To the Editor:
We congratulate the ASH for wishing to develop practice guidelines, but we believe that it may not have been a wise decision to choose ITP as the focus of its initial effort.1 There are very few randomized controlled studies of ITP that provide firm data to guide the clinician, and platelet count — a rather imprecise measure of overall hemorrhagic risk in ITP — has been the usual endpoint used to assess efficacy of therapy. Therefore, this practice guideline, developed by “explicit methods” by ASH experts, is based almost entirely on the opinions of the panel rather than on results of scientific studies. Consequently, the size and constituency of the expert panel is of critical importance.
We are senior pediatric hematologists with cumulative experience in the diagnosis and management of several thousand children with ITP. We believe that the ASH practice guideline is seriously flawed with regard to treatment of newly diagnosed children with ITP by making recommendations inconsistent with the approach practiced in many centers (including ours). The major problem relates to the recommendation (Table 8 and text) that IVIg or high-dose glucocorticoid be administered to virtually all children with ITP whose platelet counts are 20,000/μL or less, irrespective of the clinical manifestations of thrombocytopenia. The implication is that the standard of care includes administration of IVIg to, for example, a 4-year-old girl with a platelet count of 8,000/μL and no significant bleeding manifestations.
Reducing costs of health care is one of the major reasons for developing practice guidelines. Therefore, it is disconcerting that the extremely high cost of IVIg (several thousand dollars for a single dose) is not mentioned in the document. Moreover, the potential side effects of this therapy (aseptic meningitis, severe headaches, transmission of hepatitis C, etc) are addressed in just six lines of text. Recent IVIg product withdrawals because of plasma donors having Creutzfeldt-Jakob disease will also be of concern to many parents and physicians. Side effects of high-dose corticosteroids are also dealt with only briefly. Thus, the overall risk-benefit ratio of IVIg or glucocorticoids in the “typical” child with acute ITP who does not exhibit prominent mucosal hemorrhage is not addressed by the panel. There are no studies whatsoever showing that IVIg or corticosteroids prevent intracranial hemorrhage, the single most concerning and potentially devastating complication of ITP.
We acknowledge that the guideline's introduction and the accompanying editorial2 indicate that these recommendations are based primarily on opinion, are not absolute, and should not represent the final word in legal proceedings. However, we fear that busy practitioners caring for children with ITP will not have the time or interest to critically review the document or understand the 1 through 9 and A through E rating systems, but rather give IVIg to each of their new patients with ITP. We also anticipate that the recommendation will be quoted, extracted, and abstracted without any reference to the lack of supporting scientific data. Moreover, juries who are hearing aggressive contingency fee-seeking lawyers quote these guidelines will also be ill-equipped to recognize that the ASH's stamp of approval to these recommendations carries with it numerous provisos and cautions.
There are a number of other problems with the document, but space limitations do not allow for a detailed critique. In brief, contrary to the guideline, we do not believe that all children with chronic ITP require a bone marrow aspirate, and we do not think that a short course of prednisone aimed at determining platelet response before a planned splenectomy is contraindicated. Also, we are perplexed by the panelists' statement that it is inappropriate to withhold treatment for patients with platelet counts less than 10,000/μL, even when the parents request withholding therapy. Is one to administer IVIg or high-dose corticosteriods anyway, against the parents wishes?
Finally, we would like to express our view that the pediatric members of the panel are too few in number (only three) and do not represent the wide spectrum of treatment philosophies involving children with ITP. Also, we wonder why three of the adult ITP experts voted on issues related to management of children with ITP. We as a group would hesitate to recommend to our internal medicine hematology colleagues how to manage their elderly patients.
In conclusion, although we applaud the efforts of the panel for their fine work overall, we believe that the document vis-a-vis children with ITP is in urgent need of revision. Many if not the majority of children with ITP and platelet counts of 20,000/μL or less do not require IVIg, high-dose corticosteroids, or any other specific therapy. Practice guidelines recently prepared by a group of distinguished British pediatric hematologists embrace this philosophy.3 Why should things be so different on this side of the Atlantic?
Acute Idiopathic Thrombocytopenic Purpura — Management in Childhood
To the Editor:
The practice guideline developed for the management of childhood idiopathic thrombocytopenic purpura (ITP)1-1 gives cause for concern. Although a comprehensive and well-researched review of the state of the art, the investigators — and the accompanying editorial1-2 — note the lack of satisfactory evidence (controlled trials) upon which to base their opinions. The result of the “opinions” of a very small number of “experts” (only 6 of the total 13 for questions relating to children) has therefore been to arrive at consensus guidelines that are in many respects in contradiction to those already published in the UK, based on much of the same evidence.1-3 In particular, in the UK, many treaters continue to choose “no treatment” for children with clinically mild (ie, bruising and purpura only) ITP even with profound thrombocytopenia (platelet count <10 to 20 × 109/L).1-4,1-5 The emphasis is on treating the symptoms and not on the platelet count alone. In my own practice, I have only found it necessary to treat 2 of the last 23 cases. It would be a retrograde step to feel under pressure to treat these children. If therapy is required, for troublesome symptoms, the UK guidelines recommend a short course of oral steroids as first-line therapy, with a maximum recommended dose of 2 mg/kg/d, which is again in contrast to the American Society of Hematology (ASH) guidelines. Importantly, treatment with steroids should not be started until a marrow examination has been performed, in particular to exclude acute lymphoblastic leukemia. It is surprising that your guidelines do not address this issue at all and only comment that a marrow examination is not mandatory for children receiving intravenous Igs (IVIg). IVIg is reserved for emergency treatment or to cover essential surgery in the UK guidelines, because there is no evidence that it alters the very low mortality of ITP.1-6 In addition, it is invasive, expensive, and has potential adverse effects, including hepatitis C transmission.
