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X-linked myotubular myopathy (XL-MTM) is a rare life-threatening congenital myopathy caused by mutations in the MTM1 gene that encodes myotubularin, a ubiquitous enzyme required for normal development and function of skeletal muscle. The incidence of XLMTM in newborn males is 1:50,000. Recent evidence has revealed a previously unrecognized cholestatic tendency in patients with XL-MTM. EXCEL is a 48-week, prospective, observational, multicenter study to evaluate hepatobiliary health in patients with XLMTM. Approximately 50 male participants <18 years of age (up to half <5 years of age) with genetically confirmed XLMTM will be enrolled at 15–25 specialist sites in Canada, UK, and USA. The primary objective is to assess hepatobiliary health by estimating the incidence and prevalence of cholestatic complications in participants with XL-MTM. Secondary objectives are to evaluate the: (1) association between genetic variants of MTM1 and cholestasis; (2) association between environmental modifiers and cholestasis; and (3) healthcare utilization related to hepatobiliary and cholestatic complications. Participant assessments will be performed at the investigator's discretion based on standard of care at the site. A recommended schedule of assessments includes liver function tests (including serum bile acids), blood clotting parameters, creatinine, triglycerides and total cholesterol, and vitamin panel. Further clinical evaluation including liver ultrasound and Fibroscan will be used where appropriate. To reduce patient and caregiver burden, home healthcare services will collect laboratory tests when possible. Remote data collection may be used for healthcare resource utilization and patient medical history. Findings are expected to improve our understanding of cholestatic tendencies in participants with XL-MTM and provide critical information to improve the current management and treatment of XL-MTM, as well as future clinical trial designs. *Co-first authors. [ABSTRACT FROM AUTHOR]

Centronuclear myopathies (CNMs) are a group of rare inherited congenital myopathies for which there is currently no cure. The most common form is X-linked myotubular myopathy (XL-MTM) with an estimated incidence of 1 in 50,000 male births and a typically severe clinical phenotype. The international Myotubular and Centronuclear Myopathy Patient Registry collects demographic, genetic and clinical data for affected individuals (living and deceased) and female carriers of XL-MTM. In the past few years two clinical trials have taken place, ASPIRO & Unite-CNM, both of which were halted prematurely because of liver-related serious adverse events, ranging from reversible liver function abnormalities to fatal cholestatic liver failure. These events have led to an increasing awareness of liver-related pathology, including pre-existing liver dysfunction in XL-MTM and CNM which may predispose patients to treatment-related adverse events, as highlighted in a recent publication on the ASPIRO gene therapy trial for XL-MTM. Driven by two patient organisations (MTM-CNM Family Connection and Myotubular Trust UK), a group of international experts was assembled to create the 'Liver Collaborative' to better understand liver challenges experienced in the community from both a natural history perspective and in the context of emerging clinical trials. Working with the MTM & CNM Patient Registry, a liver health questionnaire was developed and implemented into the registry platform in April 2023, with 168 questionnaires completed. The Collaborative is responsive to emerging new research which is advancing the understanding of potential liver dysfunction in XLMTM and CNM. The liver health questionnaire will be updated to capture additional data on nutritional diet and patient liver testing results. Findings from the current and expanded questionnaire will be presented. The registry has been a key instrument for the longitudinal collection of this data. [ABSTRACT FROM AUTHOR]

Background: X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital disease, which is not well-defined. To our knowledge, no studies characterizing the XLMTM disease burden have been conducted in Brazil. We identified and described patients with suspected XLMTM using administrative claims data from the Brazilian public healthcare system., Methods: Data from 2015 to 2019 were extracted from the DATASUS database. As no XLMTM-specific ICD-10 code was available, a stepwise algorithm was applied to identify patients with suspected XLMTM by selecting male patients with a congenital myopathies code (G71.2), aged < 18 years at index date (first claim of G71.2), with an associated diagnostic procedure (muscle biopsy/genetic test) and without spinal muscular atrophy or Duchenne muscular dystrophy. We attempted to identify patients with suspected severe XLMTM based on use of both respiratory and feeding support, which are nearly universal in the care of XLMTM patients. Analyses were performed for the overall cohort and stratified by age at index date < 5 years old and ≥ 5 years old., Results: Of 173 patients with suspected XLMTM identified, 39% were < 5 years old at index date. Nearly all (N = 166) patients (96%) were diagnosed by muscle biopsy (91% of patients < 5 years old and 99% of patients ≥ 5 years old), six (3.5%) were diagnosed by clinical evaluation (8% of patients < 5 years old and 1% of patients ≥ 5 years old), and one was diagnosed by a genetic test. Most patients lived in Brasilia (n = 55), São Paulo (n = 33) and Minas Gerais (n = 27). More than 85% of patients < 5 years old and approximately 75% of patients ≥ 5 years old had physiotherapy at the index date. In both age groups, nearly 50% of patients required hospitalization at some point and 25% required mobility support. Respiratory and feeding support were required for 3% and 12% of patients, respectively, suggesting that between 5 and 21 patients may have had severe XLMTM., Conclusion: In this real-world study, genetic testing for XLMTM appears to be underutilized in Brazil and may contribute to underdiagnosis of the disease. Access to diagnosis and care is limited outside of specific regions with specialized clinics and hospitals. Substantial use of healthcare resources included hospitalization, physiotherapy, mobility support, and, to a lesser extent, feeding support and respiratory support., (© 2024. The Author(s).)

