- Email: [email protected]
Predicting asthma outcomes
Clinical reviews in allergy and immunology Series editors: Donald Y. M. Leung, MD, PhD, and Dennis K. Ledford, MD
Predicting asthma outcomes Malcolm R. Sears, MB, ChB
Hamilton, Ontario, Canada
INFORMATION FOR CATEGORY 1 CME CREDIT Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions. Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted. Date of Original Release: October 2015. Credit may be obtained for these courses until September 30, 2016. Copyright Statement: Copyright Ó 2015-2016. All rights reserved. Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Creditä. Physicians should
This review addresses predictors of remission or persistence of wheezing and asthma from early childhood through adulthood. Early childhood wheezing is common, but predicting who will remit or have persistent childhood asthma remains difficult. By adding parental history of asthma and selected infant biomarkers to the history of recurrent wheezing, the Asthma Predictive Index and its subsequent modifications provide better predictions of persistence than simply the observation of recurrent wheeze. Sensitization, especially to multiple allergens, increases the likelihood of development of classic childhood asthma. Remission is more likely in male subjects and those with milder disease (less frequent and less severe symptoms), less atopic sensitization, a lesser degree of airway hyperresponsiveness, and no concomitant allergic disease. Conversely, persistence is linked strongly to allergic sensitization, greater frequency and severity of symptoms, abnormal lung function, and a greater degree of airway
From the Department of Medicine, Faculty of Health Sciences, de Groote School of Medicine, McMaster University. Received for publication January 30, 2015; revised April 14, 2015; accepted for publication April 17, 2015. Corresponding author: Malcolm R. Sears, MB, ChB, Firestone Institute for Respiratory Health, St Joseph’s Healthcare Hamilton, T3219, 50 Charlton Ave E, Hamilton, Ontario L8N 4A6, Canada. E-mail: [email protected]. 0091-6749/$36.00 Ó 2015 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaci.2015.04.048
claim only the credit commensurate with the extent of their participation in the activity. List of Design Committee Members: Malcolm R. Sears, MB, ChB Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: The author declares that he has no relevant conflicts of interest. Activity Objectives: 1. To review the Asthma Predictive Index (API) and its modifications. 2. To identify factors associated with childhood asthma remission or persistence. 3. To describe the relationship between lung function and persistence of childhood asthma. Recognition of Commercial Support: This CME activity has not received external commercial support. List of CME Exam Authors: Eyas Abla, MD, Jonathan A. Olsen, DO, Mark Stevens, MD, and Jeffrey Stokes, MD. Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: The exam authors disclosed no relevant financial relationships.
hyperresponsiveness. A genetic risk score might predict persistence more accurately than family history. Remission of established adult asthma is substantially less common than remission during childhood and adolescence. Loss of lung function can begin early in life and tracks through childhood and adolescence. Despite therapy which controls symptoms and exacerbations, the outcomes of asthma appear largely resistant to pharmacologic therapy. (J Allergy Clin Immunol 2015;136:829-36.) Key words: Asthma, birth cohorts, longitudinal phenotypes, lung function, persistence, prediction, remission, wheezing
Symptoms of asthma most commonly begin in childhood, often in the first few years of life. Between 30% and 50% of preschool children experience episodes of wheezing, of whom less than half will have continuing childhood asthma. Over the last several decades, longitudinal studies have provided substantial information regarding the development and trajectories of childhood wheezing and the likely outcomes of different phenotypes of asthma. This review addresses 2 principal questions: first, can we predict which children with early childhood wheeze (often called preschool wheeze) will go on to have childhood asthma, and second, can we predict which children or adults with established asthma will experience remissions or relapse or have persistent asthma? 829
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Abbreviations used ALSPAC: Avon Longitudinal Study of Parents and Children aOR: Adjusted odds ratio API: Asthma Predictive Index BAMSE: Barn/Children, Allergy and Milieu in Stockholm, an Epidemiological study CAMP: Childhood Asthma Management Program COPD: Chronic obstructive pulmonary disease GRS: Genetic risk score mAPI: Modified Asthma Predictive Index OR: Odds ratio PIAMA: Prevention and Incidence of Asthma and Mite Allergy PPV: Positive predictive value ucAPI: University of Cincinnati Asthma Predictive Index
PREDICTING OUTCOMES OF EARLY CHILDHOOD WHEEZING An Asthma Predictive Index (API) was proposed by CastroRodriguez1 to provide a framework to predict outcomes of early childhood wheezing. Drawing on data from the Tucson Birth Cohort, the API uses 2 major criteria (physician-diagnosed parental asthma and physician-diagnosed childhood eczema) and 3 minor criteria (physician-diagnosed allergic rhinitis, _4%) as prewheezing apart from colds, and blood eosinophilia > dictors. The ‘‘stringent’’ index for prediction of asthma requires _3 episodes per year in 2- to 3-yearearly frequent wheeze (> olds) and the presence of at least 1 of the 2 major criteria or 2 of 3 minor criteria. The ‘‘loose’’ index required less than 3 episodes per year, again combined with one of the major criteria or 2 of the minor criteria (Table I). The usefulness of the API has been challenged on several grounds.2 It predicts the outcome of asthma ever and not recurrent wheeze, which is more clinically relevant and of greater concern to physicians and families. The predictive value is highly dependent on the prior probability (prevalence) of asthma in the cohort in which it is used. The higher the prevalence of asthma (eg, in high-risk populations), the poorer will be the performance on the API in predicting the outcome of preschool wheeze. The usefulness of the API has also been challenged on the grounds that it has yet to be shown that identification of children with a positive API results in interventions or treatments that reduce later asthma, although this would be the desirable benefit of such identification.3 The Tucson-derived API has been validated in the Leicester birth cohort.4 Using the loose API, the odds ratios (ORs) for asthma at age 7 were comparable (5.2 in Leicester and 5.5 in Tucson), and the positive predictive value (PPV) was 26% in both studies. For the stringent API, ORs were 8.2 and 9.8 and PPVs were 40% and 48%, respectively. These values were somewhat greater that those achieved by using a simple early wheeze criterion; in the Leicester cohort the OR for later asthma was 5.4 and the PPV was 21%, and for early frequent wheeze the values were 6.7 and 36%, respectively. The API has undergone a number of modifications. The modified Asthma Predictive Index (mAPI) requires 4 or more wheezing episodes in the last year, adds another major criterion _1 aeroallergen), and changed the minor criteria by (sensitized to > removing allergic rhinitis but adding sensitization to milk, egg, or peanut. The mAPI was evaluated in the Childhood Origins of Asthma cohort.5 Prediction of school-age asthma improved from
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ages 1 to 3 years, and the mAPI provided a high likelihood ratio of 4.9 for asthma at 6 years and even higher for older children, with likelihood ratios of up to 55 at age 11 years. Decreasing the required number of wheezing episodes from 4 or more in the past year to only 2 episodes (the m2API) decreased the predictive value and did not improve the predictive value of a negative test result. In a high-risk prospective birth cohort, the Cincinnati Childhood Allergy and Air Pollution study, Amin et al6 assessed another modified API, the University of Cincinnati Asthma Predictive Index (ucAPI). This was based on 2 or more episodes of wheeze in the last 12 months at age 3 years and 1 of 3 major _1 aeroallergen, criteria (parental asthma, allergic sensitization to > and history of eczema) or 2 of 3 minor criteria (wheezing without a cold, allergic rhinitis, and milk or egg sensitization). The ucAPI was compared with a history of persistent wheezing at age 3 years _2 episodes of wheezing in the last 12 months at both (defined as > the 2- and 3-year visits) as a predictor of objectively confirmed asthma (symptoms and a positive bronchodilator or methacholine response) at age 7 years. Confirmed asthma at 7 years was significantly associated with both a positive ucAPI (adjusted odds ratio [aOR], 13.3; 95% CI, 7.0-25.2) and the persistent wheezing phenotype (aOR, 9.8; 95% CI, 4.9-19.5). ATask Force of the European Respiratory Society proposed the terms episodic wheeze to describe children who wheeze intermittently, apparently with viral infections, and who are well between episodes and multitrigger wheeze to describe children who wheeze both during and outside discrete episodes.7 It was noted that there might be a large overlap in these phenotypes that could change over time. The debate on whether episodic wheeze and multitrigger wheeze differ in clinical features and whether differentiating these subtypes helps predict asthma at school age emphasized the limitations of predictive indices.8 Triggers might be difficult to identify precisely. In the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort, episodic wheeze and multitrigger wheeze did not correspond to specific longitudinally derived wheezing phenotypes identified by using longitudinal latent class analysis or hypothesis-based definitions of transient early and persistent wheeze.8 Recommendation for improving the API include more precise definitions of risk factors, such as sensitization (quantitative levels of IgE or multiple allergen sensitization); lung function; inclusion of maternal exposures, such as smoking and viral infections; more precise phenotyping of asthma with objective measurements; addition of noninvasive markers of inflammation; and better characterization of genetic risk and epigenetic effects. Among high-risk children with a family history of atopic disease, the nature of the viral illness associated with early childhood wheezing had value in predicting the likelihood of persistence.9 Contrary to previous understanding, wheezing illnesses associated with rhinovirus infection were more strongly associated with asthma at age 6 years than respiratory syncytial virus–associated wheezing illnesses. Almost 90% of children with rhinovirus-associated wheezing in year 3 had asthma at age 6 years. Caudri et al10 reported follow-up of 3963 children in the PIAMA cohort to age 8 years. Of these children, 55% had wheezing or coughing at night without a cold or both by age 4 years, but only 11% had asthma at age 7 to 8 years. Factors independently predicting asthma in later childhood included male sex, postterm delivery, medium or low parental education, parental use of inhaled medication, frequency of wheeze, wheezing/dyspnea
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TABLE I. Criteria for the API and its subsequent modifications
Primary criterion Major criteria
Minor criteria
Loose API
mAPI
m2API
ucAPI
> _3 Yes Yes
<3 Yes Yes
Yes Yes Yes — 1 2
Yes Yes Yes — 1 2
> _4 Yes Yes Yes — Yes Yes Yes 1 2
> _2 Yes Yes Yes — Yes Yes Yes 1 2
> _2 Yes Yes Yes Yes Yes — Yes 1 2
Criteria
Stringent API
Frequency of episodes in the last year Physician-diagnosed parental asthma Physician-diagnosed child eczema _1 aeroallergen Sensitization to > Physician-diagnosed allergic rhinitis Wheezing apart from colds _4% Blood eosinophils > _1 food allergen Sensitization to >
Required no. of major criteria OR required no. of minor criteria
wheezing, which began in the second and third years of life and persisted to 7 years, and persistent wheezing with onset after 3 years, and this association was still evident at 7 years (Fig 1 and Table II).11 Five phenotypes were identified by using longitudinal latent class analysis in the PIAMA cohort, which were generally similar in pattern to the ALSPAC classification.12 Persistent wheeze in the PIAMA cohort was related to male sex, parental allergy, and breast-feeding for less than 12 weeks.
