Comparison of bronchial challenge with ultrasonic nebulized distilled water and hypertonic saline in children with mild-to-moderate asthma

There is still controversy about the most suitable method to measure bronchial hyperresponsiveness in children. In epidemiological surveys, nonisotonic aerosols are being used increasingly for bronchial provocation testing. Our aim was to study the acceptability, safety and correlation between two published bronchial challenge tests. Two standardized protocols--the inhalation of hypertonic saline (HS) and ultrasonically-nebulized distilled water (UNDW)--were performed in 36 children: 19 patients with the clinical diagnosis of mild-to-moderate asthma (7-12 yrs of age), and 17 control subjects (8-18 yrs of age). HS challenge involved stepwise inhalation of 4.5% saline (for 0.5, 1, 2, 4 and 8 min), whereas challenge with UNDW was performed as a single step protocol with 10 min inhalation of cold UNDW. Asthma medication was withheld prior to challenge testing. Thirty five subjects completed both challenge tests (one asthmatic patient did not return after UNDW challenge) in random order within a 7 day time interval. For HS a > or = 15% reduction in forced expiratory volume in one second (FEV1) from baseline was considered a positive response, and for UNDW a > or = 10% decrease. In 13 of the 19 asthmatic patients, but in none of the controls, a positive response was observed for UNDW. Fifteen out of 18 patients and one control subject had a positive response to HS. Twelve out of 18 asthmatic children responded to both challenges, three responded only to HS and three had no response to either challenge. There was a negative correlation between log provocative dose causing a 15% reduction in FEV1 (PD15) after HS and the maximum fall in FEV1 after UNDW (rs = -0.63; p < 0.005). The HS challenge had a lower acceptability than challenge with UNDW due to the unpleasant salty taste of HS. However, this did not inhibit the completion of the tests in any subject. The results of this study suggest a good correlation between response to hypertonic saline and ultrasonically-nebulized distilled water in children with mild-to-moderate asthma. A multiple step protocol might be safer when applied in field studies involving children.     

A partial involvement of histamine in ultrasonically nebulized distilled water-induced bronchoconstriction in guinea-pigs

1. Inhalation of ultrasonically nebulized distilled water (UNDW) can induce bronchoconstriction only in asthmatics, but mechanisms of the response are not well known. We recently reported a guinea-pig model of UNDW-induced bronchoconstriction (UNDW-IB) in which UNDW induces bronchoconstriction when UNDW is inhaled 20 min after a challenge with aerosolized ovalbumin (OA) in passively sensitized, anaesthetized and artificially ventilated guinea-pigs. 2. To elucidate the role of histamine in the UNDW-IB, we examined the effects of antihistamines, diphenhydramine hydrochloride (DH) and chlorpheniramine maleate (CP), and measured histamine content in bronchoalveolar lavage fluid (BALF) in the animal model. 3. DH in doses of 0.1, 1.0 and 10 mg kg(-1) and CP in doses of 0.01, 0.1 and 1.0 mg kg(-1) administered intravenously 15 min after the OA challenge partially reduced the UNDW-IB at 1 and 2 min after the UNDW inhalation in a dose-dependent manner. Histamine content in BALF recovered 10 min after the UNDW inhalation following the OA provocation was significantly increased compared with that after saline inhalation and before the UNDW inhalation following the OA challenge. 4. Intravenous atropine in a dose of 0.5 mg kg(-1) or inhaled disodium cromoglycate in concentrations of 1 and 10 mg ml(-1) did not alter the UNDW-IB. 5. These results suggest that histamine is involved in part in the UNDW-IB in our animal model.     

