Category: Overlapping Illnesses

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 HHV-7 positivity was 29.1% (93/320; 95% CI, 24.4-34.3%) in the historical reference cohort and 76.7% (23/30; 95% CI, 59.1-88.2%) in the neurological/neuropsychiatric long COVID cohort.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retrospective study, HHV-7 positivity was substantially more frequent in the long COVID cohort than in the historical reference cohort.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.

Beyond genes: EpiSwitch® and Orion platform-powered 3D genome architecture biomarkers reveal shared biology across ME/CFS, long COVID, PTSD, rheumatoid arthritis, and multiple sclerosis

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Long COVID (LC19), post-traumatic stress disorder (PTSD), rheumatoid arthritis (RA), and multiple sclerosis (MS) are clinically distinct disorders that share substantial symptom overlap, including persistent fatigue, cognitive impairment, autonomic dysfunction, and immune dysregulation. Although these conditions differ in diagnosis and clinical presentation, their underlying biological mechanisms remain poorly understood and may involve convergent regulatory pathways.

Methods: The EpiSwitch® 3D genomics platform and Orion knowledgebase were used to integrate chromosome conformation signatures with genome-wide association study (GWAS)-derived datasets across ME/CFS, LC19, PTSD, RA, and MS. Three-dimensional genomic anchors were mapped to coding genes and analysed using STRING protein-protein interaction networks and Cytoscape-based systems biology approaches. Disease-specific anchor datasets were generated and compared at both gene and network levels to identify shared biological processes and regulatory mechanisms.

Results: Analysis of the ME/CFS dataset identified 552 unique 3D genomic anchors mapped to 567 genes, with analogous disease-specific anchor sets generated for LC19, PTSD, RA, and MS. Direct overlap between disease-associated genes was limited; however, higher-order network analyses revealed substantial interconnectivity and convergence across conditions. Shared biological pathways included immune and cytokine signalling, interferon responses, mitochondrial function, metabolic regulation, and neuroendocrine processes. Highly connected hub genes included immune regulatory nodes such as LAG3 and components of the mTOR signalling pathway, implicating T-cell exhaustion, chronic immune activation, and immunometabolic dysregulation as common mechanisms underlying these disorders.

Conclusions: These findings support a systems-level model in which clinically overlapping fatigue-associated syndromes arise from perturbations of interconnected regulatory networks rather than discrete disease-specific pathways. Despite limited genetic overlap, substantial convergence at the network level suggests shared biological architecture across ME/CFS, LC19, PTSD, RA, and MS. The identification of common regulatory pathways provides a mechanistic framework for the development of cross-disease diagnostic and therapeutic strategies. By capturing dynamic regulatory states, 3D genomic biomarkers offer significant potential for objective blood-based diagnostics, patient stratification, and the identification of shared therapeutic targets across complex chronic disorders. These findings support the application of precision medicine approaches and may accelerate the development of novel interventions for fatigue-associated multisystem diseases.

Source: Hunter E, Alshaker H, Vugrinec D, Bautista S, Gebregzabhar A, Virdi A, Croxford J, Dring A, Powell R, Salter M, Kingdon C, Green J, Akoulitchev A, Pchejetski D. Beyond genes: EpiSwitch® and Orion platform-powered 3D genome architecture biomarkers reveal shared biology across ME/CFS, long COVID, PTSD, rheumatoid arthritis, and multiple sclerosis. J Transl Med. 2026 Aug 22;24(1):1134. doi: 10.1186/s12967-026-08874-9. PMID: 42693463. https://link.springer.com/article/10.1186/s12967-026-08874-9 (Full text)

Impact of post-exertional malaise frequency and fatigue in Long COVID patients on health-related quality of lif

Abstract:

Purpose: The aim of this study was to investigate the impact of post-exertional malaise (PEM) frequency and PEM severity on health-related quality of life (HRQoL) among individuals with Long COVID.

Methods: We conducted a cross-sectional online survey including adults in Germany with self-reported Long COVID and PEM. Fatigue severity was assessed with the Fatigue Assessment Scale (FAS), and HRQoL was measured using the EQ-5D-3L (descriptive index and visual analogue scale [EQ-VAS]). Associations between PEM frequency, fatigue, and HRQoL were examined using correlations and non-parametric group comparisons. Multiple linear regression models were fitted to predict HRQoL while controlling for age, sex, employment status, and subjective social status.

Results: Higher PEM frequency was associated with significantly lower EQ-5D index scores (ρ = – 0.32, p<.001). PEM severity was also strongly correlated with reduced HRQoL (EQ-5D index: ρ = – 0.43, p<.001). In multivariable regression models, greater fatigue and higher PEM frequency independently predicted poorer HRQoL, even after adjustment for sociodemographic factors.

