Wheeze is an unreliable endpoint for bronchial methacholine challenges in preschool children

Background: Onset of wheeze is the endpoint often used in the determination of a positive bronchial challenge test (BCT) in young children who cannot perform spirometry. We sought to assess several clinical endpoints at the time of a positive BCT in young children with recurrent wheeze compared to findings in school-aged children with asthma. Methods: Positive BCT was defined in: (1) preschool children (n = 22) as either persistent cough, wheeze, fall in oxygen saturation (SpO2 ) of ≥5%, or ≥50% increase in respiratory rate (RR) from baseline; and (2) school-aged children (n = 22) as the concentration of methacholine (MCh) required to elicit a 20% decline in FEV1 (PC20 ). Results: All preschool children (mean age 3.4 years) had a positive BCT (median provocative MCh concentration 1.25 mg/ml [IQR, 0.62, 1.25]). Twenty (91%) school-aged children (mean age 11.3 years) had a positive BCT (median PC20 1.25 mg/ml [IQR, 0.55, 2.5]). At the time of the positive BCT, the mean fall in SpO2 (6.9% vs. 3.8%; p = .001) and the mean % increase in RR (61% vs. 22%; p < .001) were greater among preschool-aged than among school-aged children. A minority of children developed wheeze at time of positive BCT (23% preschool- vs. 15% school-aged children; p = .5). Conclusions: The use of wheeze as an endpoint for BCT in preschool children is unreliable, as it rarely occurs. The use of clinical endpoints, such as ≥25% increase in RR or fall in SpO2 of ≥3%, captured all of our positive BCT in preschool children, while minimizing undue respiratory distress

Use of fractional exhaled nitric oxide to guide the treatment of asthma an official american thoracic society clinical practice guideline

Background: The fractional exhaled nitric oxide (FENO) test is a point-of-care test that is used in the assessment of asthma.Objective: To provide evidence-based clinical guidance on whether FENO testing is indicated to optimize asthma treatment in patients with asthma in whom treatment is being considered.Methods: An international, multidisciplinary panel of experts was convened to form a consensus document regarding a single question relevant to the use of FENO. The question was selected from three potential questions based on the greatest perceived impact on clinical practice and the unmet need for evidencebased answers related to this question. The panel performed systematic reviews of published randomized controlled trials between 2004 and 2019 and followed the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) evidence-to-decision framework to develop recommendations. All panel members evaluated and approved the recommendations.Main Results: After considering the overall low quality of the evidence, the panel made a conditional recommendation for FENO-based care. In patients with asthma in whom treatment is being considered, we suggest that FENO is beneficial and should be used in addition to usual care. This judgment is based on a balance of effects that probably favors the intervention; the moderate costs and availability of resources, which probably favors the intervention; and the perceived acceptability and feasibility of the intervention in daily practice.Conclusions: Clinicians should consider this recommendation to measure FENO in patients with asthma in whom treatment is being considered based on current best available evidence. </p

Patterns of Growth and Decline in Lung Function in Persistent Childhood Asthma

BACKGROUND: Tracking longitudinal measurements of growth and decline in lung function in patients with persistent childhood asthma may reveal links between asthma and subsequent chronic airflow obstruction. METHODS: We classified children with asthma according to four characteristic patterns of lung-function growth and decline on the basis of graphs showing forced expiratory volume in 1 second (FEV1), representing spirometric measurements performed from childhood into adulthood. Risk factors associated with abnormal patterns were also examined. To define normal values, we used FEV1 values from participants in the National Health and Nutrition Examination Survey who did not have asthma. RESULTS: Of the 684 study participants, 170 (25%) had a normal pattern of lung-function growth without early decline, and 514 (75%) had abnormal patterns: 176 (26%) had reduced growth and an early decline, 160 (23%) had reduced growth only, and 178 (26%) had normal growth and an early decline. Lower baseline values for FEV1, smaller bronchodilator response, airway hyperresponsiveness at baseline, and male sex were associated with reduced growth (P<0.001 for all comparisons). At the last spirometric measurement (mean [±SD] age, 26.0±1.8 years), 73 participants (11%) met Global Initiative for Chronic Obstructive Lung Disease spirometric criteria for lung-function impairment that was consistent with chronic obstructive pulmonary disease (COPD); these participants were more likely to have a reduced pattern of growth than a normal pattern (18% vs. 3%, P<0.001). CONCLUSIONS: Childhood impairment of lung function and male sex were the most significant predictors of abnormal longitudinal patterns of lung-function growth and decline. Children with persistent asthma and reduced growth of lung function are at increased risk for fixed airflow obstruction and possibly COPD in early adulthood. (Funded by the Parker B. Francis Foundation and others; ClinicalTrials.gov number, NCT00000575.

