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PicturesTop of page
IdentityTop of page
Preferred Scientific Name
- Q fever
International Common Names
- English: abattoir fever; Australian Q fever; Balkan grippe; Coxiella burnetii infection; coxiellosis; Derrick-Burnet disease; hiberno-vernal bronchopneumonia; Nine Mile fever; pneumorickettsiosis; q fever, coxiellosis, coxiella burnetii in ruminants; quadrilateral fever; query fever
OverviewTop of page
Coxiella burnetii, the causal agent of an important rickettsial zoonosis called Q fever, has a worldwide distribution with the notable exception of New Zealand (Hilbink et al., 1993; Norlander, 2000). Q fever in man is characterized by abrupt onset with severe headache, chills, remittent fever, malaise; and in animals, by pneumonitis and abortion, premature birth and low birth weight.
The disease was first described by Derrick in 1935 in Queensland, Australia, during an outbreak of a febrile illness among abattoir workers (Derrick, 1937). Burnet and Freeman first isolated a fastidious intracellular bacterium from guinea pigs that had been injected with blood or urine from Derrick's patients and named it Rickettsia burnetii (Burnet and Freeman, 1937). Derrick and others investigated the epidemiology of the disease, especially the potential role of an arthropod vector. They concluded that wild animals were the natural reservoir of Q fever, with domestic animals being a secondary reservoir, and that the disease may be transmitted by ticks or other arthropods. In 1935, Gordon Davis working at the Rocky Mountain Laboratory, Hamilton, Montana, observed the febrile illness in guinea pigs, which were exposed to ticks collected from Nine Mile, Montana, USA. They demonstrated a filterable agent with properties of both viruses and rickettsiae (Davis and Cox, 1938; Cox, 1938). A laboratory-acquired infection was reported in 1938 at Rocky Mountain Laboratory, later a definitive link was established between the Nine Mile agent and the Australian Q fever agent. Cross immunity was demonstrated in guinea pigs inoculated with Q fever agent, which were challenged with Nine Mile agent. Philip (1948) classified R. burnetii in a new genus, Coxiella, named after Harold Cox, who first isolated this microorganism in the USA. He proposed renaming the aetiological agent as C. burnetii, a name to honour both Cox and Burnet, who had identified the Q fever agent as a new rickettsial species.
Coxiellaburnetii is an obligate intracellular Gram-negative organism. This organism is morphologically and biochemically similar to other Gram-negative bacteria. C.burnetii expresses two antigens, Phase I and Phase II antigens. Phase I is the natural phase found in infected animals, arthropods or humans and is very infectious. After subculture in cells or embryonated eggs, modification of the lipopolysaccharides (LPS) results in an antigenic shift to the Phase II form, which is less infectious.
Apart from its absence in New Zealand, Q fever has a worldwide distribution (Hilbink et al., 1993), however, the cycles of maintenance in animal and arthropod hosts vary from country to country (Stoker and Marmion, 1955; Derrick, 1953). In Europe, acute Q fever cases are more frequently reported in spring and early summer (Tissot-Dupont et al., 1992). The maximum incidence of Q fever during spring is thought to be related to the lambing season, and the resulting heavy contamination of the environment with C.burnetii. Q fever is an occupational hazard for people who work with infected animals, such as laboratory personnel, with the greatest risk in those having close contact with farm animals (Fournier et al., 1998). Cattle, goats, and sheep are considered the primary reservoirs besides many wild and domestic mammals, birds, and arthropods such as ticks (Babudieri, 1959). Infected mammals shed C.burnetii in their urine, faeces, milk, and birth products. Parturient fluids and placenta of infected animals are the direct sources of C.burnetii aerosols in the environment that may spread to wool, newborn animals and other susceptible hosts. C. burnetii is very resilient and may survive for several weeks in areas where animals have been present. The inhalation of C.burnetii-infected aerosol is the primary mode of human infection. Aerosols can be spread by the wind. Ingestion of raw milk from infected mothers is another route of infection in man and animals. Experimental studies were conducted in laboratory animals such as mice (Baumgärtner and Bachmann, 1992) and guinea pigs (Scola et al., 1997) for studying the pathogenesis of the disease.
The clinical presentation of Q fever in humans is polymorphic and non-specific. It may be acute, most often pneumonia or hepatitis; or chronic, usually endocarditis. In pregnant women, Q fever has been associated with abortion, premature birth and under weight newborn babies. However, infection of animals by C.burnetii is usually asymptomatic. Clinical signs of acute infection in sheep experimentally inoculated with C.burnetii include fever, loss of appetite, mild cough, rhinitis and rapid respiration (Martinov et al., 1989). Histologically, liver tissue sections show a characteristic doughnut-shaped granuloma (Galache et al., 2004). The signs associated with chronic Q fever in sheep, goats, and cattle are infertility, abortion, and the birth of full-term dead or weak, under weight offspring (To et al., 1998; Berri et al., 2000; Moeller, 2001).
The diagnosis of Q fever relies mainly on serology, with Phase I and Phase II antibodies distinguishing acute from chronic disease. Several diagnostic methods, including microagglutination, complement fixation, radioimmunoassay, indirect immunofluorescence antibody tests (immunofluorescence assay), indirect haemolysis test, ELISA, enzyme-linked immunosorbent fluorescence assay, dot immunoblotting, and Western immunoblotting have been described. Molecular techniques such as PCR have proven to be more sensitive than standard culture techniques for retrospective diagnosis.
Tetracyclines are considered the best choice for treatment of acute Q fever. The first-line therapy for acute Q fever is doxycycline or a fluoroquinilone, whereas, for chronic Q fever, a combination of doxycycline and hydroxychloroquine is preferred (Dumler, 2002).
Q fever in man could be controlled by reducing the environmental contamination originating from infected livestock. Persons at greater risk, such as veterinarians, laboratory personnel and workers in abattoirs and wool shearing units should be immunized with the available vaccine. Several vaccines produced from Phase I whole cell C.burnetii are effective in protecting against the infection in humans.
This disease is on the World Organization for Animal Health (OIE) list of Notifiable Diseases, which includes the transmissible diseases that are considered to be of socioeconomic and/or public health importance within countries and that are significant in the international trade of animals and animal products.
Hosts/Species AffectedTop of page
The range of animal hosts involved in the epidemiology of Q fever is extremely broad and ranges from ticks to primates. It is impossible to distinguish between true and unusual hosts. The organism in nature is maintained by two cycles. The basic cycle involves many species of wildlife and their ectoparasites and the second cycle involves domestic animals. Domestic ruminants are thought to be the main reservoirs for Coxiella burnetii but cats, rabbits, birds, and other animals commonly associated with humans, are also susceptible to infection are possible sources of infection (OIE, 2004). Natural infections have been shown to occur in sheep, dogs that have ingested placentas of infected farm animals (Mantovani and Benazzi, 1953). Dairy cattle with reproductive disorders are important reservoirs of C. burnetii (To et al., 1998). Infected cows may get rid of the infection after a few months but may become carriers, with the agent localized in mammary glands and excreted throughout many lactation periods. However, seroprevalence of C. burnetii has no significant correlation with fertility in herds (Literák and Kroupa, 1998). C. burnetii has also been isolated from ticks, fleas, lice and mites that parasitized domestic and wild animals.
The pathogen’s strong resistance to environmental factors ensures its survival and its ability to infect new susceptible hosts. In Europe, cases of acute Q fever are more frequently reported in spring and early summer. The maximum incidence of Q fever is thought to be related to the lambing season, which contributes to heavy contamination of the environment with C. burnetii.
DistributionTop of page
With the notable exception of New Zealand, prevalence of Q fever is worldwide. Disease occurs chiefly in countries where substantial numbers of cattle, sheep and goats are produced. The presence of serum antibodies against Coxiella burnetii has been reported in farm animals from several geographical areas. In the USA, infection among dairy herds is widespread. However, in most countries, Q fever is not included in the list of nationally notifiable diseases.
