- Email: [email protected]
Effect of asthma therapies on the natural course of asthma
Ann Allergy Asthma Immunol xxx (2016) 1e7
Contents lists available at ScienceDirect
Review
Effect of asthma therapies on the natural course of asthma Elissa M. Abrams, MD *; Stanley J. Szefler, MD y; Allan B. Becker, MD * * Department y
of Pediatrics, Section of Allergy and Clinical Immunology, University of Manitoba, Winnipeg, Manitoba, Canada Department of Pediatrics, Section of Pulmonology, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, Colorado
A R T I C L E
I N F O
Article history: Received for publication September 3, 2016. Received in revised form September 19, 2016. Accepted for publication September 23, 2016.
A B S T R A C T
Objective: To provide an evidence-based review on the role of pharmacologic (inhaled corticosteroids, leukotriene receptor antagonists, biologic therapies, aeroallergen immunotherapy) and nonpharmacologic therapies (environmental modifications, microbiome) in secondary and tertiary asthma prevention. Data Sources: A PubMed search for English-language publications regarding asthma and secondary or tertiary prevention was performed. Some articles cited in selected studies were also considered for inclusion in this review. Study Selections: Studies were included that were original research and specifically addressed the question of asthma prevention and use of pharmacologic or nonpharmacologic therapies. When possible, we selected the articles with the most robust level of evidence. Results: More than 100 articles were initially identified, 79 were reviewed in depth, and 60 were included in this review. Several studies suggest no disease-modifying effect for inhaled corticosteroids. Small studies suggest a tertiary preventive effect for leukotriene receptor antagonists. Biological therapies have somewhat conflicting evidence with a paucity of pediatric data, although some have tremendous promise. A role of allergen immunotherapy (specifically pollen) in secondary asthma prevention has been suggested, with no firm conclusions possible for tertiary prevention. One large trial suggests a role for environmental modifications in secondary asthma prevention, whereas the preponderance of evidence does not suggest a role in tertiary prevention. The microbiome is an active area of research that has promise for a disease-modifying effect. Conclusion: Further work needs to be performed to allow physicians to intervene early and alter the natural course of asthma in children. Ó 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Introduction Asthma often begins in early childhood, and lifelong complications, such as airway remodeling, can begin early in the preschool years.1e5 Studies have found that persistent lung function abnormalities are seen in children with asthma. Even mild to moderate asthma can lead to airway obstruction, which can increase in magnitude over time.2 The Childhood Asthma Management Program study noted that 75% of children aged 5 to 12 years with Reprints: Elissa M. Abrams, MD, Department of Pediatrics, Section of Allergy and Clinical Immunology, University of Manitoba, FE125-685 William Ave, Winnipeg, Manitoba, Canada R3E 0Z2; E-mail: [email protected]. Disclosures: Dr Szefler reported consulting for Aerocrine, Astra Zeneca, BoehringerIngelheim, Daiischi Sankyo, Glaxo Smith Kline, Genetech, Merck, Novartis, and Roche and receiving research support from the National institutes of Health, the National Health, Lung, and Blood Institute, the National Institute for Allergy and Infectious Diseases, the National Institute for Environmental and Health Sciences, the Environmental Protection Agency, the Colorado Cancer, Cardiovascular, and Pulmonary Disease Program, and GlaxoSmithKline. Dr Becker reported serving on the Novartis and BI advisory boards and the Global Initiative for Asthma Science Committee. No other disclosures were reported.
mild to moderate asthma had abnormal patterns of lung growth (reduced growth or early lung function decline).2 These children were at risk of fixed airway obstruction, and 11% of them met criteria for chronic obstructive pulmonary disease at a mean age of 26.0 years.2 Data from the Tucson Children’s Respiratory Study suggested that lung function parameters are established early (by 6 years of age) and do not alter significantly throughout childhood.3 Airway remodeling has also been noted early in childhood asthma. Increased reticular basement membrane thickening has been noted by 3 years of age in wheezy preschoolers.4 A study of 19 children (6e16 years of age) with asthma noted reticular basement membrane thickening that was significantly higher than nonasthmatic controls and similar to the extent seen in adults with asthma.5 Therefore, asthma often begins early in life, and early intervention provides an opportunity to prevent lung function decline and airway remodeling. There are 3 types of asthma prevention. Primary prevention is an intervention that occurs before the development of asthma or any predisposing condition (eg, eczema or rhinitis). Secondary prevention is an intervention for children at risk of asthma but who
http://dx.doi.org/10.1016/j.anai.2016.09.438 1081-1206/Ó 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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do not have active asthma. Tertiary prevention is an intervention for children who have established asthma. The goal of this article is to determine whether current asthma therapies provide a measure of secondary or tertiary asthma prevention in childhood. Both pharmacologic therapies and nonpharmacologic therapies are reviewed. Pharmacologic Therapies Inhaled Corticosteroids Some studies have suggested that inhaled corticosteroids might prevent lung function decline in children with asthma or recurrent wheeze. For example, a nonrandomized study of 216 children with mild to moderate asthma noted that treatment with inhaled budesonide improved forced expiratory volume in 1 second (FEV1) and forced midexpiratory flow (P < .001).6 This study also noted a statistically significant inverse association between duration of asthma at treatment initiation and improvement in FEV1 during therapy. Several randomized studies have examined the toddler at risk for persistent asthma and have reached the same conclusion that inhaled corticosteroids do not have a disease-modifying effect. In the Prevention of Early Asthma in Kids study, 285 children aged 2 to 3 years with a positive asthma predictive index were randomized to fluticasone propionate twice daily or placebo for 2 years, followed by a 1-year period with no medication.7 No significant difference was found between the groups in lung function, measured as reactance at 5 HZ (P ¼ .83) or resistance at 5 HZ (P ¼ .61) at the end of the observation period. In addition, no difference was found in the number of exacerbations during the observation year. The Prevention of Early Asthma in Kids study concluded that their trial did not support a disease-modifying effect of inhaled corticosteroids. The Inhaled Fluticasone Propionate in Wheezy Infants study randomized 206 toddlers (median age, 1.2 years) with parental atopy to fluticasone propionate or placebo twice daily after either 1 prolonged (>1 month) or 2 wheezy episodes.8 At 5 years, no significant difference was found in multiple measures of lung function, including prebronchodilator or postbronchodilator FEV1 (P ¼ .72 and P ¼ .73, respectively). No significant difference was found in diagnosed asthma (P ¼ .80) or current wheeze (P ¼ .53). The study concluded that early use of fluticasone did not affect the natural history of asthma or prevent lung function decline. In addition to these randomized trials examining the at risk toddler, a nested case control within the prospective birth cohort Environmental Control of Asthma noted that at a 10-year follow-up of 252 children, there was no evidence that use of inhaled corticosteroids in the first 2 years of life for recurrent bronchial obstruction affects long-term asthma risk.9 If anything, a nonsignificant increase in current asthma risk was found in the children with early inhaled corticosteroid treatment (adjusted odds ratio [OR], 1.84; range, 0.89e3.82). The Childhood Asthma Management Program study, in contrast to the previous studies, examined children with already established mild to moderate asthma and randomized them to inhaled budesonide, nedocromil, or placebo for 4 to 6 years.10 No difference in FEV1 between the groups was noted. Initial analysis revealed a smaller decline in FEV1 to forced vital capacity (FVC) before bronchodilator administration and lower airway responsiveness in the treatment group (0.2% vs 1.8%; P ¼ .001).10 However, during a 4.8-year posttrial follow-up period, no difference was found between the budesonide and placebo groups in lung function,11 suggesting that any benefit achieved with therapy was not persistent. In conclusion, the preponderance of evidence suggests no disease-modifying effect for inhaled corticosteroids in established childhood asthma or toddlers with emerging asthma.
