Characterization of the relationship between dose and blood eosinophil response following subcutaneous administration of mepolizumab A randomized, double-blind, placebo-controlled study of tumor necrosis factor-alpha blockade in severe persistent asthma. Phase 3 Study of Reslizumab in Patients With Poorly Controlled Asthma: Effects Across a Broad Range of Eosinophil Counts. Omalizumab therapy for asthma patients with poor adherence to inhaled corticosteroid therapy. Treatment of childhood asthma with anti-immunoglobulin E antibody (omalizumab). Granulocyte macrophage colony-stimulating factor is the main cytokine enhancing survival of eosinophils in asthmatic airways. Safety profile, pharmacokinetics, and biologic activity of MEDI-563, an anti-IL-5 receptor alpha antibody, in a phase I study of subjects with mild asthma. Anti-inflammatory effect of itraconazole in stable allergic bronchopulmonary aspergillosis: a randomized controlled trial. Evaluation of long-term safety of the anti-IgE antibody, omalizumab, in children with allergic asthma. Long-term Efficacy and Safety of Mepolizumab in Patients With Severe Eosinophilic Asthma: A Multi-center, Open-label, Phase IIIb Study. Reductions in eosinophil biomarkers by benralizumab in patients with asthma. Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial. Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies. Efficacy and safety of mepolizumab in Japanese patients with severe eosinophilic asthma. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. 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Efficacy and tolerability of anti‐immunoglobulin E therapy with omalizumab in patients with concomitant allergic asthma and persistent allergic rhinitis: SOLAR The anti-IgE antibody omalizumab reduces exacerbations and steroid requirement in allergic asthmatics. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsìveness, and the late asthmatic response Oral corticosteroid sparing with omalizumab in severe allergic (IgE-mediated) asthma patients A phase 1 study evaluating the pharmacokinetics, safety and tolerability of repeat dosing with a human IL-13 antibody (CAT-354) in subjects with asthma Monoclonal anti-interleukin‐5 treatment suppresses eosinophil but not T‐cell functions Assessing future need for acute care in adult asthmatics: the Profile of Asthma Risk Study: a prospective health maintenance organization-based study. Lebrikizumab in moderate-to-severe asthma: pooled data from two randomised placebo-controlled studies Isotypic and antigenic restriction of the blocking antibody response to ryegrass pollen: correlation of rye group I antigen-specific IgG1 with clinical response. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Daclizumab improves asthma control in patients with moderate to severe persistent asthma: a randomized, controlled trial. Clinical efficacy of sublingual‐swallow immunotherapy: a double‐blind, olacebo‐controlled trial of a standardized five‐grass‐pollen extract in rhinitis Mepolizumab treatment in patients with severe eosinophilic asthma. Specific cellular and humoral immunity in children with grass pollen asthma A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. A randomized trial of the efficacy and safety of quilizumab in adults with inadequately controlled allergic asthma Sputum Hyaluronan and Versican in Severe Eosinophilic Asthma A phase II placebo-controlled study of tralokinumab in moderate-to-severe asthma The beneficial effects of Xolair (omalizumab) as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available treatment (GINA 2002 step IV)--the Israeli arm of the INNOVATE study. Eosinophil's role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway. Exhaled nitric oxide in children with asthma receiving Xolair (omalizumab), a monoclonal anti-immunoglobulin E antibody. The effects of lebrikizumab in patients with mild asthma following whole lung allergen challenge The best laid schemes of airway repair Omalizumab provides long-term control in patients with moderate-to-severe allergic asthma The effects of an anti-CD4 monoclonal antibody, keliximab, on peripheral blood CD4+ T-cells in asthma. Solid-phase radioimmunoassay for the measurement of IgG antibodies specific for the house dust mite, Dermatophagoides farinae. Eosinophils in bronchial mucosa of asthmatics after allergen challenge: effect of anti‐IgE treatment Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia. Effects of omalizumab on basophil and mast cell responses using an intranasal cat allergen challenge. Benralizumab, an anti-interleukin 5 receptor α monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study. 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Allergen-specific immunotherapy with recombinant grass pollen allergens. Treatment of allergic asthma with monoclonal anti-IgE antibody. rhuMAb-E25 Study Group. Predicting response to omalizumab, an anti-IgE antibody, in patients with allergic asthma. Immunological and Clinical Changes in Allergic Asthmatics following Treatment with Omalizumab Palivizumab prophylaxis, respiratory syncytial virus, and subsequent recurrent wheezing. Efficacy and safety of an anti-IL-13 mAb in patients with severe asthma: a randomized trial. Immunotherapy in cat-induced asthma. Double-blind trial with evaluation of in vivo and in vitro responses. Safety and immunogenicity of sequential pneumococcal immunization in preschool asthmatics. Serum levels of specific IgE, soluble interleukin-2 receptor, and soluble intercellular adhesion molecule-1 in seasonal allergic rhinitis. Benefits of omalizumab as add‐on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE A Phase 2a Study of Benralizumab for Patients with Eosinophilic Asthma in South Korea and Japan A phase 1, randomized, placebo-controlled, dose-escalation study of an anti-IL-13 monoclonal antibody in healthy subjects and mild asthmatics. Omalizumab is effective in allergic and nonallergic patients with nasal polyps and asthma. Asthma symptom re-emergence after omalizumab withdrawal correlates well with increasing IgE and decreasing pharmacokinetic concentrations. Efficacy of inactivated vaccine in preventing antigenically drifted influenza type A and well-matched type B. Omalizumab for the treatment of exacerbations in children with inadequately controlled allergic (IgE-mediated) asthma. Response to pneumococcal immunization in children with and without recurrent infections. Flow cytometry to identify leukocyte sub-populations in blood and induced sputum in asthmatic and healthy volunteers exposed to diesel exhaust Specific down-regulation of anti-allergen IgE and IgG antibodies in humans associated with injections of allergen-specific antibody complexes. Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma. Effect of aerosolized anti-IgE (E25) on airway responses to inhaled allergen in asthmatic subjects. Randomized, double-blind phase II study of anti-endotoxin antibody (E5) as adjuvant therapy in humans with serious gram-negative infections. Omalizumab improves asthma-related quality of life in patients with severe allergic asthma. A randomized, controlled, phase 2 study of AMG 317, an IL-4Ralpha antagonist, in patients with asthma. Clinical and immunologic evaluation of tyrosine-adsorbed Dermatophagoides pteronyssinus extract: a double-blind placebo-controlled trial. Effect of feeding whey hydrolysate, soy and conventional cow milk formulas on incidence of atopic disease in high risk infants. Omalizumab in children with inadequately controlled severe allergic (IgE-mediated) asthma Efficacy of omalizumab in cat-allergic patients with moderate-to-severe persistent asthma. [Comparative studies of the effectiveness of specific immunotherapy in house dust mite allergy]. Effect of pretreatment with omalizumab on the tolerability of specific immunotherapy in allergic asthma. Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics. Ethical considerations and rationale of the MAKI trial: a multicenter double-blind randomized placebo-controlled trial into the preventive effect of palivizumab on recurrent wheezing associated with respiratory syncytial virus infection in children with a gestational age of 33-35 weeks. Anti-IgE (omalizumab) inhibits late-phase reactions and inflammatory cells after repeat skin allergen challenge. [An attempt to block histamine release from basophils granulocytes with antibodies obtained as a result of long-term immunization]. Omalizumab is effective in the long-term control of severe allergic asthma. Omalizumab in Severe Allergic Asthma Inadequately Controlled With Standard Therapy Cost-effectiveness analysis of omalizumab in adults and adolescents with moderate-to-severe allergic asthma. Transient impact of omalizumab in pollen allergic patients undergoing specific immunotherapy. Effect of Omalizumab on Adenosine 5′-Monophosphate Responsiveness in Subjects with Allergic Asthma Clinical trials of bivalent A/New Jersey/76-A/Victoria/75 influenza vaccines in high-risk children. Effect of SCH55700, a humanized anti-human interleukin-5 antibody, in severe persistent asthma: a pilot study. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial Evaluation of immune complexes after immunotherapy with wheat flour in bakers' asthma. AN INVESTIGATION OF POLLEN EXTRACTS FROM DIFFERENT DECIDUOUS TREES IN PATIENTS WITH SPRINGTIME ALLERGY IN SWEDEN Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial Effects of interleukin-13 blockade on allergen-induced airway responses in mild atopic asthma. Targeting membrane-expressed IgE B cell receptor with an antibody to the M1 prime epitope reduces IgE production A randomized trial of benralizumab, an antiinterleukin 5 receptor α monoclonal antibody, after acute asthma. Efficacy and tolerability of anti‐immunoglobulin E therapy with omalizumab in patients with poorly controlled (moderate‐to‐severe) allergic asthma Omalizumab, a recombinant humanized anti-IgE antibody, reduces asthma-related emergency room visits and hospitalizations in patients with allergic asthma. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial Preseasonal local allergoid immunotherapy to grass pollen in children: a double‐blind, placebo‐controlled, randomized trial Monoclonal antibody-standardized cat extract immunotherapy: risk-benefit effects from a double-blind placebo study. Anti-IL-5 (mepolizumab) therapy induces bone marrow eosinophil maturational arrest and decreases eosinophil progenitors in the bronchial mucosa of atopic asthmatics. Identification of IgG antibody as a carrier of reaginic activity in asthmatic patients. Omalizumab, an anti-IgE antibody, in the treatment of adults and adolescents with perennial allergic rhinitis. Dose-ranging study of lebrikizumab in asthmatic patients not receiving inhaled steroids. Mepolizumab and exacerbations of refractory eosinophilic asthma. Respiratory syncytial virus and recurrent wheeze in healthy preterm infants. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. Efficacy and safety of omalizumab in an Asian population with moderate-to-severe persistent asthma. Economic analysis of the phase III MENSA study evaluating mepolizumab for severe asthma with eosinophilic phenotype
Objective : Mepolizumab is a humanized IgG1 monoclonal antibody that blocks human IL-5 from binding to the IL-5 receptor , which is mainly expressed on eosinophils . Eosinophils are key cells in the inflammatory cascade of various diseases , including asthma . This study investigated the pharmacokinetic (PK)/pharmacodynamic ( PD ) relationship between exposure of mepolizumab subcutaneous ( SC ) administration and blood eosinophil reduction compared with intravenous ( IV ) administration in adult subjects with asthma . Methods : In this multi-center , r and omized , open-label , parallel-group , repeat-dose study , 70 adult subjects received one of four possible treatment regimens : mepolizumab 12.5 , 125 , or 250 mg SC or 75 mg IV . In addition to analyzing the dose and PK/PD relationship , absolute bioavailability , safety , tolerability , and incidence of anti-mepolizumab antibodies were evaluated . Results : Blood eosinophil levels decreased in a dose-dependent manner with the lowest ( 12.5 mg ) dose clearly differentiating from the other doses . A non-linear inhibition Imax model based on blood eosinophil levels at week 12 identified that the SC doses providing 50 % and 90 % of maximal blood eosinophil inhibition were 11 mg ( 95 % confidence interval ( CI ) : 5.19 – 16.85 ) and 99 mg ( 95 % CI : 47 – 152 ) , respectively . The route of administration did not affect the exposure-response relationship . The estimated mepolizumab SC absolute bioavailability ( arm ) was 74 % ( 90 % CI : 54 – 102 % ) . The safety profile of mepolizumab was favorable . Conclusions : A dose-dependent reduction in blood eosinophils across all mepolizumab doses investigated was observed . The subcutaneous absolute bioavailability was 74 % . The route of administration did not affect the mepolizumab exposure eosinophil response relationship RATIONALE The treatment effect of golimumab , a human monoclonal antibody against tumor necrosis factor (TNF)-alpha , in severe persistent asthma is unknown . OBJECTIVES To assess the safety and efficacy of golimumab in a large population of patients with uncontrolled , severe persistent asthma . METHODS From 2004 to 2006 , 309 patients with severe and uncontrolled asthma , despite high-dose inhaled corticosteroids and long-acting beta(2 ) agonists , were r and omized 1:1:1:1 to monthly subcutaneous injections of placebo or golimumab ( 50 , 100 , or 200 mg ) through Week 52 . Co primary endpoints were the change from baseline through Week 24 in prebronchodilator percent-predicted FEV(1 ) and the number of severe asthma exacerbations through Week 24 . MEASUREMENTS AND MAIN RESULTS No significant differences were observed for the change in percent-predicted FEV1 ( least squares mean : placebo , 2.44 [ 95 % confidence interval ( CI ) -0.574 to 5.461 ] ; combined 100-mg and 200-mg , 2.91 [ 0.696 - 5.116 ] ) or severe exacerbations ( mean + /- SD : placebo , 0.5 + /- 1.07 vs. combined 100-mg and 200-mg 0.5 + /- 0.97 ) through week 24 . Through Week 24 , 2.6 % of patients treated with placebo vs. 19.5 % of those treated with golimumab discontinued the study agent , and 1.3 % and 7.8 % discontinued study participation , respectively . An unfavorable risk-benefit profile led to early discontinuation of study -agent administration after the Week-24 data base lock . Through Week 76 , 20.5 % of patients treated with placebo and 30.3 % of patients treated with golimumab experienced serious adverse events , with serious infections occurring more frequently in golimumab-treated patients . One death and all eight malignancies occurred in the active groups . CONCLUSIONS Overall , treatment with golimumab did not demonstrate a favorable risk-benefit profile in this study population of patients with severe persistent asthma . Clinical trial registered with www . clinical trials.gov ( NCT00207740 ) BACKGROUND IL-5 , a mediator of eosinophil activity , is an important potential treatment target in patients with uncontrolled asthma . The efficacy of reslizumab , a humanized anti-human IL-5 monoclonal antibody , has been characterized in patients with blood eosinophils ≥ 400 cells/μL. This study further characterizes the efficacy and safety of reslizumab in patients with poorly-controlled asthma , particularly those with eosinophils < 400 cells/μL. METHODS Patients were r and omly assigned to intravenous reslizumab 3.0 mg/kg or placebo once every 4 weeks for 16 weeks . The primary end point was the change in FEV1 from baseline to week 16 . Secondary measures included Asthma Control Question naire-7 ( ACQ-7 ) scores , use of short-acting β-agonists ( SABAs ) , and FVC . RESULTS Four hundred ninety-two patients received ≥ 1 dose of placebo ( n = 97 ) or reslizumab ( n = 395 ) . In the overall population , mean FEV1 change from baseline to week 16 was not significantly different between reslizumab and placebo , and no significant relationship was detected between treatment , baseline blood eosinophils and change in FEV1 . In the subgroup of patients with baseline eosinophils < 400 cells/μL , patients treated with reslizumab showed no significant improvement in FEV1 compared with those receiving placebo . In the subgroup with eosinophils ≥ 400 cells/μL , however , treatment with reslizumab was associated with much larger improvements in FEV1 , ACQ-7 , rescue SABA use , and FVC compared with the placebo group . Reslizumab was well tolerated , with fewer overall adverse events compared with placebo ( 55 % vs 73 % ) . CONCLUSIONS Reslizumab was well tolerated in patients with inadequately controlled asthma . Clinical ly meaningful effects on lung function and symptom control were not seen in patients unselected for baseline eosinophils . TRIAL REGISTRY Clinical Trials.gov ; No. : NCT01508936 ; URL : www . clinical trials.gov BACKGROUND Omalizumab , an anti-IgE monoclonal antibody , is administered by injection once or twice monthly in offices and clinics . It offers a potential alternative intervention for patients with allergic asthma that is not well controlled because of recalcitrant poor adherence to inhaled corticosteroid therapy . OBJECTIVE To assess the effect of omalizumab therapy by measuring airway responsiveness to adenosine , a marker of allergic airway inflammation , and re source use . METHODS Patients ( N = 17 ) aged 6 to 26 years ( mean age , 16.4 years ) with poorly controlled persistent allergic asthma , less than 50 % adherence to inhaled corticosteroid therapy , a forced expiratory volume in 1 second ( FEV1 ) of 60 % predicted or higher , and adenosine provocation concentration that caused a decrease in FEV1 of 20 % ( PC20 ) of 60 mg/mL or less were r and omized to receive 4 months of omalizumab or placebo in a double-blind , crossover trial with a 3- to 4-month washout between treatments . Patients were instructed to continue taking inhaled corticosteroids throughout the study . The PC20 was measured before and after each period . RESULTS Fifteen patients completed the study . The mean baseline PC20 was 14.1 mg/mL ( 95 % CI , 10.8 - 18.4 mg/mL ) . The fold change PC20 was 0.9 ( 95 % CI , 0.5 - 1.7 ) during placebo and 3.1 ( 95 % CI , 1.6 - 6.2 ) during omalizumab treatment ; the estimated ratio was 3.4 ( 95 % CI , 1.2 - 9.3 ; P = .02 ) . Six patients required one or more short courses of oral corticosteroids for asthma exacerbations during placebo , but none required this intervention during omalizumab . During the study , the median prescription refills for inhaled corticosteroids was 0.15 ( 95 % CI , 0.00 - 0.33 ) canisters per month . CONCLUSION Omalizumab therapy is an alternative for patients with more severe poorly controlled asthma in whom adherence does not improve with conventional interventions . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00133042 BACKGROUND AND OBJECTIVE There seems to be a strong causal relationship between allergy and the origins of asthma . Susceptibility to both is determined by a combination of genetics and environment acting through a complex network of cytokines . Nearly 90 % of affected children have positive skin tests indicating the presence of specific immunoglobulin E ( IgE ) , with sensitivity to house dust mite , Alternaria , cockroach , cat , and dog most closely linked to the disease . Greater exposure to house dust mite during infancy leads to earlier onset of wheezing , and elevated serum IgE levels correlate with the appearance of asthma symptoms . Specific IgE binds to high-affinity ( FcepsilonRI ) receptors on mast cells and basophils . The IgE-mediated reactions that follow exposure of sensitized mast cells to an allergen are design ated early- and late-phase asthmatic responses ( EAR and LAR ) . EAR is characterized by release of histamine and other preformed mediators within 1 hour of allergen exposure . It is often followed by LAR , an infiltration of the airways by inflammatory cells associated with an episode of more prolonged , and usually more severe airflow obstruction , 4 to 8 hours after antigen exposure . Chronic airway symptoms result from persistent LAR caused by continuous allergen exposure . IgE antibodies are capable of passive transfer of both EAR and LAR sensitivity . IgE-mediated mast cell activation contributes to chronic tissue eosinophilia and airway remodeling , with permanent loss in pulmonary function .  Omalizumab ( rhuMAb-E25 ) is a recombinant , humanized , monoclonal anti-IgE antibody of mouse origin developed for the treatment of IgE-mediated diseases . Omalizumab binds to free IgE at the same site as the high-affinity receptor . Although it attaches to free IgE , it does not bind to IgA , IgG , or cell-bound IgE. It therefore does not induce cross-linking of cell-bound IgE , which would lead to the release of allergic mediators . It has been reported to decrease serum IgE levels in a dose-dependent manner , inhibit EAR and LAR , and cause a down-regulation of FcepsilonRI receptors on basophils . Omalizumab has been reported to be safe and effective in improving asthma control and reducing the requirement for oral and inhaled corticosteroids . This double-blind , r and omized , placebo-controlled study evaluated the safety , steroid-sparing effects , and impact on disease exacerbations of omalizumab in the treatment of childhood asthma . Methods . Participants were 334 males and premenarchal females aged 6 to 12 years , with moderate to severe allergic asthma requiring treatment with inhaled corticosteroids .  During a run-in phase , all children were switched to equivalent doses of beclomethasone dipropionate ( BDP ) , and the dose was adjusted to assure maintenance of asthma control achieved with previous corticosteroid treatment . Children were r and omized to subcutaneously administered placebo ( N = 109 ) or omalizumab ( N = 225 ) at a dose based on body weight and initial serum IgE ( 0.016 mg/kg/IgE [ IU/mL ] per 4 weeks ) . BDP dose ( initial range 168 - 420 microg/d ) was kept stable for 16 weeks ( stable-steroid phase ) , reduced over 8 weeks to the minimum effective dose ( steroid-reduction phase ) , and maintained constant for the final 4 weeks . RESULTS More participants in the omalizumab group decreased their BDP dose , and their reduction was greater than that of the placebo group ( median reduction 100 % vs 66.7 % ) . BDP was withdrawn completely in 55 % of the omalizumab group versus 39 % of the placebo group . The incidence and the frequency of asthma exacerbations requiring treatment with doubling of BDP dose or systemic corticosteroids were lower in the omalizumab group . The treatment differences were statistically significant during the steroid-reduction phase , during which fewer participants in the omalizumab group had asthma exacerbation episodes ( 18.2 % vs 38.5 % ) , and the mean number of episodes per patient was smaller than with placebo ( 0.42 vs 2.72 ) . Five asthma exacerbations requiring hospitalization all occurred in the placebo group . Participants ' and investigators ' global evaluations of treatment effectiveness were more favorable for omalizumab than placebo .  Investigators rated effectiveness excellent for 31.5 % of the omalizumab group versus 16.3 % of the placebo group and good for 44.7 % of the omalizumab group versus 32.7 % of the placebo group . There was little change in asthma symptom scores or spirometry measurements during either the stable-steroid or steroid dose-reduction phase , with minimal differences between the treatment groups . The requirement for rescue medication in the omalizumab group during both the stable-steroid and steroid dose-reduction phases was consistently lower than at baseline . At week 28 , the median number of puffs of rescue medication taken daily was 0 in the omalizumab group and 0.46 in the placebo group . The change from baseline was significant in favor of omalizumab . ( ABSTRACT TRUNCATED Interleukin (IL)-3 , IL-5 and granulocyte macrophage colony-stimulating factor ( GM-CSF ) prolong the survival of eosinophils , which are conspicuous in asthmatic airways , but it is still controversial which one plays a major role in enhancing the survival of eosinophils in asthmatic airways . The role of these cytokines in airway eosinophilia was investigated using bronchoalveolar lavage ( BAL ) fluids from 11 symptomatic and nine asymptomatic patients with asthma and eight normal subjects .  Eosinophil survival-enhancing activity ( ESEA ) was measured by a numerical change in viable eosinophils isolated from the peripheral blood of atopic patients and cultured with BAL fluids . ESEA was characterized by neutralization with antibodies to IL-3 , IL-5 and /or GM-CSF . The differential count of BAL cells was achieved using Diff-Quik stain . T-cell subsets and activated T-cells were analysed by flow cytometry with dual stain using monoclonal antibodies to CD3 , CD4 , CD8 and CD25 . ESEA was detected in eight of 11 BAL fluids of symptomatic asthma , but not in those of normal controls or asymptomatic asthmatics . In six symptomatic asthmatics , the mean percentage of inhibition in ESEA by anti-GM-CSF was higher than that of anti-IL-5 as well as anti-IL-3 ( p<0.05 ) . A mixture of antibodies to IL-3 , IL-5 and GM-CSF totally inhibited the ESEA in four cases . The ESEA correlated with the percentage of eosinophils ( p<0.05 ) and that of CD25(+)CD4 lymphocytes ( p<0.05 ) of BAL cells . In conclusion , granulocyte macrophage colony-stimulating factor , rather than interleukin-3 or -5 , is associated with eosinophil survival-enhancing activity inside the airways of symptomatic asthmatics . The activation of CD4 lymphocytes is related to the elevation of such activity BACKGROUND Increased eosinophil levels have been linked to airway inflammation and asthma exacerbations . IL-5 is responsible for eosinophil differentiation , proliferation , and activation ; IL-5 receptors are expressed on eosinophils and their progenitors , and targeting such receptors induces eosinophil apoptosis . OBJECTIVE To evaluate the safety profile , pharmacokinetics , and pharmacodynamics of MEDI-563 , a humanized mAb targeting the IL-5 receptor alpha chain . METHODS Single , escalating , intravenous doses ( 0.0003 - 3 mg/kg ) of MEDI-563 were administered to subjects with mild atopic asthma ( n = 44 ) over approximately 3 to 30 minutes in this open-label study . Pulmonary function , symptom scores , adverse events , MEDI-563 pharmacokinetics , and levels of C-reactive protein ( CRP ) , IL-6 , eosinophil cationic protein ( ECP ) , and eosinophils were evaluated . RESULTS Mean peripheral blood ( PB ) eosinophil levels decreased in a dose-dependent fashion ( baseline + /- SD , 0.27 + /- 0.2 x 10(3)/microL ; 24 hours postdose , 0.01 + /- 0.0 x 10(3)/microL ) ; 94.0 % of subjects receiving > or=0.03 mg/kg exhibited levels between 0.00 x 10(3)/microL and 0.01 x 10(3)/microL. Eosinopenia lasted at least 8 or 12 weeks with doses of 0.03 to 0.1 and 0.3 to 3 mg/kg , respectively . ECP levels were reduced from 21.4 + /- 17.2 microg/L ( baseline ) to 10.3 + /- 7.0 microg/L ( 24 hours postdose ) . The most frequently reported adverse events were reduced white blood cell counts ( 34.1 % ) , nasopharyngitis ( 27.3 % ) , and increased blood creatine phosphokinase ( 25.0 % ) . Mean C-reactive protein levels increased approximately 5.5-fold at 24 hours postdose but returned to baseline by study end ; mean IL-6 levels increased approximately 3.9-fold to 4.7-fold at 6 to 12 hours postdose , respectively . Pharmacokinetic activity was dose proportional at doses of 0.03 to 3 mg/kg . CONCLUSION Single escalating doses of MEDI-563 had an acceptable safety profile and result ed in marked reduction of PB eosinophil counts within 24 hours after dosing BACKGROUND Allergic bronchopulmonary aspergillosis ( ABPA ) complicates chronic asthma and results from hypersensitivity to the fungus Aspergillus fumigatu s , causing an intense systemic immune response and progressive lung damage . OBJECTIVE We sought to determine whether treatment with the antifungal agent itraconazole reduced eosinophilic airway inflammation in subjects with ABPA . METHODS A r and omized , double-blind , placebo-controlled trial was performed in stable subjects with ABPA ( n = 29 ) . Subjects received 400 mg of itraconazole per day ( n = 15 ) or placebo ( n = 14 ) for 16 weeks . All subjects were review ed monthly with history , spirometry , and sputum induction to measure airway inflammation , serum total IgE and IgG levels to A fumigatu s , and blood eosinophil counts . RESULTS By using regression analysis in a r and om-effects model , subjects receiving itraconazole had a decrease in sputum eosinophils of 35 % per week , with no decrease seen in the placebo arm ( P < .01 ) . Sputum eosinophil cationic protein levels decreased with itraconazole treatment by 42 % per week compared with 23 % in the placebo group ( P < .01 ) . Itraconazole reduced systemic immune activation , leading to a decrease in serum IgE levels ( 310 IU/mL ) compared with levels seen in the placebo group ( increase of 18 IU/mL , P < .01 ) and a decrease in IgG levels to A fumigatu s ( 15.4 IU/mL ) compared with levels seen in the placebo group ( increase of 3.7 IU/mL , P = .03 ) . There were fewer exacerbations requiring oral cortico-steroids in those treated with itraconazole compared with in the placebo group ( P = .03 ) . CONCLUSION Itraconazole treatment of subjects with stable ABPA reduces eosinophilic airway inflammation , systemic immune activation , and exacerbations . These results imply that itraconazole is a potential adjunctive treatment for ABPA OBJECTIVE To evaluate the long-term effects of the anti-IgE antibody omalizumab in children with asthma . METHODS This was a 28-week , double-blind , r and omized , placebo-controlled trial with a 24-week open-label extension . In the core trial 225 children ( ages 6 to 12 years ) with moderate-to-severe allergic asthma requiring inhaled beclomethasone dipropionate ( BDP ) received omalizumab every 2 or 4 weeks , and 109 received placebo .  