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The objective of this review is to provide new advances in our understanding of the clinical importance of establishing peripheral airway impairment (PAI) by impulse oscillometry (IOS) and targeted therapy, which could result in better asthma outcomes. Data sources include PubMed and Google search, limited to English language and human disease, with key words IOS and asthma. Key findings include PAI being consistently associated with uncontrolled asthma across ethnicities, using IOS reference equations factoring Hispanic and White reference algorithms. It is noted that PAI is common even in patients considered well-controlled by asthma guidelines. In a large longitudinal analysis (Assessment of Small Airways Involved in Asthma or ATLANTIS study), a composite of R5-R20, AX, and X5 ordinal scores were independently predictive of asthma control and exacerbation in a multivariate analysis, but forced expiratory volume in 1 second was not significantly predictive of morbidities. However, combining forced expiratory volume in 1 second less than 80% with PAI resulted in greater odds of identifying uncontrolled asthma and exacerbations, than either alone. Applying an external validation method in children with asthma offers the clinician the IOS reference equations best fit for their own specific population. Several clinical phenotypes can also identify PAI with high probability, useful when IOS is not available. Poor asthma outcomes for obese patients with asthma are associated with dysanapsis and PAI, not obesity alone. Extrafine inhaled corticosteroids achieve better asthma control and improve peripheral airway function with fewer exacerbations at lower dosages than nonextrafine inhaled corticosteroid aerosols. In conclusion, these data support the benefit of adding IOS to spirometry in future asthma guidelines and suggest the potential benefit from targeted therapy.

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BACKGROUND: Despite the fact that impulse oscillometry (IOS)-determined peripheral airway impairment (PAI) phenotype is a major risk factor for uncontrolled asthma, IOS is seldom used clinically. OBJECTIVE: To identify clinical characteristics that can best identify the PAI phenotype. METHODS: Clinical characteristics and spirometry results were compared in 227 patients with asthma with the PAI phenotype determined by resistance and reactance values that exceeded IOS­predictive normal values using Gochicoa-Rangel equations. Logistic regression analyses determined factors associated with PAI phenotype, with risk classification based on predicted probability from the final adjusted model. RESULTS: Analysis for identifying PAI, present in 37% of our population, revealed statistically significant odds ratio (OR) for age (4-7 years), of 3.75 (1.47-9.55) (P = .006), obesity OR of 2.59 (1.36-4.96) (P = .004), uncontrolled asthma OR of 2.77 (1.34-5.74) (P = .006), and abnormal forced expiratory flow between 25% and 75% (FEF25%-75%) (<65%) OR of 4.22 (1.59-11.20) (P = .004). For identifying PAI in those considered well controlled, key characteristics were age (4-7 years), OR of 2.81 (1.10-7.18) (P = .03), and obesity, OR of 2.18 (1.09-4.39) (P = .03). For those 4 to 7 years old, who were obese and had uncontrolled disease, probability of PAI was greater than or equal to 80%, regardless of FEF 25%-75%. Probabilities from logistic regression analyses to identify PAI were associated with an area under the curve of 0.750, and applying standard threshold of greater than or equal to 0.50 probability for identification produced sensitivity at 49.4%, specificity at 85.3%, positive predictive value at 66.1%, negative predictive value at 74.4%, and accuracy at 72.1%. CONCLUSION: Clinical characteristics of age at 4 to 7 years, obesity, uncontrolled asthma, and FEF 25%-75% (<65%) identify PAI with high specificity and accuracy. This approach offers the clinician a practical method for strongly considering the presence of PAI when IOS is not available.

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BACKGROUND: Peripheral airway impairment (PAI) has been shown to have a close association to risk of uncontrolled asthma in children. However, clear methods have not been established for the clinician to select impulse oscillometry (IOS) reference equations best suited for their population. Our study aimed to develop a practical external validation analytic approach for the clinician to determine which of the available reference equations best predicts uncontrolled asthma for their patients. METHODS: This is a post hoc analyses of data collected at baseline in a randomized controlled study that occurred from March 2016 to 2018. The study population consisted of 227 children, ages 4-18 years, with moderate to severe asthma. Discrimination and calibration predictive performance of available and suitable IOS equations were assessed by using uncontrolled asthma as the criterion outcome. Discrimination statistics of accuracy, sensitivity, and specificity served as the primary performance indicators. Rank scores were determined by the number of acceptable limit thresholds met for these measures (≥60%, ≥50%, and ≥60%, respectively) across IOS metrics (R5, R5-R20, AX, and X5) resulting in a total possible score of 12. RESULTS: External validity assessment determined the rank order of best to worst equations as being Gochicoa-Rangel (rank score = 10) > Nowowiejska (rank score = 9) > Assumapcao (rank score = 6) > Amra (rank score = 2). Gochicoa-Rangel reference equations provided the best option for universal application with accuracy of 73.1%, 72.2%, 76.7%, and 66.2% for R5, R5-R20, AX, and X5, respectively. CONCLUSIONS: External validation, particularly discrimination in asthmatic children, offers the clinician a practical approach to selecting the most suitable predictive equations for their patients.

