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Treatment of infection-associated hemophagocytic syndrome with immune globulin
332
Editorial correspondence
Treatment of infection-associated hemophagocytic syndrome with
immune globulin To the Editor: We read with interest the report by Freeman et al. I describing three patients with infection-associated hemophagocytic syndrome (IAHS) who received one or two doses of intravenously administered immune globulin (IVIG) as the only treatment. On the basis of the clinical description and laboratory data presented, two patients (Nos. I and 3) were mildly affected. Recently we successfully treated a 41/2-year-old Asian boy with IAHS. He was moribund when first seen, having severe coagulopathy, anemia, thromb0cytopenia, elevated levels of hepatic enZymes, hyperbilirubinemia, and hypertriglyceridemia. A bone marrow aspirate showed large numbers of reactive hemophagocytic histiocytes. No infectious cause could be identified by serologic testing, bacterial and viral cultures, or polymerase chain reaction testing for Epstein-Barr virus DNA. In addition to aggressive supportive measures, he was treated with acyelovir, etoposide (VP- 16), and multiple doses of IVIG. He responded within 2 weeks and is entirely well 6 months later. Although IVIG may have contributed to the favorable outcome of our patient and the patients reported by Freeman et al., 1 we caution against the use of a single agent (i.e., IVIG) as therapy for a syndrome with anundefined cause and pathogenesis and with an extremely high mortality rate. 2 Moderate doses of VP-16 and acyclovir have been beneficial in the treatment of both IAHS and its histologically similar counterpart, familial erythrophagocytic lymphohistiocytosis.L 4 These agents have minimal toxic effects. Therefore we recommend intensive supportive measures and prompt initiation of therapy with antiviral agents and VP-16, as well as with IVIG, once the diagnosis of severe IAHS has been made. •Multicenter clinical trials are required to define the best therapeutic approach to this perplexing disorder. Daniel W. Fort, MD George R. Buchanan, MD Department of Pediatrics University of Texas Southwestern Medical Center at Dallas Dallas, TX 75235-9063 9/35/52462 REFERENCES
1. Freeman B, Rathore MH, Salman E, Joyce M J, Pitel P. Intravenously administered immune globulin for the treatment of infection-associated hemophagocytic syndrome. J PEDIATR 1993;123:479-81. 2. Risdall R J, McKenna RW, Nesbit ME, et al. Virus-associated hematophagocytic syndrome: a benign histiocytic proliferation distinct from malignant histiocytosis. Cancer 1979;44:9931002. 3. Ambruso DR, Hays T, Zwartjes W J, Tubergen DG, Favara BE. Successful treatment of lymphohistiocytie reticulosis with phagocytosis with epipodophyllotoxin VP 16-213. Cancer 1980;45:2516-20. 4. McClain K. Epstein-Barr virus DNA in lymphocytes of patients with the virus-associated hemophagocytic syndrome. Am J Pediatr Hematol/OncoI 1986;8:121-7.
The Journal of Pediatrics February 1994
Reply To the Editor: We agree that multicenter clinical trials are required to refine the therapy for this syndrome. We did not intend to define the optimal therapy of all cases of infection-associated hemophagocytic syndromes; rather, we reported its efficacy in Our small group of patients. We agree that supportive care is a cornerstone of the care of these patients. However, the utility of acyclovir in cases not related to herpes simplex and varicella-zoster viruses is obscure. The use of chemotherapeutic agents (VP-16) in nonmalignant but clinically serious diseases should always be Viewed with concern. VP-16 is probably safe when utilized in this manner but can be associated with the development of nonlymphoid leukemia, l, 2 It is probably unjustified to generalize from experience with familial erythrophagocytic lymphohistiocytosis, which may have a different cause. We disagree with the routine use of acyclovir and VP-16, and we continue to believe that intravenously administered immune globulin should be considered as an agent in the care of these patients. Mobeen 14. Rathore, MD Department of Pediatrics University of Florida Health Science Center Bridget Freeman, AID Paul Pitel, MD Nemours Children's Clinic Jacksonville, Florida 9/35/52461 REFERENCES
1. Whitlock JA, Greer JP, Luken JN. Epipodophyllotoxinrelated leukemia. Cancer 1991;68:600-4. 2. Pui C-H, Behm FG, Raimondi SC, et al. Secondary acute myeloid leukemia in children treated for acute lymphoid leukemia. N Engl J Med 1989;321:136-42.
