Decreased risk of chronic fatigue syndrome following influenza vaccine: a 20-year population-based retrospective study, 2025, Chang et al.

[SNT Gatchaman]

Decreased risk of chronic fatigue syndrome following influenza vaccine: a 20-year population-based retrospective study
Chang, Hsun; Yao, Wei-Cheng; Yu, Teng-Shun; Lin, Heng-Jun; Tsai, Fuu-Jen; Ho, Shinn-Ying; Kuo, Chien-Feng; Tsai, Shin-Yi

BACKGROUND
Chronic Fatigue Syndrome (CFS) is a debilitating condition often follows infections, including influenza. Influenza frequently results in fatigue during the acute stage. However, the data regarding the association of influenza, vaccine and CFS is scarce. Thus, this study aims to investigate whether influenza increases the risk of developing CFS and examine the impact of influenza vaccination and severity of influenza on this risk.

METHODS
We conducted a national, population-based cohort study, using data from the National Health Insurance Research Database (NHIRD) of Taiwan, which identified 309,692 patients aged 20 years or older who were newly diagnosed with influenza between 2000 and 2019. An equal number of participants without influenza were also identified. Both groups were followed up until the end of CFS diagnoses. Cox proportional hazards regression analysis was used to calculate adjusted hazard ratios(aHRs) and 95% confidence intervals (CIs) for CFS as associated with influenza, adjusting for demographic factors and comorbidities. We also evaluated the effects of influenza vaccination and severe influenza.

RESULTS
After propensity matching, each cohort comprised 309,692 patients. Over an average follow-up period of approximately 12 years, influenza patients exhibited a significantly increased risk of developing CFS compared to matched controls (aHR = 1.51; 95% CI: 1.48–1.55; p < 0.001). The increased risk of CFS among patients with influenza was consistent across all age groups and both sexes, with the most pronounced elevation observed in older individuals. Patients who experienced severe influenza, as indicated by the need for mechanical ventilation, exhibited a significantly higher risk of developing CFS compared to those who did not require ventilatory support. In contrast, influenza vaccination was associated with a reduced risk of developing CFS. Patients who received the influenza vaccine—either before or following their influenza episode—exhibited a lower incidence of CFS than those who remained unvaccinated. The protective effect of vaccination was not evident in patients with severe influenza requiring ventilation.

CONCLUSIONS
Influenza infection is associated with an increased risk of developing CFS. These findings suggest that preventing influenza and mitigating its severity, such as through vaccination, could reduce the burden of CFS in at-risk populations.

Link | PDF | Journal of Translational Medicine [Open Access]

 

[SNT Gatchaman]

The primary outcome was the incidence of CFS after the index date, defined by a new diagnosis of CFS (ICD9-CM: 780.7; ICD-10-CM: R53.82, G93.3) between 2000 and 2019.

 

[Hutan]

A lot of these studies using the Taiwan NHIRD end up being rather disappointing when we poke into them. Getting a CFS diagnosis to actually mean something useful in terms of ME/CFS is difficult anywhere.

For example:

Patients who experienced severe influenza, as indicated by the need for mechanical ventilation, exhibited a significantly higher risk of developing CFS compared to those who did not require ventilatory support.

many of these people probably have some other reason for their CFS symptoms.

That said, this looks to be worth reading. It could provide evidence to support a policy of free flu injections for some group of people judged to be more at risk of ME/CFS (perhaps with a genetic risk factor, or ME/CFS in the family).

 

[Hutan]

Prior to our study, a Norwegian cohort study using the national database that infection with the 2009 pandemic influenza A(H1N1) was associated with a subsequent increase in CFS cases, while no increased risk of CFS was observed after influenza vaccination. However, several questions remained unanswered. Dose the severity of an influenza infection influence the likelihood of developing CFS? Does receiving an influenza vaccination protect individuals from CFS, even if they contract influenza? To address these gaps, we designed a large longitudinal cohort study using Taiwan’s NHIRD to explore the relationship between influenza and CFS and to evaluate the effects of influenza severity and vaccination on CFS risk.

People included in the cohorts were aged 20 or more.

(There are a lot of typos in this paper. BMC Part of Springer Nature. Journal of Translational Medicine.)

The influenza cohort had a markedly higher incidence of CFS compared to the non-influenza cohort. As shown in Table 2, having had an influenza infection was associated with a significantly increased risk of developing CFS subsequently (aHR = 1.51, 95% CI: 1.48–1.55, compared to no influenza). This elevated risk was evident across all demographic subgroups.

In particular, older age amplified the risk of CFS following influenza: individuals aged 40–64 years had about a 1.31-fold higher risk (95% CI: 1.28–1.35), and those aged ≥ 65 years had roughly a 1.91-fold higher risk (95% CI: 1.85–1.97), compared to the 20–39 year age group.

