Immunological disease mechanisms in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME)

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a common and disabling disorder characterized by fatigue, post-exertional malaise, pain, and other symptoms. The underlying disease mechanisms are poorly understood. The immune system (which protects us against infections) is moderately disturbed in CFS/ME, but it remains unclear whether this disturbance is the cause of the sufferers' symptoms. The present project aims to study details of the immune system in CFS/ME patients, with a particular focus on two distinctive parts: The inflammatory reaction, and the function of the B-cell (which is a particular type of white blood cell). Furthermore, we plan to study the relationship between immune disturbances, hormonal/neurological disturbances, and patients' symptoms. The most important data source is the international COFFI consortium (Collaborative on Fatigue Following Infection), which aggregate data from 18 post-infective cohort studies (i.e., studies that have focused on the development of CFS/ME in the aftermath of mononucleosis, COVID-19, and other infections). The COFFI consortium includes more than 22000 participants across 7 countries, and ensures a homogeneous patient population. Some patients with the post-COVID-19 condition (often labelled "Long COVID") fulful diagnostic criteria for CFS/ME. The scientific knowledge on this patient group is generally scarce. As the present project was established right before/during the COVID-19 pandemic, we havre priortisied to focus on patients developing CFS/ME following acute COVID-19. We have published/submitted several scholarly papers on immunological mechanisms in young people with COVID-19/Long COVID, and we are now (as of autumn 2023) analysing large amount of data generated from advanced immunological experiments on white blood cells obtained from this patient group.

The role of immune disturbances in the pathophysiology of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) remains unknown. We propose that immune responses in CFS/ME are skewed from adaptive to innate immunity promoted by functional neuroendocrine and autonomic alterations, but that this skewing is relatively unimportant for the clinical phenotype. More specifically, we propose…. 1. … regarding B cell function: a. CFS/ME is characterised by attenuated B cell differentiation and stimulation responses. b. Functional alterations of B cells are driven by autonomic/neuroendocrine alterations. c. Functional alterations of B cells do not cause clinical symptoms and functional disability. 2. … regarding inflammation: a. CFS/ME is characterised by general low-grade inflammation. b. Inflammation enhancement is driven by autonomic/neuroendocrine alterations. c. Inflammation does not cause clinical symptoms and functional disability. We use data from three different research initiatives: The NorCAPITAL initiative (The Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial), a clinical trial of clonidine; the CEBA initiative (Chronic fatigue following acute EBV infection in Adolescents), a prospective study of EBV-infected adolescents; and the COFFI consortium (Collaborative of Fatigue Following Infection), an aggregate of data from 12 post-infective cohort studies. NorCAPITAL and CEBA are used for hypotheses refinement, whereas COFFI is used for validation. The COFFI consortium (which includes more than 3000 participants) is an answer to the main methodological constraints of previous CFS/ME research on immunological disease mechanisms: 1) It ensures a homogeneous patient population (all cases of CFS/ME followed a documented infectious event); 2) It allows pooling of data and biosamples, thereby greatly increasing statistical power; 3) It is solely based on prospective cohort studies.