Tag: sex differences

Muscle symptoms and a latent physiological symptom-dysregulation factor in ME/CFS: exploratory analyses by sex and age-defined menopausal-status proxy group

Abstract:

Background: Muscle-related symptoms are among the most disabling manifestations of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), yet their position within the broader symptom architecture of the disease remains unclear. We hypothesized that muscle symptoms may represent a candidate integrative symptom within a broader shared symptom-dysregulation structure and their symptom associations differ according to sex and menopausal status.

Methods: Cross-sectional data from 736 individuals with physician-diagnosed ME/CFS enrolled in the APAV-ME/CFS registry were analysed. Muscle problems served as the primary outcome variable. Associations with 14 symptom domains were examined using multivariable logistic regression. Pearson and tetrachoric correlations, exploratory factor analysis, and structural equation modeling (SEM) were used to identify latent symptom structures. Exploratory analyses were stratified by sex, menopausal status, and disease duration.

Results: In the full multivariable model (non-robust estimates), breathing problems (OR 2.49 [95% Conf. Interval: 1.42-4.38], p = 0.001), flu-like symptoms (OR 1.97 [1.14-3.42], p = 0.015), and temperature-regulation disorders (OR 1.97 [1.10-3.51], p = 0.021) independently predicted muscle problems. A reduced physiological model (not-robust estimates) additionally identified cardiovascular symptoms (OR 1.87 [1.09-3.24], p = 0.024) as a significant predictor. Tetrachoric correlations demonstrated substantial latent associations between muscle problems and breathing difficulties (ρ = 0.52), cardiovascular symptoms (ρ = 0.49), temperature-regulation disorders (ρ = 0.49), visual disturbances (ρ = 0.39), and flu-like symptoms (ρ = 0.39). Factor analysis and SEM supported a single latent physiological dysregulation factor with good model fit (RMSEA = 0.046, CFI = 0.971, TLI = 0.952, SRMR = 0.026).

The sex-stratified analyses revealed differences in the pattern of statistically significant symptom associations across the subgroups. However, the overall test of the symptom-by-sex interaction terms did not provide evidence for a statistically established difference in the symptom associations by sex. Thus, the subgroup-specific patterns should primarily be interpreted as descriptive and exploratory. At the individual symptom level, the association between breathing-related symptoms and muscle problems showed a statistically significant interaction with sex, suggesting that this association may differ between women and men. However, this finding should be interpreted cautiously given the non-significant overall interaction test and the wide confidence interval of the interaction estimate.

In women, all five physiological symptoms independently predicted muscle problems, whereas in men only breathing problems and temperature-regulation disorders remained significant. Women classified as premenopausal and postmenopausal based on an age-defined proxy showed different patterns of symptom associations with muscle problems in subgroup-specific analyses. Women in the premenopausal age-proxy group showed significant associations with cardiovascular symptoms, visual disturbances, and temperature-regulation disorders, whereas women classified as postmenopausal showed significant associations with breathing difficulties and flu-like symptoms. However, the overall menopausal-by-symptom interaction was not statistically significant (Wald χ2 (5)=5.96, p = 0.310).

The specified latent physiological factor showed statistical comparability across the cross-sectional disease-duration groups. Gastrointestinal complaints loaded substantially on the latent factor despite lacking an independent association with muscle problems in multivariable regression. Urogenital symptoms also showed a smaller but significant association with the latent factor and substantial item-specific variance.

Conclusions: Muscle symptoms may represent a candidate integrative symptom within a latent physiological symptom-dysregulation factor encompassing respiratory, cardiovascular, thermoregulatory, visual, and flu-like symptoms in this ME/CFS sample. Secondary analyses suggested that gastrointestinal complaints were also part of the broader physiological symptom pattern, although they were not independently associated with muscle problems. The specified latent physiological factor showed no overall statistical evidence of measurement differences across the cross-sectional disease-duration groups. However, subgroup-specific symptom patterns differed descriptively by sex and age-defined menopausal-status proxy group.