Distribution TableTop of page
The distribution in this summary table is based on all the information available. When several references are cited, they may give conflicting information on the status. Further details may be available for individual references in the Distribution Table Details section which can be selected by going to Generate Report.
|Continent/Country/Region||Distribution||Last Reported||Origin||First Reported||Invasive||Reference||Notes|
|Afghanistan||Disease not reported||OIE Handistatus, 2005|
|Azerbaijan||No information available||OIE Handistatus, 2005|
|Bahrain||No information available||OIE Handistatus, 2005|
|Bhutan||Disease never reported||OIE Handistatus, 2005|
|Brunei Darussalam||No information available||OIE Handistatus, 2005|
|China||Widespread||Fan et al., 1987; Ning et al., 1992|
|-Hong Kong||No information available||OIE Handistatus, 2005|
|-Shandong||Localised||Zhong and Li, 1996|
|-Sichuan||Localised||Ning et al., 1992|
|-Tibet||Widespread||Zhou et al., 1998|
|Georgia (Republic of)||Disease never reported||OIE Handistatus, 2005|
|India||Widespread||Native||Malik and Yadav, 2002; Malik and Vaidya, 2005; OIE Handistatus, 2005|
|-Delhi||Widespread||Choudhury et al., 1971; Yadav and Sethi, 1979; Rana et al., 1987|
|-Haryana||Widespread||Kulshreshtha et al., 1974; Kaushik and Kulshreshtha, 1982|
|-Indian Punjab||Widespread||Randhawa et al., 1973; Sodhi et al., 1980; Sodhi et al., 1982|
|-Karnataka||Widespread||Joshi et al., 1976; Stephen and Rao, 1979|
|-Madhya Pradesh||Widespread||Tanwani et al., 1979|
|-Maharashtra||Widespread||Menon et al., 1975; Padbidri et al., 1984|
|-Odisha||Widespread||Padbidri et al., 1981|
|-Rajasthan||Widespread||Joshi et al., 1979; Mathur, 1979|
|-West Bengal||Widespread||Sen et al., 1978; Aich et al., 1980|
|Indonesia||Disease not reported||OIE Handistatus, 2005|
|-Java||Localised||Ibrahim et al., 1999|
|Iran||Native||Kovacova et al., 1996; OIE Handistatus, 2005|
|Iraq||No information available||Native||CDC, 2003; OIE Handistatus, 2005|
|Israel||Reported present or known to be present||Native||Bishara et al., 2004; OIE Handistatus, 2005|
|Japan||No information available||Native||Yoshiie et al., 1991; Htwe et al., 1992; Morita et al., 1994; OIE Handistatus, 2005|
|-Hokkaido||Widespread||Yanase et al., 1997|
|Jordan||Reported present or known to be present||Native||Aldomy et al., 1998; OIE Handistatus, 2005|
|Kazakhstan||Disease never reported||OIE Handistatus, 2005|
|Korea, DPR||Disease not reported||Native||Lee et al., 2004; OIE Handistatus, 2005|
|Korea, Republic of||Disease not reported||OIE Handistatus, 2005|
|Kuwait||Disease not reported||OIE Handistatus, 2005|
|Lebanon||Disease not reported||Native||Garabedian and Djanian, 1956; OIE Handistatus, 2005|
|-Peninsular Malaysia||Disease not reported||OIE Handistatus, 2005|
|-Sabah||Disease never reported||OIE Handistatus, 2005|
|-Sarawak||Disease never reported||OIE Handistatus, 2005|
|Mongolia||No information available||OIE Handistatus, 2005|
|Myanmar||No information available||OIE Handistatus, 2005|
|Nepal||No information available||OIE Handistatus, 2005|
|Oman||Serological evidence and/or isolation of the agent||Native||Scrimgeour et al., 2000; Scrimgeour et al., 2003; OIE Handistatus, 2005|
|Pakistan||Present||Ayaz et al., 1993|
|Philippines||Disease not reported||Native||Camer et al., 2003; OIE Handistatus, 2005|
|Qatar||Disease not reported||OIE Handistatus, 2005|
|Saudi Arabia||Al-Hajjar et al., 1997|
|Singapore||Disease never reported||OIE Handistatus, 2005|
|Sri Lanka||Disease never reported||OIE Handistatus, 2005|
|Syria||Disease not reported||OIE Handistatus, 2005|
|Taiwan||Disease never reported||OIE Handistatus, 2005|
|Tajikistan||No information available||OIE Handistatus, 2005|
|Thailand||Disease not reported||OIE Handistatus, 2005|
|Turkey||No information available||Native||Cetinkaya et al., 2000; Ongor et al., 2004; OIE Handistatus, 2005|
|Turkmenistan||Disease not reported||OIE Handistatus, 2005|
|United Arab Emirates||Disease never reported||OIE Handistatus, 2005|
|Uzbekistan||Disease never reported||OIE Handistatus, 2005|
|Vietnam||No information available||OIE Handistatus, 2005|
|Yemen||No information available||OIE Handistatus, 2005|
|Algeria||No information available||OIE Handistatus, 2005|
|Angola||No information available||Tissot-Dupont et al., 1995; OIE, 2012|
|Benin||No information available||OIE Handistatus, 2005|
|Botswana||Disease not reported||OIE Handistatus, 2005|
|Burkina Faso||No information available||Tissot-Dupont et al., 1995; OIE Handistatus, 2005|
|Burundi||Disease not reported||OIE, 2012|
|Cameroon||Disease never reported||OIE Handistatus, 2005|
|Cape Verde||Disease never reported||OIE, 2012|
|Central African Republic||Disease not reported||Tissot-Dupont et al., 1995; OIE, 2012|
|Chad||No information available||Schelling et al., 2003; OIE Handistatus, 2005|
|Comoros||Present||Tissot-Dupont et al., 1995; OIE, 2012|
|Congo Democratic Republic||Disease not reported||OIE Handistatus, 2005|
|Côte d'Ivoire||Disease not reported||Tissot-Dupont et al., 1995; OIE Handistatus, 2005|
|Djibouti||Last reported||2004||OIE, 2012|
|Egypt||Disease never reported||Sixl et al., 1989; OIE, 2012|
|Eritrea||Disease not reported||OIE Handistatus, 2005|
|Ethiopia||Disease never reported||Graham et al., 2000; OIE, 2012|
|Ghana||No information available||OIE, 2012|
|Guinea||Disease not reported||OIE Handistatus, 2005|
|Guinea-Bissau||No information available||OIE Handistatus, 2005|
|Kenya||Disease not reported||Potasman et al., 2000; OIE, 2012|
|Libya||Disease not reported||OIE Handistatus, 2005|
|Madagascar||Disease never reported||OIE, 2012|
|Malawi||No information available||OIE Handistatus, 2005|
|Mali||No information available||OIE Handistatus, 2005|
|Mauritius||Disease not reported||OIE Handistatus, 2005|
|Morocco||Disease never reported||OIE, 2012|
|Mozambique||No information available||OIE Handistatus, 2005|
|Namibia||Last reported||1991||OIE, 2012|
|Nigeria||Disease never reported||OIE, 2012|
|Réunion||No information available||OIE Handistatus, 2005|
|Rwanda||No information available||OIE Handistatus, 2005|
|Sao Tome and Principe||Disease not reported||OIE Handistatus, 2005|
|Senegal||No information available||OIE Handistatus, 2005|
|Seychelles||Disease not reported||OIE, 2012|
|Somalia||No information available||OIE, 2012|
|South Africa||Last reported||2009||OIE, 2012|
|Sudan||Disease never reported||OIE, 2012|
|Swaziland||No information available||OIE Handistatus, 2005|
|Tanzania||No information available||OIE Handistatus, 2005|
|Togo||Disease never reported||OIE, 2012|
|Tunisia||No information available||OIE Handistatus, 2005|
|Uganda||Birnie et al., 2004; OIE Handistatus, 2005|
|Zambia||Disease never reported||OIE, 2012|
|Zimbabwe||Last reported||1999||OIE, 2012|
|Bermuda||Disease not reported||OIE Handistatus, 2005|
|Canada||Reported present or known to be present||OIE Handistatus, 2005|
|-Newfoundland and Labrador||Widespread||Hatchette et al., 2002|
|Mexico||Disease never reported||Native||Salinas-Melendez et al., 2000; OIE Handistatus, 2005|
|USA||Reported present or known to be present||OIE Handistatus, 2005|
|-Florida||Localised||Conti et al., 2004|
|-Georgia||Localised||McQuiston and Childs, 2002|
|-Minnesota||Present||Gami et al., 2004|
|-Missouri||Present||Criley et al., 2001|
|-Oregon||Present||Bildfell et al., 2000|
Central America and Caribbean
|Barbados||Disease never reported||OIE Handistatus, 2005|
|Belize||Disease never reported||OIE Handistatus, 2005|
|British Virgin Islands||Disease never reported||OIE Handistatus, 2005|
|Cayman Islands||Disease never reported||OIE Handistatus, 2005|
