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Background The house dust mite (HDM) sublingual immunotherapy (SLIT) tablet (MK-8237; Merck & Co, Kenilworth, NJ/ALK-Abelló, Hørsholm, Denmark) has demonstrated beneficial effects on allergic rhinoconjunctivitis and asthma outcomes in European trials. Objective This is the first trial to assess the efficacy/safety of HDM SLIT-tablets in North American subjects with HDM-induced allergic rhinitis with or without conjunctivitis (AR/C). Methods In this double-blind, multicenter trial (NCT01700192) 1482 subjects (aged ≥12 years) with HDM-induced AR/C with or without asthma were randomized to a daily SQ HDM SLIT-tablet (12 SQ-HDM dose) or placebo for up to approximately 52 weeks. A rhinitis daily symptom score (DSS; 4 nasal symptoms, maximum score = 12) of 6 or greater, or 5 or greater with 1 symptom being severe, on 5 of 7 consecutive days before randomization was required. The primary end point was the average total combined rhinitis score, which was defined as the rhinitis DSS plus rhinitis daily medication score (DMS), during the last 8 treatment weeks. Results Treatment with 12 SQ-HDM improved the total combined rhinitis score by 17% (95% CI, 10% to 25%) versus placebo. Improvements versus placebo in the secondary end points of average rhinitis DSS, rhinitis DMS, total combined rhinoconjunctivitis score, and visual analog scale–assessed AR/C symptoms were 16%, 18%, 17%, and 16%, respectively. All nominal P values were less than .001 versus placebo, except rhinitis DMS ( P = 0.15). No treatment-related adverse events meeting the International Council on Harmonization definition of a serious adverse event were reported; 1 nonserious treatment-related systemic allergic reaction occurred (assessed as moderate intensity) at first administration under medical supervision and was treated with epinephrine. Conclusions In the first North American trial of use of a SLIT-tablet for HDM allergy, 12 SQ-HDM was well tolerated and improved HDM-induced rhinitis symptoms in adults and adolescents. [ABSTRACT FROM AUTHOR]

Background: According to meta-analyses and reviews, subcutaneous allergen immunotherapy (SCIT) and sublingual allergen immunotherapy (SLIT) are beneficial in patients with allergic rhinitis (AR) and allergic asthma (AA) induced by house dust mites (HDMs). However, the reported effect sizes have varied greatly from one study to another. Objective: We sought to perform an evidence-based medicine assessment of commercially available SCIT and SLIT formulations in patients with HDM-induced AA and HDM-induced AR. Methods: We searched for double-blind, placebo-controlled randomized clinical trials and analyzed study designs, doses, regimens, patient-reported outcomes, safety reporting, and compliance. Results: Forty-four studies met our inclusion criteria. Some studies tested both SLIT and SCIT or scored both AA and AR outcomes; therefore we reviewed 35 treatment arms in patients with AA (20 for SCIT and 15 for SLIT) and 23 treatment arms in patients with AR (7 for SCIT and 16 for SLIT). The treatment duration ranged from 6 weeks to 3 years. For SCIT, the dose of Der p 1 major allergen (when reported) ranged from 7 to 30 μg for maintenance doses and 60 to 420 μg for cumulative doses. For SLIT, the doses of Der p 1 (when reported) were 0.8 to 70 μg for maintenance doses and 60 to 23,695 μg for cumulative doses. Safety data were often absent or poorly reported. A statistically significant active versus placebo symptom score was observed more frequently for SCIT than for SLIT. Conclusion: There is no consensus on basic treatment parameters (eg, dose and duration) in HDM SCIT and SLIT. There is an urgent need for rigorous, long-term, double-blind, placebo-controlled randomized clinical trials with an efficacy criterion that reflects the particular features of HDM-induced allergic disease. [Copyright &y& Elsevier]

