Etiology

Although previously classified within the order Rickettsiales, Coxiella burnetii (the causative agent of Q fever) is genetically distinct from the genera Rickettsia, Orientia, Ehrlichia, and Anaplasma. Hence, based on small subunit rRNA gene sequencing, it has been reassigned to the order Legionellales, family Coxiellaceae. C. burnetii is highly infectious for both humans and animals; even a single organism can cause infection. The agent has been nationally notifiable since 1999 and is listed as a Category B agent of bioterrorism by the Centers for Disease Control and Prevention. Unlike Rickettsia, the organism can enter a sporogenic differentiation cycle, which renders it highly resistant to chemical and physical treatments.

C. burnetii resides intracellularly within macrophages. The organism undergoes a lipopolysaccharide phase variation similar to that described for smooth and rough strains of Enterobacteriaceae. Unlike Ehrlichia, Anaplasma, and Chlamydia, C. burnetii that express phase I lipopolysaccharide can survive and proliferate within acidified phagosomes to form aggregates of >100 bacteria. In contrast, organisms that express phase II lipopolysaccharide are killed in the phagolysosome.

Epidemiology

The disease is reported worldwide, except in New Zealand. Although seroepidemiologic studies suggest that infection occurs just as often in children as in adults, children less often present with clinical disease than do adults. Approximately 60% of infections are asymptomatic, and only 5% of symptomatic patients require hospitalization. Seroprevalence surveys show that 6-70% of children in endemic European and African communities have evidence of past infection, and in France the overall incidence of Q fever is estimated to be 50 cases per 100,000 persons. Cases in Africa are likely misdiagnosed as malaria. Reported cases of Q fever in the USA have increased by 6.5-fold from 26 cases in 2001 to 171 cases in 2007, which might reflect an increase in incidence, increased reporting after September 11, 2001, improved diagnostic tools, or a combination of factors. Reported cases in Asia and Australia have also increased. Most infections in children are identified during the lamb birthing season in Europe (January through June), following farm visits, or after exposure to placentas of dogs, cats, and rabbits. The largest community outbreak ever described occurred in the southeastern part of the Netherlands in 2008 and was associated with intensive goat farming. More than 20% of cases of clinically recognized acute or chronic Q fever occur in immunosuppressed hosts or in persons with prosthetic valves or damaged native valves or vessels. Although infections are recognized more often in men than in women, reported cases in boys and girls are equal.

Transmission

In contrast to other rickettsial infections, humans usually acquire C. burnetii by inhaling infectious aerosols (e.g., contaminated barnyard dust) or ingesting (and likely aspirating) contaminated foods. Ticks are rarely implicated. Cattle, sheep, and goats are the primary reservoirs, but infection in other livestock and domestic pets has also been described. Organisms are excreted in milk, urine, and feces of infected animals, but especially in amniotic fluids and the placenta. An increase in incidence has been associated with the seasonal mistral winds in France that coincide with lamb birthing season and with consumption of cheese among children in Greece. In Nova Scotia and Maine, exposure to newborn animals, especially kittens, has been associated with small outbreaks of Q fever in families. Exposure to domestic ruminants is the major risk in Europe and Australia, although many urban dwellers in France also acquire Q fever without such an exposure. Clinical Q fever during pregnancy can result from primary infection or reactivation of latent infection and has been associated with miscarriage, intrauterine growth retardation, and premature births. Obstetricians and other related health care workers are at risk for acquiring infection because of the quantity of C. burnetii sequestered in the placenta.

Pathology and Pathogenesis

The pathology of Q fever depends on the mode of transmission, route of dissemination, specific tissues involved, and course of the infection. When acquired via inhalation, a mild interstitial lymphocytic pneumonitis and macrophage- and organism-rich intra-alveolar exudates are often seen. When the liver is involved, a mild to moderate lymphocytic lobular hepatitis may be seen. Inflammatory pseudotumors can develop in the pulmonary parenchyma or other tissues. Classic fibrin-ring (“doughnut”) granulomas, generally associated with acute, self-limited infections, occasionally are identified in liver, bone marrow, meninges, and other organs. Typically, infected tissues are also infiltrated by lymphocytes and histiocytes.

Recovery from symptomatic or asymptomatic acute infection can result in persistent subclinical infection and may be maintained by dysregulated cytokine responses. The persistence of C. burnetii in tissue macrophages at sites of pre-existing tissue damage elicits low-grade chronic inflammation and, depending on the site of involvement, can result in irreversible cardiac valve damage, persistent vascular injury, or osteomyelitis. Endocarditis of native or prosthetic valves is characterized by infiltrates of macrophages and lymphocytes in necrotic fibrinous valvular vegetations and an absence of granulomas.

Clinical Manifestations and Complications

Only about 40-50% of people infected with C. burnetii develop symptoms. Two forms of symptomatic disease occur. Acute Q fever is more common and usually manifests as self-limited undifferentiated fever or an influenza-like illness with interstitial pneumonitis. Chronic Q fever in adults usually involves native heart valves, prosthetic valves, or other endovascular prostheses. Q fever osteomyelitis is less common but proportionally more common in children.

