Omalizumab therapy for asthma patients with poor adherence to inhaled corticosteroid therapy.

BACKGROUND: Omalizumab, an anti-IgE monoclonal antibody, is administered by injection once or twice monthly in offices and clinics. It offers a potential alternative intervention for patients with allergic asthma that is not well controlled because of recalcitrant poor adherence to inhaled corticosteroid therapy. OBJECTIVE: To assess the effect of omalizumab therapy by measuring airway responsiveness to adenosine, a marker of allergic airway inflammation, and resource use. METHODS: Patients (N = 17) aged 6 to 26 years (mean age, 16.4 years) with poorly controlled persistent allergic asthma, less than 50% adherence to inhaled corticosteroid therapy, a forced expiratory volume in 1 second (FEV1) of 60% predicted or higher, and adenosine provocation concentration that caused a decrease in FEV1 of 20% (PC20) of 60 mg/mL or less were randomized to receive 4 months of omalizumab or placebo in a double-blind, crossover trial with a 3- to 4-month washout between treatments. Patients were instructed to continue taking inhaled corticosteroids throughout the study. The PC20 was measured before and after each period. RESULTS: Fifteen patients completed the study. The mean baseline PC20 was 14.1 mg/mL (95% CI, 10.8-18.4 mg/mL). The fold change PC20 was 0.9 (95% CI, 0.5-1.7) during placebo and 3.1 (95% CI, 1.6-6.2) during omalizumab treatment; the estimated ratio was 3.4 (95% CI, 1.2-9.3; P = .02). Six patients required one or more short courses of oral corticosteroids for asthma exacerbations during placebo, but none required this intervention during omalizumab. During the study, the median prescription refills for inhaled corticosteroids was 0.15 (95% CI, 0.00-0.33) canisters per month. CONCLUSION: Omalizumab therapy is an alternative for patients with more severe poorly controlled asthma in whom adherence does not improve with conventional interventions. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00133042.

Stability of frozen methacholine solutions in unit-dose syringes for bronchoprovocation.

OBJECTIVE: Methacholine solutions < 0.25 mg/mL must be prepared fresh daily, while concentrations > or = 0.25 mg/mL must be prepared at 2-week intervals according to US Food and Drug Administration-required labeling. The purpose of this report was to determine whether freezing methacholine solutions in unit-dose syringes would allow less frequent preparation. DESIGN: Diluent containing 0.5% sodium chloride, 0.275% sodium bicarbonate, and 0.4% phenol was used to prepare 11 concentrations of methacholine ranging from 0.031 to 32.0 mg/mL. Three milliliters of each dilution was placed into 5-mL polypropylene syringes and immediately frozen. Methacholine concentrations were determined using a validated high-performance liquid chromatography assay after preparation (time zero) and at 0.5, 1, 1.5, 2, 3, 4, 5, and 6 months. On the day of analysis, the samples were allowed to thaw to room temperature. An additional set of each dilution was stored at room temperature for 24 h after thawing and then analyzed for methacholine. RESULTS: Samples > or = 0.062 mg/mL analyzed immediately after thawing retained > or = 90% of labeled potency for at least 6 months, while the 0.031-mg/mL sample retained 90% potency for 4 months. Most samples analyzed 24 h after thawing lost potency. CONCLUSION: If prepared and stored in unit-dose syringes frozen, methacholine solutions containing 0.062 to 32.0 mg/mL can be prepared at 6-month intervals, and solutions containing 0.031 mg/mL can be prepared at 4-month intervals. Once thawed, unused methacholine solutions should be discarded.

Methacholine challenge testing: comparison of the two American Thoracic Society-recommended methods.

STUDY OBJECTIVES: Recent American Thoracic Society guidelines recommend two different methods of methacholine challenge testing: the 2-min tidal breathing method with twofold increases in concentration, and the five-breath dosimeter method with fourfold increases. Since the tidal breathing method delivers more methacholine to the mouthpiece, we hypothesized that the provocative concentration of methacholine required to decrease FEV(1) by 20% (PC(20)) would be lower than with the dosimeter method. DESIGN: Twelve subjects 18 to 45 years old with stable asthma were selected on the basis of a screening PC(20) (by tidal breathing) of < 1 mg/mL, 1 to 4 mg/mL, or 4 to 16 mg/mL (4 subjects in each concentration range). On subsequent visits within a 7-day period, methacholine challenge testing with tidal breathing or dosimeter were performed on separate days, in a randomized crossover manner. RESULTS: The geometric mean PC(20) was 1.8 mg/mL (95% confidence interval [CI], 0.7 to 4.3) after tidal breathing and 1.6 mg/mL (95% CI, 0.7 to 3.7) after dosimeter (p = 0.2). There was no significant difference between the screening PC(20) and the PC(20) obtained by either method on randomized study days. The maximum decrease in FEV(1) from diluent baseline after the last concentration was 27.8% (range, 20 to 50%) during tidal breathing and 27.9% (range, 16 to 47%) during the dosimeter method (p = 0.35). CONCLUSIONS: Both methods give similar results. Fourfold increases in methacholine concentration with the dosimeter method are as safe as twofold increases with the tidal breathing method.

