Immune response evolution in peanut epicutaneous immunotherapy for peanut-allergic children.

BACKGROUND: Epicutaneous immunotherapy with investigational Viaskin™ Peanut 250 µg (DBV712) has demonstrated statistically superior desensitization versus placebo in peanut-allergic children in clinical trials. It is unclear whether serologic biomarkers predict response. METHODS: Serum-specific IgG4 and IgE (whole peanut and components) from subjects enrolled in the phase 3 Efficacy and Safety of Viaskin Peanut in Children With IgE-Mediated Peanut Allergy study were examined by exploratory univariate and multivariate analyses to determine trajectories and predictors of treatment response, based upon peanut protein eliciting dose (ED) at Month (M) 12 double-blind placebo-controlled food challenge. RESULTS: Among Viaskin Peanut-treated subjects, peanut sIgG4 significantly increased from baseline through M12 and peanut sIgE peaked at M3 and fell below baseline by M12, with sIgG4 and sIgE peanut components mirroring these trajectories. Placebo subjects had no significant changes. By univariate analysis, M12 peanut sIgG4/sIgE was higher in treatment responders (p < 0.001) and had highest area under the curve (AUC) for predicting ED ≥300 mg and ≥1000 mg (AUC 69.5% and 69.9%, respectively). M12 peanut sIgG4/sIgE >20.1 predicted M12 ED ≥300 mg (80% positive predictive value). The best performing component was Ara h 1 sIgE <15.7 kUA /L (AUC 66.5%). A multivariate model combining Ara h 1 and peanut sIgG4/sIgE had an AUC of 68.2% (ED ≥300 mg) and 67.8% (ED ≥1000 mg). CONCLUSIONS: Peanut sIgG4 rise most clearly differentiated Viaskin Peanut versus placebo subjects. sIgG4/sIgE ratios >20.1 and the combination of Ara h 1 and peanut sIgG4/sIgE had moderate ability to predict treatment response and could potentially be useful for clinical monitoring. Additional data are needed to confirm these relationships.

Differing perceptions of asthma control and treatment effectiveness by patients with severe asthma and treating subspecialists in the United States.

OBJECTIVE: For patients with severe asthma (SA), overestimation of asthma control may lead to poorer outcomes. The objective of this study was to assess concurrent patient and specialist assessments of asthma control and treatment effectiveness among a large US cohort of SA patients. METHODS: CHRONICLE is an ongoing observational study of patients with SA treated by US subspecialists. Asthma control was assessed using the patient-completed Asthma Control Test™ (ACT™) and specialist clinical assessment of control. Treatment effectiveness was measured using the Global Evaluation of Treatment Effectiveness (GETE) completed by patients and specialists. RESULTS: 1109 patients who completed online surveys at enrollment were included. 14%, 28%, 25%, and 33% of patients had ACT™ scores of 5-9, 10-15, 16-19, and 20-25, respectively. Compared with 67% of patients with uncontrolled asthma by ACT™, 44% were uncontrolled by specialist assessment. 54% of patients who were uncontrolled according to the ACT™ were rated as controlled by specialists, demonstrating overestimation of asthma control. Based on ACT™ score, asthma control was more frequent among patients treated with biologics compared to other treatments. Using the GETE, 90% of patients reported treatment effectiveness compared with 71% of specialists. Patient and specialist treatment effectiveness categorizations agreed 73% of the time. CONCLUSION: Specialists commonly overestimated asthma control relative to ACT™ scores. Patients reported treatment effectiveness more frequently than specialists. These findings emphasize the importance of validated instruments to assess asthma control and reduce potential treatment gaps associated with patient-specialist discordance. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03373045.

AR101 Oral Immunotherapy for Peanut Allergy.

