A randomized, double-blind, placebo-controlled trial of the effect of zafirlukast on upper and lower respiratory responses to cat challenge.

BACKGROUND: Zafirlukast, a leukotriene antagonist, has been shown to have protective effects against a variety of asthma triggers. OBJECTIVE: Our purpose was to evaluate zafirlukast's effects on upper and lower airway responses to cat allergen exposure with use of a well-characterized cat exposure model. METHODS: In a double-blind, placebo-controlled, cross-over trial 18 subjects with cat-induced asthma were randomly assigned to receive 1 week each of zafirlukast or placebo followed by a 1-hour cat challenge. Upper and lower respiratory symptoms were rated and spirometry and acoustic rhinometry were performed. Challenges were stopped early if the subject was too uncomfortable or had a >50% decrease in FEV(1). RESULTS: Overall changes in FEV(1) were significantly different with zafirlukast treatment (P = .02). Significant differences in FEV(1) change were detected at 15 and 30 minutes (P = .027 and .05, respectively) but not at 45 and 60 minutes. Changes in acoustic rhinometry were also significantly different at 15 and 30 minutes (P =.05 and .0005, respectively) but not at 45 and 60 minutes. Challenge length was significantly longer with zafirlukast versus placebo after adjustment for differences in allergen exposure (P = .022). Respiratory symptom scores were significantly different (lower respiratory, P < .001; upper respiratory, P = .038) through the first 30 minutes of the challenge after adjustment for allergen exposure. CONCLUSIONS: Zafirlukast was significantly more effective than placebo in preserving pulmonary function and nasal anatomy and extending challenge length when cat-sensitive asthmatic subjects were exposed to high levels of cat allergen.

The value of acoustic rhinometry in assessing nasal responses to cat exposure.

BACKGROUND: Acoustic rhinometry (AR) uses sonar principles to map the anatomy of the nasal cavity and has been used in other studies to assess acute airway responses to allergen exposure. OBJECTIVE: The purpose of this study was to evaluate the utility of AR in assessing acute airway responses to cat allergen exposure by using a well-characterized cat exposure model. METHODS: Thirty subjects with a history of cat-induced rhinitis and a positive skin prick test response to cat allergen underwent an environmental cat challenge. Of these 30 subjects, 10 also had repeat challenges at lower levels of antigen to determine whether there was a dose response. Five subjects with negative skin test responses to cat were recruited as control subjects. During the 1-hour cat exposure, upper and lower respiratory symptoms were scored every 5 minutes, and spirometry and AR were obtained every 15 minutes. RESULTS: Although 29 of 30 subjects had changes in AR measurements, no correlations were detected between upper respiratory symptom scores and any of the changes observed in AR. In comparing the baseline challenges with lower antigen level challenges, upper respiratory symptom scores differed significantly (P = .002), whereas AR responses were nearly identical. Subjects without cat allergy did exhibit less response by AR (P = .05 to .13), but the greatest differences remained in the upper respiratory symptoms scores (P < .0001). CONCLUSION: We conclude that although AR does provide an objective measure of nasal response to allergen exposure, it has significant limitations. These are evidenced by the lack of correlation with symptoms, the inability to measure a dose response, and the changes noted even among the control subjects.

Differential susceptibility to inhaled pollutants: effects of demographics and diseases.

