There is now conclusive evidence that, as a group, subjects with asthma have lower levels of lung function as compared with their peers and that a significant proportion of subjects with persistent asthma are at risk of developing non–fully reversible airflow limitation, the clinical hallmark of chronic obstructive pulmonary disease. Although at the population level the most conspicuous form of airflow limitation in asthma seems to be that of subjects who wheeze during the first years of life and whose symptoms persist into adult life, asthma-related lung deficits can be related to both acquired deficits in growth of lung function in childhood and steeper decline of lung function in adult life. These trajectories of lung function are likely to differ across subgroups of individuals with asthma, suggesting that different windows of opportunity may exist to modify the natural course of the disease before irreversible deficits are established. These observations indicate the importance of identifying biomarkers that can be used to target children and adults with asthma at increased risk for airflow limitation and determining whether pharmacological interventions can protect these patients from the development of chronic obstructive pulmonary disease.
asthma; chronic obstructive pulmonary disease; lung function; airflow limitation; FEV1
Results from birth cohort and cross-sectional studies of young children with wheezing have uncovered strong associations between both lung function and immune responses in early life and the subsequent development of persistent wheezing and chronic airway obstruction up to mid-adulthood. It is now apparent that the pattern of bronchial hyperresponsiveness, deficits in lung function, and structural airway remodeling that are characteristic of asthma may be already established during the preschool years in most patients. Interactions between acute viral infections, especially those due to rhinovirus and respiratory syncytial virus, and exposure to perennial aeroallergens may induce persistent alterations in immune responses and airway function in susceptible subjects. Similarly, deficits in airway function present shortly after birth predict airflow limitation in early adult life, which in turn is a strong predisposing factor for chronic obstructive pulmonary disease. The fact that these alterations are more likely to occur during early life and even in utero than later during childhood suggests that there a developmental window of susceptibility during which exposures can disrupt normal growth trajectories. Novel strategies for primary prevention of chronic respiratory diseases will be based on the identification of the genetic and environmental factors that interactively cause these disruptions.
asthma; COPD; infancy; spirometry
The goals of asthma treatment include preventing recurrent exacerbations. Yet there is no consensus about the terminology for describing or defining “exacerbation,” or about how to characterize an episode’s severity.
National Institutes of Health (NIH) institutes and other federal agencies convened an expert group to propose how asthma exacerbation should be assessed as a standardized asthma outcome in future asthma clinical research studies.
We utilized comprehensive literature reviews and expert opinion to compile a list of asthma exacerbation outcomes, and classified them as either core (required in future studies), supplemental (used according to study aims and standardized), or emerging (requiring validation and standardization). This work was discussed at an NIH-organized workshop in March 2010 and finalized in September 2011.
No dominant definition of “exacerbation” was found. The most widely used definitions included 3 components, all related to treatment, rather than symptoms: (1) systemic use of corticosteroids, (2) asthma-specific emergency department visits or hospitalization, and (3) use of short-acting β-agonists (SABAs) as quick-relief (sometimes referred to as “rescue” or “reliever”) medications.
The working group participants propose that the definition of “asthma exacerbation” be “a worsening of asthma requiring the use of systemic corticosteroids to prevent a serious outcome.” As core outcomes, they propose inclusion and separate reporting of several essential variables of an exacerbation. Further, they propose the development of a standardized, component-based definition of “exacerbation” with clear thresholds of severity for each component.
Asthma exacerbations; severity of acute asthma; asthma outcomes; urgent asthma care
Familial aggregation of specific response to allergens and asthma adjusted for age and sensitization to multiple allergens was assessed in two large population cohorts. Allergen skin prick tests (SPTs) were administered to 1151 families in the Tucson Children’s Respiratory Study (CRS) and 435 families in the Tucson Epidemiological Study of Airway Obstructive Disease (TESAOD). Sensitization was defined by wheal size ≥ 3 mm; physician-diagnosed asthma at age ≥ 8 years was based on questionnaires. Using S.A.G.E. 6.1 software ASSOC and FCOR, familial correlations of crude and adjusted phenotypes were evaluated. Crude estimates of parent-offspring (P-O) and sibling correlations were statistically significant for most allergens, ranging from 0.03 to 0.29. After adjusting for age of assessment and “other atopy” (SPT-positive response to additional allergens), correlations were reduced by14–71%. Sibling correlations for specific response to allergens were consistently higher than P-O correlations, but this difference was significant only for dust mite and weed mix in the TESAOD population. Familial correlation for atopic status (any positive SPTs versus none) tended to be higher than for specific allergens. Asthma, with and without adjustment, showed greater familial correlation than either specific or general SPT response and significantly higher sibling correlation in TESAOD than in CRS, probably due to the older age of the siblings and the longer period of ascertainment. In conclusion, significant familial aggregation of specific response to allergen after adjustment for other atopy appears to reflect a genetic propensity toward atopy, dependent on shared familial exposures. Results also suggest that inheritance of asthma is independent of atopic sensitization.
