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Thymic stromal lymphopoietin (TSLP) has been shown to play a central role in the initiation and persistence of allergic responses.We evaluated whether tezepelumab, a human monoclonal anti-TSLP antibody, improved the efficacy of subcutaneous allergen immunotherapy (SCIT) and promoted the development of tolerance in patients with allergic rhinitis.We conducted a double-blind parallel design trial in patients with cat allergy. A total of 121 patients were randomized to receive either intravenous tezepelumab plus subcutaneous cat SCIT, cat SCIT alone, tezepelumab alone, or placebo for 52 weeks, followed by 52 weeks of observation. Nasal allergen challenge (NAC), skin testing, and blood and nasal samples were obtained throughout the study.At week 52, the NAC-induced total nasal symptom scores (TNSS) (calculated as area under the curve [AUCInhibition of TSLP augments the efficacy of SCIT during therapy and may promote tolerance after a 1-year course of treatment. (ClinicalTrials.gov NCT02237196).

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by IgE hyperproduction and eosinophilic inflammation. The anti-IgE antibody, omalizumab, has demonstrated efficacy in patients with CRSwNP and comorbid asthma previously. Objective: Our aim was to determine omalizumab safety and efficacy in CRSwNP in phase 3 trials (POLYP 1 and POLYP 2). Methods: Adults with CRSwNP with inadequate response to intranasal corticosteroids were randomized (1:1) to omalizumab or placebo and intranasal mometasone for 24 weeks. Coprimary end points included change from baseline to week 24 in Nasal Polyp Score (NPS) and Nasal Congestion Score. Secondary end points included change from baseline to week 24 in Sino-Nasal Outcome Test-22 (SNOT-22) score, University of Pennsylvania Smell Identification Test, sense of smell, postnasal drip, runny nose, and adverse events. Results: Patients in POLYP 1 (n = 138) and POLYP 2 (n = 127) exhibited severe CRSwNP and substantial quality of life impairment evidenced by a mean NPS higher than 6 and SNOT-22 score of approximately 60. Both studies met both the coprimary end points. SNOT-22 score, University of Pennsylvania Smell Identification Test score, sense of smell, postnasal drip, and runny nose were also significantly improved for omalizumab versus placebo. In POLYP 1 and POLYP 2, the mean changes from baseline at week 24 for omalizumab versus placebo were as follows: NPS, -1.08 versus 0.06 (P < .0001) and - 0.90 versus -0.31 (P = .0140); Nasal Congestion Score, -0.89 versus -0.35 (P = .0004) and -0.70 versus -0.20 (P = .0017); and SNOT-22 score, -24.7 versus -8.6 (P < .0001) and -21.6 versus - 6.6 (P < .0001). Adverse events were similar between groups. Conclusion: Omalizumab significantly improved endoscopic, clinical, and patient-reported outcomes in severe CRSwNP with inadequate response to intranasal corticosteroids, and it was well tolerated.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) frequently remains uncontrolled despite maximal medical therapy and sinonasal surgery, presenting several unmet needs and challenges. Omalizumab previously demonstrated efficacy in CRSwNP in duplicate phase 3, randomized, placebo-controlled trials (POLYP 1, POLYP 2). Objective: This open-label extension evaluated the continued efficacy, safety, and durability of response of omalizumab in adults with CRSwNP who completed POLYP 1 or 2. Methods: After 24 weeks of omalizumab or placebo in POLYP 1 and 2, patients (n = 249) received open-label omalizumab plus background nasal mometasone therapy for 28 weeks and were subsequently followed for 24 weeks after omalizumab discontinuation. Efficacy end points assessed change from baseline for the coprimary end points, Nasal Polyp Score and Nasal Congestion Score, and the secondary end points of Sino-Nasal Outcome Test 22, Total Nasal Symptom Score and its components, and University of Pennsylvania Smell Identification Test scores. Safety objectives included incidence of adverse events and adverse events leading to omalizumab discontinuation. Results: Patients who continued omalizumab experienced further improvements across coprimary end points and secondary end points through 52 weeks. Patients who switched from placebo to omalizumab experienced favorable responses across end points through week 52 that were similar to POLYP 1 and 2 at week 24. After omalizumab discontinuation, scores gradually worsened over the 24-week follow-up, but remained improved from pretreatment levels for both groups. The safety profile was similar to previous reports. Conclusions: The efficacy and safety profile from this study supports extended omalizumab treatment up to 1 year for CRSwNP with inadequate response to nasal corticosteroids.