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BACKGROUND: Factors that determine the relationship between obesity and poor outcomes in asthmatic children are not well understood. Dysanapsis and peripheral airway impairment (PAI) could provide an explanation in the obese asthmatic patient. OBJECTIVES: To determine the effect of obesity on increased dysanapsis and PAI and establish the effect of obesity, dysanapsis, and PAI on increased risk of uncontrolled asthma. METHODS: We evaluated 206 children with moderate to severe asthma, aged 4-18 years, to determine the relationship of body mass index (BMI) to increased dysanapsis and PAI, using reference values. We examined the probability of obesity, dysanapsis, and PAI increasing the risk of uncontrolled asthma by BMI categorically and BMI z scores using generalized linear model analyses. RESULTS: Compared with normal-weight children, overweight and obese children had increased forced vital capacity % predicted and obesity increased odds of dysanapsis by 2.32 (P = .04), while PAI showed an age-dependent effect, with increased odds of 2.09 for children younger than 12 years (P = .08) and 54.14 for those 12 years and older (P = .003). For each unit increase in BMI z score, there was an increased odds ratio of 1.57 for dysanapsis (P = .009), greater in males, OR of 3.10, P = .009, and of 1.39 for PAI for those younger than 12 years (P = .042) and of 4.60 for those 12 years and older (P = .002). Obesity's relationship to uncontrolled asthma was indirect, as not significant when adjusted for the direct effect of dysanapsis and PAI, which were highly significant predictors, with increased odds of 28.01 for dysanapsis for those younger than 12 years (P < .001) and of 3.09 for PAI (P = .005). CONCLUSIONS: Overweight and obesity significantly increase odds of dysanapsis and PAI, in an age and gender-specific manner, increasing the probability of uncontrolled asthma.

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BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic period is experiencing better asthma control, fewer exacerbations, and health care utilization, with limited data on factors that could explain this phenomenon. OBJECTIVE: To confirm these improved asthma outcomes during COVID-19 and evaluate potential contributing factors. METHODS: In 18,912 pediatric patients with asthma treated in the Children's Hospital of Orange County network from 2017 to 2020, monthly asthma-related encounters and medication summaries were extracted from electronic health records, particulate matter 2.5 (PM2.5) air pollution from the California Air Resources Board, and influenza-like illness from Illness Surveillance Network for the first 6 months of each year. Changes in outcomes between January to March and April to June (post-COVID-19 shutdown in 2020) were compared with historical data using generalized estimating equations analyses for patient outcomes and generalized linear models for pollution exceedance, influenza-positive, and telehealth visit rates. RESULTS: During COVID-19, we found 78%, 90%, 68% reductions in hospitalization, emergency department visits, and exacerbations, respectively, compared with pre-COVID-19 2020, with significantly greater changes than the same time period of 2017 to 2019 and significant reductions in albuterol and inhaled corticosteroid use (P < .05). Emergency department visit reduction was not seen for African Americans. The PM2.5 and influenza rates were also significantly reduced during COVID-19 (P < .05). Increased rates in telehealth visits were greater in the publicly insured group when compared with commercially insured. CONCLUSION: Our data confirm reduced health care utilization and suggest better asthma control during COVID-19, except for African Americans. This was associated with a significant increase in telehealth visits and reductions in PM2.5 and influenza infections, but not better asthma controller adherence.

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BACKGROUND: Randomized clinical trials suggest that long-term inhaled corticosteroid (ICS) treatment significantly inhibits growth velocity (GV) assessed by centimeters/year (cm/year) in primarily prepubescent, mild asthmatics. However, several observational studies measuring normal growth variance by Z score suggest the absence of the ICS inhibitory effect. OBJECTIVE: To demonstrate the generalizability of ICS growth inhibition in cm/year by establishing whether this measure exceeds the expected normal changes in GV by Z score for similar age and sex. METHODS: This was a retrospective, observational study comparing height and GV across a 2 year period in asthmatics aged 2-10 years, receiving ICS therapy (Group 3) with non-asthmatics, and non-ICS asthmatics (Groups 1 and 2), respectively. Generalized linear model procedure compared GV measures after adjustment for age, gender, and dependence of group differences on the age of the child. RESULTS: Before initiation of ICS therapy at baseline, Group 3 patients (n = 22) were shorter than Groups 1 (n = 67) and 2 (n = 44) by mean height in cm, and height for age Z score in the adjusted model (p < .05). GV was also significantly reduced in Group 3 after initiation of ICS therapy versus Groups 1 and 2 by 1.0-1.5 cm/year, respectively, p < .05, but not significantly in comparison to expected normal GV variance determined by Z score, p ≥ .05. CONCLUSION: Our findings suggest the need to consider normal growth variance by Z scores in addition to absolute changes (cm/year) when interpreting the inhibitory effect of ICS on GV. Larger sample size studies will be necessary to confirm our findings.