Background: X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital myopathy with multisystem involvement, often requiring invasive ventilator support, gastrostomy tube feeding, and wheelchair use. Understanding healthcare resource utilization in patients with XLMTM is important for development of targeted therapies but data are limited., Methods: We analyzed individual medical codes as governed by Healthcare Common Procedure Coding System, Current Procedural Terminology, and International Classification of Diseases, 10th Revision (ICD-10) for a defined cohort of XLMTM patients within a US medical claims database. Using third-party tokenization software, we defined a cohort of XLMTM patient tokens from a de-identified dataset in a research registry of diagnostically confirmed XLMTM patients and de-identified data from a genetic testing company. After approval of an ICD-10 diagnosis code for XLMTM (G71.220) in October 2020, we identified additional patients., Results: A total of 192 males with a diagnosis of XLMTM were included: 80 patient tokens and 112 patients with the new ICD-10 code. From 2016 to 2020, the annual number of patients with claims increased from 120 to 154 and the average number of claims per patient per year increased from 93 to 134. Of 146 patients coded with hospitalization claims, 80 patients (55%) were first hospitalized between 0 and 4 years of age. Across all patients, 31% were hospitalized 1-2 times, 32% 3-9 times, and 14% ≥ 10 times. Patients received care from multiple specialty practices: pulmonology (53%), pediatrics (47%), neurology (34%), and critical care medicine (31%). The most common conditions and procedures related to XLMTM were respiratory events (82%), ventilation management (82%), feeding difficulties (81%), feeding support (72%), gastrostomy (69%), and tracheostomy (64%). Nearly all patients with respiratory events had chronic respiratory claims (96%). The most frequent diagnostic codes were those investigating hepatobiliary abnormalities., Conclusions: This innovative medical claims analysis shows substantial healthcare resource use in XLMTM patients that increased over the last 5 years. Most patients required respiratory and feeding support and experienced multiple hospitalizations throughout childhood and beyond for those that survived. This pattern delineation will inform outcome assessments with the emergence of novel therapies and supportive care measures., (© 2023. The Author(s).)

Background: Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation. In clinical studies, dupilumab reduced the risk of severe asthma exacerbations, and improved forced expiratory volume in 1 s and quality of life in patients with uncontrolled moderate-to-severe asthma., Objectives: The objectives of RAPID (NCT04287621) are to characterize patients with asthma initiating dupilumab in routine clinical practice and to collect information on long-term effectiveness and safety in these patients., Methods: RAPID is a global, prospective, observational registry that will enroll approximately 1000 patients (aged ≥ 12 years) with asthma from 150 sites globally. Dupilumab treatment will be initiated in routine clinical practice according to country-specific prescribing information, per physician discretion as part of routine care. Patients will be followed prospectively for up to 3 years, with postbaseline assessments at months 1 and 3, and every 3 months thereafter., Planned Outcomes: Baseline data collected will include patient demographics, disease characteristics, and medication history. Patient adherence and persistence will be recorded alongside health-care resource utilization, and effectiveness of dupilumab will be assessed (clinician assessment) as per standard of care. Quality of life, asthma control, type 2 inflammatory comorbidities, work productivity, and physical activity limitation will be assessed. Incidence and severity of adverse events will be recorded., Conclusion: RAPID is the first global registry to characterize patients beginning dupilumab treatment for asthma in clinical practice and will expand on prior clinical studies by providing real-world data., Clinical Trial Registration: ClinicalTrials.gov identifier NCT04287621., (© 2023. The Author(s).)

