Pediatric Pulmonology 50:621–629 (2015)

Review

Pediatric Pulmonology Year in Review 2014: Part 1 Terry L. Noah,

MD,

1

Ozge Yilmaz, MD,2* Thomas Nicolai, and Jean-Paul Praud, MD5

MD,

3

David Birnkrant,

4 MD,

Summary. Our discipline and our journal cover an extremely broad range of research and scholarly topics related to children’s respiratory disorders. To better meet the needs of our readership for updated perspectives on the rapidly expanding knowledge in our field, we here summarize the past year’s publications in our major topic areas, as well as selected publications in these areas from the core clinical journal literature outside our own pages. Pediatr Pulmonol. 2015;50:621–629. ß 2015 Wiley Periodicals, Inc. Key words: asthma and early wheeze; bronchiectasis and primary ciliary dyskinesia; bronchoscopy; gastroesophageal reflux and aspiration syndromes; interstitial lung disease (ILD).

INTRODUCTION

Our discipline and our journal cover an extremely broad range of research and scholarly topics related to children’s respiratory disorders. To better meet the needs of our readership for updated perspectives on the rapidly expanding knowledge in our field, we will summarize the past year’s publications in our major topic areas, as well as selected publications in these areas from the core clinical journal literature outside our own pages. The current review (Part 1) reviews papers published in 2014 relevant to asthma, diagnostic testing/endoscopy, sleep, and breathing disorders, respiratory complications of neuromuscular disorders, and rare lung diseases. A subsequent installment will review cystic fibrosis and other topic areas. Asthma

Asthma remains the most common chronic respiratory disorder of childhood, and in 2014 it was one of the most common topics for manuscripts submitted to and published in Pediatric Pulmonology. Studies in children continue to refine our concepts of development of immunologic and clinical phenotypes in asthma. Sarria et al.1 prospectively studied infants with eczema from infancy to age 4 years and found that spirometry and airway responsiveness track longitudinally from early in life; serum markers of atopy and cytokine production by peripheral blood mononuclear cells (PBMC) were associated with an increased risk of pre-school asthma, as well as lower lung function, and increased airway ß 2015 Wiley Periodicals, Inc.

responsiveness. A report from the Clinical Asthma Research Association cohort study in Germany identified novel immunologic phenotypes in allergic and nonallergic asthmatic children, compared to healthy controls; patients with non-allergic asthma had increased IL-17shifted immunity, and neutrophil-associated factors on analysis of stimulated PBMC.2 Investigators from the

1

Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. 2 Pediatric Allergy and Pulmonology, Celal Bayar University Department of Pediatrics, Manisa, Turkey. 3

Haunersches Kinderspital Pediatrics, Munich, Germany.

4

MetroHealth Medical Center Department of Pediatrics, Cleveland, Ohio.

5

University Sherbrooke Pediatrics, Sherbrooke, Quebec, Canada.

Funding source: none reported. Conflict of interest: None. 

Correspondence to: Terry L. Noah, MD, 260 Macnider Building, Campus Box 7220, University of North Carolina, Chapel Hill, NC 27599-7220. E-mail: [email protected] Received 23 March 2015; Accepted 29 March 2015. DOI 10.1002/ppul.23202 Published online 17 April 2015 in Wiley Online Library (wileyonlinelibrary.com).

