Accepted Manuscript

Advances in Asthma 2016: Designing Individualized Approaches to Management

William C. Anderson, III, MD, Andrea Apter, MS, MA, MSc, Cullen M. Dutmer, MD,
Daniel A. Searing, MD, Stanley J. Szefler, MD

PII: S0091-6749(17)31093-X
DOI: 10.1016/j.jaci.2017.06.015
Reference: YMAI 12904

To appear in: Journal of Allergy and Clinical Immunology

Received Date: 14 April 2017

Revised Date: 26 June 2017
Accepted Date: 27 June 2017

Please cite this article as: Anderson III WC, Apter A, Dutmer CM, Searing DA, Szefler SJ, Advances
in Asthma 2016: Designing Individualized Approaches to Management, Journal of Allergy and Clinical
Immunology (2017), doi: 10.1016/j.jaci.2017.06.015.

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1 Advances in Asthma 2016:

2 Designing Individualized Approaches to Management

4 William C. Anderson III, MD,1 Andrea Apter, MS, MA, MSc, 2 Cullen M. Dutmer, MD, 1

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5 Daniel A. Searing, MD, 1 Stanley J. Szefler, MD3

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7 Allergy & Immunology Section, Childrens Hospital Colorado and University of

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8 Colorado School of Medicine, Aurora, CO
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9 Section of Allergy & Immunology, Perelman School of Medicine, University of

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10 Pennsylvania, Philadelphia, PA AN
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11 The Breathing Institute and Pulmonary Medicine Section, Childrens Hospital Colorado

12 and University of Colorado School of Medicine, Aurora, CO

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14
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15 Disclosure of potential conflict of interest: S.J. Szefler has consulted for Aerocrine,

16 Astra Zeneca, Boehringer-Ingelheim, Glaxo Smith Kline, Genentech, Novartis, Roche,

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17 and Teva and has received research support from the National Institutes of Health, the

18 National Heart, Lung and Blood Institute, GlaxoSmithKline, and the Colorado Cancer,
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19 Cardiovascular and Pulmonary Disease Program. Dr. Apter has received research
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20 support from the National Institutes of Health, the National Heart, Lung, and Blood

21 Institute; the Patient-Centered Outcomes Research Institute, and Bristol Myers

22 Squibb/AstraZeneca. No disclosures for W. Anderson, C. M. Dutmer or D.A, Searing.

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24 Corresponding Author:

25 Stanley J. Szefler, MD

26 Director, Pediatric Asthma Research Program

27 The Breathing Institute

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28 Section of Pulmonary Medicine

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29 Children's Hospital Colorado

30 13123 E 16th Ave

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31 Box 395

32 Aurora, CO 80045

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33 Phone: 720-777-0985 AN
34 FAX: 720-777-7284

35 e-mail: Stanley.Szefler@childrenscolorado.org
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36 Abbreviations

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38 AHR - airway hyperresponsiveness

39 APIC - Asthma Phenotypes in the Inner City

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40 BAL - bronchoalveolar

41 CAMP - Childhood Asthma Management Program

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42 CHW - community health workers

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43 COPD - chronic obstructive pulmonary disease

44 DENND1B - differentially expressed in normal and neoplastic cells domain 1B

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45 DEP diesel exhaust particle

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DMRT1 - Doublesex and mab-3 related transcription factor 1

47 FDA - Food and Drug Administration

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48 FEF25-75 - forced expiratory flow between 25% and 75% of the forced vital capacity

49 FEV1 - forced expiratory flow in one second

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50 HDM - house dust mite

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51 ICS - inhaled corticosteroid

52 ILC2s - innate lymphoid cells

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53 LABA - long-acting beta-agonist

54 miRNA - microRNA
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55 NAEPP - National Asthma Education and Prevention Program

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56 NIH National Institutes of Health

57 PCORI Patient-Centered Outcomes Research Institute

58 PEF - peak expiratory flow

59 Post-AAI - postallergic airway inflammation

60 rAMs - resident alveolar macrophages

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61 RSV respiratory syncytial virus

62 RV rhinovirus

63 SABA - short-acting beta-agonist

64 SLIT sublingual immunotherapy

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65 SNP - single nucleotide polymorphism

66 TET1 - Ten-eleven translocation 1

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67 TLR toll-like receptors

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68 TRAP traffic related air pollution

69 TSLP - thymic stromal lymphopoietin

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70 WHO - World Health Organization

71 YKL-40 - chitinase 3-like protein-1

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76

77 ABSTRACT

78 In this years Advances in Asthma review we discuss viral infections in asthma and

79 potential therapeutic agents, the microbiome, novel genetic associations with asthma,

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80 air quality and climate effects on asthma, exposures during development and long term

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81 sequelae of childhood asthma, patient centered outcome research, and precision

82 medicine. In addition, we discuss application of biomarkers to precision medicine, and

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83 new information on asthma medications. New evidence indicates that rhinovirus-

84 triggered asthma exacerbations become more severe as the degree of sensitization to

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85 dust mite and mouse increase. The two biggest drivers of asthma severity were an
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86 allergy pathway starting with allergic sensitization and an environmental tobacco smoke

87 pathway. In addition, allergic sensitization and blood eosinophils can be used to select
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88 medications for management of early asthma in young children. These current findings,
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89 among others covered in this review, represent significant steps towards addressing
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90 rapidly advancing areas of knowledge that have implications for asthma management.

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92 Word Count: 5,672

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94 Key Words: air quality, airway hyperreactivity, allergen immunotherapy, allergen

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95 sensitization, allergy, asthma, biomarkers, climate, COPD, eosinophils, exacerbation,

96 exhaled nitric oxide, genetics, ligelizumab, medication adherence, microbiome, patient-

97 centered outcomes, pregnancy, prenatal exposures, respiratory syncytial virus,

98 rhinovirus, rofumilast, tiotropium

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100 Introduction

101 Last years Advances in Asthma focused on asthma across the lifespan and

102 reported on some key observations related to asthma inception, the microbiome, and

103 the epigenome. In addition, some aspects of predicting and preventing asthma

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104 exacerbations were featured (1). It is now clear that scientific advances are being made

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105 in many areas related to asthma, such as, epidemiology, immunology, microbiology,

106 genetics, biomarkers, and new medications, so much so that it is a challenge for those

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107 writing asthma guidelines and strategies to synthesize this work and rapidly apply it to

108 clinical practice. Therefore, reviews of key discoveries are important to keep the

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109 clinician abreast of these findings, so that they might be considered in the clinical setting
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110 while they await integration into asthma guidelines. This year, we discuss new findings

111 reported in the Journal and other publications that relate to respiratory infections, air
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112 quality, factors that influence long-term outcomes, patient-centered outcomes research,
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113 precision medicine and new observations related to medications and asthma
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114 management.