BACKGROUND: Peanut allergy, for which there are no approved treatment options, affects patients who are at risk for unpredictable and occasionally life-threatening allergic reactions. METHODS: In a phase 3 trial, we screened participants 4 to 55 years of age with peanut allergy for allergic dose-limiting symptoms at a challenge dose of 100 mg or less of peanut protein (approximately one third of a peanut kernel) in a double-blind, placebo-controlled food challenge. Participants with an allergic response were randomly assigned, in a 3:1 ratio, to receive AR101 (a peanut-derived investigational biologic oral immunotherapy drug) or placebo in an escalating-dose program. Participants who completed the regimen (i.e., received 300 mg per day of the maintenance regimen for approximately 24 weeks) underwent a double-blind, placebo-controlled food challenge at trial exit. The primary efficacy end point was the proportion of participants 4 to 17 years of age who could ingest a challenge dose of 600 mg or more, without dose-limiting symptoms. RESULTS: Of the 551 participants who received AR101 or placebo, 496 were 4 to 17 years of age; of these, 250 of 372 participants (67.2%) who received active treatment, as compared with 5 of 124 participants (4.0%) who received placebo, were able to ingest a dose of 600 mg or more of peanut protein, without dose-limiting symptoms, at the exit food challenge (difference, 63.2 percentage points; 95% confidence interval, 53.0 to 73.3; P<0.001). During the exit food challenge, the maximum severity of symptoms was moderate in 25% of the participants in the active-drug group and 59% of those in the placebo group and severe in 5% and 11%, respectively. Adverse events during the intervention period affected more than 95% of the participants 4 to 17 years of age. A total of 34.7% of the participants in the active-drug group had mild events, as compared with 50.0% of those in the placebo group; 59.7% and 44.4% of the participants, respectively, had events that were graded as moderate, and 4.3% and 0.8%, respectively, had events that were graded as severe. Efficacy was not shown in the participants 18 years of age or older. CONCLUSIONS: In this phase 3 trial of oral immunotherapy in children and adolescents who were highly allergic to peanut, treatment with AR101 resulted in higher doses of peanut protein that could be ingested without dose-limiting symptoms and in lower symptom severity during peanut exposure at the exit food challenge than placebo. (Funded by Aimmune Therapeutics; PALISADE ClinicalTrials.gov number, NCT02635776 .).

Effect of intravenously administered reslizumab on spirometric lung age in patients with moderate-to-severe eosinophilic asthma.

Background: Spirometric lung age expresses lung function relative to chronological age. It has been effective in encouraging smoking cessation and has been used in the assessment of asthma. Reslizumab, a humanized anti-interleukin-5 monoclonal antibody, is approved as add-on therapy for adults with severe asthma and elevated blood eosinophils. Objective: To assess the effect of reslizumab versus placebo on the change in lung age over 52 weeks and the correlation between change in lung age and quality of life in moderate-to-severe asthma. Methods: This was a post hoc analysis of two randomized, double-blind, placebo-controlled trials. Patients ages 12-75 years with moderate-to-severe, inadequately controlled asthma and elevated blood eosinophils received intravenous reslizumab 3.0 mg/kg or placebo every 4 weeks for 1 year. Spirometry was performed every 4 weeks, and the Asthma Quality of Life Questionnaire (AQLQ) score was assessed at baseline and weeks 16, 32, and 52. Results: Mean improvement in lung-age deficit at week 52 was -8.73 years for reslizumab versus -3.80 years for placebo, a treatment difference of 5 years (p < 0.0001). A statistically significant effect was seen as early as 4 weeks. In AQLQ responders (a ≥ 0.5 increase in AQLQ score), a statistically significant inverse relationship between the change from baseline in lung age and AQLQ score at weeks 16, 32, and 52 was observed among patients treated with reslizumab only. Among lung-age responders (≥5 years' reduction), a statistically significantly greater proportion of patients on reslizumab achieved ≥0.5 increase in the AQLQ score versus placebo at all time points. Conclusion: Reslizumab reduced lung-age deficit by 5 years in patients with moderate-to-severe inadequately controlled eosinophilic asthma. Improvement in lung age correlated with improved quality of life. Lung age is a simple indication of pulmonary function and could be a valuable tool in asthma education.Clinical trials NCT01287039 and NCT01285323, www.clinicaltrials.gov.

Inhaled corticosteroids: Ocular safety and the hypothalamic-pituitary-adrenal axis.

