OBJECTIVE:To assess guideline-concordant management of children with moderate to severe asthma exacerbations in general emergency departments (EDs) and whether pediatric readiness is associated with receipt of guideline-concordant care. METHODS:Retrospective cohort study of children 4-18 years treated at a general ED for asthma exacerbations and transferred and admitted to a pediatric tertiary care hospital health system. Children with complex medical conditions and those discharged from the pediatric tertiary hospital ED after transfer were excluded. General ED weighted Pediatric Readiness Scores (wPRS, range 0-100) obtained from the Colorado Emergency Medical Services for Children 2020 National Pediatric Readiness Project (NPRP) assessment were categorized by quartiles or deemed as no score if wPRS was unavailable (i.e. hospitals that had not completed the NPRP assessment or transfers from general EDs outside of Colorado). The primary outcome was receipt of asthma care in accordance with international guidelines defined as receipt of systemic corticosteroids and inhaled albuterol and ipratropium bromide. Secondary outcomes included clinical outcomes at the pediatric tertiary hospital (i.e. intensive care unit (ICU) admission, hospital length of stay). Multivariable logistic regression tested the association between wPRS and receipt of guideline-concordant asthma care, adjusting for demographics. RESULTS:There were 319 general ED visits from 87 EDs across 4 states for asthma exacerbations requiring admission to the pediatric health system; wPRS was available for 193 visits. Guideline-concordant asthma care was provided in 74% (235/319) of general ED visits. Children who were older, had lower oxygen saturation, and documented wheeze or prolonged expiratory phase were more likely to receive guideline-concordant care. There was no association between general ED wPRS and receipt of guideline-concordant care among the 193 visits with PRS data. Patients receiving guideline-concordant care had higher rates of ICU admission and longer hospital lengths of stay. CONCLUSION:In this cohort, 1 in 4 children did not receive guideline-concordant asthma exacerbation care at general EDs. Pediatric readiness was not associated with receipt of guideline-concordant care highlighting that preparedness to deliver disease-specific management for common pediatric emergencies, such as asthma, may represent an important yet insufficiently captured component of pediatric readiness.

Rationale: Recovery after pediatric emergency department (ED) treatment for acute asthma exacerbations is poorly understood. Oscillometry is a safe and effort-independent method to measure respiratory system resistance and compliance in both the ED and outpatient follow-up settings to objectively evaluate lung function recovery. The objective of this pilot study was to evaluate participant-reported symptoms and oscillometry during acute exacerbations in the ED and 7 days post-visit. Methods: Prospective study of children aged 2-18 years treated for acute asthma exacerbations in the ED. Participants completed a 17-item asthma flare-up symptom diary scored on a 1-7 scale (7=worst) in the ED and at a follow-up visit 7 days later; a change in average score ±0.55 has been deemed clinically relevant in prior literature. The Tremoflo c-100 was used to obtain oscillometry measurements at 7-41Hz after asthma treatments during the ED visit, and again at the follow-up visit. Resistance at 7Hz (R7) and area of reactance (AX) were transformed to z-scores using height-based reference equations. Descriptive statistics are reported as median (IQR). Results: Of 20 participants enrolled, median age was 7.71 (5.5, 12.2) years, 75% were male, 25% were Black/African American, 70% were publicly insured, and 45% had an asthma controller prescription. There was a clinically relevant improvement in symptom scores for all participants: the median difference between the ED visit and day 7 follow-up visit was -2.12 (-2.71, -1.02). There were 14 participants with successful oscillometry at both timepoints. The figure shows R7 and AX measured in the ED and at day 7, stratified by children with improvement (decreases) in both R7 and AX (n=6) and children without improvement (increases) in R7 and/or AX (n=8) between the visits. Among those with lung function improvement, R7 z-score decreased by -1.11 (-1.87, -0.52) and AX z-score decreased by -1.52 (-2.74, -0.57). Among those without improvement, R7 z-score increased by 0.80 (0.51, 1.45) and AX z-score increased by 0.06 (-0.03, 0.78). Conclusions: This pilot study shows variability in lung function after ED treatment for acute asthma exacerbations and in the subsequent recovery period. Oscillometry may be an important tool to objectively assess exacerbation resolution and recovery. Future studies are needed to determine associations between oscillometry measurements and clinical asthma outcomes.

OBJECTIVES:There are 750,000 emergency department (ED) visits by children for asthma exacerbations in the United States annually. Despite changing evidence and epidemiology, there have not been recent assessments of acute asthma prevalence, management, and outcomes from pediatric EDs. This 40-center retrospective evaluation utilizes the Pediatric Hospital Information System to characterize pediatric ED asthma presentations from 2015-2020. STUDY DESIGN:Children 2-18 years with asthma ICD-9/10 code and receipt of albuterol were included. Demographics, Child Opportunity Index (COI), ED management, return visits, and adjusted costs were evaluated. Data were summarized using standard descriptive statistics and trends assessed using Mann-Kendall trend test. RESULTS:There were 414,264 encounters made by 256,209 unique patients; 21% had >1 visit in 12 months. Median age was 6 years, 61.6% male, 44.5% Black, and 68.5% publicly insured; 58.3% of visits were by patients with very low/low COI. Systemic corticosteroids were administered in 86.3% of visits; 52.7% used dexamethasone. Chest radiographs were obtained in 23% of encounters. Most (74.9%) encounters resulted in ED discharge with a downward trend of visits for exacerbations per 1,000 ED visits of -9.77, 95% CI [-9.99,-9.54], increase in disposition to intensive care unit of 2.01 [1.87,2.41] and decrease in home/other of -3.77 [-4.34,-3.20]. There was no significant trend in return visits. Total adjusted costs were ∼$900 million. CONCLUSIONS:ED visits for asthma remain frequent and disproportionately affect children with lower social determinants of health. Dexamethasone has not been widely adopted as corticosteroid of choice and use of ancillary testing continues, highlighting opportunities for improvement in asthma care.