familial aggregation; specific response to allergens; atopy; asthma
A functional single nucleotide polymorphism in the 5 genomic region of CD14 (CD14/−159) is one of the most widely tested genetic variations in relation to asthma and associated traits. The results of these studies have shown a remarkable, statistically significant heterogeneity, with some studies indicating the T-allele as a risk factor, others the C-allele, and others finding no association. Recent studies in which exposure to house-dust endotoxin or to domestic sources of microbial exposure were assessed concomitantly with CD14/−159 have shown a consistent, replicable gene-environment interaction. Specifically, results suggest that the C-allele is a risk factor for allergic phenotypes at low levels of exposure, whereas the T-allele is a risk factor at high levels of exposure. This finding seems to be explained by a genetically-determined heterogeneity for the protective effect of microbial exposure on allergic phenotypes, with homozygotes for the C-allele showing a much stronger negative association between exposure and allergic outcomes than carries of the other two genotypes. These results suggest that the often encountered, limited replicability of genetic associations may, at least in part, be due to complex interactions between genes and environment in determining asthma-related outcomes.
asthma; CD14; gene–environment interaction
Many environmental factors and a large number of genetic polymorphisms have been reported to be associated with asthma risk in different locales and at different ages. It seems that what we call asthma is a heterogeneous set of conditions for which the only common feature is recurrent airway obstruction that is at least partially responsive to usual asthma therapy. Recent studies in which environmental factors and genetic variants were studied concomitantly have suggested a potential unifying concept for the disease. It seems that asthma is a genetically mediated development dysregulation of diverse immune and airway responses to a variety of specific and nonspecific exposures. It thus seems improbable that most genetic variants associated with asthma influence the disease regardless of which environmental factors trigger it and at which lifetime phase they are present. More likely, the most important gene variants for asthma are polymorphisms that exert their influence on the network system controlling biological responses to asthma-related exposures.
asthma; genetics; environment; interaction
Exacerbations are responsible for a substantial burden of morbidity and health care utilization in children with asthma. Most asthma exacerbations are triggered by viral infections, however, the underlying mechanisms have not been systematically investigated.
The objective of this study was to elucidate the molecular networks that underpin virus-induced exacerbations in asthmatic children in vivo.
We followed exacerbation-prone asthmatic children prospectively, and profiled global patterns of gene expression in nasal lavage samples obtained during an acute, moderate, Picornavirus-induced exacerbation, and 7–14 days later. Coexpression network analysis and prior knowledge was employed to reconstruct the underlying gene networks.
The data showed that an intricate, modular program consisting of more than one thousand genes was upregulated during acute exacerbations, in comparison to 7–14 days later. The modules were enriched for coherent cellular processes, including interferon-induced antiviral responses, innate pathogen sensing, response to wounding, small nucleolar RNAs, and the ubiquitin-proteosome and lysosome degradation pathways. Reconstruction of the wiring diagram of the modules revealed the presence of hyper-connected hub nodes, most notably IRF7, which was identified as a major hub linking interferon-mediated antiviral responses.
This study provides an integrated view of the inflammatory networks that are upregulated during virus-induced asthma exacerbations in vivo. A series of innate signalling hubs were identified that could be novel therapeutic targets for asthma attacks.
Asthma; exacerbation; Picornavirus; rhinovirus; gene expression; gene networks; innate immunity; interferons; systems biology
Several studies have reported associations between indicators of birth size and postnatal growth rates with levels of pulmonary function achieved as adults. The objective of this study was to determine if levels and/or rates of weight gain, measured in early life (birth-6 yrs), are associated with FVC or FEV1 levels achieved in young adulthood and if these associations differ by early childhood wheezing phenotypes.
We used data from participants in the Tucson Children's Respiratory Study (CRS), a prospective birth cohort study. Weight was measured quarterly up to age 3 yrs and again at age 6 years. Pulmonary function was assessed at ages 16 and 22. Mean weight and slope of weight growth between 3 and 6 yrs were estimated using standardized residuals. Longitudinal models were used to determine predictors of FVC and FEV1 at ages 16 and 22 yrs.