FIG 1. Phenotypes of early childhood wheezing illustrating the time course of development and the effect of atopy on the different phenotypes in the ALSPAC study. Adapted from Henderson et al.11
TABLE II. Characteristics of the different phenotypes of wheezing in childhood Phenotype
Transient early Prolonged early Intermediate Late Persistent
Asthma
Atopy
FEV1
FEF25-75
AHR
O OO OOOO OOO OOOO
— — OO OO O
Y Y YY Y YY
Y YY YY Y YY
[ [ [[ [[ [[
Adapted from Henderson et al.11 Phenotypes refer to those shown in Fig 1.
apart from colds, serious respiratory tract infections, and doctordiagnosed eczema with evident rash. The authors devised a clinical risk score (range, 0-55 points) and found that symptomatic children with a score of less than 10 had a 3% risk, whereas a score of 30 or greater had a 42% risk of asthma. Statistical techniques have been applied in several cohorts to identify phenotypes of childhood asthma, including temporal assessments, clustering of variables, and unsupervised machine analyses, examining outcomes in later childhood but not yet into adulthood. Henderson et al11 identified 6 phenotypes of wheezing through latent class analysis of data collected in the Avon Longitudinal Study of Parents and Children (ALSPAC) study for 6265 children at 7 time points from birth to age 7 years. There was a strong association of atopy with both intermediate-onset
PREDICTING OUTCOMES OF ESTABLISHED ASTHMA: REMISSION, RELAPSE, AND PERSISTENCE Two decades ago, when attempting to harmonize differing adult outcomes reported in epidemiologic studies in 2 Australian populations followed from childhood,13,14 the most obvious explanation was that severe asthma usually persisted and mild asthma frequently went into remission.15 In 2015, do we have better prediction tools or stronger evidence to guide families and health care workers in their expectations of outcomes, which in turn might influence management decisions? There is no doubt from population database studies, such as that conducted by To et al,16 that a large proportion of children with asthma experience remission. By using the Ontario (Canada) health administrative database, more than 34,000 children were identified who had received a diagnosis of asthma by age 6 years. A second health care encounter within 1 year after diagnosis occurred in more than half (54%), but by age 12 years, 48% were in apparent remission, with no hospitalizations or physician’s office visits recorded for asthma. Those with a hospitalization in the first year after diagnosis were at 3-fold risk of persistence to age 12 years, as were those with at least 4 physician’s office visits for asthma during follow-up. Covar et al17 followed children in the Childhood Asthma Management Program (CAMP) study for 4 years and showed that remission was associated with milder disease, lack of atopic sensitization, less airway hyperresponsiveness, and higher FEV1. Among older subjects, remission is less common. Gershon et al18 used the Ontario health administrative database to identify 613,394 patients of all ages with asthma in 1993 and followed claims for asthma in the database for 15 years. More than 80% _1 physician’s claims for health had active disease (indicated by > services for asthma) in subsequent years, almost all ambulatory rather than hospital based. Although it is possible that some of those without ongoing asthma activity in the ensuing 15 years might have been misclassified at the onset, some will have
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experienced true remission. Interestingly, about 75% of those with apparent remission had a gap of 2 years or more in asthma activity, suggesting relatively mild disease; longer gaps were more evident in female than male patients. Greater asthma activity was noted for those with previous asthma claims, older and younger age groups, and those with a codiagnosis of chronic obstructive pulmonary disease (COPD), illustrating some of the difficulties in interpreting database information without the opportunity for clinical assessment. It is important to distinguish between persistence and progression, with persistence referring to the continuation of symptoms and progression to worsening of symptoms and physiologic characteristics reflected in lung function over time.3 Progression certainly implies persistence, but the reverse is not always true. Andersson et al19 undertook longitudinal follow-up of 248 children initially identified with asthma through a questionnaire survey completed by parents of 7- to 8-year-old children in northern Sweden in 1996. Asthmatic children were followed to age 19 years. Remission was defined as no symptoms and no asthma medication for the 3 years before the end point of the study. At age 19 years, 21% were in remission, 38% had periodic asthma, and 41% had persistent asthma. Remission was more common in boys and less common with sensitization to furred animals (OR, 0.14) and greater severity scores (OR, 0.19); 82% of children with these latter features had persistent asthma through adolescence. Environmental factors, including damp housing, rural living, and smoking, were not indicators of remission or persistence. Consistent with many other studies, those experiencing remission or having only periodic symptoms had better childhood lung function and less airway responsiveness than those with persistent asthma.
Sex differences Although male children more commonly have symptoms of wheezing and early childhood asthma, there is a greater incidence and greater persistence of symptoms in female patients during and after puberty. In the Barn/Children, Allergy and Milieu in Stockholm, an Epidemiological study (BAMSE) cohort, there was no sex difference in the likelihood of asthma at age 8 years among those with infant wheeze before age 2 years (aOR for male sex, 1.10; 95% CI, 0.73-1.67).20 Pubertal changes were assessed in relation to the changes in asthma development and remission in 2230 adolescents in the Tracking Adolescents’ Individual Lives Survey.21 At a mean age of 11 years, the prevalence of asthma in male and female subjects was similar (7.7% in boys and 7.4% in girls), but at 16 years, although both prevalence rates had decreased, asthma was more common in girls (6.2%) than boys (4.3%). They found no significant associations between transition of pubertal stages and the presence of asthma, either in cross-sectional or longitudinal analyses, and no correlation between pubertal stages and serum IgE levels or exercise-induced bronchoconstriction. Martinez et al,22 reporting on the Tucson Children’s Respiratory Study, described early, late, and persistent phenotypes of asthma but did not differentiate these phenotypes by sex. However, in a later article from that study, remission of asthma by age 22 years was twice as common in men as in women (OR, 2.0; 95% CI, 1.2-3.2).23 Concomitant allergic disorders Childhood wheezing is frequently associated with other disorders of an allergic or atopic nature, including atopic dermatitis or
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eczema, food allergy, rhinoconjunctivitis, and occasionally anaphylaxis. Many studies have confirmed the association of atopy with more troublesome asthma and a greater likelihood of persistence. In the BAMSE cohort infant eczema increased the risk of asthma persistence to age 8 years (aOR, 2.31; 95% CI, 1.52-3.49), but infant rhinorrhea did not (aOR, 1.32; 95% CI, 0.75-2.34).20 Among children followed in the Cincinnati Childhood Allergy and Air Pollution study, those with allergic persistent wheezing has a higher risk of asthma at age 7 years than those with nonallergic persistent wheezing (aOR, 10.4; 95% CI, 4.1-26.0 vs aOR, 5.4; 95% CI, 2.014.1; P <.01).6 Follow-up of the Tasmanian Asthma Study cohort to age 44 years identified that childhood allergic rhinitis was not only associated with a 2- to 7-fold increased risk of incident asthma in preadolescence, adolescence, or adult life but also was associated with a 3-fold increased risk of childhood asthma persisting rather than remitting by middle age.24 Early sensitization and sensitization to multiple allergens are more strongly predictive of persistence throughout childhood and into adulthood. The Manchester Asthma and Allergy Study used a 5-class model of atopic vulnerability and showed that those with multiple early sensitizations (10.6% of the cohort) were most likely to have hospitalizations for asthma25 and poorer lung function.26 In the German Multicentre Allergy Study birth cohort, wheezing at age 13 years was associated with parental atopy and sensitization to common allergens, increased serum total IgE levels, and exposure to high levels of indoor allergens in early life, all of which were more evident among those with early childhood wheeze than among those who did not wheeze.27
Asthma severity Longitudinal studies have indicated that children with more severe asthma in early childhood and midchildhood are more likely to have persistence of symptoms and associated physiologic abnormalities than those with occasional, infrequent, or milder symptoms. In the Melbourne study, in which children were recruited at age 7 years, there were initially few with severe asthma, and therefore an additional group of children with more severe disease were recruited at age 10 years.28 When followed out to age 50 years, only 15% of those with severe asthma at age 10 years had experienced full remission compared with 64% of those with milder ‘‘wheezy bronchitis’’ in childhood and 47% of those with persistent (but not severe) childhood asthma.29 In the BAMSE cohort the risk of asthma at age 8 years was significantly increased among those with wheeze persistence (aOR, 5.1; 95% CI, 2.5-10.4), more than 3 episodes of wheeze in infancy (aOR, 3.4; 95% CI, 2.1-5.6), and use of inhaled steroids (aOR, 3.4; 95% CI, 2.2-5.3).20 These characteristics of severity were largely overlapping. In the Tucson Children’s Respiratory Study persistence of wheezing in early life was associated with a high risk of asthma at age 22 years (OR, 14.0; 95% CI, 6.8-28.0).23 In the Manchester Asthma and Allergy Study population-based cohort, children identified at age 8 years as having persistent troublesome wheeze by using longitudinal latent class modeling (prevalence, 3.2%) differed significantly from those with persistent controlled wheeze (prevalence, 13.1%), demonstrating decreased lung function and greater airway responsiveness compared with all other classes and experiencing more exacerbations, hospitalizations, and unscheduled visits.30 Exacerbations
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among those with persistent troublesome wheeze were almost 4-fold more frequent than among those with persistent controlled wheeze and 16 times more frequent than among those classified as having late-onset wheeze. Predictors of persistent troublesome wheeze could be identified as early as age 3 years, when these children had diminished lung function (specific airway resistance, >1.6 kPa), eczema, and a sum of all allergen wheals of 10 mm or greater and experienced 3 or more exacerbations by that age. Children demonstrating 3 of these 4 features were 40 times more likely to have persistent troublesome wheeze compared with other wheezing children (PPV, 42.9%). The key independent predictors of this severe asthma outcome at age 8 years were having a sum of skin test wheals of 10 mm or greater and a history of exacerbations by age 3 years.
