Q FEVER

Q FEVER

Q fever is a widespread zoonosis caused by Coxiella burnetii, a small, coccoid, strict intracellular gram-negative bacterium. It lives within the phagolysosome of its eukaryotic host cell at very low pH (4.5-4.8). It had previously been classified in the rickettsial family; however, recent phylogenic data based on study of the 16S rRNA gene sequence have shown that it belongs to Legionellales with the Legionella species and Francisella tularensis.

The bacterium has a sporelike life cycle, which explains its marked resistance to physicochemical agents. In cultures, C. burnetii exhibits a phase variation (from virulent phase I to avirulent phase II) caused by a spontaneous chromosome deletion. The avirulent form paradoxically generates high antibody levels in patients, but only patients with chronic infection have high antiphase I immunoglobulin G (IgG) and IgA antibody titers.

The reservoir of C. burnetii is wide, and nearly all tested mammals, birds, and ticks can be infected. Outbreaks have also been reported in association with the birth products of mammals (including ungulates and pets), raw milk, slaughterhouses, and farm work. Laboratory outbreaks have been reported. The disease is prevalent everywhere in the world but in New Zealand and South Pacific Islands, but because its clinical spectrum is wide and nonspecific, the observed incidence is directly related to physician interest in Q fever. A recent outbreak has been observed in The Netherlands.

Clinical Features

Q fever is a reportable disease in the United States. In humans, infection is symptomatic in only 50% of patients. Most symptomatic patients experience a flulike syndrome lasting 2 to 7 days and consisting of severe headaches and cough; 5% to 10% of infected patients may be sick enough to be investigated. They initially have high fever and one or several of pneumonia, hepatitis, meningoencephalitis, rash, myocarditis, and pericarditis. Routine laboratory investigation commonly shows mildly elevated transaminase levels and mild thrombocytopenia.

In special hosts such as immunocompromised patients (specifically those with splenectomy), C. burnetii can cause endocarditis. In pregnant women it can lead to recurrent miscarriage, low-birth- weight offspring, and prematurity. C. burnetii could contribute to the evolution of lymphoma.

In patients with valvular heart disease and those with arterial aneurysms or a vascular prosthesis, it can cause chronic endocarditis or vascular infection in patients in the 2 years following primary infection. The clinical picture is that of a chronic blood culture– negative endocarditis; the modified Duke criteria are of diagnostic value in such cases. It is spontaneously fatal in most cases.

Diagnosis

Because Q fever is pleomorphic, the diagnosis is based mainly on comprehensive serum testing in patients with an unexplained infectious syndrome. Liver biopsy may be of diagnostic value because the typical doughnut granuloma is quasispecific to acute Q fever.

Valves obtained at surgery or autopsy can be used for culture, direct immunostaining, and polymerase chain reaction (PCR).

Three serologic techniques are used. Complement fixation lacks sensitivity, and one third of patients with acute Q fever do not exhibit complement-fixing antibodies within 1 month after onset of the disease. However, a fourfold increase in antibodies to phase II antigen indicates acute Q fever, and antibody levels against phase I that are higher than 1:200 indicate persistent focalized Q fever. Indirect immunofluorescence assay is the reference method. A single titer of 1:200 for IgG antiphase II associated with a titer of 1:50 for IgM is diagnostic of acute infection. IgG antibody levels against phase I that are greater than 1:800 and IgA antibody levels greater than 1:50 are highly predictive of endocarditis or vascular infection. Enzyme-linked immunosorbent assay (ELISA) is useful for diagnosing acute infection in detecting IgM antiphase II.

PCR has recently been developed to detect C. burnetii DNA in the sera of patients with Q fever. Real-time PCR using multicopy gene IS1111 is the more-sensitive technique. It is positive in the sera of patients with acute Q fever before IgG antibodies to C. burnetii become apparent. It is also positive in patients with untreated chronic Q fever. Contamination of PCR can occur, and many unconfirmed results are reported in the literature. Detection of patients at risk for endocarditis may be provided by systematic echocardiography in patients with acute Q fever specifically seeking for aortic bicuspidy and serologic follow-up at 3 and 6 months after acute infection.