There were 127 non-Hispanic white subjects that had at least 4 weight measures and one or more pulmonary function measures as young adults. After adjusting for sex, height, and age, the standardized slope of weight growth, (between 3 and 6 years), was positively associated with higher levels of FVC at age 16 and 22 years (p=0.0001) among subjects who did not have pre-school wheezing. However, this association was completely absent among subjects who had wheezing lower respiratory tract illnesses in the first three years of life. Similar trends were found for FEV1.
The rate of weight gain between 3-6 yrs is significantly positively related to adult FVC and FEV1 and this association is modified by early wheezy phenotypes.
Growth velocity; allometric; adulthood lung function
Daily inhaled glucocorticoids are recommended for young children at risk for asthma exacerbations, as indicated by a positive value on the modified asthma predictive index (API) and an exacerbation in the preceding year, but concern remains about daily adherence and effects on growth. We compared daily therapy with intermittent therapy.
We studied 278 children between the ages of 12 and 53 months who had positive values on the modified API, recurrent wheezing episodes, and at least one exacerbation in the previous year but a low degree of impairment. Children were randomly assigned to receive a budesonide inhalation suspension for 1 year as either an intermittent high-dose regimen (1 mg twice daily for 7 days, starting early during a predefined respiratory tract illness) or a daily low-dose regimen (0.5 mg nightly) with corresponding placebos. The primary outcome was the frequency of exacerbations requiring oral glucocorticoid therapy.
The daily regimen of budesonide did not differ significantly from the intermittent regimen with respect to the frequency of exacerbations, with a rate per patient-year for the daily regimen of 0.97 (95% confidence interval [CI], 0.76 to 1.22) versus a rate of 0.95 (95% CI, 0.75 to 1.20) for the intermittent regimen (relative rate in the intermittent-regimen group, 0.99; 95% CI, 0.71 to 1.35; P=0.60). There were also no significant between-group differences in several other measures of asthma severity, including the time to the first exacerbation, or adverse events. The mean exposure to budesonide was 104 mg less with the intermittent regimen than with the daily regimen.
A daily low-dose regimen of budesonide was not superior to an intermittent high-dose regimen in reducing asthma exacerbations. Daily administration led to greater exposure to the drug at 1 year.
SOCS-1 is a critical regulator of multiple signaling pathways, including those activated by cytokines that regulate immunoglobulin heavy chain class switching to IgE. Analysis of mice with mutations in the SOCS-1 gene demonstrated that IgE levels increase with loss of SOCS-1 alleles. This suggested that overall SOCS-1 acts as an inhibitor of IgE expression in vivo. A genetic association study was performed in 474 children enrolled in the Tucson Children’s Respiratory Study to determine if genetic variation in the SOCS-1 locus correlates with altered levels of IgE. Carriers of the C-allele for a novel, 3′ genomic single nucleotide polymorphism (SNP) in the SOCS-1 gene (SOCS1+1125G>C; rs33932899) were found to have significantly lower levels of serum IgE as compared with homozygotes for the G-allele. Analysis demonstrated that the SOCS1+1125G>C SNP was in complete linkage disequilibrium with a SNP at position SOCS1−820G>T (rs33977706) of the SOCS-1 promoter. Carriers of the T-allele at the SOCS1−820G>T were also found to be associated with. The promoter SNP increased transcriptional activity of the SOCS-1 promoter in reporter assays and human B cells. Consistent with this observation, the presence of this polymorphism within the promoter abolished binding of Yin-Yang-1, which is identified as a negative regulator of SOCS-1 transcriptional activity. These data suggest that genetic variation in the SOCS-1 promoter may affect IgE production.
Variation in TLR2 gene (TLR2/−16934) is associated with allergic diseases amongst farmers' children, but not amongst children not living on farms.
To test the hypothesisis that the same genetic variant which confers protection in the farming environment is associated with reduced risk of developing allergic phenotypes amongst urban children attending day-care in early life.
In two population-based birth cohorts (Manchester, UK-MAAS and Tucson, USA-IIS) participants were recruited prenatally and followed prospectively (MAAS: 3, 5, 8 and 11 years; IIS: 1, 2, 3 and 5 years). We assessed allergic sensitization and atopic wheezing at each follow-up.
