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BACKGROUND: Rhinovirus frequently causes asthma exacerbations among children and young adults who are allergic. The interaction between allergen and rhinovirus-induced symptoms and inflammation over time is unclear. OBJECTIVE: Our aim was to compare the response to an experimental inoculation with rhinovirus-16 in allergic asthmatics with the response in healthy controls and to evaluate the effects of administrating omalizumab before and during the infection. METHODS: Two clinical trials were run in parallel. In one of these trials, the response to an experimental inoculation with rhinovirus-16 among asthmatics with high levels of total IgE was compared to the response in healthy controls. The other trial compared the effects of administering omalizumab versus placebo to asthmatics in a randomized, double-blind placebo-controlled investigation. The primary outcome for both trials compared lower respiratory tract symptoms (LRTSs) between study groups over the first 4 days of infection. RESULTS: Frequent comparisons of symptoms, lung function, and blood eosinophil counts revealed differences that were more pronounced among allergic asthmatics than among controls by days 2 and 3 after virus inoculation. Additionally, an augmentation of upper respiratory tract symptom scores and LRTS scores occurred among the atopic asthmatics versus the controls during the resolution of symptoms (P < .01 for upper respiratory symptom tract scores and P < .001 for LRTS scores). The beneficial effects of administering omalizumab on reducing LRTSs and improving lung function were strongest over the first 4 days. CONCLUSIONS: LRTSs and blood eosinophil counts were augmented and lung function was reduced among allergic asthmatics early after rhinovirus inoculation but increased late in the infection during symptom resolution. The effect of administering omalizumab on the response to rhinovirus was most pronounced during the early/innate phase of the infection.

Background Relative enlargement of the pulmonary artery (PA) on chest CT imaging is associated with respiratory exacerbations in patients with COPD or cystic fibrosis. We sought to determine whether similar findings were present in patients with asthma and whether these findings were explained by differences in ventricular size. Methods We measured the PA and aorta diameters in 233 individuals from the Severe Asthma Research Program III cohort. We also estimated right, left, and total epicardial cardiac ventricular volume indices (eERVVI, eELVVI, and eETVVI, respectively). Associations between the cardiac and PA measures (PA-to-aorta [PA/A] ratio, eERVVI-to-eELVVI [eRV/eLV] ratio, eERVVI, eELVVI, eETVVI) and clinical measures of asthma severity were assessed by Pearson correlation, and associations with asthma severity and exacerbation rate were evaluated by multivariable linear and zero-inflated negative binomial regression. Results Asthma severity was associated with smaller ventricular volumes. For example, those with severe asthma had 36.1 mL/m2 smaller eETVVI than healthy control subjects (P = .003) and 14.1 mL/m2 smaller eETVVI than those with mild/moderate disease (P = .011). Smaller ventricular volumes were also associated with a higher rate of asthma exacerbations, both retrospectively and prospectively. For example, those with an eETVVI less than the median had a 57% higher rate of exacerbations during follow-up than those with eETVVI greater than the median (P = .020). Neither PA/A nor eRV/eLV was associated with asthma severity or exacerbations. Conclusions In patients with asthma, smaller cardiac ventricular size may be associated with more severe disease and a higher rate of asthma exacerbations. Trial Registry ClinicalTrials.gov; No.: NCT01761630; URL: www.clinicaltrials.gov

This article presents an overview of future uses for biologic therapies in the treatment of immunologic and allergic conditions. Discussion is centered on the use of existing therapies outside of their current indication or on new therapies that are close to approval. This information may help familiarize practicing allergists and immunologists with therapies they may soon encounter in their practice as well as help identify conditions and treatments that will require further study in the near future.

Mast cells have long been recognized for their role in immediate hypersensitivity reactions, by virtue of the presence of high affinity receptors for IgE (FcepsilonRI) on their surface. More recently, mast cells have been postulated to be involved in a variety of chronic inflammatory disorders as numerous mediators released by activated mast cells are characterized. This article summarizes current information on mast cell mediators, heterogeneity, and differentiation, and it reviews studies of mast cells in the normal eye and various ocular disorders.

Objective To characterize uterine mast cells and investigate uterine muscle strips contractile responses to challenge with an allergen in nonpregnant and pregnant women. Study design A double-antibody labeling technique was used to identify tryptase positive or chymase-tryptase–positive mast cells in uterine samples from term pregnant and nonpregnant women. Longitudinal myometrial strips were prepared from biopsies of hysterectomy specimens from patients undergoing procedures for benign indications and women who had elective cesarean sections. Responses to ragweed antigen were compared in uterine tissues from allergic and nonallergic patients and with passively sensitized tissues in the absence or presence of H 1 receptor antagonist and a cyclooxygenase inhibitor. Results Tryptase-chymase–positive mast cells were predominant in nonpregnant myometrium, whereas tryptase-positive cells were dominant in pregnant myometrium. Mast cell density was significantly higher in tissue from pregnant women than those of nonpregnant women. Studies in tissues from patients with known allergy to ragweed, as well as in passively sensitized tissues, showed an immediate and substantial increase in the frequency and force of myometrial contraction after a challenge with ragweed antigen. A similar response was observed to histamine. There was no contractile response to antigen challenge in tissues from nonallergic patients. An H 1 receptor antagonist partially inhibited the response to antigen, whereas a cyclooxygenase inhibitor had no effect. Conclusion Sensitized isolated pregnant and nonpregnant human uterine tissue is capable of responding to antigen challenge with strong myometrial contractions. This ability, along with the increased density of mast cells in pregnant tissues as compared with nonpregnant tissues, indicates a possible role for mast cells in mediating uterine contractility in pregnancy.

