American Journal of Respiratory and Critical Care Medicine

Rationale: Clinical and epidemiologic approaches have identified two distinct sets of classifications for asthma and wheeze phenotypes.

Objectives: To compare epidemiologic phenotype definitions identified by latent class analysis (LCA) with clinical phenotypes based on patient histories, diagnostic work-up, and treatment responses. To relate phenotypes to genetic and environmental determinants as well as diagnostic and treatment-related parameters.

Methods: LCA was performed in an international multicenter birth cohort based on yearly questions about current wheeze until age 6 years. Associations of wheeze classes and clinical phenotypes with asthma-related characteristics such as atopy, lung function, fraction of exhaled nitric oxide, and medication use were calculated using regression models.

Measurements and Main Results: LCA identified five classes, which verified the clinically defined wheeze phenotypes with high sensitivity and specificity; the respective receiver operating characteristics curves displayed an area under the curve ranging from 84% (frequent wheeze) to 85% (asthma diagnosis) and 87% (unremitting wheeze) to 97% (recurrent unremitting wheeze). Recurrent unremitting wheeze was the most specific and unremitting wheeze at least once the most sensitive definition. The latter identified a subgroup of children with decreased lung function, increased genetic risk, and in utero smoke exposure (odds ratio, 2.03; 95% confidence interval, 1.12–3.68; P = 0.0191), but without established asthma diagnosis and treatment.

Conclusions: Clinical phenotypes were well supported by LCA analysis. The hypothesis-free LCA phenotypes were a useful reference for comparing clinical phenotypes. Thereby, we identified children with clinically conspicuous but undiagnosed disease. Because of their high area under the curve values, clinical phenotypes such as (recurrent) unremitting wheeze emerged as promising alternative asthma definitions for epidemiologic studies.

Scientific Knowledge on the Subject

Childhood asthma phenotypes have been defined by two different approaches. From a clinically oriented perspective, classification has been based on patient histories, diagnostic techniques, and treatment responses, whereas the hypothesis-free approach by latent class analysis (LCA) has been used by epidemiologists. So far these approaches have not been compared systematically.

What This Study Adds to the Field

We found that clinical definitions such as unremitting wheeze, recurrent unremitting wheeze, multitrigger wheeze, and, with reservations, also a reported asthma diagnosis, are well supported by LCA based on longitudinal data on current wheeze during the first 6 years of life. Unremitting wheeze at least once is the most sensitive, whereas recurrent unremitting wheeze is the most specific phenotype, when compared to LCA classes. Applying the sensitive phenotype definition of unremitting wheeze, we identified a group of patients with impaired lung function but without adequate diagnosis and treatment.

Asthma is a highly variable disease, in terms of presentation, disease progression over time, and response to therapy (1). Recurrent lower respiratory symptoms associated with cough, wheezing, and reversible airway obstruction support a diagnosis of asthma. A proper asthma diagnosis, however, cannot be based on a single common feature (1, 2). It has long been recognized that distinct subsets of the above characteristics are seen in some patients with asthma but not in others. Nevertheless, features suggestive of asthma run together and have elicited a search for common phenotypes following two main approaches: The clinical approach classifies clinical phenotypes based on a wealth of experience in patient histories, diagnostic techniques, and treatment responses, whereas the epidemiologic approach identifies asthma phenotypes by unsupervised, hypothesis-free statistical methods in population samples (3).

Two major clinical phenotypes have been distinguished with respect to their triggers: The first phenotype can be subdivided into the two variants multi(ple)-trigger wheeze, with a focus on episodes of wheeze being elicited by various triggers besides infections (4), and unremitting wheeze, which is defined by symptoms such as wheeze or cough at night or due to exercise also occurring between distinct episodes (5). The other major phenotype, episodic viral wheeze, is commonly triggered by infections, with the child being well between episodes (4). Beyond this dichotomy, severity of symptoms has been addressed by a higher frequency of wheezing episodes (usually more than three per year) resulting in the use of frequent wheeze as a distinct phenotype (68).

Epidemiologic studies often operate with long-term trajectories such as the triad of early transient, persistent, and late-onset wheeze (9). This classification has been confirmed in different cohort studies by latent class analysis (LCA) as a data-driven approach (10, 11).

So far, clinical and epidemiologic classifications have hardly been compared systematically. Therefore, we intended to evaluate both sets of definitions and their interrelations with respect to environmental determinants, family history of atopy, genetic risk factors, sensitization to specific allergens, fraction of exhaled nitric oxide (FeNO), lung function parameters, and medication use.