727 children participated in Manchester and 263 in Tucson. We found no significant associations between TLR2/−16934 and sensitization and atopic wheeze in either cohort. However different pattern emerged when we explored the interaction between TLR2/−16934 and day-care attendance on these outcomes. We found a significant interaction between day-care and TLR2/-16934 on the development of sensitization in the longitudinal model in MAAS, in that children carrying T allele who attended day-care were less likely to be sensitized than those who did not attend day-care, whilst amongst AA homozygotes the association tended to be in the opposite direction. In a longitudinal model in IIS, we found a significant interaction between day-care attendance and TLR2/-16934 on the development atopic wheezing. Significant interactions between TLR2/-16934 and day-care were maintained when adjusting for socioeconomic status
The effect of day-care on sensitization and atopic wheezing may differ among children with different variants of theTLR2 gene.
gene*environment interactions; asthma; allergic sensitisation; birth cohorts; TLR2
Cost-effectiveness analyses of asthma controller regimens for adults exist, but similar evaluations exclusively for children are few.
To compare the cost-effectiveness of two commonly used asthma controllers, fluticasone and montelukast, with data from the Pediatric Asthma Controller Trial.
We compared the cost-effectiveness of low-dose fluticasone with montelukast in a randomized controlled multi-center clinical trial in children with mild-moderate persistent asthma. Analyses were also conducted on subgroups based on phenotypic factors. Effectiveness measures included a) the number of asthma-control days, b) the percentage of participants with an increase over baseline of FEV1≥12%, and c) the number of exacerbations avoided. Costs were analyzed from both a US health care payer's perspective and a societal perspective.
For all cost-effectiveness measures studied, fluticasone cost less and was more effective than montelukast; e.g., fluticasone treatment cost $430 less in mean direct cost (P<0.01) and had 40 more asthma control days (P<0.01) during the 48 week study period. Considering sampling uncertainty, fluticasone cost less and was more effective at least 95% of the time. For the high eNO phenotypic subgroup (eNO≥25ppb) and more responsive PC20 subgroup (PC20<2 mg/mL), fluticasone was cost-effective compared with montelukast for all cost-effectiveness measures; whereas not all the effectiveness measures were statistically different for the other two phenotypic subgroups.
For children with mild-moderate persistent asthma, low dose fluticasone had lower cost and higher effectiveness compared with montelukast, especially in those with more airway inflammation as indicated by elevated levels of eNO and more responsivity to methacholine.
Cost-effectiveness analysis; childhood asthma; fluticasone; montelukast; PACT
A subset of children with asthma respond better to leukotriene receptor antagonists (LTRA) than to inhaled corticosteroids (ICS). Information is needed to identify children with these preferential responses.
To determine whether the ratio of urinary leukotriene E4 to fractional exhaled nitric oxide (LTE4: FENO) delineates children with preferential responsiveness to montelukast (MT) compared to fluticasone propionate (FP) therapy.
Data from 318 children with mild to moderate asthma enrolled in 2 NHLBI CARE network studies (CLIC and PACT) were analyzed. The association between LTE4: FENO ratios at baseline and improved lung function or asthma control days (ACDs) with MT and FP therapy was determined and phenotypic characteristics related to high ratios was assessed.
LTE4: FENO ratios were associated with a greater response to MT than FP therapy for forced expiratory volume in 1 second (FEV1) measurements (2.1% increase per doubling of ratio, p=0.001) and for ACDs per week (0.3 increase, p= 0.009) in the CLIC study. In PACT, the ratio was associated with greater FEV1 responsiveness to MT than FP therapy (0.6% increase, p= 0.03). In a combined study analysis, LTE4: FENO ratios were associated with greater response to MT than FP therapy for FEV1 (0.8% increase, p=0.0005) and ACDs (0.3 increase, p=0.008). Children with LTE4: FENO ratios at or above the 75th percentile were likely (p<0.05) to be younger, female and exhibit lower levels of atopic markers and methacholine reactivity.
LTE4: FENO ratios predict a better response to MT than FP therapy in children with mild to moderate asthma.
In children with mild to moderate asthma, the LTE4: FENO ratio is associated with a better response to montelukast compared to fluticasone therapy.
Data from 318 children with mild to moderate asthma enrolled in 2 NHLBI network studies (CLIC and PACT) were analyzed. Urinary LTE4: FENO ratios predicted a better response to MT than FP therapy.
asthma; biomarkers; fluticasone propionate; inhaled corticosteroids; leukotriene E4; montelukast
Recent studies have suggested that a restrictive pattern assessed with a single spirometry is associated with increased morbidity and mortality. In this study, we sought to determine demographic, clinical, and mortality profiles of subjects with either a recurrent or inconsistent restrictive spirometric pattern assessed prospectively.
