Understanding Long Covid & ME/CFS

A severe multisystem illness without a validated clinical pathway

Most people recover fully from an acute COVID-19 infection. But many continue to experience a range of symptoms that has come to be known by the umbrella term Long Covid. In its more severe form, this closely resembles the longer-established illness myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS). Because ME/CFS is correspondingly better researched and covers pretty well the more severe Long Covid cases, here is a brief description from the DACH Consensus Statement (Hoffmann et al., 2024, read the original, German):

ME/CFS is a severe, chronic multisystem illness that, depending on its severity, can lead to substantial physical and cognitive impairment, loss of the ability to work, and even care dependency including artificial nutrition — in very severe cases it can even lead to death. It is a disease that affects, among other things, the central and autonomic nervous systems, the immune system, the cardiovascular system — particularly the vascular endothelial cells — and mitochondrial energy production, as well as the gut microbiome and the perfusion of muscle, brain, and other organs. In roughly 80 % of cases, ME/CFS follows an infection and occurs in the post-acute phase. Studies suggest that the SARS-CoV-2 pandemic will at least double the number of people affected.

As a result of the sharp rise in cases since the SARS-CoV-2 pandemic, research has increased accordingly. Below, we present excerpts from this research.
At the same time, the many patients living with these conditions are gathering their own individual experiences of what helps them and what doesn't. We regard this wealth of data — known in the field as real world evidence — as a further relevant data source for identifying possible treatment approaches. One such study has already been conducted in the US by researchers from Harvard and Stanford, and we present an excerpt from it here. We are preparing an initiative that will make this kind of data collection and analysis possible for the specific circumstances of patients in Europe.

Excerpts from current research

Research is advancing across a range of disease mechanisms

On the evidence: Much of what is described on this page is based on hypotheses, observational studies, and case series. High-quality randomized trials are still largely lacking. We work with the best available knowledge and indicate where that knowledge reaches its limits.

DACH Consensus Statement on ME/CFS

Interdisciplinary, collaborative D-A-CH consensus statement on the diagnosis and treatment of myalgic encephalomyelitis / chronic fatigue syndrome

Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is a severe, chronic multisystem illness that, depending on its severity, can lead to substantial physical and cognitive impairment, loss of the ability to work, and even care dependency including artificial nutrition — in very severe cases it can even lead to death. The aim of this D-A-CH consensus statement is to 1) summarize the current state of knowledge on ME/CFS, 2) highlight the Canadian Consensus Criteria (CCC) as the recommended clinical diagnostic criteria, with a focus on the cardinal symptom post-exertional malaise (PEM), and 3) provide an overview of current options and possible future developments, particularly with regard to diagnosis and treatment. The D-A-CH consensus statement is intended to support physicians, therapists, and medical assessors in diagnosing patients with suspected ME/CFS through adequate history-taking and clinical-physical examination as well as the recommended clinical CCC, making use of the questionnaires and further diagnostic methods presented. The overview of the two pillars of ME/CFS treatment — pacing and symptom-relieving treatment options — is intended not only to guide physicians and therapists, but also to help decision-makers in health policy and insurance determine which treatment options should already be reimbursable for the indication "ME/CFS" at this point in time. (Translated from the German original.)

Hoffmann et al., 2024 · doi.org/10.1007/s00508-024-02372-y

Practical Guide to ME/CFS

Practical guide to myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS)

This guide is intended for general practice and covers: a) ME/CFS following any trigger, including SARS-CoV-2 infection; b) ME/CFS-like courses of Long or Post-COVID syndrome. (Translated from the German original.)

Renz-Polster et al., 2025 · praxisleitfaden.mecfs.de

Post-COVID and ME/CFS — Developing Curative Therapies

Fighting Post-COVID and ME/CFS — development of curative therapies

The sequelae of COVID-19 encompass a broad spectrum of symptoms summarized under the umbrella term post-COVID-19 syndrome (PCS). Immune dysregulation, autoimmunity, endothelial dysfunction, viral persistence, and viral reactivation have been identified as possible mechanisms. However, the pattern of biomarkers is heterogeneous, and it remains unclear whether they distinguish different clinical subgroups of PCS. There is an overlap in symptoms and pathomechanisms between PCS and post-infectious myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS). Curative therapies are available for neither ME/CFS nor PCS. The mechanisms identified so far provide potential targets for therapeutic intervention. To accelerate the development of therapies, the authors propose testing drugs that target different mechanisms within clinical trial networks based on harmonized diagnostic and endpoint criteria, and stratifying patients into subgroups through comprehensive clinical profiling with diagnostic and biomarker phenotyping.

