Tag: symptom clusters

Sex- and menopause-related differences in immune and gastrointestinal symptom architecture in ME/CFS: evidence from factor analysis and structural equation modeling

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystem disorder characterized by neuroimmune, autonomic, and gastrointestinal dysfunction. Previous studies identified coherent symptom domains involving Brain, Autonomic, Gut, and Immune manifestations and demonstrated pronounced sex-specific differences in neurocognitive-sensory and autonomic symptom organization. However, whether immune-related and gastrointestinal symptoms form distinct or integrated latent structures in women and men with ME/CFS remains unclear. In addition, the potential influence of menopausal status on these symptom domains has not been systematically investigated.

Methods: Data from 748 adults with a medical diagnosis of ME/CFS were included in this cross-sectional analysis (608 women, 137 men, and 3 non-binary participants). Sex-stratified analyses were restricted to women and men. Symptoms were coded dichotomously. Sex-stratified analyses included cross-tabulations, Cramér’s V, tetrachoric correlations, logistic and linear regression models, exploratory factor analysis, and structural equation modeling (SEM). Additional subgroup analyses compared pre- and postmenopausal women. Model robustness was evaluated using a stratified training dataset.

Results: In women, Immune (flu-like symptoms, susceptibility to infections) and Gut (gastrointestinal complaints, food intolerances) symptoms formed two distinct but related clusters, characterized by moderate within-cluster correlations (tetrachoric ρ = 0.47-0.60) and weaker cross-cluster associations (ρ = 0.30-0.35). Exploratory factor analysis (EFA) supported a two-factor solution. Consistent with this result, the alternative one-factor SEM showed comparatively poor fit (CFI = 0.913; RMSEA = 0.119), whereas the specified two-factor model was just-identified and therefore not suitable for global fit evaluation. In men, all four symptoms loaded onto a single integrated Gut/Immune factor, with within- and cross-domain tetrachoric correlations ranging from 0.43 to 0.68. SEM confirmed excellent fit for a one-factor model (CFI = 0.981; RMSEA = 0.074). Susceptibility to infections emerged as the dominant predictor in regression analyses. Among women, menopausal status selectively affected immune-related symptoms. Women classified as premenopausal reported flu-like symptoms more frequently than women classified as postmenopausal, whereas gastrointestinal symptoms and food intolerances remained stable across groups. These findings suggest differential hormonal sensitivity of immune versus gastrointestinal symptom trajectories.

Conclusions: Immune and gastrointestinal symptoms in ME/CFS exhibit sex-specific latent structures. Women demonstrate two partially separable but related symptom domains, whereas men show a more integrated immune-gastrointestinal architecture. Furthermore, menopausal status appears to selectively modulate immune-related symptom expression while leaving gastrointestinal symptom patterns comparatively stable. Taken together, these results provide an exploratory framework that supports the concept of sex-dependent neuroimmune-autonomic mechanisms in ME/CFS and aligns with a dynamic, hormonally modulated immune component as well as a more persistent, gut-related process. The results highlight the importance of sex- and hormone-sensitive approaches to phenotyping, mechanistic research, and therapeutic stratification in ME/CFS.

Source: Habermann-Horstmeier L, Horstmeier LM. Sex- and menopause-related differences in immune and gastrointestinal symptom architecture in ME/CFS: evidence from factor analysis and structural equation modeling. J Transl Med. 2026 Jul 27;24(1):970. doi: 10.1186/s12967-026-08699-6. PMID: 42522006. https://link.springer.com/article/10.1186/s12967-026-08699-6 (Full text)

Symptom clusters in ME/CFS reflect distinct neuroimmune and autonomic pathophysiological mechanisms: a translational model

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem disease characterized by heterogeneous symptom patterns. Previous work suggested that specific symptoms tend to co‑occur, pointing toward underlying biological mechanisms. This study aimed to empirically validate literature‑based, hypothesis‑driven symptom clusters and assess whether they reflect distinct neuroimmune and autonomic pathophysiological pathways.