BACKGROUND: Inhaled corticosteroids (ICSs) effectively deliver corticosteroids to target sites in the lungs and reduce systemic effects compared with oral corticosteroids, but long-term systemic exposure from inhaled corticosteroids remains a concern. OBJECTIVE: To discuss ICS systemic effects on the eye and the hypothalamic-pituitary-adrenal (HPA) axis. METHODS: Relevant publications were used to augment discussion. RESULTS: The most common adverse effects of exogenous corticosteroids on the eye are secondary open-angle glaucoma and posterior subcapsular cataracts. Study findings conflict about whether ICS use is associated with increased risk of glaucoma or elevated intraocular pressure, but studies might not have addressed the question in the right population. Increased risk of glaucoma may be limited to a few susceptible individuals, such as individuals with a family history of glaucoma. Large population-based studies reveal that high daily doses or high lifetime exposure of ICSs is associated with a higher risk of posterior subcapsular cataracts. More research is needed to determine the risk from low to moderate doses during long periods. For the HPA axis, there are several measures for detecting systemic effects. Short-term measures are more sensitive for detecting the systemic effects of ICSs but have less predictive value in identifying clinically important adverse effects. Several studies have found that ICSs have a dose-dependent effects on cortisol suppression that can be used to estimate equivalent dosages among ICSs. CONCLUSION: Because of systemic effects on the HPA axis, high doses of ICS should be avoided where possible. Adult patients undergoing high-dose or long-term ICS therapy should be monitored for cataracts.

Efficacy of bepotastine besilate ophthalmic solution 1.5% for seasonal allergic conjunctivitis: a randomized, placebo-controlled, natural exposure, clinical trial.

Allergic conjunctivitis (AC) affects an estimated 20% of the population in the Western world, with a large fraction suffering due to seasonal or perennial allergen exposures. Bepotastine besilate ophthalmic solution (BBOS) 1.5%, a dual-acting histamine (H(1)) receptor antagonist and mast cell stabilizer, is indicated for itching associated with AC. This study was designed to evaluate the efficacy and safety of BBOS 1.5% for reducing ocular itching associated with AC in subjects enrolled in a natural exposure trial. Eligible subjects in a multicenter, double-masked, randomized, parallel-group, placebo-controlled, natural exposure clinical trial were randomly assigned to either BBOS 1.5% or placebo eyedrops on a 1:1 basis and instilled 1 drop of the test agent into both eyes twice daily for 2 weeks. The mean change from baseline in instantaneous and reflective ocular itching scores at the end of 2 weeks of treatment were evaluated based on subject-assessed severity of instantaneous and reflective itching. Subject-reported adverse events (AEs) were also recorded for safety. Treatment with BBOS 1.5% significantly reduced instantaneous and reflective ocular itching scores from baseline compared with placebo over the 2-week study period(p = 0.007 and p = 0.005, respectively). BBOS 1.5% was well tolerated, and AEs were generally transient and mild. This clinical study indicates BBOS 1.5% effectively and safely treated ocular itching in a natural exposure allergy study and is a useful treatment option for the management of ocular itching associated with AC. (ClinicalTrials.gov identifier number: NCT01174823.)

Comparison of intranasal azelastine to intranasal fluticasone propionate for symptom control in moderate-to-severe seasonal allergic rhinitis.

Intranasal corticosteroids are considered the most effective therapy for moderate-to-severe seasonal allergic rhinitis (SAR) and recommended first line in guidelines. It is uncertain whether intranasal antihistamines have comparable efficacy. This study was designed to compare the efficacy of azelastine (AZE; 137 µg/spray) and fluticasone propionate (FP; 50 µg/spray), both given as 1 spray/nostril bid (i.e., approved dosing regimen in the United States), in SAR via a post hoc analysis of data from a previously published direct-comparison study. Six hundred ten moderate-to-severe SAR patients (≥12 years old) were randomized into a double-blind, placebo-controlled, parallel-group trial. The primary efficacy variable was change from baseline in reflective total nasal symptom score (rTNSS (morning and evening), over 14 days. Reflective total ocular symptom score (rTOSS) was a key secondary variable. Reflective total of seven symptom scores (rT7SS [nasal plus ocular symptoms]) and time to ≥50% reduction from baseline in these key parameters were also analyzed. AZE and FP reduced rTNSS from baseline by a similar degree (-3.25 versus -3.84; p = 0.2014). Patients experienced comparable improvement in rTOSS (-2.62 versus -2.17; p = 0.2371) and rT7SS (-5.83 versus -6.05; p = 0.7820). FP was superior to AZE in alleviating rhinorrhea (-1.15 versus -0.87; p = 0.0433), but AZE showed comparable efficacy for all other nasal and ocular symptoms. There was no clinically or statistically significant difference between AZE (-1.17) and FP (-1.43) for reduction in the overall rhinitis quality of life questionnaire score (although FP, but not AZE, significantly differed from placebo). A similar proportion of patients in the AZE and FP groups achieved a 50% reduction in rTNSS. However, more AZE patients (53.0%) exhibited a 50% reduction in rTOSS by day 14 versus FP (39.6%), and ≤3 days faster (p = 0.028). Intranasal AZE (137 micrograms/spray) and intranasal FP (50 micrograms/spray), both 1 spray/nostril b.i.d., had comparable efficacy in symptom control in moderate-to-severe SAR.