Sublingual immunotherapy is gaining widespread attention as a viable alternative to subcutaneous immunotherapy for the treatment of allergic rhinoconjunctivitis. In addition, sublingual immunotherapy has been studied in other allergic disorders including asthma. However, a review of published studies indicates that there are deficiencies and considerable heterogeneity in both design and data interpretation of sublingual immunotherapy studies. These deficiencies have made it somewhat difficult to assess the appropriate place of sublingual immunotherapy in guidelines for the therapy of allergic diseases. Moreover, several unpublished oral and sublingual immunotherapy studies in the United States failed to meet primary endpoints. This article reviews data from sublingual immunotherapy trials and makes recommendations about appropriate designs of future sublingual immunotherapy studies. It is hoped that these recommendations will result in more adequately designed sublingual immunotherapy trials to facilitate the appropriate placement of this therapy to treat patients with allergic rhinoconjunctivitis and other allergic diseases. [Copyright &y& Elsevier]

The English and non–English language literature on allergen immunotherapy was reviewed for studies simultaneously using 2 or more distinct allergen extracts in either subcutaneous or sublingual immunotherapy. Thirteen studies were identified, 11 using subcutaneous injections, 1 using sublingual administration, and 1 using both. In studies with adequate information, administration of 2 extracts by means of either subcutaneous immunotherapy or sublingual immunotherapy was effective. In studies using multiple allergens, 3 studies showed clear efficacy, whereas in the other 2 studies, lack of efficacy might have been due to inadequate doses of extract or omission of clinically relevant allergens in the treatment regimen. It is concluded that simultaneous administration of more than 1 allergen extract is clinically effective. However, more studies are needed, particularly with more than 2 allergen extracts and with sublingual administration. [Copyright &y& Elsevier]

Summary: Nebulized solutions of long-acting bronchodilators provide an alternative to DPI and MDI delivery, particularly for COPD patients unable to use hand-held devices easily or correctly. The long-acting β2-agonist, formoterol fumarate, is differentiated by its onset of significant bronchodilation within 5min of administration. In a randomized, double-blind, double-dummy trial, COPD subjects (n=351, mean forced expiratory volume FEV1=1.3L, 44% predicted) received nebulized formoterol fumarate (Perforomist™ inhalation solution; FFIS 20μg) or DPI (Foradil® Aerolizer®; FA 12μg), or placebo twice daily for 12 weeks. Efficacy was assessed with 12-h pulmonary function tests, and quality of life was assessed before and after treatment with the St. George''s Respiratory Questionnaire (SGRQ). At the 12-week endpoint, FFIS significantly increased FEV1 AUC0–12h relative to placebo (p<0.0001). No evidence of tachyphylaxis was observed as indicated by maintained FEV1 AUC and reduced rescue albuterol use throughout treatment. FFIS also significantly increased peak FEV1, trough FEV1, and standardized FVC AUC0–12h compared with placebo. SGRQ assessment at Week 12 demonstrated significant and clinically meaningful improvements in total score (FFIS vs placebo, −4.9, p=0.0067), symptom, and impact scores. No significant differences in efficacy were observed between the two active treatments. Drug related AEs in the FFIS arm with a frequency ⩾1% and exceeding placebo were dry mouth, nausea, and insomnia. Nebulized FFIS provided significant improvement in respiratory status and quality of life in subjects with COPD relative to placebo and was well tolerated. The efficacy and safety profile of FFIS was comparable to FA DPI. [Copyright &y& Elsevier]

