Category: Overlapping Illnesses

Precision phenotyping for curating research cohorts of patients with unexplained post-acute sequelae of COVID-19

Abstract:

Background: Scalable identification of patients with post-acute sequelae of COVID-19 (PASC) is challenging due to a lack of reproducible precision phenotyping algorithms, which has led to suboptimal accuracy, demographic biases, and underestimation of the PASC.

Methods: In a retrospective case-control study, we developed a precision phenotyping algorithm for identifying cohorts of patients with PASC. We used longitudinal electronic health records data from over 295,000 patients from 14 hospitals and 20 community health centers in Massachusetts. The algorithm employs an attention mechanism to simultaneously exclude sequelae that prior conditions can explain and include infection-associated chronic conditions. We performed independent chart reviews to tune and validate the algorithm.

Findings: The PASC phenotyping algorithm improves precision and prevalence estimation and reduces bias in identifying PASC cohorts compared to the ICD-10-CM code U09.9. The algorithm identified a cohort of over 24,000 patients with 79.9% precision. Our estimated prevalence of PASC was 22.8%, which is close to the national estimates for the region. We also provide in-depth analyses, encompassing identified lingering effects by organ, comorbidity profiles, and temporal differences in the risk of PASC.

Conclusions: PASC precision phenotyping boasts superior precision and prevalence estimation while exhibiting less bias in identifying patients with PASC. The cohort derived from this algorithm will serve as a springboard for delving into the genetic, metabolomic, and clinical intricacies of PASC, surmounting the constraints of prior PASC cohort studies.

Source: Azhir A, Hügel J, Tian J, Cheng J, Bassett IV, Bell DS, Bernstam EV, Farhat MR, Henderson DW, Lau ES, Morris M, Semenov YR, Triant VA, Visweswaran S, Strasser ZH, Klann JG, Murphy SN, Estiri H. Precision phenotyping for curating research cohorts of patients with unexplained post-acute sequelae of COVID-19. Med. 2025 Mar 14;6(3):100532. doi: 10.1016/j.medj.2024.10.009. Epub 2024 Nov 8. PMID: 39520983; PMCID: PMC11911085. https://pmc.ncbi.nlm.nih.gov/articles/PMC11911085/ (Full text)

Multimodal Web-Based Telerehabilitation for Patients With Post-COVID-19 Condition: Protocol for a Randomized Controlled Trial

Abstract:

Background: Patients with post-COVID-19 condition (PCC) experience persistent, long-term health consequences following SARS-CoV-2 infection, including fatigue, hyperventilation, cognitive impairment, and limitations in daily activities. There is emerging evidence suggesting that exercise and respiratory therapy-based telerehabilitation is safe and could potentially improve physical capacity while reducing health care costs.

Objective: This study aims to evaluate the superiority of a multimodal, symptom-titrated telerehabilitation program over standard care in patients with PCC who are severely affected, using the highest oxygen uptake rate (VO2peak [mL/min/kg]) achieved during the cardiopulmonary exercise test (CPET) and minute ventilation/carbon dioxide production slope (VE/VCO2 [full slope]) as primary outcomes. In addition, this study seeks to provide novel insights into the clinical and physiological adaptations associated with PCC, informing future rehabilitation strategies.

Methods: This prospective, randomized, waitlist-controlled trial was approved by the Rhineland-Palatinate Medical Association ethics committee. All procedures comply with the Declaration of Helsinki. This study comprises 3 examination time points, which include patient-reported outcomes, clinical assessments, and a CPET. It is structured into an 8-week intervention phase followed by an 8-week follow-up phase. Following baseline assessment, patients will be randomly assigned to either the intervention group (IG) or the control group (CG). During the intervention phase, IG participants will receive a web-based, multimodal, symptom-titrated telerehabilitation program consisting of sports medicine consultations, weekly teleconsultations, a structured pacing approach, and exercise and respiratory therapy. In contrast, CG participants will receive treatment as usual, which includes a single sports medicine consultation on healthy habits and a self-directed pacing approach for managing symptoms and daily activities. During the follow-up phase, IG participants will continue training independently without teleconsultations, whereas CG participants will undergo the same telerehabilitation intervention as the IG. A follow-up assessment will be conducted for both groups to evaluate long-term effects. This study adheres to the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines and follows the Consensus on Exercise Reporting Template.