Women classified as premenopausal were characterized primarily by cardiovascular, visual, and thermoregulatory symptom associations, whereas women classified as postmenopausal and men showed greater prominence of breathing-related symptoms. Flu-like symptoms were independently associated with muscle problems in the postmenopausal subgroup but not in the premenopausal subgroup. Because the corresponding interaction term was not statistically significant, this subgroup contrast should be interpreted as an exploratory difference in association rather than as evidence of a menopause-specific effect. More broadly, the findings are compatible with the hypothesis that the latent symptom-dysregulation factor may reflect a chronic PEM-associated multisystem response.

Whether this symptom-dysregulation factor corresponds to interacting autonomic, vascular, immunological, and metabolic processes remains to be determined by longitudinal and biomarker-based studies. ME/CFS phenotyping may improve patient stratification and facilitate the development of mechanism-based therapeutic approaches.

Source: Habermann-Horstmeier L, Horstmeier LM. Muscle symptoms and a latent physiological symptom-dysregulation factor in ME/CFS: exploratory analyses by sex and age-defined menopausal-status proxy group. J Transl Med. 2026 Sep 28;24(1):1216. doi: 10.1186/s12967-026-09018-9. PMID: 42806383. https://link.springer.com/article/10.1186/s12967-026-09018-9 (Full text)

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)

PTPRN2 hypomethylation and PHB2-associated miR-153-3p maturation define dual epigenetic features linked to symptom variability in Myalgic encephalomyelitis

Abstract:

Background: Myalgic encephalomyelitis (ME) is a chronic, debilitating condition increasingly linked to epigenetic changes. With its unclear pathophysiology and no validated diagnostic biomarkers, DNA methylation becomes of interest. Specifically, DNA methylation patterns in saliva, to study ME-related epigenetic changes.

Methods: Saliva samples from 54 ME patients and 21 sedentary healthy controls were analyzed by DNA methylation array. Symptom assessment was conducted using validated questionnaires (SF-36, MFI-20, and DSQ).

Results: A significant DNA hypomethylation at the CpG site cg19803194 (Bonferroni-corrected and adjusted for saliva composition, p = 2.14 × 10− 7) within the PTPRN2 gene body was identified. This hypomethylation was associated with cognitive impairments in both sexes, such as difficulties expressing thoughts and comprehension, commonly known as “brain fog,” and respiratory symptoms in male patients. The hypomethylation also corresponded with reduced circulating levels of miR-153-3p, an intronic microRNA of PTPRN2, which was associated with impaired memory recall in both sexes. Interestingly, the mitochondrial protein Prohibitin 2 (PHB2) was associated with reduced miR-153-3p activity. This association was consistent with a predominant cytoplasmic localization of PHB2 and selective reduction of mature miR-153-3p without changes in its immature forms, suggesting involvement at a post-transcriptional stage that may be attenuated in female patients due to increased extracellular export of PHB2.

Conclusions: These findings suggest a potential epigenetic relationship in ME involving PTPRN2 body hypomethylation and PHB2-associated variation in miR-153-3p levels. While the directionality between gene-body methylation and expression remains a biological hypothesis, these results shed light on potential molecular pathways associated with symptom variability and sex differences in ME severity.

Source: Chalder L, Elremaly W, Li D, Fang Y, Caraus I, Leveau C, Elbakry M, Franco A, Godbout C, Di Tomasso G, Nepotchatykh E, Rostami-Afshari B, Gimenez M, Legault P, Moreau A. PTPRN2 hypomethylation and PHB2-associated miR-153-3p maturation define dual epigenetic features linked to symptom variability in Myalgic encephalomyelitis. J Transl Med. 2026 Apr 20. doi: 10.1186/s12967-026-08162-6. Epub ahead of print. PMID: 42010606. https://link.springer.com/article/10.1186/s12967-026-08162-6 (Full text available as PDF file)

Temporal dynamics of the plasma proteomic landscape reveals maladaptation in ME/CFS following exertion

Abstract:

The overarching symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is post-exertional malaise (PEM), an exacerbation of symptoms following physical or mental exertion. To investigate the molecular underpinnings of PEM, we performed longitudinal plasma proteomics using the Somascan® 7K aptamer-based assay to monitor 6,361 unique plasma proteins in 132 individuals (96 females and 36 males) subjected to two maximal cardiopulmonary exercise tests separated by a 24-hour recovery period.