Nonprescription racemic epinephrine for asthma.

BACKGROUND: Inhaled racepinephrine (RE) (Asthmanefrin) became available in September 2012 as a nonprescription treatment for bronchospasm based on a 1986 US Food and Drug Administration rule. It contains 11.25 mg RE in 0.5 mL and is delivered by a handheld electronic nebulizer. In 2001, we conducted a pilot study that was never published. Now that the product is promoted as a replacement for epinephrine chlorofluorocarbon metered-dose inhaler (Primatene), we provide the results of that study. Methacholine challenge was used as a bioassay. OBJECTIVE: To determine the dose of RE that is equivalent to nebulized albuterol. METHODS: Four subjects, 18 to 45 years old, with mild stable asthma completed the pilot study. Methacholine challenge was performed on the first screening day, without pretreatment, and then on different days, 15 minutes after 1.25 mg albuterol and 2.5, 5, 10, and 20 mg RE delivered by a Pari LC Plus nebulizer. The end point was the provocative concentration of methacholine that caused a 20% decrease in FEV1. Data were log transformed and analyzed by an ANOVA for repeated measures. RESULTS: There was a significant dose response for RE. The geometric mean provocative concentration of methacholine that caused a 20% decrease in FEV1 was 44 mg/mL (95% CI, 23-85 mg/mL) after albuterol, and 10.2 mg/mL (95% CI, 3.5-30 mg/mL) after the 10-mg dose of RE (approximate nonprescription dose) (P = .001). There were no adverse effects. CONCLUSION: RE provides less bronchoprotection from methacholine than does albuterol and may be less effective in treating acute bronchospasm.

Successful use of bronchoscopic lung insufflation to treat left lung atelectasis.

We report first use of bronchoscopic lung insufflation in a child to treat acute left lung collapse. The patient is a 6-year old male asthmatic who was hospitalized with a 2-day history of cough, chest pain, and abdominal pain. He was tachypneic and hypoxemic on room air. Chest exam revealed diminished breath sounds on the left side. Chest X-ray and Chest CT showed complete left lung collapse. He underwent bronchoscopic lung insufflation procedure by injecting total of 200 ml air via flexible bronchoscope in the left upper lobe using 50cc syringe aliquots followed by similar injection of 200 ml of air in left lower lobe. After air insufflations, 6 ml of bovine surfactant (calfactant) were instilled in each lobe. Chest fluoroscopy was done immediately after procedure and showed expansion of entire left lung with no pneumothorax. The procedure was well tolerated. The patient's symptoms and hypoxemia resolved soon after procedure. However, left lower lobe atelectasis recurred next day and persisted for 6 days despite treatments with chest physical therapy, systemic steroids, oral azithromycin, nebulized dornase alpha, and endoscopic removal of secretions from left lower lobe. Bronchoscopic insufflation of left lower lobe was repeated resulting in immediate expansion of that lobe as demonstrated by intraoperative fluoroscopy. The patient was discharged home next day. This case suggests that brochoscopic lung insufflation can be safe and effective in treating acute lung collapse and in treating atelectasis which is refractory to conventional therapy.

Plastic bronchitis: resolution after heart transplantation.

Plastic bronchitis (PB) is a rare cause of obstructive airway disease in patients who have undergone partially corrective surgery for congenital heart disease (CHD). The etiology of plastic bronchitis in such patients is ill-defined, and treatment is ineffective. We report resolution of PB and severe obstructive airway disease after heart transplantation in a patient with CHD.

Enhanced IgE allergic response to Aspergillus fumigatus in CFTR-/- mice.

To gain insight into aberrant cytokine regulation in cystic fibrosis (CF), we compared the phenotypic manifestations of allergen challenge in gut-corrected CFTR-deficient mice with background-matched C57Bl6 (B6) mice. Aspergillus fumigatus (Af) antigen was used to mimic allergic bronchopulmonary aspergillosis, a peculiar hyper-IgE syndrome with a high prevalence in CF patients. CFTR-/-, C57BL/6 and FVB/NJ mice were sensitized with Af antigen by serial intraperitoneal injections. Control mice were mock sensitized with PBS. Challenges were performed by inhalation of Af antigen aerosol. After Af antigen challenge, histologic analysis showed goblet cell hyperplasia and lymphocytic infiltration in both strains. However, total serum IgE levels were markedly elevated in CF mice. Sensitized CF mice showed a five-fold greater IgE response to sensitization as compared with B6- and FVB-sensitized controls. Additional littermate controls to fully normalize for B6-FVB admixture in the strain background confirmed the role of CFTR mutation in the hyper-IgE syndrome. Cytokine mRNA levels of IL-5 and GM-CSF in the bronchoalveolar lavage (BAL) fluid, and BAL cell differentials indicated that CFTR mutation caused a shift from an IL-5-predominant to an IL-4-predominant cytokine profile. This system models a very specific type of airway inflammation in CF and could provide insights into pathogenesis and treatment of the disease.