long Covid – Page 69 – American ME and CFS Society

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

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)

A Mixed Methods System for the Assessment of Post Exertional Malaise in Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Background A central feature of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is post exertional malaise (PEM), which is an acute worsening of symptoms after a physical, emotional and/or mental exertion. PEM is also a feature of Long COVID. Dynamic measures of PEM have historically included scaled questionnaires which have not been validated in ME/CFS. To enhance our understanding of PEM and how best to measure it, we conducted semi-structured qualitative interviews (QIs) at the same intervals as Visual Analog Scale (VAS) measures after a Cardiopulmonary Exercise Test (CPET).

Methods Ten ME/CFS and nine healthy volunteers participated in a CPET. For each participant, PEM symptom VAS (7 symptoms) and semi-structured QIs were administered at six timepoints over 72 hours before and after a single CPET. QI data were used to plot the severity of PEM at each time point and identify the self-described most bothersome symptom for each patient. QI data were used to determine the symptom trajectory and peak of PEM. Performance of QI and VAS data were compared to each other using Spearman correlations.

Results QIs documented that each ME/CFS volunteer had a unique PEM experience, with differences noted in the onset, severity, trajectory over time, and most bothersome symptom. No healthy volunteers experienced PEM. Scaled QI data were able to identify PEM peaks and trajectories, even when VAS scales were unable to do so due to known ceiling and floor effects. QI and VAS fatigue data corresponded well prior to exercise (baseline, r=0.7) but poorly at peak PEM (r=0.28) and with the change from baseline to peak (r=0.20). When the most bothersome symptom identified from QIs was used, these correlations improved (r=.0.77, 0.42. and 0.54 respectively) and reduced the observed VAS scale ceiling and floor effects.

Conclusion QIs were able to capture changes in PEM severity and symptom quality over time in all the ME/CFS volunteers, even when VAS scales failed to do so. Information collected from QIs also improved the performance of VAS. Measurement of PEM can be improved by using a quantitative-qualitative mixed model approach.

Disclaimer This research/work/investigator was supported (in part) by the Division of Intramural Research of the National Institutes of Health, NINDS. The content is solely the responsibility of the author(s) and does not necessarily represent the official views of the National Institutes of Health.

Source: Barbara Stussman, Brice Calco, Gina Norato, Angelique Gavin, Snigdha Chigurupati, Avindra Nath, Brian Walitt. A Mixed Methods System for the Assessment of Post Exertional Malaise in Encephalomyelitis/Chronic Fatigue Syndrome. medRxiv 2023.04.24.23288821; doi: https://doi.org/10.1101/2023.04.24.23288821 https://www.medrxiv.org/content/10.1101/2023.04.24.23288821v1.full-text (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)

How do German General Practitioners Manage Long-/Post-COVID? A Qualitative Study in Primary Care

Abstract:

Background: Many patients with ongoing complaints after a SARS-CoV-2 infection are treated in primary care. Existing medical guidelines on how to diagnose and treat Long-/Post-COVID are far from being comprehensive. This study aims to describe how German general practitioners (GPs) deal with this situation, what problems they experience when managing such patients, and how they solve problems associated with the diagnosis and treatment of Long-/Post-COVID.

Methods and Findings: We conducted a qualitative study and interviewed 11 GPs. The most commonly described symptoms were ongoing fatigue, dyspnea, chest tightness and a decrease in physical capacity. The most common way to identify Long-/Post-COVID was by exclusion. Patients suffering from Long-/Post-COVID were generally treated by their GPs and rarely referred. A very common non-pharmacological intervention was to take a wait-and-see approach and grant sick leave. Other non-pharmacological interventions included lifestyle advices, physical exercise, acupuncture and exercises with intense aromas. Pharmacological treatments focused on symptoms, like respiratory symptoms or headaches. Our study’s main limitations are the small sample size and therefore limited generalizability of results.

Conclusions: Further research is required to develop and test pharmaceutical and non-pharmaceutical interventions for patients with Long-/Post-COVID. In addition, strategies to prevent the occurrence of Long-/Post-COVID after an acute infection with SARS-CoV-2 have to be developed. The routine collection of data on the diagnosis and management of Long-/Post-COVID may help in the formulation of best practices. It is up to policymakers to facilitate the necessary implementation of effective interventions in order to limit the huge societal consequences of large groups of patients suffering from Long-/Post-COVID.

Source: Bachmeier BE, Hölzle S, Gasser M, van den Akker M. How do German General Practitioners Manage Long-/Post-COVID? A Qualitative Study in Primary Care. Viruses. 2023; 15(4):1016. https://doi.org/10.3390/v15041016 https://www.mdpi.com/1999-4915/15/4/1016 (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)

A Review of Neurological Symptoms in Long COVID and Clinical Management

Abstract:

Long COVID is a clinical diagnosis generally referring to the persistence or development of new symptoms, affecting multiple organ systems after SARS-CoV-2 COVID-19 infection. Long COVID is thought to affect ∼20% of people after infection, including all age ranges and severity of infection. Fatigue, postexertional malaise, and respiratory and cardiac symptoms are commonly described. Neurological symptoms such as cognitive changes, sensory disturbances, headaches, and dysautonomia are common as well. The underlying pathophysiology remains unclear but immune dysregulation, autoimmunity, persistent viral reservoirs, and microvascular dysfunction have been implicated. As there are no tests at this time to diagnose long COVID, work-up should be focused on assessing reversible or treatable causes of symptoms. Furthermore, no treatments for long COVID currently exist, and management remains focused on a multimodal approach and symptom management, with many people showing improvement in symptoms over time.

Source: Navis A. A Review of Neurological Symptoms in Long COVID and Clinical Management. Semin Neurol. 2023 Apr 17. doi: 10.1055/s-0043-1767781. Epub ahead of print. PMID: 37068519. https://pubmed.ncbi.nlm.nih.gov/37068519/