Category: Overlapping Illnesses

An insight into the long/post COVID care situation in Germany-a rapid scoping review

Abstract:

in English, German

Background: Long/post COVID and related conditions such as myalgic encephalomyelitis/chronic fatigue syndrome, postural orthostatic tachycardia syndrome and post-vaccination syndrome are associated with persistent functional impairments and are met with care structures in Germany that are difficult to navigate.

Objective: The rapid scoping review offers an insight into care structures, capacities, access, care pathways and gaps in care for these patient groups in the German healthcare system. It also takes into account patient and care provider perspectives.

Methods: The study follows the recommendations of the Joanna Briggs Institute and the PRISMA ScR checklist for conducting (rapid) scoping reviews. A MEDLINE search was conducted from 2020 onwards with predefined inclusion and exclusion criteria for evidence sources related to care in Germany.

Results: 44 evidence sources were included. General practitioners and paediatricians act as the first point of contact. Specialised outpatient clinics and rehabilitation facilities take on complex diagnostics and patient treatment. Care networks are rare. Navigating the healthcare system is characteris ed by information gaps, unclear responsibilities and long waiting times, so that those affected often organise their own care. Some report stigmatisation, misdiagnoses and stressful activation recommendations despite the risk of post exertional malaise.

Conclusion: Care is unevenly accessible, poorly coordinated and only limitedly evidence based. Shared knowledge and case databases, training, better diagnostic tools and robust efficacy studies are needed to improve access, management and safety of long/post COVID care.

Source: Ebster M, Gscheidle S, Lange S, Weijburg T, Arnold M. Ein Einblick in die Long/Post COVID-Versorgungslage in Deutschland – ein Rapid Scoping Review [An insight into the long/post COVID care situation in Germany-a rapid scoping review]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2026 Oct 16. German. doi: 10.1007/s00103-026-04313-8. Epub ahead of print. PMID: 42886231. https://link.springer.com/article/10.1007/s00103-026-04313-8 (Full text in German)

Post-acute sequelae of COVID-19 (PASC) are associated with distinct clinical phenotypes two years after SARS-CoV-2 infection: A data-driven approach

Abstract:

It is important to determine whether the persistent cognitive and fatigue complaints, as part of post-acute sequelae of COVID-19 (PASC), are associated with underlying patterns and specific symptoms clusters. Therefore, the aim of the present study was to investigate symptom clusters and clinical phenotypes in PASC.

We included n = 153 individuals (53 years old, 66% female, 2 years post SARS-CoV-2 infection) categorized into groups with (n = 88) and without (n = 65) PASC, defined by severe fatigue and concentration problems using validated cut-offs. Symptom clusters (i.e., component loadings and component scores) were identified using principal component analyses (PCA, eigenvalue[EV]>1.0), using clinical, somatic, coping and sleep factors, symptom severity, neuropsychological and physical tests (totalling 19 tests and questionnaires). We then used logistic regression techniques on (participant-level) component scores (standardized) to investigate associations with PASC. Finally, K-means clustering methods to identify clinical phenotypes. Analyses were adjusted for age, sex, education, nationality and time since infection.

PCA identified 5 components, explaining 70% of the variance. We labelled these components as follows: (1) PEM, ME/CFS and sleep symptoms, coping factors (EV = 7.0, 36.9% variance), (2) information-processing speed (EV = 2.5, 13.3%), (3) executive functioning (EV = 1.5, 8.0%, (4) physical performance (EV = 1.2, 6.5%), (5) somatic comorbidities and hospital admission (EV = 1.0, 5.5%). Logistic regression showed that only the first component scores (Odds ratio [95% confidence interval] = 97.1 [16.5-570.3], p < 0.001,), and none of the others (all p > 0.05), associated with PASC.

Cluster analysis revealed two distinct clinical phenotypes among individuals with severe chronic fatigue: one marked by physical impairment and the other by diminished cognitive performance. Consistent with existing literature, we confirmed that PASC is a heterogeneous syndrome marked by extensive, interrelated symptoms. Notably, we identified specific cognitive and physical clinical phenotypes. These findings are important for future targeted diagnosis and treatment.

