Longitudinal Changes in Bronchial Hyperresponsiveness in Asthmatic and Previously Asthmatic Children

doi:10.1378/chest.101.3.624

Chest

Volume 101, Issue 3, March 1992, Pages 624-629

https://doi.org/10.1378/chest.101.3.624 Get rights and content

To determine if nonspecific bronchial hyperresponsiveness is present to the same degree in previously asthmatic children compared with currently asthmatic children, a longitudinal study was conducted. On the basis of a standardized respiratory questionnaire, 139 children from asthmatic families, between the ages of 6 and 21 years, were identified. Subjects had skin tests, a serum IgE level, and a methacholine challenge test. IgE and skin tests demonstrated atopy in both the previously and currently asthmatic children, which persisted over time. Bronchial hyperresponsiveness within the asthmatic children was not significantly different between visits. Previously asthmatic children did have significantly decreased airway hyperresponsiveness over time. Age did not affect the results of the bronchial hyperresponsiveness in the currently asthmatic children. Currently asthmatic children, however, were significantly more atopic when compared with previously asthmatic children at their initial evaluation. Currently asthmatic children were also more bronchial responsive and remained so over time. Bronchial hyperresponsiveness is persistent in children with current asthma symptoms.

Section snippets

Subjects

The subjects included in this report were part of a larger study, the Natural History of Asthma,³ conducted at Creighton University School of Medicine from 1972 to 1990. The subjects were selected from families with asthma, totaling 680 individuals, ascertained by recruitment of an asthmatic proband between the ages of 6 and 21 years and living within a 200-mile radius of Omaha. For this report, 139 subjects between the ages of 6 and 21 years at the initial visit were studied. Subjects were

RESULTS

One hundred thirty-nine children and adolescents, 6 to 21 years of age, were divided into two groups, asthmatic children (n = 117) and PAC (n = 22), and were seen at least once over a period of 18 years. In our Natural History of Asthma study, families with asthmatic members were actively recruited.

The number of PAC, however, is largely coincidental, as this classification was not a criterion for family enrollment. Of the 22 PAC, all had had asthma at least one year prior to the first visit.

Asthmatic Children

Longitudinal Comparison between Asthmatic Children Age: The mean age of the asthmatic children at initial and follow-up visits is seen in Table 3. At initial visit, age did not significantly correlate to the degree of airway responsiveness, as expressed by PD20 (Fig 1).

IgE Levels: Mean IgE levels in asthmatic children at each visit are shown in Figure 2. There was not a significant difference in the mean serum IgE levels in asthmatic children over time.

Skin Tests: The mean TPSs for the

Comparison in Asthmatic Children with and without Follow-up Visits

As seen in Table 3, there was no significant difference for IgE, area₃₅, IgE, and skin tests (TPS) in asthmatic children with only an initial visit when compared with asthmatic children with multiple follow-ups.

Longitudinal Comparison in Asthmatic Children with Follow-up Visits

We compared children with at least one follow-up visit with themselves using comparisons of two consecutive visits. Other than a small decrease in mean IgE levels at visit 2 compared with visit 3, the asthmatic children were consistently methacholine sensitive and atopic (Table 4).

Longitudinal Comparison between PAC

Age: The mean age of the PAC at initial and follow-up visits is seen in Table 3.

IgE Levels: Mean IgE levels in PAC, at each visit, is shown in Figure 2. There was not a significant difference in the mean serum IgE levels in PAC over time.

Skin Tests: The mean TPSs for the PAC, at each visit, are shown in Figure 3. The mean TPS within the PAC group is not significantly different. Previously asthmatic children were consistently skin test positive at all visits.

