Coxiella burnetii infections (Q fever)
Coxiella burnetii infections (Q fever)
Q fever is a zoonosis caused by Coxiella burnetii, an intracellular Gram-negative spore-forming bacterium, the common animal reservoirs of which are cattle, sheep, and goats, although in a large outbreak in the Netherlands it appears that rats, Rattus norvegicus and R. rattus, may have played a role in the spread of the condition. C. burnetti is trophic for the endometrium and mammary glands of female animals, and during pregnancy the organism reaches very high concentrations in the placenta such that at the time of parturition organisms are aerosolized and contamination of the environment occurs. Inhalation of even one microorganism can result in infection.
Clinical features—there are two main forms of the disease: (1) acute—can present as inapparent infection, self-limited febrile illness, pneumonia, and hepatitis, or less commonly with a variety of organ-specific manifestations such as encephalitis, pericarditis, and pancreatitis; Q fever in pregnancy is associated with a high rate of abortion or neonatal death. (2) Chronic—most often ‘culture-negative’ endocarditis or infection of aortic aneurysms, but occasionally osteomyelitis.
Diagnosis, treatment, and prevention—diagnosis is confirmed by serological testing: in acute disease antibodies to phase II antigen are higher than those to phase I, whereas the reverse is true in chronic disease. Acute Q fever is treated with doxycyline or a quinolone; chronic disease with long-term doxycycline and hydroxychloroquine; and Q fever in pregnancy with co-trimoxazole for the duration of the pregnancy and—for those with a chronic Q fever serological profile—1 year of doxycycline and hydroxyochloroquine after delivery. Vaccination should be offered to those whose occupation places them at high risk for C. burnetii infection.
In August 1935, Dr Edward Holbrook Derrick, Director of the Laboratory of Microbiology and Pathology of the Queensland Health Department in Brisbane, Australia, was asked to investigate an outbreak of undiagnosed febrile illness among workers at the Cannon Hill abattoir. Derrick realized that he was dealing with a type of fever that had not been previously described—he named it Q (for query) fever. Two years later, Sir Frank Macfarlane Burnet in Australia and Herald Rea Cox in the United States of America isolated the microorganism responsible for Q fever.
This microorganism, the sole species of its genus, has a Gram-negative cell wall and measures 0.3 × 0.7 µm (Fig. 220.127.116.11). It is an obligate phagolysosomal parasite of eukaryotes that sporulates, stains well with Gimenez’s stain, and multiplies by transverse binary fission. C. burnetii undergoes phase variation akin to the smooth to rough transition in some enteric Gram-negative bacilli. In nature and laboratory animals it exists in the phase I state. Repeated passage of phase I virulent organisms in embryonated chicken eggs leads to the conversion from phase I virulent to phase II avirulent forms. Antibodies to phase I antigens predominate in chronic Q fever, while phase II antibodies are higher than phase I antibodies in acute Q fever. The genome of C. burnetii strain Nine Mile Phase I has 1 995 275 base pairs. There are many genes with potential roles in adhesion, invasion, intracellular trafficking, host-cell modulation, and detoxification. C. burnetii can now be grown in a cell-free medium, an advance that should lead to further insight into this complex microorganism.
Immune control of C. burnetii is T-cell dependent and it does not eliminate C. burnetii from infected humans. In 80 to 90% of bone marrow aspirates from those who have recovered from Q fever, polymerase chain reaction (PCR) assays for C. burnetii DNA are positive. The use of microarrays allows insight into the complexity of the host microorganism interaction in illnesses such as Q fever. In one such experiment 335 genes in the C. burnetii-infected human monocytic leukaemia cell line THP-1 were up- or down-regulated at least twofold.
C. burnetii has survived for 586 days in tick faeces at room temperature, 160 days or more in water, 30 to 40 days in dried cheese made from contaminated milk, and up to 150 days in soil.
Q fever is a zoonosis. There is an extensive wildlife and arthropod (mainly ticks) reservoir of C. burnetii. Domestic animals are infected through inhaling contaminated aerosols or by ingesting infected material. These animals rarely become ill, but abortion and stillbirths may occur. C. burnetii localizes in the uterus and mammary glands of infected animals. During pregnancy there is reactivation of C. burnetii and it multiplies in the placenta, reaching 109 infective doses per gram of tissue. The organisms are shed into the environment at the time of parturition. Humans becomes infected after inhaling organisms aerosolized at the time of parturition, or later when organisms in dust are stirred up on a windy day. Infections have occurred up to 18 km downwind from a source. Infected cattle, sheep, goats, and cats are the animals primarily responsible for transmitting C. burnetii to humans. There have been several outbreaks of Q fever in hospitals and research institutes due to the transportation of infected sheep to research laboratories. Some studies have suggested that ingestion of contaminated milk is a risk factor for the acquisition of Q fever; volunteers seroconverted but did not become ill after ingesting contaminated milk.