Background: Effectiveness of asthma treatment, including biologics, may be different in patients with higher body mass index (BMI)., Objective: To evaluate response to omalizumab (dosed by serum immunoglobulin E level and weight) by BMI category., Methods: Pooled data from 2 randomized, double-blind, placebo-controlled studies of adults with moderate-to-severe allergic asthma were analyzed by BMI category (<25 kg/m 2 [normal or underweight], n = 397; 25 to <30 kg/m 2 [overweight], n = 330; ≥ 30 kg/m 2 [obese], n = 268). Placebo-adjusted exacerbation rate reductions were evaluated by Poisson regression modeling. Changes from baseline in forced expiratory volume in 1 second, beclomethasone dipropionate (BDP) dose, Total Asthma Symptom Score, and Asthma Quality of Life Questionnaire were evaluated by analysis of covariance., Results: Greater placebo-adjusted exacerbation rate reductions (95% confidence interval) were observed with increasing BMI (normal or underweight, -37.4% [-69.0% to 26.8%]; overweight, -52.7% [-78.4% to 3.7%]; obese, -71.9% [-86.9% to -39.5%]). There were no differences in forced expiratory volume in 1 second improvement between BMI categories at week 16 (normal or underweight, 76.2 [5.3-147.1] mL; overweight, 98.1 [13.9-182.4] mL; obese, 69.1 [-18.9 to 157.2] mL). No differences in BDP dose reduction (µg) were noted between BMI categories (normal or underweight, 23.0 [15.7-30.3]; overweight, 22.5 [13.5-31.5]; obese, 16.6 [5.8-27.3]). Fewer patients in the higher BMI categories eliminated BDP use. There were trends for smaller improvements with higher BMI in Total Asthma Symptom Score (normal/underweight, -0.52 [-0.82 to -0.22]; overweight, -0.50 [-0.80 to -0.20]; obese, -0.39 [-0.77 to 0.00]) and Asthma Quality of Life Questionnaire (normal or underweight, 0.34 [0.16-0.52]; overweight, 0.34 [0.13-0.55]; obese, 0.15 [-0.08 to 0.39])., Conclusion: Omalizumab provides benefit to patients with moderate-to-severe allergic asthma, regardless of BMI., Trial Registration: Studies 008/009 were conducted before clinical trial registration was required, and therefore clinical trial registration numbers are not available., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Although asthma is typically characterized by bronchodilator responsiveness (BDR), fixed airflow obstruction (FAO) occurs in ∼50% of patients with severe asthma., Objective: Do FAO/BDR associate with efficacy of omalizumab, a monoclonal antibody that targets IgE?, Methods: In EXTRA, patients aged 12-75 years with inadequately controlled severe allergic asthma despite high-dose inhaled corticosteroids plus long-acting β 2 -agonists were randomized to omalizumab (n = 427) or placebo (n = 423) for 48 weeks of treatment. In this post hoc analysis, high/low BDR were defined as ≥12%/<12% increases in baseline forced expiratory volume in 1 second (FEV 1 ) after bronchodilator administration, respectively. FAO presence (+)/absence (-) were defined as baseline postbronchodilator FEV 1 /forced vital capacity <70%/≥70%, respectively. Poisson regression/analysis of covariance models were used to estimate exacerbation relative rate reductions (RRRs)/least-squares mean changes in FEV 1 , respectively., Results: In patients with high BDR, omalizumab reduced exacerbations more than placebo over the 48-week treatment period regardless of FAO status (RRR [95% confidence interval (CI)]: FAO+, 59.8% [17.7-80.4%]; FAO-, 44.3% [16.6-62.8%]). Omalizumab improved FEV 1 compared with placebo in the FAO-, high BDR subgroup (FEV 1 change from baseline [95% CI] for omalizumab vs placebo, 0.065 L [-0.071 to 0.201 L] to 0.236 L [0.112-0.359 L]) across 48 weeks. This was not observed in patients with low BDR, irrespective of FAO., Conclusion: Omalizumab was more efficacious than placebo at reducing exacerbations in patients with high, but not low, BDR, regardless of the presence of FAO. Lung function improvement primarily occurred in FAO-, high BDR patients, suggesting that asthma with low BDR may represent a difficult-to-treat phenotype., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Rationale: Blood eosinophil counts are used to inform diagnosis/management of eosinophilic asthma. Objectives: Examine blood eosinophil variability and identify factors affecting eosinophil levels to inform clinical interpretation. Methods: Post hoc analysis to understand eosinophil variability using data from four randomized controlled asthma trials. We examined 1 ) influence of intrinsic/extrinsic factors (comorbidities, medication, and patient history) using baseline data ( n  = 2,612); 2 ) monthly variation using placebo-treated patient data ( n  = 713); 3 ) stability of eosinophil classification (<150, 150-299, and ⩾300 cells/μl) in placebo-treated patients with monthly measurements over a 1-year period ( n  = 751); and 4 ) impact of technical factors (laboratory-to-laboratory differences and time from collection to analysis). Results: Of intrinsic/extrinsic factors examined, nasal polyps increased eosinophil levels by 38%, whereas current smoking decreased levels by 23%. Substantial seasonal differences in eosinophil counts were observed, with differences of ∼20% between July and January. Eosinophil levels between 150 and 299 cells/μl were least stable, with 44% of patients remaining in the same classification for seven of 10 measurements versus 59% and 66% of patients in the <150 and ⩾300 cells/μl subgroups, respectively. Measurements at different laboratories showed high association (Spearman's correlation coefficient, R  = 0.89); however, eosinophil counts were reduced, with longer time from collection to analysis, and variability increased with increasing eosinophil counts. Conclusions: Several intrinsic, extrinsic, and technical factors may influence, and should be considered in, clinical interpretation of eosinophil counts. Additionally, a single measurement may not be sufficient when using eosinophil counts for diagnosis/management of eosinophilic asthma.

