Diagnosis of haemophagocytic lymphohistiocytosis in a resource-limited setting

A 24-year old male from Anuradhapura was hospitalized for a cough lasting six weeks, high fever of ten days and intermittent haemoptysis of one week. He appeared ill, febrile and dyspnoeic. Bilateral diffuse wheezes and crackles were heard on chest auscultation. Non-tender firm spleen, palpable 5 cm below left costal margin, was found in the abdomen. No liver or lymph node enlargement was detected.


Case Report
A 24-year old male from Anuradhapura was hospitalized for a cough lasting six weeks, high fever of ten days and intermittent haemoptysis of one week. He appeared ill, febrile and dyspnoeic. Bilateral diffuse wheezes and crackles were heard on chest auscultation. Non-tender firm spleen, palpable 5 cm below left costal margin, was found in the abdomen. No liver or lymph node enlargement was detected.
Full blood count revealed mild anaemia (Hb 11.4 g/dL, 3 days later decreased to 9.7 g/dL), leucopenia (0.800x10 /L, neutrophils 8%, lymphocytes 92%) and a platelet count of 190x10 /L. Peripheral blood picture showed normocytic and normochromic red cells, with marked leucopenia and neutropenia with few reactive lymphoid cells. Platelets were normal in morphology. Chest radiograph showed bilateral patchy shadows mainly in the mid and lower zones on the right side ( Figure). Abdominal 9 9 ultrasonography confirmed bulky splenomegaly without hepatomegaly or other abnormalities. Sputum culture was positive for MRSA. Sputum examination with Ziehl Neelsen staining demonstrated acid fast bacilli (2+). Bone marrow aspirate showed increased macrophages with prominent haemophagocytosis, moderate erythroid hyperplasia with moderately suppressed granulopoietic activity with no mature granulocytic series and arrest at promyelocyte-myelocyte stage. No mature neutrophils / band forms were noted or smudge cells were seen.
Trephine biopsy of the bone marrow showed hypercellular marrow spaces composed of moderately hyperplastic erythropoiesis, thrombopoiesis of normal morphology and active granulopoiesis with moderate maturation arrest at the late precursors. Macrophage activity was increased and scattered among haemopoietic tissue. Scattered lymphocytes too were seen. No lymphoid cell infiltration was noted. The possibility of His ESR was 70 mm while serum protein was 5.3 g/dL (Albumin 2.3). Serum alkaline phosphatase, ALT, AST, serum creatinine, LDH, serum Na and K were normal. Blood cultures were negative.
The presentation and the initial laboratory investigations of this patient were suggestive of a hematological malignancy associated with pulmonary tuberculosis secondary to immune suppression. However the bone marrow examination showed characteristic features of HLH which directed the investigators towards this diagnosis. Criteria 1, 2, 5 and b were found in our patent. The deranged coagulation studies with prolonged APTT, INR and elevated D-dimer level could be secondary to low fibrinogen. Leukocytopenia and the drop of haemoglobin from 11.7 to 9.7 g/dL within 3 days, too were supportive of the diagnosis. Hyperbilirubinaemia, though characteristic in this condition, is not a diagnostic criterion. Fibrinogen

Main criteria
Additional criteria HLH is rare and characterized by benign proliferation of the mature histiocyte and uncontrolled phagocytosis of the platelet, erythrocytes, lymphocytes and their hematopoietic precursors in the bone marrow causing cytopenia. Primary HLH occurs as a result of genetic inheritance. Secondary HLH occurs following infections (2), inflammatory conditions and malignancies (3). The likely causative factor in this case was pulmonary tuberculosis which is a known cause of HLH (4,5,6,7). The MRSA infection was possibly secondary to neutropenia in this patient. Management of secondary HLH is directed to the treatment of the underlying cause. He was treated with vancomycin, meropenem and CAT 1 anti-TB regimen. The patient showed good clinical response to treatment; however he died later from suicide.