Scheibenbogen et al., 2023 · doi.org/10.3389/fmed.2023.1194754

Long COVID: Key Findings, Mechanisms, and Recommendations

Long COVID: major findings, mechanisms and recommendations

Long COVID is a frequently severely disabling condition that occurs after at least 10 % of all SARS-CoV-2 infections. More than 200 symptoms affecting multiple organ systems have been identified. Worldwide, an estimated at least 65 million people are affected, with the case count growing daily. Biomedical research has made substantial progress in identifying various pathophysiological changes and risk factors and in characterizing the condition; parallels with other post-viral illnesses such as ME/CFS and postural tachycardia syndrome have laid the groundwork for further research. This review examines the current state of research, key findings, overlap with other conditions, the variable onset of symptoms, Long COVID in children, and the role of vaccination. Although these insights are central to understanding the condition, today's diagnostic and therapeutic options remain insufficient; clinical trials addressing the leading hypotheses must be prioritized. Future studies must also account for biases and methodological problems in SARS-CoV-2 testing, build on research into post-infectious illnesses, include marginalized populations, and substantially involve affected people in the research process.

Davis et al., 2023 · doi.org/10.1038/s41579-022-00846-2

Mechanisms of Long COVID and the Path Toward Therapeutics

Mechanisms of long COVID and the path toward therapeutics

Long COVID — a form of the post-acute sequelae of SARS-CoV-2 infection (PASC), characterized by medically unexplained symptoms following infection — is a newly recognized, infection-associated chronic illness that leads to disability in a proportion of those affected. Substantial progress has been made in characterizing its epidemiology, biology, and pathophysiology. Yet no cure exists for the tens of millions affected, and industry engagement in therapy development has so far been limited. The authors review the current state of knowledge on the biology and pathophysiology of Long COVID and show how the proposed mechanisms explain the syndrome's physiology and provide a framework for a broad experimental medicine and research agenda. Progress in preventing and curing Long COVID and comparable infection-associated illnesses will require deep and sustained investment from funders and industry.

Peluso & Deeks, 2024 · doi.org/10.1016/j.cell.2024.07.054

Post-Acute Sequelae in Historical Context

The lingering shadow of epidemics: post-acute sequelae across history

The SARS-CoV-2 pandemic has sparked worldwide interest in post-acute infection syndromes (PAIS) — millions are affected by the post-acute sequelae of COVID-19 infection (PASC, or Long COVID). While Long COVID is a newly defined clinical entity, PAIS have been described following epidemic infections for over a century. Numerous pathogens — including influenza, Epstein-Barr virus, and Borrelia burgdorferi — can trigger persistent, poorly understood symptoms. Chronic illnesses such as ME/CFS have long been linked to infectious triggers. This recurring association highlights critical gaps in knowledge and underscores the need for systematic investigation. Unlike in previous pandemics, advanced technologies and analytical tools are available today to close these gaps. Characterizing the biology of Long COVID could yield far-reaching insights into host-pathogen interactions and the mechanisms of chronic illness.

Miller et al., 2026 · doi.org/10.1016/j.it.2025.10.010

Understanding Post-Exertional Malaise (PEM)

Towards an understanding of physical activity-induced post-exertional malaise: Insights into microvascular alterations and immunometabolic interactions in post-COVID condition and ME/CFS

During physical activity, affected individuals show reduced systemic oxygen extraction and diminished capacity for oxidative phosphorylation. Growing evidence suggests these are mediated by dysfunction in mitochondrial performance and microcirculation, which are in turn sustained by latent immune activation and together impair peripheral bioenergetics. Under exertion, deficits in tissue perfusion and oxygen utilization worsen, leading to exercise intolerance — often accompanied by tachycardia, dyspnea, and early cessation of activity — with downstream metabolic effects. The accumulation of molecules such as lactate, reactive oxygen species, or prostaglandins can trigger local and systemic immune activation. The resulting increase in bioenergetic inflexibility, muscular ion disturbances, and modulation of central nervous system function can further worsen existing pathologies and symptoms.