Leukotriene Receptor Antagonists Only a few studies on leukotriene receptor antagonists (LTRAs) have examined lung function over time. Although the trials have significant limitations, such as short duration and small sample size, they suggest that LTRAs may have a disease-modifying effect. The largest trial on montelukast that addressed a diseasemodifying effect was a randomized, double-blind, placebocontrolled trial of 366 children 6 to 14 years of age with asthma.12 After 8 weeks of montelukast, there was a significant increase in morning FEV1 in the montelukast group compared with the placebo group (8.23% vs 3.58%; P < .001). The other studies that have examined changes in lung function are smaller. For example, in a study of 30 children aged 2 to 5 years with newly diagnosed asthma, a 4-week course of montelukast improved mean levels of exhaled nitric oxide (eNO) and mean airway resistance compared with both no treatment (P < .001) and 1 week of initial treatment (P ¼ .01).13 Murine models of asthma have also suggested a role for LTRAs in prevention of airway remodeling. For example, montelukast reduced multiple pathologic signs of airway inflammation and remodeling, including smooth muscle hyperplasia, mucous plugging, and subepithelial fibrosis, in ovalbumin-sensitized mice.14 In conclusion, although larger randomized studies are needed, some data suggest there may be a role for montelukast in the prevention of asthma disease progression. Biological Therapies There is increasing recognition that asthma is a heterogeneous disease, with multiple different phenotypes that may respond differently to targeted therapies. Research is emerging on biologic therapies, most of which target the TH2 profile (often aimed at interleukin [IL] 4, IL-5, and IL-13, which are involved in IgE class switching and eosinophilic recruitment).15 Some studies suggest that biologic therapies may alter the natural trajectory of asthma, despite significant limitations, including small sample sizes and a focus thus far on the adolescent and adult asthma population. With the exception of omalizumab, no studies thus far have enrolled children younger than 12 years. Details of studies that involve biological therapies for asthma are given in Table 1.16e30 Studies on dupilumab (antieIL-4/13), mepolizumab (antieIL-5), reslizumab (antieIL-5), and lebrikizumab (antieIL-13) have revealed improvements in multiple measures of asthma control.16e20,23,24 In light of improvements in pulmonary function and reduction in exacerbations, they may affect the natural course of asthma. These studies are few in number but are largely randomized clinical trials that trend toward the same improvements. Most of these studies are of short duration, and none have examined the long-term effect of therapy, if discontinued. None of these studies have been performed in children (although select studies of mepolizumab and reslizumab have included adolescents).18e20 Phase 2 studies on ligelizumab (a more potent anti-IgE monoclonal antibody), fevipiprant (CRTh2 receptor antagonist), and benralizumab (IL-5 receptor antagonist) are promising.21,22,29,30 However, some outcomes seem better affected than others, there may be a dose response, and some populations respond more positively than others (there was a 2-fold to 500-fold change in allergen PC15 with ligelizumab).29 These biological agents have overall been well tolerated and remain a promising area of research. Omalizumab (anti-IgE) is the only biological therapy that has been studied in the pediatric population. A study of 104 children aged 7 to 18 years with severe atopic asthma noted a striking decrease in exacerbation rates (72%; P < .001), hospitalization rates (88.5%; P < .001), and improvement in FEV1 (mean, 4.9%; P ¼ .02) and midexpiratory flows (9.5%; P ¼ .002).25 In addition, inhaled corticosteroid requirements decreased by a mean of 30% (P < .001)
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3
Table 1 Biological Therapies Used in Asthma and Their Disease-Modifying Effect Drug
Target
Study population
Outcomea
Dupilumab
AntieIL-4/13
YExacerbations, [FEV1 despite tapering ICS/LABA therapy16
Mepolizumab
AntieIL-5
Reslizumab
AntieIL-5
Benralizumab
AntieIL-5
Moderate to severe asthma taking medium- to high-dose ICSs/LABAs Recurrent exacerbations and eosinophilic phenotype Maintenance oral steroids and eosinophilic phenotypeb Poorly controlled asthma and eosinophilic phenotypeb Poorly controlled asthma and eosinophilic phenotypea Poorly controlled asthma and eosinophilic phenotype (phase 2b) Current asthma exacerbation with incomplete response and at least 1 severe exacerbation in previous year (phase 2b) Poorly controlled asthma Poorly controlled asthma Severe atopic asthmac Persistent uncontrolled atopic asthmac Moderate to severe atopic asthmac
Lebrikizumab
AntieIL-13
Omalizumab
Anti-IgE
Ligelizumab
Anti-IgE
Severe atopic asthma with maintenance OCSsc Mild allergic asthma (phase 2)
Fevipiprant
Anti-CRTh2
Mild to moderate uncontrolled allergic asthma
YExacerbations, no difference in FEV117 YExacerbations, [FEV1, YOCS18 YExacerbations, [FEV119 [FEV1, [FVC, [FEF25%e75%20 YExacerbations at higher doses, [FEV1 at all doses21 No change to FEV1, Ysome outcomes of exacerbations but not others22 [FEV123 YExacerbations, [FEV124 YExacerbations, YICS, [FEV1, [FEF25%e75%25 YExacerbations,Y hospitalizations26 YExacerbations,Y hospitalizations, NS change in pulmonary function27 YOCS, [asthma control28 [Allergen PC15 compared with omalizumab and placebo; Yskin test responses29 No overall change in FEV1; subgroup with FEV1 <70% showed [30
Abbreviations: FEF25%e75%, forced expiratory flow at 25% to 75% of the pulmonary volume; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; ICS, inhaled corticosteroid; IL, interleukin; LABA, long-acting b-agonist; NS, nonsignificant; OCS, oral corticosteroid; PC15, provocation concentration causing a 15% decrease in FEV1. a Downward arrows indicate decreased and upward arrows indicate increased. b Enrolled adolescents (>12 years old) as well as adults. c Pediatric study (children <18 years old).
during 1 year of treatment. A randomized, double-blind, placebocontrolled trial of 419 inner-city children with asthma as young as 6 years noted decreased exacerbations (48.8% vs 30.3%; P < .001), decreased hospitalizations (6.3% vs 1.5%; P ¼ .02), and lower inhaled corticosteroid use (P < .001) during a 60-week treatment period.26 Limitations to the omalizumab literature remain. The phenotype of asthma most likely to respond remains to be defined. No longterm follow-up data are available, and omalizumab has not yet been studied in preschool-aged children with asthma, in whom tertiary prevention is arguably most likely to be effective. Omalizumab has recently been licensed by the US Food and Drug Administration for treatment of asthma in children 6 years and older; it is only licensed for use in children older than 12 years in Canada. There are also limitations because of IgE requirements and weight that exclude some who would ordinarily qualify based on asthma severity. In conclusion, despite significant limitations, the biological therapies are an active area of research with tremendous promise as a therapy that might alter the natural course of asthma. Currently, the biological modifiers are primarily directed at the TH2 pathway. Although this may be relevant to those patients who have an allergic component, those who are noneosinophilic are not eligible for these medications. In addition, further work in determining the biochemical signature of patients more likely to respond to these biological agents may further increase their efficacy.
immunotherapy, significantly fewer patients undergoing SCIT had developed asthma (16/64 vs 24/53; OR, 2.5).31 A smaller study on grass sublingual immunotherapy (SLIT) revealed similar results. In this study, 113 children (aged 5e14 years) with allergic rhinitis were randomized to grass SLIT or standard symptomatic therapy for 3 years.32 Development of asthma was 3.8 times more frequent in the symptomatic therapy group. One study has examined the efficacy of SLIT in children with different aeroallergen sensitizations (tailored to individual sensitization status).33 Children with allergic rhinitis (n ¼ 216) were randomized to medication alone or medication plus SLIT for 3 years. None had persistent asthma, but some children had mild intermittent asthma at the start of treatment. In the children with intermittent asthma, persistent asthma was more frequent in the control group (1.5% vs 28.8%; number needed to treat ¼ 4), and the overall occurrence of asthma was more frequent in the control group (13.1% vs 45.4%). In addition, there was a significant difference in number of children with a positive methacholine challenge results (P < .001; OR, 0.24). These studies suggest the possibility of the role of immunotherapy in the secondary prevention of asthma, specifically in children with allergic rhinitis. However, the studies are few in number, are small in sample size, and have only studied a few aeroallergens. Further studies are required to validate the potential role of immunotherapy in this area. Tertiary Prevention
Allergen Immunotherapy Secondary prevention One large, randomized, open trial has examined the effect of grass and/or birch subcutaneous immunotherapy (SCIT) in children. The Preventative Allergy Treatment study enrolled 205 children aged 6 to 14 years with allergic rhinitis and randomized them to SCIT for 3 years or to an open control group (ie, the study was not blinded).31 None of the children at the start of the trial were taking a daily asthma medication. This study found a long-term asthma prevention effect: 7 years after completion of 3 years of
Studies on the effect of SCIT or SLIT in tertiary asthma prevention are conflicting. Select pediatric studies are highlighted in Table 2.34e41 Some studies are promising, demonstrating modification in the natural history of asthma, whereas others found no difference in markers of lung function or inflammation. As a striking example, a follow-up of 90 children with asthma who received house dust mite immunotherapy noted that both 5 and 3 years of immunotherapy had significantly higher rates of asthma remission 3 years later compared with control (54%, 50%, and 3.3%, respectively).38 However, even within a given study, the results could be interpreted in multiple ways. For example, although the study by
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Table 2 Pediatric Studies Examining Tertiary Asthma Prevention With SCIT and SLIT Study design
Outcomea
35 Children (3e16 years old) receiving daily ICSs randomized to grass SCIT or placebo for 2 pollen seasons 29 Children (7e16 years old) randomized to HDM or cat SCIT vs placebo for 3 years 14 Children given HDM SCIT for 2 years compared with 12 in control group
YAsthma symptom-medication score, NS difference airway inflammation or lung function34 [PC20 for allergen (P ¼ .01), NS difference in PC20 for histamine or ICS dose35 YCold dry air challenge-induced change in FEV1 (P ¼ .03) in SCIT group and no change in control group; [loss of BHR in SCIT group (6/14 vs 1/12; P < .05)36 YFluticasone propionate dose compared with control (P < .05; mean dose decreased from 330.3 to 151.5 mg), [PEF (þ50.7 vs þ23.55 L/min; P ¼ .03); no difference in BHR37 [Remission with SCIT (54.2% 5 year/50% 3 year/3.3% control), [FEV1 with 5 years of SCIT (P ¼ .04)38 [FVC (P ¼ .04), [FEV1 (P ¼ .048), [PEF (P ¼ .001) in intervention group and NS difference in placebo group39 YAsthma in SLIT group (31/35 baseline, 4/35 end of SLIT, 3/35 at 10 years; P .001), Yasthma medications (P .01), NS difference in either in control group; [PEF in active vs control 5 years later40 NS difference in lung function between the groups, Yasthma symptom scores41
65 Children (6e17 years old) with mild to moderate asthma randomized to HDM SCIT plus fluticasone propionate or fluticasone propionate alone for 2 years 84 Children who completed no vs 3 or 5 years of SCIT to HDM and were followed up prospectively for 3 years 97 Children (6e12 years old) with mild to moderate asthma randomized to HDM SLIT or placebo for 24 weeks Prospective, open, parallel-group controlled trial of 60 children (3e17 years old) with mild to moderate asthma and/or rhinitis treated with HDM SLIT for 4e5 years; evaluated after SLIT and 5 years later Prospective randomized clinical trial of 48 children with mild persistent asthma, comparing SLIT and SCIT with asthma medication alone
Abbreviations: BHR, bronchial hyperresponsiveness; FEV1, forced expiratory volume in 1 second; f/u, follow up; FVC, forced vital capacity; HDM, house dust mite; ICS, inhaled corticosteroid; NS, nonsignificant; PC20, provocation challenge causing a 20% decrease in FEV1; PEF, peak expiratory flow; SCIT, subcutaneous immunotherapy; SLIT, sublingual immunotherapy. a Downward arrows indicate decreased and upward arrows indicate increased.
