There are no agreed upon terminology to define “refractory” pediatric immune thrombocytopenia (ITP). Guidelines are therefore limited to arbitrary and outdated definitions. The Pediatric ITP Consortium of North America held a meeting in 2023 to define this entity. With 100% agreement, the faculty established that pediatric ITP that is refractory to emergent therapy could be defined as no platelet response after treatment with all eligible emergent pharmacotherapies. With 100% agreement, the working group established that pediatric patients with ITP that continue to demonstrate high disease burden and/or no platelet response despite treatment with multiple classes of disease-modifying therapies represent a challenging subset of ITP. These patients are at higher risk of ongoing disease burden and merit additional investigation as well as consideration for clinical trials or novel therapies. Future efforts to define disease burden and disease response will be completed in collaboration with the ITP International Working Group.
Introduction
Pediatric immune thrombocytopenia (ITP) is a heterogenous disease associated with acquired autoimmune destruction and impaired production of platelets. Although many children experience a self-limited and minimally symptomatic disease course, others demonstrate a spectrum of prolonged symptoms with variable response and/or intolerance to interventions. Those with a more challenging disease trajectory may warrant early escalation of additional therapy and consideration for clinical trials. Providers have historically labeled challenging cases to treat as “refractory”; however, the field lacks a unified definition for this term. Without agreed-upon terminology to define these challenging cases of pediatric ITP, guidelines and clinical trials as well as hematologists and payers are limited to arbitrary definitions based on platelet count and disease duration, failing to account for other important aspects of the patient’s disease manifestations.
Previous efforts to define refractory ITP, including those developed by the ITP International Working Group (IWG) and the American Society of Hematology, have centered the definition on adults with ITP and on a lack of response to, or relapse of symptoms after, splenectomy.1,2 The limitations of this definition have been acknowledged and the IWG has reported an inability to reach consensus on the definition of pediatric refractory ITP.1,3 Furthermore, the increased availability and use of novel pharmacotherapy options has greatly decreased the role for splenectomy in the standard care of pediatric ITP.4 Updated IWG and American Society of Hematology ITP guidelines published in 2019 acknowledged that defining refractory ITP in regard to splenectomy response was no longer applicable, and declined to comment further on a more relevant use of the term.5,6 In 2023, the Pediatric ITP Consortium of North America (ICON) published a systematic literature review to better understand previous and current use of the term “refractory” as it applies to pediatric ITP.7 Of 11 previously published definitions of refractory ITP, nearly half (5/11) required the criteria of failed splenectomy. Half (6/11) included increased bleeding risk without defining clinical or laboratory markers to measure risk. Half (5/11) included poor response to medication without defining criteria for medication failure, and with great variability in the number of required failed medications (eg, failure to respond to ≥2 treatment options) and/or number of failed medication mechanisms of action.
A recent online survey sent to ICON members (n = 25 respondents across 50 sites) demonstrated lack of consensus about a more relevant or standardized definition for refractory pediatric ITP and prompted an internal discussion regarding the utility of the term refractory. Inconsistent definitions for refractory used to determine eligibility for clinical trials have limited the ability to compare trial outcomes and understand the biology of ITP in these patients.8 Refractory, in its current use, functions as an ill-defined, binary label weighted with stigma capable of influencing a provider’s clinical decision-making, how patients view themselves and their disease, and payor coverage of treatment options. Given the unmet medical and research needs in this difficult-to-treat pediatric ITP population, ICON prioritized a goal to develop treatment response–based terminology that could more practically and accurately identify challenging cases of pediatric ITP. ICON, as a pediatric ITP consortium, aims to improve the treatment, outcomes, and quality of life of children with ITP and, therefore, may inform other expert groups, such as the IWG, of pediatric priorities and implications of definitions. Such consensus terminology would improve communication with patients and providers, guide clinical evaluation and treatment, help expedite appropriate medication payor coverage, allow incorporation and consideration of response to newly developed therapies, and classify patients for research trials and biologic studies.