Inhaled furosemide prevents ultrasonically nebulized water bronchoconstriction in children with both atopic and nonatopic asthma

To determine whether inhaled furosemide can modify the bronchoconstriction induced by ultrasonically nebulized distilled water (UNDW) in children with both atopic and nonatopic asthma, a single-blind, randomized, placebo-controlled study was undertaken. The UNDW inhalation challenge was performed in 21 asthmatic children (atopic, 14; nonatopic, 7; mean +/- SEM age, 11.5 +/- 0.5 years), who had a fall in FEV1 of at least 20 percent after distilled water inhalation. On separate days, these subjects underwent UNDW challenge test after inhalation of furosemide (10 mg/body square meters) or placebo (saline solution). Inhaled furosemide exerted a protective effect against bronchoconstriction induced by UNDW in children with both atopic and nonatopic asthma (p < 0.01, p < 0.05, respectively). These results indicate that the protective action of furosemide against UNDW-induced bronchoconstriction may be independent of its direct inhibitory effect on airway mast cell activation.     

Potentiating effect of inhaled acetaldehyde on bronchial responsiveness to methacholine in asthmatic subjects

BACKGROUND: It has recently been reported that acetaldehyde induces bronchoconstriction indirectly via histamine release. However, no study has been performed to assess whether acetaldehyde worsens bronchial responsiveness in asthmatic subjects so this hypothesis was tested. METHODS: Methacholine provocation was performed on three occasions: (1) after pretreatment with oral placebo and inhaled saline (P-S day), (2) after placebo and inhaled acetaldehyde (P-A day), and (3) after a potent histamine H1 receptor antagonist terfenadine and acetaldehyde (T-A day) in a double blind, randomised, crossover fashion. Nine asthmatic subjects inhaled 0.8 mg/ml acetaldehyde or saline for four minutes. After each inhalation a methacholine provocation test was performed. RESULTS: Methacholine concentrations producing a 20% fall in FEV1 (PC20-MCh) on the P-A day (0.48 mg/ml, 95% CI 0.21 to 1.08) and T-A day (0.41 mg/ml, 95% CI 0.22 to 0.77) were lower than those on the P-S day (0.85 mg/ml, 95% CI 0.47 to 1.54). There was no change in the PC20-MCh between the P-A and T-A days. A correlation was observed between the logarithmic values of PC20-MCh (log PC20-MCh) on the P-S day and the potentiating effect of acetaldehyde on the methacholine responsiveness [(log PC20-MCh on P-A day)-(log PC20-MCh on P-S day)] (rho = 0.82). CONCLUSIONS: Acetaldehyde induces bronchial hyperresponsiveness in patients with asthma by mechanisms other than histamine release.     

Effects of acute and chronic exposure to nicotine aerosol on bronchial reactivity to inhaled methacholine

Normal baboons, like humans, demonstrate a wide range of bronchial reactivity to inhaled methacholine. Cigarette-smoking baboons demonstrate reduced bronchial reactivity to inhaled methacholine compared with sham-smoking controls after 6 pack-yr of smoking. To evaluate the role of nicotine in this blunting of airway reactivity, we studied the effects of both acute and chronic nicotine inhalation on reactivity to methacholine in baboons. Inhalation of 2 mg of nicotine had no acute effect on lung function but blunted bronchial reactivity in highly reactive animals. This effect was not diminished after daily inhalation of nicotine for 90 days. Marked interindividual differences in bronchial reactivity to methacholine were not abolished by propranolol, suggesting that factors other than beta-adrenergic tone account for this intersubject variability.     

The occurrence of late asthmatic response to exercise after allergen challenge

OBJECTIVES: To evaluate the correlation between the pathological findings of stereotactic core needle biopsy (SCNB) and the prebiopsy mammographic findings, as well as the pathological findings of lesions that were subsequently removed by surgical excision. DESIGN: A retrospective review of 97 consecutive patients who underwent 100 SCNBs of suspicious nonpalpable mammographic lesions. The criterion standard is surgical excisional biopsy with needle localization. Mammographic findings were graded according to the American College of Radiology Breast Imaging Reporting and Data System. The pathological findings of SCNB were categorized into 4 groups: benign and specific, benign and nonspecific, premalignant, and malignant. Surgical excision of the lesion was performed if the pathological finding on SCNB was nonconcordant with the prebiopsy mammogram and when premalignant or malignant lesions were found. The pathological findings of lesions that were subsequently removed by surgical excision were compared with those of SCNB. SETTING: Community-based private multispecialty ambulatory practice. PATIENTS: A population-based sample composed of 97 patients who had grade III, IV, or V lesions on routine screening mammograms. INTERVENTION: Stereotactic core needle biopsy of nonpalpable mammographic lesions. MAIN OUTCOME MEASURES: Percentage of patients whose SCNB results were concordant with the mammographic findings and the pathological findings on subsequent surgical excision. RESULTS: Concordance between SCNB and mammography occurred in 97% of biopsy specimens. Concordance between the pathological findings of SCNB and those of surgically excised lesions occurred in 92.5% of biopsy specimens. We had 1 false-negative result. We had no false-positive diagnosis of cancer with SCNB. CONCLUSION: On the basis of accumulating literature and our own initial experience, SCNB is a promising, safe, and cost-effective procedure.     