Geography, generalisability, and susceptibility in clinical trials

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The Precision Interventions for Severe and/or Exacerbation-Prone (PrecISE) Asthma Network: an overview of Network organization, procedures and interventions

Asthma is a heterogeneous disease, with multiple underlying inflammatory pathways and structural airway abnormalities that impact disease persistence and severity. Recent progress has been made in developing targeted asthma therapeutics, especially for subjects with eosinophilic asthma. However, there is an unmet need for new approaches to treat patients with severe and exacerbation prone asthma, who contribute disproportionately to disease burden. Extensive deep phenotyping has revealed the heterogeneous nature of severe asthma and identified distinct disease subtypes. A current challenge in the field is to translate new and emerging knowledge about different pathobiologic mechanisms in asthma into patient-specific therapies, with the ultimate goal of modifying the natural history of disease. Here we describe the Precision Interventions for Severe and/or Exacerbation Prone Asthma (PrecISE) Network, a groundbreaking collaborative effort of asthma researchers and biostatisticians from around the U.S. The PrecISE Network was designed to conduct phase II/proof of concept clinical trials of precision interventions in the severe asthma population, and is supported by the National Heart Lung and Blood Institute of the National Institutes of Health. Using an innovative adaptive platform trial design, the Network will evaluate up to six interventions simultaneously in biomarker-defined subgroups of subjects. We review the development and organizational structure of the Network, and choice of interventions being studied. We hope that the PrecISE Network will enhance our understanding of asthma subtypes and accelerate the development of therapeutics for of severe asthma

Adherence rates during a randomized controlled trial evaluating the use of blinded acetaminophen and ibuprofen in children with asthma.

BACKGROUND / AIMS: When conducting clinical trials comparing over-the-counter (OTC) medications, the wide availability of these treatments are a potential challenge to maintaining study integrity. We seek to describe adherence to a study protocol involving widely available OTC medications. METHODS: To prospectively evaluate associations between acetaminophen use and asthma in 300 children aged 1–5 years, we conducted a double blind, randomized, controlled trial where parents administered blinded forms of either acetaminophen or ibuprofen as needed to their children over a 48 week period. Written and verbal instructions encouraged the exclusive use of the blinded study medication and discouraged OTC use. Adherence was determined by evaluating the frequency of use of per-protocol blinded study medication compared to off-protocol use of OTC medications. RESULTS: 4,195 doses of acetaminophen or ibuprofen were received by children during the study which included 3,664 doses (87.3%) of blinded study medication adhering to the protocol and 531 doses (12.7%) of OTC products deviating from the protocol with better adherence among those randomized to ibuprofen as compared to acetaminophen (89.5% vs. 85.5% of doses, p<0.01). Individually, 227 participants (75.7%) remained fully adherent by not receiving any OTC medications. Pre-study preference for either acetaminophen or ibuprofen by the participants’ families was not associated with differential rates of adherence to the blinded medication. CONCLUSION: This parallel study demonstrated greater than 85% of acetaminophen or ibuprofen doses were blinded study medications adhering to the protocol while less than 15% were OTC deviations from the protocol. This successfully implemented study design provides a template to comparatively evaluate these and other OTC medications