Haunhorst et al., 2024 · doi.org/10.1007/s15010-024-02386-8

Clinical Improvement Following Therapeutic Apheresis

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

In the wake of the COVID-19 pandemic, an unprecedented wave of post-infectious complications has emerged. Most prominently, millions of people with Long COVID report chronic exhaustion and severe post-exertional malaise. Therapeutic apheresis is being discussed as an effective treatment option for relieving and reducing symptoms in this patient group. However, little is known about the underlying mechanisms and the biomarkers that correlate with treatment success. Specific biomarkers were analyzed before and after therapeutic apheresis in various cohorts of Long COVID patients. Patients who reported significant improvement after two apheresis cycles showed a significant reduction in neurotransmitter autoantibodies, lipids, and inflammatory markers. In addition, a 70 % reduction in fibrinogen was observed; on dark-field microscopy, erythrocyte rouleaux formation and fibrin fibers had largely disappeared after apheresis. This is the first study to show a pattern of specific biomarkers correlating with clinical symptoms in this patient group. It may thus form the basis for more objective monitoring and a clinical score for treating Long COVID and other post-infectious syndromes.

Achleitner et al., 2023 · doi.org/10.1038/s41380-023-02084-1

Hyperbaric Oxygen Therapy — Short-Term Effects

Hyperbaric oxygen therapy improves neurocognitive functions and symptoms of post-COVID condition: randomized controlled trial

Post-COVID-19 syndrome encompasses a spectrum of persistent physical, neurocognitive, and neuropsychological symptoms following SARS-CoV-2 infection. Underlying causes may include direct virus-related brain tissue damage or indirect mechanisms such as neuroinflammation and hypercoagulability. This randomized, sham-controlled, double-blind trial evaluated the effect of hyperbaric oxygen therapy (HBOT) in post-COVID-19 patients with persistent symptoms for at least three months after confirmed infection. 73 patients were randomized to receive 40 daily HBOT sessions (n=37) or sham (n=36). Follow-up assessments took place at baseline and 1–3 weeks after the final session. Following HBOT, a significant group-by-time interaction was seen for global cognitive function, attention, and executive function (d=0.495, p=0.038; d=0.477, p=0.04; d=0.463, p=0.05). Significant improvements were also documented for energy (d=0.522, p=0.029), sleep (d=−0.48, p=0.042), psychiatric symptoms (d=0.636, p=0.008), and pain interference (d=0.737, p=0.001). The clinical outcomes were accompanied by significant improvements in cerebral perfusion on MRI and microstructural changes in the supramarginal gyrus, the left supplementary motor area, the right insula, the left precentral gyrus, the right middle frontal gyrus, and the superior corona radiata. HBOT can thus induce neuroplasticity and improve cognitive, psychiatric, fatigue, sleep, and pain symptoms in post-COVID-19. The effect may be based on increased cerebral perfusion and neuroplasticity in regions linked to cognitive and emotional function.

Zilberman-Itskovich et al., 2022 · doi.org/10.1038/s41598-022-15565-0

Hyperbaric Oxygen Therapy — Long-Term Effects

Long term outcomes of hyperbaric oxygen therapy in post covid condition: longitudinal follow-up of a randomized controlled trial

A previous randomized controlled trial documented significant improvements in cognitive, psychiatric, fatigue, sleep, and pain symptoms in Long COVID patients following hyperbaric oxygen therapy (HBOT). The aim of the present study was to examine the durability of these effects over a one-year period. The longitudinal long-term follow-up included 31 patients with reported cognitive symptoms after COVID-19 who had completed 40 daily HBOT sessions. Follow-up took place more than a year (486 ± 73 days) after the final HBOT session. Quality of life (assessed with the SF-36 questionnaire) showed a similar magnitude of improvement at long-term follow-up as in the short-term effects — across most dimensions. For sleep quality, improvements in the overall score and in five subdomains showed moderate effect sizes that were maintained from the short-term to the long-term follow-up (ES1 = 0.47–0.79). For neuropsychiatric symptoms (BSI-18), the short-term assessment after HBOT showed a large effect size that persisted at long-term follow-up. Both pain intensity (ES1 = 0.69) and pain interference (ES1 = 0.83) improved significantly in the short term and remained stable long term. HBOT can thus improve quality of life, sleep quality, and psychiatric and pain symptoms in Long COVID — and the clinical effects persist even a year after the final session.