BDP dosage was stable for weeks 1 to 16 , then reduced during weeks 17 to 24 using strict safety criteria . The lowest dose for optimal asthma control was maintained for 4 more weeks . During the 24-week extension , all patients ( n = 309 ) received open-label omalizumab in addition to other asthma medications . One-year safety data were analyzed . RESULTS The incidence of adverse events in patients treated with omalizumab for 52 weeks was similar to those treated for 28 weeks in the core trial , which was generally comparable with placebo . In the 52-week omalizumab group , upper respiratory tract infection and headache were the most frequently reported adverse events ( 47.1 % and 42.7 % , respectively ) . Eleven patients ( 4.9 % ) reported urticaria , which resolved spontaneously or with antihistamine , except for 1 patient who was discontinued because of severe urticaria . No anaphylactic reactions or adverse events suggestive of serum sickness or immune complex formation occurred . No anti-omalizumab antibodies were detected in any of the children . There is no evidence that new or more serious adverse events occur with long-term omalizumab treatment . CONCLUSIONS Long-term treatment with omalizumab is safe and well tolerated in children with allergic asthma PURPOSE Patients with severe eosinophilic asthma often experience recurrent asthma exacerbations despite intensive inhaled corticosteroid therapy . In 2 previous double-blind studies ( MENSA [ NCT01691521 ] and SIRIUS [ NCT01691508 ] ) , treatment with intravenous or subcutaneous mepolizumab was associated with significantly reduced annualized exacerbation rates and oral corticosteroid ( OCS ) requirements compared with placebo . The purpose of this study was to assess the long-term safety and efficacy of subcutaneous mepolizumab treatment in patients with severe eosinophilic asthma . METHODS COSMOS was a 52-week , open-label extension study in patients who received mepolizumab or placebo in MENSA or SIRIUS . Patients received subcutaneous mepolizumab regardless of prior treatment allocation and continued to receive appropriate st and ard-of-care asthma therapy throughout . The primary objective was to assess the long-term safety of  mepolizumab ;  end points included adverse events ( AEs ) and serious AEs ( SAEs ) . Efficacy assessment s included the annualized exacerbation rate and durability of response ( defined as the exacerbation rate and OCS dose reduction when combined with MENSA and SIRIUS data , respectively ) . FINDINGS In total , 558 ( 86 % ; previous mepolizumab : 358 ; previous placebo : 200 ) and 94 ( 14 % ; previous mepolizumab : 58 , previous placebo : 36 ) patients experienced on-treatment AEs and SAEs , respectively . No fatal AEs were reported . Totals of 13 ( 2 % ) and 29 ( 4 % ) patients experienced systemic and local site reactions , respectively . There were no reports of mepolizumab-related anaphylaxis . Mepolizumab treatment was shown to exert a durable response , with patients who previously received mepolizumab in MENSA or SIRIUS maintaining reductions in exacerbation rate and OCS dosing throughout COSMOS . Patients who previously received placebo in MENSA or SIRIUS demonstrated improvements in these end points following treatment with mepolizumab in COSMOS . IMPLICATION S These data demonstrate a favorable safety profile of mepolizumab and indicate a durable and stable effect over time , supporting long-term treatment in patients with severe eosinophilic asthma . Clinical Trials.gov identifier : NCT01842607 BACKGROUND Eosinophilic inflammation is frequently associated with increased asthma severity .  Benralizumab is a humanized , afucosylated , anti-interleukin-5Rα monoclonal antibody that selectively depletes eosinophils and basophils through enhanced antibody-dependent cell-mediated cytotoxicity . OBJECTIVE To study effects of benralizumab on eosinophil counts and activity following administration to asthma patients . METHODS Sera were collected from asthma patients enrolled in two clinical studies .  Placebo or benralizumab was subcutaneously administered to patients in Phase I ( 100 or 200 mg , multiple doses ; N = 14 ; NCT00659659 ) and Phase IIa ( 25 , 100 , or 200 mg every 4 weeks ; N = 24 ; NCT00783289 ) studies . Sera were also collected from healthy volunteers ( N = 20 ) for comparison . Blood eosinophils , IL-5 , eosinophil-derived neurotoxin ( EDN ) , eosinophil cationic protein ( ECP ) , eotaxin/chemokine ( C-C motif ) 11 ( CCL11 ) , eotaxin-2/CCL24 , tumor necrosis factor ( TNF ) , and interferon-γ ( IFN-γ ) were measured at baseline and post-treatment . RESULTS Increased EDN concentrations were observed in sera of patients from both studies relative to healthy volunteers ( p < 0.05 ) . At baseline , sera EDN concentrations correlated with blood eosinophil counts ( rs = 0.5 ; p < 0.05 ) . Benralizumab reduced blood eosinophil numbers and sera EDN and ECP relative to baseline ( p < 0.05 ) . No changes in TNF or IFN-γ were observed , while serum IL-5 , eotaxin/CCL11 , and eotaxin-2/CCL24 increased after benralizumab administration vs. placebo ( p < 0.05 ) . CONCLUSIONS In two independent studies , serum IL-5 , EDN , and ECP were modulated following benralizumab . Eosinophil depletion after benralizumab also result ed in significant reductions in EDN and ECP concentrations , suggesting that cytotoxic granule proteins were not released after eosinophil reduction BACKGROUND Mepolizumab , an anti-interleukin-5 monoclonal antibody approved as add-on therapy to st and ard of care for patients with severe eosinophilic asthma , has been shown in previous studies to reduce exacerbations and dependency on oral corticosteroids compared with placebo . We aim ed to further assess mepolizumab in patients with severe eosinophilic asthma by examining its effect on health-related quality of life ( HRQOL ) . METHODS We did a r and omised , double-blind , placebo-controlled , parallel-group , multicentre , phase 3b trial ( MUSCA ) in 146 hospitals or research centres in 19 countries worldwide . Eligible participants were patients aged 12 years or older with severe eosinophilic asthma and a history of at least two exacerbations requiring treatment in the previous 12 months before screening despite regular use of high-dose inhaled corticosteroids plus other controller medicines . Exclusion criteria included current smokers or former smokers with a history of at least ten pack-years . We r and omly assigned participants ( 1:1 ) by country to receive a subcutaneous injection of either mepolizumab 100 mg or placebo , plus st and ard of care , every 4 weeks for 24 weeks ( the final dose was given at week 20 ) . We did the r and omisation using an interactive voice response system and a central ised , computer-generated , permuted-block design of block size six . The two treatments were identical in appearance and administered in a masked manner ; patients , investigators , other site staff and the entire study team including those assessing outcomes data were also masked to group assignment . The primary endpoint was the mean change from baseline in the St George 's Respiratory Question naire ( SGRQ ) total score at week 24 in the modified intention-to-treat ( modified ITT ) population ( analysed according to their r and omly assigned treatment ) . Safety was assessed in all patients who received at least one dose of trial medication ( analysed according to the actual treatment received ) . This trial is registered with Clinical Trials.gov , number NCT02281318 . FINDINGS We recruited patients between Dec 11 , 2014 , and Nov 20 , 2015 , and the study was undertaken between Dec 11 , 2014 , and June 10 , 2016 . The modified ITT population comprised 274 patients assigned to mepolizumab 100 mg and 277 assigned to placebo . Mepolizumab versus placebo showed significant improvements at week 24 from baseline in SGRQ total score ( least squares mean [ SE ] change from baseline -15·6 ( 1·0 ) vs -7·9 ( 1·0 ) , a treatment difference of -7·7 ( 95 % CI -10·5 to -4·9 ; p<0·0001 ) . No deaths occurred during the study . 192 ( 70 % ) of 273 patients who received mepolizumab and 207 ( 74 % ) of 278 who received placebo reported at least one on-treatment adverse event , the most common of which were headache ( in 45 [ 16 % ] given mepolizumab vs 59 [ 21 % ] given placebo ) and nasopharyngitis ( in 31 [ 11 % ] given mepolizumab vs 46 [ 17 % ] given placebo ) . 15 ( 5 % ) and 22 ( 8 % ) patients had an on-treatment serious adverse event in the mepolizumab and placebo groups , respectively ; the most common was asthma in both groups ( in three [ 1 % ] given mepolizumab vs nine [ 3 % ] given placebo ) . INTERPRETATION Mepolizumab was associated with significant improvements in HRQOL in patients with severe eosinophilic asthma , and had a safety profile similar to that of placebo . These results add to and support the use of mepolizumab as a favourable add-on treatment option to st and ard of care in patients with severe eosinophilic asthma . FUNDING GlaxoSmithKline BACKGROUND Findings from previous studies showed that mepolizumab significantly reduces the rate of exacerbations in patients with severe eosinophilic asthma . To assess the relationship between baseline blood eosinophil counts and efficacy of mepolizumab we did a secondary analysis of data from two studies , stratifying patients by different baseline blood eosinophil thresholds . METHODS We did a post-hoc analysis of data , which was completed on Sept 25 , 2015 , from two r and omised , double-blind , placebo-controlled studies of at least 32 weeks duration ( NCT01000506 [ DREAM ] and NCT01691521 [ MENSA ] ) done between 2009 and 2014 . In these studies , mepolizumab ( DREAM 75 mg , 250 mg , or 750 mg intravenously ; MENSA : 75 mg intravenously or 100 mg subcutaneously ) versus placebo was given at 4-week intervals in addition to st and ard care ( high-dose inhaled corticosteroids plus ≥1 additional controller with or without daily oral corticosteroids ) to patients aged 12 years or older with a clinical diagnosis of asthma , a history of at least two exacerbations in the previous year that required systemic corticosteroid treatment , and evidence of eosinophilic airway inflammation . The primary endpoint in both studies was the annual rate of clinical ly significant exacerbations ( defined as worsening of asthma that required the use of systemic corticosteroids , or admission to hospital , or an emergency-room visit , or a combination of these occurrences ) . In our analysis , the primary outcome was the annualised rate of exacerbations in patients stratified by baseline eosinophil counts ( ≥150 cells per μL , ≥300 cells per μL , ≥400 cells per μL , and ≥500 cells per μL ) and baseline blood eosinophil ranges ( < 150 cells per μL , ≥150 cells per μL to < 300 cells per μL , ≥300 cells per μL to < 500 cells per μL , and ≥500 cells per μL ) . We based our analysis on the intention-to-treat population s of the two original studies , and all mepolizumab doses were combined for analysis . FINDINGS Of 1192 patients , 846 received mepolizumab and 346 received placebo  . The overall rate of mean exacerbations per person per year was reduced from 1·91 with placebo to 1·01 with mepolizumab ( 47 % reduction ; rate ratio [ RR ] 0·53 , 95 % CI 0·44 - 0·62 ; p<0·0001 ) . The exacerbation rate reduction  with mepolizumab versus placebo increased progressively from 52 % ; 0·48 , 0·39 - 0·58 ) in patients with a baseline blood eosinophil count of at least 150 cells per μL to 70 % ; 0·30 , 0·23 - 0·40 ] ) in patients with a baseline count of at least 500 cells per μL. At a baseline count less than 150 cells per μL , predicted efficacy of mepolizumab was reduced . INTERPRETATION Our analysis has shown a close relationship between baseline blood eosinophil count and clinical efficacy of mepolizumab in patients with severe eosinophilic asthma and a history of exacerbations . We noted clinical ly relevant reductions in exacerbation frequency in patients with a count of 150 cells per μL or more at baseline . The use of this baseline biomarker will help to select patients who are likely to achieve important asthma outcomes with mepolizumab . FUNDING GlaxoSmithKline BACKGROUND The MENSA trial assessed the efficacy and safety of mepolizumab in patients with severe eosinophilic asthma . This report describes the efficacy and safety of mepolizumab in Japanese patients from MENSA . METHODS A post hoc analysis of the Japanese subgroup from the r and omized , double-blind , placebo-controlled , double-dummy , Phase III MENSA trial ( NCT01691521 ) . Patients ≥12 years with severe eosinophilic asthma received mepolizumab 75 mg intravenously ( IV ) , 100 mg subcutaneously ( SC ) , or placebo , every 4 weeks for 32 weeks . The primary endpoint was the annualized rate of exacerbations . Secondary and other endpoints included annualized rate of exacerbations requiring emergency department ( ED ) visit/hospitalization , morning peak expiratory flow ( PEF ) , St George 's Respiratory Question naire ( SGRQ ) score and eosinophil counts . Adverse events ( AEs ) were monitored . RESULTS In the Japanese subgroup ( N = 50 ) , the rate of clinical ly significant exacerbations was reduced by 90 % ( rate ratio [ RR ] : 0.10 ; 95 % confidence interval [ CI ] : 0.02 - 0.57 ; P = 0.010 ) with mepolizumab IV and 62 % ( RR : 0.38 ; 95 % CI : 0.12 - 1.18 ; P = 0.094 ) with mepolizumab SC , versus placebo . No exacerbations requiring ED visit/hospitalization were reported with mepolizumab IV ; exacerbations were reduced by 73 % ( RR : 0.27 ; 95 % CI : 0.06 - 1.29 ; P = 0.102 ) with mepolizumab SC versus placebo . Compared with placebo , mepolizumab IV and SC numerically increased morning PEF from baseline by 40 L/min and 13 L/min , improved quality of life by greater than the minimal clinical ly important difference ( SGRQ : 9.5 [ P = 0.083 ] and 7.9 [ P = 0.171 ] points ) and reduced eosinophil counts . AE incidence was similar between treatments . Results were broadly consistent with the overall population . CONCLUSIONS Mepolizumab was efficacious and well tolerated in Japanese patients with severe eosinophilic asthma , producing similar responses to the overall MENSA population BACKGROUND Eosinophilic inflammation , which may be a consequence of interleukin-5 action , is a characteristic feature of some forms of asthma . However , in three previous clinical trials involving patients with asthma , blockade of this cytokine did not result in a significant improvement in outcomes . We studied the prednisone-sparing effect of mepolizumab , a monoclonal antibody against interleukin-5 , in a rare subgroup of patients who have sputum eosinophilia and airway symptoms despite continued treatment with prednisone . Secondary objectives were to examine its effect on the number of eosinophils in sputum and blood , symptoms , and airflow limitation . METHODS In this r and omized , double-blind , parallel-group trial involving patients with persistent sputum eosinophilia and symptoms despite prednisone treatment , we assigned 9 patients to receive mepolizumab ( administered in five monthly infusions of 750 mg each ) and 11 patients to receive  placebo . RESULTS There were 12 asthma exacerbations in 10 patients who received placebo , 9 of whom had sputum eosinophilia at the time of exacerbation . In comparison , only one patient who received mepolizumab had an asthma exacerbation , and this episode was not associated with sputum eosinophilia ( P=0.002 ) . Patients who received mepolizumab were able to reduce their prednisone dose by a mean ( + /-SD ) of 83.8+/-33.4 % of their maximum possible dose , as compared with 47.7+/-40.5 % in the placebo group ( P=0.04 ) . The use of mepolizumab was associated with a significant decrease in the number of sputum and blood eosinophils . Improvements in eosinophil numbers , asthma control , and forced expiratory volume in 1 second were maintained for 8 weeks after the last infusion . There were no serious adverse events . CONCLUSIONS Mepolizumab reduced the number of blood and sputum eosinophils and allowed prednisone sparing in patients who had asthma with sputum eosinophilia despite prednisone treatment . ( Clinical Trials.gov number , NCT00292877 . Background : Omalizumab has been shown to suppress responses to inhaled allergens in allergic asthma patients with pretreatment immunoglobulin E ( IgE ) ≤700 IU/ml . To extend current dosing tables , we evaluated the potential of high omalizumab doses to block allergen-induced bronchoconstriction in patients with higher IgE levels . Methods : Asthmatic adults ( 18–65 years ; body weight 40–150 kg ) were divided into groups according to screening IgE ( group 1 : 30–300 IU/ml ; group 2 : 700–2,000 IU/ml ) and r and omized 2:1 to omalizumab/placebo every 2 or 4 weeks for 12–14 weeks . Allergen bronchoprovocation ( ABP ) testing was performed before treatment and at weeks 8 and 16 . The primary efficacy endpoint , the early-phase allergic response ( EAR ) , was defined as the maximum percentage drop in forced expiratory volume in 1 s during the first 30 min after ABP . Serum free IgE was determined as a pharmacodynamic endpoint , and the exhaled fractional concentration of nitric oxide ( FENO ) was an exploratory endpoint . Results : Fifty patients were included in the study . Omalizumab  improved EAR ; at week 8 , EAR was 23.1 % for placebo , 9.3 % in group 1 ( p = 0.018 versus placebo ) and 5.6 % in group 2 ( p < 0.001 ) . At week 16 , EAR was 20 % , 11.8 % ( p = 0.087 ) and 5.1 % ( p < 0.001 ) , respectively . Free IgE decreased in groups 1 and 2 and remained < 50 ng/ml in all patients during weeks 6–16  . Omalizumab  completely suppressed FENO increases after ABP in both groups . Conclusions : Omalizumab blocked early asthmatic responses over a broad range of IgE/body weight combinations . Extending the dosing tables enables omalizumab to benefit a wider range of patients BACKGROUND In a 1-year , r and omized , open-label study in patients with moderate-to-severe allergic ( immunoglobulin E (IgE)-mediated ) asthma , adding omalizumab to best st and ard care ( BSC ) significantly improved efficacy outcomes compared with BSC alone ( control ) . We assessed the efficacy of omalizumab in the subgroup of patients with inadequately controlled severe persistent allergic asthma despite high-dose inhaled corticosteroids ( ICS ) plus a long-acting beta(2)-agonist ( LABA ) , which reflects the European Union ( EU ) label population . METHODS Efficacy outcomes included annual asthma exacerbation rate , annual asthma deterioration-related incident ( ADRI ) rate , % predicted forced expiratory volume in 1 s ( FEV(1 ) ) , asthma symptoms ( Wasserfallen score ) and quality of life ( Mini Asthma Quality of Life Question naire ( Mini-AQLQ ) ) , which were compared in the omalizumab and control groups . Outcomes were also determined for omalizumab-treated patients judged to have responded to therapy ( > or = 0.5-point improvement in Mini-AQLQ overall score at 27 weeks ) . RESULTS In total , 164 patients ( omalizumab , n=115 ; control , n=49 ) were receiving high-dose ICS plus a LABA .  Annual asthma exacerbation rate was significantly reduced by 59 % in the omalizumab group vs. control ( 1.26 vs. 3.06 ; P<0.001 ) . ADRI rate was significantly reduced by 40 % in the omalizumab group compared with control ( 5.61 vs. 9.40 ; P<0.05 ) . Significant improvements were also seen in % predicted FEV(1 ) ( 71 % vs. 60 % ; P<0.001 ) , change from baseline in asthma symptom scores ( -6.7 vs. 0.5 ; P<0.05 ) and Mini-AQLQ overall score ( 1.32 vs. 0.17 ; P<0.001 ) . In omalizumab-treated patients , 71/102 ( 70 % ) were judged to have responded to therapy . In these Mini-AQLQ-assessed responders , exacerbation rate was reduced by 64 % vs. control ( 1.12 vs. 3.06 ; P<0.001 ) , ADRI rate was reduced by 50 % vs. control ( 4.71 vs. 9.40 ; P<0.01 ) . Percent predicted FEV(1 ) ( 73 % vs. 60 % ; P<0.001 ) , change from baseline in asthma symptom scores ( -8.1 vs. 0.5 ; P<0.001 ) and Mini-AQLQ overall score ( 1.81 vs. 0.17 ; P<0.001 ) were also further significantly improved vs. control . CONCLUSIONS Adding omalizumab to BSC is efficacious in patients with inadequately controlled severe persistent allergic asthma despite high-dose ICS plus a LABA ( EU label population ) , with further efficacy observed in patients judged to have responded to therapy which may more accurately illustrate the actual benefit of omalizumab therapy in clinical practice . The naturalistic setting of this study confirms the benefits observed in double-blind r and omized clinical trials Background : Omalizumab may inhibit allergic inflammation and could contribute to decreasing airway remodeling in patients with asthma . Objective : The aim of this study was to assess the effects of omalizumab on airway wall thickness using computed tomography ( CT ) . Methods : Thirty patients with severe persistent asthma were r and omized to conventional therapy with ( n = 14 ) or without omalizumab ( n = 16 ) for 16 weeks . The following airway dimensions were assessed by a vali date d CT technique : airway wall area corrected for body surface area ( WA/BSA ) , percentage wall area ( WA% ) , wall thickness (T)/√BSA , and luminal area (Ai)/BSA at the right apical segmental bronchus . The percentage of eosinophils in induced sputum , pulmonary function and the Asthma Quality of Life Question naire ( AQLQ ) were assessed as well . Results : Treatment with omalizumab significantly decreased WA/BSA ( p < 0.01 ) , WA% ( p < 0.01 ) , and T/√BSA ( p < 0.01 ) , and increased Ai/BSA ( p < 0.05 ) , whereas conventional therapy result ed in no change . In the omalizumab group ( n = 14 ) , a significant decrease in the percentage of sputum eosinophils ( p < 0.01 ) , improved forced expiratory volume in 1 s ( FEV1 ) , and an improved AQLQ score were recorded . The changes in FEV1 % predicted and sputum eosinophils were significantly correlated with changes in WA% ( r = 0.88 , p < 0.001 , and r = 072 , p < 0.01 , respectively ) . Conclusions : These findings suggest that omalizumab  reduced airway wall thickness and airway inflammation . Larger patient studies with longer-term follow-up are needed to show whether omalizumab can truly maintain improved airway wall dimensions Background Pre clinical studies suggest that interleukin-9 may be a central mediator in the development and maintenance of airway inflammation in asthma . The aim of this study was therefore to evaluate the effects of MEDI-528 , an anti-interleukin-9 monoclonal antibody , in adults with confirmed uncontrolled moderate-to-severe asthma . Methods In this prospect i ve double-blind , multicenter , parallel-group study , 329 subjects were r and omized ( 1:1:1:1 ) to subcutaneous placebo or MEDI-528 ( 30 , 100 , 300 mg ) every 2 weeks for 24 weeks , in addition to their usual asthma medications . The primary endpoint was change in mean Asthma Control Question naire-6 ( ACQ-6 ) score at week 13 . Secondary endpoints included weighted asthma exacerbation rates and pre-bronchodilator forced expiratory volume in 1 second ( FEV1 ) at weeks 13 and 25 , as well as Asthma Quality of Life Question naire scores at weeks 12 and 25 and the safety of MEDI-528 throughout the study period . The primary endpoint was analyzed using analysis of covariance . Results The study population ( n = 327 ) was predominantly female ( 69 % ) with a mean age of 43 years ( range 18–65 ) . The mean ( SD ) baseline ACQ-6 score  for placebo ( n = 82 ) and combined MEDI-528 ( n = 245 ) was 2.8 ( 0.7 ) and 2.8 ( 0.8 ) ; FEV1 % predicted was 70.7 % ( 15.9 ) and 71.5 % ( 16.7 ) . Mean ( SD ) change from baseline to week 13 in ACQ-6 scores for placebo vs combined MEDI-528 groups was −1.2 ( 1.0 ) vs −1.2 ( 1.1 ) ( p = 0.86 ) . Asthma exacerbation rates ( 95 % CI ) at week 25 for placebo vs MEDI-528 were 0.58 ( 0.36–0.88 ) vs 0.49 ( 0.37–0.64 ) exacerbations/subject/year ( p = 0.52 ) . No significant improvements in FEV1 % predicted were observed between the placebo and MEDI-528 groups . Adverse events were comparable for placebo ( 82.9 % ) and MEDI-528 groups ( 30 mg , 76.5 % ; 100 mg , 81.9 % ; 300 mg , 85.2 % ) . The most frequent were asthma ( placebo vs MEDI-528 , 30.5 % vs 33.5 % ) , upper respiratory tract infection ( 14.6 % vs 17.1 % ) , and headache ( 9.8 % vs 9.8 % ) . Conclusions The addition of MEDI-528 to existing asthma controller medications was not associated with any improvement in ACQ-6 scores , asthma exacerbation rates , or FEV1 values , nor was it associated with any major safety concerns . Trial registration Clinical Trials.gov : NCT00968669 A humanized murine monoclonal antibody directed to the Fc epsilonR1-binding domain of human IgE ( rhuMAb-E25 ) has been shown to inhibit the binding of IgE to mast cells without provoking mast cell activation . To examine the effects of neutralizing IgE on allergic airway responses , we assessed the effects of 9 wk of treatment with rhuMAb-E25 in a parallel group , r and omized , double-blind ,  placebo-controlled study of 19 allergic asthmatic subjects . We found that treatment with rhuMAb-E25 reduced serum IgE , increased the dose of allergen needed to provoke an early asthmatic response , reduced the mean maximal fall in FEV1 during the early response ( 30 + /- 10 % at baseline to 18.8 + /- 8 % , versus 33 + /- 8 % at baseline to 34 + /- 4 % after placebo ; p = 0.01 ) , and reduced the mean maximal fall in FEV1 during the late response ( 24 + /- 20 % at baseline to 9 + /- 10 % versus 20 + /- 17 % at baseline to 18 + /- 17 % after placebo ; p = 0.047 ) . We conclude that an anti-IgE monoclonal antibody , which inhibits binding of IgE to its receptor , suppresses the early- and late-phase responses to inhaled allergen in allergic asthmatic subjects . Targeting IgE with rhuMAb-E25 might be a useful treatment for allergic asthma BACKGROUND Thymic stromal lymphopoietin ( TSLP ) is an epithelial-cell-derived cytokine that may be important in initiating allergic inflammation . AMG 157 is a human anti-TSLP monoclonal immunoglobulin G2λ that binds human TSLP and prevents receptor interaction . METHODS In this double-blind , placebo-controlled study , we r and omly assigned 31 patients with mild allergic asthma to receive three monthly doses of AMG 157 ( 700 mg ) or placebo intravenously . We conducted allergen challenges on days 42 and 84 to evaluate the effect of AMG 157 in reducing the maximum percentage decrease in the forced expiratory volume in 1 second ( FEV1 ) . We also measured the fraction of nitric oxide in exhaled air , blood and sputum eosinophils , and airway hyperresponsiveness . The primary end point was the late asthmatic response , as measured 3 to 7 hours after the allergen challenge . RESULTS AMG 157 attenuated most measures of allergen-induced early and late asthmatic responses . The maximum percentage decrease in the FEV1 during the late response was 34.0 % smaller in the AMG-157 group than in the placebo group on day 42 ( P=0.09 ) and 45.9 % smaller on day 84 ( P=0.02 ) . In addition , patients receiving AMG 157 had significant decreases in levels of blood and sputum eosinophils before and after the allergen challenge and in the fraction of exhaled nitric oxide . There were 15 adverse events in the AMG-157 group , as compared with 12 in the placebo group ; there were no serious adverse events . CONCLUSIONS Treatment with AMG 157  reduced allergen-induced bronchoconstriction and indexes of airway inflammation before and after allergen challenge . These findings are consistent with a key role for TSLP in allergen-induced airway responses and persistent airway inflammation in patients with allergic asthma . Whether anti-TSLP therapeutics will have clinical value can not be determined from these data . ( Funded by Amgen ; Clinical Trials.gov number , NCT01405963 . ) Inhaled allergens , acting through IgE-dependent mechanisms , are important triggers of asthma symptoms and inducers of airway hyperresponsiveness and airway inflammation . The effect of anti-IgE recombinant humanized monoclonal antibody-E25 ( rhuMAb-E25 ) on the provocation concentration of allergen causing a 15 % fall in FEV1 ( allergen PC15 ) during the allergen-induced early asthmatic response ( EAR ) was assessed in a multicenter , r and omized , double-blind , parallel group study . Ten of 11 allergic asthmatic subjects r and omized to receive intravenous rhuMAb-E25 , 2 mg/kg on study day 0 and 1 mg/kg on Days 7 , 14 , 28 , 42 , 56 , and 70 completed the study ; nine received intravenous placebo . The allergen PC15 was measured on Days -1 , 27 , 55 , and 77 and methacholine PC20 on Days -2 , 42 , and 76 . rhuMAb-25 was well tolerated and only one patient ( active group ) was withdrawn because of a generalized urticarial rash after the first dose . Compared with baseline values ( Day -1 ) , the median allergen PC15 on Days 27 , 55 , and 77 were increased by 2.3 , 2.2 , and 2.7 doubling doses ( delta log PC15/0.3 ) respectively with rhuMAb-E25 and -0.3 , + 0.1 , and -0.8 doubling doses with placebo ( p < or = 0.002 ) . Methacholine PC20 improved slightly after rhuMAb-E25 , this change becoming statistically significant on Day 76 ( p < 0.05 ) ; no change was observed in the placebo group . Mean serum-free IgE fell by 89 % after rhuMAb-E25 while there was no significant change after placebo . The inhibitory effects of rhuMAb-E25 on allergen-induced EAR suggest that it may be an effective , novel antiallergic treatment for asthma Background : Anti‐IgE therapy could be particularly beneficial for patients with concomitant disease as it targets a common factor in both diseases . The aim of this study was to evaluate the efficacy and safety of omalizumab in patients with concomitant moderate‐to‐severe asthma and persistent allergic rhinitis The clinical benefit and steroid-sparing effect of treatment with the anti-immunoglobulin-E ( IgE ) antibody , omalizumab , was assessed in patients with moderate-to-severe allergic asthma . After a run-in period , 546 allergic asthmatics ( aged 12 - 76 yrs ) , symptomatic despite inhaled corticosteroids ( 500 - 1,200 microg daily of beclomethasone dipropionate )  , were r and omized to receive double-blind either placebo or omalizumab every 2 or 4 weeks ( depending on body weight and serum total IgE ) subcutaneously for 7 months . A constant beclomethasone dose was maintained during a 16-week stable-steroid phase and progressively reduced to the lowest dose required for asthma control over the following 8 weeks . The latter dose was maintained for the next 4 weeks . Asthma exacerbations represented the primary variable . Compared to the placebo group , the omalizumab group showed 58 % fewer exacerbations per patient during the stable-steroid phase ( p<0.001 ) . During the steroid-reduction phase , there were 52 % fewer exacerbations in the omalizumab group versus the placebo group ( p<0.001 ) despite the greater reduction of the beclomethasone dosage on omalizumab ( p<0.001 ) . Treatment with omalizumab was well tolerated . The incidence of adverse events was similar in both groups . These results indicate that omalizumab therapy safely improves asthma control in allergic asthmatics who remain symptomatic despite regular use of inhaled corticosteroids and simultaneous reduction in corticosteroid requirement BACKGROUND Interleukin-5 ( IL-5 ) is essential for the formation of eosinophils , which are thought to have a major role in the pathogenesis of asthma and other allergic diseases . We aim ed to assess the effects of monoclonal antibody to IL-5 on blood and sputum eosinophils , airway hyper-responsiveness , and the late asthmatic reaction to inhaled allergen in patients with mild asthma . METHODS We did a double-blind r and omised placebo-controlled trial , in which a single intravenous infusion of humanised ( IgG-K ) monoclonal antibody to IL-5 ( SB-240563 ) was given at doses of 2.5 mg/kg ( n=8 ) or 10.0 mg/kg ( n=8 ) . The effects of treatment on responses to inhaled allergen challenge , sputum eosinophils , and airway hyper-responsiveness to histamine were measured at weeks 1 and 4 with monitoring of blood eosinophil counts for up to 16 weeks . FINDINGS Monoclonal antibody against IL-5 lowered the mean blood eosinophil count at day 29 from 0.25x10(9)/L ( 95 % CI 0.16 - 0.34 ) in the placebo group to 0.04x10(9)/L ( 0.00 - 0.07 ) in the 10 mg/kg group ( p<0.0001 ) , and prevented the blood eosinophilia that follows allergen challenge . After inhaled allergen challenge , 9 days after treatment , the percentage sputum eosinophils were 12.2 % in the placebo group and lowered to 0.9 % ( -1.2 to 3.0 ; p=0.0076 ) in the 10 mg/kg group , and this effect persisted at day 30 after the dose . There was no significant effect of monoclonal antibody to IL-5 on the late asthmatic response or on airway hyper-responsiveness to histamine . INTERPRETATION A single dose of monoclonal antibody to IL-5 decreased blood eosinophils for up to 16 weeks and sputum eosinophils at 4 weeks , which has considerable therapeutic potential for asthma and allergy . However , our findings question the role of eosinophils in mediating the late asthmatic response and causing airway hyper-responsiveness Abstract Background : Long-term oral corticosteroid ( OCS ) therapy and related adverse events are associated with a significant burden on patients and healthcare re sources . Methods : This subgroup analysis of a r and omized , open-label , parallel-group study evaluated the OCS-sparing effect of omalizumab ( OMA ) added to optimized asthma therapy ( OAT ) , compared with OAT alone .  