Methods
In light of the findings of the systematic review of the term refractory in pediatric ITP in published literature and lack of consensus from ICON members in a survey regarding the term refractory in pediatric ITP, the authors proposed a dedicated effort to develop a comprehensive definition to facilitate outcome comparisons of future ITP studies.7 An in-person working group of ICON members was convened with the objectives to achieve consensus on the definition of refractory in pediatric ITP and to inform ongoing international efforts to revise the prior IWG ITP terminology with a consensus-derived pediatric viewpoint. A subset of ICON members (29/53) attended the meeting held in September 2023 in Aspen, CO, with representation from 28 ICON centers across the United States, Canada, and Mexico, and an additional representative expert from Europe (total pediatric hematologists, n = 30). Over 3 days, the meeting was designed to progress from focused discussions within small groups to consensus decisions as a large group. The meeting was funded by a philanthropic donation, with no industry support.
A steering committee for the meeting selected 3 overarching components that were critical from the systematic literature review in all previous efforts to define refractory pediatric ITP: (1) timeline of disease, (2) previously trialed medications and their mechanisms, and (3) platelet count and symptoms. A 3-step process was used to achieve consensus. First, attendees of the meeting were placed into 6 small groups (n = 5 faculty per group) in order to vet in depth 1 of the 3 components outlined above and to deliver statements summarizing the contribution of these components on the definition of refractory pediatric ITP. Two subgroups (groups A1 and A2) were assigned to discuss the role of timing of diagnosis including newly diagnosed, persistent, or chronic ITP, and the acuity of presentation, in the definition of refractory pediatric ITP. Two subgroups (groups B1 and B2) were assigned to discuss the role of response to treatments and their mechanisms of action in the definition of refractory pediatric ITP. Two subgroups (groups C1 and C2) were assigned to discuss the role of platelet count and patient symptoms including bleeding, quality of life, and fatigue in the definition of refractory pediatric ITP. After this, 1 subgroup from each major component (A + B + C) combined to form 2 larger comprehensive discussion groups. Each large group was given the objective of unifying the submitted outcomes from the small groups to draft a more comprehensive definition of refractory pediatric ITP. After the creation of 2 working group comprehensive statements, all faculty were asked to participate in an anonymous voting process, using a modified Delphi methodology, in favor of, or against, draft statements. Consensus was predefined as a minimum of ≥80% agreement in favor of statements. Terminology that failed to meet this threshold on initial vote underwent review, revision, and a second vote also requiring ≥80% agreement.
Results
In an initial discussion to critically assess the definition of refractory in children with challenging cases of ITP, 50% of the faculty (15/30) felt the term refractory should no longer be used, whereas 50% continued to support the broad use of the term among hematologists. There was consensus that the overall objective was to develop agreed upon classifications that would improve communication with patients and providers and identify those challenging cases that would benefit from early escalation of therapy, participation in clinical trials, and research to better understand their disease biology.
Small group discussions and consensus voting
Timeline of the disease
The majority of faculty (93%, 28/30) agreed that the duration of a child’s diagnosis of ITP should not affect the classification of their response to a therapeutic intervention. There was consensus that response to therapy at time points of clinical exacerbation (eg, bleeding) was more important than the phase of ITP (eg, newly diagnosed, <3 months; persistent, 3-12 months; or chronic, >12 months). Two terms were proposed for clinically relevant time points that require therapeutic intervention: (1) emergent therapy and (2) disease-modifying therapy (Table 1).
Emergent therapy∗ | The use of eligible, first-line, short-acting agents (eg, corticosteroids, IVIG, and intravenous anti-Rho(D) immunoglobulin) to achieve a rapid improvement in platelet count† in the setting of active bleeding |
Disease-modifying therapy∗ | The use of pharmacotherapy agents‡ (eg, thrombopoietin-receptor agonists§, biologics|, and immunomodulating agents¶) and interventions (eg, splenectomy) to achieve a sustained, durable maintenance response in platelet count to prevent ongoing exacerbations of symptomatic ITP and improve quality of life |
Emergent therapy∗ | The use of eligible, first-line, short-acting agents (eg, corticosteroids, IVIG, and intravenous anti-Rho(D) immunoglobulin) to achieve a rapid improvement in platelet count† in the setting of active bleeding |
Disease-modifying therapy∗ | The use of pharmacotherapy agents‡ (eg, thrombopoietin-receptor agonists§, biologics|, and immunomodulating agents¶) and interventions (eg, splenectomy) to achieve a sustained, durable maintenance response in platelet count to prevent ongoing exacerbations of symptomatic ITP and improve quality of life |
Medications assumed to be administered at an effective dose and for an adequate duration.
