Tag: risk factors

Causal Effects between Gut Microbiome and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Two-Sample Mendelian Randomization Study

Abstract:

Background: Evidence from previous studies have implicated an important association between gut microbiota (GM) and Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS), but whether there is a definite causal relationship between GM and ME/CFS has not been elucidated.

Method: This study obtained instrumental variables of 211 GM taxa from the Genome Wide Association Study (GWAS), and mendelian randomization (MR) study was carried out to assess the effect of gut microbiota on ME/CFS risk from UK Biobank GWAS (2076 ME/CFS cases and 460857 controls). Inverse variance weighted (IVW) was the primary method to analyze causality in this study, and a series of sensitivity analyses was performed to validate the robustness of the results.

The inverse variance weighted (IVW) method indicated that genus Paraprevotella (OR:1.001, 95%CI:1.000-1.003, p-value<0.05) and Ruminococca-ceae_UCG_014(OR 1.003, 95% CI 1.000 to 1.005, p-value < 0.05) were positively associated with ME/CFS risk. Results from the weighted median method supported genus Paraprevotella (OR 1.003, 95% CI 1.000 to 1.005, p-value < 0.05) as a risk factor for ME/CFS.

Conclusions: This study reveals a causal relationship between genus.paraprevotella, genus.Ruminococcaceae_UCG_014 and ME/CFS, and our findings provide novel insights for further elucidating the developmental mechanisms mediated by the gut microbiota of ME/CFS.

Source: Gang He, Yu Cao, Wangzi Xu and Houzhao Wang. Causal Effects between Gut Microbiome and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Two-Sample Mendelian Randomization Study. Front. Microbiol. Volume 14 – 2023 | doi: 10.3389/fmicb.2023.1190894 https://www.frontiersin.org/articles/10.3389/fmicb.2023.1190894/abstract

Socioeconomic determinants of myalgic encephalomyelitis/chronic fatigue syndrome in Norway: a registry study

Abstract:

Background:

Previous research has shown that socioeconomic status (SES) is a strong predictor of chronic disease. However, to the best of our knowledge, there has been no studies of how SES affects the risk of Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) that has not been based upon self-reporting or retrospectively screening of symptoms. As far as we know, this is therefore the first study that isolate and describe socioeconomic determinants of ME/CFS and calculate how these factors relate to the risk of ME/CFS diagnosis by utilizing individual level registry data, which allows for objective operationalization of the ME/CFS population, and the utilization of different control groups.

Data and methods: We utilize health registry data from all adult patients diagnosed with ME/CFS from 2016-2018 in Norway, coupled with socioeconomic data from statistics Norway from 2009-2018. We operationalize SES as household income and educational attainment fixed at the beginning of the study period. We compare the effects of SES on the risk of ME/CFS diagnosis to a population of patients with hospital diagnoses that share clinical characteristics of ME/CFS and a healthy random sample of the Norwegian population. Our models are estimated by logistic regression analyses.Results: When comparing the risk of ME/CFS diagnosis with a population consisting of people with four specific chronic diseases, we find that high educational attainment is associated with a 19% increase (OR: 1.19) in the risk of ME/CFS and that high household income is associated with a 18% increase (OR:0.82) in risk of ME/CFS. In model 2, when comparing with a healthy population sample, we find that low educational attainment is associated with 69% decrease (OR:0.31) in the risk of ME/CFS and that low household income is associated with a 53% increase (OR: 1.53).

Conclusion: We find statistically significant associations between SES and the risk of ME/CFS. However, our more detailed analyses shows that our findings vary according to which population we compare the ME/CFS patients with, and that the effect of SES is larger when comparing with a healthy population sample, as opposed to controls with selected hospital diagnoses.

Source: Hilland GH, Anthun KS. Socioeconomic determinants of myalgic encephalomyelitis/chronic fatigue syndrome in Norway: a registry study. Research Square; 2023. DOI: 10.21203/rs.3.rs-2755999/v1. https://europepmc.org/article/ppr/ppr646979 (Full text available as PDF file)

Natural killer cytotoxicity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a multi-site clinical assessment of ME/CFS (MCAM) sub-study

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystem illness characterized by substantial reduction in function accompanied by profound unexplained fatigue not significantly relieved by rest, post-exertional malaise, and other symptoms. Reduced natural killer (NK) cell count and cytotoxicity has been investigated as a biomarker for ME/CFS, but few clinical laboratories offer the test and multi-site verification studies have not been conducted.

