covid-19 – Page 64 – American ME and CFS Society

Cardiovascular Manifestations of the Long COVID Syndrome.

Abstract:

While most coronavirus 2019 (COVID-19) survivors have had complete resolution of symptoms, a significant proportion have suffered from incomplete recovery. Cardiopulmonary symptoms, such as dyspnea, chest pain, and palpitations are responsible for a substantial symptom burden in COVID-19 survivors.

Studies have revealed persistent myocardial injury with late gadolinium enhancement and myocardial scar on cardiac magnetic resonance in a significant proportion of patients. Evidence of myocardial edema, active inflammation, left ventricular dysfunction, and right ventricular dysfunction, is limited to a minority of patients.

Large observational studies of COVID-19 survivors have indicated an increased risk of cardiovascular disease compared to the general population, including the risk of coronary artery disease, cardiomyopathy, and arrhythmias. Management of long COVID is focused on supportive therapy to reduce systemic inflammation. Patients with high cardiovascular risk, namely, those who had cardiovascular complications during acute illness, patients who have new onset cardiopulmonary symptoms in the postinfectious period, and competitive athletes, should be evaluated by a cardiovascular specialist.

Management of cardiovascular sequelae is currently based on general expert guideline recommendations given the lack of evidence specific to long COVID syndrome. In this review, we outline the cardiovascular manifestations of long COVID, the current evidence supporting cardiac abnormalities in the postinfectious period, and the recommended management of these patients.

Source: Lorente-Ros M, Das S, Elias J, Frishman WH, Aronow WS. Cardiovascular Manifestations of the Long COVID Syndrome. Cardiol Rev. 2023 Apr 10. doi: 10.1097/CRD.0000000000000552. Epub ahead of print. PMID: 37071080.

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

Clinical improvement of Long-COVID is associated with reduction in autoantibodies, lipids, and inflammation following therapeutic apheresis

Abstract:

In the aftermath of the COVID-19 pandemic, we are witnessing an unprecedented wave of post-infectious complications. Most prominently, millions of patients with Long-Covid complain about chronic fatigue and severe post-exertional malaise. Therapeutic apheresis has been suggested as an efficient treatment option for alleviating and mitigating symptoms in this desperate group of patients. However, little is known about the mechanisms and biomarkers correlating with treatment outcomes.

Here, we have analyzed in different cohorts of Long-Covid patients specific biomarkers before and after therapeutic apheresis. In patients that reported a significant improvement following two cycles of therapeutic apheresis, there was a significant reduction in neurotransmitter autoantibodies, lipids, and inflammatory markers. Furthermore, we observed a 70% reduction in fibrinogen, and following apheresis, erythrocyte rouleaux formation and fibrin fibers largely disappeared as demonstrated by dark field microscopy.

This is the first study demonstrating a pattern of specific biomarkers with clinical symptoms in this patient group. It may therefore form the basis for a more objective monitoring and a clinical score for the treatment of Long-Covid and other postinfectious syndromes.

Source: Achleitner, M., Steenblock, C., Dänhardt, J. et al. Clinical improvement of Long-COVID is associated with reduction in autoantibodies, lipids, and inflammation following therapeutic apheresis. Mol Psychiatry (2023). https://doi.org/10.1038/s41380-023-02084-1 https://www.nature.com/articles/s41380-023-02084-1 (Full text)

Proteomic profiling demonstrates inflammatory and endotheliopathy signatures associated with impaired cardiopulmonary exercise hemodynamic profile in Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome

Abstract:

Approximately 50% of patients who recover from the acute SARS-CoV-2 experience Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome. The pathophysiological hallmark of PASC is characterized by impaired system oxygen extraction (EO₂) on invasive cardiopulmonary exercise test (iCPET). However, the mechanistic insights into impaired EO₂ remain unclear.

We studied 21 consecutive iCPET in PASC patients with unexplained exertional intolerance. PASC patients were dichotomized into mildly reduced (EO₂peak-mild) and severely reduced (EO₂peak-severe) EO₂ groups according to the median peak EO₂ value. Proteomic profiling was performed on mixed venous blood plasma obtained at peak exercise during iCPET.