Background: Peanut allergy (PA), a common food allergy, is increasing in prevalence and is associated with high rates of anaphylaxis. Prevalence of food-related anaphylaxis is higher in children and adolescents than in adults, and the pediatric incidence is increasing. We conducted a systematic literature review and meta-analysis to determine the incidence of peanut-induced anaphylaxis in children and/or adolescents with PA., Methods: Literature searches were conducted using the PubMed database and through supplemental methods. Eligible articles for inclusion were peer-reviewed studies published in English that reported the incidence of anaphylaxis in pediatric PA using the 2006 National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network criteria, sample size, and follow-up duration. Incidence rates were calculated as person-years at risk or a crude incidence rate was calculated. Meta-analyses of pooled data were conducted using the I 2 statistic as the measure of heterogeneity., Results: A total of 830 citations were screened; 8 met the study inclusion criteria and were selected for review. Pooled meta-analysis estimates of the incidence of (1) anaphylaxis among children/adolescents with food allergies, (2) anaphylaxis among children/adolescents with PA, and (3) accidental exposure to peanuts among children/adolescents with PA were 3.72 cases per 100 person-years (95% confidence interval [CI] = 2.35, 5.10), 2.74 cases per 100 person-years (95% CI = 1.42, 4.05), and 12.28 cases per 100 person-years (95% CI = 11.51, 13.05), respectively., Conclusions: The risks of anaphylaxis among children with food allergies and those with PA contribute to the serious overall burden of PA and food allergy for children and their families., (© 2021 The Authors. Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.)

Background: Comorbidities are common in asthma and may complicate treatment response., Objective: To examine response to omalizumab in patients with moderate-to-severe allergic asthma by asthma-related and allergic comorbidities., Methods: Patients aged 12 years or more from placebo-controlled 008/009 (n = 1071), EXTRA (n = 848), and INNOVATE (n = 419), and single-armed PROSPERO (n = 801) omalizumab studies were included. Poisson regression/analysis of covariance models were used to estimate adjusted exacerbation rates and forced expiratory volume in 1 second (FEV1) change from baseline after omalizumab initiation for subgroups by number of comorbidities (0, 1 [008/009]; 0, 1, ≥2 [EXTRA and INNOVATE]; 0, 1, 2, ≥3 [PROSPERO]). Self-reported comorbidities included allergic rhinoconjunctivitis, chronic rhinosinusitis, recurrent acute sinusitis, nasal polyps, atopic and contact dermatitis, urticaria, food allergy, anaphylaxis, other allergies, gastroesophageal reflux disease, eosinophilic esophagitis, and eosinophilic granulomatosis with polyangiitis., Results: In the EXTRA and INNOVATE studies, no consistent pattern was observed for placebo-corrected relative rate reduction in normalized asthma exacerbations among omalizumab-treated comorbidity subgroups. In PROSPERO, on-study exacerbation rates in the comorbidity subgroups were similar (0, 0.68; 1, 0.70; 2, 0.77; ≥3, 0.80). FEV1 improvements were observed throughout the study for omalizumab vs placebo for all comorbidity subgroups. There were no consistent differences in FEV1 improvements among comorbidity subgroups in 008/009, EXTRA, or INNOVATE. Similarly, no among-group differences were observed for FEV1 change from baseline at month 12 in PROSPERO (0, 0.05 L; 1, 0.08 L; 2, 0.00 L; ≥3, 0.04 L). The 95% confidence intervals overlapped substantially in all instances., Conclusion: In these analyses of placebo-controlled/single-armed studies, on-study exacerbation rates and FEV1 improvements with omalizumab treatment were similar irrespective of comorbidity burden., Trial Registration: ClinicalTrials.gov identifiers are as follows: EXTRA, NCT00314574 (https://clinicaltrials.gov/ct2/show/NCT00314574); INNOVATE, NCT00046748 (https://clinicaltrials.gov/ct2/show/NCT00046748); and PROSPERO, NCT01922037 (https://clinicaltrials.gov/ct2/show/NCT01922037)., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Peanut allergy (PA) currently affects approximately 2% of the general population of Western nations and may be increasing in prevalence. Patients with PA and their families/caregivers bear a considerable burden of self-management to avoid accidental peanut exposure and to administer emergency medication (adrenaline) if needed. Compared with other food allergies, PA is associated with higher rates of accidental exposure, severe reactions and potentially fatal anaphylaxis. Approximately 