Effect of Age on Bronchial Reactivity in Children with Asthma

In contrast to an abundance of data concerning age-related changes of bronchial sensitivity, the relationship between age and rapidity of bronchoconstriction (bronchial reactivity) remains unclear. We studied age and bronchial reactivity in children with asthma. Enrolled in this study were 511 asthmatic subjects and 115 age-matched control subjects 1 to 16 years of age. Bronchial reactivity was represented by the slope of the methacholine transcutaneous oxygen pressure dose-response curve (SPO₂) in younger children and the slope of the respiratory resistance dose-response curve (SRrs) in older children. Overall, SPO₂ and SRrs were higher in asthmatic than control subjects. SPO₂ increased significantly from 1 to 6 years in asthmatic subjects, reaching a plateau after age 7. This age-related change in SPO₂ also was seen in controls. SRrs in asthmatic subjects decreased after age 13, while SRrs in controls showed no significant change between age 7 and 16. Age-related change in bronchial reactivity occurs during childhood, possibly reflecting early changes in airway smooth muscle maturity and later changes in airway wall rigidity.     

Bronchial sensitivity and bronchial reactivity in children with cough variant asthma

BACKGROUND: Cough variant asthma (CVA) is diagnosed in some children with chronic cough who do not have wheezing. However, the precise mechanism of CVA in children is unclear. OBJECTIVE: To evaluate the physiologic differences in the airways of children with classic asthma and CVA, the methacholine dose-response curves of respiratory resistance (Rrs) were studied. PATIENTS AND METHODS: CVA was diagnosed in 31 children with chronic cough (age range, 5 to 14 years; 19 boys and 12 girls; mean age, 8.5 years) on the basis of methacholine inhalation challenge using an oscillation method. For comparison, the study included 86 age-matched children with classic asthma (age range, 5 to 15 years; 42 boys and 44 girls; mean age, 9.5 years), 25 age-matched children with cough (age range, 5 to 15 years; 17 boys and 8 girls; mean age, 8.8 years), and 23 age-matched control subjects (8 boys and 15 girls; mean age, 9.2 years). Consecutive doses of methacholine were doubled until a 200% increase in Rrs from baseline was reached. The cumulative dose of methacholine at the inflection point of Rrs was considered to represent the bronchial sensitivity to inhaled methacholine (minimum dose of methacholine [Dmin]). The slope of the methacholine dose-response curve (SRrs), which was considered to represent bronchial reactivity, was measured from the increasing Rrs curve. RESULTS: The values of Dmin in classic asthma patients and in CVA patients were significantly lower than those for cough patients and control subjects. There was no significant difference in the values of Dmin between the classic asthma and CVA patients. The value of SRrs in CVA patients was significantly lower than that in classic asthma patients, cough patients, and control subjects (p < 0.05, p < 0.01, and p < 0.01, respectively). There was no significant difference in the value of SRrs between classic asthma patients, cough patients, and control subjects. CONCLUSIONS: These data show that bronchial reactivity in the children with CVA was significantly lower than that in the children with classic asthma, and this specificity has an effect on prolonged cough without wheezing in children with CVA.     

Bronchial Reactivity to Inhaled Methacholine in Infants with Asthma and Age-Matched Controls

To evaluate bronchial hyperresponsiveness (BHR) in infants with asthma and the influence of aging on BHR during the infantile period, bronchial reactivity to inhaled methacholine (BRm) in infants was monitored using the transcutaneous oxygen pressure (tcPO₂) method. One hundred thirty-seven infants with asthma (from 1 to 5 years, mean 3.4 years) and 97 age-matched children without chronic respiratory diseases (from 6 months to 5 years, mean 2.1 years) were enrolled in this study. Consecutive doses of methacholine were doubled until a 10% decrease in tcPO₂ from the baseline was reached. The cumulative dose of methacholine at the inflection point of tcPO₂ (D_min-PO₂) was considered to represent the reactivity of tcPO₂ to inhaled methacholine. D_min-PO₂ values in the asthma groups were lower than those in the control groups in each year-group from 1 to 5. There was no statistical difference in D_min-PO₂ among the 1-4-year-old asthma groups, but D_min-PO₂ in the 5-year-old asthma group was significantly lower than D_min-PO₂ in the 1 -4-year-old asthma groups. The same age-related change in D_min-Po₂ was also seen in the control groups. There was no difference in age-related D_min-PO₂ change between the female group and the male group. We concluded that BRm in asthmatic children increases during the infantile period, and that the age-related changes in BRm, observed in both asthmatic and control infants, may have an effect on the clinical symptoms of asthma during childhood.     