Genetics In 2010, Holloway et al31 wrote that ‘‘the ability of genetics alone to predict disease onset is poor’’ but noted that some polymorphisms of genes were associated with measures of asthma severity, such as exacerbations, and that there appeared to be genetic commonalities between asthma and COPD. Whether such genetic variants predispose to persistence of asthma leading to chronic airflow obstruction (which might be misdiagnosed as COPD) is as yet unclear. With the evolution of genome-wide association studies over the last decade, a number of genes have emerged as more frequent in asthmatic patients, enabling the development of a genetic risk score (GRS). Using this methodology, Belsky et al32 assessed outcomes in the Dunedin Multidisciplinary Health and Development Study, which has followed 1037 children from birth to age 38 years. Persistence of childhood asthma into midadulthood was 2 to 3 times more likely among those with a higher GRS than among those with median or lower GRS. The GRS was a stronger predictor of persistence than family history, which is traditionally used to assess hereditary influences on the persistence of asthma. Associations between replicated genes for COPD and early childhood wheezing and lung function levels in 6- to 8-year-old children were explored in 3 European cohorts: PIAMA, KOALA (a Dutch acronym for Child, Parents and Health: Lifestyle and Genetic Constitution), and ALSPAC.33 At least 3 COPD genes appeared to be implicated in lung development and lung growth. Some evidence suggested that COPD genes are involved in the response of the infant lung to smoke exposure in utero and in early life. What is not clear and requires longer follow-up is whether children with those COPD-related genes have more persistent or progressive asthma in later childhood and adulthood. Genetic variants have also been shown to modulate the effects of therapy and therefore might influence long-term outcomes; for example, among children participating in the CAMP study, a variation in TBX21 coding (replacement of histidine 33 with glutamine) affected the effect of inhaled corticosteroids on airway hyperresponsiveness,34 whereas a functional variant in GLCCI1 was associated with a decreased response to corticosteroids.35 Environmental factors Maternal smoking (both prenatal and postnatal) and exposure to damp and mold are well-recognized risk factors for the development of early childhood wheezing and asthma,36-38 but
FIG 2. Spirometric lung function in male subjects followed from age 9 to age 26 years and stratified by asthma status at age 26 years. Those with persistent wheezing or relapse by age 26 years had significantly impaired function since the first measurement at age 9 years. FVC, Forced vital capacity. Adapted from Sears et al.40
FIG 3. Data are shown for 871 white study members from the Dunedin cohort, an unselected New Zealand population followed for 38 years. Overall, 35% had reported asthma, and 27% had reported asthma with atopy. Persistent asthma demonstrated by asthma and airway hyperresponsiveness was present in 18.4%, and incompletely reversible airflow obstruction (defined as postbronchodilator FEV1/forced vital capacity >2 SDs less than the mean value in sex-stratified healthy nonsmoking study members) in 8.7%. More than 90% of those with airway hyperresponsiveness (AHR), incompletely reversible airflow obstruction, or both were atopic. Adapted from Belsky et al.32
their role in predicting long-term outcomes is less clear. However, recent studies have indicated that dampness is associated with continuing symptoms, and a ‘‘moldiness index’’ has some predictive value for persistence.39 Personal smoking by late adolescence was identified as a risk factor for continuing asthma symptoms at age 26 years in the Dunedin cohort.40 An interesting study in Sweden sheds further light on the reported persistence and apparent remission of asthma. Roel et al41 followed up a birth cohort of more than 2000 children and were surprised that almost 40% of children with a hospital or primary care diagnosis of asthma at least once between birth and age 7 years were reported by their parents at age 10 years to have
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never had asthma. The initial asthma diagnosis was confirmed through examination of medical records. Four factors were independently and significantly associated with the nonreport of asthma by age 10 years, namely not having past experience of allergic symptoms, having only 1 or 2 hospital visits for asthma between birth and age 7 years, type of residence at age 10 years (living in a villa rather than a flat), and having no previous perception of mold damage in their residence. Hence both intrinsic (atopy and severity) and environmental (residence and mold) factors appear to be associated with remission or at least failure to recall previous asthma. This study also highlights the problems of recall bias in studies of asthma outcomes in which information is obtained retrospectively.
Lung function In the Dunedin longitudinal study young adults with persistent or relapsing childhood asthma at age 26 years had significantly impaired lung function.40 By examining the trajectory of their spirometric values from age 9 to 26 years, it was evident that those with adult asthma had impaired lung function from the very first assessment at age 9 years (Fig 2).40 In subsequent follow-up to age 38 years,32 almost 9% of this general population had incompletely reversible airflow obstruction associated with asthma; of these, almost all (90%) had demonstrated airway hyperresponsiveness in childhood and adolescence, and almost all (90%) were atopic (Fig 3).32 In the Tucson Children’s Respiratory Study low lung function at 6 years and bronchial hyperresponsiveness at 6 years were independent risk factors for chronic asthma at age 22 years.23 Vonk et al42 tracked a small group (n 5 119) of allergic asthmatic patients initially seen as children aged 5 to 14 years. On review as adults 30 years later, complete remission (defined as no symptoms, no inhaled corticosteroid use, normal lung function, and absence of airway hyperresponsiveness) occurred in only 22%, whereas clinical remission (no symptoms and no ICS) occurred in a further 30%. More than half of those with clinical remission exhibited low lung function or airway hyperresponsiveness. Both complete remission and clinical remission were associated with higher FEV1 in childhood and more improvement in FEV1 from childhood to young adulthood. Measurements of airway responsiveness conducted at age 10 years (methacholine challenge and exercise-induced bronchoconstriction) in a Norwegian cohort43 were modestly predictive of active asthma at age 16 years, together explaining 14% of the variation in patients with active asthma 6 years after tests were performed. However, much stronger predictions were apparent with greater degrees of responsiveness or greater decreases in lung function with exercise, indicating the importance of not just the presence of hyperresponsiveness but also its severity in predicting outcomes.44 A provoking dose of methacholine inducing a 20% decrease in FEV1 of 1 mmol or less predicted adolescent asthma with a 54% likelihood, and if airway responsiveness was markedly increased in the presence of active asthma and rhinitis, the likelihood of persistence was close to 100%. Children participating in the CAMP study underwent serial methacholine challenges for more than 8 years on average.45 Airway responsiveness decreased with increasing age, more in boys than girls, with divergence between the sexes coinciding with the mean age for Tanner stage 2 of puberty.