Patients ( 12–75 years ) with severe allergic asthma , uncontrolled despite GINA 2004 Step 4 therapy , received  OMA or OAT for 32 weeks . The change from baseline in OCS use by Week 32 in patients requiring maintenance OCS at baseline was assessed in terms of percent OCS dose change and numbers of patients with reduced/stopped or maintained/increased OCS . Results : Eighty-two patients were receiving maintenance OCS at baseline ( OMA/OAT n = 59 , OAT n = 23 ) . Change from baseline in mean maintenance OCS dose at Week 32 was significantly greater in the OMA/OAT group compared with the OAT group ( −45 % vs. + 18.3 % , p = 0.002 ) . In the OMA/OAT group , 37 patients ( 62.7 % ) reduced/stopped OCS use at Week 32 , compared with seven patients ( 30.4 % ) receiving OAT ( p = 0.013 ) . Improvements in other efficacy outcomes were seen at Week 32 in the OMA/OAT group , irrespective of OCS use . An investigator global evaluation of treatment effectiveness at Week 16 was an effective predictor of persistent treatment response at 32 weeks for the majority of OMA/OAT patients ( 93 % ) , also irrespective of OCS use . Conclusion : In this open-label study of patients with severe allergic asthma  , OMA/OAT therapy  reduced maintenance OCS use , compared with OAT alone . Improvements in efficacy measures were observed in the OMA/OAT group , irrespective of OCS change . Clinical trials.gov identifier : NCT00264849 Background IL-13 has been implicated in the development of airway inflammation and hyperresponsiveness . This study investigated the multiple-dose pharmacokinetics and safety profile of human anti-IL-13 antibody ( CAT-354 ) in adults with asthma . Methods This was a multiple-dose , r and omised , double-blind , placebo-controlled phase 1 study in asthmatics ( forced expiratory volume in 1 second [ FEV1 ] ≥ 80 % predicted ) . Subjects were r and omised to receive three intravenous infusions of CAT-354 ( 1 mg/kg , 5 mg/kg or 10 mg/kg ) or placebo at 28-day intervals . Blood sample s were taken for pharmacokinetic measurements . Safety was assessed by adverse events , vital signs , ECGs , laboratory and pulmonary function parameters . Results Twenty-three subjects ( aged 21 - 60 years , FEV1 88 - 95 % predicted ) received ≥ 1 dose of study medication . The half-life of CAT-354 was 12 - 17 days and was dose-independent . The maximum serum concentration and area under the curve were dose-dependent . Clearance ( 2.2 - 2.6 mL/day/kg ) and volume of distribution ( 44 - 57 mL/kg ) were both low and dose-independent . The observed maximum serum concentration after each dose increased slightly from dose 1 through dose 3 at all dose levels , consistent with an accumulation ratio of 1.4 to 1.7 for area under the curve . Most adverse events were deemed mild to moderate and unrelated to study medication . One SAE was reported and deemed unrelated to study drug . There were no effects of clinical concern for vital signs , ECG , laboratory or pulmonary parameters . Conclusions CAT-354 exhibited linear pharmacokinetics and an acceptable safety profile . These findings suggest that at the doses tested , CAT-354 can be safely administered in multiple doses to patients with asthma . Trial registration NCT00974675 Influx of eosinophils in airway mucosa and airway lumen is a hallmark of bronchial asthma . In-vitro data and animal studies indicate that the T‐helper ( Th ) type‐2 cell cytokine , interleukin (IL)‐5 , plays an important role in eosinophil maturation , differentiation , recruitment , and survival . The objective of this study was to determine whether intravenous treatment with monoclonal anti-IL‐5 would affect the number of peripheral blood eosinophils , their activation status , T‐cell activation or the pattern of Th1 and Th2 cytokine production . Over a period of 6 months , 19 asthmatics were investigated in a double-blind , placebo-controlled , multicentre study with mepolizumab ( SB 240563 ) anti-IL‐5 antibody administered three times . Before each infusion and 12 weeks after the last infusion , peripheral blood leukocytes were examined , qualitative and quantitative distribution of eosinophils and lymphocyte sub population s , frequencies of IL‐2 , ‐3 , ‐4 , ‐5 , -10 , -13 , interferon‐γ‐producing CD4 T‐cells and serum eosinophil cationic protein ( ECP ) levels were determined . Treatment with mepolizumab result ed in a marked , rapid and sustained decrease of eosinophil numbers ( median values from 300 to 45 per µL ) paralleled by decreased levels of serum ECP ( median values from 15 to 5 µg·L−1 ) . Distribution of T‐cell subsets and T‐cell cytokine production were not altered during antibody treatment . In conclusion , administration of mepolizumab to asthmatic patients  markedly reduces peripheral blood eosinophils without altering the distribution and activation status of lymphocytes STUDY OBJECTIVES To develop simple clinical tools predictive of acute asthma care and to identify modifiable risk factors . DESIGN Prospect i ve cohort study . SETTING A large health maintenance organization ( 430,000 members ) . PATIENTS / PARTICIPANTS Adult members ( 18 to 55 years old ) with asthma . INTERVENTIONS Data from a question naire , skin-prick testing for inhalant allergens , and spirometry were collected at the baseline visit . Acute care utilization data were obtained from administrative data bases for a subsequent 30-month period . METHODS This two-phase study first identified and performed a split- sample validation on three clinical tools to determine their predictive ability by employing data from a question naire , question naire plus spirometry , and question naire plus spirometry and skin-prick testing . Second , it identified modifiable independent risk factors . MEASUREMENTS AND RESULTS The 554 study participants generated 173 episodes of acute care over 1,258 person-years of follow-up ( 0.14 episodes per person per year ) . Of these , 101 participants had at least one episode , and one third of this group had two or more episodes . Clinical scoring into risk groups was done by reverse stepwise regression analyses . Using relative risks ( RRs ) as a guide , high-risk , moderate-risk , and low-risk groups were identified . The high-risk groups , 13 to 21 % of the validation sample , had a 7- to 11-fold increased risk for hospital care compared to the low-risk groups . The moderate-risk groups , 46 to 50 % of the validation sample , had a twofold- to fourfold-increased risk . FEV(1 ) was the most significant predictor ( RR , 4.33 ) . Of the four potentially modifiable risk factors identified , current cigarette smoke exposure ( RR , 1.6 ) and ownership and skin-prick test positivity to cat or dog ( RR , 1.5 ) were the most significant . CONCLUSIONS These models stratify asthma patients at risk for acute care . Patients with lower FEV(1 ) values are at significantly higher risk , underscoring the importance of spirometry in asthma care Introduction In a subset of patients with asthma , st and ard-of-care treatment does not achieve disease control , highlighting the need for novel therapeutic approaches . Lebrikizumab is a humanised , monoclonal antibody that binds to and blocks interleukin-13 activity . Methods LUTE and VERSE were replicate , r and omised , double-blind , placebo-controlled studies , evaluating multiple doses of lebrikizumab in patients with uncontrolled asthma despite the use of medium-to-high-dose inhaled corticosteroid and a second controller . Patients received lebrikizumab 37.5  , 125 , 250 mg or placebo subcutaneously every four weeks . The primary endpoint was the rate of asthma exacerbations during the placebo-controlled period . Analyses were performed on prespecified subgroups based on baseline serum periostin levels . Following the discovery of a host-cell impurity in the study drug material , protocol s were amended to convert from phase III to phase IIb . Subsequently , dosing of study medication was discontinued early as a pre caution ary measure . The data collected for analysis were from a placebo-controlled period of variable duration and pooled across both studies . Results The median duration of treatment was approximately 24 weeks . Treatment with lebrikizumab reduced the rate of asthma exacerbations , which was more pronounced in the periostin-high patients ( all doses : 60 % reduction ) than in the periostin-low patients ( all doses : 5 % reduction ) ; no dose – response was evident . Lung function also improved following lebrikizumab treatment , with greatest increase in FEV1 in periostin-high patients ( all doses : 9.1 % placebo-adjusted improvement ) compared with periostin-low patients ( all doses : 2.6 % placebo-adjusted improvement ) . Lebrikizumab was well tolerated and no clinical ly important safety signals were observed . Conclusions These data are consistent with , and extend , previously published results demonstrating the efficacy of lebrikizumab in improving rate of asthma exacerbations and lung function in patients with moderate-to-severe asthma who remain uncontrolled despite current st and ard-of-care treatment . Trial registration numbers The LUTE study was registered under NCT01545440 and the VERSE study under NCT01545453 at http://www . clinical To investigate the role of blocking antibodies in allergen immunotherapy ( IT ) , we analyzed IgE , IgG , and IgG subclass 1 to 4 antibody responses to ryegrass group I antigen ( RGGI ) in a prospect i ve double-blind , heterologous allergen , allergen-controlled trial of grass-pollen IT in 18 adults with seasonal rhinitis and asthma . Serum was assayed preseasonally before starting IT and again in midseason at time of documented highest natural exposure . Antibodies were measured by ELISA , and immunogenic specificities of ryegrass extract were examined by Western immunoblots .  Nine subjects receiving grass-pollen IT and nine control subjects had similar clinical and immunologic status before IT .  RGGI-specific IgE antibodies ( sIgE ) did not change from pretreatment levels in actively treated subjects but increased in control subjects ( p less than 0.002 ) . RGGI sIgG increased approximately thirteen-fold with active IT versus threefold during natural seasonal exposure ( p less than 0.0005 ) . The IgG-blocking response to RGGI was restricted to IgG1 and IgG4 . Ten nonatopic subjects had similar RGGI sIgG1 but lower or undetectable sIgE and sIgG4 than the 18 atopic study subjects . Active IT dramatically increased RGGI sIgG4 ( p less than 0.001 ) and to a lesser extent RGGI sIgG1 ( p less than 0.01 ) . Immunoblots demonstrated eight IgE-binding ryegrass-polypeptide allergens , with RGGI ubiquitous , and 11 IgG-binding polypeptides , including all eight allergens . A negative correlation between seasonal rhinitis symptom-medication scores and RGGI sIgG1 levels was found ( r = -0.62 , p less than 0.01 ) , but no other immunologic parameters assayed were related to clinical improvement . Although RGGI sIgG4 predominates in the blocking response and is a useful marker of effective IT , early beneficial biologic effects may involve IgG1 antibodies RATIONALE T-helper type 2 ( Th2 ) inflammation , mediated by IL-4 , IL-5 , and IL-13 , is considered the central molecular mechanism underlying asthma , and Th2 cytokines are emerging therapeutic targets . However , clinical studies increasingly suggest that asthma is heterogeneous . OBJECTIVES To determine whether this clinical heterogeneity reflects heterogeneity in underlying molecular mechanisms related to Th2 inflammation . METHODS Using microarray and polymerase chain reaction analyses of airway epithelial brushings from 42 patients with mild-to-moderate asthma and 28 healthy control subjects , we classified subjects with asthma based on high or low expression of IL-13-inducible genes . We then vali date d this classification and investigated its clinical implication s through analyses of cytokine expression in bronchial biopsies , markers of inflammation and remodeling , responsiveness to inhaled corticosteroids , and reproducibility on repeat examination . MEASUREMENTS AND MAIN RESULTS Gene expression analyses identified two evenly sized and distinct subgroups , " Th2-high " and " Th2-low " asthma ( the latter indistinguishable from control subjects ) . These subgroups differed significantly in expression of IL-5 and IL-13 in bronchial biopsies and in airway hyperresponsiveness , serum IgE , blood and airway eosinophilia , subepithelial fibrosis , and airway mucin gene expression ( all P < 0.03 ) . The lung function improvements expected with inhaled corticosteroids were restricted to Th2-high asthma , and Th2 markers were reproducible on repeat evaluation . CONCLUSIONS Asthma can be divided into at least two distinct molecular phenotypes defined by degree of Th2 inflammation . Th2 cytokines are likely to be a relevant therapeutic target in only a subset of patients with asthma . Furthermore , current models do not adequately explain non-Th2-driven asthma , which represents a significant proportion of patients and responds poorly to current therapies RATIONALE Airway inflammation in asthma is associated with increased activated CD25(+ ) T cells , IL-2 , and soluble IL-2 receptors ( IL-2Rs ) . OBJECTIVES A r and omized , double-blinded , placebo-controlled study was used to evaluate the safety and efficacy of daclizumab , a humanized IgG1 monoclonal antibody against the IL-2R alpha chain ( CD25 ) of activated lymphocytes , in adults with moderate to severe persistent asthma . METHODS Patients with obstructive pulmonary functions , despite inhaled corticosteroids ( ICS ) , were switched to equivalent dose inhaled triamcinolone acetate acetonide ( TAA ) .  Patients dependent on ICS were r and omized ( 3:1 ) to daclizumab ( intravenous loading dose , 2 mg/kg , then 1 mg/kg ) or placebo every 2 weeks , added to stable-dose TAA through Week 12 ( Treatment Period 1 ) . Over Weeks 12 - 20 ( Treatment Period 2 ) , patients tapered TAA while on the study drug , and were followed for 16 weeks off the study drug . MEASUREMENTS AND MAIN RESULTS Among 115 evaluable patients ( 88 daclizumab , 27 placebo ) , groups had similar age , disease duration , and length of ICS use .  During Treatment Period 1 , daclizumab improved FEV(1 )  ( daclizumab , 4.4 + /- 1.80 % vs. placebo , 1.5 + /- 2.39 % ; P = 0.05 ) , and reduced daytime asthma symptoms ( P = 0.018 ) and short-acting inhaled beta(2)-agonist use ( P = 0.009 ) . Daclizumab treatment prolonged time to exacerbation ( P = 0.024 ) . Adverse events were evenly distributed between groups , although there were more serious adverse events in the patients treated with daclizumab . CONCLUSIONS Daclizumab improved pulmonary function and asthma control in patients with moderate to severe chronic asthma inadequately controlled on ICS . The mechanism of action likely involves inhibition of proinflammatory cytokine generation by IL-2R blockade in activated T cells . Clinical trial registered with www . clinical trials.gov ( NCT00028288 ) Sublingual‐swallow immunotherapy ( SLIT ) using high doses of st and ardized allergen extracts has been found to be effective in reducing allergic symptoms and medication needs . A double‐blind , placebo‐controlled study was carried out in a large number of patients to determine whether medication needs can be reduced by SLIT . Some 136 patients with grass‐pollen rhinitis with or without mild asthma were studied . Patients received either placebo or SLIT with a st and ardized grass‐pollen extract administered daily with increasing doses up to 300 IR ( index of reactivity ) from January to the end of July 1994 . During the grass‐pollen season , patients were instructed to use medications as required and to visit their doctors in case of asthma . Symptom‐medications scores were assessed during the pollen season , and serum‐specific IgG4 was measured before and at the end of SLIT . In the SLIT group , drug consumption dropped significantly throughout the pollen season ( P<0.02 ) . Moreover , at the peak of the pollen season , betamethasone consumption was significantly reduced in the SLIT group ( P<0.02 ) . Only one patient in the SLIT group had an asthma attack compared to eight patients in the placebo group ( P<0.02 ) . IgG4 levels increased significantly in the SLIT group ( P<0.001 ) but without correlation with symptoms . Side‐effects were comparable in both groups . This study indicates that SLIT in grass‐pollen rhinitis is well tolerated , improves overall clinical symptoms , and reduces drug consumption and the need for oral corticosteroids BACKGROUND Some patients with severe asthma have frequent exacerbations associated with persistent eosinophilic inflammation despite continuous treatment with high-dose inhaled glucocorticoids with or without oral glucocorticoids . METHODS In this r and omized , double-blind , double-dummy study , we assigned 576 patients with recurrent asthma exacerbations and evidence of eosinophilic inflammation despite high doses of inhaled glucocorticoids to one of three study groups . Patients were assigned to receive mepolizumab , a humanized monoclonal antibody against interleukin-5 , which was administered as either a 75-mg intravenous dose or a 100-mg subcutaneous dose , or placebo every 4 weeks for 32 weeks . The primary outcome was the rate of exacerbations . Other outcomes included the forced expiratory volume in 1 second ( FEV1 ) and scores on the St. George 's Respiratory Question naire ( SGRQ ) and the 5-item Asthma Control Question naire ( ACQ-5 ) . Safety was also assessed . RESULTS The rate of exacerbations was reduced by 47 % ( 95 % confidence interval [ CI ] , 29 to 61 ) among patients receiving intravenous mepolizumab and by 53 % ( 95 % CI , 37 to 65 ) among those receiving subcutaneous mepolizumab , as compared with those receiving placebo ( P<0.001 for both comparisons ) . Exacerbations necessitating an emergency department visit or hospitalization were reduced by 32 % in the group receiving intravenous mepolizumab and by 61 % in the group receiving subcutaneous mepolizumab . At week 32 , the mean increase from baseline in FEV1 was 100 ml greater in patients receiving intravenous mepolizumab than in those receiving placebo ( P=0.02 ) and 98 ml greater in patients receiving subcutaneous mepolizumab than in those receiving placebo ( P=0.03 ) . The improvement from baseline in the SGRQ score was 6.4 points and 7.0 points greater in the intravenous and subcutaneous mepolizumab groups , respectively , than in the placebo group ( minimal clinical ly important change , 4 points ) , and the improvement in the ACQ-5 score was 0.42 points and 0.44 points greater in the two mepolizumab groups , respectively , than in the placebo group ( minimal clinical ly important change , 0.5 points ) ( P<0.001 for all comparisons ) . The safety profile of mepolizumab was similar to that of placebo . CONCLUSIONS Mepolizumab administered either intravenously or subcutaneously significantly reduced asthma exacerbations and was associated with improvements in markers of asthma control . ( Funded by GlaxoSmithKline ; MENSA Clinical Trials.gov number , NCT01691521 . ) Lymphocyte stimulation , as determined by incorporation of thymidine , to rye grass extract in twenty‐three children with bronchial reactivity to rye grass and to house dust mite , did not differ significantly from four children with reactivity to house dust mite alone , or from nine children with asthma but without a bronchial response to these allergens . Sixteen children underwent  hyposensitization with rye grass extract or treatment with placebo . There was no consistent effect of hyposensitization on the lymphocyte stimulation indices to rye grass . A decrease in lymphocyte responsiveness occurred to rye grass and to house dust mite after the grass pollen season but was not statistically significant . Analysis of changes in lymphocyte responsiveness to both house dust mite and rye grass of the children most highly sensitized to rye allergen , showed that the lymphocyte responsiveness to rye grass fell during the pollen season ( P<0.05 ) but this effect was not seen with house dust mite . The study suggests that a decrease in lymphocyte responsiveness to rye grass allergen in children with large amounts of anti‐rye IgE antibodies is antigen specific and may be seen following seasonal exposure RATIONALE Accumulation of eosinophils in the bronchial mucosa of individuals with asthma is considered to be a central event in the pathogenesis of asthma . In animal models , airway eosinophil recruitment and airway hyperresponsiveness in response to allergen challenge are reduced by specific targeting of interleukin-5 . A previous small dose-finding study found that mepolizumab , a humanized anti-interleukin-5 monoclonal antibody , had no effect on allergen challenge in humans . OBJECTIVES To investigate the effect of three intravenous infusions of mepolizumab , 250 or 750 mg at monthly intervals , on clinical outcome measures in 362 patients with asthma experiencing persistent symptoms despite inhaled corticosteroid therapy ( 400 - 1,000 mug of beclomethasone or equivalent ) . METHODS Multicenter , r and omized , double-blind , placebo-controlled study . MEASUREMENTS AND MAIN RESULTS Morning peak expiratory flow , forced expiratory volume in 1 second , daily beta(2)-agonist use , symptom scores , exacerbation rates , and quality of life measures . Sputum eosinophil levels were also measured in a subgroup of 37 individuals . Mepolizumab was associated with a significant reduction in blood and sputum eosinophils in both treatment groups ( blood , P < 0.001 for both doses ; sputum , P = 0.006 for 250 mg and P = 0.004 for 750 mg ) . There were no statistically significant changes in any of the clinical end points measured . There was a nonsignificant trend for decrease in exacerbation rates in the mepolizumab 750-mg treatment group ( P = 0.065 ) . CONCLUSIONS Mepolizumab treatment does not appear to add significant clinical benefit in patients with asthma with persistent symptoms despite inhaled corticosteroid therapy . Further studies are needed to investigate the effect of mepolizumab on exacerbation rates , using protocol s specifically tailored to patients with asthma with persistent airway eosinophilia Background Quilizumab , a humanized IgG1 monoclonal antibody , targets the M1-prime segment of membrane-expressed IgE , leading to depletion of IgE-switched and memory B cells . In patients with mild asthma , quilizumab reduced serum IgE and attenuated the early and late asthmatic reaction following whole lung allergen challenge . This study evaluated the efficacy and safety of quilizumab in adults with allergic asthma , inadequately controlled despite high-dose inhaled corticosteroids ( ICS ) and a second controller . Methods Five hundred seventy-eight patients were r and omized to monthly or quarterly dosing regimens of subcutaneous quilizumab or placebo for 36 weeks , with a 48-week safety follow-up . Quilizumab was evaluated for effects on the rate of asthma exacerbations , lung function , patient symptoms , serum IgE , and pharmacokinetics . Exploratory analyses were conducted on biomarker subgroups ( periostin , blood eosinophils , serum IgE , and exhaled nitric oxide ) . Results Quilizumab was well tolerated and reduced serum total and allergen-specific IgE by 30–40 % , but had no impact on asthma exacerbations , lung function , or patient-reported symptom measures . At Week 36 , the 300 mg monthly quilizumab group showed a 19.6 % reduction ( p = 0.38 ) in the asthma exacerbation rate relative to placebo , but this was neither statistically nor clinical ly significant . Biomarker subgroups did not reveal meaningful efficacy benefits  following quilizumab treatment . Conclusions Quilizumab had an acceptable safety profile and reduced serum IgE. However , targeting the IgE pathway via depletion of IgE-switched and memory B cells was not sufficient for a clinical ly meaningful benefit for adults with allergic asthma uncontrolled by st and ard therapy . Trial registration Clinical Trials.gov Background : We examined levels of hyaluronan , a matrix glycosaminoglycan and versican , a matrix proteoglycan , in the sputum of asthmatics treated with mepolizumab ( anti-IL-5 monoclonal antibody ) versus placebo to evaluate the utility of these measurements as possible biomarkers of asthma control and airway remodeling . Methods : Patients with severe , prednisone-dependent asthma received either mepolizumab or placebo as described in a previously published r and omized , double-blind , placebo-controlled study . We measured hyaluronan and versican levels by enzyme-linked immunosorbent assay in sputum collected before and after the 16-week treatment phase . Patients underwent a predefined prednisone tapering schedule if they remained exacerbation free , and sputum eosinophil percentage , asthma control question naire ( ACQ ) and spirometry were monitored . Results : After 6 months of mepolizumab therapy and prednisone tapering , there was a significant increase in sputum hyaluronan in the placebo group compared with baseline ( p = 0.003 ) . In contrast , there was a significant decrease in sputum hyaluronan in the active treatment group compared with placebo ( p = 0.007 ) , which correlated with improvements in percent forced expiratory volume in 1 s ( FEV1 % ) ( p = 0.001 ) and ACQ scores ( p = 0.009 ) as well as a decrease in sputum eosinophils ( p = 0.02 ) . There was a nonsignificant increase in sputum versican in the placebo group ( p = 0.16 ) , a decrease in the mepolizumab group ( p = 0.13 ) and a significant inverse correlation between versican reduction and FEV1 % improvement ( p = 0.03 ) . Conclusions : Sputum hyaluronan values are reduced with mepolizumab therapy and correlate with improved clinical and spirometry values , suggesting this measurement may serve as a noninvasive biomarker of asthma control Pre- clinical data demonstrate a pivotal role for interleukin (IL)-13 in the development and maintenance of asthma . This study assessed the effects of tralokinumab , an investigational human IL-13-neutralising immunoglobulin G4 monoclonal antibody , in adults with moderate-to-severe uncontrolled asthma despite controller therapies . 