Effect of therapeutic doses of mometasone furoate on cortisol levels in children with mild asthma.

Corticosteroids are the foundation of pharmacologic treatment for children with asthma. However, high-dose inhaled corticosteroid treatment can cause hypothalamic-pituitary-adrenal (HPA) axis suppression. We investigated the effect of three doses of mometasone furoate administered via dry-powder inhaler (MF-DPI) on the HPA axis in children. Fifty children (6-11 years) with mild asthma of > or =6 months' duration were randomized to MF-DPI, 100 (n = 13), 200 (n = 13), or 400 micrograms b.i.d. (n = 12), or placebo (n = 12) for 29 days. The primary end point was change from baseline in the 12-hour area under the plasma-cortisol-concentration-time curve (AUC). Secondary parameters included plasma cortisol response to cosyntropin stimulation and 24-hour urinary free cortisol concentrations. Compared with placebo, AUC changes associated with treatments of MF-DPI, 100 or 200 micrograms b.i.d., were not significant, whereas a significant change was observed with MF-DPI, 400 micrograms b.i.d. (27%; p = 0.05). Responses to cosyntropin stimulation and urinary cortisol measurements were similar to placebo with all MF-DPI doses. All regimens were well tolerated. MF-DPI did not have a significant effect on plasma or urinary cortisol levels at doses up to 200 micrograms b.i.d. in children with mild asthma. Higher MF-DPI doses may potentially suppress the HPA axis.

Inhaled steroids and the risk of adrenal suppression in children.

Corticosteroids are the mainstay of treatment of all asthma severity levels in adults and children. With their widespread use comes a responsibility to monitor, understand, and balance their efficacy and safety. Systemic adverse effects such as adrenal suppression have been clearly associated with the use of oral corticosteroids and to a lesser degree with the use of inhaled corticosteroids (ICS). In clinical trials, adrenal suppression is more evident when ICS are used in long-term therapy and at higher doses. However, monitoring adrenal suppression during short-term therapy and at lower doses is still of value in order to ascertain the lower limit of an inhaled corticosteroid's safety profile. Significant adrenal suppression at conventional ICS doses appears to be rare in clinical practice. When evaluating the effect of ICS on the hypothalamo-pituitary-adrenal-axis (HPA-axis), one must consider sources of variability both within and among trials including test sensitivity, systemic bioavailability, degree of airway obstruction, and delivery devices. All of these factors have the potential to effect the level of adrenal suppression detected and must be considered when interpreting HPA-axis test results in research or practice. This review will discuss adrenal suppression found with common ICS.

Nasal and oral nitric oxide levels during experimental respiratory syncytial virus infection of adults.

Nitric oxide (NO) is a recognized mediator of inflammation in diseases affecting the lower respiratory tract, and has been implicated in the expression of viral upper respiratory tract infections. Here, exhaled nasal and oral NO concentrations and nitrite concentrations in nasal lavage fluids were measured, symptoms were scored and pulmonary function was evaluated before (Day 0) and after (Days 1-8) experimental exposure of 17 adult subjects to respiratory syncytial virus (RSV) type B. After exposure, RSV was recovered from 12 (70%) subjects by culture and/or specific antigen detection. Both subjects with and those without RSV recovery developed increased nasal and throat symptoms after RSV exposure, but none evidenced changes in the three measures of NO concentration. These results do not support the hypothesis of increased NO production during RSV infection and complement earlier studies that reported a lack of change in nasal NO concentration during experimental influenza and rhinovirus infections.

Effect of tetanus immunization on t-helper cytokine production in adults with and without allergic rhinitis.

