long covid immunology – Page 13 – American ME and CFS Society

An Exercise Immune Fitness test to unravel mechanisms of post-acute sequelae of COVID-19

Abstract:

The Post-Acute Sequelae of COVID-19 (PASC) Syndrome is a debilitating syndrome with onset three months post COVID-19 infection, marked by the presence of fatigue, headache, cognitive dysfunction, post-exertional malaise, orthostatic intolerance, and dyspnea that is clinically relevant and is at least as severe as fatigue in several other clinical conditions, including cancer. The onset, progression, and symptom profile of PASC patients have considerable overlap with Myalgic-Encephalopathy/Chronic Fatigue Syndrome (ME/CFS).

In people with ME/CFS, exercise (and other types of exertion) can cause serious setbacks and deterioration in function. Post-exertional malaise (PEM) appears to be a common and a significant challenge for the majority of this patient group. Of the nearly 24 million adults in the U.S. who currently have long COVID, more than 80% are having some trouble carrying out daily activities. Mechanisms of PACS remain poorly understood.

While multi-omic information gathered at the time of acute COVID-19 onset may help predict long COVID outcomes, we here propose to test the hypothesis that additional molecular immunological information collected during standardized exercise-testing for cardio-respiratory fitness after recovery from acute COVID-19 can be used to improve the understanding of mechanisms of PASC.

Source: Deng MC. An Exercise Immune Fitness test to unravel mechanisms of post-acute sequelae of COVID-19. Expert Rev Clin Immunol. 2023 May 16. doi: 10.1080/1744666X.2023.2214364. Epub ahead of print. PMID: 37190994. https://www.tandfonline.com/doi/full/10.1080/1744666X.2023.2214364 (Full text)

Increased interleukin-6 is associated with long COVID-19: a systematic review and meta-analysis

Abstract:

Background: Coronavirus disease 2019 (COVID-19) can involve persistence, sequelae, and other clinical complications that last weeks to months to evolve into long COVID-19. Exploratory studies have suggested that interleukin-6 (IL-6) is related to COVID-19; however, the correlation between IL-6 and long COVID-19 is unknown. We designed a systematic review and meta-analysis to assess the relationship between IL-6 levels and long COVID-19.

Methods: Databases were systematically searched for articles with data on long COVID-19 and IL-6 levels published before September 2022. A total of 22 published studies were eligible for inclusion following the PRISMA guidelines. Analysis of data was undertaken by using Cochran’s Q test and the Higgins I-squared (I²) statistic for heterogeneity. Random-effect meta-analyses were conducted to pool the IL-6 levels of long COVID-19 patients and to compare the differences in IL-6 levels among the long COVID-19, healthy, non-postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (non-PASC), and acute COVID-19 populations. The funnel plot and Egger’s test were used to assess potential publication bias. Sensitivity analysis was used to test the stability of the results.

Results: An increase in IL-6 levels was observed after SARS-CoV-2 infection. The pooled estimate of IL-6 revealed a mean value of 20.92 pg/ml (95% CI = 9.30-32.54 pg/ml, I² = 100%, P < 0.01) for long COVID-19 patients. The forest plot showed high levels of IL-6 for long COVID-19 compared with healthy controls (mean difference = 9.75 pg/ml, 95% CI = 5.75-13.75 pg/ml, I² = 100%, P < 0.00001) and PASC category (mean difference = 3.32 pg/ml, 95% CI = 0.22-6.42 pg/ml, I² = 88%, P = 0.04). The symmetry of the funnel plots was not obvious, and Egger’s test showed that there was no significant small study effect in all groups.

Conclusions: This study showed that increased IL-6 correlates with long COVID-19. Such an informative revelation suggests IL-6 as a basic determinant to predict long COVID-19 or at least inform on the “early stage” of long COVID-19.

Source: Yin JX, Agbana YL, Sun ZS, Fei SW, Zhao HQ, Zhou XN, Chen JH, Kassegne K. Increased interleukin-6 is associated with long COVID-19: a systematic review and meta-analysis. Infect Dis Poverty. 2023 Apr 24;12(1):43. doi: 10.1186/s40249-023-01086-z. PMID: 37095536; PMCID: PMC10123579. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10123579/ (Full text)

Deep Phenotyping of Neurologic Postacute Sequelae of SARS-CoV-2 Infection

Abstract:

Background and Objectives SARS-CoV-2 infection has been associated with a syndrome of long-term neurologic sequelae that is poorly characterized. We aimed to describe and characterize in-depth features of neurologic postacute sequelae of SARS-CoV-2 infection (neuro-PASC).

Methods Between October 2020 and April 2021, 12 participants were seen at the NIH Clinical Center under an observational study to characterize ongoing neurologic abnormalities after SARS-CoV-2 infection. Autonomic function and CSF immunophenotypic analysis were compared with healthy volunteers (HVs) without prior SARS-CoV-2 infection tested using the same methodology.