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116 Viral Infections in asthma and the promise of therapeutic targets

117 Respiratory viruses remain a key trigger of asthma exacerbations, providing

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118 insight into the evolution and pathophysiology of asthma. In a prospective observational
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119 cohort study involving 183 asthmatic children ages 6 to 17 years, Kantor et al (2) found

120 that subjects with rhinovirus (RV) infection had more severe exacerbations than those

121 participants with virus-negative exacerbations. In this cohort, RV-triggered asthma

122 exacerbations became more severe as the degree of sensitization to dust mite and

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123 mouse increased. Akin to the more severe exacerbations appreciated in the rhinovirus-

124 infected children in the aforementioned study, Ducharme et al (3) performed a large,

125 prospective, multicenter, cohort study in emergency departments revealing that viral

126 detection was associated with failure of symptom management. Analyses from a large,

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127 prospective cohort of adults enrolled in an influenza surveillance study revealed that RV

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128 infection is prevalent in adults, with 11% of nasal/throat swabs testing positive for RV in

129 adults presenting to the hospital, emergency department, or outpatient clinic with acute

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130 respiratory illness or fever (43).

131

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132 In 2016, there was elucidation into the immune response induced by virus-
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133 triggered asthma exacerbations, identifying or further characterizing potential

134 therapeutic targets. Han et al (5) illustrated the role of toll-like receptor (TLR) 2-
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135 expressing macrophages in the airway inflammatory response to RV, noting that TLR2+
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136 macrophages were required for early stages of airway inflammation in their murine
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137 model. Additionally, transfer of wild-type macrophages to Tlr2 knockout mice was

138 sufficient to confer airway inflammation after RV infection. When IL-4-treated

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139 macrophages were similarly transferred, features akin to RV-infected mice with allergic

140 airways disease were observed. Assessing the role of resident alveolar macrophages
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141 (rAMs) in respiratory syncytial virus (RSV) infection, Naessens et al (6) devised a post
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142 allergic airway inflammation (post-AAI) murine model in which treatment with GM-CSF

143 abrogated RSV-induced inflammation and airway hyperreactivity by means of maturing

144 an apparent immature phenotype appreciated in the post-AAI rAM population. Through

145 repeated inoculation of mice with low-dose virus and cockroach allergen, Lynch et al (7)

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146 showed that co-exposure of respiratory virus and cockroach allergen induced a biphasic

147 IL-33 response and impaired antiviral interferon production. Furthermore, IL-33

148 negatively regulated TLR7 signaling. Studying effects of RSV infection on group 2

149 innate lymphoid cells (ILC2s), another murine model showed proliferation and activation

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150 of IL-13-producing ILC2s via thymic stromal lymphopoietin (TSLP)-dependent

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151 mechanisms (8).

152

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153 Characterization of the airway microbiome

154 Through detailed assessments of the airway microbiome, key differences

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155 between asthmatics, non-asthmatics, and those at risk for asthma have been
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156 characterized. Regarding at-risk populations, the nasopharyngeal microbiota of over

157 one-thousand infants with bronchiolitis was analyzed as part of a large multicenter study
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158 (9). In this prospective cohort, infants with bronchiolitis due to RSV had a high
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159 abundance of Firmicutes and the genus Streptococcus and a low abundance of
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160 Proteobacteria and the genera Haemophilus and Moraxella, while infants with

161 bronchiolitis due to RV had the opposite pattern. It is not clear if viral infections
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162 increase certain bacterial populations within a community and/or microbial community

163 populations create environments suitable for viruses (9).

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164 Addressing older individuals with established atopic phenotypes, a study

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165 orchestrated by AsthmaNet obtained bronchial brushings from 42 steroid-nave, atopic

166 asthmatic adults, 21 non-asthmatic but atopic adults, and 21 healthy control adults (10).

167 By profiling samples via 16S rRNA gene sequencing, distinct differences in the

168 bronchial bacterial microbiomes were appreciated in the 3 groups. Among asthmatic

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169 adults, the bronchial microbiome at baseline differed according to their responsiveness

170 to inhaled corticosteroid treatment. In a cross-sectional retrospective study assessing

171 adult asthmatics that were not steroid-naive, Denner et al (11) noted significant

172 differences in the bronchial microbiome based on corticosteroid treatment. Further still,

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173 Sverrild et al (12) found that the level of eosinophilic airway inflammation correlates with

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174 variations in the microbiome across asthmatic patients.

175

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176 Novel genetic associations with asthma and biologic impact of known gene

177 variants

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178 By discovery of new associations and demonstration of the biologic effects of
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179 known gene variations, the link between genetic changes and asthma expanded in

180 2016 (Table 1). Doublesex and mab-3 related transcription factor 1 (DMRT1) emerged
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181 as a novel candidate to potentially explain sex-specific asthma effects during childhood
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182 (13). A single nucleotide polymorphism (SNP) on chromosome 8 was associated with
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183 early lung function decline in two asthma cohorts, which was also associated with

184 chronic obstructed pulmonary disease (COPD) (14). Exploring the mechanism by which
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185 SNPs at the differentially expressed in normal and neoplastic cells domain 1B

186 (DENND1B) locus might lead to the development of asthma in young children, a
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187 Dennd1b knockout mouse model demonstrated the role of DENND1B in T cell receptor
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188 downmodulation in TH2 cells (15). A new locus associated with time to asthma onset

189 was identified at position 16q12 (16). Investigating the role of the previously reported

190 17q21 locus in asthma, a study by Schmiedel et al (17) detailed the deleterious effects

191 exerted by asthma-risk variants on T cells. By analyzing the asthma-risk variant Glu-to-

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192 Arg substitution at position 576 of human IL-4R, new insights into the role of regulatory

193 T cells and the development of TH2-TH17 inflammation were presented (18). Further

194 assessing the known Gly-to-Arg substitution at the 16 position in the 2-adrenoceptor

195 gene, asthmatic children recruited from 5 cross-sectional studies identified the

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196 increased risk of asthma exacerbation with use of long-acting -agonists in children

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197 carrying 1 or 2 alleles of the aforementioned substitution (19).

198

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199 The influence of air quality and climate on asthma

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200 Annesi-Maesano provided an overview of allergy specific health issues emerging

201
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due to climate change, as well as future directions regarding climate related health.

202 Worldwide, only 12% of urban populations breath air that complies with World Health
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203 Organization (WHO) Air Quality Guidelines. Citing NASA data, we learn not only that

204 the earth has experienced a 0.8C/1.4F average glo bal temperature increase since the
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205 1880s, but also that two-thirds of this warming has occurred since 1975. Components
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206 and consequences of this change: air pollution, floods, and plant life adaptation will
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207 impact population health, with the most vulnerable areas most effected, as well as our

208 most vulnerable patients: the elderly, young, and poor (20). In the face of evolving
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209 climate challenges, new research has helped refine our understanding of how indoor
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210 and outdoor environments interact with the immune system and influence pulmonary

211 physiology (Table 2).

212 Multiple letters to the editor in the fall of 2016 edition of JACI examined traffic

213 related air pollutions (TRAP) influence on asthma. A median regression analysis of

214 patients in a large birth cohort showed a significant association between increased

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215 exposure to traffic-NOx in the first year of life and increased adolescent airways

216 resistance and reactance (21). Adolescent, self-reported psychosocial stress also

217 seems to influence estimated pulmonary effects of TRAP. TRAP was associated with

218 larger negative effects on lung function in households without a father present

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219 compared to homes with a father present. The authors speculate that hypothalamic

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220 axis modification secondary to stress might modulate immune function and enhance

221 susceptibility to air pollution (22).

