Randomized trial of high-dose methylprednisolone versus intravenous immunoglobulin for the treatment of acute idiopathic thrombocytopenic purpura in children

BACKGROUND: Idiopathic thrombocytopenic purpura (ITP) is an acquired disorder characterized by immune-mediated platelet destruction. The authors performed a prospective, randomized trial comparing intravenous immunoglobulin (IVIG) with high-dose intravenous methylprednisolone in the treatment of children with acute ITP. The primary aim of the study was to compare the rate of platelet increase produced by either intervention. A decision to treat was based on the clinical presentation and not an arbitrary platelet count. In general, enrolled patients exhibited extensive bruising and platelet counts less than 10 x 10 /L (10,000/microL). PATIENTS AND METHODS: Seventy-seven consecutive patients, for whom the attending hematologist determined acute treatment was warranted, were studied. Forty-two patients received IVIG (1 g/kg/dose x2) and 35 received methylprednisolone (30 mg/kg/dose x3). Patients who exhibited an increase in platelet count of more than 50,000/microL after the first IVIG dose or the second methylprednisolone dose did not receive the second IVIG dose or the third methylprednisolone dose, respectively. Patients' ages ranged from 6 months to 15 years. Platelet counts were evaluated at presentation, 24, 48, 72 hours, 1 week, and 2 to 4 weeks. RESULTS: Eighty percent of patients treated with IVIG and 60% of patients treated with methylprednisolone demonstrated an increase in platelet count of 50,000/microL or more within 48 hours. Both IVIG and methylprednisolone therapy increased platelet counts significantly above pretreatment values. In the methylprednisolone group, the mean baseline platelet count was 4,600/microL, which rose to 14,000/microL after 24 hours, 38,000/microL after 48 hours, and 65,000/microL after 72 hours. The IVIG group had a mean baseline platelet count of 4,200/microL, which rose to 32,000/microL after 24 hours, 69,000/microL after 48 hours, and 146,000/microL after 72 hours. When compared with methylprednisolone, IVIG therapy produced a greater rise in platelet counts at 24, 48, and 72 hours, with no difference at 1 week or later time points. No serious bleeding was noted in either treatment group. CONCLUSIONS: Both IVIG and methylprednisolone produce a significant early rise in platelet count that is somewhat greater with IVIG. However, the higher platelet counts produced by IVIG may not justify the additional cost and potential risks of this agent.     

Intracranial hemorrhage in immune thrombocytopenic purpura: a retrospective analysis

PURPOSE: To ascertain characteristics of children with immune thrombocytopenic purpura (ITP) and intracranial hemorrhage (ICH). METHODS: The authors identified 75 published cases of ICH in children with ITP by review of the literature from 1954 to 1998. Data pertaining to the ICH was recorded for age, gender, time from diagnosis of ITP (to ICH), platelet count, head trauma or arteriovenous malformation, concomitant medications, associated infections, other bleeding manifestations, prior treatment, and outcome.RESULTS Sixty-two cases represented 6 months to 20 years of age; 65% of patients were female. The median time from the diagnosis of ITP to ICH was 32 days (range 0 days to 8 years). Fifty of 69 ICH cases (72%) occurred within 6 months of diagnosis, but only 7 (10%) occurred within 3 days of diagnosis. The platelet count was less than 10000/microL in 71.4% of the cases. Treatment prior to the ICH was primarily steroids but also included intravenous immune globulin (IVIG), splenectomy, and others (interferon, azathioprine, or vincristine). There was no difference in mortality of patients before (56%) or after (54%) 1980. CONCLUSIONS: A very low platelet count appears permissive but not sufficient for ICH to occur in children with ITP. ICH occurs more commonly in acute ITP but can occur years after diagnosis. A significant number of patients develop an ICH despite having already initiated steroid treatment of ITP.     