7%-14% of patients with PA experience accidental peanut exposure annually, and one-third to one-half may experience anaphylaxis, although fatalities are rare. These risks impose considerably high healthcare utilization and economic costs for patients with PA and restrictions on daily activities. Measures to accommodate patients with PA are often inadequate, with inconsistent standards for food labelling and inadequate safety policies in public establishments such as restaurants and schools. Children with PA are often bullied, resulting in sadness, humiliation and anxiety. These factors cumulatively contribute to significantly reduced health-related quality of life for patients with PA and families/caregivers. Such factors also provide essential context for risk/benefit assessments of new PA therapies. This narrative review comprehensively assessed the various factors comprising the burden of PA., (© 2020 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Peanut allergy is the most common food allergy among children. Studies assessing the burden of peanut allergy in a real-world setting are limited., Objective: To estimate annual incidence and prevalence of peanut allergy cases among children aged 4 to 17 years and assess severe reaction and associated health care utilization rates., Methods: Patient longitudinal data between January 2011 and December 2017 from a geographically and payer-type representative US health care claims database were used. Peanut allergy cases were identified using diagnostic codes and/or services indicating peanut-allergy-associated severe reactions/anaphylaxis. Estimated annual incidence was defined as peanut-allergic births as a proportion of all 1-year-olds and adjusted for less than 100% data set capture, undercoding, patient underpresenting rates, and spontaneous outgrowth. Prevalence was calculated on the basis of incidence. To assess rates of severe reactions to peanut and associated health care utilization, the cohort of 720,490 peanut allergy cases identified in 2011 was evaluated over a 6-year period from 2011 to 2017., Results: Annual incidence increased from 1.7% to 5.2% between 2001 and 2017. Estimated prevalence in 4- to 17-year-olds was 1.25 million (2.2%) in 2017. Atopic comorbidities (asthma, 60.8%; atopic dermatitis, 61.7%) and other food allergies (35.3%) were common. Severe reactions (≥1) were observed in more than half (n = 399,806) the patients, and 37.9% were triggered by an accidental exposure. One in 5 patients (n = 144,883) visited the emergency department due to peanut exposure., Conclusions: Claims data suggest that the incidence and prevalence of peanut allergy in the United States may be increasing. Estimated severe reaction rates and health care utilization were high, suggesting that the burden of peanut allergy may be considerable., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Frequent exacerbations are associated with greater FEV 1 decline in patients with asthma. The effect of omalizumab versus placebo on lung function in patients experiencing asthma exacerbations has not been previously examined., Objective: To evaluate the relationship between postbaseline (treatment phase) exacerbation status and lung function decline in children, adolescents, and adults treated with omalizumab versus placebo using data from 3 pediatric and adolescent/adult studies., Methods: Changes in percent predicted FEV 1 (ppFEV 1 ) and FEV 1 by treatment (omalizumab/placebo) and postbaseline exacerbation status (exacerbators/nonexacerbators) were assessed in patients aged 6 to 11 years (IA05, n = 576) and 12 to 75 years (EXTRA/INNOVATE pooled, n = 1202). Pediatric patients were examined at treatment weeks 12, 24, 28, 40, and 52, and adolescent/adult data at weeks 4, 12, 20, and 28., Results: Omalizumab-treated patients experienced larger increases in ppFEV 1 and FEV 1 compared with placebo-treated patients in the pediatric and pooled adolescent/adult populations. The response was observed in pediatric exacerbators, with significantly larger increases in ppFEV 1 and FEV 1 at week 12 (mean difference [95% CI], 4.11% [0.93%-7.30%], P = .011 for ppFEV 1 ; 80 [10-140] mL, P = .017 for FEV 1 ) and week 28 (mean difference [95% CI], 3.65% [0.11%-7.19%], P = .043 for ppFEV 1 ; 100 [30-170] mL, P = .007 for FEV 1 ). In the adolescent/adult population, both exacerbators and nonexacerbators derived similar benefit with omalizumab compared with placebo., Conclusions: Findings from this post hoc analysis suggest that omalizumab may confer some protection against lung function decline among patients who experienced exacerbations during treatment., (Copyright © 2020. Published by Elsevier Inc.)