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Childhood Asthma Management Program defined five temporally stable asthma phenotypes on the basis of clinical parameters and responsiveness to treatment.3 While there is evidence of some progress in reducing racial disparities for asthma risk in children, recent large scale retrospective data analysis indicates that minorities, and poor children are still at higher risk for asthma prevalence and outcomes such as readmission.4,5 Moerman and colleagues6 analyzed data from the International Study on Asthma and Allergies in Childhood (ISAAC) and found that South Asian children living in Canada have a similar asthma prevalence to non-South Asian children; both of whom had higher asthma prevalence compared with children residing in South Asia. This supports that environmental and social factors play a role in asthma prevalence. Beck et al.,7 in a population-based prospective observational cohort study of children admitted for asthma, reported that African American children were twice as likely to be readmitted as whites. Socioeconomic status (SES) and social hardships (e.g., lower income, unemployment, lack of car, or home) explained about 40% of the racial disparity. In addition, data supporting exposure to traffic-related air pollution as a risk factor for childhood asthma exacerbations continue to be reported.8,9 Evidence for asthma risk from second hand smoke (SHS) exposure continues to accumulate. In a prospective cohort study, elevated cotinine in serum, and saliva (but not caregiver-reported tobacco exposure) were associated with risk for asthma admission and were related to socioeconomic factors.10 Rodriguez-Martinez et al.11 found, in a population of asthmatic Latino children admitted to hospital for asthma exacerbation, approximately one-third of the patients had at least one hospital admission for asthma during the year following admission, and maternal smoking was an independent predictor of these hospitalizations. Epigenetic changes may drive the effects of SHS on asthma in children. In a small but intriguing study of BALF in children with severe asthma, SHS-exposed children had reduced histone deacetylase-2 function, and reduced responsiveness to dexamethasone in alveolar macrophages, as well as increased markers of neutrophilic inflammation.12 Apart from SHS exposure, Gunawardhana et al.13 showed that in a small group of 12month old infants, presence of maternal asthma during pregnancy was associated with differential methylation profiles of infants’ peripheral blood DNA, which may affect risk for future asthma development. Early-life or in utero exposures to medications have been recently linked to childhood asthma risk, but new studies suggest this is at least partly confounded by indications for medication use, particularly respiratory infection. In a longitudinal pre-birth cohort14 and a systematic review and meta-analysis,15 controlling for respiratory infection attenuated risk for asthma associated with prenatal acetaminophen or ibuprofen use. Similarly, Pediatric Pulmonology

a nationwide prospective population based cohort study in Sweden found that the link between prenatal antibiotic exposure and subsequent asthma was confounded by respiratory infection.16 Early exposure to infectious agents may play a role in the development or clinical course of childhood asthma, and several studies in 2014 shed new light on this. Vicencio et al.,17 in a cross-sectional study, found that 39% of children with moderate to severe persistent asthma had evidence of sensitization to one or more fungi. Serum immunoglobulin E was significantly higher, and pulmonary function (FEV1, FEV1/FVC, and FEF25–75%) significantly lower in sensitized patients. Fungal sensitization in children with persistent asthma thus appeared to be associated with disease severity. Fungal exposures and asthma risk were also examined in a cross sectional study in Taiwan18 and a systematic review,19 with the conclusion that the presence of specific indoor fungal species increases risk of asthma exacerbation in both children and adults. Exposures to bacteria and allergens early in life impact asthma risk and immune development in a complex manner. Lluis et al.20 examined PBMC phenotypes in 149 farm children compared to 149 controls in the Protection Against Allergy: Study in Rural Environments Study Group birth cohort, and found evidence that protection against asthma in farm children may be the result of enhancement of regulatory T-cell by farm milk exposure. The Urban Environment and Childhood Asthma (UECA) study assesses risk factors associated with asthma longitudinally, in a high-risk birth cohort. Lynch et al.21 reported evidence of a complex interaction between the timing of early life exposures leading to differential risk for later wheezing, with children exposed to both allergens and bacteria in the first year of life having reduced risk. Respiratory syncytial virus (RSV) bronchiolitis in infancy has long been suspected of contributing to asthma risk in children. Backman et al.22 evaluated the prevalence of asthma and respiratory health-related quality of life in adults 30 years after hospitalization for bronchiolitis or pneumonia in infancy. They found that both doctordiagnosed asthma (31.3% vs. 10.9%) and self-reported asthma (35.4% vs. 14.5%), as well as repeated on-demand use of bronchodilators (35.4% vs. 14.5%), and regular use of inhaled corticosteroids (20.8% vs. 8.7%) were more common in former bronchiolitis patients than in controls. A recent study reported significant interaction between early-life RSV lower respiratory infection and active adult smoking, and the risk of asthma in early adult life.23 Genetic factors may influence risk for post-RSV asthma; Koponen et al.24 found that the IL10 rs1800896 SNP was significantly associated with preschool asthma after severe lower respiratory tract infection in early infancy. Nutritional factors likely also contribute to asthma risk. Rosas-Salazar and colleagues reported a case-control

