Lung function and bronchial responsiveness in children who had infantile bronchiolitis

A number of studies have shown that children who had infantile bronchiolitis are at increased risk of recurrent episodes of wheezing. A genetic predisposition to atopy is mentioned in some studies and is contested by others. Lung function abnormalities and increased bronchial responsiveness (BR) have been described after infantile bronchiolitis. We investigated children who had had the clinical syndrome of bronchiolitis during infancy and compared them with asthmatic and healthy children of the same age regarding bronchial caliber, smooth muscle tone, and responsiveness to histamine. Lung function was measured by forced oscillometry. We found that most children with current symptoms had either decreased baseline bronchial caliber, increased bronchial smooth muscle tone, or increased BR. These patients are comparable to mild asthmatics. The children without current symptoms are comparable to healthy children in these respects. Recurrent respiratory symptoms after bronchiolitis should be regarded as mild asthma and treated as such.     

Increased level of bronchial responsiveness in inactive children with asthma

We estimated the association between bronchial responsiveness and hours of exercise per week in children with and without asthma. A random sample of school children (n = 2188), 6-16 years old, was enrolled in a cross-sectional study of asthma in Oslo using the ISAAC questionnaire. Lung function and bronchial responsiveness (BR) using methacholine was measured in a random sample of 80 children with asthma, wheeze and no asthma/no wheeze. The relation between hours of exercise per week and BR [log (DRS)] was estimated by linear regression. Sex and age were included as covariates. Hours of exercise were categorized in: none, 30 min, 1 h, 2-3 h, 4-6 h and 7 h or more. The mean values of log (DRS) were different in the low and high exercise groups for children with asthma (P = 0.02), whereas there was no effect of exercise on BR for children without asthma. BR increased with decreasing hours of exercise per week in children with asthma. The bronchial responsiveness decreased with 0.11 (95% CI -0.20, -0.01) pr unit in scale. This pattern was not present in children without asthma.The results suggest that there is a relation between hours of exercise per week and bronchial responsiveness in children with asthma.     

Bronchodilator responsiveness in infants with bronchiolitis

We evaluated 34 infants with bronchiolitis, (17 of both genders; mean age, 4.6 mos; ranges, 0.7–14.5 mos). The 20 inpatients were significantly younger than the 14 outpatients (2.6 vs. 8.2 months, P < 0.05), and more females were inpatients. Forced expiratory flows at functional residual capacity (V_maxFRC) were obtained at baseline, after aerosolized normal saline (NS), and metaproterenol (0.025 mL/kg in 2 mL NS). Flows were expressed as 2-scores, the difference between the measured and predicted flows, divided by the standard deviation for the predicted value. At baseline, outpatients were more obstructed than inpatients (?1.64 vs. ?0.95, P < 0.05), infants >2 months old were more obstructed than infants s2 months old (?1.54 vs. ?0.80, P < 0.05), and males more than females (? 1.45 vs. ?1.02, P < 0.05). Following NS the whole group had a small but significant decrease in 2-scores (?1.23 to ?1.31, P <: 0.05). Following metaproferenol, the younger infants had significantly (P < 0.05) higher Z-scores compared to baseline and NS (?0.80 vs. ?0.86 vs. ?0.59). However, no significant changes occurred in older infants. Females also had an increased flow after metaproterenol and were less obstructed than after NS (?1.11 vs. ?0.86, P < 0.015). In males no increased flows occurred after metaproterenol (? 1.45 vs. ? 1.48). Bronchodilator responsiveness did not relate to severity of airway obstruction, history of family asthma, allergy, or passive smoke exposure. We conclude that inhaled metaproterenol improves airway function in a subgroup of infants with bronchiolitis, but the subgroup could not clearly be identified because age and gender were confounding factors. Pediatr Pulmonol. 1994; 17:81–85 . © 1994 Wiley-Liss, Inc.     

Atopic status in patients with sarcoidosis.

