Research Gaps
Open questions, research gaps and approaches for master theses, doctoral projects and papers – identified through AI analysis.
Hormones Orexin and GLP-1 as Key Factors in Post-Viral Syndromes
Regulatory Cycles of Orexin and Glucagon-Like Peptide-1 in Post-Viral Syndromes
The review illuminates how disrupted orexin signaling contributes to core symptoms of PASC and ME/CFS – including fatigue, sleep disorders, cognitive problems, and impaired glucose metabolism. GLP-1 is presented as a complementary factor with neuroprotective, anti-inflammatory, and vasculoprotective effects. From a therapeutic standpoint, GLP-1 receptor agonists and orexin-modulating medications are discussed as promising approaches.
Why relevant:
The work connects several central ME/CFS mechanisms (sleep, fatigue, autonomic dysfunction, metabolism) within a neuroendocrine model and proposes specific drug classes (GLP-1 RAs, orexin modulators) as potential therapies – a promising drug repurposing approach.
Understanding the Long-Term Effects of SARS-CoV-2 on the Nervous System
Understanding the long-term neurological effects of SARS-CoV-2 infection
The review summarizes the spectrum of neurological and psychiatric symptoms following SARS-CoV-2 infection, including brain fog, headaches, fatigue, anxiety, and depression. Mechanisms such as immune dysregulation, microvascular dysfunction, and volumetric changes in imaging are discussed. In addition, ongoing and completed treatment studies as well as the reciprocal relationship between neurobiological and psychiatric symptoms are examined.
Why relevant:
Long COVID shows considerable overlap with ME/CFS and PVFS. The mechanisms described here (neuroinflammation, microvascular dysfunction, immune dysregulation) are directly transferable and can provide insights for the diagnosis and treatment of post-viral fatigue syndromes.
Skeletal Muscle Involvement in ME/CFS: New Insights into Causes and Diagnosis
Pathophysiological, Translational, and Diagnostic Aspects of ME/CFS: A Focus on Skeletal Muscle Involvement
This narrative review (1990-2025) integrates clinical, biochemical, and experimental data on skeletal muscle changes in ME/CFS and Long COVID. The focus is on mitochondrial oxidative stress, redox imbalance, impaired calcium handling (excitation-contraction coupling), and changes in the muscle secretome. ME/CFS is reinterpreted as a skeletal muscle-metabolic disorder, with implications for diagnostics, biomarkers, and targeted therapies.
Why relevant:
The work provides a coherent explanatory model for the central ME/CFS symptomatology (exercise intolerance, PEM) and connects established mechanisms such as mitochondrial dysfunction with new aspects such as calcium dysregulation in muscle. It creates the foundation for muscle-related biomarkers and therapeutic approaches.
Impaired oxygen supply to the muscles in Long COVID during exercise
Impaired peripheral oxygen delivery during submaximal exercise in adults with long COVID
In a study involving 46 long COVID patients and 10 controls, near-infrared spectroscopy was used to measure oxygen saturation in the calf muscle during a two-day exercise test. The long COVID group showed a significantly shortened duration of elevated tissue oxygenation under exertion, which deteriorated further on the second day. This suggests impaired muscle oxygenation and compromised recovery under repeated physical exertion.
Why relevant:
The study provides objective measurement data for the central phenomenon of Post-Exertional Malaise (PEM) and demonstrates a combination of mitochondrial dysfunction, endothelial dysfunction, and reduced tissue perfusion as a possible mechanism. This is highly relevant for ME/CFS, as PEM is a cardinal symptom there.
ME/CFS following Pfeiffer's glandular fever compared to Long COVID
Comparing ME/CFS following mononucleosis with Long COVID
The researchers studied college students who were recorded prior to a mononucleosis infection (EBV) and developed from this a cohort with moderate and severe ME/CFS. This was compared with a matched SARS-CoV-2 cohort, some of whom developed Long COVID. The symptom burden of Long COVID fell between moderate and severe ME/CFS.
Why relevant:
The study provides important insights into the similarities and differences of two post-viral diseases and can help to better understand the underlying pathomechanisms. The direct comparison between EBV- and SARS-CoV-2-induced clinical presentations is particularly valuable from a methodological standpoint.
Severe COVID-19 courses leave long-lasting inflammatory and vascular damage
Post-Acute Sequelae Patients with Severe COVID-19 History Show a Prolonged Inflammatory, Vascular Injury Pattern
A longitudinal study of 46 patients following severe COVID-19 found persistent changes in the immune system for up to 12 months after discharge: altered CD4+/CD8+ T-cell ratio, activated T-cells, as well as elevated markers of chronic inflammation and endothelial damage. Autoantibodies against centromere structures and chronically elevated inflammation/cardiovascular markers correlated negatively with pulmonary function.