大剂量短疗程泼尼松治疗儿童急性免疫性血小板减少症的疗效观察

目的观察大剂量短疗程泼尼松(Pred)疗法对儿童急性免疫性血小板减少症(ITP)的疗效。方法 162例ITP患儿根据治疗方法不同随机分为大剂量静脉丙种球蛋白+甲基泼尼松龙组(IVIG+MP)、静脉丙种球蛋白组(IVIG)、甲基泼尼松龙组(MP)与Pred组。IVIG+MP组41例,采用IVIG(1g/kg,共1次)+MP[10 mg/(kg.d),每3天减半量,共9 d]冲击治疗,继之口服Pred[1.5～2.0 mg/(kg.d)],并逐渐减量维持治疗;IVIG组39例,采用丙种球蛋白(1 g/kg,共1次)冲击治疗,继之口服Pred[1.5～2.0 mg/(kg.d)]并逐渐减量维持治疗;MP组40例,采用MP[10 mg/(kg.d),每3天减半量,共9 d]冲击治疗,继之口服Pred[1.5～2.0 mg/(kg.d)]并逐渐减量维持治疗;Pred组42例,采用口服Pred[4 mg/(kg.d),共4 d]治疗后停药,无减量维持治疗。比较各组治疗前后血小板数、治疗有效率、不良反应发生率及药费支出。结果各治疗组治疗前后血小板数及治疗有效率差异无显著性,IVIG+MP组、IVIG组、MP组治疗不良反应发生率及药费支出均高于Pred组。结论大剂量短疗程Pred疗法治疗儿童急性ITP能有效提升血小板计数,有效率与IVIG及MP冲击治疗相比差异无显著性,不良反应少,花费低。     

Prednisone therapy for children with newly diagnosed idiopathic thrombocytopenic purpura. A randomized clinical trial

The efficacy of corticosteroids in childhood acute idiopathic thrombocytopenic purpura (ITP) is controversial and has infrequently been evaluated in a controlled randomized fashion. We administered prednisone (2 mg/kg/day for 14 days with subsequent tapering and discontinuation by day 21) or placebo to 27 children, aged 10 years or less, with newly diagnosed ITP. Platelet count, bleeding time (a test of the integrity of the platelet-microvasculature interaction), and clinical bleeding score (based on a 0-4 scale) were determined before (day 0) and six times following initiation of drug therapy (days 1-2, 3-5, 7, 14, 21, and 28). There were no statistically significant (p less than 0.05) differences between the two treatment groups in any of the three study parameters except on day 7 of therapy when children receiving prednisone had higher platelet counts and lower bleeding scores and bleeding times than those taking placebo. Bleeding time correlated inversely with the platelet count in both treatment groups. Prednisone did not appear to influence bleeding time independent of its effect on platelet count. This treatment regimen of prednisone did not clearly improve hemostasis in childhood acute ITP except transiently at the end of 1 week of treatment.     

The management of immune thrombocytopenic purpura

The most common cause of thrombocytopenia in childhood is immune. The diagnosis must be carefully considered, as there are no specific diagnostic tests. Most children have an acute disease with spontaneous remission within a few weeks. Although the platelet count may be very low, bleeding symptoms are rarely severe, and most often restricted to the skin and mucous membranes. Most children do not require active treatment, but can be managed with good advice, ongoing support and a 24-h contact point. Children with significant bleeding problems may be treated with oral steroids, reserving intravenous immunoglobulin for emergencies or to cover injuries and surgery. About 20% of children continue with thrombocytopenia beyond 6 months (chronic ITP), but expectant management can continue, treatment is rarely required. Splenectomy is rarely required and should be reserved for the very rare child with serious bleeding persisting beyond 6 or 12 months.     