We analyzed data from 2048 adult participants in the population-based TESAOD study. Normal (FEV1/FVC ratio≥70% and FVC≥80% predicted), restrictive (FEV1/FVC≥70% and FVC<80% predicted), and obstructive (FEV1/FVC<70%) patterns were assessed at the enrollment survey (1972) and in eleven subsequent follow-up surveys up to 1996. Demographic and clinical characteristics were measured at enrollment and vital status and cause of death were assessed as of January 2005.
Overall, 12% of participants had a restrictive spirometric pattern at enrollment. They were less likely to be males, to smoke and to have asthma, and had lower IgE levels as compared with subjects in the obstructive group. Among subjects with a restrictive pattern at enrollment, 38% developed an obstructive pattern during the follow-up. The remaining 62% had either a recurrent (restrictive pattern≥50% of follow-up surveys) or inconsistent (restrictive pattern<50% of follow-up surveys) longitudinal restrictive pattern. The recurrent and inconsistent restrictive groups had increased mortality risk for all-cause (adjHR: 1.7, 1.3–2.3; and 1.9, 1.4–2.6; respectively), heart disease (2.0, 1.3–3.1; and 2.7, 1.7–4.3), stroke (2.4, 0.9–6.3; and 3.5, 1.2–9.8), and diabetes (8.0, 2.9–21.8; and 6.0, 1.9–19.2).
The restrictive spirometric pattern identifies a pulmonary condition that is distinguishable from obstructive lung disease and associated with increased risk of life-threatening co-morbidities.
spirometric restrictive pattern; lung function; mortality; FVC; FEV1; FEV1/FVC; TESAOD
Asthma exacerbations are a common cause of critical illness in children.
To determine factors associated with exacerbations in children with persistent asthma.
Regression modeling was used to identify historical, phenotypic, treatment, and time-dependent factors associated with the occurrence of exacerbations, defined by need for oral corticosteroids, emergency or hospital care in the 48-week Pediatric Asthma Controller Trial (PACT) study. Children aged 6–14 with mild to moderate persistent asthma were randomized to receive either fluticasone propionate 100 mcg BID (FP monotherapy), combination fluticasone 100 mcg AM and salmeterol BID, or montelukast 5 mg once daily.
Of the 285 participants randomized, 48% had 231 exacerbations. Using a multivariate analysis, which included numerous demographic, pulmonary, and inflammatory parameters, only a history of an asthma exacerbation requiring a systemic corticosteroid in the past year (odds ratio 2.10, p<0.001) was associated with a subsequent exacerbation during the trial. During the trial, treatment with montelukast vs. FP monotherapy (OR 2.00, p=0.005), season (spring, fall, or winter vs. summer, p=<0.001), and average seasonal 5% reduction in AM peak expiratory flow (PEF) (OR 1.21, p=0.01) were each associated with exacerbations. Changes in worsening of symptoms, beta-agonist use, and low PEF track together before an exacerbation, but have poor positive predictive value of exacerbation.
Children with mild to moderate persistent asthma with prior exacerbations are more likely to have a repeat exacerbation despite controller treatment. Inhaled corticosteroids are superior to montelukast at modifying the exacerbation risk. Available physiologic measures and biomarkers, and diary card tracking are not reliable predictors of asthma exacerbations.
Airway inflammation; Asthma; Bronchial hyperresponsiveness; Childhood asthma; Exacerbations
Asthma exacerbations are associated with subsequent deficits in lung function. Here, we tested the hypothesis that a specific pattern of inflammatory responses during acute exacerbations may be associated with chronic airway obstruction. Gene coexpression networks were characterized in induced sputum obtained during an acute exacerbation, from asthmatic children with or without chronic airflow limitation. The data showed that activation of Th1-like/cytotoxic and interferon signalling pathways during acute exacerbations was decreased in asthmatic children with deficits in baseline lung function. These associations were independent of the identification of picornaviruses in nasal secretions or the use of medications at the time of the exacerbation. Th2-related pathways were also detected in the responses, but variations in these pathways were not related to chronic airways obstruction. Our findings demonstrate that decreased activation of Th1-like/cytotoxic and interferon pathways is a hallmark of acute exacerbation responses in asthmatic children with evidence of chronic airways obstruction.
Asthma exacerbations; airflow obstruction; virus infection; inflammation; gene networks; NKT cells
For children who have uncontrolled asthma despite the use of low-dose inhaled corticosteroids (ICS), evidence to guide step-up therapy is lacking.