Inhaled pollutants and respiratory disease deserve particular attention at a conference focused on susceptibility and environmental risk. Inhaled air contains diverse biological, physical and chemical stressors which may cause upper and lower respiratory inflammation and exacerbate complex polygenic disorders such as asthma and sinusitis. This paper focuses on intrinsic susceptibility factors of demographics and diseases as well as genetic background. The National Health Information Survey shows that acute and chronic respiratory conditions are common at all ages, but their incidence and prevalence vary between age groups. Susceptibility is therefore not a fixed characteristic, but the aggregate effect of changing intrinsic factors such as age and disease. While ethnicity is often cited as a risk factor for disease prevalence or severity, recent research shows that measurable factors such as nasal ellipticity determine exposure-dose relationships, while the imperfect surrogate of ethnicity does not. Studies also show that exposure-dose relationships can be modified by recent exposures, and additional information is clearly needed in this area. We propose that evidence for the genetic contribution to pollutant susceptibility be sought in inter-individual variation in responses of homogenous, well characterized individuals to short term controlled pollutant exposure. Future improvements in risk assessment models will be based on a precise identification of factors that determine exposure-dose relationships, and a mechanistic understanding of the reasons that a demographic factor or disease appears to confer altered susceptibility.

Evaluation of acoustic rhinometry and posterior rhinomanometry as tools for inhalation challenge studies.

Objective measures of upper respiratory function are needed to understand the effects of inhaled toxicants on the nasal passages. Acoustic rhinometry (AR) is a simple new technique that determines nasal volume by measuring the cross-sectional area of the upper airway as a function of the distance along the nasal passage. This study compares acoustic rhinometry with the more traditional posterior rhinomanometry (NAR) and correlates these objective measures with the symptom of nasal congestion. Healthy young adults (n = 29) were studied on 4 days, each separated by at least 1 wk, in a climate-controlled environmental chamber for 6 h, with exposure to clean air or sidestream tobacco smoke (SS) (2 h, 1, 5, and 15 ppm CO). The coefficient of variation for single measurements was 8-15% (AR) and 4% (NAR); for across-day measurements it was 15-25% (AR) and 13-15% (NAR); and for between days it was 19-27% AR and 17-21% (NAR). These coefficients were similar in subjects with a history of environmental tobacco smoke sensitivity (ETS-S) and those with no history of ETS sensitivity (ETS-NS). At baseline, the perception of unilateral nasal congestion was significantly correlated with unilateral nasal dimensions or nasal resistance; the symptom of baseline bilateral nasal congestion (estimated for both nasal passages simultaneously) correlated less well with objective measures of nasal patency. Under challenge conditions (SS at 1-15 ppm CO), there were typically significant correlations between changes in unilateral congestion and both unilateral rhinomanometry and acoustic rhinometry, but correlations of bilateral congestion and measurable dimensions were much lower. ETS-S and ETS-NS subjects differed in correlations between bilateral subjective and objective measures: ETS-S subjects showed significant correlation between baseline congestion and NAR; in contrast, ETS-NS subjects showed significant correlation between baseline congestion and acoustic rhinometry. These results indicate that NAR and AR are complementary tests for use in inhalation challenge studies and have different correlations with nasal congestion under baseline and challenge conditions.

Tobacco smoke upper respiratory response relationships in healthy nonsmokers.

This study determined exposure-response relationships to side-stream tobacco smoke (2 hrs; 0, 1, 5, and 15 ppm CO) in 29 healthy nonsmoking young adults. Sixteen subjects had no history of environmental tobacco smoke rhinitis (ETS-NS) while 13 subjects had a history of ETS rhinitis (ETS-S). Eye irritation and odor perception showed a statistically significant exposure response in both groups; headache was significant in ETS-S and nose irritation was significant in ETS-NS subjects. Significant postexposure (P1) symptoms were first reported at 1 ppm CO among both groups, but in 3/9 symptoms were significantly greater at this exposure level in ETS-S subjects. Nasal congestion, rhinorrhea, and cough increased significantly at 15 ppm CO only. In ETS-S subjects, nasal volume decreased and nasal resistance increased in an exposure-response fashion. ETS-NS subjects had a qualitatively different shape to the exposure-response curve; significant dimensional reductions in mid- and posterior nasal volume occurred with exposure at 1 ppm CO but not at 5 ppm CO and reductions in posterior nasal volume occurred at 15 ppm CO exposure. These studies indicate subjective and objective response relationships with exposure to sidestream tobacco smoke at concentrations from 1 to 15 ppm CO. Some differences are noted among the two subject groups in the magnitude of some symptoms at the lowest exposure level and in the qualitative shape of the acoustic rhinometry and nasal resistance exposure-response curves.