CLINICAL COURSE OF CHILDREN WITH IMMUNE THROMBOCYTOPENIC PURPURA TREATED WITH INTRAVENOUS IMMUNOGLOBULIN G OR MEGADOSE METHYLPREDNISOLONE OR OBSERVED WITHOUT THERAPY

The authors compared the prognosis in 50 children with acute immune thrombocytopenic purpura (ITP) who received intravenous immunoglobulin G (IVIG), megadose methylprednisolone (MDMP), or no therapy. Twenty-six children were observed with no therapy, 12 children received IVIG, and 12 children received MDMP. The percentage of the patients whose platelet counts increased at a level of > 20 &#50 10 9 /L and > 50 &#50 10 9 /L at 3 days after starting therapy was significantly higher in both IVIG and MDMP groups than in the no therapy group ( p < .01), but there was no significant difference at 10 and 30 days after initiation between the 3 groups ( p > .05 in each comparison). This result suggested that therapy does not increase the rate of recovery but shortens the duration of thrombocytopenia in the first days. Management decision in ITP is made on clinical condition rather than on platelet count and no treatment options is to be preferred even in the face of mucosal bleeding. If the patient has extensive bleeding and the decision is to treat, both IVIG and MDMP are equally effective in providing a safe platelet level early on.     

Clinical course of children with immune thrombocytopenic purpura treated with intravenous immunoglobulin G or megadose methylprednisolone or observed without therapy

The authors compared the prognosis in 50 children with acute immune thrombocytopenicpurpura (ITP) who received intravenous immunoglobulin G (IVIG), megadose methylprednisolone (MDMP), or no therapy. Twenty-six children were observed with no therapy, 12 children received IVIG, and 12 children received MDMP. The percentage of the patients whose platelet counts increased at a level of > 20 x 10(9)/L and > 50 x 10(9)/L at 3 days after starting therapy was significantly higher in both IVIG and MDMP groups than in the no therapy group (p < .01), but there was no significant difference at 10 and 30 days after initiation between the 3 groups (p > .05 in each comparison). This result suggested that therapy does not increase the rate of recovery but shortens the duration of thrombocytopenia in the first days. Management derision in ITP is made on clinical condition rather than on platelet count and no treatment options is to be preferred even in the face of mucosal bleeding. If the patient has extensive bleeding and the decision is to treat, both IVIG and MDMP are equally effective in providing a safe platelet level early on.     

Intended management of children with acute idiopathic thrombocytopenic purpura: a national survey

OBJECTIVE: In Australia acute idiopathic thrombocytopenic purpura (ITP) is mainly treated by paediatricians (either general paediatricians or paediatric haematologists/oncologists). A survey was conducted to gauge the current practice of treating children with acute ITP in Australia. METHODS: All practising Australian paediatricians registered by the Royal Australasian College of Physicians were surveyed regarding their intended management of children with acute ITP. The questionnaire, adapted from a study of paediatric haematologists/oncologists in North America, presented four clinical scenarios of children with acute ITP with a platelet count of 3000 x 10(9)/L, with and without mucosal bleeding (wet and dry purpura, respectively). Questionnaires were returned by mail or filled in online at a dedicated webpage. RESULTS: Five hundred and sixty-three of 1097 (51%) paediatricians responded to the survey. Data from 140 who had treated at least one child with ITP in the previous 12 months were analysed. Respondents indicated that children with acute ITP are usually or always hospitalised (58-92%) and that 48% would be given active treatment, even with dry purpura. Various regimens of i.v. immunoglobulin or corticosteroids are used when treatment is administered. In comparing Australian and North American management of acute ITP there were many similarities, although Australian paediatricians were less likely to arrange a bone marrow aspirate if corticosteroids were prescribed. CONCLUSIONS: There is great variation in the intended management of children with acute ITP in Australia. Previously published management recommendations regarding investigation and treatment have had little impact on intended practice. Prospective studies are required to evaluate hypotheses so as to produce evidence-based recommendations for treatment of patients with acute ITP.     