Hedlin et al35 found a difference in allergen provocation challenge causing a 20% decrease in FEV1 (PC20) between the SCIT and placebo groups, no difference was found in PC20 histamine or asthma medication dosing.35 Furthermore, although the study by Gruber et al36 noted loss of bronchial hyperreactivity in the SCIT group, at a 1-year follow-up the treatment group trended toward a return in bronchial hyperreactivity36 A systematic review of 35 studies of SCIT and SLIT in children concluded that there was moderate-strength evidence that SCIT improved asthma symptoms but low-strength evidence that it improved asthma medication scores.42 For SLIT, there was highstrength evidence that SLIT improved asthma symptoms and moderate-strength evidence that it decreased asthma medication use. When comparing SCIT and SLIT, there was low-strength evidence to support SCIT over SLIT. Disease modification was covered specifically in the SLIT section, and the conclusions were unclear. There have been recent Cochrane reviews on both SCIT and SLIT use in asthma. For SCIT, the Cochrane review concluded that although there was improvement in measures of asthma control, such as symptoms and medication use, there was no consistent effect on lung function, negating a potential modifying effect.43 For SLIT, becaxues of the heterogeneity of the studies, no firm conclusions could be reached.44 This remains an active area of research. Current studies are examining the use of biological therapies (eg, omalizumab) in combination with allergen immunotherapy, which may allow patients with more severe asthma to be treated. Whether this will modify asthma’s natural course remains to be seen. Overall, significant heterogeneity of study results remains. Identifying children who have limited aeroallergen sensitization is
also a challenge. No firm conclusions can be drawn at this stage about whether immunotherapy has a tertiary preventive effect on asthma in children. Perhaps, a single defined strategy will not be effective, but a critical combination of selected biologic response modifiers may be the key to success. Nonpharmacologic Therapies Role of the Microbiome Emerging studies have suggested that intestinal microbiota are associated with asthma development. Some studies suggest that decreased microbial diversity in infancy may increase the risk of asthma later in life.45 Other studies have found that certain bacterial genera were associated with asthma development. For example, a nested case-control study within the Canadian Healthy Infant Longitudinal Development (CHILD) study of 339 children 1 year old noted that those at high risk of asthma (because of atopy and/or wheeze) exhibited gut microbial dysbiosis (decreased Facealibacterium, Lachnospira, Veillonella, and Rothia) in the first 100 days of life.46 Most studies thus far on the role of the microbiome have focused on probiotic supplementation and primary prevention, noting no consistent effect.47 Little human research into secondary and tertiary asthma prevention has been published. The CHILD study noted that, in a murine model, there was some efficacy in tertiary prevention in a murine model of asthma: inoculation of germ-free mice with the Facealibacterium, Lachnospira, Veillonella, and Rothia bacteria ameliorated previously induced airway inflammation.46 Immune modulation through a microbiome-based approach is an ongoing area of research. There are 2 active studies examining the role of lyophilized bacterial lysate (Broncho-Vaxom) (containing lyophilized bacterial lysates of Haemophilus, Streptococcus, Klebsiella, Staphylococcus, and Moraxella). A randomized, doubleblind, placebo-controlled trial of children 1 to 6 years of age with emerging asthma noted that lyophilized bacterial lysate treatment for 3 months (10 days per month) decreased wheezing attacks (mean incidence reduction, 37.9%; P < .001) and duration (mean, 2 days shorter; P ¼ .001) compared with placebo.48 Although promising, whether this will reduce the risk of persistent asthma is unclear. The Oral Bacterial Extracts trial is enrolling children 6 to 18 months old at high risk of asthma and randomizing them to the lyophilized bacterial lysate extract or placebo for 2 years, with the outcome being asthma symptoms during the third year of life (ClinicalTrials.gov Identifier: NCT02148796). Data collection is expected in 2020. In conclusion, some literature suggests that intestinal microbiota may be associated with asthma risk, and there is preliminary evidence from a murine model that probiotic supplementation may ameliorate airway inflammation. Although human studies on secondary and tertiary prevention have not yet been published, this is an area of active research and holds some promise as a means of altering the natural course of asthma. Aeroallergen Environmental Modifications Secondary prevention Several studies have examined the role of aeroallergen environmental modifications in primary prevention of asthma,49 with the final conclusion being that reduction of exposure to multiple allergens and multifaceted interventions may reduce the likelihood of asthma (whereas monofaceted interventions were less effective). In contrast, the Study of Prevention of Allergy in Children of Europe (SPACE) is the only large trial examining secondary asthma prevention with environmental modifications. SPACE was a multicenter randomized clinical trial designed to investigate children at
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risk of asthma and was divided into 3 cohorts (newborn, toddler, schoolchild). The toddler and schoolchild cohorts focused on secondary prevention. In the toddler and preschooler cohort, the efficacy of dust mite encasements was investigated in 636 children aged 1.5 to 5 years with atopic manifestations and parental atopy.50 It found that dust mite mattress encasements decreased sensitization to dust mite (6.5% vs 3%; P ¼ .008) and that dust mite sensitized children had a higher prevalence of physician-diagnosed asthma (P ¼ .004). This finding was replicated in the schoolchildren cohort, in which 242 children aged 5 to 7 years with a personal and family history of atopy were randomized to multifaceted dust mite interventions or control.51 At 12 months, these interventions decreased sensitization to dust mite compared with control (9.38% vs 2.56%; P ¼ .03). In addition, of those children who reported current wheeze at randomization, there was a significant decrease in wheezing at 12 months in the intervention group compared with the control group (14/30 [46.7%] had stopped wheezing in the intervention group vs 5/23 [21.7%] had stopped wheezing in the control group; P ¼ .09), suggesting a role in emerging asthma as well. Although the results of SPACE are promising, further studies are required to replicate these findings and investigate aeroallergen environmental modifications other than dust mite. Tertiary prevention Most studies on tertiary asthma prevention have focused on dust mite interventions, either alone or as part of a multifaceted intervention. A few small studies have found a beneficial effect on measures of lung function. Many were performed at high altitude or in hospital settings.52,53 However, a few were performed in home environments. A small randomized study of 60 children with asthma aged 6 to 15 years who were dust sensitized noted that 1 year of dust mite protective mattress and pillow encasings reduced dose of inhaled steroids (mean decrease, 408 to 227 mg/d; P < .001) in the intervention group only.54 A randomized study of 49 children with asthma noted that dust mite encasings for the bed and acaricide treatment improved FEV1 (102.7% to 105% in intervention group; 101.8% to 98.6% in intervention group; P < .05) compared with placebo.55 However, a large randomized trial of 937 children noted that although a multifaceted intervention, including dust mite measures that were individualized to the child’s sensitization and exposure, improved symptom-free days (for every 2-week period, 3.39 vs 4.20 symptom-days; P < .001), there was no significant effect on multiple lung function measures, including FEV1, FVC, and peak flow variability.56 In addition, a Cochrane review of 55 trials, including pediatric studies, noted no effect of dust mite measures on measures of lung function, asthma symptom scores, or medication use in children with asthma and dust mite allergy.57 However, a major problem with this meta-analysis is that studies were included where there had been no success in significantly reducing dust mite. The other environmental modification that has been studied is pet reduction measures, and the data are sparse. Only one small pediatric study examined pet reduction measures in children with asthma and pet sensitization. In this double-blind, placebocontrolled, crossover study of 20 children, 3 months of air filters in the living rooms and bedrooms decreased airway responsiveness (1.2 doubling dose increase of PC20 for adenosine; P ¼ .003) and peak flow amplitude (P ¼ .04).58 However, because of the paucity of data, a Cochrane review concluded that there is not enough evidence for or against the use of air filtration units to reduce pet allergen levels in children with asthma and pet allergy.59 Overall, although some small studies on dust mite measures, mostly focused on dust mite encasings, have found a benefit, the preponderance of the evidence does not support a benefit for altering the natural course of asthma. Although preliminary
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Table 3 Summary of Pharmacologic and Nonpharmacologic Interventions and Effect on Secondary and Tertiary Asthma Prevention Intervention
Summary of prevention effect
Inhaled corticosteroids
Tertiary: Several RCTs suggest no diseasemodifying effect7e10 Tertiary: Small studies suggest a diseasemodifying effect; larger studies needed12,13 Tertiary: Conflicting evidence, small studies, paucity of pediatric data. Some biological agents (dupilumab, mepolizumab, lebrikizumab, omalizumab) showing promise16e30 Secondary: Significant limitations to the literature but suggestion of a role, specifically in children with allergic rhinitis and pollen sensitization31e33 Tertiary: Significant heterogeneity in study results; no firm conclusions can be made34e41 Secondary: Paucity of data; area of active research46e48 Tertiary: Area of active research, suggesting promise for a disease-modifying effect46e48 Secondary: One large trial suggesting a role; further studies needed50,51 Tertiary: Preponderance of evidence does not suggest a role; study limitations include a focus predominantly on dust mite measures52e59
LTRAs Biologic therapies
Allergen immunotherapy
Microbiome
Environmental modifications
Abbreviations: LTRA, leukotriene receptor antagonist; RCT, randomized clinical trial.
