A prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity

Abstract

A subset of patients has long-lasting symptoms after mild to moderate Coronavirus disease 2019 (COVID-19). In a prospective observational cohort study, we analyze clinical and laboratory parameters in 42 post-COVID-19 syndrome patients (29 female/13 male, median age 36.5 years) with persistent moderate to severe fatigue and exertion intolerance six months following COVID-19. Further we evaluate an age- and sex-matched postinfectious non-COVID-19 myalgic encephalomyelitis/chronic fatigue syndrome cohort comparatively. Most post-COVID-19 syndrome patients are moderately to severely impaired in daily live. 19 post-COVID-19 syndrome patients fulfill the 2003 Canadian Consensus Criteria for myalgic encephalomyelitis/chronic fatigue syndrome. Disease severity and symptom burden is similar in post-COVID-19 syndrome/myalgic encephalomyelitis/chronic fatigue syndrome and non-COVID-19/myalgic encephalomyelitis/chronic fatigue syndrome patients. Hand grip strength is diminished in most patients compared to normal values in healthy. Association of hand grip strength with hemoglobin, interleukin 8 and C-reactive protein in post-COVID-19 syndrome/non-myalgic encephalomyelitis/chronic fatigue syndrome and with hemoglobin, N-terminal prohormone of brain natriuretic peptide, bilirubin, and ferritin in post-COVID-19 syndrome/myalgic encephalomyelitis/chronic fatigue syndrome may indicate low level inflammation and hypoperfusion as potential pathomechanisms.

Fig. 1. Severity of fatigue and disability.

PCS/non-ME/CFS post-COVID-19 syndrome/non-myalgic encephalomyelitis/chronic fatigue syndrome; PCS/ME/CFS post-COVID-19 syndrome/myalgic encephalomyelitis/chronic fatigue syndrome; non-COVID ME/CFS non-COVID-19 myalgic encephalomyelitis/chronic fatigue syndrome; PEM post-exertional malaise; CFQ Chalder fatigue scale; SF-36 36-Item Short Form Survey. Bell disability scale (score 0–100), CFQ (score 0–33), and SF-36 physical function, vitality, role limitations, and social function (scores 0–100) were assessed in PCS (post-COVID-19 syndrome) and non-COVID-ME/CFS cohorts by questionnaires. Data were analyzed with nonparametric all-pairs Dunn-type multiple contrast tests (Bell disability score, CFQ, SF-36 physical functioning) and Brunner-Munzel tests. The p values were adjusted for multiplicity across endpoints with the Benjamini-Hochberg (BH) correction. Median are shown with IQR (interquartile range). Source data are provided as a Source Data file.

Fig. 2. Frequency, severity, and length of post-exertional malaise (PEM).

PCS/non-ME/CFS post-COVID-19 syndrome/non-myalgic encephalomyelitis/chronic fatigue syndrome; PCS/ME/CFS post-COVID-19 syndrome/myalgic encephalomyelitis/chronic fatigue syndrome; non-COVID ME/CFS non-COVID-19 myalgic encephalomyelitis/chronic fatigue syndrome; PEM post-exertional malaise. Frequency and severity of PEM was assessed on a five items scale with 0–20 points (“none” to “all of the time”/“very severe”) and the length in seven categories (from <1 h to 2–3 days), according to Cotler. Median and IQR (interquartile range) in PCS/ME/CFS (n = 19), PCS/non-ME/CFS (n = 23), and non-COVID ME/CFS patients (n = 17 for frequency and length, and n = 16 for severity) is shown. Data were analyzed with nonparametric all-pairs Dunn-type multiple contrast tests. The p values were adjusted for multiplicity across endpoints with the Benjamini-Hochberg (BH) correction. Source data are provided as a Source Data file.

Fig. 3. Hand grip strength (HGS).

HGS hand grip strength; PCS/non-ME/CFS post-COVID-19 syndrome/non-myalgic encephalomyelitis/chronic fatigue syndrome; PCS/ME/CFS post-COVID-19 syndrome/myalgic encephalomyelitis/chronic fatigue syndrome; non-COVID ME/CFS non-COVID-19 myalgic encephalomyelitis/chronic fatigue syndrome. HGS was assessed in PCS cohorts (PCS/non-ME/CFS n = 13, PCS/ME/CFS n = 14 for Fmax1 and Fmean1, n = 13 for Fmax2 and Fmean2) and non-COVID-ME/CFS (n = 13). Fmax1 and Fmean1 of ten pulls in female patients and repeat assessment after 60 min (Fmax2 and Fmean2 of ten pulls) are shown (median and IQR (interquartile range)). Cut-off values of AUC reference values for age-matched healthy females are displayed as dashed lines: <40 years black dots and narrower dashed lines; >40 years white dots and wider dashed lines. Data were analyzed with nonparametric all-pairs Dunn-type multiple contrast tests. The p values were adjusted for multiplicity across endpoints with the Benjamini-Hochberg (BH) correction. Source data are provided as a Source Data file.

Fig. 4. Sitting and standing heart rate and blood pressure in female patients.

PCS/non-ME/CFS post-COVID-19 syndrome/non-myalgic encephalomyelitis/chronic fatigue syndrome; PCS/ME/CFS post-COVID-19 syndrome/myalgic encephalomyelitis/chronic fatigue syndrome; BP blood pressure; POTS postural orthostatic tachycardia syndrome. Heart rate (pulse) as well as systolic (systole) and diastolic (diastole) BP sitting, standing, and after 2, 5, and 10 min standing in females with PCS/non-ME/CFS (n = 15) or PCS/ME/CFS (n = 14). Other symbols than blank dots represent patients with POTS (three with PCS/ME/CFS and one with PCS/non-ME/CFS) and/or orthostatic hypotension (five patients with PCS/ME/CFS and one with PCS/non-ME/CFS). Median are shown with IQR (interquartile range). Source data are provided as a Source Data file.

Fig. 5. Correlation of hand grip strength (HGS) with laboratory parameter.

PCS/non-ME/CFS post-COVID-19 syndrome/non-myalgic encephalomyelitis/chronic fatigue syndrome; PCS/ME/CFS post-COVID-19 syndrome/myalgic encephalomyelitis/chronic fatigue syndrome; non-COVID ME/CFS non-COVID-19 myalgic encephalomyelitis/chronic fatigue syndrome; Hb hemoglobin; CRP C-reactive protein; IL8 interleukin 8; NT-proBNP N-terminal prohormone brain natriuretic peptide; ACE angiotensin converting enzyme; HGS hand grip strength. Correlation of HGS parameter Fmax1, Fmean1, Fmax2, and Fmean2 with laboratory parameters of relevance for oxygen supply, inflammation, and vasoregulation. We analyzed the data within a correlation analysis using spearman’s ρ and Benjamini-Hochberg (BH) correction for multiplicity. Correlations that were significant are indicated by blue (positive) or red (negative). Source data are provided as a Source Data file.