We randomly assigned 182 children (6 to 17 years of age), who had uncontrolled asthma while receiving 100 µg of fluticasone twice daily, to receive each of three blinded step-up therapies in random order for 16 weeks: 250 µg of fluticasone twice daily (ICS step-up), 100 µg of fluticasone plus 50 µg of a long-acting beta-agonist twice daily (LABA step-up), or 100 µg of fluticasone twice daily plus 5 or 10 mg of a leukotriene-receptor antagonist daily (LTRA step-up). We used a triple-crossover design and a composite of three outcomes (exacerbations, asthma-control days, and the forced expiratory volume in 1 second) to determine whether the frequency of a differential response to the step-up regimens was more than 25%.
A differential response occurred in 161 of 165 patients who were evaluated (P<0.001). The response to LABA step-up therapy was most likely to be the best response, as compared with responses to LTRA step-up (relative probability, 1.6; 95% confidence interval [CI], 1.1 to 2.3; P = 0.004) and ICS step-up (relative probability, 1.7; 95% CI, 1.2 to 2.4; P = 0.002). Higher scores on the Asthma Control Test before randomization (indicating better control at baseline) predicted a better response to LABA step-up (P = 0.009). White race predicted a better response to LABA step-up, whereas black patients were least likely to have a best response to LTRA step-up (P = 0.005).
Nearly all the children had a differential response to each step-up therapy. LABA step-up was significantly more likely to provide the best response than either ICS or LTRA step-up. However, many children had a best response to ICS or LTRA step-up therapy, highlighting the need to regularly monitor and appropriately adjust each child’s asthma therapy. (ClinicalTrials.gov number, NCT00395304.)
Asthma increased dramatically in the last decades of the 20th century and is representative of chronic diseases that have been linked to altered microbial exposure and immune responses. Here we evaluate the effects of environmental exposures typically associated with asthma protection or risk on the microbial community structure of household dust (dogs, cats, and day care). PCR-denaturing gradient gel analysis (PCR-DGGE) demonstrated that the bacterial community structure in house dust is significantly impacted by the presence of dogs or cats in the home (P = 0.0190 and 0.0029, respectively) and by whether or not children attend day care (P = 0.0037). In addition, significant differences in the dust bacterial community were associated with asthma outcomes in young children, including wheezing (P = 0.0103) and specific IgE (P = 0.0184). Our findings suggest that specific bacterial populations within the community are associated with either risk or protection from asthma.
Together with smoking, the level of lung function attained in early adulthood is among the strongest predictors of chronic obstructive pulmonary disease. Whether airway function measured shortly after birth is a determinant of this level is currently unknown.
Non-selected infants were enrolled at birth in the Tucson Children's Respiratory Study in 1980-84. Infant maximal expiratory flows at functional residual capacity (V'maxFRC) were measured by the chest compression technique at 2 months (mean±SD: 2.3±1.9m); values were logarithmically transformed and adjusted for length. Forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and forced expiratory flow between 25% and 75% of FVC (FEF25-75) were measured at ages 11, 16 and 22 years before and after 180μg of albuterol. Participant characteristics were determined at enrollment and at each time of testing.
Airway function was available for 123 participants in infancy and at least once at ages 11, 16 or 22 years. Using a random effects model, participants in the lowest quartile for infant V'maxFRC had persistently lower values for FEV1/FVC ratio (-5.2%, p<0.001), FEF25-75 (-663ml/s, p<0.001) and FEV1 (-233ml, p=0.001) through age 22 compared to the upper three quartiles, after adjusting for height, weight, age and sex. The magnitude and significance of the effect did not change appreciably after additionally adjusting for current wheeze, smoking, atopy and parental asthma.
Diminished airway function present shortly after birth is a risk factor for airflow obstruction in early adult life.
Incidence of asthma increases during the early adult years, but the relative influence of sex and early life factors in determining newly diagnosed asthma in young adults is unknown.
Healthy newborns (n=1246) were enrolled in the Tucson Children's Respiratory Study. Parental characteristics early life wheezing phenotypes, airway function and bronchial hyperresponsiveness to cold dry air and sensitization to Alternaria were determined by age 6 years. Physician diagnosed asthma, both chronic and newly diagnosed, and airway function were determined at age 22 years.
Average incidence of asthma between 16 and 22 years was 12.6 per thousand person-years. One fourth of all cases of active asthma at age 22 were newly diagnosed, of which 71% were females. Asthma remittance by age 22 was higher among males (p=0.008). Age at diagnosis was linearly associated with FEV1/FVC ratio at age 22. Late-onset (multinomial odds ratio [M-OR]= 7.4 [95% CI:3.9,14]) and persistent wheezing (M-OR=14.0 [6.8,28]) in early life, sensitization to Alternaria (M-OR=3.6 [2.1,6.4]), low airway function at age 6 (M-OR=2.1 [1.1,3.9]) and bronchial hyperresponsiveness at age 6 (M-OR=4.5 [1.9,10]) were independently associated with chronic asthma at age 22. Bronchial hyperresponsiveness (M-OR=6.9 [2.3,21]), low airway function at age 6 (M-OR=2.8 [1.1,6.9]), late-onset (M-OR=4.6 [1.7,12]) and persistent wheezing (M-OR=4.0 [1.2,14]) predicted newly diagnosed asthma at age 22.