Methods: Symptom data from 748 adults with ME/CFS (≥20 years) participating in the APAV‑ME/CFS study were analyzed. Symptoms were assigned to predefined mechanistic groups informed by current pathophysiological hypotheses. Exploratory and Confirmatory Factor Analyses, followed by Structural Equation Modeling (SEM), evaluated the coherence, distinctiveness, and hierarchical structure of each cluster. Robustness was tested using a stratified, randomized training dataset.

Results: A coherent Brain factor (brain fog, sensory hypersensitivity, visual disturbances, sleep disturbances, headaches) showed excellent fit (RMSEA = 0.021; CFI = 0.996). Gastrointestinal symptoms demonstrated stronger internal consistency than Immune symptoms, and model comparisons supported a two‑factor Gut–Immune structure. Across all analyses, symptom groups emerged as internally consistent and statistically distinct. A higher‑order SEM including a common latent factor yielded excellent fit for the Autonomic symptom complex.

Conclusions: The findings support ME/CFS as a complex neuroimmune–autonomic multisystem disorder and suggest that symptom clusters align with functional biological systems. Mechanism-aligned symptom subgrouping may enable pathophysiology-guided diagnostics, patient stratification, and targeted therapeutic development. The proposed interpretations of underlying mechanisms derive from the integration of existing literature and were not directly measured in this study. The identified clusters therefore indicate mechanistic alignment rather than direct mechanistic validation.

Source: Habermann-Horstmeier L, Horstmeier LM. Symptom clusters in ME/CFS reflect distinct neuroimmune and autonomic pathophysiological mechanisms: a translational model. J Transl Med. 2026 Apr 28;24(1):606. doi: 10.1186/s12967-026-08159-1. PMID: 42050709; PMCID: PMC13126800. https://pmc.ncbi.nlm.nih.gov/articles/PMC13126800/ (Full text)

A pilot cross-sectional investigation of symptom clusters and associations with patient-reported outcomes in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post COVID-19 Condition

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is associated with long-term disability and poor quality of life (QoL). Cardinal ME/CFS symptoms (including post-exertional malaise, cognitive dysfunction and sleep disturbances) have been observed in Post COVID-19 Condition (PCC). To gain further insight into the potential role of ME/CFS as a post-COVID-19 sequela, this study investigates associations between symptoms and patient-reported outcomes, as well as symptom clusters.
Methods: Participants included Australian residents aged between 18 and 65 years formally diagnosed with ME/CFS fulfilling the Canadian or International Consensus Criteria or PCC meeting the World Health Organization case definition. Validated, self-administered questionnaires collected participants’ sociodemographic and illness characteristics, symptoms, QoL and functional capacity. Associations between symptoms and patient-reported outcomes were investigated with multivariate linear regression models. Hierarchical cluster analysis was performed to identify symptom clusters.
Results: Most people with ME/CFS (pwME/CFS) and people with PCC (pwPCC) were female (n = 48/60, 80.0% and n = 19/30, 63.3%, respectively; p = 0.12). PwME/CFS were significantly younger (x̄=41.75, s = 12.91 years) than pwPCC (x̄=48.13, s =10.05 years; p =0.017). Autonomic symptoms (notably dyspnoea) were associated with poorer scores in most patient-reported outcome domains for both cohorts. None of the four symptom clusters identified were unique to ME/CFS or PCC. Clusters were largely delineated by the presence of gastrointestinal and neurosensory symptoms, illness duration, ME/CFS criteria met and total symptoms.
Conclusions: Illness duration may explain differences in symptom burden between pwME/CFS and pwPCC. PCC diagnostic criteria must be refined to distinguish pwPCC at risk of long-term ME/CFS-like illness and subsequently deliver necessary care and support.
Source: Weigel B, Eaton-Fitch N, Thapaliya K, Marshall-Gradisnik S. A pilot cross-sectional investigation of symptom clusters and associations with patient-reported outcomes in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post COVID-19 Condition. Qual Life Res. 2024 Oct 3. doi: 10.1007/s11136-024-03794-x. Epub ahead of print. PMID: 39361124. https://link.springer.com/article/10.1007/s11136-024-03794-x (Full text)