Sarcoidosis is a multisystem disorder that is characterized by T helper 1 (Th1)-mediated immune response at the sites of disease. Studies showed that T cells derived from patients with sarcoidosis have been able to release Th2 cytokine profile. However, they are believed to be suppressed and nonactive. This study investigated the rate of atopy, a Th2 condition, in sarcoidosis. Atopic status was assessed in 41 patients (13 men and 28 women; mean age, 47.6 +/- 12.2 years) with sarcoidosis. Current history of atopic diseases, including asthma and allergic rhinitis, was assessed in clinical evaluation. Skin-prick tests were performed using a standardized panel. Total immunoglobulin E was measured by chemiluminescence automatic immunoassay. Results are discussed with the conjunction of previous epidemiological studies conducted in adult Turkish populations. Three patients (7%) had a diagnosis of asthma, whereas one patient (2%) had isolated allergic rhinitis. Skin-prick tests were positive in two patients (5%). This rate is much lower than the atopy prevalence in Turkey (5% versus 25%). Our data suggest that sarcoidosis may be associated with a lower incidence of atopy and allergic disease; further data are needed in other populations.     

Diurnal variation in bronchial responsiveness in asthmatic children

To establish the presence of a diurnal variation in bronchial responsiveness in asthmatic children, the increase of peak expiratory flow rate (PEFR) followins sympathomimetic inhalation and the response to bronchial provocation with histamine and hyperventilation of cold dry air (HVCDA) were studied. Twenty-nine patients (20 boys, nine girls, aged 9.3 to 17.8 years) measured PEFR before and after sympathomimetic inhalation three times a day for four weeks. A further 15 patients (eight boys, seven girls, aged 6.9 to 18.0 years) underwent bronchial provocation testing every six hours for 24 hours. A diurnal variation in bronchodilator responsiveness was demonstrated in 55% of the first group. Mean amplitude was 60.8% of patients' mean increase in PEFR following bronchodilators. On grouped data, bronchodilation was greater in the morning than in the afternoon (p < 0.0005) or in the evening (p < 0.0005). A diurnal variation in the response to bronchial provocation was also found in the second group, but the timing of the rhythm depended on the stimulus used. On grouped data, airways were most sensitive to histamine at 0400 hours and most sensitive to HVCDA at 1600 hours. The diurnal variation demonstrated in bronchial responsiveness could not be attributed to changes in baseline airway caliber and was present despite the patients' taking sufficient medication to control their asthmatic symptoms.     

Airway responsiveness in infants following bronchiolitis.

Airway responsiveness to inhaled methacholine was assessed in 18 infants, 4 and 10 months old, following bronchiolitis. Pulmonary function was measured from partial expiratory flow-volume curves generated by the rapid compression technique. Sleeping infants inhaled increasing concentrations of methacholine until maximal expiratory flows at functional residual capacity (VmaxFRC) decreased by 30% or 2.5 mg/mL was inhaled. Airway responsiveness was quantitated by: 1) the threshold concentration (log TC) required to decrease VmaxFRC by 2 standard deviations from baseline; 2) the concentration required to decrease VmaxFRC by 30% (log PC30); and 3) the slope of the dose-response curve between TC and PC30 (log SPC30). At both the first and second evaluation, the bronchiolitic infants had lower baseline VmaxFRC (% pred.) than 24 control infants. In addition, the bronchiolitic infants had heightened airway responsiveness compared to controls, demonstrating lower values for logTC and logPC30 and steeper slopes to their dose-response curves (logSPC30). After accounting for the relationship between airway responsiveness and age, the occurrence of bronchiolitis was found to be a significant independent factor 10 months but not 4 months following bronchiolitis. The bronchiolitic infants did not demonstrate the decline in airway responsiveness with increasing age that occurs in normal infants. We conclude that infants exhibit heightened airway responsiveness following bronchiolitis.     

Parental smoking enhances bronchial responsiveness in nine-year-old children

We studied the relationship between parental smoking habits and atopy and bronchial responsiveness (BR) in 9-year-old, non-selected schoolchildren. A questionnaire on respiratory disease and maternal and paternal smoking habits was administered to one parent. Skin prick tests using the most common allergens present in central Italy, a flow-volume spirometric test, and a bronchial provocation test using carbachol in increasing doses were performed. Male children with smoking parents had significantly increased BR when compared to those whose parents did not smoke (Odds Ratio (OR) = 4.3, p = 0.009). No such significant increase in BR was found in female children of smoking parents (OR = 1.5, p = 0.4). The relationship between BR in children and smoking in parents was stronger in asthmatics (p = 0.02), but was still significant after controlling for asthma and atopy. Bronchial responsiveness was significantly correlated with atopy (p = 0.001). This was also true for nonasthmatic children and for both males and females separately. Male children of smoking parents had increased reactivity to allergens as assessed by the skin prick test index (p = 0.001). It is hypothesized that passive smoking, by increasing the frequency of BR and of atopy, may increase the risk of asthma in childhood and particularly in boys.     