Source: Verfaillie SCJ, Verveen A, Visser D, Nieuwkerk P, Appelman B, Boellaard R, van Heugten CM, Horn J, Hulst HE, de Jong MD, Kuut TA, Maaden TV, van Os YMG, Prins M, Visser-Meily JMA, van Vugt M, van den Wijngaard CC, van Berckel BNM, Bosch JA, Tolboom N, Knoop H. Post-acute sequelae of COVID-19 (PASC) are associated with distinct clinical phenotypes two years after SARS-CoV-2 infection: A data-driven approach. PLoS One. 2026 Oct 15;21(10):e0359844. doi: 10.1371/journal.pone.0359844. PMID: 42879454; PMCID: PMC13671525. https://pmc.ncbi.nlm.nih.gov/articles/PMC13671525/ (Full text)

Exploratory clinical and immunological changes following Tixagevimab/Cilgavimab administration in immunodeficient patients with SARS-CoV-2-associated ME/CFS and persistent circulating spike protein

Abstract:

Background: Persistent circulating SARS-CoV-2 spike protein has been proposed as a potential contributor to long-COVID pathophysiology. Whether administration of spike-targeting monoclonal antibodies is followed by changes in spike protein concentrations, autonomic receptor autoantibodies, or clinical outcomes remains uncertain.

Methods: In this prospective, non-randomized observational study, 21 participants were enrolled. Ten immunodeficient patients with long-COVID-associated ME/CFS and detectable circulating spike protein received Tixagevimab/Cilgavimab for SARS-CoV-2 pre-exposure prophylaxis. One patient subsequently withdrew consent, leaving nine patients for paired baseline and 30-day follow-up analyses. Eleven healthy individuals with previous SARS-CoV-2 infection but without long COVID provided descriptive reference data and were not considered an efficacy control group.

Results: β1-adrenergic receptor autoantibody concentrations decreased from 26.8 ± 18.2 to 21.2 ± 14.7 U/ml (unadjusted p = 0.003). No statistically significant changes were observed for β2-adrenergic or M3/M4-muscarinic receptor autoantibodies. Median spike protein concentrations changed from 63 pg/ml (IQR 9-127) to 26 pg/ml (IQR 10-120; p = 0.63), with individual decreases observed in five of nine patients. None of the assessed clinical outcomes changed significantly at group level. Changes in spike protein concentrations were not significantly correlated with changes in the assessed autonomic receptor autoantibodies.

Conclusion: Tixagevimab/Cilgavimab administration was followed by a nominally significant within-patient reduction in β1-adrenergic receptor autoantibody concentrations, but not by conclusive changes in circulating spike protein or clinical outcomes. These findings are preliminary and hypothesis-generating. The small sample size, non-randomized design, brief 30-day follow-up, inclusion of only immunodeficient patients, and absence of an untreated disease-matched control group preclude conclusions regarding therapeutic efficacy.

Source: Seidel M, Anft M, Wiemers L, Seibert FS, Bertram S, Rosiewicz K, Stervbo U, Westhoff TH, Babel N. Exploratory clinical and immunological changes following Tixagevimab/Cilgavimab administration in immunodeficient patients with SARS-CoV-2-associated ME/CFS and persistent circulating spike protein. Immunol Lett. 2026 Oct 7:107247. doi: 10.1016/j.imlet.2026.107247. Epub ahead of print. PMID: 42843426. https://pubmed.ncbi.nlm.nih.gov/42843426/

Evidence for transcriptomic changes impacting muscle contraction in patients with post-acute COVID-19 syndrome

Abstract:

Post-acute COVID-19 syndrome (PACS) overlaps with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) but, due to frequent muscle pain and exertional intolerance, neuromuscular disorders are often suspected. We report the results of a comprehensive neuromuscular evaluation in 27 PACS patients (22F/5M; median age 41 ys).

All patients developed chronic fatigue (>6 months), post-exertional malaise, and cognitive impairment, with muscle pain in 88% but no neuromuscular deficits at clinical examination. 18/27 patients were unable to work. All patients fulfilled established ME/CFS diagnostic criteria (CDC 1994, ICC 2011, Inst Medicine 2015, NICE 2021). Electrophysiological studies and CK levels were normal.

