Q fever: still a mysterious disease

Q fever remains an incompletely understood disease (the Q is for Query). It is caused by a zoonotic agent, C. burnetii, that is widely distributed in animals.1 It can give rise to chronic infections in certain patients: chronic endocarditis, osteomyelitis, and infections of vascular aneurysms and prosthetics have all been documented by culture. When infection occurs during pregnancy, abortion may result, and chronic uterine infection, associated with recurrent miscarriages, may follow acute infection.2 In patients with valvular lesions and those with cancer, Q fever can lead to chronic endocarditis within months to years.3 Moreover, in animals that have recovered from C. burnetii, immunosuppression can induce a bacteraemic relapse.4,5 This demonstrates that any resistance to infection following recovery is non‐immune, and chronic carriage may be common. Thus C. burnetii may be involved in the aetiology of chronic illnesses, such as chronic fatigue and artherosclerosis, where the causative agent is unknown. In this issue, two papers from the same team report on the long‐term association of C. burnetii with chronic fatigue and cardiac disease in a cohort of patients from a Q fever outbreak. Chronic fatigue is an extremely difficult disease to define, and its prevalence may vary greatly. It has been reported following Q fever in Australia6 and in the UK.7 In contrast, few cases of post‐Q‐fever fatigue have been documented from France and Canada.1 Wildman et al., in this issue of the journal, found that in the follow‐up of patients with Q fever, fatigue and idiopathic chronic fatigue were found in nearly 65% of patients, twice as frequently as in controls. Whether this fatigue is psychological in origin, or directly caused by the bacterium, is unknown. The reported percentage of people with fatigue is very high in this study, with 34% in the control group. This is in contrast to a study in England where 9.9 to 11.7% of people reported fatigue8 and one in Boston, where 8.5% of people reported fatigue and 0.3% could be diagnosed with chronic fatigue syndrome.9 Because of the difficulties in quantifying subjective symptoms, one should be careful about generalizing from these data. Chronic fatigue syndrome is an entity for which many infectious agents have been proposed, but none has been confirmed. Our experience, when specifically enquiring for residual asthenia following Q fever, was that 5–10% of patients exhibited such symptoms at 6 months after onset, and only a very few at 1 year. It is difficult to know whether this reflects observational bias, cultural differences, different C. burnetii strains or different genetic susceptibilities. Ayres et al. report long‐term follow‐up in the same patients, looking for excess cardiac disease compared to controls. They confirmed two major findings. First, that patients suffering from Q fever represent a susceptible subset of the exposed population,10 with underlying disease. This may explain why an non‐specific high mortality was found in this population (12.9% in 10 years in this study). Indeed, there is an over‐representation of middle‐aged men in diagnosed cases.11 Second, unexplained endocarditis (2/147 in 10 years, compared to 1/105 in the general population) is observed in the follow‐up of patients with Q fever, which may well be C. burnetii endocarditis. This incidence is similar to that previously reported in France following Q fever.3 Patients with Q fever may be informed of this risk. The authors did not confirm the findings of the Swiss investigators who showed an excess mortality due to cardiac disease in the long‐term follow‐up of patients exposed to C. burnetii.12 However, in the Swiss study, all seroconverters (including asymptomatic cases and not only patients) were included and therefore the populations may not be comparable. Previous studies have detected C. burnetii DNA in patients with residual asthenia13 or other unexplained diseases.14 There is controversy about the use of PCR for detecting C. burnetii, as for many other diseases.15 PCR is a remarkable but double‐edged tool for diagnosis, as DNA contamination is frequent. Results must be interpreted with cautionwhen appropriate controls and precautions are not reported. For example, testing two different target genes, using real negative control samples (not water), may increase the value of the test. In our laboratory, we have generally been unable to detect C. burnetii DNA in the blood of patients with acute Q fever, and remain sceptical about the detection of C. burnetii DNA in the blood of asymptomatic people. In this context, the production of amplicons by PCR from the peripheral blood of chronic fatigue patients needs to be confirmed.13,14 Other studies, involving new tools, may allow us to examine the possibility that many incompletely understood diseases such as atherosclerosis, sarcoidosis16 and chronic fatigue are caused by intracellular bacteria such as Chlamydia, Rickettsia and Coxiella.