A Systematic Review and Meta-analysis
Vasiliki 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. Published online March 23, 2023. doi:10.1001/jamainternmed.2023.0750
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.
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.
CLINICAL SUMMARY MEDSCAPEPersistent COVID-19 symptoms in adolescents linked to stressorsLiz Scherer | 07 April 2023
Persistent COVID-19 symptoms (post-COVID-19 condition [PCC]) in adolescents and young adults appear to be related to factors other than SARS-CoV-2.
The utility of the WHO PCC case definition may be questionable.
The research was conducted by Norwegian investigators and appeared in the journal JAMA Network Open.
Why this matters
Consider nonspecific stressors as underlying factors driving persistent symptoms (e.g., fatigue, psychosocial distress) and associated disability in presumed PCC cases.
Nonpharmacological interventions, e.g., behavioural health strategies, may be useful.
382 SARS-CoV-2-positive (mean age, 18 years) and 85 SARS-CoV-2-negative (mean age, 17.7 years) individuals were evaluated; over a third in each group were male.
At 6 months follow-up, roughly the same percentage of individuals in each group was classified as having PCC. This corresponded to a point prevalence (the number of people with PCC at a specific point in time) of 48.5% in the SARS-CoV-2-positive and 47.1% in the SARS-CoV-2-negative group.
The corresponding point prevalence for post-infective fatigue syndrome (PIFS) was 14.0% (SARS-infected) and 8.2% (SARS-uninfected) persons.
Baseline risk factors for both PCC and PIFS included female sex, low self-reported physical activity level before infection, loneliness, and negative life events in the preceding year.
Multivariate analysis showed that symptom severity remained the main risk factor for both conditions (increasing risk by 1.41 times for PCC and 3.37 times for PIFS).
Prospective cohort study to determine the point prevalence of/risk factors for PCC 6 months after the acute infection in nonhospitalised Norwegian adolescents and young adults, aged 12-25 years, testing positive and negative for SARS-CoV-2.
Funding: Norwegian Research Council; DAM Foundation.
Self-selection bias (some participants might have had a preponderance of symptoms), limited generalisability, SARS-CoV-2 might increase risk for diagnoses other than PCC.
Selvakumar J, Havdal LB, Drevvatne M, Brodwall EM, Lund Berven L, Stiansen-Sonerud T, Einvik G, Leegaard TM, Tjade T, Michelsen AE, Mollnes TE, Lund-Johansen F, Holmøy T, Zetterberg H, Blennow K, Sandler CX, Cvejic E, Lloyd AR, Wyller VBB. Prevalence and Characteristics Associated With Post-COVID-19 Condition Among Nonhospitalized Adolescents and Young Adults. JAMA Netw Open. 2023;6(3):e235763. doi: 10.1001/jamanetworkopen.2023.5763. PMID: 36995712
Had COVID? Part of the Virus May Stick Around in Your BrainDamian McNamara, MA
If you or someone you know is experiencing "brain fog" after COVID-19, scientists now have a possible explanation — and it might not bring much comfort.
Researchers in Germany found that part of the virus, the spike protein, remains in the brain long after the virus clears out.
These investigators discovered the spike protein from the virus in brain tissue of animals and people after death. The finding suggests these virus fragments build up, stick around, and trigger inflammation that causes long COVID symptoms.
About 15% of COVID patients continue to have long-term effects of the infection despite their recovery, said senior study author Ali Ertürk, PhD, director of the Institute for Tissue Engineering and Regenerative Medicine at the Helmholtz Center Munich in Germany.
Reported neurological problems include brain fog, brain tissue loss, a decline in thinking abilities, and problems with memory, he said.
"These symptoms clearly suggest damages and long-term changes caused by SARS-CoV-2 in the brain, the exact molecular mechanisms of which are still poorly understood," Ertürk said.
The researchers also propose a way the spike protein can get into the brain in their preprint report published online before peer review April 5 on bioRxiv.
Delivered by circulating blood, the spike protein can stay inside small openings in the bone marrow of the skull called niches. It can also reside in the meninges, thin layers of cells that act as a buffer between the skull and the brain. From there, one theory goes, the spike protein uses channels to enter the brain itself.
The hope is researchers can develop treatments that block one or more steps in this process and help people avoid long COVID brain issues.
"This is a very concerning report that literally demonstrates the SARS-CoV-2 spike protein in the skull-meninges-brain axis in postmortem individuals," said Eric Topol, MD, director of the Scripps Research Translational Institute in La Jolla, CA, and editor-in-chief of Medscape, WebMD's sister site for medical professionals.
Having the spike protein accumulate in structures right outside the brain and causing ongoing inflammation makes sense to Topol. The clustering of spike proteins would trigger an immune response from this niche reservoir of immune cells that cause the inflammation associated with long COVID and the symptoms such as brain fog, he said.
Problems with thinking and memory after COVID infection are relatively common. One research team found 22% of people with long COVID specifically reported this issue, on average, across 43 published studies. Even people who had mild COVID illness can develop brain fog later, Ertürk and colleagues note.
So why are researchers blaming the spike protein and not the whole COVID virus? As part of the study, they found SARS-CoV-2 virus RNA in some people after death and not in others, suggesting the virus does not need to be there to trigger brain fog. They also injected the spike protein directly into the brains of mice and showed it can cause cells to die.
Researchers also found no SARS-CoV-2 virus in the brain parenchyma, the functional tissue in the brain containing nerve cells and non-nerve (called glial) cells, but they did detect the spike protein there.
Surprising FindingsInvestigators were surprised to find spike protein in the skull niches of people who survived COVID and died later from another cause. Ertürk, lead author and PhD student Zhouyi Rong, and their colleagues found spike protein in 10 of 34 skulls from people who died from non-COVID causes in 2021 and 2022.
They also found COVID can change how proteins act in and around the brain. Some of these proteins are linked to Parkinson's disease and Alzheimer's disease, but have never before been linked to the virus.
Another unexpected finding was how close the findings were in mice and humans. There was a "remarkable similarity of distribution of the viral spike protein and dysregulated proteins identified in the mouse and human samples," Ertürk said.
Future Treatments?Tests for protein changes in the skull or meninges would be invasive but possible compared to sampling the parenchyma inside the brain. Even less invasive would be testing blood samples for altered proteins that could identify people most at risk of developing brain complications after COVID illness.
It will take more brain science to get there. "Designing treatment strategies for these neurological symptoms requires an in-depth knowledge of molecules dysregulated by the virus in the brain tissues," Ertürk said.
CLINICAL SUMMARY Long COVID-19 associated with low vitamin D levels
19 April 2023
- People with persistent symptoms after 6 months post-COVID-19 hospitalisation have lower 25(OH) vitamin D levels than matched patients without long COVID-19.
- If confirmed in randomised clinical trials, findings suggest potential for reduction of long COVID-19 morbidity with vitamin D supplementation.
- Low vitamin D levels have previously been linked to worse acute clinical COVID-19 outcomes.
- Predisposing factors for long COVID-19 are poorly understood, including any potential influence of vitamin D status.
- Observational, cross-sectional, retrospective study conducted among 100 adults hospitalised with COVID-19 in a tertiary healthcare centre in Milan, Italy, during March-May 2020 and reevaluated 6 months later.
- Long COVID-19 was defined by 2 or more otherwise unexplained symptoms and signs persisting 6 months after acute SARS-CoV-2 infection.
- 50 people with long COVID-19 were matched 1:1 with 50 age-, sex-, and comorbidity-matched patients who also needed noninvasive ventilation but did not develop long COVID-19.
- Funding: Abiogen Pharma S.p.A.
- Vitamin D deficiency (<20 ng/mL) was present in 71% of people included in the study at admission and in 46% at 6 months, with no differences in 25(OH) vitamin D levels between the 2 groups at hospitalisation.
- At 6 months, 25(OH) vitamin D levels were 20.1 vs 23.2 ng/mL in those with and without long COVID-19, respectively (P=.03).
- In patients with vitamin D deficiency both at hospital admission and at 6 months, those with vs without long COVID-19 had lower 25(OH) vitamin D levels at follow-up (12.7 vs 15.2 ng/mL; P=.041).
- In the entire cohort, lower 25(OH) vitamin D levels were found in those with vs without neurocognitive symptoms at both admission and follow-up (14.6 vs 20.6 ng/mL; P=.042).
- In multivariate analysis, lower 25(OH) vitamin D levels at follow-up were the only factor significantly and independently associated with long COVID-19 occurrence (OR, 1.09; 95% CI, 1.01-1.16; P=.008).
- Limited sample size because of exclusion criteria, available data, matching.
- Retrospective study.
- Single measure of vitamin D status.
- Seasonality effect cannot be excluded.