Brain 18FDG-PET/MRI (14/27) showed posterior hypometabolism in 8/14. Muscle biopsy (7/27) showed moderate dysimmune changes in 2/7. Exploratory transcriptomic analyses performed in muscle biopsies from PACS patients and pre-COVID controls unveiled in PACS differentially expressed genes in the cytokine and autophagy pathways.

Interestingly, other genes were also differentially expressed in pathways affecting actin, the cytoskeleton, and contraction. Indeed, we found upregulated genes involved in the troponin-tropomyosin complex, a key regulator of muscle contraction through calcium binding. We also found downregulated genes involved in the formation and stabilization of actin bundles at sarcomere Z discs and in mechanical signaling.

These findings indicate that PACS patients with prominent muscular symptoms do not exhibit overt neuromuscular involvement on standard investigations but may show subtle myopathic or dysimmune changes and central metabolic alterations. At the transcriptomic level, the data show an impact on key pathways involved in contraction. The overlap with ME/CFS highlights the importance of careful differential diagnosis and suggests a complex pathophysiology beyond a basic muscle disease.

Source: Gianmarco Severa, Rakel Altabe-Mellul, Alessio Rotini, Peggy Lafuste, Sarah Souvannanorath, Edoardo Malfatti, Emmanuel Itti, Hakim Ahmed-Belkacem, Fred Relaix, Francois Jerome Authier, 3.14P Evidence for transcriptomic changes impacting muscle contraction in patients with post-acute COVID-19 syndrome, Neuromuscular Disorders, Volume 67, Supplement 1, 2026, 106984, ISSN 0960-8966, https://doi.org/10.1016/j.nmd.2026.106984. https://www.sciencedirect.com/science/article/abs/pii/S0960896626006528

FreeSurfer-based amygdala subfield volumetry in long COVID and ME/CFS: clinical and immunological correlations

Abstract:

Background: Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) share debilitating symptoms and have been associated with limbic-system dysfunction. We investigated amygdala subfield volumes to identify disease-specific neuroanatomical features and their clinical and immunological correlates.

Methods: We prospectively examined 27 patients with long COVID, 38 patients with ME/CFS, and 47 healthy controls (HCs). Amygdala subfields were segmented using high-resolution 3-T MRI and FreeSurfer software. Group comparisons were performed using analysis of covariance, and partial correlations with clinical and immunological indices, including autoantibodies, plasmablasts, regulatory T cells (Tregs), and Eomesodermin-positive helper T cells (Eomes+ Th cells), were assessed.

Results: Patients with long COVID had nominally larger right cortical nucleus volumes than HCs (raw p = 0.040; Bonferroni-adjusted p = 0.119), whereas patients with ME/CFS had a nominally larger left paralaminar nucleus (raw p = 0.048; Bonferroni-adjusted p = 0.145). In long COVID, G-protein-coupled receptor (GPCR) autoantibodies were nominally negatively associated with right medial nucleus volume. In ME/CFS, performance status was nominally positively associated with the right basal nucleus, right paralaminar nucleus, and right whole amygdala, and plasmablasts were nominally positively associated with the right corticoamygdaloid transition area. No group difference or partial correlation remained significant after correction for multiple testing.

Conclusion: Although no finding survived correction for multiple testing, the exploratory results suggest that amygdala-related structural variation may be relevant to both long COVID and ME/CFS. The nominal, uncorrected within-group patterns centered on olfactory-related amygdala nuclei and GPCR autoantibodies in long COVID, and on amygdala structure, functional severity, and plasmablasts in ME/CFS; however, these patterns do not support a conclusion of between-group differences. These observations are hypothesis-generating and do not establish disease-specific mechanisms. Prespecified validation in larger longitudinal and independent cohorts is required.

Source: Kimura Y, Sato W, Shigemoto Y, Kagaya R, Hayakawa A, Kumazawa Y, Shin I, Amano K, Yamamura T, Sato N. FreeSurfer-based amygdala subfield volumetry in long COVID and ME/CFS: clinical and immunological correlations. Front Neurol. 2026 Sep 16;17:1913553. doi: 10.3389/fneur.2026.1913553. PMID: 42819213; PMCID: PMC13623709. https://pmc.ncbi.nlm.nih.gov/articles/PMC13623709/ (Full text)

Persistent symptom burden in long-standing systemic lupus erythematosus: a subgroup-focused hypothesis for an SLE-ME/CFS research phenotype

Abstract:

Background: Despite improved control of inflammatory disease activity in systemic lupus erythematosus (SLE), many patients experience persistent fatigue, impaired physical function, cognitive symptoms, sleep disturbance, and reduced exercise tolerance, including during remission. These symptoms are multifactorial and may not be adequately explained by conventional measures of inflammatory activity. Clinical and biological parallels with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) suggest that interacting immune, metabolic, vascular, and autonomic mechanisms may contribute to persistent symptom burden in a subgroup of patients with long-standing SLE.