Childhood ITP: 12 months follow-up data from the prospective registry I of the Intercontinental Childhood ITP Study Group (ICIS)

BACKGROUND: Acute and chronic idiopathic thrombocytopenic purpura (ITP) is traditionally based on the duration of thrombocytopenia at the cut-off point of 6 months after diagnosis. Registry I evaluated the diagnosis, definition, management, and follow-up of childhood ITP. This report focuses on children with thrombocytopenia persisting more than 6 months. PROCEDURE: Data were collected by questionnaires to the physicians caring for children with ITP, at diagnosis, 6, and 12 months later. Data were compared regarding initial features and follow-up with emphasis on children with persistent thrombocytopenia, and those with ITP who recovered their platelet counts between 7 and 12 months from diagnosis. RESULTS: At 12 months from diagnosis, 79 of 308 (25.6%) evaluable children recovered from ITP and 229 had ongoing ITP. Children with recovered ITP were younger than children with ongoing ITP (P = 0.043) and exhibited a lower frequency of bleeding symptoms during the first 6 months after diagnosis (P = 0.018). Frequency of hospitalization, bone marrow aspiration, and drug treatment differed regionally. CONCLUSIONS: The high rate of recovery from ITP between 7 to 12 months demonstrates, that the cut-off point of 6 months for the definition of chronic ITP does not adequately differentiate chronic from acute ITP. The majority of children with ITP have variable time to recovery with gradual improvement of platelet counts and disappearance of bleeding signs. ITP is a heterogeneous disorder with a diverse natural history and diverse pattern of treatment response.     

原发性免疫性血小板减少症儿童生活质量及其影响因素研究进展

原发性免疫性血小板减少症(primary immune thrombocytopenia,ITP)是儿童最常见的出血性疾病,常表现为皮肤和黏膜出血,罕见颅内出血。儿童ITP为急性自限性疾病,大多数出血倾向重但预后良好;少数迁延反复,呈慢性趋势。尽管儿童ITP严重出血风险低,但慢性ITP血小板计数反复减少常引起家属的担忧,故患儿的日常活动常会受到限制。此外,治疗药物引起的相关不良反应、对病程迁延及疾病预后的担忧等都会影响到患儿的健康及相关生活质量。该文主要针对ITP儿童的生活质量及主要影响因素研究进展展开论述。     

Platelet proteins as autoantibody targets in idiopathic thrombocytopenic purpura

Idiopathic thrombocytopenic purpura (ITP), caused by autoantibodies directed against certain platelet antigens, is the most common entity of the immune thrombocytopenias. ITP is an acquired disorder and can affect both children and adults. However, the clinical syndromes of ITP are distinct between children and adults. Childhood (acute) ITP characteristically is acute in onset, occurs within 1-2 weeks of an infection, usually of viral origin, resolves spontaneously within 6 months. Adult (chronic) ITP has an insidious onset and rarely resolves spontaneously. Over the last decade considerable new information has accumulated as to the pathophysiological mechanisms of immune thrombocytopenias. In addition, most of the knowledge on this disorder has been obtained from studies of adult patients with chronic ITP. The present work gives an updated overview of the platelet autoantigens and the molecular immunological reactions in ITP.     

Treatment of childhood idiopathic thrombocytopenic purpura with Rhesus antibodies (anti-D)

We have recently reported that a rise of platelet numbers in ITP can be induced by blockade of the RES with antibody-coated red blood cells. We now present a collaborative study in which 15 Rhesus-positive children with ITP (nine boys and six girls aged 1–15 years) were treated with low-dose anti-D. Ten patients had chronic ITP (duration 6–47 months), five had acute ITP. Doses of 28–50 g anti-D/kg bodyweight per course were given intravenously. In all patients clinical signs of bleeding ceased and platelet counts were elevated. An excellent, good or fair response with platelet increments of >100, 50–100, or 20–50×10⁹/l, respectively, was observed in 19, 7, and 12 out of 45 courses in chronic ITP, and in 4, 1, and 2 out of 8 courses in acute ITP. The platelet increase (>40×10⁹/l) persisted for 10 to over 360 days in chronic ITP. There were no untoward side reactions. Haemoglobin values remained stable in all patients but laboratory signs of mild, compensated haemolysis ensued. The direct antiglobulin test became positive in all cases due to anti-D IgG. Previous therapy of patients with chronic ITP included high-dose immunoglobulins and prednisone. These regimens were both effective but remissions were short. We conclude that anti-D therapy is an effective and safe form of treatment in childhood ITP.Abbreviations ITP idiopathic thrombocytopenic purpura - IgG immunoglobulin G - RES reticuloendothelial system - RBC red blood cells - Rh Rhesus - DAT direct antiglobulin test     

Inflammatory bowel disease associated with immune thrombocytopenic purpura in children.