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222 TRAP may also affect steroid sensitivity. In a mouse model of allergen-induced

223 asthma with diesel exhaust particle (DEP) exposure, 4 days of dexamethasone

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224 treatment only partially reduced airway hyperresponsiveness (AHR) in mice exposed to
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225 both house dust mite (HDM) and DEP. These HDM + DEP exposed mice were noted to

226 have greater airway neutrophilia compared to HDM only exposed mice. Anti-IL17A
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227 treatment in combination with dexamethasone significantly reduced AHR compared with
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228 either treatment alone (23).

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229 Asthmatics suffer clinical symptoms quickly when exposed to worsening air

230 quality. Explanations of the mechanism of this rapid sensitivity are now being reported.
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231 Many articles, as well as a recent review in JACI (24), have explained how innate

232 lymphoid cells (ILCs) are emerging as key contributors to the pathogenesis of
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233 inflammatory disease. Group 2 ILCs produce type 2 cytokines, such as IL-4, IL-5, IL-9,
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234 and IL-13, upon stimulation with epithelium-derived cytokines, such as IL-33, IL-25, and

235 TSLP.

236 A recent report by Yang et al revealed that BALB/c allergen-sensitized and

237 allergen-challenged mice had elevated eosinophils in bronchoalveolar (BAL) fluid

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238 following O3 exposure (25). IL-5 release occurred within 12 hours after O3 exposure,

239 notably without increased TH2 cells in the lung. Importantly, depletion of both ILCs and

240 T cells, but not specific depletion of CD4+ TH cells, abolished IL-5 release in BAL-fluid of

241 O3 exposed mice. These findings confirmed that ILC2s were the major source of IL-5

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242 following O3 exposure. The group went on to demonstrate a relationship between ILC2

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243 and enhanced AHR in the setting of O3 exposure (25). The timeline and pattern of

244 inflammation in this study: type 2 cytokine release within hours leading to increased

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245 AHR following TRAP, helps describe how asthmatics may experience symptoms

246 quickly and have heightened sensitivity to air pollution.

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247 Previous work has shown that TRAP is associated with DNA methylation
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248 variation. Ten-eleven translocation 1 (TET1) enzyme is a promoter of DNA

249 demethylation. Cross sectional data from non-twin siblings discordant for asthma, born
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250 and raised in the same household, showed an association between asthma status and
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251 demethylation of a CpG site in the promoter region of the TET1 gene. In addition, this
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252 study showed that methylation of the same CpG site was associated with TRAP

253 exposure (26). The exact role of TET1 in influencing these associations remains
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254 unknown, and the authors suggest TET1 warrants further study as a possible systemic

255 biomarker for childhood asthma.

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256 In addition to air pollutions effects, data continues to emerge on specific

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257 microbial exposures that may influence asthma development. Fungal and bacterial

258 community characteristics were measured in the main living area of asthmatic children

259 using next-generation DNA sequencing technology. Participants were selected at the

260 extremes of asthma severity. Amongst all children, increased asthma severity was

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261 associated with high concentrations of allergenic species, high total fungal

262 concentration, and increased bacterial richness. In addition, fungal and bacterial

263 community composition shared more similarities in homes of severe asthmatics

264 compared to mild asthma. While no specific bacterial operational taxonomic units were

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265 significantly associated with asthma severity, the fungal genus Volutella was found to be

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266 associated with asthma severity (27).

267 Prior work has shown that children raised on traditional dairy farms demonstrate

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268 protection from asthma and allergic disease. Stein et al recently looked at

269 environmental exposures, genetic ancestry, and immune profiles in both Amish and

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270 Hutterite U.S. populations (28). These two groups live similar lifestyles with the notable
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271 exception that the Hutterites utilize more industrialized farming practices. Genome wide

272 SNPs compared allele frequencies and showed strong similarities between the groups,
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273 indicating similar genetic ancestry. Markers of atopy were lower in the Amish group
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274 than the Hutterite group. After 1 month of sampling from electrostatic dust collectors in
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275 10 homes from both groups, Amish homes had endotoxin 6.8 times higher than

276 Hutterite homes. Amish children had increased proportions of neutrophils, lower
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277 proportions of eosinophils, and monocytes with a more suppressive phenotype than

278 Hutterite children. The Amish also had genetic overexpression of components of the
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279 innate immune response to microbial stimuli. An ovalbumin mouse model of allergic
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280 asthma, following administration of Amish house dust intranasally, demonstrated

281 inhibited AHR, BAL eosinophilia, and ovalbumin specific IgE (28). For additional

282 information on the microbiomes influence on early asthma development, readers are

283 directed to the recent review by Erika von Mutius (29).

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284

285 Exposures during different stages of development and long term sequelae of

286 childhood asthma

287 Amongst the well described risk factors for asthma, recent research is helping to

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288 define the level of influence these risk factors have. The Inner City Asthma Consortium

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289 conducted a causal network analysis on a conceptual model of 8 potential asthma risk-

290 factor domains. They found that the model could explain about 50% of the variance in

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291 asthma severity. The two biggest drivers of asthma severity were an allergy pathway

292 starting with allergic sensitization and an environmental tobacco smoke pathway.

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293 Among the individual domains, pulmonary physiology and rhinitis severity had the
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294 largest effects on asthma severity (30). Analysis of an Australian longitudinal birth

295 cohort demonstrated that allergic sensitization by 12 months of age was associated with
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296 increased risk of wheeze during young adulthood, as well as lower FEV1, FEV1/FVC
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297 ratio, and FEF25-75 at 24 years of age (31). The contribution of allergic sensitization and
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298 respiratory pathogens (viral, as well as bacterial) was reviewed last year by Jackson

299 and colleagues for the clinical reviews series in JACI (32).
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300 In a pregnancy cohort, the relative importance of prenatal and postnatal stress on

301 asthma was assessed. After adjusting for confounders, a dose-response relationship
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302 emerged with an increase in the odds of asthma diagnosis for each increase in maternal
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303 stress category both prenatally and postnatally (33). A meta-analysis found that

304 compared with term-born children, premature children had a lower FEV1, FEV1/FVC

305 ratio, and FEF75 at a mean age of 8.5 years. Similar findings were seen in children born

306 with low birth weight. Mediation analyses suggested that FEV1, FEV1/FVC, and FEF75

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307 might explain 7-45% of the associations between early growth characteristics and

308 asthma. These associations were present across the full range of early growth, an

309 observation with possible population health implications (34).