Hadanny et al., 2024 · doi.org/10.1038/s41598-024-53091-3

Immunoadsorption in ME/CFS — Prospective Cohort Study

Efficacy of repeated immunoadsorption in patients with post-COVID ME/CFS and elevated β2-adrenergic receptor autoantibodies: a prospective cohort study

Background: Since the pandemic, SARS-CoV-2 has been the most common trigger of ME/CFS. Evidence suggests that autoimmunity plays an important pathophysiological role. The authors evaluated the efficacy of immunoadsorption (IA) in patients with post-COVID ME/CFS. Methods: This pre-post study enrolled 20 patients with post-COVID ME/CFS and elevated β2-adrenergic receptor autoantibodies (β2-AR-AB) between October 2022 and October 2023. Median disease duration was 22 months (IQR: 15–31). Treatment comprised five immunoadsorption sessions at Charité – Universitätsmedizin Berlin. Seven patients were male, thirteen female; median age was 40 years (IQR: 36–51). The primary endpoint was the change in the SF-36 "Physical Functioning" dimension (SF36 PF) from baseline to four weeks after immunoadsorption. Cardinal symptoms were tracked by questionnaire over six months. Handgrip strength and EndoPAT® measurements were used to assess muscular fatigue and vascular dysfunction. Seven patients who relapsed after an initial response received a second cycle. Results: Treatment was generally well tolerated; total IgG was reduced by 79 % (CI: 73–84 %), and β2-AR-AB by 77 % (CI: 58–95 %). SF36 PF increased by a mean of 17.75 points (CI: 13.41–26.16); the strongest improvements occurred between months two and three, and the effects remained significant through month six. 14 of 20 patients (70 %) were classified as responders (SF36 PF increase ≥ 10 points). Sustained improvements were also reported in fatigue, PEM, pain, and cognitive, autonomic, and immunological symptoms. Female patients showed improved repeated handgrip strength after six months. Interpretation: Immunoadsorption can improve symptoms in patients with post-COVID ME/CFS. The positive effects of IgG depletion support a significant role for autoantibodies and impaired B-cell function in the pathophysiology.

Stein et al., 2024 · doi.org/10.1016/j.lanepe.2024.101161

Metformin in Outpatient COVID-19 Treatment

Outpatient treatment of COVID-19 and incidence of post-COVID-19 condition over 10 months (COVID-OUT): a multicentre, randomised, quadruple-blind, parallel-group, phase 3 trial

Post-COVID-19 syndrome (Long COVID) is a new chronic condition that potentially affects millions of people. The study examined whether outpatient COVID-19 treatment with metformin, ivermectin, or fluvoxamine, given soon after SARS-CoV-2 infection, could reduce the risk of Long COVID. Outpatient metformin treatment reduced the incidence of Long COVID by about 41 % (absolute reduction: 4.1 %) compared with placebo. Metformin thus shows clinical benefit in the outpatient treatment of COVID-19 and is available worldwide, inexpensive, and safe. Between December 30, 2020, and January 28, 2022, 6,602 people were assessed for eligibility; 1,431 were enrolled and randomized. Of 1,323 participants in the modified intention-to-treat population, 1,126 consented to long-term follow-up and completed at least one further questionnaire after the day-180 Long COVID assessment (564 received metformin, 562 placebo; some were additionally assigned ivermectin or fluvoxamine). 1,074 (95 %) of the 1,126 completed at least nine months of follow-up. 632 (56.1 %) were female, 494 (43.9 %) male; 44 (7.0 %) of the women were pregnant. Median age was 45 years (IQR 37–54), median BMI 29.8 kg/m² (IQR 27.0–34.2). Overall, 93 (8.3 %) of the 1,126 reported a Long COVID diagnosis by day 300. Cumulative Long COVID incidence by day 300 was 6.3 % among metformin recipients (95 % CI 4.2–8.2) versus 10.4 % with placebo (7.8–12.9) (hazard ratio [HR] 0.59; 95 % CI 0.39–0.89; p=0.012). The metformin effect was consistent across all prespecified subgroups; when treatment started within three days of symptom onset, the HR was 0.37 (95 % CI 0.15–0.95). Neither ivermectin (HR 0.99; 95 % CI 0.59–1.64) nor fluvoxamine (1.36; 0.78–2.34) showed an effect versus placebo.

Bramante et al., 2023 · doi.org/10.1016/S1473-3099(23)00299-2

Synbiotic Preparation for Post-Acute COVID-19 Syndrome

A synbiotic preparation (SIM01) for post-acute COVID-19 syndrome in Hong Kong (RECOVERY): a randomised, double-blind, placebo-controlled trial

