS with (PACS + POTS) and without (PACS-POTS) POTS compared to healthy subjects, including a broad proteomic characterization with a focus on plasma cardiometabolic proteins, quantification of cytokines/chemokines and determination of plasma sphingolipid levels. Twenty-one healthy subjects without a prior COVID-19 infection (mean age 43 years, 95% females), 20 non-hospitalized patients with PACS + POTS (mean age 39 years, 95% females) and 22 non-hospitalized patients with PACS-POTS (mean age 44 years, 100% females) were studied. PACS patients were non-hospitalized and recruited ≈18 months after the acute infection. Cardiometabolic proteomic analyses revealed a dysregulation of ≈200 out of 700 analyzed proteins in both PACS groups vs. healthy subjects with the majority (> 90%) being upregulated. There was a large overlap (> 90%) with no major differences between the PACS groups. Gene ontology enrichment analysis revealed alterations in hemostasis/coagulation, metabolism, immune responses, and angiogenesis in PACS vs. healthy controls. Furthermore, 11 out of 33 cytokines/chemokines were significantly upregulated both in PACS + POTS and PACS-POTS vs. healthy controls and none of the cytokines were downregulated. There were no differences in between the PACS groups in the cytokine levels. Lastly, 16 and 19 out of 88 sphingolipids were significantly dysregulated in PACS + POTS and PACS-POTS, respectively, compared to controls with no differences between the groups. Collectively, these observations suggest a clear and distinct dysregulation in the proteome, cytokines/chemokines, and sphingolipid levels in PACS patients compared to healthy subjects without any clear signature associated with POTS. This enhances our understanding and might pave the way for future experimental and clinical investigations to elucidate and/or target resolution of inflammation and micro-clots and restore the hemostasis and immunity in PACS.
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Catalytic Antibodies May Contribute to Demyelination in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Cite this: Biochemistry 2024, 63, 1, 9–18 Publication Date:November 27, 2023
https://doi.org/10.1021/acs.biochem.3c00433
Copyright © 2023 The Authors. Published by American Chemical Society. This publication is licensed under
CC-BY-NC-ND 4.0.
PDF (5 MB)
Abstract
Here we report preliminary data demonstrating that some patients with myalgic encephalomyelitis/chronic fatiguesyndrome (ME/CFS) may have catalytic autoantibodies that cause the breakdown of myelin basic protein (MBP). We propose that these MBP-degradative antibodies are important to the pathophysiology of ME/CFS, particularly in the occurrence of white matter disease/demyelination. This is supported by magnetic resonance imagining studies that show these findings in patients with ME/CFS and could explain symptoms of nerve pain and muscle weakness. In this work, we performed a series of experiments on patient plasma samples where we isolated and characterized substrate-specific antibodies that digest MBP. We also tested glatiramer acetate (copaxone), an FDA approved immunomodulator to treat multiple sclerosis, and found that it inhibits ME/CFS antibody digestion of MBP. Furthermore, we found that aprotinin, which is a specific serine protease inhibitor, specifically prevents breakdown of MBP while the other classes of protease inhibitors had no effect. This coincides with the published literature describing catalytic antibodies as having serine protease-like activity. Postpandemic research has also provided several reports of demyelination in COVID-19. Because COVID-19 has been described as a trigger for ME/CFS, demyelination could play a bigger role in patient symptoms for those recently diagnosed with ME/CFS. Therefore, by studying proteolytic antibodies in ME/CFS, their target substrates, and inhibitors, a new mechanism of action could lead to better treatment and a possible cure for the disease.
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Persistent complement dysregulation with signs of thromboinflammation in active Long CovidCARLO CERVIA-HASLER HTTPS://ORCID.ORG/0000-0001-7120-8739, SARAH C. BRÜNINGK HTTPS://ORCID.ORG/0000-0003-3176-1032, TOBIAS HOCH HTTPS://ORCID.ORG/0000-0003-0319-6064, BOWEN FAN, GIULIA MUZIO HTTPS://ORCID.ORG/0000-0001-5999-2030, RYAN C. THOMPSON HTTPS://ORCID.ORG/0000-0002-0450-8181, LAURA CEGLAREK HTTPS://ORCID.ORG/0009-0005-7117-0335, ROMAN MELEDIN HTTPS://ORCID.ORG/0000-0001-6921-825X, PATRICK WESTERMANN HTTPS://ORCID.ORG/0000-0003-2894-6140, [...], AND ONUR BOYMAN HTTPS://ORCID.ORG/0000-0001-8279-5545 +18
SCIENCE 19 Jan 2024 Vol 383, Issue 6680 DOI: 10.1126/science.adg7942
Editor’s summarySome individuals can endure persistent, debilitating symptoms for many months after an initial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, the factors underpinning these health issues, called Long Covid, are poorly understood. Comparing the blood of patients with confirmed SARS-CoV-2 infection with that of uninfected controls, Cervia-Hasler et al. found that patients experiencing Long COVID exhibited changes to blood serum proteins indicating activation of the immune system’s complement cascade, altered coagulation, and tissue injury (see the Perspective by Ruf). At the cellular level, Long Covid was linked to aggregates comprising monocytes and platelets. These findings provide a resource of potential biomarkers for diagnosis and may inform directions for treatments. —Sarah H. Ross
Structured AbstractINTRODUCTIONAcute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes various clinical phenotypes, ranging from asymptomatic to life-threatening COVID-19. About 5% of all infected individuals do not recover from acute disease but develop long-term complications, called Long Covid. Current hypotheses on factors contributing to Long Covid include tissue damage, viral reservoirs, autoimmunity, and persistent inflammation. There are currently no diagnostic tests or therapeutic solutions for affected patients.
RATIONALEWe followed 39 healthy controls and 113 COVID-19 patients for up to 1 year after initial confirmation of acute SARS-CoV-2 infection to identify biomarkers associated with Long Covid. At 6-month follow-up, 40 patients had Long Covid symptoms. Repeated clinical assessments were paired with blood draws, resulting in a total of 268 longitudinal blood samples. We measured >6500 proteins in serum by proteomics. Top candidate biomarkers were identified using computational tools and further evaluated experimentally.
RESULTSLong Covid patients exhibited increased complement activation during acute disease, which also persisted at 6-month follow-up. The complement system is part of the innate immune system and contributes to immunity and homeostasis by targeting pathogens and damaged cells, among other functions. Interestingly, blood complement levels normalized in Long Covid patients recovering before their 6-month follow-up. The complement system can be activated by various triggers, resulting in formation of the terminal complement complex (TCC), made of the complement components C5b-9. These complexes can integrate into cell membranes and induce cell activation or lysis. Long Covid patients showed imbalanced TCC formation, marked by increased soluble C5bC6 complexes and decreased levels of C7-containing TCC formations that can incorporate into cell membranes. This suggested increased membrane insertion of TCCs in Long Covid patients, contributing to tissue damage. Accordingly, Long Covid patients showed elevated tissue injury markers in blood and a thromboinflammatory signature, characterized by markers of endothelial activation, such as von Willebrand factor (vWF), and red blood cell lysis. Low antithrombin III levels in Long Covid patients were accompanied by signs of increased cleavage by thrombin, a driver of TCC formation. Furthermore, Long Covid patients had elevated platelet activation markers and monocyte–platelet aggregates at 6-month follow-up, particularly in cases where Long Covid persisted for 12 months or more. These patients also showed signs of antibody-mediated activation of the classical complement pathway, which was associated with increased anti-CMV (cytomegalovirus, also known as human herpesvirus 5) and anti-EBV (Epstein-Barr virus) immunoglobulin G (IgG) antibody levels.
CONCLUSIONOur data suggest that active Long Covid is accompanied by a blood protein signature marked by increased complement activation and thromboinflammation, including activated platelets and markers of red blood cell lysis. Tissue injury may also be complement-mediated and, in turn, activate the complement system. Moreover, complement activation may be driven by antigen–antibody complexes, involving autoantibodies and antibodies against herpesviruses, as well as cross-talk with a dysregulated coagulation system. In addition to offering a basis for new diagnostic solutions, our work provides support for clinical research on complement modulators for patients suffering from Long Covid.
Medscape Medical News Lisa Rapaport January 03, 2024
While COVID has now claimed more than 1 million lives in the United States alone, these aren't the only fatalities caused at least in part by the virus. A small but growing number of Americans are surviving acute infections only to succumb months later to the lingering health problems caused by long COVID.
Much of the attention on long COVID has centered on the sometimes debilitating symptoms that strike people with the condition, with no formal diagnostic tests or standard treatments available, and the effect it has on quality of life. But new figures from the US Centers for Disease Control and Prevention (CDC) show that long COVID can also be deadly.
More than 5000 Americans have died from long COVID since the start of the pandemic, according to new estimates from the CDC.
This total, based on death certificate data collected by the CDC, includes a preliminary tally of 1491 long COVID deaths in 2023 in addition to 3544 fatalities previously reported from January 2020 through June 2022.
Guidance issued in 2023 on how to formally report long COVID as a cause of death on death certificates should help get a more accurate count of these fatalities going forward, said Robert Anderson, PhD, chief mortality statistician for the CDC.
"We hope that the guidance will help cause of death certifiers be more aware of the impact of long COVID and more likely to report long COVID as a cause of death when appropriate," Anderson said. "That said, we do not expect that this guidance will have a dramatic impact on the trend."
There's no standard definition or diagnostic test for long COVID. It's typically diagnosed when people have symptoms at least 3 months after an acute infection that weren't present before they got sick. As of the end of last year, about 7% of American adults had experienced long COVID at some point, the CDC estimated in September 2023.
The new death tally indicates long COVID remains a significant public health threat and is likely to grow in the years ahead, even though the pandemic may no longer be considered a global health crisis, experts said.
For example, the death certificate figures indicate:
- COVID-19 was the third leading cause of American deaths in 2020 and 2021, and the fourth leading cause of death in the United States in 2023.
- Nearly 1% of the more than one million deaths related to COVID-19 since the start of the pandemic have been attributed to long COVID, according to data released by the CDC.
- The proportion of COVID-related deaths from long COVID peaked in June 2021 at 1.2% and again in April 2022 at 3.8%, according to the CDC. Both of these peaks coincided with periods of declining fatalities from acute infections.
Months and even years after an acute infection, long COVID can contribute to serious and potentially life-threatening conditions that impact nearly every major system in the body, according to the CDC guidelines for identifying the condition on death certificates.
This means long COVID may often be listed as an underlying cause of death when people with this condition die of issues related to their heart, lungs, brain or kidneys, the CDC guidelines noted.
The risk for long COVID fatalities remains elevated for at least 6 months for people with milder acute infections and for at least 2 years in severe cases that require hospitalization, some previous research suggested.
As happens with other acute infections, certain people are more at risk for fatal case of long COVID. Age, race, and ethnicity have all been cited as risk factors by researchers who have been tracking the condition since the start of the pandemic.
Half of long COVID fatalities from July 2021 to June 2022 occurred in people aged 65 years and older, and another 23% were recorded among people aged 50-64 years old, according a report from CDC.
Long COVID death rates also varied by race and ethnicity, from a high of 14.1 cases per million among America Indian and Alaskan natives to a low of 1.5 cases per million among Asian people, the CDC found. Death rates per million were 6.7 for White individuals, 6.4 for Black people, and 4.7 for Hispanic people.
The disproportionate share of Black and Hispanic people who developed and died from severe acute infections may have left fewer survivors to develop long COVID, limiting long COVID fatalities among these groups, the CDC report concluded.
It's also possible that long COVID fatalities were undercounted in these populations because they faced challenges accessing healthcare or seeing providers who could recognize the hallmark symptoms of long COVID.
It's also difficult to distinguish between how many deaths related to the virus ultimately occur as a result of long COVID rather than acute infections. That's because it may depend on a variety of factors, including how consistently medical examiners follow the CDC guidelines, said Ziyad Al-Aly, MD, chief of research at the Veterans Affairs, St. Louis Health Care System and a senior clinical epidemiologist at Washington University in St. Louis.
"Long COVID remains massively underdiagnosed, and death in people with long COVID is misattributed to other things," Al-Aly said.
