Long term follow-up of children hospitalized with respiratory syncytial virus lower respiratory tract infection and randomly treated with ribavirin or placebo.

PURPOSE: To determine the long term effects of ribavirin therapy in children hospitalized for respiratory syncytial virus (RSV) lower respiratory tract infection. METHODS: Fifty-four of 60 children in randomized trials of ribavirin therapy were enrolled in a prospective follow-up study. Subjects were examined annually and had age-appropriate pulmonary function tests; interim histories were obtained from families and personal physicians. RESULTS: Recurrent lower respiratory tract illness was reported at least once for 79% of the ribavirin and 73% of placebo group. In the first 5 years after RSV, 54% of the ribavirin group and 50% of the placebo group reported wheezing. There were no significant differences between the groups in annual rates, timing, or severity of recurrent lower respiratory tract illness. No significant differences in pulmonary function were detected by tests of oxygen saturation, peak expiratory flow and spirometry. CONCLUSIONS: Children in the ribavirin treatment group did not have exacerbated respiratory symptoms compared with those in the control group, and their pulmonary function measurements were equal to those of the placebo-treated group, suggesting no long term adverse effect or benefit of ribavirin therapy.

Development of mucociliary transport in the postnatal ferret trachea.

Little is known of the developmental aspects of mucociliary transport. Previous studies have documented that newborn ferret trachea has very few ciliated cells but numerous immature secretory cells in the epithelium and only rudimentary submucosal glands. Rapid and complete maturation occurs in the first postnatal month. This study examines mucociliary transport during this period of rapid maturation. We made direct observations of particle movement across the epithelium of ferret tracheas. No mucus transport could be demonstrated on the first day of life. Transport was discernible, although sporadic and slow, by 7 days and reached adult levels (10.7 +/- 3.7 mm/min) by 28 postnatal days. The emergence of transport capability correlated well with previously described developmental changes in ciliation, mucus secretion, and ion permeability and transport. Threshold mucus transport occurred at 1 wk of age when 20-25% of the surface cells are ciliated. The neonatal ferret appears to be a useful model for assessing integrated epithelial structure-function relationships that are important not only during early development but also during repair after airway injury involving deciliation.

Effects of ozone on normal and potentially sensitive human subjects. Part II: Airway inflammation and responsiveness to ozone in nonsmokers and smokers.

Exposure to ozone at levels near the National Ambient Air Quality Standard causes respiratory symptoms, changes in lung function, and airway inflammation. Although ozone-induced changes in lung function have been well characterized in healthy individuals, the relationship between airway inflammation and changes in pulmonary function have not been prospectively examined. The purpose of this study was to determine whether individuals who differ in, lung function responsiveness to ozone also differ in susceptibility to airway inflammation and injury. A secondary goal was to determine whether ozone exposure induces airway inflammation in smokers, a population known to have airway inflammation and an increased burden of toxic oxygen species. Healthy nonsmokers (n = 56) and smokers (n = 34) were exposed to 0.22 parts per million (ppm)* ozone for 4 hours, with intermittent exercise, for the purpose of selecting ozone "responders" (decrement in forced expiratory volume in 1 second [FEV1] > 15%) and "nonresponders" (decrement in FEV1 < 5%). Selected subjects then were exposed twice to ozone (0.22 ppm for 4 hours with exercise) and once to air (with the same exposure protocol), each pair of exposures separated by at least 3 weeks, in a randomized, double-blind fashion. Nasal lavage (NL) and bronchoalveolar lavage (BAL) were performed immediately after one ozone exposure and 18 hours after the other, and either immediately or 18 hours after the air exposure. Indicators of airway effects in lavage fluid included changes in inflammatory cells, proinflammatory cytokines, protein markers of epithelial injury and repair, and generation of toxic oxygen species. In the classification exposure, fewer smokers than nonsmokers were responsive to ozone (11.8% vs. 28.6%, respectively); an insufficient number of smoker-responders were identified to study as a separate group. In the BAL study, all groups developed a similar degree of airway inflammation, consisting of increases in interleukins 6 and 8 (maximal immediately after exposure), and increases in polymorphonuclear leukocytes (PMNs), lymphocytes, and mast cells (maximal 18 hours after exposure). The increase in PMNs was inversely correlated with age (p = 0.013), but gender, nonspecific airway responsiveness, and allergy history were not predictive of inflammation. Alveolar macrophage production of toxic oxygen species decreased after ozone exposure in nonsmokers; however, not in smokers. Findings from nasal lavage did not mirror lower airway inflammatory responses in these studies. We conclude that, in response to ozone exposure, smokers experienced smaller decrements in lung function and fewer symptoms than nonsmokers; however, the intensity of the airway inflammatory response was independent of smoking status or airway responsiveness to ozone. Furthermore, the burden of toxic oxygen species following ozone exposure was greater for smokers than for nonsmokers. Subjects were young, healthy, and able to sustain exercise; the results may not be representative of nonsmokers or smokers in general. Nevertheless, the findings indicate that measuring symptoms and spirometric changes is not sufficient to assess the potential risks associated with ozone exposure.