Post-acute COVID-19 syndrome (PACS) affects more than 65 million people worldwide, yet treatment options remain scarce. The aim of the study was to evaluate a synbiotic preparation (SIM01) for relieving PACS symptoms. Between June 25, 2021, and August 12, 2022, 463 patients were randomized to SIM01 (n=232) or placebo (n=231). After six months, significantly higher proportions of the SIM01 group showed relief of fatigue (OR 2.273; 95 % CI 1.520–3.397; p=0.0001), memory loss (1.967; 1.271–3.044; p=0.0024), difficulty concentrating (2.644; 1.687–4.143; p<0.0001), gastrointestinal complaints (1.995; 1.304–3.051; p=0.0014), and general malaise (2.360; 1.428–3.900; p=0.0008) compared with placebo. Rates of adverse events were comparable between groups (SIM01 22/232 [10 %] vs. placebo 25/231 [11 %]; p=0.63). Predictors of symptom relief were treatment with SIM01, infection with Omicron variants, vaccination prior to COVID-19, and a mild acute course (p<0.0036). SIM01 thus relieves several PACS symptoms; the findings have implications for managing PACS through modulation of the gut microbiome. Further studies are needed to confirm whether the positive effects also extend to other chronic or post-infectious conditions.

Lau et al., 2023 · doi.org/10.1016/S1473-3099(23)00685-0

The Potential of H.E.L.P. Apheresis in Severe COVID-19

The potential of heparin-induced extracorporeal LDL/fibrinogen precipitation (H.E.L.P.)-apheresis for patients with severe acute or chronic Covid-19

Patients with Long COVID and acute COVID should benefit from H.E.L.P. apheresis, which has been in clinical use for 37 years. COVID-19 can trigger severe acute multi-organ disease and subsequently give rise to the chronic condition Long COVID/PASC. Alveolar tissue and adjacent capillaries show inflammatory and procoagulant activation with cell necrosis, thrombi, and massive fibrinoid deposits — unresolvable microclots — resulting in impaired gas exchange. Heparin-induced extracorporeal LDL/fibrinogen precipitation (H.E.L.P. apheresis) addresses these problems by extracorporeally supporting the entire macro- and microcirculation. The unfractionated heparin used binds the spike protein, potentially removing virus (components). It dissolves forming microclots without bleeding risk. Large amounts of fibrinogen are removed, which immediately improves oxygen supply in the capillaries. In addition, the precursors of both the procoagulant and fibrinolytic cascades are removed, de-escalating the hemostatic system overall. Myocardial, cerebral, and pulmonary perfusion as well as coronary flow reserve are increased; oxygen exchange in the capillaries is facilitated — without bleeding risk. Another factor in COVID is the "cytokine storm," which damages microcirculation in the lungs and other organs. H.E.L.P. apheresis can intercept uncontrolled coagulation and inflammatory activity by reducing cytokines such as interleukin-6, interleukin-8, and TNF-α as well as C-reactive protein, and by removing endogenous and exogenous toxins — without impairing protective IgM/IgG antibodies, leukocyte, or platelet function. It can be safely combined with antiviral agents, antibiotics, anticoagulants, or antihypertensives. Long-standing clinical experience shows that H.E.L.P. apheresis carries no potential for harm in COVID-19 patients.

Jaeger et al., 2022 · doi.org/10.3389/fcvm.2022.1007636

Here is an excerpt from the TREATME study, published in 2025 by researchers from Harvard and Stanford. In it, 3,925 patients with ME/CFS or Long Covid rate more than 150 therapies and measures. These are, of course, subjective assessments that cannot match the rigor of data collection in a well-designed clinical trial. But they are also concrete experiences from patients' actual day-to-day management of their condition — experiences that, in their sheer volume and practical relevance, can offer a wealth of clues for treatment research. You can find the full study here.

Below are the ten highest-rated therapies:

#TherapyRatingNumber of ratings
1Pacing75 %803
2Saline infusion (IV)70 %193
3Fluids and electrolytes (oral)69 %2860
4Ivabradine67 %226
5Combined H1 plus H2 antihistamine63 %352
6Compression stockings62 %952
7Intravenous or subcutaneous immunoglobulin (IVIG/SCIG)58 %91
8Maraviroc, at least 15 days57 %58
9Manual lymphatic drainage56 %97
10First-generation H1RA54 %268

We only included therapies with at least 50 ratings here.

Eckey et al., 2025 · doi.org/10.1073/pnas.2426874122

SARS-CoV-2 Reservoir in Long Covid

SARS-CoV-2 reservoir in post-acute sequelae of COVID-19 (PASC)

Millions of people are living with Long COVID, or the post-acute sequelae of COVID-19 (PASC). Several biological factors have emerged as possible drivers of PASC pathology. In some affected individuals, the SARS-CoV-2 coronavirus is not fully cleared after the acute infection. Instead, replicating virus and/or viral RNA — potentially capable of translation into viral proteins — persists in tissues as a "reservoir." This reservoir could modulate the host's immune response or release viral proteins into circulation. This review summarizes studies in which SARS-CoV-2 RNA/protein or corresponding immune responses were detected in PASC samples. The authors outline mechanisms by which a SARS-CoV-2 reservoir could contribute to PASC pathology — including coagulation, the microbiome, and neuroimmunological changes — and identify research priorities to accelerate clinical trials of antivirals or other therapeutics that could eliminate the reservoir.