|Costa Rica||Disease never reported||OIE Handistatus, 2005|
|Cuba||Disease never reported||OIE Handistatus, 2005|
|Curaçao||Disease not reported||OIE Handistatus, 2005|
|Dominica||Disease not reported||OIE Handistatus, 2005|
|Dominican Republic||Disease never reported||OIE Handistatus, 2005|
|El Salvador||Disease not reported||OIE Handistatus, 2005|
|Guadeloupe||Disease never reported||OIE Handistatus, 2005|
|Guatemala||Disease never reported||OIE Handistatus, 2005|
|Haiti||Disease never reported||OIE Handistatus, 2005|
|Honduras||Disease never reported||OIE Handistatus, 2005|
|Jamaica||Disease never reported||OIE Handistatus, 2005|
|Martinique||Disease not reported||OIE Handistatus, 2005|
|Nicaragua||Disease never reported||OIE Handistatus, 2005|
|Panama||Disease never reported||OIE Handistatus, 2005|
|Saint Kitts and Nevis||Disease never reported||OIE Handistatus, 2005|
|Saint Vincent and the Grenadines||Disease never reported||OIE Handistatus, 2005|
|Trinidad and Tobago||Disease never reported||OIE Handistatus, 2005|
|Argentina||Last reported||1998||OIE Handistatus, 2005|
|Bolivia||Disease never reported||OIE Handistatus, 2005|
|Brazil||Last reported||1983||OIE Handistatus, 2005|
|Chile||Serological evidence and/or isolation of the agent||OIE Handistatus, 2005|
|Colombia||Serological evidence and/or isolation of the agent||OIE Handistatus, 2005|
|Ecuador||Disease never reported||OIE Handistatus, 2005|
|Falkland Islands||Disease never reported||OIE Handistatus, 2005|
|French Guiana||No information available||OIE Handistatus, 2005|
|Guyana||Disease never reported||OIE Handistatus, 2005|
|Paraguay||Disease never reported||OIE Handistatus, 2005|
|Peru||Disease never reported||Native||Blair et al., 2004; OIE Handistatus, 2005|
|Uruguay||Reported present or known to be present||OIE Handistatus, 2005|
|Venezuela||Disease never reported||OIE Handistatus, 2005|
|Andorra||Serological evidence and/or isolation of the agent||OIE Handistatus, 2005|
|Austria||No information available||Native||Nowotny and Deutz, 2000; OIE Handistatus, 2005|
|Belarus||Disease never reported||OIE Handistatus, 2005|
|Belgium||No information available||OIE Handistatus, 2005|
|Bosnia-Hercegovina||Reported present or known to be present||Native||Velic et al., 2000; Zvizdic et al., 2002; OIE Handistatus, 2005|
|Bulgaria||Reported present or known to be present||OIE Handistatus, 2005|
|Croatia||Reported present or known to be present||Native||Cvetnic et al., 2003; OIE Handistatus, 2005|
|Cyprus||Native||Crowther and Spicer, 1976; OIE Handistatus, 2005|
|Czech Republic||Last reported||1996||OIE Handistatus, 2005|
|Denmark||CAB Abstracts data mining||OIE Handistatus, 2005|
|Estonia||Disease never reported||OIE Handistatus, 2005|
|Finland||Disease never reported||OIE Handistatus, 2005|
|France||Reported present or known to be present||Native||Berri et al., 2001; Ansart et al., 2004; OIE Handistatus, 2005|
|Germany||Reported present or known to be present||Native||Sting et al., 2003; OIE Handistatus, 2005|
|Greece||OIE Handistatus, 2005|
|Hungary||OIE Handistatus, 2005|
|Iceland||Disease never reported||OIE Handistatus, 2005|
|Ireland||CAB Abstracts data mining||OIE Handistatus, 2005|
|Isle of Man (UK)||Last reported||1991||OIE Handistatus, 2005|
|Italy||No information available||Native||Masala et al., 2004; Santoro et al., 2004; OIE Handistatus, 2005|
|Jersey||Disease never reported||OIE Handistatus, 2005|
|Latvia||Disease never reported||OIE Handistatus, 2005|
|Liechtenstein||Disease not reported||OIE Handistatus, 2005|
|Lithuania||Disease never reported||OIE Handistatus, 2005|
|Luxembourg||Disease never reported||OIE Handistatus, 2005|
|Macedonia||Reported present or known to be present||OIE Handistatus, 2005|
|Malta||Disease never reported||OIE Handistatus, 2005|
|Moldova||No information available||OIE Handistatus, 2005|
|Netherlands||Reported present or known to be present||OIE Handistatus, 2005|
|Norway||Disease never reported||OIE Handistatus, 2005|
|Poland||Reported present or known to be present||OIE Handistatus, 2005|
|Portugal||Reported present or known to be present||OIE Handistatus, 2005|
|Romania||Disease not reported||OIE Handistatus, 2005|
|Russian Federation||Disease not reported||OIE Handistatus, 2005|
|Slovakia||Reported present or known to be present||OIE Handistatus, 2005|
|Slovenia||CAB Abstracts data mining||OIE Handistatus, 2005|
|Spain||Native||Fernandez and Perez, 2003; Villa-Espinosa et al., 2003; OIE Handistatus, 2005|
|Sweden||Serological evidence and/or isolation of the agent||OIE Handistatus, 2005|
|Switzerland||Reported present or known to be present||OIE Handistatus, 2005|
|UK||Reported present or known to be present||OIE Handistatus, 2005|
|-Northern Ireland||CAB Abstracts data mining||OIE Handistatus, 2005|
|Ukraine||Disease never reported||OIE Handistatus, 2005|
|Yugoslavia (former)||Last reported||2003||OIE Handistatus, 2005|
|Yugoslavia (Serbia and Montenegro)||Last reported||2002||OIE Handistatus, 2005|
|Australia||Serological evidence and/or isolation of the agent||OIE Handistatus, 2005|
|-Queensland||Present||McDiarmid et al., 2000|
|French Polynesia||Disease never reported||OIE Handistatus, 2005|
|New Caledonia||Disease never reported||OIE Handistatus, 2005|
|New Zealand||Disease never reported||OIE Handistatus, 2005|
|Samoa||Disease never reported||OIE Handistatus, 2005|
|Vanuatu||Disease never reported||OIE Handistatus, 2005|
|Wallis and Futuna Islands||No information available||OIE Handistatus, 2005|
PathologyTop of page
In sheep with Q fever, gross lesions are mainly apparent in liver and spleen. Morphologically, the liver is oedemated and fragile, the spleen is enlarged, and the meninges hyperaemic and peppered with pinpoint haemorrhages (Belchev and Pavlov, 1977). A pregnant sheep with Q fever usually aborts in the late trimester. The aborted fetus may show hepatomegaly. The placenta of aborted sheep is red-brown and opaque with light-brown, soft cotyledons (Anon, 2001). Gross lesions of the fetus consist of generalized subcutaneous oedema and reddish fluid accumulation in the thoracic cavity (Anon, 2001).
In humans, gross lesions are not well documented. The most frequent outcome of Q fever in the form of endocarditis usually involves the aortic and mitral valves, although prosthetic valve endocarditis is increasingly reported (Fernandez-Guerrero et al., 1988; Siegman-Igra et al., 1997). The infection, with variable destruction of the valve, may be visible on gross examination. Perforation of valvular cusps and the Valsalva sinus, and the formation of aneurysms at the site of the valvular annulus, the membranous portion of the interventricular septum, or the subvalvular myocardium have sometimes been described (Maurin and Raoult, 1999). Granulomatous lymphadenitis (Tattevin et al., 2003) and subcutaneous nodules (Galache et al., 2004) have also been reported as an atypical presentation of Q fever in humans.
Histolopathology in sheep with Q fever includes strong diffuse activation and proliferation of the liver capillary endothelium with necrobiosis of the liver epithelial cells and a diffuse leukocyte infiltration. There is hyperplasia of the reticular cells and the lymph follicles of the spleen and the bronchial lymph nodes. The epithelial cells of the kidney tubules have vacuolar dystrophy, and fibroblastic proliferations. The kidney also has hyperaemia in the medullar section. Inflammatory changes in the brain may also been seen (Belchev and Pavlov, 1977). The placenta from infected animals shows infiltration of the chorionic stroma by mononuclear cells, necrosis of chorionic trophoblasts, and focal exudation of fibrin and neutrophils (Bildfell et al., 2000).