Sidestream tobacco smoke exposure acutely alters human nasal mucociliary clearance.

Nasal mucociliary clearance (NMC) is a biomarker of nasal mucosal function. Tobacco smokers have been shown to have abnormal NMC, but the acute effect of environmental tobacco smoke (ETS) on nonsmokers is unknown. This study evaluated acute tobacco smoke-induced alterations in NMC in 12 healthy adults. Subjects were studied on 2 days, separated by at least 1 week. Subjects underwent a 60-min controlled exposure at rest to air or sidestream tobacco smoke (SS) (15 ppm CO) in a controlled environmental chamber. One hour after the exposure, 99mTc-sulfur colloid was aerosolized throughout the nasal passage and counts were measured with a scintillation detector. Six out of 12 subjects showed more rapid clearance after smoke exposure than after air exposure, and 3/12 had rapid clearance on both days. However, substantial decreases in clearance occurred in 3/12 subjects, all of whom had a history of ETS rhinitis. In two subjects, more than 90% of the tracer remained 1 hr after tracer administration (2 hr after smoke exposure). Understanding the basis for biologic variability in the acute effect of tobacco smoke on NMC may advance our understanding of pathogenesis of chronic effects of ETS.

Nasal pressure-volume relationships determined with acoustic rhinometry.

Partitioning of ventilation has been hypothesized to be related to nasal pressure-volume relationships, relationships that have been difficult to measure. Regional differences in nasal passage pressure-volume relationships are likely because the nasal valve and anterior turbinate are structurally different, but both are altered by agents that alter vascular tone. This study determined nasal volume-to-pressure ratio (NVPR) on six healthy nonsmoking subjects by measuring nasal volume by using acoustic rhinometry at pressures ranging between -14 and +14 cmH2O on 3 days: baseline, after intranasal decongestion (oxymetazoline), and congestion (histamine). NVPR was lower in the nasal valve (0.07 +/- 0.01 cm3/cmH2O) than in the anterior portion of the turbinates (0.29 +/- 0.05 cm3/cmH2O; P < 0.005). Oxymetazoline decongestion decreased NVPR in the nasal valve by 23% and NVPR in the anterior portion of the turbinates by 47%. Histamine did not alter NVPR at either site. Nasal resistance changes correlated with changes in nasal valve and anterior turbinate volume. In summary, regional differences in nasal pressure-volume relationships exist and changes occur with pharmacologically induced vascular decongestion.

Human susceptibility to indoor contaminants.

Indoor environmental pollutants can act as irritants, allergens, carcinogens, or infectious agents. This chapter focuses on human susceptibility to indoor environmental pollutants, here defined as inherent factors that alter exposure-response relationships. The host defense system is an important determinant of human susceptibility and is composed of two portions: nonspecific immunity and specific immunity. Pollutants elicit responses from many components of the human host defense system, and human susceptibility results from biologic variability in these components. Nonspecific immunity responds to stressors based on physicochemical properties. Components include mucociliary clearance, the epithelial barrier, airway surface fluid, and neural reflexes. Specific immunity recognizes and responds to unique peptide or carbohydrate sequences present on the foreign agent, and components of the response may include lymphocytes, basophils, mast cells, and immunoglobulins. Irritants typically stimulate nonspecific immunity, allergens stimulate specific immunity, and infecting organisms and carcinogens interact with both. Additional inherent factors that may alter the toxicity of an agent include genetic background, the presence of disease or specific organ pathology, age, gender, body weight, nutritional, hormonal, and central nervous system status. Understanding the basis for human susceptibility to indoor environmental pollutants can assist in implementing practical strategies for managing indoor air quality.