Response to omalizumab using patient enrichment criteria from trials of novel biologics in asthma.

BACKGROUND: Recent efficacy studies of asthma biologics have included highly enriched patient populations. Using a similar approach, we examined factors that predict response to omalizumab to facilitate selection of patients most likely to derive the greatest clinical benefit from therapy. METHODS: Data from two phase III clinical trials of omalizumab in patients with allergic asthma were examined. Differences in rates of asthma exacerbations between omalizumab and placebo groups during the 16-week inhaled corticosteroid (ICS) dose-stable phase were evaluated with respect to baseline blood eosinophil counts (eosinophils <300/µL [low] vs ≥300/µL [high]) and baseline markers of asthma severity (emergency asthma treatment in prior year, asthma hospitalization in prior year, forced expiratory volume in 1 second [FEV1 ; FEV1 <65% vs ≥65% predicted], inhaled beclomethasone dipropionate dose [<600 vs ≥600 µg/day], and long-acting beta-agonist [LABA] use [yes/no]). RESULTS: Adults/adolescents (N = 1071) were randomized to receive either omalizumab (n = 542) or placebo (n = 529). In the 16-week ICS dose-stable phase, rates of exacerbations requiring ≥3 days of systemic corticosteroid treatment were 0.066 and 0.147 with omalizumab and placebo, respectively, representing a relative rate reduction in omalizumab-treated patients of 55% (95% CI, 32%-70%; P = .002). For patients with eosinophils ≥300/µL or with more severe asthma, this rate reduction was significantly more pronounced. CONCLUSION: In patients with allergic asthma, baseline blood eosinophil levels and/or clinical markers of asthma severity predict response to omalizumab.

Abstracts from the North American Rhinology & Allergy Conference, February 3, 2011, Puerto Rico.

INTRODUCTION: To establish the efficacy of bepotastine besilate ophthalmic solution (bepotastine) 1.5%, a dual acting histamine H1 receptor antagonist approved for treatment of ocular itching associated with allergic conjunctivitis, compared to placebo in relieving ocular itching and redness for subjects with active allergic rhinoconjunctivitis. METHODS: A randomized, double-masked, placebo-controlled, confirmatory natural exposure study of bepotastine 1.5% and placebo was conducted during allergy season at 12 clinical sites throughout the U.S. Following a 7-day screening period, eligible subjects ≥12 years old were assigned in a 1:1 ratio to dosing OU b.i.d. either bepotastine 1.5% (n = 123) or placebo (n = 122). Subjects recorded instantaneous grades for their ocular symptoms prior to their next dose for 14 consecutive days. Clinically significant reduction in ocular sign or symptom grades between treatment groups required p ≤ 0.05 as determined by ANCOVA analysis. RESULTS: Significant clinical effectiveness with bepotastine 1.5% was demonstrated over the 2-week treatment period in comparison to placebo in the intent-to-treat population for reducing mean instantaneous grades for both ocular itching (p = 0.007) and redness (p = 0.001). Investigator rating of efficacy over the 2-week treatment period across response categories was also superior for bepotastine 1.5% compared to placebo (p = 0.024). Only one subject discontinued participation in the study due to an adverse event. CONCLUSIONS: These data support bepotastine 1.5% as an effective treatment for allergen-induced signs and symptoms in a clinical study designed to closely resemble the conditions under which patients with allergic rhinoconjunctivitis would require treatment.

Extent, patterns, and burden of uncontrolled disease in severe or difficult-to-treat asthma.

BACKGROUND: Characterization of uncontrolled asthma burden in a natural treatment setting can influence treatment recommendations and clinical practice. The objective was to characterize and compare the economic burden of severe or difficult-to-treat asthma in uncontrolled and controlled patients. METHODS: Baseline patient data (age > or = 13 years; n = 3916) were obtained from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens study. Disease control was assessed using two approaches: (i) applying criteria for control based on the Gaining Optimal Asthma Control study, and (ii) using the Asthma Therapy Assessment Questionnaire (ATAQ) to identify the number of asthma control problems. Assessments were performed at baseline, and at months 12 and 24. Monetary values were assigned to productivity loss and medical resource use. Direct and indirect costs were aggregated over 24 months and compared using Student's t-test for continuous measures and chi-squared for categorical variables. RESULTS: Throughout the study, most patients had uncontrolled asthma (83% uncontrolled; 16% inconsistent control; 1.3% controlled). Controlled patients experienced fewer work or school absences and less healthcare resource use than uncontrolled patients at all study time points. Using the multilevel ATAQ control score, asthma costs increased directly with the number of asthma control problems. Costs for uncontrolled patients were more than double those of controlled patients throughout the study (14,212 vs 6,452 US Dollars; adjusted to 2002 Dollars; P < 0.0001). CONCLUSIONS: This study demonstrated that few severe or difficult-to-treat asthma patients achieved control over a 2-year period and the economic consequence of uncontrolled disease is substantial.