Airway response to carbachol in normal and asthmatic subjects: distinction between bronchial sensitivity and reactivity.

By constructing cumulative dose-response curves to inhaled carbachol in 12 normal and 17 asthmatic subjects with comparable baseline specific airway conductance, we have shown that there were wide variations among subjects in the dose of carbachol needed to cause a 25 per cent decrease in specific airway conductance (bronchial sensitivity) and in the slopes of the curves (bronchial reactivity). Furthermore, there was no significant correlation between these 2 characteristics of the bronchial response to carbachol. The mean dose-response curves of the asthmatic and the normal subjects were widely divergent, indicating that the asthmatic subjects differed from normal subjects more in terms of bronchial reactivity than in bronchial sensitivity. This suggests that different mechanisms determine the sensitivity and reactivity of the bronchial tree, and that hyper-reactivity is the main feature of the asthmatic response. Both should be assessed when the bronchial response to bronchoconstrictor agents is measured.     

Relation of Airway Reactivity and Sensitivity with Bronchial Pathology in Asthma

Airway hyperresponsiveness in asthmatics, which may result from inflammation or remodeling, is expressed as the concentration of methacholine that causes a 20% fall in FEV₁ in the concentration-response curve (PC₂₀). A decrease in PC₂₀ may be due to a steeper curve (hyperreactivity) and/or a curve shift to the left (hypersensitivity). Our purpose was to analyze the relation of airway sensitivity and reactivity to airway pathological changes. The PC₆, as sensitivity parameter, and the slope between PC₂₀ and PC₄₀ as reactivity parameter, were calculated. Total and differential cell counts in the bronchoalveolar lavage fluid, and percentage of epithelial shedding, basement membrane thickness, and submucosal thickness on bronchial biopsy, were measured. The PC₆ showed a correlation with the baseline FEV₁%. The slope was significantly correlated with the basement membrane thickness, and also demonstrated a strong association with submucosal thickness. The PC₂₀ showed a correlation with the baseline FEV₁% and the degree of epithelial shedding. These results suggest that the airway sensitivity and reactivity measurements reflect the degree of airway caliber and remodeling, respectively.     

Maximal Airway Narrowing on the Dose-Response Curve to Methacholine Is Increased After Exercise-Induced Bronchoconstriction

The changes in airway responsiveness between before and after exercise in asthma are not well defined. We investigated the effect of exercise on PC20 (bronchial sensitivity) and maximal airway narrowing (MAN) on the dose-response curve to methacholine in 56 mildly asthmatic children. High-dose methacholine inhalation tests were performed before and 7 hr after exercise challenge. Methacholine PC20 was not changed by exercise, irrespective of exercise-induced bronchoconstriction (EIB). However, the subjects with (+)EIB displayed increased MAN after exercise, whereas those with (±)EIB or (—)EIB did not. The results showed that EIB may be followed by increased MAN but not by the change of bronchial sensitivity.     

Relationship Between Exhaled Carbon Monoxide and Airway Hyperresponsiveness in Asthmatic Patients

The study objectives were to analyze the changes in exhaled carbon monoxide (COex) induced by histamine provocation challenge in asthmatic patients and to evaluate the relationship between COex and airway sensitivity and reactivity. Levels of COex were measured in 105 nonsmoking mildly asthmatic subjects before and after histamine provocation challenge. Dose-response curves were characterized by their sensitivity (PD₂₀) and reactivity. Dose-response slope (DRS), continuous index of responsiveness (CIR), and bronchial reactivity index (BRI) were determined as reactivity indices. Bronchial challenge was positive for 47 subjects and negative for 58. The COex levels rose significantly after bronchial challenge in the positive response group (4.49 ± 0.4 vs. 5.74 ± 0.57 ppm, p = 0.025) and in the negative response group (2.84 ± 0.25 vs 4.00 ± 0.41 ppm, p = 0.000). An inverse relation between basal COex and PD₂₀ was found (r = - 0.318, p = 0.030). In all subjects, a proportional direct relationship between COex and DRS (r = 0.214, p = 0.015), CIR (r = 0.401, p = 0.000), and BRI (r = 0.208, p = 0.012) was observed. On stepwise multiple linear regression analysis, COex only significantly correlated with CIR (multiple r² = 0.174, p = 0.000). In conclusion, exhaled CO determination is a noninvasive inflammatory marker of the respiratory tract, which shows an acceptable association with airway hyperresponsiveness.     