Immunogenicity of Botulinum Toxin Formulations: Potential Therapeutic Implications.

Botulinum neurotoxins (BoNTs) are proteins produced by bacteria of the Clostridium family. Upon oral ingestion, BoNT causes the neuroparalytic syndrome botulism. There are seven serotypes of BoNT (serotypes A-G); BoNT-A and BoNT-B are the botulinum toxin serotypes utilized for therapeutic applications. Treatment with BoNT injections is used to manage chronic medical conditions across multiple indications. As with other biologic drugs, immunogenicity after long-term treatment with BoNT formulations may occur, and repeated use can elicit antibody formation leading to clinical nonresponsiveness. Thus, approaching BoNT treatment of chronic conditions with therapeutic formulations that minimize stimulating the host immune response while balancing patient responsiveness to therapy is ideal. Immunogenicity is a clinical limitation in many settings that use biologic drugs for treatment, and clinically relevant immunogenicity reduction has been achieved through engineering smaller protein constructs and reducing unnecessary formulation components. A similar approach has influenced the evolution of BoNT formulations. Three BoNT-A products and one BoNT-B product have been approved by the Food and Drug Administration (FDA) for therapeutic use: onabotulinumtoxinA, abobotulinumtoxinA, incobotulinumtoxinA, and rimabotulinumtoxinB; a fourth BoNT-A product, daxibotulinumtoxinA, is currently under regulatory review. Additionally, prabotulinumtoxinA is a BoNT-A product that has been approved for aesthetic indications but not therapeutic use. Here, we discuss the preclinical and clinical immunogenicity data that exist within the scientific literature and provide a perspective for considering immunogenicity as a key factor in choice of BoNT formulation.

Health-Related Quality of Life and Productivity Among US Patients with Severe Asthma.

BACKGROUND: Health-related quality of life (HRQoL) and productivity of patients with confirmed severe asthma (SA) have not been well characterized in large, real-world populations. PURPOSE: To characterize SA impact on HRQoL, work productivity, and activity impairment in a large, real-world cohort in the United States (US). METHODS: CHRONICLE is an observational study of specialist-treated adults (≥18 years) in the US with SA receiving biologics or maintenance systemic corticosteroids (mSCS), or those persistently uncontrolled by high-dosage inhaled corticosteroids with additional controllers (HD ICS+). At enrollment, patients completed the St. George's Respiratory Questionnaire (SGRQ) and Work Productivity and Activity Impairment (WPAI) questionnaire. Results were analyzed for those enrolled between February 2018 and February 2020. RESULTS: Among patients who completed enrollment questionnaires (n = 1109), mean age was 54 years and most were women (70%). Among SGRQ respondents (n = 960), mean (SD) total score was 43 (23); 51% reported good/very good health. Among WPAI respondents (n = 1057; 566 employed), mean (SD) overall work impairment was 21% (25). Patients receiving biologics (vs mSCS, HD ICS+ only) had better SGRQ total scores (38 vs 59, 48) and lower work impairment (17% vs 34%, 27%). Patients with better SGRQ activity scores relative to symptom scores had better SGRQ impacts scores, total scores, and reported better overall health. CONCLUSION: SA significantly affects HRQoL, work productivity, and activity. The SGRQ is a valuable research instrument for evaluating HRQoL in SA. Due to its association with HRQoL and overall health, activity impairment should be a focus when monitoring patients' disease control. STUDY REGISTRATION: ClinicalTrials.gov Identifier: NCT03373045.

Continuous and Daily Oral Immunotherapy for Peanut Allergy: Results from a 2-Year Open-Label Follow-On Study.

