Category: Overlapping Illnesses

Healthcare Situation of 3,345 Long COVID Patients in Germany: Results of a Nationwide Survey

Abstract:

Long COVID includes persistent symptoms after SARS CoV 2 infection and leads to multiple physical and psychosocial burdens.Between March and April 2025, a nationwide sample of long COVID patients was recruited by means of an anonymous online survey. Demographic parameters, symptoms, use of outpatient/inpatient care services and subjective satisfaction with care were recorded.

In total, 3345 people (average age 49 ± 13 years; 81.5% women) completed the survey. 83.8% reported a medically confirmed long COVID diagnosis, with a further 12.2% reporting a post-vac syndrome. The average duration of symptoms was 2.8 ± 1.1 years, with only 36.4% reporting an improvement in their symptoms over time. Almost nine out of ten patients (89.1%) were on long-term sick leave (average 1.8 ± 1.3 years), 70.8% reported total or partial incapacity for work and 46.4% applied for a pension. General practitioner care was the first point of contact for 75.7%. Over the course of the illness, 93% consulted more than three and 21.5% more than ten different doctors. Personal financial contributions were high: 41.4% invested more than € 1,000 and 11.3% more than € 10,000 in diagnostics or therapy. 60% received a rehabilitation intervention. Overall, 97.2% rated their care as “poor” or “very poor”.

This survey highlights a high and persistent burden among long COVID patients, as well as significant socioeconomic consequences, accompanied by a predominantly negative evaluation of the current care situation. Improvements require structured, easily accessible, and cross-sectoral services. Improving the primary care system, establishing clear referral pathways, and (where clinically indicated) integrating rehabilitative interventions into an interdisciplinary care concept could help to improve the care situation of patients with long COVID.

Source: Gloeckl R, Rischer R, Schneeberger T, Jarosch I, Blome C, Koczulla R. Versorgungssituation von 3345 Long-COVID-Betroffenen in Deutschland: Ergebnisse einer bundesweiten Befragung [Healthcare Situation of 3,345 Long COVID Patients in Germany: Results of a Nationwide Survey]. Pneumologie. 2025 Nov 11. German. doi: 10.1055/a-2725-5650. Epub ahead of print. PMID: 41218624. https://pubmed.ncbi.nlm.nih.gov/41218624/  https://www.thieme-connect.de/products/ejournals/html/10.1055/a-2725-5650 (Full text available in German]

A Comparative Study of the Coagulation Systems and Inflammatory Profiles of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Patients with Long COVID