Bronchial response to methacholine in parents of asthmatic children

Cumulative dose response curves to inhaled methacholine were established in 28 parents of asthmatic children, seven parents of healthy children, and four asthmatic patients. Bronchial sensitivity was defined as the dose of methacholine causing a 25 percent decrease in specific airway conductance while bronchial reactivity was determined by the slope of the cumulative dose response curve. Results indicated that parents with allergic rhinitis or airflow limitation in small airways may represent a high risk group, while parents with no atopy and normal pulmonary functions may reflect only the inherited characteristics of bronchial response.     

Analysis of dose-response curves to methacholine. An approach suitable for population studies

Dose-response curves to methacholine were examined in 9 normal and 10 asthmatic volunteers to determine whether the relationship between dose and response can be adequately summarized by means of a single, continuous measure that is not censored at lower levels of bronchial responsiveness. Subjects underwent a standard methacholine challenge test. There was a strong linear relationship between percent decline FEV1 and cumulative dose methacholine. We summarized each dose-response curve by the slope of a line extending from the origin to the last data point obtained. This summary dose-response slope effectively separated asthmatic from normal subjects, and there was a greater than 3,000-fold difference between the least and most responsive subjects. There was a high degree of correlation between the dose-response slope determined by the standard methacholine challenge protocol and that determined by an abbreviated protocol currently being used to examine nonspecific airway responsiveness in a large, longitudinal study of aging. Among the participants of the latter study, there is a unimodal, skewed distribution of dose-response slope. Dose-response slope is proposed as a quantitative measure of nonspecific airway responsiveness that avoids censoring and that may be particularly useful in epidemiologic studies.     

Bronchoconstrictive Properties and Potentiating Effect on Bronchial Responsiveness of Inhaled Thromboxane A2 Analogue (STA2) in Guinea Pigs

Effect of subthreshold concentration of inhaled STA₂, a thromboxane A₂ (TXA₂) analogue, on bronchial responsiveness to histamine was investigated in anesthetized and artificially ventilated guinea pigs. Percent increase in pressure of the airway opening (Pao) by aerosol histamine (50, 100 /tg/ml) was significantly potentiated by subthreshold dose of aerosol STA₂ (0.10 μg/ml) which was determined by dose-response curve of % increase in Pao by inhaled STA₂ (0.033, 0.10, 0.33, 1.0 /xg/ml). These results demonstrated that thromboxane A₂ could contribute to bronchial hyperresponsiveness which is one of the major clinical features of bronchial asthma.     

The shape of the dose-response curve to histamine in asthmatic and normal subjects

In order to determine the shape of the dose-response curves of the human airways to bronchial challenge, changes in forced expiratory volume in one second (FEV1) after inhaled histamine were measured in 8 current asthmatic, 2 mildly asthmatic, and 10 normal subjects. The challenges were continued until a plateau was reached (in all the normal and in the 2 mildly asthmatic subjects), or the FEV1 had fallen by 60%. A sigmoidal equation was fitted to the data points to obtain values for alpha (the position constant) and beta (the slope constant). All the normal and the 2 mildly asthmatic subjects reached a plateau value for fall in FEV1. Current asthmatics were differentiated from normal and mildly asthmatic subjects by the failure to reach a plateau at a 60% fall in FEV1 by higher values for alpha (greater sensitivity to histamine) and by higher values for beta. Ipratropium bromide (an atropinelike drug), in doses that completely inhibited the effects of methacholine, caused no change in the shape or position of the curves in normal or asthmatic subjects. It is concluded that the nature of the airway response to histamine is different in asthmatic from that in normal subjects. It is possible that asthmatics lack a normal mechanism that inhibits severe airway narrowing during histamine challenge.     