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Adult asthma The outcomes of adult-onset asthma have been studied particularly in relation to occupational exposures. In some remission has been documented when exposure is limited or avoided altogether. Unfortunately, there is often persistence of occupational asthma requiring continuing treatment even after exposure ceases, from which remission is uncommon. Likewise, nonoccupational adult asthma remits infrequently.46 Holm et al47 followed up 1153 adults aged 20 to 44 years who participated in the European Community Respiratory Health Survey in northern Europe and who had reported asthma at the initial survey. Defining remission as no asthma symptoms in 2 consecutive years and no current use of asthma medication, a remission rate of 20 per 1000 person years was calculated. There was no significant difference according to sex, but a greater likelihood of remission was found among those who quit smoking and among those with milder disease. Participants in the Tasmanian Longitudinal Health Study recruited at age 6 to 7 years were followed up at age 44 years.24 There was no relation between childhood eczema or rhinitis and nonatopic adult asthma; however, the combination of rhinitis and eczema strongly predicted new-onset adult asthma by middle age and the persistence of childhood asthma to adult atopic asthma (ORs, 6.3 and 11.7, respectively). Rhinitis alone also predicted the persistence of childhood asthma to adult atopic asthma (OR, 2.7). Overall, almost 30% of persistent atopic asthma could be attributed to having childhood rhinitis and eczema. Treatment Although many studies of management of childhood and adult asthma demonstrate the ability of modern treatment regimens to control symptoms, reduce airflow obstruction, reduce airway responsiveness, and improve quality of life, it does not appear possible at this time to change the natural history of the disease. In the CAMP study airway responsiveness and asthma control improved with budesonide during the active treatment period,48 but this benefit did not persist after discontinuation.49 Further studies were undertaken because of the possibility that inhaled corticosteroids were not started early enough in the CAMP study. Treatment of early childhood wheezing for 2 years with inhaled fluticasone, while reducing symptoms and exacerbations during the treatment period, did not provide a sustained benefit; during a third year without treatment, outcomes reverted to those of the control group not given fluticasone.50 Bisgaard et al51 treated infants with episodic wheezing with 2-week courses of inhaled budesonide beginning after 3 days of wheezing and showed no effect on the progression from episodic to persistent wheezing or the short-term benefit of such treatment during episodes of wheezing in the first 3 years of life. The effects of treatment of participants in longitudinal cohort studies are difficult to ascertain, given that treatment is more likely to be offered to those with more severe disease (confounding by severity), as was evident in analyses of adult outcomes in the Dunedin study, in which those receiving inhaled corticosteroid therapy showed an even greater decrease in lung function over time.40 Summary There is consensus among longitudinal studies that wheezing that begins in early life and continues into the school years generally persists into adulthood.52 As noted 20 years ago, more
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severe asthma is more likely to persist, whereas mild asthma often goes into remission.15 Such persistent wheezing is associated with lower lung function and increased airway responsiveness that is established early in life. Multiple factors predict persistence, especially a strong atopic disposition, early sensitization, and greater symptom frequency, all suggesting that early airway injury from 1 or more biological exposures sets up lifelong disease. Treatment, although effectively controlling symptoms and improving lung function while taken, appears not to change the natural course of the disease. What do we know? d Many children wheeze in preschool years, but less than half of these go on to have childhood asthma. d
Remission of childhood asthma is more common in male subjects and in those with lesser degrees of atopy and higher lung function.
d
A greater degree of sensitization, especially to multiple allergens; concomitant allergic diseases; and greater severity of asthma all favor persistence.
d
Remission of symptoms can occur in the presence of persistent loss of lung function and airway hyperresponsiveness.
What is still unknown? d Usefulness of biomarkers in predicting the trajectory of early childhood wheezing to established asthma d
How to prevent the development and persistence of childhood asthma
d
Why asthma is more likely to persist in female subjects
d
What factors determine the very early loss of lung function in those destined to have persistent asthma
d
Whether children with COPD-related genes are more likely to develop persistent and progressive asthma and chronic airflow obstruction
d
Whether the outcome of childhood and adult asthma can be modified by prolonged aggressive therapy
REFERENCES 1. Castro-Rodriguez JA. The Asthma Predictive Index: early diagnosis of asthma. Curr Opin Allergy Clin Immunol 2011;11:157-61. 2. Brand PL. The Asthma Predictive Index: not a useful tool in clinical practice. J Allergy Clin Immunol 2011;127:293-4. 3. Panettieri RA Jr, Covar R, Grant E, Hillyer EV, Bacharier L. Natural history of asthma: persistence versus progression-does the beginning predict the end? J Allergy Clin Immunol 2008;121:607-13. 4. Leonardi NA, Spycher BD, Strippoli MP, Frey U, Silverman M, Kuehni CE. Validation of the Asthma Predictive Index and comparison with simpler clinical prediction rules. J Allergy Clin Immunol 2011;127:1466-72.e6. 5. Chang TS, Lemanske RF Jr, Guilbert TW, Gern JE, Coen MH, Evans MD, et al. Evaluation of the Modified Asthma Predictive Index in high-risk preschool children. J Allergy Clin Immunol Pract 2013;1:152-6. 6. Amin P, Levin L, Epstein T, Ryan P, LeMasters G, Khurana Hershey G, et al. Optimum predictors of childhood asthma: persistent wheeze or the asthma predictive index? J Allergy Clin Immunol Pract 2014;2:709-15.e2. 7. Brand PL, Baraldi E, Bisgaard H, Boner AL, Castro-Rodriguez JA, Custovic A, et al. Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach. Eur Respir J 2008;32:1096-110. 8. Savenije OE, Kerkhof M, Koppelman GH, Postma DS. Predicting who will have asthma at school age among preschool children. J Allergy Clin Immunol 2012; 130:325-31.
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9. Jackson DJ, Gangnon RE, Evans MD, Roberg KA, Anderson EL, Pappas TE, et al. Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children. Am J Respir Crit Care Med 2008;178:667-72. 10. Caudri D, Wijga A, A Schipper CM, Hoekstra M, Postma DS, Koppelman GH, et al. Predicting the long-term prognosis of children with symptoms suggestive of asthma at preschool age. J Allergy Clin Immunol 2009;124:903-10, e1-7. 11. Henderson J, Granell R, Heron J, Sherriff A, Simpson A, Woodcock A, et al. Associations of wheezing phenotypes in the first 6 years of life with atopy, lung function and airway responsiveness in mid-childhood. Thorax 2008;63:974-80. 12. Caudri D, Savenije OE, Smit HA, Postma DS, Koppelman GH, Wijga AH, et al. Perinatal risk factors for wheezing phenotypes in the first 8 years of life. Clin Exp Allergy 2013;43:1395-405. 13. Oswald H, Phelan PD, Lanigan A, Hibbert M, Bowes G, Olinsky A. Outcome of childhood asthma in mid-adult life. BMJ 1994;309:95-6. 14. Jenkins MA, Hopper JL, Bowes G, Carlin JB, Flander LB, Giles GG. Factors in childhood as predictors of asthma in adult life. BMJ 1994;309:90-3. 15. Sears MR. Growing up with asthma. The two thirds with milder symptoms should grow out of asthma. BMJ 1994;309:72-3. 16. To T, Gershon A, Wang C, Dell S, Cicutto L. Persistence and remission in childhood asthma. Arch Pediatr Adolesc Med 2007;161:1197-204. 17. Covar RA, Strunk R, Zeiger RS, Wilson LA, Liu AH, Weiss S, et al. Predictors of remitting, periodic, and persistent childhood asthma. J Allergy Clin Immunol 2010;125:359-66. 18. Gershon A, Guan J, Victor JC, Wang C, To T. The course of asthma activity: a population study. J Allergy Clin Immunol 2012;129:679-86. 19. Andersson M, Hedman L, Bjerg A, Forsberg B, Lundback B, Ronmark E. Remission and persistence of asthma followed from 7 to 19 years of age. Pediatrics 2013;132:e435-42. 20. Neuman A, Bergstrom A, Gustafsson P, Thunqvist P, Andersson N, Nordvall L, et al. Infant wheeze, comorbidities and school age asthma. Pediatr Allergy Immunol 2014;25:380-6. 21. Vink NM, Postma DS, Schouten JP, Rosmalen JG, Boezen HM. Gender differences in asthma development and remission during transition through puberty: the TRacking Adolescents’ Individual Lives Survey (TRAILS) study. J Allergy Clin Immunol 2010;126:498-504, e1-6. 22. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ, et al. Asthma and wheezing in the first six years of life. N Engl J Med 1995; 332:133-8. 23. Stern DA, Morgan WJ, Halonen M, Wright AL, Martinez FD. Wheezing and bronchial hyper-responsiveness in early childhood as predictors of newly diagnosed asthma in early adulthood: a longitudinal birth-cohort study. Lancet 2008;372:1058-64. 24. Martin PE, Matheson MC, Gurrin L, Burgess JA, Osborne N, Lowe AJ, et al. Childhood eczema and rhinitis predict atopic but not nonatopic adult asthma: a prospective cohort study over 4 decades. J Allergy Clin Immunol 2011;127:1473-9.e1. 25. Simpson A, Tan VY, Winn J, Svensen M, Bishop CM, Heckerman DE, et al. Beyond atopy. Multiple patterns of sensitization in relation to asthma in a birth cohort study. Am J Respir Crit Care Med 2010;181:1200-6. 26. Belgrave DC, Buchan I, Bishop C, Lowe L, Simpson A, Custovic A. Trajectories of lung function during childhood. Am J Respir Crit Care Med 2014;189:1101-9. 27. Matricardi PM, Illi S, Gruber C, Keil T, Nickel R, Wahn U, et al. Wheezing in childhood: incidence, longitudinal patterns and factors predicting persistence. Eur Respir J 2008;32:585-92. 28. McNicol KN, Williams HE. Spectrum of asthma in childhood. I. Clinical and physiological components. BMJ 1973;4:7-11. 29. Tai A, Tran H, Roberts M, Clarke N, Gibson AM, Vidmar S, et al. Outcomes of childhood asthma to the age of 50 years. J Allergy Clin Immunol 2014;133: 1572-8. 30. Belgrave DC, Simpson A, Semic-Jusufagic A, Murray CS, Buchan I, Pickles A, et al. Joint modeling of parentally reported and physician-confirmed wheeze identifies children with persistent troublesome wheezing. J Allergy Clin Immunol 2013;132:575-83.e12. 31. Holloway JW, Arshad SH, Holgate ST. Using genetics to predict the natural history of asthma? J Allergy Clin Immunol 2010;126:200-9. 32. Belsky D, Sears M, Hancox R, Harrington H, Houts R, Moffitt T, et al. Polygenic risk and the development and course of asthma: an analysis of data from a fourdecade longitudinal study. Lancet Respir Med 2013;1:453-61. 33. Kerkhof M, Boezen HM, Granell R, Wijga AH, Brunekreef B, Smit HA, et al. Transient early wheeze and lung function in early childhood associated with chronic obstructive pulmonary disease genes. J Allergy Clin Immunol 2014; 133:68-76, e1-4. 34. Tantisira KG, Hwang ES, Raby BA, Silverman ES, Lake SL, Richter BG, et al. TBX21: a functional variant predicts improvement in asthma with the use of inhaled corticosteroids. Proc Natl Acad Sci U S A 2004;101:18099-104.