310 In addition to defining early influencers of airflow obstruction, we are learning

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311 more about the long term effects of airflow obstruction. A latent class analysis of over

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312 12,000 participants followed from infancy into adolescence identified 6 different

313 wheezing phenotypes. Phenotypes characterized by remitting symptoms in later

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314 childhood still were associated with lung function deficits in adolescence compared to

315 the never/infrequent wheezing phenotype. All 3 phenotypes with persistent symptoms

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316 had strong associations with diagnosed asthma, bronchodilator reversibility, and high
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317 exhaled nitric oxide values in adolescence. Late onset wheezing was not associated

318 with airway obstruction by 15 years. The associations suggest wheezing illnesses with
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319 onset early in life have a greater influence on lung function than wheezing duration (35).
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320 McGeachie and colleagues highlighted long term deficiencies in lung function in
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321 Childhood Asthma Management Program (CAMP) participants followed into the third

322 decade of life. Despite this cohort comprising mild to moderate asthmatics,
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323 investigators found that a high proportion (75%) of subjects had reduced lung function

324 as adults. Notably, 11% of participants met spirometric criteria for COPD (36).
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326 Patient-centered outcomes research reflects patient priorities and engages

327 stakeholders

328 The National Asthma Education and Prevention Program (NAEPP) Expert Panel

329 Report (37), last updated in 2007, provides guidance for the management of asthma. It

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330 is informed for the most part by efficacy studies. These narrowly defined studies include

331 patients most likely to benefit and who are treated under the most promising conditions.

332 However, a limitation of these well-controlled studies is that the interventions are not

333 always effective when applied in the real-world, do not take into account the uniqueness

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334 of patients and their environments, and often exclude those with comorbidities. This

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335 limitation is particularly evident when applying recommendations to patients from low

336 income and minority communities where resources are limited and social barriers to

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337 accessing healthcare and carrying out management recommendations are common

338 (38).

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339 Additionally, interventions prompting guideline recommendations may not reflect
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340 individual patient priorities, for example a patients concern about taking many

341 medications for a variety of conditions or their cost. Thus, patient-centered studies are
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342 needed to address health disparities. The December issue of the Journal is devoted to
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343 patient-centered comparative effectiveness research focusing on research funded by

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344 the Patient-Centered Outcomes Research Institute (PCORI). PCORIs mission is to

345 fund comparative effectiveness research that allows patients and other stakeholders of
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346 research to make informed health decision (39).

347 In presenting the PCORI perspective, Anise and Hasnain-Wynia argue for the
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348 importance of engaging these stakeholders, which include patients and healthcare
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349 providers, in all aspects of the research, that is, the development of the intervention

350 design, selection of outcome measures, refinement and conduct of the research,

351 analysis, and reporting of the results (40). Bryant-Stephens and colleagues describe

352 the experiences of community health workers (CHWs) as they make home visits to

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353 asthmatic adults in low-income urban neighborhoods, many living in one-room

354 apartments or overcrowded spaces with many family members (41). Martin and

355 colleagues report the challenges of overcoming barriers in transitioning care for children

356 with asthma from the emergency department to stable consistent outpatient care (42).

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357 An analysis of the methodologies of 8 PCORI-funded studies concludes with

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358 recommendations for modifying traditional research methodology to overcome

359 obstacles in patient-centered intervention research. Modifications may include devoting

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360 more resources than in a traditional study for recruitment and conduct of the study in

361 order to maintain enrollment and to minimize but account for missing data (43).

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363 Clinical Risk Factors

364 Wells and colleagues (44) add support to this patient-centered approach by
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365 demonstrating that neither self-reported race-ethnicity nor race defined by genetic
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366 ancestry predicted ICS response; rather baseline lung function and self-reported
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367 asthma control do, emphasizing the need to find ways to ensure optimal lung function,

368 asthma control, and elimination of barriers to accessing care. Szentpetery and
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369 colleagues (45) describe asthma risk factors among Puerto Ricans, including exposure

370 to environmental tobacco, violence, pollution, and psychological stress along with
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371 personal risk factors such as obesity, difficult access to health care, and low health
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372 literacy. The authors conclude multifactorial interventions are needed (45).

373 Liu et al (30) in the longitudinal Asthma Phenotypes in the Inner City (APIC)

374 Study analyzed pathways through which risk factors contribute to asthma severity in

375 inner city children, suggesting multi-factorial interventions such as exposure to

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376 environmental tobacco smoke and to allergens, will address asthma severity (Table 3).

377 Their model explained 53.4% of the variance in asthma severity of the cohort of 561

378 children. The authors illustrated their points using a new Journal feature, a graphical

379 abstract. In another APIC analysis, Zoratti et al (46) used cluster analysis to define

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380 phenotypes of inner city children with asthma, including one phenotype of severe

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381 asthmatic children that were highly allergic. Also from the APIC Study, Pongracic et al

382 (47) examined children and adolescents with difficult to control asthma, defined as

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383 requiring high dose inhaled corticosteroids, and found them distinguishable from those

384 requiring only low dose inhaled corticosteroids by FEV1 bronchodilator responsiveness,

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385 rhinitis severity, and atopy. Other studies found exacerbations vary by season in inner-
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386 city asthma children [48] and in youth living in poverty whether urban or rural [49,

387 50]]The pathways and heterogeneity of risk factors emphasize that in multifactorial
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388 intervention studies informed by these analyses, addressing poverty and engaging the
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389 children and their caretakers in interventions is essential.

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390 In considering patient engagement in healthcare, navigating skill, the ability to

391 access healthcare and communicate with providers, is an important skill. Perez et al
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392 (51) developed and validated a questionnaire with input from patients to assess

393 navigation. More important than the development of the questionnaire, they found an
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394 item of the questionnaire, also routinely a part of a patient-provider interview (for
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395 example: Tell me the names of your asthma medications) was correlated with more

396 general health literacy. Thus, a routine interview question yields much information about

397 the patient.

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399 Precision Medicine

400 In January 2015 President Obama proposed a Precision Medicine Initiative (52)

401 considering each patients uniqueness and the need for tailoring treatment to take into

402 account individual variability in genes, environment, and lifestyle. This initiative aligns

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403 with translational and comparative effectiveness research seeking to understand

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404 environmental, clinical, and lifestyle risk factors that characterize phenotypes and

405 identifying the biomarkers to help define the pathophysiologic mechanisms or

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406 endotypes in order to tailor preventive and ongoing medical care for each individual (53

407 - 55).

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408 Berry and Busse review currently used biomarkers (56). Muraro and coauthors
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409 collaborated under PRACTALL, an initiative of the European Academy of Allergy and

410 Clinical Immunology and the American Academy of Allergy, Asthma & Immunology, to
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411 harmonize approaches and to summarize endotypes and validation of biomarkers in

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412 order to develop precision medicine for management of asthma and other atopic
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413 diseases (57). With this focus on biomarkers, how exposure to the environment

414 including the microbiome, and also how the phenotype of poverty (41) result in relevant
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415 biomarkers needs to be understood. Thus, the contributions of real-world and

416 comparative effectiveness research with participation from stakeholders are essential to
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417 complete the translation of research from bench to bedside (53).