Proal et al., 2023 · doi.org/10.1038/s41590-023-01601-2

Targeting the SARS-CoV-2 Reservoir

Targeting the SARS-CoV-2 reservoir in Long COVID

No approved therapies exist for post-COVID-19 syndrome (Long COVID) — a disabling condition following SARS-CoV-2 infection estimated to affect tens of millions of people. A growing body of evidence shows that, in a subset of affected individuals, SARS-CoV-2 persists for months to years after COVID-19 infection, and that this reservoir potentially drives symptoms or sequelae. Clinical trials targeting persistent SARS-CoV-2 are therefore urgently needed; several trials of antiviral agents or monoclonal antibodies are already underway. Because the mechanisms of SARS-CoV-2 persistence are not yet fully understood, such trials require careful consideration of the mechanism of action of investigational agents, patient selection, treatment duration, standardization of reservoir-related biomarkers, optimal endpoints, and possible combination approaches. Because individual patient subgroups may respond differently to interventions or combinations, post-hoc analyses are essential. The authors outline these and other key considerations to support the design, conduct, and interpretation of trials in this rapidly growing field. The recommendations draw on insights from studies of the HIV reservoir, hepatitis C, and other RNA viruses, as well as precision oncology, which face similar methodological challenges.

Proal et al., 2025 · doi.org/10.1016/S1473-3099(24)00769-2

Persistent Complement Dysregulation with Signs of Thromboinflammation

Persistent complement dysregulation with signs of thromboinflammation in active Long Covid

Long COVID is a disabling condition of as-yet unknown etiology. The authors performed multimodal proteomic analyses on blood serum from COVID-19 patients followed for up to 12 months after confirmed SARS-CoV-2 infection. Analysis of more than 6,500 proteins across 268 longitudinal samples showed dysregulated activation of the complement system — a central mechanism of innate immune defense and homeostasis — in people with Long COVID. Active Long COVID was characterized by dysregulation of the terminal complement pathway and sustained activation of the alternative and classical complement pathways; the latter was associated with elevated antibody titers against various herpesviruses, which may stimulate this pathway. Markers of hemolysis, tissue damage, platelet activation, and monocyte-platelet aggregates were also elevated in Long COVID. Machine learning analyses confirmed complement and thromboinflammatory proteins as the most important biomarkers, supporting diagnostic and therapeutic investigation of these systems.

Cervia-Hasler et al., 2024 · doi.org/10.1126/science.adg7942

Dysregulated Autoantibodies Correlate with Symptom Severity

Dysregulated autoantibodies targeting vaso- and immunoregulatory receptors in Post COVID Syndrome correlate with symptom severity

Most patients with post-COVID syndrome (PCS) show a wide range of symptoms without clear evidence of organ dysfunction. Some meet the diagnostic criteria for ME/CFS. The severity of ME/CFS symptoms correlates with levels of natural regulatory autoantibodies (AAB) against several G-protein-coupled receptors (GPCRs). In this exploratory study, serum levels of AAB against vaso- and immunoregulatory receptors — predominantly GPCRs — were analyzed in 80 PCS patients following mild to moderate COVID-19 infection; 40 of them met the ME/CFS criteria. Healthy seronegative controls (n=38) and asymptomatic post-COVID-19 controls (n=40) served as comparison groups. Compared with at least one control group, PCS patients showed lower levels of various AAB as well as altered correlations among the AAB. A random forest classification identified AAB against ADRB2, STAB1, and ADRA2A as the strongest classifiers of post-COVID courses. Several AAB correlated with symptom severity. Notably, the severity of fatigue and vasomotor symptoms in PCS/ME/CFS patients was associated with ADRB2-AAB levels. The study demonstrates dysregulation of AAB against various receptors of the autonomic nervous system as well as vaso- and immunoregulation, and their correlation with symptom severity — pointing to a role for these antibodies in the pathogenesis of PCS.