Conclusion: Both PEM frequency and PEM severity substantially impair HRQoL in individuals with Long COVID. These findings underscore the clinical relevance of PEM as a key symptom and highlight the need for targeted management strategies to mitigate its impact on daily life.

Clinical trial number: German Clinical Trials Register DRKS00026007; registration date: 9 September 2021.

Source: Thölking T, Müller F, Riester T, Lampe V, Theil LM, Hummers E, Sarpari K, Dopfer-Jablonka A, Happle C, Steffens S, Meier-Maiwald M, Mikuteit M, Schröder D. Impact of post-exertional malaise frequency and fatigue in Long COVID patients on health-related quality of life. Health Qual Life Outcomes. 2026 May 11;24(1):64. doi: 10.1186/s12955-026-02523-x. PMID: 42116095; PMCID: PMC13162394. https://pmc.ncbi.nlm.nih.gov/articles/PMC13162394/ (Full text)

Targeting Bioenergetic, Redox and Prostaglandin Pathways in Long COVID-Associated Post-Exertional Malaise and Brain Fog: A Nutraceutical Translational Hypothesis

Abstract:

Post-exertional malaise (PEM) and cognitive dysfunction (hereafter “cognitive dysfunction”, including the patient-reported syndrome often described as “brain fog”) are among the most disabling features of Long COVID; yet, approved disease-modifying treatments remain lacking. Emerging evidence implicates interacting disturbances in mitochondrial bioenergetics, redox regulation and neurovascular inflammation, although much of the supporting evidence remains indirect and derives from acute COVID-19, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), primary mitochondrial disease, inflammatory biology and mechanistic pharmacology rather than from direct Long COVID intervention trials.

This hypothesis-generating narrative review develops a mechanism-based translational framework: that a pathway-targeted nutraceutical programme may modulate selected elements of these three axes, subject to prior demonstration of formulation quality, pharmacokinetic feasibility, target engagement and safety. Candidate modules comprise coenzyme Q10 and alpha-lipoic acid for bioenergetic/redox support; selenium, sulforaphane and resveratrol for Nrf2-thioredoxin-related redox regulation; and Boswellia serrata, luteolin and eicosapentaenoic acid for putative prostaglandin/resolution-pathway modulation. Sonlicromanol provides a conceptual mechanistic precedent for combined redox and prostaglandin-directed pharmacology, but it is not considered pharmacologically equivalent to an eight-agent nutraceutical combination.

We summarise the mechanistic rationale, distinguish direct from indirect evidence, define qualitative evidence-grading criteria, outline safety and interaction considerations, and propose a staged translational research programme. This framework is intended to generate falsifiable hypotheses for future Long COVID studies, not to imply established clinical efficacy.

Source: Praet SFE. Targeting Bioenergetic, Redox and Prostaglandin Pathways in Long COVID-Associated Post-Exertional Malaise and Brain Fog: A Nutraceutical Translational Hypothesis. Nutrients. 2026 Aug 13;18(16):2650. doi: 10.3390/nu18162650. PMID: 42654231. https://www.mdpi.com/2072-6643/18/16/2650 (Full text)

Medical invalidation is associated with structural barriers in postacute immune mediated syndromes based on patient perspectives in Germany

Abstract:

Post-acute immune-mediated syndromes (PAIMS), including Long COVID/Post-COVID (LC/PC), Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and post-acute COVID-19 vaccination syndrome (PACVS), are characterized by persistent, multisystemic symptoms and significant healthcare challenges. A key issue is medical invalidation, defined as the dismissal or delegitimization of patients’ reports of symptoms. This cross-sectional online study, conducted in Germany between October and December 2025 (N = 577), examined healthcare experiences, access barriers, and perceived invalidation.

Although healthcare utilization was high, 87% of participants reported difficulties accessing appropriate treatment. Major barriers included lack of available therapies (60%) or not being taken seriously (26%). Perceived invalidation by medical personnel was moderate across all groups (LC: M = 2.80; ME/CFS: M = 2.99; PACVS: M = 3.03) and did not differ significantly (Welch-F(2, 190.50) = 2.87, p = 0.059) between groups. Invalidation occurred not only within healthcare settings but was particularly pronounced in interactions with authorities and workplaces. Social media and online communities served as important sources of information and support, especially among individuals with ME/CFS.

Overall, the findings reveal substantial structural barriers in the care of PAIMS and highlight the need for improved clinical education, better care coordination, and stronger institutional recognition of these conditions.