Effect of PAF-acether inhalation on nonspecific bronchial reactivity and adrenergic response in normal and asthmatic subjects

Bronchial hyperreactivity, although recognized as a hallmark of asthma, is not totally understood. Mast cell-derived mediators, including histamine, have been shown to cause immediate bronchoconstriction, but until recently, no single mediator has been shown to induce prolonged changes in airway reactivity. Recent reports indicate PAF-acether (PAF) can induce increased nonspecific bronchial reactivity in normal subjects but not in asthmatics. We sought to elucidate the role of PAF in airway hyperreactivity by comparing the effect of inhaled PAF on methacholine and isoproterenol airway responsiveness in six nonasthmatic and six asthmatic subjects. Neither nonspecific airway reactivity nor isoproterenol responsiveness was changed following PAF inhalation in the nonasthmatic subjects in the six days following PAF. Asthmatics had increased airway responsiveness to methacholine at two hours post-PAF, which did not persist. Responsiveness to isoproterenol did not change in the asthmatic subjects. Additional evaluation of the role of PAF in causing changes in airway reactivity is warranted.     

Bronchial reactivity increases soon after the immediate response in dual-responding asthmatic subjects

To determine whether bronchial reactivity is augmented soon after an allergen-induced immediate asthmatic response, we compared reactivity to histamine before and immediately upon resolution of the immediate asthmatic response in seven subjects with mild asthma who were known to develop dual asthmatic responses after inhalation of Kentucky bluegrass allergen. Using a body plethysmograph and quiet breathing technique, specific airway resistance (SRaw) and reactivity to aerosol histamine were assessed on two days prior to allergenic challenge. The dose of histamine that doubled SRaw (PC200His) was determined by interpolation from histamine dose-response curves. On the day of allergenic challenge, each subject inhaled a concentration that was sufficient to induce a dual asthmatic response. Upon resolution of the immediate asthmatic response (45 to 105 minutes) after allergen, the PC200His in all cases had decreased more than 50 percent of its original value (PC200His for the group was 0.29 +/- 1.42 mg/ml [mean +/- SE], compared to 0.84 +/- 1.23 mg/ml initially). Seven or more days after the allergen, each subject had a PC200His comparable to original values. Our data indicate that airway reactivity in dual-responding asthmatic subjects markedly increases soon after the immediate asthmatic response and much before the late asthmatic response manifests clinically. Whether this early increase in bronchial reactivity is a putative requirement for, or shares common characteristics with the late asthmatic response requires further study.     

The presence of airway reactivity before the development of asthma

Exaggerated airway reactivity is an essential component of the current asthmatic. It is not clear, however, if airway reactivity is genetically determined or acquired. To examine the possibility that increased bronchial reactivity exists prior to the development of asthma, we report on 20 subjects who were studied before and after the onset of clinical asthma. Subjects were part of a larger on-going study of the Natural History of Asthma. Thirteen subjects indicated by their answers to the National Heart, Lung, and Blood Institute respiratory questionnaire that they were not asthmatic at their initial visit. Seven subjects had pulmonary symptoms on their initial visit, but had not been diagnosed as asthmatic. Bronchial reactivity was assessed using a standardized methacholine challenge. For the 20 subjects, there was a mean interval of 3.5 yr between the initial visit and the diagnosis of asthma. Ten of 13 nonasthmatic subjects had moderate or strongly positive responses (208 breath units or less) to methacholine prior to onset of asthma. These 13 subjects were compared to age- and sex-matched controls, from both asthmatic and nonasthmatic families, who had not become asthmatic. There was a difference in bronchial responses at the initial visit between the 13 study subjects and their control subjects from nonasthmatic families, but not between the subjects and their controls from asthmatic families. Five of 7 subjects with pulmonary symptoms had responses of 100 breath units or less. Overall, 19 of 20 subjects had strongly positive responses to methacholine after the diagnosis of asthma was established. The results show that enhanced airway reactivity usually precedes the development of asthma, which could support a genetic basis for it.     