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome is a chronic condition that severely debilitates patients, yet it remains largely unfamiliar to many. Faced with scepticism as a real clinical entity for decades, the recognition of ME/CFS has improved with the emergence of Long COVID. This chronic illness manifests after an acute COVID-19 infection. With two-thirds of ME/CFS cases reported to be post-viral, a clear overlap emerges with Long COVID, as both conditions arise following an infectious illness.
The parallels between post-infectious ME/CFS and Long COVID are striking, with similarities in both symptomology and pathophysiology. One overlapping mechanism in both conditions, systemic inflammation, may be perpetuated by pathogen persistence or reactivation. While inflammation alone may not be accountable for the symptoms experienced in both conditions, it can lead to disruption in other physiological mechanisms. Owing to a bi-directional link with inflammation, coagulopathy and vascular changes may be exhibited in ME/CFS and Long COVID. Given the accessibility of blood samples, it is imperative to explore these mechanisms to uncover potential biomarkers for these conditions, both of which currently lack standardised diagnostic biomarkers.
A total of 83 participants were included in the study. The control group consisted of 19 healthy controls and 10 inflammatory controls (individuals with known inflammatory conditions), used to assess inflammation in a step-increase manner. The post-infectious group included 54 individuals, subdivided into 20 ME/CFS patients and 34 Long COVID patients. Statistical analyses were performed using GraphPad Prism 10 and R-Studio, with comparisons made using parametric or non-parametric tests, depending on data distribution. Significant results were considered at P<0.05. Multiple regression analyses were conducted to control for the effects of age and sex on the outcomes.
The techniques utilised in this dissertation focused on Virchow’s triad, a model explaining that hypercoagulability, stasis, and endothelial damage contribute to the aetiology and risk of thrombosis, particularly deep vein thrombosis. Framing the dissertation around this model offered a valuable framework to investigate potential pathological mechanisms and identify relevant biomarkers for these conditions. Common viscoelastic point-of-care devices, including TEG and ClotPro, were employed to examine the hypercoagulability component of Virchow’s triad.
These techniques demonstrated how standard laboratory tests are inefficient in revealing pathological alterations in Long COVID and ME/CFS, and how the insignificance of these results has prompted researchers and healthcare professionals to question the validity of these conditions. Despite this, newly developed fluorescent microscopy techniques revealed an increased presence of plasma structures resistant to fibrinolysis in the post-infectious groups, providing evidence of coagulopathy. This technique effectively distinguished the two conditions, with the Long COVID group showing a 2.75-fold increase in these plasma structures compared to the ME/CFS group. Additionally, the post-infectious groups displayed a marked presence of hyperactivated platelets and megakaryocytes in circulation, with platelet activation and aggregation being 1.35-fold higher in the Long COVID group compared to the ME/CFS group.
However, such microscopy techniques are low-throughput and labour-intensive, making them less practical for diagnostic purposes. An innovative high-throughput diagnostic technique known as real-time deformability cytometry was employed to investigate the second component of Virchow’s triad: alterations in blood rheology.
When isolating anomalous events and large clots in whole blood using the combined filter technique, the Long COVID group showed a 1.30-fold decrease in deformation compared to the ME/CFS group, indicating greater rigidity of these structures. Additionally, the ME/CFS group had a 1.31-fold decrease in the volume of these clots compared to the Long COVID group. Although significant differences were observed in both conditions and likely impact blood rheology, this technique requires further standardisation due to its novelty.
Lastly, endothelial biomarkers previously studied in other inflammatory diseases were investigated to better understand the extent of endothelial damage, the final aspect of Virchow’s triad. The flow luminescence immunoassay revealed a 1.29-fold reduction in cadherin-5 levels in the ME/CFS group compared to healthy controls. No significant differences were found in other endothelial biomarkers between the post-infectious groups, suggesting these biomarkers cannot be repurposed for these conditions.
Furthermore, the lack of replicability in endothelial analyte concentrations among different studies raises concerns about the reproducibility of this technique. When the findings of this dissertation are considered collectively through biomarker stratification, it becomes clear that distinct subgroups may exist within the studied populations. This highlights the importance of a multiparameter approach for diagnosis, although these novel investigations require further validation and should be replicated with larger sample sizes.
Through an examination of these mechanisms, this dissertation illustrated some commonalities between these diseases and demonstrated how Virchow’s triad may be implicated to some extent in both conditions. However, key differences were also identified between the conditions, highlighting the unique challenges each presents. As we investigate whether Long COVID signals the early onset of ME/CFS and consider whether insights gained from decades of combating ME/CFS can enlighten our understanding of Long COVID, we progress toward a deeper understanding of post-infectious conditions and the creative solutions required to address them.
Source: Arron, H. E. 2025. A Comparative Study of the Coagulation Systems and Inflammatory Profiles of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Patients with Long COVID. Unpublished doctoral thesis. Stellenbosch: Stellenbosch University [online]. Available: https://scholar.sun.ac.za/items/1a98fb4e-a91f-497b-892e-716a25ee5358

Integrated immune, hormonal, and transcriptomic profiling reveals sex-specific dysregulation in long COVID patients with ME/CFS

Abstract:

Long COVID (LC) manifests with sex-specific differences, particularly in those with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Our study reveals that female LC patients (LCF) with ME/CFS show a shift toward myelopoiesis, reduced lymphocytes, increased neutrophils/monocytes, and depleted regulatory T cells-suggesting persistent immune activation. Elevated CD71+ erythroid cells and disrupted erythropoiesis contribute to fatigue and tissue damage in LCF.

Cytokine profiling indicates a stronger pro-inflammatory response in LCF compared to males (LCM), along with markers of gut barrier dysfunction. Hormonal analysis shows reduced testosterone in LCF and estradiol in LCM. Transcriptomic data reveal neuroinflammatory signatures in LCF, potentially explaining cognitive symptoms. We also identify biomarkers that distinguish LCF from LCM and correlate with sex-specific clinical symptoms.

Overall, LC with ME/CFS is characterized by sex-specific immune, hormonal, and transcriptional alterations, with females exhibiting more severe inflammation. These insights underscore the need for sex-tailored interventions, including consideration of hormone replacement therapy.