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BACKGROUND: Although clinically useful in identifying peripheral airway impairment (PAI), impulse oscillometry (IOS) has not received universal acceptance. This may be due to variable cutoff points, and the perception that available standardized reference values may not be clinically relevant in all populations. OBJECTIVE: To establish the relationship between PAI, based on standardized IOS reference values, and uncontrolled asthma as well as interchangeability between Hispanic and white reference algorithms. METHODS: IOS reference values were established for upper and lower limits of normal (>95th and <5th percentile, respectively) using published algorithms in Hispanic and white children. Values exceeding normal limits (PAI) were compared in those uncontrolled and controlled for significance of differences. Probability estimates and odds ratio of uncontrolled asthma were determined for R5, R5-R20, AX, and X5 using adjusted generalized estimating equation analyses. Intraclass correlation coefficients determined interchangeability of Hispanic and white reference algorithm values. RESULTS: Those with uncontrolled asthma had significantly greater PAI and a higher frequency of PAI than those well controlled (P < .05), whereas odds of uncontrolled asthma increased with increasing PAI (P < .001) for all IOS measures, particularly for X5, where odds ratios ranged from 2.70 to 11.01.There was good to excellent (>70%) agreement between Hispanic and white algorithms, except for R5-R20 (<70%). CONCLUSIONS: PAI, defined by IOS reference values, not central airway markers (R20), is consistently related to the risk of uncontrolled asthma. This is true whether using Hispanic or white reference algorithms. Thus, standardized reference values in children offer the clinician readily available IOS cutoff points that are clinically relevant across ethnicity.

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Objectives: The aim of this exploratory study was to assess the impact of caregiver health literacy (HL) on health care outcomes for their child with asthma.Methods: Caregiver dyads across two different healthcare delivery systems completed a battery of validated asthma outcome instruments, including the Newest Vital Sign™ as a measure of HL for the caregivers of children ages 7-18 y. Utilization history was obtained through the electronic medical record. Descriptive analysis with bivariate associations was conducted.Results: There was no direct relationship between HL and asthma outcomes in the 34 Hispanic and African American caregiver-child dyads. However, caregiver health literacy was significantly related to language (p = 0.02). African American English-speaking caregivers, seen in an urban emergency department, demonstrated adequate health literacy. Hispanic Spanish-speaking caregivers, seeking care in a mobile asthma van, showed limited health literacy. There was no significant association between caregivers' HL and routine asthma care visits when language and child age were controlled.Conclusions: Assessing patient factors can identify persons at risk who need additional support to negotiate the healthcare system when providing care for a child with asthma.

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BACKGROUND: Despite potential value of identification of allergic inflammation with fractional exhaled nitric oxide (FeNO) in managing asthma, randomized clinical trials have not consistently shown better outcomes compared with guideline management alone. OBJECTIVE: To assess the effectiveness of FeNO vs non-FeNO-based therapeutic algorithms in managing asthma, and the phenotypic profile associated with FeNO >35 ppb yet well controlled by guidelines, as a potential model to predict better FeNO-based algorithm outcomes. METHODS: This is a randomized controlled study (RCT) in 88 high-risk children with asthma 7 to 18 years of age across 352 visits over a 1-year period. Generalized estimating equations analysis assessed algorithm group differences in outcomes and characteristics associated with higher odds uncontrolled by FeNO alone in the treatment decision algorithm. RESULTS: The FeNO treatment algorithm did not show superiority in reducing exacerbations and morbidity (P > .05). Phenotypes that more than doubled the odds FeNO alone identified uncontrolled asthma included adolescence, non-adherence, high atopy (>6+), and baseline FeNO >35 ppb, whereas obesity, FEF25-75% < 65% predicted, and bronchodilator response >10% decreased the odds. Uncontrolled asthma by FeNO alone (F) vs guidelines alone (G) showed overall F/G > 1.0 in adolescents, but <1.0 in younger patients unless the FeNO threshold was reduced to >20 ppb. CONCLUSION: Our study suggests that age and phenotypes play a key role in FeNO discordance compared with the conventional guideline-based uncontrolled asthma. The FeNO-based therapeutic algorithm, if confirmed further, could provide the clinician with an effective asthma management tool. The clinical implication could improve future FeNO-based RCTs and treatment decision algorithms in managing asthma by considering phenotypes and age-dependent FeNO thresholds.