In experimentally infected SCID mice, severe cell infiltration with macrophages was the commonest feature (Masako et al., 2003). The hearts had focal calcification and severe infiltration of vacuolated macrophages in the epicardium, endocardium and myocardium. In the kidney, glomerulonephritis was observed, with infiltration with vacuolated macrophages and the proximal tubules showed hyaline degeneration. The lungs, spleen, and liver, which are the general target organs of C. burnetii in experimental animals, had severe lesions. In the lungs, cells accumulated in intra-alveolar septa, and stroma adjacent to bronchioles. The spleen and liver did not retain their original structures. C. burnetii organisms were also seen within the hepatocytes (Masako et al., 2003).
In human patients with hepatitis, liver biopsy specimens are frequently obtained to detect granulomatous hepatitis, which is the commonest indication of C. burnetii in the liver (Silver and McLeish, 1984). Hepatic lesions, including portal triaditis, Kupffer cell hyperplasia, and moderate fatty change, have been described, but these lesions are less specific. Kupffer cells are thought to be the target cells for C. burnetii infection in liver. This may initiate local inflammation and the formation of granulomas. Histological examination of liver tissue sections reveals focal hepatocellular necrosis and cell infiltrates composed of macrophages, lymphocytes and polymorphonuclear leukocytes. Macrophages with epithelioid morphology, multinucleated giant cells, and fibrin may also be present. A characteristic feature is noted when a central clear space and a fibrin ring are observed within the granuloma or at its periphery, which is referred to as a 'doughnut granuloma' (Srigley et al., 1985; Marrie, 1990a,b; Greiner et al., 1992). In chronically infected patients, granulomas have rarely been reported and the typical doughnut granulomas have never been reported (Westlake et al., 1987). Bone marrow lesions usually correspond to granulomas similar to those found in the liver (Srigley et al., 1985). Doughnut granulomas with macrophages, lymphocytes, polymorphonuclear leukocytes, and multinucleated giant cells surrounding a central clear space and a fibrinoid ring may also be found in bone marrow. Liver and bone marrow granulomas are concurrent in many Q fever patients (Silver and McLeish, 1984).
In contrast to granulomatous hepatitis, Q fever pneumonia is rarely fatal, and therefore, the pathological descriptions of the disease in humans are scarce. Typical pulmonary lesions in Q fever pneumonia correspond to a gross consolidation, microscopic interstitial pneumonia, and alveolar exudates (Perin, 1949). Interstitial infiltrates are mostly composed of macrophages and lymphocytes and to a lesser extent polymorphonuclear leukocytes (Perin, 1949; Janigan and Marrie, 1983). Fibrin and erythrocytes, together with mononuclear cells, are found in alveolar exudates. Such pathological findings are not specific to Q fever pneumonia and may be encountered with other aetiological agents of atypical pneumonia, including Legionella pneumophila, Chlamydia pneumoniae and Chlamydia psittaci. By using specific antibodies, C. burnetii may be revealed within alveolar macrophages. Renal involvement in patients with acute C. burnetii infection has rarely been described. Glomerulonephritis should be recognized as a complication of acute C. burnetii infection and endocarditis due to chronic Q fever (Korman et al., 1998).
Histological findings in the infected cardiac valve are non-specific. The presence of thrombi composed of fibrin and platelets, necrosis and necrotic cellular debris, foci of calcification or ossification, and fibroblasts laying down collagen are frequently noticed (Brouqui et al., 1993, 1994). Inflammatory-cell infiltrates are mainly composed of lymphocytes, histiocytes, and occasionally plasma cells. C. burnetii may be visualized in the infected valve by immunohistochemistry (Brouqui et al., 1994). Histologically, Q fever endocarditis is characterized by significant fibrosis and calcifications, slight inflammation and vascularization, and small or absent vegetations (Lepidi et al., 2003).
DiagnosisTop of page
Diagnosis of Q fever is complicated by the fact that many acute infections of Q fever are either asymptomatic, mild, or resemble influenza symptoms (Maurin and Raoult, 1999). Therefore, the detailed clinical symptoms and profile of disease should be taken into account to detect it or differentiate it from other diseases.
Q fever occurs at all ages, but it is more common in adults (Fournier et al., 1998). Incubation period following exposure can ranges between 1 and 3 weeks (McQuiston et al., 2002; Tigertt et al., 1961). Symptoms of acute Q fever are generally nonspecific and can include fever (39.5-40.5°C), chills, profuse sweating, retro-orbital pain, frontal headache, myalgias and unproductive cough (Fournier et al., 1998 and McQuiston et al., 2002). Other symptoms may include light sensitivity, fatigue, rigors, night sweats, nausea, vomiting, chest pain and meningoencephalitis (Maurin and Raoult, 1999). Approximately one third of patients have pronounced respiratory signs such as cough and radiographic changes in the lungs (Marrie et al., 1988). Splenomegaly is common. Some cases of chronic fatigue syndrome have also been associated with persistent infections of C. burnetii, the organism being identified in bone marrow aspirates and liver tissue (Ayres et al., 1998; Harris et al., 2000). In chronically infected patients, the most frequent outcome is endocarditis, which may be accompanied by clubbing of fingers, and prolonged fever (Marrie et al, 1988; Marrie and Raoult, 2002). Q fever has also been linked with complications and abortions in pregnancy (Langley et al., 2003; Stein and Raoult, 1998).
Patients with acute Q fever usually have normal leukocyte counts (Fournier et al., 1998). However, 25% of the patients have an elevated leukocyte count, ranging from 14x10 9 to 21x10 9 per L. The erythrocyte sedimentation rate may be elevated and thrombocytopenia may be present. Elevation of hepatic enzymes is the most frequent laboratory finding in acute Q fever (Alarcon et al., 2003). Roughly, 40% of patients were reported with granulomatous hepatitis and over 60% with increased liver enzyme activity (McQuiston et al., 2002; Raoult et al., 2000). During chronic Q fever anemia elevated erythrocyte sedimentation rate and polyclonal hyper gamma-globulinaemia. Thrombocytopenia and elevated hepatic enzyme levels are commonly found. Renal involvement is common and is characterized by increased creatinine levels and microhaematuria.
Infection caused by C. burnetii in animals is usually asymptomatic. Clinical signs of acute infection, including fever, loss of appetite, mild cough, rhinitis and rapid respiration rate have been reported in sheep experimentally inoculated with C. burnetii, but these signs are non-specific, and they have not been described in natural infections (Belchev and Pavlov, 1977; Martinov et al., 1989). The signs associated with chronic Q fever in sheep, goats, and cattle are infertility, abortion, and the birth of full-term dead or weak, lower-weight offspring (Berri et al., 2000, Ho et al., 1995, Martinov et al., 1989, Moeller, 2001, Palmer et al., 1983; To et al., 1998). Abortions typically occur over a 2- to 4-week period and may affect 5 to 50% of the flock. Most of the abortions occur in the last trimester of pregnancy or near term. Goats naturally infected with C. burnetii may abort without obvious clinical signs, but anorexia and depression have been observed 1 to 2 days before abortion. In some affected females there is placental retention for 2 to 5 days, and agalactia may occur within 1 week of abortion (Waldham et al., 1978). In cattle, C. burnetii has been implicated as the cause of fertility problems, including abortion (Sting et al., 2000; To et al., 1998). Both dogs and cats may have weak or stillborn offspring as a result of C. burnetii infection (Buhariwalla et al., 1996; Marrie et al., 1988).
Collection and storage of specimens
C. burnetii is a highly infectious zoonotic agent and should only be handled in a biosafety cabinet (Class III). Great care should be taken during sample collection from infected subjects, as well as handling of the contaminated specimens and cultivation of this microorganism in the laboratory. Several specimens are suitable for the detection of C. burnetii, but their availability depends on the clinical presentation. Different techniques can be used to collect various types of specimens for isolation and detection of pathogen; these include, cerebrospinal fluid, bone marrow, cardiac valve biopsy, vascular aneurysm or graft, bone biopsy, or liver biopsy specimens, milk, placenta, fetal specimens in case of an abortion, and cell culture supernatants. Blood should be collected on EDTA or sodium citrate, and the leukocyte layer should be saved for the amplification.
