Devika R. Rao

The utility of forced expiratory flow between 25% and 75% of vital capacity in predicting childhood asthma morbidity and severity

Objectives. The forced expiratory volume in 1 second (FEV1) felt to be an objective measure of airway obstruction is often normal in asthmatic children. The forced expiratory flow between 25% and 75% of vital capacity (FEF25–75) reflects small airway patency and has been found to be reduced in children with asthma. The aim of this study was to determine whether FEF25–75 is associated with increased childhood asthma severity and morbidity in the setting of a normal FEV1, and to determine whether bronchodilator responsiveness (BDR) as defined by FEF25–75 identifies more childhood asthmatics than does BDR defined by FEV1. Methods. The Boston Children’s Hospital Pulmonary Function Test database was queried and the most recent spirometry result was retrieved for 744 children diagnosed with asthma between 10 and 18 years of age between October 2000 and October 2010. Electronic medical records in the 1 year prior and the 1 year following the date of spirometry were examined for asthma severity (mild, moderate, or severe) and morbidity outcomes for the three age, race, and gender-matched subgroups: Group A (n = 35) had a normal FEV1, FEV1/forced vital capacity (FVC), and FEF25–75; Group B (n = 36) had solely a diminished FEV1/FVC; and Group C (n = 37) had a normal FEV1, low FEV1/FVC, and low FEF25–75. Morbidity outcomes analyzed included the presence of hospitalization, emergency department visit, intensive care unit admission, asthma exacerbation, and systemic steroid use. Results. Subjects with a low FEF25–75 (Group C) had nearly 3 times the odds ratio (OR) (OR = 2.8, p < .01) of systemic corticosteroid use and 6 times the OR of asthma exacerbations (OR = 6.3, p > .01) compared with those who had normal spirometry (Group A). Using FEF25–75 to define BDR identified 53% more subjects with asthma than did using a definition based on FEV1. Conclusions. A low FEF25–75 in the setting of a normal FEV1 is associated with increased asthma severity, systemic steroid use, and asthma exacerbations in children. In addition, using the percent change in FEF25–75 from baseline may be helpful in identifying BDR in asthmatic children with a normal FEV1.

The School Inner-City Asthma Study: Design, Methods, and Lessons Learned

Background. Children spend a significant amount of time in school. Little is known about the role of allergen exposure in school environments and asthma morbidity. Objectives. The School Inner-City Asthma Study (SICAS) is a National Institutes of Health (NIH)-funded prospective study evaluating the school/classroom-specific risk factors and asthma morbidity among urban children. Methods/results. This article describes the design, methods, and important lessons learned from this extensive investigation. A single center is recruiting 500 elementary school-aged children, all of whom attend inner-city metropolitan schools. The primary hypothesis is that exposure to common indoor allergens in the classroom will increase the risk of asthma morbidity in children with asthma, even after controlling for home allergen exposures. The protocol includes screening surveys of entire schools and baseline eligibility assessments obtained in the spring prior to the academic year. Extensive baseline clinical visits are being conducted among eligible children with asthma during the summer prior to the academic school year. Environmental classroom/school assessments including settled dust and air sampling for allergen, mold, air pollution, and inspection data are collected twice during the academic school year and one home dust sample linked to the enrolled student. Clinical outcomes are measured every 3 months during the academic school year. Conclusion. The overall goal of SICAS is to complete the first study of its kind to better understand school-specific urban environmental factors on childhood asthma morbidity. We also discuss the unique challenges related to school-based urban research and lessons being learned from recruiting such a cohort.

Impact of Environmental Controls on Childhood Asthma

Exposure to allergens early in life can lead to sensitization and the development of childhood asthma. It is thought that increased exposure with the advent of modern housing is likely contributing to the rise in prevalence of childhood asthma during the past few decades. The progression from allergen exposure to sensitization and asthma development has been noted with respect to dust mites, pets, cockroach, mouse, mold, tobacco smoke, endotoxin, and air pollution, although some have found a protective effect with pet and endotoxin exposure. Recent studies have shown that allergen remediation may be beneficial in reducing asthma morbidity and development, although there is also some evidence to the contrary. Examples of allergen remediation that have been studied include the use of dust mite–impermeable covers, high-efficiency particulate air filtration, integrated pest management, home repairs, ventilation improvement, and pet removal. Several multifaceted, randomized controlled trials have shown that reducing multiple early allergen exposures with environmental controls is associated with a decreased risk of asthma.

