Respiratory syncytial virus (RSV) is the most common cause of infant hospitalizations and severe RSV infections are a significant risk factor for childhood asthma. The pathogenic mechanisms responsible for RSV induced immunopathophysiology remain elusive. Using an age-appropriate mouse model of RSV, we show that IL-33 plays a critical role in the immunopathogenesis of severe RSV, which is associated with higher group 2 innate lymphoid cells (ILC2s) specifically in neonates. Infection with RSV induced rapid IL-33 expression and an increase in ILC2 numbers in the lungs of neonatal mice; this was not observed in adult mice. Blocking IL-33 with antibodies or using an IL-33 receptor knockout mouse during infection was sufficient to inhibit RSV immunopathogenesis (i.e., airway hyperresponsiveness, Th2 inflammation, eosinophilia, and mucus hyperproduction); whereas administration of IL-33 to adult mice during RSV infection was sufficient to induce RSV disease. Additionally, elevated IL-33 and IL-13 were observed in nasal aspirates from infants hospitalized with RSV; these cytokines declined during convalescence. In summary, IL-33 is necessary, either directly or indirectly, to induce ILC2s and the Th2 biased immunopathophysiology observed following neonatal RSV infection. This study provides a mechanism involving IL-33 and ILC2s in RSV mediated human asthma.

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BACKGROUND Infants with acute lymphoblastic leukemia (ALL) present with aggressive disease and a poor prognosis. Early relapse within 6–9 months of diagnosis is common. Approximately 75% of infants have MLL-rearranged (MLL-R) ALL with event free survival (EFS) ranging from 20–30%. Children’s Oncology Group (COG) P9407 used shortened (46 weeks), intensified therapy to address early relapse and poor EFS. PROCEDURE P9407 therapy was modified three times for induction toxicity resulting in three cohorts of therapy. One hundred forty-seven infants were enrolled in the third cohort. RESULTS We report an overall 5-year EFS and OS of 42.3 ± 6% and 52.9 ± 6.5% respectively. Poor prognostic factors included age ≤ 90 days at diagnosis, MLL-R ALL and white cell count ≥50,000/ul. For infants ≤90 days of age, the 5-year EFS was 15.5±10.1% and 48.5±6.7% for those > 90 days (p<0.0001). Among infants >90 days of age, 5-year EFS rates were 43.8±8% for MLL-R vs. 69.1±13.6% for MLL-germline ALL (p<0.0001). CONCLUSIONS Age ≤ 90 days at diagnosis was the most important prognostic factor. Despite shortened therapy with early intensification, EFS remained less than 50% overall in MLL-R ALL.

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Rationale: Respiratory syncytial virus (RSV) causes significant morbidity and mortality in infants worldwide. Although T-helper type 2 (Th2) cell pathology is implicated in severe disease, the mechanisms underlying the development of immunopathology are incompletely understood.Objectives: We aimed to identify local immune responses associated with severe RSV in infants. Our hypothesis was that disease severity would correlate with enhanced Th2 cellular responses.Methods: Nasal aspirates were collected from infants hospitalized with severe (admitted to the pediatric ICU) or moderate (maintained in the general ward) RSV disease at 5 to 9 days after enrollment. The immune response was investigated by evaluating T-lymphocyte cellularity, cytokine concentration, and viral load.Measurements and Main Results: Patients with severe disease had increased proportions of CD8 (cluster of differentiation 8)positive T cells expressing IL-4 (Tc2) and reduced proportions of CD8 1 T cells expressing IFNg (Tc1). Nasal aspirates from patients with severe disease had reduced concentrations of IL-17. Patients with greater frequencies of Tc1, CD8 1 T cells expressing IL-17 (Tc17), and CD4 1 T cells expressing IL-17 (Th17) had shorter durations of hospitalization.Conclusions: Severe RSV disease was associated with distinct T-cell profiles. Tc1, Tc17, and Th17 were associated with shorter hospital stay and may play a protective role, whereas Tc2 cells may play a previously underappreciated role in pathology.