Why relevant:
The study provides biological evidence for persistent immune dysregulation, endothelial damage, and autoimmunity following viral infection - all central mechanisms that are also being discussed in the context of ME/CFS and Long COVID fatigue. It supports the hypothesis that post-viral fatigue is associated with measurable immunological and vascular changes.
How SARS-CoV-2 damages the brain: findings from autopsies and long COVID patients
Human brain matters: Navigating the neuropathology of COVID-19
The analysis of 352 postmortem brains as well as biofluid and imaging data from Long COVID patients (PASC) reveals typical pathological patterns: blood-brain barrier disruption, endothelial inflammation, microhemorrhages, hypoxic-ischemic damage, astrogliosis, microglial nodules, and neuronal damage particularly in the hippocampus, midbrain, and cerebellum. Elevated levels of proinflammatory cytokines (IL-6) and neuronal markers (NfL) correlate with anosmia, memory deficits, and cerebellar ataxia.
Why relevant:
The described mechanisms – chronic neuroinflammation, endothelial dysfunction, and persistent nerve damage – are central pathophysiological components of ME/CFS and post-viral fatigue. The findings in Long COVID patients could directly explain brain fog and cognitive symptoms in PVFS and provide biomarkers (e.g., NfL, IL-6) for diagnosis and monitoring of disease progression.
Hormonal abnormalities in ME/CFS: Cortisol deficiency and hypersensitive stress axis confirmed
Neuroendocrine signature of ME/CFS: Meta-analytic evidence for bioactive cortisol deficit and exaggerated feedback sensitivity
This systematic meta-analysis involving 1,388 ME/CFS patients and 1,349 controls consistently demonstrates reduced cortisol levels (saliva, urine, hair) as well as an impaired response to ACTH stimulation and excessive suppression following glucocorticoid administration. This suggests a hyporeactive HPA axis with reduced free cortisol availability and increased negative feedback sensitivity. This neuroendocrine hyporeactivity could explain core symptoms such as unrefreshing sleep, PEM, and cognitive slowing.
Why relevant:
For the first time, a comprehensive meta-analysis provides robust evidence for a specific neuroendocrine signature in ME/CFS. This could advance biomarker development, diagnostics, and targeted therapeutic approaches (e.g., low-dose hydrocortisone therapies), and explains core symptoms such as PEM and unrefreshing sleep.
Immunoglobulin Therapy in Long COVID: Case Report Shows Complete Recovery
Intravenous immunoglobulin treatment for long COVID: a case report of clinical and immunological findings
In a 39-year-old long COVID patient with elevated autoantibodies against G protein-coupled receptors, high-dose IVIG therapy was administered. Fatigue, cognition, and quality of life normalized within one year. Concurrently, a significant reduction was observed in pathogenic T cell-monocyte complexes, spontaneous IFNγ and TNF production, as well as autoantibody titers.
Why relevant:
The study provides mechanistic evidence that immunomodulation could be effective in post-viral immune dysregulation with autoantibodies against GPCRs – a mechanism that is also being discussed in ME/CFS. It also identifies T cell-monocyte synapses as a possible new pathogenic factor.
Protein pattern in the cerebrospinal fluid of ME/CFS patients decoded
Proteomic signatures in cerebrospinal fluid and their clinical associations in patients with ME/CFS
The study analyzed 902 proteins in the cerebrospinal fluid of 31 ME/CFS patients. In POTS patients, there were indications of neutrophil degranulation and platelet activation, while severely affected individuals showed abnormalities in the complement system, coagulation pathways, and IGFBP-mediated insulin growth factor transport. Four protein-based ratios correlated with disease severity and suggest cellular stress, extracellular matrix remodeling, and immune-neural interactions.
Why relevant:
The study provides direct molecular evidence of neuroinflammation, coagulation disorders, and immune activation in the central nervous system of ME/CFS patients and could lead to objective biomarkers that have been lacking until now.
ME/CFS in Post-COVID Patients: Poorer Rehabilitation Outcomes
The Role of ME/CFS Phenotype in Outpatient Post-COVID Rehabilitation
A retrospective study of 216 post-COVID rehabilitation patients identified 6.9% with an ME/CFS phenotype according to Canadian Consensus Criteria. These patients were predominantly female, younger, and showed persistently high fatigue scores without improvement through rehabilitation (FAS Δ +1.3 vs. -5.1). The 6-minute walk distance improved in both groups, however the ME/CFS phenotype remained functionally impaired.
Why relevant:
The study clearly shows that standard rehabilitation does not work for the ME/CFS phenotype and can even be counterproductive. It underscores the need for specific, PEM-avoiding therapeutic approaches and the importance of early identification of ME/CFS among Long COVID patients.