Results Participants were mostly female (83%), with a mean age of 45 ± 11 years. The median time of evaluation was 9 months after COVID-19 (range 3–12 months), and most (11/12, 92%) had a history of only a mild infection. The most common neuro-PASC symptoms were cognitive difficulties and fatigue, and there was evidence for mild cognitive impairment in half of the patients (MoCA score <26). The majority (83%) had a very disabling disease, with Karnofsky Performance Status ≤80. Smell testing demonstrated different degrees of microsmia in 8 participants (66%). Brain MRI scans were normal, except 1 patient with bilateral olfactory bulb hypoplasia that was likely congenital. CSF analysis showed evidence of unique intrathecal oligoclonal bands in 3 cases (25%). Immunophenotyping of CSF compared with HVs showed that patients with neuro-PASC had lower frequencies of effector memory phenotype both for CD4⁺ T cells (p < 0.0001) and for CD8⁺ T cells (p = 0.002), an increased frequency of antibody-secreting B cells (p = 0.009), and increased frequency of cells expressing immune checkpoint molecules. On autonomic testing, there was evidence for decreased baroreflex-cardiovagal gain (p = 0.009) and an increased peripheral resistance during tilt-table testing (p < 0.0001) compared with HVs, without excessive plasma catecholamine responses.

Discussion CSF immune dysregulation and neurocirculatory abnormalities after SARS-CoV-2 infection in the setting of disabling neuro-PASC call for further evaluation to confirm these changes and explore immunomodulatory treatments in the context of clinical trials.

Source: Yair Mina, Yoshimi Enose-Akahata, Dima A. Hammoud, Anthony J. Videckis, Sandeep R. Narpala, Sarah E. O’Connell, Robin Carroll, Bob C. Lin, Cynthia Chen McMahan, Govind Nair, Lauren B. Reoma, Adrian B. McDermott, Brian Walitt, Steven Jacobson, David S. Goldstein, Bryan R. Smith, Avindra Nath. Deep Phenotyping of Neurologic Postacute Sequelae of SARS-CoV-2 Infection. Neurol Neuroimmunol Neuroinflamm Jul 2023, 10 (4) e200097; DOI: 10.1212/NXI.0000000000200097

Risk of autoimmune diseases in patients with COVID-19: A retrospective cohort study

Abstract:

Background: There are a growing number of case reports of various autoimmune diseases occurring after COVID-19, yet there is no large-scale population-based evidence to support this potential association. This study provides a closer insight into the association between COVID-19 and autoimmune diseases and reveals discrepancies across sex, age, and race of participants.

Methods: This is a retrospective cohort study based on the TriNetX U.S. Collaborative Network. In the test-negative design, cases were participants with positive polymerase chain reaction (PCR) test results for SARS-CoV-2, while controls were participants who tested negative and were not diagnosed with COVID-19 throughout the follow-up period. Patients with COVID-19 and controls were propensity score-matched (1: 1) for age, sex, race, adverse socioeconomic status, lifestyle-related variables, and comorbidities. The primary endpoint is the incidence of newly recorded autoimmune diseases. Adjusted hazard ratios (aHRs) and 95% confident intervals (CIs) of autoimmune diseases were calculated between propensity score-matched groups with the use of Cox proportional-hazards regression models.

Findings: Between January 1st, 2020 and December 31st, 2021, 3,814,479 participants were included in the study (888,463 cases and 2,926,016 controls). After matching, the COVID-19 cohort exhibited significantly higher risks of rheumatoid arthritis (aHR:2.98, 95% CI:2.78-3.20), ankylosing spondylitis (aHR:3.21, 95% CI:2.50-4.13), systemic lupus erythematosus (aHR:2.99, 95% CI:2.68-3.34), dermatopolymyositis (aHR:1.96, 95% CI:1.47-2.61), systemic sclerosis (aHR:2.58, 95% CI:2.02-3.28), Sjögren’s syndrome (aHR:2.62, 95% CI:2.29-3.00), mixed connective tissue disease (aHR:3.14, 95% CI:2.26-4.36), Behçet’s disease (aHR:2.32, 95% CI:1.38-3.89), polymyalgia rheumatica (aHR:2.90, 95% CI:2.36-3.57), vasculitis (aHR:1.96, 95% CI:1.74-2.20), psoriasis (aHR:2.91, 95% CI:2.67-3.17), inflammatory bowel disease (aHR:1.78, 95%CI:1.72-1.84), celiac disease (aHR:2.68, 95% CI:2.51-2.85), type 1 diabetes mellitus (aHR:2.68, 95%CI:2.51-2.85) and mortality (aHR:1.20, 95% CI:1.16-1.24).