Background: Greater severity in childhood asthma negatively impacts functioning and quality of life. Omalizumab is effective in children aged 6 years or older with moderate to severe persistent asthma, but predicting responsiveness in severe disease requires further study., Objective: To assess response to omalizumab treatment among children using indicators of asthma severity., Methods: Post hoc analyses of randomized placebo-controlled studies of omalizumab (Inner-City Anti-IgE Therapy for Asthma [ICATA], IA05, and Preventative Omalizumab or Step-up Therapy for Fall Exacerbations [PROSE]) stratified by body mass index, eosinophil count, fractional exhaled nitric oxide levels, and baseline severity indicators (baseline percent predicted FEV 1 , previous hospitalizations, asthma exacerbations). Poisson regression analysis examined exacerbation rate reductions for body mass index, biomarkers, and severity indicators., Results: Children aged 6 to 11 years in IA05 (N = 576; 56% white, 17% black, 26% other/missing), ICATA (N = 237; 55% black, 43% Hispanic), and PROSE (N = 342; 59% black, 35% Hispanic) were included. Trends indicative of greater exacerbation rate change ([omalizumab - placebo]/placebo) were observed for low baseline lung function (IA05 percent predicted FEV 1 : <90%, 36% reduction, 95% CI, -53.3 to -13.5; ≥90%, 22% reduction, 95% CI, -52.1 to 27.5), previous hospitalizations (ICATA: 46% reduction with, 95% CI, -69.7 to -3.9; 24% reduction without, 95% CI, -48.1 to 10.3), frequent baseline exacerbations (IA05: ≥3, 42% reduction, 95% CI, -60.4 to -14.1; <3, 20% reduction, 95% CI, -45.2 to -15.9), and high baseline eosinophil count (IA05: ≥300 cells/μL, 39% reduction, 95% CI, -56.4 to -14.7; <300 cells/μL, 5% reduction, 95% CI, -40.6 to 52.1)., Conclusions: Omalizumab reduces exacerbations in children with moderate to severe persistent allergic asthma, and may provide greater benefit in children with more severe asthma subtypes., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Severe/difficult-to-treat disease occurs in 5% to 10% of patients with asthma, but accounts for more than 50% of related economic costs. Understanding factors associated with persistent very poorly controlled (VPC) asthma may improve outcomes., Objective: To characterize persistent VPC asthma after more than 10 years of standard of care., Methods: The Epidemiology and Natural history of asthma: Outcomes and treatment Regimens (TENOR) II (N = 341) was a multicenter, observational study of patients with severe/difficult-to-treat asthma with a single, cross-sectional visit more than 10 years after TENOR I. Persistent VPC asthma was defined as VPC asthma at TENOR I and TENOR II enrollment; without VPC asthma was defined as well- or not well-controlled asthma at either or both visits. Multivariable logistic regression assessed long-term predictors of persistent VPC asthma using TENOR I baseline variables., Results: Of 327 patients, nearly half (48.0%, n = 157) had persistent VPC asthma. Comorbidities and asthma triggers were more frequent in patients with persistent VPC asthma than in patients without VPC asthma. Total geometric mean IgE was higher in patients with persistent VPC asthma (89.3 IU/mL vs 55.7 IU/mL); there was no difference in eosinophil levels. Lung function was lower in patients with persistent VPC asthma (mean % predicted pre- and postbronchodilator FEV 1 , 63.0% vs 82.8% and 69.6% vs 87.2%, respectively). Exacerbations in the previous year were more likely in patients with persistent VPC asthma (29.7% vs 9.0%, respectively). Predictors of persistent VPC asthma were black versus white race/ethnicity, allergic trigger count (4 vs 0), systemic corticosteroid use, and postbronchodilator FEV 1 (per 10% decrease)., Conclusions: The burden of persistent VPC asthma is high in severe/difficult-to-treat disease; management of modifiable risk factors, maximization of lung function, and trigger avoidance may improve outcomes., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Individuals with X-linked myotubular myopathy (XLMTM) who survive infancy require extensive supportive care, including ventilator assistance, wheelchairs and feeding tubes. Half die before 18 months of age. We explored respiratory support and associated mortality risk in RECENSUS, particularly among patients ≤5 years old who received respiratory support at birth; this subgroup closely matches patients in the ASPIRO trial of gene therapy for XLMTM., Design: RECENSUS is an international, retrospective study of patients with XLMTM. Descriptive and time-to-event analyses examined survival on the basis of age, respiratory support, tracheostomy use, predicted mutational effects and life-sustaining care., Results: Outcomes for 145 patients were evaluated. Among 126 patients with respiratory support at birth, mortality was 47% overall and 59% among those ≤5 years old. Median survival time was shorter for patients ≤5 years old than for those >5 years old (2.2 years (IQR 0.7-5.6) vs 30.2 years (IQR 19.4-30.2)). The most common cause of death was respiratory