Category: Overlapping Illnesses

Advancing Digital Precision Medicine for Chronic Fatigue Syndrome through Longitudinal Large-Scale Multi-Modal Biological Omics Modeling with Machine Learning and Artificial Intelligence

Abstract:

We studied a generalized question: chronic diseases like ME/CFS and long COVID exhibit high heterogeneity with multifactorial etiology and progression, complicating diagnosis and treatment. To address this, we developed BioMapAI, an explainable Deep Learning framework using the richest longitudinal multi-omics dataset for ME/CFS to date.

This dataset includes gut metagenomics, plasma metabolome, immune profiling, blood labs, and clinical symptoms. By connecting multi-omics to a symptom matrix, BioMapAI identified both disease- and symptom-specific biomarkers, reconstructed symptoms, and achieved state-of-the-art precision in disease classification.

We also created the first connectivity map of these omics in both healthy and disease states and revealed how microbiome-immune-metabolome crosstalk shifted from healthy to ME/CFS.

Source: Xiong R. Advancing Digital Precision Medicine for Chronic Fatigue Syndrome through Longitudinal Large-Scale Multi-Modal Biological Omics Modeling with Machine Learning and Artificial Intelligence. ArXiv [Preprint]. 2025 Jun 18:arXiv:2506.15761v1. PMID: 40980765; PMCID: PMC12447721. https://pmc.ncbi.nlm.nih.gov/articles/PMC12447721/ (Full text available as PDF file)

Exploration of Intersections and Divergences of Long COVID and Chronic Fatigue Syndrome

Abstract:

Background: Fatigue is the most common symptom of Long COVID (LC), defined by persistent or newly emerging symptoms that develop at least three months after an initial SARS-CoV-2 infection, in the absence of other identifiable cause. This study investigates the prevalence of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) as a potential comorbidity of LC.

Methods: The study enrolled 37 adult controls with no documented SARS-CoV-2 infection and 32 individuals with a history of infection, categorized as LC-yes (with LC symptoms) and LC-no (without LC symptoms). ME/CFS diagnosis was based on the International Consensus Criteria (ICC).

Results: Among LC-yes cases, the most frequently reported symptoms included post-exertional malaise (PEM); neurosensory, perceptual, or motor disturbances; cognitive impairment; sleep disturbances; pain; impaired thermoregulation; and flu-like symptoms, all occurring significantly more than in the LC-no or control groups. All individuals in the LC-yes group reported PEM. ME/CFS was diagnosed in three LC-yes cases (18.8%), one LC-no case (6.7%), and four control subjects (10.8%), with no statistically significant differences observed among groups. Experiencing more than six symptoms during acute infection, such as fatigue, loss of taste or smell, headache, fever, cough, myalgia, sore throat, shortness of breath, rhinorrhea, and diarrhea, was associated with a twofold higher risk of developing LC.

Conclusion: A substantial proportion of LC-yes individuals experienced PEM; neurosensory, perceptual, or motor disturbances; cognitive impairment; and sleep disturbances, with rates significantly exceeding those in the LC-no and control groups. Nevertheless, only a minority of LC-yes cases (18.8%) satisfied criteria for the ME/CFS, and the prevalence did not significantly differ from LC-no and controls. These findings suggest that while many symptoms of LC overlap with those of ME/CFS, only a subset of LC cases meet established ME/CFS diagnostic criteria.

Source: Kouyoumdjian JA, Yamamoto LA, Graca CR. Exploration of Intersections and Divergences of Long COVID and Chronic Fatigue Syndrome. Cureus. 2025 Aug 20;17(8):e90607. doi: 10.7759/cureus.90607. PMID: 40978825; PMCID: PMC12448662. https://pmc.ncbi.nlm.nih.gov/articles/PMC12448662/ (Full text)

Abnormal Brain Activation Patterns in Patients With Post-Acute Sequelae of COVID-19 (PASC) During Recovery: A fNIRS Study

Abstract:

COVID-19 has increased the likelihood of cognitive impairment in patients with post-acute sequelae of COVID-19 (PASC). There is a lack of direct evidence regarding the working memory performance of mild patients during the recovery period. This study employed functional near-infrared spectroscopy (fNIRS) to construct a mixed effects model for PASC patients performing the N-back task, assessing brain activation levels and brain connectivity.

