Category: Overlapping Illnesses

Omics-based computational approaches for biomarker identification, prediction, and treatment of Long COVID

Abstract:

Long COVID, or post-acute sequelae of COVID-19 (PASC), is a major global health problem, with cumulative estimates suggesting that around 400 million people worldwide have been affected. It is characterized by persistent or new symptoms such as fatigue, cognitive impairment, and breathlessness lasting beyond four weeks after acute infection. Diverse clinical manifestations, chronic course, and incompletely understood pathophysiology-including hypotheses involving viral persistence, immune dysregulation, autoimmunity, endothelial dysfunction, and metabolic reprogramming-impede the development of diagnostic criteria, biomarkers, and targeted therapies. We conducted a critical review of 101 Long COVID omics studies, focusing on the computational methods used and their methodological quality.

Using standardized criteria, we evaluated study design, statistical rigor, reproducibility, and clinical relevance across genomics, epigenomics, transcriptomics, proteomics, metabolomics, and multiomics integration, and mapped these findings onto regulatory and translational frameworks. Despite substantial methodological heterogeneity, convergent biological signals emerged.

Genomic studies implicate risk loci in immune and cardiopulmonary pathways. Epigenomic analyses identify differentially methylated regions in immune and circadian genes. Transcriptomic studies reveal persistent dysregulation of innate immune and coagulation pathways, as well as reproducible molecular endotypes. Proteomic studies consistently show abnormalities in the complement cascade and coagulation, with a small panel of complement proteins showing highly reproducible changes across independent cohorts. Metabolomic studies demonstrate sustained mitochondrial dysfunction and altered cellular bioenergetics for up to two years after infection.

Multiomics integration supports at least two major endotypes, characterized by predominant inflammatory versus metabolic dysregulation, and provides a basis for patient stratification and computational treatment discovery. Machine learning models frequently achieve high classification performance, but are rarely externally validated. Critical limitations restrict clinical translation. Most studies are underpowered relative to analytical complexity, use heterogeneous case definitions and controls, and report platform-specific signatures with limited overlap. External validation, preregistered analysis plans, and regulatory-aligned assay development are uncommon. To date, no regulatory-approved diagnostic assay or evidence-based therapeutic intervention has directly emerged from these computational findings.

Future progress requires harmonized phenotyping protocols, adequately powered longitudinal cohorts with external validation, integration of spatial omics and explainable artificial intelligence, and early engagement with regulatory and health-technology assessment pathways. This review provides a critical assessment and a translational roadmap, outlining how methodologically robust computational omics can be advanced toward clinically actionable tools for Long COVID.

Source: Pinero S, Li X, Zhang J, Winter M, Lee SH, Nguyen T, Liu L, Li J, Le TD. Omics-based computational approaches for biomarker identification, prediction, and treatment of Long COVID. Crit Rev Clin Lab Sci. 2026 Jun;63(4):332-358. doi: 10.1080/10408363.2025.2583083. Epub 2025 Dec 9. PMID: 41368891. https://pubmed.ncbi.nlm.nih.gov/41368891/

Comprehensive Immunophenotyping of Monocytes and Dendritic Cells Suggests Distinct Pathophysiology in Chronic Fatigue Syndrome and Long COVID

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long Coronavirus Disease 2019 (long COVID) are complex chronic conditions that often follow infectious triggers with overlapping clinical features but poorly defined pathophysiological relationships. This study aimed to identify disease-specific immune signatures through multiparameter immunophenotyping of monocytes, dendritic cells, and T cell subsets.

A total of 207 participants were included (ME/CFS: n = 103; long COVID: n = 63; healthy controls: n = 41). Peripheral blood mononuclear cells were analyzed using multiparameter flow cytometry. Statistical analyses included non-parametric testing, age-adjusted Analysis of covariance (ANCOVA), correlation network analysis, and principal component analysis (PCA).