RATIONALE: Viral infections are common in early childhood, with most children either being asymptomatic or having only upper respiratory symptoms. However, some children develop lower respiratory symptoms, including wheezing, which can result in hospitalization. A subset of these children have repeated wheezing episodes, leading to a higher risk of asthma later in childhood. Wheezing illnesses are precipitated by host-virus interactions that remain poorly understood. This study investigates the viral and molecular factors differentiating viral wheezing illnesses from non-wheezing viral infections in young children with a history of with recurrent wheeze. METHODS: Children aged 18-36 months with public insurance or from high-poverty census tracts and ≥3 wheezing episodes were enrolled in the WINDOWS study during an acute wheezing illness at the emergency department (ED) or at a non-illness clinic visit. Nasal swabs were collected for RNA-sequencing, with data processed through a viral metagenomic pipeline. Viral infection rates were compared between wheezing illnesses and non-illness clinic visits. RNA-seq data was analyzed using co-expression network analysis, and gene network responses to viral infections during wheezing illnesses were compared to clinic detected, non-wheezing viral infections. RESULTS: 93.4% of children with wheezing illnesses (n=91) carried a virus compared to 39.2% without illness (n=102, OR: 26.2, p<0.001). Overall viral load was 3.3-fold higher in wheezing illness (p=0.06). HRV-C infections were more common in wheezing illnesses (57.6% vs. 42.5%, p=0.05), and HRV-A was more common without wheezing illness (16.5% vs. 32.5%, p=0.02). Eighteen of 21 networks were differentially expressed in either or both of the virus+ groups when compared to children without viral infection (Figure 1). Interferon signaling and neutrophilic/monocyte immune-response networks were similarly upregulated in both virus+ groups. In contrast, B-cell and CD8+ T-cell networks were strongly induced with virus+ non-illness group but weakly induced with virus+ wheezing illness group. The squamous/mucus secretory and T2 mast cell networks were specifically upregulated in virus+ wheezing illnesses, whereas ciliated cell networks were downregulated more strongly in this group. Notably, epithelial T2 and a mucus secretory network were downregulated in the virus+ non-illness group, but not with virus+ wheezing illness. CONCLUSIONS: Wheezing illnesses in young children are associated with HRV-C infections and higher viral loads. These viral illnesses cause normal adaptive immune responses to infection to be suppressed, but fail to suppress epithelial T2 inflammation and mucus production, resulting in squamous and mucus metaplasia. Our data suggest aberrant host airway responses to viral infection underlie wheezing illness development.

Rationale: Oscillometry is a feasible and safe method to measure pulmonary function in children with asthma exacerbations in the emergency department (ED), but its utility to measure respiratory impedance as an objective marker of response to initial acute asthma treatments is unknown. Objectives: We sought to determine the associations between respiratory impedance-derived metrics and asthma exacerbation severity and treatment response in the pediatric ED. Methods: We conducted a prospective study of children, ages 4-18 years, who presented to a tertiary-care pediatric ED for asthma exacerbations. Respiratory system impedance was measured with oscillometry before and after initial treatment with inhaled bronchodilators and systemic corticosteroids. Regression models estimated the associations between respiratory impedance-derived metrics (low-frequency resistance, R7, a measure of total airway obstruction; frequency dependence of resistance, R7-19, a measure of peripheral airway resistance; and reactance area, AX, a measure of lung tissue stiffness and variability in ventilation), vital signs, and clinical outcomes. Receiver operating characteristic analyses were used to quantify the ability of respiratory impedance-derived metrics and vital signs to discriminate outcomes. Results: Of 177 participants, 144 (81%) completed a valid initial oscillometry assessment. Forty-seven percent had moderate or severe exacerbations, and 61% met the treatment response definition. Frequency dependence of resistance (R7-19: adjusted odds ratio [aOR], 1.39; 95% confidence interval [CI] = 1.08-1.83) and area of reactance (AX: aOR, 1.28; 95% CI = 1.05-1.58), were associated with higher odds of moderate or severe exacerbation. Greater initial R7-19 was associated with decreased odds of treatment response (aOR, 0.75; 95% CI = 0.57-0.98). A combination of impedance-derived metrics and vital signs best differentiated exacerbation severity (area under the curve [AUC] = 0.73), treatment response (AUC = 0.69), and hospitalization (AUC = 0.78). Conclusions: Respiratory impedance-derived metrics (R7, R7-19, and AX), in combination with vital signs, can guide ED clinical decisions and improve outcomes for children with asthma exacerbations.