Results: Recruitment began in August 2023 and was extended until March 2025. As of March 2025, 80 participants have been recruited, and data analysis is ongoing. Final results are expected by December 2025, with a cross-sectional analysis of baseline data anticipated by July 2025.

Conclusions: This study is the first randomized controlled trial investigating the effectiveness of multimodal and symptom-titrated telerehabilitation in patients with PCC who are severely affected. The integration of various objective diagnostic systems will provide valuable insights into emerging postviral fatigue syndromes, supporting the development of CPET-based diagnostics, personalized rehabilitation strategies, and future research on long-term telerehabilitation effectiveness. The findings will be disseminated through peer-reviewed publications, professional networks, and patient advocacy groups to ensure scientific, clinical, and public impact.

Trial registration: German Clinical Trials Register (DRKS) DRKS00032394; https://drks.de/search/de/trial/DRKS00032394.

Source: Tomaskovic A, Weber V, Ochmann DT, Neuberger EW, Lachtermann E, Brahmer A, Haller N, Hillen B, Enders K, Eggert V, Zeier P, Lieb K, Simon P. Multimodal Web-Based Telerehabilitation for Patients With Post-COVID-19 Condition: Protocol for a Randomized Controlled Trial. JMIR Res Protoc. 2025 May 21;14:e65044. doi: 10.2196/65044. PMID: 40397936. https://www.researchprotocols.org/2025/1/e65044 (Full text)

Gastrointestinal Barrier Disruption in Post-COVID Syndrome Fatigue Patients

Abstract:

Background: Post-COVID Syndrome (PCS) is the term for a condition with persistent symptoms in a proportion of COVID-19 patients after asymptomatic, mild, or severe disease courses. Numbers vary, but the current estimate is that after COVID-19 approximately 10% develop PCS. The aim of our study was to evaluate the impact of SARS-CoV-2 infection on the gastrointestinal (GI) tract and associations with the development of PCS with fatigue, post-exertional malaise (PEM), orthostatic dysregulation, autonomous dysregulation, and/or neurocognitive dysregulation.

Methods: By combining medical record data from a prospective observational study with symptom analysis before, during, and after SARS-CoV-2 infection, we aimed to identify potential risk factors and predictive markers for PCS. Additionally, we analyzed blood, saliva, and stool samples from this well-characterized PCS patient cohort to biologically validate our findings.

Results: We identified significant associations between pre-existing GI complaints and the development of PCS Fatigue. PCS patients showed higher LBP/sCD14 ratios, lower IL-33 levels, and higher IL-6 levels compared to control groups. Our results highlight the critical role of the GI tract in PCS development of post-viral Fatigue.

Conclusion: We propose that the viral infection disrupts pathways related to the innate immune response and GI barrier function, evidenced by intestinal low-grade inflammation and GI barrier leakage. Monitoring GI symptoms and markers before, during, and after SARS-CoV-2 infection is crucial for identifying predictive clinical phenotypes in PCS. Understanding the interaction between viral infections, immune responses, and gut integrity could lead to more effective diagnostic and treatment strategies, ultimately reducing the burden on PCS patients.

Source: Rohrhofer J, Wolflehner V, Schweighardt J, Koidl L, Stingl M, Zehetmayer S, Séneca J, Pjevac P, Untersmayr E. Gastrointestinal Barrier Disruption in Post-COVID Syndrome Fatigue Patients. Allergy. 2025 May 15. doi: 10.1111/all.16593. Epub ahead of print. PMID: 40372110. https://onlinelibrary.wiley.com/doi/10.1111/all.16593 (Full text)

Disruptions in serotonin- and kynurenine pathway metabolism in post-COVID: biomarkers and treatment

Introduction:

This opinion article attempts to connect knowledge about post-COVID syndrome (PCS) gained in neuropsychiatry and immunology. It discusses some misunderstandings about PCS in light of the interplay between the serotonergic system and the kynurenine pathway (KP). From a new perspective, potential biomarkers for further research and therapeutic targets are identified.