Pediatric Pulmonology Year in Review 2014: Part

study of 1,127 Puerto Rican children aged 6–14 years living in Connecticut and Puerto Rico.25 After adjustment for multiple covariates, children who were breastfed for up to 6 months had 30% lower odds of asthma than those who were not breastfed. Vitamin D deficiency has recently been proposed to be a risk factor for childhood asthma, but two recent studies do not appear to support this. Baiz et al.26 reported in a birth cohort study of 239 infants in France that cord serum 25-OH vitamin D levels were inversely associated with risk of transient early wheeze, but not with asthma or allergic rhinitis at age 5. Bar Yoseph et al.27 carried out a randomized, doubleblind, placebo-controlled trial of 6 weeks of oral vitamin D (14,000 units once weekly) in mild asthmatic children aged 6–18 years currently not receiving anti-inflammatory therapy and with low vitamin D levels. Vitamin D replacement resulted in a significant increase in vitamin levels, which remained unchanged in the placebo group, but there was no change in IgE, eosinophil count, Creactive protein, FeNO levels, or airway hyperresponsiveness following treatment. Several studies in 2014 added to our knowledge about the relationships between overweight or obesity and asthma in children. Han et al.,28 analyzing data from the 2007 to 2010 National Health and Nutrition Examination Survey, found that adiposity indicators are associated with asthma in children with low FeNO; and among children with asthma, adiposity indicators are associated with worse asthma severity or control in those with high FeNO. In a longitudinal cohort of school age children in Taiwan, low physical fitness, and high sedentary/screen time led to increased risk for both central obesity and asthma.29 Wang et al.30 found a slight but significant effect of adiposity on asthma risk in children in the U.K., but the effect of BMI and percent body fat were different. In a meta-analysis of 31 birth cohort studies in Europe, it was reported that higher infant weight gain was associated with childhood asthma outcome.31 van Leeuwen et al.32 showed that dietary induced weight loss in overweight and obese asthmatic children leads to significant reduction in severity of exercise-induced bronchoconstriction (EIB) and improvement in quality of life; reduction in BMI z-score was significantly related to the improvement of EIB. Effective biomarkers for diagnosis or assessment of asthma therapy continue to be sought. In a post hoc analysis from the Best Add-On Giving Effective Response (BADGER) study in children with persistent asthma undergoing step-up therapies, higher impulse oscillometry reactance area was associated with a better FEV1 response to LABA compared to ICS step-up, and higher urinary LTE4 levels were associated with better FEV1 response to LTRA compared to LABA.33 Smolinska et al.34 identified a set of 17 volatile organic compounds (VOC) related to oxidative stress in exhaled

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breath condensates which discriminated preschool asthmatic children from transient wheezing children. CastroRodriguez et al.35 prospectively studied 95 schoolchildren with mild and moderate persistent asthma, and suggested that measured nitrite in induced sputum may be a promising biomarker for monitoring asthmatic treatment in schoolchildren. International guidelines recommend measuring fractional exhaled nitric oxide (FeNO) during a single slow exhalation with a constant flow of 50 ml/sec. van Mastrigt and colleagues36 developed a new algorithm to compute FeNO from tidal breathing measurements, and found that geometric mean FeNO values did not differ significantly between single breath and tidal breathing technique, potentially opening the way to standardized FeNO measurements in preschool children and uncooperative patients. Peirsman et al.37 investigated the potential yield of incorporating FeNO measurements into childhood allergic asthma management. In a multicenter, randomized controlled trial, 24% of the children in the FeNOmonitored group experienced one or more exacerbations per year, compared with 48% in the control group. FeNO measurements did not improve the proportion of symptom-free days, but did result in fewer asthma exacerbations associated with step-up therapy. FeNO may be useful in preschool age children as well; reference values of fraction of exhaled nitric oxide (FeNO) using the off-line tidal breathing method in 51 healthy 1–5 year olds, were reported by van der Heijden et al.38 The method was feasible in all children, and mean FeNO was 7.1 ppb. Lung function testing continues to be an important tool in the management of both childhood and adult asthma. Schifano and colleagues39 demonstrated that even when clinical guidelines are used for asthma severity assessment, spirometry results change severity assignment in 30–35% of children. In new data from the Melbourne Asthma Study, a long term prospective study begun in 1964, Tai et al. reported a strong effect of severe early childhood asthma on clinical asthma and lung function in adult life.40 The National Asthma Education and Prevention Program (NAEPP) recommends use of spirometry during asthma hospital admissions, but Tan et al.41 reported that few children admitted with asthma had spirometry as recommended; the value of performing spirometry on asthmatic children prior to hospital discharge remained unclear and will require prospective study. In a case-control study, Yoon et al.42 compared resistance and reactance in an impulse oscillometry system as a quantitative index of bronchial hyperresponsiveness. Gochicoa-Rangel et al.43 compared lung function measured by a portable electronic device, 1 PIKO-6 , and spirometry in asthmatic and healthy children. They concluded that concordance between the two methods was lower in patients with partially Pediatric Pulmonology