PASC patients exhibited abnormally low activation in the parietal lobe (β = −0.21) and abnormally high activation in the occipital lobe (β = 0.40). There was a significant reduction in brain connectivity within the frontal–parietal and frontal–occipital networks.

These findings suggest that PASC patients experience impaired fronto-parietal network connectivity, rely more on the visual cortex to compensate for executive function deficits, and use this as a compensatory mechanism to reduce overall cerebral blood oxygenation. This study provides evidence of altered brain activation patterns in PASC patients during the recovery period due to cognitive impairment.

Source: Y. Ran, S. Wu, S. Liu, et al., “ Abnormal Brain Activation Patterns in Patients With Post-Acute Sequelae of COVID-19 (PASC) During Recovery: A fNIRS Study,” Journal of Biophotonics (2025): e202500206, https://doi.org/10.1002/jbio.202500206. https://onlinelibrary.wiley.com/doi/epdf/10.1002/jbio.202500206

Long COVID Incidence Proportion in Adults and Children Between 2020 and 2024: An Electronic Health Record-Based Study From the RECOVER Initiative

Abstract:

Background: Incidence estimates of post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, also known as long COVID, have varied across studies and changed over time. We estimated long COVID incidence among adult and pediatric populations in 3 nationwide research networks of electronic health records (EHRs) participating in the RECOVER (Researching COVID to Enhance Recovery) Initiative using different classification algorithms (computable phenotypes).

Methods: This EHR-based retrospective cohort study included adult and pediatric patients with documented acute SARS-CoV-2 infection and 2 control groups: contemporary coronavirus disease 2019 (COVID-19)-negative and historical patients (2019). We examined the proportion of individuals identified as having symptoms or conditions consistent with probable long COVID within 30-180 days after COVID-19 infection (incidence proportion). Each network (the National COVID Cohort Collaborative [N3C], National Patient-Centered Clinical Research Network [PCORnet], and PEDSnet) implemented its own long COVID definition. We introduced a harmonized definition for adults in a supplementary analysis.

Results: Overall, 4% of children and 10%-26% of adults developed long COVID, depending on computable phenotype used. Excess incidence among SARS-CoV-2 patients was 1.5% in children and ranged from 5% to 6% among adults, representing a lower-bound incidence estimation based on our control groups. Temporal patterns were consistent across networks, with peaks associated with introduction of new viral variants.

Conclusions: Our findings indicate that preventing and mitigating long COVID remains a public health priority. Examining temporal patterns and risk factors for long COVID incidence informs our understanding of etiology and can improve prevention and management.

Source: Mandel H, Yoo YJ, Allen AJ, Abedian S, Verzani Z, Karlson EW, Kleinman LC, Mudumbi PC, Oliveira CR, Muszynski JA, Gross RS, Carton TW, Kim C, Taylor E, Park H, Divers J, Kelly JD, Arnold J, Geary CR, Zang C, Tantisira KG, Rhee KE, Koropsak M, Mohandas S, Vasey A, Mosa ASM, Haendel M, Chute CG, Murphy SN, O’Brien L, Szmuszkovicz J, Guthe N, Santana JL, De A, Bogie AL, Halabi KC, Mohanraj L, Kinser PA, Packard SE, Tuttle KR, Hirabayashi K, Kaushal R, Pfaff E, Weiner MG, Thorpe LE, Moffitt RA. Long COVID Incidence Proportion in Adults and Children Between 2020 and 2024: An Electronic Health Record-Based Study From the RECOVER Initiative. Clin Infect Dis. 2025 Jul 18;80(6):1247-1261. doi: 10.1093/cid/ciaf046. PMID: 39907495; PMCID: PMC12272849. https://pubmed.ncbi.nlm.nih.gov/39907495/

Metabolic neuroimaging of myalgic encephalomyelitis/chronic fatigue syndrome and Long-COVID

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long-COVID are complex, disabling conditions that have emerged as significant public health challenges, affecting millions worldwide. Despite their growing prevalence, effective diagnostics and treatments remain limited, largely due to an incomplete understanding of their underlying pathophysiology. Both conditions share hallmark symptoms of chronic fatigue, cognitive dysfunction, and postexertional malaise, but their biological underpinnings remain to be elucidated. Neuroimaging offers a promising, noninvasive window into the brain’s metabolic landscape and has the potential to uncover objective biomarkers for these conditions.