Laboratory Findings

Laboratory features in children with chronic Q fever are poorly documented; adult patients often have an erythrocyte sedimentation rate of >20 mm/hr (80% of cases), hypergammaglobulinemia (54%), and hyperfibrinogenemia (67%). In children, the presence of rheumatoid factor in >50% of cases and circulating immune complexes in nearly 90% suggest an autoimmune process, as do anti-platelet antibodies, anti–smooth muscle antibodies, anti-mitochondrial antibodies, circulating anticoagulants, and positive direct Coombs tests.

Diagnosis and Differential Diagnosis

Although uncommonly diagnosed, Q fever should be considered in children who have fever of unknown origin, atypical pneumonia, myocarditis, meningoencephalitis, culture-negative endocarditis, or recurrent osteomyelitis and who live in rural areas or who are in close contact with domestic livestock, cats, or animal products.

The diagnosis of Q fever is most easily and commonly confirmed by testing acute and convalescent sera (2-4 wk apart), which show a 4-fold increase in indirect fluorescent antibody titers to phase I and phase II C. burnetii antigens. Predominant, elevated, or increasing titers of phase II antibody are characteristic of acute Q fever, and the appearance and persistence of titers of phase II antibody greater than phase I indicate chronic Q fever. Elevated titers of phase I immunoglobulin A (IgA) antibody are reported to be diagnostic for Q fever endocarditis; however, 1 evaluation showed that a phase I IgG titer of <800 is inconsistent with chronic Q fever. Cross reaction with antibodies to Legionella and Bartonella can occur.

Although culture has been considered the gold standard, sensitivity (compared with a composite standard including serology and PCR) is low. C. burnetii has been cultivated in tissue culture cells, which can become positive within 48 hr, but isolation and antimicrobial susceptibility testing of C. burnetii should be attempted only in specialized biohazard facilities. Testing by polymerase chain reaction (PCR) can be performed on blood, serum, and tissue samples and is available in some public health, reference, or research laboratories. Although PCR has been helpful in patients with equivocal titers; sensitivity has been improved by real-time methods and use of repeated sequences as targets. Immunohistochemical staining has also been used, but suffers from simila problems similar to PCR’s.

The differential diagnosis depends on the clinical presentation. In patients with respiratory disease, Mycoplasma pneumoniae, Chlamydophila pneumoniae, legionellosis, psittacosis, and Epstein-Barr virus infection should be considered. In patients with granulomatous hepatitis, tuberculous and nontuberculous mycobacterial infections, salmonellosis, visceral leishmaniasis, toxoplasmosis, Hodgkin disease, monocytic ehrlichiosis, granulocytic anaplasmosis, brucellosis, cat scratch disease (Bartonella henselae), or autoimmune disorders such as sarcoidosis should be considered. Culture-negative endocarditis suggests infection with Brucella, Bartonella, or HACEK organisms (Haemophilus, Aggregatibacter, Cardiobacterium hominis, Eikenella corrodens, Kingella), partially treated bacterial endocarditis, or nonbacterial endocarditis.

Treatment

Selection of an appropriate antimicrobial regimen for children is difficult owing to the lack of rigorous studies, the limited therapeutic window for drugs that are known to be efficacious, and the potential length of therapy required to preclude relapse.

Most pediatric patients with Q fever have a self-limited illness that is identified only on retrospective serologic evaluation. However, to prevent potential complications, patients with acute Q fever should be treated within 3 days of onset of symptoms, because therapy started >3 days after onset of illness has little effect on the course of acute Q fever. Because early confirmatory testing is not possible now, empirical therapy is warranted in clinically suspected cases. Doxycycline (4 mg/kg/day PO or IV divided every 12 hr, maximum 200 mg/day) is the drug of choice. Tetracycline and doxycycline may be associated with tooth discoloration in children <9 yr of age; however, most experts consider the benefits of treatment with doxycycline to be greater than the risks. Tooth discoloration is dose and duration dependent, and it is unlikely that children will require multiple courses. During pregnancy, Q fever is best treated with trimethoprim-sulfamethoxazole. The fluoroquinolones have also proved effective, and success with a combination of a fluoroquinolone and rifampin has also been achieved with prolonged therapy (16-21 days). Macrolides, including erythromycin and clarithromycin, are less effective alternatives.

For chronic Q fever, especially endocarditis, therapy for 18-36 mo is mandatory. The current recommended regimen for chronic Q fever endocarditis is a combination of doxycycline and hydroxychloroquine for ≥18 mo. For patients with heart failure, valve replacement may be necessary. Interferon-γ therapy has been used as adjunct therapy for intractable Q fever.

Prevention

Recognition of the disease in livestock or other domestic animals should alert communities to the risk for human infection. Milk from infected herds must be pasteurized at temperatures sufficient to destroy C. burnetii. C. burnetii is resistant to significant environmental conditions but may be inactivated with a solution of 1% Lysol, 1% formaldehyde, or 5% hydrogen peroxide. Special isolation measures are not required because person-to-person transmission is rare, except when others are exposed to the placenta of an infected patient. A vaccine preparation is available and provides protection against Q fever for at least 5 yr in abattoir workers. Because the vaccine is strongly reactogenic and no trials in children have been conducted, it should only be used when extreme risk is judged to exist. Clusters of cases resulting from intense natural exposures, such as in slaughterhouses or on farms, are well documented. Clusters of cases that occur in the absence of such an exposure should be investigated as potential sentinel events for bioterrorism.