Interestingly, male sex was associated with a slightly lower risk of CFS than female sex (aHR = 0.91, 95% CI: 0.89–0.93)

That's not a huge difference in risk associated with sex. That equates to 52.3% of cases being female. Also a sex ratio (male to female) of 1.0 to 1.1. However, note the increased risk with older age - I think there's a lot of diagnostic error happening here.

Patients with certain comorbidities experienced significantly higher rates of CFS than those without those conditions. Notably,
a history of insomnia (aHR = 1.40, 95% CI: 1.36–1.44),
anxiety (aHR = 1.22, 95% CI: 1.17–1.26),
peptic ulcer disease (aHR = 1.18, 95% CI: 1.14–1.21),
gout (aHR = 1.18, 95% CI: 1.14–1.23),
dyslipidemia (aHR = 1.06, 95% CI: 1.03–1.10),
irritable bowel syndrome (aHR = 1.14, 95% CI: 1.08–1.20),
chronic HBV infection (aHR = 1.13, 95% CI: 1.05–1.21),
HCV infection (aHR = 1.39, 95% CI: 1.25–1.55), and
fibromyalgia (aHR = 1.26, 95% CI: 1.22–1.29)
were all associated with an increased risk of developing CFS, compared to patients without these conditions.

Obesity is reported as having a lower risk of CFS: aHR=0.93, but it isn't statistically significant.
Renal disease is reported as substantially reducing the risk, but that is likely to be due to any fatigue and feeling unwell being put down to the kidney disease in people with kidney disease.

 

[Hutan]

The increased risk of CFS in influenza patients was observed irrespective of age group, specifically, young, middle-aged, or elderly, sex (in both women and men), baseline comorbidity burden as exemplified by patients with low CCI vs. high CCI, and presence of any specific comorbidity, in other words, both in patients with and without pre-existing comorbid conditions. In other words, influenza was consistently a risk factor for CFS across all these categories, with adjusted hazard ratios generally in the 1.4–1.6 range in each subgroup.

It was observed that patients with influenza had a significantly higher risk of developing CFS compared to those in the control group, irrespective of age [age 20–39 (aHR = 1.43, 95% CI = 1.38–3.148), age 40–64 (aHR = 1.5, 95% CI = 1.53–8.164), age 65–100 (aHR = 1.4, 95% CI = 1.419–9.157)], sex [women (aHR = 1.4, 95% CI = 1.41–5.149), men (aHR = 1.6, 95% CI = 1.56–2.168)], CCI levels [CCI = 0 (aHR = 1.5, 95% CI = 1.47–1.54), CCI = 1 (aHR = 1.6, 95% CI = 1.44–4.187), CCI ≥ 2 (aHR = 1.6, 95% CI = 1.34–2.195)], and comorbidities [with comorbidities (aHR = 1.5, 95% CI = 1.53–7.162), without comorbidities (aHR = 1.4, 95% CI = 1.38–2.147)].

Not getting the flu looks to be a significant way to reduce the risk of getting a CFS diagnosis in Taiwan.

Vaccination is protective against ME/CFS

We found that influenza vaccination was associated with a protective effect against CFS. Patients who received an influenza vaccine, either prior to their influenza infection or afterward in the same influenza season, had a lower risk of developing CFS compared to those who were not vaccinated. This pattern held true even when considering the timing of vaccination relative to the index date.

Furthermore, when we focused on patients who did not require mechanical ventilation during their influenza illness, namely, those with relatively milder influenza cases, the vaccinated individuals had a significantly lower incidence of CFS than the unvaccinated individuals.

Interestingly, they seem to have found that vaccination reduced the risk when given soon after an influenza infection. It would be wonderful if giving someone who has persisting symptoms for a few weeks after a flu infection could lower the risk of ME/CFS. I think there is probably some survivor bias going on. If you get a flu infection and get ME/CFS, you may well not be heading out to get a vaccination. You might be thinking, I'm feeling pretty sick here, the last thing I need to do is stress my body further with a vaccination. Whereas perhaps other people who get the flu and recover may be reminded to get a vaccination so they are protected from other strains.

But, it's still an intriguing finding. I wonder how many people had a vaccination soon after their flu infection. It may not have been many. Is there any feasible mechanism by which a post-infection vaccination might stop ME/CFS settling in? Maybe it gives the immune system a second chance to do things right?

As far as vaccination of people with Long Covid goes, I don't think we saw any consistent evidence of a benefit. I can't recall if we have seen any study of vaccination in people with Long Covid. If it did work, I imagine the vaccination has to be done quite quickly.

 

[Hutan]

Here's Table 4.3. This is for the risk of CFS in people who had an influenza infection but didn't need mechanical ventilation.


So, quite a lot of people (10,547) only had vaccinations after getting infected (but still within the same flu season), and 54 were diagnosed with CFS.