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419 Application of biomarkers to personalized medicine

420 In 2012, the Journal published a report from the NIH Asthma Outcomes Task

421 force to summarize relevant outcomes for NIH asthma research. One of the sections

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422 was on physiology and listed various physiologic measures as core (should be included

423 in all asthma research), supplementary (applied in selected research), and exploratory

424 (intended to be evaluated for potential application) (58). AHR by methacholine

425 challenge was listed as a supplemental measure. Pralong et al (59) reported on the

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426 predictive value of nonspecific airway responsiveness in bronchial asthma. Based on

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427 data from a Canadian database of 1,012 cases, they indicated that a negative

428 methacholine challenge in a patient still exposed to the causative agent at work makes

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429 the diagnosis of occupational asthma unlikely.

430 The Outcomes Report stated that FEF25-75 is not a specific measure of small

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431 airway obstruction, but could be chosen as an endpoint, however its value is less
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432 established (58). Siroux et al (60) studied 337 participants with 142 children and 225

433 adults for persistence of current asthma and risk for uncontrolled asthma and concluded
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434 that decreased FEF25-75, as an indicator of small airway obstruction, might contribute to
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435 long-term persistence of asthma and subsequent risk for poor asthma outcomes
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436 independently from effects of the large airways.

437 Another section of the NIH Outcomes Task Force addressed biomarkers (56).
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438 Berry and Busse (56) provided an updated review on biomarkers in asthma and

439 indicated that certain biomarkers, such as sputum and blood eosinophils, can help
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440 define the specific pathophysiology of different asthma phenotypes and identify potential
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441 therapeutic agents. Similarly, Muraro et al (57) indicated that progress has been made

442 in profiling the type 2 immune-response driven asthma, but the endotype driven

443 approach for non-T2 immune response for asthma is lagging behind. It will be important

444 to define validated and qualified biomarkers for research and for precision medicine.

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445 Skevaki et al (61) indicated that biomarker discovery and validation in children with

446 disease lag behind those in adults; given the early onset and potential lifelong effect of

447 the disease. The ultimate challenge will be optimization of prevention strategies that can

448 be implemented in children identified as being at risk of a noncommunicable disease,

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449 such as asthma, through the use of biomarkers.

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450 Blood and sputum eosinophils, along with exhaled nitric oxide were listed as

451 supplementary biomarkers to be considered optional in asthma research (62) (Table 4).

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452 Zeiger et al (63) reported observations from a Kaiser-Permanente Southern California

453 database of patients 12 years and older, that a high blood eosinophil count (400

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454 cells/mm3) was an independent risk factor for 2 or more asthma exacerbations or any
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455 asthma emergency department visit or hospitalization, but not direct costs in patients

456 with severe uncontrolled asthma.

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457 A study conducted in the NHLBI AsthmaNet reported that in young children with
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458 asthma necessitating Step 2 treatment, phenotyping with allergen sensitization,

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459 considered a core biomarker in the Asthma Outcomes Report, and a blood eosinophil

460 count of 300 cells/mm3 or greater, is a useful guide for treatment selection and identifies
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461 children with a high exacerbation probability for whom treatment with a daily inhaled

462 corticosteroid is beneficial despite risks of growth suppression (64).

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463 A Paradigms and Perspectives review (65) summarized key lessons learned for
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464 the application of exhaled nitric oxide in clinical practice. Exhaled nitric oxide

465 measurement can be an important tool in the management of asthma and there is a

466 need for asthma guidelines to define its application, so that it can be more readily

467 applied in the primary care setting, where the majority of asthma patients are managed.

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468 Additional reports demonstrated that a combined high exhaled nitric oxide level and

469 blood eosinophils related to a higher likelihood of AHR and uncontrolled asthma in

470 young asthmatic patients (66).

471 Michils et al (67) measured exhaled nitric oxide in relation to 2-agonist use and

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472 identified three exhaled nitric oxide behaviors to identify the site of airway obstruction in

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473 asthmatic patients. A note of precaution was provided by Cohen et al (68) indicating that

474 exhaled nitric oxide levels were not associated with an asthma diagnosis, wheezing

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475 symptoms, lung function measures, or prior morbidity in children with sickle cell anemia

476 but were associated with markers of atopy and increased risk of future acute chest

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477 syndrome. AN
478 Periostin was a newly reported biomarker at the time of the NIH Asthma

479 Outcomes Report and thus was not fully addressed in that report and would have been
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480 considered exploratory at the time. Periostin is considered an extracellular matrix

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481 protein that is upregulated by type 2 cytokines interleukin-4 and 13 in bronchial

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482 epithelial cells and lung fibroblasts (69). Johansson et al (69) demonstrated that serum

483 periostin is not associated with asthma severity, but is associated with type 2 immunity
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484 in patients who are symptomatic despite their use of corticosteroids and potential use

485 for assessing greater response to type-2 immunity based treatment. Noguchi et al (70)
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486 reported that periostin upregulates eosinophil functions such as superoxide anion
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487 generation and eosinophil-derived neurotoxin release, along with the production of TGF-

488 and cysteinyl leukotrienes from eosinophils.

489 As further studies are being conducted, new biomarkers are being discovered.

490 Hinks et al (71) reported on 6 clinicopathobiologic clusters based on blood and induced

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491 sputum measures. They implied from their studies that IL-5 production is relatively

492 steroid insensitive and the expression of chitinase 3-like protein-1 (YKL-40) is present in

493 patients with neutrophilic inflammation along with the expression of metalloproteinases

494 in patients with severe asthma.

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495 There is increasing interest in the use of specific microRNA (miRNA) expression

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496 profiles with inflammatory cell profile and diseases severity in asthmatic patients. Maes

497 et al (72) reported that expression of miR-223-3p, miR-142-3P, and miR-629-3p is

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498 increased in sputum of patients with severe asthma and is linked to neutrophilic airway

499 inflammation, perhaps a new way to identify this asthma inflammatory phenotype.

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500 Panganiban et al (738) demonstrated that circulating miRNAs are uniquely expressed in
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501 patients with allergic rhinitis and asthma and have the potential for use as noninvasive

502 biomarkers to diagnose and characterize these diseases. Expression of miRNAs and
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503 genes associated with bronchial immune responses were demonstrated to be

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504 significantly modulated by diesel exhaust or allergens and thus might be used as
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505 biomarkers of exposure to air pollution as an indicator of epithelial wall damage (74).

506 There is also great interest in identifying biomarkers that may be reflective of
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507 asthma development in utero. Magnus et al (750) reported that high maternal levels of

508 neopterin, a marker of cellular immune activation, during pregnancy were positively
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509 associated with asthma in offspring, but further studies are needed to identify the
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510 mechanism for this observation. There is also interest in using breathomics with the

511 assessment of volatile organic compounds in assessment of asthma and COPD. Large

512 multicenter studies will be needed to validate this noninvasive technology before clinical

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513 applications can be made for chronic airways disease assessment, phenotyping and

514 monitoring (76).

