- Email: [email protected]
Immune thrombocytopenic purpura in childhood: a Lebanese perspective
Molecular Immunology 39 (2003) 1105–1107
Immune thrombocytopenic purpura in childhood: a Lebanese perspective Myrna Moussalem a,∗ , Nabil Yassine b a
Pediatric Hematology-Oncology Division, Saint Georges Hospital affiliated with Balamand University, Beirut, Lebanon b Pediatric Hematology-Oncology Division, Makassed Hospital, Beirut, Lebanon
Abstract Immune thrombocytopenic purpura (ITP), due to the production of antiplatelet antibodies, is the most prevalent etiology of thrombocytopenia in children and a frequent cause of consultation for the pediatrician. We review here a series of Lebanese pediatric patients presenting with ITP and we discuss the relevant characteristics of the group. Study: A retrospective chart analysis was performed for 40 hospitalized or out-patient children presenting with ITP between January 1998 and December 2001. All cases except two had a diagnosis confirmed by bone marrow aspirate. Patients were equally distributed between the sexes with a mean age of 56 months. More than half of the patients had an episode of fever 2 days to 8 weeks prior to the diagnosis. For 42% of them, the disease appeared in the months between January and March. Ten percent presented with epistaxis but all of these had a platelet count less than 12,000. One-third of the patients had received immunization 2–8 weeks before the diagnosis, with one patient having a relapse 4 weeks after mumps–measles–rubella (MMR) immunization, which was 1 year after the initial cure. Initial treatment consisted of either steroids or intravenous polyvalent immunoglobulin in 58 and 36% of the cases, respectively. None of the patients had life-threatening hemorrhage. Only 10% of the patients developed chronic ITP (unremitting after 6 months). Conclusion: ITP is generally a benign disease in infancy and childhood. Certain characteristics of ITP in this series, such as the seasonal variation and the post-vaccine ITP, will need to be better defined in larger prospective studies. Optimal treatment will eventually be targeted towards a better delineation of the disease phenotype. © 2003 Published by Elsevier Science Ltd. Keywords: Thrombocytopenia; Immunization; Seasonal variation
1. Introduction Immune thrombocytopenic purpura (ITP) is the most prevalent etiology of thrombocytopenia in children and a frequent cause of consultation for the pediatrician. The overall incidence rate is estimated to be 100 cases per one million persons per year, and about half of the cases occur in children (Frederiksen and Schmidt, 1999). The pathogenesis involves an autoimmune process with rapid destruction of antibody-coated platelets (Hagenstrom and Schlenke, 2000). The clinical manifestations include petechiae, bruising, and mucosal bleeding in previously healthy children (Beardsly, 1998). The diagnosis is made on the basis of the clinical finding of isolated thrombocytopenia with no evidence of other disease (Blanchette, 2002). About 10–30% of cases fail to remit over 6 months and therefore become chronic (Bolton-Maggs, 2000, Garder, 2001). The major complication is intracranial hemorrhage ∗
Corresponding author. Tel.: +961-1-582560; fax: +961-3-294046. E-mail address: [email protected] (M. Moussalem).
0161-5890/03/$ – see front matter © 2003 Published by Elsevier Science Ltd. doi:10.1016/S0161-5890(03)00066-X
(ICH), the fear of which drives physicians to initiate treatment (George et al., 1996). We present here a retrospective analysis of a group of Lebanese children presenting with ITP and we discuss the relevant characteristics of the series.
2. Patients and methods A retrospective chart review was done for children 0–14 years of age, presenting with ITP between January 1998 and December 2001. The patients were either hospitalized or were outpatients and the diagnosis of ITP was confirmed by a bone marrow aspirate in all but two patients. Patients already on medication were not excluded. For each patient the following information was noted: age, sex, date of diagnosis, place of residence, past history of personal or familial blood disorders, intake of medication, symptoms of the disease, immunization status prior to diagnosis, complete patient after 6 months. Statistical methods used for analysis were the χ2 and the Student’s t-tests.
1106
M. Moussalem, N. Yassine / Molecular Immunology 39 (2003) 1105–1107
3. Results
3.4. Immunization
3.1. General information
For 13/40 patients the immunization status was recorded in the chart, and five of these patients received immunization 2–8 weeks prior to the diagnosis. The immunizations were for hepatitis B, Hemophilus influenzae type b, measles–mumps–rubella (MMR), and diphteria–tetanus– pertussis and oral polio. The mean platelet count for post-immunization ITP was 10,000/mm3 . One patient relapsed 1 month after MMR immunization which had been given 11 months after achieving the initial cure.