Due to the severity and extent of PCS, researchers are urgently searching for its causes and treatments. For neurocognitive and autonomic nervous system problems such as present in PCS, it is common to encounter dysregulated neurotransmitter systems. Among the neurotransmitters, serotonin plays a special role in the immune system and in regulating inflammatory responses by central and peripheral mechanisms (–). Serotonin—also known as 5-hydroxytryptamine (5-HT)—is a neurotransmitter with a stimulating effect that influences memory, mood, self-confidence, sleep, emotion, orgasm and eating (–).

Serotonin not only binds to serotonergic receptors on neurons, but also to receptors on immune cells (, , , ). Many studies indicate that serotonin and its receptors, especially 5-HT3 receptors (one of the serotonin receptors), are involved in the pathogenesis of chronic inflammatory conditions (, , ). Therapeutic applications of 5-HT3 receptor antagonists for instance have been reported in rheumatoid arthritis (, , ). An essential amino acid in the serotonin system and also in the KP is tryptophan, a precursor of both serotonin and kynurenine (see Figure 1) and part of a regular diet (). The KP is a pathway creating an important energy factor and is modulated in conditions as infection and stress (, ). Kynurenine regulates the balance between two types of thymus cells (T-cells): regulatory T-cells (Treg-cells), and subsets of T helper 17 cells (Th17 cells) that produce cytokines and have a signaling function ().

In this opinion article I address the question whether disruptions in the serotonin- and kynurenine pathway metabolism lead to new biomarkers and treatment in PCS.

Source: Rus CP. Disruptions in serotonin- and kynurenine pathway metabolism in post-COVID: biomarkers and treatment. Front Neurol. 2025 Feb 13;16:1532383. doi: 10.3389/fneur.2025.1532383. PMID: 40027165; PMCID: PMC11869386. https://pmc.ncbi.nlm.nih.gov/articles/PMC11869386/ (Full text)

Therapeutic Approaches to the Neurologic Manifestations of COVID-19

Abstract:

As of May 2022, there have been more than 527 million infections with severe acute respiratory disease coronavirus type 2 (SARS-CoV-2) and over 6.2 million deaths from Coronavirus Disease 2019 (COVID-19) worldwide. COVID-19 is a multisystem illness with important neurologic consequences that impact long-term morbidity and mortality.

In the acutely ill, the neurologic manifestations of COVID-19 can include distressing but relatively benign symptoms such as headache, myalgias, and anosmia; however, entities such as encephalopathy, stroke, seizures, encephalitis, and Guillain-Barre Syndrome can cause neurologic injury and resulting disability that persists long after the acute pulmonary illness. Furthermore, as many as one-third of patients may experience persistent neurologic symptoms as part of a Post-Acute Sequelae of SARS-CoV-2 infection (Neuro-PASC) syndrome.

This Neuro-PASC syndrome can affect patients who required hospitalization for COVID-19 or patients who did not require hospitalization and who may have had minor or no pulmonary symptoms. Given the large number of individuals affected and the ability of neurologic complications to impair quality of life and productivity, the neurologic manifestations of COVID-19 are likely to have major and long-lasting personal, public health, and economic consequences.

While knowledge of disease mechanisms and therapies acquired prior to the pandemic can inform us on how to manage patients with the neurologic manifestations of COVID-19, there is a critical need for improved understanding of specific COVID-19 disease mechanisms and development of therapies that target the neurologic morbidities of COVID-19. This current perspective reviews evidence for proposed disease mechanisms as they inform the neurologic management of COVID-19 in adult patients while also identifying areas in need of further research.

Source: Graham EL, Koralnik IJ, Liotta EM. Therapeutic Approaches to the Neurologic Manifestations of COVID-19. Neurotherapeutics. 2022 Sep;19(5):1435-1466. doi: 10.1007/s13311-022-01267-y. Epub 2022 Jul 21. PMID: 35861926; PMCID: PMC9302225. https://pmc.ncbi.nlm.nih.gov/articles/PMC9302225/ (Full text)

Untargeted analysis in post-COVID-19 patients reveals dysregulated lipid pathways two years after recovery

Abstract:

Introduction: Similar to what it has been reported with preceding viral epidemics (such as MERS, SARS, or influenza), SARS-CoV-2 infection is also affecting the human immunometabolism with long-term consequences. Even with underreporting, an accumulated of almost 650 million people have been infected and 620 million recovered since the start of the pandemic; therefore, the impact of these long-term consequences in the world population could be significant. Recently, the World Health Organization recognized the post-COVID syndrome as a new entity, and guidelines are being established to manage and treat this new condition. However, there is still uncertainty about the molecular mechanisms behind the large number of symptoms reported worldwide.