An accurate test for long COVID could help lead to a more accurate count of these fatalities, Czeisler said. Some preliminary research suggests that it might one day be possible to diagnose long COVID with a blood test.
"The timeline for such a test and the extent to which it would be widely applied is uncertain," Czeisler noted, "though that would certainly be a gamechanger."
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Muscle abnormalities worsen after post-exertional malaise in long COVIDNature Communications volume 15, Article number: 17 (2024
Brent Appelman, · Braeden T. Charlton, · Richie P. Goulding, · Tom J. Kerkhoff, · Ellen A. Breedveld, · Wendy Noort, · Carla Offringa, · Frank W. Bloemers, · Michel van Weeghel, · Bauke V. Schomakers, · Pedro Coelho, · Jelle J. Posthuma, · Eleonora Aronica, · W. Joost Wiersinga, · Michèle van Vugt & · Rob C. I. Wüst
Abstract
A subgroup of patients infected with SARS-CoV-2 remain symptomatic over three months after infection. A distinctive symptom of patients with long COVID is post-exertional malaise, which is associated with a worsening of fatigue- and pain-related symptoms after acute mental or physical exercise, but its underlying pathophysiology is unclear. With this longitudinal case-control study (NCT05225688), we provide new insights into the pathophysiology of post-exertional malaise in patients with long COVID. We show that skeletal muscle structure is associated with a lower exercise capacity in patients, and local and systemic metabolic disturbances, severe exercise-induced myopathy and tissue infiltration of amyloid-containing deposits in skeletal muscles of patients with long COVID worsen after induction of post-exertional malaise. This study highlights novel pathways that help to understand the pathophysiology of post-exertional malaise in patients suffering from long COVID and other post-infectious diseases.
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Exercise Pathophysiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Postacute Sequelae of SARS-CoV-2 - More in Common Than Not?Authors: Joseph P, Singh I, Oliviera R, Capone CA, Mullen MP, Cook DB, … Systrom DM (Harvard Medical School, Boston, USA)
Publication: Chest Journal
Link: https://doi.org/10.1016/j.chest.2023.03.049
The aim of this review was to examine the capacity of invasive and noninvasive cardiopulmonary tests (iCPETs and niCPETs) to assess ME/CFS and post-acute sequelae of COVID-19 (PASC); the commonalities between both conditions, including small fiber neuropathies (SFN), dyspnea, and mitochondrial dysfunction; how symptoms in children differed to adults; and future directions. niCPET studies found that inefficient breathing in ME/CFS patients led to lower peak oxygen uptake (VO2) than in controls. Serial niCPETS (24 hours apart) assessed recovery and PEM, showing further VO2 reduction, lowered levels of exercise tolerance, and earlier anabolic thresholds (AT) in ME/CFS patients. Behavioural and psychological studies found worsened brain function, pain levels, metabolite and immune activity, and further changes to the gut microbiome. Some papers described chronotropic incompetence in both ME/CFS and PASC, but this was not shown in other larger studies.
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Cognitive impairment in post-acute sequelae of COVID-19 and short duration myalgic encephalomyelitis patients is mediated by orthostatic hemodynamic changesAuthors: Day H, Yellman B, Hammer S, Rond C, Bell J, Abbaszadeh S, … Vernon SD (Bateman Horne Centre, United States)
Publication: Frontiers in Neuroscience
Link: https://www.frontiersin.org/articles/10.3389/fnins.2023.1203514/full
Many patients with ME/CFS and post-acute sequelae of COVID-19 (PASC) experience cognitive impairment. This can include trouble with concentration, remembering and decision making. This study sought to determine whether orthostatic haemodynamic changes were associated to cognitive impairment in ME/CFS and PASC.
This study utilised a prospective, observational cohort method, and included 256 participants, in three groups: ME/CFS (140 participants, Institute of Medicine criteria), PASC (34 participants) and healthy controls (82 participants). The ME/CFS group was further divided into two subgroups: illness duration less than four years (71 participants) and illness duration greater than 10 years (69 participants). Participants completed clinical evaluation and assessment, including cognitive efficiency measurements (speed and accuracy of responses). Participants completed a cognitive test before, immediately after, and two and seven days after the orthostatic challenge. The orthostatic challenge was a 10-minute NASA lean test, measuring blood pressure and heart rate, and extrapolating pulse pressure and peripheral perfusion.
The authors found that ME/CFS and PASC participants had significantly lower cognitive efficiency scores immediately after the orthostatic challenge, when compared to healthy controls. In ME/CFS participants with disease duration of greater than 10 years, these scores remained low at two and seven days following the orthostatic challenge. Narrow pulse pressure was observed in PASC and ME/CFS participants, and in PASC participants this was associated with slowed information processing compared to healthy controls. Increased heart rate and decreased procedural reaction was observed during the orthostatic challenge in PASC and some ME/CFS participants with disease duration of less than four years.
PASC participants were seen to experience haemodynamic changes during orthostatic challenge that were associated with slowed reaction time and reduced response accuracy. ME/CFS participants with disease duration of less than 4 years experienced reduced cognitive efficiency associated with elevated heart rate in response to orthostatic challenge. ME/CFS participants with disease duration of greater than 10 years experienced cognitive impairment, but this was not correlated with haemodynamic changes associated with orthostatic challenge. The authors suggest that these findings highlight the necessity of early diagnosis to reduce the impact of haemodynamic and other physiological effects on cognitive impairment symptoms.
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Diagnosis and management of myalgic encephalomyelitis/chronic fatigue syndromeAuthors: Grach SL, Seltzer J, Chon TY, & Ganesh R (Mayo Clinic, United States)
Publication: Mayo Clinic Proceedings
Link: https://www.mayoclinicproceedings.org/article/S0025-6196(23)00402-0/fulltext
There has been an increased interest in ME/CFS as up to 50% of patients with post-COVID syndrome go on to fulfil the criteria for ME/CFS. This review sought to describe a generalist approach to the diagnosis and management of ME/CFS.
Epidemiology/Etiology
· ME/CFS affects all ages, genders, races and socioeconomic backgrounds. Presentation may differ in men compared to women, potentially resulting in underdiagnosis in men.
· Up to 80% of ME/CFS cases are preceded by an infection, most commonly viral, or by multiple smaller events followed by a final trigger causing clear onset.
Diagnosis
· ME/CFS is a diagnosis based on the presence of particular signs and symptoms, not a diagnosis of exclusion. The US Centres for Disease Control and Prevention recommend the 2015 Institute of Medicine ME/CFS diagnostic criteria.
· The lack of diagnostic biomarkers, similarity to other diseases, and reduced clinician awareness of ME/CFS contribute to delayed diagnosis – approximately one third of ME/CFS patients waited at least 5 years for their diagnosis.
· Although ME/CFS is present across a spectrum of mild (approximately 25% of ME/CFS patients), moderate (50%) to severe and very severe (25%), the IOM criteria require a 50% decrease in pre-illness capacity in order to be diagnosed.
Practical considerations in diagnosis
· Patient history: patients often report a wide range of symptoms, it is necessary to determine whether symptoms fulfil the ME/CFS diagnostic criteria. Post-exertional malaise (PEM) is a defining characteristic of ME/CFS.
· Risk factors for ME/CFS: female sex, age 10-19 or 30-39, infection (especially viral), preexisting or family history of autoimmune disease, neurologic or other multisystem chronic disease.
Co-morbidities
· 75-80% of ME/CFS patients report at least one other disease. The most commonly seen co-morbid diseases/disorders include hypermobile Ehlers-Danlos Syndrome, postural orthostatic tachycardia syndrome and other autonomic disorders, and mast cell activation syndrome.
General management
· Managing energy expenditure and avoiding PEM through effective pacing may lead to improvements in functional ability over time and improved quality of life. Identifying the heart rate threshold that triggers PEM and staying below this level may assist self-management.
· Pacing does not involve systematic increases in activity, and is not curative.
· Graded exercise therapy has not been proven to be effective for ME/CFS.
· Pharmacological medications or supplements may assist with symptom management. Patients are often sensitive to medications and may need to be started on a low dose, with gradual increase in dose over time.
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PLoS One . 2022 Mar 15;17(3):e0265315. doi: 10.1371/journal.pone.0265315. eCollection 2022.
Cardiopulmonary, metabolic, and perceptual responses during exercise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Multi-site Clinical Assessment of ME/CFS (MCAM) sub-studyDane B Cook 1 2, Stephanie VanRiper 1 2, Ryan J Dougherty 3, Jacob B Lindheimer 1 2 4, Michael J Falvo 5 6, Yang Chen 7, Jin-Mann S Lin 7, Elizabeth R Unger 7; MCAM Study Group
PMID: 35290404 PMCID: PMC8923458 DOI: 10.1371/journal.pone.0265315
AbstractBackground: Cardiopulmonary exercise testing has demonstrated clinical utility in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). However, to what extent exercise responses are independent of, or confounded by, aerobic fitness remains unclear.
Purpose: To characterize and compare exercise responses in ME/CFS and controls with and without matching for aerobic fitness.
Methods: As part of the Multi-site Clinical Assessment of ME/CFS (MCAM) study, 403 participants (n = 214 ME/CFS; n = 189 controls), across six ME/CFS clinics, completed ramped cycle ergometry to volitional exhaustion. Metabolic, heart rate (HR), and ratings of perceived exertion (RPE) were measured. Ventilatory equivalent ([Formula: see text], [Formula: see text]), metrics of ventilatory efficiency, and chronotropic incompetence (CI) were calculated. Exercise variables were compared using Hedges' g effect size with 95% confidence intervals. Differences in cardiopulmonary and perceptual features during exercise were analyzed using linear mixed effects models with repeated measures for relative exercise intensity (20-100% peak [Formula: see text]). Subgroup analyses were conducted for 198 participants (99 ME/CFS; 99 controls) matched for age (±5 years) and peak [Formula: see text] (~1 ml/kg/min-1).
Results: Ninety percent of tests (n = 194 ME/CFS, n = 169 controls) met standard criteria for peak effort. ME/CFS responses during exercise (20-100% peak [Formula: see text]) were significantly lower for ventilation, breathing frequency, HR, measures of efficiency, and CI and significantly higher for [Formula: see text], [Formula: see text] and RPE (p<0.05adjusted). For the fitness-matched subgroup, differences remained for breathing frequency, [Formula: see text], [Formula: see text], and RPE (p<0.05adjusted), and higher tidal volumes were identified for ME/CFS (p<0.05adjusted). Exercise responses at the gas exchange threshold, peak, and for measures of ventilatory efficiency (e.g., [Formula: see text]) were generally reflective of those seen throughout exercise (i.e., 20-100%).
Conclusion: Compared to fitness-matched controls, cardiopulmonary responses to exercise in ME/CFS are characterized by inefficient exercise ventilation and augmented perception of effort. These data highlight the importance of distinguishing confounding fitness effects to identify responses that may be more specifically associated with ME/CFS.
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Long-term symptom severity and clinical biomarkers in post-COVID-19/chronic fatigue syndrome: results from a prospective observational cohortFranziska Legler h https://doi.org/10.1016/j.eclinm.2023.102146
Summary
BackgroundPost-COVID-19 syndrome (PCS) is characterised by a wide range of symptoms, primarily fatigue and exertion intolerance. While disease courses in the early months post-infection have been well-described, the long-term health consequences for patients with PCS with disabling fatigue remain unclear.
MethodsIn this prospective observational cohort study, we evaluated symptom severity and various biomarkers, including hand grip strength (HGS), cardiovascular function, and laboratory parameters, in 106 patients with PCS with moderate to severe fatigue and exertion intolerance at three time points after infection (3–8, 9–16, and 17–20 months). The study was conducted at the Charité’s Fatigue Centre and the Charité’s outpatient clinic for neuroimmunology at Berlin, Germany from July 16, 2020, to February 18, 2022. A subset of patients (PCS-ME/CFS) met the diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome according to the Canadian Consensus Criteria (CCC). The aim was to determine differences in the disease course between the two patient groups (i.e., PCS vs PCS-ME/CFS) and identify correlating biomarkers.