Acoustic vs. spirometric assessment of bronchial responsiveness to methacholine in children.

To study wheezing as an indicator of bronchial responsiveness during methacholine challenge (MC) in children, we used computer analysis of respiratory sounds and compared wheeze measurements to routine spirometry. MC was performed in 30 symptomatic subjects (sympt), age 11 ± 3.1 years (mean ± SD), with suspected asthma and in 12 controls (contr), age 10 ± 3.4 years. Respiratory rate (RR), spirometry, arterial oxygen saturation (Sa, _O2), and cough were registered until the concentration provoking a ≥ 20% fall in forced expiratory flow in 1 second (FEV₁; PC₂₀), or the end point (8 mg/mL) was reached. For 1 min after each inhalation, sounds over the trachea and posterior right lower lobe were recorded together with calibrated airflow. Computer analysis of respiratory sounds was used for objective wheeze quantification. Wheezing was measured as its duration relative to inspiration (T_w/T_i,) and expiration (T_w/T_e,). Seventeen of the sympt group developed wheezing (sympt/W) with ≥ T_w/T_i, or ≥ 5% T_w/T_e Thirteen of the sympt did not wheeze (sympt/no W). Three contr developed wheeze (contr/w) while 9 did not (contr/no W). In sympt/W, RR increased from 20 ± 6.2 per min at baseline to 25 ± 9.2 (P < 0.05) at the MC concentration provoking wheeze (PC_w), and Sa_O2, decreased from 97.4 ± 1.2% to 95.3 ± 2.4 (P < 0.05). In contr/W, RR did not change, but Sa_O2, decreased from 97.3 ± 1.5% to 95.7% ± 1.2% (P < 0.05). Wheezing occurred at both recording sites and was as common during inspiration as during expiration. In subjects who had both PC_w and PC₂₀, these variables correlated well (r = 0.82, P < 0.0001). Three SW did not reach PC₂₀ (maximum fall in FEV₁ 8%, 12%, and 18%). On the other hand, 6 of 13 sympt/no W and 2 of 12 contr/no W had a positive MC. Thus, wheezing during MC had a sensitivity of 68% and a specificity of 82%. Acoustic measurements were reproducible in 14 subjects who performed a second MC within 2–10 months. We conclude that wheezing during MC in children strongly suggests airway hyperresponsiveness; however, wheeze detection cannot fully replace spirometry in bronchial provocation testing. © 1993 Wiley-Liss, Inc.     

Intestinal helminth infestation is associated with increased bronchial responsiveness in children

Non-atopic asthma is the predominant phenotype in non-affluent parts of Latin America. We recently reported that infestation with Ascaris lumbricoides increased the risk of non-atopic asthma in less affluent areas of Brazil but the mechanism is unclear. The present study was conducted to determine whether helminth infestation is associated with heightened bronchial responsiveness (BHR), a common finding in asthma. A random sample of 50 asthmatic and 50 non-asthmatic controls (mean age 10.1 years) were selected from a larger cohort (n = 1,011) without knowledge of their helminth infestation status. Three stool samples were collected from each child on different days and each sample was analyzed by the Kato-Katz method for quantitative determination of helminth eggs. Bronchial provocation tests were performed with inhaled 4.5% hypertonic saline using the ISAAC Phase II standardized protocol. There was no difference between the prevalence of positive BHR in the asthmatics (20.4%) compared with the controls (14.6%) (P = 1.0). Helminth infestation was detected in 24.0% of children, with A. lumbricoides being the most common. Children with high load infestation (>or=100 eggs/g) were five times more likely to have BHR than children with low load or no infestation. Despite the small sample size the results of the present study suggest that the link between high load helminth infestation and non-atopic asthma may be mediated via heightened bronchial responsiveness, possibly due to an inflammatory response to the pulmonary phase of the helminth life cycle.     

