Tag: pathogens

Increased risk of chronic fatigue syndrome following infection: a 17-year population-based cohort study

Abstract:

Background: Previous serological studies have indicated an association between viruses and atypical pathogens and Chronic Fatigue Syndrome (CFS). This study aims to investigate the correlation between infections from common pathogens, including typical bacteria, and the subsequent risk of developing CFS. The analysis is based on data from Taiwan’s National Health Insurance Research Database.

Methods: From 2000 to 2017, we included a total of 395,811 cases aged 20 years or older newly diagnosed with infection. The cases were matched 1:1 with controls using a propensity score and were followed up until diagnoses of CFS were made.

Results: The Cox proportional hazards regression analysis was used to estimate the relationship between infection and the subsequent risk of CFS. The incidence density rates among non-infection and infection population were 3.67 and 5.40 per 1000 person-years, respectively (adjusted hazard ratio [HR] = 1.5, with a 95% confidence interval [CI] 1.47-1.54). Patients infected with Varicella-zoster virus, Mycobacterium tuberculosis, Escherichia coli, Candida, Salmonella, Staphylococcus aureus and influenza virus had a significantly higher risk of CFS than those without these pathogens (p < 0.05). Patients taking doxycycline, azithromycin, moxifloxacin, levofloxacin, or ciprofloxacin had a significantly lower risk of CFS than patients in the corresponding control group (p < 0.05).

Conclusion: Our population-based retrospective cohort study found that infection with common pathogens, including bacteria, viruses, is associated with an increased risk of developing CFS.

Source: Chang H, Kuo CF, Yu TS, Ke LY, Hung CL, Tsai SY. Increased risk of chronic fatigue syndrome following infection: a 17-year population-based cohort study. J Transl Med. 2023 Nov 11;21(1):804. doi: 10.1186/s12967-023-04636-z. PMID: 37951920. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04636-z (Full text)

How post-infection status could lead to the increasing risks of chronic fatigue syndrome and the potential mechanisms: A 17-year population based Cohort study

Abstract:

Background: Serological studies have suggested that viruses and atypical pathogens are associated with CFS, but no study has focused on typical and common pathogens. This study aims to assess the association of infections with a variety of common pathogens with the risk of CFS and provide evidence for the hypothesis that infection triggers CFS.

Methods: The nested case-control study identified 2,000,000 adult patients from a nationwide population-based health insurance claims database from January 1, 2000, to December 31, 2017. Each case with a diagnosis of infection by pathogens was matched with one control using a propensity score. Patients with more than one potential pathogen, younger than 20 years old, or with a history of CFS or infection with certain pathogens before the index date were excluded. Univariate and multivariate Cox proportional hazard models were applied to estimate the HR, aHR, and corresponding 95% CI. The multivariate analysis had adjustments for age, sex, comorbidities, and medication confounders.

Results: A total of 395,811 cases with 1: 1 matched controls were included (58.2% female; mean age [standard deviation], 44.15 [17.02]). Among these, the aHR of the pathogen cohort was 1.5 (95% CI, 1.47 to 1.54). Pathogens were positively correlated with CFS, including influenza, candida and others.

Conclusion: The findings of this study demonstrate the association between CFS and infection with common pathogens, including bacteria, virus and fungi.

Source: Hsun Chang; Chien-Feng Kuo; Teng-Shun Yu; Liang-Yin Ke; Chung-Lieh Hung; Shin-Yi Tsai. How post-infection status could lead to the increasing risks of chronic fatigue syndrome and the potential mechanisms: A 17-year population based Cohort study. Research Square, August 30, 2023. https://assets.researchsquare.com/files/rs-3289981/v1/55890598-6f0d-4f73-a9f4-5349e07baac0.pdf (Full text)

Cardiovascular and haematological pathology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): A role for viruses

Abstract:

ME/CFS is a debilitating chronic condition that often develops after viral or bacterial infection. Insight from the study of Long COVID/Post Acute Sequelae of COVID-19 (PASC), the post-viral syndrome associated with SARS-CoV-2 infection, might prove to be useful for understanding pathophysiological mechanisms of ME/CFS. Disease presentation is similar between the two conditions, and a subset of Long COVID patients meet the diagnostic criteria for ME/CFS.

