We identified 636 reports by searches of Medline via the PubMed database (1994–2004) using the search terms “Coxiella burnetii” and “Q fever”. Large review articles were selected to incorporate data from older articles. Preference was given to articles published in journals with an impact factor higher than 2. Papers in English, French, Spanish, and Italian were read and selected. To limit the number of references, review articles or the latest publications in a series of articles from the same
ReviewNatural history and pathophysiology of Q fever
Section snippets
The disease
The natural history of Q fever in human beings is shown in figure 1. Following exposure to C burnetii, a non-immune person develops a primary infection that is asymptomatic in 60% of cases (panel).4 This infection is followed by an immune response that may or may not be symptomatic, and that results in control of bacterial multiplication. Antibodies appear, mainly directed against phase II antigen. C burnetii DNA is detectable in the serum during the early phase of the infection. When
The bacterium
C burnetii is a small, obligate intracellular Gram-negative bacterium. Phylogenically, the bacterium was reclassified from the order Rickettsiales to Legionellales, and falls in the gamma group of proteobacteria on the basis of the sequence of its 16S rRNA.21 Within this proteobacteria group, the bacterium's phylogenic neighbours include Legionellae spp, Francisella tularensis, and Rickettsiella spp.4 All these bacteria exhibit the ability to multiply within cells. The genome of the first
Survival of C burnetii in macrophages
In vertebrates, C burnetii targets monocytes/macrophages. However, C burnetii can survive in amoebae, just like Legionella spp and Francisella spp.4, 29 The internalisation pathway is different for phase I (virulent), and phase II (avirulent) forms.30, 31, 32 Attachment of phase I bacteria is mediated by αvβ3 integrin only, whereas phase II attachment is mediated by both αvβ3 and complement receptor CR3 (figure 3).32 Phase II internalisation is more efficient, resulting in better
Immune response to C burnetii
Immune control of C burnetii is T-cell dependent but does not lead to C burnetii eradication.40 C burnetii can be found in apparently cured people, as well as in the dental pulp of experimentally infected and apparently cured guineapigs.40, 45 C burnetii DNA can also be found in circulating monocytes or bone marrow of people infected months or years earlier.30
In vertebrate hosts, C burnetii infection results in the formation of granulomas in infected organs. These granulomas are made possible
Sex
The protective role of 17β oestradiol was demonstrated in mice.50 Female C57/BL6 mice have fewer granulomas and lower bacterial load than males.50 Ovarectomised mice have disease rates comparable to males50 and, when injected with 17β oestradiol, exhibit disease comparable to non-ovariectomised females.50 These experimental data show the role of female hormones in Q fever. This finding could explain why the sex ratio is biased only after puberty.8, 10 The role of female sex hormones has been
Inoculum size
Inoculum size has a role in the severity and, perhaps, the clinical manifestations of the disease. The bacterium is highly infective, since one organism is sufficient to cause infection.2 A dose-response was documented in human volunteers.61, 62 In Macacus rhesus monkeys, the dose required to kill 50% of infected animals for respiratory disease was 1·7 microorganisms.63 In human volunteers, the incubation period ranged from 10 to 17 days depending on the inoculation size.64 The inoculum size
Bacterial factors
Classifying C burnetii isolates has proved difficult because very few phenotypic characteristics have been identified. The lipopolysaccharide composition is the predominant phenotypic characteristic that differentiates isolates.67 Lipopolysaccharides have a very important role as a virulence factor in phase I C burnetii phagocytosis. In addition, several plasmids have been found in C burnetii.68 Four have been clearly identified—QpH1, QpVd,69 QpRS, and QpDG.70 Moreover, the gene sequences of
Conclusion
Substantial progress has been made in recent years. The entry and intracellular survival of C burnetii in an acidic vacuole have been extensively described. The mechanisms by which the virulent and avirulent forms are selected are now understood. The critical role of host factors in the development of chronic Q fever has been shown both in human beings and in experimental animals. Interleukin 10 seems to have a key role in the evolution of chronic infection. Basic questions such as the role of
Search strategy and selection criteria
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