Background Although clinical trials have demonstrated that rhinitis therapy improves subjective and objective measures of asthma, it is uncertain whether treatment of allergic rhinitis significantly affects the frequency of asthma exacerbations. Objective The objective of this study was to determine whether treatment with intranasal corticosteroids and/or second-generation antihistamines is associated with changes in rates of asthma exacerbations resulting in emergency room visits and/or hospitalizations in patients with asthma and allergic rhinitis. Methods This was a nested, case-control study. Results Treatment with either nasal corticosteroids or second-generation antihistamines was associated with a lower risk of asthma-related emergency room treatment and hospitalization (adjusted odds ratio [OR], 0.51; 95% CI, 0.34 to 0.77 and 0.34, 0.18 to 0.62, respectively). Patients who used nasal cortico-steroids had a significantly lower risk of both asthma-related emergency room treatment and hospitalization (adjusted OR, 0.75; 95% CI, 0.62 to 0.91 and 0.56, 0.42 to 0.76, respectively), whereas there was a trend toward lower risk of emergency room treatment and hospitalization in patients who used second-generation antihistamines (adjusted OR, 0.88; 95% CI, 0.62 to 1.26 and 0.68, 0.40 to 1.14, respectively). Combined treatment with both medications was associated with a further lowering of the risk of both emergency room treatment and hospitalization (adjusted OR, 0.37; 95% CI, 0.19 to 0.73 and 0.22, 0.07 to 0.63). Conclusions In patients with asthma, treatment of concomitant allergic rhinitis was associated with significant reductions in risk of emergency room treatment and hospitalization for asthma.

Prevention of serious asthma exacerbations is an important therapeutic goal in patients with asthma.The purpose of this study was to investigate the effect of omalizumab (Xolair), a recombinant humanized monoclonal anti-IgE antibody, on the rate of serious exacerbations during long-term therapy.A pooled analysis was completed of 3 multicenter, randomized, double-blind, placebo-controlled phase III studies with omalizumab in adults/adolescents agedor =12 years (n = 1071) and in children aged 6 to 12 years (n = 334) who required treatment with inhaled corticosteroids for allergic asthma. Rates of serious asthma exacerbations were computed and compared between omalizumab- and placebo-treated patients. Serious exacerbations were those leading to unscheduled outpatient visits, emergency room treatment, or hospitalization during 1 year of treatment.In all, 767 patients were treated with omalizumab (at least 0.016 mg/kg/IgE [IU/mL], administered subcutaneously every 4 weeks). Another 638 patients were treated with placebo. The rate of unscheduled, asthma-related outpatient visits was lower for the omalizumab-treated patients than for the placebo-treated patients (rate ratio [95% CI], 0.60 [0.44, 0.81]; P.01), as were asthma-related emergency room visits (rate ratio [95% CI], 0.47 [0.24, 1.01]; P =.05). Importantly, hospitalizations for asthma were markedly reduced in patients receiving omalizumab (rate ratio [95% CI], 0.08 [0.00, 0.25]; P.01).Omalizumab reduces the rate of serious asthma exacerbations and the need for unscheduled outpatient visits, emergency room treatment, and hospitalization in patients with moderate-to-severe allergic asthma.