Source: Shahbaz S, Osman M, Syed H, Mason A, Rosychuk RJ, Cohen Tervaert JW, Elahi S. Integrated immune, hormonal, and transcriptomic profiling reveals sex-specific dysregulation in long COVID patients with ME/CFS. Cell Rep Med. 2025 Nov 7:102449. doi: 10.1016/j.xcrm.2025.102449. Epub ahead of print. PMID: 41205594. https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(25)00522-1 (Full text)

Severe COVID-19 induces prolonged elevation of the acute-phase protein pentraxin 3

Abstract:

Introduction: During the acute-phase of COVID-19, elevated levels of several acute-phase proteins, such as C-reactive protein (CRP), mannose-binding lectin (MBL), pentraxin 3 (PTX-3), serum amyloid A (SAA) and surfactant protein D (SP-D), are associated with severe to fatal clinical outcomes. Typically, these markers return to baseline within days after resolution of the acute infection.

Methods: In this study, we assessed the plasma levels of these proteins in a well-defined cohort of 141 COVID-19 convalescent patients 10 weeks after infection and compared them to 98 non-infected controls. In addition, we performed genetic analyses in a subgroup of patients and related the findings with structural equation modelling to disease severity.

Results: In contrast to other acute-phase proteins, PTX-3 levels were significantly higher in severe COVID-19 convalescent patients than in the control group. Furthermore, a higher proportion of patients with severe COVID-19 exhibited PTX-3 levels above 5000 pg/ml even 10 months post-infection, compared to those with mild disease. To explore potential genetic influences, a genetic analysis was performed on all severely affected patients (n=36) and on an age- and sex-matched subset of mild COVID-19 patients (n=38). Results revealed a significantly higher frequency (p<0.0001) of the homozygous wildtype genotype of the PTX-3 SNP rs971145291 in severe (15 out of 36) versus mild (1 out of 38) COVID-19 patients. Using structural equation modelling, the association of this PTX-3 genotype and disease severity was shown to be mediated by elevated PTX-3 levels, with no contribution from other analyzed (clinical) confounders.

Discussion: In summary, severe COVID-19 patients show high PTX-3 serum levels which may be influenced by genetic predisposition, specifically the absence of the rs971145291 SNP variant. PTX-3 may thus serve both as a biomarker for tissue damage and/or long-term immune activation and eventually post-COVID-19 complications.

Source: Kratzer B, Stieger RB, Durmus S, Trapin D, Gattinger P, Ettel P, Sehgal ANA, Borochova K, Dorofeeva Y, Tulaeva I, Grabmeier-Pfistershammer K, Tauber PA, Gerdov M, Perkmann T, Fae I, Wenda S, Kundi M, Wrighton S, Fischer GF, Valenta R, Pickl WF. Severe COVID-19 induces prolonged elevation of the acute-phase protein pentraxin 3. Front Immunol. 2025 Oct 1;16:1672485. doi: 10.3389/fimmu.2025.1672485. PMID: 41103408; PMCID: PMC12520919. https://pmc.ncbi.nlm.nih.gov/articles/PMC12520919/ (Full text)

Post-Exertional Symptom Exacerbation after Sub-Maximal Exercise in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post-Acute Sequelae of COVID-19

Abstract:

Purpose: In individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-acute sequelae of SARS-CoV-2 infection (PASC), physical activity can exacerbate symptoms for days-to-weeks, referred to as post-exertional symptom exacerbation (PESE). This study characterized the trajectory of PESE symptoms before and for 7 days after a sub-maximal exercise task in individuals with ME/CFS or PASC.

Methods: Individuals with ME/CFS (n=30) or PASC (n=30) and matched controls (n=30) were recruited from a university hospital and the community setting. Participants completed a 25-minute moderate intensity exercise on a whole-body cycle ergometer. The trajectory of 8 commonly reported PESE symptoms (physical fatigue, mental fatigue, pain, physical function, flu-like symptoms, gastrointestinal symptoms, sleep dysfunction, anxiety) before and for 7 days after exercise.