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controlled or uncontrolled asthma compared to controlled or healthy children, but that longitudinal study of asthma 1 patients will be needed to assess the utility of PIKO-6 . The optimal use of standard asthma treatments as well as novel treatments continue to be studied. Beckhaus et al.44 carried out a systematic review and meta-analysis of studies comparing the use of inhaled (ICS) versus systemic corticosteroids (SC) in the emergency department setting. Based on eight studies meeting inclusion criteria, they found no evidence of a difference between ICS and SC in terms of hospital admission rates, unscheduled visits for asthma symptoms and need of additional course of SC in children consulting for asthma exacerbations. Berger et al.,45 in a randomized placebo controlled trial, compared bronchodilation among mometasone/formoterol (MF/F) metered-dose inhaler, formoterol alone (F-DPI), and placebo. MF/F (100/10 mg) demonstrated significant bronchodilation in children aged 5–11 years regardless of the use of a spacer. No difference in bronchodilation was observed between MF/F and FDPI. Galant et al.46 studied predictors of ICS responsiveness. The composite phenotype of female gender, atopic, and bronchodilator response (BDR) of 10% identified 73% as ICS responders. This suggested that the BDR in conjunction with gender and atopic status may be a potentially useful predictor of ICS response. Diagnostic Testing: Endoscopy

There are few widely accepted standards for training in pediatric flexible bronchoscopy. To begin to address this, Leong and colleagues47 surveyed U.S. training program directors for their opinions about the minimum number of procedures required for competency in flexible bronchoscopy. The median response was 50 procedures; the actual number of flexible bronchoscopies done during training averaged around 90 per trainee but ranged widely (10–200). Suggested standards for various aspects of bronchoalveolar lavage in children for translational research purposes were published by Radhakrishnan and colleagues.48 Several studies addressed the utility of relatively novel airway endoscopic procedures in children. Gilbert et al.49 described their experience with 56 interventional pulmonology procedures (diagnostic, therapeutic, and pleural) in 35 pediatric patients, over a 3-year period at a single center. A common diagnostic procedure was convex probe endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) for evaluation of adenopathy, whereas interventional procedures were often related to stent placement or tumor excision. Morbidity was minimal and the main limitation was airway size due to the need to use adult equipment, thus all procedures were in children 10 years or older (only 14 were 40% return) using the handheld technique. Thatte et al.52 reported using flexible bronchoscopy and tools usually used for intravascular foreign body retrieval, in 2 pediatric cases with distally impacted endobronchial foreign body retrieval in the cardiac catheterization laboratory. Another report describes bronchoscopic placement of one-way endobronchial valves for persistent air leak in 4 children.53 Gastroesophageal reflux and eosinophilic esophagitis are commonly considered in the workup of children with chronic respiratory symptoms. Rosen and colleagues54 carried out a prospective study to determine the diagnostic yield of gastroesophageal reflux testing, including multichannel intraluminal impedance with pH (pH-MII) and upper gastrointestinal endoscopy (EGD), in children undergoing bronchoscopy for chronic cough and wheezing. They found that 67% of patients had an abnormal pHMII test and 32% had abnormal esophageal biopsies. The most common pH-MII abnormality was an association between cough and reflux, and the most common EGD abnormality was reflux esophagitis. Seven percent of patients were diagnosed with eosinophilic esophagitis. Thus, there may be a fairly high yield for reflux testing and EGD in children with chronic cough and wheezing. In a separate publication, the same team reported greater incidence of bacterial growth in gastric secretions in the subset of this population being treated with acid suppressive medications (56% vs 18% for untreated), though there was no difference in lung bacteria. There were, however, significantly positive correlations between proximal nonacid reflux and lung concentrations of several bacterial oropharyngeal flora.55 Sleep and Breathing Disorders