Methacholine Challenge: Within the

DISCUSSION

Bronchial hyperresponsiveness is one entity used to define asthma. If BHR is measured by methacholine challenge, a level of airway hyperresponsiveness can be established by categorizing the response according to the amount of methacholine needed to produce a significant fall in FEV₁. In clinical studies, the severity of BHR to methacholine correlates strongly with that of asthma symptoms, with the amount of therapy required to control symptoms, and with the diurnal variation in airway function.⁹

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Phenotypic differences between asymptomatic airway hyperresponsiveness and remission of asthma
2011, Respiratory Medicine
Citation Excerpt :
The airway responsiveness in past-asthmatics varies largely. As previous studies, a subset of symptom-free past-asthmatics showed mild AHR.5,11,25 In the present study, 75% of these subjects exhibited less than 8 mg/ml of the PC20, and the overall airway responsiveness (n = 24) was similar to that in never-asthmatics with AHR.
The present study aimed to illustrate differences in characteristics and perception of dyspnea between young atopic adults who have no history of asthma (never-asthmatics) with or without asymptomatic airway hyperresponsiveness (AHR) and those who had childhood asthma and consider themselves to be grown out of the disease (past-asthmatics).
Blood parameters, lung function and methacholine PC₂₀ were measured in 88 never-asthmatics and 24 past-asthmatics. A perception score of dyspnea at 20% fall in FEV₁ (PS₂₀) was obtained by interpolation of the two last points on the perception (modified Borg scale)/fall in FEV₁ curve during methacholine challenge.
Thirty-one of 88 never-asthmatics and eighteen of 24 past-asthmatics exhibited AHR (PC₂₀ was <8 mg/ml). Higher levels of specific IgE to house dust mite in past-asthmatics were observed than never-asthmatics with and without AHR. Mean values of FEV₁ and FEF_25–75 (%predicted) were significantly lower in past-asthmatics than never-asthmatics without AHR, and the values in never-asthmatics with AHR were intermediate between never-asthmatics without AHR and past-asthmatics. PC₂₀ was not significantly different between past-asthmatics and never-asthmatics with AHR. Of particular interest was that PS₂₀ was significantly lower in never-asthmatics with AHR compared with past-asthmatics.
The present findings suggest the possibilities that presence or absence of past history of outgrow of childhood asthma might be associated with airway narrowing, sensitization to house dust mite and perception of dyspnea in young asymptomatic adults with atopy and AHR.
Rationale for the Dutch hypothesis: Allergy and airway hyperresponsiveness as genetic factors and their interaction with environment in the development of asthma and COPD
2004, Chest
Citation Excerpt :
The combination of wheeze and AHR especially distinguishes the asthmatic group with ongoing significant respiratory impairment.7 AHR is persistent in children with persisting symptoms,10 but it generally improves in young asthmatic individuals in their teens.1112 In a longitudinal study of an Australian cohort, it was shown that the coexistence of AHR and wheeze during early childhood identifies individuals who are at increased risk of persistent wheezing who might reasonably be described as having persistent asthma.13
The Dutch hypothesis, formulated in the 1960s, holds that the various forms of airway obstruction are different expressions of a single disease entity. It suggests that genetic factors (eg, airway hyperresponsiveness [AHR] and atopy), endogenous factors (eg, sex and age), and exogenous factors (eg, allergens, infections, and smoking) all play a role in the pathogenesis of chronic nonspecific lung disease. This review finds evidence that AHR and smoking are common risk factors for asthma and COPD. To prove the Dutch hypothesis definitively, however, genetic studies, preferably longitudinal, must be performed. Such studies must include subjects who have airway obstruction that does not necessarily meet the current strict definitions of asthma or COPD (ie, the extremes of these conditions) that are used in clinical studies.
Bronchial hyperresponsiveness in adolescents with long-term asthma remission: Importance of a family history of bronchial hyperresponsiveness
2003, Chest