Background: IL-4 mediates important proinflammatory functions in asthma, including induction of the IgE isotype switch, increased expression of vascular cell adhesion molecule 1 and promotion of eosinophil transmigration across the endothelium, stimulation of mucus production, and T H 2 lymphocyte differentiation, leading to release of IL-4, IL-5, IL-9, and IL-13. Objective: The current study evaluated the therapeutic potential of inhaled recombinant human soluble interleukin-4 receptor (IL-4R) as an IL-4 antagonist. Methods: This study was a randomized, double-blind, placebo-controlled study in 62 subjects involving 12 once weekly nebulizations of 0.75, 1.5, or 3.0 mg of IL-4R or placebo. During screening, subjects documented dependence on inhaled corticosteroids by an exacerbation in asthma induced by one or two 50% dose reductions at 2-week intervals. After restabilization for 2 weeks on the dose above which their asthma flared, inhaled steroids were discontinued, patients were randomized, and study medication was started on day 0. Results: IL-4R was well tolerated. Efficacy was demonstrated by a decline in FEV 1 observed in the placebo group (–0.4 L and –13% predicted), which did not occur in the group receiving 3.0 mg of IL-4R (–0.1 L and –2% predicted; P = .05 over the 3-month treatment period). Daily patient-measured morning FEV 1 also demonstrated a significant decline in the placebo group (–0.5 L and –18% predicted), which did not occur in the group receiving 3.0 mg of IL-4R (–0.1 L and –4% predicted; P = .02 over the 3-month treatment period). The efficacy of IL-4R was further confirmed by the absence of increase in asthma symptom scores in the group receiving 3.0 mg of IL-4R (Δ 0.1) compared with that seen in the placebo group (Δ 1.4 over 1 month; P = .07). Study discontinuation for asthma exacerbation was not significantly different between groups (placebo, 56%; 3.0 mg of IL-4R, 47%; P = not significant). Conclusion: These promising data suggest that IL-4R is safe and effective in the treatment of moderate persistent asthma. (J Allergy Clin Immunol 2001;107:963-70.)

Allergic rhinitis is now recognized as a chronic medical condition that markedly affects patient quality of life and is a cause of substantial medical care expenditures. Effective treatment of adults with allergic rhinitis usually requires an integrated regimen that combines allergen avoidance measures, pharmacotherapy, and possible specific-allergen immunotherapy. This approach can control bothersome symptoms with minimal adverse effects in most patients. New medications, such as anti-immunoglobulin E therapy and cytokine antagonists, may provide relief to patients who are refractory to or do not tolerate currently available treatments.

Intranasal steroids have proved to be an effective and safe form of therapy for allergic rhinitis. However, as the number of new glucocorticoid compounds has increased over the past decade, it has become important to consider whether significant differences exist between these agents. Pharmacologically, newer drugs such as mometasone furoate and fluticasone propionate appear to have substantially higher topical potencies and lipid solubilities and lower systemic bioavailabilities than do older compounds. In clinical use, however, all the available drugs appear to be equally effective in controlling symptoms of seasonal and perennial allergic rhinitis. With respect to adverse effects, emerging data suggest that mometasone furoate and fluticasone propionate may have less potential for systemic effects during prolonged use, particularly in children. Newer intranasal steroids appear to have practical advantages over older agents that may favor their use in some groups of patients with allergic rhinitis. (J Allergy Clin Immunol 1999;104:S144-9.)