Forty children were eligible for the study. Age of the patients extended from 5 months to 13 years with a median age of 56 months. For all, past medical history was negative for the following: intake of medications such as heparin, quinidine, sulfonamides or aspirin; familial thrombocytopenia or blood disorders; hemostatic problems with prior invasive surgery. No dysmorphic features, skeletal abnormalities or auditory defects were found on physical examination. Both sexes were equally affected by the disease (boys, n = 20 and girls, n = 20). More of half of the patients (23/40) were located in the capital, Beirut. The others lived in other areas as follows: Bekaa (7/40), Jounieh (5/40), Chouf (3/40), South (1/40), and North (1/40). 3.2. Seasonal variation Evaluation of the distribution of the patients according to the month of diagnosis showed a higher incidence of ITP in the first quarter of the year (January–February–March): 42.5% (n = 17/40) in comparison with 25% (n = 10/40) in the second quarter (April–May–June), 20% (n = 8/40) in the third quarter (July–August–September) and 12.5% (n = 5/40) in the fourth quarter (October–November–December). However, according to χ2 analysis there was not a statistical difference between the first quarter and the other quarters of the year (P-value = 0.16). ITP was most prevalent during the month of March with one quarter of the patients (10/40) initially diagnosed during this month.
3.5. Treatment Ninety percent (36/40) of the patients were treated. First treatment consisted of steroids or intravenous polyvalent immunoglobulin (IGIV) in 61% (22/36) and 38% (14/36) of cases, respectively. In the steroids treated group, four patients (18%) did not respond by day 7 (platelet count less than 20,000/mm3 ). In the IGIV group, all patients responded by day 5 (platelet count more than 50,000/mm3 ). 3.6. Disease evolution Ten percent of the patients (4/40) had an unremitting thrombocytopenia after 6 months from the time of diagnosis and therefore developed chronic ITP. One of these patients was cured after 18 months after receiving several courses of IGIV and two courses of Anti-D immunoglobulin. Two patients were cured after splenectomy and one patient was lost for follow-up. 4. Discussion
3.3. Symptoms of the disease All the patients (40/40) presented at the time of diagnosis with ecchymosis and/or petechiae. In only 7% of cases (3/40) these symptoms were not noted by the parents or the patients prior to the visit to the physician. In 17.5% of cases (3/40), epistaxis was present, but all these patients had a platelet count less than 12,000/mm3 . None of the patients presented with gastrointestinal, genito-urinary, or central nervous system bleeding. The duration of symptoms prior to diagnosis ranged from 12 h to 7 days with a mean duration of 61 h (2.5 days). Fifty two percent (21/40) of the patients presented with an episode of fever 8 weeks to 2 days prior to the diagnosis with a mean time of 17 days. The range of platelet count at diagnosis was from 1000 to 60,000/mm3 . The mean platelet count at diagnosis for patients who were eventually treated was 14,600/mm3 . The mean platelet count for patients diagnosed during March was 13,300/mm3 , whereas it was 16,900 for the other months of the year (not statistically different by Student’s t-test, P = 0.49).
ITP is generally a benign disease in infancy and childhood, with a peak age at diagnosis of 5 years and affecting both sexes equally (Frederiksen and Schmidt, 1999). These characteristics were also encountered in our Lebanese series. The seasonal nature of the disease was previously described (Nugent, 2002), suggesting that infectious or environmental agents may trigger the immune response to produce platelet-reactive autoantibodies 4–8 weeks following an infection. The higher incidence of the disease in the first quarter of the year, especially during the month of March, could be peculiar to our country and deserves to be further confirmed in larger series. Our study points out a temporal association between immunization and ITP. Different types of vaccines before the appearance of ITP were noted in our series. Recently, British researchers (Miller et al., 2001) have corroborated a causal association between the MMR vaccine and ITP, an observation first reported by Scandinavian investigators in the 1980s (Neiderund, 1983). The component of the MMR vaccine which is responsible for vaccine-associated ITP is still
M. Moussalem, N. Yassine / Molecular Immunology 39 (2003) 1105–1107
uncertain, but both the measles (Oski and Naiman, 1996) and rubella (Nieminen and Syrjala, 1993) components are likely candidates. In our study, we did not find any case of severe or life-threatening hemorrhage, which confirms the traditional description of ITP as a benign disease. In large series, the incidence of ICH is estimated to be around 0.2–1% (Iyori et al., 2000). However, it is this fear of ICH that is driving most physicians to treat their patients in accordance with general treatment guidelines. However, many UK (Dickerhoff and VonRuecker, 2000) and German (Welch and Vora, 2001) pediatric hematologists actually consider that most children with acute ITP do not need active treatment which is in contrast to a practice guideline in the USA (George et al., 1996). Clearly, and as was shown in our and previous studies (Blanchette et al., 1993), active treatment induces a rise in platelet count, with IVIG therapy being faster than steroids. But the clinical significance and the potential benefit of this treatment-induced rise in the platelet count has been again recently questioned (Dickerhoff and VonRuecker, 2000; Welch and Vora, 2001). If it turns out that there are two clinical phenotypes of ITP among children, as suggested by Nugent (2002), i.e. those children with polyclonal antibody production triggered by an external exposure such as infection who do not need treatment and other children with coexistent immune deficiency or dysregulation on a congenital or acquired basis who need treatment, then recognizing the discrete phenotype of the patient will greatly help in the therapeutic decision.