Rationale: Environmental exposures may play an important role in recurrent wheeze progression to persistent asthma in the early-childhood period. WINDOWS is a longitudinal cohort study of toddlers with a history of ≥3 wheezing episodes aimed at differentiating molecular, clinical, and environmental features in asthma development. The objective of this cross-sectional sub-study is to define home environment risk factors and determine their associations with type 2 inflammation (T2) biomarkers. Methods: WINDOWS participants were recruited from the Denver region and aged 18-36 months at time of enrollment. In addition to history of recurrent wheeze, inclusion required public insurance or home address in high-poverty census tracts, and gestational age >32 weeks. Caregivers completed a survey to assess the presence of 10 home environment risk factors for asthma (Figure). We developed a composite home environment risk score (HErisk) on a 0-1 scale by averaging the total number of present risk factors. T2 biomarkers (eosinophils, total and aeroallergen-specific IgE) were measured from participant blood samples. Median (IQR) and proportions are reported. Univariate generalized linear regression models were fit to evaluate relationships between HErisk, dog, cat, and mold home exposures and T2 outcomes. Results: Of the 119 participants in the cohort, 110 had paired home environment survey and biomarker results. These children were 2.64 (2.07-2.99) years old, 63% male, and 44% Hispanic. HErisk was 0.40 (0.30-0.56). Of T2 biomarkers, 47% had abnormally elevated eosinophils ≥0.24 103/mcl [0.22 (0.15-0.41)103/mcl], 44% had total IgE >45 kUA/L [31.60 (12.10-105.50)kUA/L], and 40% were sensitized to ≥1 aeroallergen (sIgE≥0.35kUA/L). The top three sensitizations were to dog (30%), cat (24%), and Alternaria alternata (11%). Cat or mold exposure and HErisk were not predictive of elevated T2 markers. Dog exposure was not associated with eosinophils. However, having a dog in the home was associated with an average 5.14 kUA/L [95%CI 0.92,9.35] increase in dog allergen IgE (p=0.017) and an average 77.48 kUA/L [95% CI 14.69,140.28] increase in total IgE (p=0.016). Conclusions: More than half of the toddler-aged participants were exposed to six of the ten home environment risk factors, and almost half exhibited elevated T2 biomarkers. Exposure to dog dander at home in 47% of participants had a measurable impact on IgE levels, emphasizing the early role of aeroallergen exposure in emerging atopy that contributes to developing asthma. Further investigation of non-T2 inflammatory responses is warranted to understand the impact of other home environment risk factors on developing asthma in high-risk toddlers.

Rationale: Rescue inhaler use after pediatric emergency department (ED) treatment for acute asthma exacerbations is poorly quantified and relies on caregiver report, which is subject to error and bias. Electronic medication monitoring (EMM) provides unbiased inhaler actuation data, though it has primarily been utilized in adults and pediatric subspecialty clinics. The objective of this study was to determine the acceptability and feasibility of EMM for monitoring short-acting β-agonist (SABA) rescue inhaler use in children with asthma exacerbations post-ED discharge. Methods: 30-day prospective study of children 4-12 years-old discharged from a pediatric ED after treatment for acute asthma exacerbations. Prior to discharge, EMM devices (Propeller Health) were placed on SABA inhalers and acceptability/feasibility surveys were completed by caregivers and ED providers. Caregivers completed remote follow-up surveys at 7, 14, and 30 days post-discharge. Feasibility of post-ED EMM-measured SABA use was based on proportion of participants with Bluetooth®-transmitted actuation data over 30 days. Poor asthma control was defined as SABA use ≥3 days/week, as per asthma guidelines-based criteria. Results: A total of 26 child/caregiver dyads and 25 ED providers participated; 16 (62%) caregivers completed at least one follow-up survey. Median age was 7.0 years [IQR 5.0-9.8], 15% were Black/African American, 69% were Hispanic/Latinx, and 69% were publicly insured. Most caregivers (23; 88%) and ED providers (23; 92%) agreed/strongly agreed that ED-initiation of EMM was acceptable; two (8%) providers reported workflow disruptions. After discharge, all caregivers reported the EMM sensor was somewhat/very easy to keep attached. EMM devices transmitted SABA actuation data for 25 (96%) participants. Participants maintained Bluetooth® connectivity for data transmission an average 27±6 days; 21 (81%) participants completed 30 days of monitoring. EMM-measured SABA actuations were variable over the 30 days post-ED visit (Figure). The median [IQR] number of days with any SABA use was 9 [3-15] with 3 [2-6] actuations/day. Of the participants with actuation data, 22 (88%) had poor symptom control in the first week after discharge, 16 (64%) at two weeks, 12 (48%) at three weeks, and 9 (36%) at four weeks. Conclusions: Initiation of EMM at ED discharge for post-ED monitoring of rescue inhaler use is acceptable and feasible for children with asthma. There was high variation in SABA actuations, and over one-third of children had rescue inhaler use reflective of poor asthma control nearly one month after ED discharge. Future studies are needed to determine associations between EMM-measured post-ED inhaler use and clinical asthma outcomes.