Study Design and Population

The Protection against Allergy—Study in Rural Environments (PASTURE) has been set up as a prospective birth cohort including children from rural areas, comprising children who live and do not live on farms, in five European countries: Austria, Finland, France, Germany, and Switzerland. The study design has been described earlier (12). In brief, pregnant women were contacted in the third trimester of pregnancy. Families living on and running livestock farms were assigned to the farm study group. For the reference study group, families from the same rural areas, but not living on a farm, were recruited. The study was approved by the ethical committees of the participating institutions, and written informed consent was obtained from the children’s parents or guardians.


Questionnaires were administered at the end of pregnancy and when the children were 2, 12, 18, 24, 36, 48, 60, and 72 months of age. Questionnaires were based on items from the International Study of Allergy and Asthma in Childhood (ISAAC) (13), the Asthma Multicenter Infants Cohort Study (AMICS) (14), the ALEX (Allergy and Endotoxin) study (15), the PARSIFAL (Prevention of Allergy Risk factors for Sensitization In children related to Farming and Anthroposophic Lifestyle) study (16), and the American Thoracic Society questionnaire (17).

Parents were asked at all time points “How often has your child wheezed during the last 12 months?” or during the respective time period between questionnaire intervals. The possible answer categories were: never, less than once a month, once a month, and at least twice a month. Children with any wheeze at the respective time point were classified as wheezers.

Clinical phenotypes were defined as displayed in Table 1 based on clinically relevant information collected by the questionnaires. LCA classes add up to 100% because LCA assigns each child only to one class. In contrast, the clinical phenotypes are not mutually exclusive (i.e., a child can be classified within different phenotypes [e.g., a child may have unremitting wheeze and also an asthma diagnosis]). Control subjects used in the regression models were defined as children without an asthma diagnosis and without wheeze at any time point.

Table 1: Definition of Clinical Phenotypes Used

Clinical PhenotypeDefinition
Asthma diagnosisA physician’s diagnosis of asthma at least once per lifetime or recurrent diagnoses of spastic, obstructive, or asthmatic bronchitis as reported by the parents at age 6 yr
Multitrigger wheezeAt least 2 out of 6 different triggers (cold, effort, dust, animals, grass, other) reported to elicit wheeze during at least one follow-up period between age 3 and 6 yr
Unremitting wheeze (at least once)Having symptoms between distinct wheezing episodes or having wheeze without a cold during at least one follow-up period between age 1 and 6 yr
Recurrent unremitting wheezeHaving symptoms between distinct wheezing episodes or having wheeze without a cold during at least two follow-up periods between age 1 and 6 yr
Frequent wheezeHaving wheeze on a monthly basis during at least one follow-up period between age 1 and 6 yr
Episodic wheezeHaving distinct wheezing episodes concomitantly with a cold, but no symptoms between those distinct wheezing episodes between age 1 and 6 yr

For details, see the online supplement.

Genetic Determinants

Genotyping was performed at the Centre National de Génotypage, Evry, France, using the iPLEX Gold technology. Of all 939 children with available DNA samples, 896 passed all quality checks. The single-nucleotide polymorphism (SNP) rs7216389 was selected to cover a major known risk locus (chromosome 17q21) for childhood asthma (1820) and was coded for its risk allele (T).

Specific IgE in Serum Samples

Specific immunoglobulin E (sIgE) levels for 6 food and 13 common inhalant allergens were assessed in children at the age of 4.5 and 6 years in peripheral blood by the Allergy Screen test panel for atopy (Mediwiss Analytic, Moers, Germany) in one central laboratory. The levels of allergen-specific IgE were dichotomized at RAST class 2 (sIgE ≥ 0.7 kU/L), and other cut-off values corresponding to RAST class 1 or 3 (sIgE ≥ 0.35 kU/L and sIgE ≥ 3.5 kU/L, respectively) were explored.

FeNO Measurements and Lung Function

At the age of 6 years, 799 children were contacted for FeNO measurements, lung function testing, and medication use. Exhaled air was collected in triplicate, and FeNO was measured as described previously (21). After exclusion of 12 participants with reported intake of inhaled steroids in the week before the field visit, 737 participants (92.2%) remained with acceptable FeNO measurements according to guidelines (see online supplement).

Spirometry was performed as described previously (21). FEV1 and maximum midexpiratory flow were determined as z scores (22) before and after application of a bronchodilator (400 μg of short-acting β-agonist [SABA]). A positive bronchodilator response was defined as a relative change of FEV1 after versus before SABA of at least 12% (23). Measurements were acceptable in 648 children before (81.1%) and 595 children after bronchodilator test (74.5%), resulting in 578 complete sets of measurements.

Medication use during the last 12 months was classified into the following categories: oral or inhaled steroids, leukotriene receptor antagonists, long-acting β-agonists, and SABA.