Since Long COVID is characterized by significant vascular pathology – including endothelial dysfunction, coagulopathy, and vascular dysregulation – the question of whether or not the same biological abnormalities are of significance in ME/CFS arises.

Cardiac abnormalities have for a while now been documented in ME/CFS cohorts, with recent studies demonstrating major deficits in cerebral blood flow, and hence vascular dysregulation. A growing body of research is demonstrating that ME/CFS is accompanied by platelet hyperactivation, anomalous clotting, a procoagulant phenotype, and endothelial dysfunction. Endothelial damage and dysregulated clotting can impair substance exchange between blood and tissues, and result in hypoperfusion, which may contribute to the manifestation of certain ME/CFS symptoms.

Here we review the ME/CFS literature to summarize cardiovascular and haematological findings documented in patients with the condition, and, in this context, briefly discuss the potential role of previously-implicated pathogens.

Overall, cardiac and haematological abnormalities are present within ME/CFS cohorts. While atherosclerotic heart disease is not significantly associated with ME/CFS, suboptimal cardiovascular function defined by reduced cardiac output, impaired cerebral blood flow, and vascular dysregulation are, and these abnormalities do not appear to be influenced by deconditioning. Rather, these cardiac abnormalities may result from dysfunction in the (autonomic) nervous system.

Plenty of recently published studies are demonstrating significant platelet hyperactivity and endothelial dysfunction in ME/CFS, as well as anomalous clotting processes. It is of particular importance to determine to what extent these cardiovascular and haematological abnormalities contribute to symptom severity, and if these two systems can be targeted for therapeutic purposes.

Viral reservoirs of herpesviruses exist in ME/CFS, and most likely contribute to cardiovascular and haematological dysfunction directly or indirectly. This review highlights the potential of studying cardiac functioning, the vasculature, and coagulation system in ME/CFS.

Source: Jean M. Nunes, Douglas B. Kell, Etheresia Pretorius. Cardiovascular and haematological pathology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): A role for viruses. Blood reviews, 20 March 2023, 101075 [Epub ahead of print]  https://www.sciencedirect.com/science/article/pii/S0268960X2300036X (Full text)

Investigating the enterovirus theory of disease etiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, multi-system disease whose etiological basis has not been established. Over the years, several pathogenic agents have been implicated with no one pathogen being conclusively identified as responsible for induction of a large number of cases. Enteroviruses (EVs) as a cause of ME/CFS have sometimes been proposed, as they are known agents of acute respiratory and gastrointestinal infections that may persist in chronic infection sites, including the central nervous system, muscle, and heart, potentially resulting in chronic conditions that have symptom constellations like those of ME/CFS.

To gain insight into the association between EVs and ME/CFS, I conducted a comprehensive review of EV studies in ME/CFS and followed this with 1) a broad serological survey of ME/CFS antibody levels to 122 pathogenic antigens and 2) designed and conducted EV-specific targeted RNA sequencing.

A review of prior ME/CFS investigations in ME/CFS revealed a strong prevalence of chronic EV infections across ME/CFS cohorts. The broad survey of anti-pathogen antibody levels in ME/CFS cases did not implicate any one pathogen as a causative factor in ME/CFS, nor do they rule out common pathogens that frequently infect the US population. However, the results did reveal sex-based differences in steady-state humoral immunity, both within the ME/CFS cohort and when compared to trends seen in the healthy control cohort.

Furthermore, I find that our EV-specific probe set allows efficient viral detection when as few as 10 molecules are present in 1ml of blood. However, whether the technology is employed directly on patient samples or following attempts at in vitro biological amplification, EVs were undetected in both ME/CFS and healthy control samples despite all approaches that were pursued.

This work establishes a thorough understanding of the current EV-ME/CFS related literature while simultaneously providing an acutely sensitive and comprehensive approach that will be useful in the future for screening biopsy or cadaver samples from any individuals suspected of having a chronic EV infection.