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BACKGROUND: Obesity is thought to be associated with poor asthma control, increased health resource utilization, and reduced responsiveness to inhaled corticosteroids. OBJECTIVE: Based on previous experience, our hypothesis was that by improved access to comprehensive guideline care, outcomes in normal weight would be comparable in obese children with asthma. METHODS: This was a retrospective cohort study of predominately Hispanic children (3-18 years of age) in underserved areas of Orange County, California, who enrolled in the Breathmobile Program from 2003 to 2012. Outcomes were examined by using Cox regression and generalized estimating equations analyses, adjusted for potential confounding factors. RESULTS: Clinical outcomes in more than 1,200 children followed up for a mean of 6 visits (standard deviation [SD] = 2.2) across 403 days (SD = 112) were improved, on average, regardless of body mass index (BMI). Morbidly obese (MOB) patients were able to achieve significant reductions of approximately 60% or more in report of emergency department (ED) visits, hospitalizations, school absenteeism, usual exercise limitations, and exacerbations to levels that were comparable those of normal weight (NW) patients. The importance of close follow-up, particularly for the MOB patient, was evidenced by achieving 80% cumulative probability of well controlled asthma by visit 3, similar to patients in lower BMI risk groups with good adherence, when the visit interval did not exceed 90 days. These outcomes were achieved across all BMI groups with similar mean step of therapy, adjusted for severity (P < .001). CONCLUSION: Access to effective community-based care where trust, education, and continuity of care consistent with National Asthma Education and Prevention Program (NAEPP) guidelines is possible, as demonstrated by the Breathmobile Program, can provide an opportunity for children with asthma in all BMI categories to achieve well-controlled disease.

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BACKGROUND: Peripheral airway impairment, although frequently unrecognized, is a risk factor for poor asthma control, loss of control, increased exacerbations, airway hyperresponsiveness, and loss of lung function with age, even in patients with well-controlled asthma. OBJECTIVE: To determine the presence of peripheral airway impairment by impulse oscillometry and forced expiratory flow between 25% and 75% (FEF25%-75%) in children whose asthma is well controlled by National Asthma Education and Prevention Program (NAEPP) guidelines. METHODS: In this retrospective, cross-sectional analysis, outcomes were evaluated across 192 encounters in 139 patients with moderate to severe asthma, ages 4-18 years. Receiver operator characteristic curves were created and oscillometry thresholds determined by maximizing the sum of sensitivity and specificity to identify those whose condition is not well controlled. Impairment was then identified for those whose condition was well controlled when these age-dependent oscillometry thresholds were met for each IOS measure or FEF25%-75% < 65% of predicted. RESULTS: Reactance at 5 Hz (X5) appeared most robust to identify peripheral airway impairment. In 96 well-controlled asthma encounters, impairment was identified by X5 in approximately 20% and 45% for those younger than 12 years and adolescents, respectively, compared with a maximum of 10% with FEF25%-75% in the adolescent cohort (P < .05). CONCLUSION: We conclude that peripheral airway impairment, determined by oscillometry, is common in patients with well-controlled asthma across age cohorts. X5 with optimal cut points ≤ -3.8, ≤ -2.5, and ≤ -1.5 cmH2O/L/s for ages 4-7, 8-11, and >12 years, provides the clinician with a practical tool to identify the presence of the peripheral airway impairment phenotype that is consistently superior to FEF25%-75%. This recognition, if confirmed, may reduce the risk of asthma-associated consequences with earlier and more targeted therapy.

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OBJECTIVE: To provide a clinical rationale for including impulse oscillometry (IOS) as a part of standard office-based asthma assessment. DATA SOURCES: PubMed and Google search, limited to English language and human disease, with the keywords IOS and asthma. STUDY SELECTIONS: Articles included in this review were based on the expert opinion and previous publications by the authors. RESULTS: In children, IOS was more useful than spirometry in identifying asthma and uncontrolled asthma and predicting loss of control and exacerbations. IOS predicts young children at risk for loss of lung function with age and the potential for early intervention to prevent further sequelae. In adults, peripheral airway impairment detected by IOS or spirometry (ie, forced expiratory flow between 25% and 75%) commonly occurs across severity, and each measure may be complementary in predicting loss of control even with normal forced expiratory volume in 1 second. Extrafine inhaled corticosteroids with or without long-acting ß-agonists proved superior to standard particle aerosols in improving IOS-detected peripheral airway obstruction. Our data also suggest that currently available commercial reference values for lung resistance at 5 Hz and lung reactance at 5 Hz are applicable across diverse populations, but further studies are needed. CONCLUSION: The findings of this review suggest that IOS can add value to traditional clinical and spirometric assessment and thus improve management of asthma in children and adults, as well as have the potential to detect early dysfunction of the peripheral airways, which may result in better outcomes.

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