Although prior studies have documented the rapid onset of action of topical intranasal levocabastine (LEV), little is known about its duration of action under nasal challenge conditions.We sought to assess the onset and duration of action of escalating doses of LEV nasal spray by using a nasal allergen challenge (NAC) model.Eighteen asymptomatic subjects with histories of seasonal allergic rhinitis were enrolled into a randomized, single-blind, placebo-controlled, dose-ranging crossover study. Each patient was randomly assigned to receive single doses of placebo and intranasal LEV 0.1, 0.2, and 0.4 mg during 2 parts of the study. In part 1 (onset of action), NAC consisted of a single dose of allergen administered 5 minutes after study drug treatment. In part 2 (duration of action), NAC consisted of increasing doses of allergen administered 0.5, 6, 12, and 24 hours on separate days after study drug treatment. Nasal symptom scores (NSSs) and nasal peak expiratory flow rates were measured after NAC in both phases of the study. Blood samples for plasma LEV concentrations were drawn after each NAC.In part 1, NSSs were significantly lower after the administration of LEV 0.1, 0.2, and 0.4 mg compared with placebo (P.05). In part 2, NSSs were significantly lower after LEV doses of 0.2 and 0.4 mg compared with placebo at 0.5, 6, 12, and 24 hours after treatment (P.05). The mean provocative dose of allergen required to elicit a positive nasal reaction was increased after LEV doses of 0.2 and 0.4 mg at 0.5, 6, and 12 hours after treatment. Nasal peak expiratory flow rates demonstrated no significant differences between LEV and placebo for any doses at any time points. Mean plasma LEV concentrations were low (range, 0 to 3. 7 ng/mL) after all doses and did not correlate with drug efficacy.Single intranasal LEV doses of 0.1, 0.2, and 0.4 mg significantly reduced the severity of the immediate nasal response to allergen when administered 5 minutes before NAC. This protective effect against NAC continued to be present 24 hours after administration of LEV doses of 0.2 and 0.4 mg. Efficacy in blocking the reaction to NAC did not correlate with plasma LEV levels, suggesting that the inhibitory effect was due largely to topical rather than systemic effects.

During the past century, practicing clinicians have frequently observed that allergic rhinitis and asthma coexist in the same patients. Despite a wealth of data supporting an association between rhinitis and asthma, it has remained controversial whether the presence of rhinitis predisposes an individual to the development of asthma and whether nasal dysfunction causes asthma to worsen. Despite these uncertainties, there is a growing body of literature suggesting that appropriate treatment of allergic rhinitis results in improvements in asthma symptoms and lower airway function. In this review, data from a variety of clinical and laboratory studies will be highlighted to help clarify our understanding of this complex and important relation.

Background: Traditional clinical outcomes have demonstrated that salmeterol improves pulmonary function and reduces asthma symptoms. However, they do not evaluate how patients perceive the effect of therapeutic intervention on day-to-day functioning and well-being. Objective: We sought to evaluate the impact of salmeterol on disease-specific quality of life with the Asthma Quality-of-Life Questionnaire, as well as the efficacy and safety of salmeterol in patients with stable asthma who were symptomatic despite daily use of inhaled corticosteroids. Methods: This was a randomized, double-blind, placebo-controlled, parallel-group study of 506 patients. Patients were treated with 42 μg salmeterol or placebo twice daily for 12 weeks delivered through a metered dose inhaler. Results: Mean change from baseline in asthma quality-of-life scores was significantly greater ( p ≤ 0.006) after 12 weeks of treatment with salmeterol compared with placebo ("as-needed" albuterol) in global scores (1.08 vs 0.61) and individual domains (activity limitations, 0.91 vs 0.54; asthma symptoms, 1.28 vs 0.71; emotional function, 1.17 vs 0.65; and environmental exposure, 0.84 vs 0.47). Patients treated with salmeterol experienced significantly greater improvements from baseline to week 12 compared with placebo in FEV 1 (0.42 L vs 0.15 L, p p p p p Conclusion: Salmeterol provided significantly greater improvement in quality-of-life outcomes in patients whose asthma symptoms are not well controlled with inhaled corticosteroids. These results demonstrate that the benefits of salmeterol are not limited to conventional clinical measures of efficacy. (J Allergy Clin Immunol 1998;101:185-95.)