Source: O’Neal, Adam James. Investigating the enterovirus theory of disease etiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Dissertation, Cornell. https://ecommons.cornell.edu/handle/1813/112023 (Full text will be made available)

Survey of Anti-Pathogen Antibody Levels in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Infectious pathogens are implicated in the etiology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) because of the occurrence of outbreaks of the disease. While a number of different infectious agents have been associated with the onset of ME/CFS, the identity of a specific organism has been difficult to determine in individual cases. The aim of our study is to survey ME/CFS subjects for evidence of an infectious trigger and/or evidence of immune dysregulation via serological testing of plasma samples for antibodies to 122 different pathogen antigens.
Immune profiles were compared to age-, sex-, and BMI-matched controls to provide a basis for comparison. Antibody levels to individual antigens surveyed in this study do not implicate any one of the pathogens in ME/CFS, nor do they rule out common pathogens that frequently infect the US population. However, our results revealed sex-based differences in steady-state humoral immunity, both within the ME/CFS cohort and when compared to trends seen in the healthy control cohort.
Source: O’Neal AJ, Glass KA, Emig CJ, Vitug AA, Henry SJ, Shungu DC, Mao X, Levine SM, Hanson MR. Survey of Anti-Pathogen Antibody Levels in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Proteomes. 2022; 10(2):21. https://doi.org/10.3390/proteomes10020021 https://www.mdpi.com/2227-7382/10/2/21/htm (Full text)

Myalgic encephalomyelitis, chronic fatigue syndrome: An infectious disease

Abstract:

The etiology of myalgic encephalomyelitis also known as chronic fatigue syndrome or ME/CFS has not been established. Controversies exist over whether it is an organic disease or a psychological disorder and even the existence of ME/CFS as a disease entity is sometimes denied. Suggested causal hypotheses have included psychosomatic disorders, infectious agents, immune dysfunctions, autoimmunity, metabolic disturbances, toxins and inherited genetic factors.

Clinical, immunological and epidemiological evidence supports the hypothesis that: ME/CFS is an infectious disease; the causal pathogen persists in patients; the pathogen can be transmitted by casual contact; host factors determine susceptibility to the illness; and there is a population of healthy carriers, who may be able to shed the pathogen.

ME/CFS is endemic globally as sporadic cases and occasional cluster outbreaks (epidemics). Cluster outbreaks imply an infectious agent. An abrupt flu-like onset resembling an infectious illness occurs in outbreak patients and many sporadic patients. Immune responses in sporadic patients resemble immune responses in other infectious diseases.

Contagion is shown by finding secondary cases in outbreaks, and suggested by a higher prevalence of ME/CFS in sporadic patients’ genetically unrelated close contacts (spouses/partners) than the community. Abortive cases, sub-clinical cases, and carrier state individuals were found in outbreaks.

The chronic phase of ME/CFS does not appear to be particularly infective. Some healthy patient-contacts show immune responses similar to patients’ immune responses, suggesting exposure to the same antigen (a pathogen). The chronicity of symptoms and of immune system changes and the occurrence of secondary cases suggest persistence of a causal pathogen.

Risk factors which predispose to developing ME/CFS are: a close family member with ME/CFS; inherited genetic factors; female gender; age; rest/activity; previous exposure to stress or toxins; various infectious diseases preceding the onset of ME/CFS; and occupational exposure of health care professionals. The hypothesis implies that ME/CFS patients should not donate blood or tissue and usual precautions should be taken when handling patients’ blood and tissue. No known pathogen has been shown to cause ME/CFS.

Confirmation of the hypothesis requires identification of a causal pathogen. Research should focus on a search for unknown and known pathogens. Finding a causal pathogen could assist with diagnosis; help find a biomarker; enable the development of anti-microbial treatments; suggest preventive measures; explain pathophysiological findings; and reassure patients about the validity of their symptoms.

 

Source: Underhill RA. Myalgic encephalomyelitis, chronic fatigue syndrome: An infectious disease. Med Hypotheses. 2015 Dec;85(6):765-73. Epub 2016 Oct 19. https://www.ncbi.nlm.nih.gov/pubmed/26604026

 

The Putative Role of Viruses, Bacteria, and Chronic Fungal Biotoxin Exposure in the Genesis of Intractable Fatigue Accompanied by Cognitive and Physical Disability

Abstract:

Patients who present with severe intractable apparently idiopathic fatigue accompanied by profound physical and or cognitive disability present a significant therapeutic challenge. The effect of psychological counseling is limited, with significant but very slight improvements in psychometric measures of fatigue and disability but no improvement on scientific measures of physical impairment compared to controls. Similarly, exercise regimes either produce significant, but practically unimportant, benefit or provoke symptom exacerbation. Many such patients are afforded the exclusionary, non-specific diagnosis of chronic fatigue syndrome if rudimentary testing fails to discover the cause of their symptoms.

