Risk factors for asthma incidence: a review of recent prospective evidence

Transcription

1 University of Kentucky From the SelectedWorks of David M. Mannino June, 2004 Risk factors for asthma incidence: a review of recent prospective evidence M. S. King David M. Mannino F. Holguin Available at:

2 ASTHMA ARTICOLI ORIGINALI PANMINERVA MED 2004;46: Risk factors for asthma incidence A review of recent prospective evidence M. E. KING 1, D. M. MANNINO 2, F. HOLGUIN 1 Aim. The aim of this study is to determine what factors have been shown, in prospective studies, to predict the incidence of asthma. Methods. We performed a systematic review of peer-reviewed literature from 1994 to 2004 to determine what factors predict the development of asthma in both children and adults. This search strategy yielded 40 studies, with 36 providing some estimate of asthma incidence for the total sample and or a specific subgroup. Results. Annual estimated incidence of physician-diagnosed asthma ranged from 0.6 to 29.5 per persons. Risk factors for incident asthma among children included: male sex, atopic sensitization, parental history of asthma, early-life stressors and infections, obesity, and exposure to indoor allergens, tobacco smoke and outdoor pollutants. Risk factors for adult-onset asthma included female sex, airway hyperresponsiveness, lifestyle factors, and work-related exposures. Conclusion. Risk factors for asthma include both modifiable and nonmodifiable ones, and they vary between children and adults. This review of prospective evidence supports tobacco and smoke avoidance as an intervention for the primary prevention of childhood asthma. During adolescence and adulthood, targeting lifestyle factors like obesity and smoking or reducing occupational exposures are the best opportunities for asthma prevention. Before specific public health recommendations can be made, however, additional longitudinal research is needed to better characterize target populations and identify appropriate settings for multifaceted asthma interventions. KEY WORDS: Asthma, epidemiology - Incidence - Risk factors. Address reprint requests to: M. E. King, PhD, National Center for Environmental Health, Centers for Disease Control and Prevention, 1600 Clifton Road, MS E-17, Atlanta, GA, 30333, USA. Mking2@cdc.gov 1Air Pollution and Respiratory Health Branch Centers for Disease Control and Prevention, Atlanta, GA, USA 2Division of Polmonary and Critical Care Medicine, University of Kentucky, Lexington, KT Asthma is a chronic inflammatory disorder of the airways characterized by bronchial hyperresponsiveness, reversible airflow limitation, and respiratory symptoms. 1, 2 The prevalence of asthma has increased over the last 3 decades, 3, 4 and trends in the incidence of asthma also appear to be rising. 5 Provocative factors for asthma exacerbations have been well documented by epidemiologic studies, ranging from familial, allergenic, and environmental, to socioeconomic and psychosocial factors Findings from these studies facilitate improved symptom management and provide prognostic information but are less useful for identifying potentially causal etiologic agents. Because the prevalence of asthma is a function of disease duration (which may be influenced by exacerbations) and incidence, risk factors for asthma prevalence and asthma incidence may differ. Evidence from longitudinal studies of birth cohorts, such as the Multicenter Allergy Study (MAS) in Germany, 13 the BAMSE study in Sweden, 14 and the Children s Respiratory Study in the United States, 15 provides the best opportunity to learn about potential initiators of asthma. Such prospective studies have been designed specifically to clarify the natural history of the disease and to describe associations between phenotypes and genetic, environmental, or lifestyle factors. 16 A better understanding of asthma incidence and its risk factors is important to, ultimately, developing multifaceted interventions for primary disease prevention. The aim of this report is to provide an overview of risk factors for the onset of asthma, based on data from prospective studies published in the scien- Vol No. 2 PANMINERVA MEDICA 97

3 KING RISK FACTORS FOR ASTHMA INCIDENCE tific literature over the last decade, and to highlight known areas that might benefit from additional longitudinal study. Materials and methods Search strategy All relevant English language articles were retrieved using an electronic search of the EMBASE and MEDLINE online databases, via both PubMed and Ovid interfaces by using the following keywords: asthma and risk factors and incidence. Results were limited to sources published between 1994 and A secondary search was made of the references listed in primary sources, using identical inclusion criteria, to identify additional studies not captured by the electronic search. Eligible studies Titles and abstracts were manually reviewed and studies were selected for inclusion if met the following criteria: a) indicated that incident asthma or wheeze was a main outcome, b) were prospective in design, and c) provided data on risk factors associated with newly diagnosed asthma. Ineligible studies Review articles, meta-analyses, and retrospective or cross-sectional studies were excluded from this review. Likewise, studies that reported results exclusively for wheeze as a proxy for asthma were excluded. In general, we excluded duplicate studies from the same cohort unless some key features from the duplicate study (i.e. - a focus on specific risk factors) merited inclusion. Search results The search, completed on March 1, 2004, yielded a combined total of 101 unique citations. A total of 40 articles met the criteria for inclusion in this review of risk factors for the development of asthma. Definitions and approach According to the Global Initiative for Asthma, 2 risk factors for asthma can be classified as host factors that predispose individuals to or protect them from developing asthma, and environmental factors that influence the susceptibility to the development of asthma in predisposed individuals. Host-specific risk factors for incident asthma include: a) demographic traits, such as age, gender, and race/ethnicity; b) history of atopy and parental asthma and c) airway hyper-responsiveness. Environmental risk factors include a) earlylife, social, and medical factors, b) lifestyle factors, c) indoor exposure to allergens and environmental tobacco smoke (ETS), d) outdoor exposures and e) occupational exposures. Because of the considerable variability in both the definition of asthma and the approach to determining risk factors and outcomes across studies, we did not attempt a formal meta-analysis. Results Asthma incidence/risk factors Our primary outcome of interest was asthma incidence, which could be estimated in 36 of the 40 studies included. The average annual incidence of physician-diagnosed asthma (used in 19 studies reporting incidence) ranged from to per persons (Figure 1). 15, Incidence estimates for other definitions of asthma were mostly in the same range (12 of 17 studies) although the highest estimate of 160 per defined asthma in infants as 2 episodes of cough or wheeze lasting >1-2 weeks and nocturnal symptoms or medication use. 23 The studies addressing specific host or environmental risk factors for asthma are listed in Table II. 14, 15, 17-22, 24, 25, 27-43, Host factors DEMOGRAPHIC TRAITS-AGE, SEX, RACE/ETHNICITY The effects of age and sex on the development of asthma are interrelated and demonstrate a characteristic shift from childhood to adolescence, the underlying mechanism of which is not completely understood. The incidence of physician-diagnosed asthma tends to increase from the 1 st year of life through adolescence, and then decrease into adulthood (Table III, 14, 15, 22, 24, 25, 29, 33, 35, 37, 38, 40, 41, 43, 44, 46, 48, 52, 53 Figure 1). A study of children, aged 0 to 24 months, 38 found that incidence of asthma, defined as wheezing-associated respiratory illness (WARI), was higher among children months of age, compared to younger children, whereas incidence of bronchiolitis was highest among children 0-6 months of age. As can be seen in 98 PANMINERVA MEDICA June 2004

4 RISK FACTORS FOR ASTHMA INCIDENCE KING TABLE I. Characteristics of prospective studies reporting incidence of asthma/wheeze, 1994 to Study/setting Number, age, sex Dates/ages of assessment Definitions Average annual asthma incidence (if available) per * Limitations/ comments Ball 2000/US , 6-13, both Age 6, 8, 11, 13 years A Not available 4 Basagana 2001/Spain , 20-50, both 1991 and 1998 B f Camargo 1999/US , 26-46, women 1989, 91, 93, and 95 A + B 5 1, 2, 5 Carey 1996/US , 5-9, both annually C Not available b Castro-Rodriguez 2001/US , 6-13, both Age 6, 8, 11, 13 years C Not available Chan-Yeung 2000/Canada , 0-1, both Pre-birth+age 2 weeks, and F , 8, 12 months Chen 2002/Canada , 20-64, both and A 1.5 (female)/0.8 (male)** Eagan 2002/Norway , 15-70, both 1985 and 1996 D 3.2 (female)/3.6 (male) Eagan 2002/Norway , 15-70, both 1985 and 1996 D El-Zein 2003/Canada , 16-46, both Baseline+2 follow-ups over G 15 1, months Gautrin 2001/Canada , 17-22, both Follow-up at 8, 20, 32 and 44 months A+G Gilliland 2003/US , 7-18, both annually A 2.4 Hesselmar 1999/Sweden , 7-13, both 1991, 1992 and 1996 B c Huovinen 1999/Finland , 30-55, both 1975, 1981 and 1990 A 1.7 (female)/1.5 (male) d Katz 1999/Israel , 17, both Baseline+30 month follow-up G 0.8 1, 9 Kull 2002/Sweden , 3-24 months, both Age 3 months, 1 and 2 years F 42.5 Laprise 1997/Canada 34 90, 14-65, both Baseline+2 follow-ups over E years Larsson 1995/Sweden , 16-19, both 1990 and 1993 A/B 11.1/12.7 e Litonjua 2001/US , 2-24 months, both Age 2 months, 1 and 2 years A/C 29.5/85 6 Lombardi 1997/US , 6-11, both Birth, 2, 3 and 6 years A+C 16.2 Lundback 2001/Sweden , adults born 1986, 92 and 96 A 3.8 (overall)/4.5 (female)/3.2 e , both (male) Marbury 1996/US , 0-24 months, both 2 questionnaires-12 months E 115 apart McConnell 2002/US , 9-16 at start, both 2 cohorts: and A 15 5 year follow-up McDonnell 1999/US , 27-87, both 1977, 87 and 92 A 2.9 (female)/2.1 (male) 7 Nicolai 2003/Germany , 10-20, both Age 10, 14, and 20 years A+B Norrman 1998/Sweden , 13-16, both 1987 and 1991 B 11 Oddy 1999/Australia , 0-6, both Birth+age 6 years A+C Not available Ownby 1996/US , 28-30, both Birth of 1 st child and 4 years A later Perzanowski 2002/Sweden , 7-11, both 1996, 97, 98 and 99 A/B 8/13.7 (overall); 7.3/10.2 (female); 8.3/15.7 (male) Romieu 2003/France , 40-65, females 1990, 92 and 93 B 1.8 1, 5 Ronmark 2001/Sweden , 7-8, both 1996 and 1997 A/B 16/14 Ronmark 2002/Sweden , 7-9, both 1996, 1997, and 1998 A/B 7.8/9.3 Settipane 2000/US , at end, both Baseline+23 year follow-up A 2.3 Shima 2002/Japan , 6-12, both annually B 16.3 a Sigurs 1995/US , 6 months-3 years, both Age 6 months, 1 and 3 years A 78 (cases)/3.4 (controls) 6 Strachan 1996/UK , 0-33, both Age 7, 11, 16, 23 and 33 years B+C 26.1 (age 0 to 7); 6.3 (age 8 to 16); 11.1 (age 17 to 33) Troisi 1995/US , 34-68, women 1980, 82, 84, 86, 88 and 90 A 0.6 (smokers)/1.0 (nonsmokers) 1, 5, c 10 year follow-up Troisi 1995/US 53 >77 000, 34-68, women 1980, 82, 84, 86, 88 and 90 A 1.4 (females<age 50)/1.1 (fema- 1, 5, c 10 year follow-up le >age 50) Wickman 20032/Sweden , 0-2 years, both Age 2 months, 1 and 2 years F 42.5 Zejda 2003/Poland , 7-16, both 1993 and 2000, 7 year follow-up A 5.6 Key for definitions: Asthma/wheezing: A) Physician diagnosed asthma or bronchial obstruction. B) Lifetime history of asthma or related symptoms over time. C) Symptoms of wheeze over time (e.g., months or lifetime). D) Physician diagnosed wheeze or related hospitalization. E) Wheezing-associated respiratory illness, American Thoracic Society, ISSAC asthma criteria. F) Combination of wheeze, airway hyperactivity, or asthma medication use. G) Probable occupational asthma. Limitations: 1) Limited to or mostly one gender. 2) No information on family history of asthma. 3) Lack of retention at follow-up (<60% of original sample). 4) Some data obtained retrospectively. 5) Limited to one occupation. 6) At-risk children selected for inclusion. 7) Limited to non-hispanic White. 8) Sample included children with past diagnosis of asthma or wheeze but no current symptoms. 9) Sample consisted of military members only. Comments: a) Incidence reported graphically per city. b) Incidence of wheeze based on analysis of a sub-cohort followed through adolescence. c) Cumulative incidence for asthma reported for subgroups, but not total sample. d) Cumulative incidence based on birth decade and p-value for age-trend analysis showing asthma increases with age. e) Reported incidence for additional definitions of asthma and symptoms, including wheeze. f) Incidence decreased with exclusion of subjects reporting respiratory of bronchial symptoms at baseline. *) Estimates rounded to nearest tenth. **) Weighted to a general population, not the study sample. Vol No. 2 PANMINERVA MEDICA 99

5 KING RISK FACTORS FOR ASTHMA INCIDENCE TABLE II. Prospective studies supporting host and environmental risk factors for incident asthma published between 1994 and Host risk factors References Age, sex, race/ethnicity 14, 15, 22, 24, 25, 29, 33, 35, 37, 38, 40, 41, 46, 48, 52, 53 Family history of asthma 14, 15, 28, 33, 34, 37, 45, 47, 48, 49, 51, 54 Personal atopy 19, 28, 29, 31, 36, 42, 45, 47, 48, 49, 50, 52, 54 Airway hyperresponsiveness 19, 21, 28, 34 Environmental risk factors Early-life and social factors 14, 15, 18, 30, 33, 34, 40, 43, 45, 47, 48, 51, 52 Lifestyle factors 17, 20, 22, 24, 25, 29, 35, 37, 40, 42, 46, 52 Indoor exposures 18, 29, 33, 45, 54 Environmental tobacco smoke 14, 29, 33, 38, 43, 52 Outdoor exposures 14, 38, 39, 40, 43, 50 Occupational exposures 25, 27, 28, 32, 40 TABLE III. Studies reporting demographic traits as a risk factor for incident asthma. Risk factor Study Specific predictor Incident outcome Significant associations (95% Confidence Interval) Age Marbury Age months Asthma Higher incidence vs children age <13 months McDonnell Younger age Decreasing risk asthma in females per RR 0.6 ( ) 16 years increment, ages 27 to 87 Ownby Age <30 (vs >30) Asthma in parents, ages 28 to 30 RR 3.7 ( ) Romieu Younger age Asthma in females, ages p<0.001 Age <45 CI CI CI CI 0.4 >60 CI 0.5 Troisi Age <50 Asthma in females 1.4 cases/1 000 person years Age >50 Asthma in females 1.1/1 000 person years Eagan Age >50 Asthma by age OR 2.0 ( ) Sex Kull Male sex Wheeze by age 2 OR 1.6 ( ) Wickman Male sex Wheeze by age 2 OR 1.7 ( ) Oddy Male sex Asthma by age 6 OR 1.5 ( ) Strachan Male sex Asthma by age 7 OR 1.3 ( ) Ronmark Male sex Asthma by age 8 OR 1.7 ( ) Castro-Rodriguez Female sex Infrequent wheeze by age 11 OR 3.5 ( ) Frequent wheeze by age 13 OR 4.8 ( ) Ball Male sex Asthma by age 13 RR 1.5 ( ) Strachan Male sex Asthma by age 16 OR 1.5 ( ) Gilliland Male sex Asthma in boys by age 18 RR 2.3 ( ) Larsson Female sex Sex difference in asthma by age 19 Female 3-years C.I.CI 4.1% vs male 2.4% (p=0.02) Nicolai Female sex Sex difference in asthma by age 20 Female 6.4% vs male 3.3% (p=0.022) Lundback Female sex Asthma by age 20 OR 1.5 ( ) Ownby Female sex Asthma 4 years after childbirth, age RR 3.4 ( ) Sex difference in asthma by ages Mothers 1-years 5.2 per vs fathers 1.5 (p=0.058) Chen Female sex Asthma by age C.I.CI 2-years 2.9 ( ) Strachan Female sex Asthma by age 33 OR 0.8 ( ) Race/ Oddy Aboriginal ethnicity Asthma by age 6 OR 1.8 ( ) ethnicity Gilliland Other race/ethnicity Asthma by age 18 RR 3.6 ( ) Non-Caucasian OR = odds ratio; RR = relative risk; APR = adjusted prevalence ratio; C.I. = cumulative incidence. 100 PANMINERVA MEDICA June 2004

6 RISK FACTORS FOR ASTHMA INCIDENCE KING the figure, there was considerable variability in estimated asthma incidence rates between studies. Overall, 14 studies included in this review found a significant association between gender and incident asthma. In general, studies of children found males to be at risk, 14, 33, 43, 48 whereas studies of adolescents or adults found females to be at risk (Table III). 24, 37, 41, 44 Although the most studies included race/ethnicity as a potential predictor of asthma, only 2 studies reported a significant independent relationship with incidence after controlling for socio-economic indicators. 17, 20, 22, 29, 39, 40, 52 Of these, only one reported a specific ethnicity; Oddy et al. studied children from birth to age 6 in Australia and determined that Aboriginal children were at significantly greater risk of asthma being diagnosed by a doctor (1.8, 1.1 to 3.27; p=0.029) than other children in the cohort 43 (Table III). HISTORY OF ATOPY AND PARENTAL ASTHMA Personal atopy or a familial history of asthma are consistent predictors of incident asthma (Table IV). 14, 15, 19, 28, 29, 31, 33, 34, 36, 37, 42, 45, 47-49, 50-52, 54 Personal atopy, defined as either a positive skin test or a history of allergic disease (hay fever, eczema or allergic rhinitis) was examined in 15 studies (Table IV). In studies of children and adolescents, positive skin tests tended to stronger predictors of incident asthma (range of odds ratios [ORs] from to ) than a history of allergic disease (range of ORs to ). The 3 studies of adults 19, 31, 49 demonstrative a 2-6 fold increased risk of incident asthma, with no clear differences between subjects with positive skin tests versus those with a history of allergic disease (Table IV). A family history of asthma, reported in 12 studies, was, similarly, a consistent predictor of incident asthma, with reported ORs ranging from to (Table IV). Additional risk of asthma in children was reported for maternal vs paternal asthma history, 15 or having 2 parents with the disease. 14 AIRWAY HYPERRESPONSIVENESS Four studies examined the relation between airway hyperresponsiveness (in asthma-free subjects) and incident asthma (Table V). 19, 21, 28, 34 All of these studies demonstrated an increased risk of either developing recurrent wheezing or asthma among subjects with reactive airways at the baseline examination. Incidence of asthma /1 000 person year Midpoint of age-range of cohort at baseline Figure 1. Incidence of physician diagnosed asthma. Environmental factors EARLY-LIFE AND SOCIAL FACTORS Early-life, social and medical factors significantly related to the onset of asthma include a) low birth weight and perinatal factors, b) having been breastfed as an infant, c) the occurrence of infections early in life and d) social factors related to the burden of infection such as daycare use and family size (Table VI). 14, 15, 18, 30, 31, 33, 34, 40, 43, 45, 47, 48, 51, 52 Three studies 45, 47, 48 reported low birth weight (<2 500 g) as a risk factor for incident asthma among children under 11 years of age, with ORs ranging from 2.1 to 6.7. Other perinatal factors associated with an increased risk of incident asthma included young maternal age, 14, 33 and maternal albuminuria during pregnancy 52 (Table VI). Factors associated with a decreased risk of incident asthma included bleeding during pregnancy and 3 rd trimester hemorrhage. 52 Three studies found that breastfeeding through the first 4 months of life was associated with a lower risk of incident asthma 14, 33, 43 (Table VI). Seven studies reported a significant association between childhood infections and incident asthma 18, 34, 40, 45, 48, 51, 52 (Table VI). These studies were stronger in young children 18, 51 compared to older children or adults. 45, 48, 52 Other medical conditions, including migraine headache, 52 recurrent abdominal pain, 52 and chronic bronchitis 31 also predicted incident asthma (Table VI). Three studies 15, 30, 43 showed that increased exposure to other children, either because of playgroup or daycare attendance or having more siblings, was associated with a decreased risk of developing asthma (Table VI). Vol No. 2 PANMINERVA MEDICA 101

7 KING RISK FACTORS FOR ASTHMA INCIDENCE TABLE IV. Studies reporting personal atopy and parental asthma as a risk factor for incident asthma. Risk factor Study Specific predictor Incident outcome Significant associations (95% Confidence Interval) Personal Lombardi Positive skin test Asthma by age 6* AHR 3.6 ( ) atopy Strachan Hay fever Asthma by age 0-7 OR 1.3 ( ) Eczema OR 1.3 ( ) Ronmark Positive skin test Asthma by age 8 OR 9.3 ( ) Ronmark Positive skin test Asthma by age 9 OR 5.6 ( ) Rhinitis OR 3.5 ( ) Eczema OR 2.2 ( ) Perzanowski, Positive skin test Asthma by age 7-11 RR 5.5 ( ) Lifetime asthma by age 11 RR 5.9 ( ) Shima History of allergic disea- Asthma by age 12 OR 2.9 ( ) ses Norrman Positive skin test Asthma by age 16 OR 2.5 ( ) Zejda History atopic eczema Asthma by age 16 OR 3.9 Strachan Hay fever Asthma by age 16 OR 1.4 ( ) Eczema OR 1.3 ( ) Gilliland History of allergy Asthma by age 18 RR 2.2 ( ) History of allergic rhinitis RR 2.8 ( ) Gautrin Positive skin test (pets) Asthma by age 22 RR 4.1 ( ) Strachan Hay fever Asthma by age OR 1.5 ( ) Eczema OR 1.2 ( ) Settipane Positive skin test age Asthma by age fold increased risk; p<0.001* Hay fever 3-fold increase risk; p < 0.002* Basagana Positive IgE (timothy Asthma by age IRR 2.2 ( ) grass) Huovinen Hay fever Asthma in men, age IRR 4.3 ( ) Hay fever Asthma in women, IRR 6.0 ( ) Family Kull Family history Wheeze by age 2 OR 1.8 ( ) history Wickman One parent with asthma Wheeze by age 2 OR 1.7 ( ) of asthma Both parents with asthma OR 3.2 ( ) Sigurs Family history 3 episodes bronchial obstruction by age 3 RR 3.2 ( ) Ronmark Family history Asthma by age 8 OR 2.2 ( ) Ronmark Family history Asthma by age 9 OR 2.8 ( ) Perzanowski Family history Asthma by age 7-11 RR 2.8 ( ) Lifetime asthma by age 11 RR 2.6 ( ) Ball History maternal asthma Asthma by age 13 RR 2.3 ( ) History paternal asthma RR 1.6 ( ) Zejda Family history Asthma by age 16 OR 4.6 Gilliland History maternal allergy Asthma in girls by age 18 RR 1.6 ( ) Family history asthma Asthma in boys by age 18 RR 2.2 ( ) Settipane Family history asthma Allergic asthma by age p<0.05 Laprise First-degree relatives with Asthma by age p=0.01 asthma Lundback Family history Asthma by age OR 4.7 ( ) OR: odds ratio; RR: relative risk; IRR: incidence rate ratio; AHR: adjusted hazard ratio. *) No estimates of association reported. TABLE V. Studies supporting airway hyperresponsiveness as a risk factor for incident asthma or probable occupational asthma. Risk factor Study Specific predictor Incident outcome Significant associations (95% Confidence Interval) Airway hyper- Carey Airway hyperresponsiveness* Wheeze by age OR 3.9 ( ) responsiveness Gautrin Bronchial responsiveness** POA, age RR 2.5 ( ) Lower FEV1 RR 0.6 ( ) Basagana Bronchial hyperresponsiveness*** Asthma by age IRR 6.2 ( ) Laprise Airway hyperresponsiveness**** Asthma by age p=0.01 OR: odds ratio; RR: relative risk; IRR: incidence rate ratio; POA: probable occupational asthma. *) Positive hyperresponsiveness measured by FEV change/fev 0.09 to cold-air or methacholine. **) PC20 32 mg/ml. ***) FEV 1 (PC20) <4 mg/ml. ****) Responsiveness measured by cold-air challenge. 102 PANMINERVA MEDICA June 2004

8 RISK FACTORS FOR ASTHMA INCIDENCE KING TABLE VI. Studies supporting early-life and social risk factors for incident asthma. Risk factor Study Specific predictor Incident outcome Significant associations (95% Confidence Interval) Low birth Ronmark Birth weight <2 500 g Asthma by age 8 OR 6.7 ( ) weight Ronmark Birth weight <2 500 g Asthma by age 9 OR 3.4 ( ) Perzanowski Birth weight <2 500 g Asthma by age 7-11 RR 2.1 ( ) Perinatal Kull Maternal age <26 years Wheeze by age 2 OR 1.8 ( ) factors Wickman Maternal age Wheeze by age 2 OR 0.6 ( ) Maternal age >31 OR 0.6 ( ) Oddy Gestational age <37 weeks Asthma by age 6 OR 1.8 ( ) Strachan rd trimester antepartum hemorrhage Asthma by age 0-7 OR 0.4 ( ) Bleeding during pregnancy Asthma by age 8-16 OR 0.6 ( ) Maternal albuminuria Asthma by age OR 1.6 ( ) Breast Kull Breastfed 4 months Wheeze by age 2 OR 0.7 ( ) feeding Breastfed 4 months Wheeze + atopy by age 2 OR 0.7 ( ) Partial breastfed 6 months Wheeze by age 2 OR 0.7 ( ) Wickman Breastfed 4-5 months Wheeze by age 2 OR 0.7 ( ) Breastfed >6 months OR 0.7 ( ) Oddy Introduction of other milk at <4 Asthma by age 6 OR 1.3 ( ) months of age History of Litonjua Recurrent LRI Asthma by age 2 RR 8.1 ( ) infections Sigurs History of RSV at age 1 Asthma by age 3 RR 21.8 ( ) and medical Strachan Pneumonia before age1 Asthma by age 0-7 OR 2.0 ( ) conditions Recurrent abdominal pain OR 1.3 ( ) Migraine OR 1.1 ( ) Ronmark History of respiratory infections Asthma by age 9 OR 1.7 ( ) Perzanowski History of respiratory infection Asthma by age 11 RR 1.8 ( ) Strachan Whooping cough by age 11 Asthma by age 16 OR 1.9 ( ) Laprise History of respiratory viral infection Asthma by age p = Strachan Migraine Asthma by age OR 1.2 ( ) Huovinen Chronic bronchitis Asthma in men, age IRR 5.8 ( ) Chronic bronchitis Asthma in women, IRR 4.3 ( ) McDonnell History of childhood pneumonia or Asthma by age RR 3.0 ( ) bronchitis among females Daycare Oddy Childcare or playgroup attendance at Asthma by age 6 OR 0.5 ( ) attendance <3 months and Hesselmar Greater number siblings (0 to >3) Asthma by age 7-13 OR 0.7 ( ) family size Ball One or more siblings in home Asthma by age 13 RR per additional sibling 0.8 ( ) Daycare attendance before age 6 Asthma by age 13 RR 0.4 ( ) months OR: odds ratio; RR: relative risk; IRR: incidence rate ratio; LRI: lower respiratory infection; RSC: respiratory syncytial virus. LIFESTYLE FACTORS Lifestyle factors associated with incident asthma include modifiable individual behaviors such as smoking, dietary habits, and, to a lesser extent, the use of oral contraceptives or postmenopausal hormones, are presented in Table VII. 17, 20, 22, 24, 25, 29, 35, 37, 40, 42, 46, 52, 53 Nine studies reported that smoking was associated with an increased risk of developing asthma among both adolescents and adults. 17, 24, 35, 37, 40, 42, 46, 52, 53 There was evidence of both a dose response 25 and an intermediate level of risk in former smokers 37, 42, 46 (Table VII). Five studies found a positive association between higher BMI and incident asthma among children and adults. 20, 22, 24, 29, 46 Perhaps reflecting overall trends in asthma incidence, a study of young children found an effect in boys, 29 whereas studies of adults found effects in women 20, 24, 46 (Table VII). Two studies noted that incident asthma was related to menopausal status and the use of hormone replacement therapy or oral contraceptives 17, 46 (Table VII). INDOOR OR OUTDOOR EXPOSURES Indoor factors related to incident asthma include passive exposure to ETS, exposure to furred pets or other allergens, and exposure to dampness. Outdoor exposures have looked at the following pollutants: ozone, particulate matter, and nitrogen dioxide. Studies report- Vol No. 2 PANMINERVA MEDICA 103

9 KING RISK FACTORS FOR ASTHMA INCIDENCE TABLE VII. Studies supporting lifestyle factors for incident asthma. Risk factor Study Specific predictor Incident outcome Significant associations (95% Confidence Interval) Personal Norrman History of smoking Asthma by age OR 2.8 ( ) smoking Current smoking Asthma by age OR 3.4 ( ) Larsson Smoking Lifetime asthma in females, OR 2.7 ( ) age Asthma in females, age OR 2.0 ( ) Wheeze in males, age OR 2.3 ( ) Strachan Current smoking Asthma by age OR 4.4 ( ) Romieu Current smoking Lifetime asthma in females, CI=0.70, p = 0.02 age Ex-smoker CI=0.66 Never smoker CI=0.49 Lundback Smoking Asthma by age OR 2.6 ( ) Ex-smoking Asthma by age OR 2.5 ( ) Troisi Current smoking Asthma in females with RR 2.02 ( ) bronchitis, age Eagan Increasing pack-years smoking Asthma by age OR 1.2 ( ) (per 10 years increment) McDonnell History of ever smoking Asthma in males, age RR 2.4 ( ) Diet/obesity Castro-Rodriguez Overweight/obese by age 6 to Infrequent wheeze in females OR 6.8 ( ) 11 age 11 and 13 Overweight/obese by age 6 to Frequent wheeze in females OR 5.5 ( ) 11 age 11 and 13 Gilliland Overweight >85 th % Asthma by age 7-18 RR 1.5 ( ) Overweight >85 th % Asthma in males, age 7-18 RR 2.1 ( ) Obese >95 th % Asthma by age 7-18 RR 1.6 ( ) Obese >95 th % Asthma in males, age 7-18 RR 2.3 ( ) Camargo Increasing BMI Asthma by age p< RR 1.1 ( ) RR 1.6 ( ) RR 1.7 ( ) 30 RR 2.7 ( ) Weight gain (kg) since age 18 Asthma by age p< kg RR 1.4 ( ) kg RR 2.0 ( ) 25 RR 2.5 ( ) Chen BMI 30 kg/m 2 Asthma in females, age OR 1.9 ( ) Romieu BMI Asthma in females, age RR 1.5 ( ) BMI 27 RR 2.0 ( ) Weight change loss 1-5 kg RR 1.5 ( ) Weight change gain >5 kg RR 1.7 ( ) Largest silhouette at menarche RR 0.7 ( ) Caloric intake p=0.02 <1 650 CI=0.62 >2 596 CI=0.70 Other lifestyle Romieu Menopausal status Asthma in females, p=0.004 factors Pre age CI=0.61 Peri CI=0.62 Post CI=0.41 Troisi Naturally menopausal status Asthma among females, RR 0.7 ( ) + never used hormones age Ever-using postmenopausal RR 1.5 ( ) hormones Past use of oral contraceptives RR 1.3 ( ) OR: odds ratio; RR: relative risk; CI: cumulative incidence; BMI: body mass index. 104 PANMINERVA MEDICA June 2004

10 RISK FACTORS FOR ASTHMA INCIDENCE KING TABLE VIII. Studies supporting indoor and outdoor risk factors for incident asthma. Risk factor Study Specific predictor Incident outcome Significant associations (95% Confidence Interval) Indoor ETS Wickman Maternal smoking Wheeze by age 2 OR 1.7 ( ) exposure Kull Maternal smoking Wheeze by age 2 OR 1.7 ( ) Marbury History of maternal smoking Asthma by age 2 RR 2.3 ( ) Oddy Smoking in household Asthma by age 6 OR 1.3 ( ) Gilliland Household ETS exposure Asthma by age 7-18 RR 1.5 ( ) Strachan Maternal smoking Asthma by age OR 2.3 ( ) Other indoor Kull Year home construction 1961 Wheeze by age 2 OR 1.5 ( ) factors Wickman Damp home environment Wheeze by age 2 OR 1.7 ( ) Pet ownership OR 0.9 ( )* Ronmark Pet ownership Wheeze by age 9** OR 2.9 ( ) Litonjua Exposure to cockroach allergen Asthma by age 2 RR 8.3 ( ) U/g 2 U/g RR 35.9 ( ) Perzonwski Cat ownership ever Asthma by age 7-11 RR 0.6 ( ) Hesselmar Pet ownership by age 1 Asthma by age CI=8.6 (Yes pet exposure) CI=13.3 (No pet) (p=0.03) Norrman Pet ownership (past/present) Asthma by age OR 0.5 ( )*/OR 0.3 ( )* Zejda Use of coal cooking/heating Asthma by age 7-16 OR 3.3 ( ) Gilliland Humidifier use Asthma in males, age RR 1.5 ( ) 7-18 Chen Pet ownership Asthma by age CI=4.2 (Yes pet exposure) CI=3.3 (No pet) Outdoor factors Wickman Home constructed after 1976 Wheeze by age 2 OR 1.8 ( ) Shima Increasing NO 2 Asthma by age 12 OR 3.6 ( ) McConnell Playing 3 team sports in a high Asthma by age 9-16 RR 3.3 ( ); CI=0.05 ozone community Playing 3 team sports in a high Asthma by age 9-16 RR 2.0 ( ); CI=0.03 PM community McDonnell year mean 8 hour ozone expo- Asthma by in RR 2.1 ( ) sure males OR: odds ratio; RR: relative risk; CI: cumulative incidence; ETS: environmental tobacco smoke; NO 2 : nitrogen dioxide; PM: particulate matter. *) Non-significant finding. **) Incidence of wheeze not a proxy for incidence of physician diagnosed asthma. ing both indoor and outdoor risk factors are presented in Table VIII. 14, 18, 24, 29, 30, 32, 33, 38-43, 45, 47, 49, 50-52, 54 Six studies have shown a modest increase in the incidence of asthma related to ETS exposure, with ORs ranging from 1.3 to , 29, 33, 38, 43, 52 Four of the 6 studies used maternal smoking as their measure of ETS exposure 14, 33, 38, 52 (Table VIII). Although 6 prospective studies investigated ownership of furred pets and incident asthma, only 1 reported an estimate of risk, with a decreased incidence of asthma associated with cat ownership (OR 0.6, 95% CI ). 45 Three additional studies reported that the proportion of children diagnosed with incident asthma by age 2, 14 9, 47 and 12 to 13 years 30 was lower among children who were exposed to furred pets during the 1 st year of life. Conversely, a Canadian study of adults found the cumulative incidence of asthma tended to be higher among those who owned pets (average of 4.2% vs 3.3%). 24 One study reported a significant association between exposure to elevated cockroach allergen levels and incident asthma, with evidence of a fairly strong doseresponse 18 (Table VIII). Two recent studies provided evidence linking indoor humidity with incident asthma, with ORs ranging from 1.5 to , 29 Other studies have shown that children living in newer homes (with, presumably, less natural air exchange) have more asthma (ORs range from 1.5 to 1.8). Finally, a European study found that use of coal for home cooking and heating was associated with more incident asthma 54 (Table VIII). Three studies have significant associations of pollutant exposures and asthma incidence, 2 for ozone 39, 40 and 1 for NO2 50 (Table VIII). Estimation of exposure has proven challenging in these types of studies, with one using number of team sports played as a surrogate for exposure 39 and another using community exposures as a surrogate for personal exposure. 40 The McDonnell et al. study found an effect in men but not women. 40 Vol No. 2 PANMINERVA MEDICA 105

11 KING RISK FACTORS FOR ASTHMA INCIDENCE TABLE IX. Studies supporting work-related risk factors for incident asthma. Risk factor Study Specific predictor Incident outcome Significant associations (95% Confidence Interval) Host factors Gautrin Positive skin test to pets Probable occupational asthma 1 RR 4.1 ( ) Bronchial responsiveness RR 2.5 ( ) Lower FEV1 (PC20 32) RR 0.6 ( ) Workplace Eagan Dust/fumes workplace exposure Probable occupational asthma 2 OR 1.6 ( ) El-Zein Exposure to welding fumes Probable occupational asthma 3 Significant reduction in FEV1% predicted (p<0.01) McDonnel 1990* 40 Years worked with smoker (risk Asthma in females (4) RR 1.2 ( ) per 7 year increment) Occupational Katz Posting to combat unit vs clerical Probable occupational asthma RR 2.0 (p<0.001) unit (5) in males, age Posting to maintenance unit vs cle- RR 1.3 (p<0.01) rical unit Probable occupational asthma defined as: 1) Physician-diagnosed asthma by questionnaire. 2) Ever hospitalized or treated by a physician for asthma by questionnaire. 3) Presence of welding-related respiratory symptoms (cough, wheezing, chest-tightness) fold increase in provocative concentration 20 by examination and questionnaire. 4) Doctor-told asthma by examination. 5) Physician-diagnosed asthma by examination. OR: odds ratio. RR: relative risk. *) Non-occupational study reporting occupational risk factor. OCCUPATIONAL EXPOSURES Five studies have examined the development of occupational asthma in adults 25, 27, 28, 32, 40 (Table IX). One was unique in that it looked at host factors such bronchial responsiveness or positive skin tests, and found an increased risk of incident occupational asthma 28 (Table IX). The other 4 found that working in an environment with dust, fumes or smoke resulted in a higher risk of asthma with ORs raning from 1.2 to , 27, 32, 40 (Table IX). Discussion One of the hallmarks of asthma is its variabilityindividuals can have substantial variability in their respiratory symptoms, lung function, and other measures of disease activity from hour to hour. 2 International surveys show that asthma prevalence has increased substantially over the past 3 decades, primarily in more affluent, English-speaking nations 4, 55 and that similar age and sex-dependent patterns in the incidence of asthma are observed in different countries. 56 Hence, it is not surprising that this review found a large degree of variability in studies reporting incidence and risk factors for asthma in cohorts. In the prospective studies from 13 countries we reviewed, the incidence of physician-diagnosed asthma varied 50 fold, from 0.6 to 29.5 case per person-years (Table I, Figure 1). If one were to expand the definition of asthma to that of wheezing with medication use 23 this becomes a 250 fold difference. This variation illustrates the difficulty of comparing epidemiologic studies from different settings and populations. For example, since most symptoms of early wheeze do not persist through adolescence, 57 case definitions based on wheezing can overestimate the rate of asthma in certain groups. We also observed a degree of variability in asthma risk-factors, although some trends did emerge. For example, asthma incidence is higher in children and people with either personal atopy or a familial history of asthma. The relation between gender and asthma incidence is influenced by age, with higher rates in boys and higher rates in adolescent girls and women. Other factors associated with an increased risk of developing asthma include low birth weight, a history of lower respiratory infection (LRI), childhood exposure to ETS, active smoking, airway hyperresponsiveness, exposure to cockroach allergen, and exposure to high levels of atmospheric ozone and NO2. Protective factors included breastfeeding for at least 4 months, menopause, daycare attendance, and pet ownership. Although not amenable to public health prevention efforts, knowledge of host risk factors can help identify individuals who may benefit from future therapeutic intervention. Studies included in this report support characteristic age and sex patterns for asthma incidence similar to those observed for asthma prevalence. 56, 58 Airway hyperresponsiveness also appears to be a useful, albeit non-prognostic, 27 predictor of subsequent asthma. Given sex-specific chang- 106 PANMINERVA MEDICA June 2004

12 RISK FACTORS FOR ASTHMA INCIDENCE KING es known to occur in airway size from infancy to adulthood, 59 airway responsiveness is likely to interact with both sex and age-related factors in the development of asthma. Further, while belonging to a racial or ethnic minority is widely acknowledged to be a risk factor for asthma mortality and hospitalizations, this review found limited evidence linking race/ethnicity with incident asthma. Environmental factors that impact fetal growth and early childhood development appear to play a significant role in the origin of asthma. The incidence of asthma has been associated with low birth weight, young maternal age, maternal smoking, and preterm birth. However, it is difficult to clearly distinguish the influence of any one perinatal factor, particularly with respect to maternal factors and subsequent asthma in children. For the primary prevention of asthma, prospective evidence supports the recommendation 16 that mother s avoid both pre- and postnatal smoking. The potential preventive benefits of breastfeeding children for the first 4 months of life have also been noted. Clearly, additional research is required to determine the level of preventive benefit imparted by these specific behaviors, independent of other factors, in the longterm development of asthma. It is well known that atopic diseases tend to cluster in families 16, 63 and data from prospective studies confirm that the risk of neonates having atopic symptoms during the first 2 decades of life strongly depend on the manifestations of the disease in their parents. 16 In addition, sensitivity to common environmental allergens, measured by specific IgE or a positive skin prick test, is associated with an increased risk for asthma among children. Among adults, having a history of allergic diseases, such as hay fever or eczema, is associated with asthma incidence. We also observed that data comparing adult discordant-twins has indicated that atopy precedes the diagnosis of asthma, suggesting that both hay fever and chronic bronchitis may be early symptoms of asthma. 31 Both genetic risk, as measured by a family history of asthma, and personal allergy, as indicated by either allergic sensitization or symptoms, can serve as useful markers for individuals at high-risk for developing asthma, although they are unlikely to be the primary cause of increasing asthma prevalence trends noted in recent years. 3 In this review, we found conflicting evidence regarding the role of exposure to infections and the incidence of asthma. The hygiene hypothesis, introduced by Strachan in 1989, 64 is based on the concept that immune responses are regulated by 2 main subtypes of lymphocyte populations. The TH1 lymphocytes, which produce IFN-[γ] and IL-2, are mediators for the development of organ-specific autoimmune disorders, and the TH2 lymphocytes, which produce interleukins (IL- 4, IL-5, IL-9, and IL-13), can promote the development of IgE-mediated atopic allergy. According to this hypothesis, early childhood infections, exposure to siblings, childcare, and/or domestic animals (less hygienic environment), may favor maturation of TH1 over TH2 lymphocytes and thereby reducing the risk for developing allergic conditions. 65 Thus, several studies looking at pet ownership, 42, 45 childcare, 15, 43 or family size 30 supported this theory, whereas others did not. 24, 40, 47, 52 Furthermore, a number of recent studies (Table VI) have reported a significant association between respiratory infections in childhood and increased risk for developing asthma. These conflicting findings may, in part, be explained by differences in timing of exposure or by individual variation in susceptibility and additional research is needed to elucidate the underlying mechanisms of infection and allergic disease. Additional potentially modifiable lifestyle-related risk factors for incident asthma included obesity 17, 53 and smoking. 52 Among children and adults, having a higher BMI and significant weight gain were both found to precede the diagnosis of asthma in at least some segments of the studied population. Active smoking among adolescents and adults was likewise a significant determinant of incident asthma. Interventions targeting these risky behaviors could play a key role is the secondary prevention of asthma, particularly among those who are unaware that they have asthma or allergies. It is well known that exposure to common indoor allergens, such as cockroach or dust mite allergens, and pollutants, such as environmental tobacco smoke, is a risk factor for exacerbations and worsening of existing asthma, although the relationship with incident cases is less certain. Prospective studies we reviewed indicate that passive exposure to tobacco smoke, particularly at very young ages, is significantly related to the incidence of asthma later in life. Housing characteristics, such as increased dampness and exposure to furred pets or cockroach allergen during childhood also appear to be linked with the subsequent diagnosis of asthma. Although some studies reported conflict- Vol No. 2 PANMINERVA MEDICA 107

13 KING RISK FACTORS FOR ASTHMA INCIDENCE ing evidence related to pet exposure, this discrepancy may be explained by the fact that children exposed early in life develop tolerance while those exposed later become sensitized. 65 Regarding outdoor exposure, there is evidence that atmospheric pollutants, like ozone and nitrogen dioxide, may be important in the pathogenesis of asthma. 40 In contrast to studies of the prevalence of atopic diseases, 66 studies of asthma incidence suggest a link between prolonged exposure to particulate matter like NO2 the development of asthma. 39, 50 This report has served to highlight a number of important host and environmental risk factors that have been included successfully in multifaceted interventions aimed at the primary prevention of asthma. One study from Canada 23 reported the effectiveness of a multifaceted program using dust mite, pet allergen, and ETS avoidance measures with breastfeeding encouragement to prevent asthma symptoms. A group of 545 high-risk infants were selected before birth and followed until 1 year of age to determine programmatic impact on possible or probable asthma, rhinitis, and sensitization to common aeroallergens. Participation in the intervention program resulted in a 34% reduction in asthma (p=0.04). More recently, a prospective birth cohort study in Sweden investigated the impact of preventive guidelines designed to reduce allergic disease in childhood. 14 Among families adhering to guidelines that advocate breastfeeding, reduced infant and child exposure to ETS, home dampness, and improved indoor ventilation, a 2-fold reduction in the incidence of asthma (5.3% intervention vs 10.5% no intervention) by age 2 years was observed among children with no heritable risk factors for asthma. Among children with heritable risk factors for wheezing or asthma, the intervention produced a 3-fold reduction in incidence (9.1% intervention vs 27.3% no intervention). Evidence emerging from such prospective, controlled intervention studies lends validity to known risk factors for the incidence of asthma and provides a necessary foundation for future confirmatory research. The primary limitation of studies included in this review is the case-definition of asthma employed to identify new cases. Most epidemiological studies use data obtained from questionnaires and define asthma based on a self-reported doctor s diagnosis. Equally common is a case-definition based on frequency of asthma-like symptoms over time, while fewer include objective measures of bronchial hyperresponsiveness and atopy. The lack of a consistent definition of asthma often makes comparison of studies from different parts of the world problematic and the inclusion or exclusion of cases presenting with wheezing early in life may result in the over- or under-estimation of the disease. Similar to this is the definition (for use in cohort studies) of who may be asthma-free at the baseline study. Furthermore, different asthma phenotypes (such as allergic, nonallergic, exercise-induced) are typically not addressed consistently (if at all) in these studies. Conclusions The aim of this report was to identify risk factors for asthma incidence. In 40 prospective epidemiologic studies from 13 countries, estimates of incidence varied widely due to the lack of a standardized case definition for the incidence of asthma. Such findings reinforce the need to better define both asthma and the criteria used to identify specific asthma phenotypes in longitudinal investigations. There was some variability in the risk factors for incident asthma found for children and adults. Risk factors for incident asthma among children included: male sex, atopic sensitization, parental history of asthma, early-life stressors and infections, obesity, and exposure to indoor allergens, tobacco smoke and outdoor pollutants. Risk factors for adult-onset asthma included female sex, airway hyperresponsiveness, lifestyle factors, and work-related exposures. From a public health perspective, it is critical to examine factors amenable to intervention at the individual or community level. Evidence emerging from prospective epidemiological studies suggests the fact that some types of asthma have origins in early fetal life or childhood. For the purposes of primary prevention, modifiable risk factors such as young maternal age, health, and smoking during pregnancy are known to place children at increased risk while breastfeeding for more the 4 months is protective. Studies included in this review provide sufficient evidence to recommend the implementation of ETS avoidance and smoking cessation strategies for the primary prevention of asthma. Although exclusive breastfeeding in early childhood appears beneficial, more studies that follow children through adulthood are called for to clarify the independent and long term preventive benefit specifically related to asthma. Knowledge of host factors, such as familial history of asthma or atopic status can be used to identify high-risk 108 PANMINERVA MEDICA June 2004