Source: Saad J, Hensen J, Bergelt C, Lerch SP. Medical invalidation is associated with structural barriers in postacute immune mediated syndromes based on patient perspectives in Germany. Sci Rep. 2026 Aug 25;16(1):26687. doi: 10.1038/s41598-026-67883-2. PMID: 42642464; PMCID: PMC13507045. https://pmc.ncbi.nlm.nih.gov/articles/PMC13507045/ (Full text)

Virus reactivation in acute and long COVID-19

Abstract:

Chronic viral infections are ubiquitous in humans, with individuals carrying multiple viruses that can reactivate during physiological stress, including severe illness1. Notably, SARS-CoV-2 infection has been shown to reactivate chronic viruses such as Epstein-Barr virus and cytomegalovirus, yet the full extent, temporal dynamics and immunological impact of viral reactivation in COVID-19 remain incompletely understood2-7.

Here, leveraging multi-omic longitudinal data from 1,154 hospitalized patients with COVID-19 from the Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study, we reveal significant reactivation of Herpesviridae and Anelloviridae during acute COVID-19, with distinct temporal dynamics for different viruses, and demonstrate that reactivation correlates with disease severity, host immune effects and clinical outcomes. Although our results do not establish causation between virus reactivation and clinical outcomes, we highlight the prevalence of chronic viral reactivation during acute COVID-19 and long COVID.

Our findings challenge the prevailing view that chronic viral reactivation is primarily a consequence of immunosuppression, demonstrating that reactivations occur frequently in immunocompetent individuals during severe illness and in association with increased systemic inflammation. Additionally, we demonstrate persistence of viral reactivation in convalescence, and report an association of Anelloviridae with long COVID.

This study provides immune, transcriptomic and metabolomic signatures of viral reactivation that could inform future strategies to prognosticate and treat acute COVID-19 and long COVID.

Source: Maguire C, Chen J, Rouphael N, Morse BA, Hoch A, Pickering H, Phan HV, Glascock A, Chu V, Dandekar R; IMPACC Network; Corry D, Kheradmand F, Baden LR, Sekaly RP, McComsey GA, Haddad EK, Cairns CB, Pulendran B, Fernandez-Sesma A, Simon V, Metcalf JP, Agudelo Higuita NI, Messer WB, Davis MM, Nadeau KC, Kraft M, Bime C, Schaenman J, Erle D, Calfee CS, Atkinson MA, Brakenridge SC, Ehrlich LIR, Montgomery RR, Shaw A, Hough CL, Hafler D, Augustine AD, Becker PM, Peters B, Ozonoff A, Kim-Schulze S, Krammer F, Bosinger SE, Eckalbar W, Altman MC, Wilson M, Guan L, Kleinstein SH, Smolen KK, Reed EF, Levy O, Maecker H, Hunt P, Steen H, Diray-Arce J, Langelier CR, Melamed E. Virus reactivation in acute and long COVID-19. Nature. 2026 Aug;656(8128):700-711. doi: 10.1038/s41586-026-10740-z. Epub 2026 Aug 5. PMID: 42557313; PMCID: PMC13489964. https://pmc.ncbi.nlm.nih.gov/articles/PMC13489964/ (Full text)

Exploring the influence of long COVID upon self-identity: a systematic literature review

Abstract:

Background: Long COVID (LC) is understood to be a multisystemic illness involving symptoms of an enduring nature. As underlying pathophysiological mechanisms of LC become better understood, attention has turned towards the psychological aspects of LC lived experience. Comparable conditions, such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), are known to significantly impact self-identity. However, no prior review has explored this topic in the LC population. This review sought to offer an original and exploratory narrative of LC patients’ experiences connected to self-identity.

Methods: A systematic literature review using a Narrative Synthesis approach. Twenty-one qualitative studies (including 613 participants), published between January 2021-March 2025, exploring the influence of LC upon perceptions of self-identity were reviewed. Narrative Synthesis (NS) and PRISMA guidelines were followed.

Results: Four main themes emerged: “Grief and Loss of the Familiar Self”, “Reflections of Self, Mirrored by Others”, “Threats to Identity”, and “Repairing Fractured Identity”.

Conclusions: For many, LC ruptures self-narratives that contribute to a stable and continuous sense of self across time. This can bring forth a strong grieving response to perceived losses and the unfamiliarity of self. Despite this, narratives of post-traumatic growth (PTG) were realised. Current guidance lacks direction for psychological interventions targeting LC-related distress. Acknowledgement of identity-based challenges must also be reflected in future guidance, with clear recommendations for clinical practice. Qualitative longitudinal exploration of LC’s influence upon self-identity should be prioritised. Similarly, the acceptability and feasibility of interventions targeting identity-transformation work require further investigation.

Trial registration: PROSPERO ID: CRD420251008410.

Source: Holmes-McCoid HJ, Lecky FE. Exploring the influence of long COVID upon self-identity: a systematic literature review. Arch Public Health. 2026 Aug 11;84(1):189. doi: 10.1186/s13690-026-02017-8. PMID: 42638142. https://link.springer.com/article/10.1186/s13690-026-02017-8 (Full text)