J Alzheimers Dis Rep. 2020; 4(1): 537–551. Published online 2020 Dec 28. Prepublished online 2020 Dec 10. doi: 10.3233/ADR-200273 PMCID: PMC7835993 PMID: 33532701
The Vagal Autonomic Pathway of COVID-19 at the Crossroad of Alzheimer’s Disease and Aging: A Review of KnowledgeClaire-Marie Rangon,a Slavica Krantic,b Emmanuel Moyse,c,1,* and Bertrand Fougèred,e,1
Coronavirus Disease 2019 (COVID-19) pandemic-triggered mortality is significantly higher in older than in younger populations worldwide. Alzheimer’s disease (AD) is related to aging and was recently reported to be among the major risk factors for COVID-19 mortality in older people. The symptomatology of COVID-19 indicates that lethal outcomes of infection rely on neurogenic mechanisms. The present review compiles the available knowledge pointing to the convergence of COVID-19 complications with the mechanisms of autonomic dysfunctions in AD and aging. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is prone to neuroinvasion from the lung along the vagus nerve up to the brainstem autonomic nervous centers involved in the coupling of cardiovascular and respiratory rhythms. The brainstem autonomic network allows SARS-CoV-2 to trigger a neurogenic switch to hypertension and hypoventilation, which may act in synergy with aging- and AD-induced dysautonomias, along with an inflammatory “storm”. The lethal outcomes of COVID-19, like in AD and unhealthy aging, likely rely on a critical hypoactivity of the efferent vagus nerve cholinergic pathway, which is involved in lowering cardiovascular pressure and systemic inflammation tone. We further discuss the emerging evidence supporting the use of 1) the non-invasive stimulation of vagus nerve as an additional therapeutic approach for severe COVID-19, and 2) the demonstrated vagal tone index, i.e., heart rate variability, via smartphone-based applications as a non-serological low-cost diagnostic of COVID-19. These two well-known medical approaches are already available and now deserve large-scale testing on human cohorts in the context of both AD and COVID-19.
Persistent Brainstem Dysfunction in Long-COVID: A HypothesisShin Jie Yong*
Cite this: ACS Chem. Neurosci. 2021, 12, 4, 573–580
Publication Date:February 4, 2021
Copyright © 2021 American Chemical Society
ACS Chemical Neuroscience
AbstractLong-COVID is a postviral illness that can affect survivors of COVID-19, regardless of initial disease severity or age. Symptoms of long-COVID include fatigue, dyspnea, gastrointestinal and cardiac problems, cognitive impairments, myalgia, and others. While the possible causes of long-COVID include long-term tissue damage, viral persistence, and chronic inflammation, the review proposes, perhaps for the first time, that persistent brainstem dysfunction may also be involved. This hypothesis can be split into two parts. The first is the brainstem tropism and damage in COVID-19. As the brainstem has a relatively high expression of ACE2 receptor compared with other brain regions, SARS-CoV-2 may exhibit tropism therein. Evidence also exists that neuropilin-1, a co-receptor of SARS-CoV-2, may be expressed in the brainstem. Indeed, autopsy studies have found SARS-CoV-2 RNA and proteins in the brainstem. The brainstem is also highly prone to damage from pathological immune or vascular activation, which has also been observed in autopsy of COVID-19 cases. The second part concerns functions of the brainstem that overlap with symptoms of long-COVID. The brainstem contains numerous distinct nuclei and subparts that regulate the respiratory, cardiovascular, gastrointestinal, and neurological processes, which can be linked to long-COVID. As neurons do not readily regenerate, brainstem dysfunction may be long-lasting and, thus, is long-COVID. Indeed, brainstem dysfunction has been implicated in other similar disorders, such as chronic pain and migraine and myalgic encephalomyelitis or chronic fatigue syndrome.
Frontiers in Neurology 2023; 17: 1125208. Published online 2023 Mar 2. doi: 10.3389/fnins.2023.1125208 PMCID: PMC10017877 PMID: 36937672
Brainstem volume changes in myalgic encephalomyelitis/chronic fatigue syndrome and long COVID patientsKiran Thapaliya, 1 , 2 , * Sonya Marshall-Gradisnik, 1 Markus Barth, 2 , 3 Natalie Eaton-Fitch, 1 and Leighton Barnden 1
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID patients have overlapping neurological, autonomic, pain, and post-exertional symptoms. We compared volumes of brainstem regions for 10 ME/CFS (CCC or ICC criteria), 8 long COVID (WHO Delphi consensus), and 10 healthy control (HC) subjects on 3D, T1-weighted MRI images acquired using sub-millimeter isotropic resolution using an ultra-high field strength of 7 Tesla. Group comparisons with HC detected significantly larger volumes in ME/CFS for pons (p = 0.004) and whole brainstem (p = 0.01), and in long COVID for pons (p = 0.003), superior cerebellar peduncle (p = 0.009), and whole brainstem (p = 0.005). No significant differences were found between ME/CFS and long COVID volumes. In ME/CFS, we detected positive correlations between the pons and whole brainstem volumes with “pain” and negative correlations between the midbrain and whole brainstem volumes with “breathing difficulty.” In long COVID patients a strong negative relationship was detected between midbrain volume and “breathing difficulty.” Our study demonstrated an abnormal brainstem volume in both ME/CFS and long COVID consistent with the overlapping symptoms.
Keywords: myalgic encephalomyelitis/chronic fatigue syndrome, brainstem, magnetic resonance imaging (MRI), pain, breathing difficulty, long COVID
Neurologic Manifestations of Long COVID Differ Based on Acute COVID-19 SeverityGina S. Perez Giraldo MD, Sareen T. Ali BS, Anthony K. Kang BA, Tulsi R. Patel BA, Shreya Budhiraja BA, Jordan I. Gaelen BA, Grace K. Lank BS, Jeffrey R. Clark BA, Shreya Mukherjee BA First published: 26 March 2023 – Annals of Neurology https://doi.org/10.1002/ana.26649
AbstractObjectiveTo characterize neurologic manifestations in post-hospitalization Neuro-PASC (PNP) and non-hospitalized Neuro-PASC (NNP) patients.
MethodsProspective study of the first 100 consecutive PNP and 500 NNP patients evaluated at a Neuro-COVID-19 clinic between 5/2020 and 8/2021.
ResultsPNP were older than NNP patients (mean 53.9 vs 44.9 y; p < 0.0001) with a higher prevalence of pre-existing comorbidities. An average 6.8 months from onset, the main neurologic symptoms were “brain fog” (81.2%), headache (70.3%), and dizziness (49.5%) with only anosmia, dysgeusia and myalgias being more frequent in the NNP compared to the PNP group (59 vs 39%, 57.6 vs 39% and 50.4 vs 33%, all p < 0.003). Moreover, 85.8% of patients experienced fatigue. PNP more frequently had an abnormal neurologic exam than NNP patients (62.2 vs 37%, p < 0.0001). Both groups had impaired quality of life in cognitive, fatigue, sleep, anxiety, and depression domains. PNP patients performed worse on processing speed, attention, and working memory tasks than NNP patients (T-score 41.5 vs 55, 42.5 vs 47 and 45.5 vs 49, all p < 0.001) and a US normative population. NNP patients had lower results in attention task only. Subjective impression of cognitive ability correlated with cognitive test results in NNP but not in PNP patients.
InterpretationPNP and NNP patients both experience persistent neurologic symptoms affecting their quality of life. However, they harbor significant differences in demographics, comorbidities, neurologic symptoms and findings, as well as pattern of cognitive dysfunction. Such differences suggest distinct etiologies of Neuro-PASC in these populations warranting targeted interventions. ANN NEUROL 2023
Efficacy and tolerability of an endogenous metabolic modulator (AXA1125) in fatigue-predominant long COVID: a single-centre, double-blind, randomised controlled phase 2a pilot studyLucy E.M. Finnigan,Mark Philip Cassar,Margaret James Koziel,Joel Pradines,Hanan Lamlum,Karim Azer,et al.
Published:April 14, 2023DOI:https://doi.org/10.1016/j.eclinm.2023.101946
SummaryBackground‘Long COVID’ describes persistent symptoms, commonly fatigue, lasting beyond 12 weeks following SARS-CoV-2 infection. Potential causes include reduced mitochondrial function and cellular bioenergetics. AXA1125 has previously increased β-oxidation and improved bioenergetics in preclinical models along with certain clinical conditions, and therefore may reduce fatigue associated with Long COVID. We aimed to assess the efficacy, safety and tolerability of AXA1125 in Long COVID.