Increased LTB4 metabolites and PGD2 in BAL fluid after methacholine challenge in asthmatic subjects

The bronchoconstrictor potency of inhaled methacholine is widely used to assess airway responsiveness. However, evidence has accumulated that methacholine inhalation challenge may lead to an inflammatory response in the lower respiratory tract. We therefore compared cellular, leukotriene and prostanoid profiles in bronchoalveolar lavages (BAL) obtained five hours after methacholine challenge to control lavages without prior challenge. Eight subjects with asymptomatic to mild bronchial asthma and nine nonatopic healthy controls were enrolled in the study. Without prior challenge, the percentage of BAL eosinophils was higher in the asthmatic subjects ((mean +/- SD), 1.1 +/- 0.9%) than in the control subjects (0.1 +/- 0.1%. Leukotriene B4 (LTB4), and its omega-oxidation products (20-OH-LTB4 and 20-COOH-LTB4) were the only leukotrienes detectable in the baseline BAL fluids in five of the eight asthmatic patients. After methacholine challenge, no change in BAL cell profile occurred, but in the asthmatic patients, the total amounts of LTB4 and its omega-oxidation products rose from 0.52 +/- 0.50 ng.ml-1 (pre-challenge) to 1.55 +/- 1.32 ng.ml-1 (post-challenge), and prostaglandin D2 (PGD2) rose from 49.1 +/- 15.7 (pre-challenge) to 94.4 +/- 25.4 pg.ml-1 (post-challenge), with no change in 6-keto-PGF1 alpha, thromboxane B2 (TXB2), and prostaglandins F2 alpha and E2 (PGF2 alpha and PGE2). In the healthy controls, no consistent change in BAL cell profile and mediators occurred after methacholine provocation. We conclude that inhaled methacholine stimulates LTB4 and PGD2 release in asthmatics, but not in healthy controls, without affecting the number of inflammatory cells in BAL fluid.     

Hypokalaemia following nebulized salbutamol in children with acute attack of bronchial asthma

OBJECTIVE: To determine whether use of nebulized salbutamol therapy for treatment of an acute attack of asthma in children is associated with hypokalaemia and if so what is its frequency, severity and effect on recovery. METHODOLOGY: Forty-six children, aged 10 months to 12 years (mean 7.9 +/- 1.5 years) with acute attack of bronchial asthma, treated initially with three doses of nebulized salbutamol 0.15-0.3 mg/kg, every 30 min participated in the study. Blood for serum potassium was obtained at the beginning and after three doses of nebulized salbutamol therapy, before administering other drugs. RESULTS: The mean +/- SD serum potassium level decreased marginally from 3.9 +/- 0.5 mEq/L to 3.7 +/- 0.5 mEq/L (P < 0.05). A decrease in serum potassium concentration was noted in 26 (56.5%) and hypokalaemia (serum potassium < 3.5 mg/L) in 17 (39%) patients. It was more frequent in patients who had received oral salbutamol for the preceding 7 days. The average time taken for recovery was longer in patients who had hypokalaemia than those who had normal serum potassium concentration (8.6 +/- 2.7 h vs 6.5 +/- 2.7 h; P < 0.005). CONCLUSIONS: Hypokalaemia may occur in about one-third of patients treated with three doses of nebulized salbutamol therapy, especially those on prior oral salbutamol therapy. The monitoring of serum potassium concentration may be warranted in such patients.     