FindingsPatients with PCS-ME/CFS reported persistently high severity of most symptoms up to 20 months after infection, while patients with PCS showed overall health improvement. Although fatigue and post-exertional malaise (PEM), hallmarks of post-infectious fatigue syndromes, were still evident in both groups, they remained more pronounced in PCS-ME/CFS. Inflammatory biomarkers decreased in both groups, but not antinuclear antibodies. Lower HGS at onset correlated with symptom persistence, particularly in patients with PCS-ME/CFS.
InterpretationOur findings suggest that PCS can persist beyond 20 months post-infection and encompass the full scope of post-infectious ME/CFS as defined by the CCC. Sub-classifying patients with PCS based on the CCC can assist in the management and monitoring of patients with PCS-ME/CFS due to their persistently higher symptom severity.
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Distinguishing features of long COVID identified through immune profilingJon Klein, Jamie Wood, Jillian R. Jaycox, Rahul M. Dhodapkar, Peiwen Lu, Jeff R. Gehlhausen, Alexandra Tabachnikova, Kerrie Greene, Laura Tabacof, Amyn A. Malik, Valter Silva Monteiro, Julio Silva, Kathy Kamath, Abhilash Dhal, Isabel Ott, Gabrielee Valle, Mario Peña-Hernández, Tianyang Mao, Takehiro Takahashi, Carolina Lucas, Eric Song, Dayna McCarthy, Akiko Iwasaki
Nature volume 623, pages139–148 Published: 25 September 2023
Abstract
Post-acute infection syndromes may develop after acute viral disease1. Infection with SARS-CoV-2 can result in the development of a post-acute infection syndrome known as long COVID. Individuals with long COVID frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions2,3,4. However, the biological processes that are associated with the development and persistence of these symptoms are unclear. Here 275 individuals with or without long COVID were enrolled in a cross-sectional study that included multidimensional immune phenotyping and unbiased machine learning methods to identify biological features associated with long COVID. Marked differences were noted in circulating myeloid and lymphocyte populations relative to the matched controls, as well as evidence of exaggerated humoral responses directed against SARS-CoV-2 among participants with long COVID. Furthermore, higher antibody responses directed against non-SARS-CoV-2 viral pathogens were observed among individuals with long COVID, particularly Epstein–Barr virus. Levels of soluble immune mediators and hormones varied among groups, with cortisol levels being lower among participants with long COVID. Integration of immune phenotyping data into unbiased machine learning models identified the key features that are most strongly associated with long COVID status. Collectively, these findings may help to guide future studies into the pathobiology of long COVID and help with developing relevant biomarkers.
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The economic burden of myalgic encephalomyelitis/chronic fatigue syndrome in AustraliaTing Zhao A , Ingrid A. Cox A , Hasnat Ahmad A , Julie A. Campbell A , Martin Hensher A , Andrew J Palmer A , Ryan M. Kelly B , Melissa J. Rogerson B , Karen Wills A and Barbara de Graaff A *
* Correspondence to: [email protected]
Australian Health Review 47(6) 707-715 https://doi.org/10.1071/AH23106
Submitted: 13 July 2023 Accepted: 7 November 2023 Published: 28 November 2023
© 2023 The Author(s) (or their employer(s)). Published by CSIRO Publishing on behalf of AHHA.
Abstract
Objective
This study aimed to estimate costs of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) to patients, government and Australian society.
Methods
Australian ME/CFS patients and their carers were recruited using convenience sampling. Patients completed an online retrospective cost diary, providing ME/CFS-related direct medical, non-medical and indirect costs. Informal care costs were collected directly from carers. Data from the Pharmaceutical Benefits Scheme and Medicare Benefits Schedule were linked to participant survey data. Annual per patient and total societal costs were estimated, broken down by category and presented in 2021 AUD. Factors associated with higher costs were investigated using generalised linear models.
Results
One hundred and seventy five patients (mean age 49 years s.d. 14, 79.4% female) completed the cost diary. Estimated total annual societal costs of ME/CFS in Australia ranged between $1.38 and $10.09 billion, with average annual total costs of $63 400/patient. Three-quarters of these costs were due to indirect costs ($46 731). Disability severity was the key factor associated with higher costs, particularly for indirect costs (being 2.27-fold higher for severe disability than no/mild disability).
Conclusions
ME/CFS poses a significant economic burden in Australia, owing mainly to high indirect and informal care costs.
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Why Are Women More Likely to Get Long COVID?
Tinker Ready January 19, 2024 Medscape
Annette Gillaspie, a nurse in a small Oregon hospital, hoped she would be back working with patients by now. She contracted COVID-19 on the job early in the pandemic and ended up with long COVID.
After recovering a bit, her fatigue and dizziness returned, and today she is still working a desk job. She has also experienced more severe menstrual periods than before she had COVID.
"Being a female with long COVID definitely does add to the roller-coaster effect of symptoms," Gillaspie said.
Long COVID affects nearly twice as many women as men, with 6.6% of women reporting long COVID compared with 4% of men, according to a recent Census Bureau survey reported by the Centers for Disease Control and Prevention (CDC). Researchers are trying to determine why, what causes the gender disparity, and how best to treat it.
Scientists are also starting to look at the impact of long COVID on female reproductive health, including menstruation, pregnancy, and menopause.
Sex differences are common in infection-associated illnesses, said Beth Pollack, a research scientist specializing in long COVID in the Massachusetts Institute of Technology's Department of Biological Engineering, Cambridge, Massachusetts. "It informs research priorities and the lens with which we understand long COVID."
For example, reproductive health issues for women, such as puberty, pregnancy, and menopause, can alter the course of illness in a subset of women in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and postural orthostatic tachycardia syndrome (POTS), a condition that can cause dizziness and worse.
"This suggests that sex hormones may play key roles in immune responses to infections," Pollack said.
ME/CFS and a Possible Link to Long COVID in Women
Some of the research into long COVID is being led by teams studying infection-associated chronic illnesses like ME/CFS.
The problem: Advocates say ME/CFS has been under-researched. Poorly understood for years, the condition is one of a handful of chronic illnesses linked to infections, including Lyme disease and now long COVID. Perhaps not coincidently, they are more likely to affect women.
Many of the research findings about long COVID mirror data that emerged in past ME/CFS research, said Jaime Seltzer, the scientific director at #MEAction, Santa Monica, California, an advocacy group. One point in particular: ME/CFS strikes women about twice as much as men, according to the CDC.
Seltzer said the response to long COVID could be much further ahead if the research community acknowledged the work done over the years on ME/CFS. Many of the potential biomarkers and risk factors emerging for long COVID were also suspected in ME/CFS, but not thoroughly studied, she said.
She also said not enough work has been done to unravel the links between gender and these chronic conditions.
"We're stuck in this Groundhog Day situation," she said. "There isn't any research, so we can't say anything definitively."
Some New Research, Some New Clues
Scientists like Pollack are slowly making inroads. She was lead author on a 2023 review investigating the impact of long COVID on female reproductive health. The paper highlights long COVID links to ME/CFS, POTS, and Ehlers-Danlos syndrome (EDS), as well as a resulting laundry list of female reproductive health issues. The hope is physicians will examine how the menstrual cycle, pregnancy, and menopause affect symptoms and illness progression of long COVID.
The Tal Research group at MIT (where Pollack works) has also added long COVID to the list of infection-associated illnesses it studies. The lab is conducting a large study looking into both Lyme disease and long COVID. The goals are to identify biomarkers that can predict who will not recover and to advance available treatments.
Another MIT program, "SEXX + Immunity" holds seminars and networking sessions for scientists looking into the role of female and male biology in immune responses to infection.
Barriers to Progress Remain
On the clinical side, female patients with long COVID also have to deal with a historical bias that still lurks in medicine when it comes to women's health, said Alba Azola, MD, an assistant professor of physical medicine at Johns Hopkins Medicine, Baltimore, Maryland.
Azola said she has discovered clinical descriptions of ME/CFE in the literature archives that describe it as "neurasthenia" and dismiss it as psychological.
Patients say that it is still happening, and while it may not be so blunt, "you can read between the lines," Azola said.
Azola, who has worked with long-COVID patients and is now seeing people with ME/CFS, said the symptoms of infection-associated chronic illness can mimic menopause, and many of her patients received that misdiagnosis. She recommends that doctors rule out long COVID for women with multiple symptoms before attributing symptoms to menopause.
Seeing that some long-COVID patients were developing ME/CFS, staff at the Bateman Horne Center in Salt Lake City, Utah, set up a program for the condition in 2021. They were already treating patients with ME/CFS and what they call "multi-symptom chronic complex diseases."
Jennifer Bell, a certified nurse practitioner at the center, said she has not seen any patients with ovarian failure but plenty with reproductive health issues.
"There definitely is a hormonal connection, but I don't think there's a good understanding about what is happening," she said.
Most of her patients are female, and the more serious patients tend to go through a worsening of their symptoms in the week prior to getting a period, she said.
One thing Bell said she's noticed in the past year is an increase in patients with EDS, which is also more common in women.
Like long COVID, many of the conditions traditionally treated at the center have no cure. But Bell said the center has developed an expertise in treating post-exertional malaise, a common symptom of long COVID, and keeps up with the literature for treatments to try, like the combination of guanfacine and the antioxidant N-acetyl cysteine to treat brain fog, an approach developed at Yale.
"It's a very challenging illness to treat," Bell said.
Since the emergence of long COVID, researchers have warned that symptoms vary so much from person to person that treatment will need to be targeted.
Pollack of MIT agrees and sees a big role for personalized medicine.
We need to "identify phenotypes within and across these overlapping and co-occurring illnesses so that we can identify the right therapeutics for each person," she said.
As for Annette Gillaspie, she still hopes her long COVID will subside so she can get out from behind the desk and return to her normal nursing duties.
"I just got to a point where I realized I'm likely never going to be able to do my job," she said. "It was incredibly heart breaking, but it's the reality of long COVID, and I know I'm not the only one to have to step away from a job I loved."
Medscape Medical News © 2024 WebMD, LLC
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The effectiveness of COVID-19 vaccines to cohort study of data from the UK, Spain, and EstoniaMartí Català, PhD Núria Mercadé-Besora, BA Raio Kolde, PhD Nhung T H Trinh, PhD Elena Roel, PhDEdward Burn, PhD et al.
Published:January 11, 2024DOI:https://doi.org/10.1016/S2213-2600(23)00414-9
SummaryBackgroundAlthough vaccines have proved effective to prevent severe COVID-19, their effect on preventing long-term symptoms is not yet fully understood. We aimed to evaluate the overall effect of vaccination to prevent long COVID symptoms and assess comparative effectiveness of the most used vaccines (ChAdOx1 and BNT162b2).
MethodsWe conducted a staggered cohort study using primary care records from the UK (Clinical Practice Research Datalink [CPRD] GOLD and AURUM), Catalonia, Spain (Information System for Research in Primary Care [SIDIAP]), and national health insurance claims from Estonia (CORIVA database). All adults who were registered for at least 180 days as of Jan 4, 2021 (the UK), Feb 20, 2021 (Spain), and Jan 28, 2021 (Estonia) comprised the source population. Vaccination status was used as a time-varying exposure, staggered by vaccine rollout period. Vaccinated people were further classified by vaccine brand according to their first dose received. The primary outcome definition of long COVID was defined as having at least one of 25 WHO-listed symptoms between 90 and 365 days after the date of a PCR-positive test or clinical diagnosis of COVID-19, with no history of that symptom 180 days before SARS-Cov-2 infection. Propensity score overlap weighting was applied separately for each cohort to minimise confounding. Sub-distribution hazard ratios (sHRs) were calculated to estimate vaccine effectiveness against long COVID, and empirically calibrated using negative control outcomes. Random effects meta-analyses across staggered cohorts were conducted to pool overall effect estimates.
FindingsA total of 1 618 395 (CPRD GOLD), 5 729 800 (CPRD AURUM), 2 744 821 (SIDIAP), and 77 603 (CORIVA) vaccinated people and 1 640 371 (CPRD GOLD), 5 860 564 (CPRD AURUM), 2 588 518 (SIDIAP), and 302 267 (CORIVA) unvaccinated people were included. Compared with unvaccinated people, overall HRs for long COVID symptoms in people vaccinated with a first dose of any COVID-19 vaccine were 0·54 (95% CI 0·44–0·67) in CPRD GOLD, 0·48 (0·34–0·68) in CPRD AURUM, 0·71 (0·55–0·91) in SIDIAP, and 0·59 (0·40–0·87) in CORIVA. A slightly stronger preventative effect was seen for the first dose of BNT162b2 than for ChAdOx1 (sHR 0·85 [0·60–1·20] in CPRD GOLD and 0·84 [0·74–0·94] in CPRD AURUM).