Long COVID was characterized by increased M2-like monocyte polarization, elevated CD80 expression across monocyte subsets, expansion of dendritic cells, and reduced expression of activation markers, indicating persistent immune activation with features of immune exhaustion.

In contrast, ME/CFS exhibited reduced costimulatory molecule expression, impaired C-C chemokine receptor type 7 (CCR7)-mediated immune cell trafficking, and less coordinated activation patterns, consistent with a state of immune suppression. Correlation network analysis revealed more extensive and integrated immune interactions in long COVID, while PCA identified distinct immunophenotypic components and enabled moderate discrimination between the two conditions.

These findings demonstrate that ME/CFS and long COVID are characterized by distinct immune profiles, supporting the concept of divergent immunopathological mechanisms. The identified signatures may contribute to biomarker development and guide targeted therapeutic approaches.

Source: Petrov S, Bozhkova M, Ivanovska M, Kalfova T, Dudova D, Todorova Y, Dimitrova R, Murdjeva M, Taskov H, Nikolova M, Maes M. Comprehensive Immunophenotyping of Monocytes and Dendritic Cells Suggests Distinct Pathophysiology in Chronic Fatigue Syndrome and Long COVID. Int J Mol Sci. 2026 May 17;27(10):4488. doi: 10.3390/ijms27104488. PMID: 42196466; PMCID: PMC13206834. https://pmc.ncbi.nlm.nih.gov/articles/PMC13206834/ (Full text)

Shared genetic risk between functional somatic syndromes, internalizing disorders, and immune-mediated diseases: a twin-sibling study

Abstract:

Functional somatic syndromes frequently co-occur with internalizing disorders such as anxiety disorders and major depressive disorder. Both show familial associations with immune-mediated diseases. Here, we estimate genetic and environmental contributions to functional somatic syndromes and their overlap with immune-mediated diseases, with internalizing disorders included for comparison.

The study sample consisted of 6,097,372 Swedish twins, full siblings, and half-siblings born between 1945 and 2003. From nationwide registers covering inpatient, outpatient and primary care, we extracted ICD diagnoses of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), irritable bowel syndrome (IBS), major depression, anxiety disorders, and immune-mediated diseases (consisting of autoimmune and autoinflammatory diseases).

We used bivariate twin-sibling structural equation modeling to estimate genetic and environmental correlations. We found that the heritability of functional somatic syndromes and internalizing disorders ranged from 15 to 44%, with the unique environment explaining 49-84% of the variance. We estimated the heritability of immune-mediated diseases at 37% (95% CI 36-38%), with a unique environmental component of 63% (95% CI 62-63%). Regarding the genetic correlations with immune-mediated diseases, fibromyalgia showed the strongest genetic correlation (rA = 0.52, 95% CI 0.45-0.63), IBS, ME/CFS, and major depression showed more modest genetic correlations (rA range 0.19-0.29), and anxiety disorders showed minimal genetic correlation (rA = 0.04, 95% CI 0.00-0.08).

In summary, fibromyalgia, and to a lesser degree other functional somatic syndromes and major depression, share genetic risk factors with immune-mediated diseases. These findings suggest that immune-related genetic risk factors contribute to the etiology of fibromyalgia and, to a lesser extent, other functional disorders and major depression.

Source: Steen OD, Ohlsson H, van Ockenburg SL, Kendler KS, Rosmalen JGM, Sundquist K, van Loo HM. Shared genetic risk between functional somatic syndromes, internalizing disorders, and immune-mediated diseases: a twin-sibling study. Brain Behav Immun. 2026 May 25:106837. doi: 10.1016/j.bbi.2026.106837. Epub ahead of print. PMID: 42190845. https://www.sciencedirect.com/science/article/pii/S0889159126005854 (Full text)

Vascular inflammation in neuropsychiatric long COVID

Highlights:

  • Long COVID is characterized by endothelial dysfunction with dysregulated inflammatory and coagulation pathways.
  • Endothelial biomarkers are elevated in Long COVID vs acute COVID-19, supporting a distinct vascular process.
  • Vascular biomarkers correlate with key cognitive and neuropsychiatric measures (fluency, memory, depression, and anxiety).
  • Vascular inflammation is a targetable mechanism in Long COVID, informing patient stratification and therapeutic trials.
  • Results highlight need to define the short- and long-term impact of vascular inflammation on brain health after COVID-19.