Sotzny et al., 2022 · doi.org/10.3389/fimmu.2022.981532

GPCR Autoantibodies Correlate with Symptom Severity in ME/CFS

Autoantibodies to Vasoregulative G-Protein-Coupled Receptors Correlate with Symptom Severity, Autonomic Dysfunction and Disability in ME/CFS

ME/CFS is an acquired, complex illness whose cardinal symptoms include fatigue, post-exertional malaise (PEM), cognitive impairment, pain, and autonomic dysfunction. In the majority of cases, ME/CFS is triggered by an infection. Early evidence for a role of natural regulatory autoantibodies (AAB) against beta-adrenergic (AdR) and muscarinic acetylcholine receptors (M-AChR) in ME/CFS comes from a small number of studies. Methods: Using ELISA, the correlation between symptom severity and AAB levels against vasoregulatory AdR, AChR, endothelin-1 receptors type A and B (ETA/B), and the angiotensin II type 1 receptor (AT1) was analyzed in a Berlin ME/CFS cohort (n = 116). Disease severity, symptoms, and autonomic dysfunction were assessed by questionnaire. Results: In patients with infection-triggered disease, levels of most AAB correlated significantly with the cardinal symptoms fatigue and muscle pain. The severity of cognitive impairment correlated with AT1-R and ETA-R AAB, and the severity of gastrointestinal complaints with alpha1/2-AdR AAB. In non-infection-triggered ME/CFS, fewer and different correlations were seen. Conclusion: The correlations between specific AAB against GPCRs and symptoms support a role for these AAB, or the corresponding receptor pathways, in the pathogenesis.

Freitag et al., 2021 · doi.org/10.3390/jcm10163675

Amyloid Fibrin Microclots in Long Covid

A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications

Post-acute sequelae of COVID (PASC), commonly referred to as "Long COVID," are a relatively frequent consequence of SARS-CoV-2 infection, in which symptoms such as breathlessness, fatigue, "brain fog," tissue damage, inflammation, and coagulopathies (disorders of the clotting system) persist long after the initial infection. The syndrome shows similarities to other post-viral syndromes and to ME/CFS. Many regulatory health authorities still do not recognize it as a distinct illness and classify it under the umbrella term "COVID," even though its demographics differ markedly from those of acute COVID-19. A few years ago, the authors discovered that fibrinogen in the blood can clot into an abnormal "amyloid" form of fibrin that — like other β-strand-rich amyloids and prions — is relatively resistant to proteolytic breakdown (fibrinolysis). This is particularly pronounced in the platelet-poor plasma (PPP) of people with Long COVID, where extensive fibrin amyloid microclots subsequently form, persist, trap additional proteins, and can contribute to the formation of various autoantibodies. These microclots can be measured relatively easily in PPP using the dye thioflavin T and a simple fluorescence microscope. Although Long COVID presents a diverse spectrum of symptoms, the authors argue that the ability of these fibrin amyloid microclots ("fibrinaloids") to block capillaries — thereby limiting the passage of red blood cells and O₂ exchange — can explain much of the symptomatology. Consistent with this, a preliminary report showed that a suitable, closely monitored "triple" anticoagulation therapy that removes the microclots also resolves the remaining symptoms. Fibrin amyloid microclots thus represent a novel and potentially significant target for understanding and treating Long COVID and related conditions.

Kell, Laubscher & Pretorius, 2022 · doi.org/10.1042/BCJ20220016

Fibrin Amyloid Microclots and Platelet Pathology

Prevalence of symptoms, comorbidities, fibrin amyloid microclots and platelet pathology in individuals with Long COVID/PASC

Fibrin(ogen) amyloid microclots and platelet hyperactivation — originally described in South African COVID-19 and Long COVID/PASC patients — could represent a suitable target for the clinical management of Long COVID symptoms. A Long COVID/PASC registry was established for systematic data collection, through which affected individuals could report symptoms and pre-existing comorbidities. The most important comorbidities were hypertension, hypercholesterolemia, cardiovascular disease, and type 2 diabetes mellitus. The sex distribution (70 % women) and the most frequently reported Long COVID/PASC symptoms (fatigue, brain fog, concentration and memory problems, breathlessness, joint and muscle pain) matched other published cohorts. Microclot and platelet pathology were associated with persistent Long COVID/PASC symptoms following acute COVID-19. Fibrin amyloid microclots, which block capillaries and thereby impede O₂ transport into tissue, provide — together with platelet hyperactivation — a plausible explanation for Long COVID/PASC symptomatology. Resolving and reversing these underlying endotheliopathies represents an important treatment option that urgently requires controlled clinical trials. The authors propose a simple scoring system for platelet and coagulation pathology.