Epidemiological evidence links T-helper type 2 (Th2) cytokine responses to the pathogenesis of atopy/asthma. It is hypothesized that certain immunizations may induce/amplify Th2 cytokine responses. The objective of this study was to determine whether Th cytokine responses to immunization with tetanus toxoid differ in adults with and without allergic rhinitis (AR). Thirty subjects were enrolled (15 AR and 15 non-AR subjects as confirmed by history and allergy skin testing). Blood was collected before (day 0) and on days 3, 7, 14, and 28 after immunization with tetanus toxoid. Peripheral blood mononuclear cells (PMNCs) were purified and cultured with either PHA or tetanus toxoid for 2 or 6 days, respectively. Supernatants were harvested and assayed for IFN-gamma and IL-13 levels (pg/mL) by EIA. Results were normalized by log transformation and analyzed by stepwise regression. Baseline (day 0) cytokine values were similar in both groups. PHA and tetanus-induced IFN-gamma were increased (p < 0.05) in non-AR (3.2 +/- 0.3 and 1.4 +/- 0.3 on day 7, and 3.5 +/- 0.2 and 1.9 +/- 0.2 on day 14, respectively) compared with AR subjects (2.3 +/- 0.3 and 0.9 +/- 0.3 on day 7, and 2.7 +/- 0.3 and 1.2 +/- 0.3 on day 14, respectively). PHA-induced, but not tetanus-induced, IL-13 production was increased (p < 0.05) in non-AR compared with AR subjects on day 7 (p < 0.05). PHA-induced IL-13 production was 3.1 +/- 0.2 in non-AR and 2.6 +/- 0.3 in AR subjects on day 7. These results indicate differential Th cytokine responses in AR and non-AR subjects after immunization with tetanus toxoid. Future studies are warranted and may result in the identification of potential prevention/treatment strategies for atopy/asthma.

Allergy skin test responses during experimental infection with respiratory syncytial virus.

BACKGROUND: Allergy skin testing is one of the most frequently performed physician office procedures. Many factors can affect the results of those tests, including the well-defined suppressive effect of systemic antihistamines. False-positive allergen skin test results are known to occur; however, contributing factors are not well understood. OBJECTIVE: To determine whether a viral upper respiratory tract infection affects allergy skin test responsiveness. METHODS: We performed skin tests with histamine and a panel of geographically relevant inhalant allergens on 16 adults before and 3, 6, and 21 days after experimental exposure to respiratory syncytial virus (RSV), a virus that causes signs and symptoms of a cold. RESULTS: The RSV exposure, with and without documented infection, caused increased wheal and flare areas to histamine and allergen and de novo positive allergen test responses in individuals with no measurable responses at baseline. These were noted as late as 21 days after RSV exposure and may be consistent with mediation by up-regulated neurogenic inflammation during RSV infection. CONCLUSION: These results may have implications for explaining the cause of such well-known complications of RSV infection as otitis media, bronchiolitis, and asthmatic exacerbation.

Cytokine levels during symptomatic viral upper respiratory tract infection.

BACKGROUND: Previous studies suggest a role for locally produced proinflammatory cytokines in the development and expression of illness during experimental infection with a variety of respiratory viruses. However, most of these studies fail to make comparisons between symptomatic and asymptomatic infected subjects. OBJECTIVE: To compare the pattern of nasal cytokine elaboration in asymptomatic and symptomatic subjects experimentally infected with rhinovirus-39 (RV-39). METHODS: Healthy adults underwent experimental intranasal inoculation with a safety-tested clinical isolate of RV-39. Nasal lavages were collected, nasal symptoms were recorded, and expelled nasal secretions were weighed before and then daily for 6 days after challenge. Nasal lavages were submitted for viral culture and assayed for cytokine protein levels by enzyme-linked immunosorbent assay. RESULTS: Twenty-nine subjects were enrolled in the study. All subjects were infected as evidenced by viral shedding and/or seroconversion. Sixteen subjects were symptomatic and 13 were asymptomatic as evaluated by subject self-report. During infection, significant increases in mean levels of nasal interleukin 6 (IL-6) (P = .01) and IL-1 (P = .02) were observed in symptomatic but not asymptomatic subjects. In symptomatic subjects, these increases were temporally related to the development of nasal symptoms and production of secretions. Mean levels of IL-8, IL-10, and tumor necrosis factor a were not increased in either group during infection. CONCLUSIONS: The results of this study demonstrate elevations in certain locally produced cytokines during symptomatic but not asymptomatic respiratory infection with RV-39. Future studies using selected anticytokine therapies may help elucidate the precise role of cytokines in mediating disease expression.