The mechanisms responsible for bronchial hyperresponsiveness (BHR) in symptomatic asthma include genetic predisposition and airway inflammation, but the causes of BHR in adolescents with asthma remission are poorly understood. It has been shown that BHR in adolescents with asthma remission was not reduced by prolonged treatment with inhaled corticosteroids, in contrast to the BHR of symptomatic asthma.
The aim of this study was to investigate whether family history of BHR may contribute to the persistence of BHR in asthma remission during adolescence.
One hundred twenty-six adolescents with long-term asthma remission (neither symptoms nor any medication used during the previous 2 years) and their parents underwent a methacholine inhalation test. The provocative concentration of methacholine causing a 20% fall in FEV₁ (PC₂₀) and the bronchial responsiveness (BR) index were calculated for each individual.
Sixty-nine adolescents (54.8%) were found to have persisting BHR (PC₂₀ < 18 mg/mL). The frequency of BHR and the BR index were significantly higher in parents (n = 138) of the BHR-persisting group (28.3% and 1.150 ± 0.103, respectively [mean ± 1 SD]) than in parents (n = 114) of BHR-nonpersisting group (16.7% [p = 0.030] and 1.124 ± 0.088 [p = 0.029], respectively). Furthermore, adolescents (n = 56) with at least one BHR-positive parent were found to have a higher frequency of BHR (66.1% vs 45.7%, p = 0.023) and a higher BR index (1.244 ± 0.090 vs 1.204 ± 0.082, p = 0.011) than adolescents (n = 70) with non-BHR parents.
Our results suggest that adolescents in asthma remission are more likely to have BHR when there is a family history of BHR. Further studies are needed to examine the possible involvement of genetic factors in the BHR of adolescents in asthma remission.
Polyclonal and allergen-induced cytokine responses in adults with asthma: Resolution of asthma is associated with normalization of IFN-γ responses
2002, Journal of Allergy and Clinical Immunology
Background: Atopic disease is associated with skewing of immune responses away from a T_H1 toward a T_H2 profile. Previous studies have implicated this cytokine imbalance in the development of disease. However, it is not known whether normalization of this imbalance is conversely associated with disease resolution. Objective: To further delineate the role of reduced T_H1 and increased T_H2 cytokine production in the pathogenesis of atopic disease and to determine whether disease resolution is associated with alteration of cytokine profiles, we investigated cytokine responses in a cohort of adult patients with asthma followed from childhood. Methods: A cohort of wheezy children and control subjects aged 7 to 10 years were recruited from 1964 to 1967. Subjects were reevaluated every 7 years to monitor the outcome of childhood asthma. At the 42-year follow-up, 89 subjects from this cohort were evaluated for mitogen and house dust mite (HDM)-induced T_H1 (IFN-γ) and T_H2 (IL-4, IL-5, and IL-13) cytokine responses. Cytokine responses were compared in patients with ongoing asthma, patients with resolved asthma, and control subjects. Results: Patients with severe ongoing asthma had significantly reduced HDM-induced IFN-γ production compared with that of control subjects and patients with resolved asthma. In contrast, HDM-induced IFN-γ production in patients with resolved asthma was equivalent to that seen in control subjects. Patients with ongoing and resolved asthma produced significantly higher levels of IL-5 in response to HDM compared with that seen in control subjects, with levels being equivalent in patients with active and resolved asthma. HDM-induced IL-13 production was significantly increased in the patients with resolved asthma when compared with that seen in the control subjects. PHA-induced cytokine responses did not parallel HDM-induced responses. Conclusion: Patients with persistent and severe atopic asthma have a reduced HDM-induced T_H1 response, whereas those with resolved asthma do not. This suggests that reduced HDM-induced IFN-γ production might be an important factor contributing to ongoing severe asthma and that normalization of allergen-induced T_H1 responses might be important for disease resolution. The finding that all subjects with a history of asthma displayed increased HDM-induced T_H2 (IL-5 and IL-13) cytokine responses, irrespective of the presence or absence of asthma, suggests that increased T_H2 responses reflect the presence of the atopic state per se rather than being specifically linked to asthma. (J Allergy Clin Immunol 2002;110:450-6.)
Effect of inhaled budesonide on bronchial hyperresponsiveness in adolescents with clinical remission of asthma
2001, Chest
Citation Excerpt :