Objective: To develop a subgroup-focused, non-linear, and testable framework for persistent symptoms in SLE by integrating established SLE evidence with carefully distinguished mechanistic insights from ME/CFS research.

Methods: This Commentary is based on a targeted, non-systematic literature synthesis of publications identified in PubMed and Web of Science. Evidence was categorized as direct SLE evidence, evidence from ME/CFS, or cross-condition mechanistic inference. Priority was given to human studies, systematic reviews, meta-analyses, and translational research addressing persistent symptoms, autonomic and endothelial dysfunction, mitochondrial and redox alterations, and neurocognitive manifestations.

Results: We propose a hypothesized SLE-ME/CFS research phenotype characterized by persistent, functionally limiting symptoms despite low inflammatory disease activity or remission. The phenotype includes fatigue lasting at least six months together with post-exertional symptom exacerbation, unrefreshing sleep, cognitive symptoms, and/or orthostatic intolerance, following structured exclusion or assessment of alternative explanations and comorbidities. Direct SLE evidence supports the relevance of residual immune activation, oxidative stress, mitochondrial alterations, endothelial dysfunction, and dysautonomia. Findings from ME/CFS further suggest potentially convergent mechanisms involving impaired cellular energetics, autonomic dysfunction, altered cerebral perfusion, and neuroimmune dysregulation. However, these cross-condition inferences require direct validation in SLE.

Conclusions: Persistent symptom burden in long-standing SLE may reflect a biologically distinct subgroup in which immune, autonomic, vascular, metabolic, and neurocognitive mechanisms interact dynamically. The proposed framework does not define a new diagnostic entity or fixed disease trajectory but provides a hypothesis-generating basis for prospective longitudinal studies. Multidimensional phenotyping may improve patient stratification, biomarker discovery, and supportive care for patients whose symptoms remain disproportionate to conventional measures of disease activity.

Source: Habermann-Horstmeier L. Persistent symptom burden in long-standing systemic lupus erythematosus: a subgroup-focused hypothesis for an SLE-ME/CFS research phenotype. J Transl Med. 2026 Sep 25;24(1):1215. doi: 10.1186/s12967-026-08867-8. PMID: 42806386. https://link.springer.com/article/10.1186/s12967-026-08867-8 (Full text)

High Frequency of HHV-7 Reactivation in Neurological and Neuropsychiatric Long COVID: A Retrospective Observational Study

Abstract:

The neurological and neuropsychiatric manifestations of long COVID remain incompletely understood. Reactivation of latent herpesviruses has been proposed as a contributing mechanism, but human herpesvirus 7 (HHV-7) has received limited attention despite its neurotropic potential. We conducted a retrospective analysis of HHV-7 polymerase chain reaction (PCR) results in 30 patients (18 women and 12 men; age range, 21-55 years) with a neurological/neuropsychiatric long COVID phenotype tested within 24 months of SARS-CoV-2 infection at R.E.D. Laboratories SA, Belgium.

HHV-7 positivity was compared with a historical pre-COVID-19 laboratory reference cohort comprising 320 diagnostic tests performed from 2012 to 2019. HHV-7 positivity was 29.1% (93/320; 95% CI, 24.4-34.3%) in the historical reference cohort and 76.7% (23/30; 95% CI, 59.1-88.2%) in the neurological/neuropsychiatric long COVID cohort. The between-cohort difference was significant using a two-sided Fisher’s exact test (p < 0.000001). All six patients tested within the first 12 months were HHV-7-positive. HHV-7-positive patients frequently reported neuropsychiatric symptoms, and in one longitudinal index case, viral load tracked self-reported symptom severity.

In this patient-initiated retrospective study, HHV-7 positivity was substantially more frequent in the long COVID cohort than in the historical reference cohort. These findings are hypothesis-generating and support prospective investigation of HHV-7 in neurological and neuropsychiatric long COVID.