Q fever results in the formation of granulomatous lesions, most commonly involving the lungs, liver and bone marrow. Macroscopically, red or grey hepatization may be present. Microscopically, interstitial oedema and infiltration by lymphocytes and macrophages occur. Alveolar spaces are filled with histiocytes, and intra-alveolar focal necrosis and haemorrhage. The hepatic lesions are different in acute and chronic Q fever. Hepatic lesions in acute cases are characterized by granulomatous lesions containing the so-called doughnut granuloma, which consist of dense fibrin rings surrounding a central lipid vacuole (Srigley et al., 1985). Usually, granulomatous changes and necrosis are also found in bone marrow. In chronic cases, pathological findings are nonspecific: lymphocytic infiltration and foci of spotty necrosis .The vegetations in Q fever endocarditis are often smooth and nodular. The valve is often infiltrated with foamy macrophages, which are filled with C. burnetii cells.
C. burnetii can be isolated by inoculation of specimens onto conventional cell cultures (monkey kidney cells, Vero cells) or into embryonated hen yolk sacs (Ormsbee, 1952) or laboratory animals, such as mice or guinea pigs (Williams et al, 1986). Embryonated eggs die 7 to 9 days after inoculation. Guinea pigs develop fever 5 to 8 days after intraperitoneal inoculation. The spleen is the most valuable organ for the recovery of C. burnetii. Ground spleen extracts should subsequently be inoculated into embryonated eggs. Although they are now used less often, these methods remain helpful in cases requiring isolation from tissues contaminated with multiple bacteria or in order to obtain Phase I Coxiella antigens from Phase II cells. The development of a cell microculture system from a commercially available method for virus culture, the shell vial cell culture system, has allowed for improvement in the isolation of intracellular bacteria, especially C. burnetii (Raoult et al., 1990). Animal inoculation is hazardous because animals shed C. burnetii in the faeces and urine (Raoult, 1990), therefore, extreme care should be taken while handling infected laboratory animals.
The pathogen is best visualized in impression smears of infected yolk sac/guinea pig spleen stained with Gimenez's stain. In the case of an abortion suspected of being caused by an infection, smears of placental cotyledon are prepared on microscope slides. Lung, liver and abomasal contents of the aborted fetus or vaginal discharge may be used in the same manner. These could be stained using several rapid methods: Gimenez, Stamp, modified Ziehl-Neelsen, Giemsa, Macchiavello and modified Koster.
Q fever diagnosis is most frequently by serological methods because culture and molecular biology techniques are difficult, may take a long time and need expertise, which is only available with the specialized laboratories. Serological diagnosis is easy to establish, although antibodies are mostly detected only after 2 to 3 weeks from the onset of the disease. Serology allows the differentiation of acute and chronic Q fever infections. Methods which have been used include capillary agglutination test (Luoto, 1953), microagglutination (Fiset et al., 1969; Kazar et al., 1981), complement fixation (Herr et al., 1985; Peter et al., 1985), radioimmunoassay (Doller et al., 1984), immunoflurescent antibody test (IFAT) (Field et al., 1983; Peter et al., 1985), indirect haemolysis test (Tokarevich et al., 1990), ELISA (Kovácová et al., 1987; Péter et al., 1988; Uhaa et al., 1994), enzyme-linked immunosorbent fluorescence assay (ELIFA) (Schmeer et al., 1988), dot immunoblotting, and Western blotting (Willems et al., 1992). The commonest used techniques include complement fixation (CFT), IFA, ELISA, and micro agglutination. The first two methods are usually available commercially. Comparison between serological tests showed that ELISA demonstrated 92% agreement with the reference method (IFAT), and gave a sensitivity of 99% and a specificity of 88% (Fournier et al., 1998). Specificity can be increased with confirmation by IFAT. The CFT has 90% specificity but relatively a low sensitivity (Field et al., 2000). In CFT, heat-inactivated sera are tested against either Phase I or Phase II C. burnetii antigens (Raoult et al., 1992). The CFT is specific but has a lower rate of sensitivity and is more time-consuming than IFA or ELISA. False-negative results have been described with the CFT in chronically infected patients with high antibody titres due to a prozone phenomenon, as well as false-positive results due to cross-reactions with hen egg antigens. Western immunoblotting was used to compare the immune response to C. burnetii Phase I and Phase II antigens of humans with acute and chronic Q fever (Marrie and Yates, 1996). ELISA, first described for diagnosis of Q fever (Field et al., 1983), has been described as more specific and sensitive technique than CFT. It has proved more sensitive than the IFTA for the serodiagnosis of Q fever (Péter et al., 1988; Cowley et al., 1992).
Monoclonal antibody (MAb I/4/H) has been used to differentiate C. burnetii isolates from man and other mammals (Sekeyová et al., 1996). The monoclonal antibody (Cox1D8) does not cross-react with other bacteria. Furthermore, fixation using formaldehyde or Bouin does not alter the reactivity of the antigen with the antibody (Raoult et al., 1994). Therefore, it can be used for early detection of C. burnetii in shell vial cell cultures and for staining C. burnetii in paraffin-embedded tissues, as well as pathological diagnosis of hepatitis and endocarditis in Q fever cases.
Several PCR assays are available for sensitive and specific detection of the pathogen in different food or clinical samples. These include trans-PCR, employing primers based on transposon-like repetitive regions of the C. burnetii genome (Berri et al., 2001), single touchdown PCR for screening vaginal swabs, milk and faeces (Berri et al., 2000), immunomagnetic separation-PCR for sheep milk (Ongor et al., 2004), and a multiplex PCR having sensitivity comparable to simplex PCR for milk (Edingloh et al., 1999). An adequate concentration of Triton X-100 enhanced immunomagnetic separation of C. burnetii from milk. PCR-ELISA was 10-fold more sensitive than conventional PCR for the detection of Coxiella (Muramatsu et al., 1997). PCR has also been developed for examining paraffin-embedded tissues from patients with chronic endocarditis (Yuasa et al., 1996). Recently, a rapid, nested PCR called Light Cycler Nested PCR (LCN-PCR) together with serology in the first 2 weeks of disease has been suggested to be helpful for early diagnosis of Q fever (Fournier and Raoult, 2003). Real-time PCR assay can also be useful for the evaluation of C. burnetii antibiotic susceptibilities (Brennan and Samuel, 2003).
Q fever should be considered in the differential diagnosis of patients whose manifestations suggest herpetic encephalitis (Sempere et al., 1993). Q fever serology should be performed in intrauterine infections associated with morbidity and mortality during pregnancy and should be differentiated from toxoplasmosis, listeriosis, and infections caused by rubella virus, cytomegalovirus and herpes viridae.
List of Symptoms/SignsTop of page
|Digestive Signs / Anorexia, loss or decreased appetite, not nursing, off feed||Sign|
|Digestive Signs / Parasites passed per rectum, in stools, faeces||Cattle & Buffaloes:All Stages,Poultry:All Stages,Other:All Stages,Pigs:All Stages,Sheep & Goats:All Stages||Sign|
|General Signs / Fever, pyrexia, hyperthermia||Cattle & Buffaloes:All Stages,Poultry:All Stages,Other:All Stages,Pigs:All Stages,Sheep & Goats:All Stages||Sign|
|Nervous Signs / Dullness, depression, lethargy, depressed, lethargic, listless||Sign|
|Reproductive Signs / Abortion or weak newborns, stillbirth||Sign|
|Urinary Signs / Proteinuria, protein in urine||Cattle & Buffaloes:Calf||Sign|
Disease CourseTop of page
The pathogen usually enters the body either by inhalation of aerosol or by ingestion. C. burnetii has been recovered from semen samples from bulls used for artificial insemination by culture in Vero cells. It is therefore suggested that C.burnetii may be sexually transmitted between cattle (Kruszewska and Tylewska-Wierzbanowska, 1997) and between humans (Kruszewska et al., 1996). The agent has been detected in spermatozoal cells by scanning electron microscopy (Kruszewska et al., 1996). The aerosol route remains the principal mode of acquisition of C. burnetii infection in humans (Babudieri, 1959). Ingestion of high doses of C.burnetii via the digestive route (especially by consumption of contaminated dairy products) is considered a rare alternative for acquiring infection (Fishbein and Raoult, 1992). The incubation period of acute Q fever may range from 1 to 3 weeks (McQuiston et al., 2002), depending on the inoculation dose of C.burnetii (Marrie, 1990a,b). The route of infectionmay influence the pathological changes in acute Q fever (Scola et al., 1997). The intranasal route has been found to result in greater airway changes whereas infection through the intraperitoneal route only causes hepatosplenomegaly (Marrie et al., 1996).