194 subjects were r and omised to receive tralokinumab  ( 150 , 300 or 600 mg ) or placebo subcutaneously every 2 weeks . Primary end-point was change from baseline in mean Asthma Control Question naire score ( ACQ-6 ; ACQ mean of six individual item scores ) at week 13 comparing placebo and combined tralokinumab dose groups . Secondary end-points included pre-bronchodilator lung function , rescue & bgr;2-agonist use and safety . Numerical end-points are reported as mean±sd . At week 13 , change from baseline in ACQ-6 was -0.76±1.04 for tralokinumab versus -0.61±0.90 for placebo ( p=0.375 ) . Increases from baseline in forced expiratory volume in 1 s ( FEV1 ) were 0.21±0.38 L versus 0.06±0.48 L ( p=0.072 ) , with a dose-response observed across the tralokinumab doses tested . & bgr;2-agonist use ( puffs per day ) was decreased for tralokinumab -0.68±1.45 versus placebo -0.10±1.49 ( p=0.020 ) . The increase in FEV1 following tralokinumab treatment remained evident 12 weeks after the final dose . Safety profile was acceptable with no serious adverse events related to tralokinumab . No improvement in ACQ-6 was observed , although tralokinumab treatment was associated with improved lung function BACKGROUND Patients with severe persistent asthma despite GINA 2002 step 4 treatment are at risk for asthma-related morbidity and mortality . This study constitutes the Israeli arm of the international INNOVATE study . OBJECTIVES To determine the efficacy and safety of Xolair as an add-on treatment in patients with severe persistent asthma . METHODS Asthma patients ( age 12 - 75 years ) not controlled with high dose inhaled corticosteroids and long-active beta-2 agonists were r and omized to receive either Xolair or placebo for 28 weeks in a double-blind study in two Israeli centers . RESULTS Thirty-three patients , 20 females and 13 males , mean age 54 + /- 11.7 years , were included in the Israeli arm of the INNOVATE study . There were neither major adverse events nor withdrawals from the study . Xolair ( omalizumab ) significantly reduced the rate of clinical ly significant asthma exacerbations ( 55 % reduction ) and all asthma-related emergency visits ( 53 % reduction ) . CONCLUSIONS In patients with severe persistent difficult-to-treat asthma , despite regular treatment with LABA and inhaled corticosteroids ( GINA 2002 step 4 ) , Xolair is a safe and effective treatment The role of eosinophils as effector cells in asthma pathogenesis has been question ed since an anti-interleukin (IL)-5 monoclonal antibody ( mepolizumab ) , which depleted blood and sputum eosinophils , failed to inhibit allergen-induced bronchoconstriction and airway hyperresponsiveness . However , the effect of IL-5 blockade on tissue eosinophils was not examined . We sought to determine whether mepolizumab depletes airway tissue eosinophils and their products . Twenty-four patients with mild asthma received three intravenous doses of either 750 mg of mepolizumab or placebo in a r and omized , double-blind , parallel-group fashion over 20 weeks . Mepolizumab produced a median decrease from baseline of 55 % for airway eosinophils ( interquartile range , 29 - 89 % ; p = 0.009 versus placebo ) , 52 % for bone marrow eosinophils ( 45 - 76 % , p = 0.003 ) , and 100 % for blood eosinophils ( range , 67 - 100 % , p = 0.02 ) . Mepolizumab had no appreciable effect on bronchial mucosal staining of eosinophil major basic protein . There were no significant changes in clinical measures of asthma ( airway hyperresponsiveness , FEV1 , and peak flow recordings ) between the mepolizumab and placebo-treated groups . Anti-IL-5 treatment reduces but does not deplete airway or bone marrow eosinophils . The role of the eosinophil remains uncertain . Further clinical studies in asthma with more effective antieosinophil strategies are required OBJECTIVE To evaluate the effect of a humanized monoclonal antibody to immunoglobulin E , omalizumab ( Xolair , Novartis Pharmaceuticals , East Hanover , NJ ; Genentech Inc , South San Francisco , CA ) , on airway inflammation in asthma , as indicated by the fractional concentration of exhaled nitric oxide ( FE(NO ) ) , a noninvasive marker of airway inflammation . Xolair was approved recently by the US Food and Drug Administration for moderate-to-severe allergic asthma in adolescents and adults . STUDY DESIGN As an addendum at 2 sites to a r and omized , multicenter double-blind , placebo-controlled trial , FE(NO ) was assessed in children with allergic asthma over 1 year . There were 3 consecutive study periods : 1 ) stable dosing of inhaled beclomethasone dipropionate ( BDP ) when the dose was optimized ( period of 16 weeks ) ; 2 ) inhaled steroid-reduction phase ( period of 12 weeks ) , during which BDP was tapered if subjects remained stable ; and 3 ) open-label extension phase , during which subjects receiving placebo were switched to active omalizumab ( period of 24 weeks ) . The primary outcome was area under the FE(NO ) versus time curve ( AUC ) for adjusted FE(NO ) , defined as the ratio of FE(NO ) at each time point compared with the value at baseline . RESULTS Twenty-nine subjects participated and were r and omized to omalizumab ( n = 18 ) and placebo ( n = 11 ) treatment groups in a 2:1 ratio dictated by the main study . There was a significant difference for age , result ing in a difference in absolute forced expiratory volume in 1 second but no difference in asthma severity based on the forced expiratory volume in 1 second percentage predicted . Baseline BDP dose was comparable between groups , as were baseline values of mean FE(NO ) ( active : 38.6 + /- 25.6 ppb ; placebo : 52.7 + /- 52.9 ppb ) . The degree of BDP dose reduction during the steroid-reduction and open-label phases was equivalent between the omalizumab and placebo-treated groups ; subjects in the omalizumab- and placebo-treated groups had reduced their BDP dose by an average of 51 % and 60 % , respectively , at the end of the steroid-reduction phase and by 68 % and 94 % , respectively , by the end of the open-label period . In the active and placebo groups , 44 % and 27 % and 75 % and 73 % of subjects had stopped use of inhaled corticosteroids at the end of the steroid-reduction and open-label phases , respectively . There was no significant difference between the active and placebo groups during the steroid-stable phase for AUC of adjusted nitric oxide ( 1.31 + /- 1.511 vs 1.45 + /- 0.736 ) . However , during the steroid-reduction phase , the variability of adjusted FE(NO ) in the placebo-treated group was greater than that of the omalizumab-treated group at most visits , with a significant difference between groups for AUC of adjusted nitric oxide ( 0.88 + /- 0.69 vs 1.65 + /- 1.06 ) . FE(NO ) fell from 82.1 + /- 55.6 ppm at the end of the steroid-reduction phase to 33.3 + /- 21.6 ppb at the end of the open-label period in the placebo group who were placed on active omalizumab . This decrease occurred while the mean dose of BDP remained very low . Analysis of FE(NO ) over 52 weeks of omalizumab treatment in the active group demonstrated that there was a significant reduction from baseline to the end of the open-label period ( 41.9 + /- 29.0 to 18.0 + /- 21.8 ppb ) despite a high degree of steroid reduction . CONCLUSION In this preliminary study based on FE(NO ) , a noninvasive marker of airway inflammation , treatment with omalizumab may inhibit airway inflammation during steroid reduction in children with allergic asthma . The degree of inhibition of FE(NO ) was similar to that seen for inhaled corticosteroids alone , suggesting an antiinflammatory action for this novel therapeutic agent in asthma . This is in keeping with recent evidence that omalizumab inhibits eosinophilic inflammation in induced sputum and endobronchial tissue Interleukin 13 ( IL13 ) is a T‐helper type 2 ( Th2 ) cytokine associated with inflammation and pathology in allergic diseases such as bronchial asthma . We have shown that treatment with lebrikizumab , an anti‐IL13 monoclonal antibody , significantly improves prebronchodilator forced expiratory volume in 1 s ( FEV1 ) in a subset of subjects with uncontrolled asthma Introduction : Reslizumab ( RES ) , a humanized anti-human interleukin-5 , is under development for patients with moderate to severe , persistent asthma with elevated eosinophils ( EOS ) . Objectives : To compare the efficacy and safety of RES vs placebo ( PBO ) in subjects with asthma and elevated EOS . Methods : This was a multicenter , PBO-controlled , double-blind , 16-week study ( [NCT01270464][1 ] ) . Subjects ( N=311 ) were 12 - 75 years of age with uncontrolled asthma on at least medium ICS , had an asthma control question naire ( ACQ ) score ≥1.5 , and blood EOS level of ≥400/µL. R and omization was to intravenous RES 0.3 or 3.0 mg/kg or PBO once every 4 weeks . Efficacy variables included pre-dose , pre-bronchodilator pulmonary function ( FEV1 , primary variable ) and ACQ scores . Results : Following 16 weeks of therapy , RES ( 0.3 and 3.0 mg/kg ) significantly improved overall FEV1 ( P ≤0.024 ) and ACQ score ( P ≤0.033 ) vs PBO ( treatment difference vs PBO : 115 and 160 mL , FEV1 and 0.238 and 0.359 ACQ , respectively ) ; improvements for RES 3.0 mg/kg vs PBO were observed in both measures ( 153 mL , FEV1 ; -0.283 , ACQ ) as early as 4 weeks ( P ≤0.015 ) and maintained over the duration of the study . Clinical ly meaningful improvements in FVC ( 130 mL , P = 0.017 ) and FEF25 - 75 % ( 0.233 L/s ; P = 0.055 ) were noted only for the 3.0 mg/kg dose . The most commonly reported AEs in any treatment group were asthma , headache , nasopharyngitis , bronchitis , and upper respiratory tract infection . Conclusion : In subjects with elevated blood EOS , 4 monthly doses of RES were well tolerated and associated with improvements in pulmonary function and patient-reported asthma control on top of st and ard-of-care therapies . [ 1 ] : /lookup/external-ref?link_type = CLINTRIALGOV&access_num = The ability of omalizumab , an anti-immnoglobulin‐E agent , to maintain long‐term disease control in patients with moderate-to-severe allergic asthma was investigated in a 24‐week double-blind extension to a 28‐week core trial . During the extension , 483 of the initial 546 patients were maintained on r and omised treatment  and the lowest sustainable dose of beclomethasone dipropionate ( BDP ) as established during the steroid-reduction phase of the core trial . The use of concomitant asthma medication was permitted and investigators were allowed to adjust the BDP dose or switch patients from BDP to other asthma medications if deemed necessary . More omalizumab-treated patients ( 33.5 % ) than placebo-treated patients ( 13.5 % ) were able to complete the extension period without requiring inhaled corticosteroid treatment . The mean BDP equivalent dose throughout the extension was lower in the omalizumab group ( 25 µg·day−1 ) than in the placebo group ( 43 µg·day−1 ) . Disease control was sustained in 76 % of omalizumab patients compared with 59.4 % of placebo patients free from an asthma exacerbation during the extension period . Compared with placebo , fewer patients in the omalizumab group used other concomitant asthma medication during the extension . Treatment with omalizumab was well tolerated and the incidence of adverse events was similar between groups . In conclusion , these results suggest that omalizumab is a promising new agent for the long-term control of allergic asthma CD4 + T-cells are likely to be involved as a source of pro-inflammatory cytokines in asthma . This study assessed the effects of an infusion of keliximab ( IDEC CE9.1 ) , an anti-CD4 + monoclonal antibody , on peripheral blood CD4 + T-cells in corticosteroid-dependent asthmatics . Three cohorts of patients ( termed C0.5 : n=6 , C1.5 : n=5 , and C3.0 : n=5 ) received a single infusion of 0.5 , 1.5 or 3.0 mg x kg(-1 ) , respectively , with a fourth receiving placebo ( Cpl : n=6 ) , and were followed-up for 4 weeks . By flow cytometry in peripheral blood , pre- and postinfusion assessment was made of : a ) CD4 and CD8 counts and mean fluorescence ; b ) CD25 , human leukocyte antigen-DR ( HLA-DR ) , CD45RO and CD45RA expression on CD4 + T-cells ; and c ) interferon (IFN)-gamma , interleukin (IL)-4 and IL-5 expression in CD4 + T-cells . Keliximab 's in vitro effects on allergen-specific peripheral blood mononuclear cells ( P BMC ) proliferation in atopic asthmatics were also evaluated . There was a significant increase in lung function ( peak expiratory flow rate ) in the C3.0 group . Following infusion in C0.5 , C1.5 and C3.0 but not Cpl : 1 ) the CD4 , but not CD8 count was significantly decreased ; 2 ) there was total loss of Leu3a staining ; 3 ) there were significant reductions in the mean fluorescence of OKT4 binding ; and 4 ) there were significant reductions in the numbers of CD25 , HLA-DR , CD45RO and CD45RA/CD4 + cells . There were no changes in CD4 + cell expression of IFN-gamma , IL-4 or IL-5 . Keliximab caused a significant reduction in T-cell proliferation as compared to a control monoclonal antibody . Keliximab , as an anti-CD4 monoclonal antibody , leads to a transient reduction in the number of CD4 + T-cells and modulation of CD4 + receptor expression in severe asthmatics . The effects of keliximab may be mediated through a decrease in CD4 + surface expression and T-lymphocyte numbers , in addition to a reduction in allergen-induced proliferation The sera from 65 asthmatic patients were studied for the measurement of IgG antibodies specific to the house dust mite , Dermatophagoides farinae ( D. farinae ) by solid-phase radioimmunoassay using polystyrene tubes coated with the antigen extract . The solid-phase radioimmunoassay had about the same sensitivity as the conventional double antibody antigen-binding assay in the detection of mite-specific IgG antibodies . The mean value of IgG antibodies was 26.1 ( + /- 39.8 ) micrograms/ml in patients hyposensitized with D. farinae , 23.9 ( + /- 29.3 ) micrograms/ml in those hyposensitized with house dust ( HD ) , and 21.6 ( + /- 35.6 ) micrograms/ml in non-treated patients . A significant difference was detected between HD-treated patients and normals ( p less than 0.05 ) . The levels of IgG antibody tended to increase with the increment of the maintenance dose of the D. farinae or HD used in immunotherapy . In addition , eight patients were evaluated for their IgG antibody levels before and after immunotherapy . In five of them , IgG antibodies increased about two to threefold above the value before immunotherapy . These results suggest that the measurement of IgG antibodies by solid-phase radioimmunoassay may be clinical ly useful in evaluating the effectiveness of immunotherapy Background : Anti‐IgE , omalizumab , inhibits the allergen response in patients with asthma . This has not been directly related to changes in inflammatory conditions . We hypothesized that anti‐IgE exerts its effects by reducing airway inflammation . To that end , the effect of anti‐IgE on allergen‐induced inflammation in bronchial biopsies in 25 patients with asthma was investigated in a r and omized , double‐blind , placebo‐controlled study BACKGROUND Many asthmatic patients exhibit sputum eosinophilia associated with exacerbations .  Benralizumab targets eosinophils by binding IL-5 receptor α , inducing apoptosis through antibody-dependent cell-mediated cytotoxicity . OBJECTIVES We sought to evaluate the safety of benralizumab in adults with eosinophilic asthma and its effects on eosinophil counts in airway mucosal/submucosal biopsy specimens , sputum , bone marrow , and peripheral blood . METHODS In this multicenter , double-blind , placebo-controlled phase I study , 13 subjects were r and omized to single-dose intravenous placebo or 1 mg/kg benralizumab ( day 0 ; cohort 1 ) , and 14 subjects were r and omized to 3 monthly subcutaneous doses of placebo or 100 or 200 mg of benralizumab ( days 0 , 28 , and 56 ; cohort 2 ) . Cohorts 1 and 2 were consecutive . RESULTS The incidence of adverse events was similar between groups . No serious adverse events related to benralizumab occurred . In cohort 1 intravenous benralizumab produced a median decrease from baseline of 61.9 % in airway mucosal eosinophil counts ( day 28 ; placebo : + 19.6 % ; P = .28 ) , as well as an 18.7 % decrease ( day 21 ) in sputum and a 100 % decrease ( day 28 ) in blood counts . Eosinophils were not detectable in bone marrow of benralizumab-treated subjects ( day 28 , n = 4 ) . In cohort 2 subcutaneous benralizumab demonstrated a combined ( 100 + 200 mg ) median reduction of 95.8 % in airway eosinophil counts ( day 84 ; placebo , 46.7 % ; P = .06 ) , as well as an 89.9 % decrease ( day 28 ) in sputum and a 100 % decrease ( day 84 ) in blood counts . CONCLUSION Single-dose intravenous and multiple-dose subcutaneous benralizumab reduced eosinophil counts in airway mucosa/submucosa and sputum and suppressed eosinophil counts in bone marrow and peripheral blood . The safety profile supports further development . Additional studies are needed to assess the clinical benefit in asthmatic patients BACKGROUND Omalizumab treatment suppresses FcepsilonRI expression faster on blood basophils than skin mast cells . OBJECTIVE We used omalizumab to eluci date the relative contributions of basophil versus mast cell FcepsilonRI activation in a nasal allergen challenge ( NAC ) model . METHODS Eighteen subjects with cat allergy were enrolled in a 3.5-month , double-blind , r and omized ( 3.5:1 ) , placebo-controlled trial of omalizumab using st and ard dosing . At baseline , subjects underwent NAC with lavage for prostagl and in D(2 ) measurement , skin prick test titration ( SPTT ) , and blood sampling for basophil histamine release ( BHR ) and basophil IgE/FcepsilonRI measurements . Basophil studies were repeated at day 3 and then weekly until cat allergen-induced BHR was < 20 % of baseline or until day 45 . Baseline visit procedures were repeated after the BHR reduction ( mid study NAC ) and at the treatment period 's completion ( final NAC ) . RESULTS Subjects treated with omalizumab who completed all NACs ( n = 12 ) demonstrated significant mean reduction in BHR to an optimal dose of cat allergen by mid study NAC compared with baseline ( 74 % decrease ; P = .001 ) . In addition , these subjects demonstrated significant decreases in mean combined nasal symptom scores ( 50 % decrease ; P = .007 ) and total sneeze counts ( 59 % decrease ; P = .01 ) by mid study NAC relative to baseline NAC . In contrast , measures of mast cell response ( SPTT and nasal lavage prostagl and in D(2 ) ) were only significantly reduced by the final NAC . Subjects on placebo ( n = 4 ) did not experience a shift in basophil , NAC symptom , or mast cell measures . CONCLUSION Reduction in nasal symptom scores occurred when the basophil , but not mast cell , response was reduced on omalizumab , implicating a role for basophils in the acute NAC response BACKGROUND Persistent eosinophilic airway inflammation in asthma increases the risk of exacerbations . In a phase 2b dose-ranging study , we aim ed to assess the efficacy and safety of benralizumab , an anti-interleukin 5 receptor α monoclonal antibody that depletes blood and airway eosinophils , in adults with uncontrolled eosinophilic asthma . METHODS We did a r and omised , controlled , double-blind , dose-ranging phase 2b study . Eligible participants were adults aged 18 - 75 years with uncontrolled asthma using medium-dose or high-dose inhaled corticosteroids and longacting β agonists , with two to six exacerbations in the past year . Current or former smokers were excluded . We used the ELEN index ( an algorithm to predict elevated sputum eosinophils ) or baseline fraction of exhaled nitric  oxide to stratify patients by eosinophilic status , and with an interactive web-voice response system r and omly assigned eosinophilic individuals in a 1:1:1:1 ratio to receive placebo , 2 mg benralizumab , 20 mg benralizumab , or 100 mg benralizumab , and non-eosinophilic individuals in a 1:1 ratio to receive placebo or 100 mg benralizumab . Study drugs were given as two subcutaneous injections every 4 weeks for the first three doses , then every 8 weeks , for 1 year . Patients , treating physicians , and study investigators were masked to treatment allocation . The primary endpoint was annual exacerbation rate in eosinophilic individuals after 1 year of follow-up . Analysis was by modified intention to treat . This study was design ed with a two-sided α of 0·2 and powered at 78 % for the primary outcome in the eosinophilic population . This study is registered with Clinical Trials.gov , number NCT01238861 . FINDINGS Between Jan 3 , 2011 , and March 6 , 2012 , we r and omly assigned 324 eosinophilic individuals  to placebo ( n=80 ) or benralizumab 2 mg dose ( n=81 ) , 20 mg dose , ( n=81 ) , or 100 mg dose ( n=82 ) , and 285 non-eosinophilic individuals to 100 mg benralizumab ( n=142 , 140 included in analysis ) or placebo ( n=143 , 142 included in analysis ) . In eosinophilic individuals ,  benralizumab reduced exacerbation rates compared with placebo in the 100 mg group ( 0·34 vs 0·57 , reduction 41 % , 80 % CI 11 to 60 , p=0·096 ) but not in the 2 mg group ( 0·65 vs 0·57 , difference -9 % , 80 % CI -59 to 26 , p=0·781 ) or the 20 mg group ( 0·37 vs 0·57 , reduction 36 % , 80 % CI 3 to 58 , p=0·173 ) . In patients with a baseline blood eosinophil cutoff of at least 300 cells per μL , exacerbation rates in the benralizumab 20 mg group ( n=70 ) and 100 mg group ( n=97 ) were lower than in the placebo group ( n=83 ; 0·30 vs 0·68 , reduction 57 % , 80 % CI 33 to 72 , p=0·015 for 20 mg dose ; 0·38 vs 0·68 , difference 43 % , 80 % CI 18 to 60 , p=0·049 for 100 mg dose ) . Our findings suggested that benralizumab 20 mg and 100 mg resided at the dose-response plateau . Treatment-emergent adverse events occurred in 277 ( 72 % ) of 385 participants receiving any benralizumab dose compared with 143 ( 65 % ) of 221 receiving  placebo . Nasopharyngitis ( 44 [ 11 % ] patients receiving benralizumab vs 13 [ 6 % ] patients receiving placebo ) and injection site reactions ( 60 [ 16 % ] vs eight [ 4 % ] ) occurred more frequently with benralizumab than with placebo . INTERPRETATION Benralizumab at 20 mg and 100 mg doses seemed to reduce asthma exacerbations in adults with uncontrolled eosinophilic asthma and baseline blood eosinophils of at least 300 cells per μL , possibly due to targeting of the interleukin 5 receptor rather than interleukin 5 lig and . Further investigation of benralizumab treatment in phase 3 studies is warranted . FUNDING MedImmune BACKGROUND A recombinant humanized anti-IgE mAb , omalizumab , forms complexes with free IgE , blocking its interaction with mast cells and basophils ; as a consequence , it might be effective in the treatment of asthma . OBJECTIVE The purpose of this study was to evaluate the efficacy and safety of omalizumab in the treatment of inhaled corticosteroid-dependent asthma . METHODS In this phase III , double-blinded , placebo-controlled trial , 525 subjects with severe allergic asthma requiring daily inhaled corticosteroids were r and omized to receive placebo or omalizumab subcutaneously every 2 or 4 weeks , depending on baseline IgE level and body weight . Inhaled corticosteroid doses were kept stable over the initial 16 weeks of treatment and tapered during a further 12-week treatment period . RESULTS Omalizumab treatment result ed in significantly fewer asthma exacerbations per subject and in lower percentages of subjects experiencing an exacerbation than placebo treatment during the stable steroid phase ( 0.28 vs 0.54 [ P = .006 ] and 14.6 % vs 23.3 % [ P = .009 ] , respectively ) and during the steroid reduction phase ( 0.39 vs 0.66 [ P = .003 ] and 21.3 % vs 32.3 % [ P = .004 ] , respectively ) . Beclomethasone dipropionate reduction was significantly greater with omalizumab treatment than with placebo ( median 75 % vs 50 % [ P < .001 ] ) , and beclomethasone dipropionate discontinuation was more likely with omalizumab ( 39.6 % vs 19.1 % [ P < .001 ] ) . Improvements in asthma symptoms and pulmonary function occurred along with a reduction in rescue beta-agonist use .  Omalizumab was well tolerated , with an adverse-events profile similar to that of placebo . CONCLUSION The addition of omalizumab to st and ard asthma therapy reduces asthma exacerbations and decreases inhaled corticosteroid and rescue medication use Twenty asthematic children and 48 patients with severe psychomotor retardation were inoculated intranasally with trivalent cold-adapted recombinant ( CR ) influenza vaccine containing CR-125 ( H1N1 ) , CR-159 ( H3N2 ) and CRB-117 ( B ) . The vaccinees were mostly seropositive . Severe adverse reactions or asthmatic attacks were not observed , but 7 ( 15 % ) of 48 vaccinees with severe psychomotor retardation developed mild to moderate fever . Significant antibody responses in hemagglutination-inhibition tests were demonstrated in 33 ( 49 % ) vaccinees to CR-125 , 20 ( 29 % ) to CR-159 and 8 ( 12 % ) to CRB-117 . Two nosocomial outbreaks of influenza were observed in the subsequent winter . During an outbreak with H3N2 in one ward of severe psychomotor retardation patients . 2 ( 11 % ) of 18 vaccinees became infected compared with 10 ( 48 % ) of 21 placebo controls in the same ward ( P < 0.05 ) . In the other outbreak , with influenza B virus , 2 ( 14 % ) of 14 vaccinees and 13 ( 52 % ) of 25 controls in the ward for asthmatic children were infected ( P < 0.05 ) . The results indicate that trivalent CR vaccine  is safe and effective against nosocomial outbreaks of influenza We have previously demonstrated that peanut oil is not allergenic to peanut-sensitive individuals . Seven soybean-sensitive patients were enrolled in a double-blind crossover study to determine whether ingestion of soybean oil can induce adverse reactions in such patients . All subjects had histories of systemic allergic reactions ( urticaria , angioedema , wheezing , dyspnea , and /or vomiting ) after soybean ingestion and had positive puncture skin tests with a 1:20 w/v glycerinated-saline whole soybean extract .  Sera from six of the seven subjects were tested by RAST assay for the presence of specific IgE antibodies to soybean allergens . All patients had elevated levels of serum IgE antibodies to the crude soybean extract ; binding values ranged from 2.3 to 28.1 times that of a negative control serum . Before the oral challenges , all patients demonstrated negative puncture skin tests to three commercially available soybean oils and to olive oil ( control ) . On four separate days , patients were challenged with the individual soybean oils and olive oil in r and om sequence . At 30-minute intervals , under constant observation , patients ingested 2 , 5 , and 8 ml of one of the soybean oils or olive oil contained in 1 ml capsules . No untoward reactions were observed with either the commercially available soybean oils or olive oil . Soybean oil ingestion does not appear to pose a risk to soybean-sensitive individuals BACKGROUND This phase 3 study further characterizes the efficacy and safety of reslizumab ( a humanized anti-IL-5 monoclonal antibody ) in patients aged 12 to 75 years with asthma inadequately controlled by at least a medium-dose inhaled corticosteroid and with a blood eosinophil count ≥ 400 cells/μL. METHODS Patients were r and omized to receive reslizumab 0.3 or 3.0 mg/kg or placebo administered once every 4 weeks for 16 weeks ( total four doses ) . The primary end point was change from baseline in pre-bronchodilator FEV1 over 16 weeks . Secondary end points included FVC , forced expiratory flow at 25 % to 75 % of FVC ( FEF25%-75 % ) , patient-reported control of asthma symptoms , short-acting β-agonist ( SABA ) use , blood eosinophil levels , and safety . RESULTS Reslizumab significantly improved FEV1 ( difference vs placebo [ reslizumab 0.3 and 3.0 mg/kg ] , 115 mL [ 95 % CI , 16 - 215 ; P = .0237 ] and 160 mL [ 95 % CI , 60 - 259 ; P = .0018 ] ) . Clinical ly meaningful increases in FVC ( 130 mL ) and FEF25%-75 % ( 233 mL/s ) were observed with reslizumab 3.0 mg/kg . Reslizumab improved scores on the Asthma Control Question naire ( ACQ ) and Asthma Quality of Life Question naire ( AQLQ ) vs placebo ( greater effects seen with 3.0 mg/kg ; P < .05 ) . The minimally important difference was reached for the AQLQ  ( reslizumab 3.0 mg/kg ) but not on the ACQ . Scores on the Asthma Symptom Utility Index and SABA use were improved with reslizumab . The most common adverse events were worsening of asthma , headache , and nasopharyngitis ; most events were mild to moderate in severity . CONCLUSIONS Reslizumab improved lung function , asthma control and symptoms , and quality of life . It was well tolerated in patients with inadequately controlled asthma ( despite st and ard therapy ) and elevated blood eosinophil levels . Overall , the 3.0-mg/kg dose of reslizumab provided greater improvements in asthma outcomes vs the 0.3-mg/kg dose , with comparable safety . TRIAL REGISTRY Clinical Trials.gov ; No. : NCT01270464 ; URL : www . clinical trials.gov Cutaneous and bronchial immediate allergic reactivity and the serum level of IgE specific for each of four common inhalant allergens were determined for 153 asthmatic patients .  