Results: There was variability in the proportion of those who experienced increased symptoms ranging from 46/60 reporting physical fatigue to only 18/30 reporting anxiety. There was no change in any of the symptoms across the 7-day period when analyzed individually. An aggregate score of 4-5 symptoms that includes physical fatigue, mental fatigue, physical function and flu-like symptoms, with or without pain, was more comprehensive in capturing maximal changes in PESE. Changes were greatest during the 72h post-exercise and for those with ME/CFS. The aggregate score shows 8/30 of individuals with ME/CFS and 12/30 with PASC show minimal-to-no increase in PESE, while 6-7/30 show increases greater than 3/10 points.

Conclusions: PESE to a clinically relevant exercise task is variable in individuals with ME/CFS and PASC as submaximal exercise does not exacerbate symptoms for some, while modifications of intensity may be necessary to minimize PESE in others.

Source: Berardi G, Janowski A, McNally S, Post A, Garg A, Sluka KA. Post-Exertional Symptom Exacerbation after Sub-Maximal Exercise in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post-Acute Sequelae of COVID-19. Med Sci Sports Exerc. 2025 Nov 4. doi: 10.1249/MSS.0000000000003891. Epub ahead of print. PMID: 41185151. https://pubmed.ncbi.nlm.nih.gov/41185151/

The Gut-Brain-Immune Axis in Environmental Sensitivity Illnesses: Microbiome-Centered Narrative Review of Fibromyalgia Syndrome, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, and Multiple Chemical Sensitivity

Abstract:

Environmental sensitivity illnesses-including fibromyalgia syndrome (FMS), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and multiple chemical sensitivity (MCS)-are chronic, disabling disorders characterized by hypersensitivity to environmental stimuli, persistent fatigue, widespread pain, and neurocognitive and autonomic dysfunction. Although their diagnostic criteria differ, increasing evidence suggests overlapping clinical features and shared biological mechanisms. A unifying hypothesis highlights the gut-brain-immune axis, where alterations in the intestinal microbiome, epithelial barrier dysfunction, and aberrant immune signaling interact with central sensitization and systemic metabolic dysregulation.

Recent studies demonstrate reduced microbial diversity, depletion of anti-inflammatory taxa (e.g., Faecalibacterium prausnitzii, Bifidobacterium), and enrichment of pro-inflammatory Clostridium species across these conditions. These shifts likely alter production of short-chain fatty acids, amino acid metabolites, and complex lipids, with downstream effects on mitochondrial function, neuroinflammation, and host energy metabolism. Moreover, emerging clinical interventions-including probiotics, prebiotics, synbiotics, and fecal microbiota transplantation-suggest a potential role for microbiome-targeted therapies, though controlled evidence remains limited.

This review synthesizes current knowledge on microbiome alterations in FMS, ME/CFS, and MCS, emphasizing their convergence on metabolic and immune pathways. By integrating microbial, immunological, and neurophysiological perspectives, we propose a microbiome-centered framework for understanding environmental sensitivity illnesses and highlight avenues for translational research and therapeutic innovation.

Source: Watai K, Taniguchi M, Azuma K. The Gut-Brain-Immune Axis in Environmental Sensitivity Illnesses: Microbiome-Centered Narrative Review of Fibromyalgia Syndrome, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, and Multiple Chemical Sensitivity. Int J Mol Sci. 2025 Oct 14;26(20):9997. doi: 10.3390/ijms26209997. PMID: 41155291. https://www.mdpi.com/1422-0067/26/20/9997 (Full text)

Autonomic phenotyping, brain blood flow control, and cognitive-motor-integration in Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome: A pilot study

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and the prolonged sequelae after COVID-19 (>3 months; Long COVID) have similar symptomology, are both associated with autonomic dysfunction, and a growing proportion of Long COVID patients are developing ME/CFS. We aimed to determine an autonomic phenotype of patients with ME/CFS vs Long COVID. We hypothesized that the groups would differ from controls yet be similar to one another.

We recruited sedentary controls (n = 10), mild/moderate ME/CFS patients (n = 12), and Long COVID patients (n = 9) to undergo 1) breathing 5 % CO2, 2) breathing 10 % O2, and 3) 5-minutes of 70° head-up tilt. Respiratory, hemodynamic, and cerebrovascular variables were measured throughout the 3 trials. Resting vascular function and cognitive-motor-integration were also assessed. ME/CFS and Long COVID were similar to the healthy controls and each other with regard to resting vascular function and the hemodynamic responses to hypoxia, hypercapnia, and head-up tilt (p > 0.05). However, in ME/CFS we observed a greater reduction of cerebrovascular resistance (p = 0.041) and impaired autoregulation (p = 0.042) during hypercapnia alongside impaired cognitive-motor integration (p < 0.02), and in Long COVID we observed reduced peripheral and end-tidal oxygen (p < 0.04) and less vagal withdrawal during tilt (p = 0.028).

