Rationale: Asthma is associated with increased airway responsiveness (AR), but the age when this relationship becomes established is not clear. The present study tested the hypothesis that the association between increased AR and asthma is established after 1 month of age.
Objectives: To relate AR in infancy to asthma in childhood.
Methods: As part of a birth cohort study, AR was determined at 1 (early infancy), 6 (mid-infancy), and 12 months of age (late infancy). At 11 years of age (childhood), AR and the presence of asthma symptoms were determined.
Measurements and Main Results: Of the 253 study subjects enrolled, AR was determined in 202 in early infancy, 174 in mid-infancy, 147 in late infancy, and 176 in childhood. Increased AR in late infancy, but not in early or mid-infancy, was associated with increased wheeze at 11 years of age (P = 0.016). Increased AR in infancy persisted into childhood in association with male gender, early respiratory illness, and maternal smoking and asthma. Among the 116 subjects assessed in late infancy and childhood, recent wheeze was present in 35% of children with increased AR at both ages, 13% with increased AR in childhood only, 12% for those with increased AR in late infancy only, and 0% for those who did not have increased AR at either age (P = 0.023); the proportions of children with diagnosed asthma in the corresponding groups were 27, 20, 12, and 0% (P = 0.038).
Conclusions: The association between increased infantile AR and childhood asthma emerges at the end of the first year of life.
Asymptomatic children with increased AR are at increased risk for later asthma symptoms (5, 6), but the relationship between increased AR in infancy and asthma is more complex. Asymptomatic infants between 1 and 2 months of age who demonstrate increased AR are at increased risk for early-onset asthma-like symptoms (7–9), but this relationship is transient and does not persist beyond 4 (10) and 6 years of age (11). In a study where AR was determined in wheezy infants older than 6 months of age, increased AR was associated with persistent asthma symptoms at 10 years of age (12), and this could indicate that increased AR in later infancy may be important to persisting asthma symptoms.
In a cohort recruited by our department, AR was ascertained in early infancy (1 month of age), mid-infancy (6 months of age), and later infancy (12 months of age). In the present study, we tested the hypothesis that the association between increased AR and asthma is established after 1 month of age. These data have previously been presented as an abstract (13).
Infants were recruited antenatally from a normal population. There was no selection for parental asthma or atopy. The full details of recruitment have been published elsewhere (14). Parents completed a respiratory questionnaire (15) at enrolment. At 1 month (early infancy), 6 months (mid-infancy), and 12 months (late infancy) of age, infant lung function and AR were determined. During infancy, a monthly questionnaire was completed, from which a history of lower respiratory illness (presence of cough and nasal discharge) and wheeze were ascertained. At 11 years of age (childhood), study participants attended an assessment that included measurement of lung function, AR, skin prick reactivity, and respiratory questionnaire. Childhood asthma was defined as an affirmative response to the question “Does your child currently have asthma diagnosed by a doctor?” Childhood wheeze was defined as an affirmative response to the question “Has your child wheezed in the past year?” This study was conducted with the approval of our institutional ethics committee. Written parental consent was obtained, and verbal assent was obtained from children.
These have been described in detail previously (11). Briefly, the rapid thoracoabdominal technique was used to determine VmaxFRC in infancy, which was expressed as a percentage of predicted (16). Spirometry was performed in childhood. The response of lung function to histamine was expressed as the concentration provoking a 40% reduction in VmaxFRC (PC40) in infants and dose response slope (DRS) in children. Fuller details are presented in the online supplement.
The skin prick test (17) was used to determine reactivity to the following allergens at each assessment during infancy: cows milk, egg white, rye grass, and Dermatophagoides farinae. The following allergens were also used at 11 years of age: mixed grass (No.7), D. pteronyssinus, cat dander, dog dander, Alternaria alternans, and Aspergillus fumigatus. Allergens were supplied by Hollister-Stier (Elkhart, IN). A positive control (histamine sulfate 10 mg/ml) and a negative control (0.9% saline) were used. A positive skin test was defined as a weal of at least 3 mm in any dimension.
