Increased risk of chronic fatigue syndrome following infection: a 17-year population-based cohort study, 2023, Chang et al

[Dolphin]

Preprint details in this post

Final publication is linked in a post below - see here

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Free:
https://assets.researchsquare.com/f...-6f0d-4f73-a9f4-5349e07baac0.pdf?c=1693414746

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

Hsun Chang Mackay Memorial Hospital
Chien-Feng Kuo Mackay Memorial Hospital
Teng-Shun Yu China Medical University Hospital
Liang-Yin Ke Kaohsiung Medical University
Chung-Lieh Hung Mackay Memorial Hospital
Shin-Yi Tsai (  stsai22@jhu.edu ) Johns Hopkins University https://orcid.org/0000-0001-7978-778X

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.

 

[LarsSG]

"CFS was defined as ICD-9-CM 780.7 and ICD-10-CM G93.3, R53.8" so much broader than ME, this includes "malaise and fatigue" in general. Common issue with studies from Taiwan.

 

[Hutan]

Chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME), is a mysterious disorder

And that might be the most accurate statement in the introduction. There's an awful lot of saying things confidently when we really don't know.

However, the exact etiology of CFS remains unclear.

Although the exact pathogenesis of CFS warrants additional research, the immune system is believed to play an important role.

Never mind the exact pathogenesis, I don't think we have yet narrowed down which ball park we are operating in.

CFS is associated with elevated levels of proinflammatory cytokines (TNF-α, IFN-γ, IL-6, and IL-1) [7]

Yeah, but is it though? I've pretty sure I've seen a lot of papers where these cytokines aren't different.

and dysregulation of immune cells (decreased T-regulatory cells,

Same for this. I've had moderately higher levels of t-regs, and I think I've seen that reported elsewhere

persistence of autoantibody-generating autoreactive B cells

maybe it's true, but I don't think we have evidence

and reduced cytotoxicity of natural killer cells)

I think the jury might even still be out on that one.

Triggering events—such as pathogen exposure, metal exposure, and environmental factors—initiate immune responses and generate oxidative stress that harms mitochondria.[7–10]

Metal exposure? Environmental factors? I don't know that we can say with any confidence that these are triggering events. And I don't think we know how pathogen exposure triggers ME/CFS.

The accumulation of stress through these triggering events elicits autoimmunity in genetically predisposed populations and eventually leads to clinical manifestation of diseases.[10, 11]

We don't know that this is what is going on in ME/CFS.

Additionally, inflammation dysregulates the HPA axis[12].

We don't know if that is relevant in ME/CFS.

This can result in a vicious cycle in which hypocortisolism worsens control over the production of proinflammatory cytokines.[8, 9]

There's no good evidence for hypocortisolism driving ME/CFS symptoms, despite so many people wanting out to be true. And there's the pro inflammatory cytokines again.

Furthermore, the circulating cytokines increase blood–brain barrier permeability, activate glial cells, and sensitize neurons to nonnoxious stimuli.[13]

Uhh

These manifestations of neuroinflammation may explain the neurological symptoms of CFS, such as fatigue and pain.

At least there's a 'may' there.

It's not good enough. People with ME/CFS can't be blamed for saying 'there's so much biological evidence' when researchers just trot out a whole lot of speculation as fact. (Happy to be proven wrong on any of those).

 

[Hutan]

The immunomodulatory properties of some antibiotics—such as macrolides, tetracyclines, and quinolones—have been described and applied in trials to treat various diseases, including multiple sclerosis (MS), chronic obstructive pulmonary disease (COPD), abdominal aneurysm, and cancer.[31–34] Hence, our study investigated the associations between immunomodulatory antibiotics and the risk of CFS.

That's an interesting question.

Patients with dementia (aHR = 0.65, 95% CI = 0.42–0.98) and those taking doxycycline (aHR = 0.1, 95% CI = 0.07–0.15), azithromycin (aHR = 0.07, 95% CI = 0.05–0.1), moxifloxacin (aHR = 0.05, 95% CI = 0.04–0.08), levofloxacin (aHR = 0.04, 95% CI = 0.03–0.06), or ciprofloxacin (aHR = 0.51, 95% CI = 0.31–0.83) had signicantly lower risk of CFS than patients in the corresponding control group.

That seems pretty significant. Look at the hazard ratio for people taking doxycycline (0.1). It goes against the idea that the antibiotics, and especially (cipro)floxacin might be predisposing factors for ME/CFS onset.

I expect that are plenty ifs and buts to apply to the finding, but it looks worth looking into. The lower risk in patients with dementia might just be because whatever symptoms the dementia patient has, they are attributed to dementia.

 

[Hutan]

Regarding the viruses, an association between inuenza and CFS was observed in this study, and this result has not been reported previously.

I don't think the authors looked hard enough.
e.g.CFS/ME is associated with pandemic influenza infection, but not with an adjuvanted pandemic influenza vaccine, 2015, Magnus, Hornig, Lipkin et al

 

[Hutan]

Several studies have veried, mostly through serological approaches, that EBV infection increases the risk of developing CFS.[40, 41] However, in the present study, the associations of EBV and CMV with CFS were considered nonsignicant due to the limited number of identied cases. Similarly, signicance could not be established for several other pathogens with limited cases, including Chlamydia pneumoniae, mycoplasma, dengue fever, scrub typhus, and Lyme disease.

No association found with EBV... Due to a limited number of cases, but even so.
And nothing for dengue fever or Lyme or rickettsias.

I don't know. The Taiwanese health database should be a gold mine of information, but it's hard to know what can be trusted.

 

[Sly Saint]

Merged thread. Final publication

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

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 = 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.

https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04636-z

 

[Andy]

"The study defined CFS as ICD-9-CM 780.7 and ICD-10-CM G93.3, R53.8."

ICD-9-CM 780.7 being "Malaise and fatigue", ICD-10-CM G93.3 is "Postviral and related fatigue syndromes" and ICD-10-CM R53.8 is "Other malaise and fatigue".

 

[ME/CFS Skeptic]

Among individual pathogens, infection with Borrelia burgdorferi (the bacteria that causes Lyme Disease) seems to have resulted in the highest incidence rate (11.77).

 

[Wonko]

Were they also amazed to find that people given a diagnostic code for broken bones in the leg were found to have broken legs?