InterpretationVaccination against COVID-19 consistently reduced the risk of long COVID symptoms, which highlights the importance of vaccination to prevent persistent COVID-19 symptoms, particularly in adults.
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Impact of COVID-19 vaccination on symptoms and immune phenotypes in vaccine-naïve individuals with Long COVID View ORCID ProfileConnor B Grady, Bornali Bhattacharjee, Julio Silva, Jillian Jaycox, Lik Wee Lee, Valter Silva Monteiro, Mitsuaki Sawano, Daisy Massey, César Caraballo, Jeff R. Gehlhausen, Alexandra Tabachnikova, Tianyang Mao, Carolina Lucas, Mario A. Peña-Hernandez, Lan Xu, Tiffany J. Tzeng, Takehiro Takahashi, Jeph Herrin, Diana Berrent Güthe, Athena Akrami, Gina Assaf, Hannah Davis, Karen Harris, Lisa McCorkell, Wade L Schulz, Daniel Grffin, Hannah Wei, Aaron M Ring, Leying Guan, Charles Dela Cruz, Akiko Iwasaki, View ORCID ProfileHarlan M Krumholz
doi: https://doi.org/10.1101/2024.01.11.24300929
This article is a preprint and has not been peer-reviewed It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.
000020126
AbstractBackground Long COVID contributes to the global burden of disease. Proposed root cause hypotheses include the persistence of SARS-CoV-2 viral reservoir, autoimmunity, and reactivation of latent herpesviruses. Patients have reported various changes in Long COVID symptoms after COVID-19 vaccinations, leaving uncertainty about whether vaccine-induced immune responses may alleviate or worsen disease pathology.
Methods In this prospective study, we evaluated changes in symptoms and immune responses after COVID-19 vaccination in 16 vaccine-naïve individuals with Long COVID. Surveys were administered before vaccination and then at 2, 6, and 12 weeks after receiving the first vaccine dose of the primary series. Simultaneously, SARS-CoV-2-reactive TCR enrichment, SARS-CoV-2-specific antibody responses, antibody responses to other viral and self-antigens, and circulating cytokines were quantified before vaccination and at 6 and 12 weeks after vaccination.
Results Self-report at 12 weeks post-vaccination indicated 10 out of 16 participants had improved health, 3 had no change, 1 had worse health, and 2 reported marginal changes. Significant elevation in SARS-CoV-2-specific TCRs and Spike protein-specific IgG were observed 6 and 12 weeks after vaccination. No changes in reactivities were observed against herpes viruses and self-antigens. Within this dataset, higher baseline sIL-6R was associated with symptom improvement, and the two top features associated with non-improvement were high IFN-β and CNTF, among soluble analytes.
Conclusions Our study showed that in this small sample, vaccination improved the health or resulted in no change to the health of most participants, though few experienced worsening. Vaccination was associated with increased SARS-CoV-2 Spike protein-specific IgG and T cell expansion in most individuals with Long COVID. Symptom improvement was observed in those with baseline elevated sIL-6R, while elevated interferon and neuropeptide levels were associated with a lack of improvement.
Plain language summary The impact of the COVID-19 vaccine on vaccine-naïve individuals suffering from Long COVID is uncertain. This study assessed the experience and immune signatures of 16 unvaccinated participants with Long COVID. A total of 10 participants had improved health status after vaccination, and one person reported only worsening health. As expected, vaccination increased immune cells and antibodies against the viral spike protein. Immune signatures may prove to be predictors of health status after vaccination. However, given the small number of participants, these initial findings need further validation.
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Five Bold Predictions for Long COVID in 2024Sara Novak January 25, 2024 Medscape Medical News
With a number of large-scale clinical trials underway and researchers on the hunt for new therapies, long COVID scientists are hopeful that this is the year patients — and doctors who care for them — will finally see improvements in treating their symptoms.
Here are five bold predictions — all based on encouraging research — that could happen in 2024. At the very least, they are promising signs of progress against a debilitating and frustrating disease.
#1: We'll gain a better understanding of each long COVID phenotype
This past year, a wide breadth of research began showing that long COVID can be defined by a number of different disease phenotypes that present a range of symptoms.
Researchers identified four clinical phenotypes: Chronic fatigue-like syndrome, headache, and memory loss; respiratory syndrome, which includes cough and difficulty breathing; chronic pain; and neurosensorial syndrome, which causes an altered sense of taste and smell.
Identifying specific diagnostic criteria for each phenotype would lead to better health outcomes for patients instead of treating them as if it were a "one-size-fits-all disease," said Nisha Viswanathan, MD, director of the long COVID program at UCLA Health, Los Angeles, California.
Ultimately, she hopes that this year her patients will receive treatments based on the type of long COVID they're personally experiencing, and the symptoms they have, leading to improved health outcomes and more rapid relief.
"Many new medications are focused on different pathways of long COVID, and the challenge becomes which drug is the right drug for each treatment," said Viswanathan.
#2: Monoclonal antibodies may change the game
We're starting to have a better understanding that what's been called "viral persistence" as a main cause of long COVID may potentially be treated with monoclonal antibodies. These are antibodies produced by cloning unique white blood cells to target the circulating spike proteins in the blood that hang out in viral reservoirs and cause the immune system to react as if it's still fighting acute COVID-19.
Smaller-scale studies have already shown promising results. A January 2024 study published in The American Journal of Emergency Medicine followed three patients who completely recovered from long COVID after taking monoclonal antibodies. "Remission occurred despite dissimilar past histories, sex, age, and illness duration," wrote the study authors.
Larger clinical trials are underway at the University of California, San Francisco, California, to test targeted monoclonal antibodies. If the results of the larger study show that monoclonal antibodies are beneficial, then it could be a game changer for a large swath of patients around the world, said David F. Putrino, PhD, who runs the long COVID clinic at Mount Sinai Health System in New York City.
"The idea is that the downstream damage caused by viral persistence will resolve itself once you wipe out the virus," said Putrino.
#3: Paxlovid could prove effective for long COVID
The US Food and Drug Administration granted approval for Paxlovid last May for the treatment of mild to moderate COVID-19 in adults at a high risk for severe disease. The medication is made up of two drugs packaged together. The first, nirmatrelvir, works by blocking a key enzyme required for virus replication. The second, ritonavir, is an antiviral that's been used in patients with HIV and helps boost levels of antivirals in the body.
In a large-scale trial headed up by Putrino and his team, the oral antiviral is being studied for use in the post-viral stage in patients who test negative for acute COVID-19 but have persisting symptoms of long COVID.
Similar to monoclonal antibodies, the idea is to quell viral persistence. If patients have long COVID because they can't clear SAR-CoV-2 from their bodies, Paxlovid could help. But unlike monoclonal antibodies that quash the virus, Paxlovid stops the virus from replicating. It's a different mechanism with the same end goal.
It's been a controversial treatment because it's life-changing for some patients and ineffective for others. In addition, it can cause a range of side effects such as diarrhea, nausea, vomiting, and an impaired sense of taste. The goal of the trial is to see which patients with long COVID are most likely to benefit from the treatment.
#4: Anti-inflammatories like metformin could prove useful
Many of the inflammatory markers persistent in patients with long COVID were similarly present in patients with autoimmune diseases like rheumatoid arthritis, according to a July 2023 study published in JAMA.
The hope is that anti-inflammatory medications may be used to reduce inflammation causing long COVID symptoms. But drugs used to treat rheumatoid arthritis like abatacept and infliximabcan also have serious side effects, including increased risk for infection, flu-like symptoms, and burning of the skin.
"Powerful anti-inflammatories can change a number of pathways in the immune system," said Grace McComsey, MD, who leads the long COVID RECOVER study at University Hospitals Health System in Cleveland, Ohio. Anti-inflammatories hold promise but, McComsey said, "some are more toxic with many side effects, so even if they work, there's still a question about who should take them."
Still, other anti-inflammatories that could work don't have as many side effects. For example, a study published in The Lancet Infectious Diseases found that the diabetes drug metformin reduced a patient's risk for long COVID up to 40% when the drug was taken during the acute stage.
Metformin, compared to other anti-inflammatories (also known as immune modulators), is an inexpensive and widely available drug with relatively few side effects compared with other medications.
#5: Serotonin levels — and selective serotonin reuptake inhibitors (SSRIs) — may be keys to unlocking long COVID
One of the most groundbreaking studies of the year came last November. A study published in the journal Cell found lower circulating serotonin levels in patents with long COVID than in those who did not have the condition. The study also found that the SSRI fluoxetine improved cognitive function in rat models infected with the virus.
Researchers found that the reduction in serotonin levels was partially caused by the body's inability to absorb tryptophan, an amino acid that's a precursor to serotonin. Overactivated blood platelets may also have played a role.
Michael Peluso, MD, an assistant research professor of infectious medicine at the UCSF School of Medicine, San Francisco, California, hopes to take the finding a step further, investigating whether increased serotonin levels in patients with long COVID will lead to improvements in symptoms.
"What we need now is a good clinical trial to see whether altering levels of serotonin in people with long COVID will lead to symptom relief," Peluso said last month in an interview with Medscape Medical News.
If patients show an improvement in symptoms, then the next step is looking into whether SSRIs boost serotonin levels in patients and, as a result, reduce their symptoms.
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Nature: A randomized open-label clinical trial on the effect of Amantadine on post Covid 19 fatigueJanuary 17, 2024 A A Harandi et al 2024 Scientific Reports
Abstract
Many COVID-19 survivors experience lingering post-COVID-19 symptoms, notably chronic fatigue persisting for months after the acute phase. Despite its prevalence, limited research has explored effective treatments for post-COVID-19 fatigue. This randomized controlled clinical trial assessed the impact of Amantadine on patients with post-COVID-19 fatigue. The intervention group received Amantadine for two weeks, while the control group received no treatment. Fatigue levels were assessed using the Visual Analog Fatigue Scale (VAFS) and Fatigue Severity Scale (FSS) questionnaires before and after the trial. At the study's onset, VAFS mean scores were 7.90 ± 0.60 in the intervention group and 7.34 ± 0.58 in the control group (P-value = 0.087). After two weeks, intervention group scores dropped to 3.37 ± 0.44, significantly lower than the control group's 5.97 ± 0.29 (P-value < 0.001). Similarly, FSS mean scores at the trial's commencement were 53.10 ± 5.96 in the intervention group and 50.38 ± 4.88 in the control group (P-value = 0.053). At the trial's end, intervention group scores decreased to 28.40 ± 2.42, markedly lower than the control group's 42.59 ± 1.50 (P-value < 0.001). In this study, we report the safety, tolerability, and substantial fatigue-relieving effects of Amantadine in post-COVID-19 fatigue. The intervention demonstrates a statistically significant reduction in fatigue levels, suggesting Amantadine's potential as an effective treatment for this persistent condition.
Discussion
Amantadine's effectiveness in relieving MS-related fatigue has been frequently shown, and its prescription is recommended by the German MS Society as well as in clinical practice guidelines published by NICE. Given the high incidence rate of post-COVID-19 fatigue and lack of treatment options, the satisfactory result obtained in our study with treatment with Amantadine is considerable. However, to our knowledge, there is no study investigating the effect of Amantadine on fatigue in post-COVID-19 patients to compare their results with ours.
Results
Our results showed a significant difference in the improvement of fatigue in patients receiving Amantadine compared to the control group. This improvement was evident in the FSS and the VAFS scores since the average of both reached less than half of the initial value after two weeks of treatment with Amantadine.
In conclusion, our study demonstrated that consuming Amantadine has a favorable effect on relieving post-COVID-19 fatigue. Our results reveal the safety and tolerability of two-weeks treatment with Amantadine in post-COVID-19 patients. We recommend well-designed double-blind, randomized studies with placebo and larger sample sizes to validate our results.
