What is in a name: defining pediatric refractory ITP.

ABSTRACT: 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 Guidelines are therefore limited to arbitrary and outdated definitions.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.

Moderate aplastic anemia in children: preliminary outcomes for treatment versus observation from a single-institutional experience.

INTRODUCTION: Because of the variety of definitions used to describe moderate aplastic anemia (MAA), we review our institutional experience period with patients who met a proposed set of criteria for this disorder. On an exploratory basis, we sought to evaluate the influence of treatment with immunosuppressive therapy (IST) versus observation on long-term outcomes. MATERIALS AND METHODS: Records from 1999 to 2010 were screened for patients who met the criteria for MAA: (1) bone marrow cellularity of 20% to 50%; (2) cytopenias in at least 1 cell line (absolute neutrophil count<1000/µL, hemoglobin<9 g/dL, platelet count<100,000/µL); (3) mean corpuscular volume ≥90; (4) persistence >6 months; and (5) negative Fanconi studies. Data were collected for patient/disease characteristics, treatments, and outcomes. RESULTS: Eight patients met the criteria for MAA. Three of 8 patients received IST. Of 3 patients who received IST, complete response was observed in 2 and transfusion independence in 1, as compared with 2 of 5 and 3 of 5 in the group who were observed without IST. Median duration of follow-up was 48 months. DISCUSSION: As several patients spontaneously resolved, and none developed severe aplastic anemia, acute myelogenous leukemia, or myelodysplastic syndrome, the criteria used here may identify a group of children with favorable prognosis who can be managed supportively.

Contemporary pediatric splenectomy: continuing controversies.

PURPOSE: We undertook the current study to update the literature on pediatric splenectomy in the age of minimally invasive proficiency among pediatric surgeons. The study is designed to address specific concerns among surgeons about the suitability of the laparoscopic approach in specific situations and among hematologists about the relative benefits and risks of splenectomy in children. METHODS: Retrospective analysis of clinicopathologic data for 118 children who underwent open (OS) or laparoscopic (LS) splenectomy at an urban tertiary children's hospital from January 2000 to July 2008. RESULTS: One hundred and three cases (87%) were started as LS. Operative times were equivalent for LS and OS (P = 0.8). In the LS group, there were four conversions (3.9%) from LS to OS and five early post-operative complications (4.9%). Median length of stay was 2 days for LS and 4 days for both OS and LS converted to OS (P < 0.0001). The ten largest spleens removed by LS had greater mass (P = 0.02) and tended to have greater volume (P = 0.1) than those removed by OS. Children with hereditary spherocytosis, ITP, and hemoglobinopathy had favorable clinical outcomes, regardless of operative approach. There were no cases of overwhelming post-splenectomy sepsis in this series. CONCLUSIONS: Laparoscopic splenectomy is the preferred approach for splenectomy in children with hematological diseases, with or without splenomegaly. Compared to open splenectomy, laparoscopic splenectomy has equivalent operative time and improved length of stay. Both approaches have excellent therapeutic outcomes for appropriate indications.

Predicting response to splenectomy in children with immune thrombocytopenic purpura.

PURPOSE: Predicting the response to splenectomy in children with immune thrombocytopenic purpura (ITP) continues to be a clinical challenge. The purpose of this study is to identify preoperative predictors of outcome for splenectomy in children with ITP. METHODS: The charts of 19 children who underwent splenectomy for ITP were retrospectively reviewed. Platelet responses to treatment are categorized as complete response (CR, > or =150,000/microL), partial response (PR, > or =50,000 but <150,000/microL), or nonresponse (NR, <50,000/microL). RESULTS: After splenectomy, 13 patients (68%) had CR, 3 (16%) had PR, and 3 (16%) had NR. No correlation existed between CR to splenectomy and any of the following: age, platelet count at diagnosis, last platelet count before splenectomy, platelet count on postoperative day 1, or responses to preoperative intravenous immunoglobulin, WinRho, or Rituximab. However, all 7 patients who had NR to a full course of steroids subsequently had CR to splenectomy. Nonresponse to steroid therapy was directly correlated with CR to splenectomy (P = .01, Fisher's Exact test). Furthermore, postsplenectomy platelet counts were inversely related to peak platelet response to steroids (correlation coefficient = -0.68, P = .01). CONCLUSIONS: Preoperative responsiveness to steroid therapy, as measured by peak platelet count, predicts NR to splenectomy for ITP in children, whereas NR to steroid therapy is highly correlated with CR to splenectomy. These findings challenge the widely held notion that steroid responsiveness portends a favorable outcome after splenectomy.