Our findings suggest unique phenotypes when comparing ME/CFS and Long COVID whereby we have shown that Long COVID patients experience hypoxia while upright contributing to less vagal withdrawal, and ME/CFS patients experience impaired cerebrovascular control during potentially leading to reduced cognitive-motor integration. These differences could stem from disease severity/duration or some unique aspect of the COVID-19 virus.

Source: Badhwar S, Pereira TJ, Kerr K, Bray R, Tabassum F, Sergio L, Edgell H. Autonomic phenotyping, brain blood flow control, and cognitive-motor-integration in Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome: A pilot study. Auton Neurosci. 2025 Oct 14;262:103358. doi: 10.1016/j.autneu.2025.103358. Epub ahead of print. PMID: 41138391. https://www.autonomicneuroscience.com/article/S1566-0702(25)00120-1/fulltext (Full text)

HLA and pathogens in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and other post-infection conditions

Abstract:

Viral infections have been widely implicated in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) pathogenesis. Recent evidence has also identified certain Human Leukocyte Antigen (HLA) alleles that are significantly associated with ME/CFS risk/protection. Here we tested the hypothesis that ME/CFS risk or protection conferred from those HLA alleles is associated with binding affinity to antigens of HHV viruses, a critical step in initiating the adaptive immune system response to foreign antigens.

Specifically, we determined in silico the predicted binding affinity of two susceptibility alleles (C*07:04, DQB1*03:03) and two protective alleles (B*08:01, DPB1*02:01) to > 10,000 antigens of the 9 Human Herpes Viruses (HHV1, HHV2, HHV3, HHV4, HHV5, HHV6A, HHV6B, HHV7, HHV8) which have been implicated in the etiology of ME/CFS. We found that the binding affinity of all HHV antigens to the susceptibility alleles was significantly weaker than the binding affinity to the protective alleles (P < 0.001). In fact, none of the HHV antigens showed strong binding to the susceptibility alleles, in contrast to the strong bindings showed by the protective alleles. These findings are in keeping with the hypothesis that the effect of a putative HHV insult in contributing to ME/CFS is modulated by the host’s HLA immunogenetic makeup.

We speculate that strong HLA-antigen binding likely protects against ME/CFS via elimination of virus antigens; conversely, weak HLA-antigen binding may permit persistence of foreign antigens, contributing to ME/CFS and other chronic conditions. Finally, with respect to the latter, we determined the binding affinities to the 4 HLA alleles above to pathogens causing two chronic diseases with very similar symptomatology to ME/CFS, namely Long COVID and post-treatment Lyme disease syndrome (PTLDS).

We found that the 2 ME/CFS susceptibility HLA alleles above had very weak binding with SARS-CoV-2 virus glycoprotein (involved in Long COVID) and 5 proteins of Borrelia burgdorferi (involved in PTLDS), in contrast to the ME/CFS protective alleles that showed strong bindings. These findings support the hypothesis that ME/CFS, long COVID and PTLDS are caused by persistent pathogenic antigens that could not be eliminated due to inadequate protection by the patient’s HLA makeup.

Source: Georgopoulos AP, James LM, Peterson PK. HLA and pathogens in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and other post-infection conditions. Sci Rep. 2025 Oct 24;15(1):37303. doi: 10.1038/s41598-025-21230-z. PMID: 41136524. https://www.nature.com/articles/s41598-025-21230-z (Full text)

Autonomic symptom burden, comorbidities and quality of life in women with Hypermobility Spectrum Disorders and hypermobile Ehlers-Danlos syndrome

Abstract:

Background: Hypermobility Spectrum Disorders (HSD) and hypermobile Ehlers-Danlos syndrome (h-EDS) are multisystemic connective tissue disorders involving joint hypermobility and numerous other manifestations. Autonomic dysfunction, chronic pain, and chronic fatigue are known comorbidities of HSD and h-EDS that can affect patient quality of life (QoL), but there are limited data on the severity of autonomic symptoms, prevalence of comorbid conditions and QoL in patients with HSD/h-EDS.