Among young adults, females preferentially develop newly diagnosed asthma, but most had already wheezed in early life and had bronchial hyperresponsiveness by age 6. The roots of early adult onset asthma can be found in the preschool years.
In children with mild-moderate persistent asthma, identification of phenotypic predictors to guide selection of a controller regimen is essential.
Identify phenotypic characteristics retaining predictive value for the difference in treatment responses between twice daily fluticasone and once-daily montelukast.
Data from the Pediatric Asthma Controller Trial (PACT) were assessed with multivariate analysis. Outcomes included the change in asthma control days (ACDs), FEV1, peak expiratory flow and time to first asthma exacerbation measured over a one-year treatment period.
The mean age was 9.6 +/- 2.1 years, 60% were male, 50% had a parental history of asthma and 78% had positive aeroallergen skin prick tests. The mean %-predicted pre-bronchodilator FEV1 was 97.8 +/-12.9, median PC20 was 0.93 mg/ml and median exhaled nitric oxide (eNO) was 25.2 ppb. A history of parental asthma best predicted the expected treatment benefit with fluticasone compared to montelukast in terms of gain in ACDs (adjusted p=0.02) and time to first exacerbation (adjusted p=0.05). Elevated baseline eNO predicted the differential treatment response for fluticasone regarding the gain in ACDs (adjusted p=0.01). Prior inhaled corticosteroid (ICS) use (adjusted p=0.01) and low PC20 (adjusted p=0.03) each predicted the expected treatment benefit with fluticasone over montelukast regarding time to first exacerbation. No phenotypic characteristics predicted treatment benefits for montelukast over fluticasone for either outcome.
Physicians treating children with parental history of asthma, elevated eNO, low PC20, or history of ICS use can expect the best long-term outcomes with ICS therapy, as compared to treatment with leukotriene receptor antagonists.
asthma; biomarkers; exhaled nitric oxide; fluticasone propionate; inhaled corticosteroids; montelukast; pulmonary response
Acute wheezing illnesses in preschoolers need better management strategies to reduce morbidity.
To examine the effectiveness of episodic use of an inhaled corticosteroid and a leukotriene receptor antagonist in preschoolers with intermittent wheezing.
In a randomized, double-blind placebo-controlled twelve-month trial, 238 children aged 12-59 months with moderate-severe intermittent wheezing received 7-days of either budesonide inhalation suspension (1mg twice daily), montelukast (4mg daily), or placebos in addition to albuterol with each identified respiratory tract illness. Proportion of episode-free days (EFDs) during the 12-month trial was the primary outcome.
The three treatment groups did not differ in proportions of EFDs, with adjusted mean (95% CI) EFDs of 76% (70%, 81%) for budesonide, 73% (66%, 79%) for montelukast, and 74% (65%, 81%) for conventional therapy (p=0.66). The three groups did not differ in oral corticosteroid use, health care utilization, quality of life, or linear growth. However, during respiratory tract illnesses, budesonide and montelukast therapy led to modest reductions in trouble breathing [(38% (p=0.003) and 37% (p=0.003)] and interference with activity scores [32% (p=0.01) and 40% (p=0.001)], most evident in those with positive asthma predictive indices.
In preschool children with moderate-to-severe intermittent wheezing, episodic use of either budesonide or montelukast early in respiratory tract illnesses, when added to albuterol, did not increase the proportion of EFDs or decrease oral corticosteroid use over a twelve-month period. However, indicators of severity of acute illnesses were reduced, particularly in children with positive asthma predictive indices.
The episodic use of budesonide or montelukast in preschool children with moderate-to-severe intermittent wheezing does not increase the proportion of episode free days, but decreases symptom severity during acute respiratory tract illnesses.
Wheezing; preschool children; montelukast; budesonide
Clinical trials in children with moderate to severe persistent asthma are limited.
To determine if azithromycin or montelukast are inhaled corticosteroid-sparing.
