Paul Imbach

HIGH-DOSE INTRAVENOUS GAMMAGLOBULIN FOR IDIOPATHIC THROMBOCYTOPENIC PURPURA IN CHILDHOOD

Seven children with chronic or intermittent and six with acute idiopathic thrombocytopenic purpura (ITP) were treated with large intravenous doses of polyvalent, intact immunoglobulin (Ig). In all patients the platelet count rose sharply within 5 days, but the initial response and the subsequent course varied from patient to patient. Among children with chronic ITP the initial response was more marked in splenectomised than in non-splenectomised patients. Among those with acute ITP the two who remained Ig dependent had a smaller initial response than the four patients who required no maintenance treatment. During the 90-110 days of observation five of six patients with chronic ITP could be maintained with Ig alone. No untoward effects of Ig therapy were observed.

Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group

Diagnosis and management of immune thrombocytopenic purpura (ITP) remain largely dependent on clinical expertise and observations more than on evidence derived from clinical trials of high scientific quality. One major obstacle to the implementation of such studies and in producing reliable meta-analyses of existing data is a lack of consensus on standardized critical definitions, outcome criteria, and terminology. Moreover, the demand for comparative clinical trials has dramatically increased since the introduction of new classes of therapeutic agents, such as thrombopoietin receptor agonists, and innovative treatment modalities, such as anti-CD 20 antibodies. To overcome the present heterogeneity, an International Working Group of recognized expert clinicians convened a 2-day structured meeting (the Vicenza Consensus Conference) to define standard terminology and definitions for primary ITP and its different phases and criteria for the grading of severity, and clinically meaningful outcomes and response. These consensus criteria and definitions could be used by investigational clinical trials or cohort studies. Adoption of these recommendations would serve to improve communication among investigators, to enhance comparability among clinical trials, to facilitate meta-analyses and development of therapeutic guidelines, and to provide a standardized framework for regulatory agencies.

International consensus report on the investigation and management of primary immune thrombocytopenia

Previously published guidelines for the diagnosis and management of primary immune thrombocytopenia (ITP) require updating largely due to the introduction of new classes of therapeutic agents, and a greater understanding of the disease pathophysiology. However, treatment-related decisions still remain principally dependent on clinical expertise or patient preference rather than high-quality clinical trial evidence. This consensus document aims to report on new data and provide consensus-based recommendations relating to diagnosis and treatment of ITP in adults, in children, and during pregnancy. The inclusion of summary tables within this document, supported by information tables in the online appendices, is intended to aid in clinical decision making.

Randomised trial of intravenous immunoglobulin G, intravenous anti-D, and oral prednisone in childhood acute immune thrombocytopenic purpura

The most serious complication of childhood acute immune thrombocytopenic purpura (ITP), intracranial haemorrhage, occurs in about 1% of children with platelet counts below 20 x 10(9)/L. We conducted a randomised study to explore three treatment options in this high-risk group. 146 children (> 6 months and < 18 years old) with typical acute ITP and platelet counts of 20 x 10(9)/L or lower were randomised to receive high-dose intravenous immunoglobulin G (IVIgG) 1 g/kg on 2 consecutive days (n = 34), 0.8 g/kg once (n = 35), intravenous anti-D 25 micrograms/kg on 2 consecutive days (n = 38), or oral prednisone 4 mg/kg per day with tapering and discontinuation of prednisone by day 21 (n = 39). The rate of response as reflected by the number of days with platelet counts at 20 x 10(9)/L or lower and the time taken to achieve a platelet count 50 x 10(9)/L or more was significantly faster for both IVIgG groups than for the anti-D group (p < 0.05); the difference between prednisone and IVIgG was significant (p < 0.05) only for the IVIgG 0.8 g/kg group, and responses to the two IgG groups were similar. These differences in response rates were reflected in the percentages of children with platelet counts of 20 x 10(9)/L or lower at 72 hours following the start of treatment: 3% (IVIgG 0.8 g/kg x 1), 6% (IVIgG 1 g/kg x 2), 18% (anti-D), and 21% (oral prednisone 4 mg/kg/day). Treatment-associated toxicities included a fall in haemoglobin with anti-D (to less than 100 g/L in 24% of cases); weight gain with oral prednisone; and fever, nausea, vomiting, and headache with IVIgG. On the basis of these results, intravenous anti-D cannot be recommended as initial therapy for children with acute ITP and platelet counts of 20 x 10(9)/L or lower. A single dose of 0.8 g/kg IVIgG offers the fastest recovery for the least treatment; additional IgG or oral prednisone can be reserved for the one-third of children who continue to have platelet counts of 20 x 10(9)/L or less at 48-72 hours after the start of treatment.