OBJECTIVE: Previous reports suggest an association between inflammatory bowel disease (IBD) and immune thrombocytopenic purpura (ITP) in adults. To date, only five children with both diseases have been described. The aim of the study was to describe the characteristics of children with IBD and ITP. METHODS: Cases were obtained from the pediatric gastroenterology community by means of the pediatric gastroenterology internet bulletin board in June 1999. Eight cases were submitted from seven medical centers. Medical records were reviewed by two pediatric gastroenterologists and a pediatric hematologist. RESULTS: The age range of the patients was 2.1 to 16.5 years, with a mean age of 9.6 +/- 5.2 years. Four children had ulcerative colitis, three had Crohn disease, and one had indeterminate colitis. All had colonic involvement of IBD. Of eight patients, three had IBD first, three had ITP first, and two had both simultaneously. At ITP diagnosis, platelet count was less than 10,000/mL in five children, 17,000/mL in one child, and 50,000 to 60,000/mL in two children. Of the three children diagnosed with ITP first, two initially had rectal bleeding at the time of ITP diagnosis. Bone marrow evaluations, performed in six of eight children, were consistent with ITP. Six of the eight children had chronic ITP, including three children who were 5 years of age or younger. Therapy for ITP included steroids (n = 6), intravenous immunoglobulin (n = 6), Rh o (D) intravenous immunoglobulin (n = 2), and splenectomy (n = 1). CONCLUSIONS: The authors describe the largest pediatric case series of children with IBD and ITP. More than 50% of the children had the chronic form of ITP. Most patients responded to conventional therapy for ITP and IBD.     

儿童免疫性血小板减少症与幽门螺杆菌感染

目的探讨幽门螺杆菌(Hp)感染与儿童免疫性血小板减少症(ITP)发病的关系。方法应用酶联免疫法检测54例ITP患儿粪便Hp抗原,观察Hp抗原阳性与阴性患儿的临床表现、血小板减少程度及对治疗的反应。结果 54例患儿,Hp阳性率19%(10例),不同发病年龄患儿阳性率差异无显著性。47例急性ITP患儿中Hp阳性9例(19%),治疗后血小板恢复正常平均需7.3 d;38例Hp阴性患儿血小板恢复正常平均需5.1 d,两组间差异无显著性(P>0.05)。慢性ITP患儿Hp阳性率14%,与急性ITP差异无显著性。结论未发现ITP患儿Hp感染率高于一般人群;Hp阳性率与患儿年龄无明显相关;Hp感染不影响ITP患儿对治疗的反应。     

Idiopathic thrombocytopenic purpura: beyond consensus

Idiopathic thrombocytopenic purpura (ITP) is the most common acquired bleeding disorder encountered by pediatricians. Most children with ITP have minimal bleeding and complete platelet count recovery within weeks to months. Therapy for ITP has ranged from close observation without medical intervention to aggressive management with corticosteroids, intravenous immunoglobulin G, or anti-D immune globulin. The topic of ITP has incited great debate among practitioners, and this debate prompted the development of ITP practice guidelines by the British Paediatric Haematology Group in 1992 and by the American Society of Hematology in 1996. A better understanding of the clinical course of, risk for significant bleeding in, and optimal evaluation and therapy of childhood ITP will require carefully designed, multicenter, clinical trials.     

Use of intravenous methylprednisolone in acute idiopathic thrombocytopenic purpura

Twenty newly diagnosed children with acute idiopathic thrombocytopenic purpura (ITP) with a platelet count (PC) of less than 20,000 were treated with intravenous methyl prednisolone (IVMP) 5 mg/kg/day in four divided doses until the platelet count increased to 50,000/mm3. They were then placed on oral prednisone at conventional doses for a total of three weeks of steroid therapy. The platelet counts increased by an average of 55,000/mm3 within 48 h of treatment. Within 72 h (day 3) of treatment all patients achieved a PC of greater than 20,000/mm3. By day 5, all 20 patients achieved a PC of greater than 50,000. IVMP is highly effective in rapidly raising the PC in acute ITP above the critical level of 20,000, thereby reducing the duration of risk for intracranial hemorrhage (ICH).     

