Introduction

Q fever is a zoonosis caused by Coxiella burnetii, a strictly intracellular bacteria with a worldwide distribution and high infectivity. Humans are typically infected after contact with farm animals, including cattle, goats and sheep, mainly through inhalation of contaminated aerosols.¹ The acute form of the disease can have a wide range of clinical manifestations, from asymptomatic seroconversion or a self-limited flu-like syndrome to severe disease with different organ involvement, most commonly pneumonia and hepatitis.^1,2The diagnosis is usually confirmed by serology.^1,3This requires a high degree of suspicion, as the epidemiological information, physical exam and routine laboratory results are non-specific. Some patients may develop a chronic or persistent localized infection.

We report a case of acute Q fever with isolated bone marrow involvement, which is a rare manifestation of an infrequent disease. This case highlights the difficulties that can arise in its diagnosis, the benefits of following small diagnostic clues and the histopathologic features of bone marrow involvement in Q fever.

Case Report

A 71-year-old man, working as a manager, presented to the emergency department with a high fever of 38.8ºC for 3 weeks, asthenia and night sweats. He did not report myalgias, headache or other symptoms. He had previously received 7 days of prulifloxacin without clinical improvement.

He had a history of high blood pressure, type 2 diabetes mellitus, both controlled with medication, and had been recently diagnosed with atrial fibrillation, taking rivaroxaban. He lived in an urban area, consumed bottled water and had no pets or contact with animals, including cats, dogs and cattle. The symptoms started one week after a leisure trip to Madeira, but he also had a business trip to Cairo three months before, having stayed in the city and mostly at the hotel. During these trips, he denied having had contact with animals or consuming dairy products.

On physical examination, he was febrile, with low blood pressure (80/60 mmHg), heart rate 75 bpm and peripheral oxygen saturation of 96%. The physical exam was otherwise unremarkable.

His initial blood tests revealed anaemia (hemoglobin 11.5 g/dL), thrombocytopenia (platelets 39.000/μL), total white blood cell 16.280/μL, 59% neutrophils and 32% lymphocytes, international normalized ratio (INR) 1.87, C-reactive protein (CRP) 30.25 mg/dL (normal < 0.5 mg/dL) and ferritin 2956 μg/L (normal 21.8-274.7 μg/L). There was mild elevation of creatinine (1.31 mg/dL, normal 0.6-1.3 mg/dL) and urea (81 mg/dL, normal 22-52 mg/dL), with a normal urinalysis. Total and direct bilirubin were slightly elevated (1.68/0.76 mg/dL, normal 0.2-1.2/<0.5 mg/dL), with normal liver enzymes. Computed tomography (CT) of the chest, abdomen and pelvis was unremarkable. Transthoracic and transoesophageal echocardiogram were negative for endocarditis and valvular disease. Blood cultures and serologies for human immunodeficiency virus (HIV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), hepatitis B and C virus, Salmonella, syphilis, malaria, dengue, Rickettsia spp., Borrelia spp. and Leptospira spp. were negative. Initial Coxiella burnetii serologies (indirect immunofluorescence technique) were: phase I IgG 20, phase I IgM 80, phase II IgG 40 and phase II IgM 40 (Table 1).

Table 1: Titter evolution during the follow-up. Reference cut-off < 20. Note the 4-fold increase of phase II IgG, which supports the diagnosis of acute infection. 

While awaiting laboratory results, and considering the haematological abnormalities the sole discriminator of the fever, a bone marrow myelogram and biopsy were performed which revealed erythroid and myeloid hyperplasia and multiple ring epithelioid granulomas, consisting of a central lipid vacuole surrounded by epithelioid histiocytes and some neutrophils (Fig. 1). Periodic acid-Schiff and Giemsa stains were negative. Peripheral blood and bone marrow immuno-phenotyping by flow cytometry showed no abnormal populations.

Figure 1: Haematoxylin and eosin staining of bone marrow biopsy. Ring granuloma of epithelioid histiocytes and some neutrophils around a central clear space composed of fat (*). 

The histopathological findings supported the diagnosis of Q fever, which was later confirmed by repeating the Coxiella burnetii serology, which showed seroconversion to the phase II antigen (Table 1). Polymerase chain reaction (PCR) in a blood sample to detect Coxiella burnetii after treatment was negative.

Treatment with doxycycline 100 mg two times daily was initiated. After starting treatment, the fever resolved and the patient showed an improvement on well-being and activity level.

After completing 14 days of treatment, without reporting any side effects, he remained asymptomatic, anaemia and thrombocytopenia had resolved, and CPR levels were normal. Follow-up at two, four and six months after treatment showed no signs of persistent infection. Coxiella burnetii serologies six months after the initial treatment were negative.

Discussion

Q fever is an acute febrile and occasionally persistent infection that occurs worldwide. Humans are infected mostly by contaminated aerosol inhalation and, after an incubation period of 1 to 39 days, about 40% of individuals develop acute febrile disease, with severe headache, chills, fatigue and myalgia, sometimes with pneumonia and/or hepatitis.¹ Hepatitis is a frequent presentation of acute Q fever in countries where the disease is endemic, like Portugal.^4,5Bone marrow involvement is rarely mentioned in the literature.^6,7

Primary (acute) C. burnetii infection is defined by the association of acute clinical symptoms with the following serologic criteria: phase II IgG titers≥ 200 and phase II IgM titers≥ 508 or a fourfold rise in anti-phase II IgG from two serum samples taken apart.³

In recent years, studies have shown the usefulness of PCR to detect C. Burnetii in blood.^1,3These techniques can overcome the delay in diagnosis based on serology, as it has high sensitivity and specificity for acute Q fever if collected during the acute phase (optimally during the first 2 weeks of symptoms) and either before or shortly (24-48 hours) after antibiotic administration.³

In our case, the distinct feature that helped the diagnosis was the ring granulomas, also sometimes called “doughnut” granulomas, found in the bone marrow biopsy. Historically described as pathognomonic of Q fever, these granulomas can appear in different organs, being more frequent in the liver, and are known to appear in different infections, including EBV, CMV, Hepatitis A virus, Brucella melitensis, Salmonella spp. and other intracellular bacteria such as mycobacterial infections,^6,9as well as secondary to Hodgkin and non-Hodgkin lymphomas,^9,10autoimmune disorders and drugs such as allopurinol.⁹ The ring epithelioid granulomas in the Q fever consist of histiocytes, lymphocytes and eosinophils surrounding a central lipid vacuole with a fibrinoid outer ring. The pathophysiology is not well understood, but it has been suggested that these lesions are related to focal vasculitis with endothelial injury and deposition of immune complexes^.11,12

When adequate treatment is initiated, prognosis is usually good. One to five per cent of the infected patients can develop a persistent focalized infection, mainly as endocarditis, osteoarticular infection or persistent lymphadenitis.^2,13Patients with prosthetic valves, valvular abnormalities like aortic bicuspid or mitral prolapse, vascular graft, prosthetic joint, pregnant women or immunocompromised hosts have a higher risk of persistent infection.¹ Long-term studies show that patients with acute Q fever are at risk of developing post-Q fever fatigue syndrome.¹⁴ Although there are some concerns about a link between Q fever, especially if affecting the bone marrow or lymph nodes, and non-Hodgkin lymphoma,⁷ more studies are needed.¹⁵

To our knowledge, this is the only case in the literature that describes an isolated bone marrow involvement of Q fever, especially without elevated liver enzymes or pneumonia, making the diagnosis of this rare entity even more challenging.