The Hematology Journal (2002) 3, 114 115 2002 The European Hematology Association All rights reserved 1466

6 4680/02 $25.00 www.nature.com/thj

LETTER

Chronic persistent hemolysis in an infant: can we aord to forget malaria as a cause?

DOI: 10.1038/sj/thj/6200155

There are innumerable causes of hemolytic anemia in newborn and infants,1 most of which are hereditary in nature such as hemoglobinopathies, enzymopathies and membrane disorders. Acquired causes of anemia such as Rh isoimmunization and exposure to drugs in G6PD decient infants are also known. Malaria infection is usually rare during early months of life with maternal antibodies against malaria parasites and high levels of Hb-F, protecting neonates from acute malarial infection.2 However this protection is not absolute and neonatal malaria due to passage of malarial parasite from mother to fetus has been reported.3 Malaria is a relatively rare cause of hemolytic anemia in an infant and parasitemia may be missed in the peripheral smear examination, especially when the clinical presentation is atypical. We are presenting here an unusual case of chronic hemolytic anemia in an infant due to malarial infection. A four-month-old boy, full-term normal delivery, presented with pallor, hepatosplenomegaly and unexplained chronic hemolysis for three months. The patient was admitted to a leading hospital (PD Hinduja Hospital and Research Centre) in Mumbai where he was managed symptomatically with packed cell transfusions and folic acid. Finally he was referred to

our institute for detailed investigation of hemolytic anemia. He had no fever and his growth was normal (6 kg at four months). His head circumference was 38 cm, midarm circumference 11.6 cms, chest 37 cms and height 58 cms. His liver was just palpable and spleen descended 3 cms below costal margin. Peripheral smear showed polychromasia, punctate basophilia, macrocytosis, anisocytosis and occasional spherocytes. Laboratory investigations from our institute are shown in Table 1. The parents were investigated for various parameters of hemolysis and were found to be normal with no family history of any hemolytic disorder. Repeated examination of peripheral smears revealed a few gametocytes and ring forms of Plasmodium falciparum (Figure 1). Treatment with chloroquine cleared this parasitemia and controlled the hemolysis. The child has now been followed for six months and is maintaining a hemoglobin level of 12.9 to 13.5 gm/dl. Malarial infection is a well-known cause of acquired hemolysis. In most cases, the evident parasitemia in blood makes the diagnosis obvious. The problem occurs when parasitemia is extremely low and the likelihood of an inherited disorder leading to hemolysis is extremely high as in the present case. With the advent of automated and semiautomated blood cell counters there has been a tendency to omit the

Table 1 Laboratory parameters of the propositus at one and four months. Parameters Hemoglobin Hb-A2 Hb-F WBC RBC Reticulocyte Platelet MCV Hb-H inclusion G6PD Pyruvate kinase 2,3 Di phosphoglycerate Adenosine tri-phosphate Reduced glutathione Pyrimidine 5' nucleotidase ratio Bilirubin (direct) Bilirubin (total) Direct Coombs Test Indirect Coombs Test Unstable hemoglobin Nd=not done. Propositus 1 month 6.5 2.3 33.0 9.9 2.47 8.5 178 92 Nd Normal Nd Nd Nd Nd Nd 0.5 1.3 Negative Negative Nd Propositus 4 months 6.6 2.6 3.4 8 2.09 18 166 87.2 Negative 3.51 11.9 8.86 3.91 56.82 2.53 1.0 1.5 Negative Negative Negative Reference range 12 16 g/dl 0.0 4.0% 0.0 2.0% 6 176109/l 3.8 4.961012/l 51.0% 210 6506109/l 84 100 Negative 2.5 5.5 IU/ml RBC/min 12.5 15.26 IU/g Hb 8.16 14.76 mmoles/g Hb 3.22 5.20 mmoles/g Hb 45 90 mg% 2.54 2.86 0.0 0.4 mg% 0.0 1.0 mg% Negative Negative Negative

