Category: Overlapping Illnesses

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)

‘I Want Everyone to Have It, and Everyone to Be on It’: A Feasibility Study of the Transforming Long Covid Intervention

Abstract:

Background: An understanding of the nature of long Covid (LC) is evolving, with recent evidence highlighting the role of increased sympathetic activation and decreased parasympathetic response. Building upon this emerging science, the ‘Transforming Long COVID’ (TLC) programme was developed to support participants in their recovery by (i) introducing education on the neuroscience underpinning persistent symptoms (with a particular focus on the autonomic nervous system) and (ii) the development of self-management strategies to support recovery. The aim of this study was to examine the feasibility of the TLC programme with a cohort of people significantly affected by LC.

Methods: Seventeen participants took part in the 8-week TLC programme which comprised of seven content sessions and one discussion (Q&A) session. Participants completed survey scales (investigating anxiety, pain-related interference, pain catastrophising, sleep disturbance and fatigue) at baseline, immediately post-programme (at 8 weeks), and retention (at 13 weeks). Participants also took part in focus group interviews to investigate their experiences of the programme.

Results: Fourteen participants (82%) attended at least six of the seven TLC content sessions. Decreases in mean values over time were observed across all measures, indicating a positive (non-significant) change. Participants reported an increase in understanding of LC, new hope for recovery, belief that they now had a realistic pathway for recovery, validation of their experiences and symptoms, meaningful improvements in function, and enhanced ability to respond to and attenuate physical symptoms. No adverse events were reported. Participants highlighted a number of programme strengths, along with some potential areas for improvement.

Conclusion: The TLC programme was shown to be feasible based on engagement, adherence, acceptable completion of surveys, and no adverse events. Study findings point to the potential for this programme to be refined, trialled and evaluated with a larger sample.

Patient or public contribution: Four people (living with LC, ME/CFS, chronic migraine and chronic Lyme, fibromyalgia, and centralised pain syndrome), who have experience of applying a recovery approach aligned with the TLC programme, acted in a PPI (Public and Patient Involvement in research) capacity on this study. In addition, the lead author has personal experience with the illness, and developing the recovery approach, which helped inform programme structure and development [1]. These individuals provided advice and guidance on the potential structure for the group programme, course duration, tool selection, and language and wording of the programme and materials. Further detail is provided in the Supplementary Materials.

Source: Belton S, Goss H, Whyte E, McCaffrey N, Gibney S, Sheridan K. ‘I Want Everyone to Have It, and Everyone to Be on It’: A Feasibility Study of the Transforming Long Covid Intervention. Health Expect. 2026 Jun;29(3):e70681. doi: 10.1111/hex.70681. PMID: 42076812. https://onlinelibrary.wiley.com/doi/10.1111/hex.70681 (Full text)

Post-Exertional Malaise in Post-COVID-19 Syndrome: A Shift in the Frequency Across Pandemic Phases

Abstract:

Background: Post-exertional malaise (PEM), which is the cardinal feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is also reported in a proportion of patients with post-COVID-19 syndrome (PCS). Our objective was to identify determinants that may be linked to the emergence of PEM in PCS patients.

Methods: Patients fulfilling the World Health Organization definition for PCS who attended the post-COVID unit of the Internal Medicine Department of Angers University Hospital, France, between June 2020 and December 2023 were included retrospectively. Their medical records were reviewed to extract information on COVID-19 infection history, characteristics of post-exertional malaise (PEM), fatigue severity, and relevant epidemiological variables.

Results: The study included 220 patients, grouped according to whether post-exertional malaise was present (PCS/PEM+) or absent (PCS/PEM-). PEM was observed in 26.4% of patients and was significantly linked to earlier COVID onset in 2020/2021 (OR 5.68 (95% CI: 1.66-19.45), p = 0.006), as well as higher fatigue levels (OR 2.07 (95% CI: 1.22-3.50), p = 0.007).

Conclusions: Patients who contracted COVID-19 during the pre-Omicron period reported PEM more frequently than those infected in later waves. This observation could reflect differences in viral characteristics following the emergence of the Omicron variant; however, alternative explanations-such as increasing vaccination coverage, accumulating post-infectious immunity, or other unmeasured factors-cannot be ruled out. Based on the observed link between PEM and symptom severity, PCS patients should be systematically assessed for the presence of PEM.

Source: Ghali A, Lavigne C, Ghali M, Lacombe V. Post-Exertional Malaise in Post-COVID-19 Syndrome: A Shift in the Frequency Across Pandemic Phases. J Clin Med. 2026 Apr 13;15(8):2948. doi: 10.3390/jcm15082948. PMID: 42074751. https://www.mdpi.com/2077-0383/15/8/2948 (Full text)

Regulatory Cycles of Orexin and Glucagon-Like Peptide-1 in Post-Viral Syndromes

Abstract:

Post-viral syndromes are heterogeneous multisystem diseases without a uniform etiology that occur as a result of acute viral infections. During the COVID-19 pandemic, the number of patients increased dramatically due to infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This is known as post-acute sequelae of COVID-19 (PASC), with many cases also meeting the criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), the most severe form of a post-viral disease, characterized by severe fatigue, post-exertional malaise (PEM), unrefreshing sleep, neurocognitive impairment, and autonomic and immune dysregulation.

Orexin (OX) neuropeptides, which regulate arousal, metabolism, and neuroendocrine functions, may serve as a central link between stress, immune activation, and metabolic changes in these syndromes. Notable phenotypic similarities between OX system dysfunction and core features of PASC and ME/CFS, including fatigue, sleep issues, impaired glucose metabolism, and neuropsychiatric symptoms, support a mechanistic model in which impaired OX signaling contributes to post-viral endocrine and metabolic dysfunction.

This review examines the role of OX in regulating glucose metabolism, HPA axis activity, and systemic homeostasis, with a specific focus on sexually dimorphic expression and function in relation to post-viral syndromes. We also highlight the effect of glucagon-like peptide-1 (GLP-1), another key player in metabolism, which also has neuroprotective, anti-inflammatory, vasoprotective, and immunomodulatory effects. We further emphasize emerging therapeutic strategies, such as GLP-1 receptor agonists (GLP-1RAs) and drugs targeting the OX system.

Together, these insights provide an integrated framework for understanding and targeting the neuroendocrine-metabolic underpinnings of PASC, ME/CFS, and other post-viral syndromes.

Source: Ruhrländer J, Schieffer E, Schieffer B. Regulatory Cycles of Orexin and Glucagon-Like Peptide-1 in Post-Viral Syndromes. Endocr Rev. 2026 Apr 27:bnag009. doi: 10.1210/endrev/bnag009. Epub ahead of print. PMID: 42037238. https://pubmed.ncbi.nlm.nih.gov/42037238/