Perceived neighborhood safety and asthma morbidity in the school inner-city asthma study.

The aim of this study was to investigate whether neighborhood safety as perceived by primary caregivers is associated with asthma morbidity outcomes among inner‐city school children with asthma.

Impact of Cilia Ultrastructural Examination on the Diagnosis of Primary Ciliary Dyskinesia

Ultrastructural examination of cilia is the “gold standard” for diagnosing primary ciliary dyskinesia. There is little evidence suggesting the most effective method of procuring a ciliary biopsy and scant benchmark data on rates of conclusive biopsies or on the diagnostic impact of such biopsies. To critically assess rates of inconclusive, positive, and negative ciliary biopsies and to identify clinical factors associated with conclusive results, we reviewed ciliary biopsies submitted for electron microscopy from 2006 to 2011, noting whether specimens were adequate for analysis and whether the ciliary structure was normal. The biopsy site, method used, procedurists specialty, and clinical diagnoses were determined. Biopsy findings were categorized by diagnostic impact. Over 5 years, 187 patients had 211 biopsies. Conclusive results were obtained on 133/211 biopsies (63%); the remainder were insufficient. The rate of inconclusive biopsies did not vary significantly (P > 0.05; Fishers exact) among sampling methods. Abnormal results were identified in 8/133 (6.0%) of the adequate specimens. Forceps compared to brush biopsies (abnormal in 4/12 versus 4/121 of the adequate specimens, P = 0.002), along with multiple biopsy samples (taken on same or different days) compared with a single biopsy sample (abnormal in 3/12 versus 1/110 of the adequate specimens, P = 0.01), were more likely to yield an abnormal result. Only 63% of pediatric ciliary biopsies provide adequate morphology for analysis, the large majority of these samples showing normal ciliary anatomy. The method of obtaining biopsies did not significantly affect result conclusiveness. Understanding the diagnostic impact of ultrastructural analysis is important as new diagnostic algorithms are developed for primary ciliary dyskinesia.

Association between allergic sensitization and exhaled nitric oxide in children in the School Inner-City Asthma Study

