Pancytopenia resulting from hemophagocytosis in malaria

Pancytopenia in an acutely ill child is commonly a result of bone marrow suppression. Rarely pancytopenia is a manifestation of inappropriate macrophage activation associated with hemophagocytosis. Viral infections account for most cases of secondary hemophagocytosis. We report a case of malaria-associated hemophagocytosis in a child from an endemic area. Systemic parasitic infections should be included in the differential diagnosis of pancytopenia and infection-associated hemophagocytosis. In this rare subgroup of hemophagocytosis, malaria caused by Plasmodium falciparum is the most common parasitic infection. The most important diagnosis to consider in evaluation of an acutely ill child with pancytopenia is lymphoreticular malignancy or aplastic anemia. Other common causes of bone marrow (BM) suppression include viral diseases, septicemia and drug reactions. Rarely pancytopenia is a manifestation of hemophagocytosis. Hemophagocytosis is classified into three clinically distinct groups: familial hemophagocytic lymphohistiocytosis (FHL); infection-associated hemophagocytic syndrome (IAHS); and malignancy-associated hemophagocytic syndrome (MAHS). 1 The most common etiologies for IAHS are viral and bacterial infections, whereas parasitic infections are extremely rare in this context. 2 We report a rare case of malaria-associated hemophagocytosis in an immigrant child from an endemic area. Case report. The patient was an 11-year-old girl who was admitted to our hospital because of fever, headache and vomiting that appeared 2 days before admission. The girl was born at term in Israel to a Jewish mother and non-Jewish African father. At the age of 4 years the child emigrated to Cameroon with her family, where they lived until recently. Reportedly the patient had several febrile illnesses during the past 6 years that were presumed to be malaria and treated as such, although no documentation was available. The family history was remarkable for the death of the patient’s mother because of possible lung cancer. Recently the patient immigrated to Israel from Cameroon with her father and brother. On admission the patient was afebrile, in good general condition, but weak with slightly jaundiced sclerae. There was mild hepatosplenomegaly. The rest of the physical examination was unremarkable. Initial laboratory findings showed erythrocyte sedimentation rate 30 mm/h, white blood cells (WBC) 4400/mm3 (polymorphonuclear neutrophils 38%, lymphocytes 50%, monocytes 11%), red blood cells (RBC) 4700/mm3, hemoglobin 10.1 g/dl, maximum cell volume 77 fl, mean cell hemoglobin 24 pg, mean cell hemoglobin concentration 31 g/dl, reticulocytes 0.6%, platelets 78 000/mm3. Blood chemistry revealed unconjugated hyperbilirubinemia of 2.5 mg/dl (conjugated bilirubin, 0.1 mg/dl), albumin 3.1 g/dl and globulin 3.9 g/dl. Blood cultures, liver and kidney function tests and urinalysis were normal. Although the headaches and vomiting ceased spontaneously after admission, the patient had once or twice daily spikes of fever during her first 3 days at the hospital. Repeated complete blood count showed neutropenia (nadir absolute neutrophil count 660/mm3), hemoglobin 10.1 g/dl and platelets 73 000/mm3. On peripheral blood smear phagocytosis of RBC by macrophages was observed; RBC morphology was unremarkable. Abundant intracellular single young ring forms of Plasmodium vivax were revealed, as well as occasional erythrocytes with multiple rings and gametocytes of Plasmodium falciparum. In addition to occasional intracellular parasites, BM aspirate revealed phagocytosis of WBC and RBC by marrow phagocytes. The erythroid:myeloid ratio in the BM was normal. Natural killer cell activity performed during the acute phase, with and without overnight incubation with alpha-interferon and interleukin 2, was normal. The child was treated with mefloquine 250 mg four times a day for 1 day and with primaquine 15 mg daily for 2 weeks. This therapy resulted in prompt resolution of fever and other symptoms without side effects. Within 1 week after the initiation of the therapy WBC and platelet counts were normal, whereas the anemia persisted and was attributed to iron deficiency (iron, 14 μg/dl; iron saturation, 4%; iron-binding capacity, 335 μg/dl). No recurrence of parasitemia or fever was observed for >1 year after the patient’s discharge from our hospital. Discussion. Common clinical features of IAHS include fever, malaise and fatigue; maculopapular rash; hepatosplenomegaly; jaundice and neurologic symptoms or signs. The classic laboratory findings are anemia, thrombocytopenia, neutropenia, hypofibrinogenemia and hypertriglyceridemia. In 1991 the FHL study group proposed diagnostic guidelines for hemophagocytic syndromes. 3 Because many reported cases did not fit these guidelines, other modified diagnostic criteria were proposed. 4 The most consistent features of the syndrome are fever (>1 week duration), cytopenia affecting at least two cell lineages and hemophagocytosis observed in BM or in the liver, spleen or lymph nodes. 4 Although the relatively short duration of fever in our case precludes fulfillment of all the required criteria for IAHS, the observed pancytopenia and hemophagocytosis illustrate the spectrum of inappropriate activation of macrophages that encompass FHL, IAHS and MAHS. Anemia is the major and the most common hematologic finding in patients with malaria. In addition the array of hematologic changes in the disease includes leukocytosis, monocytosis, neutropenia and thrombocytopenia. 5 Although hemophagocytosis has been stated as one of the pathogenic mechanisms of anemia in malaria, 6 it was not found in a review of more than 2000 bone marrow aspirates from patients with malaria. 7 Furthermore malaria is not usually considered in the differential diagnosis of hemophagocytosis and pancytopenia. 8 Infection-associated hemophagocytic syndrome has been reported in a great variety of viral, bacterial, fungal and, rarely, parasitic infections 2, 4, 9 (Table 1). Occasional case reports of parasitic infections implicated in IAHS include visceral leishmaniasis, 10, 11 toxoplasmosis, 12 babesiosis 13, 14 and disseminated strongyloidiasis. 15 Meticulous search of medical literature revealed only five previously reported cases of malaria-associated hemophagocytosis. 16–20 In all of these reported cases, the offending parasite was P. falciparum.TABLE 1: Infections associated with hemophagocytosis (compiled from References 2 and 8 to 20)Generally the prognosis of IAHS is better than in FHL or MAHS. Epstein-Barr virus infection has the worst prognosis among IAHS cases with mortality rate up to 30%. 4 Unless associated with underlying immunodeficiency, 19 the outcome for IAHS caused by parasitic infections is generally good, as occurred in our patient. In conclusion systemic parasitic infections should be included in the differential diagnosis of pancytopenia and IAHS. In this rare subgroup of IAHS, malaria caused by P. falciparum is the most common parasitic infection.