Abstract: Background: Recently, there have been concerns about the tolerability of long-acting ²-agonists, including possible adverse cardiovascular effects—a particular concern in patients with chronic obstructive pulmonary disease (COPD), who are at elevated risk for cardiovascular disease. Objective: The aim of this study was to assess the cardiac safety profile of nebulized formoterol fumarate inhalation solution. Methods: Cardiac safety was assessed as part of a 12-week, randomized, double-blind, double-dummy, placebo- and active-controlled trial that was conducted at 38 centers across the United States. Male and female patients aged ≥40 years with COPD and without other significant disease were enrolled. After a 4- to 14-day, single-blind placebo run-in period, patients with COPD were randomly assigned to receive formoterol fumarate inhalation solution 20 µg BID via nebulizer (FFIS group), formoterol fumarate 12 µg BID via dry powder inhaler (FA group), or placebo. Cardiac effects—measured by changes in heart rate (HR) and ventricular premature beats; incidence of proarrhythmic events; change in corrected QT (QTc) interval; and incidence of maximum mean change in QTc ≥60 ms—were assessed using 24-hour Holter monitoring at baseline and 12 weeks; 12-lead electrocardiography at screening and weeks 4, 8, and 12; and patient diary cards. Results: A total of 351 patients with COPD were randomized (mean age, 62.8 years; 56.1% male; mean postbronchodilator forced expiratory volume in 1 second, 1.5 L). Holter monitoring found no clinically meaningful effects of FFIS or FA treatment on mean or maximum HR, ventricular premature beats, or inci dence of arrhythmic events compared with placebo. At week 12, mean (SD) changes from baseline in mean HR were -0.6 (10.9), +0.1 (11.6), and -1.4 (9.4) bpm in the FFIS, FA, and placebo groups, respectively. The incidence of mean maximum changes in QTc ≥60 ms at any time during the 12-week treatment period were 1.6%, 1.8%, and 1.8% with FFIS, FA, and placebo, respectively. Treatment-emergent cardiac adverse events (AEs) occurred in 4.1%, 3.5%, and 4.4% of patients in the FFIS, FA, and placebo groups; withdrawals due to possible cardiac AEs occurred in 1 patient per treatment group. No deaths or serious cardiac AEs occurred during the treatment period. Conclusion: In this COPD population, no clinically significant cardiac effects were found with twicedaily treatment with nebulized formoterol fumarate inhalation solution. [Copyright &y& Elsevier]

The purpose of this review is to highlight important articles on upper airway diseases and immunotherapy that appeared during 2006. Studies from Europe continue to examine the usefulness of the Allergic Rhinitis and its Impact on Asthma classification of allergic rhinitis as intermittent or persistent and its levels of severity as mild or moderate/severe. A number of physical agents were shown to effect nasal inflammation: sudden temperature changes in patients with allergic rhinitis increased eosinophilic inflammation; in children with allergic asthma, the personal exposure to particles <2.5 μm air pollution correlated with percent of nasal eosinophils and levels of markers of nasal exudation; and in patients who developed rhinorrhea on exposure to cold and windy weather, nasal challenge with cold dry air caused sloughing of nasal epithelial cells. A 3-month double-blind, placebo-controlled study of nasal washes with amphoteracin B showed no benefit in patients with chronic rhinosinusitis. Studies of immunotherapy with grass and dog dander extracts confirmed the need for doses containing 15 to 20 μg of the major allergen for optimal effectiveness. The protective effect of immunotherapy on the development of asthma in children with allergic rhinitis was shown to still be present 2 years after completion of a 3-year course of treatment. Injection immunotherapy with a moderate dose of house dust mite extract in house dust–sensitive adults with atopic dermatitis reduced symptoms and use of corticosteroids and antihistamines compared with treatment with about 1/1000 of that dose of the same extract. Pretreatment for 9 weeks with the monoclonal anti-IgE antibody omalizumab reduced systemic reactions during rush immunotherapy 5-fold and allowed further build-up at weekly intervals without systemic reactions. A review of sublingual immunotherapy confirmed both efficacy and safety, but evidence for appropriate dosing and for the effectiveness of sublingual immunotherapy employing multiple allergen mixes was still lacking. Two studies with a sublingual grass pollen extract tablet showed a clear dose response and the ability to initiate sublingual immunotherapy without an up-dosing phase. A pilot study with cytosine phosphorothionate quanosine DNA conjugated to the major allergen of ragweed reported impressive improvement in symptoms the first pollen season that persisted during the second pollen season without any further administration of the conjugate. In conclusion, studies on rhinitis and sinusitis explored the pathophysiology of the disease more than offering new therapeutic approaches. Studies on immunotherapy addressed optimal dosing, but also a variety of safer and more convenient approaches such as reduction of IgE with omalizumab, conjugating allergen to immunostimulatory DNA sequences, or administration by the sublingual route. [Copyright &y& Elsevier]