Exhaled Nitric Oxide and Bronchial Wall Thickening in Asthmatics During and After Acute Exacerbation: Evidence of Bronchial Wall Remodeling

To assess whether bronchial wall thickening during asthma exacerbations is due to active inflammation in severe asthmatics, we measured bronchial wall thickness and exhaled nitric oxide (FeNO) following treatment. Nine asthmatics were compared with seven controls with high-resolution computed tomography, spirometry, and FeNO measurements. The asthmatic bronchial wall area percent and FeNO was greater than controls. Following treatment, the FEV₁ markedly improved, FeNO decreased modestly, and bronchial wall area percent did not change significantly. Bronchial wall thickening persisted after treatment of acute asthma exacerbation despite improvement in spirometry and decline in FeNO, possibly due to chronic airway remodeling.     

Prostaglandin D2 potentiates airway responsiveness to histamine and methacholine

In the bronchi of asthmatic subjects many bronchoconstrictor mediators and neurotransmitters might be released together, and therefore, potential interactions might occur that could be important in airway hyperreactivity. We have studied the effect of inhaled methacholine, bradykinin, and prostaglandin D2 (PGD2) on bronchial reactivity to inhaled histamine in 6 mild asthmatic subjects, 22 to 36 yr of age. All of the test spasmogens were given at equivalent bronchoconstricting concentrations. Simultaneous dosing with PGD2 caused a significant increase in reactivity to histamine, mean dose of histamine causing a 35% fall in specific airway conductance being 0.72 mumol before, and 0.32 mumol with, PGD2; (p less than 0.01). This was not seen with histamine itself, methacholine, or bradykinin. Prostaglandin D2 caused a similar increase in bronchial reactivity to inhaled methacholine, suggesting a postreceptor potentiation of airway smooth muscle contractility. This positive interaction between inflammatory mediators known to be released in asthma has important implications for understanding bronchial hyperreactivity.     

Cough flow-volume relationships in normal and asthmatic children

The flow-volume profile of a maximum voluntary cough resembles that of a maximum expiratory flow-volume (MEFV) curve with superimposed transient peak flows at the onset of each cough effort and portions of zero flow corresponding to periods of glottis closure. A straight line (the cough slope) can be drawn through the transient peak flows, and the ratio of MEFV-equivalent flow to the cough peak flow can be calculated. This cough ratio has been shown to fall during adult life and may be related to changes in airway compliance and cross-sectional area with age. The present study investigated the cough ratio, cough slope, and maximum flows measured from the cough flow-volume curve in a group of normal children aged 7 to 16 years. Maximum flows and the cough slope increased with height, but the cough ratio did not change with growth or age. In a similar group of asthmatic children, baseline measurements of cough showed a reduction in cough peak flow rates, MEFV-equivalent flow, and the cough ratio. These changes are related to alterations in airway compliance and cross-sectional area and are partly reversed following inhalation of a bronchodilator.     

Usefulness of bronchial reactivity analysis in the diagnosis of bronchial asthma in patients with bronchial hyperresponsiveness

We examined the usefulness of some bronchial reactivity indices to identify bronchial asthma in patients with airway hyperresponsiveness. Eighty-eight consecutive patients with positive response to histamine bronchial challenge (> or = 20% fall in FEV1) were included in the study. Dose-response curves were characterised by their sensitivity (PD20) and reactivity. Dose-response slope, continuous index of responsiveness (CIR) and bronchial reactivity index (BRI) with respect to baseline and post-diluent baseline values were determined as reactivity indices. The clinical diagnosis remaining in the case history 2 years after the bronchial challenge was considered the definitive diagnosis. Asthmatic patients had higher baseline BRI (12.121+/-0.412 vs. 11.615+/-0.201; P<0.001) and post-diluent baseline BRI (12.054+/-0.368 vs. 11.563+/-0.531; P = 0.003) than other subjects. Area beneath their receiver operating characteristic (ROC) curve was 82.68% (standard error: 0.77) for the baseline BRI and 81.73 (standard error: 0.76). By multiple logistic regression analysis, baseline BRI was the only independent variable identified as a predictor for diagnosis of bronchial asthma (r = 0.387, P = 0.0007). A cut-off of 11.76 for baseline BRI reached an 87.2% sensitivity and an 80% specificity for bronchial asthma diagnosis. In conclusion, BRI calculated with respect to baseline FEV1 should be useful in identifying asthmatic patients among subjects with airway hyperresponsiveness.     

Relationship between exhaled carbon monoxide and airway hyperresponsiveness in asthmatic patients.

