The history of ME/CFS is rather well described. However, the article is very speculative and I am especially concerned with the claims that are made about the involvement of stress in ME/CFS (paragraphs 5.5.3, 5.5.5 & discussion). For example:
One of the hypotheses that could explain the low cortisol levels reported in patients with ME/CFS is related to the nature of the dysregulation of the stress response. It is noteworthy to remark that since 1998, Scott et al. [
142] have suggested the ME/CFS is a stress-related disorder.
There is evidence suggesting that stressors, including emotional distress, may exacerbate ME/CFS symptoms, with fatigue being the most prevalent [
138]. Emotional distress reactions, such as environmental challenges, may trigger physical symptoms in ME/CFS [
150]. (...) It can be concluded that using stress reduction interventions, such as perceived stress management skills in patients suffering from ME/CFS, could be useful to mitigate the symptomatology [
143,
148]. ME/CFS patients reveal a flatter cortisol awakening response, as well as a flatter diurnal slope of salivary cortisol output compared to healthy individuals [
31], particularly in patients with early adverse life stressors [
146]. It is plausible that persons with better stress management skills have less anxiety and negative mood (...)
Their argument about the involvement of the HPA axis is based off of studies of hypocortisolism in CFS, and seems to have been inspired at least in part (according to Table 1) by a
poor review by Tomas et al. (ref. 14, from Julia Newton's group) that discusses:
- hypocortisolism, from a
meta-analysis of cortisol levels in functional somatic disorders which fails to account for many confounding factors -- especially sleep disturbance in ME/CFS -- and does not reach statistical significance when some are (medication, physical activity levels, depression)
- speculation on childhood trauma based on studies in rodents...
- the positive upregulation of mineralocorticoid & glucocorticoids receptors, but Newton et al. contradict this hypothesis:
The enhanced suppression of cortisol during the dexamethasone [36, 37] and prednisolone suppression test [38] supports the notion that increased functional activity of GR and possibly MR may have pathophysiological significance in CFS. However, as dexamethasone is metabolised via cortisol metabolic pathways, the enhanced cortisol suppression during the DST may therefore be caused not by GR upregulation but by reduced dexamethasone metabolism (as a consequence of the enzyme inhibition secondary to persistent hypocortisolaemia [39]).
Newton et al. are also aware of the confounding factors:
Despite the temporal relationship, it is not yet established whether the endocrine dysregulation is causal, consequent, or an epiphenomenon of the disorder.
[...]
Nonetheless the abnormalities are subtle, and there is marked variation in basal and challenge tests in CFS patients and a real risk that these so-called abnormalities are simply confounds or epiphenomena.
The main review they cite for HPA axis dysfunction in ME/CFS is
that of Maes' group (2017) which, similarly, contains conflicting findings from CFS studies, where the assessment of PEM is uncertain.
Strangely, Cortes et al. also contradict themselves. First quote from paragraph 5.5.5, second one from the discussion:
Reviewing the literature, there is a wealth of studies that have conflicting conclusions about the dysfunction in the HPA axis in patients with ME/CFS.
[...]
However, there is no convincing evidence that any HPA axis disturbance is specific to ME/CFS, or that it is a primary cause of the disorder rather than being related to the many possible consequences or comorbidities of the illness [138].
ME/CFS patients show heightened negative feedback inhibition of the HPA axis, which is associated with hypocortisolism and heightened GR sensitivity [224]. As a result, patients with ME/CFS often show heightened immune responses owing to the combined effects of chronic stress with activated microglia [130, 223] and increased HPA-axis sensitivity [224]. The HPA axis has been of great importance for the understanding of the pathophysiology of the disease
None of the references here -- 224, 130, 223 and also 222 earlier -- are about ME/CFS, so they are cited on a speculative basis, and in a vague way: it is unclear how they support the authors' claims. For example:
The immune system is involved in the stress response, since stress activates the immune system, leading to peripheral inflammation that may ultimately contribute to the onset of a part of the symptomatology of the disease [222].
[...]
222. Yirmiya, R.; Goshen, I. Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav. Immun. 2011, 25, 181–213.
224. Yehuda, R.; Bierer, L.; Sarapas, C.; Makotkine, I.; Andrew, R. Cortisol metabolic predictors of response to psychotherapy for symtpms of PTSD in survivors of the World Trade Center attacks on September 11, 2001. Psychoneuroendocrinology 2009, 34, 1304–1312.
There also are some typos throughout the paper (repeated occurrences of "ME/CSF"). Brett Lidbury is both a co-author of the paper and the guest editor of the special issue it was published in, so this double role makes me question the extent to which he was involved in peer reviewing & editing it (review reports are unavailable).
Given the emphasis that Cortes et al. give to the neuroendocrine system (including emotional distress, stress as factors in the pathophysiology of ME/CFS) despite the issues with the quality of the evidence they present, I would not recommend this review to someone who is trying to get an overview of biomedical research on ME/CFS.
Komaroff's short article in JAMA (2019) is probably a better resource.