The scientific basis and the proof of clinical effectiveness of allergen immunotherapy administered by subcutaneous injection (SCIT) are well established. It is effective treatment for sensitivity to Hymenoptera venom and for allergic rhinitis and allergic asthma. SCIT administered in the proper setting reduces the development of new sensitivities and progression from rhinitis to asthma. Further, the beneficial effects persist long after completion of a course of treatment. Although many people enjoy the benefits of SCIT, extension of its use to the many others who might be candidates for this treatment is limited by its drawbacks of safety concerns and the inconvenience of repeated clinic visits over several years to receive the injections. There are many attempts underway to improve on the safety and convenience while still retaining the benefits of SCIT. These include approaches using current allergen extracts, especially by administering them sublingually. Alternatively, through recombinant technology, extracts are being modified to reduce their allergenicity without reducing their immunogenicity. They are being linked to immunostimulatory DNA sequences that will modify their in vivo processing resulting in an enhanced nonallergic response or they are being incorporated into fusion proteins with inhibitory properties for mast cells and basophils. [Copyright &y& Elsevier]

Background: The immunologic response to immunotherapy with dog extract is not well characterized. Objective: The purpose of this study was to examine the immunologic response to 3 doses of dog extract expressed as their Can f 1 content. Methods: Cluster immunotherapy was administered to 28 patients with dog allergy who were randomly assigned to 1 of 4 treatment arms: placebo or acetone-precipitated extract containing 0.6 μg, 3.0 μg, or 15.0 μg Can f 1 per 0.5 mL maintenance dose. Studies included titrated skin prick tests, the late cutaneous response, titrated nasal challenge with dog extract, and serum allergen-specific IgE and IgG4. Dog allergen-stimulated lymphocyte proliferation was performed with measurement of secreted cytokines by ELISA and of intracellular cytokines by flow cytometry. Results: There was a significant dose-dependent response in suppression of titrated skin prick tests and suppression of the late cutaneous response. There was a significant increase from baseline in dog-specific IgG4 in both the high-dose and low-dose groups and a dose-dependent suppression of secreted TNF-α and increase in secreted TGF-β. There was a dose-dependent trend in suppression of secreted IL-4 with a significant decrease from baseline in the high-dose group. There were no significant changes in symptom scores; lymphocyte proliferation; secreted IFN-γ, IL-10, or IL-5; or intracellular cytokine production. Conclusion: The dose-response in immunologic parameters after immunotherapy with dog extract is similar to that previously demonstrated with cat extract. Clinical implications: The greatest and most consistent response is seen with a dose containing 15 μg Can f 1. [Copyright &y& Elsevier]

The purpose of this review is to highlight important articles on upper airway disease and immunotherapy that appeared in the Journal of Allergy and Clinical Immunology and elsewhere during 2005. In recent studies of tissue from patients with chronic hypertrophic eosinophilic sinusitis, increased leukotriene C4 synthase and 5-lipoxygenase activity and increased levels of cysteinyl leukotriene production were demonstrated that correlated with disease severity but not with whether the patient was aspirin sensitive. However, the cysteinyl leukotriene 1 receptor was increased in leukocytes in the sinus tissue only in those patients with aspirin sensitivity. Major basic protein, released by eosinophils into the mucus in the paranasal sinus lumen, was found to reach concentrations capable of damaging the sinus epithelium, predisposing to bacterial infections. Testing the hypothesis that chronic hypertrophic eosinophilic sinusitis represents a reaction to common fungi, a double-blind trial of intranasal instillation of amphotericin B was conducted. There were marginal but significant differences in favor of amphotericin B treatment for sinus mucosal thickening on the basis of computed tomography and the evidence of eosinophilic inflammation in the sinus mucus. The effectiveness of topical nasal corticosteroids for treatment of nasal polyps was confirmed in 2 large studies. Improvement in sleep quality and daytime drowsiness in patients with allergic rhinitis treated with nasal corticosteroids was reported to correlate with reduction in nasal obstruction. The statistical analysis behind studies that reported a decrease in asthma exacerbations with nasal corticosteroids or oral antihistamines has been questioned. It appears that the results of at least one of these studies are indeed too good to be true. Although caution is still indicated in administering immunotherapy to patients receiving β-adrenergic blocking agents, the prohibition might not be absolute. A study in patients with Hymenoptera sensitivity given venom immunotherapy revealed no increase in serious adverse reactions to venom injections and no greater incidence of reactions to insect stings in those taking β-blocking agents. Sublingual immunotherapy for 8 to 12 weeks in patients with hazelnut sensitivity significantly increased their tolerance to hazelnut in double-blind, placebo-controlled challenges while inducing increased IgG4 and IL-10 levels, indicating induction of regulatory T cells. There were a number of articles in the Journal of Allergy and Clinical Immunology in 2005 that addressed the entity of chronic hypertrophic eosinophilic sinusitis. In addition, an update of the “Practice parameters on sinusitis” was published. The major focus in allergen immunotherapy continues to be sublingual administration. [Copyright &y& Elsevier]