The study objectives were to analyze the changes in exhaled carbon monoxide (COex) induced by histamine provocation challenge in asthmatic patients and to evaluate the relationship between COex and airway sensitivity and reactivity. Levels of COex were measured in 105 nonsmoking mildly asthmatic subjects before and after histamine provocation challenge. Dose-response curves were characterized by their sensitivity (PD20) and reactivity. Dose-response slope (DRS), continuous index of responsiveness (CIR), and bronchial reactivity index (BRI) were determined as reactivity indices. Bronchial challenge was positive for 47 subjects and negative for 58. The COex levels rose significantly after bronchial challenge in the positive response group (4.49 +/- 0.4 vs. 5.74 +/- 0.57 ppm, p = 0.025) and in the negative response group (2.84 +/- 0.25 vs. 4.00 +/- 0.41 ppm, p = 0.000). An inverse relation between basal COex and PD20 was found (r = -0.318, p = 0.030). In all subjects, a proportional direct relationship between COex and DRS (r = 0.214, p = 0.015), CIR (r = 0.401, p = 0.000), and BRI (r = 0.208, p = 0.012) was observed. On stepwise multiple linear regression analysis, COex only significantly correlated with CIR (multiple r2 = 0.174, p = 0.000). In conclusion, exhaled CO determination is a noninvasive inflammatory marker of the respiratory tract, which shows an acceptable association with airway hyperresponsiveness.     

Abstract

TITLE: Concomitant Chronic Sinusitis Treatment in Children with Mild Asthma. The Effect on Bronchial Hyperresponsiveness

AUTHORS: Tsao CH, Chen LC, Yeh KW.

JOURNAL: CHEST 2003; 123:750-764

Background. Bronchial hyperresponsiveness is an indicator of airways abnormalities and is central to pathophysiology of asthma. Frequent association of asthma and sinusitis has been noted with 80%-90% of children with asthma having concomitant nasal symptoms, and half of all individuals with asthma having radiographic evidence of sinusitis. Several investigators have noted an incidence of chronic sinusitis in the range of 40%-60% of children with bronchial asthma

Objective. The objective of the authors was to ascertain whether effective treatment of sinusitis could decrease bronchial hyperresponsiveness.

The clinical population included 61 children with a history of mild asthma with an age range of 7-10 years, and 10 age-matched health controls followed from 1999 to 2000. All children were mite sensitive in the asthmatic group. They also had occasional symptoms controlled only by betaagonists; 41 of the 61 children with mild asthma had allergic rhinitis.

The children with chronic sinusitis were placed in two groups; one group was treated with amoxicillin clavulanate for 6 weeks and then with nasal saline irrigation for 6 weeks. In the other group, the treatment order was reversed. The children without chronic sinusitis received nasal saline irrigation for 12 weeks.

Clinical Findings. The clinical findings were that there was a significant amelioration in clinical signs and symptoms of sinusitis, but not in FEV₁, after antibiotic treatment. Following aggressive therapy for sinusitis, it was discovered that the provocative concentration of methacholine causing a 20% decline in FEV₁ of children with mild asthma and sinusitis was significantly higher than before antibiotic treatment. PC₂₀s values of children with normal radiographic findings, who were only treated with intranasal salinc for 12 weeks, did not change significantly from baseline.

Conclusion. The result indicate that every asthmatic subject needs to be carefully assessed for concomitant sinusitis. Respiratory infections that meet the criteria for sinusitis even if they do not apparently trigger asthma should be aggressively treated. This study suggests that sinusitis should be kept in mind as a possible factor for producing increased bronchial hyperresponsiveness, and then aggressive therapy for chronic sinusitis is indicated when dealing with an asthmatic patient who has an unacceptable response to appropriate therapy.

Reviewer's Comment. In this study sign and symptoms of sinusitis disappeared after treatment. In a number of patients, nocturnal cough also markedly declined. In contrast with previous reports, however, there is no difference in FEV₁ before and after treatment for sinusitis and this maybe due to the fact that the subjects enrolled had only mild asthma, unlike subjects in previous reports. This study supports the relationship between sinusitis and asthma, the bronchial hyperresponsiveness, and the importance of aggresively treating chronic sinusitis to minimize symptoms of sinusitis, as well as to improve bronchial hyperresponsiveness.

Christopher Randolph, M.D.

Waterbury, CT