Monocytes-macrophages are the only known target cells for Coxiella in man and animals (Meconi et al., 2001). Alveolar macrophages are the primary cells to be infected in acute Q fever after infection through the respiratory system. Kupffer cells in the liver are also susceptible and may be infected via the bloodstream or the digestive route, but the incidence of this event is very low. The microorganisms then take enter the eukaryotic cells with the use of specific eukaryotic receptors such as integrins to invade the host cells. C.burnetii Phase II enters human monocyte-derived macrophages by engaging the CR3 receptor (Mege et al., 1997). In contrast, the infectious Phase I C. burnetii blocks entry via the CR3 receptor and binds to human monocytes via the complex of LRI (leukocyte response integrin, v3) and IAP (integrin-associated protein) (Mege et al., 1997). The natural Phase I C. burnetii is only poorly internalized by monocytes and macrophages but can survive within these cells. In contrast, Phase II C. burnetii is readily internalized by monocytes and macrophages (Mege et al., 1997) but is rapidly killed via the phagolysosomal pathway. The receptor used by each C. burnetii phase for entry into monocytes and macrophages is probably critical for its survival within these phagocytic cells.
After passive entry into the host cell, C. burnetii is internalized within eukaryotic cells in phagosomes, which fuse rapidly with lysosomes to form phagolysosomes. The early phagolysosomes fuse progressively to form a large unique vacuole (Hackstadt and Williams, 1981). C. burnetii is an acidophilic bacterium whose metabolism is enhanced at acidic pH. Acidity is needed for C. burnetii to assimilate nutrients necessary for its metabolism, including synthesis of nucleic acids (Chen et al., 1990) and amino acids (Hendrix and Mallavia, 1984; Zuerner and Thompson, 1983). For maturation of C. burnetii, parasitophorous vacuole requires bacterial protein synthesis but not replication (Howe et al., 2003). C. burnetii displays a complex intracellular cycle, leading to the formation of two types of spore-like forms (McCaul, 1991) called the 'small-cell variant' (SCV) and 'large-cell variant' (LCV) (Wachter et al., 1975; McCaul and Williams, 1981). SCVs are 204 by 450 nm in size and rod shaped, with densely stained walls and electron-dense nucleoids. LCVs are up to 2 µm long, more pleomorphic, rounded, granular, sometimes with fibrillar cytoplasm and with dispersed nucleoid filaments. SCVs are metabolically inactive and resistant to osmotic pressure and correspond to the extracellular form of the bacterium. SCVs attach to the eukaryotic cell membrane to enter phagocytic cells. After phagolysosomal fusion, acid activation of the metabolism of SCVs may lead to the formation of LCVs. Thus, LCVs correspond to the metabolically active intracellular form of C. burnetii. The endogenous spore-like forms undergo further development to the metabolically inactive SCVs, which are then released from the infected host cell either by cell lysis or possibly by exocytosis. Physical or biochemical factors, which may induce the sporulation-like process in C. burnetii, are unknown. However, nutrient deprivation is commonly the signal for the initiation of sporulation in sporulated Gram-positive bacteria such as Bacillus or Clostridium species. Whatever the mode of acquisition of C. burnetii, spread of the pathogen in the blood stream may lead to involvement of other organs including the liver, spleen, lungs, bone marrow, and female genital tract.
C. burnetii causes persistent infections both in man and animals (Baca and Paretsky, 1983). Chronically infected animals shed the pathogen in faeces and urine. The slow intracellular multiplication of C. burnetii, with a doubling time of about 20 h, similar to that of eukaryotic cells, may be one reason why the bacterium does not damage infected cells despite prolonged infection. Most infected patients, however, will have a transient bacteraemia with C. burnetii, usually late in the incubation period. Acute Q fever has two primary clinical presentations; atypical pneumonia, and hepatitis. It has been hypothesized that the route of acquisition C. burnetii infection may influence the clinical presentation of the disease (Maurin and Raoult, 1999). Q fever endocarditis is the most frequent clinical presentation of chronic Q fever, and also the most severe, with a spontaneous death rate that may exceed 65%.
EpidemiologyTop of page
Human coxiellosis manifests in sporadic cases or outbreaks. Human infection is often asymptomatic, and its mild form can be mistaken for other febrile diseases. Q fever is usually benign, but mortality occurs in between 1 and 11% of patients with chronic Q fever (Raoult, 1990). It has been estimated that the patients persistently infected with C. burnetii will develop chronic Q fever in 1-16% of reported patients worldwide (Siegman-Igra et al., 1997), which is most commonly endocarditis, but can also manifest as an infection of vascular grafts or aneurysms, osteomyelitis, or hepatitis. In southern France, 5 to 8% of cases of endocarditis are due to Coxiella burnetii (Tissot-Dupont et al., 1992).
The cycles of maintenance of C. burnetii in animal and arthropod hosts vary from country to country. There are two interacting cycles in effect, one in wild animals with their ticks, the other in domestic animals, which is not dependent on arthropod transmission. Human infections are associated with the second cycle and only very rarely with the first (Stoker and Marmion, 1955). C.burnetii, like Chlamydia, has a complex life cycle with at least two forms; a metabolically active large cell variant (LCV) comparable to the Chlamydia spp. reticulate body, and a spore-like small cell variant (SCV) comparable to the Chlamydia spp. elementary body. Unlike Chlamydia with only the elementary body being infectious, both cell forms of C. burnetii are infectious. Furthermore, the SCV (or another resilient form) can survive in the environment outside a host for years while remaining infectious, and is small enough to be carried and dispersed for miles by wind. Due to its resistance to physical agents, probably related to its sporulation process (McCaul,1991), C.burnetii survives for long periods in the environment. Experiments with cattle, sheep and small laboratory animals have shown that C. burnetii persists for a long time in tissues such as liver, spleen, lymph nodes, kidney, ovary and brain. C.burnetii has also been found to survive in a free-living amoeba for 30 days (Scola and Raoult, 2001).
The reservoirs of C. burnetii are extensive, but only partially known, and include domestic and wild mammals, birds and arthropods, mainly ticks. The commonest sources of human infection are farm animals such as cattle, goats and sheep. In addition to farm livestock, parturient cats and newborn kittens have also been found to cause outbreaks. In Canada, 6 to 20% of cats have been found to possess anti-C.burnetii antibodies (Higgins and Marrie, 1990). Small wild rodents, including wild rats are also suspected to be an important reservoir (Webster et al., 1995). Mixed infection in patients of Rickettsiaconorii and C. burnetii was thought to have been caused by tick bites (Janbon et al., 1989).
Epidemiological data show that dairy cows are more frequently and chronically infected compared with sheep, and therefore, represent the most important source of human infection. Seroprevalence studies indicate an upward trend in the seropositivity of cattle against C. burnetii (Lang, 1990). Transmission of C.burnetii to humans from infected goats may be significant in areas where they replace cows as a source of milk. Goats also share a predisposition with dairy cows to remain chronically infected (Lang, 1990). In animals that subsequently become pregnant, the pathogens multiply in large numbers in the placenta (Marmion, 1990). Q fever causes abortions in goats and, less frequently in sheep and causes reproductive problems in cattle (Maurin and Raoult, 1999). All the infected mammals shed the desiccation-resistant organisms in urine, faeces, milk and especially, birth materials (Bouvery et al., 2003). Reactivation of infection occurs in female mammals during pregnancy. High concentrations of C.burnetii are found in the placentas of infected animals (Babudieri, 1959). Dogs and cats infected by tick bite, consumption of placentas or milk from infected ruminants, and the aerosol route represent another important reservoir of C.burnetii (Mantovani and Benazzi, 1953).