evidence is promising, further studies are required to determine whether pet environmental measures are effective in tertiary prevention. Conclusion In a recent commentary, Drazen stated, “We still do not have a way to work up a given patient with asthma and to easily delineate the specific pathobiology that leads to her or his airway dysfunction. It is like treating infectious disease without a culture.”60 Childhood asthma may have different histologic changes, phenotypes, endotypes, and treatment responses. Much more work needs to be done to understand the underlying pathophysiologic mechanisms of childhood asthma. Perhaps as a result of this heterogeneity, currently used first-line pharmacologic therapies (namely, inhaled corticosteroids) have not been found to modify its natural course (Table 3). Biological therapies, theoretically more tailored to individual asthma phenotypes, have shown promise, but there continue to be study limitations. As more work is done to delineate asthma phenotypes, particularly in children, biological agents hold promise to modify the natural history of asthma. Environmental modifications should theoretically play a role in both secondary and tertiary asthma prevention because exposure to an aeroallergen that a child is sensitized to would logically worsen disease. However, although one large trial suggested a role in secondary prevention, the preponderance of evidence does not suggest that environmental modifications alter the natural history of asthma, once established. A systematic review suggested that multifaceted environmental modifications have a role in primary asthma prevention.49 Although the data remain controversial and somewhat contradictory, it appears that environmental modifications are only effective before asthma is established. Similarly, although allergen immunotherapy was found to have a secondary prevention role in one large trial, evidence of tertiary prevention remains weak and inconclusive. Future directions will also include further work in the microbiome. Studies are ongoing, and there is potential that altering the
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gut microbiome could play a role in secondary and tertiary asthma prevention (as well as primary prevention). Further work needs to be performed so that we can intervene early and alter the natural course of asthma in young children. References [1] Yunginger JW, Reed CE, O’Connell EJ, Melton LJ III, O’Fallon WM, Silverstein MD. A community-based study of the epidemiology of asthma. Incidence rates, 1964-1983. Am Rev Respir Dis. 1992;146:888e894. [2] McGeachie MJ, Yates KP, Zhou X, et al. Patterns of growth and decline in lung function in persistent childhood asthma. N Engl J Med. 2016;374:1842e1852. [3] Morgan WJ, Stern DA, Sherrill DL, et al. Outcome of asthma and wheezing in the first 6 years of life: a follow-up through adolescence. Am J Respir Crit Care Med. 2005;172:1253e1258. [4] Saglani S, Payne DN, Zhu J, et al. Early detection of airway remodeling and eosinophilic inflammation in preschool wheezers. Am J Respir Crit Care Med. 2007;176:858e864. [5] Payne DN, Rogers AV, Adelroth E, et al. Early thickening of the reticular basement membrane in children with difficult asthma. Am J Respir Crit Care Med. 2003;167:78e82. [6] Agertoft L, Pederson S. Effects of long-term treatment with an inhaled corticosteroid on growth and pulmonary function in asthmatic children. Respir Med. 1994;88:373e381. [7] Guilbert TW, Morgan WJ, Zeiger RS, et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med. 2006;354: 1985e1997. [8] Murray CS, Woodcock A, Langley SJ, Morris J, Custovic A. Secondary prevention of asthma by the use of inhaled fluticasone propionate in wheezy infants (IFWIN): double-blind, randomized, controlled study. Lancet. 2006;368: 754e762. [9] Devulapalli CS, Lodrup Carlsen KC, Haland G, et al. No evidence that early use of inhaled corticosteroids reduces current asthma at 10 years of age. Respir Med. 2007;101:1625e1632. [10] The Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med. 2000;343:1054e1063. [11] Strunk RC, Sternberg AL, Szefler SJ, Zeiger RS, Bender B, Tonascia J. Long-term budesonide or nedocromil treatment, once discontinued, does not alter the course of mild to moderate asthma in children and adolescents. J Pediatr. 2009;154:682e687. [12] Knorr B, Matz J, Bernstein JA, et al. Montelukast for chronic asthma in 6- to 14-year old-children: a randomized, double-blind trial. JAMA. 1998;279: 1181e1186. [13] Straub DA, Minocchieri S, Moeller A, Hamacher J, Wildhaber JH. The effect of montelukast on exhaled nitric oxide and lung function in asthmatic children 2 to 5 years old. Chest. 2005;127:509e514. [14] Henderson WR Jr, Tang LO, Chu SJ, et al. A role for cysteinyl leukotrienes in airway remodeling in a mouse asthma model. Am J Respir Crit Care Med. 2002; 165:108e116. [15] Anderson WC, Szefler SJ. New and future strategies to improve asthma control in children. J Allergy Clin Immunol. 2015;136:848e859. [16] Wenzel S, Ford L, Pearlman D, et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med. 2013;368:2455e2466. [17] Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicenter, double-blind, placebo-controlled trial. Lancet. 2012;380:651e659. [18] Bel EH, Wenzel SE, Thompson PJ, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371:1189e1197. [19] Castro M, Mathur S, Hargreave F, et al. Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med. 2011;184:1125e1132. [20] Bjermer L, Lemiere C, Maspero J, Weiss S, Zangrilli J, Germaniro M. Reslizumab for inadequately controlled asthma with elevated blood eosinophil levels: a randomized phase 3 study [published online April 4, 2016]. Chest. http://dx.doi.org/10.1016/j.chest.2016.03.032. [21] Castro M, Wenzel SE, Bleecker ER, et al. Benralizumab, an anti-interleukin 5 receptor alpha monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomized dose-ranging study. Lancet Respir Med. 2014;2:879e890. [22] Nowak RM, Parker JM, Silverman RA, et al. A randomized trial of benralizumab, an antiinterleukin 5 receptor alpha monoclonal antibody, after acute asthma. Am J Emerg Med. 2015;33:14e20. [23] Corren J, Lemanske RF, Hanania NA, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med. 2011;365:1088e1098. [24] Hanania NA, Noonan M, Corren J, et al. Lebrikizumab in moderate-to-severe asthma: pooled data from two randomized placebo-controlled studies. Thorax. 2015;70:748e756. [25] Deschildre A, Marguet C, Salleron J, et al. Add-on omalizumab in children with severe allergic asthma: a 1-year real life survey. Eur Respir J. 2013;42: 1224e1233. [26] Busse WW, Morgan WJ, Gergen PJ, et al. Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children. N Engl J Med. 2011;364: 1005e1015.
