A Man With Fever and Deranged Liver Function - ANSWER

Figure 1. A, Low-power view, bone marrow trephine. Several ring granulomata are shown in the trephine biopsy (arrows; hematoxylin-eosin stain, magnification ×200). B, High-power view, bone marrow trephine. Epithelioid histiocytes and neutrophils surround central lipid droplets forming a doughnut-shaped granuloma (arrows; hematoxylin-eosin stain, magnification ×400).

Diagnosis: Doughnut-shaped granuloma in a patient with acute Q fever.

Trephine biopsy showed a normocellular marrow with normoblastic erythropoiesis, active granulopoiesis, and adequate megakaryocytes. Numerous epitheloid granulomas with “doughnut-ring” appearance (Figure 1A and 1B) were found.

Special stains for mycobacterium and fungus were negative.

Serological examination for Coxiella burnetii antibodies by immunofluorescence assay (IFA) showed a rise of both phase II polyvalent IFA and immunoglobulin M titers from <25 to 200. The phase I polyvalent titers were both <25. 

Polymerase chain reaction (PCR) for C. burnetii performed on the first serum sample was also positive. The findings were compatible with acute Q fever. 

Transthoracic echocardiography showed no significant valvulopathy or vegetation. Our patient was treated with 14 days of doxycycline with good clinical response. 

Q fever is caused by C. burnetii, an obligate intracellular, gram-negative bacterium. It can infect humans and animals (eg. cattle, sheep, and goats). Humans can be infected when exposed to contaminated milk, excreta, and products of conception. Clinical presentation is highly variable, depending on host factors, bacterial virulence, and extent of exposure.

After exposure, 60% of the individuals are asymptomatic, whereas only 2%–5% of symptomatic patients require hospitalization because of severe diseases such as hepatitis, pneumonia,

and endocarditis.

Because of the heterogenous clinical presentation, prompt diagnosis requires a high index of suspicion. In this case, bone marrow aspiration and biopsy were performed to investigate

the cause of fever and thrombocytopenia. The doughnut-ring granuloma, together with the clinical presentation and epide-miological association, suggested Q fever as one of the differential diagnoses.

Doughnut-ring granuloma is characterized by a central vacuole surrounded by histiocytes, polymorphonuclear cells, macrophages, and eosinophils, while the ring of the granuloma consists of fibrin. Apart from bone marrow, doughnut-ring granuloma may also be found in liver; typically, bone marrow involvement is concurrent with liver disease. There is still no concrete explanation for the pathogenesis of ring-shaped granuloma in the bone marrow and liver. One possibility is the deposition of fibrin at the margin induced by macrophage with incorporation of lipid within the granuloma, which corresponds with the central vacuole. 

Font et al postulated focal vasculitis in liver due to immune complex deposition as a possible mechanism, and similar vasculitic changes have been previously described in the bone marrow.

Other histopathological features of Q fever in liver biopsies are focal hepatocellular necrosis, infiltrates by macrophages, lymphocytes, and polymorphonuclear cells. 

Skin involvement is rare. 

Pulmonary histopathological findings are nonspecific and consist of microscopic interstitial pneumonia and alveolar exudates.

Doughnut-ring granuloma is not pathognomonic of Q fever. It can also be found in acute typhoid fever, infections due to cytomegalovirus and Epstein-Barr virus, and leishmaniasis, as well as noninfectious diseases such as Hodgkin’s lymphoma, peripheral T-cell lymphoma, and drug hypersensitivity (eg, allopurinol). Some advocate the use of PCR detection of targeted gene fragments in bone marrow to provide direct evidence of C. burnetii infection. 

Serological testing remains the diagnostic tool of choice owing to poor sensitivity and availability of culture and molecular techniques. A 4-fold rise in titers of phase II antibody in paired sera indicates acute Q fever, and titers of ≥1:800 of phase I antibody are required for diagnosis of chronic cases.

Clinical Infectious Diseases 2012;55(11):1531

DOI: 10.1093/cid/cis652