MethodsPatients with fatigue dominant Long COVID were recruited in this single-centre, double-blind, randomised controlled phase 2a pilot study completed in the UK. Patients were randomly assigned (1:1) using an Interactive Response Technology to receive either AXA1125 or matching placebo in a clinical based setting. Each dose (33.9 g) of AXA1125 or placebo was administered orally in a liquid suspension twice daily for four weeks with a two week follow-up period. The primary endpoint was the mean change from baseline to day 28 in the phosphocreatine (PCr) recovery rate following moderate exercise, assessed by 31P-magnetic resonance spectroscopy (MRS). All patients were included in the intention to treat analysis. This trial was registered at ClinicalTrials.gov, NCT05152849.
FindingsBetween December 15th 2021, and May 23th 2022, 60 participants were screened and 41 participants were randomised and included in the final analysis. Changes in skeletal muscle phosphocreatine recovery time constant (τPCr) and 6-min walk test (6MWT) did not significantly differ between treatment (n = 21) and placebo group (n = 20). However, treatment with AXA1125 was associated with significantly reduced day 28 Chalder Fatigue Questionnaire [CFQ-11] fatigue score when compared with placebo (least squares mean difference [LSMD] −4.30, 95% confidence interval (95% CI) −7.14, −1.47; P = 0.0039). Eleven (52.4%, AXA1125) and four (20.0%, placebo) patients reported treatment-emergent adverse events; none were serious, or led to treatment discontinuation.
InterpretationAlthough treatment with AXA1125 did not improve the primary endpoint (τPCr-measure of mitochondrial respiration), when compared to placebo, there was a significant improvement in fatigue-based symptoms among patients living with Long COVID following a four week treatment period. Further multicentre studies are needed to validate our findings in a larger cohort of patients with fatigue-dominant Long COVID.
High risk of autoimmune diseases after COVID-19 Chetan Sharma & Jagadeesh Bayry Nature Reviews Rheumatology (2023)Cite this articleThe full picture of post-COVID-19 autoimmune diseases and their prevalence is lacking despite numerous case reports and small series. Two studies that use large cohorts now highlight that SARS-CoV-2 infection is linked to a substantially increased risk of developing a diverse spectrum of new-onset autoimmune diseases.
Refers to: Chang, R. et al. Risk of autoimmune diseases in patients with COVID-19: a retrospective cohort study. eClinicalMedicine 56, 101783 (2023).
The triggering of autoimmune conditions by viral infections has been of interest to the scientific community for decades. The COVID-19 pandemic provides a unique opportunity to understand this link and the underlying pathogenesis. SARS-CoV-2 infection leads to a spectrum of symptoms in the host, with respiratory symptoms dominating the clinical picture. SARS-CoV-2 was originally thought to mostly cause respiratory illness, with comparisons being made to common influenza. However, in a steep learning curve, the spectrum of SARS-CoV-2 infection was observed to range from self-limiting mild infection to critical respiratory distress, with symptoms including fever, cough, myalgia, fatigue and dyspnea1. Severe COVID-19 cases have demonstrated a substantial inflammatory response with pro-inflammatory cytokines and chemokines that stimulate pulmonary inflammation1. As the burden of COVID-19 cases increases worldwide, so does our understanding of the condition. Owing to worldwide vaccination efforts, mortality due to COVID-19 has been decreasing, but we continue to witness considerable morbidity and increased rates of post-COVID-19 conditions and in particular, new-onset autoimmune and inflammatory diseases in individuals who have had COVID-19. The range and incidence of these post-COVID-19 disorders have now been highlighted in two large retrospective cohort studies2,3.
Some of the earliest evidence that SARS-CoV-2 infection leads to dysregulated immune responses came from paediatric patients who presented with multisystem inflammatory syndrome in children (MIS-C), which, as the name indicates, involves diffuse organ system involvement and a clinical spectrum that overlaps with other hyperinflammatory syndromes, such as Kawasaki disease, toxic-shock syndrome, and macrophage activation syndrome4. Since the start of the pandemic, many researchers have also reported isolated cases of adults with various post-COVID-19 autoimmune conditions5. But like the tip of an iceberg, the true spectrum of autoimmune conditions, their prevalence, and the risk of their development in individuals with COVID-19 as compared with those without remain unknown. Lack of data from a large cohort of individuals was the main stumbling block to precisely understanding these facts. Using electronic health record data from large cohorts of individuals, Chang et al.2 and Tesch et al.3 attempted to fill this important gap.
Chang et al.2 used the TriNetX network, which maintains the largest global COVID-19 dataset, and identified a study population of over 5.9 million adults from 48 global health care organizations. Propensity score matching was used to generate two cohorts (COVID-19 and non-COVID-19) of 887,455 individuals each to identify the incidence of autoimmune conditions during the study period (1 January 2020 to 31 December 2021). As SARS-CoV-2 vaccination could be a potential confounding factor, only unvaccinated individuals were included in the analyses. The incidence of autoimmune conditions at 6 months follow-up was significantly higher in the COVID-19 cohort than in the non-COVID-19 group. The unique aspect of the autoimmune diseases after exposure to SARS-CoV-2, as compared with other previously known viral pathogens (such as coxsackie type 1, coronaviruses and Epstein–Barr virus), is the spectrum of conditions seen. In this COVID-19 cohort, an entire range of autoimmune conditions was noted, including rheumatoid arthritis (adjusted hazard ratio (aHR) 2.98; 95% confidence interval (CI) 2.78–3.20), systemic lupus erythematosus (aHR 2.99; 95% CI 2.68–3.34) and vasculitis (aHR 1.96; 95% CI 1.74–2.20) as well as inflammatory bowel disease (aHR 1.78; 95% CI 1.72–1.84) and type 1 diabetes mellitus (aHR 2.68; 95% CI 2.51–2.85)2. The risk of autoimmune conditions was generally consistent across all age groups.
A similar study by Tesch et. al.3, which has not yet been peer-reviewed, evaluated a cohort of 640,701 vaccination-naive individuals with PCR-confirmed COVID-19 during 2020 for the risk of autoimmune conditions. The researchers identified a 42.6% higher likelihood of acquiring an autoimmune condition 3–15 months after infection compared with a non-COVID-19 cohort of 1,560,357 individuals matched for age, sex and whether they had a preexisting autoimmune disease3. The highest incidence rate ratios were found for vasculitis conditions, which are relatively rare autoimmune diseases. The results also emphasize that among individuals with preexisting autoimmune conditions, COVID-19 increased the risk of developing another autoimmune disease by 23%. Owing to the inherent nature of their design (retrospective cohort), these two studies do not prove a causal link between SARS-CoV-2 and the development of autoimmune diseases; however, based on the temporal association with a history of COVID-19, they provide compelling and reliable evidence that SARS-CoV-2 infection is linked to a substantially increased risk of developing diverse new-onset autoimmune diseases after the acute phase of SARS-CoV-2 infection.
In general, autoimmune and inflammatory pathologies have been linked to various infectious diseases, including COVID-19. Therefore, most of the autoimmune conditions listed in these articles are not specific for COVID-19. But an important aspect of COVID-19 is a notable increase in the overall incidence and range of autoimmune conditions in individuals after infection. Various theories have been proposed to explain the molecular basis of COVID-19-related immune dysregulation, which include molecular mimicry by viral proteins, systemic manifestation and multiorgan involvement of COVID-19 due to widespread expression of the SARS-CoV-2 receptor ACE2, bystander activation of immune cells, release of autoantigens from tissue damaged by the virus, superantigen-mediated activation of lymphocytes and epitope spreading6,7. In addition, a variety of host factors such as age, comorbidities and genetic factors may also contribute. Liu et al.8 compared similarities in the immune response in COVID-19 and autoimmune disease and concluded that organ damage in COVID-19 is largely immune-mediated, similar to autoimmune diseases. They also highlighted the detection of various autoantibodies in individuals with COVID-19 (such as antinuclear antibodies, lupus anticoagulant cold agglutinins and anti-Ro/SSA antibodies) that are also seen in autoimmune conditions.
The reports by Chang et al.2 and Tesch et al.3 provide a comprehensive overview of diverse new-onset autoimmune conditions after COVID-19. In addition, an earlier preprint of a retrospective matched cohort analysis using data from the Clinical Practice Research Datalink Aurum database of 458,147 SARS-CoV-2-infected and 1,818,929 uninfected adults across England between 31 January 2020 and 30 June 2021 reported that the incidence of type 1 diabetes mellitus, inflammatory bowel disease and psoriasis are significantly associated with SARS-CoV-2 infection9. All these studies should prompt various national health authorities to conduct similar studies to obtain nationwide data. Although the definitive molecular mechanisms such as genetic and epigenetic predisposition and pathophysiology are still unknown, the many potential theories suggest future investigations using specific gene-deficient experimental animal models, bioinformatics and systems biology approaches. For example, by analyses of more than 45,000 transcriptomic datasets of viral pandemics, Ghosh et al.10 extracted a 166-gene signature panel to evaluate the host immune response to viral triggers. Importantly, with the exception of MIS-C, the new-onset autoimmune diseases reported to follow COVID-19 are known entities and effective treatments are already available for many of them. Even for MIS-C, owing to overlapping symptoms with Kawasaki disease, patients with MIS-C receive many of the treatments that were established for Kawasaki disease4. Therefore, understanding how COVID-19 affects the risk of post-COVID-19 complications such as autoimmune disease will help to implement preventive measures and early treatment in individuals who have had COVID-19 to prevent morbidity and mortality. This knowledge will also be highly pertinent for future pandemics and for analysing the long-term effects of SARS-CoV-2 vaccines, particularly those that obtained emergency use authorization without undergoing vigorous clinical trials.