Bleeding is rare with a platelet count of >20× 109/L to 30 × 109/L, therefore the platelet count is used as a surrogate of treatment response, which eliminates bleeding in the emergent context.
Pharmacotherapy agents with different mechanisms of action are currently in development and in clinical trials. Examples of currently available mechanisms of actions are listed here.
Thrombopoietin-receptor agonists: for example, eltrombopag and romiplostim.
Biologics: for example, rituximab and bortezomib.
Immunomodulating agents: for example, sirolimus, mycophenolate mofetil, azathioprine, and hydroxychloroquine.
Trialed medications and mechanisms
Previous attempts to define refractory ITP in relation to medications have typically included failing a specific number of medications (eg, having failed ≥2 medications) or a finite number of mechanisms of action (eg, having failed ≥2 mechanisms of action). The faculty did not agree on a specific number of failed medications or number of mechanisms of action to define refractory ITP. The faculty discussed that refractory could imply failing all possible treatments of all possible mechanisms of action, but this would not be a clinically useful definition. The faculty agreed that, in the emergent setting, the term refractory described ITP that failed to respond to “all eligible emergent therapies” including corticosteroids, intravenous immunoglobulin (IVIG), and/or anti-Rho(D) immunoglobulin. The term “all eligible” was chosen given that drug availability may vary between institutions, states, or countries, and that individual patients may not be eligible for all therapies (eg, an Rh-negative patient who is ineligible for anti-Rho(D) immunoglobulin). In terms of disease-modifying therapy, there was agreement that refractory is an imprecise term to describe challenging cases of ITP that fail to respond to therapy given the significantly different mechanisms of drug action. With increasing advances in drug development that exploit novel targets/mechanisms of action, the group agreed that refractory could describe a highly heterogeneous group of patients who fail multiple but nonoverlapping types of disease-modifying therapy and therefore may describe patients with variable treatment nonresponse and underlying ITP biology.
The trialed medications and mechanisms subgroups outlined key treatment response terminology applicable to pediatric ITP. The majority (83%, 25/30) agreed that the term “no response” should refer to ITP failing to meet an adequate platelet and/or symptom response to an intervention, “complete response” (CR) should refer to ITP that has demonstrated an adequate platelet and/or symptom response, and “partial response” (PR) should refer to ITP that demonstrates limited response to an intervention that fails to meet criteria for CR. Faculty further suggested key modifiers to better subclassify a PR or CR be considered including the term “transient” indicating loss of a PR or CR, or “durable” indicating the maintained stability of a PR or CR. Drug intolerance, secondary to side-effects or nonadherence, was thought to represent a separate, unrelated classification from these response-based definitions.
Platelet count and symptoms
Several tools have been developed to quantify bleeding9,10 and survey quality of life and fatigue,11 but the field still struggles to adhere to any single standardized definition of disease burden in either the research or clinical setting. The majority of participants (93%, 28/30) agreed that a response-based definition should be described as either symptom refractory, platelet refractory, or both. The majority (96%, 29/30) agreed that criteria to define symptom refractory should include standardized measures of (1) bleeding, (2) quality of life, and (3) fatigue. The majority (93%, 28/30) also agreed that platelet refractory should be defined by the previously published IWG definition of a peripheral platelet count failing to double from baseline and achieve a platelet count of ≥30 103/μL.1 The groups similarly recommended consideration of additional outcome modifiers including: no response, PR (transient or durable), and CR (transient or durable). However, the duration of response to define these modifiers has yet to be agreed upon but is the subject of an upcoming IWG initiative.
Large group discussions and consensus voting
The larger groups agreed that the subgroup consensus derived definitions represented ITP qualifiers that, when combined, provide the construct for comprehensive definitions for challenging cases of pediatric ITP (Table 2).
ITP qualifiers = indications + treatments + response + platelets/symptoms . | |
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Indications for treatment |
|
Prior trialed treatments |
|
Treatment response | |
Platelet response/symptom response |
|
ITP qualifiers = indications + treatments + response + platelets/symptoms . | |
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Indications for treatment |
|
Prior trialed treatments |
|
Treatment response | |
Platelet response/symptom response |
|
The duration of response to define modifiers (transient and durable) to be determined in collaboration with the IWG.