failure (66.7%). Median survival time was longer for patients with a tracheostomy than for those without (22.8 years (IQR 8.7-30.2) vs 1.8 years (IQR 0.2-not estimable)). The proportion of patients living without a tracheostomy was 50% at age 6 months and 28% at age 2 years. Median survival time was longer with provision of life-sustaining care than without (19.4 years (IQR 3.1-not estimable) vs 0.2 years (IQR 0.1-2.1))., Conclusions: High mortality, principally due to respiratory failure, among patients with XLMTM ≤5 years old despite respiratory support underscores the need for early diagnosis, informed decision-making and disease-modifying therapies., Trial Registration Number: NCT02231697., Competing Interests: Competing interests: RJG, IH, MLY, NLK and SWY report no conflicts of interest with respect to this study. RJG is an unpaid member of Audentes Therapeutics Board of Scientific and Clinical Advisors. RA is a volunteer for Cure CMD and has no financial interest in Audentes or related to this study. LBL received financial compensation for medical writing, and TH is a consultant to Audentes Therapeutics. ESJ, MN, SR and SP are employees and shareholders of Audentes Therapeutics. AHB is a member of the Audentes Therapeutics Board of Scientific and Clinical Advisors and has received support from a sponsored research agreement with Audentes Therapeutics to cover running costs for this study., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Omalizumab improves clinical outcomes in patients with asthma. Several studies have shown lung function improvements with omalizumab; however, this has not been examined exclusively in adolescents., Objective: To assess the effect of omalizumab on lung function and eosinophil counts in adolescents with uncontrolled moderate-to-severe allergic asthma., Methods: In this post hoc analysis, data from adolescents aged 12 to 17 years from 8 randomized trials of omalizumab were pooled (studies 008, 009, and 011, and SOLAR, INNOVATE, ALTO, ETOPA, and EXTRA). Changes from baseline to end of study in forced expiratory volume in 1 second (FEV 1 ), percent predicted FEV 1 (ppFEV 1 ), forced vital capacity (FVC), and blood eosinophil counts were assessed by fitting an analysis of covariance model and calculating least squares mean (LSM) difference for omalizumab vs placebo., Results: A total of 340 adolescents were identified (omalizumab, n = 203 [59.7%]; placebo, n = 137 [40.3%]). Omalizumab increased all baseline lung function variables more than placebo by end of study: LSM treatment differences (95% confidence interval) were 3.0% (0.2%-5.7%; P = .035), 120.9 mL (30.6-211.2 mL; P = .009), and 101.5 mL (8.3-194.6 mL; P = .033) for ppFEV 1 , absolute FEV 1 , and FVC, respectively. The LSM difference demonstrated a greater reduction in eosinophil counts for omalizumab vs placebo: -85.9 cells/μL (-137.1 to -34.6 cells/μL; P = .001)., Conclusion: Omalizumab was associated with lung function improvements and circulating eosinophil counts reductions in adolescents with moderate-to-severe uncontrolled asthma. Findings emphasize the effect of omalizumab in young patients and the need to optimize treatment early in the disease course. https://clinicaltrials.gov/: NCT00314574, NCT00046748, NCT00401596., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Currently, there is no Food and Drug Administration-approved therapy for food allergy. Several new potential treatments are under investigation, including food allergen immunotherapy via various routes of administration, such as oral immunotherapy, epicutaneous immunotherapy, subcutaneous immunotherapy, and sublingual immunotherapy. The double-blind, placebo-controlled food challenge (DBPCFC) has traditionally been used for diagnostic purposes, but extrapolation of the specific terminology used in food allergy diagnosis to interpretation of efficacy in clinical trials is incongruent and difficult to apply. There is a need for standardization of the terminology used in food allergy clinical trials, because inconsistencies can lead to potential misinterpretation of end points. The reactive dose, previously referred to as the eliciting dose, is defined as the dose given that induces the onset of unequivocal allergic symptoms, or the dose that stops the challenge based on physician discretion. Conversely, the single highest tolerated dose is defined as the highest dose given during a food challenge that elicits either no symptoms or symptoms that do not meet stopping criteria per the study protocol. The evolving field of food allergy provides a novel opportunity to define those end points that are most meaningful for patients, which is fundamental for successful implementation, education, and safety., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: There are limited data that examine differences in asthma etiology between black and white children with severe or difficult-to-treat asthma., Objective: To describe demographic, clinical, and asthma-related outcomes in black and white children and examine whether differences in outcomes