Methods: We determined NK cell counts and cytotoxicity in 174 (65%) ME/CFS, 86 (32%) healthy control (HC) and 10 (3.7%) participants with other fatigue associated conditions (ill control [IC]) from the Multi-Site Clinical Assessment of ME/CFS (MCAM) study using an assay validated for samples shipped overnight instead of testing on day of venipuncture.

Results: We found a large variation in percent cytotoxicity [mean and (IQR) for ME/CFS and HC respectively, 34.1% (IQR 22.4-44.3%) and 33.6% (IQR 22.9-43.7%)] and no statistically significant differences between patients with ME/CFS and HC (p-value = 0.79). Analysis stratified on illness domain measured with standardized questionnaires did not identify an association of NK cytotoxicity with domain scores. Among all participants, NK cytotoxicity was not associated with survey results of physical and mental well-being, or health factors such as history of infection, obesity, smoking, and co-morbid conditions.

Conclusion: These results indicate this assay is not ready for clinical implementation and studies are needed to further explore immune parameters that may be involved in the pathophysiology of ME/CFS.

Source: Querec TD, Lin JS, Chen Y, Helton B, Kogelnik AM, Klimas NG, Peterson DL, Bateman L, Lapp C, Podell RN, Natelson BH, Unger ER; MCAM Study Group. Natural killer cytotoxicity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a multi-site clinical assessment of ME/CFS (MCAM) sub-study. J Transl Med. 2023 Apr 3;21(1):242. doi: 10.1186/s12967-023-03958-2. PMID: 37013608. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-03958-2 (Full text)

Towards a Better Understanding of the Complexities of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex condition arising in susceptible people, predominantly following viral infection, but also other stressful events. The susceptibility factors discussed here are both genetic and environmental although not well understood.

While the dysfunctional physiology in ME/CFS is becoming clearer, understanding has been hampered by different combinations of symptoms in each affected person.

A common core set of mainly neurological symptoms forms the modern clinical case definition, in the absence of an accessible molecular diagnostic test. This landscape has prompted interest in whether ME/CFS patients can be classified into a particular phenotype/subtype that might assist better management of their illness and suggest preferred therapeutic options.

Currently, the same promising drugs, nutraceuticals, or behavioral therapies available can be beneficial, have no effect, or be detrimental to each individual patient. We have shown that individuals with the same disease profile exhibit unique molecular changes and physiological responses to stress, exercise and even vaccination.

Key features of ME/CFS discussed here are the possible mechanisms determining the shift of an immune/inflammatory response from transient to chronic in ME/CFS, and how the brain and CNS manifests the neurological symptoms, likely with activation of its specific immune system and resulting neuroinflammation.

The many cases of the post viral ME/CFS-like condition, Long COVID, following SARS-CoV-2 infection, and the intense research interest and investment in understanding this condition, provide exciting opportunities for the development of new therapeutics that will benefit ME/CFS patients.

Source: Tate WP, Walker MOM, Peppercorn K, Blair ALH, Edgar CD. Towards a Better Understanding of the Complexities of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID. International Journal of Molecular Sciences. 2023; 24(6):5124. https://doi.org/10.3390/ijms24065124 (Full text)

Presence of depression and anxiety with distinct patterns of pharmacological treatments before the diagnosis of chronic fatigue syndrome: a population-based study in Taiwan

Abstract:

Objective: An increased prevalence of psychiatric comorbidities (including depression and anxiety disorder) has been observed among patients with chronic fatigue syndrome (CFS). However, few studies have examined the presence of depression and anxiety disorder before the diagnosis of CFS. This study aimed to clarify the preexisting comorbidities and treatments associated with patients with subsequent CFS diagnosis in a population-based cohort in Taiwan.

Methods: An analysis utilizing the National Health Insurance Research Database of Taiwan was conducted. Participants included were 6303 patients with CFS newly diagnosed between 2000 and 2010 and 6303 age-/sex-matched controls.

Results: Compared with the control group, the CFS group had a higher prevalence of depression and anxiety disorder before the diagnosis of CFS. Sampled patients who took specific types of antidepressants, namely, selective serotonin reuptake inhibitors (adjusted odds ratio [aOR] = 1.21, 95% confidence interval [CI] 1.04-1.39), serotonin antagonists and reuptake inhibitors (SARI; aOR = 1.87, 95% CI 1.59-2.19), and tricyclic antidepressants (aOR = 1.46, 95% CI 1.09-1.95), had an increased risk of CFS. CFS risk was also higher among participants taking benzodiazepine, muscle relaxants, and analgesic drugs.