More sophisticated investigations often reveal the presence of a range of pathogens capable of establishing life-long infections with sophisticated immune evasion strategies, including Parvoviruses, HHV6, variants of Epstein-Barr, Cytomegalovirus, Mycoplasma, and Borrelia burgdorferi. Other patients have a history of chronic fungal or other biotoxin exposure. Herein, we explain the epigenetic factors that may render such individuals susceptible to the chronic pathology induced by such agents, how such agents induce pathology, and, indeed, how such pathology can persist and even amplify even when infections have cleared or when biotoxin exposure has ceased. The presence of active, reactivated, or even latent Herpes virus could be a potential source of intractable fatigue accompanied by profound physical and or cognitive disability in some patients, and the same may be true of persistent Parvovirus B12 and mycoplasma infection. A history of chronic mold exposure is a feasible explanation for such symptoms, as is the presence of B. burgdorferi. The complex tropism, life cycles, genetic variability, and low titer of many of these pathogens makes their detection in blood a challenge. Examination of lymphoid tissue or CSF in such circumstances may be warranted.

 

Source: Morris G, Berk M, Walder K, Maes M. The Putative Role of Viruses, Bacteria, and Chronic Fungal Biotoxin Exposure in the Genesis of Intractable Fatigue Accompanied by Cognitive and Physical Disability. Mol Neurobiol. 2016 May;53(4):2550-71. doi: 10.1007/s12035-015-9262-7. Epub 2015 Jun 17. https://www.ncbi.nlm.nih.gov/pubmed/26081141

 

Current studies on the neurobiology of chronic fatigue syndrome

Abstract:

Cytokines are soluble mediators which are released by activated immune cells during infection and inflammation. The possibility that fatigue is mediated by the effects of cytokines on the central nervous system is supported by several converging lines of evidence: 1) infusions of cytokines to immunocompromised patients induce flu-like symptoms including fatigue and malaise; 2) peripheral and central injection of cytokines to laboratory rodents induce sickness behaviour; 3) symptoms of sickness behaviour occurring during experimental infections can be abrogated by administration of anti-cytokine treatments; 4) although many pitfalls in the detection of cytokines still exist, patients afflicted with the chronic fatigue syndrome have been found in some studies to display instances of excessive production of cytokines.

Experimental studies have confirmed that cytokines are interpreted by the brain as internal signals for sickness. Furthermore, there is evidence that sickness is a motivation which reorganizes the organism’s priorities in face of this particular threat which is represented by infectious pathogens. The elucidation of the mechanisms that are involved in these effects and in particular, the role of the cytokines which are produced in the brain in response to peripheral immune stimuli and to stressors, should give new insight on the way sickness and recovery processes are organized in the brain.

 

Source: Dantzer R. Current studies on the neurobiology of chronic fatigue syndrome. Encephale. 1994 Nov;20 Spec No 3:597-602. [Article in French] http://www.ncbi.nlm.nih.gov/pubmed/7843056

Chronic fatigue syndrome: influence of histamine, hormones and electrolytes

Abstract:

The chronic fatigue syndrome is poorly understood. We believe the underlying causes in many atopics and women are a persistent infection and hypersensitivity to the immune-suppressive effects of histamine and certain pathogens.

We believe much of the symptomatology can be explained by all four types of hypersensitivity (Gell and Coombs classification) in reaction to a pathogen, electrolyte disturbances which include sometimes permanent changes in cell membranes’ ability to pass electrolytes, sometimes permanent biochemical changes in mitochondrial function, and disturbances of insulin and T3-thyroid hormone functions. We also explain in detail what ‘fatigue’ means for these patients. We present evidence from the medical literature for the plausibility of our hypotheses.

 

Source: Dechene L. Chronic fatigue syndrome: influence of histamine, hormones and electrolytes. Med Hypotheses. 1993 Jan;40(1):55-60. http://www.ncbi.nlm.nih.gov/pubmed/8455468