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35. Tantisira KG, Lasky-Su J, Harada M, Murphy A, Litonjua AA, Himes BE, et al. Genomewide association between GLCCI1 and response to glucocorticoid therapy in asthma. N Engl J Med 2011;365:1173-83. 36. Subbarao P, Mandhane PJ, Sears MR. Asthma: epidemiology, etiology and risk factors. CMAJ 2009;181:E181-90. 37. Gold DR, Burge HA, Carey V, Milton DK, Platts-Mills T, Weiss ST. Predictors of repeated wheeze in the first year of life. The relative roles of cockroach, birth weight, acute lower respiratory illness, and maternal smoking. Am J Respir Crit Care Med 1999;160:227-36. 38. Tager IB, Hanrahan JP, Tosteson TD, Castile RG, Brown RW, Weiss ST, et al. Lung function, pre- and post-natal smoke exposure, and wheezing in the first year of life. Am Rev Respir Dis 1993;147:811-7. 39. Reponen T, Vesper S, Levin L, Johansson E, Ryan P, Burkle J, et al. High environmental relative moldiness index during infancy as a predictor of asthma at 7 years of age. Ann Allergy Asthma Immunol 2011;107:120-6. 40. Sears MR, Greene J, Willan AR, Wiecek EM, Taylor DR, Flannery EM, et al. A longitudinal population-based cohort study of childhood asthma followed to adulthood. N Engl J Med 2003;349:1414-22. 41. Roel E, Zetterstrom O, Trell E, Faresjo T. Why are some children with early onset of asthma getting better over the years? Diagnostic failure or salutogenetic factors. Int J Med Sci 2009;6:348-57. 42. Vonk JM, Postma DS, Boezen HM, Grol MH, Schouten JP, Koeter GH, et al. Childhood factors associated with asthma remission after 30 year follow up. Thorax 2004;59:925-9. 43. Riiser A, Hovland V, Carlsen KH, Mowinckel P, Lodrup Carlsen KC. Does bronchial hyperresponsiveness in childhood predict active asthma in adolescence? Am J Respir Crit Care Med 2012;186:493-500.
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44. Sears MR. Predicting new and persistent asthma. Am J Respir Crit Care Med 2012;186:469-70. 45. Tantisira KG, Colvin R, Tonascia J, Strunk RC, Weiss ST, Fuhlbrigge AL, et al. Airway responsiveness in mild to moderate childhood asthma: sex influences on the natural history. Am J Respir Crit Care Med 2008;178: 325-31. 46. Ronmark E, Jonsson E, Lundback B. Remission of asthma in the middle aged and elderly: report from the Obstructive Lung Disease in Northern Sweden study. Thorax 1999;54:611-3. 47. Holm M, Omenaas E, Gislason T, Svanes C, Jogi R, Norrman E, et al. Remission of asthma: a prospective longitudinal study from northern Europe (RHINE study). Eur Respir J 2007;30:62-5. 48. The Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med 2000;343:1054-63. 49. Bender B, Sternberg AL, Strunk RC, Szefler SJ, Tonascia J, Zeiger RS, et al. Long-term budesonide or nedocromil treatment, once discontinued, does not alter the course lf mild to moderate asthma in children and adolescents. J Pediatr 2009; 154:682-7. 50. Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Boehmer SJ, Szefler SJ, et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med 2006;354:1985-97. 51. Bisgaard H, Hermansen MN, Loland L, Halkjaer LB, Buchvald F. Intermittent inhaled corticosteroids in infants with episodic wheezing. N Engl J Med 2006; 354:1998-2005. 52. Grad R, Morgan WJ. Long-term outcomes of early-onset wheeze and asthma. J Allergy Clin Immunol 2012;130:299-307.
Predicting asthma outcomes Malcolm R. Sears, MB, ChB
Hamilton, Ontario, Canada
INFORMATION FOR CATEGORY 1 CME CREDIT Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions. Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted. Date of Original Release: October 2015. Credit may be obtained for these courses until September 30, 2016. Copyright Statement: Copyright Ó 2015-2016. All rights reserved. Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Creditä. Physicians should
This review addresses predictors of remission or persistence of wheezing and asthma from early childhood through adulthood. Early childhood wheezing is common, but predicting who will remit or have persistent childhood asthma remains difficult. By adding parental history of asthma and selected infant biomarkers to the history of recurrent wheezing, the Asthma Predictive Index and its subsequent modifications provide better predictions of persistence than simply the observation of recurrent wheeze. Sensitization, especially to multiple allergens, increases the likelihood of development of classic childhood asthma. Remission is more likely in male subjects and those with milder disease (less frequent and less severe symptoms), less atopic sensitization, a lesser degree of airway hyperresponsiveness, and no concomitant allergic disease. Conversely, persistence is linked strongly to allergic sensitization, greater frequency and severity of symptoms, abnormal lung function, and a greater degree of airway
From the Department of Medicine, Faculty of Health Sciences, de Groote School of Medicine, McMaster University. Received for publication January 30, 2015; revised April 14, 2015; accepted for publication April 17, 2015. Corresponding author: Malcolm R. Sears, MB, ChB, Firestone Institute for Respiratory Health, St Joseph’s Healthcare Hamilton, T3219, 50 Charlton Ave E, Hamilton, Ontario L8N 4A6, Canada. E-mail: [email protected]. 0091-6749/$36.00 Ó 2015 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaci.2015.04.048
claim only the credit commensurate with the extent of their participation in the activity. List of Design Committee Members: Malcolm R. Sears, MB, ChB Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: The author declares that he has no relevant conflicts of interest. Activity Objectives: 1. To review the Asthma Predictive Index (API) and its modifications. 2. To identify factors associated with childhood asthma remission or persistence. 3. To describe the relationship between lung function and persistence of childhood asthma. Recognition of Commercial Support: This CME activity has not received external commercial support. List of CME Exam Authors: Eyas Abla, MD, Jonathan A. Olsen, DO, Mark Stevens, MD, and Jeffrey Stokes, MD. Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: The exam authors disclosed no relevant financial relationships.