Explanation Proposed for Long-COVID Symptoms in the CNS
Ted Bosworth April 25, 2023 Medscape medical news
BOSTON — The neurologic symptoms of long COVID appear to be explained by a phenomenon known as antigenic imprinting, which involves a misdirected immune response to the SARS-CoV2 virus, according to a collaborative study presented at the 2023 annual meeting of the American Academy of Neurology.
Already documented in several other viral infections, such as influenza and human immunodeficiency virus, antigenic imprinting results in production of antibodies to previously encountered viral infections rather than to the immediate threat, according to Marianna Spatola, MD, PhD, a research fellow at the Ragon Institute, Harvard University, Cambridge, Mass.
Original antigenic sin
In the case of persistent neurologic symptoms after COVID, a condition known as neuroPASC (neurological postacute sequelae of SARS-CoV2 infection), antibodies produced for previously encountered coronaviruses rather than for SARS-CoV2 might explain most or all cases, according to the data Dr. Spatola presented.
The evidence for this explanation was drawn from a study of 112 patients evaluated months after an acute episode of COVID-19. Of these, 18 patients had persistent neurologic dysfunction. When compared with the 94 whose infection resolved without sequelae, the patients with prolonged neurologic impairments had relatively low systemic antibody response to SARS-CoV2. However, they showed relatively high antibody responses against other coronaviruses.
This is a pattern consistent with antigenic imprinting, a concept first described more than 60 years ago as original antigenic sin. When the immune system becomes imprinted with an antigen from the first encountered virus from a family of pathogens, it governs all subsequent antibody responses, according to several published studies that have described and evaluated this concept.
In Dr. Spatola's study, other differences, particularly in regard to the cerebrospinal fluid (CSF), further supported the role of antigenic imprinting as a cause of neuroPASC. For one, those with elevated immune responses to other common coronaviruses rather than SARS-CoV2 in the CSF relative to the periphery were more likely to have a bad outcome in regard to neurologic symptoms.
Moreover, the CSF in neuroPASC patients "was characterized by increased IgG1 and absence of IgM, suggesting compartmentalized humoral responses within the CSF through selective transfer of antibodies from the serum to the CSF across the blood-brain barrier rather than through intrathecal synthesis," Dr. Spatola reported.
In the case of COVID-19, the propensity for antigenic imprinting is not difficult to understand.
"The common cold coronaviruses are pretty similar to SARS-CoV2, but they are not exactly the same," Dr. Spatola said. Her work and studies by others suggest that when antigenic imprinting occurs, "it prevents full maturation of the antibody response."
NeuroPASC is one of many manifestations of long COVID, but Dr. Spatola pointed out that the immune response in the CSF is unique and the causes of prolonged neurologic impairment after COVID-19 are likely to involve different mechanisms than other long-COVID symptoms.
"Antibodies in the brain are functionally different," said Dr. Spatola, noting for example that antibody-directed defenses against viral threats show a greater relative reliance on phagocytosis. This might become important in the development of therapeutics for neurologic symptoms of long COVID.
A different phenomenonThe manifestations of neuroPASC are heterogeneous and can include confusion, cognitive dysfunction, headache, encephalitis, and other impairments. Neurologic symptoms occur during acute SARS-CoV2 infections, but neuroPASC appears to be a different phenomenon. These symptoms, which develop after the initial respiratory disease has resolved, were attributed by Dr. Spatola to persistent inflammation that is not necessarily directly related to ongoing infection.
"The reason why some patients develop neuroPASC is unknown, but I think the evidence has pointed to a role for the immune system rather than the virus itself," Dr. Spatola said.
Currently, neuroPASC is a clinical diagnosis but Dr. Spatola and her coinvestigators are conducting research to identify biomarkers. A viable diagnostic test is not expected imminently. They have identified 150 different features with potential relevance to neuroPASC.
In their comparison of those who did relative to those who did not develop neuroPASC, the initial studies were undertaken 2-4 months after the acute COVID-19 symptoms had resolved. The patients with neuroPASC and those without neurologic sequelae have now been followed for 6-8 months, which Dr. Spatola said was too short to draw firm conclusions about outcomes.
An evolving conceptDespite the small sample size of this study, these are "very interesting data" for considering the pathogenesis of neuroPASC, which is "a concept that is still evolving," according to Natalia S. Rost, MD, chief of the stroke division, department of neurology, Massachusetts General Hospital, Boston.
Applied to SARS-CoV2, the concept of original antigenic sin "is new" but Dr. Rost said that it might help differentiate neuroPASC from acute neurologic symptoms of COVID-19, which include stroke. She indicated that the work performed by Dr. Spatola and others might eventually explain the pathology while leading to treatment strategies. She cautioned that the concepts explored in this study "need to be further developed" through larger sample sizes and the exploration of other variables that support the hypothesis.
Dr. Spatola and Dr. Rost report no potential conflicts of interest.
This article originally appeared on MDedge.com, part of the Medscape Professional Network.
Medicina (Kaunas) . 2023 Mar 15;59(3):571. doi: 10.3390/medicina59030571.
Recovery from Exercise in Persons with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)Geoffrey E Moore 1, Betsy A Keller 1 2, Jared Stevens 3, Xiangling Mao 4, Staci R Stevens 3, John K Chia 5, Susan M Levine 6, Carl J Franconi 1, Maureen R Hanson 1
Affiliations expand PMID: 36984572 PMCID: PMC10059925 DOI: 10.3390/medicina59030571
AbstractBackground and Objectives: Post-exertional malaise (PEM) is the hallmark of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), but there has been little effort to quantitate the duration of PEM symptoms following a known exertional stressor. Using a Symptom Severity Scale (SSS) that includes nine common symptoms of ME/CFS, we sought to characterize the duration and severity of PEM symptoms following two cardiopulmonary exercise tests separated by 24 h (2-day CPET). Materials and Methods: Eighty persons with ME/CFS and 64 controls (CTL) underwent a 2-day CPET. ME/CFS subjects met the Canadian Clinical Criteria for diagnosis of ME/CFS; controls were healthy but not participating in regular physical activity. All subjects who met maximal effort criteria on both CPETs were included. SSS scores were obtained at baseline, immediately prior to both CPETs, the day after the second CPET, and every two days after the CPET-1 for 10 days. Results: There was a highly significant difference in judged recovery time (ME/CFS = 12.7 ± 1.2 d; CTL = 2.1 ± 0.2 d, mean ± s.e.m., Chi2 = 90.1, p < 0.0001). The range of ME/CFS patient recovery was 1-64 days, while the range in CTL was 1-10 days; one subject with ME/CFS had not recovered after one year and was not included in the analysis. Less than 10% of subjects with ME/CFS took more than three weeks to recover. There was no difference in recovery time based on the level of pre-test symptoms prior to CPET-1 (F = 1.12, p = 0.33). Mean SSS scores at baseline were significantly higher than at pre-CPET-1 (5.70 ± 0.16 vs. 4.02 ± 0.18, p < 0.0001). Pharmacokinetic models showed an extremely prolonged decay of the PEM response (Chi2 > 22, p < 0.0001) to the 2-day CPET. Conclusions: ME/CFS subjects took an average of about two weeks to recover from a 2-day CPET, whereas sedentary controls needed only two days. These data quantitate the prolonged recovery time in ME/CFS and improve the ability to obtain well-informed consent prior to doing exercise testing in persons with ME/CFS. Quantitative monitoring of PEM symptoms may provide a method to help manage PEM.
Keywords: 2-day cardiopulmonary exercise test; chronic fatigue syndrome; exercise recovery; myalgic encephalomyelitis; post-exertional malaise; specific symptom severity.
Two symptoms can accurately identify post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndromeIssue title: Special Section: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID
Guest editors: Amy Mooney
Article type: Research Article
Authors: Davenport, Todd E.a; b; * | Chu, Lilyc | Stevens, Staci R.b | Stevens, Jaredb | Snell, Christopher R.b | Van Ness, J. Marka; b
Affiliations: [a] University of the Pacific, Stockton, CA, USA | [b] Workwell Foundation, Ripon, CA, USA | [c] Independent Consultant, Burlingame, CA, USA
Correspondence: [*] Address for correspondence: Todd E. Davenport, University of the Pacific, Stockton, CA, USA. E-mail: email@example.com.