Genotyping for the two single-nucleotide polymorphisms of the beta 2 adrenoceptor gene (Arg16Gly and Gln27Glu) was completed as previously described (25).
Nonparametric tests were used to compare PC40 in infancy with wheeze, asthma, and DRS in childhood. To determine asthma outcomes for individuals with increased AR in infancy who did and did not have increased AR in childhood, values of PC40 and DRS were dichotomized about the median value with individuals categorized as normal or increased AR. Individuals were then grouped by AR status in early, mid- or late infancy, and childhood. Using AR in late infancy and childhood as an example, groups were (1) normal AR at both ages, (2) increased AR in late infancy only, (3) increased AR in childhood only, and (4) increased AR in late infancy and childhood. The outcomes of interest in childhood were current wheeze and asthma, spirometry, and skin prick reactivity. Outcomes were compared across groups using ANOVA (with Bonferroni correction), the Kruskal-Wallis, or Chi square tests where appropriate. Logistic regression models were then created to adjust for the potential influence of % VmaxFRC in early infancy and %FEV1 in childhood on the relationship between AR groups and asthma and wheeze in childhood. Logistic regression models were created to explore the interaction between continuous indices of AR (i.e., log PC40 in infancy and log DRS in childhood) for asthma and wheeze in childhood, adjusting for %VmaxFRC and %FEV1. Standard statistical software (SPSS version 15.0) was used, and significance was assumed at the 5% level.
The original cohort included 253 individuals for whom AR was determined in 202 in early infancy, 174 in mid-infancy, 147 in late infancy, and 176 in childhood. Airway responsiveness was determined at early infancy and childhood in 142 individuals, at mid-infancy and childhood in 133 individuals, and at late infancy and childhood in 116 individuals. There were no differences in the outcomes studied between where AR was and was not assessed on each occasion (Table 1). The AR status (i.e., normal or increased) was maintained between assessments in 79 (59%) of the 135 individuals tested in early and mid-infancy, in 81 (62%) of the 130 individuals tested in mid- and late infancy, and in 52 (45%) of the 116 individuals tested in late infancy and childhood. There was a correlation between % VmaxFRC in early infancy and PC40 in mid-infancy (rho 0.17; P = 0.034; n = 164) but not with PC40 in early or late infancy. Details of respiratory symptoms during infancy were complete in 103 individuals.
AR Assessed on One Occasion (n = 37)
AR Assessed on Two Occasions (n = 57)
AR Assessed on Three Occasions (n = 72)
AR Assessed on Four Occasions (n = 83)
|Males, % (n)||51 (19)||56 (32)||57 (41)||58 (47)|
|At least one parent with asthma, % (n)*||29 (9)||23 (13)||37 (26)||32 (26)|
|Maternal smoking during pregnancy, % (n)||32 (12)||23 (13)||19 (14)||20 (17)|
|Mean % VmaxFRC at 1 mo of age (SD)†||97 (44)||91 (55)||97 (47)||108 (44)|
|Median PC40 at 1 mo of age, mg/ml histamine (SEM)||1.05 (0.72); n = 29||0.83 (0.85); n = 38||0.80 (0.52); n = 52||0.89 (0.34); n = 83|
|Median PC40 at 6 mo of age, mg/ml histamine (SEM)||—‡||2.01 (1.25); n = 28||1.68 (0.96); n = 61||1.55 (0.65); n = 83|
|Median PC40 at 12 mo of age, mg/ml histamine (SEM)||—§||2.50 (2.03); n = 16||3.00 (1.14); n = 47||2.80 (0.80); n = 83|
|Median dose response slope at 11 years of age (SEM)||2.67 (0.92); n = 5||1.66 (1.16); n = 32||2.25 (1.21); n = 56||1.49 (0.27); n = 83|
|Asthma at 11 yr of age, % (n)||38 (5/13)||14 (5/35)||15 (9/61)||12 (10/83)|
|Wheeze at 11 yr of age, % (n)||20 (2/10)||20 (7/35)||21 (13/61)||12 (10/83)|
|Atopic at 11 yr of age, % (n)||43 (3/7)||38 (13/34)||57 (33/58)||54 (45/83)|
Of the 176 individuals for whom AR was assessed in childhood, there were 122 individuals with increased AR on at least one occasion during infancy, of whom 61 (50%) had increased AR in childhood (Figure 1). Increased AR during infancy was more likely to also be present in childhood for individuals with at least one parent with asthma (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.2–5.8; P = 0.016), a history of lower respiratory tract illness in the first 6 months of life (OR, 3.1, 95% CI, 1.0–9.3; P = 0.041), and atopy in childhood (OR, 3.1; 95% CI, 1.5–6.7; P = 0.002). Maternal smoking during pregnancy was not associated with persistence or remission of increased AR in infancy, and there was a trend for infantile AR to persist into childhood for boys compared with girls (OR, 2.0; 95% CI, 1.0–4.1; P = 0.06). The Arg16Gly and Gln27Glu polymorphisms were not associated with altered AR (expressed as high/normal, PC40 or DRS) in mid- or late infancy, nor were these variations associated with the persistence of increased AR from infancy to childhood.