Sublingual immunotherapy (SLIT) has been used with increasing frequency in Europe and is viewed with increasing interest by allergists in the United States. To address this interest, a Joint Task Force of the American College of Allergy, Asthma and Immunology and the American Academy of Allergy, Asthma and Immunology''s Immunotherapy and Allergy Diagnostic Committees reviewed the available literature on SLIT and prepared this report. The task force concluded that despite clear evidence that SLIT is an effective treatment, many questions remained unanswered, including effective dose, treatment schedules, and overall duration of treatment. Until these have been determined, an assessment of the cost/benefit ratio of the treatment cannot be made. SLIT does appear to be associated with few serious side effects, but it has not been administered in high-risk asthmatic patients, nor in the studies reviewed has it been administered as a mixture of non–cross-reacting allergens. Furthermore, there is currently no allergy extract approved for this use in the United States, nor is there a Current Procedural Terminology code for billing purposes. All of these factors should be given careful consideration by anyone contemplating initiating SLIT treatment for their allergic patients. [Copyright &y& Elsevier]

Short-acting β2-agonists are effective in relieving acute symptoms of asthma and in the short-term prevention of symptoms from stimuli, such as exercise. They are ineffective when used on a regular schedule to improve asthma control. Long-acting β2-agonists, on the other hand, provide sustained bronchodilation and improve asthma control. Regular use of long-acting β2-agonists is not associated with significant tolerance to their bronchodilator action, impairment in the response to albuterol, decreased baseline pulmonary function, increased response to methacholine, or increased risk of adverse cardiac events. Case-control studies do not suggest an increased risk for death or intensive care unit admissions with use of long-acting β2-agonists. In prospective studies in which there has been an increase in asthma deaths or serious asthma exacerbations, this increased risk has not been observed in subjects using inhaled corticosteroids. Where increased deaths have occurred in relation to either short- or long-acting β2-agonists, the events have not occurred equally throughout the exposed population. This suggests that these outcomes were not a direct toxic effect of the drugs and increases the possibility that they resulted from an interaction between relief of symptoms by β2-agonists and delay in seeking medical care. [Copyright &y& Elsevier]

Evidence of an increased prevalence of rhinitis in patients with asthma, and asthma in patients with rhinitis, supports the 1 airway concept. However, there are basic differences between the upper and lower airways, such as the virtual absence of remodeling in the nose compared with the bronchi, despite the presence of similar inflammation. Etiologic factors in chronic rhinosinusitis (CRS) attract increasing interest. Peripheral blood monocytes from patients with CRS release IL-4, IL-13, and IFN-γ on stimulation with fungal antigens, especially those from Alternaria. This is not seen with cells from normal controls. However, a double-blind trial of intranasal amphotericin in CRS was negative. Evidence continues to accumulate of the pivotal role of regulatory T-lymphocytes secretion of IL-10 in the response to allergen immunotherapy. In patients with asthma and house dust mite allergy who are receiving appropriate pharmacotherapy and have instituted environmental controls, house dust mite immunotherapy provides marginal additional benefits in asthma control. Immunotherapy with cat dander extract at a maintenance dose containing 15 μg Fel d 1 produces a more consistent immunologic response than with maintenance doses containing 3.0 μg, whereas doses containing only 0.6 μg are no more effective than placebo. Sublingual immunotherapy for seasonal grass allergy can be safely administered by general practitioners, but symptom relief begins only in the second season of therapy. Sublingual immunotherapy for seasonal grass allergy in children reduced symptoms and onset of new asthma symptoms but, again, beginning only in the second year of treatment. A course of 6 weekly injections of ragweed Amb a 1 bound to cytosine phosphorothionate guanosine containing DNA produced a shift from TH2 to TH1 cytokine release both in peripheral blood cells and in the nose after allergen challenge. No symptom improvement was seen the first year, but symptoms were reduced the second year without further treatment. [Copyright &y& Elsevier]