In this mini review, we highlight recent advancements in metabolic neuroimaging, particularly positron emission tomography and magnetic resonance imaging/magnetic resonance spectroscopy, that reveal alterations in glucose and oxygen metabolism, neurotransmitter balance, and oxidative stress. These insights point toward shared disruptions in brain energy metabolism and neuroinflammatory processes, which may underlie the persistent symptoms in both ME/CFS and Long-COVID.

Importantly, while some findings overlap, inconsistencies in metabolite profiles between ME/CFS and Long-COVID underscore the need for further stratification and longitudinal research. Standardizing definitions, such as identifying Long-COVID patients who meet ME/CFS diagnostic criteria, could help improve study comparability.

By summarizing current imaging evidence, this review underscores the potential of neuroimaging to identify imaging biomarkers to advance the clinical diagnosis of Long-COVID and identify therapeutic targets for treatment development. As we continue to face the growing burden of Long-COVID and ME/CFS, metabolic imaging may serve as a powerful tool to bridge gaps in knowledge and accelerate progress toward effective care.

Source: Zhu Y, Quan P, Yamazaki T, Norweg A, Natelson B, Xu X. Metabolic neuroimaging of myalgic encephalomyelitis/chronic fatigue syndrome and Long-COVID. Immunometabolism (Cobham). 2025 Sep 12;7(4):e00068. doi: 10.1097/IN9.0000000000000068. PMID: 40958852; PMCID: PMC12435251. https://pmc.ncbi.nlm.nih.gov/articles/PMC12435251/ (Full text)

A multi-omics recovery factor predicts long COVID in the IMPACC study

Abstract:

Background. Following SARS-CoV-2 infection, ~10-35% of COVID-19 patients experience long COVID (LC), in which debilitating symptoms persist for at least three months. Elucidating biologic underpinnings of LC could identify therapeutic opportunities.

Methods. We utilized machine learning methods on biologic analytes provided over 12-months after hospital discharge from >500 COVID-19 patients in the IMPACC cohort to identify a multi-omics “recovery factor”, trained on patient-reported physical function survey scores. Immune profiling data included PBMC transcriptomics, serum O-link and plasma proteomics, plasma metabolomics, and blood CyTOF protein levels. Recovery factor scores were tested for association with LC, disease severity, clinical parameters, and immune subset frequencies. Enrichment analyses identified biologic pathways associated with recovery factor scores.

Results. LC participants had lower recovery factor scores compared to recovered participants. Recovery factor scores predicted LC as early as hospital admission, irrespective of acute COVID-19 severity. Biologic characterization revealed increased inflammatory mediators, elevated signatures of heme metabolism, and decreased androgenic steroids as predictive and ongoing biomarkers of LC. Lower recovery factor scores were associated with reduced lymphocyte and increased myeloid cell frequencies. The observed signatures are consistent with persistent inflammation driving anemia and stress erythropoiesis as major biologic underpinnings of LC.

Conclusion. The multi-omics recovery factor identifies patients at risk of LC early after SARS-CoV-2 infection and reveals LC biomarkers and potential treatment targets.

Trial Registration. ClinicalTrials.gov NCT04378777.

Funding. This study was funded by NIH, NIAID and NSF.

Source: Gisela Gabernet, Leying Guan, Lauren I.R. Ehrlich, et al. A multi-omics recovery factor predicts long COVID in the IMPACC study. J Clin Invest. September 9, 2025. https://doi.org/10.1172/JCI193698. https://www.jci.org/articles/view/193698/ (Full study available as PDF file)

Post-COVID-19 Vaccination (or Long Vax) Syndrome: Putative Manifestation, Pathophysiology, and Therapeutic Options

Abstract:

With the global rollout of COVID-19 vaccines, vaccine safety remains a priority. Emerging concerns have raised the potential risk of a long COVID-like syndrome following vaccination, informally called long Vax and provisionally termed post-COVID-19 vaccination syndrome (PCVS). Our narrative review describes the putative manifestation, pathophysiology, and therapeutic approaches of PCVS based on the available evidence, mostly from case reports/series and observational studies.