The effects of intranasal triamcinolone acetonide and intranasal fluticasone propionate on short-term bone growth and HPA axis in children with allergic rhinitis.

OBJECTIVE: The purpose of this study was to evaluate the effects of triamcinolone acetonide (TAA) and fluticasone propionate (FP) aqueous nasal sprays on short-term lower-leg growth velocity and hypothalamic-pituitary-adrenal (HPA-axis function in pediatric subjects. METHODS: In this controlled, double-blinded (TAA) or single-blinded (FP), four-way crossover trial, 59 subjects (mean age: 7.2 years) were randomized to receive each of four 2-week treatments in random order: TAA nasal spray 110 microg, TAA nasal spray 220 microg, FP nasal spray 200 microg, and placebo, administered by a third party once daily with a 2-week washout period between treatments. Lower-leg growth velocity was measured by knemometry, and HPA-axis function was measured using 12-hour overnight urinary cortisol levels. RESULTS: Forty-nine subjects completed all four treatments and were included in the analyses. Mean growth velocity (+/- standard error) was 0.46 (+/- 0.06) mm/week for placebo, 0.37 (+/- 0.06) and 0.31 (+/- 0.06) mm/week for TAA nasal spray 110 and 220 microg, respectively, and 0.37 (+/- 0.06) mm/week for FP nasal spray. The treatment effect on mean growth velocity compared with placebo was -19.6% with TAA 110 microg, -32.6% with TAA 220 microg, and -21.7% with FP; none of these effects was considered statistically or clinically significant according to predefined criteria. No significant differences in changes in urine cortisol/creatinine ratios were observed between TAA 110 microg or 220 microg and placebo (4.38, 3.60, and -0.67, respectively, P > or = 0.157). In contrast, the change in mean urine cortisol/creatinine ratio values for FP (-3.59) were significantly lower compared with TAA 220 microg (P = 0.033) and placebo (P = 0.003). Knemometry exhibited less time-dependent variability than overnight urinary cortisol measurements. CONCLUSIONS: Neither TAA nor FP had a clinically significant effect on lower-leg growth velocity. In contrast to FP, TAA nasal spray did not significantly affect HPA-axis function when used over a 2-week interval.

Association between environmental tobacco smoke and diminished dendritic cell interleukin 10 production during infancy.

BACKGROUND: Diminished interleukin 10 (IL-10) production has been documented in children and adults with asthma and atopy. Environmental tobacco smoke (ETS) is recognized as a risk factor for the development of childhood asthma. OBJECTIVE: To determine whether there is an association between ETS and dendric cell (DC) IL-10 production during infancy. METHODS: ETS was evaluated by questionnaire, and blood samples were obtained at 2 weeks, 3 months, and 5 months of age in 37 healthy infants. DCs were cultured and stimulated, and supernatants were assayed for IL-10 by enzyme immunoassay. RESULTS: Sixteen infants had no history of exposure to ETS, and 21 infants had a history of ETS exposure. The frequency of subjects with detectable IL-10 levels was similar in both groups at 2 weeks and 3 months but significantly different at 5 months (P < .001). In those without ETS exposure, the frequency with detectable IL-10 levels increased during the observation period (25% at 2 weeks, 20% at 3 months, and 36% at 5 months; P = .03 vs 2 weeks). In contrast, in those with ETS exposure, the frequency with detectable IL-10 levels decreased during the observation period (33% at 2 weeks, 19% at 3 months; P = .02 vs 2 weeks; and 7% at 5 months; P < .001 vs 2 weeks). CONCLUSIONS: Our study results demonstrate an association between ETS and diminished DC IL-10 production during infancy. Future studies need to expand on these sample sizes and explore whether diminished DC IL-10 production is the mechanism by which ETS predisposes patients to the development of asthma and/or atopy.

Comparison of objective and subjective measurements of cough frequency in patients with seasonal allergic rhinitis.