Statistical Analyses

LCA was conducted in MPLUS Version 5 (Muthén and Muthén, 1998–2007) to determine subtypes of related cases from multivariable categorical data on wheezing over time. Individuals were assigned to the class for which they had the highest posterior probability of belonging. The resulting classes were then compared with clinical phenotypes by the polychoric correlation coefficient (rho) and with respect to true- and false-positive rates using receiver operating characteristics curves (24). To compare the respective area under the curve values, confidence intervals (CIs) were calculated according to DeLong and colleagues (25).

FeNO values in parts per billion were log transformed, resulting in approximately normally distributed values. SNP data were analyzed in an additive model with respect to the increase of risk alleles. Associations of outcomes with potential determinants were calculated by linear or logistic regression using SAS 9.2 (The SAS Institute, Cary, NC) and R 2.14 ( Effect estimates are given with 95% CIs as odds ratios (ORs) for dichotomous outcomes, β-estimates for linear continuous outcomes such as lung function parameters, and geometric mean ratios for log-transformed values. All regression analyses were adjusted for farming status and center because of the study design, and potential interactions with farming and center were explored.

Study Population

Of the 1,133 enrolled children of the PASTURE birth cohort, 953 (84%) had complete data on wheeze during the last 12 months at no less than five of six yearly intervals under investigation and served as study population for the present LCA. Complete information on genetic risk was available for 896 children, and RAST tests were successfully performed in 745 children at the age of 6 years. Information about medication use, FeNO measurements, and lung function testing was available in 799, 737, and 648 children, respectively (see Figure E1 in the online supplement). In these subsamples, children with low parental education and in vitro smoke exposure were somewhat underrepresented (Table E1).

Interrelations of LCA-defined and Clinical Phenotypes

Taking Akaike's information criterion, entropy, and interpretability into account, the LCA solution with five classes was superior to the four- and six-class solutions (Figure E2). Prevalences of LCA classes are shown in Table 2, and were rather consistent across the study centers (Table E2). The LCA classes followed individual trajectories of wheeze prevalences (Figure 1A) irrespective of the study group (Figure E3). Clinical phenotypes followed relatively parallel trajectories with little segregation before age 3 years (Figure 1B).

Table 2: Prevalences of Latent Class Analysis Phenotypes and Clinical Phenotypes

 Persistent wheeze3.3%
 Late-onset wheeze4.0%
 Intermediate wheeze5.9%
 Transient wheeze16.8%
 No/infrequent wheeze70.0%
 Asthma diagnosis8.4%
 Multitrigger wheeze11.4%
 Unremitting wheeze22.6%
 Recurrent unremitting wheeze8.1%
 Frequent wheeze8.5%
 Episodic wheeze19.5%

Definition of abbreviation: LCA = latent class analysis.

LCA phenotypes are mutually exclusive, whereas clinical phenotypes are correlated.

Except for episodic wheeze, the proportions of children with the respective clinical phenotypes increased consistently across the LCA classes (Figure 2).

LCA classes correlated very well with unremitting wheeze at least once, recurrent unremitting wheeze, and multitrigger wheeze as determined by a polychoric correlation coefficient rho greater than 0.8. In contrast, episodic wheeze correlated badly with the LCA classes and was thus not considered for further analyses. For internal validation we compared the correlation coefficients of clinical phenotypes and LCA classes across study centers and found a rather homogeneous pattern, with low coefficients of variation across countries (Table E3).

Identification and Prediction of Clinical Phenotypes by LCA Classes

Based on the clear increase of clinical phenotype prevalences across the LCA classes (Figure 2), we used the LCA classes also as an ordinal variable with five categories ranking the classes as in Figure 2. For the four different cut-offs of this ordered variable, true-positive rates were plotted against false-positive rates (Figure 3A). The resulting receiver operating characteristic curves revealed informative differences between the clinical phenotypes. Recurrent unremitting wheeze displayed the significantly highest area under the curve value, with the lower confidence limit being higher than the upper limits of all other phenotypes. Irrespective of any particular LCA classes, unremitting wheeze at least once displayed the highest positive predictive values and recurrent unremitting wheeze the highest negative predictive values (Figure 3B). In other words, when considering LCA classification as a reference, unremitting wheeze is the most sensitive and recurrent unremitting wheeze the most specific phenotype. The shaded area in Figure 3B reflects the difference in sensitivity between unremitting wheeze and asthma diagnosis.

Characteristics of LCA-defined and Clinical Phenotypes

Key characteristics are summarized in Figure 4. Details on environmental and genetic determinants are given in Table E4, on atopic sensitization in Table E5, and on lung function parameters and medication use in Table E6.