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News Medical: Long COVID and ME/CFS patients could benefit from a coordinated treatment strategyJanuary 23, 2024 News Medical Life Sciences
“Given the important clinical and pathological overlaps between ME/CFS and Long Covid co-ordinated research is something that the MEA has been calling for since May 2020 – when it became clear that Covid-19 was also triggering a post viral disease with symptoms that were identical to those found in ME/CFS
Sadly, it has taken over three years for many of the researchers involved in Long Covid research to accept that these overlaps occur
However the message is now getting through
Hopefully, this will lead to a better understanding of what causes post viral disease and the development of effective forms of treatment aimed at the underlying disease process in both Long Covid and ME/CFS“
Dr Charles Shepherd,
Trustee and Hon. Medical Adviser to the ME Association.
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Published: 12 December 2023
A pilot study on the immune cell proteome of long COVID patients shows changes to physiological pathways similar to those in myalgic encephalomyelitis/chronic fatigue syndromeKatie Peppercorn, Christina D. Edgar, Torsten Kleffmann & Warren P. Tate
Scientific Reports volume 13, Article number: 22068 (2023)
Abstract
Of those infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), ~ 10% develop the chronic post-viral debilitating condition, long COVID (LC). Although LC is a heterogeneous condition, about half of cases have typical post-viral fatigue with onset and symptoms that are very similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). A key question is whether these conditions are closely related. ME/CFS is a post-stressor fatigue condition that arises from multiple triggers. To investigate the pathophysiology of LC, a pilot study of patients (n = 6) and healthy controls (n = 5) has used quantitative proteomics to discover changes in peripheral blood mononuclear cell (PBMC) proteins. A principal component analysis separated all long COVID patients from healthy controls. Analysis of 3131 proteins identified 162 proteins differentially regulated, of which 37 were related to immune functions, and 21 to mitochondrial functions. Markov cluster analysis identified clusters involved in immune system processes, and two aspects of gene expression-spliceosome and transcription. These results were compared with an earlier dataset of 346 differentially regulated proteins in PBMC’s from ME/CFS patients (n = 9) analysed by the same methodology. There were overlapping protein clusters and enriched molecular pathways particularly in immune functions, suggesting the two conditions have similar immune pathophysiology as a prominent feature, and mitochondrial functions involved in energy production were affected in both conditions.
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Sci.Rep. 2024; 14: 1343.
Published online 2024 Jan 16. doi: 10.1038/s41598-024-51904-z
PMCID: PMC10792128nnnnPMID: 38228731
A randomized open-label clinical trial on the effect of Amantadine on post Covid 19 fatigue
Ali Amini Harandi, 1 Hossein Pakdaman,1 Aida Medghalchi,1 Negin Kimia,1 Alireza Kazemian,1 Fatemeh Siavoshi,1 Siavash Shirzadeh Barough,1 Akram Esfandani,1 Mohammad Hossein Hosseini,1 and Seyed Ali Sobhanian2
Author information Article notes Copyright and License information PMC Disclaimer
Abstract
Many COVID-19 survivors experience lingering post-COVID-19 symptoms, notably chronic fatigue persisting for months after the acute phase. Despite its prevalence, limited research has explored effective treatments for post-COVID-19 fatigue. This randomized controlled clinical trial assessed the impact of Amantadine on patients with post-COVID-19 fatigue. The intervention group received Amantadine for two weeks, while the control group received no treatment. Fatigue levels were assessed using the Visual Analog Fatigue Scale (VAFS) and Fatigue Severity Scale (FSS) questionnaires before and after the trial. At the study's onset, VAFS mean scores were 7.90 ± 0.60 in the intervention group and 7.34 ± 0.58 in the control group (P-value = 0.087). After two weeks, intervention group scores dropped to 3.37 ± 0.44, significantly lower than the control group's 5.97 ± 0.29 (P-value < 0.001). Similarly, FSS mean scores at the trial's commencement were 53.10 ± 5.96 in the intervention group and 50.38 ± 4.88 in the control group (P-value = 0.053). At the trial's end, intervention group scores decreased to 28.40 ± 2.42, markedly lower than the control group's 42.59 ± 1.50 (P-value < 0.001). In this study, we report the safety, tolerability, and substantial fatigue-relieving effects of Amantadine in post-COVID-19 fatigue. The intervention demonstrates a statistically significant reduction in fatigue levels, suggesting Amantadine's potential as an effective treatment for this persistent condition.
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New Tests May Finally Diagnose Long COVIDSara Novak November 29, 2023 Medscape Medical News
One of the biggest challenges facing clinicians who treat long COVID is a lack of consensus when it comes to recognizing and diagnosing the condition. But a new study suggests testing for certain biomarkers may identify long COVID with accuracy approaching 80%.
Effective diagnostic testing would be a game-changer in the long COVID fight, for it’s not just the fatigue, brain fog, heart palpitations, and other persistent symptoms that affect patients. Two out of three people with long COVID also suffer mental health challenges like depression and anxiety. Some patients say their symptoms are not taken seriously by their doctors. And as many as 12% of long COVID patients are unemployed because of the severity of their illness and their employers may be skeptical of their condition.
Quick, accurate diagnosis would eliminate all that. Now a new preprint study suggests that the elevation of certain immune system proteins are a commonality in long COVID patients and identifying them may be an accurate way to diagnose the condition.
Researchers at Cardiff University School of Medicine in Cardiff, Wales, United Kingdom, tracked 166 patients, 79 of whom had been diagnosed with long COVID and 87 who had not. All participants had recovered from a severe bout of acute COVID-19.
In an analysis of the blood plasma of the study participants, researchers found elevated levels of certain components. Four proteins in particular — Ba, iC3b, C5a, and TCC — predicted the presence of long COVID with 78.5% accuracy.
"I was gobsmacked by the results. We’re seeing a massive dysregulation in those four biomarkers," says study author Wioleta Zelek, PhD, a research fellow at Cardiff University. "It’s a combination that we showed was predictive of long COVID."
The study revealed that long COVID was associated with inflammation of the immune system causing these complement proteins to remain dysregulated. Proteins like C3, C4, and C5 are important parts of the immune system because they recruit phagocytes, cells that attack and engulf bacteria and viruses at the site of infection to destroy pathogens like SARS-coV-2.
In the case of long COVID, these proteins remain chronically elevated. While the symptoms of long COVID have seemed largely unrelated to one another, researchers point to elevated inflammation as a connecting factor that causes various systems in the body to go haywire.
"Anything that could help to better diagnose patients with long COVID is research we’re greatly appreciative of within the clinical community," said Nisha Viswanathan, MD, director of the University of California Los Angeles Long COVID program at UCLA Health in Los Angeles.
Testing for biomarkers highlighted in the study, as well as others like serotonin and cortisol, may help doctors separate patients who have long COVID from patients who have similar symptoms caused by other conditions, said Viswanathan. For example, a recent study published in the journal Cell found lower serotonin levels in long COVID patients compared with patients who were diagnosed with acute COVID-19 but recovered from the condition.
Viswanathan cautions that the biomarker test does not answer all the questions about diagnosing long COVID. For example, Viswanathan said scientists don’t know whether complement dysregulation is caused by long COVID and not another underlying medical issue that patients had prior to infection, because "we don’t know where patients’ levels were prior to developing long COVID." For example, those with autoimmune issues are more likely to develop long COVID, which means their levels could have been elevated prior to a COVID infection.
It is increasingly likely, said Viswanathan, that long COVID is an umbrella term for a host of conditions that could be caused by different impacts of the virus. Other research has pointed to the different phenotypes of long COVID. For example, some are focused on cardiopulmonary issues and others on fatigue and gastrointestinal problems.
"It looks like these different phenotypes have a different mechanism for disease," she said. This means that it’s less likely to be a one-size-fits-all condition and the next step in the research should be identifying which biomarker is aligned with which phenotype of the disease.
Better diagnostics will open the door to better treatments, Zelek said. The more doctors understand about the mechanism causing immune dysregulation in long COVID patients, the more they can treat it with existing medications. Zelek’s lab has been studying certain medications like pegcetacoplan (C3 blocker), danicopan (anti-factor D), and iptacopan (anti-factor B) that can be used to break the body’s cycle of inflammation and reduce symptoms experienced in those with long COVID.
These drugs are approved by the US Food and Drug Administration for the treatment of a rare blood disease called paroxysmal nocturnal hemoglobinuria. The C5 inhibitor zilucoplan has also been used in patients hospitalized with COVID-19 and researchers have found that the drug lowered serum C5 and interleukin-8 concentration in the blood, seeming to reduce certain aspects of the immune system’s inflammatory response to the virus.
The Cardiff University research is one of the most detailed studies to highlight long COVID biomarkers to date, said infectious disease specialist Grace McComsey, MD, who leads the long COVID RECOVER study at University Hospitals Health System in Cleveland, Ohio. The research needs to be duplicated in a larger study population that might include the other biomarkers like serotonin and cortisol to see if they’re related, she said.
Researchers are learning more everyday about the various biomarkers that may be linked to long COVID, she added. This Cardiff study showed that a huge percentage of those patients had elevated levels of certain complements. The next step, said McComsey, "is to put all these puzzle pieces together" so that clinicians have a common diagnostic tool or tools that provide patients with some peace of mind in starting their road to recovery.
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Why Are Women More Likely to Get Long COVID?Tinker Ready Medscape medical news January 19, 2024
Annette Gillaspie, a nurse in a small Oregon hospital, hoped she would be back working with patients by now. She contracted COVID-19 on the job early in the pandemic and ended up with long COVID. After recovering a bit, her fatigue and dizziness returned, and today she is still working a desk job. She has also experienced more severe menstrual periods than before she had COVID. "Being a female with long COVID definitely does add to the roller-coaster effect of symptoms," Gillaspie said.
Long COVID affects nearly twice as many women as men, with 6.6% of women reporting long COVID compared with 4% of men, according to a recent Census Bureau survey reported by the Centers for Disease Control and Prevention (CDC). Researchers are trying to determine why, what causes the gender disparity, and how best to treat it.Scientists are also starting to look at the impact of long COVID on female reproductive health, including menstruation, pregnancy, and menopause.
Sex differences are common in infection-associated illnesses, said Beth Pollack, a research scientist specializing in long COVID in the Massachusetts Institute of Technology's Department of Biological Engineering, Cambridge, Massachusetts. "It informs research priorities and the lens with which we understand long COVID." For example, reproductive health issues for women, such as puberty, pregnancy, and menopause, can alter the course of illness in a subset of women in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and postural orthostatic tachycardia syndrome (POTS), a condition that can cause dizziness and worse. "This suggests that sex hormones may play key roles in immune responses to infections," Pollack said.
ME/CFS and a Possible Link to Long COVID in Women
Some of the research into long COVID is being led by teams studying infection-associated chronic illnesses like ME/CFS.
The problem: Advocates say ME/CFS has been under-researched. Poorly understood for years, the condition is one of a handful of chronic illnesses linked to infections, including Lyme disease and now long COVID. Perhaps not coincidently, they are more likely to affect women. Many of the research findings about long COVID mirror data that emerged in past ME/CFS research, said Jaime Seltzer, the scientific director at #MEAction, Santa Monica, California, an advocacy group. One point in particular: ME/CFS strikes women about twice as much as men, according to the CDC.
Seltzer said the response to long COVID could be much further ahead if the research community acknowledged the work done over the years on ME/CFS. Many of the potential biomarkers and risk factors emerging for long COVID were also suspected in ME/CFS, but not thoroughly studied, she said. She also said not enough work has been done to unravel the links between gender and these chronic conditions. "We're stuck in this Groundhog Day situation," she said. "There isn't any research, so we can't say anything definitively."
Some New Research, Some New Clues
Scientists like Pollack are slowly making inroads. She was lead author on a 2023 review investigating the impact of long COVID on female reproductive health. The paper highlights long COVID links to ME/CFS, POTS, and Ehlers-Danlos syndrome (EDS), as well as a resulting laundry list of female reproductive health issues. The hope is physicians will examine how the menstrual cycle, pregnancy, and menopause affect symptoms and illness progression of long COVID.
