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Letters to the Editor

Indian Pediatrics 2005; 42:1253-1255

EBV-associated Hemophagocytic Lymphohistiocytosis with Spontaneous Regression


A 9-year-old boy, previously healthy, was referred to our center with 10 days of fever, weakness, epistaxis and purpura. Examination revealed a febrile child who had marked pallor; petechiae over limbs and trunk; 1-1.5 cm multiple sub-mental lymph nodes; 3 cm hepatomegaly and 5 cm splenomegaly below costal margins respectively. Investigations (Table I) showed pancytopenia with lymphocytosis; elevated ALT and AST; repeated blood cultures were sterile. Bone marrow aspiration (BMA) revealed dyserythropoiesis and several histiocytes, some of which were exhibiting erythrophagocytosis suggestive of hemophagocytic lymphohistiocytosis (HLH). Further investigations revealed corroborative evidence of HLH in the form of elevated serum LDH, triglyceride and ferritin levels. Hepatitis virus serology was suggestive of an old infection with hepatitis B virus. Serology for Ebstein Barr Virus (EBV) was suggestive of recent infection. Serum immunoglobulins revealed mild reduction in IgA and IgM levels. Thus final diagnosis was EBV associated HLH. Patient showed remarkable clinical improvement with supportive care including intravenous antibiotics, platelet and blood trans-fusions. Within a week, he was asymptomatic and follow-up showed gradual improvement with normalization of bio-chemical abnormalities and BMA at 6 weeks. At 15 months of follow-up, he remains asymptomatic.

TABLE I

Investigation Profile of the Patient

A. Primary Investigations
 
Hemoglobin 
6.4 g/dL 
Platelet 
41, 000/m3 
White Blood Cell 
1900/m3 
Differential 
N18, L81, M1; anisocytosis and macrocytic anemia, 
nucleated RBC 1-2/100 WBC; no blasts. 
Renal Function Tests 
Normal 
Aspartate aminotransferase 
196 IU/L (N: <50 IU/L) 
Alanine transferase 
134 IU/L (N: <50IU/L) 
Chest Radiograph 
Normal 
USG Abdomen 
Hepatosplenomegaly with no focal lesions 
B. Investigations for corroborative evidence of HLH
DIC 
Profile Normal except thrombocytopenia 
Fibrinogen 
380 mg/dL (200-450 mg/dL) 
Lactate dehydrogenase 
973 U/L (N: 100-190 U/L) 
Triglyceride 
459 mg/dL (N: 50-150 mg/dL) 
Ferritin 
2450 ng/L (N: 15-400 ng/L) 
C. Investigations for corroborative evidence of HLH
 
Hepatitis B Surface antigen
Positive 
Hepatitis B core IgM antibody 
Negative 
Hepatitis C Serology
Negative 
Parvovirus IgM 
5.8 U/mL (N: <17 U/mL) 
Cytomegalovirus IgM
0.35 A.I. (0-0.9) 
Human immunodeficiency virus 
Negative 
EBV IgM 
40.63 U/L (N: <12U/L) 
EBV IgG 
106.6 U/L (N: <12U/L) 
IgG 
2860 mg/dL (N: 960-1968 mg/dL) 
IgA 
90 mg/dL (N: 125-380 mg/dL) 
IgM 
65 mg/dL (N: 90-242 mg/dL) 

 

HLH is a disorder of mononuclear phagocytic system characterized by proliferation and activation of histiocytes and macrophages. HLH comprises primary HLH (familial or hereditary HLH) and secondary HLH(1). Secondary HLH could be due to infections(2) which is termed as infection-associated hemophagocytic syndrome (IAHS); rheumatic disease and malignancies. HLH is an uncommon manifestation of many common tropical infections such as tuberculosis, leishmaniasis and salmonella. IAHS has a fatality rate of more than 50% in children. EBV-HLH is the most common reported IAHS resulting in severe disease. Clinical features of EBV-HLH include high fever, hepato-slenomegaly, cytopenia, liver dysfunction, coagulopathy, lipid changes because of hypercytokinemia and organ infiltration by phagocytosing histiocytes(3).

Specific treatment includes using immuno-suppressants such as steroids and cyclosporine A and cytotoxic agents such as etoposide. For FHLH and relapsed/aggressive EBV-HLH, stem cell transplantation is the only curative option. The main causes of early death are hemorrhage and infection. The initial management of EBV-HLH is aimed at reducing the likelihood of this early death, which includes careful monitoring of hemostatic parameters, blood products administration, treatment of infection and prompt introduction of cyclosporine A. The decision whether to treat a child with presumed secondary HLH with specific drugs should depend solely on the clinical condition of the patient and associated laboratory changes(4). The progression to lymphoma or leukemia also seems to be a special problem in these cases(5); which is why the patient is, and will be on continued follow-up and monitoring.

Sameer Bakhshi,
Jeremy L. Pautu,

Department of Medical Oncology,
Dr. B.R.A. Intstitute Rotary Cancer Hospital,
All India Institute of Medical Sciences,
New Delhi 110 029, India.
E-mail: [email protected]  

 

References

 

1. Imashuku S. Advances in the management of Hemophagocytic Lymphohistiocytosis. Inter J Hematol 2000; 72: 1-11.

2. Janka GE, Imashuku S, Elinder G, Schneider M, Henter JI. Infection and malignancy associated hemophagocytic syndromes. Secondary hemophagocytic lymphohistiocytosis. Hematol Oncol Clin North Am 1998; 12: 435-444.

3. Henter JI, Elinder G, Ost A. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. Semin Onco1 1991; 18: 29 -33.

4. Janka GE, Schneider EM. Modem management of children with hemophagocytic lymphohistiocytosis. Br J Hematol 2004; 124: 4-14.

5. Imashuku S, Hibi S, Ohara T, Iwai A, Sake M, Kato M, et al. Effective control of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis with immunochemotherapy. Blood 1999; 93: 1869-1874.

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