The particular LCA classes varied substantially with respect to major features. Persistent wheeze was strongly related to the asthma risk locus on chromosome 17 but unrelated to environmental determinants; compromised lung function resolved almost completely after bronchodilator administration. The hallmark of late-onset wheeze was an extremely strong association with FeNO and sensitization to inhalant allergens at 6 years (Figure 4) and at 4 years (adjusted OR [aOR] = 4.35; 95% CI, 1.89–10.02; P < 0.001); lung function was severely and irreversibly compromised, and medication use was as common as in an asthma diagnosis. In intermediate wheeze, associations with atopy were restricted to pollen sensitization; relevant associations were also found with environmental determinants and genetic risk. Transient wheeze was hardly related to atopy and genetic risk; lung functions were mildly impaired, and medication use was very uncommon.

The characteristics of multitrigger and unremitting wheeze were very similar. They were strongly associated with genetic risk, with atopic sensitization particularly to mites and pollen, and with elevated FeNO levels. Lung function parameters were compromised but responded well to bronchodilators. Medication use was common. For the parameters given in Figure 4, the effect estimate of multitrigger wheeze ranged between unremitting wheeze and recurrent unremitting wheeze, with the latter showing the most pronounced effects.

Multitrigger and (recurrent) unremitting wheeze were positively associated with in utero smoke exposure and considerably with a family history of asthma and atopy. In contrast, an asthma diagnosis was not related to in utero smoke exposure but was related strongly to a family history. With respect to all other characteristics, however, asthma diagnosis resembled the above-mentioned clinical phenotypes.

The phenotype frequent wheeze was not related to genetic risk factors and hardly to atopic sensitization. Lung functions were only mildly impaired, and bronchodilator response was observable.

Relation of Asthma Diagnosis and Unremitting Wheeze

As demonstrated by the shaded area in Figure 3B, there was a considerable sensitivity gap between an asthma diagnosis and unremitting wheeze comprising 115 children. Hence, we stratified children with unremitting wheeze for the presence or absence of an established asthma diagnosis (Table 3). Children without a diagnosis were nevertheless affected by impaired lung function and inadequate response to bronchodilators. With few exceptions, they were not treated with asthma drugs. In contrast to children with an asthma diagnosis, they were significantly more exposed to smoke in utero than healthy control subjects. In turn, the 16 children with an asthma diagnosis but not covered by unremitting wheeze had strong associations with a family history of asthma (aOR = 2.84; 95% CI, 0.86–9.46; P = 0.088) and atopic sensitization (aOR = 4.29; 95% CI, 1.33–13.9; P = 0.015).

Table 3: Associations of Unremitting Wheeze with Various Characteristics Stratified for the Presence or Absence of an Asthma Diagnosis

 Stratum with Asthma Diagnosis (n = 60)Stratum without Asthma Diagnosis (n = 115)
 aOR95% CIP ValueaOR95% CIP Value
Girls vs. boys0.390.22 to 0.710.00190.820.54 to 1.250.3628
Parental atopy3.181.63 to 6.200.00071.761.12 to 2.770.0138
Parental asthma4.402.28 to 8.50<0.00011.871.03 to 3.420.0407
SNP rs7216389 of GSDMB*2.281.40 to 3.720.00091.481.05 to 2.070.0238
Sensitization against inhalant allergens3.031.63 to 5.610.00041.721.04 to 2.840.0332
Farmer vs. nonfarmer0.600.34 to 1.060.07650.840.55 to 1.280.4177
In utero smoke exposure1.540.69 to 3.460.29362.031.12 to 3.680.0191
FeNO, aGMR1.231.04 to 1.450.01401.070.96 to 1.210.2259
FEV1, z-score before bronchodilation, β-coefficient−0.64−1.03 to −0.260.0011−0.33−0.64 to −0.020.0382
BDR3.361.60 to 7.040.00140.740.32 to 1.710.4829
Steroids, %, n/N50.0%27/54 3.3%3/91 

Definition of abbreviations: aGMR = adjusted geometric mean ratio; aOR = adjusted odds ratio; BDR = bronchodilator response; CI = confidence interval; FeNO = fraction of exhaled nitric oxide; GSDMB = Gasdermin B; SNP = single-nucleotide polymorphism.

All analyses are adjusted for center and farming status and given with 95% CIs. Significant results (P < 0.05) are printed in bold.

*Effect given for an increase of the risk allele.

Sensitization against inhalant allergens is based on RAST class 2 measured at age 6 yr.

No. of children with intake of steroid medication (n) of all children with information about medication (N).

In children with unremitting wheeze but no asthma diagnosis, in utero smoke exposure was strongly related to a reduced FEV1 at borderline significance (β = −0.53; 95% CI, −1.12 to 0.06; P = 0.084), whereas in the entire population FEV1 was not related to in utero smoke exposure (β = −0.03; 95% CI, −0.31 to 0.25; P = 0.824).