BACKGROUND: The randomized, controlled PALISADE trial demonstrated the benefit of daily oral immunotherapy with Peanut (Arachis Hypogaea) allergen powder-dnfp (PTAH, formerly AR101) in peanut-allergic children and adolescents. OBJECTIVE: ARC004, the open-label follow-on study to PALISADE, used 5 dosing cohorts to explore PTAH treatment beyond 1 year and alternative dosing regimens in peanut-allergic individuals. METHODS: Active arm (PTAH-continuing) PALISADE participants who tolerated 300-mg peanut protein at the exit double-blind placebo-controlled food challenge and placebo arm (PTAH-naive) participants could enter ARC004. PTAH-continuing participants were assigned to receive daily (cohorts 1 and 3A) or non-daily (cohorts 2, 3B, and 3C) dosing regimens; PTAH-naive participants were built up to 300 mg/d PTAH, followed by maintenance dosing. At study completion, participants underwent an exit double-blind placebo-controlled food challenge with doses up to 2000 mg peanut protein. Data were assessed using descriptive statistics. RESULTS: Overall, 358 (87.5%) eligible participants (4-17 years) entered ARC004 (PTAH-continuing, n = 256; PTAH-naive, n = 102). Among PTAH-continuing participants, exposure-adjusted adverse event rates were 12.94 to 17.54/participant-year and 25.95 to 42.49/participant-year in daily and non-daily dosing cohorts, respectively; most participants (83%) experienced mild or moderate adverse events. Daily dosing cohorts appeared to have higher desensitization rates than non-daily dosing cohorts. Of all PTAH-continuing cohorts, cohort 3A had the longest daily dosing duration and the highest desensitization rates. Changes in immune markers with PTAH continuation demonstrated ongoing immunomodulation. Outcomes in PTAH-naive participants mirrored those of the PALISADE active arm. CONCLUSIONS: Continued daily PTAH treatment beyond 1 year showed sustained safety and efficacy. Ongoing immunomodulation was observed during the second year of treatment.

The CHRONICLE Study of US Adults with Subspecialist-Treated Severe Asthma: Objectives, Design, and Initial Results.

BACKGROUND: Approximately 5-10% of patients with asthma have severe disease. High-quality real-world studies are needed to identify areas for improved management. OBJECTIVE: Aligned with the International Severe Asthma Registry, the CHRONICLE study (ClinicalTrials.gov: NCT03373045) was developed to address this need in the US. STUDY DESIGN: Learnings from prior studies were applied to develop a real-world, prospective, noninterventional study of US patients with confirmed severe asthma who are treated by subspecialist physicians and require biologic or maintenance systemic immunosuppressant therapy or who are uncontrolled by high-dosage inhaled corticosteroids and additional controllers. Target enrollment is 4000 patients, with patient observation for ≥3 years. A geographically diverse sample of allergist/immunologist and pulmonologist sites approach all eligible patients under their care and report patient characteristics, treatment, and health outcomes every 6 months. Patients complete online surveys every 1-6 months. INITIAL RESULTS: From February 2018 to February 2019, 102 sites screened 1428 eligible patients; 936 patients enrolled. Study sites (40% allergist/immunologist, 42% pulmonologist, 18% both) were similar to other US asthma subspecialist samples. Enrolled patients were 67% female with median ages at enrollment and diagnosis of 55 (range: 18-89) and 26 (0-80) years, respectively. Median body mass index was 31 kg/m2; 3% and 29% were current or former smokers, respectively, and >60% reported ≥1 exacerbation in the prior year and suboptimal symptom control. CONCLUSION: CHRONICLE will provide high-quality provider- and patient-reported data from a large, real-world cohort of US adults with subspecialist-treated severe asthma.

Bepotastine besilate ophthalmic solution 1.5% for alleviating nasal symptoms in patients with allergic conjunctivitis.

BACKGROUND: Bepotastine besilate ophthalmic solution (BBOS) 1.5% is a topical antihistamine for the treatment of ocular itching associated with allergic conjunctivitis (AC). Allergic rhinitis and AC are common comorbid conditions. We explored the efficacy of BBOS 1.5% in alleviating nasal symptoms in an integrated analysis of two Phase III conjunctival allergen challenge (CAC) studies and a Phase IV environmental allergen study. METHODS: In the Phase III trials, a CAC was performed 15 minutes, 8 hours, and 16 hours following ocular instillation of BBOS 1.5% (n=78) or placebo (n=79), and subjects evaluated nasal symptoms. In the environmental study, subjects instilled BBOS 1.5% (n=123) or placebo (n=122) twice daily and nasal symptoms were evaluated over 2 weeks. RESULTS: In the Phase III trials, BBOS 1.5% had reduced CAC-induced nasal congestion and pruritus at 15 minutes and 8 hours postdosing and rhinorrhea and a non-ocular composite-symptom score (sum of nasal scores plus ear or palate pruritus) at all time points postdosing (all P≤0.01 vs placebo). In the Phase IV environmental study, BBOS 1.5% reduced sneezing and nasal pruritus over 2 weeks and median number of days to improvement of nasal pruritus and total nasal symptom score (sum for rhinorrhea, sneezing, nasal pruritus, and nasal congestion; P≤0.04 vs placebo). Additionally, investigator-reported improvement in overall ocular (pruritus, hyperemia, tearing) and nasal symptoms was greater with BBOS 1.5% vs placebo (P≤0.03). CONCLUSION: Results of these exploratory analyses indicate that topical ocular BBOS 1.5% reduced nasal symptoms, supporting its use for alleviating rhinitis symptoms associated with AC.