5. Conclusion ITP is certainly a common disease of infancy and childhood. In any retrospective study the potential for selection bias must be recognized. However, certain characteristics of ITP should be better defined in a national prospective study such as the seasonal variation and the specificity of the post-vaccine ITP. Fundamental questions remain related to immunological phenotype of the patient and management of the disease. Continued research, including well designed clinical trials that incorporate economic analyses and clinically relevant end points rather than platelet count thresh-
1107
old, is needed to optimize the care of the patients with this disease. References Beardsly, D.S., 1998. Platelet abnormalities in infancy and childhood. In: Nathan, D.G., Oski, F.A. (Eds.), Hematology of Infancy and Childhood, fifth ed. WB Saunders, Philadelphia, pp.1585–1630. Blanchette, V., 2002. Childhood chronic immune thrombocytopenia. Blood Rev. 16, 23–26. Blanchette, V., Luke, B., Andrew, M., et al., 1993. A prospective, randomized trial of high-dose intravenous immune globulin G therapy, oral prednisone therapy, and no therapy in childhood immune thrombocytopenic purpura. J. Pediatr. 123, 989–995. Bolton-Maggs, P.H.B., 2000. Immune thrombocytopenic purpura. Arch. Dis. Child. 83, 220–222. Dickerhoff, R., VonRuecker, A., 2000. The clinical course of immune thrombocytopenic purpura in children who did not receive intravenous immunoglobulins or sustained prednisone treatment. J. Pediatr. 137, 629–632. Frederiksen, H., Schmidt, K., 1999. The incidence of idiopathic thrombocytopenic purpura in adults increases with age. Blood 94, 909–913. Garder, H., 2001. Management of immune thrombocytopenic purpura in children. Rev. Clin. Exp. Hematol. 5, 201–221. George, J.N., Woolf, S.H., Raskob, G.E., et al., 1996. Immune thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood 88, 3–40. Hagenstrom, H., Schlenke, P., 2000. Platelet-associated IgG for differential diagnosis of patients with thrombocytopenia. Thromb. Haemost. 84, 779–783. Iyori, H., Bessho, F., Ookawa, H., et al., 2000. Japanese study group on childhood ITP. Ann. Hematol. 79, 691–695. Miller, E., Waight, P., Farrington, P., et al., 2001. Immune thrombocytopenic purpura and MMR vaccine. Arch. Dis. Child. 84, 227–229. Neiderund, J., 1983. Thrombocytopenic purpura after a combined vaccine against morbili, parotitis, and rubella. Acta Paediatr. Scand. 72, 613– 614. Nieminen, U., Syrjala, M.T., 1993. Acute thrombocytopenic purpura following measles, mumps and rubella vaccination. A report in 23 patients. Acta Pediatr. 82, 267–270. Nugent, D.J., 2002. Childhood immune thrombocytopenic purpura. Blood Rev. 16, 27–29. Nugent, D.J., 2002. Controversies in the treatment of pediatric immune thrombocytopenias. Blood Rev. 16, 15–17. Oski, F.A., Naiman, J.L., 1996. Effect of live measles vaccine on the platelet count. N. Engl. J. Med. 275, 352–356. Welch, J.C., Vora, A.J., 2001. Non-interventionist management of children with acute immune thrombocytopenic purpura. In: Proceedings of the 43rd Annual Meeting and Exposition. American Society of Hematology, Orlando, FL.