Abstract

The role of vascular inflammation in neuropsychiatric Long COVID (LC) is suspected but not well understood. This study evaluated whether vascular inflammation is present in individuals with neuropsychiatric LC and how it relates to cognitive and mental health symptoms.

This cross-sectional, case-control study included individuals with acute COVID-19 (AC), neuropsychiatric LC, and recovered controls. Participants were enrolled from the COVID Mind Study and the Yale IMPACT Study (hospitalized), and an independent cohort from the Johns Hopkins University (JHU) Long COVID Study. Fifty individuals with neuropsychiatric LC (new symptoms a median of 368 days post-COVID), 28 with AC, and 29 recovered controls (>3 months post-COVID) were evaluated. All underwent blood sampling and neuropsychiatric testing. The JHU cohort included 114 individuals with late LC (median 1065 days post-COVID illness associated with LC onset) and 31 recovered controls (median 852 days).

Fourteen plasma biomarkers of vascular inflammation were measured. ANCOVA was used to compare groups, adjusting for comorbidities. Non-hospitalized participants completed the Global Neuropsychological Assessment, GAD-7, and PHQ-9. LC and recovered groups were demographically similar, while AC participants had higher obesity and hypertension rates. LC participants had elevated circulating biomarkers of endothelial, leukocyte, and platelet adhesion (sL-selectin, ADAMTS13, sP-selectin, sICAM-1) compared to recovered controls.

Coagulation markers (D-dimer, fibrinogen) did not differ. Most biomarkers were highest in AC and lower in LC; however, fetuin, sL-selectin, and α-2 macroglobulin were higher in LC than AC. In LC, higher sP-selectin correlated with lower fluency and verbal learning. Lower α1-acid glycoprotein levels were strongly associated with poorer verbal memory, verbal learning, fluency, depression, and anxiety. In the JHU cohort, late LC and recovered controls showed no differences in biomarkers or demographics, suggesting normalization over time. Persistent dysregulation at the intersection of inflammation, platelet adhesion, and endothelial dysfunction is strongly linked to neuropsychiatric Long COVID.

Elevated markers of endothelial adhesion in LC suggest distinct pathophysiology from AC. These biomarkers correlate with lower fluency and verbal learning, linking vascular dysfunction to brain function. This study underscores the critical need for longitudinal, within-person investigations to elucidate how vascular inflammation evolves over time.

Source: McAlpine LS, Shorer EF, Chiarella J, Nelson A, Veenhuis R, Azola A, Lee A, Pierce R, Farhadian S, Rubin LH, Spudich SS; Yale COVID Mind; IMPACT Study Groups. Vascular inflammation in neuropsychiatric long COVID. Brain Behav Immun Health. 2026 Apr 28;54:101247. doi: 10.1016/j.bbih.2026.101247. PMID: 42099668; PMCID: PMC13147379. https://pmc.ncbi.nlm.nih.gov/articles/PMC13147379/ (Full text)

Designing studies for post-treatment Lyme disease and other infection-associated chronic illnesses

Abstract:

Infection-associated chronic illnesses (IACIs) encompass a spectrum of poorly understood syndromes often marked by significant neurologic and multisystem symptoms following an infectious event. This review focuses on several diseases representative of the IACI spectrum. These are post-treatment Lyme disease syndrome (PTLDS), long COVID, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and multiple sclerosis (MS). Their clinical and biological complexity, combined with a lack of clear diagnostic criteria and objective available laboratory biomarkers, makes them difficult to distinguish from conditions with overlapping features.

