Detection of growth suppression in children during treatment with intranasal beclomethasone dipropionate.

OBJECTIVE: Intranasal beclomethasone dipropionate (BDP) has generally been considered to have no systemic activity at recommended doses, but the potential for long-term effects on growth has not previously been evaluated. This study was undertaken to assess the effects of 1 year of treatment with intranasal BDP on growth in children. STUDY DESIGN: In this double-blind, randomized, parallel-group study, 100 prepubertal children 6 to 9 years old with perennial allergic rhinitis were treated with aqueous BDP 168 microg twice daily (n = 51) or placebo (n = 49) for 1 year. Subjects' baseline heights were required to be between the 5th and 95th percentile, and skeletal age as determined by left wrist radiograph was required to be within 2 years of chronological age. Washout periods for medications known to affect growth, including other forms of corticosteroids, were established, and these medications were prohibited during the study. However, short courses of oral prednisolone lasting no more than 7 days, and short courses of dermatologic corticosteroids lasting no more than 10 days, were allowed. Height was measured with a stadiometer after 1, 2, 4, 6, 8, 10, and 12 months of treatment. The hypothalamic-pituitary-adrenocortical axis was assessed by measurements of 8 AM basal cortisol concentrations and response to. 25 mg cosyntropin stimulation. The primary safety parameter was the rate of change in standing height. Statistical analyses were based on all randomized subjects who received at least 1 dose of medication (intent-to-treat principle). The rate of change in standing height was analyzed for all subjects who entered the study and for those completing the full 12 months of treatment (n = 80). The rate of change in standing height over the 1-year study was calculated as the slope of a linear regression line fitted to each subject's height measurements over time. Because there was a statistically significant between-group difference in standing height at baseline, an analysis of covariance was performed for all analyses of standing height data. RESULTS: Of the 100 subjects enrolled, 90 completed the study. The 2 treatment groups were generally comparable at baseline; however, at baseline, mean age and mean height were significantly greater in the BDP treatment group that the in placebo treatment group. In both analyses, overall growth rate was significantly slower in BDP-treated subjects than placebo-treated subjects. The mean change in standing height after 1 year was 5.0 cm in the BDP-treated subjects compared with 5.9 cm in the placebo-treated subjects. The difference in growth rates was evident as early as the 1-month treatment visit, suggesting that the effect on growth occurred initially. The growth-suppressive effect of BDP remained consistent across all age and gender subgroups, and among subjects with and without a previous history of corticosteroid use. Use of additional exogenous corticosteroids during the study was similar in both groups and did not affect the results. Because there was a baseline imbalance in height, a supplemental analysis of the differences in prestudy growth rates was performed. This analysis found no baseline imbalance in prestudy growth rates. To determine whether the difference in growth rates during the study could be attributed to preexisting growth rates, a z score analysis was performed. The heights of both groups were normalized at baseline and at the end of the study using the US National Center for Health Statistics data for mean and standard deviations of height. This analysis confirmed that the difference in growth rates between the 2 groups was primarily attributable to the treatment rather than to any preexisting difference in growth. Additional analyses confirmed that the results were not influenced by outlier values. No significant between-group difference were found in the hypothalamic-pituitary-adrenocortical axis assessments. No unusual adverse events were observed. (ABSTRACT

Symptoms in pediatric asthmatics and air pollution: differences in effects by symptom severity, anti-inflammatory medication use and particulate averaging time.