A review of the role of inhaled corticosteroids in the treatment of acute asthma.

Systemic corticosteroids (CSs) are generally accepted as treatment for acute exacerbations of asthma. In contrast, inhaled corticosteroids (ICs) have been used for the long-term management of asthma but are not widely accepted for the treatment of asthma exacerbations. The onset of action of ICs in acute asthma begins in 1 hour. In patients with mild to moderate exacerbation, administration of high-dose ICs may decrease the need for hospital admission and the number of symptomatic days.

Infants undergoing pyloromyotomy are not at risk for postoperative apnea. Staff of Sutter Community Hospitals Sleep Disorders Center.

Thirty term infants undergoing general anesthesia and pyloromyotomy had pre- and postoperative sleep studies to determine whether these infants were at risk for postoperative apnea. Sleep studies showed an improved respiratory disturbance index (RDI) after surgery. Postoperatively, apnea indices were lower and lowest oxygen saturation values were increased compared to the infants' preoperative status. We conclude that pyloromyotomy does not elicit postoperative apnea in term infants.

Approach to the difficult pediatric asthmatic.

Wheezing in infants and children presents a difficult differential diagnosis contingent on the presenting symptoms and age of the child. A determination of the anatomy of the lower airway, combined with allergic, infectious, and noninfectious irritants, is requisite to a complete evaluation. The intervention strategies to decrease wheezing and bronchial hyperresponsiveness may include both nonpharmacologic and pharmacologic management. The nonpharmacologic management of asthma in children is contingent on aggressive treatment of dietary protein sensitivity and strict environmental control. The treatment of bronchial hyperresponsiveness with pharmacologic intervention in infants and children is relegated to the optimal use of sodium cromoglycate and inhaled corticosteroid.

Alpha-2A-interferon for treatment of bronchiolitis caused by respiratory syncytial virus.

Alpha-2a-interferon (IFN) has been shown to provide important local defense against some viral infections. In vitro, IFN inhibits the growth of respiratory syncytial virus in bovine monolayer cultures, but respiratory syncytial virus is known to be a poor inducer of IFN in infected infants. When IFN was administered by daily intramuscular injection in a double blind, placebo-controlled study of 22 infants with bronchiolitis caused by respiratory syncytial virus, there was no statistically significant difference in clinical course, duration of oxygen requirement or physical assessment between the treatment and control groups. Likewise viral isolation showed no difference between the groups. Further studies are needed to determine whether higher dosing or aerosol or other alternative route of delivery of IFN might lead to therapeutic benefit.

High-frequency jet ventilation in children with the adult respiratory distress syndrome complicated by pulmonary barotrauma.

High-frequency jet ventilation (HFJV) was used in 29 children with severe ARDS complicated by pulmonary barotrauma (PBT). Treatment with HFJV was begun when PBT was progressing over a 24-h period while receiving conventional ventilation (CV). The mean (+/- SD) age was 0.95 +/- 1.21 years (range, 0.03-4 years). The most common diagnosis was viral pneumonia (n = 17); other diagnoses included aspiration pneumonitis (n = 4), bacterial pneumonia (n = 3), multiple trauma (n = 2), and near-drowning (n = 3). The Bunnell Life-Pulse ventilator was used at a rate of 240/min or 300/min, with inspiratory time of 0.02 sec. Twenty children survived (69%). Survivors and nonsurvivors had equal disease severity prior to HFJV as assessed by ventilator settings, alveolar-to-arterial oxygen tension gradient, oxygenation index, and blood gas values. Survivors had spent significantly less time on conventional ventilation prior to HFJV than nonsurvivors, with a mean (+/- SD) of 3.7 +/- 2.1 days vs 9.6 +/- 4.5 days, respectively (P < 0.05). Survivors underwent an average of 4.4 +/- 3.9 days of HFJV, which supported adequate gas exchange with lower airway pressures, and produced resolution or significant improvement in airleak on chest radiograph. In conclusion, we speculate that the application of HFJV early in the course of severe hypoxemic respiratory failure complicated by airleak, allows the reduction of airway pressures, thereby minimizing pulmonary barotrauma and allowing the lung to recover from the underlying insult. Further controlled evaluation of HFJV in this high risk group of patients is warranted.