Background Data comparing the treatment effect of allergy immunotherapy and pharmacotherapy are lacking. Objective We sought to indirectly compare the treatment effect of sublingual immunotherapy (SLIT)-tablets with pharmacotherapy for seasonal allergic rhinitis (SAR) and perennial allergic rhinitis (PAR). Methods Pooled data from randomized, double-blind, placebo-controlled trials for the clinical development programs of selected allergic rhinitis treatments were evaluated. Total nasal symptom scores (TNSSs) relative to placebo were compared. Subjects scored symptoms daily during entire pollen seasons in 6 timothy grass SLIT-tablet trials (n = 3094) and 2 ragweed SLIT-tablet trials (n = 658) and during the last 8 weeks of treatment in 2 house dust mite (HDM) SLIT-tablet trials (n = 1768). Subjects scored symptoms daily in 7 montelukast (10 mg, n = 6799), 9 desloratadine (5 mg, n = 4455), and 8 mometasone furoate nasal spray (MFNS; 200 μg daily, n = 2140) SAR or PAR trials. SLIT-tablet trials allowed rescue medication use, whereas most pharmacotherapy trials did not. A fixed-effect meta-analysis method estimated differences in on-treatment average TNSSs. Results In grass and ragweed SLIT-tablet trials, overall improvement in TNSSs relative to placebo was 16.3% and 17.1%, respectively. In HDM SLIT-tablet trials, TNSS overall improvement relative to placebo was 16.1%. In the montelukast, desloratadine, and MFNS trials, TNSS overall improvement relative to placebo was 5.4%, 8.5%, and 22.2%, respectively, for SAR trials, and 3.7%, 4.8%, and 11.2%, respectively, for PAR trials. Conclusions Although comparisons were limited by study design heterogeneity and use of rescue medications in SLIT-tablet trials, effects on nasal symptoms with timothy grass and ragweed SLIT-tablets were nearly as great as with MFNS and numerically greater than with montelukast and desloratadine for SAR. HDM SLIT-tablet effects were numerically greater than all pharmacotherapies for PAR. SLIT-tablets offer the additional benefit of long-term efficacy. [ABSTRACT FROM AUTHOR]

Background The magnitude of effect of sublingual immunotherapy for house dust mite (HDM)–induced allergic rhinitis with or without conjunctivitis is uncertain, partly because there are few well-controlled trials with well-defined doses. Objective We sought to determine the dose-related efficacy and onset of action of the HDM sublingual immunotherapy tablet MK-8237 (Merck/ALK-Abelló) using the Vienna Challenge Chamber. Methods In this randomized, double-blind, single-site trial, adults with HDM-induced allergic rhinitis with or without conjunctivitis and with or without asthma (n = 124) received 12 developmental units (DU) of MK-8237, 6 DU of MK-8237, or placebo daily for 24 weeks. Subjects underwent 6-hour exposure challenges at screening and weeks 8, 16, and 24. The total nasal symptom score (TNSS) during chamber challenge at week 24 was the primary end point. The TNSS was the sum of 4 nasal symptom scores (maximum = 12). Total ocular symptom scores (TOSSs; 2 symptoms; maximum = 6) and total symptom scores (TSSs; TSS = TNSS plus TOSS; maximum = 18) were secondary end points. Results Dose- and time-dependent improvements with MK-8237 versus placebo were observed. At week 24, TNSS improvement relative to placebo was 48.6% (95% CI, 35.3% to 60.2%) with 12 DU of MK-8237 and 26.6% (95% CI, 11.2% to 39.6%) with 6 DU of MK-8237. Statistically significant improvements for TNSSs were also observed at weeks 8 (12 DU of MK-8237) and 16 (6 and 12 DU of MK-8237) and for TOSSs and TSSs by both doses at week 24. MK-8237 was well tolerated. No investigator-assessed anaphylactic allergic reactions or reactions requiring epinephrine were observed. Conclusions MK-8237, 12 DU, reduced nasal and ocular symptoms and exceeded World Allergy Organization–established clinical efficacy criteria (≥20% improvement vs placebo). The onset of action for 12 DU of MK-8237 was week 8. MK-8237, 12 DU, is appropriate for further evaluation to determine the magnitude of effect in an uncontrolled allergen exposure environment. [ABSTRACT FROM AUTHOR]