Immune thrombocytopenic purpura in childhood: a Lebanese perspective Myrna Moussalem a,∗ , Nabil Yassine b a
Pediatric Hematology-Oncology Division, Saint Georges Hospital affiliated with Balamand University, Beirut, Lebanon b Pediatric Hematology-Oncology Division, Makassed Hospital, Beirut, Lebanon
Abstract Immune thrombocytopenic purpura (ITP), due to the production of antiplatelet antibodies, is the most prevalent etiology of thrombocytopenia in children and a frequent cause of consultation for the pediatrician. We review here a series of Lebanese pediatric patients presenting with ITP and we discuss the relevant characteristics of the group. Study: A retrospective chart analysis was performed for 40 hospitalized or out-patient children presenting with ITP between January 1998 and December 2001. All cases except two had a diagnosis confirmed by bone marrow aspirate. Patients were equally distributed between the sexes with a mean age of 56 months. More than half of the patients had an episode of fever 2 days to 8 weeks prior to the diagnosis. For 42% of them, the disease appeared in the months between January and March. Ten percent presented with epistaxis but all of these had a platelet count less than 12,000. One-third of the patients had received immunization 2–8 weeks before the diagnosis, with one patient having a relapse 4 weeks after mumps–measles–rubella (MMR) immunization, which was 1 year after the initial cure. Initial treatment consisted of either steroids or intravenous polyvalent immunoglobulin in 58 and 36% of the cases, respectively. None of the patients had life-threatening hemorrhage. Only 10% of the patients developed chronic ITP (unremitting after 6 months). Conclusion: ITP is generally a benign disease in infancy and childhood. Certain characteristics of ITP in this series, such as the seasonal variation and the post-vaccine ITP, will need to be better defined in larger prospective studies. Optimal treatment will eventually be targeted towards a better delineation of the disease phenotype. © 2003 Published by Elsevier Science Ltd. Keywords: Thrombocytopenia; Immunization; Seasonal variation
1. Introduction Immune thrombocytopenic purpura (ITP) is the most prevalent etiology of thrombocytopenia in children and a frequent cause of consultation for the pediatrician. The overall incidence rate is estimated to be 100 cases per one million persons per year, and about half of the cases occur in children (Frederiksen and Schmidt, 1999). The pathogenesis involves an autoimmune process with rapid destruction of antibody-coated platelets (Hagenstrom and Schlenke, 2000). The clinical manifestations include petechiae, bruising, and mucosal bleeding in previously healthy children (Beardsly, 1998). The diagnosis is made on the basis of the clinical finding of isolated thrombocytopenia with no evidence of other disease (Blanchette, 2002). About 10–30% of cases fail to remit over 6 months and therefore become chronic (Bolton-Maggs, 2000, Garder, 2001). The major complication is intracranial hemorrhage ∗
Corresponding author. Tel.: +961-1-582560; fax: +961-3-294046. E-mail address: [email protected] (M. Moussalem).
0161-5890/03/$ – see front matter © 2003 Published by Elsevier Science Ltd. doi:10.1016/S0161-5890(03)00066-X
(ICH), the fear of which drives physicians to initiate treatment (George et al., 1996). We present here a retrospective analysis of a group of Lebanese children presenting with ITP and we discuss the relevant characteristics of the series.
2. Patients and methods A retrospective chart review was done for children 0–14 years of age, presenting with ITP between January 1998 and December 2001. The patients were either hospitalized or were outpatients and the diagnosis of ITP was confirmed by a bone marrow aspirate in all but two patients. Patients already on medication were not excluded. For each patient the following information was noted: age, sex, date of diagnosis, place of residence, past history of personal or familial blood disorders, intake of medication, symptoms of the disease, immunization status prior to diagnosis, complete patient after 6 months. Statistical methods used for analysis were the χ2 and the Student’s t-tests.
1106
M. Moussalem, N. Yassine / Molecular Immunology 39 (2003) 1105–1107
3. Results
3.4. Immunization
3.1. General information
For 13/40 patients the immunization status was recorded in the chart, and five of these patients received immunization 2–8 weeks prior to the diagnosis. The immunizations were for hepatitis B, Hemophilus influenzae type b, measles–mumps–rubella (MMR), and diphteria–tetanus– pertussis and oral polio. The mean platelet count for post-immunization ITP was 10,000/mm3 . One patient relapsed 1 month after MMR immunization which had been given 11 months after achieving the initial cure.