Aims and Methods: In this study we aimed to evaluate the clinical and lipidomic profiles (using non-targeted lipidomics) of recovered patients who had a mild and severe COVID-19 infection (acute phase, first epidemic wave); the assessment was made two years after the initial infection.

Results: Fatigue (59%) and musculoskeletal (50%) symptoms as the most relevant and persistent. Functional analyses revealed that sterols, bile acids, isoprenoids, and fatty esters were the predicted metabolic pathways affected in both COVID-19 and post-COVID-19 patients. Principal Component Analysis showed differences between study groups. Several species of phosphatidylcholines and sphingomyelins were identified and expressed in higher levels in post-COVID-19 patients compared to controls. The paired analysis (comparing patients with an active infection and 2 years after recovery) show 170 dysregulated features. The relationship of such metabolic dysregulations with the clinical symptoms, point to the importance of developing diagnostic and therapeuthic markers based on cell signaling pathways.

Source: López-Hernández Y, Oropeza-Valdez JJ, García Lopez DA, Borrego JC, Murgu M, Valdez J, López JA, Monárrez-Espino J. Untargeted analysis in post-COVID-19 patients reveals dysregulated lipid pathways two years after recovery. Front Mol Biosci. 2023 Mar 3;10:1100486. doi: 10.3389/fmolb.2023.1100486. PMID: 36936993; PMCID: PMC10022496. https://pmc.ncbi.nlm.nih.gov/articles/PMC10022496/ (Full text)

Long-COVID in children and their parents: A prospective cohort study

Abstract:

Background: Long-COVID is a significant global health concern, regardless of age. However, few reports have longitudinally evaluated the characteristics, prevalence, and risk factors of long-COVID in children.

Methods: Participants were Japanese children younger than 18 years hospitalized for COVID-19 between November 2021 and October 2022, along with their COVID-19 affected parents. During hospitalization and at 1-, 3-, and 6-month follow-ups, participants completed age-appropriate questionnaires on long-COVID symptoms. The quality of life (QOL) score was assessed in children older than 2 years. The prevalence of long-COVID symptoms by age group was compared. Multivariable logistic regression analysis was conducted to investigate risk factors affecting long-COVID. Analysis of covariance adjusted for potential confounders was conducted to determine which symptoms affect QOL score.

Results: Of 108 children enrolled, the prevalence of long-COVID was 44.9%, 37.8%, and 22.8% at 1, 3, and 6 months, respectively, after SARS-CoV-2 infection. There were no specific risk factors for long-COVID. Cough, fatigue, and sleep disturbance were the most common long-COVID symptoms, with sleep disturbance associated with a change in lower QOL score from admission at all three follow-ups (mean difference 9.25, 20.15, and 19.81; 95% CI, 1.58-16.91, 3.38-36.92, and 5.51-34.11). The prevalence of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) symptoms among 0-6 years was significantly lower than among 7-17 years and parents; there was no significant difference between 7 and 17 years and parents.

Conclusion: Even 6 months after SARS-CoV-2 infection, 22.8% of pediatric patients still had long-COVID symptoms. Some of these symptoms were similar to those of ME/CFS, potentially affecting children’s QOL.

Source: Iijima H, Funaki T, Kubota M. Long-COVID in children and their parents: A prospective cohort study. Pediatr Int. 2025 Jan-Dec;67(1):e70042. doi: 10.1111/ped.70042. PMID: 40351239. https://onlinelibrary.wiley.com/doi/full/10.1111/ped.70042 (Full text)

Post-exertional malaise in Long COVID: subjective reporting versus objective assessment

Abstract:

Background: Post-exertional malaise (PEM) is a central feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and has emerged as a prominent feature of Long COVID. The optimal clinical approach to PEM is inconclusive, and studies of the impact of exercise have yielded contradictory results.