Tacrolimus as an alternative to cyclosporine in the maintenance phase of immunosuppressive therapy for severe aplastic anemia in children.

OBJECTIVE: Given the paucity of data on the use of agents other than cyclosporine (CsA) in the maintenance phase of immunosuppressive therapy (IST) for severe aplastic anemia (SAA) in children, we sought to describe our experience with tacrolimus in pediatric SAA, and to compare outcomes with a preceding series of patients who received CsA. METHODS: Eight patients with SAA diagnosed between 2003 and 2008 for whom no human leukocyte antigen (HLA)-matched sibling donor was identified underwent tacrolimus-based IST. These children were compared with a previously described series of 13 patients who had undergone CsA-based IST at our institution between 1990 and 2003. All patients initially received equine antithymocyte globulin (ATG) and corticosteroids. RESULTS: Complete response (CR) rate was 88% for tacrolimus and 85% for CsA. Median time to CR was approximately 7 months in both groups. Median follow-up duration was 2.4 years for tacrolimus and 8.4 years for CsA. Among responders with de novo SAA, relapse rate was 25% (n = 1) at 2 years for tacrolimus and 0% at 2 years and 23% (n = 3) at 5 years for CsA; no significant difference in relapse-free survival was detected between the two groups (P = 0.07). Paroxysmal nocturnal hemoglobinuria was seen in one patient on tacrolimus who had relapsed after CsA-based IST. Tacrolimus-based IST was well-tolerated. CONCLUSION: These data provide evidence that tacrolimus may be a suitable alternative to CsA as part of an IST regimen for SAA in children who lack an HLA-matched sibling and may have a more favorable profile of side effects than CsA.

Lemierre's and Lemierre's-like syndromes in children: survival and thromboembolic outcomes.

OBJECTIVE: Lemierre's syndrome, or jugular vein thrombosis (JVT) associated with anaerobic infection of the head and neck and frequently complicated by septic pulmonary embolism (PE), has historically been described as a disease of young adults. In recent years, an increasing number of case reports of childhood Lemierre's syndrome have been published, focusing mostly on the clinical and laboratory findings at disease presentation and the outcomes of infection. Given the potentially life-threatening thromboembolic complications of this disorder, we reviewed our single-institutional experience with pediatric Lemierre's and Lemierre's-like syndromes (LALLS) from within the context of a larger cohort study of thrombosis in children. METHODS: Children who were aged from birth to 21 years and had received a diagnosis of JVT and Lemierre's syndrome at the Children's Hospital (Denver, CO) between 2001 and 2005 were identified for inclusion. Case designation of LALLS required all the following: (1) radiologic confirmation of JVT, (2) clinical diagnosis of pharyngitis or other febrile illness, and (3) intraoperative evidence of loculated infection in the head and neck region or radiologic demonstration of bilateral pulmonary infiltrates. Isolation of a causative organism by microbiologic culture of blood, tissue, or purulent fluid was also a necessary diagnostic criterion among patients who had not been treated with antibiotics before culture. A designation of classic Lemierre's syndrome was reserved for documented cases of anaerobic infection. Children in whom JVT was associated with the presence of an ipsilateral central venous catheter were excluded from the analysis. Analysis included information on underlying medical conditions, microbiologic and radiologic findings, and comprehensive hypercoagulability testing results from the time of diagnosis, as well as antimicrobial and anticoagulant therapies administered. In addition, clinical outcomes were evaluated via serial follow-up and included bleeding complications, thrombus resolution on serial radiologic studies, symptomatic recurrent venous thromboembolism (VTE), and mortality. RESULTS: From January 2001 to January 2005, 9 children with LALLS were identified. Median age was 15 years (range: 2.5-20 years). Clinical presentation was consistent with septic PE in 5 cases and septic shock in 2. Thrombophilia was present in 100% (7 of 7) of children tested, consisting principally of antiphospholipid antibodies and elevated factor VIII activity. Anticoagulation was given in 89% (8 of 9), for a median duration of 3 months (range: 7 weeks-1 year). After a median follow-up time of 1 year, all children had survived without recurrent VTE or anticoagulant-associated major hemorrhage. JVT failed to resolve at 3 to 6 months in 38% of anticoagulated children. CONCLUSIONS: Our experience suggests that LALLS is an emerging pediatric concern with serious acute (eg, septic PE) and chronic (eg, persistent vascular occlusion) complications. Septic JVT may not be uniquely anaerobic, and the inflammatory prothrombotic state is often characterized by antiphospholipid antibodies and elevated factor VIII levels. Early diagnosis and aggressive antimicrobial and antithrombotic therapies in LALLS may be necessary for optimal long-term outcomes.