Keywords: Myalgic encephalomyelitis, chronic fatigue syndrome, post-exertional malaise, symptoms, diagnosis
Journal: Work, vol. 74, no. 4, pp. 1199-1213, 2023
Received 28 September 2022 Accepted 8 November 2022 Published: 18 April 2023
AbstractBACKGROUND:Post-exertional malaise (PEM) is the hallmark symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) yet its diverse manifestations make it difficult to recognize. Brief instruments for detecting PEM are critical for clinical and scientific progress.
OBJECTIVE:To develop a clinical prediction rule for PEM.
METHOD:49 ME/CFS and 10 healthy, sedentary subjects recruited from the community completed two maximal cardiopulmonary exercise tests (CPETs) separated by 24 hours. At five different times, subjects reported symptoms which were then classified into 19 categories. The frequency of symptom reports between groups at each time point was compared using Fisher’s exact test. Receiver operating characteristics (ROC) analysis with area under the curve calculation was used to determine the number of different types of symptom reports that were sufficient to differentiate between ME/CFS and sedentary groups. The optimal number of symptoms was determined where sensitivity and specificity of the types of symptom reports were balanced.
RESULTS:At all timepoints, a maximum of two symptoms was optimal to determine differences between groups. Only one symptom was necessary to optimally differentiate between groups at one week following the second CPET. Fatigue, cognitive dysfunction, lack of positive feelings/mood and decrease in function were consistent predictors of ME/CFS group membership across timepoints.
CONCLUSION:Inquiring about post-exertional cognitive dysfunction, decline in function, and lack of positive feelings/mood may help identify PEM quickly and accurately. These findings should be validated with a larger sample of patients.
Chest 2023 Apr 11;S0012-3692(23)00502-0. doi: 10.1016/j.chest.2023.03.049.
Exercise Pathophysiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post-Acute Sequelae of SARS-CoV-2: More in Common Than Not?Phillip Joseph 1, Inderjit Singh 1, Rudolf Oliveira 2, Christine A Capone 3, Mary P Mullen 4, Dane B Cook 5, Mary Catherine Stovall 6, Johanna Squires 6, Kristine Madsen 6, Aaron B Waxman 6, David M Systrom 7
PMID: 37054777 PMCID: PMC10088277
AbstractTopic importance: Post-Acute Sequelae of SARS-CoV-2 (PASC) is a long-term consequence of acute infection from coronavirus disease 2019 (COVID-19). Clinical overlap between PASC and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has been observed, with shared symptoms including intractable fatigue, postexertional malaise, and orthostatic intolerance. The mechanistic underpinnings of such symptoms are poorly understood.
Review findings: Early studies suggest deconditioning as the primary explanation for exertional intolerance in PASC. Cardiopulmonary exercise testing (CPET) reveals perturbations related to systemic blood flow and ventilatory control associated with acute exercise intolerance in PASC, which are not typical of simple detraining. Hemodynamic and gas exchange derangements in PASC have substantial overlap with those observed with ME/CFS, suggestive of shared mechanisms.
Summary: This review aims to illustrate exercise pathophysiologic commonalities between PASC and ME/CFS that will help guide future diagnostics and treatment.
Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.
Autoimmunity Reviews Volume 21, Issue 3, March 2022, 103015The autoimmune aetiology of unexplained chronic painAndreas Goebel a 1, David Andersson b 1, Zsuzsanna Helyes c 1, J. David Clark d 1, Debra Dulake e 1, Camilla Svensson f 1
https://doi.org/10.1016/j.autrev.2021.103015Get rights and content
Chronic pain is the leading cause of life years lived with disability worldwide. The aetiology of most chronic pain conditions has remained poorly understood and there is a dearth of effective therapies. The WHO ICD-11 has categorised unexplained chronic pain states as ‘chronic primary pains’ (CPP), which are further defined by their association with significant distress and/or dysfunction. The new mechanistic term, ‘nociplasticic pain’ has been developed to illustrate their presumed generation by a structurally intact, but abnormally functioning nociceptive system. Recently, researchers have unravelled the surprising, ubiquitous presence of pain-sensitising autoantibodies in four investigated CPP indicating autoimmune causation. In persistent complex regional pain syndrome, fibromyalgia syndrome, chronic post-traumatic limb pain, and non-inflammatory joint pain associated with rheumatoid arthritis, passive transfer experiments have shown that either IgG or IgM antibodies from patient-donors cause symptoms upon injection to rodents that closely resemble those of the clinical disorders. Targets of antibody-binding and downstream effects vary between conditions, and more research is needed to elucidate the molecular and cellular details. The central nervous system appears largely unaffected by antibody binding, suggesting that the clinically evident CNS symptoms associated with CPP might arise downstream of peripheral processes. In this narrative review pertinent findings are described, and it is suggested that additional symptom-based disorders might be examined for the contribution of antibody-mediated autoimmune mechanisms.
J Clin Invest . 2023 Feb 1;133(3):e163669. doi: 10.1172/JCI163669.
Chronic viral coinfections differentially affect the likelihood of developing long COVIDMichael J Peluso 1, Tyler-Marie Deveau 2, Sadie E Munter 2, Dylan Ryder 2, Amanda Buck 2, Gabriele Beck-Engeser 2, Fay Chan 2, Scott Lu 3, Sarah A Goldberg 3, Rebecca Hoh 1, Viva Tai 1, Leonel Torres 2, Nikita S Iyer 2, Monika Deswal 1, Lynn H Ngo 1, Melissa Buitrago 1, Antonio Rodriguez 1, Jessica Y Chen 1, Brandon C Yee 4, Ahmed Chenna 4, John W Winslow 4, Christos J Petropoulos 4, Amelia N Deitchman 5, Joanna Hellmuth 6, Matthew A Spinelli 1, Matthew S Durstenfeld 7, Priscilla Y Hsue 7, J Daniel Kelly 3, Jeffrey N Martin 3, Steven G Deeks 1, Peter W Hunt 2, Timothy J Henrich 2
- PMID: 36454631 PMCID: PMC9888380 Abstract
. 2023;74(4):1179-1186. doi: 10.3233/WOR-220581.
Post-exertional malaise among people with long COVID compared to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)Suzanne D Vernon 1, Megan Hartle 2, Karen Sullivan 1, Jennifer Bell 1, Saeed Abbaszadeh 1, Derya Unutmaz 3 4, Lucinda Bateman 1 PMID: 36911963
Background: Long COVID describes a condition with symptoms that linger for months to years following acute COVID-19. Many of these Long COVID symptoms are like those experienced by patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Objective: We wanted to determine if people with Long COVID experienced post-exertional malaise (PEM), the hallmark symptom of ME/CFS, and if so, how it compared to PEM experienced by patients with ME/CFS.
Methods: A questionnaire that asked about the domains of PEM including triggers, experience, recovery, and prevention was administered to 80 people seeking care for Long COVID at Bateman Horne Center. Their responses were compared to responses about PEM given by 151 patients with ME/CFS using chi-square tests of independence.
Results: All but one Long COVID respondent reported having PEM. There were many significant differences in the types of PEM triggers, symptoms experienced during PEM, and ways to recover and prevent PEM between Long COVID and ME/CFS. Similarities between Long COVID and ME/CFS included low and medium physical and cognitive exertion to trigger PEM, symptoms of fatigue, pain, immune reaction, neurologic, orthostatic intolerance, and gastrointestinal symptoms during PEM, rest to recover from PEM, and pacing to prevent PEM.
Conclusion: People with Long COVID experience PEM. There were significant differences in PEM experienced by people with Long COVID compared to patients with ME/CFS. This may be due to the newness of Long COVID, not knowing what exertional intolerance is or how to manage it.
2023 Mar 16;11(6):865. doi: 10.3390/healthcare11060865.
A Case Study of Successful Application of the Principles of ME/CFS Care to an Individual with Long COVIDLindsay S Petracek 1, Camille A Broussard 1, Renee L Swope 1, Peter C Rowe 1
PMID: 36981522 PMCID: PMC10048325
AbstractPersistent fatigue is one of the most common symptoms of post-COVID conditions, also termed long COVID. At the extreme end of the severity spectrum, some individuals with long COVID also meet the criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), raising the possibility that symptom management approaches for ME/CFS may benefit some long COVID patients. We describe the long-term outcomes of a 19-year-old male who developed profound impairment consistent with ME/CFS after a SARS-CoV-2 infection early in the pandemic. We evaluated and treated him using our clinic's approach to ME/CFS. This included a history and physical examination that ascertained joint hypermobility, pathological reflexes, physical therapy maneuvers to look for a range of motion restrictions in the limbs and spine, orthostatic testing, and screening laboratory studies. He was found to have profound postural tachycardia syndrome, several ranges of motion restrictions, and mast cell activation syndrome. He was treated according to our clinic's guidelines for managing ME/CFS, which included manual physical therapy maneuvers and both non-pharmacologic measures and medications directed at postural tachycardia syndrome and mast cell activation. He experienced significant improvement in his symptoms over 30 months. His case emphasizes how the application of the principles of treating ME/CFS has the potential to provide a direction for treating long COVID.