Management of allergic rhinitis in the era of effective over-the-counter treatments.

Allergic rhinitis (AR) may be regarded as a trivial issue unworthy of the doctor's time, and with the availability of many different over-the-counter (OTC) treatments, up to two thirds of patients self-manage AR before seeking medical care. Yet, AR can have a significant impact on health-related quality of life and is associated with a greater detriment to work productivity than other chronic diseases such as diabetes and hypertension. For many patients, the impact on quality of life is greater than suggested by reported symptoms and should also be a focus of treatment. Although many patients can effectively manage AR symptoms independently, a significant percentage will need direction from a physician to obtain optimal results. The availability of several different classes of treatment - including decongestants, sedating and non-sedating antihistamines, and more recently intranasal corticosteroids (INS) - has increased the complexity of self-management, leaving patients confused about the best approach to treatment. Treatment guidelines universally classify INS as the most effective medical agents available for use in the OTC and primary care settings. Many patients are unaware that INS are available OTC and that they are more effective than other therapies. Patients may have negative perceptions about the safety of INS and may have experienced unpleasant taste, scent, and feel with nasal sprays. Unless a patient volunteers the information, healthcare professionals (HCPs) may be unaware that the patient has significant AR and is using one or more OTC AR therapies. To address this gap in communication, HCPs must be proactive in identifying, assessing, and advising patients with AR, including best strategies to assess allergen trigger symptoms, which treatments are appropriate, and when and how to use them. Proper use of delivery devices is especially important. This article reviews the primary care management of AR in the context of the availability of effective OTC medicines.

Acute eosinophilic pneumonia among US Military personnel deployed in or near Iraq.

CONTEXT: Acute eosinophilic pneumonia (AEP) is a rare disease of unknown etiology characterized by respiratory failure, radiographic infiltrates, and eosinophilic infiltration of the lung. OBJECTIVES: To describe a case series of AEP, illustrate the clinical features of this syndrome, and report the results of an epidemiologic investigation. DESIGN, SETTING, AND PARTICIPANTS: Epidemiologic investigation of cases of AEP identified both retrospectively and prospectively from March 2003 through March 2004 among US military personnel deployed in or near Iraq. Survivors were offered a follow-up evaluation. MAIN OUTCOME MEASURE: Morbidity and mortality related to AEP. RESULTS: There were 18 cases of AEP identified among 183,000 military personnel deployed in or near Iraq during the study period, yielding an AEP incidence of 9.1 per 100,000 person-years (95% confidence interval, 4.3-13.3). The majority of patients (89%) were men and the median age was 22 (range, 19-47) years. All patients used tobacco, with 78% recently beginning to smoke. All but 1 reported significant exposure to fine airborne sand or dust. Known causes of pulmonary eosinophilia (eg, drug exposures or parasitic disease) were not identified. Epidemiologic investigation revealed no evidence of a common source exposure, temporal or geographic clustering, person-to-person transmission, or an association with recent vaccination. Six patients underwent bronchoalveolar lavage (median eosinophilia of 40.5%). All patients developed peripheral eosinophilia (range, 8%-42%). Mechanical ventilation was required in 67% for a median of 7 (range, 2-16) days. Two soldiers died; the remainder responded to corticosteroids and/or supportive care. Twelve individuals were reevaluated a median of 3 months after diagnosis. At that point, 3 patients reported mild dyspnea and 1 reported wheezing. All patients had finished treatment and had either normal or nearly normal spirometry results. None had recurrent eosinophilia. CONCLUSIONS: AEP occurred at an increased rate among this deployed military population and resulted in 2 deaths. Failure to consider AEP in the differential diagnosis of respiratory failure in military personnel can result in missing this syndrome and possibly death. The etiology of AEP remains unclear, but the association with new-onset smoking suggests a possible link.