[27] Milgrom H, Berger W, Nayak A, et al. Treatment of childhood asthma with anti-immunoglobulin E antibody. Pediatrics. 2011;108:E36. [28] Brodlie M, McKean MC, Moss S, Spencer DA. The oral corticosteroid-sparing effect of omalizumab in children with severe asthma. Arch Dis Child. 2012; 97:604e609. [29] Gauvreau GM, Arm JP, Boulet LP, et al. Efficacy and safety of multiple doses of QGE031 (ligelizumab) versus omalizumab and placebo in inhibiting allergeninduced early asthmatic responses [published online April 7, 2016]. J Allergy Clin Immunol. http://dx.doi.org/10.1016/j.jaci.2016.02.027. [30] Erpenbeck VJ, Popov TA, Miller D, et al. The oral CRTh2 antagonist QAW039 (fevipiprant): a phase II study in uncontrolled allergic asthma [published online June 21, 2016]. Pulm Pharmacol Ther. http://dx.doi.org/10.1016/j.pupt. 2016.06.005. [31] Jacobsen L, Niggemann B, Dreborg S, et al. Specific immunotherapy has longterm preventive effect of seasonal and perennial asthma: a 10-year follow-up on the PAT study. Allergy. 2007;62:943e948. [32] Novembre E, Galli E, Landi F, et al. Coseasonal sublingual immunotherapy reduces the development of asthma in children with allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2004;114:851e857. [33] Marogna M, Tomassetti D, Bernasconi A, et al. Preventive effects of sublingual immunotherapy in childhood: an open randomized controlled study. Ann Allergy Asthma Immunol. 2008;101:206e211. [34] Roberts G, Hurley C, Turcanu V, Lack G. Grass pollen immunotherapy as an effective therapy for childhood seasonal allergic asthma. J Allergy Clin Immunol. 2006;117:263e268. [35] Hedlin G, Wille S, Browaldh L, et al. Immunotherapy in children with allergic asthma: effect on bronchial hyperreactivity and pharmacotherapy. J Allergy Clin Immunol. 1999;103:609e614. [36] Gruber W, Eber E, Mileder P, Modl M, Weinhandl E, Zach MS. Effect of specific immunotherapy with house dust mite extract on the bronchial responsiveness of paediatric asthma patients. Clin Exp Allergy. 1999;29:176e181. [37] Zielen S, Kardos P, Madonini E. Steroid-sparing effects with allergen-specific immunotherapy in children with asthma: a randomized controlled trial. J Allergy Clin Immunol. 2010;126:942e949. [38] Stelmach I, Sobocinska A, Majak P, Smejda K, Jerzynska J, Stelmach W. Comparison of the long-term efficacy of 3- and 5-year house dust mite allergen immunotherapy. Ann Allergy Asthma Immunol. 2012;109:274e278. [39] Niu CK, Chen WY, Huang JL, Lue KH, Wang JY. Efficacy of sublingual immunotherapy with high-dose mite extracts in asthma: a multi-center, doubleblind, randomized, and placebo-controlled study in Taiwan. Respir Med. 2006; 100:1374e1383. [40] Di Renzo V, Marcucci F, Puccinelli P, et al. Long-lasting effect of sublingual immunotherapy in children with asthma due to house dust mite: a 10-year prospective study. Clin Exp Allergy. 2003;33:206e210. [41] Karakoc-Aydiner E, Eifan AO, Baris S, et al. Long-term effect of sublingual and subcutaneous immunotherapy in dust mite-allergic children with asthma/rhinitis: a 3-year prospective randomized controlled trial. J Investig Allergol Clin Immunol. 2015;25:334e342. [42] Kim JM, Lin SY, Suarez-Cuervo C, et al. Allergen-specific immunotherapy for pediatric asthma and rhinoconjunctivitis; a systematic review. Pediatrics. 2013;131:1155e1167. [43] Abramson MJ, Puy RM, Weiner JM. Injection allergen immunotherapy for asthma. Cochrane Database Syst Rev. 2010;4:CD001186. [44] Normansell R, Kew KM, Bridgman AL. Sublingual immunotherapy for asthma. Cochrane Database Syst Rev. 2015;8:CD011293. [45] Abrahamsson TR, Jakobsson HE, Andersson AF, Bjorksten B, Engstrand L, Jenmalm MC. Low gut microbiota in early infancy precedes asthma at school age. Clin Exp Allergy. 2014;44:842e850. [46] Arrieta MC, Stiemsma LT, Dimitriu PA, et al. Early infancy microbial and metabolic alterations affect risk of childhood asthma. Sci Transl Med. 2015;7: 307ra152. [47] Azad MB, Conveys JG, Kozyrskyj AL, et al. Probiotic supplementation during pregnancy or infancy for the prevention of asthma and wheeze: systematic review and meta-analysis. BMJ. 2013;347:f6471. [48] Razi CH, Harmanci K, Abaci A, et al. The immunostimulant OM-85 BV prevents wheezing attacks in preschool children. J Allergy Clin Immunol. 2010;126: 763e769. [49] Mass T, Kaper J, Sheikh A, et al. Mono and multifaceted inhalant and/or food allergen reduction interventions for preventing asthma in children at high risk of developing asthma. Cochrane Database Syst Rev. 2009;3:CD0006480. [50] Tsitoura S, Nestoridou K, Botis P, et al. Randomized trial to prevent sensitization to mite allergens in toddlers and preschoolers by allergen reduction and education: one-year results. Arch Pediatr Adolesc Med. 2002;156: 1021e1027. [51] Arshad SH, Bojarskas J, Tsitoura S, et al. Prevention of sensitization to house dust mite by allergen avoidance in school age children: a randomized controlled study. Clin Exp Allergy. 2002;32:843e849. [52] Platts-Mills TA, Tovey ER, Mitchell EB, Moszoro H, Nock P, Wilkins SR. Reduction of bronchial hyperreactivity during prolonged allergen avoidance. Lancet. 1982;2:675e678. [53] Boner AL, Niero E, Antolini I, Valletta EA, Gaburro D. Pulmonary function and bronchial hyperreactivity in asthmatic children with house dust mite allergy during prolonged stay in the Italian Alps. Ann Allergy. 1985;54:42e45. [54] Halken S, Host A, Niklassen U, et al. Effect of mattress and pillow encasings on children with asthma and house dust mite allergy. J Allergy Clin Immunol. 2003;111:169e175.
E.M. Abrams et al. / Ann Allergy Asthma Immunol xxx (2016) 1e7 [55] Carswell F, Birmingham K, Oliver J, Crewes A, Weeks J. The respiratory effects of reduction of mite allergen in the bedrooms of asthmatic children-a doubleblind controlled trial. Clin Exp Allergy. 1996;26:386e396. [56] Morgan WJ, Crain EF, Gruchalla RS, et al. Results of a home-based environmental intervention among urban children with asthma. N Engl J Med. 2004; 351:1068e1080. [57] Gotzsche PC, Johansen HK. House dust mite control measures for asthma. Cochrane Database Syst Rev. 2008;2:CD001187.
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[58] van der Heide S, van Aalderen WM, Kauffman HF, Dubois AE, de Monchy JG. Clinical effects of air cleaners in homes of asthmatic children sensitized to pet allergens. J Allergy Clin Immunol. 1999;104:447e451. [59] Kilburn S, Lasserson TJ, McKean M. Pet allergen control measures for allergic asthma in children and adults. Cochrane Database Syst Rev. 2003; 1:CD002989. [60] Drazen JM. Asthma: the paradox of heterogeneity. J Allergy Clin Immunol. 2012;129:1200e1201.
Contents lists available at ScienceDirect
Review
Effect of asthma therapies on the natural course of asthma Elissa M. Abrams, MD *; Stanley J. Szefler, MD y; Allan B. Becker, MD * * Department y
of Pediatrics, Section of Allergy and Clinical Immunology, University of Manitoba, Winnipeg, Manitoba, Canada Department of Pediatrics, Section of Pulmonology, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, Colorado
A R T I C L E
I N F O
Article history: Received for publication September 3, 2016. Received in revised form September 19, 2016. Accepted for publication September 23, 2016.
A B S T R A C T
Objective: To provide an evidence-based review on the role of pharmacologic (inhaled corticosteroids, leukotriene receptor antagonists, biologic therapies, aeroallergen immunotherapy) and nonpharmacologic therapies (environmental modifications, microbiome) in secondary and tertiary asthma prevention. Data Sources: A PubMed search for English-language publications regarding asthma and secondary or tertiary prevention was performed. Some articles cited in selected studies were also considered for inclusion in this review. Study Selections: Studies were included that were original research and specifically addressed the question of asthma prevention and use of pharmacologic or nonpharmacologic therapies. When possible, we selected the articles with the most robust level of evidence. Results: More than 100 articles were initially identified, 79 were reviewed in depth, and 60 were included in this review. Several studies suggest no disease-modifying effect for inhaled corticosteroids. Small studies suggest a tertiary preventive effect for leukotriene receptor antagonists. Biological therapies have somewhat conflicting evidence with a paucity of pediatric data, although some have tremendous promise. A role of allergen immunotherapy (specifically pollen) in secondary asthma prevention has been suggested, with no firm conclusions possible for tertiary prevention. One large trial suggests a role for environmental modifications in secondary asthma prevention, whereas the preponderance of evidence does not suggest a role in tertiary prevention. The microbiome is an active area of research that has promise for a disease-modifying effect. Conclusion: Further work needs to be performed to allow physicians to intervene early and alter the natural course of asthma in children. Ó 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Introduction Asthma often begins in early childhood, and lifelong complications, such as airway remodeling, can begin early in the preschool years.1e5 Studies have found that persistent lung function abnormalities are seen in children with asthma. Even mild to moderate asthma can lead to airway obstruction, which can increase in magnitude over time.2 The Childhood Asthma Management Program study noted that 75% of children aged 5 to 12 years with Reprints: Elissa M. Abrams, MD, Department of Pediatrics, Section of Allergy and Clinical Immunology, University of Manitoba, FE125-685 William Ave, Winnipeg, Manitoba, Canada R3E 0Z2; E-mail: [email protected]. Disclosures: Dr Szefler reported consulting for Aerocrine, Astra Zeneca, BoehringerIngelheim, Daiischi Sankyo, Glaxo Smith Kline, Genetech, Merck, Novartis, and Roche and receiving research support from the National institutes of Health, the National Health, Lung, and Blood Institute, the National Institute for Allergy and Infectious Diseases, the National Institute for Environmental and Health Sciences, the Environmental Protection Agency, the Colorado Cancer, Cardiovascular, and Pulmonary Disease Program, and GlaxoSmithKline. Dr Becker reported serving on the Novartis and BI advisory boards and the Global Initiative for Asthma Science Committee. No other disclosures were reported.