Clinical comparison of Gentle-Haler Actuator and Aerochamber Spacer for Metered Dose Inhaler (MDI) use by asthmatics.

UNLABELLED: Spacing devices such as the Aerochamber have been shown to improve delivery of medication from MDIs in patients who could not use proper technique with an MDI alone, but the Aerochamber may be inconvenient to carry & use because of its bulkiness. We therefore compared clinical responses of asthmatics using a new, smaller MDI actuator (Gentle-Haler) with no spacer to their responses using a standard MDI actuator & spacer (Aerochamber). METHODS: We treated 30 asthmatic patients in 2 sessions with the beta-agonist albuterol using the above-mentioned devices. Both devices were utilized in each treatment session, with one delivering albuterol & the other generating a placebo. During the second session on a different day, the albuterol & placebo were reversed with respect to the two devices. On each study day, physiologic measurements of FEV1, FVC, FEF25-75, blood pressure, & pulse were obtained at pretreatment (baseline) & after treatment at 15 & 30 minutes & 1, 2, 3, 4, 5 & 6 hours. Analysis of variance & Student's t test were used to compare the ratio of physiologic responses to albuterol delivered with the two devices. RESULTS: Both devices were equally effective in eliciting desirable increases in FEV1, FEF25-75, & FVC. No statistically significant differences (5% significance level) in effectiveness of the albuterol were associated with the use of either device. A very small (< 7%) but statistically significant reduction in diastolic blood pressure (3 of 8 time points) & systolic pressure (1 of 8 time points) was associated with the use of the Gentle-Haler.(ABSTRACT TRUNCATED AT 250 WORDS)

Respiratory papillomas: presentation before six months.

The prognosis of respiratory papillomatosis (RP) in newborns appears to be less favorable than in infants and older children. In this series of four patients who developed symptoms of the disease within the first 6 months of life, the mortality was 100%. In these premature and term newborn infants, endoscopic laser surgery and medical and immunologic therapy were unable to control the growth of RP. Meticulous local removal of the airway lesions is the most reliable form of management.

Reduction of serum testosterone levels during chronic glucocorticoid therapy.

The effect of chronic glucocorticoid therapy on serum testosterone levels was studied in men aged 67 +/- 4 (SD) years with chronic pulmonary disease. The serum testosterone level was reduced in 14 of 16 patients to a mean value of 211 +/- 93 ng/dL, compared with 449 +/- 111 ng/dL in 11 age- and disease-matched control patients (p less than 0.001). The corticosteroid dosage and the serum testosterone level were inversely related (r = -0.78). Testosterone binding to serum proteins was not significantly affected. Basal gonadotrophin levels were not elevated while their secretory responses to exogenous gonadotrophin-releasing hormone (GnRH) were intact. We conclude that glucocorticoid therapy commonly reduces serum testosterone levels in older men due to alteration of hypothalamic GnRH secretion.

Sudden infant death syndrome in infants evaluated by apnea programs in California.

Home apnea/bradycardia monitoring is frequently used in the management of infants at increased risk for sudden infant death syndrome (SIDS). However, some infants have died despite evaluation by infant apnea programs, and the benefits of home monitoring remain unproven. To determine the SIDS rate and risk factors of infants evaluated by infant apnea programs, 31 apnea programs and ten home monitor vendors in California were surveyed. Eleven (35%) of the apnea programs and four (40%) of the vendors responded. Information was obtained on 26 infants who died. Thirteen (50%) deaths were due to SIDS. Abnormal sleep studies did not predict death. Fifteen infants died despite a recommendation for home monitoring. Seven deaths occurred in association with technical errors or noncompliance with monitoring. Four deaths were due to nonaccidental trauma. The apnea programs evaluated 3,406 infants during a 5-year period; 1,841 had monitoring recommended. Term infants with apnea, subsequent siblings of SIDS victims, and infants evaluated at referral centers were more likely to have monitoring recommended than premature infants with apnea or infants evaluated at nonreferral centers (P less than .0001). Infants who had monitoring recommended were at equal risk of dying of SIDS as those who did not.

Diurnal variation of air and helium-oxygen flow-volume curves in asthmatic children.