Childhood wheeze was associated with reduced PC40 (i.e., increased AR) in late infancy but not in mid- or early infancy (Figure 2). The median PC40 in late infancy in 18 children with wheeze was 1.67 (SEM, 1.06) compared with 3.12 (SEM, 0.72) among 107 children without wheeze (P = 0.016, Mann Whitney U test). A PC40 of 0.81 in late infancy had a sensitivity of 88% and a specificity of 46% for childhood wheeze, and a PC40 of 2.38 had corresponding figures of 61 and 83%. Childhood wheeze was present in 28% (12/43) of individuals in the tertile with lowest PC40 values (i.e., highest AR), 7% (3/45) in the middle tertile of PC40 values, and 8% (3/37) in the tertile with highest PC40 values (χ22 = 9.7; P = 0.008). The median PC40 in mid-infancy in 21 children with wheeze was 0.90 (SEM, 0.50), compared with 1.68 (SEM, 0.58) among 120 children without wheeze (P = 0.162, Mann Whitney U test) and remained nonsignificant when restricted to those assessed in late infancy. Median values for PC40 in early infancy were 0.69 (SEM, 0.87) for 25 children with wheeze and 0.89 (SEM, 0.28) for the 130 children without wheeze (P = 0.274). PC40 in infancy was not associated with current diagnosed asthma or DRS at 11 years of age.
Individuals with increased AR in late infancy and childhood were at greatest risk for asthma compared with other groups (P = 0.038) (Figure 3 and Table 2) and for wheeze (P = 0.023) (Figure 4 and Table 2). Individuals with increased AR in late infancy and childhood had reduced FEV1 and FEF25–75 in childhood but not reduced %VmaxFRC in early infancy (Table 2). Increased AR in mid-infancy and childhood was not associated with increased asthma and wheeze or reduced FEV1/FVC in childhood but was associated with a reduction in FEF25–75 (Table 3). Increased AR in early infancy and childhood was not associated with increased asthma or wheeze or any index of lung function at 11 years of age (Table 4). When the analysis was repeated using continuous measures of AR in late infancy and childhood, there was a significant interaction between PC40 at 12 months of age and DRS at a11 years of age for wheeze (P = 0.013) but not asthma (P = 0.112). Interaction terms between PC40 in early or mid-infancy and childhood DRS were not significant (P ≥ 0.376) for wheeze or asthma.