Emergent therapy
Emergent therapy has a straightforward therapeutic objective to eliminate a singular symptom: bleeding. Because spontaneous bleeding in ITP is rare with a platelet count of >20 × 109/L to 30 × 109/L, the platelet count is used as a correlate of a treatment response, which eliminates bleeding in the emergent context.12 There was faculty agreement that “refractory to emergent therapy” could appropriately be used to describe ITP that fails to demonstrate a platelet response after administration of all eligible emergent, first-line, short-acting pharmacotherapy at an effective dose for adequate duration. Additional important ITP qualifiers to define refractory in the setting of emergent therapy include (1) eligible treatments (corticosteroids, IVIG, and/or anti-Rho(D) immunoglobulin) and (2) platelet response.
Disease-modifying therapy
Given the more complex treatment objectives, the faculty agreed that refractory was an inexact term to describe a lack of response to disease-modifying therapy. Arguments to support this included the perpetual evolution of algorithms used to guide administration of existing or new therapies, new introduction of ITP-directed therapies with novel mechanisms of action in the future, and the potential use of this term to describe patients with nonresponse to varied therapies.
The faculty carried out a prolonged debate to discuss whether symptom response (representative of disease burden including bleeding, quality of life, and fatigue) should be included as an ITP qualifier for disease-modifying therapy. The difficulty was defining a measurable outcome in both the research and clinical setting for disease-modifying therapy. Several of the faculty argued that the purist definition would be based on qualifiers outlining treatments and interventions and the platelet response alone, assuming that an improved platelet response implied a favorable outcome. However, a majority of the faculty advocated for the inclusion of symptom response because the platelet count and presumed risk of bleeding are not the only determinants of disease burden of ITP in children. Bleeding, quality of life, and/or fatigue may have a greater impact on disease burden than platelet count alone in children with ITP as compared with adults. Agreement was achieved to include symptom response as an ITP qualifier for disease-modifying therapy (Table 3).
Indication for treatment . | ITP qualifiers . |
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Emergent therapy | Eligible treatments Platelet response |
Disease-modifying therapy | Treatments/interventions Platelet response Symptom response |
Indication for treatment . | ITP qualifiers . |
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Emergent therapy | Eligible treatments Platelet response |
Disease-modifying therapy | Treatments/interventions Platelet response Symptom response |
The faculty achieved agreement (100%, 30/30) on a summary statement defining refractory for pediatric ITP in emergent therapy and a summary statement defining pediatric patients with ITP receiving disease-modifying therapy at higher risk for ongoing disease burden and who merit additional evaluation (Table 4).
Consensus classification of challenging pediatric ITP . |
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Refractory to emergent therapy is defined as no platelet response after treatment with all eligible∗ emergent pharmacotherapies. |
Current emergent therapies: corticosteroids, IVIG, anti-D immune globulin |
Assuming medications administered at effective dose and for adequate duration |
Pediatric patients with ITP who are platelet nonresponsive and/or continue to demonstrate high disease burden despite treatment with multiple classes of disease-modifying therapies (≥2 mechanisms of action) represent a challenging subset of ITP. They are at higher risk of ongoing disease burden and poor response to additional therapies. They merit additional investigation to identify alternative etiologies of both immune and non-ITP, and they warrant consideration for clinical trials or novel therapies. |
Requires documentation of all ITP medications trialed |
Assuming medications administered at effective dose and for adequate duration |
Definition of response is pending publication of the updated IWG definitions of platelet and symptom response |
Consensus classification of challenging pediatric ITP . |
---|
Refractory to emergent therapy is defined as no platelet response after treatment with all eligible∗ emergent pharmacotherapies. |
Current emergent therapies: corticosteroids, IVIG, anti-D immune globulin |
Assuming medications administered at effective dose and for adequate duration |
Pediatric patients with ITP who are platelet nonresponsive and/or continue to demonstrate high disease burden despite treatment with multiple classes of disease-modifying therapies (≥2 mechanisms of action) represent a challenging subset of ITP. They are at higher risk of ongoing disease burden and poor response to additional therapies. They merit additional investigation to identify alternative etiologies of both immune and non-ITP, and they warrant consideration for clinical trials or novel therapies. |
Requires documentation of all ITP medications trialed |
Assuming medications administered at effective dose and for adequate duration |
Definition of response is pending publication of the updated IWG definitions of platelet and symptom response |
All eligible emergent pharmacotherapies include all drugs available in the patient’s institution.