Forty children were eligible for the study. Age of the patients extended from 5 months to 13 years with a median age of 56 months. For all, past medical history was negative for the following: intake of medications such as heparin, quinidine, sulfonamides or aspirin; familial thrombocytopenia or blood disorders; hemostatic problems with prior invasive surgery. No dysmorphic features, skeletal abnormalities or auditory defects were found on physical examination. Both sexes were equally affected by the disease (boys, n = 20 and girls, n = 20). More of half of the patients (23/40) were located in the capital, Beirut. The others lived in other areas as follows: Bekaa (7/40), Jounieh (5/40), Chouf (3/40), South (1/40), and North (1/40). 3.2. Seasonal variation Evaluation of the distribution of the patients according to the month of diagnosis showed a higher incidence of ITP in the first quarter of the year (January–February–March): 42.5% (n = 17/40) in comparison with 25% (n = 10/40) in the second quarter (April–May–June), 20% (n = 8/40) in the third quarter (July–August–September) and 12.5% (n = 5/40) in the fourth quarter (October–November–December). However, according to χ2 analysis there was not a statistical difference between the first quarter and the other quarters of the year (P-value = 0.16). ITP was most prevalent during the month of March with one quarter of the patients (10/40) initially diagnosed during this month.
3.5. Treatment Ninety percent (36/40) of the patients were treated. First treatment consisted of steroids or intravenous polyvalent immunoglobulin (IGIV) in 61% (22/36) and 38% (14/36) of cases, respectively. In the steroids treated group, four patients (18%) did not respond by day 7 (platelet count less than 20,000/mm3 ). In the IGIV group, all patients responded by day 5 (platelet count more than 50,000/mm3 ). 3.6. Disease evolution Ten percent of the patients (4/40) had an unremitting thrombocytopenia after 6 months from the time of diagnosis and therefore developed chronic ITP. One of these patients was cured after 18 months after receiving several courses of IGIV and two courses of Anti-D immunoglobulin. Two patients were cured after splenectomy and one patient was lost for follow-up. 4. Discussion
3.3. Symptoms of the disease All the patients (40/40) presented at the time of diagnosis with ecchymosis and/or petechiae. In only 7% of cases (3/40) these symptoms were not noted by the parents or the patients prior to the visit to the physician. In 17.5% of cases (3/40), epistaxis was present, but all these patients had a platelet count less than 12,000/mm3 . None of the patients presented with gastrointestinal, genito-urinary, or central nervous system bleeding. The duration of symptoms prior to diagnosis ranged from 12 h to 7 days with a mean duration of 61 h (2.5 days). Fifty two percent (21/40) of the patients presented with an episode of fever 8 weeks to 2 days prior to the diagnosis with a mean time of 17 days. The range of platelet count at diagnosis was from 1000 to 60,000/mm3 . The mean platelet count at diagnosis for patients who were eventually treated was 14,600/mm3 . The mean platelet count for patients diagnosed during March was 13,300/mm3 , whereas it was 16,900 for the other months of the year (not statistically different by Student’s t-test, P = 0.49).
ITP is generally a benign disease in infancy and childhood, with a peak age at diagnosis of 5 years and affecting both sexes equally (Frederiksen and Schmidt, 1999). These characteristics were also encountered in our Lebanese series. The seasonal nature of the disease was previously described (Nugent, 2002), suggesting that infectious or environmental agents may trigger the immune response to produce platelet-reactive autoantibodies 4–8 weeks following an infection. The higher incidence of the disease in the first quarter of the year, especially during the month of March, could be peculiar to our country and deserves to be further confirmed in larger series. Our study points out a temporal association between immunization and ITP. Different types of vaccines before the appearance of ITP were noted in our series. Recently, British researchers (Miller et al., 2001) have corroborated a causal association between the MMR vaccine and ITP, an observation first reported by Scandinavian investigators in the 1980s (Neiderund, 1983). The component of the MMR vaccine which is responsible for vaccine-associated ITP is still
M. Moussalem, N. Yassine / Molecular Immunology 39 (2003) 1105–1107
uncertain, but both the measles (Oski and Naiman, 1996) and rubella (Nieminen and Syrjala, 1993) components are likely candidates. In our study, we did not find any case of severe or life-threatening hemorrhage, which confirms the traditional description of ITP as a benign disease. In large series, the incidence of ICH is estimated to be around 0.2–1% (Iyori et al., 2000). However, it is this fear of ICH that is driving most physicians to treat their patients in accordance with general treatment guidelines. However, many UK (Dickerhoff and VonRuecker, 2000) and German (Welch and Vora, 2001) pediatric hematologists actually consider that most children with acute ITP do not need active treatment which is in contrast to a practice guideline in the USA (George et al., 1996). Clearly, and as was shown in our and previous studies (Blanchette et al., 1993), active treatment induces a rise in platelet count, with IVIG therapy being faster than steroids. But the clinical significance and the potential benefit of this treatment-induced rise in the platelet count has been again recently questioned (Dickerhoff and VonRuecker, 2000; Welch and Vora, 2001). If it turns out that there are two clinical phenotypes of ITP among children, as suggested by Nugent (2002), i.e. those children with polyclonal antibody production triggered by an external exposure such as infection who do not need treatment and other children with coexistent immune deficiency or dysregulation on a congenital or acquired basis who need treatment, then recognizing the discrete phenotype of the patient will greatly help in the therapeutic decision.