Asthma is not a single disease entity but rather a syndrome subsuming various wheezing-associated disorders. To disentangle these various phenotypes, seemingly incompatible approaches have been pursued. Here we intended to reconcile clinical and epidemiologic perspectives by exploring clinical definitions of wheeze and contrasting them with a data-driven classification by LCA.

The LCA revealed five classes similar to those seen in more urban cohorts (10, 11). The class transient wheeze was not associated with atopic predisposition and only weakly with lung function parameters, as published previously (11, 26). The hallmark of persistent wheeze was a strong association with the asthma locus on chromosome 17q21 (27). In contrast, late-onset wheeze showed weaker associations with genetic risk but was strongly related to atopic sensitization at 6 years and substantially higher FeNO levels. The class intermediate wheeze is a genuine contribution of LCA (10, 11) to the four classes of never/infrequent, early transient, persistent, and late-onset wheeze, which have long been postulated based on epidemiologic observations (9). In contrast to the other LCA classes, intermediate wheeze comprises a rather heterogeneous group having only relatively strong environmental determinants in common.

Any LCA is never completely agnostic, because the choice of parameters entered into the model is usually based on prior knowledge. The present analysis was based only on temporal variations of wheeze symptoms inquired in yearly intervals; information on wheezing intensity, symptoms between episodes, or other concomitant features was ignored. Other LCA approaches integrating information on frequency of wheeze, relation to cough, and other characteristics revealed somewhat distinct categories but no completely novel wheeze phenotypes (28, 29).

Among the clinical phenotypes, we assessed an asthma diagnosis at age 6 years in all countries based on the German ISAAC definition (i.e., an established diagnosis of asthma or recurrent wheezy bronchitis). This was chosen because, particularly in the German language, the term asthma used to be avoided and replaced by spastic or obstructive bronchitis. Previously, this definition was validated against cold-air provocation in German schoolchildren (30). When ignoring wheezy bronchitis in a sensitivity analysis we missed half the cases of the German ISAAC definition (data not shown). Asked at school age, parents reported a lifetime prevalence of wheeze of 16.9%. However, the cumulative prevalence of yearly questions on wheeze was 56.8%. This discrepancy indicates that parents tend to forget early wheeze episodes; in other words, only wheeze episodes impressive enough to be recalled at school age might be relevant for an asthma diagnosis, thereby supporting the appropriateness of the German ISAAC definition.

The statistical association with family history was particularly strong for an asthma diagnosis consistently exceeding those for all other clinical and LCA phenotypes. To avoid labeling bias, clinicians should consider this issue cautiously when deliberating an asthma diagnosis.

Another major phenotype under investigation, frequent wheeze, has been proposed to quantify severity of symptoms. However, its correlation with LCA classes was substantially weaker as compared with (recurrent) unremitting/multitrigger wheeze. Therefore, and because of the relatively weak associations with atopy, the mildly reduced lung function parameters, and the rare drug usage, we would rather not recommend frequent wheeze as a surrogate for disease severity.

Episodic wheeze was originally defined as wheeze in discrete episodes, with the child being well between episodes (4, 5). Episodes occur seasonally and are usually triggered by viral infections (4, 31). The condition of being well between episodes produces a rather mild phenotype, which is reflected by the comparably high proportion of children with transient or infrequent wheeze and the low correlation with LCA. Episodic wheeze is unlikely to describe a chronic condition with deteriorating lung function. Rather, it might reflect an initially disproportionate response to viral infections with altered airway mechanics, which resolves in the course of further growth (32).

In contrast to the above monotrigger phenotype, multitrigger wheeze has been introduced to collect children responding with airway obstruction readily to all sorts of environmental triggers, including viruses. Multitrigger and unremitting wheeze resembled each other most closely with respect to all other parameters under investigation. This is not surprising, because both are variants of the same phenotype. In our definition, unremitting wheeze was partially based on wheeze without a cold, which means any trigger in addition to the most common trigger of wheeze (i.e., a cold). The second component of unremitting wheeze was symptoms, mostly cough, between wheeze episodes. Similarly, this component reflects an increased vulnerability of the respiratory tract.

The most important findings of this analysis were the high correlations of (recurrent) unremitting wheeze and multitrigger wheeze with the LCA classes. Essentially, this is not self-evident because the clinical definitions focus on disease intensity and triggers of episodes, whereas the LCA was based on longitudinal patterns of wheeze ignoring disease intensity and trigger factors. Remarkably, two systematically different approaches yielded congruent results; thereby they support distinction of wheeze phenotypes as a genuine phenomenon. Clinical definitions hereby emerge as valid instruments for epidemiologic studies, and clinicians may benefit from phenotype classifications anchored in general populations.