Home oxygen and ventilation therapies in pediatric patients.

Home oxygen and ventilation therapies are used to treat children who have varying degrees of chronic respiratory insufficiency from many causes. Potential sequelae to even mild or intermittent respiratory insufficiency have been identified. Infants with bronchopulmonary dysplasia who still require oxygen can be discharged earlier from hospitals with appropriate discharge planning and family support. Children with progressive diseases may eventually require oxygen or ventilation therapies to improve the duration or quality of their lives. Obstructive sleep apnea has been treated with supplemental oxygen and nasal continuous positive airway pressure. Guidelines exist for initiation and home management of oxygen and invasive or noninvasive mechanical ventilation.

Diagnostic tests of lung function.

Objective measurements of a wide variety of aspects of respiratory function can be useful in the evaluation and management of children and adolescents who have respiratory symptoms or disorders. Many of the tests described in this article can be performed reasonably in the pediatrician's office. Pediatricians can be comfortable in measuring and interpreting pulse oximetry, blood gas analysis, spirometry, and peak flow. They also should be familiar with the indications for the less common tests of pulmonary function that now are widely available.

Lower respiratory illness in early childhood and lung function and bronchial reactivity in adolescent males.

We examined the relationship between lower respiratory illness (LRI) experience in early childhood and lung function and bronchial reactivity in 57 boys, 11 to 22 yr of age, whose histories of outpatient physician visits for wheezing and nonwheezing LRI had been documented prospectively during their first 6 yr of life. These boys were a subpopulation of 159 children whose early childhood LRI experience and spirometric performance had been studied an average of 4 yr previously. The majority of boys had been free of chronic respiratory symptoms in the 2 yr before evaluation. Boys with histories of 2 or more preschool wheezing illnesses had lower mean levels of performance for FEV1, FEF25-75, FEF50, FEF75, and FEV1/FVC than did boys who had zero or 1 preschool wheezing illness, replicating observations that had been made when the boys had been studied 4 yr previously. Boys with lower spirometric performance relative to the study population on initial testing continued to have lower relative levels of spirometric performance 4 yr later. Neither preschool wheezing nor nonwheezing illness experience was associated with the degree of methacholine sensitivity measured in adolescence. Increasing degrees of methacholine sensitivity were associated with lower levels of spirometric performance; however, preschool wheezing illness experience remained a significant correlate of spirometric performance after adjustment for level of methacholine sensitivity. We conclude that recurrent preschool wheezing illness in these adolescent boys was associated with persistently lower lung function, but not enhanced methacholine sensitivity, during the middle to late school years.

Ozone responsiveness in smokers and nonsmokers.

Short-term exposure to ozone causes decrements in lung function, but predictors of responsiveness remain largely unknown. Ninety healthy volunteers (56 never-smokers, age [mean +/- SD] 25 +/- 4 yr; 34 current smokers, 13 +/- 9 pack-yr, age 28 +/- 1 yr) were exposed to 0.22 ppm ozone for 4 h, with exercise, in an environmental chamber. We measured spirometry and specific airway conductance before, during, and immediately after exposure, and assessed symptoms by questionnaire. Smokers experienced a smaller increase in respiratory symptoms following exposure to ozone than did nonsmokers. Decrements in FEV1 were significantly less than for smokers than for nonsmokers (p = 0.0013). Ozone responsiveness (> 15% fall in FEV1) occurred in 16 of 56 never-smokers (28.6%) and 4 of 34 smokers (11.8%). Multiple logistic regression analysis found pack-yr of smoking to be associated with decreased ozone responsiveness (odds ratio [OR] 0.87, p = 0.017). Age, gender, and methacholine responsiveness were not predictive of responder status. Fourteen smokers and 25 nonsmokers were subsequently exposed once to air and twice to ozone; smokers as well as nonsmokers were consistent in their subsequent responsiveness (or lack of responsiveness) to ozone. Healthy smokers have smaller decrements in lung function and fewer symptoms in response to ozone exposure than do nonsmokers.

Sulfuric acid aerosol exposure in humans assessed by bronchoalveolar lavage.

Epidemiologic and experimental evidence suggests that exposure to acidic aerosols may affect human health. Brief exposures to acidic aerosols alter mucociliary clearance and increase airway responsiveness, but effects on host defense mechanisms at the alveolar level have not been studied in humans. Twelve healthy, nonsmoking volunteers between 20 and 39 yr of age were exposed for 2 h to aerosols of approximately 1,000 micrograms/m3 sulfuric acid (H2SO4) or sodium chloride (NaCl [control]), with intermittent exercise, in a randomized, double-blind fashion. Each subject received both exposures, separated by at least 2 wk. Bronchoalveolar lavage (BAL) was performed 18 h after exposure in order to detect evidence of an inflammatory response, changes in alveolar cell subpopulations, or changes in alveolar macrophage (AM) function, which is important in host defense. When compared with NaCl, exposure to H2SO4 did not increase polymorphonuclear leukocytes in BAL fluid. The percentage of T lymphocytes decreased in association with H2SO4 exposure, but the difference was not statistically significant (14.9% after NaCl, 11.5% after H2SO4; p = 0.14). Antibody-mediated cytotoxicity of AM increased in association with H2SO4 exposure (percent lysis 19.1 after NaCl, 23.6 after H2SO4; p = 0.16). No significant change was seen in release of superoxide anion or inactivation of influenza virus in vitro. Brief exposures to H2SO4 aerosol at 1,000 micrograms/m3 do not cause an influx of inflammatory cells into the alveolar space, and no evidence was found for alteration in antimicrobial defense 18 h after exposure.