Ticks transmit C. burnetii to domestic mammals but not to humans (Kazar, 1996). Ticks may play a significant role in the transmission of coxiellosis among the wild vertebrates, especially in rodents, lagomorphs, and wild birds (Marrie et al., 1986). However, these may not be essential in the maintenance of the natural cycle of C.burnetii infection in livestock (Babudieri, 1959). Over 40 tick species have been found to be naturally infected with C. burnetii, including Rhipicephalus sanguineus on dogs (Mantovani and Benazzi, 1953), Haemaphysalis humerosa on marsupial bandicoots (Smith and Derrick, 1940) and Amblyomma triguttatum on kangaroos (Pope et al., 1960). Other species of ticks found infected with the pathogen include Dermacentor occidentalis, Amblyomma americanum, Haemaphysalis leporis-palustris, Ixodes dentatus and Otobius megnini.Experimental transmission of C. burnetiifrom infected to uninfected guinea pigs through tick bite has been observed with Ixodes holocyclus, Haemaphysalis bispinosa and Rhipicephalus sanguineus (Maurin and Raoult, 1999).
C. burnetii has been detected in the semen of bulls (Kruszewska and Tylewska, 1997), and it has been suggested that C. burnetii may be sexually transmitted in mice (Kruszewska and Tylewska, 1991), cattle (Kruszewska and Tylewska, 1997) and humans (Kruszewska et al., 1996). Of late, the sexual transmission of Q fever from a man with occupationally acquired Q fever to his wife has been reported (Millazzo et al., 2001).
The incidence of Q fever among humans is probably underestimated as the clinical presentation is very pleomorphic and nonspecific, and the diagnosis relies upon physician's awareness of the symptoms and availability of a reliable diagnostic laboratory. Seroepidemiological surveys have shown that 18.3% of blood donors in Morocco, 26% in Tunisia (Grist and Ross, 1968), 37% in Zimbabwe, 44% in Nigeria (Andrews and Marmion, 1959), 10 to 37% in northeast Africa, and 14.6 to 36.6% in different areas of Canada (Freeman and Hodson, 1972; Fritz et al., 1995) had anti-C. burnetii antibodies. Large outbreaks of Q fever have also been reported in the Basque Country in Spain (Ackland et al., 1994), in Switzerland (Brezina et al., 1975), in UK (Clark and Lennette, 1952), in Berlin, Germany (Kazar et al., 1982), and more recently, in southern France. Antibodies against C. burnetii have also been detected in bulk tank milk as well as in dairy herds with C. burnetii infection (Paiba et al., 1999).
Impact: EconomicTop of page
Coxiellosis as a zoonosis assumes greater public health and economic importance where there is close and frequent association between man and animals, such as in rural areas, where agriculture and animal husbandry are the main sources of income. Moreover, C.burnetii infection in animals reared for consumption has been associated with abortions, especially in sheep and goats, and infertility in cattle (Ho et al., 1995; Schmeer et al., 1987) and may have an economic impact on production.
In an economic evaluation of the National Q Fever Management Programme in Australia, increased vaccine uptake from 65 to 100% among meat industry workers, and from zero to 20% in agricultural industry workers resulted in an incremental cost per life year gained of $20,002 and $24,950 [$A ?], respectively, and a cost per QALY (quality adjusted life year) of $6,294 and $7,984. This included some indirect costs in the form of work-cover payments resulting in cost savings for both the industry groups (Kermode et al., 2003).
In another economic impact study conducted in Switzerland, the disease-related annual cost per cow and per calf was estimated to be FS 139.44 and FS 4.18, respectively, whereas annual disease prevention cost per cow was FS 10.18. Antibodies against Leptospira hardjo, Coxiella burnetti, Mycobacterium paratuberculosis and bovine diarrhoea virus were detected in 68.1, 61.9, 8.0 and 99.1% of farms, respectively. The cows from 63.7% of farms were found to be infested with gastrointestinal strongylids, and the average rate of veterinary assistance required per cow was 1.96 (Stärk et al., 1997).
Zoonoses and Food SafetyTop of page
Q fever, with the notable exception of New Zealand, is a worldwide zoonosis. The commonest route of transmission of the disease to humans is through inhalation of contaminated aerosols from amniotic fluid, placenta or contaminated wool. Q fever is an important occupational hazard, especially for those in close contact with farm animals such as veterinarians, dairymen, abattoir workers and animal transport workers, as well as laboratory personnel who handle infected animals or cultures of the pathogen. Coxiella organisms could potentially be used in biological weapons (Spencer and Wilcox, 1993).
The age and sex distribution of human cases of Q fever varies in different epidemiological situations. The disease usually affects adult males (sex ratio, 5:1) aged between 20 and 50 years, and has no apparent seasonal incidence. In Australia, Q fever activity is still significantly associated with livestock and the meat industry. The incidence of chronic Q fever is unknown in Australia, and only five deaths attributed to Q fever were reported between 1982 and 1994 (Maurin and Raoult, 1999).
The seroprevalence of Q fever has been found to be three times higher in HIV-positive patients than in blood donors (Raoult et al., 1993). In most European countries, California (USA), and Australia (Garner et al., 1997; Thomas et al., 1995; Sanzo et al., 1993), the disease most often affects the active population between 30 to 60 years of age and more frequently in men. A sex ratio of 1:1 was reported in Nova Scotia, Canada (Marrie and Pollak, 1995). Mammals also shed C. burnetii in milk and consumption of raw milk (Gikas et al., 1994) and milk products (Fishbein and Raoult, 1992) could be a source of infection to humans and newborn animals. Humans may acquire Q fever from infected domestic poultry by consumption of raw eggs or inhalation of infected fomites. Anti-C. burnetii antibodies have been found in snakes and tortoises in India (Yadav and Sethi, 1980), but C. burnetii has not been isolated from these animals. The possibility of acquiring human Q fever from infected dogs has also been reported. Sexual transmission of Q fever has been reported in mice (Kruszewska and Tylewska-Wierzbanowska, 1992), cattle (Kruszewska and Tylewska-Wierzbanowska, 1997) and humans (Kruszewska et al., 1996; Millazzo et al., 2001).
Sporadic cases of human-to-human transmission following contact with infected pregnant women have been reported and have been suspected to occur by direct aerosol transmission. Nosocomial transmission of Q fever has also been described (Osorio et al., 2003).
Q fever has also been proven to be transmitted through the placenta, resulting in congenital infections (Htwe et al., 1993), through intradermal inoculation (Brouqui et al., 1992), and through blood transfusion (Becker, 2003). Ticks transmit C. burnetii to domestic mammals but not to humans (Doller et al., 1984). However, tick faeces on cattle hide could be the source of infection of abattoir workers (Marmion, 1990). C. burnetii may persist without symptoms in humans throughout life. An occupational risk of zoonotic infections was reported in Dutch forestry workers and muskrat catchers (Moll-van-Charante et al., 1998). However, conditions like pregnancy, a cardiac valvular abnormality, a vascular aneurysm or prosthesis, haemodialysis and immunodeficiency, including AIDS may promote reactivation of dormant C. burnetii (Maurin and Raoult, 1999).
There are many people who are exposed risk factors associated with C. burnetii: students studying for food inspection and technology qualifications or specializing in animal production; those practising with living animals in general and particularly with ruminants and people in frequent contact with those working with animals, particularly veterinarians, farmers and animal traders (Simon-Valencia et al., 2000). Seroepidemiological studies show that children are frequently exposed to C. burnetii. However, children are less frequently symptomatic than adults following infection and may have milder symptoms (Maltezou and Raoult, 2002).
Ovine manure used as a garden fertilizer is suspected to be a source of C. burnetii infection of humans (Berri et al., 2003). Recently, an outbreak of human coxiellosis in a prison in northern Italy around which flocks of sheep used to graze has been reported. The 133 people affected included prison officers, prisoners, people exposed to the grazing area and veterinarians who attended the autopsies of sheep that died whilst infected (Santoro et al., 2004).
Disease TreatmentTop of page
Most cases of acute Q fever heal spontaneously. However, treatment is strongly recommended as sometimes the disease may assume a chronic course with severe complications like endocarditis and hepatitis. The preferred drug regime consists mainly of tetracycline or one of its derivatives, particularly doxycycline, for two to three weeks. Several combinations have been tried for the treatment of chronic Q fever, for example, tetracycline combined with trimethoprim-sulfamethoxazole and rifampicin with doxycycline. Chronic Q fever endocarditis requires prolonged treatment (several years) with a combination of quinolones or hydroxychloroquine (Acha and Szyfres, 2003).