BACKGROUND: Cough is a frequent complaint of patients with a variety of respiratory disorders, including seasonal allergic rhinitis (SAR), and it is often evaluated subjectively to determine disease status and response to treatment. However, it is not known whether subjective reports of cough from patients with SAR are accurate. OBJECTIVE: To compare a novel objective measurement with subjective reports of cough frequency in a subset of 28 patients (aged > or = 12 years) with active SAR who were enrolled in a large, multicenter trial examining the efficacy of an active treatment for SAR. METHODS: In this supplemental pilot study, subjective data were collected on a diary card and objective data were collected using home-based telemetry. Three 24-hour recording sessions were conducted with each patient: 2 consecutive baseline sessions (day 1 and day 2) and 1 session after randomization to placebo or active cough treatment (day 3). RESULTS: Strong correlations existed between cough frequency data for days 1 and 2 (Spearman correlation coefficient = 0.91; P < .001) and between subjective and objective data for days 1, 2, and 3 (daytime greater than nighttime) (Spearman correlation coefficient = 0.51; P < .001). CONCLUSION: These results have implications for the design and interpretation of results from clinical trials that evaluate cough frequency as a treatment outcome.

Diminished dendritic cell interleukin 10 production in atopic children.

BACKGROUND: Diminished interleukin 10 (IL-10) and/or IL-12 production may contribute to the pathogenesis of asthma and atopy. Dendritic cells (DCs) produce these cytokines and have been implicated in the pathogenesis of these disorders. OBJECTIVE: To determine whether DC IL-10 and/or IL-12 production is diminished in children aged 6 to 12 years with allergic rhinitis (AR) and with or without asthma. METHODS: Monocyte-derived DCs were isolated from 20 subjects without AR or asthma (group 1), 20 subjects with AR without asthma (group 2), and 20 subjects with AR and asthma (group 3). Asthma was defined as a history of physician-diagnosed disease, and AR was defined as a positive history and positive puncture skin test responses (wheal > or = 5 mm) to relevant inhalant allergens. DCs were stimulated with either lipopolysaccharide (LPS) or diluent and cultured for 24 hours. Supernatants were assayed for IL-10 and IL-12 levels by enzyme-linked immunosorbent assay. RESULTS: DC IL-10 production was diminished in groups 2 and 3 compared with group 1. Median LPS-induced IL-10 levels were 11.0 pg/mL in group 1, 6.1 pg/mL in group 2, and 1.5 pg/mL in group 3. The frequencies of subjects with detectable IL-10 levels were 85%, 20%, and 20% in groups 1, 2 and 3, respectively. Median LPS-induced IL-12 levels were similar in all groups. CONCLUSIONS: These data support the hypothesis that atopic subjects have an intrinsic inability to up-regulate DC IL-10 production. Future studies in this area could lead to a better understanding of the pathogenesis of atopy.

Comparison of subject-reported allergy versus skin test results in a common cold trial.

BACKGROUND: Few studies have examined the relationship between subject-reported allergy and results of allergy skin testing in large unselected or unbiased cohorts. The objective of this study was to compare the results of self-reported allergy via verbal questioning with the results of allergy skin testing by the puncture method in 237 healthy adult subjects enrolled in a common cold study. METHODS: On enrollment, all subjects were verbally asked if they had a history of allergy and then underwent puncture skin testing to 19 relevant aeroallergens, as well as appropriate positive and negative controls. A skin test was considered positive if its wheal diameter was at least 3 mm larger than that obtained with the negative control. RESULTS: Forty-eight (20%) subjects reported a history of allergy and 124 (52%) subjects had at least one positive skin test response. A history of allergy was reported in 40 (32%) of the skin test-positive subjects and 8 (7%) of the skin test-negative subjects. At least one positive skin test response was found in 40 (83%) of those subjects reporting a history of allergy and 84 (44%) of those subjects denying a history of allergy. CONCLUSION: These data indicate that there is a relatively poor correlation between self-reported history of allergy and skin test results in subjects enrolled in a common cold study. These results have implications in both clinical practice and research settings.