Repeatability of bronchial responsiveness to mannitol dry powder in children with asthma

Our objective was to determine the repeatability of bronchial responsiveness to mannitol dry powder (MDP) as an objective marker of asthma in children. MDP challenge was performed in children with stable asthma at the same time of the day on two separate occasions within a week. The test was terminated after a 15% fall of forced expiratory volume in 1 sec (FEV1) and the provocative dose to produce a 15% fall in FEV1 (PD15) were calculated. Seventeen children (aged 9-16 years) on inhaled corticosteroids (200-1,500 mcg) were studied. Mean baseline FEV1 before the challenges were 95% (81-119) and 96% (74-121), respectively, with a standard deviation of differences of 5.2%. PD(15) values ranged from 7-387 mg, with a geometric mean of 38 mg for the first and 49 mg for the second test. Of the 17, all but two pairs of tests achieved a PD15 within one dose of capsules. Four children had a negative challenge on two occasions. A high relative reliability was reflected by a concordance coefficient of 0.86. In conclusion, MDP is a convenient challenge which is easy to administer and is well-tolerated by children. It is a highly reproducible test of airway responsiveness in children with moderate to severe persistent asthma on inhaled corticosteroids within 7 days under laboratory conditions.     

Effect of inhaled steroid therapy on exhaled nitric oxide and bronchial responsiveness in children with asthma.

Inhaled steroid therapy is reported to reduce the level of exhaled nitric oxide (eNO), but the effects of inhaled corticosteroids (ICS) on bronchial hyperresponsiveness (BHR) have been controversial. The aim of this study was to determine the effects of ICS on the relationship between eNO and BHR. Twenty-six children with asthma were recruited, including 14 children who were receiving ICS (ICS group) and 12 who were not (ICS-naive group). The fractional exhaled nitric oxide concentration (FE(NO)) was examined by the recommended online method. To evaluate BHR, an acetylcholine challenge test was performed. In the ICS-naive group, FE(NO) was significantly correlated with PC20 (p < 0.05, r = -0.70), but not in the ICS group. In conclusion, FE(NO) was significantly correlated with BHR in the ICS-naive group, but this relationship was not present in the ICS group. Our results suggest that the use of ICS should be taken into consideration when evaluating the relation between BHR and airway inflammation.     

Agreement between spirometry and tracheal auscultation in assessing bronchial responsiveness in asthmatic children.

We have recently found that changes in lung sounds correspond well with a 20% fall in the forced expiratory volume in 1 s (FEV1) after methacholine challenge in asthmatic children. Up to now, little was known about the agreement between a 20% fall in FEV1 and a change in lung sounds after repeated bronchial challenge. In this study we investigated the agreement between the total cumulative histamine dose causing a fall in FEV1 of 20% or more (PD20) and the detection of a change in lung sounds (PDlung sounds) after two bronchial challenges on different occasions in asthmatic children. Fifteen asthmatic children (nine boys), mean age 10.8 years (range 9-15), were studied. All performed two histamine challenge tests on 2 days, with a 24 h to 1 week interval. Lung sounds were recorded over the trachea for 1 min and stored on tape. Lung sounds were analysed directly and also scored from the tape-recording by a blinded second investigator. Wheeze, cough, and an increase in respiratory rate were assessed. The relationship between PD20 and PDlung sounds was calculated by Bland and Altman's measurement of agreement. Eleven children had a positive challenge test (PD20 < or = 16.0 mg ml-1) on both test days; four had a positive challenge on one test day. In 24 out of 26 positive challenges, wheeze, cough, prolonged expiration and/or increased respiratory rate were detected one dose-step before, or at the dose-step of histamine that induced a fall in FEV1 of 20% or more. In two challenges, PD20 was not detected by a change in lung sounds. In four out of four negative challenges (PD20 > 16.0 mg ml-1) no change in lung sounds could be detected. Good agreement between the logarithm of PD20 and the logarithm of PDlung sounds was found on both test days. The mean difference was 0.04 and the limits of agreement (d +/- 2 SD of the differences) were 0.04 +/- 0.41. A good agreement was found between the total cumulative histamine dose causing a fall in FEV1 of 20% or more and the detection of a change in lung sounds after two bronchial challenges on different occasions in asthmatic children.     

Bronchodilator testing "confidence intervals" based on the level of bronchial responsiveness.