Due to the high cost of polysomnography (PSG), there is interest in defining useful clinical parameters predictive of PSG abnormalities, especially in resource constrained environments. Alexopoulos et al.,56 in a 12-year retrospective study, found that children referred for PSG due to snoring who had tonsillar hypertrophy and parental history of adenoidectomy and/or tonsillectomy (AT) had high specificity for and likelihood of AHI >5. The same group reported that nocturnal enuresis was associated with moderate to severe sleep disordered breathing in snoring children.57 Kalampouka et al.58 reported that parental history of AT was a significant predictor of tonsillar hypertrophy in children referred to a pediatric pulmonary clinic for wheezing.

Pediatric Pulmonology Year in Review 2014: Part

Other means to diagnose obstructive sleep disordered breathing have been investigated. A treatment algorithm for AT based on nocturnal pulse oximetry (McGill Oximetry Score) was found to be safe and cost effective in a retrospective analysis.59 On the contrary, Tan et al.60 showed that the systematic underestimation of AHI impacts clinical decisions, especially for children with mild to moderate obstructive sleep disordered breathing. Boudewyns et al.61 reported that the use of sedation endoscopy was helpful to tailor the treatment of obstructive sleep disordered breathing in a small group of children aged 2–6 years; these results need to be confirmed. Becker et al.62 reported promising data for the use of urine biomarkers to recognize OSA in children. A retrospective study showed poor correlation between symptom questionnaire and PSG results in children with craniofacial disorders.63 Children with Down syndrome were reported to have more severe OSAS and poorer gas exchange than age matched controls with similar symptom profiles.64 Optimal use of PSG in infants is unclear due to relative lack of knowledge about normal parameters, compared to older children, and adults. Ramgopal et al.65 reported a 7year retrospective analysis of the indications and clinical courses of infants diagnosed with obstructive sleep apnea based on AHI >1. Underlying conditions were heterogeneous, and a large proportion of the infants had genetic or anatomic upper airway abnormalities; the majority of infants improved with surgical or medical treatment, based on clinical improvement, or repeat sleep study. Sleep apnea may be associated with non-respiratory complications in children. Cerebral near infrared spectroscopy (NIRS) can detect regional tissue hypoxia, and was used as an adjunct to PSG in a series of children undergoing evaluation for sleep apnea by Ullman et al.66 Scoring of PSG using regional tissue oxygenation measured by cerebral NIRS, in place of standard pulse oximetry, yielded higher AHI in children. NIRS may thus be a novel tool with potential to provide more specific information about the effects of sleep apnea in children. Patacchioli et al.67 measured salivary cortisol and amylase levels in children with OSAS, and reported evidence that OSAS is associated with dysregulation of the HPA axis. Periodic limb movements during sleep may be either triggered or unmasked by initiation of positive airway pressure in adults, and Pai et al.68 reported a retrospective study of a similar phenomenon in children, in which PLM was identified in 5% of CPAP or BiPAP titration studies. Systemic hypertension as a complication of OSAS in children appeared to be confirmed in a long term followup study reported by Li et al.69 Adenotonsillectomy is a mainstay of treatment for OSAS in children, but few randomized trials have been carried out to evaluate its impact. Katz et al.70 reported a randomized controlled trial in which children with OSAS

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(average AHI 5.1) were randomized to either early surgery or watchful waiting and supportive care. The early AT group developed obesity in the 7 months following surgery. Thus, monitoring weight, nutritional counseling, and encouragement of physical activity should be considered after AT for OSAS. Using a longitudinal database analysis of 13,500 children, Bhattacharjee et al.71 showed that AT was associated with significant improvements in several asthma outcomes, including acute asthma exacerbations, asthma-related emergency room visits, and hospitalizations, as well as decreased use of asthma medications. Validation from prospective studies is needed. Kheirandish-Gozal and colleagues72 reported their retrospective analysis of a 5-year experience with use of antiinflammatory medications (nasal corticosteroids and montelukast) for 752 children with mild OSAS. Overall, beneficial effects occurred in >80% of the children, with AT being ultimately performed in 12.3%. Follow-up PSG in a subset of 445 patients showed normalization of sleep findings in 62%, while those who showed no improvement or worsening of their OSAS tended to be older or obese. Neuromuscular Disease and Rare Lung Disorders

