David G. Tinkelman

Use of an anti-IgE humanized monoclonal antibody in ragweed-induced allergic rhinitis☆☆☆★★★

BACKGROUND Increased serum levels of antigen-specific IgE are often associated with allergic respiratory disorders. RhuMAb-E25, a recombinant humanized monoclonal antibody, decreases free serum IgE by forming biologically inactive immune complexes with free IgE. OBJECTIVE We hypothesized that rhuMAb-E25 would decrease total serum IgE and reduce symptoms. METHODS Two hundred forty subjects were enrolled into five groups to determine the safety, tolerance, and efficacy of repeated administration of rhuMAb-E25 in adults with ragweed-induced allergic rhinitis and to explore the pharmacodynamic relationship of rhuMAb-E25 and IgE. One hundred eighty-one subjects received an initial intravenous loading dose (day 0, 1 month before ragweed season), followed by administration of rhuMAb-E25 (in mg/kg body weight) of 0.15 mg/kg subcutaneously, 0.15 mg/kg intravenously, or 0.5 mg/kg intravenously on days 7, 14, 28, 42, 56, 70, and 84. A subcutaneous placebo group and an intravenous placebo group were included. The total evaluation time included the 84-day treatment period, followed by a 42-day observation period. RESULTS Adverse events were mild, and no differences were observed in the rates between the three active and two placebo treatment groups. Ragweed-specific IgE levels correlated with symptom scores. RhuMAb-E25 decreased serum free IgE levels in a dose- and baseline IgE-dependent fashion. However, only 11 subjects had IgE levels that were suppressed to undetectable levels (< or = 24 ng/ml), a sample too small to demonstrate significant differences and clinical efficacy. Thus the case for efficacy was not proven. Nonetheless, the study confirms that it is safe to repeatedly administer rhuMAb-E25 over a period of months. CONCLUSIONS Because rhuMAb-E25 decreased serum free IgE in a dose-dependent fashion and because symptom scores correlated with antigen-specific IgE levels, the results suggest that if given in adequate doses, rhuMAb-E25 should be an effective therapy for allergic diseases.

Misdiagnosis of COPD and Asthma in Primary Care Patients 40 Years of Age and Over

Chronic obstructive pulmonary disease (COPD) is often misdiagnosed as asthma, leading to inappropriate treatment and suboptimal patient outcomes. As part of a prospective study of patients with a history consistent with obstructive lung disease, we compared prior diagnostic labels with a study diagnosis based on spirometric results. We enrolled persons 40 years of age or older with prior diagnoses or medications consistent with obstructive lung disease. Patients were recruited via random mailing to primary care practices in Aberdeen, Scotland, and Denver, Colorado. Prior diagnoses of chronic bronchitis or emphysema (CBE) and asthma were reported by the subjects. Participants underwent pre- and post-bronchodilator spirometry. A study diagnosis of COPD was defined using post-bronchodilator forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) < 0.70. Spirometric examination was complete in 597 patients, of whom 235 (39.4%) had a study diagnosis of COPD. Among subjects with a spirometry-based study diagnosis of COPD, 121 (51.5%) reported a prior diagnosis of asthma without concurrent CBE diagnosis, 89 (37.9%) reported a prior diagnosis of CBE, and 25 (10.6%) reported no prior diagnosis of obstructive lung disease. Despite the availability of consensus guideline diagnostic recommendations, diagnostic confusion between COPD and asthma appears common. Increased awareness of the differences between the two conditions is needed to promote optimal patient management and treatment.

Growth in asthmatic children treated with fluticasone propionate

OBJECTIVE To determine whether inhaled fluticasone propionate has long-term effects on growth in children with persistent asthma. STUDY DESIGN In a double-blind, randomized, parallel-group, multicenter study, 325 prepubescent children with persistent asthma and normal growth rates were treated with placebo or inhaled fluticasone propionate powder 50 microg or 100 microg administered twice daily by a breath-actuated device for 1 year. Growth was evaluated monthly, whereas other safety variables and pulmonary function were evaluated periodically. RESULTS The prepubescent patients showed no statistically significant differences in mean height, mean growth velocity, or mean skeletal age between any of the treatment groups at any time. Over a period of 1 year, mean height (+/- SE) increased 6.15 +/- 0.17 cm in the placebo group, 5.94 +/- 0.16 cm in the fluticasone propionate 50 microg group, and 5.73 +/- 0.13 cm in the fluticasone propionate 100 microg group (p = 0.308, overall). CONCLUSIONS Prepubescent children treated with fluticasone propionate 50 microg and 100 microg administered twice daily for 1 year grew at rates similar to placebo-treated control subjects and at rates equal to expected growth velocity for age.