A sub-group analysis revealed that SARI use was related to an increased risk of CFS in the depression, anxiety disorder, male, and female groups. In the depression and anxiety disorder groups, analgesic drug use was associated with an increased CFS risk. Nonpharmacological treatment administration differed between men and women.

Conclusion: This population-based retrospective cohort study revealed an increased risk of CFS among populations with preexisting depression and anxiety disorder, especially those taking SARI and analgesic drugs.

Source: Chen C, Yip HT, Leong KH, Yao WC, Hung CL, Su CH, Kuo CF, Tsai SY. Presence of depression and anxiety with distinct patterns of pharmacological treatments before the diagnosis of chronic fatigue syndrome: a population-based study in Taiwan. J Transl Med. 2023 Feb 8;21(1):98. doi: 10.1186/s12967-023-03886-1. PMID: 36755267; PMCID: PMC9907887. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9907887/ (Full text)

Different risk factors distinguish myalgic encephalomyelitis/chronic fatigue syndrome from severe fatigue

Abstract:

Fatigue is a common reason that patients seek medical care. Only a fraction of these patients meet criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). To determine if ME/CFS is just a more extreme form of fatigue, or a qualitatively different condition, we assessed whether risk factors for ME/CFS and for Severe Fatigue were similar.

An email questionnaire that inquired about symptoms of Severe Fatigue and ME/CFS was completed by 41,802 US female nurses from whom detailed medical and lifestyle information had been collected since 1989: 102 met criteria for ME/CFS, 522 had Severe Fatigue, and 41,178 individuals were without significant chronic fatigue.

We used Cox proportional hazards regression to estimate the Hazard Ratio (HR) of Severe Fatigue and of ME/CFS with each of several potential risk factors, according to the level of exposure to each risk factor. The risk of Severe Fatigue was significantly increased among participants who were older, had a higher BMI in adulthood, used hormone therapy, had increased alcohol intake and decreased caffeine intake.

In contrast, these risk factor associations were not seen in people with ME/CFS. A self-reported past history of acute infectious mononucleosis was associated with a non-significantly increased Hazard Ratio of later ME/CFS (HR 1.77, 0.87–3.61) and, to a lesser extent, of Severe Fatigue (HR 1.28, 0.98–1.66). The different contribution of various risk factors to Severe Fatigue and ME/CFS suggests that ME/CFS has a qualitatively different underlying biology from the more common state of Severe Fatigue.

Source: Palacios, N., Molsberry, S., Fitzgerald, K.C. et al. Different risk factors distinguish myalgic encephalomyelitis/chronic fatigue syndrome from severe fatigue. Sci Rep 13, 2469 (2023). https://doi.org/10.1038/s41598-023-29329-x https://www.nature.com/articles/s41598-023-29329-x (Full text)

Saliva antibody-fingerprint of reactivated latent viruses after mild/asymptomatic COVID-19 is unique in patients with myalgic-encephalomyelitis/chronic fatigue syndrome

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic disease considered to be triggered by viral infections in a majority of cases. Symptoms overlap largely with those of post-acute sequelae of COVID-19/long-COVID implying common pathogenetic mechanisms. SARS-CoV-2 infection is risk factor for sustained latent virus reactivation that may account for the symptoms of post-viral fatigue syndromes. The aim of this study was first to investigate whether patients with ME/CFS and healthy donors (HDs) differed in their antibody response to mild/asymptomatic SARS-CoV-2 infection. Secondly, to analyze whether COVID-19 imposes latent virus reactivation in the cohorts.

Methods: Anti-SARS-CoV-2 antibodies were analyzed in plasma and saliva from non-vaccinated ME/CFS (n=95) and HDs (n=110) using soluble multiplex immunoassay. Reactivation of human herpesviruses 1-6 (HSV1, HSV2, VZV, EBV, CMV, HHV6), and human endogenous retrovirus K (HERV-K) was detected by anti-viral antibody fingerprints in saliva.

