In this study, various pathogens—bacteria, viruses, and fungi—were associated with an increased incidence of CFS (Table 2). Only ICD codes for infections were included in our data; codes of colonization were excluded. (By definition, “colonization” describes that pathogens are presented on body sites without causing damage. On the other hand, “infection” means the colonized pathogens start causing damage to body tissue.) Thus, the evidence of increased CFS risk following infection with a common pathogen was obtained (Fig. 2). The hazard ratios of CFS were positively correlated with age. Older adults were more likely to develop CFS after an episode of infection (Table 2). Moreover, infection increased the incidence of CFS in most of the comorbidity subgroups but not in all of them (Table 5). The mechanisms behind the variation in incidence among different age groups and comorbidity subgroups remain unclear.
Previous studies of CFS have focused primarily on atypical bacteria and viruses. Nevertheless, we observed an association between CFS and typical bacteria, including those that are intracellular (i.e., Salmonella), that are extracellular (i.e., E. coli) and with both properties (i.e., Staphylococcus aureus). A few studies have addressed this topic. In 2007, Maes et al. found that serum immunoglobulin A and M against lipopolysaccharides of enterobacteria—such as Pseudomonas aeruginosa, Proteus mirabilis and Klebsiella pneumonia—was elevated in patients with CFS.[38] However, typical bacteria have been indicated to influence the human immune system. For example, Staphylococcus is known for its immunomodulation ability, which is achieved by affecting T cells.[39]
Regarding the viruses, an association between influenza and CFS was observed in this study, and this result has not been reported previously. Several studies have verified, 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 nonsignificant due to the limited number of identified cases. Similarly, significance could not be established for several other pathogens with limited cases, including Chlamydia pneumoniae, mycoplasma, dengue fever, scrub typhus, and Lyme disease.
Studies involving multiple cohorts and cross-sectional studies have reported similarities between the symptoms of long COVID and CFS, such as cognitive impairment and fatigue, over a follow-up duration ranging from 12 weeks to 6 months.[42, 43] Similar to CFS, long COVID presents with IL-6 dysregulation and disrupted T cell responses.[44] Moreover, elevated CD8 + T cells and increased type 1 cytokines were linked to abnormal chest X-ray findings in patients who had had COVID 6 months after their discharge from hospital.[45] Although the common mechanisms of long COVID and CFS are unclear, these overlapping features warrant future research exploring both CFS and long COVID.
With regard to fungi, based on our review of the literature, the present study is the first to demonstrate a significant association between Candida and CFS. Nevertheless, increased Candida albicans in fecal microflora was previously observed in patients with CFS.[46] Scientists are increasingly recognizing the role of the gut–brain axis in patients with CFS. Multiple pathways have been proposed to explain gut–brain communication, such as the immune system (i.e., cytokines), hormones (i.e., gamma-aminobutyric acid), the neuron system (i.e., vagus nerve), and metabolites (i.e., short-chain fatty acids).[47] An altered gut microbiome composition is associated with not only CFS but a variety of diseases, including inflammatory bowel disease, multiple sclerosis, and systemic lupus erythematosus.[48–50] With regard to other fungi, mycotoxins detected in the urine of patients with CFS raised concern over the role of mycotoxin-producing mold, such as aspergillus, in CFS.[51]
In terms of immunomodulatory antibiotics, the use of doxycycline, azithromycin, moxifloxacin, ciprofloxacin, or levofloxacin was significantly associated with decreased incidence of CFS (Tables 2 and Table 4). The exact mechanism underlying how these antibiotics prevent CFS is unknown, but they influence the immune system in different ways. Azithromycin is probably the most widely investigated antibiotic among this group. Azithromycin inhibits transcription factors and their downstream inflammatory cytokines, such as the PI3K/AKT/NF-ҡB, ERK1/2/NF-ҡB, and AP-1 pathways.[52, 53] One study revealed that fluoroquinolones increased production of anti-inflammatory cytokines such as TGF-β and IL-10 and decreased that of proinflammatory cytokines such as IL-1β, IL-6, and TNF-α.[31] In addition to inhibiting TNF-α, doxycycline exerts immunomodulatory effects by downregulating proinflammatory enzymes, such as nitric oxide synthetase and matrix metalloproteinases.[32, 33, 54] A randomized controlled trial revealed that long-term doxycycline treatment offered no benefit in reducing fatigue in patients with Q Fever fatigue syndrome.[55] However, few trials have focused on the effects of immunomodulatory antibiotics on CFS. Our laboratory has already investigated the treatments on CFS[36], and found mild psoriasis increased the risk of CFS, but the patients with severe psoriasis but receiving immunomodulatory agents didn’t significantly suffer from CFS[50], so the effect of immunomodulation on CFS has merits of being further investigated and our current study provides insight into further potential therapies for preventing from CFS.
Our study has several limitations. First, it was impossible to include all pathogens in our analysis. Moreover, the association of rare pathogens with CFS could have been affected by the limited numbers of cases. Second, we could not conduct a real-time evaluation of the severity of each infectious disease because the patients’ vital signs and laboratory data were not available in the NHIRD. Even though not all factors were considered to measure the risk of CFS, we accounted for these related factors by using comorbidities. Third, because the data are anonymous, data on the renal or hepatic dose adjustment of antibiotics for each patient were unavailable. Nevertheless, we have presented most relevant pathogens that might cause CFS and considered the comorbidities which we have adjusted the hazard ratio accordingly. However, our study has some strengths, such as the large number of cases and controls. Furthermore, to the best of our knowledge, this study provides the first demonstration of the association between pan-pathogens and CFS. Our results reveal that many pathogens are associated with CFS, not only atypical bacteria and viruses as was previously believed. This evidence supports the theory that pathogens play a role in “triggering” CFS.
In conclusion, our findings indicate that the risk of CFS is higher following common infections and demonstrated the triggering role of infection in CFS. Moreover, the incidence of CFS was discovered to be lower when antibiotics with immunomodulatory properties were being taken, which may shed light on treatment strategies for CFS.