Acute Q fever is most often a mild disease that resolves spontaneously within 2 weeks. Tetracycline administered at 500 mg four times a day (q.i.d.) is known to reduce the duration of fever by 50%. Doxycycline therapy is now recommended instead of tetracycline due to its improved pharmacokinetic properties and less frequent gastric intolerance. Doxycycline at 200 mg daily for 14 days is the current recommended regimen for acute Q fever. This treatment regime has been found effective for rapid and complete recovery in patients with mononeuritis multiplex (Sommer et al., 2002). Erythromycin (500 mg q.i.d.) has been used successfully to treat Q fever pneumonia cases. However, erythromycin has been found ineffective in the treatment of severe cases of Q fever pneumonia, even with a daily intravenous dosage of 4 g (Marrie, 1982, 1990a,b). Anecdotal reports indicate that other antibiotics, including lincomycin, co-trimoxazole and chloramphenicol, may be effective in treating Q fever pneumonia (Maurin and Rauolt, 1999).
Fluoroquinolones such as ofloxacin (200 mg three times a day, t.i.d.) and pefloxacin (400 mg twice daily) have been used successfully to treat acutely infected patients. However, these antibiotics had to be administered for 14 to 21 days to be effective. In patients with Q fever meningoencephalitis, the fluoroquinolones are considered to be a reliable alternative, because they penetrate the cerebrospinal fluid. Both tetracyclines and fluoroquinolones are also contraindicated in children and pregnant women, but more clinical data is needed for their evaluation.
Q fever endocarditis is the most frequent clinical presentation of chronic Q fever and also the most severe, with a death rate that may exceed 65%. The optimum duration of the antibiotic therapy cannot be accurately determined because no definite criteria for C. burnetii cure are currently available. Suggestions have ranged from 1 year of antibiotic therapy (Wilson et al., 1976) to indefinite administration of antibiotics. Initial antibiotic combinations used were of tetracycline with either lincomycin or co-trimoxazole (Haldane et al., 1983), however, no significant clinical improvement over tetracycline alone was noted. Monotherapy with alternative drugs, including co-trimoxazole, rifampin, and fluoroquinolones, has been administered to Q fever endocarditis patients, especially because of gastric intolerance to tetracyclines. However, in some instances, the cases of Q fever endocarditis have been successfully treated with doxycycline at 200 mg/day for two months (Dalmau et al., 1997).
Recently, the combination of rifampin with a fluoroquinolone has been shown to be effective in vitro (Dumler, 2002). Current recommendations for antibiotic treatment of Q fever endocarditis are at least 18 months of therapy with doxycycline (100 mg twice daily, b.i.d.) and chloroquine (200 mg t.i.d.), or at least 3 years of therapy with doxycycline (100 mg b.i.d.) and ofloxacin (200 mg t.i.d.) in patients to whom the first antibiotic regimen cannot be administered (Dumler, 2002).
Prevention and ControlTop of page
Q fever vaccines
Q fever is enzootic among wild and domestic animals; hence, controlling C. burnetii infection in susceptible animals is difficult. Q fever vaccine is commercially available in Australia (Acha and Szyfres, 2003). Safe use of these vaccines requires screening of potential vaccines by skin tests, serological tests, or in vitro lymphocyte proliferation assay (Zhang and Samuel, 2004). Since C. burnetii infection is an occupational hazard and could develop into severe chronic disease in humans, vaccination should be considered to protect individuals at-risk of contact with naturally infected animals or exposure to the agents. Abattoir workers should be immunized with ten complement fixation units of antigen given intramuscularly. Before vaccination, each recipient should be skin tested with a 1:50 dilution of vaccine before sensitization to C. burnetii (Luoto et al., 1963). Imported animals should be quarantined where there is a risk of their infection with C. burnetii.
The first human vaccines available were composed of formaldehyde-inactivated whole C. burnetii cells preparation made with Phase I antigen, which confers much greater protection than those made with Phase II antigens. The disadvantage of using whole cell culture vaccine with Phase I antigens is that they can cause undesirable side effects, such as local erythema, induration, granulomas, sterile abscesses and systemic reactions in people previously exposed to C. burnetii infection. The whole cell vaccine should not be used in those who have had a positive serological or cutaneous reaction (Acha and Szyfres, 2003). To counteract these problems, a chloroform-methanol residue of C. burnetii cells was proposed (Schmeer et al., 1987; Brooks et al., 1986). Chloroform-methanol residue vaccines (CMRV) were shown to be better tolerated in animals than C. burnetii whole-cell vaccines (Elliott et al., 1998; Williams et al., 1992). A soluble vaccine containing trichloroacetic acid-extracted antigen from Phase I C. burnetii Nine Mile strain was also proposed and successfully used in people whose work was likely to lead to their exposure to C. burnetii in former-Czechoslovakia (Kazar et al., 1982). Trichloroacetic acid-extract antigen treated with chloroform-methanol was also tested and displayed fewer side effects but less immunogenicity than the same antigen without chloroform-methanol treatment (Kazár et al., 1987).
Q fever vaccines vary composition, including the strain and phase of C. burnetii used. Vaccines prepared from Phase I C. burnetii organisms were more protective than those prepared from the Phase II form, whereas cross-protection among various C. burnetii strains was found in vaccinated guinea pigs (Ormsbee et al., 1962). When tested on cattle and sheep, these vaccines showed different protective effects against experimental and natural C. burnetii infection in sero-negative animals (Williams et al., 1992; Schmeer et al., 1987). Q fever vaccination was also shown to protect cattle against abortion (Behymer et al., 1976), low fetal weight (Brooks et al., 1986), and chronic infertility (Schmeer et al., 1987). In contrast, vaccination did not eradicate C. burnetii in animals naturally infected before vaccination and C. burnetii shedding persisted unchanged. In Europe, a vaccine containing both Phase II C. burnetii and Chlamydia psittaci has been marketed to protect cattle and goats against fertility problems caused by these two agents. However, a Q fever outbreak was reported in France in people in contact with vaccinated goats. Moreover, this Phase II-containing vaccine was suspected of increasing the shedding of C. burnetii in milk for several months when administered to previously infected animals (Schmeer et al., 1987). Q fever vaccination of domestic animals (mainly cattle, sheep and goats) is currently not widely used because it is protective and safe only in animals that are uninfected at the time of vaccination (Maurin and Rauolt, 1999).
General hygiene and sanitary practices
Human Q fever
Raw milk should not be used for consumption (Acha and Szyfres, 2003). Raw milk should be pasteurized at 78°C for 15 s to destroy C. burnetii and all dairy products should be prepared from pasteurized milk (Enright et al., 1957a,b).
Veterinarians are specifically at risk and should take measurements to prevent infection; veterinarians should also play a role in advising pet owners and persons of other professions at high risk on measures to reduce the chance of infection (Nowotny and Deutz, 2000). The laboratory personnel must take utmost care to protect themselves and others while collecting and handling clinical materials and cultures, including the use of biosafety cabinet class III. Farmers and livestock owners should take all necessary precautions while handling newborn or aborted animals. The occupational groups at high risk should be vaccinated. The contact of children with newborn and pregnant animals at the time of parturition should be avoided.
Animal Q fever
All animals, particularly sheep, used for experimental purposes, should undergo serological testing before they are accepted at research institutes. Imported animals can be quarantined. It is recommended to separate pregnant females before they give birth and to bury or burn the placenta and all material surrounding the fetus (Acha and Szyfres, 2003). Tick populations should be controlled on farm animals and farm premises. The amount of agent can be reduced in the environment by regular cleaning and disinfection of animal facilities. Particular care should be taken to clean parturition areas using 10% bleach.
In many countries Q fever remains under diagnosed on account of varied clinical signs and lack of diagnostic facilities, the exact impact of the disease needs to be assessed in man and animals.
The pathogen could also be used as a potent biological weapon because of its infectivity, stability, ease of preservation, presence in high titres, and ease of dissemination. It is therefore even more necessary to develop sensitive and specific diagnostic tests, especially molecular biology-based tests (Malik and Vaidya, 2005). Several national level programmes across the globe have been started to streamline, strengthen and coordinate the research work on diagnosis, prevention and control the disease, such as the 'National Q Fever Management Programme' introduced by the Australian Government in October 2000 (Kermode et al., 2003), and 'Task Force on Rickettsioses' initiated by the Indian Council of Medical Research Head Quarters, New Delhi, India (Malik and Yadav, 2002). In many countries there is a need to educate the public through mass media about the infection, its transmission, clinical presentation, and most importantly, its prevention.
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