Topical calcineurin inhibitors for atopic dermatitis: review and treatment recommendations.

Atopic dermatitis (AD) is an inflammatory skin disease commonly affecting children and managed by pediatricians, primary care physicians, allergists, and dermatologists alike. For many years, the only available topical pharmacological treatment was topical corticosteroids. This changed in 2000-2001, when topical formulations of two calcineurin inhibitors (tacrolimus and pimecrolimus) were approved for short-term or chronic intermittent treatment of AD in patients ≥ 2 years of age, in whom other treatments have been ineffective or contraindicated. These topical calcineurin inhibitors (TCIs) quickly became a popular treatment option due at least in part to concerns over adverse events associated with prolonged topical corticosteroid use, especially in children. However, based on theoretical concerns about a possible risk of lymphoma associated with TCI use, a Boxed Warning was placed on both products in 2006. Since then, despite an extensive body of evidence, no causal relationship has been demonstrated between TCI use and an increased risk of lymphoma; however, the US FDA has concluded that a link cannot be ruled out. In fact, based on post-marketing surveillance of spontaneous, literature, and solicited reports, we report here that the lymphoma incidence in the topical pimecrolimus-exposed population is up to approximately 54-fold less than that seen in the general US population. This review summarizes the mechanism of action of TCIs, the factors that prompted the Boxed Warning, and recent TCI safety and efficacy data. Based on these data, both topical corticosteroids and TCIs should have defined roles in AD management, with TCIs favored for sensitive skin areas (e.g., face) and instances where topical corticosteroids have proven ineffective, thereby minimizing the risk of adverse effects with both drug classes.

New therapeutic options for allergic rhinitis: back to the future with intranasal corticosteroid aerosols.

BACKGROUND: Under current guidelines, intranasal corticosteroids (INSs) are considered the most effective first-line therapy to improve allergic rhinitis (AR) symptoms and burden of disease. In the late 1980s-1990s, chlorofluorocarbon (CFC)-propelled corticosteroid aerosol nasal sprays formed the standard of care for the treatment of AR. Because of environmental concerns, CFC aerosols were gradually phased out, and aqueous INS formulations of nasal sprays became the standard of care. Although many aqueous INS sprays are available, specific product-related factors can reduce patient adherence to an INS and subsequently reduce treatment efficacy. The purpose of this paper was to review the evolution of AR therapeutics and drug devices and how it may have an effect on patient adherence/compliance and patient satisfaction with current available therapies and show the unmet need to improve INS delivery systems. METHODS: Although aqueous INSs are effective and well tolerated, use in some patients may be compromised because of patient sensory perception and device preference. A historical review of the evolution of intranasal delivery of INSs was undertaken to provide further insight into improving treatment options for patients with AR. RESULTS: Although the various approved INSs appear to be equivalent in terms of reducing AR disease burden, the method in which an INS is delivered to a patient has significant bearing on the overall success of each specific drug product. CONCLUSION: Hydrofluoroalkane-propelled INS drug products offer a back-to-the-future delivery approach that may be further tailored to the individual patient's needs. Past experiences and the development of new devices are paving the way toward further therapy choices, ultimately affording health care providers access to the most effective treatments for patients with AR.

Management of allergic conjunctivitis: an evaluation of the perceived comfort and therapeutic efficacy of olopatadine 0.2% and azelastine 0.05% from two prospective studies.

PURPOSE: Results from 2 patient-reported outcome studies of allergic conjunctivitis sufferers who used olopatadine 0.2% and azelastine 0.05% are analyzed. METHODS: The PACE (Pataday Allergic Conjunctivitis Evaluation) multi-center, prospective, open-label study examined patient perceptions of olopatadine 0.2% once daily (qd) and previous twice daily (bid) allergic conjunctivitis medications via questionnaire in allergic conjunctivitis sufferers who had previously used bid medication and then initiated olopatadine. A second conjunctival antigen challenge (CAC) study evaluated comfort of 4 allergic conjunctivitis medications. RESULTS: Forty-nine patients from the PACE study (N = 125) with prior azelastine use were examined. Significantly more patients rated themselves "very satisfied" with current olopatadine use compared with past azelastine use on drop comfort (p < 0.0001), speed of relief (p = 0.0004), and overall satisfaction (70% vs 16%, p < 0.0001). Significantly more patients reported olopatadine "very effective" against swelling compared with azelastine (47% vs 8%, p = 0.0404). In the CAC study (N = 36), data from olopatadine (n = 8), azelastine (n = 9) and placebo (N = 36) groups were reported. Olopatadine was rated significantly more comfortable than azelastine upon instillation (p = 0.0223), at 30 seconds (p = 0.0479), and at 1 minute after instillation (p = 0.0240). CONCLUSION: In the reported studies, olopatadine 0.2% qd was more comfortable than azelastine 0.05% and preferred by patients with allergic conjunctivitis by a ratio of 4:1.