Novel diagnostic and treatment approaches were reported in children with respiratory insufficiency due to neuromuscular disorders (NMD). Chen et al.73 reported a prospective study of 15 children with NMD including muscular dystrophies and SMA, with acute respiratory failure due to pneumonia, who were supported with a combination of BiPAP and in-exsufflation cough assist. Three-quarters of patients successfully avoided intubation, and rapid improvement in gas exchange was also documented. The effectiveness of nocturnally assisted ventilation to treat neuromuscular hypoventilation in motor neuron disease and Duchenne muscular dystrophy (DMD) was endorsed in a Cochrane Report.74 Studies provided additional support for the feasibility of continuous noninvasive ventilation for long-term support of DMD patients with advanced respiratory failure and for the use of noninvasive ventilation and mechanically assisted coughing to facilitate extubation and recovery after spinal fusion surgery in children with NMDs.75,76 Finkel and colleagues77 carried out a novel exploratory study measuring respiratory muscle function in 7 infants with type I spinal muscular atrophy (SMA-I). A variety of measures of respiratory muscle strength and fatigability were performed in unsedated infants, in some cases repeatedly over time, and found to be safe and potentially useful for clinical care or as outcomes for clinical trials. A study of the relatively passive forced oscillation technique for measuring respiratory impedance in 12 children with type 2 or type 3 SMA suggested that this technique may yield data significant correlation with data from spirometry and sleep studies.78 Khirani et al.79 reported a Pediatric Pulmonology

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comprehensive panel of lung function tests over time in a cohort of children with DMD, confirming that FVC, and nasal inspiratory pressures are important noninvasive parameters documenting the evolution of respiratory weakness. Finally, LoMauro et al.80 described reduced abdominal contribution to tidal breathing among patients with DMD and inefficient cough. Our understanding of diffuse and interstitial lung diseases of childhood continues to advance. Hamvas and colleagues81 summarized presentations from a 2012 conference on childhood diffuse lung diseases (DLD). This conference highlighted research relevant to genetic surfactant protein disorders, proteomic approaches, genomic, and epigenomic factors, experimental mouse models of DLD, airway epithelial progenitor cells, and pluripotent stem cells. Wambach et al.82 reviewed all ABCA3 sequence and phenotype data from their prospective genetic studies of symptomatic infants and children at 2 centers, and found that frameshift or nonsense ABCA3 mutations are predictive of neonatal presentation and poor outcome, whereas other mutation types have more variable outcomes. Avital et al.83 described 5 adults with known surfactant protein C mutations (3 with p.I73T and one each with p.I38F and p.V39L) who received hydroxychloroquine treatment as young children and had good long term outcomes. While these disorders often have a genetic basis, in some cases environmental exposures play a role. Kim and colleagues84 reported a remarkable epidemiologic study linking an annual spike in severe, often fatal interstitial lung disease cases among previously-healthy Korean infants, over a 5-year period, to the use of a humidifier disinfectant; suspension of sales of the disinfectant eliminated the pattern. The genetic basis and clinical course of primary ciliary dyskinesia (PCD) are becoming clearer. Knowles et al. reported that patients with mutations in RSPH1 are associated with a milder PCD clinical phenotype. The association between PCD and specific features of respiratory distress in full-term neonates was further explored by Mullowney et al.85 in a single-center, casecohort study. Maglione et al.86 analyzed spirometry, BMI and other factors over a 6-year period in 158 children with PCD followed at several European centers. H. influenzae was the most common pathogen isolated (65% of patients), while P. aeruginosa was found in 37%, but neither pathogen was associated with spirometry changes. A randomized crossover study compared the effect of short term conventional chest percussion/postural drainage versus high frequency chest wall oscillation on lung function in children with PCD, and found that both techniques improved spirometric indices.87 In a retrospective study of 18 pediatric sarcoidosis cases over a 16-year period, Sileo et al.88 found that highresolution CT findings were similar to adults (nodules, ground-glass opacities). While HRCT findings at Pediatric Pulmonology