The robust clinical phenotype of unremitting wheeze in its both flavors (i.e., the more sensitive at-least-once variant and the more specific recurrent variant) might be a promising outcome definition in epidemiologic studies. This applies particularly to cross-sectional studies, where exact information on the course of disease is difficult to collect retrospectively. For instance, the more restrictive variant of recurrent unremitting wheeze excluded transient wheezers almost completely.

The usefulness of the more inclusive variant of unremitting wheeze is exemplified by the inclusion of 115 children without a (reported) asthma diagnosis, which reflects 12% of the study population. The combination of impaired lung function, nonresponse to bronchodilators, association with in utero smoke exposure, and the prediction of reduced lung function by in utero smoke exposure restricted to this subgroup suggests a distinct disease entity with similarities to early stages of chronic obstructive pulmonary disease. Alternatively, this group might comprise children with an incomplete diagnostic work-up for asthma and accordingly inadequate treatment. In any case, clinicians should be made aware of the importance of in utero smoke exposure in children presenting with wheeze and intermittent symptoms.

Likewise, the dichotomy of the clinical phenotypes in episodic viral wheeze versus unremitting or multitrigger wheeze might be complemented by epidemiologic phenotypes defined by trajectories of wheezing or LCA classes. For instance, the time course of late-onset wheeze implicitly carries information on the likelihood of early sensitization and worsening lung function. The strong association of late-onset wheeze with sensitization to inhalant allergens already at 4 years suggests atopy as an antecedent element in this phenotype. Correspondingly, we detected the most strongly impaired lung function in late-onset wheezers, which is in line with the observation that atopic sensitization at 3 years predicts decreased lung function at school age (33).

Our analyses are limited by slight discrepancies from published phenotype definitions, because some questionnaire items were not asked consistently over time (Table 1). Nevertheless, the sensitivity analyses performed justified our approximations. Furthermore, clinical records were not available for the definition of the clinical phenotypes; however, we think that the extensive parent-reported questionnaire information on hand was sufficient for this comparison within the limits of an epidemiologic study.

A further drawback of this international study might be seen in country heterogeneity and linguistic inconsistencies; for example, the German language does not own a proper translation of wheeze. When comparing the correlation coefficients of LCA asthma with the clinical phenotypes across countries, we found a considerable homogeneity across languages and countries (Table E3). Whether the current phenotype definitions are useful throughout puberty and adolescence remains to be seen during subsequent follow-ups of the PASTURE birth cohort.

Taken together, we have replicated previously published LCA findings in an international multicenter birth cohort. Beyond that, we have corroborated existing clinical phenotypes by LCA. Furthermore, we have identified recurrent unremitting wheeze as a specific and unremitting wheeze at least once as a sensitive alternative to an asthma diagnosis as an outcome definition in epidemiologic studies. Finally, we spotted a group of children with in utero smoke exposure who merit greater awareness in asthma research and everyday medical care.

The members of the PASTURE study group are (in alphabetical order): Sondhja Bitter (Swiss Tropical and Public Health Institute, Basel, Switzerland; University of Basel, Basel, Switzerland), Gisela Büchele (Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany), Marie-Laure Dalphin (Department of Respiratory Disease, UMR/CNRS 6249 Chrono-environnement, University Hospital of Besançon, France), Gert Doekes (Utrecht University, Institute for Risk Assessment Sciences [IRAS], Division of Environmental Epidemiology, Utrecht, Netherlands), Remo Frei (University of Zurich, Children’s Hospital, and Christine Kühne-Center for Allergy Research and Education, Zurich, Switzerland), Maija-Riitta Hirvonen (Department of Environmental Science, University of Eastern Finland, Kuopio, Finland), Georg Loss (Swiss Tropical and Public Health Institute, Basel, Switzerland; University of Basel, Basel, Switzerland; Dr. von Hauner Children’s Hospital, Ludwig Maximilians University Munich, Munich, Germany), Sami Remes (Department of Paediatrics, Kuopio University Hospital, Kopio, Finland), Harald Renz (Institute for Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Philipps University of Marburg, Marburg, Germany), Marjut Roponen (Department of Environmental Science, University of Eastern Finland, Kuopio, Finland), Pekka Tiittanen (Department of Environmental Health, National Institute for Health and Welfare, Kuopio, Finland).

