Long-term persistence of Coxiella burnetii after acute primary Q fever

Q Fever Research Group, Infectious Diseases LAboratories, IMVS and Hanson Institute, Adelaide, South Australia.
QJM: monthly journal of the Association of Physicians (Impact Factor: 2.46). 02/2005; 98(1):7-20. DOI: 10.1093/qjmed/hci009
Source: PubMed

ABSTRACT Long-term persistence of C. burnetii in infected animals was established in the 1950s and 60s, but the implications for human Q fever are not fully explored.
To compare the prevalence of markers of infection in a cohort of Q fever patients in Australia (up to 5 years after infection) with those in the 1989 Birmingham cohort (12 years after infection).
Case follow-up study.
C. burnetii was tested for by: (i) antibodies to Phase 1 and 2 antigens in the three immunoglobulin classes; (ii) detection of DNA in bone marrow and peripheral blood mononuclear cells by PCR assays directed against several different targets in the genome; and (iii) attempts to isolate coxiellas in cell culture or mice from PCR-positive samples. Amplicon specificity was verified by fluorometric probing and by sequencing. Cross-contamination was excluded by extensive use of non-template controls, and in particular by the use of certain IS1111a target sequences.
Irrespective of clinical state, both groups remained seropositive, principally exhibiting medium levels of IgG antibody against C. burnetii Phase 2 antigen. C. burnetii genomic DNA was detected by PCR in 65% of bone marrow aspirates from Australian patients and approximately 88% of Birmingham patients. No coxiella were isolated from PCR positive samples.
We propose a provisional model for persistence. In Q fever without sequelae, the process is largely confined to the bone marrow. In Q fever fatigue syndrome (QFS), it is modulated by the patient's immunogenetic background to give higher levels of coxiella genomes in bone marrow and increased shedding into the peripheral blood. In Q fever endocarditis, late pregnancy, or during iatrogenic or other immunosuppression, the multiplication cycle is prolonged, and a potential source of live organisms.

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    • "In contrast to Mycobacterium and Salmonella little is known about the interaction of DCs with intracellular bacteria that do not typically receive clinical attention. This review focuses particularly on zoonotic Coxiella, Brucella and Francisella, which are often under-diagnosed, partially due to their ability to induce only idle immune response, yet can cause life-threatening complications (Cooper et al., 1999; Brouqui and Raoult, 2001; Marmion et al., 2005; Baud et al., 2009; Buzgan et al., 2010; Kaya et al., 2011; Wegdam-Blans et al., 2012). We feel there may be a connection between the outcome of the early DC interactions and the mild nature of the infection initial phase. "
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    • "Purified DNA was then stored at -20°C prior to further analysis. Real-time PCR analysis Primer sets targeting the Com1, IS1111 (Marmion et al. 2005 "
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    ABSTRACT: Abstract Wild animals and the tick species that feed on them form the natural transmission cycle and reservoir of Coxiella burnetii. The objective of this study was to determine whether C. burnetii was present in the blood of host animals and their ticks in northern Queensland, Australia. Three genomic targets were detected using real-time PCR assays-the Coxiella-specific outer membrane protein coding gene (Com1), the multicopy insertion element (IS1111), and the isocitrate dehydrogenase gene (Icd). Quantification of the single-copy targets identified a range of 1.48×10(1) to 4.10×10(3) C. burnetii genome equivalents per microliter in the ticks tested. The detection of Coxiella based on the presence of the genomic targets indicated the occurrence of C. burnetii in both the ticks and whole blood of a variety of native Australian marsupials and confirms these animals are capable of acting as reservoirs of Q fever in northern Queensland.
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    • "To our knowledge, this paper reports the first documented case of C. burnetii present in a BAL sample obtained from a patient after MTX therapy. At present, C. burnetii has only been isolated from urine, semen and bone marrow samples obtained from patients with Q fever (Kruszewska et al. 1996, Maurin & Raoult 1999, Marmion et al. 2005). Q fever is not a common diagnosis and it may easily be overlooked in immunocompetent or immunodeficient individuals and pregnant women, being misinterpreted as several other infectious diseases. "
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    ABSTRACT: Q fever is caused by Coxiella burnetii, a small obli-gate intracellular Gram-negative bacterium of the order Legionellales (Stein et al. 1993). C. burnetii has a vari-ety of hosts, including many vertebrates and ticks. The transmission of C. burnetii in humans typically occurs via the inhalation of contaminated aerosols from fresh or desiccated urine, faeces, milk and birth products; less commonly, transmission occurs through the consump-tion of raw milk and milk products (Maurin & Raoult 1999, Tissot-Dupont & Raoult 2008). The incubation period for C. burnetii is variable, de-pending on the infecting dose and the health status of the patient. Primary infection with C. burnetii is commonly asymptomatic. In the symptomatic acute disease, flu-like syndrome, pneumonia and hepatitis are considered to be the classic presentations, but rash, pericarditis, myocarditis, aseptic meningitis, encephalitis and osteo-myelitis have also been described. Fatalities are rare and are typically associated with other debilitating health conditions. In most patients, the acute disease either has a self-limited course or responds to appropriate therapy (Maurin & Raoult 1999, Tissot-Dupont & Raoult 2008). Following the acute phase of Q fever, a small number of patients present symptoms of Q fever fatigue syndrome (QFS), characterised by headache, joint and muscle pain and fatigue (Ayres et al. 1996, Raoult et al. 2000, Pap-pas et al. 2003, Arashima et al. 2004, Hickie et al. 2006, Ledina et al. 2007). Chronic Q fever occurs in 1% of in-fected patients months or years after the initial infection. The most common form of chronic Q fever is endocar-ditis, which is typically associated with an underlying valvulopathy and immunosuppression. Less-common presentations of chronic Q fever include granulomatous lesions in the bones, joints, liver, lung, testis and soft tis-sues (Ralph et al. 2007, Tissot-Dupont & Raoult 2008). Studies have shown that C. burnetii can be reactivated during pregnancy and in patients with immunosup-pression. Studies suggest that C. burnetii persists after most instances of acute Q fever, regardless of clinical status and that immunogenic variation in the response to persistent infection can lead to cytokine dysregula-tion (Penttila et al. 1998, Harris et al. 2000, Pappas et al. 2003, Ledina et al. 2007). Although impaired T-cell immunity in patients with human immunodeficiency virus (HI�), cancer, lympho-immunodeficiency virus (HI�), cancer, lympho-virus (HI�), cancer, lympho-ma and pregnancy has been associated with the failure to eradicate C. burnetii and progression to the chronic disease, there are no previous reports of an association between Q fever and the use of methotrexate (MTX) for immunosuppressive therapy (Maurin & Raoult 1999, Nausheen & Cunha 2007). Low doses of MTX have been used effectively for various rheumatic and non-rheumatic diseases and opportunistic infections caused by Histoplasma, Cryptococcus, Nocardia, Mycobac-terium, human herpesvirus, the hepatitis virus and the Epstein-Barr virus in patients receiving MTX therapy (Boerbooms et al.
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