RATIONALE: Toddler-aged children with recurrent wheezing exacerbations are at risk of developing persistent asthma in childhood, but objective evaluation of lung function to guide treatment decisions remains a challenge. This study used oscillometry to characterize lung function and bronchodilator response in toddlers with recurrent wheeze and investigate relationships with parent-reported respiratory control. METHODS:Critical Windows in the Development of Asthma Endotypes and Phenotypes in High-Risk Toddlers (WINDOWS) is an ongoing 4-year longitudinal study of 119 children (61% male, 45% Hispanic/Latino) from the Denver region enrolled at age 18-36 months. At time of enrollment, children had a history of ≥3 severe wheezing episodes and either public insurance or residence in high-poverty census tracts. At each visit, participants complete pre- and post-bronchodilator (BD) oscillometry with the Tremoflo c-100 7-41Hz waveform (Thorasys) to obtain respiratory system resistance (R7) and area of reactance (AX). Success is ≥2 acceptable measurements averaged together with R7 CV≤15%. R7 and AX are transformed to z-scores using height-based reference equations, with abnormal z-score>1.645. Parents are asked about their child's frequency of breathing problems, albuterol use, and oral corticosteroid (OCS) courses with the Test for Respiratory and Asthma Control (TRACK, 0-100 scale, <80=uncontrolled). Univariate generalized linear regression modeled symptom control-lung function relationships. Values are median (IQR). RESULTS: Of 241 visits conducted 2022-2024, oscillometry was attempted at 155 (64%), with 122/155 (79%) successful pre-BD attempts from 80 individuals. Of these, 60 individuals had successful post-BD tests. Children were aged 36.8 (32.1,41.5) months at the time of their first successful oscillometry attempt (youngest=21.8 months). The majority (59%) had uncontrolled respiratory symptoms (TRACK=75 (60,85)). 46% reported symptoms ≥1/week in the past 4 weeks, 35% used albuterol ≥1/week in the past 3 months, and 42.5% had ≥2 OCS courses in the past year. The figure shows pre- and post-BD z-scores and percent change in measured R7 and AX relative to the pre-BD measure. TRACK did not correspond to worse pre-BD R7Z or AXZ. A 10-point increase in TRACK (better symptom control) was associated with an average 3% [95%CI 0.4%,5.9%] greater improvement in post-BD AX (p=0.024). CONCLUSIONS: More than half of toddlers with recurrent wheeze had patterns of increased airway obstruction and lung stiffness when not ill, and respiratory symptom control may be related to degree of bronchodilator responsiveness. Oscillometry is a successful technique to objectively track early life lung function deficits and treatment responses in this young high-asthma-risk group, which can inform clinical decisions.

Recurrent wheeze is highly common in preschool-age children. The prevalence of recurrent wheeze has tripled over the past 30 years and approximately 50% of children experience a wheezing illness in the first 6 years of life.1,2 These young children experience significant morbidity, with nearly double the rate of emergency department visits and 3 times the rate of hospitalizations of older children.3,4 Notably, preschool-age children who wheeze, whether transiently or persistently through childhood, exhibit a greater decline in lung function that continues into later childhood.

ObjectiveTo evaluate dexamethasone prescribing practices, patient adherence, and outcomes by dosing regimen in children with acute asthma discharged from the emergency department (ED).Study designProspective study of children 2-18 years treated with dexamethasone for acute asthma prior to discharge from an urban, tertiary care ED between 2018 and 2022. Demographics, clinical characteristics, ED treatment, and discharge prescriptions were collected via chart review. The exposure was discharge prescription (additional dose) versus no discharge prescription for dexamethasone. The primary outcome was treatment failure, defined as return ED visit, unplanned primary care visit, and/or ongoing bronchodilator use. Secondary outcomes included medication adherence, symptom persistence, quality-of-life, and school/work absenteeism. Outcomes were assessed by telephone 7-10 days after discharge.Results564 subjects were enrolled; 338 caregivers (60%) completed follow-up. Children were a median age 7 years, 30% Black or African American, 49% Hispanic, and 79% had public insurance. A discharge prescription for dexamethasone was written for 482 (86%) children and was significantly associated with exacerbation severity, number of combined albuterol/ipratropium treatments, and longer length of stay. There was no difference in treatment failure between the discharge prescription and no discharge prescription groups (RR 0.87; 0.67, 1.12), including after adjusting for potential confounders; there was no difference between groups in secondary outcomes.ConclusionsPrescription for an additional dexamethasone dose was not associated with reduced treatment failure or improved outcomes for children with acute asthma discharged from the ED. Single, ED-dose of dexamethasone prior to discharge may be sufficient for children with mild to moderate asthma exacerbations.

OBJECTIVES:To describe clinical characteristics of young children presenting to the emergency department (ED) for early recurrent wheeze, and determine factors associated with subsequent persistent wheeze and risk for early childhood asthma. METHODS:Retrospective cohort study of Medicaid-enrolled children 0-3 years old with an index ED visit for wheeze (e.g. bronchiolitis, reactive airway disease) from 2009 to 2013, and at least one prior documented episode of wheeze at an ED or primary care visit. The primary outcome was persistent wheeze between 4 and 6 years of age. Demographics and clinical characteristics were collected from the index ED visit. Logistic regression was used to estimate the association between potential risk factors and subsequent persistent wheeze. RESULTS:During the study period, 41,710 children presented to the ED for recurrent wheeze. Mean age was 1.3 years; 59% were male, 42% Black, and 6% Hispanic. At index ED visits, the most common diagnosis was acute bronchiolitis (40%); 77% of children received an oral corticosteroid prescription. Between 4 and 6 years of age, 11,708 (28%) children had persistent wheeze. A greater number of wheezing episodes was associated with an increased odds of ED treatment with asthma medications. Subsequent persistent wheeze was associated with male sex, Black race, atopy, prescription for bronchodilators or corticosteroids, and greater number of visits for wheeze. CONCLUSIONS:Young children with persistent wheeze are at risk for childhood asthma. Thus, identification of risk factors associated with persistent wheeze in young children with recurrent wheeze might aid in early detection of asthma and initiation of preventative therapies.