PASC patients as a group exhibited depressed peak exercise aerobic capacity (peak VO₂; 85 ± 18 vs. 131 ± 45% predicted; p = 0.0002) with normal systemic oxygen delivery, DO₂ (37 ± 9 vs. 42 ± 15 mL/kg/min; p = 0.43) and reduced EO₂ (0.4 ± 0.1 vs. 0.8 ± 0.1; p < 0.0001). PASC patients with EO₂peak-mild exhibited greater DO₂ compared to those with EO₂peak-severe [42.9 (34.2-41.2) vs. 32.1 (26.8-38.0) mL/kg/min; p = 0.01]. The proteins with increased expression in the EO₂peak-severe group were involved in inflammatory and fibrotic processes. In the EO₂peak-mild group, proteins associated with oxidative phosphorylation and glycogen metabolism were elevated.

In PASC patients with impaired EO2, there exist a spectrum of PASC phenotype related to differential aberrant protein expression and cardio-pulmonary physiologic response. PASC patients with EO₂peak-severe exhibit a maladaptive physiologic and proteomic signature consistent with persistent inflammatory state and endothelial dysfunction, while in the EO₂peak-mild group, there is enhanced expression of proteins involved in oxidative phosphorylation-mediated ATP synthesis along with an enhanced cardiopulmonary physiological response.

Source: Singh I, Leitner BP, Wang Y, Zhang H, Joseph P, Lutchmansingh DD, Gulati M, Possick JD, Damsky W, Hwa J, Heerdt PM, Chun HJ. Proteomic profiling demonstrates inflammatory and endotheliopathy signatures associated with impaired cardiopulmonary exercise hemodynamic profile in Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome. Pulm Circ. 2023 Apr 1;13(2):e12220. doi: 10.1002/pul2.12220. PMID: 37091121; PMCID: PMC10113513. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10113513/ (Full text)

Symptom presentation and quality of life are comparable in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and post COVID-19 condition

Abstract:

Background and Οbjective: Considerable overlap exists in the clinical presentation of Post COVID-19 Condition and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). The current study aimed to compare symptoms and patient-reported Quality of Life (QoL) among people with Post COVID-19 Condition and ME/CFS in Australia. Methods: QoL data was collected from n=61 ME/CFS patients, n=31 Post COVID-19 Condition patients, and n=54 Healthy Controls (HCs) via validated instruments. The ME/CFS and Post COVID-19 Condition participants also provided self-reported severity and frequency of symptoms derived from the Canadian and International Consensus Criteria for ME/CFS and the World Health Organization case definition for Post COVID-19 Condition. Study variables were compared with Chi-square, Fisher’s exact, Fisher-Freeman-Halton, Mann-Whitney U, and Kruskal-Wallis H tests using Statistical Package for the Social Sciences version 29. Symptom clusters among the two illness cohorts were identified with hierarchical cluster analysis.

Results: ME/CFS was associated with a higher prevalence of short-term memory loss (p=0.039), muscle weakness (p<0.001), lymphadenopathy (p=0.013), and nausea (p=0.003). People with ME/CFS also reported more severe light-headedness (p=0.011) and more frequent unrefreshed sleep (p=0.011), but less frequent heart palpitations (p=0.040). Symptom prevalence, severity, and frequency were otherwise comparable. Few differences existed in the QoL of the two illness cohorts, both of which returned significantly impaired QoL scores when compared with HCs (p<0.001). Cluster analysis of symptom prevalence revealed four clusters: 1) Low gastrointestinal, low neurosensory; 2) Moderate gastrointestinal, low orthostatic and memory loss; 3) Moderate gastrointestinal, high orthostatic and memory loss; and 4) High gastrointestinal, high pain, which did not differ in sociodemographic information, illness status, or diagnostic criteria met.

Conclusions: Post COVID-19 Condition and ME/CFS are remarkably similar in presentation and, like ME/CFS, Post COVID-19 Condition has a profound and negative impact on patient QoL. Gastrointestinal symptoms may have a role in determining ME/CFS and Post COVID-19 Condition subtypes.