This presents challenges for research studies, as well as diagnosis and clinical management. This diagnostic ambiguity, coupled with heterogeneous patient presentations, has led to challenges in research, including misclassification of study participants and inconsistent or irreproducible findings. Some PTLDS research exemplifies these issues, which also extend to other IACIs.

To advance the field, we highlight key methodological refinements and approaches for studying IACIs, including rigorous participant selection, standardized sample collection protocols, and the use of appropriate control groups, including those with microbiologic proof of the initial infection when known and technologically feasible. We also address broader influences on research quality, such as stigma, historical neglect, and the urgency to find treatments, which have contributed to the proliferation of poorly controlled studies and questionable practices. Drawing lessons from past challenges, we propose a path forward grounded in fit-for-purpose methodological rigour to improve scientific understanding and support evidence-based therapeutic development for IACIs.

Source: Arnaboldi PM, Becker J, Nath A, Coyle PK, Handel A, Sellati TJ, Gomes-Solecki M, Garcet S, Henderson MK, Mullins P, Cowan E, McCombie WR, Wellins AM, Allegretta M, Bergquist J, Schutzer SE. Designing studies for post-treatment Lyme disease and other infection-associated chronic illnesses. Brain. 2026 May 18:awag016. doi: 10.1093/brain/awag016. Epub ahead of print. PMID: 42148664. https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awag016/8586348 (Full text)

Feasibility, Adherence, Acceptance and Usability of a Multimodal Telemonitoring for Pediatric Post-COVID Syndrome: A Bicentric Pilot Study

Abstract:

Existing healthcare infrastructure struggles to meet the complex care required for pediatric Post-COVID Syndrome (pPCS). Telemonitoring offers potential to enhance care access, reduce patient burden, and ensure continuity. This study introduces and evaluates a novel, multimodal telemonitoring concept for pPCS with high translational potential for broader pediatric chronic and post-infectious conditions. Telemonitoring included a patient app, digital sensors (spirometer, smartwatch), Patient Reported Outcome Measures, chat/video consultations (VC), and a medical telemonitoring platform.

Patients aged 12-17 years with diagnosed PCS were recruited from two pPCS outpatient university clinics in Bielefeld and Munich, Germany. Monitoring lasted three months. Evaluation focused on feasibility, adherence, acceptance, and usability, using monitoring data, the System Usability Scale (SUS), Technology Usage Inventory (TUI), and a custom survey completed by patients and parents. 30 patients (mean age: 15y ± 1.9; 57% female (17/30); mean Baseline Bell-Score: 36.4) and 30 parents participated.

Adherence was high, with an average of 3.4 (smartwatch) to 4.6 (spirometry) measurements/week. Questionnaire response rate was 86% (411/480) and 97% (58/60) of VCs were conducted. SUS scores indicated very high usability (patients: 81.25/100; parents: 75.42/100). TUI results showed low skepticism, and high interest. Telemonitoring supported symptom management independent of in-person visits, despite sensor connectivity issues.

This is the first study to demonstrate successful integration of telemonitoring in pPCS, with high adherence and positive feedback from all stakeholders supporting its potential. Despite occasional technical challenges and resource needs, this concept shows promise for broader hybrid telemonitoring care implementation in PCS and other post-infectious syndromes.

TRIAL REGISTRATION: German Clinical Trials Register (DRKS), trial registration number: DRKS00029354. Registered 07 February 2023 – Retrospectively registered https://drks.de/search/en/trial/DRKS00029354/entails.

Source: Oftring ZS, Schmidt J, Greenfield J, Hägele M, Farzaneh A, Hamelmann E, Behrends U, Kuhn S. Feasibility, Adherence, Acceptance and Usability of a Multimodal Telemonitoring for Pediatric Post-COVID Syndrome: A Bicentric Pilot Study. J Med Syst. 2026 May 9;50(1):76. doi: 10.1007/s10916-026-02409-x. PMID: 42105038. https://link.springer.com/article/10.1007/s10916-026-02409-x (Full text)

Interpreting hand grip strength in hospital employees with post-COVID syndrome compared to non-infected controls: a case-control study

Abstract:

Post-COVID syndrome (PCS) is characterized by a variety of persistent symptoms following SARS-CoV-2 infection, including fatigue among others. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a related neurological disorder primarily characterized by severe fatigue and post-exertional malaise. This exploratory study aimed to assess hand grip strength (HGS) in individuals with PCS to evaluate muscular performance and fatigability and to explore potential HGS-derived parameters associated with PCS.

