• Enteroviruses
• chronic fatigue syndrome

In the paper by Lane et al(see pp 1382–1386)¹ an association was found between abnormal exercise lactate response and enterovirus sequences in the muscle of some patients with chronic fatigue syndrome (CFS). The paper rekindles the old saga of enteroviruses, muscle inflammation, and fatigue.

CFS remains an elusive entity. When all known factors causing fatigue are excluded, a number of patients have organic disease. Because some CFS patients have impaired muscle energy metabolism,² the cause of fatigue may not be “in their head” but “in their muscle”. Now, Lane et al propose that such metabolic impairment is more common in patients with enteroviral sequences in the muscle. The paper raises a fundamental question: can enteroviruses infect human muscle and cause persistent infection that affects only the metabolic machinery of the cells without muscle destruction? If so, is this clinically relevant to CFS patients?

Although coxsackieviruses in mice cause acute myositis, there is no convincing evidence that they also infect human muscle.³ Cases of epidemic pleurodynia, myoglobinuria, or myocarditis attributed to coxsackieviruses, remain unsubstantiated. The evidence is even weaker for chronic diseases, such as CFS or inflammatory myopathies.³ Unfortunately, the application of modern molecular virology techniques have not cleared the field; instead, they keep the controversy alive. Furthermore, data on viral persistence emerging from the mouse model and tissue cultures, fuel the scientific interest. After an acute enteroviral infection, mice develop a chronic, T cell dependent, myositis; viral RNA is detectable in the muscle but declines over a 12 month period, as the inflammation resolves. Non-dividing cells, such as myofibres, if survived the acute cytopathic damage, regenerate and may harbour viral RNA, trapped in the cytoplasm.^3,4 These viral material mutate, become less lytic or infective and under certain conditions, may produce interferon or other cell mediators that upregulate transcription of cytokine genes through activation of nuclear factor kappa B (NFκB). The induced nitric oxide synthase and cytokines, such as tumour necrosis factor alpha or interleukin 1, may either cause a slow muscle fibre injury or deprive the cells of their luxury functions, resulting in indolent metabolic dysfunction.^3,4

Accordingly, the findings of Lane et al are theoretically relevant to CFS even though a causal relationship between viral persistence and reduced muscle endurance was not demonstrated. In the past, such findings have turned out to be epiphenomena because enteroviruses are ubiquitous in humans and technical flaws inherently connected to contamination in laboratories working with these viruses are inevitable. Lane et al have performed a careful study and their findings deserve attention because, if proved to be specific, they will provide the first indirect indication of a viral related fatigue in a subset of CFS patients.

CFS is a common problem and any clues regarding its cause are welcome. The authors need, however, to demonstrate enterovirus within the muscle fibres by in situ PCR; prove that viral persistence alters the metabolic machinery of the cell; and show that such abnormalities cause clinical symptomatology. This is a laborious, but worthwhile effort that may prove rewarding for the millions of CFS patients because anti-enteroviral agents are now available (pleconaril) or in the offing. The authors may be on the right target but there are no shortcuts in pursuing it.