Ozone exposure and the production of reactive oxygen species by bronchoalveolar cells in humans.

Exposure to ozone injures respiratory epithelium, and the mechanisms may involve the generation of reactive oxygen species (ROS). This study tested the hypothesis that ozone exposure increases the airway burden of ROS to a greater degree in smokers than nonsmokers, and that this effect is independent of ozone-induced changes in spirometry. Healthy subjects were selected as either responders (decrement in FEV1 > 15%) or nonresponders (decrement in FEV1 < 5%) to ozone; each underwent 2 exposures to ozone and 1 to air, with bronchoalveolar lavage (BAL) performed 30 min (early) and 18 h (late) after exposure. Release of superoxide anion (O2(-)) was used as a measure of ROS release by all BAL cells, and flow cytometry was used to detect ROS production in alveolar macrophages (AM) only. Recovery of AM was approximately threefold greater in smokers than nonsmokers. Unstimulated, but not stimulated, cells obtained by BAL from smokers released approximately twofold greater amounts of O2(-) than cells from nonsmokers, both early and late after ozone exposure (p =.012 and p =.046, respectively). Stimulated, but not unstimulated, ROS generation by AM from smokers increased following ozone exposure, but the ozone effect was not significant. ROS production by AM decreased in nonsmokers (air vs. ozone late, p =.014). Total protein, albumin, and immunoglobulin M (IgM) increased in BAL fluid, consistent with an increase in epithelial permeability. In addition, the concentration of alpha2-macroglobulin increased approximately threefold 18 h after exposure in nonsmokers (p <.001). No relationship was found between measures of ROS production and lung function responsiveness to ozone. These studies suggest the airways of smokers experience a greater burden of ROS than those of nonsmokers following ozone exposure.

Respiratory allergy and the relationship between early childhood lower respiratory illness and subsequent lung function.

In a study of 159 school-age children whose histories of outpatient visits for lower respiratory illness (LRI) had been documented from early infancy, we observed lower mean levels of small airway function in boys who had experienced two or more episodes of wheezing-associated LRI before 6 yr of age. To determine whether allergy was an important factor influencing this result, we examined relationships among the results of RAST tests for seven common inhalant allergens and concurrent lung function in 126 subjects who consented to venipuncture. Increasing values for the sum of scores for the seven RAST tests were associated with progressively lower mean levels of small airways function in boys with histories of recurrent wheezing LRI during the preschool years. The association of allergy with lower levels of lung function was largely accounted for by dust mite allergy. RAST results were not correlated with lung function in boys who had experienced zero or 1 wheezing LRI before 6 yr of age or in girls. A history of recurrent wheezing LRI during the preschool years was also associated with significantly lower mean levels of small airways function in boys who had negative RAST tests. A subset of 49 boys was reevaluated after an average interval of 4 yr with RAST tests, spirometry, and methacholine challenge. Dust mite allergy was associated with an increased prevalence of bronchial hyperreactivity independent of early childhood wheezing LRI history.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway inflammation in smokers and nonsmokers with varying responsiveness to ozone.

Exposure to ozone causes symptoms, changes in lung function, and airway inflammation. We studied whether individuals who differ in lung-function responsiveness to ozone, or in smoking status, also differ in susceptibility to airway inflammation. Healthy subjects were selected on the basis of responsiveness to a classifying exposure to 0.22 ppm ozone for 4 h with exercise (responders, with a decrease in FEV1 > 15%; and non-responders, with a decrease in FEV1 < 5%). Three groups were studied: nonsmoker-nonresponders (n = 12), nonsmoker-responders (n = 13), and smokers (n = 13, 11 nonresponders and two responders). Each subject underwent two exposures to ozone and one to air, separated by at least 3 wk; bronchoalveolar and nasal lavages were performed on three occasions: immediately (early) and 18 h (late) after ozone exposure, and either early or late after air exposure. Recovery of polymorphonuclear leukocytes (PMN) increased progressively in all groups, and by up to 6-fold late after ozone exposure. Interleukin-6 (IL-6) and IL-8 increased early (by up to 10-fold and up to 2-fold, respectively), and correlated with the late increase in PMN. Lymphocytes, mast cells, and eosinophils also increased late after exposure. We conclude that ozone-induced airway inflammation is independent of smoking status or airway responsiveness to ozone.