Normal AR, Late Infancy and Childhood (n = 26)
Increased AR, Late Infancy Only (n = 34)
Increased AR, Childhood Only (n = 30)
Increased AR, Late Infancy and Childhood (n = 26)
P Value for Difference across Groups
|Males, % (n)||50 (13)||56 (19)||57 (17)||73 (19)||0.363|
|Mean %VmaxFRC at 1 mo of age (SD)||111 (62)||109 (43)||106 (48)||84 (40)||0.184|
|Median PC40 at late infancy (SEM)||6.60 (1.57)||1.65 (0.13)||4.70 (1.43)||1.06 (0.55)||<0.001|
|Median DRS at 11 yr of age (SEM)||0.55 (0.11)||0.86 (0.10)||3.20 (0.52)||3.56 (1.69)||<0.001|
|Wheeze in the first year, % (n)||37% (7/19)||20% (4/20)||20% (4/20)||29% (4/14)||0.582|
|Atopic in infancy, % (n)||12% (3)||18% (6)||20% (6)||19% (5)||0.843|
|Mean FEV1/FVC at 11 yr of age (SD)||0.92 (0.05)||0.94 (0.06)||0.91 (0.06)||0.89 (0.06)||0.025|
|Mean % FEF25–75 at 11 yr of age (SD)||104 (20)||108 (19)||96 (20)||90 (21)||0.004|
|Atopic at 11 yr of age, % (n)||27 (7)||47 (16)||73 (22)||54 (14)||0.006|
|Asthma at 11 yr of age,* % (n)||0||12 (4)||20 (6)||27 (7)||0.038|
|Wheeze at 11 yr of age,* % (n)||0||12 (4)||13 (4)||35 (9)||0.023|
Normal AR, Mid-infancy and Childhood (n = 33)
Increased AR, Mid-infancy Only (n = 35)
Increased AR, Childhood Only (n = 30)
Increased AR, Mid-infancy and Childhood (n = 36)
P Value for Difference across Groups
|Males, % (n)||42% (14)||54% (19)||53% (16)||69% (25)||0.159|
|Mean % V'maxFRC aged one month (SD)||116 (51)||99 (50)||91 (34)||91 (48)||0.121|
|Median PC40 mid infancy (SEM)||4.40 (1.19)||0.70 (0.06)||4.45 (1.31)||0.73 (0.06)||<0.001|
|Median DRS aged 11 yr (SEM)||0.69 (0.11)||0.76 (0.10)||2.67 (0.29)||3.85 (1.18)||<0.001|
|Wheeze in the first year, % (n)||32% (7/22)||40% (8/20)||36% (8/22)||20% (3/15)||0.633|
|Mean FEV1/FVC aged eleven years (SD)||0.92 (0.05)||0.93 (0.05)||0.92 (0.05)||0.91 (0.07)||0.405|
|Mean % FEF25-75 aged eleven years (SD)||105 (20)||105 (18)||98 (17)||94 (22)||0.048|
|Atopic aged 11 yr, % (n)||48% (16)||37% (13)||50% (15)||83% (30)||0.001|
|Asthma aged 11 yr, % (n)*||9% (3)||6% (2)||13% (4)||19% (7)||0.301|
|Wheeze aged 11 yr, % (n)*||9% (3)||11% (4)||10% (3)||28% (10)||0.056|
Normal AR, Early Infancy and Childhood (n = 39)
Increased AR, Early Infancy Only (n = 34)
Increased AR, Childhood Only (n = 32)
Increased AR, Early Infancy and Childhood (n = 38)
P Value for # across Groups
|Males, % (n)||56 (22)||59 (20)||57 (18)||68 (26)||0.678|
|Mean % VmaxFRC at 1 mo of age (SD)||107 (44)||110 (48)||101 (41)||108 (49)||0.854|
|Median PC40, early infancy (SEM)||2.00 (0.63)||0.42 (0.04)||1.83 (0.85)||0.51 (0.04)||<0.001|
|Median DRS at 11 yr of age (SEM)||0.55 (0.09)||0.99 (0.11)||2.79 (1.66)||3.49 (1.00)||<0.001|
|Wheeze in the first year, % (n)||26 (6/23)||44 (7/16)||24 (5/21)||29 (5/17)||0.573|
|Mean FEV1/FVC at 11 yr of age (SD)||0.93 (0.06)||0.92 (0.05)||0.91 (0.06)||0.91 (0.06)||0.565|
|Mean %FEF25–75 at 11 yr of age (SD)||106 (18)||104 (19)||98 (19)||95 (21)||0.087|
|Atopic at 11 yr of age, % (n)||44 (17)||41 (14)||69 (22)||68 (26)||0.019|
|Asthma at 11 yr of age, % (n)*||5 (2)||12 (4)||22 (7)||18 (7)||0.076|
|Wheeze at 11 yr of age, % (n)*||8 (3)||21 (7)||19 (6)||21 (8)||0.142|