mild to moderate asthma had abnormal patterns of lung growth (reduced growth or early lung function decline).2 These children were at risk of fixed airway obstruction, and 11% of them met criteria for chronic obstructive pulmonary disease at a mean age of 26.0 years.2 Data from the Tucson Children’s Respiratory Study suggested that lung function parameters are established early (by 6 years of age) and do not alter significantly throughout childhood.3 Airway remodeling has also been noted early in childhood asthma. Increased reticular basement membrane thickening has been noted by 3 years of age in wheezy preschoolers.4 A study of 19 children (6e16 years of age) with asthma noted reticular basement membrane thickening that was significantly higher than nonasthmatic controls and similar to the extent seen in adults with asthma.5 Therefore, asthma often begins early in life, and early intervention provides an opportunity to prevent lung function decline and airway remodeling. There are 3 types of asthma prevention. Primary prevention is an intervention that occurs before the development of asthma or any predisposing condition (eg, eczema or rhinitis). Secondary prevention is an intervention for children at risk of asthma but who
http://dx.doi.org/10.1016/j.anai.2016.09.438 1081-1206/Ó 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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do not have active asthma. Tertiary prevention is an intervention for children who have established asthma. The goal of this article is to determine whether current asthma therapies provide a measure of secondary or tertiary asthma prevention in childhood. Both pharmacologic therapies and nonpharmacologic therapies are reviewed. Pharmacologic Therapies Inhaled Corticosteroids Some studies have suggested that inhaled corticosteroids might prevent lung function decline in children with asthma or recurrent wheeze. For example, a nonrandomized study of 216 children with mild to moderate asthma noted that treatment with inhaled budesonide improved forced expiratory volume in 1 second (FEV1) and forced midexpiratory flow (P < .001).6 This study also noted a statistically significant inverse association between duration of asthma at treatment initiation and improvement in FEV1 during therapy. Several randomized studies have examined the toddler at risk for persistent asthma and have reached the same conclusion that inhaled corticosteroids do not have a disease-modifying effect. In the Prevention of Early Asthma in Kids study, 285 children aged 2 to 3 years with a positive asthma predictive index were randomized to fluticasone propionate twice daily or placebo for 2 years, followed by a 1-year period with no medication.7 No significant difference was found between the groups in lung function, measured as reactance at 5 HZ (P ¼ .83) or resistance at 5 HZ (P ¼ .61) at the end of the observation period. In addition, no difference was found in the number of exacerbations during the observation year. The Prevention of Early Asthma in Kids study concluded that their trial did not support a disease-modifying effect of inhaled corticosteroids. The Inhaled Fluticasone Propionate in Wheezy Infants study randomized 206 toddlers (median age, 1.2 years) with parental atopy to fluticasone propionate or placebo twice daily after either 1 prolonged (>1 month) or 2 wheezy episodes.8 At 5 years, no significant difference was found in multiple measures of lung function, including prebronchodilator or postbronchodilator FEV1 (P ¼ .72 and P ¼ .73, respectively). No significant difference was found in diagnosed asthma (P ¼ .80) or current wheeze (P ¼ .53). The study concluded that early use of fluticasone did not affect the natural history of asthma or prevent lung function decline. In addition to these randomized trials examining the at risk toddler, a nested case control within the prospective birth cohort Environmental Control of Asthma noted that at a 10-year follow-up of 252 children, there was no evidence that use of inhaled corticosteroids in the first 2 years of life for recurrent bronchial obstruction affects long-term asthma risk.9 If anything, a nonsignificant increase in current asthma risk was found in the children with early inhaled corticosteroid treatment (adjusted odds ratio [OR], 1.84; range, 0.89e3.82). The Childhood Asthma Management Program study, in contrast to the previous studies, examined children with already established mild to moderate asthma and randomized them to inhaled budesonide, nedocromil, or placebo for 4 to 6 years.10 No difference in FEV1 between the groups was noted. Initial analysis revealed a smaller decline in FEV1 to forced vital capacity (FVC) before bronchodilator administration and lower airway responsiveness in the treatment group (0.2% vs 1.8%; P ¼ .001).10 However, during a 4.8-year posttrial follow-up period, no difference was found between the budesonide and placebo groups in lung function,11 suggesting that any benefit achieved with therapy was not persistent. In conclusion, the preponderance of evidence suggests no disease-modifying effect for inhaled corticosteroids in established childhood asthma or toddlers with emerging asthma.
Leukotriene Receptor Antagonists Only a few studies on leukotriene receptor antagonists (LTRAs) have examined lung function over time. Although the trials have significant limitations, such as short duration and small sample size, they suggest that LTRAs may have a disease-modifying effect. The largest trial on montelukast that addressed a diseasemodifying effect was a randomized, double-blind, placebocontrolled trial of 366 children 6 to 14 years of age with asthma.12 After 8 weeks of montelukast, there was a significant increase in morning FEV1 in the montelukast group compared with the placebo group (8.23% vs 3.58%; P < .001). The other studies that have examined changes in lung function are smaller. For example, in a study of 30 children aged 2 to 5 years with newly diagnosed asthma, a 4-week course of montelukast improved mean levels of exhaled nitric oxide (eNO) and mean airway resistance compared with both no treatment (P < .001) and 1 week of initial treatment (P ¼ .01).13 Murine models of asthma have also suggested a role for LTRAs in prevention of airway remodeling. For example, montelukast reduced multiple pathologic signs of airway inflammation and remodeling, including smooth muscle hyperplasia, mucous plugging, and subepithelial fibrosis, in ovalbumin-sensitized mice.14 In conclusion, although larger randomized studies are needed, some data suggest there may be a role for montelukast in the prevention of asthma disease progression. Biological Therapies There is increasing recognition that asthma is a heterogeneous disease, with multiple different phenotypes that may respond differently to targeted therapies. Research is emerging on biologic therapies, most of which target the TH2 profile (often aimed at interleukin [IL] 4, IL-5, and IL-13, which are involved in IgE class switching and eosinophilic recruitment).15 Some studies suggest that biologic therapies may alter the natural trajectory of asthma, despite significant limitations, including small sample sizes and a focus thus far on the adolescent and adult asthma population. With the exception of omalizumab, no studies thus far have enrolled children younger than 12 years. Details of studies that involve biological therapies for asthma are given in Table 1.16e30 Studies on dupilumab (antieIL-4/13), mepolizumab (antieIL-5), reslizumab (antieIL-5), and lebrikizumab (antieIL-13) have revealed improvements in multiple measures of asthma control.16e20,23,24 In light of improvements in pulmonary function and reduction in exacerbations, they may affect the natural course of asthma. These studies are few in number but are largely randomized clinical trials that trend toward the same improvements. Most of these studies are of short duration, and none have examined the long-term effect of therapy, if discontinued. None of these studies have been performed in children (although select studies of mepolizumab and reslizumab have included adolescents).18e20 Phase 2 studies on ligelizumab (a more potent anti-IgE monoclonal antibody), fevipiprant (CRTh2 receptor antagonist), and benralizumab (IL-5 receptor antagonist) are promising.21,22,29,30 However, some outcomes seem better affected than others, there may be a dose response, and some populations respond more positively than others (there was a 2-fold to 500-fold change in allergen PC15 with ligelizumab).29 These biological agents have overall been well tolerated and remain a promising area of research. Omalizumab (anti-IgE) is the only biological therapy that has been studied in the pediatric population. A study of 104 children aged 7 to 18 years with severe atopic asthma noted a striking decrease in exacerbation rates (72%; P < .001), hospitalization rates (88.5%; P < .001), and improvement in FEV1 (mean, 4.9%; P ¼ .02) and midexpiratory flows (9.5%; P ¼ .002).25 In addition, inhaled corticosteroid requirements decreased by a mean of 30% (P < .001)
E.M. Abrams et al. / Ann Allergy Asthma Immunol xxx (2016) 1e7
3
Table 1 Biological Therapies Used in Asthma and Their Disease-Modifying Effect Drug
Target
Study population
Outcomea
Dupilumab
AntieIL-4/13
YExacerbations, [FEV1 despite tapering ICS/LABA therapy16
Mepolizumab
AntieIL-5
Reslizumab
AntieIL-5
Benralizumab
AntieIL-5
Moderate to severe asthma taking medium- to high-dose ICSs/LABAs Recurrent exacerbations and eosinophilic phenotype Maintenance oral steroids and eosinophilic phenotypeb Poorly controlled asthma and eosinophilic phenotypeb Poorly controlled asthma and eosinophilic phenotypea Poorly controlled asthma and eosinophilic phenotype (phase 2b) Current asthma exacerbation with incomplete response and at least 1 severe exacerbation in previous year (phase 2b) Poorly controlled asthma Poorly controlled asthma Severe atopic asthmac Persistent uncontrolled atopic asthmac Moderate to severe atopic asthmac
Lebrikizumab
AntieIL-13
Omalizumab
Anti-IgE
Ligelizumab
Anti-IgE
Severe atopic asthma with maintenance OCSsc Mild allergic asthma (phase 2)
Fevipiprant
Anti-CRTh2
Mild to moderate uncontrolled allergic asthma
YExacerbations, no difference in FEV117 YExacerbations, [FEV1, YOCS18 YExacerbations, [FEV119 [FEV1, [FVC, [FEF25%e75%20 YExacerbations at higher doses, [FEV1 at all doses21 No change to FEV1, Ysome outcomes of exacerbations but not others22 [FEV123 YExacerbations, [FEV124 YExacerbations, YICS, [FEV1, [FEF25%e75%25 YExacerbations,Y hospitalizations26 YExacerbations,Y hospitalizations, NS change in pulmonary function27 YOCS, [asthma control28 [Allergen PC15 compared with omalizumab and placebo; Yskin test responses29 No overall change in FEV1; subgroup with FEV1 <70% showed [30
Abbreviations: FEF25%e75%, forced expiratory flow at 25% to 75% of the pulmonary volume; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; ICS, inhaled corticosteroid; IL, interleukin; LABA, long-acting b-agonist; NS, nonsignificant; OCS, oral corticosteroid; PC15, provocation concentration causing a 15% decrease in FEV1. a Downward arrows indicate decreased and upward arrows indicate increased. b Enrolled adolescents (>12 years old) as well as adults. c Pediatric study (children <18 years old).