Although some fluctuations occurred in individual subjects, a small but nonsignificant improvement in PC20 was observed in the placebo group. This is in agreement with the results of a previous study,18 showing that former asthmatic patients had persistence of BHR over time. A similar trend in PC20 was observed in the budesonide group, and there was no significant difference in the PC20 changes between the budesonide and placebo groups.
Many children with asthma go into long-term clinical remission at adolescence, but bronchial hyperresponsiveness (BHR) persists in some of these subjects. The regular use of inhaled corticosteroids improves BHR in patients with symptomatic asthma. The aim of this study was to determine whether BHR in adolescents with asthma remission could be reduced by prolonged treatment with inhaled corticosteroids.
A randomized, double-blind, placebo-controlled, parallel study.
Thirty-seven adolescents with BHR and long-term remission of their asthma (neither symptoms nor any medication use during the previous 2 years).
Subjects received inhaled budesonide (two 200-μg puffs bid; budesonide group, n = 19) or identical placebo (placebo group, n = 18) for 9 months. A separate group of patients with symptomatic asthma (symptomatic group, n = 19), using the same regimen of budesonide, was also studied.
The provocative concentration of methacholine producing a 20% fall in FEV₁ (PC₂₀) was measured before and every 3 months during treatment. There was no significant difference among the three groups for the baseline PC₂₀. In neither the placebo nor the budesonide group did the geometric mean of PC₂₀ change significantly over the 9-month period. In contrast, a significant increase in PC₂₀ was noted in the symptomatic group as a result of the budesonide treatment.
Our data have shown that budesonide inhaled regularly for 9 months did not cause a significant improvement in the BHR of adolescents with long-term asthma remission. This suggests that the mechanism underlying BHR in this clinical setting may be different from that in symptomatic asthma.
The spectrum of irritant-induced asthma: Sudden and not-so-sudden onset and the role of allergy
1998, Chest
A retrospective investigation of 86 asthmatic subjects defined clinical features of irritant-induced asthma and assessed the contributory role of an allergic predisposition. Three categories of asthma were evaluated: (1) occupational asthma due to a sensitizer (11 subjects, 13%); (2) irritant-induced asthma (54 persons, 63%); and (3) not occupational/environmental exposure-related asthma (21 subjects, 24%). Two distinct clinical presentations of irritant-induced asthma emerged: the first was sudden onset (29 subjects) and the second was not so sudden in onset (25 subjects). Sudden-onset, irritant-induced asthma was analogous to the reactive airways dysfunction syndrome. Clinical manifestations began immediately or within a few hours (always within 24 h) following an accidental, brief, and massive exposure. In contrast, for the not-so-sudden-onset asthma subjects, the causative irritant exposure was not brief, usually not massive, continued for >24 h, and the initiation of asthma took longer to evolve. Eighty-eight percent of individuals with not-so-sudden irritant-induced asthma displayed an atopy/allergy status (p<0.01). Some of the atopy/allergy subjects with presumed new-onset asthma were found to have suffered preexisting asthma that had been clinically quiescent for at least 1 year before the triggering exposure (16 persons). We conclude that preexisting allergic/atopy and/or preexisting asthma were significant contributors to the pathogenesis of not-so-sudden, irritant-induced asthma and emphasizes a critical interaction between environmental and host factors in the pathogenesis of asthma.

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Chest

Longitudinal Changes in Bronchial Hyperresponsiveness in Asthmatic and Previously Asthmatic Children

Section snippets

Subjects

RESULTS

Asthmatic Children

Comparison in Asthmatic Children with and without Follow-up Visits

Longitudinal Comparison in Asthmatic Children with Follow-up Visits

Longitudinal Comparison between PAC

DISCUSSION

Chest

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Inhalation methods for the study of airway responsiveness

J Allergy Clin Immunol

American Thoracic Society Executive Committee: epidemiology standardization project

Am Rev Respir Dis

Proceedings First NHLBI Epidemiology Workship

Reference spirometric values using techniques and equipment that meet ATS recommendations

Am Rev Respir Dis