Source: Ducret D, Mijatovic T. High Frequency of HHV-7 Reactivation in Neurological and Neuropsychiatric Long COVID: A Retrospective Observational Study. Viruses. 2026 Sep 20;18(9):1043. doi: 10.3390/v18091043. PMID: 42797874. https://www.mdpi.com/1999-4915/18/9/1043 (Full text)

Knowing or not knowing: the practical and moral complexity of diagnostic-seeking pathways in situations of medical uncertainty

Abstract:

In this paper, we discuss the practical and moral complexities of diagnostic-seeking pathways for three uncertain medical conditions: fibromyalgia, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and long COVID. We analyse qualitative data collected in the UK between 2023 and 2025, comprising in-depth interviews with medical professionals, researchers, and patients, as well as documentary sources.

Drawing on the anthropology and sociology of diagnosis, this paper discusses how chronic illness can be marked by challenging and unstable pathways, influenced by the organisation of the medical system and the resources patients have to navigate it. Diagnoses further do not guarantee a solution to the condition, and can, on the other hand, produce stigma. Medical professionals recognise the uncertain nature of these conditions and emphasise how diagnosis can play an instrumental role in providing patients with access to therapies, benefits, or acceptance. Patients discuss the complexity of the strategies they deploy not only to obtain a diagnosis but also to navigate the practical and moral complexities associated with their condition.

Analysing the practical and moral complexity of diagnostic-seeking pathways represents a way to enrich anthropological reflections on diagnosis by demonstrating how this key concept of biomedicine is strongly influenced by social, economic, and moral, as well as biological, factors.

Source: Greco C, Cross S. Knowing or not knowing: the practical and moral complexity of diagnostic-seeking pathways in situations of medical uncertainty. Anthropol Med. 2026 Sep 25:1-16. doi: 10.1080/13648470.2026.2709278. Epub ahead of print. PMID: 42788232. https://www.tandfonline.com/doi/full/10.1080/13648470.2026.2709278 (Full text)

DNA methylation: unifying framework for complex chronic conditions

Abstract:

Complex chronic conditions represent a growing health burden that is poorly understood and inadequately managed within current health systems. This review focuses on the potential of epigenetic DNA methylation to provide a pathway for better understanding of four closely related conditions: myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), long COVID (LC), fibromyalgia (FM), and hypermobile Ehlers-Danlos syndrome (hEDS).

These conditions have extensive overlapping symptoms, suggesting shared underlying pathophysiological mechanisms. Epigenetic regulation, particularly DNA methylation, provides a powerful framework for comparative and longitudinal studies across these clinically overlapping conditions.

Here, we synthesise evidence from current DNA methylation studies in ME/CFS, LC, and FM, and consider how an integrated cross-condition approach could advance mechanistic insight, enable diagnostic stratification, and improve patient outcomes.

Source: Sharma S, Rodger EJ, Chatterjee A, Tate WP. DNA methylation: unifying framework for complex chronic conditions. Trends Genet. 2026 Sep 24:S0168-9525(26)00221-0. doi: 10.1016/j.tig.2026.09.001. Epub ahead of print. PMID: 42786072. https://www.cell.com/trends/genetics/fulltext/S0168-9525(26)00221-0 (Full text)

When do infections lead to long COVID? Scientists close in on triggers and treatments for post-viral syndromes

Hundreds of millions of people have long-term conditions as a result of an infection. Researchers are working out how to help them.
By Simon Makin

In 2004, Amy Proal got an infection that changed her life. “I was in my pre-med, last year of college, and totally tanked,” she says. “No one could tell me what it was, everybody said my blood work was fine — sent to a psychiatrist, the usual story.” She started reading papers from her sickbed and soon realized that she wasn’t the only one with unexplained symptoms that lingered after an infection.

A year later, she was diagnosed with ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome). She managed to improve her symptoms with antivirals and other drugs, and went on to do a PhD in microbiology, studying the lasting consequences of pathogens. In 2018, she co-founded PolyBio, a foundation in Medford, Massachusetts, that advances research on infection-associated chronic illnesses. “Then,” Proal says, “COVID hit.”

Read the rest of this Nature article HERE.