14% of children with SARS-CoV-2 infections had radiographic pneumonia. Hypoxemia, cough, higher temperature, and older age were associated with pneumonias. In children tested, SARS-CoV-2 test results were not associated with radiographic pneumonia.

BACKGROUND:Although respiratory viruses are common triggers of asthma exacerbations, the influence of viral infection characteristics on exacerbation presentation and treatment response in the pediatric emergency department (ED) is unclear. OBJECTIVE:To assess viral infection characteristics of children experiencing ED asthma exacerbations and to test their associations with severity and treatment response. METHODS:This is a prospective study of children, aged 4 to 18 years, who received standard ED asthma exacerbation treatment with inhaled bronchodilators and systemic corticosteroids. Nasal swabs collected for viral metagenomic analyses determined virus presence, load, and species. Outcomes included exacerbation severity (Pediatric Asthma Severity [PAS] score, clinician impression, and vital signs) and treatment response (discharge home without needing additional asthma therapies). RESULTS:Of 107 children, 47% had moderate/severe exacerbations by PAS and 64% demonstrated treatment response. Viral metagenomic analysis on nasal swabs from 73 children detected virus in 86%, with 10 different species identified, primarily rhinovirus A (RV-A), RV-C, and enterovirus D68. Exacerbations involving RV-A were milder (odds ratio [OR] = 0.25; 95% confidence interval [CI] = 0.07-0.83) and tended to be more responsive to treatment than non-RV-A infections, whereas exacerbations involving enterovirus D68 were more severe (OR = 8.3; 95% CI = 1.3-164.7) and had no treatment response association. Viral load was not associated with treatment response but exhibited a strong linear relationship with heart rate (rpartial = 0.48), respiratory rate (rpartial = 0.25), and oxygen saturation (rpartial = -0.25), indicative of severity. CONCLUSIONS:The majority of ED asthma exacerbations are triggered by respiratory viruses. Viral species are associated with severity and treatment response, suggesting that early pathogen detection could inform ED treatment decisions. Additional studies are needed to identify differences in pathobiology underlying exacerbations triggered by different viral species, and how to effectively treat these heterogeneous exacerbations.

The objective of this study is to determine predictors of resource use among pediatric providers for common respiratory illnesses. We surveyed pediatric primary care, emergency department (ED)/urgent care (UC), and hospital medicine providers at a free-standing children’s hospital system. Five clinical vignettes assessed factors affecting resource use for upper respiratory infections, bronchiolitis, and pneumonia, including provider-type, practice location, tolerance to uncertainty, and medical decision-making behaviors. The response rate was 75.3% (168/223). The ED/UC and primary care providers had higher vignette scores, indicating higher resource use, compared with inpatient providers; advanced practice providers (APPs) had higher vignette scores compared with physicians. In multivariate analysis, being an ED/UC provider, an APP, and greater concern for bad outcomes were associated with higher vignette scores. Overall, provider type and location of practice may predict resource use for children with respiratory illnesses. Interventions targeted at test-maximizing providers may improve quality of care and reduce resource burden.

BACKGROUND: An agreed-upon definition of treatment response for clinical trials of pediatric acute asthma does not exist, limiting meaningful comparisons among therapeutic in-terventions and advances in asthma management.OBJECTIVE: To develop a consensus definition of treatment response for clinical trials of pediatric acute asthma.METHODS: A multidisciplinary panel of 22 experts participated in a Web-based modified Delphi process to achieve consensus on a definition of treatment response. Round 1 con-sisted of closed-and open-ended questions in which panelists ranked measures of treatment response developed by literature review, suggested additional measures, and explained their responses. In rounds 2 and 3, panelists reviewed summary sta-tistics of the panel's rating from prior rounds and reconsidered their rankings. In round 3, pairwise ranking was performed to determine the ranked importance of components. Consensus was defined as 70% or greater agreement among panelists choosing Likert-scale values of 1 to 6 (extremely unimportant to extremely important) and an interquartile range less than 2.RESULTS: Drawing on results from the expert panel, we developed a definition of treatment response that includes Clinical Severity Score, need for additional therapies, and hospitalization. Clinical Severity Score encompassed most ranked criteria (eg, respiratory distress, wheeze) for a treatment response definition. Panelists recommended that a valid and pragmatic severity score be used consistently across institutions. Panelists also achieved consensus on the top 10 criteria that appropriately classify need for hospitalization.CONCLUSIONS: This consensus definition of treatment response can be used in clinical trials of children with acute asthma to standardize outcome measurement and report meaningful outcomes. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology

There has been long-standing interest in the role of the microbiome in asthma pathogenesis. The airways are known to be constantly colonized by microorganisms that engage with the host immune system. Early studies determined that the microbiome of the lower airways is distinct in patients with and without asthma.1Hilty M. Burke C. Pedro H. Cardenas P. Bush A. Bossley C. et al.Disordered microbial communities in asthmatic airways.PLoS One. 2010; 5e8578Crossref PubMed Scopus (1303) Google Scholar Colonization of the hypopharynx of neonates by similar bacteria was later associated with increased risk of recurrent wheeze and asthma diagnosis in childhood.2Bisgaard H. Hermansen M.N. Buchvald F. Loland L. Halkjaer L.B. Bønnelykke K. et al.Childhood asthma after bacterial colonization of the airway in neonates.N Engl J Med. 2007; 357: 1487-1495Crossref PubMed Scopus (815) Google Scholar These studies elucidate the need to understand the role of the microbiome and microbiome-host interactions in the development of asthma and its multiple phenotypes, a challenging endeavor given the heterogeneous and multifactorial nature of asthma. Staphylococcus aureus has received increased consideration for its potential in inducing a more severe asthma phenotype. S. aureus is a gram-positive bacterium that colonizes the upper airways with higher rates of colonization in patients with asthma and nasal polyps.3Bachert C. Humbert M. Hanania N.A. Zhang N. Holgate S. Buhl R. et al.Staphylococcus aureus and its IgE-inducing enterotoxins in asthma: current knowledge.Eur Respir J. 2020; 551901592Crossref PubMed Scopus (59) Google Scholar S. aureus interacts with the airway mucosa at multiple levels to induce a host immune response. Specific to asthma, a subset of S. aureus extracellular components such as Staphylococcal enterotoxins (SE) are IgE reactive and induce a type 2 inflammatory response. SE can act as typical antigens stimulating a specific IgE (SE-IgE) response, as well as superantigens inducing a polyclonal IgE response and subsequent type 2 inflammatory cascade reflected by activation of innate lymphoid cells, type 2 cytokine release, IgE formation, and eosinophil attraction.3Bachert C. Humbert M. Hanania N.A. Zhang N. Holgate S. Buhl R. et al.Staphylococcus aureus and its IgE-inducing enterotoxins in asthma: current knowledge.Eur Respir J. 2020; 551901592Crossref PubMed Scopus (59) Google Scholar,4Schreiber J. Bröker B.M. Ehmann R. Bachert C. Nonatopic severe asthma might still be atopic: sensitization toward Staphylococcus aureus enterotoxins.J Allergy Clin Immunol. 2019; 143: 2279-2280Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar Twenty-nine percent of participants in a study of a general population in Europe were sensitized to SE, and SE sensitization was associated with increased odds of asthma (odds ratio [OR]: 2.1, 95% confidence interval [CI]: 1.6-2.8).5Tomassen P. Jarvis D. Newson R. Van Ree R. Forsberg B. Howarth P. et al.Staphylococcus aureus enterotoxin-specific IgE is associated with asthma in the general population: a GA(2)LEN study.Allergy. 2013; 68: 1289-1297Crossref PubMed Scopus (76) Google Scholar Thus, through colonization of upper airways and sensitization against its proteins, S. aureus has a role in asthma pathogenesis and severity. The association between S. aureus and asthma has questioned the long-time characterization of asthma by 2 main phenotypes: allergic and nonallergic. Previously, allergic and nonallergic asthma phenotypes were differentiated by the presence of reaction to common aeroallergens, either by the skin prick test or circulating specific IgE. However, in a study of patients with severe asthma, Schreiber et al4Schreiber J. Bröker B.M. Ehmann R. Bachert C. Nonatopic severe asthma might still be atopic: sensitization toward Staphylococcus aureus enterotoxins.J Allergy Clin Immunol. 2019; 143: 2279-2280Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar demonstrated that 51.5% of patients who were previously diagnosed as nonallergic showed reactions to other allergens on an extended allergy panel. The most commonly found sensitizations were to SE A (15%) and SE B (25%), and monosensitization (SE-IgE) was noted in 7.5%. Thus, suggesting an overlap between allergic and nonallergic phenotypes that was previously unknown due to the limitation of prior methods of testing for allergen sensitization. Several studies have also established a link between SE sensitization and asthma severity. Bachert et al6Bachert C. van Steen K. Zhang N. Holtappels G. Cattaert T. Maus B. et al.Specific IgE against Staphylococcus aureus enterotoxins: an independent risk factor for asthma.J Allergy Clin Immunol. 2012; 130: 376-381Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar demonstrated that adults with SE-IgE positivity have an increased risk of severe asthma, oral steroid use, hospitalizations, and lower lung function. Further dissecting SE subgroups, Tanaka et al7Tanaka A. Suzuki S. Ohta S. Manabe R. Furukawa H. Kuwahara N. et al.Association between specific IgE to Staphylococcus aureus enterotoxins A and B and asthma control.Ann Allergy Asthma Immunol. 2015; 115: 191-197Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar determined that sensitization to SEA-IgE compared with SEB-IgE was associated with higher exhaled nitric oxide (FeNO) levels, lower Asthma Control Test scores, and poor asthma control. The association between SE sensitization and severe asthma elucidated in these cross-sectional studies was further confirmed in a longitudinal study that demonstrated that sensitization to SE was associated with subsequent risk of severe asthma (adjusted OR [aOR]: 2.7, 95% CI: 1.2-6.1) and asthma exacerbations (aOR: 4.6, 95% CI: 1.4-15.1) assessed at 10 to 20 years.8Sintobin I. Siroux V. Holtappels G. Pison C. Nadif R. Bousquet J. et al.Sensitisation to Staphylococcal enterotoxins and asthma severity: a longitudinal study in the EGEA cohort.Eur Respir J. 2019; 541900198Crossref PubMed Scopus (40) Google Scholar This association was independent of sensitization to house dust mite indicating that sensitization to SE might be a unique predictor of the natural course of severe asthma development. Tomassen et al5Tomassen P. Jarvis D. Newson R. Van Ree R. Forsberg B. Howarth P. et al.Staphylococcus aureus enterotoxin-specific IgE is associated with asthma in the general population: a GA(2)LEN study.Allergy. 2013; 68: 1289-1297Crossref PubMed Scopus (76) Google Scholar similarly demonstrated that sensitization to SE occurs independently of sensitization to other common aeroallergens as the risk factors for SE-IgE differ from those of IgE against other aeroallergens. Given the existing evidence for the association between SE sensitization and asthma outcomes, further exploration into the role of SE as a prominent allergen in severe asthma pathogenesis is warranted. In this issue of JACI: In Practice, Schleich et al9Schleich F. Moermans C. Gerday S. Ziant S. Louis G. Bougard N. et al.Patients with asthma only sensitized to Staphylococcus aureus enterotoxins have more exacerbations, airflow limitation, and higher levels of sputum IL-5 and IgE.J Allergy Clin Immunol Pract. 2023; 11: 3055-3061Abstract Full Text Full Text PDF Scopus (2) Google Scholar further investigate if SE functions independently in severe asthma by comparing patients with asthma with sensitization to SE but not to common aeroallergens. The authors report their prospective study evaluating characteristics of 110 patients from a general asthma clinic according to their sensitization to SE and/or common aeroallergens. Atopy was defined by having at least 1 positive specific IgE (>0.35 kU/L) for a common aeroallergen. Total serum IgE and specific IgE for SE A, B, and C were measured with a lower limit of detection set at 0.10 kU/L. Sputum cytokines including IgE, IL-5, and IL-4 were also assessed. The authors found that 21% of participants had sensitization to SE alone, which was associated with later onset of disease, higher rate of exacerbations in the prior year, nasal polyps, and more severe airway obstruction (lower forced expiratory volume in 1 second/forced vital capacity ratio). Those sensitized to SE also demonstrated markers of type 2 inflammation including higher FeNO, sputum IgE and IL-5, and total serum IgE. Although the study by Schleich et al is limited by a small sample size, their results add to the growing body of literature supporting the prominent and independent association of SE with a severe asthma phenotype. Similar to Schreiber et al,4Schreiber J. Bröker B.M. Ehmann R. Bachert C. Nonatopic severe asthma might still be atopic: sensitization toward Staphylococcus aureus enterotoxins.J Allergy Clin Immunol. 2019; 143: 2279-2280Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar 21% of the cohort in this study would have been classified as nonatopic if SE-IgE was not included in allergen testing, a notable proportion who would benefit from a distinct targeted treatment strategy. However, S. aureus sensitization cannot per se be ascribed to atopy in which a hereditary component is in the definition. Thus, S. aureus sensitization is an IgE-nonatopic disease. Similar to Bachert et al,6Bachert C. van Steen K. Zhang N. Holtappels G. Cattaert T. Maus B. et al.Specific IgE against Staphylococcus aureus enterotoxins: an independent risk factor for asthma.J Allergy Clin Immunol. 2012; 130: 376-381Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar this study also exhibited an association between SE sensitization and worse asthma outcomes. Although the proportion of participants classified as sensitized to aeroallergens or SE changed with the use of different cutoff values (sigE cutoff ≥0.1 kU/L or ≥0.35 kU/L for both aeroallergens and SE), the statistical significance of findings did not change, further strengthening their results. Schleich et al additionally elucidate mechanisms underlying SE-IgE induction of type 2 inflammation by evaluating sputum cytokines. The authors demonstrate that SE-sensitized patients had higher levels of sputum IgE and IL-5 and also serum IgE well above those only sensitized to common aeroallergens.9Schleich F. Moermans C. Gerday S. Ziant S. Louis G. Bougard N. et al.Patients with asthma only sensitized to Staphylococcus aureus enterotoxins have more exacerbations, airflow limitation, and higher levels of sputum IL-5 and IgE.J Allergy Clin Immunol Pract. 2023; 11: 3055-3061Abstract Full Text Full Text PDF Scopus (2) Google Scholar Sputum cytokine analysis was limited by a smaller sample size preventing comparison among SE subgroups and the evaluation of non–type 2 cytokines. Nevertheless, their results generate interest in the role of anti-IgE therapy, such as omalizumab, in the treatment of SE-sensitized severe asthmatic patients. Omalizumab is a recombinant monoclonal anti-IgE antibody directed against IgE and used for treatment of severe allergic asthma. In a small retrospective, single-center study of 54 severe asthmatics treated with omalizumab, the prevalence of sensitization to SE was 61% (52.2% sensitized to SE only), and no differences were noted in asthma control or reduction in exacerbations by SE sensitization status even after adjustment for gender, body mass index, total IgE count, chronic rhinosinusitis with nasal polyps, oral corticosteroid at baseline, and sensitization with common aeroallergens.10Migueres N. Poirot A. Zhang N. Bachert C. de Blay F. Omalizumab effectiveness is independent of Staphylococcal enterotoxin sensitization.Respir Med Res. 2023; 83100986PubMed Google Scholar Overall, Schleich et al add to the growing body of literature supporting the need to test for sensitization to SE during the phenotyping process of allergic asthma. This would allow for identification of a subgroup of patients with more severe type 2 inflammation. Future research is warranted in a large, multicenter study to further determine the mechanisms underlying SE-induced inflammation (ie, non–type 2 cytokines, subgroups of SE, and patients with nasal polyps) and the effectiveness of different treatment strategies (ie, specific SA immunotherapy in sensitized patients, and anti-IgE and anti-IL-5 therapy) to better treat this severe asthma phenotype. Patients With Asthma Only Sensitized to Staphylococcus aureus Enterotoxins Have More Exacerbations, Airflow Limitation, and Higher Levels of Sputum IL-5 and IgEThe Journal of Allergy and Clinical Immunology: In PracticeVol. 11Issue 10PreviewStaphylococcus aureus enterotoxins (SE) may act as superantigens and induce an intense T-cell activation, causing local production of polyclonal IgE and resultant eosinophil activation. Full-Text PDF Open Access

