Tag: long Covid

Post-acute infection: before we forget it again

Abstract:

Long COVID did not invent the post-acute phase of infection; it made it impossible to ignore. Acute infections are still often framed as time-limited events that end in recovery, deterioration or death, but this view fails to capture patients who remain biologically and clinically unwell after the acute infection has passed. The problem extends beyond SARS-CoV-2. Post-acute morbidity has been described after influenza, Epstein-Barr virus infection, Q fever, sepsis, and other infections, yet definitions, coding systems, and clinical pathways remain fragmented.

We argue that post-acute infection should not be organized only by the initiating pathogen. Such pathogen-centric labels may be clinically tidy, but they risk producing heterogeneous cohorts, diluted biomarker signals, and disease-specific silos that obscure shared mechanisms of incomplete recovery. Instead, the field needs a second axis: the host-recovery state.

Persistent inflammation, immune remodelling, loss of tolerance, antigenic stimulation, endothelial dysfunction, mitochondrial impairment, and tissue injury may represent overlapping immunometabolic failure modes across infections. Defining these states over time could help transform post-acute infection from a residual clinical label into a mechanism-informed framework for research, biomarkers, and care.

Source: Madsen HB, Desler C. Post-acute infection: before we forget it again. Clin Exp Immunol. 2026 Jan 6;220(1):uxag061. doi: 10.1093/cei/uxag061. PMID: 42931812; PMCID: PMC13701074. https://pmc.ncbi.nlm.nih.gov/articles/PMC13701074/ (Full text)

Overlapping Post-COVID Conditions: A Case of Myalgic Encephalomyelitis and Postural Orthostatic Tachycardia Syndrome Triggered by Sequential Epstein-Barr Virus (EBV) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infections

Abstract:

The rise in post-infectious syndromes following COVID-19, such as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Postural Orthostatic Tachycardia Syndrome (POTS), has become increasingly common in clinical practice, representing an emerging clinical challenge. This case highlights a possible clinical scenario involving the interaction between sequential viral infections – such as the Epstein-Barr virus (EBV) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) – in triggering overlapping chronic conditions. This report presents the case of a patient who developed ME/CFS and POTS following SARS-CoV-2 infection, with a prior history of EBV mononucleosis, and discusses the diagnostic, therapeutic, and pathophysiological implications.

A 48-year-old woman with a history of mononucleosis in childhood developed persistent and disabling symptoms after COVID-19 in January 2022. She presented with extreme fatigue, orthostatic intolerance, paresthesia, cognitive dysfunction, and multisystem symptoms. After extensive investigation, she was diagnosed with ME/CFS (early 2023) and POTS (later that year). Mast Cell Activation Syndrome (MCAS) was considered as a hypothesis during follow-up, but objective testing was not confirmatory. Management included pharmacological therapy (including low-dose naltrexone, duloxetine, and palmitoylethanolamide (PEA)), activity adjustments (pacing), and a multidisciplinary approach, with partial and fluctuating responses.

This case illustrates how viral infections such as EBV and SARS-CoV-2 may act as sequential triggers in an individual clinical trajectory compatible with the development of ME/CFS and POTS. The symptomatic overlap, the lack of readily available objective biomarkers in this patient, and the need for a predominantly clinical and functional diagnostic approach in her evaluation highlight the complexity of these conditions. This experience also underscores the importance of continued efforts in research, clinical training, and integrated care models to improve the management of patients presenting with post-COVID conditions (PCC).

Source: Mayrink Magalhães VR, Ribeiro Oliveira LA, Lourenço AJ, Ribeiro Camargos I, Da Silva LG, Filgueiras PS, De Souza Lima AE, Marques Contin SV, Costa M, Istilli P, Ferreira da Costa Gomes M, Pedretti CB, Correa PRL, Grenfell RF. Overlapping Post-COVID Conditions: A Case of Myalgic Encephalomyelitis and Postural Orthostatic Tachycardia Syndrome Triggered by Sequential Epstein-Barr Virus (EBV) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infections. Cureus. 2026 Sep 24;18(9):e116844. doi: 10.7759/cureus.116844. PMID: 42927133; PMCID: PMC13695498. https://pmc.ncbi.nlm.nih.gov/articles/PMC13695498/ (Full text)

The Glymphatic–Meningeal Lymphatic System and Autophagy in ME/CFS and Long COVID: A Mechanistic Perspective

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Post-Acute Sequelae of SARS-CoV-2 infection (Long COVID) are complex multisystem disorders affecting 60–400 million individuals globally. They are considered post-infectious illnesses and share similar biological mechanisms, including immune dysregulation, orthostatic intolerance and cognitive dysfunction, highlighting a substantial overlap between the two conditions. Persistent fatigue, sleep dysfunction, post-exertional malaise and brain fog are among some of their most common and debilitating symptoms.
Despite extensive research, they remain incurable, with no effective treatments, or simple diagnostic tests. They are increasingly understood as heterogeneous, multisystem diseases, involving neurological symptoms, with varying severities and diverse underlying biological abnormalities. More recently, the possibility of glymphatic dysfunction and autophagy impairment have been proposed as parts of the mechanistic features of the pathophysiology of these conditions, which are discussed more fully in the present perspective.
With the glymphatic and meningeal lymphatic systems being operationally integrated, we will try to delineate how the metabolic waste removal mechanism afforded by this system may work together with autophagy to maintain brain homeostasis. We will provide some of the established mechanistic features of toxicity of misfolded proteins, explore their role in causing glymphatic dysfunction and impairing autophagy, and discuss the potential for therapeutic interventions.
Source: Nemat-Gorgani M, Jensen MA, Davis RW. The Glymphatic–Meningeal Lymphatic System and Autophagy in ME/CFS and Long COVID: A Mechanistic Perspective. International Journal of Molecular Sciences. 2026; 27(20):9351. https://doi.org/10.3390/ijms27209351 https://www.mdpi.com/1422-0067/27/20/9351 (Full text)

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)

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)