Q Fever Workup

The diagnosis of Q fever relies on a high index of suspicion as suggested by the epidemiologic features and is proven by serologic analysis. The organism is very infectious, and isolation ought to be done in biosafety level 3 laboratories.^[20] If a clinician thinks Q fever is a likely diagnosis, the laboratory should be notified so that they can take appropriate precautions.

Electrocardiography (ECG) may show T-wave abnormalities if myocarditis and pericarditis are present.

Acute Q fever may present with the following laboratory results:

• A complete blood cell (CBC) count usually shows a normal white blood cell (WBC) count (70-90%) (elevated WBC in as many as 30%.), mild thrombocytopenia (25%) (followed by a reactive thrombocytosis during the convalescent period^[9] ), and, in rare cases, hemolytic anemia
• Liver function tests usually show mild elevation of transaminases (2-3 times the reference range in 70-85% of patient) and alkaline phosphatase (2-3 times the reference range) without hyperbilirubinemia
• The erythrocyte sedimentation rate (ESR) is usually elevated (55 mm/h ± 30 mm/h)
• Several positive autoimmune antibodies, including antismooth muscle and antiphospholipid, may be seen
• Blood cultures are typically negative (Note that, although possible, attempting to isolate the organism from blood is a dangerous practice; cases of Q fever have developed in laboratory technicians)

C burnetii can be seen on smears or frozen tissue prepared with a routine Giemsa stain. Histopathologic changes consistent with doughnut granulomata the liver and bone marrow may be observed, but these are not specific for C burnetii. They can also occur in Hodgkin lymphoma, typhoid fever, cytomegalovirus infection, infectious mononucleosis, and allopurinol hypersensitivity.

In chronic Q fever, the following laboratory results may be observed:

• Anemia of chronic disease
• Elevated ESR
• Elevated gamma globulins (polyclonal)
• Elevated rheumatoid factor (RF)
• Increased creatinine levels

Most cases of Q fever are diagnosed based on detection of phase I and II antibodies (between acute and convalescent paired sera); a 4-fold rise in complement-fixing antibody titer against phase II antigen occurs and yields the highest specificity. This requires a baseline sample and another sample in 3-4 weeks. Thus, serologic tests are not helpful acutely but may later confirm the diagnosis: Seroconversion generally occurs between days 7 and 15 and is almost always present by 21 days.

The 3 serologic techniques used for diagnosis include indirect immunofluorescence (IIF) (method of choice), complement fixation, and enzyme-linked immunosorbent assay (ELISA) (comparable to IIF). As noted above, significant titers may take 2-4 weeks to appear. Laboratory values vary considerably, so clinicians must interpret results according to their local standards.

Raoult et al recommended serologic testing 2 years following treatment in patients with valvulopathy after acute infection,^[21] whereas Healy et al recommended serial testing every 4 months for 2 years, with additional investigation in those with elevated phase 1 immunoglobulin G (IgG) titers greater than 800.^[22]

Serologic follow-up to detect a rise in phase I IgG titers of 1:800 or more can be performed twice every 3 months. If detected, transesophageal echocardiography and serum real-time polymerase chain reaction (PCR) techniques can be performed in an attempt to diagnose endocarditis.^{[12, 23]} Sensitivities may be as low as 18% in early disease.

Interpretation of Q fever serology is challenging in regard to discordance of the serologic results from different reference laboratories.^[24] None of these results should be used in isolation, and their interpretation should always be applied in the appropriate clinical context. False-positive serologic results may occur in legionellosis and leptospirosis.

Indirect immunofluorescence assay

IIF findings in acute Q fever include the following:

• A rise in IgG and IgM against phase II antigen^[6]
• Phase II IgM of 1:50 or more; usually undetectable after 4 months but can last 12 months or more
• Phase II IgG of 1:200 or more
• Phase II titers of 1:100 or less make the diagnosis of acute Q fever unlikely
• In a reference French laboratory, these values showed 100% specificity

IIF findings in chronic Q fever include the following:

• A rise in IgG and IgA against phase I antigen^[6]
• Phase I IgG of 1:800 or more is considered diagnostic of endocarditis (one of major modified Duke criteria)
• Phase II IgM titers are lower or absent
• Phase II IgG titers are usually greater than 1:1600; they can last up to 12 years after an outbreak
• The main predictive criterion of clinical cure is detection of phase I IgG titer of less than 1:200

Complement fixation

Complement fixation is less sensitive and specific than IIF, and the time to positivity may take longer than IIF. Different cutoff values are also used. IgG levels usually fall within 3 years.

In acute Q fever, the anti-IgG titer is at least 200, and the anti- IgM titer level is at least 50. In chronic Q fever, the anti-IgA titer for phase I is greater than 50, and the anti-IgG titer for phase I is greater than 800.

In certain reference laboratories, polymerase chain reaction (PCR) techniques can be used with tissue specimens, such as resected cardiac valves, with greater sensitivity than serum assays, but these are not generally available commercially. C burnetii organisms can persist in tissues even after prolonged antimicrobial treatment.^[15] Although still controversial, serum PCR may be used to diagnose acute Q fever in the first 2 weeks of the disease. It should also be reserved for seronegative patients in the subsequent 2 weeks and not used later than 4 weeks following onset.^[23]

In the rare patient with prominent neurologic symptoms, computed tomography (CT) scanning of the brain may be indicated; otherwise, a chest radiograph is the only imaging study that is likely to be useful. An atypical pneumonia pattern may be observed, similar to the pattern seen with pneumonia caused by viruses and Mycoplasma, Chlamydia, and Legionella species. Opacities more specific to Q fever resemble a coin lesion.^[9]

In acute Q fever, chest radiographic findings are variable. Nonspecific segmental or lobar abnormalities may be seen (see the following image), such as opacities of both lungs, most consistent with an atypical pneumonia. Multiple round opacities and pleural effusions are the hallmark of Q fever pneumonia, but they are uncommon. In chronic illness, signs of interstitial fibrosis and pseudotumor may be observed.

Ultrasonography, primarily of the liver, is indicated because chronic hepatomegaly is frequently associated with endocarditis. Granulomatous hepatitis, even in asymptomatic patients, may be revealed.^[9]

Echocardiography is recommended to exclude underlying cardiac lesions. About 30-50% of patients with valvular lesions develop chronic endocarditis (most commonly, aortic valve; prosthetic valves are also prone to being affected). In cases of Q fever endocarditis, the cardiac echocardiogram demonstrates vegetations in only 12% of cases. These vegetations tend to be smaller than observed with other organisms and are located beneath endothelial surfaces.^[15] Other findings include valvular abscesses, valvular regurgitation, and prosthetic valve dehiscence. Pericardial effusion may also be seen with pericarditis in Q fever.