Brucellosis presenting as myelofibrosis: First case report

Introduction 

Brucellosis is a major zoonotic disease in several parts of the world including the Mediterranean region; it can affect any organ and can have various presentations.1, 2 Pancytopenia is a known complication of brucellosis.2, 3 Causes of pancytopenia in brucellosis include hypersplenism and/or bone marrow involvement with granuloma, hemophagocytosis, and rarely bone marrow hypoplasia.4, 5

Here, we describe a case of brucellosis presenting with pancytopenia secondary to myelofibrosis. To our knowledge this is the first report of such a complication resulting from brucellosis.

Case report 

A 29-year-old woman, who used to drink raw milk, was healthy until July 2007 when she started to complain of fever, dry cough, arthralgia, loss of appetite, and generalized weakness. She presented to our hospital one month after the onset of her symptoms.

Physical examination showed a sick, pale female, with blood pressure of 125/80 mmHg, temperature 38.5°C, hepatosplenomegaly, purpuric rash on the lower extremities, and a tender and swollen left knee. Laboratory examination showed hemoglobin 7.5g/dl, white blood cell count 1.3×109/l (neutrophils 37%, lymphocytes 55%), and platelets 20.8×109/l. A blood film showed dimorphic red blood cells and no blast cells. Lactate dehydrogenase was 1479U/l (normal range 240–480U/l). Both the prothrombin and partial thromboplastin times were normal. Coombs’ test was positive. Tests for hepatitis viruses B and C and HIV were all negative.

A bone marrow biopsy (Figure 1) revealed myelofibrosis with proliferative phase. Initially, the patient received imipenem and fluconazole (days 1–2), which was then switched to ceftazidime and caspofungin (days 3–9). However, the patient remained febrile. Eight days after admission, a blood culture (BACTEC 9240) taken on the day of admission grew Brucella melitensis identified by culture, Gram staining, biochemical, and serotyping methods. Therefore, doxycycline 100mg twice daily and rifampin 600mg once daily were started, and her fever abated after 2 days. The serum agglutination titer for Brucella was 320. A transthoracic echocardiogram did not show any vegetation. Abdominal computed tomography (CT) showed hepatosplenomegaly with a liver size of 19cm and spleen size of 22cm. A chest CT showed right hilar lymphadenopathy.

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Figure 1. Bone marrow biopsy before treatment showing (A) fibrosis and hypocellular elements (H&E ×20); (B) marked fibrosis (reticulin, ×20).

The patient finished 3 months of doxycycline and rifampin. Her hemoglobin rose to 13g/l, white blood cell count to 5.8×109/l, and platelets to 101×109/l. A repeat bone marrow biopsy (Figure 2) in November 2007 showed hypercellular marrow with no evidence of fibrosis, malignancy, or granulomatous process. A repeat CT of the abdomen in May 2008 showed spleen and liver sizes of 16cm. The patient continued to do well one year following her initial presentation. Her spleen became non-palpable and her repeat Brucella titer was 40.

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Figure 2. Bone marrow biopsy after treatment showing (A) marked hypercellularity (H&E ×20); (B) reticulin not increased in the marrow (reticulin, ×20).

Discussion 

Infection with Brucella is known to cause anemia, leukopenia, and to a lesser extent thrombocytopenia and pancytopenia. The frequency of pancytopenia ranges from 3% to 21%.6 Bone marrow findings in cases complicated by pancytopenia include normocellular or hypercellular marrow, granuloma, hemophagocytosis, and rarely hypoplasia.3, 4, 5, 6, 7, 8, 9, 10, 11 In these situations, neutropenia resolves following treatment of the infection. The cause of pancytopenia is poorly understood. However, due to the tendency to marrow hyperplasia, and splenomegaly and absence of hemolysis, hypersplenism was implicated as the cause of pancytopenia; it is also possible that Brucella organisms exert a direct inhibitory effect on marrow cells or they induce lymphocytes to release mediators that inhibit hematopoeisis.5, 9

Considering that brucellosis can occur with leukemia, febrile neutropenia, and solid tumors,4, 12, 13 we could not determine initially whether the patient had myelofibrosis secondary to brucellosis, or the brucellosis occurred in a preexisting myelofibrosis. However, the remarkable clinical and bone marrow response after the treatment of the infection support the hypothesis that Brucella was the cause of the myelofibrosis.

To our knowledge, this is the first report of myelofibrosis due to brucellosis. Myelofibrosis can be seen in a variety of conditions, including chronic granulocytic leukemia, acute myeloid leukemia, multiple myeloma, and chronic lymphocytic leukemia. Infectious causes include kala-azar,14 disseminated tuberculosis, histoplasmosis,15 and Epstein–Barr virus.16 Myelofibrosis can occur in cases of tuberculosis either due to hemophagocytosis,8 or through the effect of transforming growth factor (TGF)-β which is produced from the tuberculosis granuloma and promotes fibrosis in the bone marrow.17

The mechanism of development of myelofibrosis here is not completely understood. We did not find any evidence of hemophagocytosis in the bone marrow; therefore the development of myelofibrosis could be due to overproduction of cytokines such as TGF-β. In this regard Rafiei et al.18 reported that patients with brucellosis have an increased frequency of TGF-β1 high producer genotype, but on the other hand Akbulut et al.19 did not find significant differences in TGF-β levels between controls and patients with brucellosis. Alternatively, myelofibrosis could occur secondary to an antibody-mediated autoimmune mechanism.20 In support of this possibility is the positive Coombs’ test, and the fact that brucellosis has been described with several autoimmune conditions such as glomerulonephritis,21 Henoch–Schonlein purpura,22 and thrombocytopenia.23

In conclusion, this is the first report describing brucellosis complicated by myelofibrosis. Physicians in endemic areas should be aware of this possible association and test for Brucella in cases of myelofibrosis.

Conflict of interest: No conflict of interest to declare.