Category: Etiology

Editorial: Current Insights Into Complex Post-infection Fatigue Syndromes With Unknown Aetiology: The Case of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Beyond

Introduction:

Black plague epidemics in Medieval Europe, the Spanish Flu pandemic during the first world war, and the pandemic of COVID-19 disease are just three devastating examples of the fragile co-existence between human beings and the microbial world. Remarkably, the human immune system with its innate and adaptive arms recognizes and clears the invading pathogens in most cases. However, like a scar after an injury, some people who had suffered from acute infections remain ill long after the clearance of the pathogen itself. These individuals develop complex fatigue-related syndromes whose pathological mechanisms remain poorly understood. A prime example of such syndromes is the Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) characterized by persistent fatigue and post-exertional malaise among other symptoms (1). Unfortunately, its diagnosis remains challenging due to the inexistence of objective biomarkers that could identify cases. However, researchers are gathering around multidisciplinary networks, such as the US ME/CFS Clinician Coalition and the European Network on ME/CFS, with the aim of fostering collaboration, standardizing research and clinical practices, while accelerating biomarker discovery (2–5). Less-known fatigue-related syndromes have been recently reported after the outbreaks of Ebola virus, Dengue virus, and Chikungunya virus in the Tropics (6–8). However, it is still unclear whether these syndromes constitute clinical entities beyond ME/CFS itself.

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Source: Westermeier F, Lacerda EM, Scheibenbogen C and Sepúlveda N (2022) Editorial: Current Insights Into Complex Post-infection Fatigue Syndromes With Unknown Aetiology: The Case of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Beyond. Front. Med. 9:862953. doi: 10.3389/fmed.2022.862953  https://www.frontiersin.org/articles/10.3389/fmed.2022.862953/full (Full text)

Prevalence of Aspergillus-Derived Mycotoxins (Ochratoxin, Aflatoxin, and Gliotoxin) and Their Distribution in the Urinalysis of ME/CFS Patients

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a known complex, multi-organ system disorder with a sudden or subacute onset. ME/CFS occurs most commonly among women between 30 and 50 years of age. The current diagnostic criteria of ME/CFS, as defined by the Centers for Disease Control and Prevention, includes: profound fatigue and post-exertional malaise (>6 mo) unrelieved by rest, persistent cognitive impairment or orthostatic intolerance, and chronic unrefreshing sleep.

Despite reported associations between ME/CFS onset and exposure to infectious agents (viral, bacterial, or fungal), the pathophysiology of ME/CFS remains unknown. In this prevalence study, we investigated the rates of Aspergillus-derived toxin levels, Aflatoxin (AF), Ochratoxin A (OTA), and Gliotoxin (GT), in the urinalysis of 236 ME/CFS patients with a history of chronic exposure to mold (i.e., from water-damaged buildings).

Among ME/CFS patients reporting chronic exposure to mold, we found evidence of exposure in 92.4 percent of patients, with OTA being the most prevalent mycotoxin. Mold distributions (OTA, AF, and GT) in the urinalysis all demonstrated right skewness, while the distribution of age of ME/CFS patients diagnosed showed no deviation from normality.

This study aims to provide preliminary, epidemiological evidence among ME/CFS patients who were diagnosed in South Florida with a history of exposure to mycotoxins. Based on these findings, we proposed how future control studies should approach investigating the association between chronic mold exposure and the diagnosis of ME/CFS.

Source: Wu TY, Khorramshahi T, Taylor LA, Bansal NS, Rodriguez B, Rey IR. Prevalence of Aspergillus-Derived Mycotoxins (Ochratoxin, Aflatoxin, and Gliotoxin) and Their Distribution in the Urinalysis of ME/CFS Patients. Int J Environ Res Public Health. 2022 Feb 12;19(4):2052. doi: 10.3390/ijerph19042052. PMID: 35206241. https://www.mdpi.com/1660-4601/19/4/2052 (Full text)

How mycobacterium tuberculosis infection could lead to the increasing risks of chronic fatigue syndrome and the potential immunological effects: a population-based retrospective cohort study

Abstract:

Background: Chronic fatigue syndrome (CFS) has been shown to be associated with infections. Tuberculosis (TB) is a highly prevalent infectious disease. Patients with chronic fatigue syndrome and post-tuberculosis experience similar symptoms. Furthermore, chronic fatigue syndrome and tuberculosis share similar plasma immunosignatures. This study aimed to clarify the risk of chronic fatigue syndrome following the diagnosis of Mycobacterium tuberculosis infection (MTI), by analyzing the National Health Insurance Research Database of Taiwan.

Methods: 7666 patients aged 20 years or older with newly diagnosed Mycobacterium tuberculosis infection during 2000-2011 and 30,663 participants without Mycobacterium tuberculosis infection were identified. Both groups were followed up until the diagnoses of chronic fatigue syndrome were made at the end of 2011.