Objective To determine the association between adjunct corticosteroid therapy and quality of life (QoL) outcomes in children with signs and symptoms of lower respiratory tract infection and clinical suspicion for community-acquired pneumonia (CAP) in the emergency department (ED). Methods Secondary analysis from a prospective cohort study of children aged 3 months to 18 years with signs and symptoms of LRTI and a chest radiograph for suspected CAP in the ED, excluding children with recent (within 14 days) systemic corticosteroid use. The primary exposure was receipt of corticosteroids during the ED visit. Outcomes were QoL measures and unplanned visits. Multivariable regression was used to evaluate the association between corticosteroid therapy and outcomes. Results Of 898 children, 162 (18%) received corticosteroids. Children who received corticosteroids were more frequently boys (62%), Black (45%), had history of asthma (58%), previous pneumonia (16%), presence of wheeze (74%), and more severe illness at presentation (6%). Ninety-six percent were treated for asthma as defined by report of asthma or receipt of ß-agonist in the ED. Receipt of corticosteroids was not associated with QoL measures: days of activity missed (adjusted incident rate ratio [aIRR], 0.84; 95% confidence interval [CI], 0.63–1.11) and days of work missed (aIRR, 0.88; 95% CI, 0.60–1.27). There was a statistically significant interaction between age (>2 years) and corticosteroids receipt; the patients had fewer days of activity missed (aIRR, 0.62; 95% CI, 0.46–0.83), with no effect on children 2 years or younger (aIRR, 0.83; 95% CI, 0.54–1.27). Corticosteroid treatment was not associated with unplanned visit (odds ratio, 1.37; 95% CI, 0.69–2.75). Conclusions In this cohort of children with suspected CAP, receipt of corticosteroids was associated with asthma history and was not associated with missed days of activity or work, except in a subset of children aged older than 2 years.