HGS was measured in 19 hospital employees with PCS (mean age 47.8; 89.5% female; 7 fulfilling ME/CFS criteria) and compared with 23 healthy controls (mean age 43.7; 69.6% female). Measurements were performed in two sessions separated by 60 min, each consisting of ten consecutive HGS measurements. Linear mixed model analysis indicated that HGS tended to be lower in PCS at specific measurement points, although no consistent overall group effect was observed. HGS was reduced in the second session in PCS but not in controls, suggesting possible alterations in recovery following repeated exertion.

Exploratory analysis of 30 HGS-derived parameters using logisitic regression models in female participants identified parameters based on maximum, minimum, and mean force values as showing the most promising discriminatory patterns: however, predictive performace was moderate and should be interpreted with caution.

Overall, HGS may provide insights into funcitional impairment in PCS and could serve as a supportive adjunct in clinical assessment, although its diagnostic utility requires validation in larger cohorts.

Source: Tack M, Gruber R, Betting L, Herbrandt S, Schlang G, Mattner F. Interpreting hand grip strength in hospital employees with post-COVID syndrome compared to non-infected controls: a case-control study. Sci Rep. 2026 May 9. doi: 10.1038/s41598-026-51666-w. Epub ahead of print. PMID: 42103832. https://www.nature.com/articles/s41598-026-51666-w (Full study available as PDF file)

Erythroid-hormonal axis in long COVID

Abstract:

Long COVID may reflect a failure of coordinated physiological recovery rather than persistent infection. Emerging evidence identifies inflammation-driven disruption of erythropoiesis and hormonal balance as central mechanisms linking immune dysregulation, metabolic stress, and persistent symptoms. This framework positions erythroid-endocrine pathways as key determinants of recovery and promising therapeutic targets.

Source: Elahi S. Erythroid-hormonal axis in long COVID. Trends Mol Med. 2026 May 4:S1471-4914(26)00088-2. doi: 10.1016/j.molmed.2026.04.006. Epub ahead of print. PMID: 42086409. https://pubmed.ncbi.nlm.nih.gov/42086409/

Risk factors for severe post-COVID condition in children, adolescents, and young adults

Abstract:

Post-COVID condition (PCC) in children and young people (CYP, PCCcyp) remains a significant health burden. Early identification of patients at risk for severe disease, including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is crucial for timely and adequate care. This monocentric, observational registry study, performed at a tertiary pediatric hospital in Germany, included CYP aged 7-25 years with PCCcyp at diagnosis. Standardized clinical assessment tools and patient-reported outcome measures were applied, including the novel Munich Long COVID Symptom Questionnaire (MLCSQ).

Severe PCC was defined by chronic symptom clusters, Fatigue Severity Scale (FSS), Total Composite Autonomic Symptom Score-31 (COMPASS-31), SF-36 composite scores, Bell Score, and confirmed ME/CFS diagnosis. Among 120 participants, severe PCCcyp was associated with a higher number of acute symptoms (ORadj 1.22, P < 0.001), acute orthostatic intolerance (ORadj 9.87, P = 0.002), acute trouble concentrating (ORadj 11.8, P = 0.005), and female sex (OR 3.31, P = 0.031).

Categorizing acute symptoms at a threshold of ≥ 12 yielded optimal model performance (AUC 0.857; sensitivity 65.6%; specificity 90.2%). ME/CFS was diagnosed in 24% of participants, all within the severe PCCcyp cluster, and was characterized by greater acute symptom complexity, more fatigue, more autonomic symptoms, and poorer function.

