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Epidemiology and risk factors for asthma

Open ArchivePublished:January 31, 2019DOI:https://doi.org/10.1016/j.rmed.2019.01.014

      Highlights

      • Both asthma incidence as well as prevalence have increased dramatically both globally and in the United States over the past 50 years.
      • Distinct populations including children and ethnic minorities show a disproportionate disease burden.
      • Multiple risk factors have been implicated in the development of the various childhood and adult phenotypes of asthma.
      • Increased knowledge of predisposing factors could facilitate public health measures as well as primary prevention strategies.

      1. Introduction

      The diagnosis of asthma has increased exponentially in recent decades parallel with urbanization and industrialization, and is now considered a global public health issue. According to the Global Burden of Disease report for 2015, asthma was the most common chronic respiratory disorder, with an estimated prevalence of 358 million cases [
      • Collaborators GBDCRD
      Global, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015.
      ]. Assessment of the scope and burden of disease is however confounded by misdiagnosis and bias in surveillance reports that result in over- or underestimation of cases. Nonetheless, despite this heterogeneity in data collection, there is little doubt that asthma has markedly increased in the past 50 years in terms of both incidence as well as prevalence. In recent cohorts, up to 15–20% of the general population have a diagnosis of asthma in some countries which is highly concerning [
      • Eder W.
      • Ege M.J.
      • von Mutius E.
      The asthma epidemic.
      ]. In fact, the World Health Organization, through extrapolation from existing data, predicts a further increase in the number of asthmatics by an additional 100 million in 2025 [
      • Croisant S.
      Epidemiology of asthma: prevalence and burden of disease.
      ]. This highlights the need for application of standardized and validated methods to enable improved evaluation of temporal trends of asthma prevalence.
      The objective of this review is to summarize the trends in asthma burden in the United States and internationally. Further, in view of the heterogeneity of severe asthma, we seek to highlight environmental exposures during early childhood and later in life that are potential stimuli for programming of asthma. Our search strategy included a systematic review of the existing English literature. The Pubmed electronic database (1970–2018) was screened including the search terms asthma, epidemiology, and risk factors (“asthma” [All Fields] AND “epidemiology” [MeSH Terms] AND “risk factors” [MeSH Terms]). (See Fig. 1)

      2. International prevalence

      The prevalence of asthma varies significantly in different regions of the world. Prevalence trends are best estimated through the repeated survey of large random samples in the same region, within the same age-range, using identical validated methods. Such studies are expensive to conduct and time consuming, however, a few studies that fulfill these criteria have delineated asthma trends among children and adults. The two largest global evaluations of asthma are the European Community Respiratory Health Survey (ECRHS) and International Study of Asthma and Allergy in Children (ISAAC). The ISAAC project is the most extensive international survey regarding asthma symptoms. Phase III of ISAAC reported a 12-month prevalence of asthma symptoms among adolescents ranging from 2.1% in Indonesia to 32.2% in the United Kingdom [
      • Pearce N.
      • Ait-Khaled N.
      • Beasley R.
      • Mallol J.
      • Keil U.
      • Mitchell E.
      • et al.
      Worldwide trends in the prevalence of asthma symptoms: phase III of the international study of asthma and allergies in childhood (ISAAC).
      ]. The highest 12-month prevalence of wheeze was found in Westernized, English speaking countries, but also in some Latin American countries (32.1% prevalence among 6–7-year old children in Costa Rica).
      The European Community Respiratory Health Survey (ECHRS) is the only other comparable international asthma survey [
      • Janson C.
      • Anto J.
      • Burney P.
      • Chinn S.
      • de Marco R.
      • Heinrich J.
      • et al.
      The European Community Respiratory Health Survey: what are the main results so far? European Community Respiratory Health Survey II.
      ]. This study included male and female subjects between 20 and 44 years mostly from European centers. Among countries that overlapped with those in ISAAC, the ranking of asthma symptom prevalence was similar. The highest rates were found in the English-speaking countries and the lowest in Italy and Greece. Eder et al. collated data from epidemiological surveillance studies, which show overall robust increase in asthma prevalence in most countries during the second half of the 20th century through the 1990s [
      • Eder W.
      • Ege M.J.
      • von Mutius E.
      The asthma epidemic.
      ]. Following this, the prevalence appears to have plateaued in some areas of the Western world, especially in Western/Northern Europe and Australia. However, it has been on the uprise in developing countries over recent decades of westernization, particularly childhood onset asthma.
      While asthma is more prevalent in higher income countries, the relationship between gross national product (GNP) and asthma frequency is non-linear. Rather, there appears to be a threshold below which countries have lowest asthma rates. Within the population of a given GNP, there is a prominent urban to rural gradient in decreasing prevalence of asthma [
      • Wang D.
      • Xiao W.
      • Ma D.
      • Zhang Y.
      • Wang Q.
      • Wang C.
      • et al.
      Cross-sectional epidemiological survey of asthma in Jinan, China.
      ].
      The importance of geographic location in the development of asthma has been highlighted by migration studies. While immigrants from developing countries initially demonstrate a lower prevalence of asthma than natives, this rises to similar rates proportional with increasing duration of residence [
      • Cabieses B.
      • Uphoff E.
      • Pinart M.
      • Anto J.M.
      • Wright J.
      A systematic review on the development of asthma and allergic diseases in relation to international immigration: the leading role of the environment confirmed.
      ]. These studies have also demonstrated higher rates of asthma in children of immigrants born in host countries [
      • Wang H.Y.
      • Wong G.W.
      • Chen Y.Z.
      • Ferguson A.C.
      • Greene J.M.
      • Ma Y.
      • et al.
      Prevalence of asthma among Chinese adolescents living in Canada and in China.
      ].
      International trends in mortality rates from asthma provide a barometer of asthma burden and the influences of changing management guidelines. For instance, asthma mortality epidemics between the 1960s–1980s were identified to be secondary to overuse of high dose β2 agonists, that ended with their withdrawal. Between 1985 and 2005, the surge in use of inhaled corticosteroids (ICS) for asthma management led to a progressive decline in estimated asthma mortality. Ebmeier et al. collated asthma mortality rates in those aged 5–34 years from 46 nations using the online WHO Mortality Database, and demonstrated a fall in the estimated mean global asthma mortality rate by 57% (from 0.44 per 100,000 in 1993 to 0.19 per 100,000 in 2006) [
      • Ebmeier S.
      • Thayabaran D.
      • Braithwaite I.
      • Benamara C.
      • Weatherall M.
      • Beasley R.
      Trends in international asthma mortality: analysis of data from the WHO Mortality Database from 46 countries (1993-2012).
      ]. This is reflected in the decline of annual age-standardized disability adjusted life year (DALY) rates for asthma by 42.8% between 1990 and 2015 [
      • Collaborators GBDCRD
      Global, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015.
      ], most of which stems from a reduction in mortality.
      However, the reductions in years lived with disability (YLDs) have been much smaller. Also, global asthma mortality rates in the past decade appear to have plateaued without further decline since 2006, indicating the need for novel strategies to achieve further reduction. Additionally, subjects with asthma have increased mortality from all causes [
      • Ali Z.
      • Dirks C.G.
      • Ulrik C.S.
      Long-term mortality among adults with asthma: a 25-year follow-up of 1,075 outpatients with asthma.
      ].

      3. United States prevalence

      The Center for Disease Control and Prevention (CDC) has implemented various surveillance activities to determine the burden of asthma in terms of prevalence, health care utilization, and mortality. Much of this data is collected through National Center for Health Statistics (NCHS) surveys and the Vital Statistics System. The current prevalence within the United States according to CDC data for 2015 is 7.8%, and is almost equally pervasive in adults and children [
      • Guilbert T.
      • Zeiger R.S.
      • Haselkorn T.
      • Iqbal A.
      • Alvarez C.
      • Mink D.R.
      • et al.
      Racial disparities in asthma-related health outcomes in children with severe/difficult-to-treat asthma.
      ]. Overall, the CDC reports a decline in the annual age-adjusted asthma mortality rate per 1 million persons in the United States between 1999 and 2016 (13.59–9.34 in women, and 9.14 to 7.78 among men) [
      • Guilbert T.
      • Zeiger R.S.
      • Haselkorn T.
      • Iqbal A.
      • Alvarez C.
      • Mink D.R.
      • et al.
      Racial disparities in asthma-related health outcomes in children with severe/difficult-to-treat asthma.
      ].
      Despite improved asthma outcomes on the whole, there is a disproportionate disease burden among children and ethnic minorities. A recent report from the TENOR observational study highlights racial disparities in pediatric asthma-related health outcomes [
      • Guilbert T.
      • Zeiger R.S.
      • Haselkorn T.
      • Iqbal A.
      • Alvarez C.
      • Mink D.R.
      • et al.
      Racial disparities in asthma-related health outcomes in children with severe/difficult-to-treat asthma.
      ]. It has been known for decades that inner city children are more likely to develop asthma as well as severe asthma symptoms. Black race and Puerto Rican ethnicity have become clear risk factors for asthma, although the extent of influence by urban environmental exposures as opposed to underlying genetic susceptibility alone remains unknown. While the degree of African ancestry has been associated with asthma [
      • Flores C.
      • Ma S.F.
      • Pino-Yanes M.
      • Wade M.S.
      • Perez-Mendez L.
      • Kittles R.A.
      • et al.
      African ancestry is associated with asthma risk in African Americans.
      ], these analyses are frequently confounded by inherent social factors such as socioeconomic status, access to health care and medications, and further compounded by a host of environmental exposures which will be discussed further. Thus, the relative contributions of ethnicity versus poverty and other circumstantial neighborhood factors to inner city related asthma disparities remain unclear.
      Overall, black or Puerto Rican ethnicity and household poverty are the major risk factors rather than residing in an urban area in itself. Poverty may increase susceptibility to asthma via several pathways, due to increased presence of smoking, prematurity, indoor allergens, stress, and exposure to pollution, in poorer households. Despite black children requiring a higher level of therapy, they fared worse than Caucasian children in terms of health care utilization parameters as well as patient reported outcome measures.
      These findings are an extension of severe asthma outcomes in black and white adult populations. When categorized by ethnicity, the highest incidence for 2015 is recorded in non-Hispanic blacks (10.3%), followed by white non-Hispanic (7.8%), other non-Hispanic (6.9%), and Hispanic populations (6.6%), respectively. The mortality rate for that year approaches 1.1/100,000 population, with a three fold greater burden in non-Hispanic blacks as compared with other races. There has been a nearly 50% increase in asthma diagnosis among the black population over the past decade. African Americans are also known to have a higher asthma related mortality than other races [
      • Mushtaq A.
      Asthma in the USA: the good, the bad, and the disparity.
      ]. More than a quarter of black adults report being unable to purchase their asthma prescriptions, and one in four black adult asthmatics indicated that they were unable to afford primary care physician visits [
      • Mushtaq A.
      Asthma in the USA: the good, the bad, and the disparity.
      ].
      There is also a distinct social gradient in asthma, with the occurrence rising with each successive level of poverty [
      • Loftus P.A.
      • Wise S.K.
      Epidemiology of asthma.
      ]. From 2001–10, asthma prevalence was 11.2% among persons with a family income less than 100% of the federal poverty threshold, as compared with 7.3% for those with incomes of greater than 200% of the poverty level. Financial barriers also account for medication non-adherence as evidenced by a 2009 study, in which the rates of filling asthma prescriptions declined with out-of-pocket costs of more than USD 12 per prescription [
      • Mushtaq A.
      Asthma in the USA: the good, the bad, and the disparity.
      ]. This aligns with the finding that 40.3% of those without health insurance were unable to afford asthma medications as opposed to 11.5% of those with insurance not being able to afford therapy [
      • Centers for Disease C, Prevention
      Vital signs: asthma prevalence, disease characteristics, and self-management education: United States, 2001--2009.
      ].

      4. Financial impact

      Despite stable prevalence in recent years, asthma expenditures have continued to progressively increase. The national medical expenditure secondary to adult asthma was calculated at USD 18 billion per year for 2003 to 2005 [
      • Sullivan P.W.
      • Ghushchyan V.H.
      • Slejko J.F.
      • Belozeroff V.
      • Globe D.R.
      • Lin S.L.
      The burden of adult asthma in the United States: evidence from the Medical Expenditure Panel Survey.
      ]. Estimates of total asthma related costs to the United States healthcare system continue to rise, and jumped from USD 53 billion for 2007 to USD 56 billion for 2009 [
      • Nunes C.
      • Pereira A.M.
      • Morais-Almeida M.
      Asthma costs and social impact.
      ], and most recently USD 82 billion in 2013 [
      • Nurmagambetov T.
      • Kuwahara R.
      • Garbe P.
      The economic burden of asthma in the United States, 2008-2013.
      ].
      Patients with severe asthma are thought to represent between 5 and 10% of all subjects. Difficult to control asthma accounts for the bulk of the socioeconomic burden associated with the disease. These include both direct health care related costs as well as indirect costs, in terms of lost productivity. In the TENOR cohort, there was a direct relationship between costs and loss of asthma control [
      • Szefler S.J.
      • Zeiger R.S.
      • Haselkorn T.
      • Mink D.R.
      • Kamath T.V.
      • Fish J.E.
      • et al.
      Economic burden of impairment in children with severe or difficult-to-treat asthma.
      ]. Throughout the three-year study, the average cost for every uncontrolled asthma patient was $14,212 as compared with $6452 for controlled asthmatics.
      Asthma is also the leading cause of school absenteeism in the US, and accounts for approximately 13 million days of missed school annually. 36,000 children miss school on a daily basis due to asthma in the US and this has been linked with poor academic performance especially among inner city youth [
      • Rutkowski K.
      • Sowa P.
      • Rutkowska-Talipska J.
      • Sulkowski S.
      • Rutkowski R.
      Allergic diseases: the price of civilisational progress.
      ]. Thus, focused attention on patients with poorly controlled asthma may significantly reduce the socioeconomic burden of disease.

      5. Risk factors

      Despite therapeutic advances, the continued rise in asthma prevalence suggests that the fundamental causes of asthma are yet poorly understood. Akin to prevalence data, the study of risk factors and protective relationships in asthma has proven difficult due to the myriad of related factors. Of note, there is an extensive degree of overlap between risk factors for childhood and adult onset asthma.

      5.1 Childhood onset asthma

      Recognition of the so called “asthma epidemic” has led to the initiation of over 150 birth cohorts on asthma around the world in the past three decades [
      • Bousquet J.
      • Gern J.E.
      • Martinez F.D.
      • Anto J.M.
      • Johnson C.C.
      • Holt P.G.
      • et al.
      Birth cohorts in asthma and allergic diseases: report of a NIAID/NHLBI/MeDALL joint workshop.
      ], and data gathered has significantly elucidated origins of childhood asthma. International collaborations have been implemented in recent years to better understand information from these birth cohorts, however, this has been hampered by differences in definition and methodology.
      In view of the distinct predilection of the inner-city population for development of pediatric asthma, the Inner-City Asthma Network Program was established almost three decades ago to improve outcomes for these high-risk children in urban environments. While a wide breadth of variables influence disease, the two most significant drivers of asthma development were allergic sensitization and tobacco smoke exposure in a causal network analysis of an inner-city asthma cohort [
      • Liu A.H.
      • Babineau D.C.
      • Krouse R.Z.
      • Zoratti E.M.
      • Pongracic J.A.
      • O'Connor G.T.
      • et al.
      Pathways through which asthma risk factors contribute to asthma severity in inner-city children.
      ].

      5.2 Genetics

      A strong genetic basis for asthma has long been established. In monozygotic twins, asthma concordance is approximately 50%. Genome-wide association studies (GWAS) in large pediatric and adult cohorts have identified significant (P < 10−8) asthma related single nucleotide polymorphisms (SNPs) that have been replicated across studies [
      • Ober C.
      Asthma genetics in the post-GWAS era.
      ]. These results have underscored the importance of genetic variants in genes recognized as contributory to asthma such as HLA-DQ, SMAD3, TSLP, IL1RL1/IL18R1, and IL33. Yet, the individual contributions of these genetic variants is generally modest (odds ratios ∼1.2) even for the most replicated loci. The combined risk for all these genetic variants is estimated to predict ∼10% of asthma heritability and prevalence.
      The gasdermin B/orosomucoid like 3 (GSDMB-ORMDL3) locus on chromosome 17q21 has been most consistently replicated in GWAS of asthma. Involved genes incriminate epithelial barrier function abnormalities as contributory to asthma. In the Avon Longitudinal Study of Parents and Children, this genetic locus posed the strongest risk for persistent wheeze in children with a relative risk ratio of 1.6 [
      • Granell R.
      • Henderson A.J.
      • Timpson N.
      • St Pourcain B.
      • Kemp J.P.
      • Ring S.M.
      • et al.
      Examination of the relationship between variation at 17q21 and childhood wheeze phenotypes.
      ]. SNPs in the ch17q21 region have also been reproducibly associated with severe acute asthma flares requiring oral steroids and/or hospitalization [
      • Tavendale R.
      • Macgregor D.F.
      • Mukhopadhyay S.
      • Palmer C.N.
      A polymorphism controlling ORMDL3 expression is associated with asthma that is poorly controlled by current medications.
      ].
      It is well known that epigenetic modifications regulate the expression of cytokines and transcription factors responsible for T-cell differentiation. In addition, epigenetic mechanisms, including DNA methylation, may influence childhood asthma by regulation of IgE levels and other asthma genes (ALOX15, CAPN14, and POSTN) [
      • Yang I.V.
      • Pedersen B.S.
      • Liu A.
      • O'Connor G.T.
      • Teach S.J.
      • Kattan M.
      • et al.
      DNA methylation and childhood asthma in the inner city.
      ,
      • Liang L.
      • Willis-Owen S.A.G.
      • Laprise C.
      • Wong K.C.C.
      • Davies G.A.
      • Hudson T.J.
      • et al.
      An epigenome-wide association study of total serum immunoglobulin E concentration.
      ].

      5.3 Indoor allergen exposure

      The relationship between sensitization to inhalant allergens and onset of asthma is also well-recognized. A significantly increased risk of asthma occurs with aeroallergen sensitization at less than five years of age [
      • Rubner F.J.
      • Jackson D.J.
      • Evans M.D.
      • Gangnon R.E.
      • Tisler C.J.
      • Pappas T.E.
      • et al.
      Early life rhinovirus wheezing, allergic sensitization, and asthma risk at adolescence.
      ]. Indoor allergens including house dust mite, mice, cockroach, animal dander, and fungi are of especial interest due to the possibility of intervention during childhood.
      The first of the Inner-City Asthma Networks was the National Cooperative Inner-City Asthma Study which sought to identify causal environmental factors in childhood asthma. This resulted in several key environmental observations, such as the association of cockroach, dust mite, and mouse sensitization with uncontrolled asthma [
      • Kattan M.
      • Mitchell H.
      • Eggleston P.
      • Gergen P.
      • Crain E.
      • Redline S.
      • et al.
      Characteristics of inner-city children with asthma: the national cooperative inner-city asthma study.
      ]. In a pediatric cohort, dust mite sensitization at ages 1 and 2 were predictive of 3.3- and 6.4-times odds of wheezing at follow up in adolescence [
      • Lodge C.J.
      • Lowe A.J.
      • Gurrin L.C.
      • Hill D.J.
      • Hosking C.S.
      • Khalafzai R.U.
      • et al.
      House dust mite sensitization in toddlers predicts current wheeze at age 12 years.
      ]. Two separate birth cohorts of at-risk children demonstrated a significant dose-response relationship between HDM exposure and related atopic asthma [
      • Tovey E.R.
      • Chapman M.D.
      • Wells C.W.
      • Platts-Mills T.A.
      The distribution of dust mite allergen in the houses of patients with asthma.
      ,
      • Celedon J.C.
      • Milton D.K.
      • Ramsey C.D.
      • Litonjua A.A.
      • Ryan L.
      • Platts-Mills T.A.
      • et al.
      Exposure to dust mite allergen and endotoxin in early life and asthma and atopy in childhood.
      ]. Conversely, in an early childhood study at three centers, there was no association between HDM-specific IgE and levels of exposure in early life in two of these cohorts, whereas a positive association was found in the third [
      • Torrent M.
      • Sunyer J.
      • Garcia R.
      • Harris J.
      • Iturriaga M.V.
      • Puig C.
      • et al.
      Early-life allergen exposure and atopy, asthma, and wheeze up to 6 years of age.
      ]. This may indicate that the dose-response relationship between allergen exposure and sensitization may differ according to geographical locale.
      Cockroach exposure is an even more potent inducer of sensitization, with a threshold 10- to 100- fold lower than other indoor allergens [
      • Matsui E.C.
      • Wood R.A.
      • Rand C.
      • Kanchanaraksa S.
      • Swartz L.
      • Curtin-Brosnan J.
      • et al.
      Cockroach allergen exposure and sensitization in suburban middle-class children with asthma.
      ]. Recent data suggests that exposure and allergic sensitization to mouse antigen is a stronger predictor of severe asthma than cockroach allergen [
      • Ownby D.R.
      Will the real inner-city allergen please stand up?.
      ]. In a US cohort of inner-city residences, 95% had detectable mouse allergen, increased levels being associated with cockroach infestation [
      • Phipatanakul W.
      • Eggleston P.A.
      • Wright E.C.
      • Wood R.A.
      Mouse allergen. I. The prevalence of mouse allergen in inner-city homes. The National Cooperative Inner-City Asthma Study.
      ].
      In contrast, the association between furred pet exposure and atopic risk is contradictory. Due to the ubiquity of cat and dog allergens, surveys that hinge upon presence of pets in the home alone may be insufficient to measure exposure [
      • Liccardi G.
      • Salzillo A.
      • Calzetta L.
      • Piccolo A.
      • Menna G.
      • Rogliani P.
      Can the presence of cat/dog at home be considered the only criterion of exposure to cat/dog allergens? A likely underestimated bias in clinical practice and in large epidemiological studies.
      ]. Overall, pet allergen exposure does not appear to increase atopic risk, with decreased asthma risk with cat exposure in one study [
      • Takkouche B.
      • Gonzalez-Barcala F.J.
      • Etminan M.
      • Fitzgerald M.
      Exposure to furry pets and the risk of asthma and allergic rhinitis: a meta-analysis.
      ].
      In the context of fungi, both qualitative and quantitative measures of fungal exposure have been linked with an enhanced allergy and asthma risk. The allergenic significance of domestic exposure to Alternaria alternata in urban settings is underrecognized relative to HDM, mouse and cockroach. Sensitization to Alternaria has been implicated in increased asthma-related morbidity independent of sensitization to other aeroallergens. Fungal exposure is recognized to increase the risk for life-threatening asthma exacerbations possibly through the release of IL-33 [
      • Snelgrove R.J.
      • Gregory L.G.
      • Peiro T.
      • Akthar S.
      • Campbell G.A.
      • Walker S.A.
      • et al.
      Alternaria-derived serine protease activity drives IL-33-mediated asthma exacerbations.
      ]. Mold sensitization is common amongst patients with severe asthma requiring multiple hospital admissions [
      • Neukirch C.
      • Henry C.
      • Leynaert B.
      • Liard R.
      • Bousquet J.
      • Neukirch F.
      Is sensitization to Alternaria alternata a risk factor for severe asthma? A population-based study.
      ,
      • Pulimood T.B.
      • Corden J.M.
      • Bryden C.
      • Sharples L.
      • Nasser S.M.
      Epidemic asthma and the role of the fungal mold Alternaria alternata.
      ].
      However, there is also evidence that increased fungal diversity may actually be protective against allergic disease [
      • Tischer C.
      • Weikl F.
      • Probst A.J.
      • Standl M.
      • Heinrich J.
      • Pritsch K.
      Urban dust microbiome: impact on later atopy and wheezing.
      ]. This mirrors the protective effects conferred by diversity in the human microbiome, as detailed below.
      On the other hand, the Urban Environment and Childhood Asthma (URECA) birth cohort was established over a decade ago to establish the influence of early life exposures on clinical outcomes in a high-risk urban population. Contrary to expectations, greater concentrations of mouse, cat and cockroach allergens during the first years of life were inversely related to asthma risk [
      • Gern J.E.
      The urban environment and childhood asthma study.
      ]. The authors postulated that this finding may be secondary to an altered indoor microbiome associated with pest and furred animals.
      The second Inner City Asthma Network - the Inner-City Asthma Study (ICAS) - validated the role of environmental exposures by subsequent multifaceted intervention studies that demonstrated improved control with household remediation measures. ICAS enrolled children with atopic asthma and sensitization to perennial allergens. Interventions targeted at reducing the predominant allergen incriminated in asthma morbidity within a community have translated into decreased asthma symptoms and to a lesser degree, acute asthma flares [
      • Morgan W.J.
      • Crain E.F.
      • Gruchalla R.S.
      • O'Connor G.T.
      • Kattan M.
      • Evans 3rd, R.
      • et al.
      Results of a home-based environmental intervention among urban children with asthma.
      ].

      5.4 Microbiome exposures

      The hygiene hypothesis implicates our microbial environment in early life as integral to immune development, and protective against atopy and asthma. In the past decade, several studies have investigated the protective effects of being raised on a farm as opposed to rural communities or cities [
      • Wlasiuk G.
      • Vercelli D.
      The farm effect, or: when, what and how a farming environment protects from asthma and allergic disease.
      ,
      • Ege M.J.
      • Mayer M.
      • Normand A.C.
      • Genuneit J.
      • Cookson W.O.
      • Braun-Fahrlander C.
      • et al.
      Exposure to environmental microorganisms and childhood asthma.
      ]. These studies on farm life have provided a compelling argument in support of the hygiene theory. Microbial exposures from living in proximity with domestic animals in early life appear to afford protection against development of atopic asthma [
      • Ege M.J.
      • Mayer M.
      • Normand A.C.
      • Genuneit J.
      • Cookson W.O.
      • Braun-Fahrlander C.
      • et al.
      Exposure to environmental microorganisms and childhood asthma.
      ]. The generally accepted hypothesis is that the microbial diversity of the farm environment triggers protective immune responses. Gender also appears to influence the impact of exposure with lower cumulative incidence of asthma in girls raised on a farm as compared to boys [
      • Genuneit J.
      Sex-specific development of asthma differs between farm and nonfarm children: a cohort study.
      ].
      Most recently, the prevalence of atopy and asthma was shown to be significantly lower in Amish, as opposed to Hutterite children despite similar lifestyle and ancestry [
      • Stein M.M.
      • Hrusch C.L.
      • Gozdz J.
      • Igartua C.
      • Pivniouk V.
      • Murray S.E.
      • et al.
      Innate immunity and asthma risk in amish and hutterite farm children.
      ]. This has been attributed to differences in farming practices and endotoxin levels which were 6.8 times higher in Amish homes. These surveys replicated stronger protection with exposure in utero and in early life. Similarly, Amish children have a much lower prevalence of atopic asthma compared with farm and non-farm children (5.2% vs 6.8% vs 11.2%, respectively) [
      • Holbreich M.
      • Genuneit J.
      • Weber J.
      • Braun-Fahrlander C.
      • Waser M.
      • von Mutius E.
      Amish children living in northern Indiana have a very low prevalence of allergic sensitization.
      ]. This makes the notion that the global increase in atopy and asthma is influenced by lifestyle and environment even more provocative.
      This is supported by studies showing that reduced stool microbial diversity at 1 month of age is predictive of atopy at 2 and 6 years of age [
      • Abrahamsson T.R.
      • Jakobsson H.E.
      • Andersson A.F.
      • Bjorksten B.
      • Engstrand L.
      • Jenmalm M.C.
      Low diversity of the gut microbiota in infants with atopic eczema.
      ]. The risk of asthma is similarly greater in children born via cesarean section, implicating microbial colonization pattern in these children versus vaginal delivery [
      • Dominguez-Bello M.G.
      • Costello E.K.
      • Contreras M.
      • Magris M.
      • Hidalgo G.
      • Fierer N.
      • et al.
      Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns.
      ]. In addition to vaginal delivery, increasing numbers of older siblings also appear to have favorable effects on the infant microbiome [
      • Penders J.
      • Gerhold K.
      • Stobberingh E.E.
      • Thijs C.
      • Zimmermann K.
      • Lau S.
      • et al.
      Establishment of the intestinal microbiota and its role for atopic dermatitis in early childhood.
      ].
      In the Canadian Healthy Infant Longitudinal Development (CHILD) study, Arrieta et al. found that the first 100 days of life are crucial in terms of microbiome establishment and the risk of asthma and atopy [
      • Arrieta M.C.
      • Stiemsma L.T.
      • Dimitriu P.A.
      • Thorson L.
      • Russell S.
      • Yurist-Doutsch S.
      • et al.
      Early infancy microbial and metabolic alterations affect risk of childhood asthma.
      ]. This focus on early life biodiversity has stimulated pregnancy and early childhood interventions for the prevention of atopy and asthma, however none have proven effective thus far.

      5.5 Respiratory viruses

      Respiratory viruses influence subsequent wheeze and asthma acting either independently or in conjunction with atopy. Respiratory syncytial virus (RSV) and human rhinovirus (HRV) are the most common respiratory viruses associated with wheeze in early childhood. Influenza has also been associated with exacerbation of ongoing disease [
      • Edwards M.R.
      • Bartlett N.W.
      • Hussell T.
      • Openshaw P.
      • Johnston S.L.
      The microbiology of asthma.
      ]. In one series, influenza A virus was detected in 2.6% of hospitalized children and 14.1% (P < .001) of ambulatory-treated patients with asthma flares [
      • Mandelcwajg A.
      • Moulin F.
      • Menager C.
      • Rozenberg F.
      • Lebon P.
      • Gendrel D.
      Underestimation of influenza viral infection in childhood asthma exacerbations.
      ].
      HRV triggered wheeze appears to confer particular predilection for future atopic asthma comparable with the risk associated with allergen sensitization when followed up at ages 7 and 13 in the Childhood Origins of Asthma (COAST) study [
      • Lukkarinen M.
      • Koistinen A.
      • Turunen R.
      • Lehtinen P.
      • Vuorinen T.
      • Jartti T.
      Rhinovirus-induced first wheezing episode predicts atopic but not nonatopic asthma at school age.
      ]. HRV induced asthma flares also increase in severity parallel with the degree of mouse and dust mite sensitization [
      • Phan J.A.
      • Kicic A.
      • Berry L.J.
      • Fernandes L.B.
      • Zosky G.R.
      • Sly P.D.
      • et al.
      Rhinovirus exacerbates house-dust-mite induced lung disease in adult mice.
      ]. On the other hand, RSV induced wheeze during infancy was associated with non-atopic asthma at 7 years of age. In another cohort, ∼50% of infants with RSV induced wheeze during infancy developed persistent asthma when followed up to 7 years [
      • Bacharier L.B.
      • Cohen R.
      • Schweiger T.
      • Yin-Declue H.
      • Christie C.
      • Zheng J.
      • et al.
      Determinants of asthma after severe respiratory syncytial virus bronchiolitis.
      ]. However, RSV triggered wheezing in the first three years of life was not associated with a similar risk of future asthma at 13 years in one study [
      • Rubner F.J.
      • Jackson D.J.
      • Evans M.D.
      • Gangnon R.E.
      • Tisler C.J.
      • Pappas T.E.
      • et al.
      Early life rhinovirus wheezing, allergic sensitization, and asthma risk at adolescence.
      ].

      5.6 Environmental tobacco smoke (ETS)

      Environmental tobacco exposure (ETS) is well recognized to increase the risk for asthma in early life. A meta-analysis of 79 papers evaluating ETS and asthma grouped studies by type and timing of ETS (prenatal maternal, postnatal maternal, postnatal paternal, or household) and the age at which outcomes were measured (≤2, 3–4, or 5–18 years) [
      • Burke H.
      • Leonardi-Bee J.
      • Hashim A.
      • Pine-Abata H.
      • Chen Y.
      • Cook D.G.
      • et al.
      Prenatal and passive smoke exposure and incidence of asthma and wheeze: systematic review and meta-analysis.
      ]. Both prenatal and postnatal maternal smoking significantly increased the incidence of asthma at all ages (OR 1.18–1.70). Paternal smoking was also associated with a significantly increased odds of asthma in 5–18 year olds (OR 1.39); limited data precluded analysis in children less than five.

      5.7 Air pollution

      Epidemiologic studies of air pollution and asthma have identified increased risk of both exacerbation of lung disease with acute exposure as well as development and/or impairment of asthma with chronic exposure to ambient air pollutants. Various pollutants have been incriminated including ozone, nitrogen dioxide (NO2), particulate matter (PM) and others, even at levels less than the current National Ambient Air Quality Standards [
      • Bernstein J.A.
      • Alexis N.
      • Barnes C.
      • Bernstein I.L.
      • Bernstein J.A.
      • Nel A.
      • et al.
      Health effects of air pollution.
      ]. Living in specific locations with especially poor air quality such as near a highway confers a higher exposure risk. Genetics also factor into determining susceptibility to air pollution, the most well-known being glutathione-S-transferase polymorphisms that are involved in antioxidant defenses.
      Global climate change is also responsible for altered exposure to aeroallergens. Global warming has been incriminated in increasing the duration and intensity of the pollen season [
      • D'Amato G.
      • Vitale C.
      • De Martino A.
      • Viegi G.
      • Lanza M.
      • Molino A.
      • et al.
      Effects on asthma and respiratory allergy of Climate change and air pollution.
      ]. Pollutants also enhance early and delayed-phase responses to various allergens, and contribute to disease development through augmentation of primary sensitization to allergens. This increased exposure to allergens combined with pollutants acts synergistically to enhance the allergic response. Data from the National Allergen Bureau has shown significant recent increases in annual pollen exposures [
      • Ziska L.
      • Knowlton K.
      • Rogers C.
      • Dalan D.
      • Tierney N.
      • Elder M.A.
      • et al.
      Recent warming by latitude associated with increased length of ragweed pollen season in central North America.
      ], which has been linked with pollutant induced production of plant-based pathogenic allergens [
      • Ziska L.H.
      • Beggs P.J.
      Anthropogenic climate change and allergen exposure: the role of plant biology.
      ]. There is also accumulating evidence about the possible effects of diesel exhaust particles, not just as a direct lung irritant but in relation to sensitization.
      Children who live near major roadways and exposed to traffic-related air pollution have increased susceptibility to asthma. A recent study has shown that exposure to air ozone levels at sub-NAAQS thresholds is associated with pulmonary and systemic changes in African American adolescents with asthma [
      • Hernandez M.L.
      • Dhingra R.
      • Burbank A.J.
      • Todorich K.
      • Loughlin C.E.
      • Frye M.
      • et al.
      Low-level ozone has both respiratory and systemic effects in African American adolescents with asthma despite asthma controller therapy.
      ]. In general, the burden of air pollution related asthma is associated with a lower socioeconomic status, and is thus a health equity issue [
      • Landrigan P.J.
      • Fuller R.
      • Acosta N.J.R.
      • Adeyi O.
      • Arnold R.
      • Basu N.N.
      • et al.
      The Lancet Commission on pollution and health.
      ]. Holistic strategies to minimize the effects of air pollutants on health are thus imperative.

      5.8 Adult onset asthma

      As opposed to pediatric asthma, there is a conspicuous absence of longitudinal studies on the adult side that track disease course from early adulthood for an adequate duration. However, there are well recognized risk factors for disease onset as well as exacerbation.

      5.9 Smoking

      It is clear that asthmatics who smoke have significantly increased morbidity and mortality than non-smokers. Continued smoking itself predisposes to developing asthma with an odds ratio of 2.0–2.6 [
      • Godtfredsen N.S.
      • Lange P.
      • Prescott E.
      • Osler M.
      • Vestbo J.
      Changes in smoking habits and risk of asthma: a longitudinal population based study.
      ] and has been linked with accelerated loss of lung function over time in adult onset asthma [
      • Teague W.G.
      Up in smoke: accelerated loss of lung function in two clusters of smokers identified in a longitudinal cohort study of adult-onset asthma.
      ]. The prevalence of active smoking in adult asthmatics from low- and middle-income countries is ∼25% placing them at particularly increased risk of severe symptoms and reduced response to steroid therapy [
      • Croisant S.
      Epidemiology of asthma: prevalence and burden of disease.
      ].
      A new diagnosis - asthma-COPD overlap syndrome (ACOS) - is now used to classify those with clinical features of both entities, such as COPD patients with airway eosinophilia and asthmatic smokers with fixed obstruction or neutrophilic inflammation. Approximately 13% of 3500 patients in the COPD gene consortium met criteria for ACOS [
      • Hardin M.
      • Cho M.
      • McDonald M.L.
      • Beaty T.
      • Ramsdell J.
      • Bhatt S.
      • et al.
      The clinical and genetic features of COPD-asthma overlap syndrome.
      ]. The proportion of patients with ACOS is expected to be even higher in an asthma population due to concomitant smoking and those with fixed airway obstruction.
      The burgeoning use of e-cigarettes has prompted investigation of their deleterious effects [
      • Dinakar C.
      • O'Connor G.T.
      The health effects of electronic cigarettes.
      ], and recent data demonstrates that chronic use alters the bronchial epithelial proteome of the human airway [
      • Ghosh A.
      • Coakley R.C.
      • Mascenik T.
      • Rowell T.R.
      • Davis E.S.
      • Rogers K.
      • et al.
      Chronic E-cigarette exposure alters the human bronchial epithelial proteome.
      ]. Similarly, smoking e-cigarettes during pregnancy has equivalent risk to conventional cigarettes for asthma development [
      • Spindel E.R.
      • McEvoy C.T.
      The role of nicotine in the effects of maternal smoking during pregnancy on lung development and childhood respiratory disease. Implications for dangers of E-cigarettes.
      ]. Thus, cessation of all forms of smoking is essential to the management of asthmatics.

      5.10 Obesity

      Obesity increases the risk for late onset asthma in both men and women by approximately 50% [
      • Ronmark E.
      • Andersson C.
      • Nystrom L.
      • Forsberg B.
      • Jarvholm B.
      • Lundback B.
      Obesity increases the risk of incident asthma among adults.
      ], especially in non-allergic individuals with a more pronounced effect in females. Obese asthmatics are known to have worse asthma control and increased rates of healthcare utilization due to asthma [
      • Peters U.
      • Dixon A.E.
      • Forno E.
      Obesity and asthma.
      ].
      There appears to be a gender bias in the interaction of obesity with asthma, which may be due to sex hormones (discussed later) or other gender-specific factors, such as inherent collapsibility of the distal airways in non-allergic obese females with adult-onset asthma [
      • Al-Alwan A.
      • Bates J.H.
      • Chapman D.G.
      • Kaminsky D.A.
      • DeSarno M.J.
      • Irvin C.G.
      • et al.
      The nonallergic asthma of obesity. A matter of distal lung compliance.
      ]. This gender dimorphism is apparent from early childhood, where asthma has been linked with obesity only in young girls and not in boys [
      • Peters U.
      • Dixon A.E.
      • Forno E.
      Obesity and asthma.
      ]. Both the European Network For Understanding Mechanisms of Severe Asthma (ENFUMOSA) and Severe Asthma Research Program (SARP) found a higher female to male ratio (4.4:1) in severe asthma [
      • Jarjour N.N.
      • Erzurum S.C.
      • Bleecker E.R.
      • Calhoun W.J.
      • Castro M.
      • Comhair S.A.
      • et al.
      Severe asthma: lessons learned from the national heart, lung, and blood institute severe asthma Research Program.
      ,
      • Gaga M.
      • Papageorgiou N.
      • Yiourgioti G.
      • Karydi P.
      • Liapikou A.
      • Bitsakou H.
      • et al.
      Risk factors and characteristics associated with severe and difficult to treat asthma phenotype: an analysis of the ENFUMOSA group of patients based on the ECRHS questionnaire.
      ].
      Several hypotheses have been postulated to explain the obesity-asthma relationship, such as oxidative stress and mechanical effects of obesity on the respiratory system [
      • Peters U.
      • Dixon A.E.
      • Forno E.
      Obesity and asthma.
      ]. Increased airway oxidative stress has been found especially in obese adults with late onset disease. The deficiency of dietary antioxidants further increases susceptibility to oxidative lung damage. Abdominal and mediastinal fat accumulation can alter respiratory mechanics, thus changing lung physiology and function.
      The most recently proposed theory implicates inflammatory mechanisms including the effects of adipokines and inflammatory cytokines released from adipose tissue [
      • Jarjour N.N.
      • Erzurum S.C.
      • Bleecker E.R.
      • Calhoun W.J.
      • Castro M.
      • Comhair S.A.
      • et al.
      Severe asthma: lessons learned from the national heart, lung, and blood institute severe asthma Research Program.
      ]. Adipokines are mediators that may be pro- (eg. leptin) or anti-inflammatory (eg. adiponectin) in function. Leptin has been implicated in the pathogenesis of asthma in obese females through Th1 mediated airway inflammation [
      • Sood A.
      • Qualls C.
      • Schuyler M.
      Leptin, adiponectin, and asthma: findings from a population-based cohort study.
      ]. Among adolescents, higher leptin levels correlate inversely with lung function and the expression of visceral fat leptin correlates with airway hyperreactivity in adults. While the mechanisms of obesity related asthma are not fully understood, weight reduction interventions may improve asthma control.
      The metabolic consequences of obesity including insulin resistance, type 2 diabetes, and the metabolic syndrome likely contribute significantly to the pathogenesis of “obese asthma” [
      • Baffi C.W.
      • Wood L.
      • Winnica D.
      • Strollo Jr., P.J.
      • Gladwin M.T.
      • Que L.G.
      • et al.
      Metabolic syndrome and the lung.
      ]. The association between obesity and asthma is even greater in the setting of insulin resistance [
      • Cardet J.C.
      • Ash S.
      • Kusa T.
      • Camargo Jr., C.A.
      • Israel E.
      Insulin resistance modifies the association between obesity and current asthma in adults.
      ]. Insulin resistance has also been linked with lower lung function among obese adolescents with asthma [
      • Forno E.
      • Han Y.Y.
      • Muzumdar R.H.
      • Celedon J.C.
      Insulin resistance, metabolic syndrome, and lung function in US adolescents with and without asthma.
      ]. The literature also suggests a bidirectional relationship independent of obesity between T2DM and asthma.

      5.11 Occupational exposures

      Approximately 10–25% of adult-onset asthma is estimated to drive from work related exposures that may be sensitizers or irritants in nature [
      • Smith A.M.
      The epidemiology of work-related asthma.
      ]. Occupational asthma (OA) may be caused by high molecular weight (HMW) proteins or low molecular weight (LMW) chemicals (eg. diisocyanates), which drive asthma via IgE and non-IgE mechanisms respectively. HMW factors from biological sources such as wheat allergens account for most cases of OA. In a recent review by Baur et al., exposure to laboratory animals was most robustly associated with development of OA [
      • Baur X.
      • Bakehe P.
      Allergens causing occupational asthma: an evidence-based evaluation of the literature.
      ]. The acute exposure to high levels of irritants also cause asthma through non-immunologic inhalation injury. Most cases of OA require cessation of exposure, and even with avoidance does not warrant complete recovery.

      5.12 Sex hormones

      As previously discussed, gender is known to be differently distributed between adult and pediatric populations. In the Epidemiology and Natural history of asthma: Outcomes and treatment Regimens (TENOR) severe asthma cohort, 71% of adult patients were women in contrast with 34% of children. This parallels the observations of Zein et al. who noted a shift from male to female predominance of severe asthma post-adolescence [
      • Zein J.G.
      • Erzurum S.C.
      Asthma is different in women.
      ]. Although boys have increased onset of atopic asthma compared to girls during early childhood, there is a recognized switch in asthma prevalence from males to females that coincides with the onset of puberty [
      • Vink N.M.
      • Postma D.S.
      • Schouten J.P.
      • Rosmalen J.G.
      • Boezen H.M.
      Gender differences in asthma development and remission during transition through puberty: the TRacking Adolescents' Individual Lives Survey (TRAILS) study.
      ]. The Childhood Asthma Management Program (CAMP) study showed an increase in asthma symptoms parallel with the Tanner stages of puberty in girls [
      • Fu L.
      • Freishtat R.J.
      • Gordish-Dressman H.
      • Teach S.J.
      • Resca L.
      • Hoffman E.P.
      • et al.
      Natural progression of childhood asthma symptoms and strong influence of sex and puberty.
      ]. While the precise role for sex hormones in regulating asthma is not completely understood, overall ovarian hormones enhance and testosterone dampens airway inflammation in asthma [
      • Fuseini H.
      • Newcomb D.C.
      Mechanisms driving gender differences in asthma.
      ].

      5.13 Stress events

      The association of psychosocial stressors with asthma may reflect disproportionate exposure among those from lower socioeconomic classes and ethnic minorities. An accumulating body of evidence suggests a causal relationship between these stressors and asthma development as well as morbidity. Stress can modulate lung development, as well neuroendocrine and autonomic responses, and potentiate reactivity to allergens and infections [
      • Rosenberg S.L.
      • Miller G.E.
      • Brehm J.M.
      • Celedon J.C.
      Stress and asthma: novel insights on genetic, epigenetic, and immunologic mechanisms.
      ]. There also appear to be specific pathways through which stress influences epigenetic activity in asthma related cells.
      Pediatric studies have previously reproduced a causal link between stress events and asthma onset [
      • Rosenberg S.L.
      • Miller G.E.
      • Brehm J.M.
      • Celedon J.C.
      Stress and asthma: novel insights on genetic, epigenetic, and immunologic mechanisms.
      ]. More recently, observational studies have confirmed this association in adults. In a longitudinal cohort study of 327 adolescents without asthma at age 16, an increase in stressful life events as measured by a validated questionnaire was associated with a 4-fold higher incidence of new asthma onset between 18 and 29 years [
      • Oren E.
      • Gerald L.
      • Stern D.A.
      • Martinez F.D.
      • Wright A.L.
      Self-reported stressful life events during adolescence and subsequent asthma: a longitudinal study.
      ]. Elucidation of these mechanisms may improve asthma outcomes particularly in ethnic minorities and the economically disadvantaged.

      5.14 Very late onset asthma

      The age cutoff for the definition of very late-onset asthma varies but diagnosed as > 50 years in some papers [
      • Pite H.
      • Pereira A.M.
      • Morais-Almeida M.
      • Nunes C.
      • Bousquet J.
      • Fonseca J.A.
      Prevalence of asthma and its association with rhinitis in the elderly.
      ] and >65 years in others [
      • Gibson P.G.
      • McDonald V.M.
      • Marks G.B.
      Asthma in older adults.
      ]. The aging lung is associated with decreased lung function due to mechanical disadvantages and loss of elastic recoil. In addition to these consequences of normal aging, immunosenescence likely has important consequences in elderly asthmatics [
      • Dunn R.M.
      • Busse P.J.
      • Wechsler M.E.
      Asthma in the elderly and late-onset adult asthma.
      ]. Emerging data suggest that older asthmatics have increased sputum neutrophilia secondary to Th1 and Th17 inflammation [
      • Nyenhuis S.M.
      • Schwantes E.A.
      • Evans M.D.
      • Mathur S.K.
      Airway neutrophil inflammatory phenotype in older subjects with asthma.
      ].

      5.15 Medication related asthma triggers

      Beta blockers have the potential to cause acute bronchoconstriction in asthma on a dose dependent basis, the risk of which is mitigated to some degree by the use of cardioselective agents [
      • Morales D.R.
      • Jackson C.
      • Lipworth B.J.
      • Donnan P.T.
      • Guthrie B.
      Adverse respiratory effect of acute beta-blocker exposure in asthma: a systematic review and meta-analysis of randomized controlled trials.
      ]. Their use in asthmatics should thus be contingent upon a risk benefit analysis in individual patients using the lowest dose possible. While ACE-inhibitors by themselves do not potentiate asthma, their possible side effect of cough may be confused for asthmatic symptoms.

      6. Conclusion

      Despite advances in our understanding of asthma, it continues to be a significant global source of morbidity and mortality. The future of asthma appears largely reliant on precision medicine. Several strategies for prevention have been attempted in recent years, none of which have succeeded to date in decreasing morbidity. Longitudinal studies from pregnancy progressing through childhood and adulthood will further elucidate the complex pathways underlying asthma and facilitate personalized therapies.

      Conflict of interest statement

      None.

      References

        • Collaborators GBDCRD
        Global, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015.
        Lancet Respir Med. 2017; 5: 691-706
        • Eder W.
        • Ege M.J.
        • von Mutius E.
        The asthma epidemic.
        N. Engl. J. Med. 2006; 355: 2226-2235
        • Croisant S.
        Epidemiology of asthma: prevalence and burden of disease.
        Adv. Exp. Med. Biol. 2014; 795: 17-29
        • Pearce N.
        • Ait-Khaled N.
        • Beasley R.
        • Mallol J.
        • Keil U.
        • Mitchell E.
        • et al.
        Worldwide trends in the prevalence of asthma symptoms: phase III of the international study of asthma and allergies in childhood (ISAAC).
        Thorax. 2007; 62: 758-766
        • Janson C.
        • Anto J.
        • Burney P.
        • Chinn S.
        • de Marco R.
        • Heinrich J.
        • et al.
        The European Community Respiratory Health Survey: what are the main results so far? European Community Respiratory Health Survey II.
        Eur. Respir. J. 2001; 18: 598-611
        • Wang D.
        • Xiao W.
        • Ma D.
        • Zhang Y.
        • Wang Q.
        • Wang C.
        • et al.
        Cross-sectional epidemiological survey of asthma in Jinan, China.
        Respirology. 2013; 18: 313-322
        • Cabieses B.
        • Uphoff E.
        • Pinart M.
        • Anto J.M.
        • Wright J.
        A systematic review on the development of asthma and allergic diseases in relation to international immigration: the leading role of the environment confirmed.
        PLoS One. 2014; 9e105347
        • Wang H.Y.
        • Wong G.W.
        • Chen Y.Z.
        • Ferguson A.C.
        • Greene J.M.
        • Ma Y.
        • et al.
        Prevalence of asthma among Chinese adolescents living in Canada and in China.
        CMAJ (Can. Med. Assoc. J.). 2008; 179: 1133-1142
        • Ebmeier S.
        • Thayabaran D.
        • Braithwaite I.
        • Benamara C.
        • Weatherall M.
        • Beasley R.
        Trends in international asthma mortality: analysis of data from the WHO Mortality Database from 46 countries (1993-2012).
        Lancet. 2017; 390: 935-945
        • Ali Z.
        • Dirks C.G.
        • Ulrik C.S.
        Long-term mortality among adults with asthma: a 25-year follow-up of 1,075 outpatients with asthma.
        Chest. 2013; 143: 1649-1655
        • Guilbert T.
        • Zeiger R.S.
        • Haselkorn T.
        • Iqbal A.
        • Alvarez C.
        • Mink D.R.
        • et al.
        Racial disparities in asthma-related health outcomes in children with severe/difficult-to-treat asthma.
        J Allergy Clin Immunol Pract. 2018 Aug 29; (pii: S2213-2198(18)30546-4. [Epub ahead of print] PMID: 30172020)https://doi.org/10.1016/j.jaip.2018.07.050
        • Flores C.
        • Ma S.F.
        • Pino-Yanes M.
        • Wade M.S.
        • Perez-Mendez L.
        • Kittles R.A.
        • et al.
        African ancestry is associated with asthma risk in African Americans.
        PLoS One. 2012; 7e26807
        • Mushtaq A.
        Asthma in the USA: the good, the bad, and the disparity.
        Lancet Respir Med. 2018; 6: 335-336
        • Loftus P.A.
        • Wise S.K.
        Epidemiology of asthma.
        Curr. Opin. Otolaryngol. Head Neck Surg. 2016; 24: 245-249
        • Centers for Disease C, Prevention
        Vital signs: asthma prevalence, disease characteristics, and self-management education: United States, 2001--2009.
        MMWR Morb. Mortal. Wkly. Rep. 2011; 60: 547-552
        • Sullivan P.W.
        • Ghushchyan V.H.
        • Slejko J.F.
        • Belozeroff V.
        • Globe D.R.
        • Lin S.L.
        The burden of adult asthma in the United States: evidence from the Medical Expenditure Panel Survey.
        J. Allergy Clin. Immunol. 2011; 127 (e1-3): 363-369
        • Nunes C.
        • Pereira A.M.
        • Morais-Almeida M.
        Asthma costs and social impact.
        Asthma Res Pract. 2017; 3: 1
        • Nurmagambetov T.
        • Kuwahara R.
        • Garbe P.
        The economic burden of asthma in the United States, 2008-2013.
        Ann Am Thorac Soc. 2018; 15: 348-356
        • Szefler S.J.
        • Zeiger R.S.
        • Haselkorn T.
        • Mink D.R.
        • Kamath T.V.
        • Fish J.E.
        • et al.
        Economic burden of impairment in children with severe or difficult-to-treat asthma.
        Ann. Allergy Asthma Immunol. 2011; 107: 110-119 e1
        • Rutkowski K.
        • Sowa P.
        • Rutkowska-Talipska J.
        • Sulkowski S.
        • Rutkowski R.
        Allergic diseases: the price of civilisational progress.
        Postepy Dermatol Alergol. 2014; 31: 77-83
        • Bousquet J.
        • Gern J.E.
        • Martinez F.D.
        • Anto J.M.
        • Johnson C.C.
        • Holt P.G.
        • et al.
        Birth cohorts in asthma and allergic diseases: report of a NIAID/NHLBI/MeDALL joint workshop.
        J. Allergy Clin. Immunol. 2014; 133: 1535-1546
        • Liu A.H.
        • Babineau D.C.
        • Krouse R.Z.
        • Zoratti E.M.
        • Pongracic J.A.
        • O'Connor G.T.
        • et al.
        Pathways through which asthma risk factors contribute to asthma severity in inner-city children.
        J. Allergy Clin. Immunol. 2016; 138: 1042-1050
        • Ober C.
        Asthma genetics in the post-GWAS era.
        Ann Am Thorac Soc. 2016; 13: S85-S90
        • Granell R.
        • Henderson A.J.
        • Timpson N.
        • St Pourcain B.
        • Kemp J.P.
        • Ring S.M.
        • et al.
        Examination of the relationship between variation at 17q21 and childhood wheeze phenotypes.
        J. Allergy Clin. Immunol. 2013; 131: 685-694
        • Tavendale R.
        • Macgregor D.F.
        • Mukhopadhyay S.
        • Palmer C.N.
        A polymorphism controlling ORMDL3 expression is associated with asthma that is poorly controlled by current medications.
        J. Allergy Clin. Immunol. 2008; 121: 860-863
        • Yang I.V.
        • Pedersen B.S.
        • Liu A.
        • O'Connor G.T.
        • Teach S.J.
        • Kattan M.
        • et al.
        DNA methylation and childhood asthma in the inner city.
        J. Allergy Clin. Immunol. 2015; 136: 69-80
        • Liang L.
        • Willis-Owen S.A.G.
        • Laprise C.
        • Wong K.C.C.
        • Davies G.A.
        • Hudson T.J.
        • et al.
        An epigenome-wide association study of total serum immunoglobulin E concentration.
        Nature. 2015; 520: 670-674
        • Rubner F.J.
        • Jackson D.J.
        • Evans M.D.
        • Gangnon R.E.
        • Tisler C.J.
        • Pappas T.E.
        • et al.
        Early life rhinovirus wheezing, allergic sensitization, and asthma risk at adolescence.
        J. Allergy Clin. Immunol. 2017; 139: 501-507
        • Kattan M.
        • Mitchell H.
        • Eggleston P.
        • Gergen P.
        • Crain E.
        • Redline S.
        • et al.
        Characteristics of inner-city children with asthma: the national cooperative inner-city asthma study.
        Pediatr. Pulmonol. 1997; 24: 253-262
        • Lodge C.J.
        • Lowe A.J.
        • Gurrin L.C.
        • Hill D.J.
        • Hosking C.S.
        • Khalafzai R.U.
        • et al.
        House dust mite sensitization in toddlers predicts current wheeze at age 12 years.
        J. Allergy Clin. Immunol. 2011; 128: 782-788 e9
        • Tovey E.R.
        • Chapman M.D.
        • Wells C.W.
        • Platts-Mills T.A.
        The distribution of dust mite allergen in the houses of patients with asthma.
        Am. Rev. Respir. Dis. 1981; 124: 630-635
        • Celedon J.C.
        • Milton D.K.
        • Ramsey C.D.
        • Litonjua A.A.
        • Ryan L.
        • Platts-Mills T.A.
        • et al.
        Exposure to dust mite allergen and endotoxin in early life and asthma and atopy in childhood.
        J. Allergy Clin. Immunol. 2007; 120: 144-149
        • Torrent M.
        • Sunyer J.
        • Garcia R.
        • Harris J.
        • Iturriaga M.V.
        • Puig C.
        • et al.
        Early-life allergen exposure and atopy, asthma, and wheeze up to 6 years of age.
        Am. J. Respir. Crit. Care Med. 2007; 176: 446-453
        • Matsui E.C.
        • Wood R.A.
        • Rand C.
        • Kanchanaraksa S.
        • Swartz L.
        • Curtin-Brosnan J.
        • et al.
        Cockroach allergen exposure and sensitization in suburban middle-class children with asthma.
        J. Allergy Clin. Immunol. 2003; 112: 87-92
        • Ownby D.R.
        Will the real inner-city allergen please stand up?.
        J. Allergy Clin. Immunol. 2013; 132: 836-837
        • Phipatanakul W.
        • Eggleston P.A.
        • Wright E.C.
        • Wood R.A.
        Mouse allergen. I. The prevalence of mouse allergen in inner-city homes. The National Cooperative Inner-City Asthma Study.
        J. Allergy Clin. Immunol. 2000; 106: 1070-1074
        • Liccardi G.
        • Salzillo A.
        • Calzetta L.
        • Piccolo A.
        • Menna G.
        • Rogliani P.
        Can the presence of cat/dog at home be considered the only criterion of exposure to cat/dog allergens? A likely underestimated bias in clinical practice and in large epidemiological studies.
        Eur Ann Allergy Clin Immunol. 2016; 48: 61-64
        • Takkouche B.
        • Gonzalez-Barcala F.J.
        • Etminan M.
        • Fitzgerald M.
        Exposure to furry pets and the risk of asthma and allergic rhinitis: a meta-analysis.
        Allergy. 2008; 63: 857-864
        • Snelgrove R.J.
        • Gregory L.G.
        • Peiro T.
        • Akthar S.
        • Campbell G.A.
        • Walker S.A.
        • et al.
        Alternaria-derived serine protease activity drives IL-33-mediated asthma exacerbations.
        J. Allergy Clin. Immunol. 2014; 134: 583-592 e6
        • Neukirch C.
        • Henry C.
        • Leynaert B.
        • Liard R.
        • Bousquet J.
        • Neukirch F.
        Is sensitization to Alternaria alternata a risk factor for severe asthma? A population-based study.
        J. Allergy Clin. Immunol. 1999; 103: 709-711
        • Pulimood T.B.
        • Corden J.M.
        • Bryden C.
        • Sharples L.
        • Nasser S.M.
        Epidemic asthma and the role of the fungal mold Alternaria alternata.
        J. Allergy Clin. Immunol. 2007; 120: 610-617
        • Tischer C.
        • Weikl F.
        • Probst A.J.
        • Standl M.
        • Heinrich J.
        • Pritsch K.
        Urban dust microbiome: impact on later atopy and wheezing.
        Environ. Health Perspect. 2016; 124: 1919-1923
        • Gern J.E.
        The urban environment and childhood asthma study.
        J. Allergy Clin. Immunol. 2010; 125: 545-549
        • Morgan W.J.
        • Crain E.F.
        • Gruchalla R.S.
        • O'Connor G.T.
        • Kattan M.
        • Evans 3rd, R.
        • et al.
        Results of a home-based environmental intervention among urban children with asthma.
        N. Engl. J. Med. 2004; 351: 1068-1080
        • Wlasiuk G.
        • Vercelli D.
        The farm effect, or: when, what and how a farming environment protects from asthma and allergic disease.
        Curr. Opin. Allergy Clin. Immunol. 2012; 12: 461-466
        • Ege M.J.
        • Mayer M.
        • Normand A.C.
        • Genuneit J.
        • Cookson W.O.
        • Braun-Fahrlander C.
        • et al.
        Exposure to environmental microorganisms and childhood asthma.
        N. Engl. J. Med. 2011; 364: 701-709
        • Genuneit J.
        Sex-specific development of asthma differs between farm and nonfarm children: a cohort study.
        Am. J. Respir. Crit. Care Med. 2014; 190: 588-590
        • Stein M.M.
        • Hrusch C.L.
        • Gozdz J.
        • Igartua C.
        • Pivniouk V.
        • Murray S.E.
        • et al.
        Innate immunity and asthma risk in amish and hutterite farm children.
        N. Engl. J. Med. 2016; 375: 411-421
        • Holbreich M.
        • Genuneit J.
        • Weber J.
        • Braun-Fahrlander C.
        • Waser M.
        • von Mutius E.
        Amish children living in northern Indiana have a very low prevalence of allergic sensitization.
        J. Allergy Clin. Immunol. 2012; 129: 1671-1673
        • Abrahamsson T.R.
        • Jakobsson H.E.
        • Andersson A.F.
        • Bjorksten B.
        • Engstrand L.
        • Jenmalm M.C.
        Low diversity of the gut microbiota in infants with atopic eczema.
        J. Allergy Clin. Immunol. 2012; 129 (40 e1-2): 434-440
        • Dominguez-Bello M.G.
        • Costello E.K.
        • Contreras M.
        • Magris M.
        • Hidalgo G.
        • Fierer N.
        • et al.
        Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns.
        Proc. Natl. Acad. Sci. U. S. A. 2010; 107: 11971-11975
        • Penders J.
        • Gerhold K.
        • Stobberingh E.E.
        • Thijs C.
        • Zimmermann K.
        • Lau S.
        • et al.
        Establishment of the intestinal microbiota and its role for atopic dermatitis in early childhood.
        J. Allergy Clin. Immunol. 2013; 132: 601-607 e8
        • Arrieta M.C.
        • Stiemsma L.T.
        • Dimitriu P.A.
        • Thorson L.
        • Russell S.
        • Yurist-Doutsch S.
        • et al.
        Early infancy microbial and metabolic alterations affect risk of childhood asthma.
        Sci. Transl. Med. 2015; 7 (307ra152)
        • Edwards M.R.
        • Bartlett N.W.
        • Hussell T.
        • Openshaw P.
        • Johnston S.L.
        The microbiology of asthma.
        Nat. Rev. Microbiol. 2012; 10: 459-471
        • Mandelcwajg A.
        • Moulin F.
        • Menager C.
        • Rozenberg F.
        • Lebon P.
        • Gendrel D.
        Underestimation of influenza viral infection in childhood asthma exacerbations.
        J. Pediatr. 2010; 157: 505-506
        • Lukkarinen M.
        • Koistinen A.
        • Turunen R.
        • Lehtinen P.
        • Vuorinen T.
        • Jartti T.
        Rhinovirus-induced first wheezing episode predicts atopic but not nonatopic asthma at school age.
        J. Allergy Clin. Immunol. 2017; 140: 988-995
        • Phan J.A.
        • Kicic A.
        • Berry L.J.
        • Fernandes L.B.
        • Zosky G.R.
        • Sly P.D.
        • et al.
        Rhinovirus exacerbates house-dust-mite induced lung disease in adult mice.
        PLoS One. 2014; 9e92163
        • Bacharier L.B.
        • Cohen R.
        • Schweiger T.
        • Yin-Declue H.
        • Christie C.
        • Zheng J.
        • et al.
        Determinants of asthma after severe respiratory syncytial virus bronchiolitis.
        J. Allergy Clin. Immunol. 2012; 130: 91-100 e3
        • Burke H.
        • Leonardi-Bee J.
        • Hashim A.
        • Pine-Abata H.
        • Chen Y.
        • Cook D.G.
        • et al.
        Prenatal and passive smoke exposure and incidence of asthma and wheeze: systematic review and meta-analysis.
        Pediatrics. 2012; 129: 735-744
        • Bernstein J.A.
        • Alexis N.
        • Barnes C.
        • Bernstein I.L.
        • Bernstein J.A.
        • Nel A.
        • et al.
        Health effects of air pollution.
        J. Allergy Clin. Immunol. 2004; 114: 1116-1123
        • D'Amato G.
        • Vitale C.
        • De Martino A.
        • Viegi G.
        • Lanza M.
        • Molino A.
        • et al.
        Effects on asthma and respiratory allergy of Climate change and air pollution.
        Multidiscip Respir Med. 2015; 10: 39
        • Ziska L.
        • Knowlton K.
        • Rogers C.
        • Dalan D.
        • Tierney N.
        • Elder M.A.
        • et al.
        Recent warming by latitude associated with increased length of ragweed pollen season in central North America.
        Proc. Natl. Acad. Sci. U. S. A. 2011; 108: 4248-4251
        • Ziska L.H.
        • Beggs P.J.
        Anthropogenic climate change and allergen exposure: the role of plant biology.
        J. Allergy Clin. Immunol. 2012; 129: 27-32
        • Hernandez M.L.
        • Dhingra R.
        • Burbank A.J.
        • Todorich K.
        • Loughlin C.E.
        • Frye M.
        • et al.
        Low-level ozone has both respiratory and systemic effects in African American adolescents with asthma despite asthma controller therapy.
        J. Allergy Clin. Immunol. 2018; 142 (1974-7 e3)
        • Landrigan P.J.
        • Fuller R.
        • Acosta N.J.R.
        • Adeyi O.
        • Arnold R.
        • Basu N.N.
        • et al.
        The Lancet Commission on pollution and health.
        Lancet. 2018; 391: 462-512
        • Godtfredsen N.S.
        • Lange P.
        • Prescott E.
        • Osler M.
        • Vestbo J.
        Changes in smoking habits and risk of asthma: a longitudinal population based study.
        Eur. Respir. J. 2001; 18: 549-554
        • Teague W.G.
        Up in smoke: accelerated loss of lung function in two clusters of smokers identified in a longitudinal cohort study of adult-onset asthma.
        J Allergy Clin Immunol Pract. 2017; 5: 979-980
        • Hardin M.
        • Cho M.
        • McDonald M.L.
        • Beaty T.
        • Ramsdell J.
        • Bhatt S.
        • et al.
        The clinical and genetic features of COPD-asthma overlap syndrome.
        Eur. Respir. J. 2014; 44: 341-350
        • Dinakar C.
        • O'Connor G.T.
        The health effects of electronic cigarettes.
        N. Engl. J. Med. 2016; 375: 1372-1381
        • Ghosh A.
        • Coakley R.C.
        • Mascenik T.
        • Rowell T.R.
        • Davis E.S.
        • Rogers K.
        • et al.
        Chronic E-cigarette exposure alters the human bronchial epithelial proteome.
        Am. J. Respir. Crit. Care Med. 2018; 198: 67-76
        • Spindel E.R.
        • McEvoy C.T.
        The role of nicotine in the effects of maternal smoking during pregnancy on lung development and childhood respiratory disease. Implications for dangers of E-cigarettes.
        Am. J. Respir. Crit. Care Med. 2016; 193: 486-494
        • Ronmark E.
        • Andersson C.
        • Nystrom L.
        • Forsberg B.
        • Jarvholm B.
        • Lundback B.
        Obesity increases the risk of incident asthma among adults.
        Eur. Respir. J. 2005; 25: 282-288
        • Peters U.
        • Dixon A.E.
        • Forno E.
        Obesity and asthma.
        J. Allergy Clin. Immunol. 2018; 141: 1169-1179
        • Al-Alwan A.
        • Bates J.H.
        • Chapman D.G.
        • Kaminsky D.A.
        • DeSarno M.J.
        • Irvin C.G.
        • et al.
        The nonallergic asthma of obesity. A matter of distal lung compliance.
        Am. J. Respir. Crit. Care Med. 2014; 189: 1494-1502
        • Jarjour N.N.
        • Erzurum S.C.
        • Bleecker E.R.
        • Calhoun W.J.
        • Castro M.
        • Comhair S.A.
        • et al.
        Severe asthma: lessons learned from the national heart, lung, and blood institute severe asthma Research Program.
        Am. J. Respir. Crit. Care Med. 2012; 185: 356-362
        • Gaga M.
        • Papageorgiou N.
        • Yiourgioti G.
        • Karydi P.
        • Liapikou A.
        • Bitsakou H.
        • et al.
        Risk factors and characteristics associated with severe and difficult to treat asthma phenotype: an analysis of the ENFUMOSA group of patients based on the ECRHS questionnaire.
        Clin. Exp. Allergy. 2005; 35: 954-959
        • Sood A.
        • Qualls C.
        • Schuyler M.
        Leptin, adiponectin, and asthma: findings from a population-based cohort study.
        Ann. Allergy Asthma Immunol. 2010; 104 (author reply -6): 355
        • Baffi C.W.
        • Wood L.
        • Winnica D.
        • Strollo Jr., P.J.
        • Gladwin M.T.
        • Que L.G.
        • et al.
        Metabolic syndrome and the lung.
        Chest. 2016; 149: 1525-1534
        • Cardet J.C.
        • Ash S.
        • Kusa T.
        • Camargo Jr., C.A.
        • Israel E.
        Insulin resistance modifies the association between obesity and current asthma in adults.
        Eur. Respir. J. 2016; 48: 403-410
        • Forno E.
        • Han Y.Y.
        • Muzumdar R.H.
        • Celedon J.C.
        Insulin resistance, metabolic syndrome, and lung function in US adolescents with and without asthma.
        J. Allergy Clin. Immunol. 2015; 136: 304-311 e8
        • Smith A.M.
        The epidemiology of work-related asthma.
        Immunol. Allergy Clin. 2011; 31: 663-675
        • Baur X.
        • Bakehe P.
        Allergens causing occupational asthma: an evidence-based evaluation of the literature.
        Int. Arch. Occup. Environ. Health. 2014; 87: 339-363
        • Zein J.G.
        • Erzurum S.C.
        Asthma is different in women.
        Curr. Allergy Asthma Rep. 2015; 15: 28
        • Vink N.M.
        • Postma D.S.
        • Schouten J.P.
        • Rosmalen J.G.
        • Boezen H.M.
        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 (e1-6): 498-504
        • Fu L.
        • Freishtat R.J.
        • Gordish-Dressman H.
        • Teach S.J.
        • Resca L.
        • Hoffman E.P.
        • et al.
        Natural progression of childhood asthma symptoms and strong influence of sex and puberty.
        Ann Am Thorac Soc. 2014; 11: 939-944
        • Fuseini H.
        • Newcomb D.C.
        Mechanisms driving gender differences in asthma.
        Curr. Allergy Asthma Rep. 2017; 17: 19
        • Rosenberg S.L.
        • Miller G.E.
        • Brehm J.M.
        • Celedon J.C.
        Stress and asthma: novel insights on genetic, epigenetic, and immunologic mechanisms.
        J. Allergy Clin. Immunol. 2014; 134: 1009-1015
        • Oren E.
        • Gerald L.
        • Stern D.A.
        • Martinez F.D.
        • Wright A.L.
        Self-reported stressful life events during adolescence and subsequent asthma: a longitudinal study.
        J Allergy Clin Immunol Pract. 2017; 5: 427-434 e2
        • Pite H.
        • Pereira A.M.
        • Morais-Almeida M.
        • Nunes C.
        • Bousquet J.
        • Fonseca J.A.
        Prevalence of asthma and its association with rhinitis in the elderly.
        Respir. Med. 2014; 108: 1117-1126
        • Gibson P.G.
        • McDonald V.M.
        • Marks G.B.
        Asthma in older adults.
        Lancet. 2010; 376: 803-813
        • Dunn R.M.
        • Busse P.J.
        • Wechsler M.E.
        Asthma in the elderly and late-onset adult asthma.
        Allergy. 2018; 73: 284-294
        • Nyenhuis S.M.
        • Schwantes E.A.
        • Evans M.D.
        • Mathur S.K.
        Airway neutrophil inflammatory phenotype in older subjects with asthma.
        J. Allergy Clin. Immunol. 2010; 125: 1163-1165
        • Morales D.R.
        • Jackson C.
        • Lipworth B.J.
        • Donnan P.T.
        • Guthrie B.
        Adverse respiratory effect of acute beta-blocker exposure in asthma: a systematic review and meta-analysis of randomized controlled trials.
        Chest. 2014; 145: 779-786