"Confidence intervals" based upon inhalation of placebo have been proposed as criteria for defining a significant response to an inhaled bronchodilator. The published intervals were derived from a clinically heterogeneous population. We calculated the difference (delta) between spirometric data before and after placebo in 109 consecutive patients referred for methacholine bronchoprovocation challenge testing. The mean delta, expressed both as a percent change and as actual volume change for both the FVC and FEV1, was not significantly different in patients with bronchial hyperresponsiveness, as compared to subjects with a negative methacholine challenge test; however, the variance of measurements in hyperresponsive subjects was significantly greater than that of the normal population. In addition, as the category of responsiveness increased from mild to moderate to severe hyperresponsiveness, so did the variance within these groups. A negative correlation between the measured PC20FEV1 and the volume and percent change was noted. We conclude that patients with hyperresponsive airways may display increased spirometric variation before and after placebo. This general approach for establishing normal limits for defining a significant response appears to be valid, but the actual values used may vary, depending on the composition of the population tested and the goals of the study. Also, the use of the term, "confidence intervals," in this context is inappropriate; and we propose, instead, the use of percentiles and the simpler terms, upper 90th or 95th percentiles.     

Determinants of bronchial responsiveness at school age in prematurely born children

The bronchial challenge test using isocapnic hyperventilation of cold air (IHCA) was used to evaluate bronchial responsiveness in 63 offspring of multiple pregnancies when they were 8-15 years old. At birth, 27 (43%) children had had intrauterine growth retardation (IUGR, birth weight <-2 SD, or birth weight difference between twin pairs >1.3 SD). The median birth weight was 2,050 g (range, 800-3, 150), and the median gestational age was 35 weeks (range, 28-38). None of the children had asthma or suffered from asthma-like symptoms. In the interpretation of the IHCA test, a fall of 9% or more in the forced expiratory volume in 1 sec (FEV(1)) was considered as abnormal, and these children were classified as "cold air responders." The number of responders was 16 (25%); their baseline FEV(1)/forced vital capacity ratio (FEV(1)/FVC) and forced expiratory flow between 25-75% FVC (FEF(25-75)), but not FEV(1) were significantly lower than the corresponding values in nonresponders. No differences were found in perinatal or neonatal factors between responders or nonresponders. Eight (30%) of the 27 IUGR and 8 (22%) of the 36 appropriate for gestational age (AGA) children were IHCA responders. In particular, IUGR was not correlated with maximal FEV(1) falls following the IHCA test. Respiratory infections after the neonatal period were equally common in IUGR and AGA children; but infections were associated with subsequent IHCA responsiveness. Adenoidectomy, tonsillectomy, and/or myringotomy had been performed significantly more often in the responders than in the nonresponders. At least one of the above invasive procedures had been performed in 20 (32%) of the children; this group was termed the "ENT (ear, nose, throat) surgery group." Fifty-six percent of the responders, but only 26% of the nonresponders, belonged to the ENT surgery group (P = 0.02). We conclude that intrauterine growth retardation or prematurity is not associated with abnormal cold air responsiveness in the IHCA test.     

Effect of corticosteroids on bronchial responsiveness to methacholine in asthmatic children

To elucidate the effects of corticosteroids on nonspecific bronchial reactivity in asthmatic children, inhaled challenges with methacholine were conducted in 10 atopic asthmatic subjects (9 to 15 yr of age) before and after consecutive week-long trials of daily orally administered placebo and prednisone (60 mg/day). Pharmacologic bronchial sensitivity was evaluated as the log dose of methacholine producing a 20% fall in FEV1 (PD20-FEV1). The week-long trial of placebo had no effect on either baseline lung function or PD20-FEV1. On the other hand, after the 1-wk course of prednisone: (1) both baseline FEV1 and FEF25-75 systematically improved in the patients who initially had (i.e., before prednisone) lower values, and (2) PD20-FEV1 significantly increased (p less than 0.001) in all the subjects studied. The magnitude of increase in PD20-FEV1 after prednisone was significantly inversely related (i.e., inverse hyperbola) to the initial degree of airway obstruction (i.e., FEV1) obtained prior to prednisone treatment. Moreover, whereas 6 of 10 patients only minimally changed their baseline FEV1 after prednisone, collectively for all the subjects, the percent increase in PD20-FEV1 after prednisone was directly related (correlation coefficient, 0.70; p less than 0.05) to the corresponding percent increase in baseline FEV1 after prednisone. These findings demonstrate that after a week-long course of high-dose prednisone therapy: (1) a significant reduction occurs in bronchial sensitivity to inhaled methacholine in the asthmatic child, and (2) the degree of diminution in airway sensitivity to methacholine is inversely related to the patient's baseline status of airway obstruction.