Neutrophils infiltrate sensory ganglia and mediate chronic widespread pain in fibromyalgiaSara Caxaria, Sabah Bharde https://orcid.org/0000-0001-5852-5932, Alice M. Fuller, +8, and Shafaq Sikandar
Edited by Allan Basbaum, University of California San Francisco, San Francisco, CA; received July 7, 2022; accepted February 5, 2023
April 18, 2023 120 (17) e2211631120 https://doi.org/10.1073/pnas.2211631120 Vol. 120 | No. 17
SignificanceWe used a back-translational approach in mice to demonstrate the pronociceptive role of neutrophils in fibromyalgia. Adoptive transfer of neutrophils from mice with chronic widespread pain or from patients with fibromyalgia can confer mechanical pain to recipient naïve mice, sensitize evoked action potential firing of spinal cord neurons, and produce phenotypic changes in cell surface expression of neutrophil proteins that cause infiltration of neutrophils into dorsal root ganglia. These data provide the framework for an immunological basis of chronic widespread pain in fibromyalgia mediated by polymorphonuclear granulocytes.
AbstractFibromyalgia is a debilitating widespread chronic pain syndrome that occurs in 2 to 4% of the population. The prevailing view that fibromyalgia results from central nervous system dysfunction has recently been challenged with data showing changes in peripheral nervous system activity. Using a mouse model of chronic widespread pain through hyperalgesic priming of muscle, we show that neutrophils invade sensory ganglia and confer mechanical hypersensitivity on recipient mice, while adoptive transfer of immunoglobulin, serum, lymphocytes, or monocytes has no effect on pain behavior. Neutrophil depletion abolishes the establishment of chronic widespread pain in mice. Neutrophils from patients with fibromyalgia also confer pain on mice. A link between neutrophil-derived mediators and peripheral nerve sensitization is already established. Our observations suggest approaches for targeting fibromyalgia pain via mechanisms that cause altered neutrophil activity and interactions with sensory neurons.
Low Vitamin D Levels Are Associated With Long COVID Syndrome in COVID-19 Survivors Luigi di Filippo, Stefano Frara, Fabrizio Nannipieri, Alice Cotellessa, Massimo Locatelli, Patrizia Rovere Querini, Andrea Giustina
The Journal of Clinical Endocrinology & Metabolism, dgad207, https://doi.org/10.1210/clinem/dgad207 Published: 13 April 2023
Long COVID is an emerging syndrome affecting 50% to 70% of COVID-19 survivors that still lacks predicting factors.
Due to the extraskeletal effects of vitamin D, we retrospectively assessed the association between 25(OH) vitamin D levels and long COVID in COVID-19 survivors 6 months after hospitalization.
Long COVID was defined according to NICE guidelines. Fifty long COVID and 50 non–long-COVID subjects matched on a 1:1 basis were enrolled from an outpatient clinic post-COVID cohort seen from August to November 2020. Therapies/comorbidities affecting calcium/vitamin D/bone metabolism, and/or admission to the intensive care unit during hospitalization were exclusion criteria. 25(OH) Vitamin D was measured at hospital admission and 6 months after discharge.
We observed lower 25(OH) vitamin D levels, evaluated at follow-up, in subjects with long COVID than those without (20.1 vs 23.2 ng/mL, P = .03). Regarding the affected health areas evaluated in the entire cohort, we observed lower 25(OH) vitamin D levels in those with neurocognitive symptoms at follow-up (n = 7) than those without (n = 93) (14.6 vs 20.6 ng/mL, P = .042). In patients presenting vitamin D deficiency (<20 ng/mL), both at admission and at follow-up (n = 42), those affected by long COVID (n = 22) presented lower 25(OH) vitamin D levels at follow-up than those not affected (n = 20) (12.7 vs 15.2 ng/mL, P = .041). In multiple regression analyses, lower 25(OH) vitamin D levels at follow-up were the only variable significantly associated with long COVID in our cohort (P = .008, OR 1.09, CI 1.01-1.16).
COVID-19 survivors with long COVID have lower 25(OH) vitamin D levels than matched patients without long COVID. Our data suggest that vitamin D levels should be evaluated in COVID-19 patients after hospital discharge. The role of vitamin D supplementation as a preventive strategy of COVID-19 sequelae should be tested in randomized controlled trials.
Nat Commun. 2023; 14: 1772. Published online 2023 Mar 30. doi: 10.1038/s41467-023-37368-1 PMCID: PMC10061413 PMID: 36997530
Post-acute sequelae of COVID-19 is characterized by diminished peripheral CD8+β7 integrin+ T cells and anti-SARS-CoV-2 IgA responseAndré Santa Cruz, #1,2,3,4 Ana Mendes-Frias,#1,2 Marne Azarias-da-Silva,5 Sónia André,5 Ana Isabel Oliveira,3 Olga Pires,3 Marta Mendes,3 Bárbara Oliveira,3 Marta Braga,3 Joana Rita Lopes,3 Rui Domingues,3 Ricardo Costa,3 Luís Neves Silva,3 Ana Rita Matos,3 Cristina Ângela,3 Patrício Costa,1,2 Alexandre Carvalho,1,2,3,4 Carlos Capela,1,2,3,4 Jorge Pedrosa,1,2 António Gil Castro,1,2 Jérôme Estaquier, 5,6 and Ricardo Silvestre 1,2AbstractSeveral millions of individuals are estimated to develop post-acute sequelae SARS-CoV-2 condition (PASC) that persists for months after infection. Here we evaluate the immune response in convalescent individuals with PASC compared to convalescent asymptomatic and uninfected participants, six months following their COVID-19 diagnosis. Both convalescent asymptomatic and PASC cases are characterised by higher CD8+ T cell percentages, however, the proportion of blood CD8+ T cells expressing the mucosal homing receptor β7 is low in PASC patients. CD8 T cells show increased expression of PD-1, perforin and granzyme B in PASC, and the plasma levels of type I and type III (mucosal) interferons are elevated. The humoral response is characterized by higher levels of IgA against the N and S viral proteins, particularly in those individuals who had severe acute disease. Our results also show that consistently elevated levels of IL-6, IL-8/CXCL8 and IP-10/CXCL10 during acute disease increase the risk to develop PASC. In summary, our study indicates that PASC is defined by persisting immunological dysfunction as late as six months following SARS-CoV-2 infection, including alterations in mucosal immune parameters, redistribution of mucosal CD8+β7Integrin+ T cells and IgA, indicative of potential viral persistence and mucosal involvement in the etiopathology of PASC.
News > Medscape
André Santa Cruz, #1,2,3,4 Ana Mendes-Frias,#1,2 Marne Azarias-da-Silva,5 Sónia André,5 Ana Isabel Oliveira,3 Olga Pires,3 Marta Mendes,3 Bárbara Oliveira,3 Marta Braga,3 Joana Rita Lopes,3 Rui Domingues,3 Ricardo Costa,3 Luís Neves Silva,3 Ana Rita Matos,3 Cristina Ângela,3 Patrício Costa,1,2 Alexandre Carvalho,1,2,3,4 Carlos Capela,1,2,3,4 Jorge Pedrosa,1,2 António Gil Castro,1,2 Jérôme Estaquier, 5,6 and Ricardo Silvestre 1,2
Several millions of individuals are estimated to develop post-acute sequelae SARS-CoV-2 condition (PASC) that persists for months after infection. Here we evaluate the immune response in convalescent individuals with PASC compared to convalescent asymptomatic and uninfected participants, six months following their COVID-19 diagnosis. Both convalescent asymptomatic and PASC cases are characterised by higher CD8+ T cell percentages, however, the proportion of blood CD8+ T cells expressing the mucosal homing receptor β7 is low in PASC patients. CD8 T cells show increased expression of PD-1, perforin and granzyme B in PASC, and the plasma levels of type I and type III (mucosal) interferons are elevated. The humoral response is characterized by higher levels of IgA against the N and S viral proteins, particularly in those individuals who had severe acute disease. Our results also show that consistently elevated levels of IL-6, IL-8/CXCL8 and IP-10/CXCL10 during acute disease increase the risk to develop PASC. In summary, our study indicates that PASC is defined by persisting immunological dysfunction as late as six months following SARS-CoV-2 infection, including alterations in mucosal immune parameters, redistribution of mucosal CD8+β7Integrin+ T cells and IgA, indicative of potential viral persistence and mucosal involvement in the etiopathology of PASC.