The Tal Research group at MIT (where Pollack works) has also added long COVID to the list of infection-associated illnesses it studies. The lab is conducting a large study looking into both Lyme disease and long COVID. The goals are to identify biomarkers that can predict who will not recover and to advance available treatments. Another MIT program, "SEXX + Immunity" holds seminars and networking sessions for scientists looking into the role of female and male biology in immune responses to infection.
Barriers to Progress Remain
On the clinical side, female patients with long COVID also have to deal with a historical bias that still lurks in medicine when it comes to women's health, said Alba Azola, MD, an assistant professor of physical medicine at Johns Hopkins Medicine, Baltimore, Maryland. Azola said she has discovered clinical descriptions of ME/CFE in the literature archives that describe it as "neurasthenia" and dismiss it as psychological. Patients say that it is still happening, and while it may not be so blunt, "you can read between the lines," Azola said. Azola, who has worked with long-COVID patients and is now seeing people with ME/CFS, said the symptoms of infection-associated chronic illness can mimic menopause, and many of her patients received that misdiagnosis. She recommends that doctors rule out long COVID for women with multiple symptoms before attributing symptoms to menopause.
Seeing that some long-COVID patients were developing ME/CFS, staff at the Bateman Horne Center in Salt Lake City, Utah, set up a program for the condition in 2021. They were already treating patients with ME/CFS and what they call "multi-symptom chronic complex diseases." Jennifer Bell, a certified nurse practitioner at the center, said she has not seen any patients with ovarian failure but plenty with reproductive health issues. "There definitely is a hormonal connection, but I don't think there's a good understanding about what is happening," she said. Most of her patients are female, and the more serious patients tend to go through a worsening of their symptoms in the week prior to getting a period, she said. One thing Bell said she's noticed in the past year is an increase in patients with EDS, which is also more common in women.
Like long COVID, many of the conditions traditionally treated at the center have no cure. But Bell said the center has developed an expertise in treating post-exertional malaise, a common symptom of long COVID, and keeps up with the literature for treatments to try, like the combination of guanfacine and the antioxidant N-acetyl cysteine to treat brain fog, an approach developed at Yale. "It's a very challenging illness to treat," Bell said.
Since the emergence of long COVID, researchers have warned that symptoms vary so much from person to person that treatment will need to be targeted. Pollack of MIT agrees and sees a big role for personalized medicine. We need to "identify phenotypes within and across these overlapping and co-occurring illnesses so that we can identify the right therapeutics for each person," she said.
As for Annette Gillaspie, she still hopes her long COVID will subside so she can get out from behind the desk and return to her normal nursing duties. "I just got to a point where I realized I'm likely never going to be able to do my job," she said. "It was incredibly heart breaking, but it's the reality of long COVID, and I know I'm not the only one to have to step away from a job I loved."
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Medicina (Kaunas). 2023 May; 59(5): 978.
Published online 2023 May 18. doi: 10.3390/medicina59050978PMCID: PMC10224216
PMID: 37241210
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Comorbidities: Linked by Vascular Pathomechanisms and Vasoactive Mediators?
Klaus J. Wirth and Matthias Löhn* Modra Murovska, Academic Editor
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is often associated with various other syndromes or conditions including mast cell activation (MCA), dysmenorrhea and endometriosis, postural tachycardia (POTS) and small fiber neuropathy (SFN). The causes of these syndromes and the reason for their frequent association are not yet fully understood. We previously published a comprehensive hypothesis of the ME/CFS pathophysiology that explains the majority of symptoms, findings and chronicity of the disease. We wondered whether some of the identified key pathomechanisms in ME/CFS are also operative in MCA, endometriosis and dysmenorrhea, POTS, decreased cerebral blood flow and SFN, and possibly may provide clues on their causes and frequent co-occurrence. Our analysis indeed provides strong arguments in favor of this assumption, and we conclude that the main pathomechanisms responsible for this association are excessive generation and spillover into the systemic circulation of inflammatory and vasoactive tissue mediators, dysfunctional β2AdR, and the mutual triggering of symptomatology and disease initiation. Overall, vascular dysfunction appears to be a strong common denominator in these linkages.
Keywords: ME/CFS, long COVID, MCA, endometriosis, dysmenorrhea, orthostatic intolerance, small fiber neuropathy, cerebral blood flow, brain fog, β2-adrenergic receptors
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New Evidence Suggests Long COVID Could Be a Brain InjurySara Novak February 08, 2024 Medscape Medical News
Brain fog is one of the most common, persistent complaints in patients with long COVID. It affects as many as 46% of patients who also deal with other cognitive concerns like memory loss and difficulty concentrating.
Now, researchers believe they know why. A new study has found that these symptoms may be the result of a viral-borne brain injury that may cause cognitive and mental health issues that persist for years.
Researchers found that 351 patients hospitalized with severe COVID-19 had evidence of a long-term brain injury a year after contracting the SARS-CoV-2 virus. The findings were based on a series of cognitive tests, self-reported symptoms, brain scans, and biomarkers.
Brain Deficits Equal to 20 Years of Brain AgingAs part of the preprint study, participants took a cognition test with their scores age-matched to those who had not suffered a serious bout of COVID-19. Then a blood sample was taken to look for specific biomarkers, showing that elevated levels of certain biomarkers were consistent with a brain injury. Using brain scans, researchers also found that certain regions of the brain associated with attention were reduced in volume.
Patients who participated in the study were "less accurate and slower" in their cognition, and suffered from at least one mental health condition, such as depression, anxiety, or posttraumatic stress disorder, according to researchers.
The brain deficits found in COVID-19 patients were equivalent to 20 years of brain aging and provided proof of what doctors have feared: that this virus can damage the brain and result in ongoing mental health issues.
"We found global deficits across cognition," said lead study author Benedict Michael, PhD, director of the Infection Neuroscience Lab at the University of Liverpool in Liverpool, England. "The cognitive and memory problems that patients complained of were associated with neuroanatomical changes to the brain."
Proof That Symptoms Aren't 'Figment' of Patients' ImaginationsCognitive deficits were common among all patients, but the researchers said they don't yet know whether the brain damage causes permanent cognitive decline. But the research provides patients who have been overlooked by some clinicians with proof that their conditions aren't a figment of their imaginations, said Karla L. Thompson, PhD, lead neuropsychologist at the University of North Carolina School of Medicine's COVID Recovery Clinic.
"Even though we're several years into this pandemic, there are still a lot of providers who don't believe that their patients are experiencing these residual symptoms," said Thompson, "That's why the use of biomarkers is important, because it provides an objective indication that the brain has been compromised in some way."
Some patients with long COVID have said that getting their doctors to believe they have a physical ailment has been a persistent problem throughout the pandemic and especially as it relates to the sometimes-vague collection of symptoms associated with brain fog. One study found that as many as 79% of study respondents reported negative interactions with their healthcare providers when they sought treatment for their long-COVID symptoms.
How Do COVID-Related Brain Injuries Happen?Researchers are unsure what's causing these brain injuries, though they have identified some clues. Previous research has suggested that such injuries might be the result of a lack of oxygen to the brain, especially in patients who were hospitalized, like those in this study, and were put on ventilators.
Brain scans have previously shown atrophy to the brain's gray matter in COVID-19 patients, likely caused by inflammation from a heightened immune response rather than the virus itself. This inflammatory response seems to affect the central nervous system. As part of the new study, researchers found some neuroprotective effects of using steroids during hospitalization to reduce brain inflammation.
The results suggest that clinicians should overcome their skepticism and consider the possibility that their patients have suffered a brain injury and should be treated appropriately, said James C. Jackson, PsyD, a neuropsychiatrist at Vanderbilt University School of Medicine. "The old saying is that if it walks like a duck and talks like a duck, it's a duck," said Jackson.
He contends that treatments used for patients who have brain injuries have also been shown to be effective in treating long COVID–related brain fog symptoms. These may include speech, cognitive, and occupational therapy as well as meeting with a neuropsychiatrist for the treatment of related mental health concerns.
A New Path ForwardTreating long-COVID brain fog like a brain injury can help patients get back to some semblance of normalcy, researchers said. "What we're seeing in terms of brain injury biomarkers and differences in brain scans correlates to real-life problems that these patients are dealing with on a daily basis," said Jackson. These include problems at work and in life with multitasking, remembering details, meeting deadlines, synthesizing large amounts of information, and maintaining focus on the task at hand, he said.
There's also a fear that even with treatment, the aging of the brain caused by the virus might have long-term repercussions and that this enduring injury may cause the early onset of dementia and Alzheimer's disease in those who were already vulnerable to it. One study, from the National Institute of Neurological Disorders and Stroke (NINDS), found that in those infected with COVID-19 who already had dementia, the virus "rapidly accelerated structural and functional brain deterioration."
"We already know the role that neuroinflammation plays in the brains of patients with Alzheimer's disease," said Thompson. "If long COVID is involved in prolonged inflammation of the brain, it goes a long way in explaining the mechanism underlying [the study's reported] brain aging."
Still More to LearnIn some ways, this study raises nearly as many questions as it does answers. While it provides concrete evidence around the damage the virus is doing to the brains of patients who contracted severe COVID-19, researchers don't know about the impact on those who had less serious cases of the virus.
For Ziyad Al-Aly, MD, chief of research and development at the Veterans Affairs St. Louis Health Care System, the concern is that some long-COVID patients may be suffering from cognitive deficits that are more subtle but still impacting their daily lives, and that they're not getting the help they need.
What's more, said Al-Aly, it's unclear whether the impacts of the brain damage are permanent or how to stop them from worsening. Researchers and clinicians need a better understanding of the mechanism that allows this virus to enter the brain and do structural damage. If it's inflammation, will anti-inflammatory or antiviral medications work at preventing it? Will steroids help to offset the damage? "It's critical we find some answers," he said.
"SARS-CoV-2 isn't going anywhere. It will continue to infect the population, so if this is indeed a virus that damages the brain in the long term or permanently, we need to figure out what can be done to stop it," said Al-Aly.
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Infectious Diseases February 14, 2024
Cognitive Symptoms of Post–COVID-19 Condition and Daily FunctioningAbhishek Jaywant, PhD1; Faith M. Gunning, PhD1; Lauren E. Oberlin, PhD1; et alMauricio Santillana, PhD2,3; Katherine Ognyanova, PhD4; James N. Druckman, PhD5; Matthew A. Baum, PhD6; David Lazer, PhD7,8,9,10; Roy H. Perlis, MD, MSc11,12
JAMA Netw Open. 2024;7(2):e2356098. doi:10.1001/jamanetworkopen.2023.56098
Key Points
Question How are post–COVID-19 condition self-reported cognitive symptoms associated with employment status, functional outcomes, and mood?
Findings In this survey study including 14 767 individuals with post–COVID-19 condition surveyed in late 2022 to early 2023, 57% reported experiencing cognitive symptoms daily, compared with 27% with prior SARS-CoV-2 infection who did not develop post–COVID-19 condition. In those with post–COVID-19 condition, cognitive symptoms were associated with greater levels of depressive symptoms, greater reported functional impairment, and lesser likelihood of full-time employment.
Meaning The findings of this study suggest that self-reported cognitive symptoms are prevalent in post–COVID-19 condition, often co-occur with depressive symptoms, and are associated with functional impairment.
Abstract
Importance The frequent occurrence of cognitive symptoms in post–COVID-19 condition has been described, but the nature of these symptoms and their demographic and functional factors are not well characterized in generalizable populations.
Objective To investigate the prevalence of self-reported cognitive symptoms in post–COVID-19 condition, in comparison with individuals with prior acute SARS-CoV-2 infection who did not develop post–COVID-19 condition, and their association with other individual features, including depressive symptoms and functional status.
Design, Setting, and Participants Two waves of a 50-state nonprobability population-based internet survey conducted between December 22, 2022, and May 5, 2023. Participants included survey respondents aged 18 years and older.
Exposure Post–COVID-19 condition, defined as self-report of symptoms attributed to COVID-19 beyond 2 months after the initial month of illness.
Main Outcomes and Measures Seven items from the Neuro-QoL cognition battery assessing the frequency of cognitive symptoms in the past week and patient Health Questionnaire-9.