The cohort included 79 ME/CFS cases compared to 53 age- and BMI-matched sedentary controls, allowing us to distinguish disease-specific molecular alterations from those due to physical deconditioning. Longitudinal profiling revealed widespread proteomic changes following exertion, with the most pronounced alterations observed in ME/CFS participants during the recovery phase, coinciding with the onset of PEM.

Compared to controls, ME/CFS subjects showed persistent dysregulation of immune, metabolic, and neuromuscular pathways. Key findings included suppression of T and B cell signaling, downregulation of IL-17 and cell-cell communication pathways, and upregulation of glycolysis/gluconeogenesis, suggestive of mitochondrial stress and impaired immune recovery from exercise. Proteomic associations with physiological performance (VO2max, anaerobic threshold) revealed disruptions between protein abundance and exercise capacity in ME/CFS versus controls.

Correlations with symptom severity linked changes in immune-related proteins and ME/CFS symptoms including muscle pain, recurrent sore throat, and lymph node tenderness. Sex-stratified analyses revealed distinct molecular responses between females and males, emphasizing the importance of considering sex as a biological variable in ME/CFS research.

Finally, our analysis of sedentary controls contributes new data of molecular responses to acute exertion in a predominantly female sedentary cohort, a population historically underrepresented in exercise physiology studies. Together, these findings underscore the value of dynamic, proteomic profiling over time for characterizing maladaptive responses to exertion in ME/CFS and provide a foundation for deeper mechanistic investigation into PEM.

Source: Germain A, Glass KA, Eckert MA, Giloteaux L, Hanson MR. Temporal dynamics of the plasma proteomic landscape reveals maladaptation in ME/CFS following exertion. Mol Cell Proteomics. 2025 Nov 12:101467. doi: 10.1016/j.mcpro.2025.101467. Epub ahead of print. PMID: 41237904. https://www.mcponline.org/article/S1535-9476(25)00566-3/fulltext (Full text)

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)

Fatigue, interoplastic and nociplastic distress in myalgic encephalomyelitis/chronic fatigue syndrome, Gulf War Illness, and chronic idiopathic fatigue

Abstract:

Introduction: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Gulf War Illness (GWI) have similar profiles of pain (nociception), visceral interoception, and tenderness (central sensitization) that may be due to dysfunction of midbrain and medulla descending antinociceptive and antiinteroceptive mechanisms. If so, then dolorimetry, a proxy for tenderness, may be correlated with subjective symptoms. The relationship with fatigue was assessed in Chronic Idiopathic Fatigue (CIF).

Methods: Cohorts of ME/CFS, GWI, and sedentary control subjects completed questionnaires and had dolorimetry. Spearman correlations were calculated between central sensitization (dolorimetry), fatigue (Chalder Fatigue), pain (McGill Pain), interoception (Chronic Multisymptom Inventory), disability (SF36), psychological constructs, and other symptoms. Females were more tender than males and were thus analyzed separately.

Results: GWI and ME/CFS groups were more tender than controls for females (p < 0.0045) and males (p < 10-6). Receiver operating characteristics area under the curve for female ME/CFS (0.730) and GWI (0.792) and male ME/CFS (0.816) and GWI (0.831) were not optimal for diagnostic purposes. Pain and interoception were highly correlated. Dolorimetry correlated better with pain (Spearman R = -0.574 to -0.629) than interoception (R = -0.417 to -0.545) questionnaires. Dolorimetry correlated weakly with fatigue and disability (|R| < 0.42). CIF was defined by receiver operating characteristics with elevated fatigue, postexertional malaise, and reduced vitality. CIF had intermediate tenderness.