News > Medscape Medical News
New Guidance on Neurological Complications of Long-COVIDAlicia Ault May 18, 2023
The American Academy of Physical Medicine and Rehabilitation (AAPM&R) has issued new consensus guidance on the assessment and treatment of neurologic sequelae in patients with long COVID, also known as post-acute sequelae of SARS-CoV-2 infection (PASC).
The new recommendations, which were published online May 16 in Physical Medicine & Rehabilitation, are the result of a collaboration between experts from a variety of medical specialties at 41 long COVID clinics across the US.
Because physical medicine specialists treat individuals with disability and functional impairments, the AAPM&R was among the first organizations to initiate guidance for the assessment and treatment of long COVID and issued its first consensus statement that addressed long COVID-related fatigue in 2021.
Even though the number of COVID cases and hospitalizations has declined from the peak, long COVID continues to be a major public health issue, Steven Flanagan, MD, AAPM&R president-elect and Howard A. Rusk Professor of Rehabilitation Medicine at NYU Grossman School of Medicine, New York City, told reporters attending a press briefing.
"There is some evidence that some of the antivirals may actually help reduce the incidence but not everybody gets them," said Flanagan, in a briefing with reporters. "In our own clinic here, we continue to see many, many people with problems associated with long COVID," he added.
According to the consensus guidelines, about 80% of patients hospitalized with acute COVID-19 have neurological symptoms. But these symptoms are not just limited to people who had severe illness, said Leslie Rydberg, MD, co-author of the neurology long COVID guidance statement.
"What we know is that many people with mild or moderate COVID infection end up with neurologic sequelae that last longer than 4 weeks," said Rydberg, the Henry and Monika Betts Medical Student Education Chair and assistant residency program director at Shirley Ryan AbilityLab, Chicago, Illinois.
Rydberg added that patients who have symptoms for longer than a month after the initial infection should be evaluated. Although the definition of what constitutes PASC is evolving, the guidance states that the literature indicates that it should be defined as the persistence of symptoms 4 weeks beyond the initial infection.
The most common neurological symptoms are headache, weakness, muscular pain, nerve pain, tremors, peripheral nerve issues, sleep issues, and cognitive effects, Rydberg told reporters.
She added that "identifying patients with progressive or ominous 'red flag' neurological symptoms is essential for emergent triaging."
Among the red flags are sudden or progressive weakness or sudden or progressive sensory changes, because those could indicate an acute neurologic condition — either due to long COVID or other illnesses — such as a stroke or a problem with the spinal cord, Guillain-Barre syndrome, or myopathy.
While those signs and symptoms would likely be flagged by most clinicians, some of the emergent or urgent signs — such as upper motor neuron changes on physical exam — are more subtle, said Rydberg.
The new guidance spells out steps for initial evaluation, including identification of red flag symptoms, and also provides treatment recommendations.
Experts also recommend clinicians do the following:
- Treat underlying medical conditions such as pain, psychiatric, cardiovascular, respiratory, and other conditions that may be contributing to neurologic symptoms.
- Consider polypharmacy reduction, looking especially closely at medications with a known impact on neurologic symptoms.
- Urge patients to get regular physical activity, as tolerated, while avoiding overuse syndrome.
- Work with physical, occupational, and speech therapists to increase function and independence.
- Refer patients to counseling and community resources for risk factor modification.
The guidance also includes a special statement on the importance of ensuring equitable access to care. Underserved, marginalized, and socioeconomically disadvantaged communities had notably higher rates of infection, hospitalization, and death with less access to rehabilitation services before the pandemic, said Monica Verduzco-Gutierrez, MD, chair of the Department of Rehabilitation Medicine at the Long School of Medicine at UT Health San Antonio and a guideline co-author.
"We know that these communities have been historically underserved, that there's already access issues, and that they're disproportionately impacted by the pandemic," said Verduzco-Gutierrez. "This continues as patients develop PASC, or long COVID," she said, adding that these individuals are still less likely to receive rehabilitation services. "This can lead to poorer outcomes and widened disparities."
The AAPM&R PASC Multi-Disciplinary Collaborative has previously issued consensus guidance on fatigue, breathing discomfort and respiratory distress, cognitive symptoms, cardiovascular complications, pediatrics, and autonomic dysfunction, and will be publishing guidance on mental health soon.
The collaborative is also putting together a compilation of all the guidance — "a 'greatest hits' if you like," said Verduzco-Gutierrez.
For clinicians who are unaccustomed to caring for patients with long COVID, the hope is that this new guidance will help them manage the condition, Rydberg said.
J Inf Diseases: 2023 May 11;jiad131. doi: 10.1093/infdis/jiad131. Online ahead of print.
Reduced exercise capacity, chronotropic incompetence, and early systemic inflammation in cardiopulmonary phenotype Long COVIDMatthew S Durstenfeld 1 2, Michael J Peluso 1 3, Punita Kaveti 1 4, Christopher Hill 5, Danny Li 2, Erica Sander 4, Shreya Swaminathan 2, Victor M Arechiga 2, Scott Lu 3, Sarah A Goldberg 5, Rebecca Hoh 2, Ahmed Chenna 6, Brandon C Yee 6, John W Winslow 6, Christos J Petropoulos 6, J Daniel Kelly 7 8 9, David V Glidden 10, Timothy J Henrich 1 9, Jeffrey N Martin 10, Yoo Jin Lee 11, Mandar A Aras 1 4, Carlin S Long 1 4, Donald J Grandis 1 4, Steven G Deeks 1 3, Priscilla Y Hsue 1 2
Affiliations expand PMID: 37166076
AbstractBackground: Mechanisms underlying persistent cardiopulmonary symptoms following SARS-CoV-2 infection (post-acute sequelae of COVID-19 "PASC" or "Long COVID") remain unclear. This study sought to elucidate mechanisms of cardiopulmonary symptoms and reduced exercise capacity.
Methods: We conducted cardiopulmonary exercise testing (CPET), cardiac magnetic resonance imaging (CMR) and ambulatory rhythm monitoring among adults > 1 year after confirmed SARS-CoV-2 infection in a post-COVID cohort, compared those with or without symptoms, and correlated findings with previously measured biomarkers.
Results: Sixty participants (median age 53, 42% female, 87% non-hospitalized) were studied at median 17.6 months following SARS-CoV-2 infection. On CPET, 18/37 (49%) with symptoms had reduced exercise capacity (<85% predicted) compared to 3/19 (16%) without symptoms (p = 0.02). Adjusted peak VO2 was 5.2 ml/kg/min lower (95%CI 2.1-8.3; p = 0.001) or 16.9% lower percent predicted (95%CI 4.3-29.6; p = 0.02) among those with symptoms. Chronotropic incompetence was common. Inflammatory markers and antibody levels early in PASC were negatively correlated with peak VO2 more than 1 year later. Late-gadolinium enhancement on CMR and arrhythmias were absent.
Conclusions: Cardiopulmonary symptoms >1 year following COVID-19 were associated with reduced exercise capacity, which was associated with elevated inflammatory markers early in PASC. Chronotropic incompetence may explain exercise intolerance among some with cardiopulmonary Long COVID.
Keywords: Ebstein-Barr Virus (EBV); Long COVID; Post-acute sequelae of COVID-19; SARS-CoV-2; cardiac ambulatory rhythm monitoring; cardiac magnetic resonance imaging; cardiopulmonary exercise testing; chronotropic incompetence.
IBRO Neuroscience Reports Available online 2 May 2023Orthostatic chronotropic incompetence in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)Author links open overlay panelC. (Linda) M.C. van Campen a, Freek W.A. Verheugt b, Peter C. Rowe c, Frans C. Visser a
https://doi.org/10.1016/j.ibneur.2023.04.005Get rights and content
Adults with ME/CFS experience a 3-fold greater reduction in cerebral blood flow during end-tilt tilt compared to healthy controls, confirming orthostatic intolerance.
During tilt testing we found that in 134/362 (37%) patients with ME/CFS without POTS or hypotension, the heart rate increase was below the lower limit of the 95% prediction interval of the heart rate increase of controls, indicative of orthostatic chronotropic incompetence.
These novel findings represent the first description of orthostatic chronotropic incompetence during tilt testing, confirming another abnormality in the circulatory response to upright posture in ME/CFS.
AbstractBackgroundOrthostatic intolerance (OI) is a core diagnostic criterion in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The majority of ME/CFS patients have no evidence of hypotension or postural orthostatic tachycardia syndrome (POTS) during head-up tilt, but do show a significantly larger reduction in stroke volume index (SVI) when upright compared to controls. Theoretically a reduction in SVI should be accompanied by a compensatory increase in heart rate (HR). When there is an incomplete compensatory increase in HR, this is considered chronotropic incompetence. This study explored the relationship between HR and SVI to determine whether chronotropic incompetence was present during tilt testing in ME/CFS patients.