5. Conclusion ITP is certainly a common disease of infancy and childhood. In any retrospective study the potential for selection bias must be recognized. However, certain characteristics of ITP should be better defined in a national prospective study such as the seasonal variation and the specificity of the post-vaccine ITP. Fundamental questions remain related to immunological phenotype of the patient and management of the disease. Continued research, including well designed clinical trials that incorporate economic analyses and clinically relevant end points rather than platelet count thresh-
1107
old, is needed to optimize the care of the patients with this disease. References Beardsly, D.S., 1998. Platelet abnormalities in infancy and childhood. In: Nathan, D.G., Oski, F.A. (Eds.), Hematology of Infancy and Childhood, fifth ed. WB Saunders, Philadelphia, pp.1585–1630. Blanchette, V., 2002. Childhood chronic immune thrombocytopenia. Blood Rev. 16, 23–26. Blanchette, V., Luke, B., Andrew, M., et al., 1993. A prospective, randomized trial of high-dose intravenous immune globulin G therapy, oral prednisone therapy, and no therapy in childhood immune thrombocytopenic purpura. J. Pediatr. 123, 989–995. Bolton-Maggs, P.H.B., 2000. Immune thrombocytopenic purpura. Arch. Dis. Child. 83, 220–222. Dickerhoff, R., VonRuecker, A., 2000. The clinical course of immune thrombocytopenic purpura in children who did not receive intravenous immunoglobulins or sustained prednisone treatment. J. Pediatr. 137, 629–632. Frederiksen, H., Schmidt, K., 1999. The incidence of idiopathic thrombocytopenic purpura in adults increases with age. Blood 94, 909–913. Garder, H., 2001. Management of immune thrombocytopenic purpura in children. Rev. Clin. Exp. Hematol. 5, 201–221. George, J.N., Woolf, S.H., Raskob, G.E., et al., 1996. Immune thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood 88, 3–40. Hagenstrom, H., Schlenke, P., 2000. Platelet-associated IgG for differential diagnosis of patients with thrombocytopenia. Thromb. Haemost. 84, 779–783. Iyori, H., Bessho, F., Ookawa, H., et al., 2000. Japanese study group on childhood ITP. Ann. Hematol. 79, 691–695. Miller, E., Waight, P., Farrington, P., et al., 2001. Immune thrombocytopenic purpura and MMR vaccine. Arch. Dis. Child. 84, 227–229. Neiderund, J., 1983. Thrombocytopenic purpura after a combined vaccine against morbili, parotitis, and rubella. Acta Paediatr. Scand. 72, 613– 614. Nieminen, U., Syrjala, M.T., 1993. Acute thrombocytopenic purpura following measles, mumps and rubella vaccination. A report in 23 patients. Acta Pediatr. 82, 267–270. Nugent, D.J., 2002. Childhood immune thrombocytopenic purpura. Blood Rev. 16, 27–29. Nugent, D.J., 2002. Controversies in the treatment of pediatric immune thrombocytopenias. Blood Rev. 16, 15–17. Oski, F.A., Naiman, J.L., 1996. Effect of live measles vaccine on the platelet count. N. Engl. J. Med. 275, 352–356. Welch, J.C., Vora, A.J., 2001. Non-interventionist management of children with acute immune thrombocytopenic purpura. In: Proceedings of the 43rd Annual Meeting and Exposition. American Society of Hematology, Orlando, FL.