ME/CFS is characterised by persistent or recurrent fatigue and the occurrence of PEM, which is a key feature of this debilitating illness. Due to the heterogeneous character of ME/CFS and the absence of biological marker, many studies tried to subtype ME/CFS patients on the basis of clinical or biological variables. Mitochondrial dysfunction has been shown in some of ME/CFS patients14,15,16,17,18,19,20,21,22. In the current study we identified a group of ME/CFS patients with elevated blood lactate in resting conditions and displaying more severe PEM.

The demographic characteristics, clinical manifestations, and comorbid conditions of our population were comparable to that reported in prior studies. For instance, the age peak in the age range 30–39 (34% of patients) and the median age of disease onset of 34 [26–41] years23, the higher prevalence of women and the median duration of illness1, and the family history of chronic fatigue syndrome (CFS) in one or more first-degree relatives (11% of patients)24 were in accord with that previously reported. Nevertheless, the percentage of patients who identified at least one ME/CFS precipitating factor (70.7%) and that of those who reported an infectious trigger (47.2%) was somewhat lower than that of prior studies24,25.

One or more comorbidities were found in 76 (61.8%) patients, which corresponds to previous reports that found comorbidities prevalence between 50 and 65%26,27 but higher prevalence was reported in one study28.

Laboratory anomalies observed in our population including reduced 8am and/or 8 pm plasma cortisol levels (18.7%), low serum zinc (32%), and low serum 25-hydroxy vitamin D (49.6%) were comparable to that reported in literature29,30,31.

Blood lactate assay results showed elevated lactate levels in resting conditions in 55 (44.7%) patients. Lane et al. found elevated lactate concentrations in a proportion of CFS patients (31/96; 32%) after short periods of exercise below the predicted anaerobic threshold19. They also reported that patients displaying abnormal lactate responses to exercise had relative deficiency of mitochondria type I fibres on muscle biopsies, which may explain elevated lactate responses to exercise32, and low intracellular pH during recovery phase when examined by magnetic resonance spectroscopy of muscle33. Other teams showed elevated ventricular lactates in CFS patients pointing to metabolic dysfunction in these patients16,17. In the current study, almost half of patients had elevated blood lactate concentrations in resting conditions. To the best of our knowledge, our study is the first to show these results. Lactate values were significantly different between the 2 groups and this difference was observed for each time point. Nevertheless, this difference appeared to be more prominent at T2. A hypothesis that could explain, at least in part, the predominant elevation of lactate levels at T2 is that eating after 16-hour fasting would abolish the beneficial effect of fasting on mitochondrial functioning and redox signalling34, leading to a sort of rebound effect responsible for mitochondrial dysfunction with increased blood lactate concentration after breakfast. The positive effect of fasting was reported in FM patients35, which could be interesting to evaluate its impact in ME/CFS patients.

When we classified our study population into two groups with or without elevated lactate to compare their phenotypic characteristics, we found that they only differ in the number of patients experiencing more severe PEM, which was significantly higher in patients with elevated lactate. This association persisted after adjusting for age at disease onset, sex, and comorbidities (OR 2.47, 95% CI: 1.10–5.55; p = 0.03). PEM severity was assessed in all patients by the standardised CDC SI self-reported questionnaire36, which includes an item designed to measure the presence, frequency, and intensity of PEM. The CDC SI is one of two tools proposed by the IOM2 for PEM assessment. We used the median PEM score on the CDC SI questionnaire to set the cut-off score ≥12 defining more severe PEM in our study.

Elevated blood lactate in resting conditions in ME/CFS patients was not reported before. In our study, patients did not display a state of extreme fatigue at the time of lactate assay, and strict resting conditions were followed carefully in all patients all over the period of different samples’ collection during hospitalisation. As well, all patients received standardised meals. Thus, the rise of lactate levels in a proportion of patients could not be related to exertion or due to variation in caloric intake.

It is interesting to note that although the whole study population was suffering from high levels of fatigue and fatigue-related impairment, results of fatigue scales showed that fatigue severity was comparable between both groups; FS median score (elevated lactate group 24 [21–28] vs. normal lactate group 23 [17–27]; p = 0.14) and FSS median score = (elevated lactate group 5.6 [4.8–6.2] vs. normal lactate group 5.4 [5.1–6]; p = 0.90). In this way, elevated lactate levels were correlated with PEM severity, but not with fatigue severity. One can expect that patients who display severe PEM are suffering from high level of general fatigue, however some authors report that some of patients who experienced severe PEM did not report high fatigue levels because they were reducing their activities to stay within their energy envelope and so their fatigue levels may be low but they can experience exhaustion if they exceed their functional capacities or exposed to a PEM trigger37,38. Another possible explanation is that there is currently no gold standard measurement of fatigue, and a ceiling effect for FSS and FS was reported39 so these scales would not accurately reflect fatigue severity.

Study’s limitations

Although data of our study were collected retrospectively, all patients were examined and diagnosed by the same physician, and all patients underwent a same standardised procedure in terms of clinical assessment including PEM, and laboratory investigations, especially lactate assay.

One source of weakness in this study was the lack of data concerning fatigue assessment as well its impact on function in some of our patients. However, these data were not statistically different in the 2 groups. As well, data concerning mode of onset of the disease were unavailable for a great number of patients and thus unexploitable. Finally, the MFIS scale that we used to measure the impact of the fatigue on function has been mainly validated in multiple sclerosis patients, but not in those with ME/CFS. Nevertheless, we have used this scale alongside two other scales, FS and FSS, which explore fatigue severity as recommended by the CDC-NINDS project40.

At the best of our knowledge, this is the first study that reports elevated blood lactate in resting conditions in a significant proportion of patients with ME/CFS. Patients who showed abnormal elevation of blood lactate at rest displayed more frequent severe PEM than those with normal lactate concentrations. This finding brings supplementary evidence for mitochondrial dysfunction in ME/CFS patients, and may contribute to a better understanding the illness. Subtyping ME/CFS patients adds to the growing body of evidence that ME/CFS is heterogeneous, and allows identifying patients with more risk for severe PEM who must adhere more closely to pacing strategies in order to avoid PEM occurrence and prevent disease exacerbation. Furthermore, our study allowed describing clinical and biological characteristics of a French population with MPE/CFS. Shedding light on these characteristics may improve knowledge and raise awareness of this public health issue.