Experimental research in humans and animals points to the importance of adverse respiratory effects from short-term particle exposures and to the importance of proinflammatory effects of air pollutants, particularly O(subscript)3. However, particle averaging time has not been subjected to direct scientific evaluation, and there is a lack of epidemiological research examining both this issue and whether modification of air pollutant effects occurs with differences in asthma severity and anti-inflammatory medication use. The present study examined the relationship of adverse asthma symptoms (bothersome or interfered with daily activities or sleep) to O(3) and particles (less than or equal to)10 micrometer (PM10) in a Southern California community in the air inversion zone (1200-2100 ft) with high O(3) and low PM (R = 0.3). A panel of 25 asthmatics 9-17 years of age were followed daily, August through October 1995 (n = 1,759 person-days excluding one subject without symptoms). Exposures included stationary outdoor hourly PM10 (highest 24-hr mean, 54 microgram/m(3), versus median of 1-hr maximums, 56 microgram/m(3) and O(3) (mean of 1-hr maximums, 90 ppb, 5 days (greater than or equal to)120 ppb). Longitudinal regression analyses utilized the generalized estimating equations (GEE) model controlling for autocorrelation, day of week, outdoor fungi, and weather. Asthma symptoms were significantly associated with both outdoor O(3) and PM(10) in single pollutant- and co-regressions, with 1-hr and 8-hr maximum PM(10) having larger effects than the 24-hr mean. Subgroup analyses showed effects of current day PM(10) maximums were strongest in 10 more frequently symptomatic (MS) children: the odds ratios (ORs) for adverse symptoms from 90th percentile increases were 2.24 [95% confidence interval (CI), 1.46-3.46] for 1-hr PM10 (47 microgram/m(3); 1.82 (CI, 1.18-2.81) for 8-hr PM10 (36 microgram/m(3); and 1.50 (CI, 0.80-2.80) for 24-hr PM10 (25 microgram/m(3). Subgroup analyses also showed the effect of current day O(subscript)3 was strongest in 14 less frequently symptomatic (LS) children: the ORs were 2.15 (CI, 1.04-4.44) for 1-hr O(3) (58 ppb) and 1.92 (CI, 0.97-3.80) for 8-hr O(3) (46 ppb). Effects of 24-hr PM10 were seen in both groups, particularly with 5-day moving averages (ORs were 1.95 for MS and 4. 03 for LS; p(less than or equal to)0.05). The largest effects were in 7 LS children not on anti-inflammatory medications [5-day, 8-hr PM10, 9.66 (CI, 2.80-33.21); current day, 1-hr O(3), 4.14 (CI, 1.71-11.85)]. Results suggest that examination of short-term particle excursions, medication use, and symptom severity in longitudinal studies of asthma yields sensitive measures of adverse respiratory effects of air pollution.

The effect of outdoor fungal spore concentrations on daily asthma severity.

The relationship between day-to-day changes in asthma severity and combined exposures to community air pollutants and aeroallergens remains to be clearly defined. We examined the effects of outdoor air pollutants, fungi, and pollen on asthma. Twenty-two asthmatics ages 9-46 years were followed for 8 weeks (9 May-3 July 1994) in a semirural Southern California community around the air inversion base elevation (1,200 ft). Daily diary responses included asthma symptom severity (6 levels), morning and evening peak expiratory flow rates (PEFR), and as-needed beta-agonist inhaler use. Exposures included 24-hr outdoor concentrations of fungi, pollen, and particulate matter with a diameter < 10 microns (PM10; maximum = 51 micrograms/m3) and 12-hour day-time personal ozone (O3) measurements (90th percentile = 38 ppb). Random effects longitudinal regression models controlled for autocorrelation and weather. Higher temperatures were strongly protective, probably due to air conditioning use and diminished indoor allergens during hot, dry periods. Controlling for weather, total fungal spore concentrations were associated with all outcomes: per minimum to 90th percentile increase of nearly 4,000 spores/m3, asthma symptom scores increased 0.36 (95% CI, 0.16-0.56), inhaler use increased 0.33 puffs (95% CI, -0.02-0.69), and evening PEFR decreased 12.1 l/min (95% CI, -1.8-22.3). These associations were greatly enhanced by examining certain fungal types (e.g., Alternaria, basidiospores, and hyphal fragments) and stratifying on 16 asthmatics allergic to tested deuteromycete fungi. There were no significant associations to low levels of pollen or O3, but inhaler use was associated with PM10 (0.15 inhaler puffs/10 micrograms/m3; p < 0.02). These findings suggest that exposure to fungal spores can adversely effect the daily respiratory status of some asthmatics.

Daily asthma severity in relation to personal ozone exposure and outdoor fungal spores.

Epidemiologic investigations of ambient ozone (O3) effects on daily asthma status have not used personal O3 exposures and have often lacked well-characterized allergen exposures. To address this, we studied 12 asthmatic subjects aged 9 to 16 yr, who recorded daily asthma symptoms (functional levels 0 to 5) and as-needed inhaler use during September and October 1993 in San Diego, California, Outdoor aeroallergens, O3, and fine particle concentrations were measured at a central outdoor site, and personal 12-h daytime exposures to O3 were measured daily. Personal O3 differed greatly between subjects and was 27% of mean outdoor O3. In random-effects autoregression models controlling for weekend days and fungal spores, personal O3 was associated with asthma severity: for a 90th percentile increase in O3 (25 ppb), symptom scores increased by 25% (95% CI: 0 to 49%) and inhaler use increased by 26% (95% CI: 3 to 48%) over their averages. Outdoor 12-h O3, but not 1-h maximum O3, was associated with inhaler use (p < 0.03). Fungal spores were significantly associated with symptoms (scores increased by 0.1 to 0.3/1,000 spores/m3) and inhaler use (0.1 to 0.4 puffs/1,000 spores/m3) across speciated groups. Pollen and fine particles (low levels) were not associated with any outcomes. These findings illustrate that the epidemiologic importance of O3 and allergenic cofactors can be underestimated by failure to account for personal O3 and fungal exposures.

