Single aetiological agent may not be feasible in CFS patients.

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D ear S ir, I would like to thank Dr Baschetti for his very interesting letter. I hope clinicians and CFS patients will be able to benefit from its contents. We agree that chronic fatigue syndrome (CFS) is an illness with uncertain aetiology. Although it is true that no single infectious agent has been identified as a primary cause of CFS, a variety of pathogens, including HTLV-II, EBV, cytomegalovirus, herpes simplex viruses 1 and 2, and human herpes viruses 6, 7 and 8, have been identified in CFS patients [1–7]. In addition to the pathogens previously mentioned, a recent study by our laboratory has identified Mycoplasma fermentans in a statistically significant number of CFS patients over non-CFS control subjects [8]. Further investigation is necessary to determine whether these pathogens are occurring secondarily to some immunological disturbances, as some investigators believe, or whether they are involved as a primary cause of symptoms characteristic of CFS. As mentioned by Dr Baschetti, various measures of immune function have been reported to be altered in CFS subjects, thereby suggesting an association rather than demonstrating a causative link. Abnormalities that have been reported include increased circulating immune complexes, reduced CD4 and CD8 T-lymphocyte subsets, diminished natural killer cell activity, reduction in IgG subclasses, reduced mitogenic response of lymphocytes, altered cytokine production, elevated titres of antibodies to a number of viruses and abnormal production of IFN [9–15]. However, similar immune functional abnormalities have been reported in patients exposed to toxic chemicals without evidence of viral infection or reactivation [16, 17]. Moreover, the symptomatologies described in these patients overlap with CFS patients, thus making the differentiation between the two groups extremely difficult [18–21]. In these articles, the substantial overlap between chemical sensitivity, fibromyalgia and CFA was discussed. It was concluded that the latter two conditions may involve chemical sensitivity and may even be the same disorder. In fact, in a separate study strictly with CFS patients without evidence of viral reactivation but exposed to methyl tertiary-butyl ether (MTBE) and benzene, we showed that programmed cell death and cell cycle were abnormal in both groups [22]. Similarly, in our original article published in this journal, we reported elevated apoptosis and abnormal cell cycle in CFS patients without a history of exposure to toxic chemicals. The interferon-induced protein kinase RNA (PKR) was found to be elevated in these patients as well and was therefore proposed as a possible mechanism of induction of apoptosis and cell cycle abnormalities [23]. Other stressors, such as ethanol, dimethyl sulphoxide, butyric acid, corticoid hormones and platelet-derived growth factors, have also been shown by different investigators to induce 2-5 A synthetase and PKR [24–28], and one should not be surprised by these findings. Recently, we examined the activity of these interferon-inducible proteins (2-5 A and PKR) in two different patient populations, one with active viral genome(s) in the blood but without a history of exposure to toxic chemicals, and a second group negative for viral genomes (which previously had been implicated in CFS patients) but with a history of exposure to MTBE- and benzene-contaminated water. We found that, despite differences in their causative agents and their symptomatologies, high levels of both 2-5 A and PKR activity were induced. This similarity in upregulation of 2-5 A and PKR between the viral genome-positive CFS group and the chemically exposed group made the differentiation between the cause and effect more difficult (A. Vojdani et al., submitted ). Whilst the search for the aetiology of CFS continues, the observation of Dr Baschetti with regard to hypocortisolism in CFS is very intriguing. In fact, experience from our clinical laboratory indicates that CFS patients very often exhibit antibodies against the adrenal gland, which may be one explanation for hypocortisolism in CFS. Small daily doses of hydrocortisone and fludrocortisone for treatment of CFS should be considered by clinicians. Clinicians should definitely take advantage of this suggestion by Dr Baschetti and investigate the possible reduction of apoptosis and PKR, and improvement in immune function in CFS by using small doses of hydrocortisone and fludrocortisone. Whilst we hope that many CFS patients will benefit from this treatment, we still have not pinpointed the cause of elevation of interferon-induced proteins (2-5 A synthetase and PKR) and abnormal immune function, especially low natural killer cell activity and abnormal T-helper-2 cytokines, in CFS patients. It seems that CFS may be induced by multiple factors and the search for a single aetiological agent may be in vain . Received 7 September 1998; accepted 2 October 1998.