Application of consensus classification of challenging pediatric ITP
A 5-year-old girl with new onset of petechiae, bruising, and epistaxis has a platelet count of 2 103/μL and is diagnosed with ITP by a pediatric hematologist. Given ongoing epistaxis, she is treated with prednisone, 4 mg/kg per day for 5 days. Her platelet count remains <10 103/μL. She is treated with IVIG, 1 g/kg × 1 dose. Four days later, her platelet count remains <10 103/μL. Due to ongoing epistaxis, her hemoglobin has dropped to 8 g/dL, and her hematologist feels it is unsafe to give her anti-Rho(D) immunoglobulin.
The platelet count failed to respond to all eligible emergent therapies. This patient has ITP that is refractory to emergent therapy.
A 12-year-old boy was diagnosed with ITP after presenting with new bruising and a platelet count of 10 103/μL. Although his physician and parents opted for a strategy of close observation without intervention initially, his platelet count remained very low, and he was experiencing fatigue and was depressed that he was no longer allowed to play on his competitive hockey team. He was started on eltrombopag at 50 mg daily, which was increased to 75 mg daily after 2 weeks. His platelet count remained unchanged after 4 weeks on the maximum dose, taken appropriately, separated from food. He was then treated with rituximab, 375 mg/m2 × 4 doses, and 2 months later still had no change in his platelet count. He remains very fatigued and feels socially isolated and worries that he will not be able to play on the high school hockey team.
This patient continues to have high disease burden with nonresponse to ≥2 different classes of disease-modifying therapy. His challenging disease should be recognized as higher risk of ongoing disease burden and poor response to additional therapies. He merits additional investigation to identify alternative etiologies of both immune and non-ITP, and also warrants consideration for clinical trials or novel therapies as appropriate.
Discussion
A general definition of refractory is an unmanageable state, resistant to treatment or cure. Refractory malignancies and refractory infections imply high-risk disease with a poor clinical prognosis. The definition of refractory within ITP has never been agreed upon and the term is often used in challenging cases that may still be naïve to certain therapies and require more extensive diagnostic evaluation. A working group of pediatric hematologists was tasked with determining terminology to classify challenging cases of ITP.
Pediatric hematologists from the United States, Canada, Mexico, and France discussed the framework necessary to accurately define a child with symptomatic ITP who is challenging to treat. Although the group was initially divided on the continued use of the term refractory in pediatric ITP, it was clear that this term and a single definition could be more readily applied to the setting of emergent therapy compared with disease-modifying therapy. With 100% agreement, the faculty established that “refractory to emergent therapy” could be defined as no platelet response after treatment with all eligible emergent pharmacotherapies.
What does this definition of refractory to emergent therapy achieve? It defines a subset of pediatric ITP cases of acutely symptomatic ITP that have failed first-line standard-of-care intervention and may have a higher risk of ongoing disease burden. These complicated cases require immediate identification to rapidly escalate use of disease-modifying therapies (eg, rituximab, thrombopoietin-receptor agonists, and immunomodulating agents), to expand evaluation for secondary immune-mediated thrombocytopenias, which may be more severe and less responsive to standard ITP therapy (eg, Evans syndrome) or other causes of thrombocytopenia that require a different mechanism of treatment (eg, thrombotic thrombocytopenic purpura or hemolytic uremic syndrome), and to define a group of children who should be offered participation in clinical trials to identify optimal/novel therapies and understand the biology of their disease.
Terminology to describe patients who fail to respond to disease-modifying therapies was more difficult to develop. There was a lengthy debate discussing how many medications of how many different mechanisms of action a patient would have to fail to be considered refractory to disease-modifying therapies. The working group agreed that, for the indication of disease-modifying therapy, refractory is an inexact term, because patients who have failed different therapies could be described as refractory. However, the group agreed that children with challenging cases of ITP require early identification to receive additional therapy and clinical evaluation. With 100% agreement, the working group established that pediatric patients with ITP who are platelet nonresponsive and/or continue to demonstrate high disease burden despite treatment with multiple classes of disease-modifying therapies (≥2 mechanisms of action) represent a challenging subset of ITP.