Use of a positron emission tomography (PET) scanner may help in the diagnosis of endocarditis (and may reveal mycotic aneurisms), vascular infection, and joint infection.

Treatment

To be active against Q fever, an antibiotic compound has to enter the cell, be effective at an acidic pH (where C. burnetii multiplies), and have activity against C. burnetii. No antibiotic is bactericidal, but bactericidal activity can be achieved by the addition of hydroxychloroquine (Plaquenil)1 to doxycycline (Vibramycin).

For acute Q fever, the reference treatment is doxycycline 100 mg orally twice daily for 2 to 3 weeks. Other compounds have been reported to be effective, such as trimethoprim-sulfamethoxazole (TMP-SMX) (Bactrim),1 Rifampin (Rifadin)1 300 mg twice daily, and ofloxacin (Floxin)1 200 mg twice daily. In the case of Q fever in pregnant women, one double-strength TMP-SMX tablet (trimethoprim 160 mg, sulfamethoxazole 800 mg)1 twice daily until delivery prevents fetal death (Table 1).

Table 1

Treatment

1  Not FDA approved for this indication.

3  Exceeds dosage recommended by the  manufacturer.

Chronic endocarditis should be treated for 18 months to 2 years, and antibody levels should be monitored. Patients with prosthetic valves may be treated for 2 years. Two protocols have been evaluated: doxycycline 200 mg daily combined with ofloxacin1 400 mg daily for 4 years to lifetime, and doxycycline combined with hydroxychloroquine1 for 1.5 to 2 years in an amount to achieve a 1 ± 1.20 µg/mL plasma concentration. Doxycycline serum levels greater than 4.5 µg/mL of serum are associated with a more rapidly favorable outcome. This last regimen is apparently more efficacious in terms of relapse. However, regular ophthalmologic surveillance is critical to detect the accumulation of chloroquine in the retina. Both regimens expose the patient to a major risk of photosensitization.

The combination of doxycycline and hydroxychloroquine for 1 year has demonstrated efficacy in preventing endocarditis.

Prevention

Prevention depends on avoiding exposure, particularly by pregnant women and patients with valvulopathy. No vaccine is currently available outside Australia.

References

1.     Klee S.R., et al. Highly sensitive real-time PCR for specific detection and quantification of Coxiella burnetii. BMC Microbiol. 2006;19:2.

2.     Maurin M., Raoult D. Q fever. Clin Microbiol Rev. 1999;12:518– 553.

3.     Merhej V., Cammilleri S., Piquet P., et al. Relevance of the positron emission tomography in the diagnosis of vascular graft infection with Coxiella burnetii. Comp Immunol Microbiol Infect Dis. 2012;35(1):45–49.

4.     Million M., Roblot F., Carles D., D’Amato F., Protopopescu C., Carrieri M.P., et al. Reevaluation of the risk of fetal death and malformation after q fever. Clin Infect Dis. 2014;59(2):256–260.

5.     Million M., Thuny F., Richet H., Raoult D. Long-term outcome of Q fever endocarditis: a 26-year personal survey. Lancet Infect Dis. 2010;10:527–535.

6.     Million M., Walter G., Thuny F., Habib G., Raoult D. Evolution from acute Q fever to endocarditis is associated with underlying valvulopathy and age and can be prevented by prolonged antibiotic treatment. Clin Infect Dis. 2013;57(6):836– 844.

7.     Raoult D. Chronic Q fever: expert opinion versus literature analysis and consensus, J Infect 65:102–108, 2012.

8.     Rolain J.M., Maurin M., Raoult D. Bacteriostatic and bactericidal activities of moxifloxacin against Coxiella burnetii. Antimicrob Agents Chemother. 2001;45:301–302.

1  Not FDA approved for this  indication.

KNOWLEDGE BASE
About Genomic Medicine UK

Genomic Medicine UK is the home of comprehensive genomic testing in London. Our consultant medical doctors work tirelessly to provide the highest standards of medical laboratory testing for personalised medical treatments, genomic risk assessments for common diseases and genomic risk assessment for cancers at an affordable cost for everybody. We use state-of-the-art modern technologies of next-generation sequencing and DNA chip microarray to provide all of our patients and partner doctors with a reliable, evidence-based, thorough and valuable medical service.

X