Letter Author et al

115

examination of well-stained peripheral smears and this can contribute in some cases to misdiagnosis. The child was investigated extensively because the parasitemia was extremely low and was not picked up in the face of persistent and chronic hemolysis and because the patient did not have the characteristic fever of malarial infection. Hemolysis in malaria is multifactorial.4 The direct eect of parasites on the red cell, activated the monocyte macrophage system leading directly to hypersplenism.5 Coombs-positive hemolytic anemia6 associated with G6PD-deciency, drug eects and genuine autoimmune hemolytic anemia, are some of the mechanisms by which malaria infection can produce hemolysis. Our patient was not initially treated with anti malarial drugs. He was not G6PD-decient and his direct and indirect Coombs tests were negative. It would seem that the direct eect of the parasite on red

blood cells and hypersplenism due to activated monocyte-macrophage system are the most likely cause of hemolysis in this case. Antigen capture assays7,8 and immunochromatographic tests9 are today widely available in many countries and can detect malarial antigens even when parasitemia is low. Had this test been available for our patient, parasitemia would have been detected much earlier and costly investigations and repeated red cell transfusions would not have been necessary. (The family spent the equivalent of US$3200 for this patient.) The mother was questioned retrospectively and it was determined she had malarial infection days preceding delivery. There is no rm evidence to suggest that the malaria infection in the present case could have occurred by transplacental passage but it cannot be totally excluded. The present case clearly demonstrates how frustrating it is to investigate hemolytic anemia presumed to be congenital in nature in a child with essentially negative laboratory parameters. However examination of a thick smear also detects lower levels of parasitemia in a more sensitive fashion at a lower cost, but this test would have been done only if the suspicion of malaria was very strong. Hence a high level of suspicion should be maintained to rule out malaria infection when unexplained chronic hemolysis occurs, even in an infant in a malaria endemic area. This case also highlights the fact that much of the expenditure on this patient's management could have been avoided if careful and repeated peripheral smear examination with thick and thin smears had been resorted to during the early part of his hospitalization. Prabhakar S Kedar, Kanjaksha Ghosh*, Roshan B Colah, Dipika Mohanty

Figure 1 Microphotograph of peripheral blood smear showing gametocyte (Arrow) of P. falciparum from newborn boy with hepatosplenomegaly at presentation. 61500.

Institute of Immunohaematology, K.E.M. Hospital, Parel, Mumbai-400012, India *Correspondence: E-mail: kanjakshaghosh@hotmail.com

References 1 Lilleyman J, Hann I, Blanchette V. (eds). Pediatric Hematology. 2nd edn. Churchill Livingstone: New York; 1999. pp 191 192. 2 Pasvol G, Weatherall DJ, Wilson RJM. Eect of faetal Hemoglobin on susceptibility of red cells to Plasmodium falciparum. Nature 1977; 270: 171 173. 3 Conrad ME. Pathophysiology of malaria: hematologic observation in human and animal studies. Ann Intern Med 1969; 70: 134 141. 4 Lukehart SA, Holmes KK. Syphilis. In: Wilson JD, Braunwald E, Isselbacher K (eds). Harrison's principles of internal medicine. 12th edn. McGraw Hill Inc: New York; 1991. pp 651 661. 5 Looaresuwan S, Ho M, Wattanagoon Y. Dynamic alteration in splenic function during acute falciparum malaria. New Engl J Med 1987; 317: 675 679. 6 Ghosh K, Javeri KN, Mohanty D, Parmar BD, Surati RR, Joshi SH. False-positive serological tests in acute malaria. Br J Biol Sci 2001; 58: 20 23. 7 Mishra B, Samantaray JC, Mirdha BR. Evaluation of a rapid antigen captures assay for the diagnosis of falciparum malaria. Indian J Med Res 1999; 109: 16 19. 8 Beadle C, Long GW, Weiss WR. Diagnosis of malaria by detection of Plasmodium falciparum HRP-antigen with rapid dipstick antigen captures assay. Lancet 1994; 343: 564 569. 9 Mohanty S, Mishra SK, Mohanty A, Das BS. Immunochromatographic test for the diagnosis of falciparum malaria. J Assoc Physician India 1999; 47: 201 202.

The Hematology Journal