Aetiology
The infection is caused by the gram-negative, pleomorphic, intracellular bacterium Coxiella burnetii.[1][2] It was originally classified in the genus Rickettsia but, based on 16S rDNA and genome sequencing, it has since been classified along with Francisella and Legionella into the order Legionellales, a subdivision of Proteobacteria.[5][32]
C burnetii infection is acquired through inhalation or possibly ingestion of aerosolised particles containing the organism.[33] The bacterium is present in animal reservoirs. The most common hosts are sheep, goats, and calves, although multiple species may be infected and potentially transmit the disease to humans. The bacterium has also been isolated from ticks, but arthropod-borne transmission is thought to play only a minor role in the epidemiology of human infection. Humans get infected when exposed to animal products of conception or, less commonly, faeces, milk, or urine. These products can contaminate the soil and environment, posing a risk for wind-borne spread of contaminated dust. Products of parturition contain high numbers of bacteria that may become aerosolised after drying and remain infectious for months. The placenta of infected sheep contains up to 10⁹ organisms per gram of tissue. Direct exposure with animals is not needed to acquire infection; cases have been reported without evidence of direct contact with animal reservoirs.[34]
The disease is primarily a zoonosis, but human-to-human transmission has occurred in the healthcare setting.[35] Rare cases of sexual transmission and transmission via blood transfusion have been reported.[36][37]
Pathophysiology
A low dose (1 to 10 bacteria) can cause infection.[1][38] The incubation period is approximately 2 to 3 weeks (range: 1 to 6 weeks). After the infected particles enter the host, the organism proliferates in the phagolysosomes of the macrophages and monocytes, thus avoiding phagocytosis. If the bacteria have been inhaled, the infected pulmonary macrophages mainly spread the infection systemically to the liver, spleen, and bone marrow. Systemic invasion of the bacteria into the host results in the onset of symptoms and various clinical manifestations, which depend on the size of the inoculum and the host response.[39] In immunocompetent hosts, an inflammatory response may be elicited by immune mechanisms that manifest as the formation of non-necrotising granulomata in the liver or bone marrow, known as doughnut granulomata. [Figure caption and citation for the preceding image starts]: Liver 'doughnut granuloma' characteristic of acute Coxiella burnetii hepatitis. Note the specific granuloma morphology as a doughnut. No bacteria may be seen in this granulomaHubert Lepidi, Institut Hospitalo-Universitaire Méditerranée Infection [Citation ends].
In a small proportion of patients, primary infection leads to persistent focalised infections.[3] This evolution depends both on host and bacterial factors. For example, in a small number of patients, macrophages are unable to kill the organism because of increased secretion of interleukin (IL)-10, which is produced by the infected monocytes.[40] Patients diagnosed with persistent focalised infections have been identified as producers of high levels of IL-10. Patients at risk of developing persistent focalised infection include pregnant women and patients with pre-existing valvulopathy or vasculopathy, or an immunocompromised status as a result of HIV infection or cancer chemotherapy.[38][41]
Although the life cycle of C burnetii remains unclear, there are two variants (small and large) of the organism that are easily distinguishable by electron microscopy.[5][42] The small cell variants ('pseudospores') are resistant to heat, desiccation, and multiple disinfectants, allowing the organism to remain viable for prolonged periods of time. For example, the bacterium can survive in cold temperatures in stored meat for 1 month and in skimmed milk at room temperature for 40 months.[43]
C burnetii has two antigenic states.[5] Bacteria obtained from patients or laboratory animals have phase I antigen, and the organism is considered to be virulent. Bacteria obtained after subculture in cells or embryonated eggs have an antigenic shift and have phase II antigen, which is the avirulent form. Phase I and II cells contain plasmids, but their role in disease pathogenesis has not been well described.[38] Antibodies to phase I and phase II antigens are evaluated for diagnostic confirmation. [Figure caption and citation for the preceding image starts]: Coxiella burnetii in the vacuole. A dry fracture of a vero cell exposing the contents of a vacuole where Coxiella burnetii are growingNational Institute of Allergy and Infectious Diseases (NIAID); National Institutes of Health (NIH) [Citation ends].
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