Fractional exhaled nitric oxide (FeNO) is increased in children with asthma and is thought to reflect eosinophilic lung inflammation.1, 2 It is not known whether sensitization to one particular allergen is more strongly associated with worsened lung inflammation over any other particular allergen. Our aim was to determine whether children with asthma and allergic sensitization have higher levels of lung inflammation as measured by FeNO compared to children without allergic sensitization, and whether sensitization to one specific allergen was most predictive of elevated FeNO in a school-based setting. We studied 128 children consecutively enrolled in the School Inner-City Asthma Study (SICAS) from 2008–2012 for whom we obtained skin prick testing for indoor allergens, outdoor allergens and FeNO (NIOX TM System, Aerocrine, Sweden). Further details regarding SICAS methods have been previously reported3. The FeNO was obtained at the same time as the skin prick testing utilizing standard methods3, and a wheal size of >3 mm compared with a saline control was used to define a positive sensitization test. FeNO was collected according to standard ATS procedures.4 The primary outcome was FeNO, and the logarithmic value of FeNO was used to obtain an approximately normal distribution. We performed an independent t-test of the mean FeNO (log transformed) between sensitized and unsensitized children, and the Mann-Whitney U test was used to compare untransformed FeNO levels in sensitized vs. unsensitized children. Univariate regression was utilized to determine the relationship between sensitization to allergens and FeNO (log transformed). In the multiple regression model, we adjusted for age, gender, inhaled corticosteroid use and multiple sensitizations, all variables that were significantly associated with model outcome. Analyses were conducted using SPSS version 19 (SPSS, Chicago, IL) and SAS v9.2 (Cary, NC: SAS Institute Inc, 2011). The mean FeNO level was 24.75 ppb, and the median was 15 ppb (range, 5–143) for the 128 children studied (eTable 1). Only 6% of children were white, while 40.6% and 28.1% of children were black and Hispanic respectively. The mean age at the time of FeNO measurement was 8.8 years. Over 70% of SICAS children were sensitized to more than one allergen, and over 60% were sensitized to more than two allergens. The most common allergens to which children were sensitized were cat (40.6%), dust mite (35%), tree pollen (32%), mouse (37.5%), cockroach (24.2%), grass (25%), rat (25.8%) and ragweed (20.3%). We found that log-transformed FeNO significantly increased as the number of positive skin prick tests per child increased. Mean FeNO levels (ppb) were significantly different between those children with no sensitization and those children with 1–3, 4–5 and ≥ 6 positive skin prick tests. In comparing FeNO levels between children with and without sensitization to specific indoor allergens, we found that for cat, mouse, dust mite, rat and cockroach, the FeNO levels were significantly higher in children who were sensitized to that specific allergen compared to those who were not. Sensitization to cat, rat, mouse, tree pollen, dust mite, and cockroach were significant predictors of increased FeNO in the univariate model (Table 1). When adjusted for age, gender, inhaled corticosteroid use, asthma control and multiple sensitizations (more than one positive skin prick test), sensitization to cat and rat allergen were significant predictors of increased FeNO with p values of <0.01 and 0.016 respectively. Table 1 Predictors of FeNO, Multivariate regression; Outcome is the natural log of FeNO Our study focused on the relationship between allergic sensitization and FeNO levels, an objective measure of lung inflammation in children with asthma. The children enrolled in SICAS were highly allergic, with over 70% being sensitized to more than one allergen. This high degree of allergic sensitization translated to higher FeNO levels in comparison to unsensitized children. The mean FeNO for our cohort was above 20 ppb (24.75 ppb), indicating that significant eosinophilic airway inflammation is likely present.5 In attempting to identify which allergens contribute most to elevated FeNO levels, we found sensitization to cat and rat, and also multiple sensitizations to be significant independent predictors of increased FeNO after adjusting for age, gender and ICS use. To our knowledge, no other studies have shown sensitization to rat allergen to be a significant independent predictor of increased FeNO levels, adjusting for other factors. There may be unique characteristics of this allergen that correlate with allergic airway inflammation. In our multiple regression model, sensitization to six or more allergens carried the strongest beta-coefficient of 0.608. This is in contrast to some studies that have demonstrated that sensitization to specific allergens such as dust mite are major determinants of increased FeNO in children.6 Our study highlights the importance of rat allergen sensitization as well and the dose-response relationship of polysensitization and airway inflammation. Other studies have demonstrated that sensitization to multiple specific allergens is associated with elevated FeNO levels7–9, and our study adds to this body of literature by confirming this relationship in a population that is more diverse compared to other communities that have been studied. Our results are therefore generalizable to other diverse, urban populations with a high proportion of non-white ethnicities. The clinical implications of our results are important. A study from the National Cooperative Inner City Asthma Study showed that children with asthma who were both exposed and sensitized to rat allergen had higher rates of hospitalization and unscheduled doctor visits.10 Our study adds to these findings by showing that sensitization to rat allergy also predicts airway inflammation. Finding that rat and multiple sensitization predicts high FeNO levels is important as FeNO levels have been shown to be predictive of asthma exacerbations.11 We acknowledge that we are limited by sample size in that limited resources allowed us to obtain FeNO in a subset of children. We found that in our school-based cohort of ethnically diverse, highly allergic children, that FeNO levels were predicted by cat and rat sensitization, and most strongly by having multiple sensitizations. Future studies should be aimed at reducing cat and rat allergen exposure and assessing the effect on asthma morbidity as well as markers of airway inflammation

An Overview of Fractional Exhaled Nitric Oxide and Children with Asthma

ABSTRACT Asthma is the most common pediatric chronic disease and is characterized by lung inflammation. Fractional exhaled nitric oxide (FeNO) is thought to reflect the presence of eosinophilic airway inflammation, and is an easy, non-invasive test that has held promise in providing additional objective data. However, not all studies have shown a clinical benefit in the use of FeNO to guide management of asthma in children. This review will describe the results of the most recent studies examining the use of FeNO in the diagnosis and treatment of asthma in infants, preschool-aged children and in school-aged children. It will aid the clinician in providing a clinical context in which FeNO may be most useful in treating pediatric asthma.