Optimal dose of omeprazole in infants and children To the Editor." We read with interest the article by Gunasekaran and Hassall ~ on the efficacy and safety of omeprazole for severe gastroesophageal reflux in children. They studied 15 children, aged 0.8 to 17 years (mean, 8.1 years), of whom 8 were neurologically impaired. All had esophagitis grade 3 to 4, which was resistant to treatment with histamine type 2 (H2) blockers and prokinetic agents. The effective dosage range of omeprazole in their study was 0.7 to 3.3 mg/kg per day (mean, 1.9 mg/kg). We also have experience on the use of omeprazole in four neurologically normal infants, aged 3 to 8 months (mean 5.7 months). Our first case was'published in detail. 2 In all four patients, peptic esophagitis was diagnosed endoscopically at a mean age of 2.9 months (range, 2 to 4.5 months). A 2-month course of cisapride (0.2 mg/kg three times a day), cimetidine (I 0 mg/kg three times a day), and a mucosal protective agent
Editorial correspondence
Treatment of infection-associated hemophagocytic syndrome with
immune globulin To the Editor: We read with interest the report by Freeman et al. I describing three patients with infection-associated hemophagocytic syndrome (IAHS) who received one or two doses of intravenously administered immune globulin (IVIG) as the only treatment. On the basis of the clinical description and laboratory data presented, two patients (Nos. I and 3) were mildly affected. Recently we successfully treated a 41/2-year-old Asian boy with IAHS. He was moribund when first seen, having severe coagulopathy, anemia, thromb0cytopenia, elevated levels of hepatic enZymes, hyperbilirubinemia, and hypertriglyceridemia. A bone marrow aspirate showed large numbers of reactive hemophagocytic histiocytes. No infectious cause could be identified by serologic testing, bacterial and viral cultures, or polymerase chain reaction testing for Epstein-Barr virus DNA. In addition to aggressive supportive measures, he was treated with acyelovir, etoposide (VP- 16), and multiple doses of IVIG. He responded within 2 weeks and is entirely well 6 months later. Although IVIG may have contributed to the favorable outcome of our patient and the patients reported by Freeman et al., 1 we caution against the use of a single agent (i.e., IVIG) as therapy for a syndrome with anundefined cause and pathogenesis and with an extremely high mortality rate. 2 Moderate doses of VP-16 and acyclovir have been beneficial in the treatment of both IAHS and its histologically similar counterpart, familial erythrophagocytic lymphohistiocytosis.L 4 These agents have minimal toxic effects. Therefore we recommend intensive supportive measures and prompt initiation of therapy with antiviral agents and VP-16, as well as with IVIG, once the diagnosis of severe IAHS has been made. •Multicenter clinical trials are required to define the best therapeutic approach to this perplexing disorder. Daniel W. Fort, MD George R. Buchanan, MD Department of Pediatrics University of Texas Southwestern Medical Center at Dallas Dallas, TX 75235-9063 9/35/52462 REFERENCES
1. Freeman B, Rathore MH, Salman E, Joyce M J, Pitel P. Intravenously administered immune globulin for the treatment of infection-associated hemophagocytic syndrome. J PEDIATR 1993;123:479-81. 2. Risdall R J, McKenna RW, Nesbit ME, et al. Virus-associated hematophagocytic syndrome: a benign histiocytic proliferation distinct from malignant histiocytosis. Cancer 1979;44:9931002. 3. Ambruso DR, Hays T, Zwartjes W J, Tubergen DG, Favara BE. Successful treatment of lymphohistiocytie reticulosis with phagocytosis with epipodophyllotoxin VP 16-213. Cancer 1980;45:2516-20. 4. McClain K. Epstein-Barr virus DNA in lymphocytes of patients with the virus-associated hemophagocytic syndrome. Am J Pediatr Hematol/OncoI 1986;8:121-7.
The Journal of Pediatrics February 1994
Reply To the Editor: We agree that multicenter clinical trials are required to refine the therapy for this syndrome. We did not intend to define the optimal therapy of all cases of infection-associated hemophagocytic syndromes; rather, we reported its efficacy in Our small group of patients. We agree that supportive care is a cornerstone of the care of these patients. However, the utility of acyclovir in cases not related to herpes simplex and varicella-zoster viruses is obscure. The use of chemotherapeutic agents (VP-16) in nonmalignant but clinically serious diseases should always be Viewed with concern. VP-16 is probably safe when utilized in this manner but can be associated with the development of nonlymphoid leukemia, l, 2 It is probably unjustified to generalize from experience with familial erythrophagocytic lymphohistiocytosis, which may have a different cause. We disagree with the routine use of acyclovir and VP-16, and we continue to believe that intravenously administered immune globulin should be considered as an agent in the care of these patients. Mobeen 14. Rathore, MD Department of Pediatrics University of Florida Health Science Center Bridget Freeman, AID Paul Pitel, MD Nemours Children's Clinic Jacksonville, Florida 9/35/52461 REFERENCES
1. Whitlock JA, Greer JP, Luken JN. Epipodophyllotoxinrelated leukemia. Cancer 1991;68:600-4. 2. Pui C-H, Behm FG, Raimondi SC, et al. Secondary acute myeloid leukemia in children treated for acute lymphoid leukemia. N Engl J Med 1989;321:136-42.
Optimal dose of omeprazole in infants and children To the Editor." We read with interest the article by Gunasekaran and Hassall ~ on the efficacy and safety of omeprazole for severe gastroesophageal reflux in children. They studied 15 children, aged 0.8 to 17 years (mean, 8.1 years), of whom 8 were neurologically impaired. All had esophagitis grade 3 to 4, which was resistant to treatment with histamine type 2 (H2) blockers and prokinetic agents. The effective dosage range of omeprazole in their study was 0.7 to 3.3 mg/kg per day (mean, 1.9 mg/kg). We also have experience on the use of omeprazole in four neurologically normal infants, aged 3 to 8 months (mean 5.7 months). Our first case was'published in detail. 2 In all four patients, peptic esophagitis was diagnosed endoscopically at a mean age of 2.9 months (range, 2 to 4.5 months). A 2-month course of cisapride (0.2 mg/kg three times a day), cimetidine (I 0 mg/kg three times a day), and a mucosal protective agent