INTRAVENOUS IMMUNOGLOBULIN VERSUS ORAL CORTICOSTEROIDS IN ACUTE IMMUNE THROMBOCYTOPENIC PURPURA IN CHILDHOOD

In a randomised, multicentre study intravenous IgG was compared with oral corticosteroids in 108 children with untreated acute immune thrombocytopenic purpura. IgG was an efficient treatment with no severe untoward reactions. The effects of corticosteroids and IgG were identical for rapid responders, who accounted for 62% of all patients. In contrast, patients requiring more than initial treatment responded better if randomised to IgG. The serum IgG level increased two-fold after IgG. A significant rise in IgM levels was observed after both IgG and corticosteroids. The platelet-associated IgG index was high in 75% of all patients. No significant differences between the two treatment groups were found, but rapid responders had a smaller mean initial platelet-associated IgG index which returned more rapidly and more permanently to normal than that of slow responders.

Newly diagnosed idiopathic thrombocytopenic purpura in childhood: an observational study

BACKGROUND Diagnosis and management of idiopathic thrombocytopenic purpura (ITP) have been based primarily on expert opinion and practice guidelines rather than on evidence. We have used a registry to prospectively survey the presenting features and the diagnostic evaluation and management practices used for children with ITP worldwide. METHODS We used the Intercontinental Childhood ITP Registry which had been widely advertised. 209 physicians from 136 institutions in 38 countries participated by submitting data for each of their newly diagnosed patients. Data from 2031 children with ITP was registered between June, 1997, and May, 2000, and we analysed 6-month follow-up data from 1496 children. FINDINGS There was a peak in occurrence of childhood ITP during spring and a nadir in the autumn. Mean initial platelet count was 15.4x10(9)/L (SD 19.7). 1447 (73%) of 1976 children were admitted to hospital. Initial management consisted of no drug treatment in 612 (31%), intravenous immunoglobulin in 576 (29%), corticosteroids in 651 (33%), or both in 137 (7%) patients. Intracranial haemorrhage was reported in two patients. INTERPRETATION The variable approaches to management of childhood ITP demonstrate the need for prospective clinical trials, which should be feasible within such a study group.

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

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.

Severe hemorrhage in children with newly diagnosed immune thrombocytopenic purpura

Controversy exists regarding management of children newly diagnosed with immune thrombocytopenic purpura (ITP). Drug treatment is usually administered to prevent severe hemorrhage, although the definition and frequency of severe bleeding are poorly characterized. Accordingly, the Intercontinental Childhood ITP Study Group (ICIS) conducted a prospective registry defining severe hemorrhage at diagnosis and during the following 28 days in children with ITP. Of 1106 ITP patients enrolled, 863 were eligible and evaluable for bleeding severity assessment at diagnosis and during the subsequent 4 weeks. Twenty-five children (2.9%) had severe bleeding at diagnosis. Among 505 patients with a platelet count less than or equal to 20 000/mm(3) and no or mild bleeding at diagnosis, 3 (0.6%), had new severe hemorrhagic events during the ensuing 28 days. Subsequent development of severe hemorrhage was unrelated to initial management (P = .82). These results show that severe bleeding is uncommon at diagnosis in children with ITP and rare during the next 4 weeks irrespective of treatment given. We conclude that it would be difficult to design an adequately powered therapeutic trial aimed at demonstrating prevention of severe bleeding during the first 4 weeks after diagnosis. This finding suggests that future studies of ITP management should emphasize other outcomes.

Possible mechanisms of intravenous immunoglobulin treatment in childhood idiopathic thrombocytopenic purpura (ITP).

Childhood ITP is an acquired condition which often represents a sequela of infection. It is characterized by marked thrombocytopenia despite an increased platelet production in the bone marrow, resulting from a drastically shortened lifespan of platelets. In most patients an increased amount of platelet-associated IgG is observed. Whereas the disease normally regresses regardless of therapeutic intervention, it lasts for more than one year in about 10% of the cases and becomes a condition comparable to chronic ITP observed in adults. Although the topic of ITP has been reviewed extensively [15, 17, 22], etiology and pathogenesis of ITP remain obscure. The observation of a rapid increase of platelet numbers in 13 children with r iP after high intravenous dose of ImmunoglobulinSRK (IgG-SRK, identical with Sandoglobulin) [14], prorated us to discuss immunological aspects of childhood ITP and possible mechanisms by which high doses of intravenous immunoglobulin mayfavourably influence this condition.

Polymorphisms in inflammatory cytokines and Fcγ receptors in childhood chronic immune thrombocytopenic purpura: a pilot study

Inflammatory cytokines and low‐affinity Fcγ receptor (FcγR) polymorphisms were investigated in 37 children with chronic immune thrombocytopenic purpura (cITP) and 218 controls. Genotype analysis included common variants in the regulatory regions of cytokines, TNF, LTA, IL1RN, IL1A, IL1B, IL4, IL6 and IL10, and structural variants of the low affinity FcγRs, FCGR2A, FCGR3A and FCGR3B. Associations were observed for TNF (P = 0·0032), LTA (P = 0·019), FCGR3A (P = 0·038) and FCGR3B (P = 0·0034). Two combinations of genotypes (TNF and FCGR3A;P = 0·0003, and LTA and FCGR3B;P = 0·011) were significantly associated with cITP. These results provide preliminary evidence that variant genotypes of FcγRs and cytokines contribute to cITP pathogenesis.