Despite the comment in the editorial that “recommendations are not intended to be standards,” it is very likely that readers will receive these as authoritative views — “this is what my professional society says I can and/or should do for my patient.1-2
A national audit of practice against the UK guidelines has been undertaken over the past year. Preliminary analysis of the data confirms that there continues to be wide variation in management that is not caused by the presentation or platelet count alone; so, doubtless the debate will continue.
REFERENCES
Response
The letter by Buchanan et al regarding the ASH practice guideline on ITP directly addresses the major issues related to the development of this publication. When ASH decided to develop a practice guideline, the motive was to define parameters of diagnosis and management for hematologic disorders. The selection of ITP as the topic for the initial ASH practice guideline was chosen because it is clearly a hematologic disorder (without overlap into other medical specialty areas), it is rather common, it involves both pediatric and adult hematologists, and there are many unresolved issues regarding diagnosis and management, some of which may involve major cost considerations. In principle, this selection was appropriate; in execution, the issues were complex. Buchanan et al emphasize that ITP is a disorder in which there is little firm clinical evidence and that this may be a reason to have avoided ITP as a topic. However, we consider that the revelation of the limitations of our knowledge on ITP was an important and helpful conclusion of this effort. Buchanan's criticism of the size and composition of the panel is an obvious and important criticism. However, a larger panel would have been unmanageable. The criticism reflects specifically on the perception that the composition of the panel may not reflect the consensus of opinion among pediatric hematologists. However, it is clear that there is no consensus among pediatric hematologists on the indications for initial treatment of children with ITP.
The major issue raised by these letters is whether children presenting with ITP and a low platelet count should receive specific treatment (eg, prednisone, IVIg) or should be observed without specific treatment. Buchanan et al and Bolton-Maggs favor the latter approach; the practice guideline made recommendations that specific treatment was appropriate for children with the most severe thrombocytopenia and some bleeding symptoms. The panel, of course, recognized that this is a controversial area. The guideline specifically acknowledged “that some pediatric hematologists who were not represented on the panel do not recommend specific treatment for children presenting with severe thrombocytopenia; these hematologists believe that careful observation is sufficient and preferable.”1 Furthermore, we emphasized the strong difference of opinion even among the panel's hematologists in a question addressing the appropriateness of offering no specific initial treatment for children (Fig 2).2-1 For the lowest platelet count, four panel members voted for the strongest opinion that no specific initial treatment was inappropriate, whereas one panel member voted with the strongest opinion that no specific treatment was appropriate. The opinions of our panel or of Buchanan et al and Bolton-Maggs are no substitute for good science. This issue can only be resolved by well-designed trials measuring long-term clinical outcomes of bleeding and mortality. As Buchanan et al, Bolton-Maggs, and the guideline text2-1 all emphasize, even though well-designed clinical trials have shown that specific treatment can result in a more rapid increase in the platelet count, whether this difference is clinically important regarding outcomes of bleeding and mortality and whether benefits outweigh potential harms remain unresolved.
Additionally, Bolton-Maggs states that “treatment with steroids should not be started until a marrow examination has been performed, in particular to exclude acute lymphoblastic leukemia.” There is no evidence to support this statement. The guideline addressed this issue by citing the one published study of bone marrow aspirations on 127 consecutive children with suspected ITP; other causes for thrombocytopenia were identified in only 5 children, all of whom had atypical presenting features.2-2 Therefore, throughout the guideline text we repeatedly state that recommendations for additional diagnostic tests are based on the assumption “that the history, physical examination, and initial blood counts and smear are compatible with the diagnosis of ITP and do not include atypical findings that are uncommon in ITP or suggest other disease etiologies.”1
This debate is a constructive outcome of the ASH practice guideline. It illustrates the diversity of opinion and the absence of evidence on which to base a firm recommendation. No change of panel composition, no change of voting patterns, and no assembly of committees to promote rational therapy can compensate for the absence of data. Because Buchanan et al have “experience in the diagnosis and management of several thousand children with ITP,” clearly there is an important opportunity to conduct clinical trials that will resolve this issue and provide firm evidence on the most appropriate management for children with ITP.
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