Methods: We utilized the Composite Autonomic Symptom Scale (COMPASS-31) to assess autonomic symptom severity, Short-Form 36 (SF-36) to assess QoL, and the Beck Depression Inventory Second Edition (BDI-II) in a cohort of women with physician-diagnosed HSD or h-EDS, who completed these questionnaires anonymously.

Results: 84 women (mean age of 37.1 ± 8.4 years) completed the study. 58.3 % reported having physician-diagnosed postural orthostatic tachycardia syndrome (POTS), 32.1 % had mast cell activation syndrome (MCAS), 54.8 % had migraine, 26.2 % had myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and 98.8 % reported experiencing chronic pain. Importantly, 25 % of patients reported having all three diagnoses: HSD/h-EDS, POTS and MCAS. Mean COMPASS-31 score was 54.45 (range 18.79-80.93), indicating severe autonomic dysfunction, which was significantly higher than in patients with multiple sclerosis, diabetic neuropathy, scleroderma, and psoriatic arthritis as shown in prior studies. Mean SF-36 score was 32.38 (SD = 22.91) indicating poor QoL, which was worse than in patients with POTS, multiple sclerosis, rheumatoid arthritis, and lupus as determined by prior studies.

Conclusions: This study demonstrates that women with HSD/h-EDS experience severe autonomic dysfunction, chronic pain, chronic comorbid conditions and reduced QoL. More than half of participants in this cohort had POTS and migraine, with one in four having a clinical triad of HSD/h-EDS, POTS and MCAS.

Source: Collins Hutchinson ML, Liang E, Fuster E, Blitshteyn S. Autonomic symptom burden, comorbidities and quality of life in women with Hypermobility Spectrum Disorders and hypermobile Ehlers-Danlos syndrome. Auton Neurosci. 2025 Oct 14;262:103356. doi: 10.1016/j.autneu.2025.103356. Epub ahead of print. PMID: 41118678. https://pubmed.ncbi.nlm.nih.gov/41118678/

Corticosteroids with low glucocorticoid activity as a potential therapeutic strategy for post-COVID-19 myalgic encephalomyelitis/chronic fatigue syndrome in patients with bipolar affective disorder: A case report

Abstract:

Background: The COVID-19 pandemic has led to an increase in post-acute sequelae, including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), potentially mediated by dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis. Corticosteroids are occasionally administered to ameliorate fatigue symptoms in ME/CFS; however, their psychiatric adverse effects, particularly in individuals with preexisting mood disorders, necessitate careful consideration.

Case presentation: We report the case of a 32-year-old woman with bipolar disorder who developed ME/CFS following COVID-19 infection. Initial corticosteroid therapy with betamethasone and prednisolone, agents with potent glucocorticoid receptor (GR) activity, resulted in a manic episode with psychotic features, necessitating psychiatric hospitalization. Although mood stabilization was achieved with olanzapine and valproate, corticosteroid withdrawal subsequently led to metabolic alkalosis and hypoxemia, secondary to hypothalamic hypoadrenalism. Following a comprehensive endocrinological assessment, physiological replacement therapy with hydrocortisone, characterized by relatively higher mineralocorticoid receptor (MR) activity and lower GR potency, was initiated, resulting in the resolution of physical symptoms without destabilization of psychiatric status.

Conclusion: The clinical course suggests that GR-dominant corticosteroids may exacerbate psychiatric instability in patients with mood disorders. Simultaneously, MR-favoring agents, such as hydrocortisone, may offer a safer therapeutic alternative for managing HPA axis dysfunction. This case underscores the critical role of receptor selectivity in corticosteroid therapy, particularly in patients with comorbid psychiatric conditions, and highlights the necessity for individualized treatment strategies that integrate both endocrine and neuropsychiatric considerations.

Source: Nakajima K, Ayani N, Matsuoka T, Kasahara K, Nakajima Y, Ikawa H, Kitaoka R, Akimoto T, Narumoto J. Corticosteroids with low glucocorticoid activity as a potential therapeutic strategy for post-COVID-19 myalgic encephalomyelitis/chronic fatigue syndrome in patients with bipolar affective disorder: A case report. PCN Rep. 2025 Oct 12;4(4):e70222. doi: 10.1002/pcn5.70222. PMID: 41089430; PMCID: PMC12515714.