The biological pathogenesis of Chronic Fatigue Syndrome / Myalgic Encephalomyelitis
This editorial (1) comes from authors from two of three CFS/ME centres whose prolific academic production in CFS/ME provides almost the sole support for a supposed psychiatric basis for the disease; these centres are Kings College London, Nijmegen Medical Centre in the Netherlands, and the University of New South Wales, Sydney, Australia. However, the scientific basis on which the treatments, Cognitive Behavioural Therapy (CBT) and Graded Exercise Therapy (GET), are offered is critically flawed. The original PACE trial conducted by Kings College London, enrolled patients using the 1991 Oxford criteria (2), which allows inclusion of patients with affective disorders. This is in direct conflict with the internationally accepted 1994 CDC criteria which specifically excludes patients with affective disorders. This means that this study was performed using patients whose exact diagnoses are unknown. However, despite this flaw, global insurance companies do not pay sickness benefit to CFS/ME patients on the basis that effective treatments are available. Yet these interventions are not effective in CFS/ME.
CBT helps only a fraction of patients and GET has been shown to exacerbate the symptoms of patients with CFS/ME, which is logical as one of the cardinal symptoms of CFS/ME is post-exertional malaise, and so GET should not be used for CFS/ME patients. Furthermore, the Institute of Medicine in the USA has recently recommended that the name, CFS/ME, should be changed to Systemic Exercise Intolerance Disease (SEID) (3), which again reinforces the truth that exercise therapy should not be used for CFS/ME.
We know that CFS/ME can be triggered by a variety of infections, vaccines, exposure to organophosphate chemicals, and that the pathogenesis involves prolonged immune activation, which results in a flu-like illness that persists for months to years, and we all know how we feel during a flu-like illness, and there is no dispute that flu-like illnesses are caused by viruses. Several infection models have been presented which illustrate very well this progression in patients followed from the time of acute infection to development of CFS/ME. Parvovirus B19 triggers CFS/ME and this is predisposed to by carriage of HLA-DRB1*01, *04 and *07 alleles, is characterised by raised levels of circulating TNF-α and IFN-γ, and CFS/ME triggered by B19 has been cured with intravenous immunoglobulin (IVIG) which is the specific treatment for B19 infection (4). Coxiella burneti also triggers CFS/ME and this is predisposed to by carriage of HLA-DRB1*11 and certain IFN-γ polymorphisms, is associated with chronic immune activation and Q fever-associated CFS/ME is treated successfully with tetracyclines which are the specific treatment for Q fever (5). Epstein-Barr virus triggers CFS/ME, and patients with EBV-triggered CFS/ME have been successfully treated with valacyclovir (6), which is a specific treatment for EBV infection. In all of these models, the infectious agent persists long-term with chronic genomic persistence and antigen presentation, which appears to be important. The diversity of infectious triggers and individual responses likely account for the heterogeneity observed in CFS/ME, and the existence of subtypes, which are recognised to be important for the optimal management of patients.
Maybe the big breakthrough in CFS/ME comes when we are free to apply our significant existing knowledge of CFS/ME towards the best investigation and treatment of INDIVIDUAL patients, whom we know have different pathogenetic processes which account for the existence of disease subtypes. Disease subtypes are a feature of multiple chronic inflammatory autoimmune diseases and are taken into account in their management, and therefore CFS/ME is typical of such a biological disease.
References
1. Lloyd AR, Meer JW. The long wait for a breakthrough in chronic fatigue syndrome. BMJ. 2015;350:h2087. doi: 10.1136/bmj.h2087.
2. Sharpe MC, Archard LC, Banatvala JE, Borysiewicz LK, Clare AW, David A, Edwards RH, Hawton KE, Lambert HP, Lane RJ, et al. A report--chronic fatigue syndrome: guidelines for research. J R Soc Med.1991 Feb;84(2):118-21.
3. Institute of Medicine. Beyond myalgic encephalomyelitis/chronic fatigue syndrome: redefining an illness. Washington, DC: National Academies Pr; 2015
4. Kerr JR, Cunniffe VS, Kelleher P, Bernstein RM, Bruce IN. Successful intravenous immunoglobulin therapy in 3 cases of parvovirus B19-associated chronic fatigue syndrome. Clin Infect Dis.
2003;36(9):e100-6.
5. Sukocheva OA, Marmion BP, Storm PA, Lockhart M, Turra M, Graves S. Long-term persistence after acute Q fever of non-infective Coxiella burnetii cell components, including antigens. QJM. 2010;103(11):847-63.
6. Lerner AM, Beqaj SH, Deeter RG, Fitzgerald JT. Valacyclovir treatment in Epstein-Barr virus subset chronic fatigue syndrome: thirty-six months follow-up. In Vivo. 2007;21(5):707-13.
Competing interests: No competing interests
07 May 2015
Jonathan R Kerr
Professor of Epidemiology
Universidad del Rosario
Quinta de Mutis, Bogota, Colombia
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