Our review noted that PCVS typically manifests within days to weeks post-vaccination, with symptoms lasting months to years. PCVS may present as recognized diagnoses such as postural orthostatic tachycardia syndrome (POTS), small-fibre neuropathy (SFN), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), or as long-term sequelae of myocarditis, vaccine-induced thrombotic thrombocytopaenia (VITT), or immune thrombocytopaenia purpura (ITP). Symptomatically, PCVS overlaps with long COVID, such as fatigue and brain fog, but PCVS may involve more frequent paraesthesia and less dyspnoea.

We also review pathophysiological hypotheses of PCVS, focussing on the vaccine-derived spike protein and related immune responses. Finally, we discuss potential therapies used to treat patients with PCVS or related conditions, primarily documented in case reports/series, which could guide future clinical research. Overall, PCVS remains a poorly understood condition that requires more research to elucidate its prevalence, prognosis, risk factors, and treatments.

Source: Yong SJ, Kenny TA, Halim A, Munipalli B, Alhashem YN, AlSaihati H, Al-Subaie MF, Al Kaabi NA, Al Fares MA, Garout M, Sabour AA, Alshiekheid MA, Almansour ZH, Alotaibi J, Alrasheed HA, Alamri AA, Albayat H, Alamodi AS, Tombuloglu H, Mohapatra RK, Hazazi A, Rabaan AA. Post-COVID-19 Vaccination (or Long Vax) Syndrome: Putative Manifestation, Pathophysiology, and Therapeutic Options. Rev Med Virol. 2025 Sep;35(5):e70070. doi: 10.1002/rmv.70070. PMID: 40944962. https://pubmed.ncbi.nlm.nih.gov/40944962/

Postural orthostatic tachycardia syndrome is associated with platelet storage pool deficiency

Abstract:

Mechanisms have been postulated to explain postural orthostatic tachycardia syndrome (POTS), however, the etiology of this often debilitating disorder remains unknown. We conducted a retrospective case-control study of 181 POTS patients who exhibited/reported bleeding symptoms for a specific platelet (PL) dysfunction disorder, delta granule storage pool deficiency (δ-SPD).Patients were included only if results of blood tests for δ-SPD were available.

Electron microscopy was utilized to diagnose δ-SPD. An ELISA assay was used to determine serotonin (5HT) concentration in PLs and medical record review was employed to collect patients’ clinical symptoms.The most common bleeding symptom was easy bruising (71%) but frequent nose bleeds, heavy menstrual bleeding, and a family history of bleeding were also commonly reported. Of the patients studied, 81% were diagnosed with δ-SPD.

Our investigation of 5HT concentration extracted from PLs revealed significantly lower levels of 5HT in POTS patients when compared to that of control subjects. Our data suggest that patients with POTS have significant comorbidities including bleeding symptoms and/or family bleeding histories, and have diminished PL 5HT levels supporting the hypothesis that POTS is a low 5HT level disorder.

While we describe a significant relationship with POTS and δ-SPD, this finding does not constitute an etiology for POTS.Our results establish an additional comorbidity frequently seen in POTS that could explain a number of disparate symptoms often affecting the severity of POTS.

Source: Gunning WT 3rd, Karabin BL, Blomquist TM, Grubb BP. Postural orthostatic tachycardia syndrome is associated with platelet storage pool deficiency. Medicine (Baltimore). 2016 Sep;95(37):e4849. doi: 10.1097/MD.0000000000004849. PMID: 27631244; PMCID: PMC5402587. https://pmc.ncbi.nlm.nih.gov/articles/PMC5402587/ (Full text)

A Perspective on the Role of Metformin in Treating Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID (LC) are increasingly recognized as debilitating postinfectious conditions that impact both individuals and society. Recent research highlights the potential of metformin, an antidiabetic agent, as a treatment for these syndromes by targeting their underlying mechanisms. This review assesses the effectiveness of metformin in ME/CFS and LC, which involve complex dysfunctions related to cytokines, glycolysis, ATP generation, oxidative stress, gastrointestinal microbiomes, and vascular endothelial function.