Results: The relationship between Mycobacterium tuberculosis infection and the subsequent risk of chronic fatigue syndrome was estimated through Cox proportional hazards regression analysis, with the incidence density rates being 3.04 and 3.69 per 1000 person-years among the non-Mycobacterium tuberculosis infection and Mycobacterium tuberculosis infection populations, respectively (adjusted hazard ratio [HR] = 1.23, with 95% confidence interval [CI] 1.03-1.47). In the stratified analysis, the Mycobacterium tuberculosis infection group were consistently associated with a higher risk of chronic fatigue syndrome in the male sex (HR = 1.27, 95% CI 1.02-1.58) and age group of ≥ 65 years old (HR = 2.50, 95% CI 1.86-3.38).

Conclusions: The data from this population-based retrospective cohort study revealed that Mycobacterium tuberculosis infection is associated with an elevated risk of subsequent chronic fatigue syndrome.

Source: Yang TY, Lin CL, Yao WC, Lio CF, Chiang WP, Lin K, Kuo CF, Tsai SY. How mycobacterium tuberculosis infection could lead to the increasing risks of chronic fatigue syndrome and the potential immunological effects: a population-based retrospective cohort study. J Transl Med. 2022 Feb 21;20(1):99. doi: 10.1186/s12967-022-03301-1. PMID: 35189895. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03301-1 (Full text)

Commonalities in the Features of Cancer and Chronic Fatigue Syndrome (CFS): Evidence for Stress-Induced Phenotype Instability?

Abstract:

Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) and Cancer-Related Fatigue (CRF) are syndromes with considerable overlap with respect to symptoms. There have been many studies that have compared the two conditions, and some of this research suggests that the etiologies of the conditions are linked in some cases. In this narrative review, CFS/ME and cancer are introduced, along with their known and putative mechanistic connections to multiple stressors including ionizing radiation.

Next, we summarize findings from the literature that suggest the involvement of HPA-axis dysfunction, the serotonergic system, cytokines and inflammation, metabolic insufficiency and mitochondrial dysfunction, and genetic changes in CRF and CFS/ME. We further suspect that the manifestation of fatigue in both diseases and its causes could indicate that CRF and CFS/ME lie on a continuum of potential biological effects which occur in response to stress. The response to this stress likely varies depending on predisposing factors such as genetic background.

Finally, future research ideas are suggested with a focus on determining if common biomarkers exist in CFS/ME patients and those afflicted with CRF. Both CFS/ME and CRF are relatively heterogenous syndromes, however, it is our hope that this review assists in future research attempting to elucidate the commonalities between CRF and CFS/ME.

Source: Rusin A, Seymour C, Cocchetto A, Mothersill C. Commonalities in the Features of Cancer and Chronic Fatigue Syndrome (CFS): Evidence for Stress-Induced Phenotype Instability? Int J Mol Sci. 2022 Jan 8;23(2):691. doi: 10.3390/ijms23020691. PMID: 35054876. https://pubmed.ncbi.nlm.nih.gov/35054876/

Epstein-Barr Virus and the Origin of Myalgic Encephalomyelitis or Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) affects approximately 1% of the general population. It is a chronic, disabling, multi-system disease for which there is no effective treatment. This is probably related to the limited knowledge about its origin. Here, we summarized the current knowledge about the pathogenesis of ME/CFS and revisit the immunopathobiology of Epstein-Barr virus (EBV) infection. Given the similarities between EBV-associated autoimmune diseases and cancer in terms of poor T cell surveillance of cells with EBV latency, expanded EBV-infected cells in peripheral blood and increased antibodies against EBV, we hypothesize that there could be a common etiology generated by cells with EBV latency that escape immune surveillance.

Albeit inconclusive, multiple studies in patients with ME/CFS have suggested an altered cellular immunity and augmented Th2 response that could result from mechanisms of evasion to some pathogens such as EBV, which has been identified as a risk factor in a subset of ME/CFS patients. Namely, cells with latency may evade the immune system in individuals with genetic predisposition to develop ME/CFS and in consequence, there could be poor CD4 T cell immunity to mitogens and other specific antigens, as it has been described in some individuals.

Ultimately, we hypothesize that within ME/CFS there is a subgroup of patients with DRB1 and DQB1 alleles that could confer greater susceptibility to EBV, where immune evasion mechanisms generated by cells with latency induce immunodeficiency. Accordingly, we propose new endeavors to investigate if anti-EBV therapies could be effective in selected ME/CFS patients.