Objective: The objective of this study was to examine PEM in Long COVID by assessing the prevalence of self-reported PEM across study cohorts and symptom responses of Long COVID patients to a standardized exercise stressor. Secondarily, Long COVID symptom responses to exercise were compared to those of ME/CFS and healthy volunteers.

Methods: Data from three registered clinical trials comprised four cohorts in this study: Long COVID Questionnaire Cohort (QC; n = 244), Long COVID Exercise Cohort (EC; n = 34), ME/CFS cohort (n = 9), and healthy volunteers (HV; n = 9). All cohorts completed questionnaires related to physical function, fatigue, and/or PEM symptoms. EC also performed a standardized exercise test (cardiopulmonary exercise test, CPET), and the PEM response to CPET was assessed using visual analog scales and qualitative interviews (QIs) administered serially over 72 h. EC PEM measures were compared to ME/CFS and HV cohorts. A secondary analysis of QI explored positive responses to CPET among EC, ME/CFS and HV.

Results: Self-reported PEM was 67% in QC and estimated at 27% in EC. Only 2 of 34 EC patients (5.9%) were observed to develop PEM after a CPET. In addition, PEM responses after CPET in Long COVID were not as severe and prolonged as those assessed in ME/CFS. Twenty-two of 34 EC patients (64.7%) expressed at least one of 7 positive themes after the CPET.

Conclusion: Self-report of PEM is common in Long COVID. However, observable PEM following an exercise stressor was not frequent in this small cohort. When present, PEM descriptions during QI were less severe in Long COVID than in ME/CFS. Positive responses after an exercise stressor were common in Long COVID. Exercise testing to determine the presence of PEM may have utility for guiding clinical management of Long COVID.

Source: Stussman B, Camarillo N, McCrossin G, Stockman M, Norato G, Vetter CS, Ferrufino A, Adedamola A, Grayson N, Nath A, Chan L, Walitt B, Chin LMK. Post-exertional malaise in Long COVID: subjective reporting versus objective assessment. Front Neurol. 2025 Apr 23;16:1534352. doi: 10.3389/fneur.2025.1534352. PMID: 40337174; PMCID: PMC12055772. https://pmc.ncbi.nlm.nih.gov/articles/PMC12055772/ (Full text)

Case Report: The intersection of psychiatry and medicine: diagnostic and ethical insights from case studies

Abstract:

The intersection of psychiatry and medicine presents unique diagnostic and ethical challenges, particularly for conditions involving significant brain-body interactions, such as psychosomatic, somatopsychic, and complex systemic disorders. This article explores the historical and contemporary issues in diagnosing such conditions, emphasizing the fragmentation of medical and psychiatric knowledge, biases in clinical guidelines, and the mismanagement of complex illnesses.

Diagnostic errors often arise from insufficient integration between general medicine and psychiatry, compounded by the reliance on population-based guidelines that neglect individual patient needs. Misclassification of conditions like myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Lyme disease, and fibromyalgia as psychosomatic or psychogenic has led to stigmatization and delayed care. While these conditions are referenced as emblematic examples of misclassified and poorly understood disorders, the five clinical cases discussed in this article do not directly illustrate these diseases. Instead, they exemplify shared diagnostic and ethical dilemmas at the medicine–psychiatry interface, including uncertainty, fragmentation, and the risk of epistemic injustice.

The article critically examines terms like medically unexplained symptoms and functional disorders, highlighting their limitations and potential for misuse. Case examples underscore the consequences of diagnostic inaccuracies and the urgent need for improved approaches. Ethical considerations are also explored, emphasizing respecting patient experiences, promoting individualized care, and acknowledging the inherent uncertainties in medical diagnosis.

Advances in technologies such as brain imaging and molecular diagnostics offer hope for bridging the gap between psychiatry and medicine, enabling more accurate assessments and better patient outcomes. The article concludes by advocating comprehensive training at the medicine-psychiatry interface and a patient-centered approach that integrates clinical observation, research insights, and a nuanced understanding of mind-body dynamics.