during 1 year of treatment. A randomized, double-blind, placebocontrolled trial of 419 inner-city children with asthma as young as 6 years noted decreased exacerbations (48.8% vs 30.3%; P < .001), decreased hospitalizations (6.3% vs 1.5%; P ¼ .02), and lower inhaled corticosteroid use (P < .001) during a 60-week treatment period.26 Limitations to the omalizumab literature remain. The phenotype of asthma most likely to respond remains to be defined. No longterm follow-up data are available, and omalizumab has not yet been studied in preschool-aged children with asthma, in whom tertiary prevention is arguably most likely to be effective. Omalizumab has recently been licensed by the US Food and Drug Administration for treatment of asthma in children 6 years and older; it is only licensed for use in children older than 12 years in Canada. There are also limitations because of IgE requirements and weight that exclude some who would ordinarily qualify based on asthma severity. In conclusion, despite significant limitations, the biological therapies are an active area of research with tremendous promise as a therapy that might alter the natural course of asthma. Currently, the biological modifiers are primarily directed at the TH2 pathway. Although this may be relevant to those patients who have an allergic component, those who are noneosinophilic are not eligible for these medications. In addition, further work in determining the biochemical signature of patients more likely to respond to these biological agents may further increase their efficacy.
immunotherapy, significantly fewer patients undergoing SCIT had developed asthma (16/64 vs 24/53; OR, 2.5).31 A smaller study on grass sublingual immunotherapy (SLIT) revealed similar results. In this study, 113 children (aged 5e14 years) with allergic rhinitis were randomized to grass SLIT or standard symptomatic therapy for 3 years.32 Development of asthma was 3.8 times more frequent in the symptomatic therapy group. One study has examined the efficacy of SLIT in children with different aeroallergen sensitizations (tailored to individual sensitization status).33 Children with allergic rhinitis (n ¼ 216) were randomized to medication alone or medication plus SLIT for 3 years. None had persistent asthma, but some children had mild intermittent asthma at the start of treatment. In the children with intermittent asthma, persistent asthma was more frequent in the control group (1.5% vs 28.8%; number needed to treat ¼ 4), and the overall occurrence of asthma was more frequent in the control group (13.1% vs 45.4%). In addition, there was a significant difference in number of children with a positive methacholine challenge results (P < .001; OR, 0.24). These studies suggest the possibility of the role of immunotherapy in the secondary prevention of asthma, specifically in children with allergic rhinitis. However, the studies are few in number, are small in sample size, and have only studied a few aeroallergens. Further studies are required to validate the potential role of immunotherapy in this area. Tertiary Prevention
Allergen Immunotherapy Secondary prevention One large, randomized, open trial has examined the effect of grass and/or birch subcutaneous immunotherapy (SCIT) in children. The Preventative Allergy Treatment study enrolled 205 children aged 6 to 14 years with allergic rhinitis and randomized them to SCIT for 3 years or to an open control group (ie, the study was not blinded).31 None of the children at the start of the trial were taking a daily asthma medication. This study found a long-term asthma prevention effect: 7 years after completion of 3 years of
Studies on the effect of SCIT or SLIT in tertiary asthma prevention are conflicting. Select pediatric studies are highlighted in Table 2.34e41 Some studies are promising, demonstrating modification in the natural history of asthma, whereas others found no difference in markers of lung function or inflammation. As a striking example, a follow-up of 90 children with asthma who received house dust mite immunotherapy noted that both 5 and 3 years of immunotherapy had significantly higher rates of asthma remission 3 years later compared with control (54%, 50%, and 3.3%, respectively).38 However, even within a given study, the results could be interpreted in multiple ways. For example, although the study by
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Table 2 Pediatric Studies Examining Tertiary Asthma Prevention With SCIT and SLIT Study design
Outcomea
35 Children (3e16 years old) receiving daily ICSs randomized to grass SCIT or placebo for 2 pollen seasons 29 Children (7e16 years old) randomized to HDM or cat SCIT vs placebo for 3 years 14 Children given HDM SCIT for 2 years compared with 12 in control group
YAsthma symptom-medication score, NS difference airway inflammation or lung function34 [PC20 for allergen (P ¼ .01), NS difference in PC20 for histamine or ICS dose35 YCold dry air challenge-induced change in FEV1 (P ¼ .03) in SCIT group and no change in control group; [loss of BHR in SCIT group (6/14 vs 1/12; P < .05)36 YFluticasone propionate dose compared with control (P < .05; mean dose decreased from 330.3 to 151.5 mg), [PEF (þ50.7 vs þ23.55 L/min; P ¼ .03); no difference in BHR37 [Remission with SCIT (54.2% 5 year/50% 3 year/3.3% control), [FEV1 with 5 years of SCIT (P ¼ .04)38 [FVC (P ¼ .04), [FEV1 (P ¼ .048), [PEF (P ¼ .001) in intervention group and NS difference in placebo group39 YAsthma in SLIT group (31/35 baseline, 4/35 end of SLIT, 3/35 at 10 years; P .001), Yasthma medications (P .01), NS difference in either in control group; [PEF in active vs control 5 years later40 NS difference in lung function between the groups, Yasthma symptom scores41
65 Children (6e17 years old) with mild to moderate asthma randomized to HDM SCIT plus fluticasone propionate or fluticasone propionate alone for 2 years 84 Children who completed no vs 3 or 5 years of SCIT to HDM and were followed up prospectively for 3 years 97 Children (6e12 years old) with mild to moderate asthma randomized to HDM SLIT or placebo for 24 weeks Prospective, open, parallel-group controlled trial of 60 children (3e17 years old) with mild to moderate asthma and/or rhinitis treated with HDM SLIT for 4e5 years; evaluated after SLIT and 5 years later Prospective randomized clinical trial of 48 children with mild persistent asthma, comparing SLIT and SCIT with asthma medication alone
Abbreviations: BHR, bronchial hyperresponsiveness; FEV1, forced expiratory volume in 1 second; f/u, follow up; FVC, forced vital capacity; HDM, house dust mite; ICS, inhaled corticosteroid; NS, nonsignificant; PC20, provocation challenge causing a 20% decrease in FEV1; PEF, peak expiratory flow; SCIT, subcutaneous immunotherapy; SLIT, sublingual immunotherapy. a Downward arrows indicate decreased and upward arrows indicate increased.