Short-course oral prednisone therapy in children presenting with acute immune thrombocytopenic purpura (ITP)

Immune thrombocytopenic purpura (ITP) is a disorder for which management remains controversial. The ongoing goal is to define the minimal therapy required for children with acute ITP. A pilot study of short-course oral prednisone (4 mg⁻¹ kg⁻¹ d⁻¹ for 4 d with no tapering) was undertaken in 25 consecutive children with acute ITP and platelet counts under 20 × 10⁹ 1⁻¹. Of the 25 children, 22 responded to the prednisone therapy by achieving a platelet count higher than 20 × 10⁹ 1⁻¹ within 1 week of commencing treatment. This regimen was found to be safe, inexpensive and effective in increasing the platelet count of children to a haemostatically safe level.     

Relationships among bleeding severity,health‐related quality of life,and platelet count in children with immune thrombocytopenic purpura

Important outcomes for children with immune thrombocytopenic purpura (ITP) include health‐related quality of life (HRQOL) and bleeding severity. A HRQOL instrument for children with ITP, the Kids' ITP Tools (KIT), was recently validated. Secondary analysis of the KIT database was performed to determine relationships among platelet count, bleeding severity and HRQOL. Bleeding severity grade correlated with platelet count in chronic ITP but not in acute ITP. Platelet count and bleeding severity failed to have any statistically significant correlations with the KIT scores. These findings suggest that relationships among outcome measures in children with ITP, using currently available instruments, remain poorly defined. Pediatr Blood Cancer 2009;53:652–654. © 2009 Wiley‐Liss, Inc.     

ITP in childhood: difficulties in the individual treatment

To date, immunoglobulin preparations and corticosteroids are the most important therapeutic principles in idiopathic thrombocytopenic purpura (ITP). Initial treatment with high-dose immunoglobulins (HD-IgG) as well as the following prednisone therapy, however, were only of short lasting success in three children with newly diagnosed ITP. Recurrent bleeding tendency tempted to combine both drugs. A desired longterm elevation of platelet counts, however, was not achieved. Administration of Anti-Rho (D) to two of the patients was also disappointing. Splenectomy which could not be postponed any longer has already led to 17 and 21 months lasting remissions in 2 patients, respectively. The third patient who required monthly single doses of HD-IgG for 6 months after surgery, is in a partial remission since 27 months now. All types of drug administration--alone, consecutive or even combined--must be considered to defer splenectomy. As experienced in our patients, however, splenectomy still seems to be justified in case even such individually adapted therapeutic approaches fail.     

Immune thrombocytopenic purpura in childhood in Norway: a prospective, population-based registration

A prospective, population-based registration of children with immune thrombocytopenic purpura (ITP) was performed in Norway in 1996 and 1997. Ninety-two cases were identified, indicating an incidence of 5.3 per 100,000 children under 15 years. The sex ratio (female/male) was 1.2/1. Fifty-six percent presented with cutaneous signs only. The lowest platelet count was < 20 x 10(9)/L in 91%. In spite of mild bleeding symptoms, medical treatment was given in 68%, in most cases (57/63) with intravenous immunoglobulin. A total of 41/44 patients with platelet counts of < or = 5 x 10(9)/L were treated, regardless of whether they had mucous bleedings or not. Eighteen percent had platelet counts < 150 x 10(9)/L at 6 months, and 9% at 12 months following diagnosis. One patient with therapy-resistant chronic ITP died 16 months after diagnosis from an anesthesia complication related to profound epistaxis. This study shows a relatively high incidence. As in other studies, there was a tendency to treat platelet counts rather than bleeding symptoms.