Conclusions: The number and pattern of acute symptoms during SARS-CoV-2 infection may serve as early, specific predictors of severe PCCcyp. Patients with ≥ 12 acute symptoms should be closely monitored to enable early diagnosis of severe PCCcyp and ME/CFS. A distinct cluster of severely affected patients, frequently with ME/CFS, was identified.

Trial registration: ClinicalTrials.gov: NCT05638724; Ethics approval (511/21, 2025-465-S-SB).

Source: Donath Q, Haegele M, Schindler D, Welzhofer T, Christa C, Grabbe A, Leone A, Ilhan C, Weidmann C, Eberhartinger M, Bechtold S, Bursch N, Wolf H, Hieber H, Peo LC, Bucka LA, Stojanov S, Warlitz C, Alberer M, Gerrer K, Hausruckinger A, Mittelstrass K, Wendtner CM, Hoechstetter MA, Grübl A, Toepfner N, Pricoco R, Scheibenbogen C, Mihatsch LL, Behrends U. Risk factors for severe post-COVID condition in children, adolescents, and young adults. Eur J Pediatr. 2026 May 4;185(5):344. doi: 10.1007/s00431-026-06995-3. PMID: 42082813. https://link.springer.com/article/10.1007/s00431-026-06995-3 (Full text available as PDF file)

Involvement of autoantibodies against G protein-coupled receptors in post-COVID condition and Chronic Fatigue Syndrome

Abstract:

Post-COVID condition (PCC) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) are chronic disorders marked by fatigue, autonomic dysfunction, and cognitive impairment. Autoantibodies (AAbs) targeting adrenergic and muscarinic receptors have been implicated in their pathophysiology. This study aimed to investigate the association between these AAbs, autonomic nervous system (ANS) function, and cognitive performance in PCC and ME/CFS.

We included 96 PCC patients, 59 ME/CFS patients, and 36 healthy controls (HCs). Plasma AAbs against α1, β1, β2 adrenergic and M1-M4 muscarinic receptors were measured via ELISA. ANS function was evaluated using COMPASS-31, Sudoscan, hemodynamic tests (deep breathing, Valsalva, tilt test), and heart rate variability. Cognitive domains assessed included attention, fluency, processing speed, memory, visuoconstruction, perception, and executive functions.

ME/CFS patients had significantly higher β2 adrenergic AAb titers than PCC and HCs (F₂,₁₈₆ = 3.15, p = 0.046). PCC patients showed more borderline/pathological M3 muscarinic AAb results compared to HCs. β2 AAb levels correlated with increased autonomic symptoms in PCC (r = 0.27, p = 0.048) and sympathovagal imbalance in ME/CFS (r = 0.45, p = 0.001). In ME/CFS, M1, M3, and M4 AAb titers positively correlated with verbal and working memory performance.

Distinct AAb profiles in PCC and ME/CFS suggest potential differences in immunological mechanisms. β2 adrenergic receptor AAbs were associated with measures of autonomic dysfunction in PCC patients, and with sympathovagal parameters in ME/CFS patients. Muscarinic AAbs were correlated with cognitive performance in ME/CFS, supporting a potential role of these autoantibodies in autonomic and cognitive dysfunction. These findings support further investigation of AAbs as biomarkers and therapeutic targets.

Source: Azcue N, Prada A, Del Pino R, Acera M, Fernández-Valle T, Ayo-Mentxakatorre N, Pérez-Concha T, Murueta-Goyena A, Lafuente JV, López de Munain A, Ruiz Irastorza G, Ribacoba L, Gabilondo I, Tijero-Merino B, Gómez-Esteban JC. Involvement of autoantibodies against G protein-coupled receptors in post-COVID condition and Chronic Fatigue Syndrome. Sci Rep. 2026 May 5. doi: 10.1038/s41598-026-49131-9. Epub ahead of print. PMID: 42082542. https://www.nature.com/articles/s41598-026-49131-9 (Full text available as PDF file)