Q Fever

In the United States, male sex and older age (> 60 years) have been associated with higher prevalence of both acute and chronic Q fever (1).Cases of Q fever occur among people whose occupation bring them in close contact with farm animals (which are often asymptomatic) or animal products. People at increased risk of exposure include veterinarians, personnel working at dairy or meat plants, farmers, ranchers, and animal researchers (2). Transmission is usually by inhalation of infectious aerosols that can travel long distances and affect people living downwind of a farm that has infected goats or sheep. The disease can also be contracted by ingesting infective raw milk.

In addition to people at risk of occupational exposure, people at increased risk of developing chronic Q fever include those with a history of cardiac valvular defects, arterial aneurysms, or vascular grafts. Pregnancy and immunosuppression have also been linked to the development of chronic Q fever. These risk factors lead to an increased susceptibility to infection from inhaling contaminated dust (eg, remnants of birth products, urine, feces, milk) from infected animals.

Children with preexisting cardiac valve disease, or who are immunocompromised, or have delayed Q fever diagnosis and have been ill for 2 weeks without resolution of symptoms are also considered to be at high risk of developing severe disease (3).

Clinical features usually develop within 2 to 3 weeks of exposure (1). About half of infected people can be asymptomatic.

Acute Q fever is characterized by a febrile illness that often affects the respiratory system, but the liver may sometimes be involved. Pregnant patients have an increased risk of spontaneous abortion and preterm delivery. Acute Q fever may often be asymptomatic; however, in some patients, it can begin abruptly with nonspecific febrile illness–like symptoms: fever, severe headache, chills, severe malaise, myalgia, anorexia, and sweats. Fever may rise to 40° C and persist for 1 to > 3 weeks.

Respiratory symptoms (a dry nonproductive cough, pleuritic chest pain) appear 4 to 5 days after onset of illness. Acute interstitial pneumonitis is a major pulmonary manifestation of acute disease, often presenting with fever, headache, and cough. During examination, lung crackles are commonly noted, and findings suggesting consolidation may be present. Unlike rickettsial diseases, acute Q fever does not cause a rash.

Acute hepatic involvement, occurring in some patients, resembles viral hepatitis, with fever, malaise, hepatomegaly with right upper abdominal pain, and possibly jaundice. Headache and respiratory signs are frequently absent.

Approximately 40% of patients with acute Q fever and a history of valvular disease develop Q fever endocarditis (2). Rarely, acute Q fever manifests as encephalitis or meningoencephalitis.

A post-Q fever fatigue syndrome has been reported to occur in up to 20% of patients with acute Q fever (2). Patients report severe fatigue, myalgias, headache, photophobia, and/or mood and sleep changes.

Chronic Q fever occurs in < 5% of patients (3). It may manifest within a few weeks to many years after the initial infection. Chronic Q fever usually manifests as endocarditis or hepatitis; osteomyelitis may occur. Interstitial pulmonary fibrosis may occur. Hepatitis may manifest as fever of unknown origin. Liver biopsy may show granulomas, which should be differentiated from other causes of liver granulomas (eg, tuberculosis, sarcoidosis, histoplasmosis, brucellosis, tularemia, syphilis) (4).

Endocarditis resembles culture-negative subacute bacterial endocarditis; the aortic valve is most commonly affected, but vegetations may occur on any cardiac valve. Marked finger clubbing, arterial emboli, hepatomegaly, splenomegaly, and a purpuric rash may occur.

• Immunofluorescence assay (IFA)

• Molecular diagnostic testing (polymerase chain reaction [PCR]) of infected tissue or blood specimens

• Acute and convalescent serologic tests

The nonspecificity of symptoms of Q fever can make a clinical diagnosis challenging in both the acute and chronic forms of the disease. Early on, Q fever resembles many infections (eg, influenza, other viral infections, salmonellosis, malaria, hepatitis, brucellosis). Later, it resembles many forms of bacterial, viral, and mycoplasmal and other atypical pneumonias. Occupational history, particularly contact with animals or animal products, is an important diagnostic clue.

The United States Centers for Disease Control and Prevention (CDC) recommends that the diagnosis of Q fever be based on serologic testing in combination with PCR testing for early-stage acute Q fever (1). IFA of infected tissue is the diagnostic method of choice; alternatively, enzyme-linked immunosorbent assay (ELISA) may be done. Acute and convalescent serum specimens (typically complement fixation) may be used. Antibodies to phase II antigen are used to diagnose acute disease, and antibodies to both phase I and phase II antigens are used to diagnose chronic disease.