Percutaneous infection, such as when an infected tick is crushed between the fingers, may occur but is rare. Transmission via a contaminated blood transfusion has rarely occurred. Vertical transmission from mother to child has been infrequently reported. A 2007 review documents 74 cases of Q fever in pregnant women. The authors found that Q fever was present in 1 in 540 pregnancies in an area of endemic Q fever in southern France. Person-to-person transmission has been documented on a few occasions. To date, 45 countries on five continents have reported cases of Q fever. Q fever is estimated to cost $A1 million in Australia each year and results in the loss of more than 1700 weeks of work.
There are several studies where young age seems to be protective of infection with C. burnetii. In a large outbreak of Q fever in Switzerland, symptomatic infection was 5 times more likely to occur in those over 15 years of age compared with those younger than 15. In many outbreaks of Q fever, men were affected more commonly than women. It had been assumed that this was due to the fact that certain occupations in which men predominate were more likely to be associated with Q fever. However, in France, despite similar exposures, the male to female ratio is 2.45 to 1. The explanation for this gender difference is that female sex hormones are protective against Q fever infection.
Currently Q fever is common in several European countries with ongoing outbreaks in Germany and the Netherlands. There are a considerable number of sporadic cases of Q fever in England, France, and Spain. Currently Q fever is common in several European countries with recent outbreaks in Germany and the Netherlands. There are a considerable number of sporadic cases of Q fever in England, France, and Spain. The outbreak in the Netherlands is the largest to date, with over 4000 cases from 2007 to 2010, and many lessons have been learned from it. In 2007 a total of 168 individual human Q fever cases were notified, occurring after visits to dairy farms with abortion problems. The outbreak was concentrated around a single village, where a case-control study found that contact with manure, hay, and straw were risk factors. Moreover, people living in the eastern part of the village close to ruminant farms, one of which was a dairy goat farm with a recent history of abortion problems, were at higher risk than people living in other parts of the village. In 2008, 1000 human cases were notified, with average age 51 years (range 7–87 years), and 21% were hospitalized. In April 2009 a further sharp increase in human cases was observed, resulting in the total number of 2355. For patients reported in 2008 from whom clinical details were available, 545 were diagnosed with pneumonia, 33 with hepatitis, and 115 with other febrile illness. The gender ratio was 1 female to 1.7 males. In general, 59% of the notified human cases in 2009 lived within a 5-km zone around the notified dairy goat, dairy sheep farm, while 12% of the Dutch population lived within such as zones. Genotyping of C.burnetii isolates found that one unique genotype predominated in dairy goat herds and one sheep herd, and this genotype was similar to the human isolates.
Humans are the only species known consistently to develop illness following infection with C. burnetii. There is an incubation period of about 2 weeks (range 2–29 days) following inhalation of C. burnetii. A dose–response effect has been demonstrated experimentally and clinically. C. burnetii is one of the most infectious agents known; a single microorganism is able to initiate infection in humans. The resulting illness can be divided into acute and chronic varieties.
Acute Q fever
Self-limiting febrile illness
The most common manifestation of acute Q fever is a self-limiting febrile illness that is dismissed as a ‘cold’. Serosurveys reveal that in most endemic areas 5 to 10% of the population have antibodies to C. burnetii but never remember the illness that resulted in seroconversion.
Q fever pneumonia
This is the most commonly recognized manifestation of Q fever. There is often a seasonal distribution, most of the cases occurring between February and May (consistent with the birthing season in the small ruminant reservoirs). The onset is nonspecific with fever, fatigue, and headache. The headache may be very severe, occasionally so severe that it prompts a lumbar puncture. A dry cough of mild to moderate intensity is present in 24 to 90% of patients. About one-third of patients have pleuritic chest pain. Nausea, vomiting, and diarrhoea occur in 10 to 30% of patients. Most cases of C. burnetii pneumonia are mild; however, about 10% are severe enough to require admission to hospital and, rarely, assisted ventilation is necessary. Death is rare in Q fever pneumonia and is usually due to comorbid illness. The white blood cell count is usually normal, but is elevated in one-third of patients. Liver enzyme levels may be mildly elevated at 2 to 3 times normal. Alkaline phosphatase is raised in up to 70% of patients and 28% are hyponatraemic. Reactive thrombocytosis is surprisingly common and microscopic haematuria is a common finding.
