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Pitfalls to look out for when diagnosing CFS

Dr Gavin Spickett on which tests can identify the causes of tiredness

At present chronic fatigue syndrome is defined on symptoms, in the absence of clinical and laboratory evidence of other disease, medical and psychiatric. Unfortunately, fatigue is a common symptom of many medical and some psychiatric disorders.

In particular, systemic lupus erythematosus, Sjogren's syndrome and other autoimmune diseases often present in the early stages with fatigue alone. Fatigue has been a noted side-effect of some cytokines, such as interferons, used therapeutically. It has therefore been suggested the cause of the fatigue in CFS must be immunologically based. However, although there are immunological abnormalities that can be measured, there is little evidence to suggest these represent the primary cause of CFS.

The royal colleges' joint report suggests an investigation strategy based on simple tests, as the initial screen of tired patients. This includes a full blood count and differential white cell count, liver and thyroid function, creatinine and electrolytes, glucose, and a marker of an acute phase response (ESR/CRP), together with urine dipstick.

This screen will identify most common medical problems. Further investigation should only be carried out as a result of clues derived from a detailed history and/ or examination. Routine use of other immunological and virological tests as part of screening of tired patients is not justified by the pick-up rate of abnormalities which change the clinical management.

The only test that may be valuable, as part of the screen of tired patients in general practice, that was not listed by the colleges' report, is a serological test for coeliac disease. Research data published after the report has shown an increased prevalence of coeliac disease in patients presenting with non-specific fatigue. Testing should be by endomysial or tissue transglutaminase antibodies but not by gliadin antibodies which are non-specific.

In our clinic, just under 20 per cent of patients referred with 'chronic fatigue' were found to have alternative diagnoses. These were identifiable on history and examination.

Additional investigations were frequently carried out, but yielded no diagnoses that had not been identified clinically.

Additional tests, above the colleges' recommendations, should only be carried out to confirm alternative clinical diagnoses.

Typically, CFS patients may have minor abnormalities of serum immunoglobulins, and IgG subclasses, usually with insignificant reductions. Any patient with significant reductions should be formally investigated for immunodeficiency. Likewise, abnormalities of lymphocyte subsets may be seen, including minor reduction of the CD4+ T cell count and elevation of the CD8+ T cell count, in the early stages. These changes are non-specific and are seen in viral infections.

Obviously, they are also seen in HIV infection, so this needs to be considered in the differential if the history gives pointers to lifestyle factors that might increase the risk of acquisition of HIV.

It has been reported that patients with CFS may have unusual nuclear autoantibodies in their serum, but this has not been confirmed in other studies. Viral infections, particularly adenovirus and EBV, are strongly associated with the development of transient autoantibodies, not necessarily associated with clinical disease, and are also associated with triggering chronic fatigue.

This can be very confusing and it can be difficult to know whether a patient truly has an autoimmune disease or has a post-viral fatigue with virally-induced transient autoantibodies of no clinical significance.

Often the only way to tell is watch the trend in the titres of the autoantibodies with time: virally-triggered antibodies will gradually disappear with time (six-12 months). Significant antibodies will persist or increase in titre.

Routine measurement of autoantibodies in tired patients is not recommended, unless there are other pointers to autoimmune disease on the history or on the basic screen (for example thrombocytopenia, neutropenia, raised ESR).

Where there is doubt about results, they should be discussed with an immunologist.

Gavin Spickett is consultant clinical immunologist,

Royal Victoria Infirmary, Newcastle upon Tyne

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