Interpretation: COVID-19 is associated with a different degree of risk for various autoimmune diseases. Given the large sample size and relatively modest effects these findings should be replicated in an independent dataset. Further research is needed to better understand the underlying mechanisms.

Source: Chang R, Yen-Ting Chen T, Wang SI, Hung YM, Chen HY, Wei CJ. Risk of autoimmune diseases in patients with COVID-19: A retrospective cohort study. EClinicalMedicine. 2023 Feb;56:101783. doi: 10.1016/j.eclinm.2022.101783. Epub 2023 Jan 10. PMID: 36643619; PMCID: PMC9830133. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9830133/ (Full text)

High risk of autoimmune diseases after COVID-19

The 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 studies^2,3.

Source: Sharma, C., Bayry, J. High risk of autoimmune diseases after COVID-19. Nat Rev Rheumatol (2023). https://doi.org/10.1038/s41584-023-00964-y (Full text)

Changes in the State of Vital Systems with Long COVID-19

Abstract:

Long COVID-19 is a chronic disease that continues to be studied. Data on epidemiology and the main symptoms typical for long COVID-19 are presented. Issues related to the pathogenesis of the disease are discussed. At the same time, special attention is paid to the inflammation process (including of the vascular wall endothelium), the state of the immune system (cytokine storm), the hemostasis system (the mechanism for the development of microangiopathy and thrombosis), and oxidative stress. During the analysis, a special place is given to central nervous system disorders (including organic brain damage) and disorders of cognitive functions. In addition, currently known complications from the cardiovascular system and respiratory organs are described. The treatment and rehabilitation of patients with long COVID-19 is not only a medical, but also a significant social problem.

Source: Kuznik, B.I., Shapovalov, K.G. & Chalisova, N.I. Changes in the State of Vital Systems with Long COVID-19. Biol Bull Rev 13, 112–123 (2023). https://doi.org/10.1134/S2079086423020044 (Full text)

Unique immune and inflammatory cytokine profiles may define long COVID syndrome

Abstract:

Purpose: Long COVID is estimated to occur in 5-10% of individuals after acute SARS-CoV-2 infection. However, the pathophysiology driving the disease process is poorly understood.

Methods: We evaluated urine and plasma inflammatory and immune cytokine profiles in 33 individuals with long COVID compared to 33 who were asymptomatic and recovered, and 34 without prior infection.

Results: Mean urinary leukotriene E4 was significantly elevated among individuals with long COVID compared to asymptomatic and recovered individuals (mean difference 774.2 pg/mL; SD 335.7) and individuals without prior SARS-CoV-2 infection (mean difference 503.1 pg/ml; SD 467.7). Plasma chemokine ligand 6 levels were elevated among individuals with long COVID compared to individuals with no prior SARS-CoV-2 infection (mean difference 0.59 units; SD 0.42). We found no significant difference in angiotensin-converting enzyme 2 antibody levels. Plasma tumor necrosis factor receptor-associated factor 2 (TRAF2) levels were reduced among individuals with long COVID compared to individuals who were asymptomatic and recovered (mean difference = 0.6 units, SD 0.46). Similarly, the mean level of Sarcoma Homology 2-B adapter protein 3 was 3.3 units (SD 1.24) among individuals with long COVID, lower than 4.2 units (SD 1.1) among individuals with recovered, asymptomatic COVID.

Conclusion: Our findings suggest that further studies should be conducted to evaluate the role of leukotriene E4 as a potential biomarker for a diagnostic test. Furthermore, based on reductions in TRAF2, long COVID may be driven in part by impaired TRAF2-dependent immune-mediated inflammation and potentially immune exhaustion.

Source: Allan-Blitz LT, Akbari O, Kojima N, Saavedra E, Chellamuthu P, Denny N, MacMullan MA, Hess V, Shacreaw M, Brobeck M, Turner F, Slepnev VI, Ibrayeva A, Klausner JD. Unique immune and inflammatory cytokine profiles may define long COVID syndrome. Clin Exp Med. 2023 Apr 16:1–6. doi: 10.1007/s10238-023-01065-6. Epub ahead of print. PMID: 37061998; PMCID: PMC10105906. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10105906/ (Full text)

NETosis induction reflects COVID-19 severity and Long COVID: insights from a two-center patient cohort study in Israel

Abstract:

Background: COVID-19 severity and its late complications continue to be poorly understood. Neutrophil extracellular traps (NETs) form in acute COVID-19, likely contributing to morbidity and mortality. This study evaluated immunothrombosis markers in a comprehensive cohort of acute and recovered COVID-19 patients, including the association of NETs with LongCOVID.

Methods: One-hundred-seventy-seven patients were recruited from clinical cohorts at two Israeli centers: acute COVID-19 (mild/moderate, severe/critical), convalescent COVID-19 (recovered and Long COVID), along with 54 non-COVID controls. Plasma was examined for markers of platelet activation, coagulation, and NETs. Ex vivo NETosis induction capability was evaluated after neutrophil incubation with patient plasma.