PCR can identify the organism in biopsy or blood specimens, but negative results do not rule out the diagnosis. Specimens should ideally be obtained in the first 2 weeks of illness and before or early into empiric treatment.

C. burnetii may be isolated from clinical specimens, but only by special research laboratories; routine blood and sputum cultures are negative.

Patients with respiratory symptoms or signs require chest radiography; findings may include atelectasis, pleural-based opacities, pleural effusion, and lobar consolidation. The gross appearance of the lungs may resemble bacterial pneumonia but, histologically, more closely resembles psittacosis and some viral pneumonias.

In acute Q fever, complete blood count may be normal, but about 30% of patients have an elevated white blood cell count. Alkaline phosphatase, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels are mildly elevated to 2 to 3 times the normal level in typical cases. If obtained, liver biopsy specimens often show diffuse granulomatous changes.

The diagnosis of Q fever endocarditis can be difficult because routine blood cultures are negative and vegetative cardiac valve lesions are small and are visualized by echocardiography in only about 12% of patients. A high clinical suspicion for endocarditis should be maintained for patients with acute Q fever and an abnormal or prosthetic valve (1).

• For acute Q fever, doxycyclineFor acute Q fever, doxycycline

• For chronic Q fever (including endocarditis), doxycycline and hydroxychloroquineFor chronic Q fever (including endocarditis), doxycycline and hydroxychloroquine

For acute Q fever, first-line treatment is doxycycline until the patient improves, has been afebrile for approximately 5 days, and has received treatment for 14 days; longer treatment may be needed for severe disease. Tetracycline resistance has not been documented.until the patient improves, has been afebrile for approximately 5 days, and has received treatment for 14 days; longer treatment may be needed for severe disease. Tetracycline resistance has not been documented.

Although some tetracyclines can cause tooth staining in children < 8 years of age, the CDC advises that a course of doxycycline is warranted (Although some tetracyclines can cause tooth staining in children doxycycline is warranted (1), given for 5 days for mild illness and for 10 days for high-risk children. Research indicates that short courses of doxycycline (5 to 10 days, as used for rickettsial disease) can be used in children without causing tooth staining or weakening of tooth enamel (1). Pregnant patients may be given trimethoprim/sulfamethoxazole but not beyond 32 weeks gestation.). Pregnant patients may be given trimethoprim/sulfamethoxazole but not beyond 32 weeks gestation.

Chronic Q fever requires combination therapy with doxycycline and hydroxychloroquine. For requires combination therapy with doxycycline and hydroxychloroquine. Forendocarditis, treatment is similar, but duration of therapy needs to be prolonged (months to years), typically for at least 18 months (2). Consultation with an infectious disease specialist may help with managing treatment and the complexities of the disease. Frequently, antibiotic treatment is only partially effective, and damaged valves must be replaced surgically, but some patients have been cured without surgery.

Hydroxychloroquine plasma levels should be maintained at 0.8 to 1.2 mcg/mL and doxycycline levels at ≥ 5 mcg/mL (Hydroxychloroquine plasma levels should be maintained at 0.8 to 1.2 mcg/mL and doxycycline levels at ≥ 5 mcg/mL (3). Owing to the cardiac adverse effects of hydroxychloroquine, patients on this medication should have a baseline ophthalmologic (ie, fundoscopic) examination that is repeated every 6 months to monitor retinal toxicity and should have their QTc interval monitored with repeated ECGs. Additionally, clinical signs, erythrocyte sedimentation rate, blood count, and monthly antibody titers (IgG and IgM) should be monitored to help determine when to stop treatment.

For chronic granulomatous hepatitis, the optimal regimen has not been definitively established.

The case fatality rate of untreated acute Q fever is very low (3). Untreated chronic Q fever endocarditis is always fatal. Adequate antibiotic treatment reduces the mortality rate of Q fever endocarditis to < 5% (4). Some patients with neurologic involvement have residual impairment.

Vaccines are effective, and in Australia, where a Q fever vaccine is commercially available, vaccination is recommended to protect people with occupational risk (eg, slaughterhouse and dairy workers, veterinarians, laboratory workers, rendering-plant workers, herders, woolsorters, farmers) (1). Implementation efforts outside Australia have been largely limited by strong immunologic reactivity in patients with prior exposure to C. burnetii (2).

Prevaccination screening with skin and blood tests should be done to identify preexisting immunity to Q fever because vaccinating people who already have immunity can cause severe local reactions.