Symptom-based questionnaire for identifying COPD in smokers

Background: Symptom-based questionnaires may enhance chronic obstructive pulmonary disease (COPD) screening in primary care. Objectives: We prospectively tested questions to help identify COPD among smokers without prior history of lung disease. Methods: Subjects were recruited via random mailing to primary care practices in Aberdeen, UK, and Denver, Colo., USA. Current and former smokers aged 40 or older with no prior respiratory diagnosis and no respiratory medications in the past year were enrolled. Participants answered questions covering demographics and symptoms and then underwent spirometry with reversibility testing. A study diagnosis of COPD was defined as fixed airway obstruction as measured by postbronchodilator FEV1/FVC <0.70. We examined the ability of individual questions in a multivariate framework to correctly discriminate between persons with and without COPD. Results: 818 subjects completed all investigations and proceeded to analysis. The list of 54 questions yielded 52 items for analysis, which was reduced to 17 items for entry into multivariate regression. Eight items had significant relationships with the study diagnosis of COPD, including age, pack-years, body mass index, weather-affected cough, phlegm without a cold, morning phlegm, wheeze frequency, and history of any allergies. Individual items yielded odds ratios ranging from 0.23 to 12. This questionnaire demonstrated a sensitivity of 80.4 and specificity of 72.0. Conclusions: A simple patient self-administered questionnaire can be used to identify patients with a high likelihood of having COPD, for whom spirometric testing is particularly important. Implementation of this questionnaire could enhance the efficiency and diagnostic accuracy of current screening efforts.

A dose-ranging study of fluticasone propionate aqueous nasal spray for seasonal allergic rhinitis assessed by symptoms, rhinomanometry, and nasal cytology

Fluticasone propionate is a new glucocorticosteroid with potent topical activity. In a double-blind, randomized, parallel-group study, 423 adult patients with moderate to severe seasonal allergic rhinitis received placebo or fluticasone propionate aqueous nasal spray at doses of 25, 100, or 400 micrograms twice daily (b.i.d.) for 2 weeks. Efficacy was evaluated by nasal symptom scores, nasal airflow, nasal cytology, and global evaluation. All doses of fluticasone propionate were significantly better than placebo in reducing symptoms of seasonal allergic rhinitis. Patients receiving the largest dose of fluticasone propionate (400 micrograms b.i.d.) had a slightly greater reduction (not significant) in symptom scores than patients receiving the smallest dose (25 micrograms b.i.d.). Symptom improvement was evident within 3 days of treatment. Nasal airflow improved in the groups treated with fluticasone propionate, 100 and 400 micrograms b.i.d. Examination of nasal cytograms revealed a striking decrease in both eosinophils and basophils in all three groups receiving active treatment compared with placebo. There were few adverse events and no treatment-related abnormalities in laboratory assays or evaluations of hypothalamo-pituitary-adrenocortical axis function. Comparison of treatment groups indicated that fluticasone propionate aqueous nasal spray was as safe as placebo at the doses studied.

Immunotherapy: A one-year prospective study to evaluate risk factors of systemic reactions

BACKGROUND We did a prospective study in Atlanta, Georgia, during 1991 on the rate of systemic reactions caused by immunotherapy in a clinic that uses aqueous allergen extracts. METHODS Immunotherapy reactions were monitored. Symptoms were recorded with respect to time of onset, involvement of respiratory tract or skin, and presence of hypotension. RESULTS There were 98 systemic reactions in 96 patients (1 per 1600 visits or 1 per 47 patients). There was no direct relationship to seasonal pollen counts. There was, however, a correlation with the August to October increase in mold counts. There was no correlation between reactions and the age of the patient or the age of the extract. Patients were more likely to experience a reaction during the buildup phase than during maintenance therapy. The time of onset and the severity of the reaction were in agreement with previous reports. Severe reactions that included hypotension all occurred less than 30 minutes after the injection. In contrast to previous reports, patients with asthma were not at higher risk for a systemic reaction. CONCLUSION Immunotherapy has a significant but low rate of systemic reaction. Potentially serious reactions may be mitigated by taking extra precautions during the earlier phases of an immunotherapy program and during seasons when mold counts are high.

The Impact of Uncontrolled Asthma on Absenteeism and Health-Related Quality of Life

Objective. To evaluate the impact of uncontrolled asthma on the absenteeism and health-related quality of life (HRQOL) of adults and children with asthma and the caregivers of pediatric patients. Patients and methods. Patient information was obtained from datasets maintained by National Jewish Health for this cross-sectional study. Participants in the study were 12 years of age or older. Participants younger than 18 years had their information provided by caregivers. Caregivers also provided 6 months of absenteeism and QOL data. Participants were classified as having uncontrolled asthma based on a treatment and symptom guideline-based algorithm. Absenteeism was assessed from the self-reported number of work or school days missed due to asthma during the previous 6 months. HRQOL among adults was measured using the validated Marks Asthma Quality of Life Questionnaire (Marks-AQLQ) and among caregivers using the validated Pediatric Asthma Caregivers Quality of Life Questionnaire (PACQLQ). To account for the positive skew in absenteeism data, a zero-inflated Poisson regression model was used to compare group differences. HRQOL was analyzed for adults and caregivers using the Wilcoxon-Mann-Whitney test. Results. A total of 15,149 patients met the inclusion criteria for the study and were included in the analysis. Adults with uncontrolled asthma and caregivers of children with uncontrolled asthma reported significantly higher absenteeism than their controlled counterparts: 43% vs 24% adults reported missing days of work, with a median 6 days vs 3 days missed; 31% vs 16% of caregivers reported missing days of work, with 4 days vs 2 days missed; and caregivers reported that more than 70% vs 45% pediatric patients missed school, with a median of 6 days vs 4 days missed (uncontrolled vs controlled asthma, respectively). Adult uncontrolled asthmatics and caregivers of uncontrolled pediatric patients had significantly lower HRQOL as indicated by the Marks-AQLQ (scores 1.5 points higher, p < 0.001) and PACQLQ (scores < 0.5 points lower, p < 0.001), respectively. Conclusions. Uncontrolled asthma has far-reaching impact on the productivity and quality of life of asthma patients and their caregivers. Proper assessment, treatment, and disease management to improve asthma control may reduce the impact of uncontrolled asthma on asthmatic adults, children, and the caretakers of pediatric asthmatic patients.