Comparison between nasal and bronchial inflammation in asthmatic and control subjects

Although asthma and rhinitis often coexist, it is still unknown whether they are characterized by a similar inflammatory profile. We studied eosinophilic infiltration, epithelial shedding and reticular basement membrane thickness in nasal and bronchial biopsies of six control subjects, 15 untreated allergic asthmatics with perennial rhinitis, and six corticosteroid-dependent (CSD) asthmatics. In nasal and bronchial biopsies, eosinophils were greater in untreated asthmatics than in control subjects and CSD asthmatics (p = 0.001). In untreated asthmatics, eosinophils were higher in bronchial than in nasal biopsies (p = 0.002). In nasal and bronchial biopsies, reticular basement membrane thickness was greater in untreated and CSD asthmatics than in control subjects (nasal: p < 0.008 and p < 0. 004; bronchial: p < 0.001 and p < 0.008). In untreated and CSD asthmatics, reticular basement membrane thickness was greater in bronchial than in nasal biopsies (p = 0.001; Wilcoxon's W test). Nasal epithelium was not shed in all the study groups. In untreated asthmatics, bronchial epithelium shedding was greater than in control subjects or CSD asthmatics (p < 0.005), and it was greater than nasal epithelium shedding (p < 0.006). This study has shown that, although concomitant, the extent of eosinophilic inflammation of reticular basement membrane thickness and of the epithelium shedding is greater in bronchial than in nasal mucosa of asthmatic patients with perennial rhinitis.     

A longitudinal evaluation of bronchial responsiveness to methacholine in children: role of baseline lung function, gender, and change in atopic status

A longitudinal study was done to evaluate the determinants of bronchial responsiveness (BR) to methacholine in children and adolescents. A cohort of 892 7- to 11-yr-old schoolchildren was restudied after a 3.5-yr interval. The same protocol for methacholine challenge (up to 64.0 mg/ml) and skin prick testing was employed at both the baseline survey and follow-up. An overall decline in the level of BR was observed, the geometric mean slope (percent decline in FEV1 per mg/ml of methacholine) decreasing from 0.68 (95% CI=0.61 to 0.75) to 0.51 (95% CI=0.46 to 0.57) (p<0.001). At both surveys, the strongest determinants of slope were baseline pulmonary function level (FEF25-75) and degree of atopic status. After adjusting for log FEF25-75, no gender difference was found in the first survey, whereas girls had greater BR than boys at follow-up. Longitudinal changes in skin prick test reactivity were associated with the BR level. Subjects in whom an initially positive skin prick test became negative (5.3%) had an increased slope at baseline but a follow-up slope similar to that of never skin-reactors. Conversely, those whose skin prick test converted from negative to positive (13.0%) had a slope similar to that of never-reactors at baseline but became stronger responders to methacholine than never-reactors at follow-up. Finally, responsiveness was highest in the presence of persistently positive skin prick testing (13.5%). In conclusion, BR declines from childhood to adolescence, paralleling the increase in lung function during this period; the decline is less pronounced in females. Changes in atopic status are associated with modifications in the BR level.     

The level of RANTES and interleukin-8 in serum of children with bronchial asthma after an exercise test

The study was carried out on 20 children with bronchial asthma. After the exercise induced test we observed decreased serum level of RANTES both in children with positive and negative results of the test. Serum level of IL-8 was increased in all examined group. We found strong correlation between serum level of RANTES and peripheral blood eosinophil counts in children with positive result of the test before and after the exercise.     

Long-term efficacy and safety of nebulized metaproterenol solution in bronchial asthma

Chyluria is a rare manifestation of tuberculosis. A patient in whom it was a presenting symptom is described.     