Source: Monaco F, Vignapiano A, D’Angelo M, Raffone F, Di Stefano V, Boccia A, Longobardi A, Gruttola BD, Fornaro M, Corrivetti G, Martino I, Steardo L, Steardo L Jr. Case Report: The intersection of psychiatry and medicine: diagnostic and ethical insights from case studies. Front Psychiatry. 2025 Apr 22;16:1576179. doi: 10.3389/fpsyt.2025.1576179. PMID: 40330647; PMCID: PMC12053010. https://pmc.ncbi.nlm.nih.gov/articles/PMC12053010/ (Full text)

Exercise Pathophysiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID: Commonalities Detected by Invasive Cardiopulmonary Exercise Testing

Abstract:

Rationale: There is substantial overlap of exertional symptoms in Long COVID (LC) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) including intractable fatigue, post-exertional malaise (PEM), and orthostatic intolerance, but very little objective data liking the two. This study compares exercise pathophysiology in the two disorders and normal controls using invasive cardiopulmonary exercise testing (iCPET).

Methods: Between January 2019 and December 2024, 1,518 patients underwent a clinical iCPET at Brigham and Women’s Hospital. Exclusion criteria included morbid obesity (BMI>40 kg/m2), severe anemia ([Hb]<9.0 g/dL), elite athletes (peak VO2 (pVO2)>120% predicted), sub-maximum effort (RER<1.05), a primary pulmonary mechanical limit (VE @ AT/MVV>0.7), and comorbidities such as active/treated cancer, interstitial lung disease, or other respiratory related diseases. iCPET results from 438 ME/CFS patients, 73 LC patients, and 43 symptomatic but otherwise normal controls were analyzed. pV02, peak cardiac output (pQc), peak right atrial pressure (pRAP), peak systemic oxygen extraction (pSOE; Ca-vO2/[Hb]), and ventilatory inefficiency (VE/VCO2 slope) were compared among groups. Statistical significance was determined using Kruskal-Wallis tests for global comparisons, with post-hoc Dunn tests for pairwise group comparisons. Holm-Bonferroni adjustments were applied to control for multiple comparisons.

Results: LC and ME/CFS displayed reduced pVO2 % predicted compared to controls (LC: 78.4 ± 18%, ME/CFS: 78.1 ± 17%, Controls: 97.5 ± 10%, P≤0.0001). Reduced pQc % predicted was also observed compared to controls (LC: 91.1 ± 18%, ME/CFS: 96.3%, Controls: 101 ± 11%, P≤0.001). pRAP were significantly less compared to controls (LC: 1.1 ± 3.1 mmHg, ME/CFS: 1.3 ± 2.8 mmHg, Controls: 3.6 ± 3.4 mmHg, P≤0.001). Significant reductions in pSOE were seen for LC and ME/CFS (LC: 0.81 ± 0.1, ME/CFS: 0.81 ± 0.1, Controls, 0.91 ± 0.1, P≤0.0001). The only measure with no significant difference between disease and control was VE/VCO2 slope (LC: 31.4 ± 8.4, ME/CFS: 31.6 ± 6.9, Controls: 32.0 ± 6.7, P≥0.261). Most interestingly, no significant differences were seen between the two diseases for any of the analyzed measures (P≥0.245).

Conclusions: We report the largest cohort of ME/CFS and LC investigated with iCPET to date. ME/CFS and LC share symptomatic, reduced aerobic capacity at peak exercise, which is driven by preload insufficiency and impaired systemic O2 extraction, the latter compatible with peripheral left-to-right shunting and/or limb skeletal muscle dysfunction. These findings should drive future diagnostics and personalized medicine in both diseases. We hope these data inform the pending prospective NIH RECOVER iCPET study of LC.

Source: J. Squires, S. Palwayi, P. Li, W. Xiao, K. LeWine, S.W. Johnson, D. Felsenstein, A.B. Waxman, and D.M. Systrom. Exercise Pathophysiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID: Commonalities Detected by Invasive Cardiopulmonary Exercise Testing [abstract]. Am J Respir Crit Care Med 2025;211:A7881. https://www.atsjournals.org/doi/​10.1164/ajrccm.2025.211.Abstracts.A7881