Results: Soluble P-selectin, Factor VIII, von Willebrand factor, and platelet factor 4 were significantly elevated in COVID-19 patients versus controls. Myeloperoxidase (MPO)-DNA complex levels were increased only in severe COVID-19 and did not differentiate between COVID-19 severities or correlate with thrombotic markers. NETosis induction levels strongly correlated with illness severity/duration, platelet activation markers, and coagulation factors, and were significantly reduced upon dexamethasone treatment and recovery. Long COVID patients maintained higher NETosis induction, but not NET fragments, compared to recovered convalescent patients.

Conclusions: Increased NETosis induction can be detected in Long COVID patients. NETosis induction appears to be a more sensitive NET measurement than MPO-DNA levels in COVID-19, differentiating between disease severity and Long COVID patients. Ongoing NETosis induction capability in Long COVID may provide insights into pathogenesis and serve as a surrogate marker for persistent pathology. This study emphasizes the need to explore neutrophil-targeted therapies in acute and chronic COVID-19.

Source: Krinsky N, Sizikov S, Nissim S, Dror A, Sas A, Prinz H, Pri-Or E, Perek S, Raz-Pasteur A, Lejbkowicz I, Cohen-Matsliah SI, Almog R, Chen N, Kurd R, Jarjou’i A, Rokach A, Ben-Chetrit E, Schroeder A, Caulin AF, Yost CC, Schiffman JD, Goldfeder M, Martinod K. NETosis induction reflects COVID-19 severity and Long COVID: insights from a two-center patient cohort study in Israel. J Thromb Haemost. 2023 Apr 11:S1538-7836(23)00274-X. doi: 10.1016/j.jtha.2023.02.033. Epub ahead of print. PMID: 37054916; PMCID: PMC10088279. https://www.jthjournal.org/article/S1538-7836(23)00274-X/fulltext (Full text available as PDF file)

Cytokine deficiencies in patients with Long-COVID

Abstract:

Up to half of individuals who contract SARS-CoV-2 develop symptoms of long-COVID approximately three months after initial infection. These symptoms are highly variable, and the mechanisms inducing them are yet to be understood. We compared plasma cytokine levels from individuals with long-COVID to healthy individuals and found that those with long-COVID had 100% reductions in circulating levels of Interferon Gamma (IFNγ) and Interleukin-8 (IL-8). Additionally, we found significant reductions in levels of IL-6, IL-2, IL-17, IL-13, and IL-4 in individuals with long-COVID.

We propose immune exhaustion as the driver of long-COVID, with the complete absence of IFNγ and IL-8 preventing the lungs and other organs from healing after acute infection, and reducing the ability to fight off subsequent infections, both contributing to the myriad of symptoms suffered by those with long-COVID.

Source: Williams ES, Martins TB, Shah KS, Hill HR, Coiras M, Spivak AM, Planelles V. Cytokine Deficiencies in Patients with Long-COVID. J Clin Cell Immunol. 2022;13(6):672. Epub 2022 Nov 18. PMID: 36742994; PMCID: PMC9894377. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9894377/ (Full text)

A review of cytokine-based pathophysiology of Long COVID symptoms

Abstract:

The Long COVID/Post Acute Sequelae of COVID-19 (PASC) group includes patients with initial mild-to-moderate symptoms during the acute phase of the illness, in whom recovery is prolonged, or new symptoms are developed over months. Here, we propose a description of the pathophysiology of the Long COVID presentation based on inflammatory cytokine cascades and the p38 MAP kinase signaling pathways that regulate cytokine production.

In this model, the SARS-CoV-2 viral infection is hypothesized to trigger a dysregulated peripheral immune system activation with subsequent cytokine release. Chronic low-grade inflammation leads to dysregulated brain microglia with an exaggerated release of central cytokines, producing neuroinflammation. Immunothrombosis linked to chronic inflammation with microclot formation leads to decreased tissue perfusion and ischemia. Intermittent fatigue, Post Exertional Malaise (PEM), CNS symptoms with “brain fog,” arthralgias, paresthesias, dysautonomia, and GI and ophthalmic problems can consequently arise as result of the elevated peripheral and central cytokines.

There are abundant similarities between symptoms in Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). DNA polymorphisms and viral-induced epigenetic changes to cytokine gene expression may lead to chronic inflammation in Long COVID patients, predisposing some to develop autoimmunity, which may be the gateway to ME/CFS.

Source: Low RN, Low RJ, Akrami A. A review of cytokine-based pathophysiology of Long COVID symptoms. Front Med (Lausanne). 2023 Mar 31;10:1011936. doi: 10.3389/fmed.2023.1011936. PMID: 37064029; PMCID: PMC10103649. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10103649/ (Full text)