Metformin, traditionally known for its antihyperglycemic properties may offer broader therapeutic benefits by influencing these pathological pathways. It works by inhibiting complexes I and IV of the electron transport chain, which reduces the strain on malfunctioning complex V and decreases the production of harmful free radicals. Additionally, metformin’s impact on mTOR signaling could improve energy metabolism in ME/CFS and LC by downregulating an overactive but underperforming protein, thereby alleviating symptoms. Beyond the impact on cellular metabolism, metformin has shown to have anti-inflammatory, vascular, gastrointestinal, neuroprotective and epigenetic effects.

We explore this impact of metformin and the potential role it could play to help people with ME/CFS. While metformin shows promise, it is unlikely to be a stand-alone solution. Instead, it may be part of a broader treatment strategy that includes other therapies targeting neurocognitive and autonomic impairments.

Source: David Fineberg, Alain Moreau, Elena K. Schneider-Futschik, and Christopher W. Armstrong. A Perspective on the Role of Metformin in Treating Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID. ACS Pharmacology & Translational Science Article ASAP. DOI: 10.1021/acsptsci.5c00229 https://pubs.acs.org/doi/full/10.1021/acsptsci.5c00229 (Full text)

Fatigue, interoplastic and nociplastic distress in myalgic encephalomyelitis/chronic fatigue syndrome, Gulf War Illness, and chronic idiopathic fatigue

Abstract:

Introduction: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Gulf War Illness (GWI) have similar profiles of pain (nociception), visceral interoception, and tenderness (central sensitization) that may be due to dysfunction of midbrain and medulla descending antinociceptive and antiinteroceptive mechanisms. If so, then dolorimetry, a proxy for tenderness, may be correlated with subjective symptoms. The relationship with fatigue was assessed in Chronic Idiopathic Fatigue (CIF).

Methods: Cohorts of ME/CFS, GWI, and sedentary control subjects completed questionnaires and had dolorimetry. Spearman correlations were calculated between central sensitization (dolorimetry), fatigue (Chalder Fatigue), pain (McGill Pain), interoception (Chronic Multisymptom Inventory), disability (SF36), psychological constructs, and other symptoms. Females were more tender than males and were thus analyzed separately.

Results: GWI and ME/CFS groups were more tender than controls for females (p < 0.0045) and males (p < 10-6). Receiver operating characteristics area under the curve for female ME/CFS (0.730) and GWI (0.792) and male ME/CFS (0.816) and GWI (0.831) were not optimal for diagnostic purposes. Pain and interoception were highly correlated. Dolorimetry correlated better with pain (Spearman R = -0.574 to -0.629) than interoception (R = -0.417 to -0.545) questionnaires. Dolorimetry correlated weakly with fatigue and disability (|R| < 0.42). CIF was defined by receiver operating characteristics with elevated fatigue, postexertional malaise, and reduced vitality. CIF had intermediate tenderness.

Discussion: The outcomes generate several hypotheses about ME/CFS and GWI pathophysiology. Disease pathologies may involve injury to midbrain and medulla regulatory pathways causing central sensitization with the loss of descending antiinteroceptive and antinociceptive inhibitory mechanisms and increased perceptions of widespread visceral complaints and pain. The diseases can be re-conceptualized as chronic disabling fatigue with heightened interoceptive and nociceptive symptoms. Variations in antiinteroceptive control may provoke unpredictable shifts in symptom spectrum and severity that contribute to exertional exhaustion and symptom exacerbation. Subjective criteria were found to define CIF prospectively.

Source: Chen E, Rudder T, Nwankwere C, Baraniuk JN. Fatigue, interoplastic and nociplastic distress in myalgic encephalomyelitis/chronic fatigue syndrome, Gulf War Illness, and chronic idiopathic fatigue. Front Neurosci. 2025 Aug 25;19:1530652. doi: 10.3389/fnins.2025.1530652. PMID: 40927423; PMCID: PMC12415031. https://pmc.ncbi.nlm.nih.gov/articles/PMC12415031/ (Full text)