Positive bronchial reactivity to an extract was not detected in any of the patients with a negative prick test reaction to that extract but did occur in 9 % of the patients in whom the serum tests results for IgE specific to that allergen fell within the range regarded as negative . Highly significant correlation coefficients between the degree of bronchial and cutaneous allergic reactivity to the allergen extracts were found and these were slightly but significantly less than the correlation between the serum level of allergen specific IgE and the degree of bronchial allergic reactivity to the allergen extracts . These findings indicate that the results both of prick testing with appropriate extracts and estimation of the serum level of allergen specific IgE can be used to predict not only the presence of detectable bronchial reactivity to inhalant allergens but also the degree of this reactivity . However , for the routine investigation of asthmatic patients measurement of the serum level of allergen specific IgE would appear to have little advantage over properly performed prick tests BACKGROUND While up to 50 % of patients with severe asthma have no evidence of allergy , IgE has been linked to asthma , irrespective of atopic status . Omalizumab , an anti-IgE monoclonal antibody , is reported to significantly benefit a subset of patients with severe , persistent , allergic asthma . Therefore , we investigated whether omalizumab has biologic and clinical effects in patients with refractory nonatopic asthma . METHODS Forty-one adult patients who , despite daily treatment with or without maintenance oral corticosteroids , had severe , nonatopic , refractory asthma according to GINA ( Global Initiative for Asthma ) step 4 , were r and omized to receive omalizumab or placebo in a 1:1 ratio . The primary end point was the change in expression of high-affinity IgE receptor ( FcεRI ) on blood basophils and plasmacytoid dendritic cells ( pDC2 ) after 16 weeks . The impact of omalizumab on lung function and clinical variables was also examined . RESULTS Compared with placebo , omalizumab result ed in a statistically significant reduction in FcεRI expression on basophils and pDC2 ( P < .001 ) . The omalizumab group also showed an overall increase in FEV1 compared with baseline ( + 250 mL , P = .032 ; + 9.9 % , P = .029 ) . A trend toward improvement in global evaluation of treatment effectiveness and asthma exacerbation rate was also observed . CONCLUSIONS Omalizumab negatively regulates FcεRI expression in patients with severe nonatopic asthma , as it does in severe atopic asthma . Omalizumab may have a therapeutic role in severe nonatopic asthma . Nonetheless , our preliminary findings support further investigation to better assess the clinical efficacy of omalizumab . TRIAL REGISTRY Clinical Trials.gov ; No. : NCT01007149 ; URL : www . clinical trials.gov and European Clinical Trials Data base , EudraCT ; No. : 2009 - 010937 - 38 ; URL : https://www . clinical trialsregister.eu Few studies have been published on the efficacy and safety of immunotherapy with fungal extracts , possibly because of difficulties arising from antigenic variability among different strains of fungus . The aim of the study was to analyze changes in the in vivo and in vitro parameters in response to immunotherapy with an Alternaria alternata extract . We studied 28 patients with rhinitis , bronchial asthma , or both caused by Alternaria . The patients were r and omized to the active immunotherapy or placebo group , and a conventional schedule of immunotherapy was used . We recorded changes for a year in skin reactivity ( skin prick test ) , conjunctival reactivity ( conjunctival provocation test ) , and in vitro parameters ( serum-specific IgE , IgG , IgG1 and IgG4 for A. alternata complete extract and for natural and recombinant Alt a 1 ) . Twenty-three patients completed the study and all attained the maintenance dose . There were no changes in skin reactivity in the active treatment group , and reactivity increased at the end of the study period in the placebo group . Conjunctival sensitivity decreased only in the active treatment group when the maintenance dose was reached . Allergen-specific IgE decreased , and IgG , IgG1 and IgG4 increased in all periods of study in the active treatment group , with no changes in the placebo group . Allergen-specific immunotherapy with the A. alternata extract tested here led to a decrease in conjunctival reactivity and induced a significant immunologic response The OX40/OX40L interaction contributes to an optimal T cell response following allergic stimuli and plays an important role in the maintenance and reactivation of memory T effector cells To evaluate the preventive role of immunotherapy in severe perennial asthma , we investigated cockroach asthma as a model . Twenty-eight subjects with bronchial asthma due to cockroach hypersensitivity ( BACR ) were divided into two groups in alternating order : 15 were started with cockroach antigen immunotherapy ( CRa-IT )  and 13 were given control immunotherapy .  Eleven in the former group and two in the latter group completed the study after 5 years . The changes in symptoms and medication scores were assessed ; blocking antibody factor in the paired pre- and postimmune serum of the two groups was measured and compared . Cellular sensitivity ( HR50 ) was measured using the basophil-rich leukocytes ( BRLs ) obtained from the two treated asthma groups , and the result was compared with that of the untreated cockroach asthmatic cells . The average symptom score changed from 7.2 + /- 2.7 to 1.2 + /- 0.4 in the CRa-IT group . The control-IT group showed no change . The medication score changed from 11.4 + /- 1.6 to 5.2 + /- 1.4 in the CRa-IT group only ( p less than 0.01 ) . The mean blocking antibody factor in the immune serum of the CRa-IT group showed a 2.5 x 10(2)-fold increase [ 1.3 + /- 0.3 x 10(-1 ) in postimmune serum/5.2 + /- 2.0 + /- 10(-4 ) in preimmune serum ( p less than 0.001 ) ] . No difference was noted in the HR50 of the BRLs in the post- and preimmune serum of the control-IT group . Antihuman IgG absorption of the post-CRa-IT serum reduced the blocking antibody to 1/1000-fold ; no difference in the HR50 of the BRLs was noted between the post-control-IT and the pre-CRa-IT serum ( p greater than 0.2 ) . The BRLs of the CRa-IT asthmatics , however , showed blunted sensitivity not affected by the serum factor ( 5.8 + /- 1.5 x 10(-2 ) micrograms/ml in post-CRa-IT serum and 5.6 + /- 1.3 x 10(-2 ) micrograms/ml in pre-CRa-IT serum ) ( p greater than 0.2 ) . The BRLs of the control-IT group retained their cell sensitivity as well as the blocking effect of the CRa-immune serum . This study thus demonstrated that CRa-IT reduces symptom and medication scores clinical ly in cockroach-asthmatic subjects , and the CRa-IT produces the CRa-specific blocking antibody of the IgG type . It also reduces anaphylactic leukocyte sensitivity , which is not affected by humoral factor BACKGROUND Allergen-specific immunotherapy uses aqueous extracts of natural source material s as a basis for preparations to down regulate the allergic response . Recombinant DNA technology has enabled the cloning of many allergens , thus facilitating investigations aim ed at improving efficacy and safety of immunotherapy . OBJECTIVE To determine the effectiveness of a mixture of 5 recombinant grass pollen allergens in reducing symptoms and need for symptomatic medication in patients allergic to grass pollen . METHODS A r and omized , double-blind , placebo-controlled study of subcutaneous injection immunotherapy was performed in subjects with allergic rhinoconjunctivitis , with or without asthma . Primary endpoint was a symptom medication score compiled from separate symptom and medication scores . Secondary endpoints included a rhinitis quality of life question naire , conjunctival provocation , and specific antibody responses . RESULTS The symptom medication score showed significant improvements in subjects receiving recombinant allergens as opposed to placebo , with reductions in both symptoms and medication usage . The rhinitis quality of life question naire revealed clinical ly relevant significant improvements in overall assessment and in 5 of 7 separate domains , and conjunctival provocation showed a clear trend in favor of active treatment . All treated subjects developed strong allergen-specific IgG(1 ) and IgG(4 ) antibody responses . Some patients were not sensitized to Ph l p 5 but nevertheless developed strong IgG antibody responses to that allergen . CONCLUSION A recombinant allergen vaccine can be a effective and safe treatment to ameliorate symptoms of allergic rhinitis . The clinical benefit is associated with modification of the specific immune response with promotion of IgG(4 ) and reduction of IgE antibodies consistent with the induction of IL-10-producing regulatory T cells BACKGROUND Immune responses mediated by IgE are important in the pathogenesis of allergic asthma . A recombinant humanized monoclonal antibody ( rhuMAb-E25 ) forms complexes with free IgE and blocks its interaction with mast cells and basophils . We studied the efficacy of rhuMab-E25 as a treatment for moderate-to-severe  allergic asthma .  METHODS After a 4-week run-in period , we r and omly assigned 317 subjects ( age range , 11 to 50 years ) who required inhaled or oral corticosteroids ( or both ) to receive either  placebo or one of two regimens of rhuMAB-E25 : high-dose rhuMAb-E25 ( 5.8 microg per kilogram of body weight per nanogram of IgE per milliliter or low-dose rhuMAb-E25 ( 2.5 microg per kilogram per nanogram of IgE per milliliter ) intravenously on days 0 ( half a dose ) , 4 ( half a dose ) , and 7 ( full dose ) and then once every 2 weeks thereafter for 20 weeks . For the first 12 weeks of the study , the subjects continued the regimen of corticosteroids they had received before enrollment . During the following eight weeks , the doses of corticosteroids were tapered in an effort to discontinue this therapy . The primary outcome measure was an improvement in the asthma symptom score at 12 weeks , according to a 7-point scale , in which a score of 1 indicated no symptoms and a score of 7 the most severe symptoms . RESULTS A total of 106 subjects were assigned to receive a high dose of rhuMAb-E25 , 106 were assigned to receive a low dose , and 105 were assigned to receive placebo . At base line , the mean asthma symptom score was 4.0 . After 12 weeks of therapy , the mean ( + /-SE ) scores were 2.8+/-0.1 in the high-dose group ( P=0.008 ) and 2.8+/-0.1 in the low-dose group ( P=0.005 ) , as compared with 3.8+/-0.1 in the placebo group . At 20 weeks , the mean scores were 2.7+/-0.1 in both the high-dose group ( P=0.048 ) and the low-dose group ( P=0.14 ) , as compared with 2.9+/-0.1 in the placebo group . More subjects in the two rhuMAb-E25 groups were able to decrease or discontinue their use of corticosteroids than in the placebo group , but only some of the differences were significant . After 20 weeks , serum free IgE concentrations decreased by a mean of more than 95 percent in both rhuMAb-E25 groups . The therapy was well tolerated . After 20 weeks , none of the subjects had antibodies against rhuMAb-E25 . CONCLUSIONS A recombinant humanized monoclonal antibody directed against IgE has potential as a treatment for subjects with moderate or severe allergic asthma STUDY OBJECTIVE To determine baseline characteristics predictive of response to omalizumab , an anti-IgE antibody , in patients with allergic asthma . DESIGN Pooled analysis of two multicenter , double-blind , r and omized , placebo-controlled phase III studies with omalizumab . PATIENTS One thous and seventy allergic asthma patients symptomatic despite moderate-to-high doses ( mean , 725 micro g/d ) of inhaled beclomethasone dipropionate ( BDP ) .  INTERVENTIONS Omalizumab ( n = 542 ) or placebo ( n = 528 ) were administered at a 4-weekly subcutaneous dose of at least 0.016 mg/kg/IgE ( IU/mL ) for 16 weeks in addition to stable BDP therapy . MEASUREMENTS AND RESULTS Univariate logistic regression was performed to explore baseline variables predictive of best response . Various aspects of response ( reduced symptom scores , reduced usage of rescue medication , improved lung function , improved quality of life [ QoL ] ) were explored as well as a composite definition of response ( response in at least one of these four aspects with no asthma exacerbation during 16 weeks of treatment ) . Time to onset of response as well as the ability to predict eventual response were also determined for the composite definition of response . A consistent pattern of predictive covariates was seen over all definitions of response ( except for QoL ) . For the composite definition , a history of emergency asthma treatment in the past year was the factor most predictive ( p = 0.015 ) of best response on active treatment ( response rate for those with such history was 67 % for omalizumab and 42 % for placebo ; for those without a history the response rates were 63 % and 54 % , respectively ) . Another factor predictive of best response on active treatment was high BDP dose ( p = 0.037 ; response rate for those treated with > or= 800 micro g/d was 65 % for omalizumab and 40 % for placebo ; for those treated with < 800 micro g/d , the response rates were 63 % and 55 % , respectively ) . A low FEV(1 ) was also predictive ( p = 0.072 ; response rates for those with FEV(1 ) < or= 65 % predicted were 60 % for omalizumab and 40 % for placebo ; for those with FEV(1 ) > or= 65 % predicted , the response rates were 67 % and 53 % , respectively ) . Seventy-six percent of patients had at least one of these factors . This subgroup showed odds of being a responder ( composite definition ) 2.25 times higher ( 95 % confidence interval , 1.68 to 3.01 ) than placebo . Some 38 % of patients treated with omalizumab showed a response ( composite definition ) at the first evaluation time point at 4 weeks , increasing to 64 % at week 16 ( vs 48 % for placebo ; p < 0.001 ) . Among omalizumab responders at 16 weeks , only 61 % had responded at 4 weeks whereas 87 % had responded at 12 weeks . CONCLUSIONS Patients who benefit most when omalizumab is administered as add-on therapy are those receiving high doses of BDP , those with a history of frequent emergency asthma treatment , and those with poor lung function . Patients should be treated with omalizumab for a minimum duration of 12 weeks IgE plays a key role in allergic asthma . We investigated whether omalizumab treatment of patients with moderate to severe allergic asthma leads to changes in inflammatory mediators and clinical symptoms . This sub- study was conducted on 35 patients with a positive skin prick test ( SPT ) requiring daily administration of beclomethasone dipropionate ( 500–1,000 µg ) , who participated in a multicentre , r and omised , double-blind , placebo-controlled study . Omalizumab or placebo was administered at 0.016 mg/kg/IgE every 4 weeks . Patients recorded peak expiratory flow , asthma symptom score and β2-agonist use in daily diaries and spirometry was performed at each visit . β2-Agonist use and SPT wheal reaction decreased significantly ( p < 0.05 ) . Circulating levels of IL-5 , IL-6 , IL-8 , IL-10 , IL-13 and s-ICAM were measured before and after 16 weeks of treatment . IL-13 and s-ICAM were measured before and after 16 weeks of treatment . IL-13 decreased significantly ( p < 0.01 ) . IL-5 and IL-8 decreased in the omalizumab group compared to baseline . The other circulating mediators did not demonstrate any changes . Histamine release was significantly reduced ( p < 0.01 ) . Airway resistance ( p < 0.05 ) and the provocative concentration inducing a 20 % decrease in FEV1 ( p < 0.05 ) were measured before , after 16 weeks , and 3 months after completion of treatment . Both parameters decreased significantly ( p < 0.05 ) . Peripheral eosinophil count decreased significantly compared to placebo ( p < 0.01 ) . These findings suggest that omalizumab has potential as a novel treatment for allergic asthma OBJECTIVE Children who experience respiratory syncytial virus ( RSV ) lower respiratory tract infections ( LRTIs ) early in life have high rates of subsequent recurrent wheezing .  Palivizumab , an anti-RSV monoclonal antibody , has 78 % to 80 % efficacy in preventing RSV hospitalization in premature infants without chronic lung disease . We hypothesized that palivizumab , by ameliorating or preventing early RSV LRTI in preterm infants , might decrease later recurrent wheezing . STUDY DESIGN A cohort of preterm infants who had received palivizumab and were not hospitalized for RSV ( n = 191 ) or who never received palivizumab ( n = 230 ; 76 who were hospitalized for RSV and 154 who were not ) , were prospect ively followed for 24 months beginning at a mean age of 19 months . The subjects were assessed for recurrent wheezing by caretaker or physician report . RESULTS The incidences of recurrent wheezing and physician-diagnosed recurrent wheezing were significantly lower in the 191 palivizumab-treated  subjects ( 13 % and 8 % , respectively ) compared with all 230 untreated subjects ( 26 % , P = .001 and 16 % , P = .011 , respectively ) and with the 154 patients in the subgroup not hospitalized for RSV LRTI ( 23 % , P = .022 and 16 % , P = .027 , respectively ) . The effect of palivizumab treatment remained significant after adjustment for potential confounding variables . CONCLUSIONS Our study suggests that preventing RSV LRTI with palivizumab may reduce subsequent recurrent wheezing in premature infants BACKGROUND Approximately 5 % to 10 % of asthmatic patients achieve incomplete symptom control on current therapies . The association of IL-13 with asthma pathology and reduced corticosteroid sensitivity suggests a potential benefit of anti-IL-13 therapy in refractory asthma .  GSK679586 , a humanized mAb , inhibits IL-13 binding to both IL-13 receptor α1 and α2 . OBJECTIVES We sought to evaluate the efficacy and safety of GSK679586 in patients with severe asthma refractory to maximally indicated doses of inhaled corticosteroids . METHODS Patients who remained symptomatic ( Asthma Control Question naire score ≥1.5 ) after uptitration to 1000 μg/d fluticasone propionate or greater were r and omized  to 3 once-monthly intravenous infusions of 10 mg/kg GSK679586 ( n = 99 ) or placebo ( n = 99 ) . RESULTS Treatment differences in adjusted mean change from baseline over 12 weeks were nonsignificant for Asthma Control Question naire symptom scores ( the primary end point ; GSK679586 = -0.31 , placebo = -0.17 , P = .058 ) and FEV₁ ( GSK679586 = -0.01 , placebo = 0.03 , P = .276 ) . Similar analyses in patients with increased serum IgE levels , blood eosinophil counts , or both were also negative . Incidence of asthma exacerbations was similar between treatments . Most adverse events were nonserious and unrelated to treatment . Two GSK679586-treated patients had treatment-related serious adverse events ( lethargy and supraventricular extrasystoles ) . CONCLUSIONS Although well tolerated , GSK679586 did not demonstrate clinical ly meaningful improvements in asthma control , pulmonary function , or exacerbations in patients with severe asthma . Further studies are needed to determine whether therapies targeting IL-13 , the functionally related IL-4 cytokine , or both can provide clinical benefit in patients with severe refractory asthma or a sub population of these patients beyond that achievable with high-dose corticosteroids The efficacy of immunotherapy in cat-induced asthma was studied by use of a purified fraction of cat-pelt extract and a double-blind protocol . Nine active-treatment subjects who received a mean cumulative dose of cat allergen , 1 of 10.9 units , and eight placebo-treatment subjects completed the study . Active treatment result ed in significant reductions in bronchial sensitivity ( p less than 0.05 ) and prick test titer ( p less than 0.01 ) . In addition , active treatment result ed in a significant delay in the onset of ocular ( p less than 0.05 ) and pulmonary ( p less than 0.02 ) symptoms on exposure to living cats . Significant increases in IgG antibody to cat allergen 1 ( p less than 0.001 ) and cat albumin ( p less than 0.01 ) also occurred with active treatment . There was no significant change in bronchial reactivity to methacholine or in the sensitivity of circulating basophils . These results confirm the validity of immunotherapy in allergic asthma where there is careful patient selection and well defined treatment preparations OBJECTIVE Respiratory infections are major triggers of exacerbations in preschool asthma . Many countries ' guidelines recommend immunization against pneumococci for patients suffering from chronic airway disease . Beyond infancy , however , data on the immunogenicity and safety are scarce . Also , the interval between priming and booster is a matter of debate . PATIENTS AND METHODS Seventy preschool asthmatics ( 2 - 5-year-old ; mild to moderate asthma ) underwent sequential immunization : one dose of seven-valent pneumococcal conjugate vaccine ( PCV-7 ) followed by a single dose of 23-valent pneumococcal polysaccharide vaccine ( PPV-23 ) . We r and omly assigned half of the vaccinees to receive PPV-23 eight weeks after PCV-7 ( group A ) , and the rest to a 10-month interval ( group B ) . Pneumococcal antibody concentrations to serotype 4 , 5 , 6B , 7 , 9V , 14 , 18c , 19F and 23F were determined initially , after two and 12 months after PCV-7 . Local and systemic reactions to each vaccine were recorded . RESULTS Initially , depending on the serotype , up to 79.4 % ( group A ) or 80.4 % ( group B ) individuals did not reach the protective antibody threshold of 0.35 microg/ml . Sequential pneumococcal immunization was immunogenic in preschool asthmatics , inducing protection in the majority of our children . Subjects boostered after eight weeks had significantly lower antibody levels than those boostered after 10 months . Local and systemic adverse events were mild in character and self-limiting . CONCLUSIONS Although both sequential pneumococcal vaccine regimens were safe and immunogenic among preschool asthmatics , immunogenicity was higher when the booster was given after 10 months BACKGROUND There is increasing evidence that soluble interleukin-2 receptor ( sIL-2R ) might reflect T cell activation in vivo and soluble intercellular adhesion molecule-1 ( sICAM-1 ) might reflect the ongoing inflammatory response in the inflamed site . OBJECTIVE The aim of this study was to determine the effect of antihistamine tablets and allergen-specific immunotherapy on the seasonal changes in specific IgE , sIL-2R , and sICAM-1 in the serum of patients with seasonal allergic rhinitis . METHODS This prospect i ve study included 99 patients with seasonal allergic rhinitis due to Japanese cedar pollens and 27 nonatopic healthy volunteers . The patients were divided into an antihistamine-treated group and an immunotherapy group . Serum sample s were collected before and during the pollen season from each patient to determine specific IgE , sIL-2R , and sICAM-1 . RESULTS Levels of sIL-2R before the pollen season did not differ significantly among the nonatopic group , the antihistamine-treated group , and the immunotherapy group . The levels of sICAM-1 before the pollen season were significantly higher in the antihistamine-treated group and in the immunotherapy group than in the nonatopic group . Seasonal increase in specific IgE was significant in the antihistamine-treated group regardless of their clinical outcomes . In contrast , significant increase in specific IgE was observed during the pollen season in poor responders but not in good responders to immunotherapy . Serum levels of sIL-2R and sICAM-1 were significantly increased during the pollen season in poor responders of the antihistamine-treated group and the immunotherapy group . On the other h and , neither seasonal increase in sIL-2R nor sICAM-1 was significant in good responders of the antihistamine-treated group and the immunotherapy group . CONCLUSIONS Serum levels of sICAM-1 are higher in patients with seasonal allergic rhinitis , even outside of the pollen season when the allergen does not naturally exist . Seasonal changes in serum sICAM-1 as well as sIL-2R and specific IgE are probably objective markers to indicate the clinical efficacy of antihistamines and immunotherapy on seasonal allergic rhinitis Background : Patients with severe persistent asthma who are inadequately controlled despite Global Initiative for Asthma ( GINA ) 2002 step 4 therapy are a challenging population with significant unmet medical need . We determined the effect of omalizumab on clinical ly significant asthma exacerbations ( requiring systemic corticosteroids ) in the first omalizumab study to exclusively enrol patients from this difficult‐to‐treat patient population Background : Airway eosinophils are considered to play an important role in the pathogenesis of asthma . Interleukin-5 is believed to be a key cytokine for the development , proliferation and activation of eosinophils . Benralizumab is an anti-interleukin-5 receptor α monoclonal antibody that depletes blood and airway eosinophils . We conducted a phase 2a study in South Korea and Japan to evaluate the effect of benralizumab in an East Asian population . The primary objective was to evaluate the effect of benralizumab in adults with uncontrolled eosinophilic asthma with 2 - 6 incidences of exacerbations in the past year using a medium/high dose of inhaled corticosteroids and long-acting β2-agonists . Methods : This was a multicenter , r and omized , double-blind , placebo-controlled study . The subjects ( n = 106 ) were r and omized into four groups : placebo ( n = 27 ) or benralizumab 2 mg ( n = 27 ) , 20 mg ( n = 26 ) and 100 mg ( n = 26 ) . Benralizumab or placebo were administered subcutaneously on weeks 0 ( day 1 ) , 4 , 8 , 16 , 24 , 32 and 40 . The primary endpoint was the asthma exacerbation rate at week 52 . Results : The asthma exacerbation rate was reduced by 33 , 45 or 36 % versus the placebo group when treated with 2 , 20 or 100 mg of benralizumab , respectively . The percent mean change in forced expiratory volume at 1 s increased with each of the three doses in subjects treated with benralizumab . Conclusions : Benralizumab reduced asthma exacerbation and improved lung function and asthma control in adults with uncontrolled eosinophilic asthma AIMS IL-13 is implicated as an important mediator of the pathology of asthma . This first clinical study with GSK679586 , a novel humanized anti-IL-13 IgG1 monoclonal antibody , evaluated the safety , pharmacokinetics and pharmacodynamics of escalating single and repeat doses of GSK679586 . METHODS In this r and omized , double-blind study , healthy subjects received single intravenous infusions of GSK679586 ( 0.005 , 0.05 , 0.5 , 2.5 , 10 mg kg(-1 ) ) or placebo and mild intermittent asthmatics received two once monthly intravenous infusions of GSK679586 ( 2.5 , 10 , 20 mg kg(-1 ) ) or placebo . RESULTS GSK679586 displayed approximately linear pharmacokinetics ( based on AUC and C(max ) ) with limited accumulation upon repeat administration . In mild intermittent asthmatics , treatment with GSK679586 produced an increase in serum total IL-13 concentrations , indicative of GSK679586-IL-13 complex formation . Additionally , mean levels of exhaled nitric oxide ( FeNO ) , a marker of pulmonary inflammation , were reduced relative to baseline at 2.5 , 10 and 20 mg kg(-1 ) doses of GSK679586 at both 2 weeks ( 19 % , 44 % and 52 % decreases ) and 8 weeks ( 29 % , 55 % and 42 % decreases ) after the second infusion . GSK679586 was well tolerated ; the incidence of AEs was comparable across all presumed biologically active doses and there were no treatment-related SAEs . CONCLUSIONS GSK679586 demonstrated dose-dependent pharmacological activity in the lungs of mild intermittent asthmatics . These findings , together with the favourable safety profile and advantageous PK characteristics of a monoclonal antibody ( e.g. a long half-life supporting less frequent dosing ) , warrant further investigation of GSK679586 in a broader asthma patient population BACKGROUND Adult patients with nasal polyps often have comorbid asthma , adding to the serious effect on the quality of life of these patients . Nasal polyps and asthma might represent a therapeutic challenge ; inflammation in both diseases shares many features , such as airway eosinophilia , local IgE formation , and a T(H)2 cytokine profile . Omalizumab is a human anti-IgE mAb with proved efficacy in patients with severe allergic asthma .  