Discussion: The outcomes generate several hypotheses about ME/CFS and GWI pathophysiology. Disease pathologies may involve injury to midbrain and medulla regulatory pathways causing central sensitization with the loss of descending antiinteroceptive and antinociceptive inhibitory mechanisms and increased perceptions of widespread visceral complaints and pain. The diseases can be re-conceptualized as chronic disabling fatigue with heightened interoceptive and nociceptive symptoms. Variations in antiinteroceptive control may provoke unpredictable shifts in symptom spectrum and severity that contribute to exertional exhaustion and symptom exacerbation. Subjective criteria were found to define CIF prospectively.

Source: Chen E, Rudder T, Nwankwere C, Baraniuk JN. Fatigue, interoplastic and nociplastic distress in myalgic encephalomyelitis/chronic fatigue syndrome, Gulf War Illness, and chronic idiopathic fatigue. Front Neurosci. 2025 Aug 25;19:1530652. doi: 10.3389/fnins.2025.1530652. PMID: 40927423; PMCID: PMC12415031. https://pmc.ncbi.nlm.nih.gov/articles/PMC12415031/ (Full text)

Mitochondrial function is impaired in long COVID patients

Abstract:

Background: The Long COVID syndrome is a major global health problem, affecting approximately 10–20% of individuals infected with SARS-CoV-2 virus with many remaining symptomatic beyond one year. Fatigue, reduced exercise tolerance and hyperlactataemia on minimal exertion have led to the suggestion of a bioenergetic defect. We hypothesised that mitochondrial dysfunction is a pathological feature in Long COVID cases and would correlate with clinical outcome.

Methods: This prospective, case-controlled, observational study recruited 27 participants with an established diagnosis of Long COVID syndrome from a single tertiary clinic together with 16 age-matched controls aged 25–65 years. Seahorse-based mitochondrial flux analysis and bioenergetics profile of isolated peripheral blood mononuclear cells (PBMCs) was performed and correlated with clinical phenotype.

Findings: Long COVID cases had an increased baseline and ATP-induced oxygen consumption rate with a significant attenuation in tetramethylrhodamine methyl ester perchlorate fluorescence response to oligomycin. Correlations were observed between mitochondrial function and autonomic health, quality of life and time from index infection. Sex-specific differences were also observed.

Interpretation: PBMCs from Long COVID subjects exhibit an exceptional and distinctive change in ATP synthase, as it contributes to the mitochondrial membrane potential rather than using it exclusively to generate ATP. The findings suggest that the enzyme runs both forward and reverse reactions, synthesising and hydrolysing ATP. The correlation of mitochondrial function with clinical phenotype in Long COVID may indicate a causal relationship and warrants further validation in larger scale studies.

Source: Macnaughtan, J., Chau, K. Y., Brennan, E., Toffoli, M., Spinazzola, A., Hillman, T., … Schapira, A. H. V. (2025). Mitochondrial function is impaired in long COVID patients. Annals of Medicine, 57(1). https://doi.org/10.1080/07853890.2025.2528167 https://www.tandfonline.com/doi/full/10.1080/07853890.2025.2528167 (Full text)

PASC (Post Acute Sequelae of COVID-19) is associated with decreased neutralizing antibody titers in both biological sexes and increased ANG-2 and GM-CSF in females

Abstract:

Post-acute sequelae of COVID-19 (PASC) or the continuation of COVID-19 (Coronavirus disease 2019) symptoms past 12 weeks may affect as many as 30% of people recovering from a SARS-CoV-2 (severe acute respiratory coronavirus 2) infection. The mechanisms regulating the development of PASC are currently not known; however, hypotheses include virus reservoirs, pre-existing conditions, microblood clots, immune dysregulation, as well as poor antibody responses. Importantly, virus neutralizing antibodies are essential for COVID-19 recovery and protection from reinfection but there is currently limited information on these immune regulators and associated cytokines in PASC patients. Understanding the key drivers of general and specific symptoms associated with Long COVID and the presence of virus neutralizing antibodies in PASC will aid in the development of therapeutics, diagnostics, and vaccines which currently do not exist.