Successful treatment of severe aplastic anemia in children using standardized immunosuppressive therapy with antithymocyte globulin and cyclosporine A.

BACKGROUND: Given the heterogeneity of published data in US children, we sought to evaluate outcomes of a standardized immunosuppressive therapy (IST) regimen for severe aplastic anemia (SAA) at The Children's Hospital (Denver, CO). METHODS: We retrospectively analyzed the records of 16 children diagnosed from 1990 to 2003 and treated by IST, among whom 14 received the standardized regimen of antithymocyte globulin (ATG) and cyclosporine A (CsA). Serial hematologic parameters, complications, transfusion requirements, and time to response were assessed. RESULTS: One child who died from a pre-existing Aspergillus infection prior to expected IST response was excluded from the analysis. Overall (transfusion-independent) response to IST was 100% (13/13), without any relapses or clinically evident leukemic/myelodysplastic transformations after a median follow-up time of 4.4 years (range: 10 months-13.3 years). CONCLUSIONS: This report documents excellent outcome using combination ATG and CsA IST for pediatric SAA.

Low-dose tissue plasminogen activator thrombolysis in children.

PURPOSE: To compare results of low-dose tissue plasminogen activator (TPA) in children with arterial and venous thrombi relative to standard published dosing. METHODS: Subjects consisted of all consecutive children with objectively confirmed thrombi for whom TPA thrombolysis was clinically ordered by the authors. Initial dosing used published standard dose (0.1-0.5 mg/kg per hour). With experience, a low-dose regimen (0.01-0.06 mg/kg per hour) was given in an attempt to derive a minimal effective dose. RESULTS: Thirty-five children were treated with TPA. Either standard or low-dose infusions of TPA resulted in complete thrombolysis of 28 of 29 (97%) acute thrombi, while all 6 chronic thrombi had a partial response. In contrast to the recommended adult-derived dosages of 0.1 to 0.5 mg/kg per hour, the authors found that initial doses of less than 0.01 mg/kg per hour were effective in 12 of 17 patients with acute thrombosis. Neonates required 0.06 mg/kg per hour. Route of administration (local or systemic) did not affect efficacy. Major bleeding occurred in only one extremely preterm infant. Minor bleeding, primarily oozing at intravenous sites, occurred in 27% of children during TPA infusions. Prophylactic unfractionated or low-molecular-weight heparin was infused concomitant with TPA in 42% of the children and did not increase the risk of bleeding. CONCLUSIONS: TPA in very low doses appears to be safe and effective for thrombolysis of acute thromboses in most children, given appropriate patient selection.