Double-strength beclomethasone dipropionate (84 micrograms/spray) aqueous nasal spray in the treatment of seasonal allergic rhinitis.

BACKGROUND: The use of intranasally administered corticosteroid sprays is an established treatment option for seasonal allergic rhinitis. METHODS: In this double-blind, placebo-controlled, multicenter study, 438 patients with moderate to severe symptoms of seasonal allergic rhinitis were treated for 4 weeks with double-strength beclomethasone dipropionate (BDP) aqueous nasal spray (84 micrograms/spray: BDP-ds), once daily; regular-strength BDP (42 micrograms/spray: BDP-rs), twice daily; high-strength BDP (336 micrograms/spray: BDP-hs), once daily; or placebo. BDP-hs was included as a safety comparison group. All treatments were given as two sprays per nostril. RESULTS: Physician-rated nasal symptom scores were significantly improved in all three active treatment groups compared with those of the placebo group within the initial 3 days of treatment. Improvement was maintained throughout the 4-week treatment period. BDP-ds and BDP-rs were equivalent at all time points. The BDP-ds, BDP-rs, and BDP-hs groups had greater numbers of patients with a good or excellent therapeutic response at end point than the placebo group. All treatments were well-tolerated, and no unexpected adverse events were reported. No effects on laboratory evaluations or vital signs were evident for any treatment group. CONCLUSIONS: The results of this study show that BDP-ds given once a day and BDP-rs given twice a day in the same total daily dose are comparably safe and effective in the treatment of patients with seasonal allergic rhinitis.

Safety of salmeterol in the maintenance treatment of asthma.

BACKGROUND: Salmeterol is the first long-acting inhaled beta 2-agonist available in the US for the maintenance treatment of asthma. OBJECTIVE: To compare the safety of salmeterol with that of the short-acting beta 2-agonist albuterol. METHODS: Two identically designed, prospective, randomized, double-blind, parallel studies were conducted comparing salmeterol 42 micrograms twice daily, albuterol 180 micrograms four times daily, and placebo over 12 weeks in 556 patients (12 to 73 years old) with mild-to-moderate chronic asthma. Patients in each treatment group could use albuterol as needed to control acute symptoms. RESULTS: The incidence of potentially drug-related adverse events was similar among the treatment groups (range: 22% to 23%), with headache being the most commonly reported (range: 9% to 10%). No deaths occurred during the studies. Concomitant use of > 4 puffs of supplemental albuterol per day in the salmeterol group produced no increase in the incidence of adverse events either in general or of a cardiovascular nature. There were no statistically significant differences among treatment groups or clinically significant changes from pretreatment values in mean pulse rate, systolic/diastolic blood pressure, or clinical laboratory values after 12 weeks. There were no clinically significant differences among groups in heart rates nor were there differences in the frequency of supraventricular or ventricular ectopic beats during 24-hr Holter monitoring. The frequency of asthma exacerbations was lowest among patients receiving salmeterol (and highest among those who received placebo), and this rate did not increase over the 12 weeks. Asthma exacerbations were treated successfully with nebulized albuterol (2.5 mg), with no evidence of any increased risk of cardiovascular events. CONCLUSIONS: Salmeterol 42 micrograms twice daily is well-tolerated in patients with asthma, having a similar safety profile as that of albuterol 180 micrograms inhaled four times daily or placebo (plus as-needed albuterol). Concomitant use of albuterol, either by MDI or nebulization, did not affect the safety of salmeterol. Extensive cardiovascular monitoring revealed no significant cardiovascular adverse effects or arrhythmogenic effects associated with salmeterol over 12 weeks.

Biologic contaminants.