Pretorius et al., 2022 · doi.org/10.1186/s12933-022-01579-5

Microclots and Neutrophil Extracellular Traps (NETs)

Circulating Microclots Are Structurally Associated With Neutrophil Extracellular Traps and Their Amounts Are Elevated in Long COVID Patients

The persistence of vascular-thrombotic complications is discussed as a possible contributor to Long COVID syndrome (LC). Since elevated levels of both heterogeneous fibrin(ogen) amyloid particles (microclots) and neutrophil extracellular traps (NETs) — both closely linked to thromboinflammation — have recently been documented separately in LC, this work investigates the relationship between the two. NETs markers (myeloperoxidase, neutrophil elastase, and circulating DNA) were quantitatively and structurally associated with the size and number of microclots in LC patients; the markers showed strong diagnostic performance both individually and in combination. NETs could thus be a component of circulating microclots. The authors suggest that increased NET formation promotes the stabilization of microclots in circulation, giving rise to potentially harmful effects that causally contribute to LC syndrome.

Thierry et al., 2025 · doi.org/10.1002/jmv.70613

Platelets and Microclots in ME/CFS

The Occurrence of Hyperactivated Platelets and Fibrinaloid Microclots in ME/CFS

The authors have previously shown that platelet-poor plasma (PPP) from people with Long COVID/PASC is characterized by a hypercoagulable state and contains hyperactivated platelets as well as a substantial number of already-formed fibrin(ogen)/fibrinaloid microclots. Given the extensive overlap in symptoms and etiology between Long COVID/PASC and ME/CFS, the authors investigated whether the coagulation abnormalities documented in Long COVID/PASC — hypercoagulability, platelet hyperactivation, and fibrinaloid microclots — are also present in people with ME/CFS and age- and sex-matched healthy controls. ME/CFS samples showed significant hypercoagulability on thromboelastography of whole blood and PPP. The area of fibrinaloid microclots in untreated PPP was typically more than tenfold greater in ME/CFS patients than in healthy controls; a comparable difference was seen after thrombin treatment. Using fluorescently labeled PAC-1 (which recognizes glycoprotein IIb/IIIa) and CD62P (which binds P-selectin), platelet hyperactivation was observed in ME/CFS hematocrit samples. On a quantitative scoring system, ME/CFS platelets reached a mean spreading score of 2.72 ± 1.24 versus 1.00 in healthy controls (activation with pseudopodia formation). ME/CFS is thus accompanied by substantial and measurable changes in coagulability, platelet activation, and the formation of fibrinaloid microclots. However, the microclot burden is lower than previously observed in Long COVID/PASC. In particular, fibrinaloid microclots could explain many ME/CFS symptoms (such as fatigue) via the temporary blockage of microcapillaries and resulting ischemia; they could also damage the endothelium. The discovery of these biomarkers is an important development in ME/CFS research and points to possible treatment strategies using known agents and/or supplements that target systemic vascular pathology and endothelial inflammation.

Nunes et al., 2022 · doi.org/10.3390/ph15080931

Fibrin Drives Thromboinflammation and Neuropathology

Fibrin drives thromboinflammation and neuropathology in COVID-19

Life-threatening thrombotic events and neurological symptoms are common in COVID-19 and persist in Long COVID. Despite clinical evidence, the underlying mechanisms of the coagulopathy and its consequences for inflammation and neuropathology remain poorly understood; treatment options are limited. Fibrinogen — the central structural component of blood clots — is deposited abundantly in the lungs and brain of COVID-19 patients, correlates with disease severity, and serves as a predictive biomarker for cognitive deficits after COVID-19. The authors show that fibrin binds the SARS-CoV-2 spike protein and forms pro-inflammatory clots that drive systemic thromboinflammation and neuropathology in COVID-19. Fibrin — acting through its inflammatory domain — is required for oxidative stress and macrophage activation in the lungs following SARS-CoV-2 infection, while suppressing natural killer cells. Fibrin promotes neuroinflammation and neuronal loss after infection, as well as activation of the innate immune response in the brain and lungs — independent of active infection. A monoclonal antibody against the inflammatory fibrin domain protects against microglial activation and neuronal damage as well as pulmonary thromboinflammation after infection. A fibrin-targeted immunotherapy could thus represent a therapeutic option for patients with acute COVID-19 and Long COVID.

Ryu et al., 2024 · doi.org/10.1038/s41586-024-07873-4

Why Sharpa exists

This is the picture that led us to build Sharpa.

The demands of serious Long Covid care are high — and today met in hardly any one place. Sharpa builds the care pathway that doesn't yet exist: mechanism-based, at home where possible, at the patient's own pace, with one dedicated contact. We don't provide therapy ourselves; the medical decision lies with the physician. We carry the load on the way.

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