Results: At 3-6 months after mild/asymptomatic SARS-CoV-2 infection, virus-specific antibodies in saliva were substantially induced signifying a strong reactivation of latent viruses (EBV, HHV6 and HERV-K) in both cohorts. In patients with ME/CFS, antibody responses were significantly stronger, in particular EBV-encoded nuclear antigen-1 (EBNA1) IgG were elevated in patients with ME/CFS, but not in HDs. EBV-VCA IgG was also elevated at baseline prior to SARS-infection in patients compared to HDs.

Conclusion: Our results denote an altered and chronically aroused anti-viral profile against latent viruses in ME/CFS. SARS-CoV-2 infection even in its mild/asymptomatic form is a potent trigger for reactivation of latent herpesviruses (EBV, HHV6) and endogenous retroviruses (HERV-K), as detected by antibody fingerprints locally in the oral mucosa (saliva samples). This has not been shown before because the antibody elevation is not detected systemically in the circulation/plasma.

Source: Apostolou Eirini, Rizwan Muhammad, Moustardas Petros, Sjögren Per, Bertilson Bo Christer, Bragée Björn, Polo Olli, Rosén Anders. Saliva antibody-fingerprint of reactivated latent viruses after mild/asymptomatic COVID-19 is unique in patients with myalgic-encephalomyelitis/chronic fatigue syndrome. Frontiers in Immunology, Vol 13, 2022. https://www.frontiersin.org/articles/10.3389/fimmu.2022.949787/full (Full text)

Risk of long COVID associated with delta versus omicron variants of SARS-CoV-2

The omicron variant of SARS-CoV-2 (PANGO B.1.1.529) spread rapidly across the world, out-competing former variants soon after it was first detected in November, 2021. According to the Our World in Data COVID-19 database, In Europe, the number of confirmed cases reported between December, 2021, and March, 2022 (omicron period) has exceeded all previously reported cases. Omicron appears to cause less severe acute illness than previous variants, at least in vaccinated populations. However, the potential for large numbers of people to experience long-term symptoms is a major concern, and health and workforce planners need information urgently to appropriately scale resource allocation.
In this case-control observational study, we set out to identify the relative odds of long-COVID (defined following the National Institute for Health and Care Excellence guidelines as having new or ongoing symptoms 4 weeks or more after the start of acute COVID-19) in the UK during the omicron period compared with the delta period. We used self-reported data from the COVID Symptom Study app. (King’s College London Research Ethics Management Application System number 18210, reference LRS-19/20-18210). Data were extracted and pre-processed using ExeTera13 (version 0.5.5).
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Source: Antonelli M, Pujol JC, Spector TD, Ourselin S, Steves CJ. Risk of long COVID associated with delta versus omicron variants of SARS-CoV-2. Lancet. 2022 Jun 18;399(10343):2263-2264. doi: 10.1016/S0140-6736(22)00941-2. PMID: 35717982; PMCID: PMC9212672. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)00941-2/fulltext (Full text)

Increased risks of cancer and autoimmune disease among the first-degree relatives of patients with myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS)

Background: Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is a disabling multi-system complex disorder with prevalence of 875 per 100,000 (up to 3.4 million people) in the United States. There are no known etiologic or risk factors and no approved treatments for ME/CFS. We conducted a molecular epidemiologic study to test the hypothesis that ME/CFS may be an autoimmune disease (AID) and explore the link between ME/CFS and cancer, specifically hematologic malignancies.Methods: Our clinic-based study involved carefully selected cases with confirmed diagnosis of ME/CFS (n=59) and healthy controls (n=54) frequency matched to cases on age, gender and ethnicity. During structured interviews, detailed multi-generation pedigrees, epidemiologic and medical questionnaires, and biospecimen were obtained on all subjects. Statistical analysis of pedigree data involved comparison of cases and controls with respect to the prevalence and cumulative incidence of AID and cancer among their first-degree relatives. For unadjusted analysis, risk ratios, 95% confidence intervals (CI), and p-values were calculated. For age-adjusted analyses, cumulative incidence estimates were compared using the log-rank test.