diagnosis did not correlate with lung function, specific dynamic compliance and spirometric changes over time did correlate with HRCT changes, suggesting that lung function might be used to reduce the need for some radiation exposures in these patients. REFERENCES 1. Sarria EE, Mattiello R, Yao W, Chakr V, Tiller CJ, Kisling J, Tabbey R, Yu Z, Kaplan MH, Tepper RS. Atopy, cytokine production, and airway reactivity as predictors of pre-school asthma and airway responsiveness. Pediatr Pulmonol 2014;49:132–139. 2. Raedler D, Ballenberger N, Klucker E, Bock A, Otto R, Prazeres da Costa O, Holst O, Illig T, Buch T, von Mutius E, et al. Identification of novel immune phenotypes for allergic and nonallergic childhood asthma. J Allergy Clin Immunol 2015;135:81–91. 3. Howrylak JA, Fuhlbrigge AL, Strunk RC, Zeiger RS, Weiss ST, Raby BA. Classification of childhood asthma phenotypes and long-term clinical responses to inhaled anti-inflammatory medications. J Allergy Clin Immunol 2014;133:1289–1300. 1300 e1281–1212. 4. Akinbami LJ, Moorman JE, Simon AE, Schoendorf KC. Trends in racial disparities for asthma outcomes among children 0 to 17 years, 2001–2010. J Allergy Clin Immunol 2014;134:547– 553. e545. 5. Kenyon CC, Melvin PR, Chiang VW, Elliott MN, Schuster MA, Berry JG. Rehospitalization for childhood asthma: timing, variation, and opportunities for intervention. J Pediatr 2014;164:300–305. 6. Moerman JN, Ratjen F, Subbarao P, Sears MR, Anand SS, Stanojevic S. The prevalence of asthma in Canadian children of South Asian descent. Pediatr Pulmonol 2014;49:43–48. 7. Beck AF, Huang B, Simmons JM, Moncrief T, Sauers HS, Chen C, Ryan PH, Newman NC, Kahn RS. Role of financial and social hardships in asthma racial disparities. Pediatrics 2014;133:431–439. 8. Newman NC, Ryan PH, Huang B, Beck AF, Sauers HS, Kahn RS. Traffic-related air pollution and asthma hospital readmission in children: a longitudinal cohort study. J Pediatr 2014;164:1396– 1402. e1391. 9. Brandt S, Perez L, Kunzli N, Lurmann F, Wilson J, Pastor M, McConnell R. Cost of near-roadway and regional air pollutionattributable childhood asthma in Los Angeles County. J Allergy Clin Immunol 2014;134:1028–1035. 10. Howrylak JA, Spanier AJ, Huang B, Peake RW, Kellogg MD, Sauers H, Kahn RS. Cotinine in children admitted for asthma and readmission. Pediatrics 2014;133:e355–e362. 11. Rodriguez-Martinez CE, Sossa-Briceno MP, Castro-Rodriguez JA. Predictors of hospitalization for asthma in children: results of a 1-year prospective study. Pediatr Pulmonol 2014;49:1058–1064. 12. Kobayashi Y, Bossley C, Gupta A, Akashi K, Tsartsali L, Mercado N, Barnes PJ, Bush A, Ito K. Passive smoking impairs histone deacetylase-2 in children with severe asthma. Chest 2014;145:305–312. 13. Gunawardhana LP, Baines KJ, Mattes J, Murphy VE, Simpson JL, Gibson PG. Differential DNA methylation profiles of infants exposed to maternal asthma during pregnancy. Pediatr Pulmonol 2014;49:852–862. 14. Sordillo JE, Scirica CV, Rifas-Shiman SL, Gillman MW, Bunyavanich S, Camargo CA, Jr., Weiss ST, Gold DR, Litonjua AA. Prenatal and infant exposure to acetaminophen and ibuprofen and the risk for wheeze and asthma in children. J Allergy Clin Immunol 2015;135:441–448.

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