hyperresponsiveness. A genetic risk score might predict persistence more accurately than family history. Remission of established adult asthma is substantially less common than remission during childhood and adolescence. Loss of lung function can begin early in life and tracks through childhood and adolescence. Despite therapy which controls symptoms and exacerbations, the outcomes of asthma appear largely resistant to pharmacologic therapy. (J Allergy Clin Immunol 2015;136:829-36.) Key words: Asthma, birth cohorts, longitudinal phenotypes, lung function, persistence, prediction, remission, wheezing
Symptoms of asthma most commonly begin in childhood, often in the first few years of life. Between 30% and 50% of preschool children experience episodes of wheezing, of whom less than half will have continuing childhood asthma. Over the last several decades, longitudinal studies have provided substantial information regarding the development and trajectories of childhood wheezing and the likely outcomes of different phenotypes of asthma. This review addresses 2 principal questions: first, can we predict which children with early childhood wheeze (often called preschool wheeze) will go on to have childhood asthma, and second, can we predict which children or adults with established asthma will experience remissions or relapse or have persistent asthma? 829
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Abbreviations used ALSPAC: Avon Longitudinal Study of Parents and Children aOR: Adjusted odds ratio API: Asthma Predictive Index BAMSE: Barn/Children, Allergy and Milieu in Stockholm, an Epidemiological study CAMP: Childhood Asthma Management Program COPD: Chronic obstructive pulmonary disease GRS: Genetic risk score mAPI: Modified Asthma Predictive Index OR: Odds ratio PIAMA: Prevention and Incidence of Asthma and Mite Allergy PPV: Positive predictive value ucAPI: University of Cincinnati Asthma Predictive Index
PREDICTING OUTCOMES OF EARLY CHILDHOOD WHEEZING An Asthma Predictive Index (API) was proposed by CastroRodriguez1 to provide a framework to predict outcomes of early childhood wheezing. Drawing on data from the Tucson Birth Cohort, the API uses 2 major criteria (physician-diagnosed parental asthma and physician-diagnosed childhood eczema) and 3 minor criteria (physician-diagnosed allergic rhinitis, _4%) as prewheezing apart from colds, and blood eosinophilia > dictors. The ‘‘stringent’’ index for prediction of asthma requires _3 episodes per year in 2- to 3-yearearly frequent wheeze (> olds) and the presence of at least 1 of the 2 major criteria or 2 of 3 minor criteria. The ‘‘loose’’ index required less than 3 episodes per year, again combined with one of the major criteria or 2 of the minor criteria (Table I). The usefulness of the API has been challenged on several grounds.2 It predicts the outcome of asthma ever and not recurrent wheeze, which is more clinically relevant and of greater concern to physicians and families. The predictive value is highly dependent on the prior probability (prevalence) of asthma in the cohort in which it is used. The higher the prevalence of asthma (eg, in high-risk populations), the poorer will be the performance on the API in predicting the outcome of preschool wheeze. The usefulness of the API has also been challenged on the grounds that it has yet to be shown that identification of children with a positive API results in interventions or treatments that reduce later asthma, although this would be the desirable benefit of such identification.3 The Tucson-derived API has been validated in the Leicester birth cohort.4 Using the loose API, the odds ratios (ORs) for asthma at age 7 were comparable (5.2 in Leicester and 5.5 in Tucson), and the positive predictive value (PPV) was 26% in both studies. For the stringent API, ORs were 8.2 and 9.8 and PPVs were 40% and 48%, respectively. These values were somewhat greater that those achieved by using a simple early wheeze criterion; in the Leicester cohort the OR for later asthma was 5.4 and the PPV was 21%, and for early frequent wheeze the values were 6.7 and 36%, respectively. The API has undergone a number of modifications. The modified Asthma Predictive Index (mAPI) requires 4 or more wheezing episodes in the last year, adds another major criterion _1 aeroallergen), and changed the minor criteria by (sensitized to > removing allergic rhinitis but adding sensitization to milk, egg, or peanut. The mAPI was evaluated in the Childhood Origins of Asthma cohort.5 Prediction of school-age asthma improved from
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ages 1 to 3 years, and the mAPI provided a high likelihood ratio of 4.9 for asthma at 6 years and even higher for older children, with likelihood ratios of up to 55 at age 11 years. Decreasing the required number of wheezing episodes from 4 or more in the past year to only 2 episodes (the m2API) decreased the predictive value and did not improve the predictive value of a negative test result. In a high-risk prospective birth cohort, the Cincinnati Childhood Allergy and Air Pollution study, Amin et al6 assessed another modified API, the University of Cincinnati Asthma Predictive Index (ucAPI). This was based on 2 or more episodes of wheeze in the last 12 months at age 3 years and 1 of 3 major _1 aeroallergen, criteria (parental asthma, allergic sensitization to > and history of eczema) or 2 of 3 minor criteria (wheezing without a cold, allergic rhinitis, and milk or egg sensitization). The ucAPI was compared with a history of persistent wheezing at age 3 years _2 episodes of wheezing in the last 12 months at both (defined as > the 2- and 3-year visits) as a predictor of objectively confirmed asthma (symptoms and a positive bronchodilator or methacholine response) at age 7 years. Confirmed asthma at 7 years was significantly associated with both a positive ucAPI (adjusted odds ratio [aOR], 13.3; 95% CI, 7.0-25.2) and the persistent wheezing phenotype (aOR, 9.8; 95% CI, 4.9-19.5). ATask Force of the European Respiratory Society proposed the terms episodic wheeze to describe children who wheeze intermittently, apparently with viral infections, and who are well between episodes and multitrigger wheeze to describe children who wheeze both during and outside discrete episodes.7 It was noted that there might be a large overlap in these phenotypes that could change over time. The debate on whether episodic wheeze and multitrigger wheeze differ in clinical features and whether differentiating these subtypes helps predict asthma at school age emphasized the limitations of predictive indices.8 Triggers might be difficult to identify precisely. In the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort, episodic wheeze and multitrigger wheeze did not correspond to specific longitudinally derived wheezing phenotypes identified by using longitudinal latent class analysis or hypothesis-based definitions of transient early and persistent wheeze.8 Recommendation for improving the API include more precise definitions of risk factors, such as sensitization (quantitative levels of IgE or multiple allergen sensitization); lung function; inclusion of maternal exposures, such as smoking and viral infections; more precise phenotyping of asthma with objective measurements; addition of noninvasive markers of inflammation; and better characterization of genetic risk and epigenetic effects. Among high-risk children with a family history of atopic disease, the nature of the viral illness associated with early childhood wheezing had value in predicting the likelihood of persistence.9 Contrary to previous understanding, wheezing illnesses associated with rhinovirus infection were more strongly associated with asthma at age 6 years than respiratory syncytial virus–associated wheezing illnesses. Almost 90% of children with rhinovirus-associated wheezing in year 3 had asthma at age 6 years. Caudri et al10 reported follow-up of 3963 children in the PIAMA cohort to age 8 years. Of these children, 55% had wheezing or coughing at night without a cold or both by age 4 years, but only 11% had asthma at age 7 to 8 years. Factors independently predicting asthma in later childhood included male sex, postterm delivery, medium or low parental education, parental use of inhaled medication, frequency of wheeze, wheezing/dyspnea
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TABLE I. Criteria for the API and its subsequent modifications
Primary criterion Major criteria
Minor criteria
Loose API
mAPI
m2API
ucAPI
> _3 Yes Yes
<3 Yes Yes
Yes Yes Yes — 1 2
Yes Yes Yes — 1 2
> _4 Yes Yes Yes — Yes Yes Yes 1 2
> _2 Yes Yes Yes — Yes Yes Yes 1 2
> _2 Yes Yes Yes Yes Yes — Yes 1 2
Criteria
Stringent API
Frequency of episodes in the last year Physician-diagnosed parental asthma Physician-diagnosed child eczema _1 aeroallergen Sensitization to > Physician-diagnosed allergic rhinitis Wheezing apart from colds _4% Blood eosinophils > _1 food allergen Sensitization to >
Required no. of major criteria OR required no. of minor criteria
wheezing, which began in the second and third years of life and persisted to 7 years, and persistent wheezing with onset after 3 years, and this association was still evident at 7 years (Fig 1 and Table II).11 Five phenotypes were identified by using longitudinal latent class analysis in the PIAMA cohort, which were generally similar in pattern to the ALSPAC classification.12 Persistent wheeze in the PIAMA cohort was related to male sex, parental allergy, and breast-feeding for less than 12 weeks.
FIG 1. Phenotypes of early childhood wheezing illustrating the time course of development and the effect of atopy on the different phenotypes in the ALSPAC study. Adapted from Henderson et al.11
TABLE II. Characteristics of the different phenotypes of wheezing in childhood Phenotype
Transient early Prolonged early Intermediate Late Persistent
Asthma
Atopy
FEV1
FEF25-75
AHR
O OO OOOO OOO OOOO
— — OO OO O
Y Y YY Y YY
Y YY YY Y YY
[ [ [[ [[ [[
Adapted from Henderson et al.11 Phenotypes refer to those shown in Fig 1.
apart from colds, serious respiratory tract infections, and doctordiagnosed eczema with evident rash. The authors devised a clinical risk score (range, 0-55 points) and found that symptomatic children with a score of less than 10 had a 3% risk, whereas a score of 30 or greater had a 42% risk of asthma. Statistical techniques have been applied in several cohorts to identify phenotypes of childhood asthma, including temporal assessments, clustering of variables, and unsupervised machine analyses, examining outcomes in later childhood but not yet into adulthood. Henderson et al11 identified 6 phenotypes of wheezing through latent class analysis of data collected in the Avon Longitudinal Study of Parents and Children (ALSPAC) study for 6265 children at 7 time points from birth to age 7 years. There was a strong association of atopy with both intermediate-onset
PREDICTING OUTCOMES OF ESTABLISHED ASTHMA: REMISSION, RELAPSE, AND PERSISTENCE Two decades ago, when attempting to harmonize differing adult outcomes reported in epidemiologic studies in 2 Australian populations followed from childhood,13,14 the most obvious explanation was that severe asthma usually persisted and mild asthma frequently went into remission.15 In 2015, do we have better prediction tools or stronger evidence to guide families and health care workers in their expectations of outcomes, which in turn might influence management decisions? There is no doubt from population database studies, such as that conducted by To et al,16 that a large proportion of children with asthma experience remission. By using the Ontario (Canada) health administrative database, more than 34,000 children were identified who had received a diagnosis of asthma by age 6 years. A second health care encounter within 1 year after diagnosis occurred in more than half (54%), but by age 12 years, 48% were in apparent remission, with no hospitalizations or physician’s office visits recorded for asthma. Those with a hospitalization in the first year after diagnosis were at 3-fold risk of persistence to age 12 years, as were those with at least 4 physician’s office visits for asthma during follow-up. Covar et al17 followed children in the Childhood Asthma Management Program (CAMP) study for 4 years and showed that remission was associated with milder disease, lack of atopic sensitization, less airway hyperresponsiveness, and higher FEV1. Among older subjects, remission is less common. Gershon et al18 used the Ontario health administrative database to identify 613,394 patients of all ages with asthma in 1993 and followed claims for asthma in the database for 15 years. More than 80% _1 physician’s claims for health had active disease (indicated by > services for asthma) in subsequent years, almost all ambulatory rather than hospital based. Although it is possible that some of those without ongoing asthma activity in the ensuing 15 years might have been misclassified at the onset, some will have
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experienced true remission. Interestingly, about 75% of those with apparent remission had a gap of 2 years or more in asthma activity, suggesting relatively mild disease; longer gaps were more evident in female than male patients. Greater asthma activity was noted for those with previous asthma claims, older and younger age groups, and those with a codiagnosis of chronic obstructive pulmonary disease (COPD), illustrating some of the difficulties in interpreting database information without the opportunity for clinical assessment. It is important to distinguish between persistence and progression, with persistence referring to the continuation of symptoms and progression to worsening of symptoms and physiologic characteristics reflected in lung function over time.3 Progression certainly implies persistence, but the reverse is not always true. Andersson et al19 undertook longitudinal follow-up of 248 children initially identified with asthma through a questionnaire survey completed by parents of 7- to 8-year-old children in northern Sweden in 1996. Asthmatic children were followed to age 19 years. Remission was defined as no symptoms and no asthma medication for the 3 years before the end point of the study. At age 19 years, 21% were in remission, 38% had periodic asthma, and 41% had persistent asthma. Remission was more common in boys and less common with sensitization to furred animals (OR, 0.14) and greater severity scores (OR, 0.19); 82% of children with these latter features had persistent asthma through adolescence. Environmental factors, including damp housing, rural living, and smoking, were not indicators of remission or persistence. Consistent with many other studies, those experiencing remission or having only periodic symptoms had better childhood lung function and less airway responsiveness than those with persistent asthma.