Many potential users of the H1 antihistamine cetirizine are asthmatic and may be using inhaled albuterol. This study was conducted to assess the possible bronchodilatory effect of cetirizine in patients with mild-to-moderate asthma and to determine whether cetirizine interacts with albuterol.In a randomized, double-blind, placebo-controlled, crossover study, the effects on pulmonary function of 5, 10, and 20 mg oral doses of cetirizine with and without inhaled albuterol (180 micrograms) were determined in 12 patients at 11 time points over 8 hours. The primary measure of efficacy was forced expiratory volume in 1 second (FEV1).Cetirizine with or without albuterol significantly increased FEV1, peak expiratory flow rate, and forced expiratory flow rate between 25% and 75% of vital capacity relative to baseline and placebo but did not have a significant effect on forced vital capacity. The effect of 20 mg of cetirizine on FEV1 was generally greater than that of 10 or 5 mg, but the difference was statistically significant only at the 30-minute time point (p0.05). All three cetirizine doses produced significantly greater increases than placebo in FEV1 and forced expiratory flow rate between 25% and 75% of vital capacity for 8 hours and in peak expiratory flow rate for 7 hours (p0.02). Albuterol alone had a significant effect on the four pulmonary function variables from 1 to 5 hours after baseline (p0.05), which is consistent with albuterol's recommended dosing frequency of every 4 to 6 hours. Albuterol alone increased FEV1 significantly more than 5 mg of cetirizine alone but not 10 mg or 20 mg of cetirizine alone at 60, 90, and 120 minutes after baseline, but all three doses of cetirizine increased FEV1 significantly more than albuterol 7 and 8 hours after baseline (p0.05), indicating that the bronchodilatory action of cetirizine lasts longer than that of albuterol. Cetirizine neither potentiated nor inhibited the bronchodilatory action of albuterol, but the two drugs appeared to have an additive bronchodilatory effect. None of the cetirizine treatments caused a worsening of pulmonary function, and all were well tolerated.Cetirizine has a significant bronchodilatory effect in patients with mild-to-moderate asthma and can be used to treat concomitant conditions (e.g., allergic rhinitis) without concern that it will interfere with the bronchodilatory effect of albuterol or cause worsening of asthma by itself.

Sarah W. Spriet, DO, Taylor A. Banks, MD, Cecilia Mikita, MD, MPH, FAAAAI; Walter Reed National Military Medical Center, Bethesda, MD. RATIONALE: Rabies post-exposure treatment is a medical necessity. Two rabies vaccines are available in the United States; purified chick embryo cell culture vaccine (PCECV, RabAvert ) and gelatin-free human diploid cell vaccine (HDCV, Imovax ). We report a case of PCECV-triggered anaphylaxis. METHODS: After clinical evaluation, patient and a volunteer control underwent skin prick and intradermal testing to the rabies vaccines, vaccine components, and rabies immunoglobulin. Vaccine challenge was then performed. RESULTS: A healthy 15 year old male presented to the Emergency Department after a live bat was found in his home, captured, and found to have rabies.Mucousmembrane exposure could not be ruled out and human rabies immunoglobulin (ImogamRabies – HT ) and PCECVwere administered. Within minutes, he developed dyspnea, stridor and generalized hives. Symptoms resolved within one hour after treatment with antihistamines and IV corticosteroids and he was referred to AllergyImmunology. On day 3 post-exposure, patient and control underwent skin prick testing to undiluted PCECV, egg, gelatin, HDCVand Imogam. Skin prick was positive to PCECV and gelatin. Intradermal testing (IDT) using 0.02 mL of 1:100 dilution to HDCV and Imogam was negative. IDT using 0.02 mL of 1:10 dilution was negative to Imogam, positive to HDCV; however, considered an irritating dose given identical results in control. Patient tolerated a 10/90 challenge to HDCV and completed post-exposure series using this vaccine. CONCLUSIONS: Skin test results and successful challenge to HDCV suggest gelatin allergy. Awareness of the potential for IgE-mediated reactions to rabies vaccine is important. Challenge to HDCV should be considered in select patients.