Dr. Seltzer lays the groundwork for a discussion of the importance of a healthy environment by pointing out that most Americans spend at least 90% of their time indoors. He describes conditions that promote biologic contamination, ways that these contaminants induce illness, the key components of any evaluation of an indoor environment, and methods of decontamination and prevention.

Creating healthy indoor environments. A road map for the future.

This road map for the future describes 12 steps toward the creation of healthy indoor environments. Pointing out that funding for indoor air issues pales in comparison to that spent on outdoor pollution, the author argues that a multidisciplinary approach is necessary to improve the existing knowledge base concerning IAQ.

Biological contaminants.

"The potential economic impact of indoor air pollution is quite high and is estimated in the tens of billions of dollars per year. Such impacts includes direct medical costs and lost earnings due to major illness as well as increased employee sick days and lost productivity." The health consequences of biological contamination range from uncomfortable odors to end-stage lung disease to fatality. What factors predispose to biologic contamination? Which contaminants cause adverse health effects? What illnesses are associated with which contaminants, and how do these occur? This discussion will help answer these questions, leaving the discussion of environmental sampling, interpretation of sampling results, and remediation to other speakers who presented this information. A few interesting ideas for consideration regarding the implications of biological contamination will also be presented.

Building-related illnesses.

As we develop a better understanding of the adverse effects of the indoor environment on health, the pathophysiologic mechanisms contributing illnesses caused by indoor environmental factors will become more clearly defined. The term building-related illness applies to those adverse health effects for which we have a well-defined link between environmental agents in a specific building and the resultant health disorders. This class of illnesses frequently involves the skin and respiratory tract because of the ease with which indoor environmental contaminants come in contact with these tissues. Agents that cause building-related illnesses generally induce illness by one of four mechanisms: (1) immunologic, (2) infectious, (3) toxic, or (4) irritant. Some agents may work through more than one mechanism. This article discusses the different mechanisms that cause building-related illness, the different types of this class of illnesses, and the evidence validating the connection between the environmental agents and the diseases they cause.

Once daily fluticasone propionate is as effective for perennial allergic rhinitis as twice daily beclomethasone diproprionate.

BACKGROUND: Fluticasone propionate aqueous nasal spray, a new potent corticosteroid, is effective when given once or twice daily for seasonal allergic rhinitis. METHODS: Fluticasone propionate was compared with beclomethasone dipropionate in a multicenter double-blind, randomized, placebo-controlled, parallel-group study in 466 patients with perennial allergic rhinitis. Adults and adolescents (aged 12 to 71 years) with moderate to severe symptoms, nasal eosinophilia, and a positive skin test reaction (> or = 2+) to a perennial allergen received fluticasone propionate aqueous nasal spray 100 micrograms twice daily or 200 micrograms once daily, or beclomethasone dipropionate aqueous nasal spray 168 micrograms twice daily, or placebo for 6 months. RESULTS: Clinician- and patient-rated scores for nasal obstruction (including obstruction on awakening), rhinorrhea, sneezing, and nasal itching were reduced by the first visit at 7 days after initiation of active treatment and remained lower than those of patients receiving placebo throughout the 6-month treatment period. Nasal eosinophilia was reduced in significantly more patients receiving active treatment. The incidence of adverse events was similar in all four treatment groups except for blood in nasal mucus, which was reported by significantly more patients in the two twice-daily active treatment groups compared with the placebo group. There was no evidence of systemic effects of fluticasone propionate. There were no significant differences between fluticasone propionate given once or twice daily or beclomethasone dipropionate given twice daily for any efficacy or safety evaluation. CONCLUSIONS: Fluticasone propionate aqueous nasal spray given once daily in the morning is safe and effective therapy for perennial allergic rhinitis and is as effective as twice daily dosing with fluticasone propionate or beclomethasone dipropionate.

A comparison of salmeterol with albuterol in the treatment of mild-to-moderate asthma.