Source: Weigel B, Eaton-Fitch N, Thapaliya K, Marshall-Gradisnik S. Symptom presentation and quality of life are comparable in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and post COVID-19 condition. Population Medicine. 2023;5(Supplement):A372. doi:10.18332/popmed/165669. http://www.populationmedicine.eu/Symptom-presentation-and-quality-of-life-are-comparable-in-Myalgic-Encephalomyelitis,165669,0,2.html

Typing myalgic encephalomyelitis by infection at onset: A DecodeME study

Abstract:

Background: People with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) daily experience core symptoms of post-exertional malaise, unrefreshing sleep, and cognitive impairment or brain fog. Despite numbering 0.2-0.4% of the population, no laboratory test is available for their diagnosis, no effective therapy exists for their treatment, and no scientific breakthrough regarding their pathogenesis has been made. It remains unknown, despite decades of small-scale studies, whether individuals experience different types of ME/CFS separated by onset-type, sex or age.

Methods: DecodeME is a large population-based study of ME/CFS that recruited 17,074 participants in the first 3 months following full launch. Their detailed questionnaire responses provided an unparalleled opportunity to investigate illness severity, onset, course and duration.

Results: The well-established sex-bias among ME/CFS patients is evident in the initial DecodeME cohort: 83.5% of participants were females. What was not known previously was that females’ comorbidities and symptoms tend to be more numerous than males’. Moreover, being female, being older and being over 10 years from ME/CFS onset are significantly associated with greater severity. Five different ME/CFS onset types were examined in the self-reported data: those with ME/CFS onset (i) after glandular fever (infectious mononucleosis); (ii) after COVID-19 infection; (iii) after other infections; (iv) without an identified infectious onset; and, (v) where the occurrence of an infection at or preceding onset is not known.

Conclusions: This revealed that people with a ME/CFS diagnosis are not a homogeneous group, as clear differences exist in symptomatology and comorbidity.

Source: Bretherick AD, McGrath SJ, Devereux-Cooke A et al. Typing myalgic encephalomyelitis by infection at onset: A DecodeME study [version 1; peer review: awaiting peer review]. NIHR Open Res 2023, 3:20 https://doi.org/10.3310/nihropenres.13421.1 (Full text)

Female reproductive health impacts of Long COVID and associated illnesses including ME/CFS, POTS, and connective tissue disorders: a literature review

Long COVID disproportionately affects premenopausal women, but relatively few studies have examined Long COVID’s impact on female reproductive health. We conduct a review of the literature documenting the female reproductive health impacts of Long COVID which may include disruptions to the menstrual cycle, gonadal function, ovarian sufficiency, menopause, and fertility, as well as symptom exacerbation around menstruation.

Given limited research, we also review the reproductive health impacts of overlapping and associated illnesses including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), postural orthostatic tachycardia syndrome (POTS), connective tissue disorders like Ehlers-Danlos syndrome (EDS), and endometriosis, as these illnesses may help to elucidate reproductive health conditions in Long COVID.

These associated illnesses, whose patients are 70%–80% women, have increased rates of dysmenorrhea, amenorrhea, oligomenorrhea, dyspareunia, endometriosis, infertility, vulvodynia, intermenstrual bleeding, ovarian cysts, uterine fibroids and bleeding, pelvic congestion syndrome, gynecological surgeries, and adverse pregnancy complications such as preeclampsia, maternal mortality, and premature birth. Additionally, in Long COVID and associated illnesses, symptoms can be impacted by the menstrual cycle, pregnancy, and menopause.

We propose priorities for future research and reproductive healthcare in Long COVID based on a review of the literature. These include screening Long COVID patients for comorbid and associated conditions; studying the impacts of the menstrual cycle, pregnancy, and menopause on symptoms and illness progression; uncovering the role of sex differences and sex hormones in Long COVID and associated illnesses; and addressing historical research and healthcare inequities that have contributed to detrimental knowledge gaps for this patient population.

Source: Pollack Beth, von Saltza Emelia, McCorkell Lisa, Santos Lucia, Hultman Ashley, Cohen Alison K., Soares Letícia. Female reproductive health impacts of Long COVID and associated illnesses including ME/CFS, POTS, and connective tissue disorders: a literature review. Frontiers in Rehabilitation Sciences, Vol 4, 2023, ISSN=2673-6861. DOI: 10.3389/fresc.2023.1122673 https://www.frontiersin.org/articles/10.3389/fresc.2023.1122673 (Full text)

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)