Omalizumab could be a treatment option for patients with nasal polyps and asthma . OBJECTIVE The goal of this study was to investigate the clinical efficacy of omalizumab in patients with nasal polyps and comorbid asthma . METHODS A r and omized , double-blind , placebo-controlled study of allergic and nonallergic patients with nasal polyps and comorbid asthma ( n = 24 ) was conducted . Subjects received 4 to 8 ( subcutaneous ) doses of omalizumab ( n = 16 ) or placebo ( n = 8) . The primary end point was reduction in total nasal endoscopic polyp scores after 16 weeks . Secondary end points included a change in sinus computed tomographic scans , nasal and asthma symptoms , results of vali date d question naires ( Short-Form Health Question naire , 31-item Rhinosinusitis Outcome Measuring Instrument , and Asthma Quality of Life Question naire ) , and serum/nasal secretion biomarker levels . RESULTS There was a significant decrease in total nasal endoscopic polyp scores after 16 weeks in the omalizumab-treated group ( -2.67 , P = .001 ) , which was confirmed by means of computed tomographic scanning ( Lund-Mackay score ) . Omalizumab had a beneficial effect on airway symptoms ( nasal congestion , anterior rhinorrhea , loss of sense of smell , wheezing , and dyspnea ) and on quality -of-life scores , irrespective of the presence of allergy . CONCLUSION Omalizumab demonstrated clinical efficacy in the treatment of nasal polyps with comorbid asthma , supporting the importance and functionality of local IgE formation in the airways BACKGROUND Physicians have question ed whether omalizumab can be discontinued or the dose reduced after clinical improvement is seen in patients with severe asthma . OBJECTIVES To examine the relationships among omalizumab , free IgE , and clinical outcomes in a r and omized , placebo-controlled trial in patients with severe persistent allergic asthma following a posology based on pretreatment total IgE and body weight . METHODS A pharmacokinetic-pharmacodynamic binding model was used to calculate  free IgE , omalizumab  , and  total IgE concentrations during the 28-week treatment and 16-week follow-up of the INvestigation of Omalizumab in seVere Asthma TrEatment ( INNOVATE ) study . These were plotted against the mean changes in the total asthma symptom score , morning peak expiratory flow , and rescue medication use for physician-defined treatment responders and nonresponders . RESULTS The model accurately fitted omalizumab and free and total IgE , allowing reconstruction of the entire time course for each patient . Free IgE was rapidly suppressed below the 50 ng/mL ( 20.8 IU/mL ) target , although there was a notable period before clinical measures stabilized . After treatment cessation , free IgE and omalizumab returned toward baseline and , after a delay , asthma symptoms re-emerged . Model-derived omalizumab and free IgE concentrations correlated well with changes in clinical outcomes , particularly in omalizumab-treated responders . Asthma symptoms exhibited different correlations during response onset compared with response offset ( hysteresis ) , indicative of physiological time delays between changes in IgE levels and pulmonary function . CONCLUSION Omalizumab and free IgE correlated well with clinical symptoms . Reducing omalizumab doses below those in the dosing table can not be recommended ; the result ing increase in free IgE would cause a deterioration in asthma control OBJECTIVE To evaluate the efficacy of currently used inactivated influenza vaccine during a severe epidemic caused by antigenically drifted influenza type A(H3N2 ) and well-matched type B viruses during the 1992 - 1993 season . DESIGN Prospect i ve nonr and omized controlled trial . SETTING An urban general hospital pediatric asthma clinic in Japan . PARTICIPANTS A total of 137 children with moderate to severe asthma ( mean age , 7.0 years ; range , 2 to 14 years ) . INTERVENTION Eighty-five children received trivalent split-antigen vaccine containing A/Beijing/352/89 ( H3N2 ) and B/Bangkok/163/90 ( B/Panama/45/90-like strain ) . Fifty-two were unvaccinated . MAIN OUTCOME MEASURES Protection against infection was determined using hemagglutination inhibition test and virus isolation . Clinical efficacy was estimated based on febrile episodes with antibody rise or virus isolation . RESULTS Although marked antigenic drift in hemagglutinin was demonstrated in the epidemic virus ( A/Beijing/32/92-like strain ) , the protection against influenza type A(H3N2 ) infection was 67.5 % ( P < .01 ) . The protection against influenza type B infection was 43.7 % ( P < .01 ) , although the epidemic influenza type B viruses were antigenically almost identical to the vaccine strain . Inactivated vaccine was not effective for protection against influenza type B infection in children younger than 7 years . High clinical effectiveness was demonstrated in children at least 7 years of age during the epidemic . CONCLUSIONS Our data suggest that current inactivated vaccine is highly effective for protection against influenza type A(H3N2 ) virus infection regardless of antigenic drift . In contrast , the protective efficacy obtained by vaccination may not be sufficient against influenza type B virus infection , and especially in young children , it does not offer protection BACKGROUND Many children with asthma continue to experience symptoms despite available therapies . OBJECTIVE This study evaluated the efficacy and safety of omalizumab , a humanized anti-IgE mAb , in children with moderate-to-severe persistent allergic ( IgE-mediated ) asthma that was inadequately controlled despite treatment with medium-dose or high-dose inhaled corticosteroids ( ICSs ) with or without other controller medications . METHODS A r and omized , double-blind , placebo-controlled trial enrolled children age 6 to < 12 years with perennial allergen sensitivity and history of exacerbations and asthma symptoms despite at least medium-dose ICSs . Patients were r and omized 2:1 to receive omalizumab ( 75 - 375 mg sc , q2 or q4 wk ) or placebo over a period of 52 weeks ( 24-week fixed-steroid phase followed by a 28-week adjustable-steroid phase ) . RESULTS A total of 627 patients ( omalizumab , n = 421 ; placebo , n = 206 ) were r and omized , with efficacy analyzed in 576 ( omalizumab , n = 384 ; placebo , n = 192 ) . Over the 24-week fixed-steroid phase , omalizumab reduced the rate of clinical ly significant asthma exacerbations ( worsening symptoms requiring doubling of baseline ICS dose and /or systemic steroids ) by 31 % versus placebo ( 0.45 vs 0.64 ; rate ratio , 0.69 ; P = .007 ) . Over a period of 52 weeks , the exacerbation rate was reduced by 43 % versus placebo ( P < .001 ) . Omalizumab significantly reduced severe exacerbations . Over a period of 52 weeks , omalizumab had an acceptable safety profile , with no difference in overall incidence of adverse events compared with placebo . CONCLUSION Add-on omalizumab is effective and well tolerated as maintenance therapy in children ( 6 to < 12 years ) with moderate-to-severe persistent allergic ( IgE-mediated ) asthma whose symptoms are inadequately controlled despite medium to high doses of ICSs Many children with recurrent sinopulmonary infections fail to mount an adequate humoral response following immunization with polysaccharide antigens . At present there are no controlled studies comparing responses to pneumococcal immunization in children with recurrent infections and a healthy , age-matched cohort .  Immunological evaluation was performed on 66 children with recurrent sinopulmonary infections , aged 2 - 5 years ( mean 3.06 + /- 0.92 ) . A control group included 28 healthy , age-matched controls ( mean 3.14 + /- 0.88 years ) . Both groups were immunized with 23 valent pneumococcal vaccine , and titers were measured before and 4 weeks after immunization . Antibody levels to 12 pneumococcal serotypes were measured via radioimmunoassay .  Geometric preimmunization mean titers in the control group were 215.5 + /- 157 ngAbN/ml rising to 989.5 + /- 745 ngAbN/ml compared to 77.71 + /- 38.4 ngAbN/ml increasing to 446.7 + /- 406 ngAbN/ml in the study group ( p < .05 ) . Serotypes 3 , 4 , 7F , 8 , 9N , and 18C were the most immunogenic , while serotypes 6A and 14 were the least . Overall , the control group responded to 7.71 + /- 1.24 serotypes versus 5.1 + /- 2.0 in the study group ( p < .05 ) , where postimmunization titers at least doubled and rose to > or = 300 ngAbN/ml . All controls responded to at least five or more serotypes , 26/28 responded to 6 or more . In contrast , only 38/66 ( 57 % ) of study patients responded to five or more serotypes , and only 27/66 ( 41 % ) responded to at least 6 of 12 . Preimmunization titers of greater than 300 ngAbN/ml were present in 30 % ( 102/336 ) of the control serotypes ; however , only 53 of these ( 52 % ) doubled post immunization ; 22 % of the elevated titers decreased post immunization . Markedly elevated titers > or = 500 ngAbN/ml were present in 20 % ( 69/336 ) of the preimmunization serotypes , only 39 % of these doubled post immunization . Twenty-three valent pneumococcal vaccine is immunogenic in young , healthy children . A significant percentage of children with recurrent sinopulmonary infections fail to produce adequate serotype specific antibodies following pneumococcal immunization Methods Mild asthmatics and normal controls were recruited as study subjects . This crossover study was double-blinded , r and omized and counter-balanced to the order of three conditions : diesel exhaust with anti-oxidant , diesel exhaust with placebo , or filtered air with placebo . The subjects were exposed to either filtered air or diesel exhaust ( 300 ug PM2.5/m ) in a state-of-the-art diesel exhaust exposure facility . An anti-oxidant , N-acetylcysteine ( 600 mg ) , or a placebo was taken orally for five days preceding , and on the day of the exposure . Each subject was exposed to each of the three conditions .  Peripheral blood sample s were taken pre-exposure , and also at 2 , 6 , and 30 hours after the beginning of exposure . Sputum induction was performed by inhalation of hypertonic saline according to ATS guidelines pre-exposure , and also at 6 , and 30 hours after the beginning of exposure . FACSCanto II ( BD Biosciences ) was used for flow cytometry . A 5-colour , 12-marker ( CD3/CD9/ CD14/CD16/CD19/CD20/CD45/CD56/CD83/CD206/ CD326/HLA-DR ) combination was used to identify dendritic cells , macrophages , monocytes , neutrophils , eosinophils , and bronchial epithelial cells . Direct immunolabelling was performed on whole peripheral blood . After incubation , red blood cells were lysed . Remaining cells were washed and resuspended in PBS with 0.5 % paraformaldehyde . Sputum plugs were homogenized with 0.1 % DTT , filtered , and then centrifuged to remove supernatant . Sputum cells were resuspended in PBS at 1 million per mL. Direct immunolabelling was performed . After incubation , cells were washed and resuspended in PBS with 0.5 % paraformaldehyde . Spectral compensation for flow cytometry was performed using an automatic calibration technique ( BD CompBeads ) . Cellular debris was eliminated on the SSC/FSC scattergram . A gating strategy was design ed to identify the leukocyte sub- population s and bronchial epithelial cells . Surface markers were chosen based on differential cell-specific expression according to existing literature Several approaches have recently been put forward describing attempts to suppress the IgE immune response towards allergens , which is thought to be the key event in allergic diseases . In a series of clinical trials we have shown that injections of complexes made up from allergen and specific antibodies are an effective treatment for allergic bronchial asthma and atopic dermatitis . In the work presented here we have examined the humoral immunity changes associated with the use of such complexes in a group of 19 adult patients suffering from atopic dermatitis and hypersensitive to Dermatophagoides pteronyssinus ( Dp ) , and in whom a significant clinical improvement was observed . By comparing serum sample s taken prior to and after 4 months of therapy , we show that the administration of immune complexes is associated with : ( i ) a significant and selective reduction of IgG and IgE antibodies specific for Dp allergens ; ( ii ) a down-regulation that affects only the antibodies present in the complexes ; ( iii ) the induction of corresponding anti-idiotypic antibodies . To our knowledge , this is the first demonstration in humans that an anti-allergen antibody response can be down-regulated in a highly selective manner and that this is accompanied by significant clinical improvement . Moreover , the selective reduction of IgG antibodies could be of value in the treatment of some forms of auto-immune diseases IgE plays an important role in allergic asthma . We hypothesized that reducing IgE in the airway mucosa would reduce airway inflammation .  Forty-five patients with mild to moderate persistent asthma with sputum eosinophilia of 2 % or more were treated with humanized monoclonal antibody against IgE ( omalizumab ) ( n = 22 ) or placebo ( n = 23 ) for 16 weeks . Outcomes included inflammatory cells in induced sputum and bronchial biopsies , and methacholine responsiveness . Treatment with omalizumab result ed in marked reduction of serum IgE and a reduction of IgE+ cells in the airway mucosa . The mean percentage sputum eosinophil count decreased significantly ( p < 0.001 ) from 6.6 to 1.7 % in the omalizumab group , a reduction significantly ( p = 0.05 ) greater than with placebo ( 8.5 to 7.0 % ) . This was associated with a significant reduction in tissue eosinophils ; cells positive for the high-affinity Fc receptor for IgE ; CD3 + , CD4 + , and CD8 + T lymphocytes ; B lymphocytes ; and cells staining for interleukin-4 , but not with improvement in airway hyperresponsiveness to methacholine . This study shows antiinflammatory effects of omalizumab treatment and provides clues for mechanisms whereby omalizumab reduces asthma exacerbations and other asthma outcomes in more severe asthma . The lack of effect of omalizumab on methacholine responsiveness suggests that IgE or eosinophils may not be causally linked to airway hyperresponsiveness to methacholine in mild to moderate asthma Intravenous administration of a humanized monoclonal antibody of IgE ( E25 ) attenuates the early and late phase response to inhaled allergen in allergic asthmatic subjects . To test whether direct delivery of E25 to the airway might have the same effect , we conducted a r and omized , double-blind , three group study in 33 subjects with mild allergic asthma ( 20 to 46 yr of age , 21 men , FEV(1 ) > 70 % predicted ) . The airway responses to aerosolized allergen were determined at baseline , after 2 and 8 wk of once daily treatment with aerosolized placebo ( n = 11 ) , aerosolized E25 1 mg ( n = 12 ) , or aerosolized E25 10 mg ( n = 10 ) , and after 4 wk of treatment withdrawal . We found that E25 was detectable in the serum during aerosol treatment , although serum IgE did not change significantly in any of the three groups during treatment . In addition , both doses of E25 were no more effective than placebo in attenuating the early phase responses to allergen at both times during treatment . Although aerosolized E25 was generally well tolerated , one subject receiving aerosolized E25 10 mg daily was found to have serum IgG and IgA antibodies to E25 . We conclude that aerosol administration of an anti-IgE monoclonal antibody does not inhibit the airway responses to inhaled allergen in allergic asthmatic subjects . We speculate that the observed lack of efficacy may be due to the inability of aerosol route of delivery to result in high enough concentrations of E25 in the tissue compartments surrounding IgE effector cells to neutralize IgE arising from local airway and pulmonary sources and IgE arising from the vascular space . Additionally , the aerosol route of delivery of monoclonal antibodies may be more immunogenic than the parenteral route Xomen-E5 ( E5 ) is a murine monoclonal IgM antibody ( MAb ) that binds to the lipid A epitope of endotoxin . The MAb was developed by immunization against the J5 mutant of Escherichia coli . Prior studies in humans have shown safety and T1/2 of 18.4 hours . In this double blind study patients suspected to have life threatening gram-negative infections were r and omized to receive 2 doses , 24 hours apart , of placebo ( P ) , 2.5 mg/kg E5 , or 7.5 mg/kg E5 . Overall 23 patients had a documented serious gram-negative infection and received at least one dose of study drug . Mortality 3 days after last infusion was 2 of 9 for P , 0 of 9 for 2.5 mg/kg , and 0 of 5 for 7.5 mg/kg . By 21 days after therapy one E5 treated patient had died . Wheezes occurred in one E5 treated patient . Eight of 15 E5 patients treated had IgG anti-murine antibodies by 3 weeks after therapy . These data suggest the need to pursue studies design ed to verify that E5 reduced mortality and morbidity in seriously ill patients with gram-negative infections BACKGROUND We have previously shown that omalizumab , a recombinant humanized monoclonal anti-IgE antibody , reduces asthma exacerbations and decreases inhaled corticosteroid ( ICS ) requirement in patients with severe allergic asthma who were symptomatic despite moderate-to-high doses of ICSs . OBJECTIVE The aim of the present study was to assess the effects of omalizumab on asthma-related quality of life ( QOL ) . METHODS These analyses were part of a multicenter , 52-week , r and omized , double-blind , placebo-controlled study assessing the efficacy , safety , and tolerability of subcutaneous omalizumab ( > or = 0.016 mg/kg of IgE [ in international unit per milliliter ] per 4 weeks ) in 525 adults with severe allergic asthma . A 16-week steroid-stable phase was followed by a 12-week steroid-reduction phase and a 24-week double-blind extension phase . The effect of treatment on asthma-related QOL was evaluated by using the Asthma Quality of Life Question naire ( AQLQ ) administered at baseline and at weeks 16 , 28 , and 52 . RESULTS The 2 treatment groups were comparable in terms of baseline AQLQ scores . At weeks 16 , 28 , and 52 , omalizumab-treated patients demonstrated statistically significant improvements across all AQLQ domains , as well as in overall score . Moreover , a greater proportion of patients receiving omalizumab achieved a clinical ly meaningful improvement in asthma-related QOL during each phase of the study . Greater than 50 % of both patients and investigators rated treatment similarly with omalizumab as excellent or good compared with less than 40 % of placebo recipients . CONCLUSION In patients requiring moderate-to-high doses of ICSs for severe allergic asthma , the measurably improved disease control afforded by add-on omalizumab therapy is paralleled by clinical ly meaningful improvements in asthma-related QOL RATIONALE IL-4 and IL-13 share many biological functions important in the development of allergic airway inflammation and are implicated in the pathogenesis of asthma . AMG 317 is a fully human monoclonal antibody to IL-4Ralpha that blocks both IL-4 and IL-13 pathways . OBJECTIVES To evaluate efficacy and safety of AMG 317 in patients with moderate to severe asthma . METHODS In this phase 2 , r and omized , double-blind , placebo-controlled study , patients received weekly subcutaneous injections of  placebo or AMG 317 ( 75 - 300 mg ) for 12 weeks , followed by a 4-week follow-up period . The primary endpoint was change from baseline at Week 12 in Asthma Control Question naire ( ACQ ) symptom score . MEASUREMENTS AND MAIN RESULTS Mean ACQ change ( SE ) was -0.49 ( 0.09 ) in placebo ( n = 74 ) , and -0.43 ( 0.11 ) , -0.58 ( 0.12 ) , and -0.70 ( 0.09 ) in the AMG 317 75 mg ( n = 73 ) , 150 mg ( n = 73 ) , and 300 mg ( n = 74 ) groups , respectively ( treatment effect P = 0.25 ) . No statistically significant differences were observed in the secondary endpoints . Numerical decreases in number of and time to exacerbations were noted in patients receiving AMG 317 150 mg and 300 mg . Preplanned analyses by tertile of baseline ACQ revealed that patients with higher baseline ACQ scores ( > or=2.86 ) were more likely to respond to AMG 317 . Serious adverse events were reported in three patients , each noted as not related to study drug . CONCLUSIONS AMG 317 did not demonstrate clinical efficacy across the overall group of patients . Clinical ly significant improvements were observed in several outcome measures in patients with higher baseline ACQ scores . AMG 317 was safe and well tolerated in this study population . Clinical trial registered with www . clinical trials.gov ( NCT 00436670 ) We evaluated the clinical efficacy and immunologic changes associated with the administration of tyrosine-adsorbed Dermatophagoides pteronyssinus ( Dpt ) extract . The study was carried out in a double-blind , placebo-controlled fashion in 18 patients with Dpt-induced asthma during a trial period of at least 12 mo . Patients initially received six increasing doses once a week ; the top dose of 400 Noon units was repeated at monthly intervals . Clinical response was on the basis of diary cards on which symptoms and medication scores were recorded ; daily lung function measurements were made by use of a mini Wright 's peak flow meter . The entire spectrum of physiologic measurements , medications , and symptoms were taken into account by computing daily scores over a 2-week period . Total IgE , Dpt-specific IgE antibodies , and leukocyte histamine release were measured before treatment and during hyposensitization . Changes in Dpt-specific IgG were evaluated with a double antibody antigen-binding assay by use of the purified fraction of mite extract F4P1 . All patients had measurable levels of IgG antibodies to F4P1 before treatment . Treatment with tyrosine-adsorbed Dpt extract result ed in a significant increase of specific-IgG antibodies in the treated group at 2 and 6 mo only ( nonparametric rank sum test ) . Variations relative to the pretreatment values of total and specific IgE were not significantly different in the treated and in the control patients after 2.6 and 12 mo . No significant decrease in leukocyte sensitivity was observed after treatment . It was only possible to demonstrate a significant diminution in the mean medication score ( nonparametric sign test ) in the first 6 mo for the treated group ; independently of the beginning of the treatment , the treated group demonstrated a reduction of the mean medication score and an improvement in peak expiratory flow rate lung function before the midsummer months when seasonal increase in mite density can occur . Particular attention was paid to the method ological problems raised during this study and inherent in a trial in house dust-mite asthma The effect of feeding different infant formulas on incidence of atopic disease was assessed in a prospect i ve double-blind r and omized controlled trial among " high risk " infants with family history of atopy among first-degree relatives . The incidence of atopic eczema , wheezing , rhinitis , gastrointestinal symptoms , and colic was noted and serum IgE antibodies to milk were estimated . Seventy-two infants were recruited into each of the following groups : cow milk whey hydrolysate formula ( NAN/HA ) , conventional cow milk formula ( Similac ) , soy-based formula ( Isomil ) , and exclusive breast feeding for greater than or equal to 4 months .  The number of infants who exited for reasons other than atopy and were excluded from analysis were 4 , 5 , 4 , and 12 in the four groups , respectively . The incidence of one or more symptoms of possible allergic etiology was five of 68 infants fed NAN/HA , 24 of 67 infants fed Similac , 25 of 68 infants fed Isomil , and 12 of 60 breast-fed infants . Among symptomatic infants , skin prick test to milk proteins was positive in four out of five infants fed NAN/HA , 16 of 24 fed Similac , 2 of 25 fed Isomil , and 7 of 12 breast-fed . IgE antibodies to milk were found in 2 of 68 , 9 of 67 , 0 of 68 , and 6 of 60 infants in the four groups , respectively . It is concluded that exclusive breast feeding for more than 4 months is partially protective against the development of atopic disease among high risk infants . ( ABSTRACT TRUNCATED AT 250 WORDS Abstract Background : Many children with severe persistent allergic ( IgE-mediated ) asthma remain inadequately controlled despite treatment with high-dose inhaled corticosteroids ( ICS ) plus a long-acting β2-agonist ( LABA ) . Research and design methods : This pre-specified analysis of a r and omized , double-blind , placebo-controlled trial evaluated the efficacy and safety of omalizumab  in children ( 6–<12 years ) with perennial allergen sensitivity , and history of asthma exacerbations and symptoms despite treatment with ICS ( fluticasone ≥500 µg · day−1 or equivalent ) plus a LABA . Patients received omalizumab ( 75–375 mg once or twice a month by subcutaneous injection , as determined from dosing tables ) or placebo over 52 weeks ( 24-week fixed-steroid then 28-week adjustable-steroid phases ) . Results : Out of 246 r and omized patients ( omalizumab , n = 166 ; placebo , n = 80 ) , efficacy  was analysed in 235 (  omalizumab , n = 159 ; placebo , n = 76 ) . Over the 24-week fixed-steroid phase , omalizumab reduced the rate of clinical ly significant asthma exacerbations ( worsening symptoms requiring doubling of baseline ICS dose and /or systemic steroids ) by 34 % versus placebo ( 0.42 vs 0.63 , rate ratio 0.662 ; P = 0.047 ) . Over 52 weeks , the exacerbation rate was reduced by 50 % ( P < 0.001 ) . Omalizumab had an acceptable safety profile , with no statistically significant ( P < 0.05 ) differences in adverse events observed between omalizumab and placebo . Conclusion : Add-on omalizumab is well-tolerated and reduces exacerbations in children ( 6–<12 years ) with severe persistent allergic asthma , inadequately controlled despite high-dose ICS plus a LABA . It should be noted that the sample size was not based on providing statistical power in the severe subgroup , and no corrections were made for multiple comparisons ; however , outcomes consistently favoured omalizumab . Trial registration : Clinical Trials.gov identifier : NCT00079937 Cat allergen ( Fel d 1 ) is a pervasive and common trigger of exacerbations in sensitized patients with IgE-mediated asthma . This study was design ed to evaluate the effect on asthma-related outcome measures of adding omalizumab to current treatment in patients with moderate-to-severe persistent asthma and cat allergen sensitivity . A pooled analysis was conducted of two double-blind , placebo-controlled , 28-week pivotal U.S. registration trials . In all patients , asthma was inadequately controlled with moderate-high dose inhaled corticosteroids . Patients were r and omized to receive subcutaneous omalizumab ( minimum , 0.016 mg/kg per IgE IU/mL every 4 weeks ) or matched placebo . The effects of omalizumab on asthma-related outcomes were assessed for patients with cat allergen sensitivity ( n = 811 ) , identified by positive skin-prick test . The mean number of asthma exacerbations requiring treatment with systemic steroid bursts in cat allergen-sensitive patients was lower in those receiving omalizumab versus placebo ( 0.6 versus 1.3 , respectively ; relative risk = 0.50 , p < 0.001 ) . Compared with placebo , omalizumab treatment led to significantly lower asthma symptom scores ( least squares means ( LSMs ) treatment difference [ 95 % confidence interval { CI } ] : -0.57 [ -0.77 , -0.37 ] ; p < 0.001 ) , less rescue medication use ( LSMs treatment difference [ 95 % CI ] : -0.75 puffs of rescue beta-agonist per day [ -1.04 , -0.46 ] ; p < 0.001 ) , and improvement in forced expiratory volume in 1 second ( LSMs treatment difference [ 95 % CI ] : 100.84 mL [ 51.86 , 149.81 ] ; p < 0.001 ) . Patient and investigator global evaluations of treatment effectiveness paralleled these outcomes . Omalizumab improved asthma control by reducing exacerbations and decreasing symptoms in cat-allergic patients with moderate-to-severe persistent IgE-mediated asthma In a prospect i ve study , 60 patients with allergic rhinoconjunctivitis and /or asthma due to house dust mites were chosen for  hyposensitization treatment with Migen ( M ) or Pharmalgen ( P ) . Immunotherapy stretched over a whole year and every 3 months clinical results were evaluated by the patient 's symptom score , by results of skin prick and conjunctival provocation tests , as well as by RIA and ELISA regarding the total and specific IgE and also specific IgG and IgG4 levels . Out of 30 patients of the M group , 15 were followed up over the whole therapeutic regimen , 4 of whom showed a very good , 7 a good to moderate clinical outcome and 4 showed no improvement at all . In the P group , 17 out of 30 patients were followed up whereby 9 showed a very good and 8 a good to moderate response . In both groups of patients a statistically significant decrease in skin and conjunctival sensitivity to mite allergens was observed after 12 months of therapy . However , there was no correlation between this observation and the failure or success of immunotherapy . Furthermore , in both groups there was significant increase in total and specific IgE ( with a slight decrease after 6 to 12 months ) and also in specific IgG and IgG4 ( especially in the P group ) , but again these changes in antibody levels gave no indication of a good or bad clinical outcome . Hence , we believe other reasons than the usually presented thesis of inducing " blocking antibodies " by immunotherapy to be responsible for the well-known effects of hyposensitization BACKGROUND Although specific immunotherapy is a valuable treatment option for patients with allergic asthma , the potential for systemic allergic reactions has limited its use , especially for patients with symptomatic disease . OBJECTIVE To evaluate omalizumab 's effect on the tolerability of specific immunotherapy in patients with symptomatic persistent asthma not adequately controlled with inhaled corticosteroids . METHODS This multicenter , double-blind , parallel-group study r and omized patients to treatment with omalizumab or placebo  , after which they received specific immunotherapy to at least 1 of 3 perennial aeroallergens ( cat , dog , and house dust mite ) according to a 4-week , 18-injection cluster regimen , followed by 7 weeks of maintenance therapy . The primary efficacy variable , a systemic allergic reaction after immunotherapy , was analyzed by using the Cochrane-Mantel-Haenszel test . RESULTS A total of 248 r and omized patients ( 126 omalizumab  , 122  placebo )  received at least 1 dose of immunotherapy and were evaluated for efficacy . Patients receiving omalizumab experienced significantly fewer systemic allergic reactions to immunotherapy than those receiving placebo ( 17/126 [ 13.5 % ] vs 32/122 [ 26.2 % ] ; P = .017 ; 95 % CI , 2.91 % to 22.56 % ) and had fewer respiratory-related ( grade 3 ) systemic allergic reactions ( 6 vs 24 , respectively ) . Grade 4 reactions were reported in 2 patients in each group . More omalizumab patients were able to reach the target maintenance immunotherapy dose ( 110 [ 87.3 % ] vs 88 [ 72.1 % ] , respectively ; P = .004 ) . CONCLUSION Use of omalizumab in patients whose asthma was symptomatic despite use of inhaled corticosteroids was associated with fewer systemic allergic reactions to specific immunotherapy and enabled more patients to achieve the target immunotherapy maintenance dose Eosinophil-derived TGF-beta has been implicated in remodeling events in asthma . We hypothesized that reduction of bronchial mucosal eosinophils with anti-IL-5 would reduce markers of airway remodeling . Bronchial biopsies were obtained before and after three infusions of a humanized , anti-IL-5 monoclonal antibody ( mepolizumab ) in 24 atopic asthmatics in a r and omized , double-blind , placebo-controlled study . The thickness and density of tenascin , lumican , and procollagen III in the reticular basement membrane ( RBM ) were