Progressive bronchial obstruction during the acute stage of respiratory tract infection in asthmatic children

To study the time-course of infectious asthma, we retrospectively examined FEV1 from 5 days before to 10 days after the onset of illness in 31 asthmatic children (20 boys and 11 girls), aged 8 to 12 years. Infections were confirmed by a rise of at least fourfold in serum compliment fixation titers (respiratory syncytial virus, adenovirus, and Mycoplasma pneumoniae) and hemoagglutination inhibition titers (parainfluenza virus types 1, 2, and 3). All the patients had 20 percent or more fall in FEV1 from baseline value during acute phase, but were clinically tolerable and required minimum or no bronchodilators. Regardless of infectious agent, FEV1 began to fall on the first disease day or the previous day, and deteriorate for the first few days. Mean(SD) maximum fall in FEV1 ranged from 39(12) percent to 45(20) percent. Thereafter, FEV1 began to improve and returned to the preillness level by the seventh to tenth day. These results suggest that progressive bronchial obstruction may be inevitable during the acute stage of any infectious asthma.     

Airway response of children with primary ciliary dyskinesia to exercise and beta2-agonist challenge

In primary ciliary dyskinesia (PCD), chest physiotherapy for airway clearance is essential. Exercise and inhaled beta2-agonists can produce bronchodilation thereby augmenting physiotherapy. However, both can also cause bronchoconstriction, and the effects of these stimuli in PCD are not known. In a preliminary study, the mean coefficients of variation for forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and peak expiratory flow rate (PEFR) in children with PCD were determined. They were 5.4%, 4.4% and 8.4%, respectively. Twelve children with PCD and 12 normal children performed pulmonary functions under resting conditions; during and after a validated treadmill exercise test; and before and 15 min after 200 microg of inhaled salbutamol. At baseline, FEV1, FVC, forced mid-expiratory flow (FEF25-75%) and PEFR were significantly reduced in the PCD group compared with the control group. Exercise produced a significant increase in PEFR in the PCD group. There was no significant difference between the groups in response to salbutamol. Within the PCD group, exercise produced a significantly greater increase in PEFR than beta2-agonist therapy. In conclusion, in children with primary ciliary dyskinesia there is evidence of obstructive pulmonary disease. In these children, exercise is a more potent stimulus for bronchodilation than by inhaled beta2-agonists. Enhancement of airway clearance may best be achieved by encouraging patients to exercise before physiotherapy rather than by inhaling beta2-agonists, but the effects of each should be assessed for each individual before instigating treatment.     

Using distilled water for the extraction of mucosal antibodies and the subsequent application in RSV neutralization test

Virus neutralization (VN) is an important functional test for evaluating RSV vaccines, also encompassing in mucosal secretion of the respiratory tract considering the infection route. In our previous study, an immunoglobin extraction method described by Bergquist et al. was adopted for RSV ELISA, but it was not suitable for virus neutralization test due to the cell toxicity of the 2% saponin solution used for the antibody extraction. In order to overcome this problem, several solvents including distilled water were tested in the present study for the capacity to extract immunogloblins. Antibodies in the extracts were evaluated and compared by ELISA. Distilled water was as efficient as the 2% saponin solution for extraction of total IgA, RSV specific IgA and IgG. More importantly, the organ extracts obtained subsequently could be used for virus neutralization test without causing adverse effect on the cell culture. Therefore, distilled water was finally chosen as the solvent for immunoglobulin extraction from mucosal organs when both ELISA and virus neutralization test are required.     