Results The 14 767 individuals reporting test-confirmed COVID-19 illness at least 2 months before the survey had a mean (SD) age of 44.6 (16.3) years; 568 (3.8%) were Asian, 1484 (10.0%) were Black, 1408 (9.5%) were Hispanic, and 10 811 (73.2%) were White. A total of 10 037 respondents (68.0%) were women and 4730 (32.0%) were men. Of the 1683 individuals reporting post–COVID-19 condition, 955 (56.7%) reported at least 1 cognitive symptom experienced daily, compared with 3552 of 13 084 (27.1%) of those who did not report post–COVID-19 condition. More daily cognitive symptoms were associated with a greater likelihood of reporting at least moderate interference with functioning (unadjusted odds ratio [OR], 1.31 [95% CI, 1.25-1.36]; adjusted [AOR], 1.30 [95% CI, 1.25-1.36]), lesser likelihood of full-time employment (unadjusted OR, 0.95 [95% CI, 0.91-0.99]; AOR, 0.92 [95% CI, 0.88-0.96]) and greater severity of depressive symptoms (unadjusted coefficient, 1.40 [95% CI, 1.29-1.51]; adjusted coefficient 1.27 [95% CI, 1.17-1.38). After including depressive symptoms in regression models, associations were also found between cognitive symptoms and at least moderate interference with everyday functioning (AOR, 1.27 [95% CI, 1.21-1.33]) and between cognitive symptoms and lower odds of full-time employment (AOR, 0.92 [95% CI, 0.88-0.97]).
Conclusions and Relevance The findings of this survey study of US adults suggest that cognitive symptoms are common among individuals with post–COVID-19 condition and associated with greater self-reported functional impairment, lesser likelihood of full-time employment, and greater depressive symptom severity. Screening for and addressing cognitive symptoms is an important component of the public health response to post–COVID-19 condition.
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Original Investigation March 23, 2023
Risk Factors Associated With Post−COVID-19 ConditionA Systematic Review and Meta-analysisVasiliki Tsampasian, MD, MSc1,2; Hussein Elghazaly, MBBS3; Rahul Chattopadhyay, MBBS, MSc1,4; et alMaciej Debski, MD, PhD1,2; Thin Kyi Phyu Naing, MBBS1,2; Pankaj Garg, PhD1,2; Allan Clark, PhD2; Eleana Ntatsaki, MD(Res), MA5,6; Vassilios S. Vassiliou, MBBS, PhD1,2
JAMA Intern Med. 2023;183(6):566-580. doi:10.1001/jamainternmed.2023.0750
COVID-19 Resource Center
Key Points
Question Which individuals are at risk of developing post−COVID-19 condition (PCC)?
Findings This systematic review and meta-analysis of 41 studies including 860 783 patients found that female sex, older age, higher body mass index, smoking, preexisting comorbidities, and previous hospitalization or ICU admission were risk factors significantly associated with developing PCC, and that SARS-CoV-2 vaccination with 2 doses was associated with lower risk of PCC.
Meanings The findings of this systematic review and meta-analysis provide a profile of the characteristics associated with increased risk of developing PCC and suggest that vaccination may be protective against PCC.
Abstract
Importance Post−COVID-19 condition (PCC) is a complex heterogeneous disorder that has affected the lives of millions of people globally. Identification of potential risk factors to better understand who is at risk of developing PCC is important because it would allow for early and appropriate clinical support.
Objective To evaluate the demographic characteristics and comorbidities that have been found to be associated with an increased risk of developing PCC.
Data sources Medline and Embase databases were systematically searched from inception to December 5, 2022.
Study Selection The meta-analysis included all published studies that investigated the risk factors and/or predictors of PCC in adult (≥18 years) patients.
Data Extraction and Synthesis Odds ratios (ORs) for each risk factor were pooled from the selected studies. For each potential risk factor, the random-effects model was used to compare the risk of developing PCC between individuals with and without the risk factor. Data analyses were performed from December 5, 2022, to February 10, 2023.
Main Outcomes and Measures The risk factors for PCC included patient age; sex; body mass index, calculated as weight in kilograms divided by height in meters squared; smoking status; comorbidities, including anxiety and/or depression, asthma, chronic kidney disease, chronic obstructive pulmonary disease, diabetes, immunosuppression, and ischemic heart disease; previous hospitalization or ICU (intensive care unit) admission with COVID-19; and previous vaccination against COVID-19.
Results The initial search yielded 5334 records of which 255 articles underwent full-text evaluation, which identified 41 articles and a total of 860 783 patients that were included. The findings of the meta-analysis showed that female sex (OR, 1.56; 95% CI, 1.41-1.73), age (OR, 1.21; 95% CI, 1.11-1.33), high BMI (OR, 1.15; 95% CI, 1.08-1.23), and smoking (OR, 1.10; 95% CI, 1.07-1.13) were associated with an increased risk of developing PCC. In addition, the presence of comorbidities and previous hospitalization or ICU admission were found to be associated with high risk of PCC (OR, 2.48; 95% CI, 1.97-3.13 and OR, 2.37; 95% CI, 2.18-2.56, respectively). Patients who had been vaccinated against COVID-19 with 2 doses had a significantly lower risk of developing PCC compared with patients who were not vaccinated (OR, 0.57; 95% CI, 0.43-0.76).
Conclusions and Relevance This systematic review and meta-analysis demonstrated that certain demographic characteristics (eg, age and sex), comorbidities, and severe COVID-19 were associated with an increased risk of PCC, whereas vaccination had a protective role against developing PCC sequelae. These findings may enable a better understanding of who may develop PCC and provide additional evidence for the benefits of vaccination.
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Opinion: Toward Solving the Long COVID PuzzleEric Topol February 23, 2024 Medscape medical news
The following first appeared in the Substack of Eric Topol, MD, called Ground Truths.
In recent days, there were several important new reports that help explain the pathophysiology of long COVID. By coincidence, we published a Perspective in Science today to summarize the progress that has been made and the vital work that lies ahead.
Here, we'll summarize the new findings:
The Leaky Blood-Brain BarrierA systematic study of people with long COVID and controls, using MRI, brain-specific S100β protein, RNA-seq of white blood cells, endothelial cell response in culture provided new insights about the disrupted blood-brain barrier (BBB) in individuals with long COVID and symptoms of brain fog. They are well summarized by Prof Katerina Akassoglou from the Gladstone Institutes, who was not involved in the study and is a highly regarded scientist in the field of neurovascular inflammation: "This study is the first report of BBB disruption correlating with brain fog in patients with long COVID by dynamic contrast enhanced MRI. The MRI findings are in line with neuropathology reporting blood protein accumulation in brains from patients with COVID-19, and I expect that it will be the foundation for future studies at the blood–brain and immune interface for the discovery of mechanisms, biomarkers and therapies for neurological manifestations in long COVID."
The numbers of participants in each group was small, but the phenotyping was extraordinarily deep. Beyond the BBB, the notable findings were dysregulation of the clotting system and pro-inflammatory effects of endothelial cells.
Persistent Infections of SARS-CoV-2 as a Risk FactorFrom a large community surveillance project in the UK, 381 participants were found to have evidence of persistent infections of SARS-CoV-2 for 30 days or more. That was considerably higher than anticipated.
One percent to 3% had persistent infections for more than 30 days. In addition, 0.1%-0.5% had persistent infections for more than 60 days.
Serial assessment of viral loads indicated many of the people had rebounding high levels, indicating that there was likely actively replicating virus.
The risk for long COVID was increased by 55% in people with 12 weeks or more of persistent infection and by 24% in those with infection for 26 weeks or more.
Interferon Gamma as a Possible Biomarker for Diagnosis and TreatmentA new report assayed interferon gamma, part of the first line of defense of innate immunity to a SARS-CoV-2 infection. Individuals with long COVID had persistent elevation after the acute phase, and during follow-up serial assessment of this biomarker showed resolution among the participants with symptom resolution. This will need further assessment, but if replicated and extended, it might fulfill a major unmet need for both confirmation of diagnosis and a surrogate measure for treatments that are being assessed in prospective clinical trials, no less an objective metric for correlation with symptoms.
Myalgic Encephalomyelitis (ME/CFS) Deep PhenotypingThe 8-year, long-awaited NIH project results were published in a 70-page manuscript. Like the BBB study above, the number of participants studies was small but compensated by extensive characterization and suitable matched controls. With the considerable overlap of many of the symptoms of ME/CFS and long COVID, the results are notable: signs of persistent chronic antigen stimulation with immune system dysregulation (with T-cell exhaustion) along with multisystem disruption, some of which is central nervous system regulated, with specific regions of the brain implicated.
On a related note, The Economist had an article about postinfectious neurologic syndrome that occurs with COVID, ME/CFS, Lyme disease, and several other viruses. "Michelle Monje, a neuro-oncologist at Stanford School of Medicine, homed in on precisely how COVID-induced neurological damage might occur — particularly focusing on glial cells, as brain cells other than neurons are known."
Prof Monje has just recorded a new Ground Truths podcast on this topic, which will be posted very soon.
Two New Reports of Vaccination Protection vs Long COVIDFrom a study in the Annals of Epidemiology, Michiganders derived an important protective benefit against long COVID: Long COVID prevalence was 40%-60% lower among adults vaccinated (vs unvaccinated) prior to their COVID-19. This level of protection is consistent with many recent reports and has not been emphasized enough regarding an added benefit of booster shots. The data were previously reviewed on Ground Truths here.
And a new preprint report on protection in children and adolescents looked at different variants (Delta and Omicron) and cause and effect relationship for direct benefit of vaccination. More protection was found in teens than children, with the range of 60%-75%.
Our Science PerspectiveAnd finally, our essay in Science, in which we tried to encapsulate a lot of information on what has been learned so far and what is desperately needed to be done now. Ziyad Al-Aly put together a great thread that reviews the key points.
A Brief SummaryWe're making considerable headway on understanding what drives long COVID, along with the possibility of another biomarker candidate, which would be a big help as randomized clinical trials move forward. Clearly finding effective and safe treatments is an urgent matter and not enough is being done to pursue that yet, despite a long list of potential alluring interventions based on mechanistic insights. Hopefully that will get going now — it cannot happen soon enough.
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Study IDs Immune Abnormality Possibly Causing Long COVIDTinker Ready February 22, 2024 - Medscape
Swiss scientists have identified immune system abnormalities in patients with long COVID that might open the door to new diagnostic tests and treatments.
The researchers found that a group of proteins in the blood that are part of the body's immune response called the "complement system" are not working properly in patients with long COVID.
Blood samples turned up important differences between those who recovered from COVID and those who did not. These differences might be used as biomarkers to diagnose long COVID and might even point the way to new treatments for the condition, the researchers said.
By testing for 6500 blood proteins in about 300 patients, the Swiss researchers found that dysfunctional complement system proteins could possibly explain fatigue and "smoldering inflammation," said Onur Boyman, MD, a professor of immunology from University Hospital Zurich in Zurich, Switzerland.
Long COVID has been linked to hundreds of symptoms including brain fog, chronic fatigue, pain, and digestive issues. Various factors drive the condition and likely work with one another other, said David Putrino, PhD, from the Icahn School of Medicine at Mount Sinai in New York City. The Swiss study is useful because "we're trying to best understand how we can explain all of this far-reaching pathobiology," he said.
Testing Across ContinentsBoyman's team collected blood samples from people with COVID in Europe and New York and tracked them. They compared those who developed long COVID with those who did not. One protein that was most unique to patients with long COVID is a blood complement that activates the immune system, Boyman said. But in people with long COVID, the immune response stays activated after the virus is gone. He described the response as "smoldering inflammation" in multiple organs, including the lungs and the gastrointestinal system.
The complement system also plays a role in clearing the body of dead cells. If the cells "lie around too much," they can trigger an immune response, he said.
That may explain exercise intolerance in people with long COVID, Boyman said. Some people with long COVID have inflammation in the epithelium — the inner layer of their blood vessels. This would make it harder for the circulatory systems to recover from exercise, Boyman said.
"We think this regulated complement system is actually quite a central piece of the puzzle," he said.
The Microclot ConnectionThe findings also support past research linking blood clots to long COVID. He suggested that clinicians and researchers consider testing drugs that regulate or inhibit the complementary system as a treatment of long COVID. Boyman said they are currently used for rare immune diseases.