Purpose To assess the incidence of clinical allergy and end-Induction anti-asparaginase antibodies in children with high-risk acute lymphoblastic leukemia treated with pegylated E. coli asparaginase (PEG ASNase) and determine if they carry any prognostic significance. Patients and Methods Of 2057 eligible patients, 1155 patients were allocated to “augmented” arms where PEG ASNase replaced native ASNase post-Induction. Erwinia ASNase could replace native ASNase after allergy, if available. Allergy and survival data were complete for 990 patients. End-Induction antibody titers were available for 600 patients. Results During Consolidation, 29.2% (289/990 patients) had an allergic reaction. There were less allergic reactions to Erwinia ASNase than native ASNase (OR=4.33; p<0.0001) or PEG ASNase (OR=3.08; p<0.0001) during Interim Maintenance #1 only. There was no significant difference in 5-year EFS between patients who received PEG ASNase throughout the entire study post-Induction versus those who developed an allergic reaction to PEG ASNase during Consolidation and received Erwinia ASNase subsequently (80.8 ± 2.8% and 81.6 ± 3.8% (p=0.66), respectively). Patients with positive antibody titers post-Induction were more likely to have an allergic reaction to PEG ASNase (OR=2.4; p<0.001). Neither the 5-year EFS between patients with a negative versus positive antibody titer (80 ± 2.6% and 77.7 ± 4.3%, respectively, p=0.68) nor patients who did not receive any asparaginase post-Consolidation and patients who received PEG ASNase throughout the study (p=0.22) were significantly different. Conclusion We demonstrate differences in the incidence rates of toxicity between asparaginase preparations, but not in EFS. The presence of anti-asparaginase antibodies did not affect EFS.

BackgroundInfants (<366 days of age) with acute lymphoblastic leukemia (ALL) have a poor prognosis. Most treatment failures occur within 6–9 months of diagnosis, primarily from relapse.ProcedureThe Children's Oncology Group P9407 study was designed to test if early intensified treatment would improve outcome for infants with ALL. Due to a significant number of early deaths (< 90 days from enrollment), Induction therapy was amended three times. Cohorts 1 + 2 (n = 68), received identical Induction therapy except for reduced daunorubicin dose in Cohort 2. Cohort 3 (n = 141) received prednisone (40 mg/m2/day) instead of dexamethasone (10 mg/m2/day) and short infusion daunorubicin (30 minutes) instead of continuous infusion (48 hours), as well as additional supportive care measures throughout therapy.ResultsEarly deaths occurred in 17/68 (25%) infants in Cohorts 1 + 2 and 8/141 (5.7%) infants in Cohort 3 (P < 0.0001). Among infants ≤90 days of age at diagnosis, early death occurred in 10/17 (58.8%) in Cohorts 1 + 2 and 4/27 (14.8%) in Cohort 3 (P = 0.006). Among infants >90 days of age at diagnosis, early death occurred in 7/51 (13.7%) in Cohorts 1 + 2 and 4/114 (3.5%) in Cohort 3 (P = 0.036). Bacterial, viral, and fungal infections were more common in Cohorts 1 + 2 versus Cohort 3.ConclusionsEarly morbidity and mortality for infants with ALL were reduced by substitution of prednisone (40 mg/m2/day) for dexamethasone (10 mg/m2/day), the delivery of daunorubicin over 30 minutes instead of a continuous infusion for 48 hours, and the provision of more specific supportive care measures. Pediatr Blood Cancer 2012; 59: 834–839. © 2012 Wiley Periodicals, Inc.

Background Infants with acute lymphoblastic leukemia (ALL) have a poor prognosis. Intensification of therapy has resulted in fewer relapses but increased early deaths, resulting in failure to improve survival. Procedure AALL0631 is a Phase 3 study for infants (< 366 days of age) with newly diagnosed ALL. Induction initially (Cohort 1) consisted of 3 weeks of therapy based on COG P9407. Due to excessive early mortality, induction was amended to a less intensive 5 weeks of therapy based on Interfant-99. Additionally, enhanced supportive care guidelines were incorporated with hospitalization during induction until evidence of marrow recovery and recommendations for prevention/treatment of infections (Cohort 2). Results Induction mortality was significantly lower for patients in Cohort 2 (2/123, 1.6%) versus Cohort 1 (4/26, 15.4%; p=0.009). All induction deaths were infection related except one due to progressive disease (Cohort 2). Sterile site infections were lower for patients in Cohort 2 (24/123, 19.5%) versus Cohort 1 (15/26, 57.7%; p=0.0002), with a significantly lower rate of Gram positive infections during induction for patients in Cohort 2, p=0.0002. No clinically significant differences in grades 3–5 non-infectious toxicities were observed between the two cohorts. Higher complete response rates were observed at end induction intensification for Cohort 2 (week 9, 94/100, 94%) versus Cohort 1 (week 7, 17/25, 68%; p=0.0.0012). Conclusion De-intensification of induction therapy and enhanced supportive care guidelines significantly decreased induction mortality and sterile site infections, without decreasing complete remission rates.