Hedlin et al35 found a difference in allergen provocation challenge causing a 20% decrease in FEV1 (PC20) between the SCIT and placebo groups, no difference was found in PC20 histamine or asthma medication dosing.35 Furthermore, although the study by Gruber et al36 noted loss of bronchial hyperreactivity in the SCIT group, at a 1-year follow-up the treatment group trended toward a return in bronchial hyperreactivity36 A systematic review of 35 studies of SCIT and SLIT in children concluded that there was moderate-strength evidence that SCIT improved asthma symptoms but low-strength evidence that it improved asthma medication scores.42 For SLIT, there was highstrength evidence that SLIT improved asthma symptoms and moderate-strength evidence that it decreased asthma medication use. When comparing SCIT and SLIT, there was low-strength evidence to support SCIT over SLIT. Disease modification was covered specifically in the SLIT section, and the conclusions were unclear. There have been recent Cochrane reviews on both SCIT and SLIT use in asthma. For SCIT, the Cochrane review concluded that although there was improvement in measures of asthma control, such as symptoms and medication use, there was no consistent effect on lung function, negating a potential modifying effect.43 For SLIT, becaxues of the heterogeneity of the studies, no firm conclusions could be reached.44 This remains an active area of research. Current studies are examining the use of biological therapies (eg, omalizumab) in combination with allergen immunotherapy, which may allow patients with more severe asthma to be treated. Whether this will modify asthma’s natural course remains to be seen. Overall, significant heterogeneity of study results remains. Identifying children who have limited aeroallergen sensitization is
also a challenge. No firm conclusions can be drawn at this stage about whether immunotherapy has a tertiary preventive effect on asthma in children. Perhaps, a single defined strategy will not be effective, but a critical combination of selected biologic response modifiers may be the key to success. Nonpharmacologic Therapies Role of the Microbiome Emerging studies have suggested that intestinal microbiota are associated with asthma development. Some studies suggest that decreased microbial diversity in infancy may increase the risk of asthma later in life.45 Other studies have found that certain bacterial genera were associated with asthma development. For example, a nested case-control study within the Canadian Healthy Infant Longitudinal Development (CHILD) study of 339 children 1 year old noted that those at high risk of asthma (because of atopy and/or wheeze) exhibited gut microbial dysbiosis (decreased Facealibacterium, Lachnospira, Veillonella, and Rothia) in the first 100 days of life.46 Most studies thus far on the role of the microbiome have focused on probiotic supplementation and primary prevention, noting no consistent effect.47 Little human research into secondary and tertiary asthma prevention has been published. The CHILD study noted that, in a murine model, there was some efficacy in tertiary prevention in a murine model of asthma: inoculation of germ-free mice with the Facealibacterium, Lachnospira, Veillonella, and Rothia bacteria ameliorated previously induced airway inflammation.46 Immune modulation through a microbiome-based approach is an ongoing area of research. There are 2 active studies examining the role of lyophilized bacterial lysate (Broncho-Vaxom) (containing lyophilized bacterial lysates of Haemophilus, Streptococcus, Klebsiella, Staphylococcus, and Moraxella). A randomized, doubleblind, placebo-controlled trial of children 1 to 6 years of age with emerging asthma noted that lyophilized bacterial lysate treatment for 3 months (10 days per month) decreased wheezing attacks (mean incidence reduction, 37.9%; P < .001) and duration (mean, 2 days shorter; P ¼ .001) compared with placebo.48 Although promising, whether this will reduce the risk of persistent asthma is unclear. The Oral Bacterial Extracts trial is enrolling children 6 to 18 months old at high risk of asthma and randomizing them to the lyophilized bacterial lysate extract or placebo for 2 years, with the outcome being asthma symptoms during the third year of life (ClinicalTrials.gov Identifier: NCT02148796). Data collection is expected in 2020. In conclusion, some literature suggests that intestinal microbiota may be associated with asthma risk, and there is preliminary evidence from a murine model that probiotic supplementation may ameliorate airway inflammation. Although human studies on secondary and tertiary prevention have not yet been published, this is an area of active research and holds some promise as a means of altering the natural course of asthma. Aeroallergen Environmental Modifications Secondary prevention Several studies have examined the role of aeroallergen environmental modifications in primary prevention of asthma,49 with the final conclusion being that reduction of exposure to multiple allergens and multifaceted interventions may reduce the likelihood of asthma (whereas monofaceted interventions were less effective). In contrast, the Study of Prevention of Allergy in Children of Europe (SPACE) is the only large trial examining secondary asthma prevention with environmental modifications. SPACE was a multicenter randomized clinical trial designed to investigate children at
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risk of asthma and was divided into 3 cohorts (newborn, toddler, schoolchild). The toddler and schoolchild cohorts focused on secondary prevention. In the toddler and preschooler cohort, the efficacy of dust mite encasements was investigated in 636 children aged 1.5 to 5 years with atopic manifestations and parental atopy.50 It found that dust mite mattress encasements decreased sensitization to dust mite (6.5% vs 3%; P ¼ .008) and that dust mite sensitized children had a higher prevalence of physician-diagnosed asthma (P ¼ .004). This finding was replicated in the schoolchildren cohort, in which 242 children aged 5 to 7 years with a personal and family history of atopy were randomized to multifaceted dust mite interventions or control.51 At 12 months, these interventions decreased sensitization to dust mite compared with control (9.38% vs 2.56%; P ¼ .03). In addition, of those children who reported current wheeze at randomization, there was a significant decrease in wheezing at 12 months in the intervention group compared with the control group (14/30 [46.7%] had stopped wheezing in the intervention group vs 5/23 [21.7%] had stopped wheezing in the control group; P ¼ .09), suggesting a role in emerging asthma as well. Although the results of SPACE are promising, further studies are required to replicate these findings and investigate aeroallergen environmental modifications other than dust mite. Tertiary prevention Most studies on tertiary asthma prevention have focused on dust mite interventions, either alone or as part of a multifaceted intervention. A few small studies have found a beneficial effect on measures of lung function. Many were performed at high altitude or in hospital settings.52,53 However, a few were performed in home environments. A small randomized study of 60 children with asthma aged 6 to 15 years who were dust sensitized noted that 1 year of dust mite protective mattress and pillow encasings reduced dose of inhaled steroids (mean decrease, 408 to 227 mg/d; P < .001) in the intervention group only.54 A randomized study of 49 children with asthma noted that dust mite encasings for the bed and acaricide treatment improved FEV1 (102.7% to 105% in intervention group; 101.8% to 98.6% in intervention group; P < .05) compared with placebo.55 However, a large randomized trial of 937 children noted that although a multifaceted intervention, including dust mite measures that were individualized to the child’s sensitization and exposure, improved symptom-free days (for every 2-week period, 3.39 vs 4.20 symptom-days; P < .001), there was no significant effect on multiple lung function measures, including FEV1, FVC, and peak flow variability.56 In addition, a Cochrane review of 55 trials, including pediatric studies, noted no effect of dust mite measures on measures of lung function, asthma symptom scores, or medication use in children with asthma and dust mite allergy.57 However, a major problem with this meta-analysis is that studies were included where there had been no success in significantly reducing dust mite. The other environmental modification that has been studied is pet reduction measures, and the data are sparse. Only one small pediatric study examined pet reduction measures in children with asthma and pet sensitization. In this double-blind, placebocontrolled, crossover study of 20 children, 3 months of air filters in the living rooms and bedrooms decreased airway responsiveness (1.2 doubling dose increase of PC20 for adenosine; P ¼ .003) and peak flow amplitude (P ¼ .04).58 However, because of the paucity of data, a Cochrane review concluded that there is not enough evidence for or against the use of air filtration units to reduce pet allergen levels in children with asthma and pet allergy.59 Overall, although some small studies on dust mite measures, mostly focused on dust mite encasings, have found a benefit, the preponderance of the evidence does not support a benefit for altering the natural course of asthma. Although preliminary
5
Table 3 Summary of Pharmacologic and Nonpharmacologic Interventions and Effect on Secondary and Tertiary Asthma Prevention Intervention
Summary of prevention effect
Inhaled corticosteroids
Tertiary: Several RCTs suggest no diseasemodifying effect7e10 Tertiary: Small studies suggest a diseasemodifying effect; larger studies needed12,13 Tertiary: Conflicting evidence, small studies, paucity of pediatric data. Some biological agents (dupilumab, mepolizumab, lebrikizumab, omalizumab) showing promise16e30 Secondary: Significant limitations to the literature but suggestion of a role, specifically in children with allergic rhinitis and pollen sensitization31e33 Tertiary: Significant heterogeneity in study results; no firm conclusions can be made34e41 Secondary: Paucity of data; area of active research46e48 Tertiary: Area of active research, suggesting promise for a disease-modifying effect46e48 Secondary: One large trial suggesting a role; further studies needed50,51 Tertiary: Preponderance of evidence does not suggest a role; study limitations include a focus predominantly on dust mite measures52e59
LTRAs Biologic therapies
Allergen immunotherapy
Microbiome
Environmental modifications
Abbreviations: LTRA, leukotriene receptor antagonist; RCT, randomized clinical trial.
evidence is promising, further studies are required to determine whether pet environmental measures are effective in tertiary prevention. Conclusion In a recent commentary, Drazen stated, “We still do not have a way to work up a given patient with asthma and to easily delineate the specific pathobiology that leads to her or his airway dysfunction. It is like treating infectious disease without a culture.”60 Childhood asthma may have different histologic changes, phenotypes, endotypes, and treatment responses. Much more work needs to be done to understand the underlying pathophysiologic mechanisms of childhood asthma. Perhaps as a result of this heterogeneity, currently used first-line pharmacologic therapies (namely, inhaled corticosteroids) have not been found to modify its natural course (Table 3). Biological therapies, theoretically more tailored to individual asthma phenotypes, have shown promise, but there continue to be study limitations. As more work is done to delineate asthma phenotypes, particularly in children, biological agents hold promise to modify the natural history of asthma. Environmental modifications should theoretically play a role in both secondary and tertiary asthma prevention because exposure to an aeroallergen that a child is sensitized to would logically worsen disease. However, although one large trial suggested a role in secondary prevention, the preponderance of evidence does not suggest that environmental modifications alter the natural history of asthma, once established. A systematic review suggested that multifaceted environmental modifications have a role in primary asthma prevention.49 Although the data remain controversial and somewhat contradictory, it appears that environmental modifications are only effective before asthma is established. Similarly, although allergen immunotherapy was found to have a secondary prevention role in one large trial, evidence of tertiary prevention remains weak and inconclusive. Future directions will also include further work in the microbiome. Studies are ongoing, and there is potential that altering the
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