ObjectiveTo evaluate the role of virus detection on disease severity among children presenting to the emergency department (ED) with suspected community-acquired pneumonia (CAP).MethodsWe performed a single-center prospective study of children presenting to a pediatric ED with signs and symptoms of a lower respiratory tract infection and who had a chest radiograph performed for suspected CAP. We included patients who had virus testing, with results classified as negative for virus, human rhinovirus, respiratory syncytial virus (RSV), influenza, and other viruses. We evaluated the association between virus detection and disease severity using a 4-tiered measure of disease severity based on clinical outcomes, ranging from mild (discharged from the ED) to severe (receipt of positive-pressure ventilation, vasopressors, thoracostomy tube placement, or extracorporeal membrane oxygenation, intensive care unit admission, diagnosis of severe sepsis or septic shock, or death) in models adjusted for age, procalcitonin, C-reactive protein, radiologist interpretation of the chest radiograph, presence of wheeze, fever, and provision of antibiotics.ResultsFive hundred seventy-three patients were enrolled in the parent study, of whom viruses were detected in 344 (60%), including 159 (28%) human rhinovirus, 114 (20%) RSV, and 34 (6%) with influenza. In multivariable models, viral infections were associated with increasing disease severity, with the greatest effect noted with RSV (adjusted odds ratio [aOR], 2.50; 95% confidence interval [CI], 1.30-4.81) followed by rhinovirus (aOR, 2.18; 95% CI, 1.27-3.76). Viral detection was not associated with increased severity among patients with radiographic pneumonia (n = 223; OR, 1.82; 95% CI, 0.87-3.87) but was associated with severity among patients without radiographic pneumonia (n = 141; OR, 2.51; 95% CI, 1.40-4.59).ConclusionsThe detection of a virus in the nasopharynx was associated with more severe disease compared with no virus; this finding persisted after adjustment for age, biomarkers, and radiographic findings. Viral testing may assist with risk stratification of patients with lower respiratory tract infections.