Megan E. Roerink

Interleukin-1 as a mediator of fatigue in disease: a narrative review

Fatigue is commonly reported in a variety of illnesses, and it has major impact on quality of life. Previously, it was thought that fatigue originates in the skeletal muscles, leading to cessation of activity. However, more recently, it has become clear that the brain is the central regulator of fatigue perception. It has been suggested that pro-inflammatory cytokines, especially interleukin-1 alpha (IL-1α) and interleukin-1 beta (IL-1β), play a prominent role in the development of central fatigue, and several studies have been performed to elucidate the connection between inflammation and these central processes.In this narrative review, mechanisms of action of IL-1 are described, with special attention to its effect on the central nervous system. In addition, we present a summary of studies that (i) investigated the relationship between circulating IL-1α and IL-1β and fatigue severity and/or (ii) evaluated the effect of inhibiting IL-1 on fatigue. We aim to improve the understanding of fatigue in both inflammatory and non-inflammatory illnesses, which could help develop strategies to treat fatigue more effectively.Reviewing the studies that have been performed, it appears that there is a limited value of measuring circulating IL-1. However, inhibiting IL-1 has a positive effect on severe fatigue in most studies that have been conducted.

Metabolome of chronic fatigue syndrome.

Naviaux et al. (1) report on a distinct metabolic signature present in patients who have myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) compared with healthy controls. Metabolic pathway analysis is a growing field of interest, and could offer relevant pathophysiological or diagnostic clues in complex illnesses such as CFS. However, reviewing the patient selection and statistical methods used, we have some concerns.

Postural orthostatic tachycardia is not a useful diagnostic marker for chronic fatigue syndrome

Postural orthostatic tachycardia syndrome (POTS) is considered a diagnostic marker for chronic fatigue syndrome (CFS).

Cytokine signature in chronic fatigue syndrome

One of the major findings in the publication by Montoya et al. (1) on cytokine signatures in chronic fatigue syndrome is elevation of circulating TGF-β in patients with chronic fatigue syndrome (CFS). Unfortunately, the materials and methods of ref. 1 do not give much information on how the controls were recruited, and how the blood samples of … [↵][1]1To whom correspondence should be addressed. Email: jos.vandermeer{at}radboudumc.nl. [1]: #xref-corresp-1-1

Hair and salivary cortisol in a cohort of women with chronic fatigue syndrome

ABSTRACT Hypocortisolism has been found in CFS patients in blood, urine, and saliva. It is unclear if hypocortisolism can also be demonstrated using long‐term cortisol measurements, such as cortisol in hair. In addition, the interaction between the HPA axis and the immune system, both expected to play an important role in CFS, is unclear. The objective of the current study was to compare hair and salivary cortisol concentrations in a cohort of female CFS patients to those in healthy controls, and to test the effect of an interleukin‐1 receptor antagonist (anakinra) on the HPA axis. Salivary cortisol concentrations of 107 CFS patients were compared to 59 healthy controls, with CFS patients showing a decreased cortisol awakening response (4.2nmol/L±5.4 vs 6.1nmol/L±6.3, p=0.036). Total cortisol output during the day did not differ significantly in saliva, but there was a trend to lower hair cortisol in a subset of 46 patients compared to 46 controls (3.8pg/mg±2.1 vs 4.3pg/mg±1.8, p=0.062). After four weeks of treatment with either daily anakinra (100mg/day) or placebo, there was a slight decrease of hair cortisol concentrations in the anakinra group compared to an increase in the placebo group (p=0.022). This study confirms the altered dynamics of the HPA axis in a group of CFS patients, and for the first time shows that this might also be present for long‐term cortisol measures. HIGHLIGHTSHypocortisolism has been described in CFS.CFS patients have a decreased cortisol awakening response compared to healthy controls.Long‐term functioning of the HPA‐axis has not been assessed previously in CFS.There was a trend to lower hair cortisol concentrations in CFS patients.

Cytokine Inhibition in Patients With Chronic Fatigue Syndrome

IN RESPONSE: We agree that patients with CFS frequently report flu-like symptoms. However, in our experience, the presence of sore throat and tender lymph nodes does not properly discriminate patients with an inflammatory signature from those without. In our study population, 68% of patients regularly had sore throat and 56% regularly had tender lymph nodes, whereas 78% had 1 of these symptoms once. We evaluated treatment effects in subgroups of patients with an infectious onset versus those with a noninfectious start and found no differences between these 2 groups. We also agree that tumor necrosis factor may be involved in the experience of fatigue, as our study group previously showed in an animal study (1). Nevertheless, the studies that Dr. Chu cited involving etanercept (2, 3) did not show an effect of this drug in patients with CFS. Because we believe that cytokine disturbances are largely situated in the central nervous system of patients with CFS, we contend that etanercept, with its large molecular weight, is not a proper drug to inhibit tumor necrosis factor in the brain. As our trial shows, performing such studies using a placebo-controlled design and with inhibitors that access the central nervous system is essential.