Results: The prevalence of AID was significantly higher among the first-degree relatives of cases compared to those of controls (OR=5.30; 95%CI: 1.83-15.38; p=0.001). The prevalence of AID among mothers was 14% for cases and 1.9% for controls (p=0.03). 11.2% of the first-degree relatives of cases had an AID compared to 3.1% of the relatives of controls (prevalence ratio=3.71; 95% CI: 1.74-7.88; p=0.0007). The cumulative incidence of AID among the first-degree relatives of ME/CFS cases was 9.4% compared to 2.7% for those of the controls (p=0.0025). First-degree relatives of ME/CFS cases had a significantly higher prevalence of any cancer compared to the relatives of unrelated controls (OR=4.06, 95%CI: 1.84-8.96, p=0.0005). Age-adjusted analysis revealed significantly higher (p=0.03) cumulative incidence of any cancer among the first-degree relatives of cases (20%) compared to the relatives of controls (15.4%). The cumulative incidence of hematologic cancers was also significantly higher among the relatives of cases (p<0.05).

Conclusions: We found statistically significant increased risks of AID and cancer among the first-degree relatives of ME/CFS cases. Our findings implicate immune dysregulation as an underlying mechanism, providing etiologic clues and leads for prevention. Given symptomatic similarities between ‘long COVID’ and ME/CFS, it is predicted that there will be a significant increase in incidence of ME/CFS as the result of COVID-19 pandemic. Our findings may enable defining a subset of COVID-19 patients who could be at risk of developing ME/CFS, and who may benefit from treatments used for certain AIDs.

Source: Roxana Moslehi, Anil Kumar, Amiran Dzutsev. Increased risks of cancer and autoimmune disease among the first-degree relatives of patients with myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 34. https://aacrjournals.org/cancerres/article/82/12_Supplement/34/700144

 

Post-COVID Condition in Adults and Children Living in the Same Household in Italy: A Prospective Cohort Study Using the ISARIC Global Follow-Up Protocol

Abstract:

Background: Emerging evidence shows that both adults and children may develop post-acute sequelae of SARS-CoV-2 infection (PASC). The aim of this study is to characterise and compare long-term post-SARS-CoV-2 infection outcomes in adults and children in a defined region in Italy.

Methods: A prospective cohort study including children (≤18 years old) with PCR-confirmed SARS-CoV-2 infection and their household members. Participants were assessed via telephone and face-to-face visits up to 12 months post-SARS-CoV-2 diagnosis of household index case, using the ISARIC COVID-19 follow-up survey.

Results: Of 507 participants from 201 households, 56.4% (286/507) were children, 43.6% (221/507) adults. SARS-CoV-2 positivity was 87% (249/286) in children, and 78% (172/221) in adults. The mean age of PCR positive children was 10.4 (SD = 4.5) and of PCR positive adults was 44.5 years (SD = 9.5), similar to the PCR negative control groups [children 10.5 years (SD = 3.24), adults 42.3 years (SD = 9.06)]. Median follow-up post-SARS-CoV-2 diagnosis was 77 days (IQR 47-169). A significantly higher proportion of adults compared to children reported at least one persistent symptom (67%, 68/101 vs. 32%, 57/179, p < 0.001) at the first follow up. Adults had more frequently coexistence of several symptom categories at both follow-up time-points. Female gender was identified as a risk factor for PASC in adults (p 0.02 at 1-3 months and p 0.01 at 6-9 months follow up), but not in children. We found no significant correlation between adults and children symptoms. In the paediatric group, there was a significant difference in persisting symptoms between those with confirmed SARS-CoV-2 infection compared to controls at 1-3 months follow up, but not at 6-9 months. Conversely, positive adults had a higher frequency of persisting symptoms at both follow-up assessments.

Conclusion: Our data highlights that children can experience persistent multisystemic symptoms months after diagnosis of mild acute SARS-CoV-2 infection, although less frequently and less severely than co-habitant adults. There was no correlation between symptoms experienced by adults and children living in the same household. Our data highlights an urgent need for studies to characterise PASC in whole populations and the wider impact on families.

Source: Buonsenso D, Munblit D, Pazukhina E, Ricchiuto A, Sinatti D, Zona M, De Matteis A, D’Ilario F, Gentili C, Lanni R, Rongai T, Del Balzo P, Fonte MT, Valente M, Zampino G, De Rose C, Sigfrid L, Valentini P; FIMP-Roma. Post-COVID Condition in Adults and Children Living in the Same Household in Italy: A Prospective Cohort Study Using the ISARIC Global Follow-Up Protocol. Front Pediatr. 2022 Apr 21;10:834875. doi: 10.3389/fped.2022.834875. PMID: 35529336; PMCID: PMC9070551.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9070551/ (Full text)