BACKGROUND: An effective, long-acting bronchodilator could benefit patients with asthma who have symptoms not controlled by antiinflammatory drugs. We compared a new long-acting, inhaled beta 2-adrenoceptor agonist, salmeterol, with a short-acting beta 2-agonist, albuterol, in the treatment of mild-to-moderate asthma. METHODS: We randomly assigned 234 patients (150 male and 84 female patients 12 to 73 years old) to one of three treatment groups: one group received 42 micrograms of salmeterol twice daily, one received 180 micrograms of albuterol four times daily, and one received placebo. Treatment was assigned in a double-blind fashion, and all patients could use supplemental inhaled albuterol as needed during the 12-week treatment period. RESULTS: Measurements of the forced expiratory volume in one second, performed hourly for 12 consecutive hours, showed that a single dose of salmeterol produced a greater mean area under the curve than two doses of albuterol taken 6 hours apart (6.3 vs. 4.9 liter.hr, P < 0.05). The difference was significant on day 1 and at week 4 of the study, but not at week 8 or 12. Salmeterol was also more effective than albuterol or placebo (with albuterol taken as needed) in increasing the morning peak expiratory flow rate: salmeterol induced a mean increase of 24 liters per minute over the pretreatment values, as compared with a decrease of 6 liters per minute with albuterol (P < 0.001) and an increase of 1 liter per minute with placebo (P = 0.002). The mean overall symptom score was improved most by salmeterol treatment (P < 0.05), with the number of days with symptoms and of nights with awakenings decreasing by 22 percent and 52 percent, respectively; there were no differences in results between albuterol treatment and placebo administration. We found no evidence of tolerance to the bronchodilating effects of salmeterol, and adverse reactions to all the treatments were infrequent and mild. CONCLUSIONS: For the management of mild-to-moderate asthma, salmeterol given twice daily is superior to albuterol given either four times daily or as needed.

Evaluation of symptom relief, nasal airflow, nasal cytology, and acceptability of two formulations of flunisolide nasal spray in patients with perennial allergic rhinitis.

A new formulation of intranasal flunisolide containing less propylene glycol was compared with the original formulation for efficacy and acceptability in more than 200 patients with symptoms of perennial allergic rhinitis. In this multicenter, randomized, double-blind, parallel group study, symptomatic patients were treated with either the new or the original formulation of 0.025% solution of intranasal flunisolide for 4 weeks to provide 200 micrograms flunisolide daily. Both formulations were highly effective in decreasing symptom scores as evident from patient diary reports before and after treatment (P less than .001). Similarly, nasal airflow was improved with each treatment as measured by anterior rhinomanometry (P less than .0002) and the number of patients with nasal eosinophilia decreased (P less than .01). Finally, fewer patients using the new formulation reported nasal burning or stinging and the acceptability rating of the new formulation was higher.

Comparison of parallel line skin test assay (PLST) and ELISA inhibition (EI) methods for determination of relative potency of polymerized grass and ragweed antigenic extracts.

Relative potency estimates were performed by parallel line skin test assay (PLST) and ELISA inhibition methods for three polymerized allergen extracts (Bermuda grass, orchard grass, and a copolymer of short and giant ragweed) versus four unmodified RAST standardized reference extracts (Bermuda grass, orchard grass, and giant and short ragweed) in nine subjects. One subject experienced a systemic reaction, requiring treatment at the end of the PLST assay. Another subject had a systemic reaction during limited skin testing performed approximately 72 hours after completion of PLST. Relative potency values for the polymerized extracts obtained by PLST were much lower than those obtained by ELISA inhibition, but results were significantly (r = 0.95; p less than 0.01) correlated. Because polymerized allergen extracts are designed to be hypoallergenic, a skin test assay may underestimate their potency relative to an unmodified reference extract.

Correlation of allergy test results obtained by IgE FAST, RAST, and prick-puncture methods.

Prick skin testing and IgE FASTTM results were compared in eight atopic patients, using a comparable class system. Identical results were found in 53.5% of the cases; a total of 85.7% of the results were within one class difference. Sera from 436 patients were assayed for specific IgE to 94 allergens for a total of 436 test comparisons using IgE FASTTM and modified RAST. Identical results were found in 41.7% of cases; a total of 81.4% of the tests differed by one class or less. The IgE FAST showed good correlation both with prick testing and modified RAST. IgE FAST appears to be a valid non-radioactive, time-efficient method for detecting specific IgE to common inhalant and environmental allergens.

Histamine contamination of pokeweed mitogen.

The histamine content of commercial preparations of pokeweed mitogen was measured by amino acid analysis technique, automated fluorometry, and bioassay employing the guinea pig ileum. Ten samples from 5 companies were examined and found to contain between 0.026 micrograms and 167.5 micrograms of histamine per ml of solution. The protein content of 9 of these putative 5 mg samples measured by folin assay and by amino acid analysis varied from 0.56 to 4.4 mg. Their amino acid compositions were similar, except for notable variations in 3 of the 16 residues quantitated.