The chest radiographic manifestations of Q fever pneumonia are usually indistinguishable from those of other bacterial pneumonias (Fig. 18.104.22.168); however, rounded opacities are suggestive of this infection (Fig. 22.214.171.124). Some investigators have reported delayed clearing of the pneumonia; however, in our experience resolution is usually complete within 3 weeks.
The liver is probably involved in all patients with acute Q fever. There are three clinical pictures:
◆ Pyrexia of unknown origin with mild to moderate elevation of liver function tests.
◆ A hepatitis-like picture: liver biopsy shows distinctive doughnut granulomas consisting of a granuloma with a central lipid vacuole and fibrin deposits. Prolonged fever unresponsive to antibiotics is common in these patients.
◆ ‘Incidental hepatitis’.
Q fever in pregnancy
Acute Q fever occasionally complicates pregnancy. In 23 published cases 35% had premature birth, and 43% ended in abortion or neonatal death. In a serosurvey of 4588 pregnant women in Halifax, Nova Scotia, Canada, women seropositive for C. burnetii were 3 times more likely to have a current or previous neonatal death. A study of 1174 pregnant women during the recent outbreak of Q fever in the Netherlands found that antibodies against phase II C. burnetii were not significantly associated with preterm delivery, low birth weight babies, and several other outcomes. Adverse outcomes attributable to Q fever were not seen in a recent study from Germany of 11 women with this infection during pregnancy. Whether these differences are due to properties of the infecting strain is not known. In a number of animal species (other than humans) Q fever is associated with abortions and stillbirths. Clearly, more information is need on Q fever in pregnancy in humans.
Encephalitis, encephalomyelitis, toxic confusional states, optic neuritis, and demyelinating polyradiculoneuritis are uncommon manifestations of Q fever.
These include myocarditis, pericarditis including constrictive pericarditis, bone marrow necrosis, rhabdomyolysis, glomerulonephritis, lymphadenopathy, pancreatitis, splenic rupture, acalculous cholecystitis, mesenteric panniculitis, erythema nodosum, epididymitis, orchitis, priapism, and erythema annulare centrifugum. Chronic fatigue may be a sequel of Q fever in some patients.
Chronic Q fever
The usual manifestation of chronic Q fever is that of culture-negative endocarditis. Some 70% of these patients have fever and nearly all have abnormal native or prosthetic heart valves. Hepatomegaly and or splenomegaly occur in about one-half of these patients and one-third have finger clubbing. A purpuric rash due to immune complex-induced leucocytoclastic vasculitis and arterial embolism occurs in about 20% of patients. Hyperglobulinaemia (up to 60 g/litre) is common and is a useful clue to chronic Q fever in a patient with the clinical picture of culture-negative endocarditis.
Other manifestations of chronic Q fever include osteomyelitis, infection of aortic aneurysm, and infection of vascular prosthetic grafts.
The strains of C. burnetii that cause chronic Q fever do not differ from those that cause acute Q fever. Peripheral blood lymphocytes from patients with Q fever endocarditis are unresponsive to C. burnetii antigens in vitro, while responding normally to other antigens.
A strong clinical suspicion based on the epidemiology and clinical features as outlined above is the cornerstone of the diagnosis of Q fever. This suspicion is confirmed by determining a fourfold or greater increase in antibody titre between acute and 2- to 3-week convalescent serum samples. A variety of serological tests are available including complement fixation, microimmunofluorescence (IFA), and enzyme immunoassay. The immunofluorescence antibody test is the best test. In acute Q fever the antibody titre to phase II antigen is higher than that to phase I antigen, while the reverse occurs in chronic Q fever. In chronic Q fever, antibody phase I titres are extremely high, in the order of 1:8192 and higher. In acute Q fever, antibody titres to phase I antigen are rarely in excess of 1:512 (usually 1:8 to 1:32), while peak antibody titres to phase II antigen are between 1:1024 and 1:2048. The microorganism can be isolated in embryonated eggs or in tissue culture; however, a biosafety level 3 laboratory is required. The PCR can be used to amplify C. burnetii DNA from tissues or other biological specimens.
Good laboratory practice, with known positive and negative controls is extremely important in the diagnosis of Q fever. Three different laboratories (in France, the United Kingdom, and Australia) tested the same serum samples using an IFA test. However the antigen used in the test differed in each laboratory—Nine Mile strain in France; Nine Mile strain clone 4 as phase II antigen and Henzerling strain as phase 1 antigen in Australia; patient Lane strain ST 12 group for phase 1 and II antigens in the United Kingdom.