1. Chipps BE, Bacharier LB, Harder JM. Phenotypic expressions of childhood wheezing and asthma: implications for therapy. J Pediatr 2011;158:878884.e1.
2. Eder W, Ege MJ, von Mutius E. The asthma epidemic. N Engl J Med 2006;355:22262235.
3. Siroux V, Garcia-Aymerich J. The investigation of asthma phenotypes. Curr Opin Allergy Clin Immunol 2011;11:393399.
4. Brand PL, Baraldi E, Bisgaard H, Boner AL, Castro-Rodriguez JA, Custovic A, de Blic J, de Jongste JC, Eber E, Everard ML, et al. Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach. Eur Respir J 2008;32:10961110.
5. Frey U, von Mutius E. The challenge of managing wheezing in infants. N Engl J Med 2009;360:21302133.
6. Caudri D, Wijga A, Schipper CM, Hoekstra M, Postma DS, Koppelman GH, Brunekreef B, Smit HA, de Jongste JC. Predicting the long-term prognosis of children with symptoms suggestive of asthma at preschool age. J Allergy Clin Immunol 2009;124:903910.e1–e7.
7. Remes ST, Castro-Rodriguez JA, Holberg CJ, Martinez FD, Wright AL. Dog exposure in infancy decreases the subsequent risk of frequent wheeze but not of atopy. J Allergy Clin Immunol 2001;108:509515.
8. Tromp II, Kiefte-de Jong JC, de Vries JH, Jaddoe VW, Raat H, Hofman A, de Jongste JC, Moll HA. Dietary patterns and respiratory symptoms in pre-school children: the Generation R Study. Eur Respir J 2012;40:681689.
9. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ; The Group Health Medical Associates. Asthma and wheezing in the first six years of life. N Engl J Med 1995;332:133138.
10. Henderson J, Granell R, Heron J, Sherriff A, Simpson A, Woodcock A, Strachan DP, Shaheen SO, Sterne JA. Associations of wheezing phenotypes in the first 6 years of life with atopy, lung function and airway responsiveness in mid-childhood. Thorax 2008;63:974980.
11. Savenije OE, Granell R, Caudri D, Koppelman GH, Smit HA, Wijga A, de Jongste JC, Brunekreef B, Sterne JA, Postma DS, et al. Comparison of childhood wheezing phenotypes in 2 birth cohorts: ALSPAC and PIAMA. J Allergy Clin Immunol 2011;127:15051512.e14.
12. Ege MJ, Herzum I, Buchele G, Krauss-Etschmann S, Lauener RP, Roponen M, Hyvarinen A, Vuitton DA, Riedler J, Brunekreef B, et al. Prenatal exposure to a farm environment modifies atopic sensitization at birth. J Allergy Clin Immunol 2008;122 407412.e1–e4.
13. Asher MI, Keil U, Anderson HR, Beasley R, Crane J, Martinez F, Mitchell EA, Pearce N, Sibbald B, Stewart AW, et al. International Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods. Eur Respir J 1995;8:483491.
14. Basagaña X, Torrent M, Atkinson W, Puig C, Barnes M, Vall O, Jones M, Sunyer J, Cullinan P; AMICS study. Domestic aeroallergen levels in Barcelona and Menorca (Spain). Pediatr Allergy Immunol 2002;13:412417.
15. Riedler J, Braun-Fahrländer C, Eder W, Schreuer M, Waser M, Maisch S, Carr D, Schierl R, Nowak D, von Mutius E; ALEX Study Team. Exposure to farming in early life and development of asthma and allergy: a cross-sectional survey. Lancet 2001;358:11291133.
16. Alfvén T, Braun-Fahrländer C, Brunekreef B, von Mutius E, Riedler J, Scheynius A, van Hage M, Wickman M, Benz MR, Budde J, et al.; PARSIFAL study group. Allergic diseases and atopic sensitization in children related to farming and anthroposophic lifestyle—the PARSIFAL study. Allergy 2006;61:414421.
17. Ferris BG. Epidemiology Standardization Project (American Thoracic Society). Am Rev Respir Dis 1978;118:1120.
18. Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S, von Mutius E, Farrall M, Lathrop M, Cookson WO; GABRIEL Consortium. A large-scale, consortium-based genomewide association study of asthma. N Engl J Med 2010;363:12111221.
19. Moffatt MF, Kabesch M, Liang L, Dixon AL, Strachan D, Heath S, Depner M, von Berg A, Bufe A, Rietschel E, et al. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 2007;448:470473.
20. Torgerson DG, Ampleford EJ, Chiu GY, Gauderman WJ, Gignoux CR, Graves PE, Himes BE, Levin AM, Mathias RA, Hancock DB, et al.; Mexico City Childhood Asthma Study (MCAAS); Children’s Health Study (CHS) and HARBORS study; Genetics of Asthma in Latino Americans (GALA) Study, Study of Genes-Environment and Admixture in Latino Americans (GALA2) and Study of African Americans, Asthma, Genes & Environments (SAGE); Childhood Asthma Research and Education (CARE) Network; Childhood Asthma Management Program (CAMP); Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity (SAPPHIRE); Genetic Research on Asthma in African Diaspora (GRAAD) Study. Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations. Nat Genet 2011;43:887892.
21. Fuchs O, Genuneit J, Latzin P, Buchele G, Horak E, Loss G, Sozanska B, Weber J, Boznanski A, Heederik D, et al. Farming environments and childhood atopy, wheeze, lung function, and exhaled nitric oxide. J Allergy Clin Immunol 2012;130:382388.e6.
22. Stanojevic S, Wade A, Stocks J, Hankinson J, Coates AL, Pan H, Rosenthal M, Corey M, Lebecque P, Cole TJ. Reference ranges for spirometry across all ages: a new approach. Am J Respir Crit Care Med 2008;177:253260.
23. Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, Coates A, van der Grinten CP, Gustafsson P, Hankinson J, et al. Interpretative strategies for lung function tests. Eur Respir J 2005;26:948968.
24. Robin X, Turck N, Hainard A, Tiberti N, Lisacek F, Sanchez JC, Müller M. pROC: an open-source package for R and S+ to analyze and compare ROC curves. BMC Bioinformatics 2011;12:77.
25. DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 1988;44:837845.
26. Simon MR, Havstad SL, Wegienka GR, Ownby DR, Johnson CC. Risk factors associated with transient wheezing in young children. Allergy Asthma Proc 2008;29:161165.
27. Granell R, Henderson AJ, Timpson N, St Pourcain B, Kemp JP, Ring SM, Ho K, Montgomery SB, Dermitzakis ET, Evans DM, et al. Examination of the relationship between variation at 17q21 and childhood wheeze phenotypes. J Allergy Clin Immunol 2013;131:685694.
28. Herr M, Just J, Nikasinovic L, Foucault C, Le Marec AM, Giordanella JP, Momas I. Risk factors and characteristics of respiratory and allergic phenotypes in early childhood. J Allergy Clin Immunol 2012;130:389396.e4.
29. Spycher BD, Silverman M, Brooke AM, Minder CE, Kuehni CE. Distinguishing phenotypes of childhood wheeze and cough using latent class analysis. Eur Respir J 2008;31:974981.
30. Nicolai T, Mutius EV, Reitmeir P, Wjst M. Reactivity to cold-air hyperventilation in normal and in asthmatic children in a survey of 5,697 schoolchildren in southern Bavaria. Am Rev Respir Dis 1993;147:565572.
31. Papadopoulos NG, Kalobatsou A. Respiratory viruses in childhood asthma. Curr Opin Allergy Clin Immunol 2007;7:9195.
32. Fuchs O, von Mutius E. Prenatal and childhood infections: implications for the development and treatment of childhood asthma. Lancet Respir Med 2013;1:743–754.
33. Illi S, von Mutius E, Lau S, Niggemann B, Grüber C, Wahn U; Multicentre Allergy Study (MAS) group. Perennial allergen sensitisation early in life and chronic asthma in children: a birth cohort study. Lancet 2006;368:763770.
Correspondence and requests for reprints should be addressed to Martin Depner, Ph.D., Ludwig Maximilians University Munich, Dr. von Hauner Children’s Hospital, Lindwurmstrasse 4, 80337 Munich, Germany. E-mail:

*A complete list of members may be found before the beginning of the References.

Supported by the European Commission research grants QLK4-CT-2001-00250, FOOD-CT-2006-31708, and KBBE-2007-2-2-06.

Author Contributions: M.D., O.F., J.P., J.-C.D., J.R., C.B.-F., E.v.M., and M.J.E. planned the study; O.F., J.G., A.M.K., A.H., V.K., C.R., J.W., U.F., B.S., R.L., M.K., P.I.P., and the PASTURE Study Group were involved in acquisition, management, and interpretation of data; M.D. performed statistical analyses; M.D., O.F., E.v.M., and M.J.E. wrote the manuscript; all authors provided substantial revisions and approval to the final manuscript.

This article has an online supplement, which is accessible from this issue’s table of contents at

Originally Published in Press as DOI: 10.1164/rccm.201307-1198OC on November 27, 2013

Author disclosures are available with the text of this article at


No related items
Comments Post a Comment

New User Registration

Not Yet Registered?
Benefits of Registration Include:
 •  A Unique User Profile that will allow you to manage your current subscriptions (including online access)
 •  The ability to create favorites lists down to the article level
 •  The ability to customize email alerts to receive specific notifications about the topics you care most about and special offers
American Journal of Respiratory and Critical Care Medicine

Click to see any corrections or updates and to confirm this is the authentic version of record