Sex differences Although male children more commonly have symptoms of wheezing and early childhood asthma, there is a greater incidence and greater persistence of symptoms in female patients during and after puberty. In the Barn/Children, Allergy and Milieu in Stockholm, an Epidemiological study (BAMSE) cohort, there was no sex difference in the likelihood of asthma at age 8 years among those with infant wheeze before age 2 years (aOR for male sex, 1.10; 95% CI, 0.73-1.67).20 Pubertal changes were assessed in relation to the changes in asthma development and remission in 2230 adolescents in the Tracking Adolescents’ Individual Lives Survey.21 At a mean age of 11 years, the prevalence of asthma in male and female subjects was similar (7.7% in boys and 7.4% in girls), but at 16 years, although both prevalence rates had decreased, asthma was more common in girls (6.2%) than boys (4.3%). They found no significant associations between transition of pubertal stages and the presence of asthma, either in cross-sectional or longitudinal analyses, and no correlation between pubertal stages and serum IgE levels or exercise-induced bronchoconstriction. Martinez et al,22 reporting on the Tucson Children’s Respiratory Study, described early, late, and persistent phenotypes of asthma but did not differentiate these phenotypes by sex. However, in a later article from that study, remission of asthma by age 22 years was twice as common in men as in women (OR, 2.0; 95% CI, 1.2-3.2).23 Concomitant allergic disorders Childhood wheezing is frequently associated with other disorders of an allergic or atopic nature, including atopic dermatitis or
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eczema, food allergy, rhinoconjunctivitis, and occasionally anaphylaxis. Many studies have confirmed the association of atopy with more troublesome asthma and a greater likelihood of persistence. In the BAMSE cohort infant eczema increased the risk of asthma persistence to age 8 years (aOR, 2.31; 95% CI, 1.52-3.49), but infant rhinorrhea did not (aOR, 1.32; 95% CI, 0.75-2.34).20 Among children followed in the Cincinnati Childhood Allergy and Air Pollution study, those with allergic persistent wheezing has a higher risk of asthma at age 7 years than those with nonallergic persistent wheezing (aOR, 10.4; 95% CI, 4.1-26.0 vs aOR, 5.4; 95% CI, 2.014.1; P <.01).6 Follow-up of the Tasmanian Asthma Study cohort to age 44 years identified that childhood allergic rhinitis was not only associated with a 2- to 7-fold increased risk of incident asthma in preadolescence, adolescence, or adult life but also was associated with a 3-fold increased risk of childhood asthma persisting rather than remitting by middle age.24 Early sensitization and sensitization to multiple allergens are more strongly predictive of persistence throughout childhood and into adulthood. The Manchester Asthma and Allergy Study used a 5-class model of atopic vulnerability and showed that those with multiple early sensitizations (10.6% of the cohort) were most likely to have hospitalizations for asthma25 and poorer lung function.26 In the German Multicentre Allergy Study birth cohort, wheezing at age 13 years was associated with parental atopy and sensitization to common allergens, increased serum total IgE levels, and exposure to high levels of indoor allergens in early life, all of which were more evident among those with early childhood wheeze than among those who did not wheeze.27
Asthma severity Longitudinal studies have indicated that children with more severe asthma in early childhood and midchildhood are more likely to have persistence of symptoms and associated physiologic abnormalities than those with occasional, infrequent, or milder symptoms. In the Melbourne study, in which children were recruited at age 7 years, there were initially few with severe asthma, and therefore an additional group of children with more severe disease were recruited at age 10 years.28 When followed out to age 50 years, only 15% of those with severe asthma at age 10 years had experienced full remission compared with 64% of those with milder ‘‘wheezy bronchitis’’ in childhood and 47% of those with persistent (but not severe) childhood asthma.29 In the BAMSE cohort the risk of asthma at age 8 years was significantly increased among those with wheeze persistence (aOR, 5.1; 95% CI, 2.5-10.4), more than 3 episodes of wheeze in infancy (aOR, 3.4; 95% CI, 2.1-5.6), and use of inhaled steroids (aOR, 3.4; 95% CI, 2.2-5.3).20 These characteristics of severity were largely overlapping. In the Tucson Children’s Respiratory Study persistence of wheezing in early life was associated with a high risk of asthma at age 22 years (OR, 14.0; 95% CI, 6.8-28.0).23 In the Manchester Asthma and Allergy Study population-based cohort, children identified at age 8 years as having persistent troublesome wheeze by using longitudinal latent class modeling (prevalence, 3.2%) differed significantly from those with persistent controlled wheeze (prevalence, 13.1%), demonstrating decreased lung function and greater airway responsiveness compared with all other classes and experiencing more exacerbations, hospitalizations, and unscheduled visits.30 Exacerbations
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among those with persistent troublesome wheeze were almost 4-fold more frequent than among those with persistent controlled wheeze and 16 times more frequent than among those classified as having late-onset wheeze. Predictors of persistent troublesome wheeze could be identified as early as age 3 years, when these children had diminished lung function (specific airway resistance, >1.6 kPa), eczema, and a sum of all allergen wheals of 10 mm or greater and experienced 3 or more exacerbations by that age. Children demonstrating 3 of these 4 features were 40 times more likely to have persistent troublesome wheeze compared with other wheezing children (PPV, 42.9%). The key independent predictors of this severe asthma outcome at age 8 years were having a sum of skin test wheals of 10 mm or greater and a history of exacerbations by age 3 years.
Genetics In 2010, Holloway et al31 wrote that ‘‘the ability of genetics alone to predict disease onset is poor’’ but noted that some polymorphisms of genes were associated with measures of asthma severity, such as exacerbations, and that there appeared to be genetic commonalities between asthma and COPD. Whether such genetic variants predispose to persistence of asthma leading to chronic airflow obstruction (which might be misdiagnosed as COPD) is as yet unclear. With the evolution of genome-wide association studies over the last decade, a number of genes have emerged as more frequent in asthmatic patients, enabling the development of a genetic risk score (GRS). Using this methodology, Belsky et al32 assessed outcomes in the Dunedin Multidisciplinary Health and Development Study, which has followed 1037 children from birth to age 38 years. Persistence of childhood asthma into midadulthood was 2 to 3 times more likely among those with a higher GRS than among those with median or lower GRS. The GRS was a stronger predictor of persistence than family history, which is traditionally used to assess hereditary influences on the persistence of asthma. Associations between replicated genes for COPD and early childhood wheezing and lung function levels in 6- to 8-year-old children were explored in 3 European cohorts: PIAMA, KOALA (a Dutch acronym for Child, Parents and Health: Lifestyle and Genetic Constitution), and ALSPAC.33 At least 3 COPD genes appeared to be implicated in lung development and lung growth. Some evidence suggested that COPD genes are involved in the response of the infant lung to smoke exposure in utero and in early life. What is not clear and requires longer follow-up is whether children with those COPD-related genes have more persistent or progressive asthma in later childhood and adulthood. Genetic variants have also been shown to modulate the effects of therapy and therefore might influence long-term outcomes; for example, among children participating in the CAMP study, a variation in TBX21 coding (replacement of histidine 33 with glutamine) affected the effect of inhaled corticosteroids on airway hyperresponsiveness,34 whereas a functional variant in GLCCI1 was associated with a decreased response to corticosteroids.35 Environmental factors Maternal smoking (both prenatal and postnatal) and exposure to damp and mold are well-recognized risk factors for the development of early childhood wheezing and asthma,36-38 but
FIG 2. Spirometric lung function in male subjects followed from age 9 to age 26 years and stratified by asthma status at age 26 years. Those with persistent wheezing or relapse by age 26 years had significantly impaired function since the first measurement at age 9 years. FVC, Forced vital capacity. Adapted from Sears et al.40
FIG 3. Data are shown for 871 white study members from the Dunedin cohort, an unselected New Zealand population followed for 38 years. Overall, 35% had reported asthma, and 27% had reported asthma with atopy. Persistent asthma demonstrated by asthma and airway hyperresponsiveness was present in 18.4%, and incompletely reversible airflow obstruction (defined as postbronchodilator FEV1/forced vital capacity >2 SDs less than the mean value in sex-stratified healthy nonsmoking study members) in 8.7%. More than 90% of those with airway hyperresponsiveness (AHR), incompletely reversible airflow obstruction, or both were atopic. Adapted from Belsky et al.32
their role in predicting long-term outcomes is less clear. However, recent studies have indicated that dampness is associated with continuing symptoms, and a ‘‘moldiness index’’ has some predictive value for persistence.39 Personal smoking by late adolescence was identified as a risk factor for continuing asthma symptoms at age 26 years in the Dunedin cohort.40 An interesting study in Sweden sheds further light on the reported persistence and apparent remission of asthma. Roel et al41 followed up a birth cohort of more than 2000 children and were surprised that almost 40% of children with a hospital or primary care diagnosis of asthma at least once between birth and age 7 years were reported by their parents at age 10 years to have
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never had asthma. The initial asthma diagnosis was confirmed through examination of medical records. Four factors were independently and significantly associated with the nonreport of asthma by age 10 years, namely not having past experience of allergic symptoms, having only 1 or 2 hospital visits for asthma between birth and age 7 years, type of residence at age 10 years (living in a villa rather than a flat), and having no previous perception of mold damage in their residence. Hence both intrinsic (atopy and severity) and environmental (residence and mold) factors appear to be associated with remission or at least failure to recall previous asthma. This study also highlights the problems of recall bias in studies of asthma outcomes in which information is obtained retrospectively.