Resia Pretorius, PhD, a professor of physiological sciences at Stellenbosch University in Stellenbosch, South Africa, said scientists studying the role of microclots in patients with long COVID often see complementary proteins inside the clots, so it has already been associated with long COVID. But she likened this clotting process to a garbage can that "just rolls along and collects everything that gets in its way. I think they are actively driving inflammation and disease."
One factor complicating long COVID diagnosis and treatment is that it is a complex condition that involves multiple organ systems. That's why the latest research suggests an underlying driver for the multiple symptoms of long COVID, Putrino said.
"Not every person has every symptom; not every person has every organ system affected," Putrino said. "Whatever is happening is decided across the whole body."
Research Offers New DirectionThe Swiss paper contributes to the effort to identify systemic issues contributing to long COVID. It gives researchers one more thing to test for and link to specific, long COVID symptoms, opening the door to new treatments, Putrino said.
He doesn't think the study supports treating the complement dysfunction if researchers don't know what's driving it. It may be complicated by the body's failure to clear the virus completely, he said.
Pretorius recommended doctors test patients with long COVID for specific symptoms that may be treated using existing therapies. "If you think your patient had vascular pathology, you can test for it," she said.
Some patients have found certain supplements and over-the-counter products helpful, she said. Among them: Coenzyme Q 10 and clot-busters such as streptokinase and Nattokinase (though she noted some doctors may not be comfortable with supplements).
"It's the only thing we have until we've got trials," she said.
Putrino said more research is needed to identify potential root causes and symptoms. A common refrain, but the only thing that will lead to specific treatments.
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Worsening Symptoms Is Associated with Larger Cerebral Blood Flow Abnormalities during Tilt-Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
C. (Linda) M. C. van Campen 1,* , Peter C. Rowe 2 and Frans C. Visser
Abstract:
Background and Objectives: During tilt testing, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients experience an abnormal reduction in cerebral blood flow (CBF). The relationship between this CBF reduction and symptom severity has not been examined in detail. Our hypothesis was that ME/CFS severity is related to the degree of the CBF reduction during tilt testing.
Materials and Methods:
First, from our database, we selected ME/CFS patients who had undergone assessments of ME/CFS symptomatology and tilt tests on the same day, one at the first visit and the second during a follow-up. The change in symptomatology was related to the change in CBF during the tilt test.
Second, we combined the data of two previously published studies (n = 219), where disease severity as defined by the 2011 international consensus criteria (ICC) was available but not published.
Results: 71 patients were retested because of worsening symptoms. The ICC disease severity distribution (mild-moderate-severe) changed from 51/45/4% at visit-1 to 1/72/27% at follow-up (p < 0.0001). The %CBF reduction changed from initially 19% to 31% at followup (p < 0.0001). Of 39 patients with stable disease, the severity distribution was similar at visit-1 (36/51/13%) and at follow-up (33/49/18%), p = ns. The %CBF reduction remained unchanged: both 24%, p = ns. The combined data of the two previously published studies showed that patients with mild, moderate, and severe disease had %CBF reductions of 25, 29, and 33%, respectively (p < 0.0001).
Conclusions: Disease severity and %CBF reduction during tilt testing are highly associated in ME/CFS: a more severe disease is related to a larger %CBF reduction. The data suggest a causal relationship where a larger CBF reduction leads to worsening symptoms.
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- Published: 19 November 2023 - Nature
Scientific Reports volume 13, Article number: 20230 (2023)
AbstractPost-acute COVID-19 (PACS) are associated with cardiovascular dysfunction, especially postural orthostatic tachycardia syndrome (POTS). Patients with PACS, both in the absence or presence of POTS, exhibit a wide range of persisting symptoms long after the acute infection. Some of these symptoms may stem from alterations in cardiovascular homeostasis, but the exact mechanisms are poorly understood. The aim of this study was to provide a broad molecular characterization of patients with PACS with (PACS + POTS) and without (PACS-POTS) POTS compared to healthy subjects, including a broad proteomic characterization with a focus on plasma cardiometabolic proteins, quantification of cytokines/chemokines and determination of plasma sphingolipid levels. Twenty-one healthy subjects without a prior COVID-19 infection (mean age 43 years, 95% females), 20 non-hospitalized patients with PACS + POTS (mean age 39 years, 95% females) and 22 non-hospitalized patients with PACS-POTS (mean age 44 years, 100% females) were studied. PACS patients were non-hospitalized and recruited ≈18 months after the acute infection. Cardiometabolic proteomic analyses revealed a dysregulation of ≈200 out of 700 analyzed proteins in both PACS groups vs. healthy subjects with the majority (> 90%) being upregulated. There was a large overlap (> 90%) with no major differences between the PACS groups. Gene ontology enrichment analysis revealed alterations in hemostasis/coagulation, metabolism, immune responses, and angiogenesis in PACS vs. healthy controls. Furthermore, 11 out of 33 cytokines/chemokines were significantly upregulated both in PACS + POTS and PACS-POTS vs. healthy controls and none of the cytokines were downregulated. There were no differences in between the PACS groups in the cytokine levels. Lastly, 16 and 19 out of 88 sphingolipids were significantly dysregulated in PACS + POTS and PACS-POTS, respectively, compared to controls with no differences between the groups. Collectively, these observations suggest a clear and distinct dysregulation in the proteome, cytokines/chemokines, and sphingolipid levels in PACS patients compared to healthy subjects without any clear signature associated with POTS. This enhances our understanding and might pave the way for future experimental and clinical investigations to elucidate and/or target resolution of inflammation and micro-clots and restore the hemostasis and immunity in PACS.
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Catalytic Antibodies May Contribute to Demyelination in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
- Michael Anthony Jensen*Miranda Lee Dafoe,Julie Wilhelmy,Layla Cervantes,nna N Okumu,,Lucas Kipp, Nemat-Gorgani,, and Ronald Wayne Davis
Cite this: Biochemistry 2024, 63, 1, 9–18 Publication Date:November 27, 2023
https://doi.org/10.1021/acs.biochem.3c00433
Copyright © 2023 The Authors. Published by American Chemical Society. This publication is licensed under
CC-BY-NC-ND 4.0.
PDF (5 MB)
Abstract
Here we report preliminary data demonstrating that some patients with myalgic encephalomyelitis/chronic fatiguesyndrome (ME/CFS) may have catalytic autoantibodies that cause the breakdown of myelin basic protein (MBP). We propose that these MBP-degradative antibodies are important to the pathophysiology of ME/CFS, particularly in the occurrence of white matter disease/demyelination. This is supported by magnetic resonance imagining studies that show these findings in patients with ME/CFS and could explain symptoms of nerve pain and muscle weakness. In this work, we performed a series of experiments on patient plasma samples where we isolated and characterized substrate-specific antibodies that digest MBP. We also tested glatiramer acetate (copaxone), an FDA approved immunomodulator to treat multiple sclerosis, and found that it inhibits ME/CFS antibody digestion of MBP. Furthermore, we found that aprotinin, which is a specific serine protease inhibitor, specifically prevents breakdown of MBP while the other classes of protease inhibitors had no effect. This coincides with the published literature describing catalytic antibodies as having serine protease-like activity. Postpandemic research has also provided several reports of demyelination in COVID-19. Because COVID-19 has been described as a trigger for ME/CFS, demyelination could play a bigger role in patient symptoms for those recently diagnosed with ME/CFS. Therefore, by studying proteolytic antibodies in ME/CFS, their target substrates, and inhibitors, a new mechanism of action could lead to better treatment and a possible cure for the disease.
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Persistent complement dysregulation with signs of thromboinflammation in active Long CovidCARLO CERVIA-HASLER HTTPS://ORCID.ORG/0000-0001-7120-8739, SARAH C. BRÜNINGK HTTPS://ORCID.ORG/0000-0003-3176-1032, TOBIAS HOCH HTTPS://ORCID.ORG/0000-0003-0319-6064, BOWEN FAN, GIULIA MUZIO HTTPS://ORCID.ORG/0000-0001-5999-2030, RYAN C. THOMPSON HTTPS://ORCID.ORG/0000-0002-0450-8181, LAURA CEGLAREK HTTPS://ORCID.ORG/0009-0005-7117-0335, ROMAN MELEDIN HTTPS://ORCID.ORG/0000-0001-6921-825X, PATRICK WESTERMANN HTTPS://ORCID.ORG/0000-0003-2894-6140, [...], AND ONUR BOYMAN HTTPS://ORCID.ORG/0000-0001-8279-5545 +18
SCIENCE 19 Jan 2024 Vol 383, Issue 6680 DOI: 10.1126/science.adg7942
Editor’s summarySome individuals can endure persistent, debilitating symptoms for many months after an initial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, the factors underpinning these health issues, called Long Covid, are poorly understood. Comparing the blood of patients with confirmed SARS-CoV-2 infection with that of uninfected controls, Cervia-Hasler et al. found that patients experiencing Long COVID exhibited changes to blood serum proteins indicating activation of the immune system’s complement cascade, altered coagulation, and tissue injury (see the Perspective by Ruf). At the cellular level, Long Covid was linked to aggregates comprising monocytes and platelets. These findings provide a resource of potential biomarkers for diagnosis and may inform directions for treatments. —Sarah H. Ross
Structured AbstractINTRODUCTIONAcute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes various clinical phenotypes, ranging from asymptomatic to life-threatening COVID-19. About 5% of all infected individuals do not recover from acute disease but develop long-term complications, called Long Covid. Current hypotheses on factors contributing to Long Covid include tissue damage, viral reservoirs, autoimmunity, and persistent inflammation. There are currently no diagnostic tests or therapeutic solutions for affected patients.
RATIONALEWe followed 39 healthy controls and 113 COVID-19 patients for up to 1 year after initial confirmation of acute SARS-CoV-2 infection to identify biomarkers associated with Long Covid. At 6-month follow-up, 40 patients had Long Covid symptoms. Repeated clinical assessments were paired with blood draws, resulting in a total of 268 longitudinal blood samples. We measured >6500 proteins in serum by proteomics. Top candidate biomarkers were identified using computational tools and further evaluated experimentally.
RESULTSLong Covid patients exhibited increased complement activation during acute disease, which also persisted at 6-month follow-up. The complement system is part of the innate immune system and contributes to immunity and homeostasis by targeting pathogens and damaged cells, among other functions. Interestingly, blood complement levels normalized in Long Covid patients recovering before their 6-month follow-up. The complement system can be activated by various triggers, resulting in formation of the terminal complement complex (TCC), made of the complement components C5b-9. These complexes can integrate into cell membranes and induce cell activation or lysis. Long Covid patients showed imbalanced TCC formation, marked by increased soluble C5bC6 complexes and decreased levels of C7-containing TCC formations that can incorporate into cell membranes. This suggested increased membrane insertion of TCCs in Long Covid patients, contributing to tissue damage. Accordingly, Long Covid patients showed elevated tissue injury markers in blood and a thromboinflammatory signature, characterized by markers of endothelial activation, such as von Willebrand factor (vWF), and red blood cell lysis. Low antithrombin III levels in Long Covid patients were accompanied by signs of increased cleavage by thrombin, a driver of TCC formation. Furthermore, Long Covid patients had elevated platelet activation markers and monocyte–platelet aggregates at 6-month follow-up, particularly in cases where Long Covid persisted for 12 months or more. These patients also showed signs of antibody-mediated activation of the classical complement pathway, which was associated with increased anti-CMV (cytomegalovirus, also known as human herpesvirus 5) and anti-EBV (Epstein-Barr virus) immunoglobulin G (IgG) antibody levels.
CONCLUSIONOur data suggest that active Long Covid is accompanied by a blood protein signature marked by increased complement activation and thromboinflammation, including activated platelets and markers of red blood cell lysis. Tissue injury may also be complement-mediated and, in turn, activate the complement system. Moreover, complement activation may be driven by antigen–antibody complexes, involving autoantibodies and antibodies against herpesviruses, as well as cross-talk with a dysregulated coagulation system. In addition to offering a basis for new diagnostic solutions, our work provides support for clinical research on complement modulators for patients suffering from Long Covid.
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