Experimental studies have demonstrated that induction of a nasal allergic reaction can lead to an increase in bronchial responsiveness (BR). To assess the clinical relevance of these experimental changes to chronic asthma, we sought to determine the effect of nasal beclomethasone dipropionate (Bdp) on BR in patients with seasonal allergic rhinitis and asthma. Eighteen subjects with histories of seasonal allergic rhinitis and asthma during the fall pollen season with positive skin tests to short ragweed and bronchial hyperresponsiveness to inhaled methacholine were assigned to receive either nasal Bdp (336 micrograms/day) or placebo for the entire ragweed season. Patients recorded daily nasal and chest symptoms, nasal blockage index, oral peak expiratory flow rates, and supplemental medication use. BR to methacholine was measured during the baseline period and 6 weeks into the ragweed season. Although the Bdp group did have a significant improvement in nasal blockage index, there was no improvement in daily asthma symptom scores, oral peak expiratory flow, or asthma medication use. However, subjects treated with Bdp were protected from the increase in BR seen in the placebo group (geometric mean PC20 placebo group: baseline = 0.70, week 6 = 0.29; Bdp group: baseline = 0.80, week 6 = 0.93; intergroup difference, p = 0.022). We conclude that nasal corticosteroid therapy can prevent the increase in BR associated with seasonal pollen exposure in patients with allergic rhinitis and asthma.

The relationship between upper airway inflammation and asthma is controversial. In the current study, we sought to investigate the relationship between allergic rhinitis and lower airway dysfunction by performing double-blind, randomized nasal challenges with allergen or placebo. Subjects were selected for a prior history of asthma exacerbations after the onset of seasonal allergic rhinitis symptoms. After the induction of a marked nasal-allergic reaction (with a technique of nasal provocation that limited allergen delivery to the nose), there were no changes in FEV 1 , specific conductance, or lung volumes either 30 minutes or 412 hours after nasal allergen challenge, nor any changes in peak flow rates followed hourly until the next day. However, nasal provocation with allergen resulted in a relative increase in bronchial responsiveness to methacholine compared with that to placebo ( p = 0.011 at 30 minutes and p = 0.0009 at 412 hours after challenge). Our study suggests that, although a nasal-allergic response does not induce airflow limitation of the lower airways, it can alter bronchial responsiveness.

Mycoplasma species are recognized as important pathogens in patients with hypogammaglobulinemia. In this article we describe, for the first time, a patient with hypogammaglobulinemia who developed osteomyelitis of the hip caused by Ureaplasma urealyticum. This article emphasizes the need for considering infection with Mycoplasma species in patients with antibody deficiency.

Background Multiple strengths of mometasone furoate/formoterol (MF/F) MDI combination therapy are under investigation as new treatments for asthma. We report efficacy/ safety findings from a 3-month MF/F study in subjects with severe asthma. Materials and methods This was a 3-month, randomized, double-blind, parallelgroup, multicenter study with a 2-3-week open-label, run-in period of mometasone furoate (MF) 400 μg twice-daily (BID). Subjects (≥12 years) were randomized to MF/F (200/10 μg or 400/10 μg BID) or MF (400 μg BID). The primary endpoint was the area under the curve (AUC) of the change in serial FEV1 (0-12 hours) for MF/F 400/10 μg vs MF 400 μg from baseline to Week 12. Adverse events (AEs) and other clinical safety measures were recorded. Results A total of 728 subjects (mean: age = 47.9 y, asthma duration = 14.0 y, FEV1 % predicted = 66.3, reversibility = 22.9%, Asthma Control Questionnaire [ACQ] score = 1.93) were randomized. Improvements in mean changes from baseline in FEV1 AUC0-12 h (L ×h ) at Week 12 were MF/F 200/10 μg = 3.59, MF/F 400/10 μg = 4.19, and MF 400 μg = 2.04, with both MF/F doses significantly better than MF (p < 0.001). These FEV1s correspond to average hourly increases of 0.30, 0.35, and 0.17 L, respectively. MF/F was associated with rapid (