are explained by confounding factors in sequential multivariable models., Methods: Black (n = 86) and white (n = 262) children aged 6-11 years from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens 3-year observational study were analyzed. Baseline demographics and clinical characteristics were described for both cohorts, and outcomes at month 12 were analyzed using statistical models, sequentially adjusting for potential confounders., Results: Black children were more likely to be male (79.1% vs 66.4%; P < .05), obese (12.8% vs 1.5%; P < .001), and from a lower income stratum (USD43,400 vs 55,770; P < .001) than white children. Black children had higher geometric mean IgE levels (434.8 vs 136.8 IU/mL; P < .001), were more likely to have very poorly controlled asthma (72.1% vs 53.4%), use long-term systemic corticosteroids (30.2% vs 9.2%; P < .001), have poorer quality of life (5.5 vs 6.1; P < .001), and have an emergency department visit (27.4% vs 7.7%, P < .001) in the 3 months before month 12. Differences in asthma control and the severity of exacerbations persisted even after accounting for all confounding factors., Conclusions: Among children with severe or difficult-to-treat asthma, asthma burden is greater in black than white children particularly related to several clinical and patient-reported outcome measures that are not explained by differences in background or clinical characteristics., (Copyright © 2018. Published by Elsevier Inc.)

Pirfenidone and nintedanib are oral antifibrotic agents approved for the treatment of idiopathic pulmonary fibrosis (IPF). Real-world data on factors that influence IPF treatment decisions are limited. Physician characteristics associated with antifibrotic therapy initiation following an IPF diagnosis were examined in a sample of US pulmonologists. An online, self-administered survey was fielded to pulmonologists between April 10, 2017, and May 17, 2017. Pulmonologists were included if they spent >20% of their time in direct patient care and had ≥5 patients with IPF receiving antifibrotics. Participants answered questions regarding timing and reasons for considering the initiation of antifibrotic therapy after an IPF diagnosis. A total of 169 pulmonologists participated. The majority (81.7%) considered initiating antifibrotic therapy immediately after IPF diagnosis all or most of the time (immediate group), while 18.3% considered it only some of the time or not at all (delayed group). Pulmonologists in the immediate group were more likely to work in private practice (26.1%), have a greater mean percentage of patients receiving antifibrotic therapy (60.8%), and decide to initiate treatment themselves (31.2%) versus those in the delayed group (16.1%, 30.5%, and 16.1%, respectively). Most pulmonologists consider initiating antifibrotic treatment immediately after establishing an IPF diagnosis all or most of the time versus using a "watch-and-wait" approach. Distinguishing characteristics between pulmonologists in the immediate group versus the delayed group included practice setting, percentage of patients receiving antifibrotic therapy, and the decision-making dynamics between the patient and the pulmonologist.

Objective: To evaluate the long-term safety of rituximab in an observational cohort of patients with rheumatoid arthritis (RA) who had an inadequate response to ≥ 1 antitumor necrosis factor therapies in the United States (SUNSTONE Registry)., Methods: In this prospective, observational cohort study, patients received rituximab according to their physician's standard practice and were evaluated at standard-of-care follow-up visits at least every 6 months. The primary outcome was the incidence of protocol-defined significant infections. Secondary outcomes included serious adverse events potentially associated with rituximab, cardiovascular or thrombotic (CVT) events, seizures, deaths and pregnancies. Posthoc analyses assessed outcomes by concomitant medication use., Results: Overall, 989 patients (safety-evaluable population) received ≥ 1 dose of rituximab, with a total follow-up of 3844 patient-years (PYs; mean duration, 3.9 years). In total, 341 significant infections occurred in 197 patients (19.9%). The incidence rates (95% CI) for significant infections, CVT events, and seizures were 8.87 (7.98, 9.86), 1.95 (1.56, 2.45), and 0.18 (0.09, 0.38) per 100 PYs, respectively. The incidence of significant infections did not increase with time or with cumulative rituximab exposure. During the study, 64 patients died (crude mortality [95% CI]: 1.66 per 100 PYs [1.30, 2.13]). The most common causes of death were infections (19 patients), malignancy (14), and cardiovascular events (13). Eight pregnancies were reported in 7 patients., Conclusion: In patients with RA treated with rituximab for up to 5 years, the rates of significant infections were stable over time and higher in patients who received long-term systemic steroid treatment. This article is protected by copyright. All rights reserved., (This article is protected by copyright. All rights reserved.)