In order to assess diurnal variation of flow-volume curves and to determine whether small airways are involved in the diurnal variation of pulmonary function in asthmatic children, we studied eight asthmatics who were attending an asthma summer camp. Spirometry and maximal expiratory flow-volume curves with air and a helium-oxygen mixture were obtained in the morning and afternoon over a 10-day period. We found that significant increases in maximal expiratory flows at all lung volumes occurred in the afternoon. However, the increase in flows with helium (helium response) was unchanged from morning to afternoon. These results suggest that both large and small airways are involved in the diurnal variation of pulmonary function in asthmatic children.

A double-blind controlled trial of anti-Pseudomonas chemotherapy of acute respiratory exacerbations in patients with cystic fibrosis.

A double-blind controlled trail of anti-Pseudomonas chemotherapy was carried out in 24 exacerbations of pulmonary disease in patients with cystic fibrosis. Fifteen exacerbations were treated with oxacillin plus sisomicin and carbenicillin (treatment group); nine were treated with oxacillin alone (control group). The planned length of treatment was 14 days. The difference between the failure rate in the treatment group (3/15) and the control group (7/9) was statistically significant (P less than 0.015). The difference in improvement of forced expiratory volume in 1 second was also significant (P less than 0.025). At the end of the study, Pseudomonas aeruginosa was still present in the sputum of all nine patients in the control group, but was not isolated from six of the 15 patients in the treatment group. The data suggest a beneficial role for anti-Pseudomonas chemotherapy in the treatment of acute pulmonary exacerbations in patients with cystic fibrosis.

Diagnosis and treatment of anaphylactic reactions to Hymenoptera stings in children.

Forty-four children (mean age 9.6 years) with a history of an allergic reaction(s) to an insect sting and with positive insect venom skin tests were studied. IgE antibodies (RAST) to honeybee phospholipase A and to yellow jacket venom were found in the sera of 78% and 77%, respectively, of these patients. The patients were immunized with the appropriate venoms over a 15-week course and most were then subjected to an in-hospital sting; there was a 3% reaction rate (1/37). Clinical protection as associated with a fivefold increase in anti-venom IgG. Five patients did not develop a significant increase in IgG antibody and they were treated more vigorously; four were stung subsequently without reaction. Two patients did not react when stung in the field; positive identification of the culprit insect was obtained. Twenty patients were re-stung after one year of maintenance therapy; there was a single mild, delayed reaction. Immunotherapy also increased the IgE antibody against venom 3.7-fold at three months; after one year of therapy the IgE antibody level had decreased but was still 40% greater than at the outset. Immunotherapy was associated with a 25% incidence of local pain and swelling and a 6% incidence of systemic reactions. We conclude that venom therapy in children is safe and effective. The indications for initiating immunotherapy require further definition.

Nocturnal oxygen saturation in normal and asthmatic children.

At sea level, it appears that oxygen desaturation does not occur in normal children at night and that the desaturation that occurs in moderately severe asthmatic children with therapeutic levels of theophylline does not approach dangerously low levels.

Detection of pulmonary aspiration in infants and children with respiratory disease: concise communication.

Twenty children with respiratory disease ingested 500 muCi of Tc-99m sulfur colloid orally, and scintigrams of the thorax were obtained to determine whether pulmonary aspiration of gastric contents could be detected. The children ranged in age from 1 mo to 14 yr; 13 were 8 mo of age or younger. Children were studied at 5 min and 4 hr after ingestion of Tc-99m sulfur colloid using a high sensitivity computer oscilloscope to record 100K-count images. Additional images were obtained after the children had slept overnight. Five children (25%) showed definite pulmonary accumulation of activity; four of these also had a barium swallow and three showed either pulmonary aspiration of barium or moderately severe gastroesophageal reflux. Oral ingestion of Tc-99m sulfur colloid provides a noninvasive means for diagnosing pulmonary aspiration under physiologic conditions in infants and children.

A physiologic assessment of segmental bronchial atresia.

A child with congenital atresia of the apical posterior bronchus was followed from birth. The obstructed segment, ventilated through collateral pathways, was documented to be aerated by day 6. At 10 yr of age, the anomalous and adjacent normal segments were resected because of respiratory symptoms. Preoperatively, pulmonary function studies showed a mild obstructive ventilatory defect. Postoperatively, although asymptomatic, the patient's obstruction persisted. Collateral resistance (Rcoll) measured between the atretic and adjacent normal segments of the resected lung was comparable to Rcoll in young adults, but markedly greater than Rcoll for emphysematous lungs. Pathologic examination revealed gross emphysematous changes in the anomalous segment. We conclude that collateral pathways exist early in life and that ventilation of lung distal to congenitally absent airways is slow and may contribute to the development of emphysema; we speculate that this lesion should be resected early in life to permit optimal growth and development of the remaining lung.