Source: Ruiz-Pablos M, Paiva B, Montero-Mateo R, Garcia N, Zabaleta A. Epstein-Barr Virus and the Origin of Myalgic Encephalomyelitis or Chronic Fatigue Syndrome. Front Immunol. 2021 Nov 15;12:656797. doi: 10.3389/fimmu.2021.656797. PMID: 34867935; PMCID: PMC8634673. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8634673/ (Full text)

Plasma and Urinary Carnitine and Acylcarnitines in Chronic Fatigue Syndrome

Abstract:

Contradictory reports have suggested that serum free carnitine and acylcarnitine concentrations are decreased in patients with chronic fatigue syndrome (CFS) and that this is a cause of the muscle fatigue observed in these patients. Others have shown normal serum free carnitine and acylcarnitines in similar patients. We report here studies on free, total and esterified (acyl) carnitines in urine and blood plasma from UK patients with CFS and three control groups.

Plasma and timed urine samples were obtained from 31 patients with CFS, 31 healthy controls, 15 patients with depression and 22 patients with rheumatoid arthritis. Samples were analysed using an established radioenzymatic procedure for total, free and esterified (acyl) carnitine.

There were no significant differences in plasma or urinary total, free or esterified (acyl) carnitine between UK patients with CFS and the control groups or in renal excretion rates of these compounds. The data presented here show that, in the CFS patients studied, there are no significant abnormalities of free or esterified (acyl) carnitine. It is thus unlikely that abnormalities in carnitine homeostasis have any significant role in the aetiology of their chronic fatigue.

Source: Jones MG, Goodwin CS, Amjad S, Chalmers RA. Plasma and urinary carnitine and acylcarnitines in chronic fatigue syndrome. Clin Chim Acta. 2005 Oct;360(1-2):173-7. doi: 10.1016/j.cccn.2005.04.029. PMID: 15967423. https://pubmed.ncbi.nlm.nih.gov/15967423/

Complement Component C1q as a Potential Diagnostic Tool for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Subtyping

Abstract:

Background: Routine blood analytics are systematically used in the clinic to diagnose disease or confirm individuals’ healthy status. For myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a disease relying exclusively on clinical symptoms for its diagnosis, blood analytics only serve to rule out underlying conditions leading to exerting fatigue. However, studies evaluating complete and large blood datasets by combinatorial approaches to evidence ME/CFS condition or detect/identify case subgroups are still scarce.

Methods: This study used unbiased hierarchical cluster analysis of a large cohort of 250 carefully phenotyped female ME/CFS cases toward exploring this possibility.

Results: The results show three symptom-based clusters, classified as severe, moderate, and mild, presenting significant differences (p < 0.05) in five blood parameters. Unexpectedly the study also revealed high levels of circulating complement factor C1q in 107/250 (43%) of the participants, placing C1q as a key molecule to identify an ME/CFS subtype/subgroup with more apparent pain symptoms.

Conclusions: The results obtained have important implications for the research of ME/CFS etiology and, most likely, for the implementation of future diagnosis methods and treatments of ME/CFS in the clinic.

Source: Castro-Marrero J, Zacares M, Almenar-Pérez E, Alegre-Martín J, Oltra E. Complement Component C1q as a Potential Diagnostic Tool for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Subtyping. J Clin Med. 2021 Sep 15;10(18):4171. doi: 10.3390/jcm10184171. PMID: 34575280. https://pubmed.ncbi.nlm.nih.gov/34575280/

Patient perceptions of infectious illnesses preceding Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Objectives: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is often reported to be caused by an infectious agent. However, it is unclear whether one infectious agent might be the cause or whether there might be many different infectious agents. The objective of this study was to identify self-reported infectious illnesses associated with the onset of ME/CFS.

Methods: The present study involved data from multiple sites in several countries. 1773 individuals diagnosed with either ME, CFS or ME/CFS provided qualitative data concerning infectious triggers which were coded and classified for analysis.

Results: 60.3% of patients report a variety of infectious illnesses some time before onset of ME/CFS. The most frequently reported infectious illness was Mononucleosis, which occurred in 30% of infections. However, over 100 other infectious illnesses were mentioned.

Discussion: The findings suggest that many infectious agents might be associated with the onset of ME/CFS.

Source: Jason LA, Yoo S, Bhatia S. Patient perceptions of infectious illnesses preceding Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Chronic Illn. 2021 Sep 20:17423953211043106. doi: 10.1177/17423953211043106. Epub ahead of print. PMID: 34541918. https://pubmed.ncbi.nlm.nih.gov/34541918/

Infections in temporal proximity to HPV vaccination and adverse effects following vaccination in Denmark: A nationwide register-based cohort study and case-crossover analysis

Abstract:

Background: Public trust in the human papilloma virus (HPV) vaccination programme has been challenged by reports of potential severe adverse effects. The reported adverse symptoms were heterogeneous and overlapping with those characterised as chronic fatigue syndrome (CFS) and have been described as CFS-like symptoms. Evidence suggests that CFS is often precipitated by an infection. The aim of the study was to examine if an infection in temporal proximity to HPV vaccination is a risk factor for suspected adverse effects following HPV vaccination.