Pediatric allergic rhinitis: current and future state of the art.

Allergic rhinitis (AR) is the most common cause of allergic disease in the pediatric population. This chronic condition impacts quality of life, exacerbates comorbid conditions, and results in a significant economic burden. With an accurate diagnosis, there are many available therapies to reduce the burden of AR. Options include allergen avoidance, pharmacotherapy, and immune modulation. This review provides a comprehensive discussion of the current and future state of the art in the treatment of pediatric AR.

Managing rhinitis: Strategies for improved patient outcomes.

Allergic rhinitis affects more than 40 million Americans, with estimated costs reaching $5.3 billion annually. The global impact includes negative effects on quality of life (QOL), sleep, diminished work productivity, and exacerbation of comorbid conditions. An accurate diagnosis of allergic or nonallergic rhinitis is needed before selecting optimal treatment, which can include antihistamines, decongestants, intranasal corticosteroids, immunotherapy, and anticholinergics. It is also important to understand that pharmacologic properties of these different interventions may affect patient satisfaction, compliance, and overall clinical response. This article reviews currently available therapies for allergic rhinitis with a focus on improving patient outcomes.

Half- vs full-dose trivalent inactivated influenza vaccine (2004-2005): age, dose, and sex effects on immune responses.

BACKGROUND: Optimal public health strategies for managing influenza vaccine shortages are not yet defined. Our objective was to determine the effects of age, sex, and dose on the immunogenicity of intramuscular trivalent inactivated vaccine (TIV). METHODS: Healthy adults aged 18 to 64 years, stratified by age (18-49 and 50-64 years) and sex, were randomized to receive full- or half-dose TIV. Hemagglutination inhibition titers against vaccine antigens were measured before and 21 days after immunization. A primary outcome of noninferiority was defined as a difference of less than 20% in the upper 95% confidence interval (CI) of the proportion of subjects with strain-specific hemagglutination inhibition antibody titers of 1:40 or higher after vaccination. Secondary outcomes included geometric mean titers, after vaccination side effects, and occurrences of influenza-like illnesses. RESULTS: Among previously immunized subjects (N = 1114) receiving half- vs full-dose TIV (age, 18-49 years, n = 284 [half] and n = 274 [full]; and age 50-64 years, n = 276 [half] and n = 280 [full]), CIs for proportions of subjects with hemagglutination inhibition antibody titers of 1:40 or higher excluded substantial reduction for all antigens in the 18- to 49-year age group and for B/Shanghai/361/2002 (B) and A/Fujian/411/2002 (A/H3N2) in the 50- to 64-year age group. Geometric mean titer in the female 18- to 49-year age group exceeded male responses for all strains: responses to half-dose TIV that were comparable with male full-dose responses for A/New Caledonia/20/99 (A/H1N1) antigen, 25.4 (95% CI, 20.9-30.9) vs 25.6 (95% CI, 21.3-30.9); A/H3N2 antigen, 60.8 (95% CI, 50.8-72.7) vs 44.1 (95% CI, 37.6-51.8); and B antigen, 64.4 (95% CI, 53.9-76.9) vs 60.7 (95% CI, 51.4-71.7) (findings were similar for the 50- to 64-year age group). Some injection site and systemic reactions (myalgias and/or arthralgias [P < .05], headache [P < .001], and impact of fatigue [P < .05]) were significantly lower in men. The relative risk of medical visits and hospitalizations for influenza-like illnesses were similar in the half- and full-dose groups regardless of age. CONCLUSIONS: Antibody responses to intramuscular half-dose TIV in healthy, previously immunized adults were not substantially inferior to the full-dose vaccine, particularly for ages 18 to 49 years. Significantly higher geometric mean titer responses in women were identified for all ages, regardless of dose or influenza strain. Half-dose vaccination may be an effective strategy for healthy adults younger than 50 years in the setting of an influenza vaccine shortage.