A longitudinal analysis was undertaken to explore whether increased AR in early or mid-infancy that persisted in late infancy was relevant to asthma outcomes in childhood. There were 103 individuals in whom AR was determined in mid- and late infancy and in childhood, of whom 14 had increased AR on each occasion (including four with asthma and six with wheeze at 11 years of age), 74 had changing AR status (including four with asthma and eight with wheeze), and 15 had normal AR on each occasion (including none with either asthma or wheeze); trend tests for asthma and wheeze across these groups were χ22 = 5.5 (P = 0.063) and χ22 = 13.4 (P = 0.001), respectively (Table 5). Of the 94 individuals in whom AR was determined in early and late infancy and in childhood, 14 had increased AR on each occasion (including four with asthma and four with wheeze), 66 had changing AR status (including 10 with asthma and nine with wheeze), and 14 had normal AR on each occasion (none of whom had asthma or wheeze); trend tests for asthma and wheeze across these groups were χ22 = 4.5 (P = 0.104) and χ22 = 4.8 (P = 0.091), respectively. For safety reasons, AR was not assessed in early infancy for those with the lowest VmaxFRC (flow limitation); the longitudinal analysis was repeated assuming that all flow-limited individuals had increased AR in early infancy, but the results were not substantially changed (χ22 = 3.5, P = 0.175 for asthma and χ22 = 5.1, P = 0.077 for wheeze; n = 104).
No Increased AR (n = 15)
Intermittent Increased AR (n = 74)
Persistently Increased AR (n = 14)
P Value for Difference Across Groups
|Males, % (n)||47 (7)||54 (40)||71 (10)||0.373|
|Mean % VmaxFRC at 1 mo of age (SD)||125 (70)||102 (42)||75 (48)||0.032|
|Median PC40, mid-infancy (SEM)||4.20 (2.06)||1.55 (0.65)||0.68 (0.09)||<0.001|
|Median PC40, late infancy (SEM)||6.20 (2.03)||2.48 (0.82)||1.35 (0.18)||<0.001|
|Median DRS at 11 yr of age (SEM)||0.68 (0.16)||1.154 (0.19)||4.59 (2.86)||<0.001|
|Wheeze in the first year, % (n)||49 (4/9)||25 (12/48)||17 (1/6)||0.404|
|Mean FEV1/FVC at 11 yr of age (SD)||0.92 (0.056)||0.92 (0.06)||0.87 (0.07)||0.019|
|Mean % FEF25–75 at 11 yr of age (SD)||109 (22)||101 (19)||85 (21)||0.004|
|Atopic at 11 yr of age, % (n)||33 (5)||50 (37)||79 (11)||0.046|
|Asthma at 11 yr of age, % (n)*||0 (0)||5 (4)||29 (4)||0.063|
|Wheeze at 11 yr of age, % (n)*||0 (0)||11 (8)||43 (6)||0.001|
This study is based on a unique birth cohort where serial assessments of AR were made during infancy and childhood. In our initial analysis, we observed an association between reduced PC40 (i.e., increased AR) in late infancy and wheeze 10 years later. We then observed that increased AR did not persist from infancy to childhood in all individuals. Our final analyses considered asthma outcomes in different groups categorized by AR status in infancy and childhood; the important finding here was that individuals with increased AR in late infancy and childhood were at greatest risk for wheeze, asthma, and reduced lung function (i.e., the usual asthma phenotype). Although the relationship between increased AR and asthma was not exclusive, the absence of increased AR during infancy and at 11 years of age was not associated with asthma. Collectively, these findings indicate that the presence or—perhaps more importantly—the absence of increased AR by the end of infancy is important to the presence of asthma 10 years later.