Symptom-Based Questionnaire for Differentiating COPD and Asthma

Background: Many patients with obstructive lung disease (OLD) carry an inaccurate diagnostic label. Symptom-based questionnaires could identify persons likely to need spirometry. Objectives: We prospectively tested questions derived from a comprehensive literature review and an international Delphi panel to help identify chronic OLD (COPD) in persons with prior evidence of OLD. Methods: Subjects were recruited via random mailing to primary-care practices in Aberdeen, Scotland, and Denver, Colorado. Persons aged 40 and older reporting any prior diagnosis of OLD or any respiratory medications in the past year were enrolled. Participants answered 54 questions covering demographics and symptoms and underwent spirometry with reversibility testing. A study diagnosis of COPD was defined by fixed airway obstruction as measured by post-bronchodilator FEV1/FVC <0.70. We examined ability of individual questions in a multivariate framework to discriminate between persons with and without the study diagnosis of COPD. Results: 597 persons completed all investigations and proceeded to analysis. The list of 54 questions yielded 52 items for analyses, which was reduced to 19 items for entry into a multivariate regression model. Nine items had significant relationships with the study diagnosis of COPD, including increased age, pack-years, worsening cough, breathing-related disability or hospitalization, worsening dyspnea, phlegm quantity, cold going to the chest, and receipt of treatment for breathing. Individual items yielded odds ratios ranging from 0.33 to 20.7. This questionnaire demonstrated a sensitivity of 72.0 and a specificity of 82.7. Conclusions: A short, symptom-based questionnaire identifies persons more likely to have COPD among persons with prior evidence of OLD.

Retention of asthmatic patients in a longitudinal clinical trial

BACKGROUND Prevention of study patient attrition and assessment of its impact on outcome data are problems that receive little attention despite their obvious importance in asthma research. OBJECTIVE The medical, demographic, and psychologic characteristics of asthmatic children and adults who dropped out of a yearlong medication trial were assessed to determine whether this group differed from those who completed the study, potentially introducing bias into the data set and interfering with completion of the studys objectives. METHODS Profiles of 362 adult and pediatric asthmatic patient dropouts from the multicenter trial were contrasted with profiles of those who completed the study. Despite a 1-month prerandomization screening, 24% of patients failed to complete the trial for varied reasons, which largely included noncompliance and treatment dissatisfaction. RESULTS Although attrition rates were equal among adults and children, dropout-completer differentiation was not. Adult completers did not differ from dropouts in any variables. However, pediatric dropouts were more likely than completers to be female (67% and 36%, p = 0.008) and to have more reactive airways (PD20, 2.29 +/- 1.32 and 5.2 +/- 1.23, p = 0.05), to have reduced scores on tests of intelligence (Full Scale IQ, 102.2 +/- 2.6 and 112.5 +/- 1.6, p = 0.002) and problem solving (Wisconsin Card Sorting Test Error Scores, 39.8 +/- 4.1 and 29.1 +/- 2.0, p = 0.01), and to have increased behavioral problems (Child Behavior Checklist Total Problem Score, 60.7 +/- 2.5 and 53.6 +/- 1.1, p = 0.003). CONCLUSION These findings demonstrate the potential of patient attrition to bias outcome in clinical trials and underscore the necessity of: (1) preventing its occurrence, (2) correctly assessing its causes, and (3) determining its ultimate impact on study results. Strategies for each of these three tasks should be implemented at the studys initial planning stages.

Use of ipratropium bromide nasal spray in chronic treatment of nonallergic perennial rhinitis, alone and in combination with other perennial rhinitis medications

To study the long-term safety and effectiveness of ipratropium bromide nasal spray 0.03% in the treatment of nonallergic perennial rhinitis, we administered this medication for 1 year in an open-label trial involving 285 patients. Our intention was to maintain the highest protocol dose possible to gain a clearer picture of the long-term side effect profile of the compound. Ipratropium bromide was well tolerated with no serious side effects in this patient population. It provided a significant improvement in rhinorrhea throughout the year-long trial; only 17 of 285 patients (6%) were considered treatment failures. There was an improvement in patient quality of life, as well as a substantial reduction in the need for other medications (antihistamines, decongestants, and nasal steroids) used to treat perennial rhinitis symptoms.