The budesonide dose [with salmeterol (50 mcg) twice daily] necessary to achieve control was determined in children 6–17 years of age with moderate to severe persistent asthma. After a budesonide-stable period of 6 weeks, children were randomized in a double-masked, parallel, multi-center study to receive once nightly azithromycin, montelukast, or matching placebos, plus the established controlling dose of budesonide (minimum 400 mcg BID) and salmeterol twice daily. Primary outcome was time from randomization to inadequate asthma control following sequential budesonide dose reduction.
Of 292 children screened, only 55 were randomized. Inadequate adherence to study medication (n=80) and improved asthma control under close medical supervision (n=49) were the major reasons for randomization failure. A futility analysis was requested by the Data Safety Monitoring Board. In data available for analyses, no differences were noted for either treatment compared to placebo in time to inadequate control status (median, weeks (95% CL) azithromycin: 8.4 (4.3, 17.3), montelukast 13.9 (4.7, 20.6), placebo 19.1 (11.7, infinity)), with no difference between the groups (logrank test, p = 0.49). The futility analysis indicated that even if the planned sample size was reached, results of this negative study were unlikely to be different and the trial was prematurely terminated.
Based upon these results, neither azithromycin nor montelukast is likely to be an effective ICS-sparing alternative in children with moderate to severe persistent asthma.
Asthma; Moderate to severe; Children; Macrolide; Leukotriene receptor antagonist; Clinical trial
Most patients who develop persistent airflow limitation do so either as a manifestation of chronic obstructive pulmonary disease that is largely related to smoking or as a consequence of persistent asthma. We sought to compare the natural course of lung function associated with persistent airflow limitation in subjects with and without asthma from early to late adult life.
We studied 2552 participants aged 25 or more who had multiple questionnaire and lung function data from the long-term prospective population-based Tucson Epidemiological Study of Airway Obstructive Disease. Persistent airflow limitation was defined as FEV1/FVC ratio consistently < 70% in all completed surveys subsequent to the first survey with airflow limitation. Participants were divided into nine groups based on the combination of their physician-confirmed asthma status (never, onset ≤ 25 years, or onset > 25 years) and the presence of airflow limitation during the study follow-up (never, inconsistent, or persistent).
Among subjects with an asthma onset ≤ 25 years, blood eosinophilia increased significantly the odds of developing persistent airflow limitation (adjOR: 3.7, 1.4–9.5), whereas cigarette smoking was the strongest risk factor for persistent airflow limitation among non-asthmatics and among subjects with asthma onset after age 25 years. Among subjects with persistent airflow limitation, the natural course of lung function differed between subjects with asthma onset ≤ 25 years and non-asthmatics, with the former having lower FEV1 levels at age 25 (predicted value for a 175-cm tall male of 3,400 versus 4,090 ml, respectively; p<0.001) and the latter having greater FEV1 loss between age 25 and 75 (1,590 versus 2,140 ml; p=0.003).
In subjects who have asthma onset before 25 years of age and persistent airflow limitation in adult life, the bulk of the FEV1 deficit is already established before age 25 years.
asthma; COPD; eosinophilia; airflow limitation
Rationale: The protective effect of breastfeeding on early respiratory infections is well established, but its relationship to the development of subsequent asthma remains controversial.
Objectives: To clarify these complex issues, we examined the association between lung function and infant-feeding practices.
Methods: In the Tucson Children's Respiratory Study, feeding practices were assessed prospectively based on questionnaires completed at enrollment and well-child visits. Formula introduction was categorized as having occurred before 2 months (n = 143, “early formula introduction”), from 2 and before 4 months (n = 336), or at 4 months and older (n = 200, “longer breastfed”). Lung function was measured at age 11 and 16 years. A random-effects model was used to assess the relationship of infant-feeding practices to measures of lung function.
Measurements and Main Results: FVC by age 16 was increased by 103 ± 40.0 ml (P = 0.01), and the FEV1/FVC ratio was lower (−1.9 ± 0.6%, P = 0.004) in the longer breastfed children compared with children with early formula introduction. This effect was modified after stratifying by maternal asthma. Compared with children with early formula introduction, longer breastfed children with asthmatic mothers had an FVC that was not increased (P = 0.7) and an FEV1/FVC ratio (−5.7 ± 2.4%, P = 0.02) that was significantly decreased by age 16. Longer breastfed children with nonatopic, nonasthmatic mothers demonstrated an increased FVC (142 ± 71.1 ml, P = 0.047) and no decrease in FEV1/FVC (P = 0.7) compared with children with early formula introduction.
Conclusions: Longer duration of breastfeeding favorably influences lung growth in children. However, in the presence of maternal asthma, longer breastfeeding is associated with decreased airflows.
breastfeeding; formula feeding; lung function; epidemiology; lower respiratory tract infections; asthma