What does this definition of failure of response to ITP disease-modifying therapy achieve? It discourages use of the term refractory to imprecisely and blanketly describe every patient with ITP who fails disease-modifying therapy. The terminology also incorporates both platelet response and symptom response into the description of disease burden. The terminology helps clinicians to be more precise in describing the ways in which individual patients are symptomatic (bleeding, quality of life, and/or fatigue) and nonresponsive to treatment (by specific treatment types and mechanisms of action). This classification helps to identify different types of challenging cases of ITP that require more intensified evaluation and therapy. Such an expanded evaluation may include a comprehensive immune evaluation such as a quantitative screen of peripheral blood immunoglobulins, T/B/natural killer cell subsets, a qualitative screen of vaccine response, among other immune tests. A comprehensive bone marrow evaluation could be considered before enhanced immune modulating/suppressing therapy and, if pursued, should include an aspirate, biopsy, cytogenetics, and flow cytometry. Comprehensive molecular studies should also be discussed to rule out germ line genetic predisposition to immune dysregulation or inherited platelet disorders.13
Conclusion and future direction
The field of hematology lacks consensus definitions to describe ITP response to emergent and disease-modifying therapies in children. The ICON Aspen working meeting, attended by a diverse group of experts in pediatric ITP, successfully developed terminology to identify children with challenging ITP that would benefit from early escalation of therapy, additional evaluation, and inclusion in clinical trials and ITP research. Ongoing efforts by the IWG can also integrate this pediatric terminology in their revised ITP definitions. To test the utility and functionality of these classification schema, the faculty proposed designing 3 future research studies: (1) a retrospective cohort study to evaluate the application of this terminology and correlation to disease burden and risk of disease persistence or progression; (2) focus group discussions carried out in collaboration with patient advocacy groups to gather patient feedback on the terminology and definitions; and (3) a prospective, multicenter database to assess the clinical utility, biology, and patient outcomes of children categorized by these treatment response–based definitions. Future efforts to define disease burden and disease response in pediatric ITP are ongoing and will be completed in collaboration with the IWG.
Acknowledgments
The ICON Aspen meeting faculty acknowledge and thank Henry Gordon and family for their generous donation to advance therapy for children with ITP, and Taru Hays and Bill Hays for additional funding support.
Authorship
Contribution: T.A.N., A.B.G., R.J.K., M.P.L., C.N., J.A.R., K.A.S., and R.F.G. designed and implemented the methodology; T.A.N. and R.F.G. drafted the manuscript; and T.A.N., A.B.G., R.J.K., M.P.L., C.N., J.A.R., K.A.S., C.A., M.A., S.M.B., J.M.B., V.B., S.C., M.D., S.F.L., M.G., T.H., K. Hege, K. Hillier, A.J.-K., S.K., T.O.K., M.K., T.L., M.M., M.N., A.R., C.S., R.S., and R.F.G. analyzed consensus results and finalized the manuscript.
Conflict-of-interest disclosure: A.B.G. receives research support from Novartis. R.J.K. receives consultancy fees from Agios, Amgen, Bayer Canada, F. Hoffman-La Roche, Novo Nordisk, Octapharma AG, Sanofi, and Takeda. M.P.L. serves on an advisory board for Octapharma, Dova, Principia, Rigel, Argenx, Platelet Disorder Support Association, 22q Society, and CdLS Foundation; receives consultancy fees from Agios, Novartis, Dova, Principia, Argenx, Rigel, Sobi, Sanofi, and Janssen; and receives research support from the Foundation for Women and Girls with Blood Disorders, the Platelet Disorder Support Association, the National Institutes of Health, Sysmex, Novartis, Principia, Argenx, Dova, Octapharma, and Sanofi. C.N. receives research support and consultancy fees from Novartis, and consultancy fees from Argenx, Sanofi, and Sobi. K.A.S. receives research support from Novartis, Sobi, and Sanofi. S.C. serves on an advisory board for Sanofi, and receives consultancy fees from Novartis, Pfizer, and Medexus. S.F.L. receives research support from Sobi and Octapharma. A.R. receives consultancy fees from bluebird bio, Horizon Therapeutics, and Novartis. R.F.G. receives research support from Novartis, Sobi, and Agios, and consultancy fees from Agios and Sanofi. The remaining authors declare no competing financial interests.
Correspondence: Amanda B. Grimes, Texas Children’s Hospital, Baylor College of Medicine, 6701 Fannin St, Houston, TX 77030; email: [email protected].