515 Another biomarker considered exploratory by the Biomarkers Committee (56)

516 was airway imaging. This field continues to move along and holds promise for new ways

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517 to assess airway disease. Gonem et al (772) used hyperpolarized 3He diffusion

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518 magnetic resonance to determine the nature of acinar airway involvement in asthmatic

519 patients. They demonstrated alterations in long-range diffusion within the acinar airways

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520 and gas trapping but the precise anatomic nature and mechanistic role in patients with

521 severe asthma requires further evaluation. Hartley et al (78), using thoracic quantitative

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522 computed tomography, reported that in asthmatic patients and patients with COPD, lung
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523 function impairment is strongly associated with air trapping, with a contribution from

524 proximal airway narrowing in asthmatic patients.

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525 Therefore, since the 2012 report on biomarkers for the NIH Asthma Outcomes
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526 Task Force, information regarding certain biomarkers has been refined, new biomarkers
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527 discovered, and information is being rapidly accumulated on the exploratory category of

528 biomarkers to refine their application.

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529
530 New information on asthma medications
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531 In 2016, promising new medications as add-on management for poorly controlled
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532 asthma were introduced, and the safety of well-established medications, namely

533 LABAs, was revisited. The addition of roflumilast, a selective phosphodiesterase 4

534 inhibitor, in conjunction with montelukast to the controller regimen of adult patients with

535 inadequately controlled asthma despite the use of at least medium-dose ICSs with a

536 LABA resulted in a statistically significant increase in pre-bronchodilator FEV1 from

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537 baseline, improved morning PEF, and improved daytime symptom scores compared to

538 placebo with montelukast (79). However, there was no change in pre-bronchodilator

539 PEF or asthma control questionnaire scores (79).

540 QGE031 (ligelizumab), an anti-IgE antibody with a higher binding affinity for IgE

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541 than omalizumab, elicited a 3-fold and 16-fold greater increase in provocative allergen

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542 concentrations to decrease the FEV1 by 15% compared to omalizumab and placebo,

543 respectively, in adult patients with mild allergic asthma (80). QGE031 also elicited a

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544 suppression of allergen-induced skin prick test responses that was greater than that of

545 placebo or omalizumab (80).

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546 Once-daily tiotropium delivered via the Respimat Soft Mist inhaler (Boehringer
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547 Ingelheim; Ingelheim am Rhein, Germany) in addition to background ICS therapy, with

548 or without a leukotriene receptor antagonist, improved the peak and trough FEV1,
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549 FEF25-75, and pre-dose morning and evening PEF in adolescent patients (81).
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550 In adults with not well controlled house dust mite (HDM) allergy-related asthma,
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551 HDM sublingual immunotherapy (SLIT) improved the time to the first moderate or

552 severe asthma exacerbation, primarily due to an effect on moderate asthma

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553 exacerbations, compared to placebo during an ICS reduction phase (82). HDM SLIT

554 did not change asthma control questionnaire or asthma-related quality of life scores
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555 compared to placebo (82).

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556 The benefit of the aforementioned add-on medications primarily center on their

557 ability to improve lung function (79-81). Additional studies to examine their impact on

558 asthma control, including risk and impairment, would be beneficial as they are explored

559 as novel controller therapies.

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560 The United States Food and Drug Administration (FDA) issued a public health

561 advisory on the safety of LABA-containing products in 2005 in response to the

562 Salmeterol Multicenter Asthma Research Trial findings (78). Following this activity,

563 there was statistically significant decrease in fixed-dose ICS-LABA use in children and

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564 adults, with a concurrent increase in ICS and leukotriene modifier use, based on

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565 prescription database analysis (83).

566 Subsequently, the FDA mandated post-marketing safety studies examining the

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567 effect of ICS-LABA combination therapy on serious asthma-related events, including

568 death, intubation, and hospitalization (84-86). In adolescents and adults, fixed-dose

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569 budesonide-formoterol and fluticasone-salmeterol combination therapies were non-
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570 inferior to budesonide or fluticasone alone, respectively, for serious-asthma related

571 events (84, 85). Similarly, in pediatric patients, fluticasone-salmeterol was non-inferior
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572 to fluticasone alone for serious asthma-related events (86). The risk of a severe asthma
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573 exacerbation was significantly lower in adult and adolescent patients treated with
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574 combination ICS-LABA therapy compared to ICS therapy alone (84,85), but this

575 medication effect was not observed in pediatric patients (86). The impact of these
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576 studies on the FDAs overall assessment of fixed-dose ICS-LABA controller therapy

577 safety remains to be seen.

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578
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579 Management

580 In 2016, emphasis was placed upon the assessment of medication adherence

581 and the creation of comprehensive school-based asthma support networks (Table 5). In

582 a population-based cohort study, only 33% of pediatric patients demonstrated high ICS

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583 adherence (87). Similarly, using reimbursement data, only 24% of adults and pediatric

584 patients maintained regular ICS adherence one year after a period of regular ICS use

585 (88). The unique barriers for poor medication adherence are age-specific requiring

586 tailored approaches (89). In addition, inhaled medications pose a unique challenge to

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587 adherence, requiring proper technique for adequate drug delivery (90).

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588 Technological advances are exploring ways to address poor adherence. Use of

589 the Propeller Health Asthma Platform (Propeller Health; Madison, WI), an electronic

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590 monitoring device system, decreased SABA use and increased SABA-free days in

591 children and adults (91). Utilization of an acoustic recording device attached to an

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592 inhaler found that only 20% of patients used their inhaler in the correct manner at the
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593 correct interval, emphasizing the need to address not only number of actuations but

594 also technique errors (92).

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595 The School-based Asthma Management Program (SAMPRO) was developed to

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596 foster multidirectional communication between children, families, clinicians, school-

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597 based personnel, and the community to promote better pediatric asthma care (88).

598 SAMPRO identified four essential components to create this partnership: a circle of
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599 support between the aforementioned groups, asthma management plans,

600 comprehensive asthma education for school personnel, and assessment and
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601 remediation of school-based asthma triggers (93).

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602 The benefit of such a multidisciplinary, school-based program was highlighted

603 through the Step-Up Asthma Program, which utilized asthma counselors as a bridge

604 between subspecialty asthma care, primary care providers, school nurses, and families

605 (94). Over a 2-year period, the program increased the number of asthma action plans,

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606 increased rescue and controller medications in schools, improved asthma knowledge

607 scores, improved inhaler technique, and reduced asthma exacerbations (89).

608

609 Summary

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610 As indicated in this summary, there are rapid areas of development related to the

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611 natural history of asthma and the impact of the environment (Table 6). There has been

612 no previous era in asthma management that has witnessed the introduction of so many

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613 new classes of medications. It will be a challenge for clinicians and those contributing to

614 asthma guidelines to select relevant pieces of information that should be incorporated

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615 into clinical practice. Meanwhile, clinicians must keep up with these new findings in
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616 order to provide benefits to patients by implementing strategies that are most likely to be

617 effective. We will continue to monitor this literature and highlight those key findings that
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618 have the potential to alter asthma management and report on them in our annual
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619 review.
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620 Table 1: Summary of novel genetic associations with asthma and biologic impact
621
622 Doublesex and mab-3 related transcription factor 1 (DMRT1) potentially explains

623 sex-specific asthma effects during childhood (13).