We designed a cross-sectional study to investigate systemic antibody and cytokine responses during COVID-19 recovery and PASC. In total, 195 participants were recruited in one of four groups: (1) Those who never had COVID-19 (No COVID); (2) Those in acute COVID-19 recovery (Acute Recovery) (4–12 weeks post infection); (3) Those who recovered from COVID-19 (Recovered) (+ 12 weeks from infection); and (4) those who had PASC (PASC) (+ 12 weeks from infection). Participants completed a questionnaire on health history, sex, gender, demographics, experiences with COVID-19 acute and COVID-19 recovery/continuing symptoms. Serum samples collected were evaluated for antibody binding to viral proteins, virus neutralizing antibody titers, and serum cytokine levels using Ella SimplePlex Immunoassay™ panels.

We found participants with PASC reported more pre-existing conditions (e.g. such as hypertension, asthma, and obesity), and PASC symptoms (e.g. fatigue, brain fog, headaches, and shortness of breath) following COVID-19 than COVID-19 Recovered individuals. Importantly, we found PASC individuals to have significantly decreased levels of neutralizing antibodies toward both SARS-CoV-2 and the Omicron BA.1 variant. Sex analysis indicated that female PASC study participants had sustained antibody levels as well as levels of the inflammatory cytokines GM-CSF and ANG-2 over time following COVID-19.

Our study reports people experiencing PASC had lower levels of virus neutralizing antibodies; however, the results are limited by the collection time post-COVID-19 and post-vaccination. Moreover, we found females experiencing PASC had sustained levels of GM-CSF and ANG-2. With lower levels of virus neutralizing antibodies, this data suggests that PASC individuals not only have had a suboptimal antibody response during acute SARS-CoV-2 infection but may also have increased susceptibility to subsequent infections which may exacerbate or prolong current PASC illnesses. We also provide evidence suggesting GM-CSF and ANG-2 to play a role in the sex-bias of PASC. Taken together, our findings maybe important for understanding immune molecular drivers of PASC and PASC subgroups.

Source: Jansen EB, Ostadgavahi AT, Hewins B, Buchanan R, Thivierge BM, Sganzerla Martinez G, Goncin U, Francis ME, Swan CL, Scruten E, Bell J, Darbellay J, Facciuolo A, Falzarano D, Gerdts V, Fenton ME, Hedlin P, Kelvin DJ, Kelvin AA. PASC (Post Acute Sequelae of COVID-19) is associated with decreased neutralizing antibody titers in both biological sexes and increased ANG-2 and GM-CSF in females. Sci Rep. 2024 Apr 29;14(1):9854. doi: 10.1038/s41598-024-60089-4. PMID: 38684819; PMCID: PMC11058778. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11058778/ (Full text)

The Effect of Sex on the Risk of Long-COVID and Cardiovascular Complications in Healthy Patients without Comorbidities: Data from a Polish Long-COVID Cardiovascular (PoLoCOV-CVD) Study

Abstract:

Background: The prevalence of long-COVID (LC) presents a significant challenge to healthcare systems globally. There are still some discrepancies on the role of sex as an independent risk factor of LC complications. Thus, we aimed to determine the differences in clinical and cardiovascular complications between males and females without comorbidities after COVID-19.
Methods: Clinical data on the course of the disease with the accompanying symptoms and post-COVID-19 symptoms were compiled from both male and female subjects with a minimum 12-week interval after COVID-19 recovery. Next, the patients were followed for 12 months. ECG, echocardiography, 24 h ECG monitoring, 24 h ambulatory blood pressure monitoring (ABPM), and selected biochemical tests were performed. LC was diagnosed based on the World Health Organization (WHO) definition. To reduce the impact of confounders, i.e., body mass index (BMI) and age, on the results of the study, the nearest neighbour (NN) propensity score matching (PSM) method with a 1:1 ratio was used.
Results: The results were obtained following the removal of cases with comorbidities from the database consisting of 1237 males and 2192 females, and PSM of the new database included 886 cases (443 males and 443 females). At both the 3-month and 1-year post-recovery marks, females consistently reported a higher frequency of LC symptoms compared to males (p < 0.001 for both comparisons). Moreover, after 1 year of follow-up, females exhibited a higher prevalence of LC compared to males, with rates of 14% versus 8.3%, respectively (p = 0.013).
The symptoms that significantly differed between females and males in the 12-month follow-up were hair loss (5.4 vs. 0.7%, p < 0.001), memory and concentration disturbances (8.4 vs. 4.3%, p = 0.013), and headaches (4.3 vs. 1.4%, p = 0.008). Females presented lower mean arterial pressure (MAP) [89 (83–95) mmHg versus (vs.) 94 (89–100); p < 0.001] and lower pulse pressure (PP) [46 (42–52) mmHg vs. 51 (48–57); p < 0.001] in 24 h ABPM and more elevated heart rates (HRs) in 24 h ECG monitoring as well as arrhythmia (p < 0.001 and p = 0.018, respectively). Males had a higher occurrence of ECG abnormalities such as QRS >= 120 ms, ST-T changes, T inversion, arrhythmia, and QRS fragmentation (27.3% vs. 19.2%; p = 0.004). No significant differences were observed between males and females concerning physical activity levels, stress, fatigue, alcohol consumption, and smoking habits.
Conclusions: One year post-COVID-19 recovery, regardless of age and BMI, healthy females more often suffered from LC symptoms than males. They had lower MAP and PP in 24 h ABPM, more often had higher HRs and arrhythmia in 24 h ECG monitoring, and fewer ECG abnormalities than males.
Source: Bielecka-Dabrowa A, Sakowicz A, Gryglewska-Wawrzak K, Kapusta J, Banach M, Jankowski P, Chudzik M. The Effect of Sex on the Risk of Long-COVID and Cardiovascular Complications in Healthy Patients without Comorbidities: Data from a Polish Long-COVID Cardiovascular (PoLoCOV-CVD) Study. Journal of Clinical Medicine. 2024; 13(6):1559. https://doi.org/10.3390/jcm13061559 https://www.mdpi.com/2077-0383/13/6/1559 (Full text)

Sex differences in symptomatology and immune profiles of Long COVID

Abstract:

Strong sex differences in the frequencies and manifestations of Long COVID (LC) have been reported with females significantly more likely than males to present with LC after acute SARS-CoV-2 infection1-7. However, whether immunological traits underlying LC differ between sexes, and whether such differences explain the differential manifestations of LC symptomology is currently unknown.

Here, we performed sex-based multi-dimensional immune-endocrine profiling of 165 individuals8 with and without LC in an exploratory, cross-sectional study to identify key immunological traits underlying biological sex differences in LC.

We found that female and male participants with LC experienced different sets of symptoms, and distinct patterns of organ system involvement, with female participants suffering from a higher symptom burden. Machine learning approaches identified differential sets of immune features that characterized LC in females and males. Males with LC had decreased frequencies of monocyte and DC populations, elevated NK cells, and plasma cytokines including IL-8 and TGF-β-family members.

Females with LC had increased frequencies of exhausted T cells, cytokine-secreting T cells, higher antibody reactivity to latent herpes viruses including EBV, HSV-2, and CMV, and lower testosterone levels than their control female counterparts. Testosterone levels were significantly associated with lower symptom burden in LC participants over sex designation.

These findings suggest distinct immunological processes of LC in females and males and illuminate the crucial role of immune-endocrine dysregulation in sex-specific pathology.

Source: Julio Silva, Takehiro Takahashi, Jamie Wood, Peiwen Lu, Sasha Tabachnikova, Jeffrey Gehlhausen, Kerrie Greene, Bornali Bhattacharjee, Valter Silva Monteiro, Carolina Lucas, Rahul Dhodapkar, Laura Tabacof, Mario Pena-Hernandez, Kathy Kamath, Tianyang Mao, Dayna Mccarthy, Ruslan Medzhitov, David van Dijk, Harlan Krumholz, Leying Guan, David Putrino, Akiko Iwasaki. Sex differences in symptomatology and immune profiles of Long COVID. medRxiv 2024.02.29.24303568; doi: https://doi.org/10.1101/2024.02.29.24303568 https://www.medrxiv.org/content/10.1101/2024.02.29.24303568v1 (Full study available as PDF file)