Predictors of early- and late-phase reactions to bronchial allergen challenge

The influence of inhaled steroids and predictive factors on the response to bronchial allergen challenge (BCA) was evaluated in 80 asthmatics allergic to Dermatophagoides pteronyssinus (Der p). All underwent BCA with Der p and measurement of early (EAR) and late asthmatic reaction (LAR). The cumulative dose of allergen producing 20% fall in FEV1 in the EAR (PD20) was calculated. Bronchial histamine provocation, conjunctival provocation test (CPT), and skin prick test with Der p extract were performed. Specific IgE to Der p in serum (RAST), blood eosinophil (EOS) count, serum eosinophil cationic protein, and eosinophil protein X were measured. Thirty patients (38%) were treated with inhaled steroids. All patients had at least a 20% fall in FEV1 in EAR. Some 42% of nonsteroid- and 33% of steroid-treated patients had LAR with fall in peak flow of at least 20%. For patients not treated with steroid, 35% of variation in PD20 was explained by RAST and histamine reactivity, and 53% of variation of observed PD20 could be predicted. The baseline FEV1, EOS, and EAR explained 28% of variation in LAR, and 28% of variation in observed LAR could be predicted. For patients treated with steroids, 38% of variation in PD20 was explained by EOS and histamine reactivity, and only 18% of variation of observed PD20 could be predicted. For patients treated with steroids, it was impossible to predict LAR. We conclude that to achieve a quantitative estimation of allergen-specific EAR and LAR, BCA cannot be replaced by the tests used in this study. Treatment with inhaled steroids modifies the response to BCA, making quantitative prediction of EAR less accurate and prediction of the magnitude of LAR impossible.     

Relationship between bronchial reactivity, airway caliber, and severity of asthma

Electrocardiographic tests were applied to slaughter pigs and showed continuous rise of the heart rate from anaesthetisation to the debleeding prick at which point its maximum was 86% beyond the original value. The duration of the intraventricular electric systoles was 0.290 s prior to the debleeding prick and 0.281 s thereafter. The intraventricular electric diastoles were 0.241 s prior to debleeding and 0.303 s after it. No significant modification in diastolic time was observed prior to the debleeding prick. ST duration dropped from an original level of 0.222 s to a minimum of 0.173 at the point of pricking.     

Frequencies of T cells expressing interleukin-4 and interleukin-5 in atopic asthmatic children. Comparison with atopic asthmatic adults

T-cell-derived cytokines have been implicated in the pathogenesis of asthma and it has been suggested that Th2-type cytokines (interleukin-4 [IL-4], interleukin-5 [IL-5]) are pivotal in the allergic inflammation. However, there are little data on human cytokine production by individual T cells at the protein level, in particular in asthmatic children. In this study we analyzed the cytokine production at the single cell level in peripheral blood from mild atopic asthmatic (AA) children and adults and age-matched atopic nonasthmatic (AN) and nonatopic nonasthmatic (NN) control subjects (n = 9 in each group) using the technique of intracellular cytokine detection by flow cytometry. Comparing asthmatic children with atopic and nonatopic control subjects, an increased percentage of IL-5-producing T cells (AA: median 4.9% [range 1.1 to 8.9%]; AN: 0.3% [0.2 to 0.9%], p = 0.003; NN: 0.4% [0.1 to 3.8%], p = 0.001) was detectable, with a positive correlation to the number of peripheral eosinophils and to bronchial hyperresponsiveness. The frequency of IL-4-producing T cells was increased in both atopic groups compared with nonatopic controls (AA: 1.2% [0.2 to 2.6%], p = 0.011; AN: 0.8% [0.4 to 3.7%], p = 0.007; NN: 0.4% [0.2 to 0.9%]) with a positive correlation to total IgE concentration. In adults there were no differences in IL-5- or IL-4-producing T cells between all three groups. A substantial proportion of T cells coproducing IL-4 and IL-5 was not detectable in children and adults. These findings indicate that in asthmatic children the frequencies of Th2-type-producing T cells are increased and that expression of IL-4 and IL-5 is regulated independently.     

Pulmonary metabolism of beta-endorphin in asthmatic patients in asymptomatic periods and after bronchospasm induced by methacholine

Blood concentration of endogenous beta-endorphines can change during the clinical evolution of chronic bronchopneumopathies. The authors assessed the beta-endorphine concentrations in the pulmonary arterial and systemic arterial blood in 8 asthmatic patients during a symptom-free period and after methacholine-induced bronchospasm. The beta-endorphine analysis was performed in duplicate dor each sample, by means of a RIA assay. There is not difference in the systemic arterial blood concentration of beta-endorphines between asthmatic patients and normal subjects. Furthermore, there is no change in the beta-endorphine blood concentration during the passage through the pulmonary tissue after methacoline-induced bronchospasm.