quantified immunohistochemically by confocal microscopy . Expression of TGF-beta1 mRNA by airway eosinophils was assessed by in situ hybridization , and TGF-beta1 protein was measured in bronchoalveolar lavage ( BAL ) fluid by ELISA . At baseline , airway eosinophil infiltration and ECM protein deposition was increased in the RBM of asthmatics compared with nonasthmatic controls . Treating asthmatics with anti-IL-5 antibody , which specifically decreased airway eosinophil numbers , significantly reduced the expression of tenascin , lumican , and procollagen III in the bronchial mucosal RBM when compared with placebo . In addition , anti-IL-5 treatment was associated with a significant reduction in the numbers and percentage of airway eosinophils expressing mRNA for TGF-beta1 and the concentration of TGF-beta1 in BAL fluid . Therefore eosinophils may contribute to tissue remodeling processes in asthma by regulating the deposition of ECM proteins BACKGROUND Respiratory syncytial virus ( RSV ) lower respiratory tract infection ( LRTI ) is the most frequent cause of bronchiolitis during infancy . Long-term airway morbidity with recurrent post bronchiolitis wheezing ( PBW ) episodes , which are probably associated with respiratory infections , occurs in 30 to 70 % of infants that were hospitalised with RSV LRTI . METHODS We set up a multicenter , placebo-controlled double-blind r and omized clinical trial in healthy preterm infants born between 33 and 35 weeks gestational age ( WGA ) . The children received either one-monthly intramuscular palivizumab or placebo injection during the RSV season with a minimum of 2 injections . RESULTS The primary objective was to determine the preventive effect of RSV immunoprophylaxis ( palivizumab ) on the development of recurrent wheezing during the first year of life . The primary outcome measure was the number of wheezing days during the first year of life as obtained by daily logs . As a secondary outcome nasal swabs were taken for viral analysis in case of respiratory symptoms . We will also examine wheezing at age 1 , 3 and 6 years both reported by the parents and the general practitioner and quality of life as secondary outcomes . This trial is possible because RSV immunoprophylaxis , although effective in this population , is not completely used in the Netherl and s due to its high costs . CONCLUSION The Institutional review board ( IRB ) concluded the study has high clinical relevance because the benefit of 50 % chance of protection by palivizumab outweighs the risk of side adverse events due to intramuscular administration of placebo BACKGROUND Anti-IgE ( omalizumab ) inhibited early and late  asthmatic reactions and infiltration of inflammatory cells in asthmatic bronchial biopsies at baseline . The effect of chronic allergen exposure on these outcomes is unknown . Repeat allergen challenge in human skin represents a suitable model to address this question . OBJECTIVE To study the effect of anti-IgE ( omalizumab ) on early-phase ( EPR ) and late-phase ( LPR ) skin reactions and cellular infiltration by using a repeat skin allergen challenge design ed to imitate chronic allergen exposure . METHODS Twenty-four atopic allergic volunteers received  omalizumab or placebo for 12 weeks . Paired intradermal challenges of allergen ( 30 biological units ) and diluent control were administered on 9 occasions at 2-week intervals . Early-phase and late-phase skin reactions and cellular infiltration in skin biopsies ( using immunohistochemistry and in situ hybridization ) were measured at intervals . RESULTS Compared with placebo , omalizumab-treated patients had a progressive reduction in the LPR that was significantly greater than its effect on the EPR ( median , --63 % vs--24 % respectively ; P=.009 ) . In addition , significant reduction of the LPR was reached within 2 weeks of commencing treatment , compared with 8 weeks for the EPR . There was a priming effect of repeated allergen challenge on infiltration of eosinophil , neutrophil , T(H)2 ( CD3(+)/IL-4(+ ) ) , and total FcepsilonRI(+ ) cells in patients on placebo that was abrogated in those receiving omalizumab . CONCLUSION The more marked effect of omalizumab on the LPR and prevention of the repeat-dose priming effect on several inflammatory cell types support a role for anti-IgE treatment in conditions associated with chronic allergic inflammation UNLABELLED Pathogenetic mechanisms responsible for efficacy of specific immunotherapy still remain to be fully explained . This concerns both desensitization with classic allergens and very rarely used specific immunotherapy with bacteria . Microbes can play important role as hypersensitivity factor in some allergo-inflammatory processes . Bacterial products may act as basophil histamine liberators through immunological ( IgE-mediated ) and nonimmunological -- particular lectin-sugar way . The aim of study was to verify if histamine release triggered by microbes could be modified ( blocked ) with specific antibacterial antibodies -- taking into consideration both of mechanisms of basophil degranulation . The size of immediate ( in healthy persons -- Tab . 3 , 4 ) and late as well as delayed ( in asthmatic patients --Tab . 8) skin reactivity to examined microorganisms and the degree of basophil histamine release induced with these bacteria were compared . Human basophils were isolated from peripheral blood on Ficoll-Hypaque gradient  , next challenged with whole , formalin-killed bacteria and with the same bacteria after incubation with specific and nonspecific sera . To differentiate between IgE-dependent and non-immunological mechanisms of histamine release , the IgE molecules were removed from the surface of the basophils by exposure to pH 3.6 ( stripping ) . In each experiment histamine release induced by anti-IgE antibodies was used as control of stripping ( Tab . 5 , 9 ) . Levels of histamine from the basophils ( without and after stripping ) incubated with non-coated and specific antibodies coated bacteria were compared . The results were expressed as a percentage of total histamine content in the sample . Histamine release was assayed spectrofluorometrically by using Shore method in Norn modification . The main investigations concerned the basophils from 12 healthy , non-atopic individuals , who had positive immediate skin reactions with at least 1 from 3 microbial strains : Staphylococcus aureus 9615 ( unencapsulated ) , Staphylococcus aureus Smith ( encapsulated ) and Escherichia coli . Sera containing specific antibodies for these microorganisms were obtained from immunized rabbits . As negative control served sera collected from animals after immunization . Additionally the basophils of 6 asthmatic ( intrinsic asthma ) patients treated with autovaccines were examined . All patients demonstrated positive late and delayed skin reactions , 3 of them also immediate , to autologous Neisseria and Moraxella species cultured from upper respiratory tract . The bacteria were used as a component of autovaccine and as a basophils stimulating factor in histamine assay . Microbes were incubated with patients own sera before ( unspecific serum ) and after treatment ( source of " specific " antibodies ) . CONCLUSIONS 1 . Bacteria induced basophil histamine release through two ways : immunological ( IgE-mediated ) and non-immunological ( sugar-lectin interactions ) . 2 . Non-immunological interactions played the main role in basophil histamine release induced by bacteria -- both in normal individuals and asthmatic patients . 3 . Sera of immunized with bacteria animals partially reduced basophil histamine release induced by homologous strains ( Tab . 7 ) . 4 . An incubation of autologous bacterial strains with asthmatic patients 's sera collected after autovaccines treatment has no influence on basophil histamine release induced by these microbes ( Tab . 9 ) . 5 . There was no correlation between the  skin reactivity  to bacteria ( both in healthy persons and in asthmatic patients ) and the intensity of basophil histamine release induced by microbes BACKGROUND Previous reports show that addition of omalizumab to st and ard therapy reduces asthma exacerbations and simultaneously decreases use of inhaled corticosteroids ( ICSs ) and rescue medication in patients with allergic asthma . OBJECTIVE To determine the effect of omalizumab on long-term disease control in patients with severe allergic asthma . METHODS The present study concerns the 24-week , double-blind extension phase to a previous 28-week core study in which patients received subcutaneous omalizumab or matching placebo ( at least 0.016 mg/kg/IgE [ IU/mL ] every 4 weeks ) for 16 weeks in addition to their existing ICS therapy ( beclomethasone dipropionate [ BDP ] ; steroid-stable phase ) , followed by a 12-week phase in which controlled attempts were made to gradually reduce ICS therapy ( steroid-reduction phase ) . During the extension phase patients were maintained on r and omized treatment ( omalizumab or placebo ) and the lowest sustainable dose of BDP . The use of other asthma medications was permitted during the extension phase . Investigators were also allowed to switch patients from BDP to other ICS medications if considered necessary . RESULTS A total of 460 patients ( omalizumab , n = 245 ; placebo , n = 215 ) entered the extension phase . Overall , omalizumab-treated patients experienced significantly fewer exacerbations vs placebo during the extension phase ( 0.60 and 0.83 exacerbations per patient , respectively ; P = 0.023 ) , despite a sustained significant reduction in their use of ICS ( mean BDP equivalent dose : omalizumab , 227 microg/d ; placebo , 335 microg/d ; P < 0.001 ) . Treatment with omalizumab was well tolerated and the incidence of adverse events was similar in both treatment groups . CONCLUSIONS These results indicate that omalizumab is effective in the long-term control of severe allergic asthma BACKGROUND Inhaled corticosteroids ( ICS ) and long-acting β(2)-agonists ( LABAs ) are recommended in patients with asthma that is not well-controlled ; however , many patients continue to have inadequately controlled asthma despite this therapy . OBJECTIVE To evaluate the efficacy and safety of omalizumab in patients with inadequately controlled severe asthma who are receiving high-dose ICS and LABAs , with or without additional controller therapy . DESIGN Prospect i ve , multicenter , r and omized , parallel-group , double-blind , placebo-controlled trial . ( Clinical Trials.gov registration number : NCT00314575 ) . SETTING 193 investigational sites in the United States and 4 sites in Canada . PATIENTS 850 patients aged 12 to 75 years who had inadequately controlled asthma despite treatment with high-dose ICS plus LABAs , with or without other controllers . INTERVENTION Omalizumab ( n = 427 ) or placebo ( n = 423 ) was added to existing medication regimens for 48 weeks . MEASUREMENTS The primary end point was the rate of protocol -defined exacerbations over the study period . Secondary efficacy end points included the change from baseline to week 48 in mean daily number of puffs of albuterol , mean total asthma symptom score , and mean overall score on the st and ardized version of the Asthma Quality of Life Question naire ( AQLQ[S ] ) . Safety end points included the frequency and severity of treatment-emergent adverse events . RESULTS During 48 weeks , the rate of protocol -defined asthma exacerbations was significantly reduced for omalizumab compared with placebo ( 0.66 vs. 0.88 per patient ; P = 0.006 ) , representing a 25 % relative reduction ( incidence rate ratio , 0.75 [ 95 % CI , 0.61 to 0.92 ] ) . Omalizumab improved mean AQLQ(S ) scores ( 0.29 point [ CI , 0.15 to 0.43 ] ) , reduced mean daily albuterol puffs ( -0.27 puff/d [ CI , -0.49 to -0.04 puff/d ] ) , and decreased mean asthma symptom score ( -0.26 [ CI , -0.42 to -0.10 ] ) compared with placebo during the 48-week study period . The incidence of adverse events ( 80.4 % vs. 79.5 % ) and serious adverse events ( 9.3 % vs. 10.5 % ) were similar in the omalizumab and placebo groups , respectively . LIMITATIONS The results are limited by early patient discontinuation ( 20.8 % ) . The study was not powered to detect rare safety events or the treatment effect in the oral corticosteroid subgroup . CONCLUSION In this study , omalizumab provided additional clinical benefit for patients with severe allergic asthma that is inadequately controlled with high-dose ICS and LABA therapy . PRIMARY FUNDING SOURCE Genentech and Novartis Pharmaceuticals BACKGROUND Omalizumab can reduce hospitalization and emergency department visits and improve quality of life in patients with moderate-to-severe , suboptimally controlled allergic asthma . Given the high cost and modest efficacy of this agent , it is not clear that it is cost-effective if given to a broad population with asthma . OBJECTIVE The purpose of this study was to evaluate the cost-effectiveness of omalizumab in adults and adolescents with moderate-to-severe allergic asthma . METHODS A retrospective economic analysis was performed to determine the cost-effectiveness of omalizumab using 52-week data from 2 r and omized controlled clinical trials in adults and adolescents with moderate-to-severe allergic asthma . The analysis was conducted from a third-party payer 's perspective , and only direct costs were considered . RESULTS The incremental cost-effectiveness ratios showed that the cost to achieve an additional successfully controlled day was $ 523 , and the daily cost to achieve at least a 0.5-point increase in Asthma Quality of Life Question naire score was $ 378 in 2003 dollars . CONCLUSION From a pharmacoeconomic st and point , omalizumab would be better used in allergic asthmatic patients with poorly controlled symptoms despite maximal therapy , given the high cost and modest efficacy of this agent . It could be cost saving if given to nonsmoking patients who are hospitalized 5 or more times or 20 days or longer per year despite maximal asthma therapy BACKGROUND Recently , we showed that combination of omalizumab with specific immunotherapy ( SIT ) for treatment of patients with seasonal allergic rhinitis ( SAR ) and comorbid seasonal allergic asthma ( SAA ) is safe and reduced the symptom load in a statistically significant and clinical ly meaningful manner during the first pollen season . OBJECTIVE The aim of this study was to investigate long-lasting effects of an initial combination treatment with SIT+omalizumab , a monoclonal anti-IgE antibody , in a follow-up period with SIT treatment only in patients with SAR and comorbid SAA incompletely controlled by conventional pharmacotherapy . METHODS A r and omized , double-blind , placebo-controlled , multicenter trial was performed to assess the efficacy and safety of omalizumab ( Xolair ( ® ) ) vs. placebo in combination with SIT ( depigmented allergoid vaccine , Depigoid ( ® ) ) during the first grass pollen season . Omalizumab or placebo therapy was started 2 wk before SIT ; the whole treatment lasted 18 wk . After the first pollen season , SIT was given for two subsequent years without omalizumab . Primary end-point was daily ' symptom load ' , the sum of daily scores for symptom severity and rescue medication use in the second and third year . RESULTS A total of 140 patients ( age 11 - 46 yr ) were r and omized ; 130 , 128 , and 114 patients finished the study after 1 , 2 , and 3 yr , respectively . The main efficacy variable was the mean daily symptom load as assessed in the patients ' diary . No systematic differences between both analysis groups were detected in the findings from symptom load , symptom severity score , or rescue medication score . Further subjective data did not show differences between both groups in the quality -of-life data as assessed with the ACQ , AQLQ , and the RQLQ . Investigators ' assessment of treatment effectiveness in the first and second year of study extension showed more patients with favorable long-term treatment outcome ( ' excellent ' and ' good ' ) in the SIT plus omalizumab group than in the SIT plus placebo group . In line with these findings , FEV1 improved at the end of both years in the group which was treated with the combination therapy in the double-blind study compared with the Depigoid plus placebo group . CONCLUSION Eighteen weeks ' treatment of omalizumab in combination with SIT in patients with SAR and comorbid SAA reduced the symptom load during the treatment period but showed no prolonged effect during treatment with SIT only . A slight increase in lung function ( FEV1 ) in patients formerly treated with the omalizumab/SIT combination therapy should encourage further evaluation of long-term effects of omalizumab Background : The objective of this study was to evaluate the effects of omalizumab on bronchoconstriction induced by methacholine and adenosine 5′-monophosphate ( AMP ) . Methods : Thirty-four subjects with mild to moderate allergic asthma were r and omized to receive placebo ( n = 16 ) or omalizumab ( n = 18 ) subcutaneously during 12 weeks . Airway responsiveness to AMP was measured at baseline and after 4 and 12 weeks of treatment , whereas the response to methacholine was measured at baseline and after 12 weeks of treatment . Results : After 4 weeks of treatment , the increase in AMP PC20 ( provocative concentration required to produce a 20 % fall in FEV1 ) was significantly greater in the omalizumab group than in the placebo group , the mean difference in the change between the groups being 1.52 doubling concentrations ( 95 % CI , 0.25–2.79 , p = 0.02 ) . Compared with baseline , the mean AMP PC20 values at 12 weeks were increased by 1.91 doubling concentrations with omalizumab ( p < 0.001 ) and 1.01 doubling concentrations with placebo ( p = 0.16 ) , but changes were not significantly different between the treatment groups . Changes in methacholine PC20 values were not significantly different between the omalizumab and placebo groups . Conclusions : In subjects with allergic asthma  , omalizumab reduces the response to AMP without decreasing the response to methacholine . These findings are consistent with the conclusion that the contribution of IgE to the development of AMP bronchoconstriction is more important than their role in the induction of methacholine hyperresponsiveness Various doses of two whole-virus and one split-product bivalent influenza A/New Jersey/76-A/Victoria/75 vaccines were administered to 253 children aged six to 18 years . There were no statistically significant differences in either reactivity or humoral antibody response among the 167 children in seven chronic disease categories and 86 healthy children . The whole-virus vaccines were associated with unacceptably high rates of reaction when given in sufficiently antigenic initial doses but were relatively nonreactive when used for booster immunization . Split-product vaccines were no more reactive than placebo . All vaccine preparations induced adequate seroconversion rates and protective titers of antibody to A/Victoria virus after one dose and to A/New Jersey virus after two doses Antagonizing the effect of interleukin (IL)-5 is a potential new treatment strategy in allergic disorders . We evaluated the safety , biological activity , and pharmacokinetics of SCH55700 , a humanized anti-human IL-5 antibody , in subjects with severe persistent asthma treated with oral or high doses of inhaled steroids . In a double-blind , r and omized , multicenter trial , a rising single dose of SCH55700 ( 0.03 mg/kg [ n = 2 ] , 0.1 mg/kg [ n = 4 ] , 0.3 mg/kg [ n = 6 ] , or 1.0 mg/kg [ n = 12 ] ) or placebo ( n = 8) was administered intravenously . SCH55700 dose dependently reduced circulating eosinophil counts . At a dose of 1.0 mg/kg , the decrease remained significant up to Day 30 [ ( 0.07 + /- 0.01 ) x 10(9)/L versus ( 0.23 + /- 0.04 ) x 10(9)/L at baseline ] ( mean + /- SEM ) ( p = 0.05 ) . After administration of SCH55700 at 0.3 and 1.0 mg/kg , a trend toward improvement in baseline FEV1 was observed , which reached significance 24 hours after the 0.3-mg/kg dose ( p = 0.019 versus placebo ) . No significant changes occurred in other clinical indices of disease activity . Adverse events were not different between active treatment and placebo . We conclude that SCH55700 is a biologically active anti-human IL-5 antibody that can be safely used in severe steroid-treated asthma . Its therapeutic potential needs to be addressed in specifically design ed efficacy trials BACKGROUND Elevated numbers of blood eosinophils are a risk factor for asthma exacerbations . Reslizumab is a humanised anti-interleukin 5 monoclonal antibody that disrupts eosinophil maturation and promotes programmed cell death . We aim ed to assess the efficacy and safety of reslizumab in patients with inadequately controlled , moderate-to-severe asthma . METHODS We did two duplicate , multicentre , double-blind , parallel-group , r and omised , placebo-controlled phase 3 trials . Both trials enrolled patients with asthma aged 12 - 75 years ( from 128 clinical research centres in study 1 and 104 centres in study 2 ) from Asia , Australia , North America , South America , South Africa , and Europe , whose asthma was inadequately controlled by medium-to-high doses of inhaled corticosteroid based therapy and who had blood eosinophils of 400 cells per μL or higher and one or more exacerbations in the previous year . Patients were r and omly assigned ( 1:1 ) to receive either intravenous reslizumab ( 3·0 mg/kg ) or placebo every 4 weeks for 1 year by computerised central r and omisation . Patients and investigators were masked to treatment assignment during the study . Each patient received a specific volume of study drug ( reslizumab or matching placebo ) on the basis of the patient 's body weight and r and omly assigned treatment group . Additionally , the sponsor 's clinical personnel involved in the study were masked to the study drug identity until the data base was locked for analysis and the treatment assignment revealed . The primary outcome was the annual frequency of clinical asthma exacerbations and was analysed by intention to treat . We assessed safety outcomes in the patients who had received one or more dose of the drug . The trials have been completed and are registered with Clinical Trials.gov , numbers NCT01287039 ( study 1 ) and NCT01285323 ( study 2 ) . FINDINGS Study 1 was done between April 12 , 2011 , and March 3 , 2014 and study 2 between March 22 , 2011 , and April 9 , 2014 . Of 2597 patients screened , 953 were r and omly assigned to receive either reslizumab ( n=477 [ 245 in study 1 and 232 in study 2 ] ) or placebo ( n=476 [ 244 and 232 ] ) . In both studies , patients receiving reslizumab had a significant reduction in the frequency of asthma exacerbations ( study 1 : rate ratio [ RR ] 0·50 [ 95 % CI 0·37 - 0·67 ] ; study 2 : 0·41 [ 0·28 - 0·59 ] ; both p<0·0001 ) compared with those receiving placebo . Common adverse events on reslizumab were similar to placebo . The most common adverse events were worsening asthma symptoms ( 127 [ 52 % ] for placebo and 97 [ 40 % ] for reslizumab in study 1 ; 119 [ 51 % ] for placebo and 67 [ 29 % ] for reslizumab for study 2 ) , upper respiratory tract infections ( 32 [ 13 % ] and 39 [ 16 % ] ; 16 [ 7 % ] and eight [ 3 % ] ) , and nasopharyngitis ( 33 [ 14 % ] and 28 [ 11 % ] ; 56 [ 24 % ] and 45 [ 19 % ] ) . Two patients in the reslizumab group had anaphylactic reactions ; both responded to st and ard treatment at the study centre and resolved , and the patients were withdrawn from the study . INTERPRETATION These results support the use of reslizumab in patients with asthma and elevated blood eosinophil counts who are inadequately controlled on inhaled corticosteroid-based therapy . FUNDING Teva Br and ed Pharmaceutical Products BACKGROUND Benralizumab is a humanised , afucosylated , anti-interleukin-5 receptor α monoclonal antibody that induces direct , rapid , and nearly complete depletion of eosinophils . We aim ed to assess the efficacy and safety of benralizumab as add-on therapy for patients with severe , uncontrolled asthma and elevated blood eosinophil counts . METHODS In this r and omised , double-blind , parallel-group , placebo-controlled , phase 3 study ( CALIMA ) undertaken at 303 sites in 11 countries , we enrolled patients aged 12 - 75 years with severe asthma uncontrolled by medium-dosage to high-dosage inhaled corticosteroids plus long-acting β₂-agonists ( ICS plus LABA ) and a history of two or more exacerbations in the previous year . Patients were r and omly assigned ( 1:1:1 ) to receive 56 weeks of benralizumab 30 mg every 4 weeks ( Q4W ) , benralizumab 30 mg every 8 weeks ( Q8W ; first three doses 4 weeks apart ) , or placebo ( all subcutaneous injection ) . Patients were stratified ( 2:1 ) by baseline blood eosinophil counts 300 cells per μL or greater and less than 300 cells per μL , respectively . Patients and study centre staff were masked to treatment allocation . The primary endpoint was annual exacerbation rate ratio versus placebo for patients receiving high-dosage ICS plus LABA with baseline blood eosinophils 300 cells per μL or greater ( intention-to-treat analysis ) . Key secondary endpoints were pre-bronchodilator forced expiratory volume in 1 s ( FEV1 ) and total asthma symptom score . This study is registered with Clinical Trials.gov , number NCT01914757 . FINDINGS Between Aug 21 , 2013 , and March 16 , 2015 , 2505 patients were enrolled , of whom 1306 patients were r and omised ; 425 patients were r and omly assigned to and received benralizumab 30 mg Q4W , 441 to benralizumab 30 mg Q8W , and 440  to  placebo . 728 patients were included in the primary analysis population . Benralizumab result ed in significantly lower annual exacerbation rates with the Q4W regimen ( rate 0·60 [ 95 % CI 0·48 - 0·74 ] , rate ratio 0·64 [ 95 % CI 0·49 - 0·85 ] , p=0·0018 , n=241 ) and Q8W regimen ( rate 0·66 [ 95 % CI 0·54 - 0·82 ] , rate ratio 0·72 [ 95 % CI 0·54 - 0·95 ] , p=0·0188 , n=239 ) compared with placebo ( rate 0·93 [ 95 % CI 0·77 - 1·12 ] , n=248 ) . Benralizumab also significantly improved pre-bronchodilator FEV1 ( Q4W and Q8W ) and total asthma symptom score ( Q8W only ) in these patients . The most common adverse events were nasopharyngitis ( 90 [ 21 % ] in the Q4W group , 79 [ 18 % ] in the Q8W group , and 92 [ 21 % ] in the placebo group ) and worsening asthma ( 61 [ 14 % ] in the Q4W group , 47 [ 11 % ] in the Q8W group , and 68 [ 15 % ] in the group ) . INTERPRETATION Benralizumab significantly reduced annual exacerbation rates and was generally well tolerated for patients with severe , uncontrolled asthma with blood eosinophils 300 cells per μL or greater . Our data further refine the patient population likely to receive the greatest benefit from benralizumab treatment . FUNDING AstraZeneca and Kyowa Hakko Kirin Inhalant food allergy has been described many times in literature , but double-blind clinical trials to support successful hyposensitization to these allergens has seldom been reported . Some authors have suspected that certain adverse reactions after immunotherapy may be mediated by immune complexes . Furthermore , the FDA does not recommend injection therapy with food extracts . We present a study on the detection of adverse effects after immunotherapy with an inhalant food ( wheat flour ) in a double-blind clinical trial in 26 patients with bakers ' asthma . We investigated the presence of circulating immune complexes ( CICs ) after 2 years of treatment with hyposensitization to wheat flour Allergy to pollen from deciduous trees is a common cause of  allergic rhinitis and asthma during the spring in Sweden . Juhlin-Dannfelt discovered ( z ) that patients with these disorders often get allergic symptoms from eating nuts or raw fruits . Using intracutaneous tests ( i. c. tests ) and , in some cases , provocation tests and Prausnitz-Kiistner tests , he could also detect the kind of tree pollen which usually caused the symptoms , i. e. mainly hirch but also hazel , alder , ash , sailowwillow and oak . Humoral reagins of the IgE class directed against different allergens can be detected with the radioallergosorbent test ( RAST ) ( 4 ) . This test can also be used to study allergenic activities and to obtain information on relationships between various allergens . In the present investigation the RAST , i. c. tests and provocation tests have been used to study pollen extracts from different deciduous trees . The present study has been made in order to compare the extracts and illustrate whether they have any allergens in common BACKGROUND Eosinophilia is associated with worsening asthma severity and decreased lung function , with increased exacerbation frequency . We assessed the safety and efficacy of benralizumab , a monoclonal antibody against interleukin-5 receptor α that depletes eosinophils by antibody-dependent cell-mediated cytotoxicity , for patients with severe , uncontrolled asthma with eosinophilia . METHODS We did a r and omised , double-blind , parallel-group , placebo-controlled phase 3 study at 374 sites in 17 countries . We recruited patients ( aged 12 - 75 years ) with a physician-based diagnosis of asthma for at least 1 year and at least two exacerbations while on high-dosage inhaled corticosteroids and long-acting β2-agonists ( ICS plus LABA ) in the previous year . Patients were r and omly assigned ( 1:1:1 ) by an interactive web-based voice response system to benralizumab 30 mg either every 4 weeks ( Q4W ) or every 8 weeks ( Q8W ; first three doses every 4 weeks ) or placebo Q4W for 48 weeks as add on to their st and ard treatment . Patients were stratified 2:1 according to blood eosinophil counts of at least 300 cells per μL and less than 300 cells per μL. All patients and investigators involved in patient treatment or clinical assessment were masked to treatment allocation . The primary endpoint was annual exacerbation rate ratio versus placebo , and key secondary endpoints were prebronchodilator forced expiratory volume in 1 s ( FEV1 ) and total asthma symptom score at week 48 , for patients with blood eosinophil counts of at least 300 cells per μL. Efficacy analyses were by intention to treat ( based on the full analysis set ) ; safety analyses included patients according to study drug received . This study is registered with Clinical Trials.gov , number NCT01928771 . FINDINGS Between Sept 19 , 2013 , and March 16 , 2015 , 2681 patients were enrolled , 1205 of whom met the study criteria and were r and omly assigned : 407 to placebo , 400 to benralizumab 30 mg Q4W , and 398 to benralizumab 30 mg Q8W . 