Previous reports have given insight into the age at onset of relationships between asthma and associated features, such as obstructed lung function and atopy, but this is the first to do so for age at onset of increased AR. The presence of obstructed lung function by 1 month of age is associated with later asthma symptoms (11, 18), whereas the association between atopy and asthma may emerge after 12 months of age (19, 20). The results of the present study, where increased AR at 12 months was more consistently associated with asthma outcomes than at 6 months, suggest that the age at onset of increased AR associated with asthma occurs between 6 and 12 months of age. These epidemiologic studies suggest that a succession of insults to the respiratory system at critical stages of development, before and after birth, result in the usual asthma phenotype of obstructed lung function, atopy, and increased AR. An intervention timed to prevent any one of these insults may be sufficient to prevent or palliate asthma.
There are no studies of similar design with which to compare the results of the present study. Our findings are consistent with the study of Saga and colleagues (12), who found that increased AR in wheezy young children was associated with increased respiratory symptoms at 10 years of age, although AR was not assessed in childhood. The results are not consistent with a second study of AR in wheezy infants and young children with follow-up over 4 years and which found that higher values of AR at enrollment were not associated with persisting symptoms (21).
In our analysis we have demonstrated that the association between AR in later infancy and asthma outcomes at 11 years of age was independent of VmaxFRC in early infancy. This finding is important because we have previously reported relationships between reduced VmaxFRC in early infancy and outcomes in childhood, including reduced FEF25–75 (11, 22, 23), increased AR (22), and wheeze (11). Our analysis has also considered a second potential bias that AR was not determined in the group of flow-limited individuals likely to have the highest values for AR at 1 month of age (22) and thus skewing the distribution of AR at this age; however, we assumed that flow-limited individuals had increased AR, and this did not substantially change the outcome of the longitudinal analysis. Although reduced lung function in early infancy seems to be related to outcomes in later childhood, including reduced lung function (24) and wheeze, the emergence of increased AR in later infancy seems to be an additional factor that is relevant to asthma outcomes in childhood.
In our study, increased AR resolved in half of the infants. Factors associated with persistence of increased AR were established risk factors for asthma and included early respiratory illness, parental asthma, and childhood atopy. Atopy in infancy was not associated with the persistence of increased AR in the present study, but, using a different approach, we have reported an interaction between infantile atopy, asthma, and the DRS to histamine (2). A mechanism whereby increased AR resolves is not known. One possibility is that factors such as parental smoking (14) and the Arg16Gly polymorphism of the β2 adrenoceptor (25) influence AR in early life (and possibly before birth), but environmental factors such as early infections and the development of atopy predominate after the neonatal period.
Although we observed an association between increased AR in late infancy and childhood asthma outcomes, the relationship was not exclusive. Table 2 demonstrates similar numbers of children with increased AR at 11 years of age who did and did not have increased AR at 12 months of age; the proportion of children with an asthma diagnosis in these groups was comparable. Measurements of AR are challenging in infants, and increased AR may not have been detected in some infants. Additionally, increased AR may genuinely have developed after infancy in some individuals.
There are some potential limitations to this study. First, the follow-up was incomplete, but in Table 1 we have demonstrated that there was no enrichment of children with asthma and related outcomes among those who participated with all assessments. Second, there have been many comparisons across the groups, and some of the significant results may have been by chance; however, the consistency of the results and the significant P values in Table 2 demonstrate that our findings are unlikely to be random. Third, we considered AR to be a qualitative (dichotomous) measure for the principle analyses, and this approach was based on our prior experience (26). However, we also report an interaction between quantitative measures of AR (i.e., PC40 and DRS) at 12 months and 11 years of age for wheeze, and, although the association with diagnosed asthma failed to achieve significance, we are assured that the results are similar whether AR was considered as a quantitative or qualitative variable.
In summary, evaluation of this unique birth cohort study finds that, as a group, individuals with increased AR in later infancy and childhood have the usual characteristics of asthma. The absence of increased AR in both infancy and childhood was associated with a zero incidence of asthma and wheeze. Although increased AR in early infancy is a specific pathology that predicts transient airway dysfunction, increased AR seen in later infancy that persists into childhood is strongly associated with asthma.
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