New research shows that COVID-19 survivors, especially older adults and non-hospitalized patients, are at an increased risk for chronic fatigue syndrome—underscoring the need for comprehensive care for vulnerable populations.

Study: Risk of chronic fatigue syndrome after COVID-19: A retrospective cohort study of 3227281 patients. Image Credit: DimaBerlin / Shutterstock

In a recent study published in the Journal of Infection and Public Health, researchers carried out a retrospective cohort study comprising 3,227,281 pairs of patients with and without COVID-19 from a larger dataset of over 115 million patients to investigate the associations between severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infections and chronic fatigue syndrome (CFS) risk, particularly in the presence of comorbidities.

Non-hospitalized patients showed the highest risk of developing chronic fatigue syndrome (CFS) compared to those who were hospitalized, challenging previous assumptions about severity-related outcomes.

Cox proportional hazard models revealed that patients with prior SARS‑CoV‑2 infections were at increased risk of contracting CFS (HR = 1.59), with adults above the age of 65, Asians (HR = 1.75), females, and those with comorbidities including diabetes, obesity, hypertensive disease, and hyperlipidemia being identified as the highest risk populations. The omicron variant was associated with slightly higher CFS risk (HR = 1.40) than older SARS‑CoV‑2 strains (alpha HR = 1.33, delta HR = 1.40), with risk levels for Omicron similar to Delta, despite Omicron typically causing milder acute illness.

Furthermore, contrary to previous studies, this research found that non-hospitalized patients had a higher risk of developing CFS (HR = 1.64) compared to those who were hospitalized (HR = 1.22), challenging assumptions that more severe initial infections increase long-term fatigue risk.

Background

The coronavirus disease 2019 (COVID-19) pandemic remains one of the worst in human history, infecting more than 700 million humans and claiming more than 7 million lives in only four years. While social distancing measures and vaccination campaigns have substantially curbed disease spread and dampened infection severity, many COVID-19 survivors report persistent or novel symptoms that cause debilitation for months or years following initial infection recovery.

Alarmingly, these conditions, collectively termed “long COVID,” are estimated to plague up to 78% of survivors, leaving them with chronic chest pain, lung diseases, muscle aches, and chronic fatigue syndrome (CFS). While studies aimed at establishing the association between SARS‑CoV‑2 infection and CFS risk have been carried out, none have evaluated the effects of covariates, particularly comorbidities and other preexisting medical conditions.

A growing body of evidence suggests the positive feedback loop between long COVID and other chronic conditions, observing that the presence of one increases the risk and severity of the other. Furthermore, long COVID is a multi-organ condition, highlighting the need for comprehensive, extensive cohort investigations into the associations between CFS and long COVID risk factors.

About the study

Vaccinated COVID-19 patients were at a lower risk of developing CFS (HR = 1.25) compared to unvaccinated individuals (HR = 1.62), highlighting the protective impact of vaccination.

The present study uses an extensive cohort (COVID-19 cases; n = 3,227,281 pairs) across a spectrum of infection severity, age, sex, race/ethnicity, vaccination status, and comorbidities to establish the risk associations between prior COVID-19 infections and CFS risk. Study data was obtained from the United States (US) TriNetX database, a collaborative network comprising electronic health records of more than 115 million patients, between January 2020 and December 2023. Participant selection was carried out by first identifying CFS patients from the database (n = 3,227,281) and then 1:1 propensity score-matching (PSM) matching them with CFS-free patients (non-COVID-19 controls).

Relevant data included demographics, infection and comorbidity diagnoses, ongoing medications, procedures, and laboratory test results. Covariates under investigation included age, sex, COVID-19 vaccination status and disease severity, hypertensive diseases, race, ischemic heart diseases, hyperlipidemia, cerebrovascular diseases, chronic kidney disease, chronic obstructive pulmonary disease, and depression. Patients were further divided into subcohorts based on the wave (alpha, delta, or omicron) of initial SARS-CoV-2 infection. The outcome of interest was medically confirmed CFS diagnoses.

Standardized Mean Differences (SMD) were used to compare covariates across COVID-19 and non-COVID-19 participants, with Kaplan–Meier analysis computing CFS incidence rates and univariate Cox proportional hazard models computing hazard ratios (HRs; CFS risk) in case and control cohorts.

Study findings

Asian patients faced the highest racial risk for CFS after COVID-19 infection (HR = 1.75), a novel finding that differs from previous research focusing mainly on White or Black populations.

Of the 115,675,909 patients represented in the TriNetX database, 3,227,281 were confirmed to have experienced a prior COVID-19 infection and were included as cases. All cases were 1:1 PSM to COVID-free controls, doubling the size of the study dataset. Cases were predominantly female (54.4%), White (58.7%), and had a history of hypertensive disease (17%). Furthermore, obesity (8.1%), type 2 diabetes mellitus (7.8%), hyperlipidemia (14.2%), and depression (5.5%) were frequently observed as COVID-19-associated comorbidities.

SMD analysis and HRs revealed that COVID-19 patients presented both higher incidence (~0.6%) and risk (~59%, HR = 1.59) of CFS compared to non-COVID-19 ones. Notably, significant variable-associated differences in CFS risk were observed, with patients aged 65 and older (HR = 1.74), female sex (HR = 1.62), and Asian (HR = 1.75) patients revealed to be at highest CFS risk. Unvaccinated patients (HR = 1.62) were found to be more likely to contract CFS than vaccinated (HR = 1.25) ones. Contrary to previous research, non-hospitalized patients had a significantly higher risk of developing CFS (HR = 1.64) than those hospitalized (HR = 1.22), which may suggest that early medical care during acute infection mitigates long-term fatigue risk. This is one of the first reports of race/ethnicity altering post-COVID-19 CFS risk.

Omicron and delta variant patients were found to be at slightly higher CFS risk (HR = 1.40, respectively) compared to alpha variant patients (HR = 1.33), with Omicron showing similar risk levels to Delta despite typically causing less severe acute illness. Infection severity outcomes on HR ranged from 1.22 (the most severe infection requiring immediate hospitalization) to 1.64 (no hospitalization required).

Conclusions

The present study uses a cohort of more than 6 million patients to elucidate the risk associations between COVID-19 and its comorbidities and subsequent CFS risk. Supporting previous research, the study established a higher CFS risk (HR = 1.59) in COVID-19 patients compared to their COVID-19-free counterparts. Unlike earlier studies, this research highlighted the significant influence of race, with Asian patients showing the highest CFS risk (HR = 1.75), and emphasized the importance of comorbidities, with chronic obstructive pulmonary disease (COPD) also contributing to increased risk (HR = 1.43), in addition to the known comorbidities of obesity, diabetes, and hypertension.

The findings on hospitalization severity were unexpected, as non-hospitalized patients had a significantly higher risk of developing CFS (HR = 1.64) compared to those hospitalized on the same day (HR = 1.22), suggesting that prompt medical care during acute infection may mitigate long-term fatigue risk.

Together, these findings provide a comprehensive evaluation of the landscape of CFS risk, helping clinicians better understand the needs of COVID-19 patients and potentially improving their quality of life.