Lung function In the Dunedin longitudinal study young adults with persistent or relapsing childhood asthma at age 26 years had significantly impaired lung function.40 By examining the trajectory of their spirometric values from age 9 to 26 years, it was evident that those with adult asthma had impaired lung function from the very first assessment at age 9 years (Fig 2).40 In subsequent follow-up to age 38 years,32 almost 9% of this general population had incompletely reversible airflow obstruction associated with asthma; of these, almost all (90%) had demonstrated airway hyperresponsiveness in childhood and adolescence, and almost all (90%) were atopic (Fig 3).32 In the Tucson Children’s Respiratory Study low lung function at 6 years and bronchial hyperresponsiveness at 6 years were independent risk factors for chronic asthma at age 22 years.23 Vonk et al42 tracked a small group (n 5 119) of allergic asthmatic patients initially seen as children aged 5 to 14 years. On review as adults 30 years later, complete remission (defined as no symptoms, no inhaled corticosteroid use, normal lung function, and absence of airway hyperresponsiveness) occurred in only 22%, whereas clinical remission (no symptoms and no ICS) occurred in a further 30%. More than half of those with clinical remission exhibited low lung function or airway hyperresponsiveness. Both complete remission and clinical remission were associated with higher FEV1 in childhood and more improvement in FEV1 from childhood to young adulthood. Measurements of airway responsiveness conducted at age 10 years (methacholine challenge and exercise-induced bronchoconstriction) in a Norwegian cohort43 were modestly predictive of active asthma at age 16 years, together explaining 14% of the variation in patients with active asthma 6 years after tests were performed. However, much stronger predictions were apparent with greater degrees of responsiveness or greater decreases in lung function with exercise, indicating the importance of not just the presence of hyperresponsiveness but also its severity in predicting outcomes.44 A provoking dose of methacholine inducing a 20% decrease in FEV1 of 1 mmol or less predicted adolescent asthma with a 54% likelihood, and if airway responsiveness was markedly increased in the presence of active asthma and rhinitis, the likelihood of persistence was close to 100%. Children participating in the CAMP study underwent serial methacholine challenges for more than 8 years on average.45 Airway responsiveness decreased with increasing age, more in boys than girls, with divergence between the sexes coinciding with the mean age for Tanner stage 2 of puberty.
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Adult asthma The outcomes of adult-onset asthma have been studied particularly in relation to occupational exposures. In some remission has been documented when exposure is limited or avoided altogether. Unfortunately, there is often persistence of occupational asthma requiring continuing treatment even after exposure ceases, from which remission is uncommon. Likewise, nonoccupational adult asthma remits infrequently.46 Holm et al47 followed up 1153 adults aged 20 to 44 years who participated in the European Community Respiratory Health Survey in northern Europe and who had reported asthma at the initial survey. Defining remission as no asthma symptoms in 2 consecutive years and no current use of asthma medication, a remission rate of 20 per 1000 person years was calculated. There was no significant difference according to sex, but a greater likelihood of remission was found among those who quit smoking and among those with milder disease. Participants in the Tasmanian Longitudinal Health Study recruited at age 6 to 7 years were followed up at age 44 years.24 There was no relation between childhood eczema or rhinitis and nonatopic adult asthma; however, the combination of rhinitis and eczema strongly predicted new-onset adult asthma by middle age and the persistence of childhood asthma to adult atopic asthma (ORs, 6.3 and 11.7, respectively). Rhinitis alone also predicted the persistence of childhood asthma to adult atopic asthma (OR, 2.7). Overall, almost 30% of persistent atopic asthma could be attributed to having childhood rhinitis and eczema. Treatment Although many studies of management of childhood and adult asthma demonstrate the ability of modern treatment regimens to control symptoms, reduce airflow obstruction, reduce airway responsiveness, and improve quality of life, it does not appear possible at this time to change the natural history of the disease. In the CAMP study airway responsiveness and asthma control improved with budesonide during the active treatment period,48 but this benefit did not persist after discontinuation.49 Further studies were undertaken because of the possibility that inhaled corticosteroids were not started early enough in the CAMP study. Treatment of early childhood wheezing for 2 years with inhaled fluticasone, while reducing symptoms and exacerbations during the treatment period, did not provide a sustained benefit; during a third year without treatment, outcomes reverted to those of the control group not given fluticasone.50 Bisgaard et al51 treated infants with episodic wheezing with 2-week courses of inhaled budesonide beginning after 3 days of wheezing and showed no effect on the progression from episodic to persistent wheezing or the short-term benefit of such treatment during episodes of wheezing in the first 3 years of life. The effects of treatment of participants in longitudinal cohort studies are difficult to ascertain, given that treatment is more likely to be offered to those with more severe disease (confounding by severity), as was evident in analyses of adult outcomes in the Dunedin study, in which those receiving inhaled corticosteroid therapy showed an even greater decrease in lung function over time.40 Summary There is consensus among longitudinal studies that wheezing that begins in early life and continues into the school years generally persists into adulthood.52 As noted 20 years ago, more
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severe asthma is more likely to persist, whereas mild asthma often goes into remission.15 Such persistent wheezing is associated with lower lung function and increased airway responsiveness that is established early in life. Multiple factors predict persistence, especially a strong atopic disposition, early sensitization, and greater symptom frequency, all suggesting that early airway injury from 1 or more biological exposures sets up lifelong disease. Treatment, although effectively controlling symptoms and improving lung function while taken, appears not to change the natural course of the disease. What do we know? d Many children wheeze in preschool years, but less than half of these go on to have childhood asthma. d
Remission of childhood asthma is more common in male subjects and in those with lesser degrees of atopy and higher lung function.
d
A greater degree of sensitization, especially to multiple allergens; concomitant allergic diseases; and greater severity of asthma all favor persistence.
d
Remission of symptoms can occur in the presence of persistent loss of lung function and airway hyperresponsiveness.
What is still unknown? d Usefulness of biomarkers in predicting the trajectory of early childhood wheezing to established asthma d
How to prevent the development and persistence of childhood asthma
d
Why asthma is more likely to persist in female subjects
d
What factors determine the very early loss of lung function in those destined to have persistent asthma
d
Whether children with COPD-related genes are more likely to develop persistent and progressive asthma and chronic airflow obstruction
d
Whether the outcome of childhood and adult asthma can be modified by prolonged aggressive therapy
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44. Sears MR. Predicting new and persistent asthma. Am J Respir Crit Care Med 2012;186:469-70. 45. Tantisira KG, Colvin R, Tonascia J, Strunk RC, Weiss ST, Fuhlbrigge AL, et al. Airway responsiveness in mild to moderate childhood asthma: sex influences on the natural history. Am J Respir Crit Care Med 2008;178: 325-31. 46. Ronmark E, Jonsson E, Lundback B. Remission of asthma in the middle aged and elderly: report from the Obstructive Lung Disease in Northern Sweden study. Thorax 1999;54:611-3. 47. Holm M, Omenaas E, Gislason T, Svanes C, Jogi R, Norrman E, et al. Remission of asthma: a prospective longitudinal study from northern Europe (RHINE study). Eur Respir J 2007;30:62-5. 48. The Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med 2000;343:1054-63. 49. Bender B, Sternberg AL, Strunk RC, Szefler SJ, Tonascia J, Zeiger RS, et al. Long-term budesonide or nedocromil treatment, once discontinued, does not alter the course lf mild to moderate asthma in children and adolescents. J Pediatr 2009; 154:682-7. 50. Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Boehmer SJ, Szefler SJ, et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med 2006;354:1985-97. 51. Bisgaard H, Hermansen MN, Loland L, Halkjaer LB, Buchvald F. Intermittent inhaled corticosteroids in infants with episodic wheezing. N Engl J Med 2006; 354:1998-2005. 52. Grad R, Morgan WJ. Long-term outcomes of early-onset wheeze and asthma. J Allergy Clin Immunol 2012;130:299-307.