624 A single nucleotide polymorphism (SNP) on chromosome 8 was associated with

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625 early lung function decline and chronic obstructed pulmonary disease (COPD) (14).

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626 A new locus associated with time to asthma onset is at position 16q12 (16).

627 Gly-to-Arg substitution at the 16 position in the 2-adrenoceptor gene in

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628 asthmatic children was associated with an increased risk of asthma exacerbation with

use of long-acting -agonists in children carrying 1 or 2 alleles of this substitution (19).

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629

630
631
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632 Table 2: New findings related to studies on air quality, pollution, climate,
633 environment and asthma
634
635 Patients in a large birth cohort showed a significant association between

636 increased exposure to traffic-NOx in the first year of life and increased adolescent

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637 airways resistance and reactance (21).

638 A mouse model of allergen-induced asthma with diesel exhaust particle (DEP)

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639 exposure, demonstrated that 4 days of dexamethasone treatment only partially reduced

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640 airway hyperresponsiveness (AHR) in mice exposed to both house dust mite (HDM)

641 and DEP (23).

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642 A causal network analysis on an inner city asthma cohort demonstrated that the

643
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two biggest drivers of asthma severity appears to be an allergy pathway starting with

644 allergic sensitization and an environmental tobacco smoke pathway (30).

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645 Analysis of an Australian longitudinal birth cohort demonstrated that allergic
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646 sensitization by 12 months of age was associated with increased risk of wheeze during

647 young adulthood, as well as lower FEV1, FEV1/FVC ratio, and FEF25-75 at 24 years of
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648 age (31).

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649 After adjusting for confounders in a pregnancy cohort, a dose-response

650 relationship emerged with an increase in the odds of asthma diagnosis in children for
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651 each increase in maternal stress category both prenatally and postnatally (33).
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652

653

654

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655 Table 3: Analyzing predictors of severe asthma from NIAID Inner City Asthma
656 Consortium
657
658 Multi-factorial interventions, such as exposure to environmental tobacco smoke

659 and to allergens, must be used to address asthma severity (30).

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660 A cluster analysis methodology was used to define phenotypes of inner city

661 children with asthma, including one phenotype of severe asthmatic children that is

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662 highly allergic (46).

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663 Children and adolescents with difficult to control asthma, defined as requiring

664 high dose inhaled corticosteroids, are distinguishable from those requiring only low dose

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665 inhaled corticosteroids by FEV1 bronchodilator responsiveness, rhinitis severity, and

666 atopy (47).

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669 Table 4: Useful biomarkers for personalized medicine for asthma

670
671 In patients with severe uncontrolled asthma, 12 years and older, a high blood

672 eosinophil count (400 cells/mm3) was an independent risk factor for 2 or more asthma

673 exacerbations or any asthma emergency department visit or hospitalization, but not

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674 direct costs (63).

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675 In young children with asthma necessitating Step 2 treatment, phenotyping with

676 allergen sensitization and a blood eosinophil count of 300 cells/mm3 or greater,

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677 identifies children with a high exacerbation probability for whom treatment with a daily

678 inhaled corticosteroid is beneficial despite risks of growth suppression (64).

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679 A combined high exhaled nitric oxide level and blood eosinophils related to a
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680 higher likelihood of airway hyperresponsiveness and uncontrolled asthma in young
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681 asthmatic patients (66).

682 Serum periostin is not associated with asthma severity, but is associated with
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683 type 2 immunity in patients who are symptomatic despite their use of corticosteroids and
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684 potential use for assessing greater response to type-2 immunity based treatment (69).

685 Expression of microRNAs and genes associated with bronchial immune

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686 responses were demonstrated to be significantly modulated by diesel exhaust or

687 allergens and thus might be used as biomarkers of exposure to air pollution as an
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688 indicator of epithelial wall damage (74).

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689

690

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691 Table 5: New insights relevant to asthma management

692
693 Using reimbursement data, only 24% of adults and pediatric patients maintained

694 regular ICS adherence one year after a period of regular ICS use (88).

695 Use of an electronic monitoring device system, decreased SABA use and

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696 increased SABA-free days in children and adults (91).

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697 The mission of the Patient-Centered Outcomes Research Institute (PCORI) is to

698 fund comparative effectiveness research that allows patients and other stakeholders of

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699 research to make informed health decision (39).

700 The School-based Asthma Management Program (SAMPRO) was developed to

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701 foster multidirectional communication between children, families, clinicians, school-
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702 based personnel, and the community to promote better pediatric asthma care (88).
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703 A multidisciplinary, school-based program can increase the number of asthma

704 action plans, increase rescue and controller medications in schools, improve asthma
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705 knowledge scores, improve inhaler technique, and reduce asthma exacerbations (89).
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706

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708 Table 6. Key advances in 2016

709 Rhinovirus-triggered asthma exacerbations become more severe as the degree

710 of sensitization to dust mite and mouse increased (2).

711 Co-exposure of respiratory virus and cockroach allergen induced a biphasic IL-33

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712 response and impaired antiviral interferon production (7).

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713 Infants with bronchiolitis due to RSV had a high abundance of Firmicutes and the

714 genus Streptococcus and a low abundance of Proteobacteria and the genera

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715 Haemophilus and Moraxella, while infants with bronchiolitis due to rhinovirus had the

716 opposite pattern (9).

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717 Cross sectional data from non-twin siblings discordant for asthma, born and
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718 raised in the same household, showed an association between asthma status and
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719 demethylation of a CpG site in the promoter region of the TET1 gene (26).

720 The two biggest drivers of asthma severity were an allergy pathway starting with
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721 allergic sensitization and an environmental tobacco smoke pathway (30).

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722 Wheezing illnesses with onset early in life have a greater influence on lung

723 function than wheezing duration (35).

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724 Precision Medicine and patient-centered research including the contributions of

725 stakeholders are needed (40).

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Ability to list asthma medications is associated with higher levels of health

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726

727 literacy (51).

728 Biomarkers including exhaled nitric oxide and eosinophil counts have potential as

729 indicators of endotypes (56).

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730 Allergen sensitization and blood eosinophils can be used to select medications

731 for management of asthma in young children (64).

732 In a population-based cohort study, only 33% of pediatric patients demonstrated

733 high ICS adherence (87).

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734 Utilization of an acoustic recording device attached to an inhaler found that only

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735 20% of patients used their inhaler in the correct manner at the correct interval,

736 emphasizing the need to address not only number of actuations but also technique

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737 errors (92).

738

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739
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740 References

741 1. Liu AH, Anderson WC, Dutmer CM, Searing DA, Szefler SJ. Advances in

742 asthma 2015: across the lifespan. J Allergy Clin Immunol 2016;138:397-404.

743 2. Kantor DB, Stenquist N, McDonald MC, Schultz BJ, Hauptman M,

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744 Smallwood CD, et al. Rhinovirus and serum IgE are associated with acute

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745 asthma exacerbation severity in children. J Allergy Clin Immunol 2016;

746 138:1467-71 e9.