267 patients in the placebo group , 275 in the benralizumab 30 mg Q4W group , and 267 in the benralizumab 30 mg Q8W group had blood eosinophil counts at least 300 cells per μL and were included in the primary analysis population . Compared with placebo , benralizumab reduced the annual asthma exacerbation rate over 48 weeks when given Q4W ( rate ratio 0·55 , 95 % CI 0·42 - 0·71 ; p<0·0001 ) or Q8W ( 0·49 , 0·37 - 0·64 ; p<0·0001 ) . Both benralizumab dosing regimens significantly improved prebronchodilator FEV1 in patients at week 48 compared with placebo ( least-squares mean change from baseline : Q4W group 0·106 L , 95 % CI 0·016 - 0·196 ; Q8W group 0·159 L , 0·068 - 0·249 ) . Compared with  placebo , asthma symptoms were improved by the Q8W regimen ( least-squares mean difference -0·25 , 95 % CI -0·45 to -0·06 ) , but not the Q4W regimen ( -0·08 , -0·27 to 0·12 ) . The most common adverse events were worsening asthma ( 105 [ 13 % ] of 797 benralizumab-treated patients vs 78 [ 19 % ] of 407 placebo-treated patients ) and nasopharyngitis ( 93 [ 12 % ] vs 47 [ 12 % ] ) . INTERPRETATION These results confirm the efficacy and safety of benralizumab for patients with severe asthma and elevated eosinophils , which are uncontrolled by high-dosage ICS plus LABA , and provide support for benralizumab to be an additional option to treat this disease in this patient population . FUNDING AstraZeneca and Kyowa Hakko Kirin RATIONALE Extensive evidence in animal models supports a role for IL-13 in the pathobiology of asthma .  IMA-638 and IMA-026 are fully humanized IgG(1 ) antibodies that bind to different epitopes and neutralize IL-13 bioactivity . OBJECTIVES We hypothesized that anti-IL-13 treatment would inhibit allergen-induced late-phase asthmatic responses , airway hyperresponsiveness , and inflammation in subjects with asthma . METHODS Fifty-six subjects with mild , atopic asthma were recruited for two double-blind , r and omized , placebo-controlled , parallel group trials to compare IMA-638 and IMA-026 IL-13 antibody treatments with placebo treatment . Drug was administered on Days 1 and 8 , and allergen challenges were performed on Days 14 and 35 . The primary outcome variable was the late-phase area under the curve ( AUC ) , and secondary outcome variables were the early- and late-phase maximum percent fall in FEV(1 ) , early AUC , allergen-induced shift in airway hyperresponsiveness , and sputum eosinophils . MEASUREMENTS AND MAIN RESULTS The treatment difference with IMA-638 on Day 14 was -19.1 FEV(1 ) × hour ( 95 % confidence interval : -36.2 , -1.9 ) for the allergen-induced early AUC and -23.8 FEV(1 ) × hour ( 95 % confidence interval : -46.4 , -1.2 ) for the late AUC ( both P < 0.05 ) , but this effect was lost by Day 35 . Treatment with IMA-026 did not attenuate the asthmatic responses on Day 14 or Day 35 . There was no effect of either antibody on allergen-induced airway hyperresponsiveness or sputum eosinophils . The frequency of adverse events after administration of the IL-13 antibodies was similar to placebo . CONCLUSIONS IL-13 has a role in allergen-induced airway responses in humans . Further study is required to determine whether anti-IL-13 monoclonal antibodies will be beneficial clinical ly A humanized monoclonal antibody that targets the membrane IgE B cell receptor was associated with improvements in  asthmatic airway responses .  Asthma Antibody Clears the Air A humanized antibody may be the key for treating allergic asthma . Gauvreau et al. report that quilizumab — a humanized monoclonal antibody that targets the membrane immunoglobulin E ( IgE ) B cell receptor — led to reductions in total and allergen-specific serum IgE that were sustained for 6 months after dosing and were associated with improvements in allergen-induced early and late asthmatic airway responses . A monoclonal antibody that neutralizes IgE can effectively treat asthma in the clinic ; however , use is limited by dosing restrictions and it does not prevent new IgE production . Inhibiting IgE production by targeting membrane IgE – expressing cells may enable more subjects to be treated and less frequent dosing , and has the potential for sustained effects upon the cessation of therapy . Elevated serum levels of both total and allergen-specific immunoglobulin E ( IgE ) correlate with atopic diseases such as allergic rhinitis and allergic asthma . Neutralization of IgE by anti-IgE antibodies can effectively treat allergic asthma . Pre clinical studies indicate that targeting membrane IgE – positive cells with antibodies against M1 prime can inhibit the production of new IgE and significantly reduce the levels of serum IgE. We report results from two trials that investigated the safety , pharmacokinetics , and activity of quilizumab , a humanized monoclonal antibody targeting specifically the M1 prime epitope of membrane IgE , in subjects with allergic rhinitis ( NCT01160861 ) or mild allergic asthma ( NCT01196039 ) . In both studies , quilizumab treatment was well tolerated and led to reductions in total and allergen-specific serum IgE that lasted for at least 6 months after the cessation of dosing . In subjects with allergic asthma who were subjected to an allergen challenge  , quilizumab treatment blocked the generation of new IgE , reduced allergen-induced early and late asthmatic airway responses by 26 and 36 % , respectively , and reduced allergen-induced increases in sputum eosinophils by ~50 % compared with placebo . These studies indicate that targeting of membrane IgE – expressing cells with anti-M1 prime antibodies can prevent IgE production in humans BACKGROUND Patients with frequent asthma exacerbations result ing in emergency department ( ED ) visits are at increased risk for future exacerbations . We examined the ability of 1 dose of benralizumab , an investigational antiinterleukin 5 receptor α monoclonal antibody , to reduce recurrence after acute asthma exacerbations . METHODS In this r and omized , double-blind , placebo-controlled study , eligible subjects presented to the ED with an asthma exacerbation , had partial response to treatment , and greater than or equal to 1 additional exacerbation within the previous year . Subjects received 1 intravenous infusion of placebo ( n = 38 ) or benralizumab ( 0.3 mg/kg , n = 36 or 1.0 mg/kg , n = 36 ) added to outpatient management . The primary outcome was the proportion of subjects with greater than or equal to 1 exacerbation at 12 weeks in placebo vs the combined benralizumab groups . Other outcomes included the time-weighted rate of exacerbations at week 12 , adverse events , blood eosinophil counts , asthma symptom changes , and health care re source utilization . RESULTS The proportion of subjects with greater than or equal to 1 asthma exacerbation at 12 weeks was not different between placebo and the combined benralizumab groups ( 38.9 % vs 33.3 % ; P = .67 ) . However , compared with placebo , benralizumab reduced asthma exacerbation rates by 49 % ( 3.59 vs 1.82 ; P = .01 ) and exacerbations result ing in hospitalization by 60 % ( 1.62 vs 0.65 ; P = .02 ) in the combined groups . Benralizumab reduced blood eosinophil counts but did not affect other outcomes , while demonstrating an acceptable safety profile . CONCLUSIONS When added to usual care , 1 dose of benralizumab reduced the rate and severity of exacerbations experienced over 12 weeks by subjects who presented to the ED with acute asthma Background : Patients with poorly controlled asthma have greater morbidity and mortality . This study evaluated the efficacy and tolerability of omalizumab in patients with poorly controlled , moderate‐to‐severe allergic asthma BACKGROUND Prevention of serious asthma exacerbations is an important therapeutic goal in patients with asthma . OBJECTIVE 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 . METHODS A pooled analysis was completed of 3 multicenter , r and omized , double-blind , placebo-controlled phase III studies with omalizumab  in adults/adolescents aged > or = 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 . RESULTS 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 ) . CONCLUSION 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 Some patients with severe asthma have recurrent asthma exacerbations associated with eosinophilic airway inflammation . Early studies suggest that inhibition of eosinophilic airway inflammation with mepolizumab-a monoclonal antibody against interleukin 5-is associated with a reduced risk of exacerbations . We aim ed to establish efficacy , safety , and patient characteristics associated with the response to mepolizumab . METHODS We undertook a multicentre , double-blind , placebo-controlled trial at 81 centres in 13 countries between Nov 9 , 2009 , and Dec 5 , 2011 . Eligible patients were aged 12 - 74 years , had a history of recurrent severe asthma exacerbations , and had signs of eosinophilic inflammation . They were r and omly assigned ( in a 1:1:1:1 ratio ) to receive one of three doses of intravenous mepolizumab ( 75 mg , 250 mg , or 750 mg ) or matched placebo ( 100 mL 0·9 % NaCl ) with a central telephone-based system and computer-generated r and omly permuted block schedule stratified by whether treatment with oral corticosteroids was required . Patients received 13 infusions at 4-week intervals . The primary outcome was the rate of clinical ly significant asthma exacerbations , which were defined as vali date d episodes of acute asthma requiring treatment with oral corticosteroids , admission , or a visit to an emergency department . Patients , clinicians , and data analysts were masked to treatment assignment . Analyses were by intention to treat . This trial is registered with Clinical Trials.gov , number NCT01000506 . FINDINGS 621 patients were r and omised : 159 were assigned to placebo , 154 to 75 mg mepolizumab , 152 to 250 mg mepolizumab , and 156 to 750 mg mepolizumab . 776 exacerbations were deemed to be clinical ly significant . The rate of clinical ly significant exacerbations was 2·40 per patient per year in the placebo group , 1·24 in the 75 mg mepolizumab group ( 48 % reduction , 95 % CI 31 - 61 % ; p<0·0001 ) , 1·46 in the 250 mg mepolizumab group ( 39 % reduction , 19 - 54 % ; p=0·0005 ) , and 1·15 in the 750 mg mepolizumab group ( 52 % reduction , 36 - 64 % ; p<0·0001 ) . Three patients died during the study , but the deaths were not deemed to be related to treatment . INTERPRETATION Mepolizumab is an effective and well tolerated treatment that reduces the risk of asthma exacerbations in patients with severe eosinophilic asthma . FUNDING GlaxoSmithKline Background : We assessed the efficacy of preseasonal local allergoid immunotherapy in a group of children with asthma and /or rhinitis and /or rhinoconjunctivitis due to grass pollen Twenty-eight patients ( 14 in an active treatment group and 14 in a placebo group ) with rhinoconjunctivitis and asthma caused by cat hypersensitivity took part in a placebo-controlled , r and omized , double-blind study to evaluate the risk-benefit quotient of the maintenance dose corresponding to 13.2 micrograms Fel d I antigen . The cat extract was biologically st and ardized and quantified with monoclonal antibodies ( 100 biological units : 33 microgram of Fel d I antigen , 650 micrograms of albumin , and 99 micrograms of Fel d Bd/K30 antigen ) . After 1 year of treatment , the systemic reactions to cat extract immunotherapy were mild and infrequent . Improvement was observed in the active treatment group in comparison with the placebo group in the medication-symptoms score ( p < 0.001 ) ; in skin prick test ( p < 0.001 ) , conjunctival provocation test ( p < 0.001 ) , and allergen bronchoprovocation test ( p < 0.05 ) results , and in nonspecific bronchial hyperreactivity measured with methacholine , which was not statistically significant . This study demonstrates the favorable risk-benefit quotient of the dose of 13.2 micrograms of Fel d I antigen , which may serve as a future reference in defining the optimum dose and appropriate proportion of antigens that should be administered in cat extract immunotherapy BACKGROUND Eosinophils develop from CD34(+ ) progenitors under the influence of IL-5 . Atopic asthmatic individuals have increased numbers of mature eosinophils and eosinophil pro-genitors within their bone marrow and bronchial mucosa . We have previously reported that anti-IL-5 monoclonal antibody treatment decreases total bone marrow and bronchial mucosal eosinophil numbers in asthma . OBJECTIVE Using an anti-IL-5 monoclonal antibody , we examined the role of IL-5 in eosinophil development within the bone marrow and bronchial mucosa in asthma . METHODS Blood , bone marrow , and airway mucosal biopsy specimens were examined before and after  anti-IL-5 ( mepolizumab ) treatment of asthmatic individuals in a double-blind , placebo-controlled trial . Numbers of mature and immature eosinophils were measured by histologic stain ( bone marrow myelocytes , metamyelocytes , and mature eosinophils ) , flow cytometry ( bone marrow and blood CD34(+)/IL-5Ralpha(+ ) cells ) , enumeration of bone marrow-derived eosinophil/basophil colony-forming units in methylcellulose culture , and sequential immunohistochemistry and in situ hybridization ( bronchial mucosal CD34(+)/IL-5Ralpha mRNA(+ ) cells ) . RESULTS Mepolizumab decreased mature eosinophil numbers in the bone marrow by 70 % ( P = .017 ) in comparison with placebo and decreased numbers of eosinophil myelocytes and metamyelocytes by 37 % ( P = .006 ) and 44 % ( P = .003 ) , respectively . However , mepolizumab had no effect on numbers of blood or bone marrow CD34(+ ) , CD34(+)/IL-5Ralpha(+ ) cells , or eosinophil/basophil colony-forming units . There was a significant decrease in bronchial mucosal CD34(+)/IL-5Ralpha mRNA(+ ) cell numbers in the anti-IL-5 treated group ( P = .04 ) . CONCLUSION These data suggest that anti-IL-5 therapy might induce partial maturational arrest of the eosinophil lineage in the bone marrow . The reduction in airway CD34(+)/IL-5 mRNA(+ ) cell numbers suggests that IL-5 might also be required for local tissue eosinophilopoiesis In a previous study it was reported that a group of asthmatic patients , in whom cromolyn sodium did not inhibit bronchial immediate allergic reactions  , had reaginic antibodies that did not appear to belong to the IgE class . This study was design ed to extend these observations , and it was shown that the IgG fractions from these patients ' sera , purified by ion exchange chromatography and specific immunosorbents , had skin-sensitizing activity to the antigen studied , while the IgE fractions did not . The skin-sensitizing activity in the IgG fractions was not removed by anti-IgE antiserum and was not inactivated by heating at 56 degrees C or by reduction/alkylation . It is proposed that IgG antibodies may mediate immediate allergic reactions in some asthmatic patients , that these patients can be detected by means of serum total IgE and allergen-specific IgE estimation , and that cromolyn sodium is not an effective inhibitor of bronchial immediate allergic reactions in these patients BACKGROUND Treatment with omalizumab , an anti-IgE antibody , improves symptoms and quality of life in patients with seasonal allergic rhinitis but has not previously been investigated in patients with perennial symptoms . OBJECTIVE To investigate the efficacy , safety , and tolerability of omalizumab in the treatment of perennial allergic rhinitis ( PAR ) . METHODS Two hundred eighty-nine patients ( aged 12 to 70 years ) with moderate-to-severe symptomatic PAR were r and omized to 16 weeks ' double-blind subcutaneous treatment with either placebo ( n = 145 ) or omalizumab ( at least 0.016 mg/kg/IgE [ IU/mL ] per 4 weeks ; n = 144 ) . The primary efficacy variable was the mean daily nasal severity score , as determined from patient daily diary cards . Secondary efficacy variables included use of rescue antihistamine , rhinoconjunctivitis-specific quality of life ( RQoL ) , and patients ' evaluation of treatment efficacy . Safety and tolerability were evaluated from adverse event reports and laboratory safety parameters . RESULTS Throughout 16 weeks of treatment , the mean daily nasal severity score was significantly lower in omalizumab-treated patients than with placebo ( P < 0.001 ) . The improvement in symptoms when taking omalizumab was paralleled by a reduction in use of rescue antihistamine ( P < or = 0.005 overall ) and improved RQoL relative to placebo . Patients ' evaluation of treatment efficacy significantly favored omalizumab over placebo ( P = 0.001 ) . Omalizumab therapy was well tolerated . There were no safety concerns . CONCLUSIONS Omalizumab was safe and well tolerated in the treatment of patients with PAR , providing effective control of symptoms and improved RQoL while simultaneously minimizing reliance on rescue antihistamines BACKGROUND Asthma is a disease with marked heterogeneity in its clinical course and response to treatment . IL-13 is central to type 2 inflammation , which contributes to many key features of asthma . Lebrikizumab is an anti-IL-13 mAb previously reported to significantly improve lung function in patients with inadequately controlled asthma despite inhaled corticosteroid therapy , especially in periostin-high patients . OBJECTIVE This phase II study investigated the efficacy and safety of IL-13 blockade with different doses of lebrikizumab in asthmatic patients not receiving inhaled corticosteroids . METHODS Patients were r and omized to receive 125 , 250 , or 500 mg of lebrikizumab or placebo subcutaneously monthly for 12 weeks with an 8-week follow-up period . The primary efficacy end point was the relative change in prebronchodilator FEV1 from baseline to week 12 . RESULTS A total of 212 patients were r and omized . The mean relative change in FEV1 was numerically higher in all lebrikizumab dose groups versus the placebo group , although the difference was neither statistically nor clinical ly significant . There were no meaningful differences in changes in FEV1 between the dose groups and the placebo group by the periostin subgroup . Lebrikizumab treatment was associated with a reduced risk of treatment failure at all doses versus placebo ( P < .001 ) , and results were similar by the periostin subgroup , with no apparent differences between doses of lebrikizumab . Lebrikizumab was generally well tolerated . CONCLUSION Blocking IL-13 , a single cytokine , in this population of asthmatic patients is insufficient to improve lung function . There is evidence that IL-13 blockade may improve disease control , as measured by prevention of protocol -defined treatment failure in these patients BACKGROUND Exacerbations of asthma are associated with substantial morbidity and mortality and with considerable use of health care re sources . Preventing exacerbations remains an important goal of therapy . There is evidence that eosinophilic inflammation of the airway is associated with the risk of exacerbations . METHODS We conducted a r and omized , double-blind , placebo-controlled , parallel-group study of 61 subjects who had refractory eosinophilic asthma and a history of recurrent severe exacerbations . Subjects received infusions of either mepolizumab , an anti-interleukin-5 monoclonal antibody ( 29 subjects ) , or placebo ( 32 ) at monthly intervals for 1 year . The primary outcome measure was the number of severe exacerbations per subject during the 50-week treatment phase . Secondary outcomes included a change in asthma symptoms , scores on the Asthma Quality of Life Question naire ( AQLQ , in which scores range from 1 to 7 , with lower values indicating more severe impairment and a change of 0.5 unit considered to be clinical ly important ) , forced expiratory volume in 1 second ( FEV(1 ) ) after use of a bronchodilator , airway hyperresponsiveness , and eosinophil counts in the blood and sputum . RESULTS Mepolizumab was associated with significantly fewer severe exacerbations than placebo over the course of 50 weeks ( 2.0 vs. 3.4 mean exacerbations per subject ; relative risk , 0.57 ; 95 % confidence interval [ CI ] , 0.32 to 0.92 ; P=0.02 ) and with a significant improvement in the score on the AQLQ ( mean increase from baseline , 0.55 vs. 0.19 ; mean difference between groups , 0.35 ; 95 % CI , 0.08 to 0.62 ; P=0.02 ) . Mepolizumab significantly lowered eosinophil counts in the blood ( P<0.001 ) and sputum ( P=0.002 ) . There were no significant differences between the groups with respect to symptoms , FEV(1 ) after bronchodilator use , or airway hyperresponsiveness . The only serious adverse events reported were hospitalizations for acute severe asthma . CONCLUSIONS Mepolizumab therapy reduces exacerbations and improves AQLQ scores in patients with refractory eosinophilic asthma . The results of our study suggest that eosinophils have a role as important effector cells in the pathogenesis of severe exacerbations of asthma in this patient population . ( Current Controlled Trials number , IS RCT N75169762 . BACKGROUND Respiratory syncytial virus ( RSV ) infection is associated with subsequent recurrent wheeze . Observational studies can not determine whether RSV infection is the cause of recurrent wheeze or the first indication of preexistent pulmonary vulnerability in preterm infants . The monoclonal antibody palivizumab has shown efficacy in preventing severe RSV infection in high-risk infants . METHODS In the double-blind , placebo-controlled MAKI trial , we r and omly assigned 429 otherwise healthy preterm infants born at a gestational age of 33 to 35 weeks to receive either monthly palivizumab injections  ( 214 infants ) or placebo ( 215 infants ) during the RSV season . The prespecified primary outcome was the total number of parent-reported wheezing days in the first year of life . Nasopharyngeal swabs were taken during respiratory episodes for viral analysis . RESULTS Palivizumab treatment result ed in a relative reduction of 61 % ( 95 % confidence interval , 56 to 65 ) in the total number of wheezing days during the first year of life ( 930 of 53,075 days in the RSV-prevention group [ 1.8 % ] vs. 2309 of 51,726 days [ 4.5 % ] in the placebo group ) . During this time , the proportion of infants with recurrent wheeze was 10 percentage points lower in patients treated with palivizumab ( 11 % vs. 21 % , P=0.01 ) . CONCLUSIONS In otherwise healthy preterm infants , palivizumab treatment result ed in a significant reduction in wheezing days during the first year of life , even after the end of treatment . These findings implicate RSV infection as an important mechanism of recurrent wheeze during the first year of life in such infants . ( Funded by Abbott Laboratories and by the Netherl and s Organization for Health Research and Development ; MAKI Controlled Clinical Trials number , IS RCT N73641710 . ) BACKGROUND Many patients with severe asthma require regular treatment with oral glucocorticoids despite the use of high-dose inhaled therapy . However , the regular use of systemic glucocorticoids can result in serious and often irreversible adverse effects . Mepolizumab , a humanized monoclonal antibody that binds to and inactivates interleukin-5 , has been shown to reduce asthma exacerbations in patients with severe eosinophilic asthma . METHODS In a r and omized , double-blind trial involving 135 patients with severe eosinophilic asthma , we compared the glucocorticoid-sparing effect of mepolizumab ( at a dose of 100 mg ) with that of placebo administered subcutaneously every 4 weeks for 20 weeks . The primary outcome was the degree of reduction in the glucocorticoid dose ( 90 to 100 % reduction , 75 to less than 90 % reduction , 50 to less than 75 % reduction , more than 0 to less than 50 % reduction , or no decrease in oral glucocorticoid dose , a lack of asthma control during weeks 20 to 24 , or withdrawal from treatment ) . Other outcomes included the rate of asthma exacerbations , asthma control , and safety . RESULTS The likelihood of a reduction in the glucocorticoid-dose stratum was 2.39 times greater in the mepolizumab group than in the placebo group ( 95 % confidence interval , 1.25 to 4.56 ; P=0.008 ) . The median percentage reduction from baseline in the glucocorticoid dose was 50 % in the mepolizumab group , as compared with no reduction in the placebo group ( P=0.007 ) . Despite receiving a reduced glucocorticoid dose , patients in the mepolizumab group , as compared with those in the placebo group , had a relative reduction of 32 % in the annualized rate of exacerbations ( 1.44 vs. 2.12 , P=0.04 ) and a reduction of 0.52 points with respect to asthma symptoms ( P=0.004 ) , as measured on the Asthma Control Question naire 5 ( in which the minimal clinical ly important difference is 0.5 points ) . The safety profile of mepolizumab was similar to that of placebo . CONCLUSIONS In patients requiring daily oral glucocorticoid therapy to maintain asthma control , mepolizumab had a significant glucocorticoid-sparing effect , reduced exacerbations , and improved control of asthma symptoms . ( Funded by GlaxoSmithKline ; SIRIUS Clinical Trials.gov number , NCT01691508 . ) BACKGROUND AND OBJECTIVE The efficacy and safety of the anti-IgE antibody , omalizumab , has been widely studied in patients with asthma . However to date , no large studies have been performed in Asian population s. The aim of this study was to compare the efficacy and safety of omalizumab with placebo , as add-on therapy in Asian patients with moderate-to-severe persistent asthma . METHODS Japanese patients ( 20 - 75 years of age ) with uncontrolled asthma , despite receiving high-dose inhaled corticosteroids and other st and ard therapies  , were r and omized to receive add-on treatment with omalizumab or placebo in a 16-week , double-blind , parallel-group , multicentre study . RESULTS Altogether , 315 treated patients were included in the efficacy and safety analyses . The change from baseline in morning PEF was 15.45 L/min ( least squares mean ) with omalizumab versus 2.25 L/min with placebo , a statistically significant difference of 13.19 L/min ( P = 0.0004 ) . Clinical ly significant asthma exacerbations occurred in six patients ( 4.0 % ) treated with omalizumab and in 18 patients ( 11.0 % ) treated with placebo . The odds ratio for the risk of experiencing an asthma exacerbation was 0.32 in favour of omalizumab ( P = 0.0192 ) . Changes in asthma symptom scores , daily life activity scores , sleep scores and rescue medication use were in favour of omalizumab , but group differences did not reach statistical significance . Adverse event rates were similar between omalizumab and placebo , except for injection site reactions , which were more frequently observed in the omalizumab group . CONCLUSIONS Add-on treatment with omalizumab improved asthma control without significant adverse events in Japanese patients with moderate-to-severe persistent asthma ABSTRACT Background : Severe eosinophilic asthma patients are at risk of exacerbations , which are associated with substantial costs . Mepolizumab lowers eosinophil levels and reduces exacerbation risk in severe eosinophilic asthma . We evaluated asthma-related exacerbation costs in  mepolizumab-treated patients ( versus  placebo ) . Methods : A within-trial economic analysis of the  Mepolizumab as Adjunctive Therapy in Patients with Severe Asthma ( MENSA ) trial . Objectives were to quantify the incremental : ( 1 ) medical costs of asthma-related exacerbation ; ( 2 ) asthma-related exacerbation emergency department visit/hospitalization costs ; and ( 3 ) asthma-related total healthcare re source utilization . Results : Mean medical costs of asthma-related exacerbations at 8 months were $ 969 , $ 852 , and $ 1692 in the mepolizumab 75 mg intravenous ( IV ) , mepolizumab 100 mg subcutaneous ( SC ) , and placebo groups , respectively ( p = 0.16 ) . Mean medical costs from emergency department visits or hospitalizations due to asthma-related exacerbations were $ 901 , $ 795 , and $ 1557 in the mepolizumab 75 mg IV , mepolizumab 100 mg SC , and placebo groups ( p = 0.020 ) . Asthma-related healthcare re source utilization ( all services ) was lower for the mepolizumab groups versus placebo . Conclusions : Adding mepolizumab to st and ard-of-care treatment for severe eosinophilic asthma lowered asthma exacerbation-related medical costs/healthcare re source utilization ; although the cost savings ranged from $ 723–$840 per patient , differences were not statistically significant
BACKGROUND This review is the first up date of a previously published review in The Cochrane Library ( Issue 7 , 2015 ) .
Interleukin-5 ( IL-5 ) is the main cytokine involved in the activation of eosinophils , which cause airway inflammation and are a classic feature of asthma .
Monoclonal antibodies targeting IL-5 or its receptor ( IL-5R ) have been developed , with recent studies suggesting that they reduce asthma exacerbations , improve health-related quality of life ( HRQoL ) and lung function .
These are being incorporated into asthma guidelines .
OBJECTIVES To compare the effects of therapies targeting IL-5 signalling ( anti-IL-5 or anti-IL-5Rα ) with placebo on exacerbations , health-related qualify of life ( HRQoL ) measures , and lung function in adults and children with chronic asthma , and specifically in those with eosinophilic asthma refractory to existing treatments .