Methods and findings: The study was a nationwide register-based cohort study and case-crossover analysis. The study population consisted of all HPV vaccinated females living in Denmark, born between 1974 and 2006, and vaccinated between January 1, 2006 and December 31, 2017. The exposure was any infection in the period ± 1 month around time of first HPV vaccination and was defined as (1) hospital-treated infection; (2) redemption of anti-infective medication; or (3) having a rapid streptococcal test done at the general practitioner. The outcome was referral to a specialised hospital setting (5 national HPV centres opened June 1, 2015) due to suspected adverse effects following HPV vaccination.

Multivariable logistic regression was used to estimate the association between infection and later HPV centre referral. The participants were 600,400 HPV-vaccinated females aged 11 to 44 years. Of these, 48,361 (9.7%) females had a hospital-treated infection, redeemed anti-infective medication, or had a rapid streptococcal test ± 1 month around time of first HPV vaccination. A total of 1,755 (0.3%) females were referred to an HPV centre. Having a hospital-treated infection in temporal proximity to vaccination was associated with significantly elevated risk of later referral to an HPV centre (odds ratio (OR) 2.75, 95% confidence interval (CI) 1.72 to 4.40; P < 0.001). Increased risk was also observed among females who redeemed anti-infective medication (OR 1.56, 95% CI 1.33 to 1.83; P < 0.001) or had a rapid streptococcal test (OR 1.45, 95% CI 1.10 to 1.93; P = 0.010).

Results from a case-crossover analysis, which was performed to adjust for potential unmeasured confounding, supported the findings. A key limitation of the study is that the HPV centres did not open until June 1, 2015, which may have led to an underestimation of the risk of suspected adverse effects, but stratified analyses by year of vaccination yielded similar results.

Conclusions: Treated infection in temporal proximity to HPV vaccination is associated with increased risk for later referral with suspected adverse vaccine effects. Thus, the infection could potentially be a trigger of the CFS-like symptoms in a subset of the referred females. To our knowledge, the study is the first to investigate the role of infection in the development of suspected adverse effects after HPV vaccination and replication of these findings are needed in other studies.

Source: Krogsgaard LW, Petersen I, Plana-Ripoll O, Bech BH, Lützen TH, Thomsen RW, Rytter D. Infections in temporal proximity to HPV vaccination and adverse effects following vaccination in Denmark: A nationwide register-based cohort study and case-crossover analysis. PLoS Med. 2021 Sep 8;18(9):e1003768. doi: 10.1371/journal.pmed.1003768. Epub ahead of print. PMID: 34495975. https://pubmed.ncbi.nlm.nih.gov/34495975/

Are enteroviruses behind mysterious outbreaks of chronic fatigue syndrome?

Chronic fatigue syndrome is a long-term illness with a wide range of symptoms, no known treatment, and undetermined origins. However, with as many as 65m people across the world living with the illness, researchers continue to search for answers.

Now, Prof Maureen Hanson of Cornell University discusses how she and graduate student James O’Neal searched through the research archives to see whether a genus of RNA viruses called enteroviruses are the most likely culprits and whether the findings have implications in future ‘long Covid’ research.

Like SARS-CoV-2, which causes Covid-19, viruses, enteroviruses (EVs) are RNA viruses that can lead to cause serious illness and death. One type of EV causes poliomyelitis, which is now largely conquered through near-universal vaccination.

But no vaccine exists against many other types of EVs, which are free to circulate widely. Indeed, the Centers for Disease Control and Prevention estimates between 10m-15m enteroviral infections occur each year in the US.

EVs have long been suspected as causal agents in outbreaks of an illness that is now usually named ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome). Outbreaks have been documented since the turn of the previous century and may have occurred earlier.

Many are unaware that ME/CFS can occur in epidemic form. The pathogen(s) inciting most of these outbreaks remain unidentified. One reason for this lamentable situation is that earlier virus identification technology was not as powerful as today’s methods.

Consider how quickly the complete sequence of SARS-CoV-2 was obtained not long after a new illness arose. But another reason that ME/CFS triggers are not known is the existing technology was not deployed to identify the agents causing multiple outbreaks in the mid-1980s. The failure of federal agencies to nor investigate these outbreaks, often dismissed as hysteria or unimportant, is well documented in investigative journalist Hillary Johnson’s Osler’s Web.

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Source: Frontiers Science News, August 12, 2o21. https://blog.frontiersin.org/2021/08/12/chronic-fatigue-syndrome-viruses-maureen-hanson-cornell-university/