Concordance was only 35%. The Australian and United Kingdom results had the greatest concordance and French and United Kingdom results the lowest. Serological testing revealed no chronic serological profiles when tested in either France or Australia but 10 when tested in the United Kingdom. Serological results from a patient with treated Q fever endocarditis suggested treated (France), chronic (United Kingdom), and borderline chronic (Australia) infection. How the antigens were prepared can also make a difference in the test results, and this paper does not indicate whether the strains were grown in tissue culture or egg yolk sac.
Acute Q fever is treated with a 2-week course of tetracycline or doxycycline. Quinolones can also be used. Any patients who develop acute Q fever and have lesions of their native valves (e.g. congenital bicuspid aortic valve), prosthetic valves, or prosthetic intravascular material should have serological monitoring every 4 months for 2 years, and if the phase I IgG titre exceeds 1:800 further investigation is warranted. Some authorities recommend that patients with valvulopathy who have acute Q fever should receive 12 months of doxycycline and hydroxychloroquine to prevent chronic Q fever.
The duration of treatment for chronic Q fever is determined by monitoring the serum antibody titres to C. burnetii, although some authorities recommend lifelong therapy for chronic Q fever. In general, antibiotics can be discontinued when the IgA antibody titre to phase I antigen is less than 1:200. The treatment of choice for chronic Q fever is doxycycline 100 mg twice daily and hydroxychloroquine 200 mg three times daily to maintain a plasma level of between 0.8 and 1.2 µg/ml. This regimen is given for 18 months. Photosensitivity is a potential adverse reaction and patients should be warned to take preventive measures. In addition, an ophthalmologist must examine the optic fundus every 6 months for chloroquine accumulation. We have used rifampicin 300 mg twice a day and ciprofloxacin 750 mg twice a day to treat patients with chronic Q fever. Rifampicin and doxycycline or tetracycline and trimethoprim/sulfamethoxazole have also been used to treat chronic Q fever. Antibody titres should be measured every 6 months for the first 2 years. A progressive decline in antibody titre reflects the successful treatment of chronic fever. Cardiac valve replacement may be necessary as part of the management of chronic Q fever.
Many patients with granulomatous hepatitis due to Q fever have a prolonged febrile illness that does not respond to antibiotics. For these individuals treatment with prednisone 0.5 mg/kg has resulted in defervescence within 2 to 15 days. Once defervescence has occurred the dose of steroids is tapered over the next month.
Q fever occurring during pregnancy should be treated with co-trimoxazole for the duration of the pregnancy. In one retrospective study this approach reduced obstetrical complications from 81 to 44%. There were no intrauterine fetal deaths in the co-trimoxazole-treated group. Those with a chronic Q fever serological profile should be treated with doxycycline and hydroxychloroquine for 1 year following delivery.
A formalin-inactivated C. burnetii whole-cell vaccine is protective against infection and has a low rate of side effects; 1% of vaccinees developed an abscess at the inoculation site and another 1% had a lump at this site 2 months after vaccination. The vaccine should be offered to those whose occupation places them at high risk for C. burnetii infection.
Good animal husbandry practices are important in preventing widespread contamination of the environment by C. burnetii. Prevention of zoonotic spread is best accomplished by isolating aborting animals for up to 14 days, raising feeding troughs to prevent contamination of feed by excreta, destroying aborted materials by burning and burying fetal membranes and stillborn animals, and wearing masks and gloves when handling aborted materials.
Only seronegative pregnant animals should be brought into the facilities where research is to be done. In addition only seronegative animals should be used in petting zoos.
Blood donation should be suspended in outbreak areas for up to 4 weeks following cessation of the outbreak.
Carcopino X, et al. (2007). Managing Q fever during pregnancy: the benefits of long-term cotrimoxazole therapy. Clin Infect Dis, 45, 548–55.Find this resource:
Raoult D, Tissot-Dupont H, Foucault C (2000). Q fever 1985–1998: clinical and epidemiological features of 1,383 infections. Medicine (Baltimore), 79, 110–23.Find this resource:
Raoult D, et al. (1999). Treatment of Q fever endocarditis: comparison of 2 regimens containing doxycycline and ofloxacin or hydroxychloroquine. Arch Intern Med, 159, 167–73.Find this resource:
Roest HIJ, et al. (2011). The Q fever epidemic in the Netherlands: history, onset, response and reflection. Epidemiol Infect, 139, 1–12.Find this resource: