Brucellosis accompanied by haemophagocytic lymphohistiocytosis and multiple splenic abscesses in a patient with depression

Abstract

A 39-year-old woman was being treated for depression in our clinic. She subsequently developed a fever and was diagnosed with pancytopenia and moderate splenomegaly. Laboratory and bone marrow results, including markedly increased serum ferritin levels, suggested haemophagocytic lymphohistiocytosis. CT showed multiple splenic abscesses and ovarian vein thrombosis. All laboratory values returned to normal after treatment for culture-positive brucellosis.

Background

Brucellosis is a systemic disease endemic to the Middle East.¹ It has several presentations and serious complications (eg, endocarditis, neurobrucellosis and disabilities) and is sometimes misdiagnosed as a haematological malignancy.² Among the 787 patients with brucellosis in a previous study, 14% had thrombocytopenia, 12% had leucopenia, 5% had pancytopenia and 4% had bicytopenia.³ In a large study performed in Turkey, pancytopenia was more common in acute cases (8.8%) than subacute (1.4%) and chronic (0.1%) cases.² Although pancytopenia is associated with hypersplenism, the concomitant occurrence of hepatosplenomegaly and pancytopenia raises the possibility of Brucella-induced haemophagocytic lymphohistiocytosis (HLH).⁴ Infections contribute to 41.1% of HLH cases, while 28.8% of cases have an associated malignancy and 17% have no identifiable underlying cause.⁵ A marked release of inflammatory cytokines, lymphocyte activation and multiorgan (eg, liver, spleen and brain) histiocyte infiltration account, in part, for the signs and symptoms of HLH. Triglyceride levels also increase owing to a tumour necrosis factor α-mediated inhibition of lipoprotein lipase activity. Additional diagnostic criteria for HLH are based on secretions of ferritin and plasminogen activator that contribute to fibrinolysis, by activated macrophages.⁶ Brucella-induced (unlike malignancy induced) histiocytic haemophagocytosis is usually treatable.

We report this case to remind practitioners in endemic areas to consider brucellosis when patients present with acutely depressed mood, particularly if accompanied by fever. Unexplained haemophagocytosis and multiple splenic abscesses also warrant consideration of brucellosis in endemic areas.

Case presentation

A 39-year-old woman was seen in the clinic with generalised fatigability, anorexia, lassitude and mood disturbance. She was diagnosed with depression and started on citalopram 10 mg once daily. One week later, she experienced fever, chills and rigors and headache. Her temperature on admission was 36.7°C and her blood pressure, pulse and respiratory rates were normal. The general examination was unremarkable apart from splenomegaly, identified by the splenic edge measured at 4 cm below the left costal margin. Laboratory investigations revealed pancytopenia and an extremely elevated serum ferritin of 78 777 ng/mL (normal range: 13–150 ng/mL). Both liver function tests and renal profiles were abnormal on admission but reverted to normal prior to discharge (table 1). Leukaemia, systemic lupus erythematosus (SLE), HIV and aplastic anaemia were suspected initially. Ultrasound of the abdomen showed moderate hepatomegaly and splenomegaly measuring 20 cm in craniocaudal dimensions. A repeat CT scan confirmed a moderate splenomegaly showing innumerable small hypodense lesions (figure 1). In addition, right ovarian vein thrombosis was noted (figure 2). No vegetations were detected on echocardiogram. Serum tests for HIV, hepatitis B surface antigen, hepatitis C virus, Epstein-Barr virus and cytomegalovirus were all negative. Antinuclear antibodies, antineutrophil cytoplasmic antibodies and antiphospholipid antibodies were negative. Bone marrow aspiration showed that some of the erythroid precursors had degrees of dysplasia. Myeloid precursors were also present, along with cells in all stages of maturation, but there was no increase in blast cells, and megakaryocytes were occasionally seen. Prominent phagocytic activity was noted (figure 3). A blood culture grew gram-negative coccobacillus which was further identified to be a fully sensitive Brucella species with a high minimum inhibitory concentration to rifampicin of 3.0. She received intravenous gentamicin 5 mg/kg/day for 10 days and doxycycline 100 mg twice daily for 12 weeks. In addition, she was anticoagulated with heparin then warfarin for 6 months.

Table 1.

Investigations before and after treatment

Item	Before treatment	Normal values	Follow-up values
White cell count	2.2×109/L	4.0–11.0×109/L	8.0×109/L
Neutrophils	1.0×109/L
Haemoglobin	10.3 g/dL	11.5–16.5 g/dL	14.0 g/dL
Platelets	45×109/L	150–450×109/L	259×109/L
Urea	12.7 mmol/L	2.0–6.7 mmol/L	3.4 mmol/L
Creatinine	134 µmol/L	45–84 µmol/L	63 µmol/L
Potassium	3.1 mmol/L	3.2–5.0 mmol/L	3.6 mmol/L
Ferritin	78 777 ng/mL	13–150 ng/mL	94 ng/mL
Cholesterol	6.00 mmol/L		4.94 mmol/L
Triglyceride	3.0 mmol/L		2.11 mmol/L
Low-density lipoprotein cholesterol	3.85 mmol/L		3.34 mmol/L
Lactate dehydrogenase	616 U/L	135–214 U/L
Total bilirubin	17 µmol/L	2–21 µmol/L	10 µmol/L
Albumin	24 g/L	36–51 g/L	35 g/L
Alkaline phosphatase	371 U/L	35–104 U/L	138 U/L
Alanine transaminase	84 U/L	2–40 U/L	22 U/L
CA-125	150 U/mL	0–35 U/mL
CA15-3	72 U/mL	0–25 U/mL
C-reactive protein	89 mg/L	0–6 mg/L	21 mg/L

Figure 1.

CT scan of the abdomen (liver view) showing multiple splenic abscesses.

Figure 2.

CT scan of the abdomen showing right (R) ovarian vein thrombosis (arrow).

Figure 3.

Bone marrow aspirate showing hemophagocytosis (erythroid precursors and platelets are engulfed by macrophage).

Differential diagnosis

For our differential diagnosis, we suggested brucellosis, with or without endocarditis, leading to splenic abscesses, hypersplenism or HLH causing pancytopenia. Miliary tuberculosis can present with varied haematological changes including pancytopenia, splenomegaly and HLH. Further, SLE should be considered in a female with psychiatric symptoms, thrombocytopenia, splenomegaly and pancytopenia as well as HLH. Haematological malignancies including leukaemia and lymphoma can also present with pancytopenia, splenomegaly and HLH.

Treatment

1. Intravenous gentamicin 5 mg/kg per day for 1 week.

2. Doxycycline 100 mg orally twice daily for 3 months.

3. Enoxaparin sodium followed by warfarin (initiated and adjusted based on the international normalised ratio) for a total of 6 months.

Outcome and follow-up

The patient’s condition and mood improved on treatment. C-reactive protein and ferritin levels and blood counts returned to normal (Table 1).

Discussion

This case highlights several recognised, although uncommon, complications of brucellosis. The patient in our case presented with only vague symptoms of depression and fatigue. In a pooled analysis of 35 studies performed in Turkey, depression was detected in 5% of 187 neurobrucellosis cases.⁷ Importantly, brucellosis treatment alleviates cognitive and emotional disturbances in infected patients, as seen in our case, without additional antidepressant therapy.⁸

Diagnostic criteria for HLH include fever, splenomegaly, cytopenias affecting ≥2 of 3 lineages in the peripheral blood, hypertriglyceridaemia and/or hypofibrinogenaemia, haemophagocytosis in bone marrow or spleen or lymph nodes, low or absent natural killer cell activity, ferritin ≥500 µg/L and soluble CD25 (ie, soluble interleukin-2 receptor) ≥2400 U/mL. Five of these eight criteria need to be present to establish the diagnosis.⁹ In our case, Brucella-induced haemophagocytic syndrome was suggested by the presence of six of these criteria including fever, splenomegaly, cytopenia (neutropaenia, thrombocytopenia and anaemia), bone marrow haemophagocytosis, hypertriglyceridaemia and hyperferritinaemia exceeding 70 000. HLH was identified in 48.9% of children and 14.2% of adults with ferritin >10 000 µg/L.¹⁰ Other factors associated with this syndrome were not examined in our case. Early reports of Brucella-induced HLH were described by Zuazu in 1979.¹¹ Mild haemophagocytosis was observed in the bone marrows of nine (1.4%) patients of 622 children with brucellosis. On the other hand, mild to moderate haemophagocytosis on the bone marrow smear was detected in 8% (18/233) of cases.¹² Unlike malignancy-induced HLH, Brucella-induced HLH is potentially curable by treating the brucellosis alone.¹³

Ovarian vein thrombosis (OVT) is a relatively rare disorder that classically occurs in postpartum women.¹⁴ Most (70%–90%) OVT cases involve the right ovarian vein owing to lengthy antegrade flow and the presence of dysfunctional valves in this vein. Although there are no previous reports of OVT in brucellosis, numerous thrombotic disorders, including thromboses of the cerebral venous system, portal vein and inferior vena cava, have been described.¹⁵ Vascular complications in brucellosis occur in less than 1.0% of cases, with only 14 cases of Brucella-related thrombosis reported so far.¹⁶ The exact pathogenesis of Brucella-related deep vein thrombosis is unclear. Suggested causes include endothelial infection and induction of inflammation, granulomatous endophlebitis, a transient hypercoagulable state and an immune reaction to a Brucella antigen.¹⁷

In our study, the abdominal CT showed multiple hypodense lesions distributed in almost a ‘miliary’ pattern. Such lesions are characteristic of miliary tuberculosis, which is also endemic to the Middle East; however, chest imaging (CT and X-ray) and the bone marrow examination did not support this diagnosis. Moreover, an echocardiogram appeared to rule out Brucella-induced endocarditis, as no vegetations were revealed.

In a previous study, approximately 0.4% of patients with brucellosis (n=2475) had splenic abscesses and only 1.2% had hepatosplenic lesions.¹⁸ Abscesses occur mainly in the liver, less frequently in the spleen (28%) and rarely in both organs (2%). Solitary abscesses with central calcifications occur most commonly in the liver and are indicative of brucellosis. Less indicative are multiple small abscesses, which tend to occur in the spleen. Splenic abscesses with calcifications are less common than liver abscesses with calcifications and occur in 24%–25% of brucellosis splenic abscesses, irrespective of their number.¹⁸

Learning points.

1. Depression is a potential, but often overlooked, presenting symptom of brucellosis.

2. Pancytopenia, splenomegaly and high ferritin should raise the possibility of haemophagocytic lymphohistiocytosis in patients with brucellosis.

3. ‘Miliary-like’ splenic abscesses characteristic of disseminated tuberculosis can accompany brucellosis.

4. Venous thrombosis and arterial thrombosis are recognised features of brucellosis.