Betty Angelini

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

OBJECTIVEnThe 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.nnnMETHODSnIn 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.nnnRESULTSnForty-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.nnnCONCLUSIONSnNeither 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.

Efficacy and Safety of Oral Immunotherapy with Short Ragweed Extract

BACKGROUNDnOral immunotherapy, if proven safe and effective, could be an alternative to subcutaneous immunotherapy.nnnOBJECTIVEnThis pilot study investigated the clinic and immunologic effects of ragweed immunotherapy using a new microencapsulated, pH-sensitive, oral delivery system.nnnMETHODSnA double-blind, placebo-controlled trial was conducted in 23 patients with allergic rhinitis to short ragweed. Following a baseline nasal challenge with ragweed allergen, oral immunotherapy with encapsulated short ragweed extract or placebo was administered once daily, 6 days/week. Dosed began at 3 micrograms Amb a 1 per day and were increased by 3 micrograms every three days as tolerated, to a maximum daily maintenance dose of 24 micrograms. A nasal challenge was repeated 6 weeks, later, followed by the continuation of maintenance therapy through the natural ragweed season. Daily allergy symptoms and relief medication usage was recorded. A final nasal challenge was performed at the end of the natural season. Short ragweed-specific serum IgE, IgG, and IgG4 antibody levels were measured every 2 weeks during the study.nnnRESULTSnMaximum tolerated doses ranged from 6 to 24 micrograms Amb a 1 per day (74% reached 24 micrograms). Adverse events were not serious or different between the active and placebo groups. The active group showed increased in short ragweed-specific serum IgG and IgG4 antibody levels. Symptom scores during the natural season were numerically but not statistically lower in the active treatment group. This group also experienced a greater reduction from baseline in nasal reactivity as assessed by nasal challenge.nnnCONCLUSIONSnThese pilot data suggest that the encapsulated, pH-sensitive oral immunotherapy delivery system was safe, induced a brisk serologic response, and attenuated the symptomatic response to both experimental and environmental ragweed exposure.

Diminished dendritic cell interleukin 10 production in atopic children

BACKGROUNDnDiminished 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.nnnOBJECTIVEnTo 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.nnnMETHODSnMonocyte-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.nnnRESULTSnDC 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.nnnCONCLUSIONSnThese 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.

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

BACKGROUNDnDiminished 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.nnnOBJECTIVEnTo determine whether there is an association between ETS and dendric cell (DC) IL-10 production during infancy.nnnMETHODSnETS 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.nnnRESULTSnSixteen 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).nnnCONCLUSIONSnOur 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.

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.

Cytokine levels during symptomatic viral upper respiratory tract infection

BACKGROUNDnPrevious 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.nnnOBJECTIVEnTo compare the pattern of nasal cytokine elaboration in asymptomatic and symptomatic subjects experimentally infected with rhinovirus-39 (RV-39).nnnMETHODSnHealthy 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.nnnRESULTSnTwenty-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.nnnCONCLUSIONSnThe 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.

Effect of intranasal challenge with interleukin-6 on upper airway symptomatology and physiology in allergic and nonallergic patients

BACKGROUNDnInterleukin-6 (IL-6) is a potent regulator of airway inflammation and an important component of biologic homeostasis. Previously, a temporal relationship between the local elaboration of IL-6 and the development of upper airway symptoms and pathophysiologic findings was reported for patients experimentally infected with influenza A virus or rhinovirus.nnnOBJECTIVEnThe objective of this study was to determine the provocative effects of direct, intranasal administration of IL-6 on those symptoms, signs, and pathophysiologic findings that accompany viral upper respiratory infection.nnnMETHODSnIn this double-blind, placebo-controlled, crossover trial, 10 symptomatic allergic, 10 asymptomatic allergic, and 10 nonallergic adult patients were pretreated with intranasal histamine and, after 15 minutes, were challenged with repeated doses of placebo (saline) or with increasing doses (0, 0.01, 0.1, and 1 microg/mL) of recombinant IL-6 at 20-minute intervals, during randomized paired sessions. Symptom scores, sneeze and cough counts, nasal secretion weights, nasal conductance (rhinomanometry), middle ear pressure (tympanometry), Eustachian tube function (sonotubometry), and pulmonary function (spirometry) were evaluated before and after the histamine challenge, after each dose of IL-6 or placebo, and then at 90 minutes and 2, 3, 4, 6, and 24 hours.nnnRESULTSnAt the doses used, intranasal challenge with IL-6 was well tolerated. At the 90-minute postchallenge endpoint, a significant effect of challenge substance and group assignment was documented for nasal secretion weight. Paired comparisons showed that the effect was greater for the allergic patients when compared with the nonallergic patients. There were no differences between placebo and IL-6 challenge for any of the other measured parameters.nnnCONCLUSIONSnThese results show that local IL-6 at relatively low doses can provoke increased nasal secretions in patients with allergic rhinitis.

Allergy skin test responses during experimental infection with respiratory syncytial virus

BACKGROUNDnAllergy 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.nnnOBJECTIVEnTo determine whether a viral upper respiratory tract infection affects allergy skin test responsiveness.nnnMETHODSnWe 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.nnnRESULTSnThe 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.nnnCONCLUSIONnThese results may have implications for explaining the cause of such well-known complications of RSV infection as otitis media, bronchiolitis, and asthmatic exacerbation.

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

BACKGROUNDnCough 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.nnnOBJECTIVEnTo 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.nnnMETHODSnIn 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).nnnRESULTSnStrong 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).nnnCONCLUSIONnThese results have implications for the design and interpretation of results from clinical trials that evaluate cough frequency as a treatment outcome.

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.