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747 3. Ducharme, F. M., Zamek FM, Chauhen BF, Gravel J, Chalut D, Poonai N et

748 al. Factors associated with failure of emergency department management in

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749 children with acute moderate or severe asthma: a prospective, multicentre,
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750 cohort study. Lancet Respir Med 2016;4: 990-998.

751 4. Miller EK, Linder J, Kraft D, Johnson M, Lu P, Saville BR, et al.

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752 Hospitalizations and outpatient visits for rhinovirus-associated acute

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753 respiratory illness in adults. J Allergy Clin Immunol 2016; 137:734-43 e1.
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754 5. Han M, Chung Y, Young Hong J, Rajput C, Lei J, Hinde JL, et al. Toll-like

755 receptor 2-expressing macrophages are required and sufficient for rhinovirus-
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756 induced airway inflammation. J Allergy Clin Immunol 2016; 138:1619-30.

757 6. Naessens T, Schepens B, Smet M, Pollard C, Van Hoecke L, De

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758 Beuckelaer A, et al. GM-CSF treatment prevents respiratory syncytial virus-

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759 induced pulmonary exacerbation responses in postallergic mice by

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761 137:700-9 e9.

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762 7. Lynch JP, Werder RB, Simpson J, Loh Z, Zhang V, Haque A, et al.

763 Aeroallergen-induced IL-33 predisposes to respiratory virus-induced asthma

764 by dampening antiviral immunity. J Allergy Clin Immunol 2016; 138:1326-37.

765 8. Stier MT, Bloodworth MH, Toki S, Newcomb DC, Goleniewska K, Boyd

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766 KL, et al. Respiratory syncytial virus infection activates IL-13-producing group

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767 2 innate lymphoid cells through thymic stromal lymphopoietin. J Allergy Clin

768 Immunol 2016; 138:814-24 e11.

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769 9. Mansbach JM, Hasegawa K, Henke DM, Ajami NJ, Petrosino JF, Shaw

770 CA, et al. Respiratory syncytial virus and rhinovirus severe bronchiolitis are

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771 associated with distinct nasopharyngeal microbiota. J Allergy Clin Immunol
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773 10. Durack J, Lynch SV, Nariya S, Bhakta NR, Beigelman A, Castro M, et al.
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774 Features of the bronchial bacterial microbiome associated with atopy,

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775 asthma, and responsiveness to inhaled corticosteroid treatment. J Allergy Clin

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776 Immunol 2016.

777 11. Denner DR, Sangwan N, Becker JB, Hogarth DK, Oldham J, Castillo J, et
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778 al. Corticosteroid therapy and airflow obstruction influence the bronchial

779 microbiome, which is distinct from that of bronchoalveolar lavage in asthmatic

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780 airways. J Allergy Clin Immunol 2016; 137:1398-405 e3.

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781 12. Sverrild, A., Killerich P, Bjejnrod A, Pedersen R, Porsbjerg C, Bergqvist A et al..

782 Eosinophilic airway inflammation in asthmatic patients is associated with an altered

783 airway microbiome. J Allergy Clin Immunol 2016;

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784 13. Schieck M, Schouten JP, Michel S, Suttner K, Toncheva AA, Gaertner VD,

785 et al. Doublesex and mab-3 related transcription factor 1 (DMRT1) is a sex-

786 specific genetic determinant of childhood-onset asthma and is expressed in

787 testis and macrophages. J Allergy Clin Immunol 2016; 138:421-31.

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788 14. McGeachie MJ, Yates KP, Zhou X, Guo F, Sternberg AL, Van Natta ML,

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789 et al. Genetics and genomics of longitudinal lung function patterns in

790 individuals with asthma. Am J Respir Crit Care Med 2016; 194:1465-74.

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791 15. Yang CW, Hojer CD, Zhou M, Wu X, Wuster A, Lee WP, et al. Regulation

792 of T cell receptor signaling by DENND1B in TH2 cells and allergic disease.

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793 Cell 2016; 164:141-55. AN
794 16. Sarnowski C, Sugier PE, Granell R, Jarvis D, Dizier MH, Ege M, et al.

795 Identification of a new locus at 16q12 associated with time to asthma onset. J
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796 Allergy Clin Immunol 2016; 138:1071-80.

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797 17. Schmiedel BJ, Seumois G, Samaniego-Castruita D, Cayford J, Schulten

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798 V, Chavez L, et al. 17q21 asthma-risk variants switch CTCF binding and

799 regulate IL-2 production by T cells. Nat Commun 2016; 7:13426.

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800 18. Massoud AH, Charbonnier LM, Lopez D, Pellegrini M, Phipatanakul W,

801 Chatila TA. An asthma-associated IL4R variant exacerbates airway

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802 inflammation by promoting conversion of regulatory T cells to TH17-like cells.

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803 Nat Med 2016; 22:1013-22.

804 19. Turner S, Francis B, Vijverberg S, Pino-Yanes M, Maitland-van der Zee

805 AH, Basu K, et al. Childhood asthma exacerbations and the Arg16 beta2-

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806 receptor polymorphism: A meta-analysis stratified by treatment. J Allergy Clin

807 Immunol 2016; 138:107-13 e5.

808 20. Annesi-Maesano I. United Nations Climate Change Conferences: COP21

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810 Clin Immunol. 2016;138(1):57-8.

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811 21. Schultz ES, Hallberg J, Gustafsson PM, Bottai M, Bellander T, Bergstrom

812 A, et al. Early life exposure to traffic-related air pollution and lung function in

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813 adolescence assessed with impulse oscillometry. J Allergy Clin Immunol.

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815 22. Bandoli G, von Ehrenstein O, Ghosh JK, Ritz B. Synergistic effects of air
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818 23. Brandt EB, Khurana Hershey GK. A combination of dexamethasone and
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819 anti-IL-17A treatment can alleviate diesel exhaust particle-induced steroid

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820 insensitive asthma. J Allergy Clin Immunol. 2016;138(3):924-8 e2.

821 24. Morita H, Moro K, Koyasu S. Innate lymphoid cells in allergic and
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822 nonallergic inflammation. J Allergy Clin Immunol. 2016;138(5):1253-64.

823 25. Yang Q, Ge MQ, Kokalari B, Redai IG, Wang X, Kemeny DM, et al. Group
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824 2 innate lymphoid cells mediate ozone-induced airway inflammation and

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825 hyperresponsiveness in mice. J Allergy Clin Immunol. 2016;137(2):571-8.

826 26. Somineni HK, Zhang X, Biagini Myers JM, Kovacic MB, Ulm A, Jurcak N,

827 et al. Ten-eleven translocation 1 (TET1) methylation is associated with

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828 childhood asthma and traffic-related air pollution. J Allergy Clin Immunol.

829 2016;137(3):797-805 e5.

830 27. Dannemiller KC, Gent JF, Leaderer BP, Peccia J. Indoor microbial

831 communities: Influence on asthma severity in atopic and nonatopic children. J

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832 Allergy Clin Immunol. 2016;138(1):76-83 e1.

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833 28. Stein MM, Hrusch CL, Gozdz J, Igartua C, Pivniouk V, Murray SE, et al.

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