MethodsFrom a database of individuals who had undergone tilt testing with Doppler measurements for SVI both supine and end-tilt, we selected ME/CFS patients and healthy controls (HC) who had no evidence of POTS or hypotension during the test. To determine the relation between the HR increase and SVI decrease during the tilt test in patients, we calculated the 95% prediction intervals of this relation in HC. Chronotropic incompetence in patients was defined as a HR increase below the lower limit of the 95th % prediction interval of the HR increase in HC.
ResultsWe compared 362 ME/CFS patients with 52 HC. At end-tilt, tilt lasting for 15 (4) min, ME/CFS patients had a significantly lower SVI (22 (4) vs. 27 (4) ml/m2; p<0.0001) and a higher HR (87 (11) vs. 78 (15) bpm; p<0.0001) compared to HC. There was a similar relationship between HR and SVI between ME/CFS patients and HC in the supine position. During tilt ME/CFS patients had a lower HR for a given SVI; 37% had an inadequate HR increase. Chronotropic incompetence was more common in more severely affected ME/CFS patients.
ConclusionThese novel findings represent the first description of orthostatic chronotropic incompetence during tilt testing in ME/CFS patients.
P065 - Post COVID-19 Syndrome in patients with autoimmune rheumatic diseases: Results from the COVID-19 Vaccination in Autoimmune Diseases (COVAD) study
British Society for Rheumatology - Annual Conference 2023 Home
Latika Gupta et al
Background/Aims: Post COVID-19 syndrome (PCS) is an emerging cause of morbidity and poor quality of life in COVID-19 survivors. We aimed to assess the prevalence, risk factors, outcomes, and association with disease flares of PCS in patients with autoimmune rheumatic diseases (AIRDs) and non-rheumatic autoimmune diseases (nrAIDs), both vulnerable groups understudied in the current literature using data from the 2nd COVID-19 Vaccination in Autoimmune Diseases (COVAD) global multicentre patient self-reported e-survey.
Methods: The survey was circulated from February to July 2022 by the international COVAD Study Group (157 collaborators from 106 countries), and demographics, comorbidities, AIRD/nrAID status, COVID-19 history, vaccination details, and PROMIS physical and mental function were recorded. PCS was defined as symptom resolution time >90 days following acute COVID-19. Predictors of PCS were analysed using regression models for the different groups.
Results: 7666 total respondents completed the survey. Of these, 2650 respondents with complete responses had positive COVID-19 infection, and 1677 (45.0% AIRDs, 12.5% nrAIDs, 42.5% HCs) completed the survey >90 days post acute COVID-19. Of these, 136 (8.1%) had PCS. Prevalence of PCS was higher in AIRDs (10.8%) than healthy controls HCs (5.3%) (OR: 2.1; 95%CI: 1.4-3.1, p=0.002).
Across the entire cohort, a higher risk of PCS was seen in women (OR: 2.9; 95%CI: 1.1-7.7, p=0.037), patients with long duration of AIRDs/nrAIDs (OR 1.01; 95%CI: 1.0-1.02, p=0.016), those with comorbidities (OR: 2.8; 95%CI: 1.4-5.7, p=0.005), and patients requiring oxygen supplementation for severe acute COVID-19 (OR: 3.8; 95%CI: 1.1-13.6, p=0.039).
Among patients with AIRDs, comorbidities (OR 2.0; 95%CI: 1.08-3.6, p=0.026), and advanced treatment (OR: 1.9; 95%CI: 1.08-3.3, p=0.024), or intensive care (OR: 3.8; 95%CI: 1.01-14.4, p=0.047) for severe COVID-19 were risk factors for PCS.
Notably, patients who developed PCS had poorer PROMIS global physical [15 (12-17) vs 12 (9-15)] and mental health [14 (11-16) vs 11 (8-14)] scores than those without PCS.
Conclusion: Individuals with AIRDs have a greater risk of PCS than HCs. Associated comorbid conditions, and advanced treatment or intensive care unit admission for severe COVID-19 confer a higher risk of PCS. It is imperative to identify risk factors for PCS for immediate multidisciplinary management in anticipation of poor physical and mental health.
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Article Stress-Induced Transcriptomic Changes in Females with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Reveal Disrupted Immune Signatures
Derek J. Van Booven 1 , Jackson Gamer 2,3, Andrew Joseph 2,3, Melanie Perez 2,3, Oskar Zarnowski 2,3 , Meha Pandya 4,5, Fanny Collado 6,7, Nancy Klimas 2,6, Elisa Oltra 8 and Lubov Nathanson 2,
Abstract: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, complex multi-organ illness characterized by unexplained debilitating fatigue and post-exertional malaise (PEM), which is defined as a worsening of symptoms following even minor physical or mental exertion. Our study aimed to evaluate transcriptomic changes in ME/CFS female patients undergoing an exercise challenge intended to precipitate PEM. Our time points (baseline before exercise challenge, the point of maximal exertion, and after an exercise challenge) allowed for the exploration of the transcriptomic response to exercise and recovery in female patients with ME/CFS, as compared to healthy controls (HCs). Under maximal exertion, ME/CFS patients did not show significant changes in gene expression, while HCs demonstrated altered functional gene networks related to signaling and integral functions of their immune cells. During the recovery period (commonly during onset of PEM), female ME/CFS patients showed dysregulated immune signaling pathways and dysfunctional cellular responses to stress. The unique functional pathways identified provide a foundation for future research efforts into the disease, as well as for potential targeted treatment options.
Keywords: myalgic encephalomyelitis; chronic fatigue syndrome; transcriptomics; dysregulated immune pathways; post-exertional malaise
Differences in Symptoms among Black and White Patients with ME/CFSLeonard A. Jason * and Chelsea Torres
Center for Community Research, DePaul University, 990 W. Fullerton Ave., Chicago, IL 60614, USA
J. Clin. Med. 2022, 11(22), 6708; https://doi.org/10.3390/jcm11226708
Received: 27 October 2022 / Revised: 7 November 2022 / Accepted: 11 November 2022 / Published: 12 November 2022
(This article belongs to the Special Issue Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: Epidemiology, Treatment and Prognosis)
Study samples of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have primarily involved White subjects, so the literature on ethnic differences is sparse. The current study identified a sample of 19 Black patients diagnosed with ME/CFS and compared them with White patients with ME/CFS, as well as with healthy controls. The studies used a similar psychometrically sound assessment tool to assess symptoms in all subjects. Findings indicated there were significant differences between patients with ME/CFS versus controls, but few differences between patients who identified as Black or White. The results suggest there might be few symptom differences between patients with ME/CFS in these two ethnic groups. The implications of these findings are discussed.
ethnicity; fatigue; gender; myalgic encephalomyelitis/chronic fatigue syndrome
The health impact of long COVID during the 2021–2022 Omicron wave in Australia: a quantitative burden of disease study Samantha Howe, Joshua Szanyi, Tony Blakely International Journal of Epidemiology, yad033, https://doi.org/10.1093/ije/dyad033Published: 03 April 2023
Long COVID symptoms occur for a proportion of acute COVID-19 survivors, with reduced risk among the vaccinated and for Omicron compared with Delta variant infections. The health loss attributed to pre-Omicron long COVID has previously been estimated using only a few major symptoms.
The years lived with disability (YLDs) due to long COVID in Australia during the 2021–22 Omicron BA.1/BA.2 wave were calculated using inputs from previously published case-control, cross-sectional or cohort studies examining the prevalence and duration of individual long COVID symptoms. This estimated health loss was compared with acute SARS-CoV-2 infection YLDs and years of life lost (YLLs) from SARS-CoV-2. The sum of these three components equals COVID-19 disability-adjusted life years (DALYs); this was compared with DALYs from other diseases.
A total of 5200 [95% uncertainty interval (UI) 2200–8300] YLDs were attributable to long COVID and 1800 (95% UI 1100-2600) to acute SARS-CoV-2 infection, suggesting long COVID caused 74% of the overall YLDs from SARS-CoV-2 infections in the BA.1/BA.2 wave. Total DALYs attributable to SARS-CoV-2 were 50 900 (95% UI 21 000-80 900), 2.4% of expected DALYs for all diseases in the same period.
This study provides a comprehensive approach to estimating the morbidity due to long COVID. Improved data on long COVID symptoms will improve the accuracy of these estimates. As data accumulate on SARS-CoV-2 infection sequelae (e.g. increased cardiovascular disease rates), total health loss is likely to be higher than estimated in this study. Nevertheless, this study demonstrates that long COVID requires consideration in pandemic policy planning, given it is responsible for the majority of direct SARS-CoV-2 morbidity, including during an Omicron wave in a highly vaccinated population.