Objective To review the current data and treatment options for mild persistent asthma. Data Sources A MEDLINE search was performed for relevant articles. Study Selection The expert opinion of the author was used to select studies for inclusion in this review. Results Current data suggest that asthma severity is determined early in life and that disease progression may not occur outside early childhood. Furthermore, no therapy has been demonstrated to clearly prevent or reverse structural airway changes in patients with persistent asthma. Thus, the primary goal of asthma therapy is to prevent disease exacerbations rather than to halt disease progress, at least in patients past early childhood. Published reports of severe exacerbations in patients with reported mild asthma may actually reflect inclusion of patients with more severe forms of the disease who were inappropriately classified in terms of asthma severity. Conclusion Unlike the case for moderate and severe asthma, where regular therapy with inhaled corticosteroids is clearly the treatment of choice, clear guidelines for treating patients with mild persistent asthma have not been established. Patients with mild disease without severe exacerbations may require only the minimum therapy necessary for disease control.

Background The initial 12-week, double-blind phases of three studies demonstrated that budesonide inhalation suspension (BIS) is effective and well tolerated in infants and young children (6 months to 8 years of age) with persistent asthma. Objective Open-label, 52-week extensions to these studies were conducted to evaluate long-term safety of BIS, including effects of treatment with the lowest effective dose of BIS on hypothalamic-pituitary-adrenal (HPA)-axis function, as compared with conventional asthma therapy (CAT). Complete results of the earlier phases of the studies and of long-term safety are reported elsewhere; only results pertaining to HPA-axis function are summarized here. Methods Patients eligible for the open-label phases of the three trials were randomized to treatment with nebulized BIS (n = 447) or CAT (n = 223). CAT included short-acting oral or inhaled β 2 -agonists, methylxanthines, or cromolyn sodium; in two of the studies, CAT could have included other inhaled corticosteroids. HPA-axis function, which had been evaluated during the 12-week double-blind studies, was again evaluated at the beginning and end of the 52-week study period using basal plasma cortisol concentrations and response to stimulation with a 250-μg dose of adrenocorticotropic hormone. Results There was no evidence of altered HPA-axis function attributable to BIS treatment. No clinically or statistically significant differences in basal or adrenocorticotropic hormone-stimulated plasma cortisol concentrations were observed between BIS and CAT in either the 12-week, double-blind or 52-week, open-label phases of the three studies. Conclusions The results indicate that treatment with BIS does not result in clinically significant suppression of HPA-axis function in infants and young children.

Background: Disialoganglioside GD3 is expressed on the surface of selected cell types. Anti-GD3 mAb administered to human subjects with malignant melanoma produces signs and symptoms of immediate hypersensitivity reactions. Objective: The expression of GD3 by human mast cells was assessed during mast cell development in vitro and in samples of lung and skin. Methods: GD3 on tissue- and in vitro–derived mast cells was analyzed after double labeling of cells for tryptase (G3 mAb) or Kit (YB5.B8 mAb) and GD3 (R24 mAb). Glycolipids in extracts of fetal liver–derived mast cells were examined by using high-performance thin-layer chromatography. Results: Flow cytometry showed that the percentage of GD3 + cells increased in parallel to Kit + cells during the recombinant human stem cell factor–dependent development of fetal liver–derived mast cells. Double-labeling experiments showed that GD3 + cells were also surface Kit + and granule tryptase positive, identifying them as mast cells in preparations of lung-, skin-, fetal liver–, and cord blood–derived cells. The major acidic glycolipid detected was NeuAcα2-8NeuAcα2-3Galβ1-4Glcβ1-1′Cer (GD3). Among peripheral blood leukocytes, only basophils and about 10% of the T cells were labeled with anti-GD3 mAb. Anti-GD3 mAb–conjugated magnetic beads were used to purify mast cells to greater than 90% purity from dispersed skin cells enriched to approximately 12% purity by means of density-dependent sedimentation but were less proficient for dispersed human lung mast cells, most likely because of other cell types that express GD3. Conclusion: GD3 is expressed on the surface of developing human mast cells in parallel to tryptase in secretory granules and, like Kit, can serve as a target for their enrichment by immunoaffinity techniques. (J Allergy Clin Immunol 2001;107:322-30.)

Background: Human basophils are difficult to detect with classic histochemical stains at sites of allergic inflammation. The 2D7+ anti-basophil monoclonal antibody was used to identify basophils in skin during the late-phase response to a cutaneous allergen challenge. Methods: The 2D7+ monoclonal antibody was used on protease-digested sections of skin biopsy specimens obtained 6 and 24 hours after an allergen or buffer challenge. The skin chamber technique was used to compare buffer- and allergen-challenged sites at 6 hours, and intradermal injection of allergen was used to compare allergen-challenged sites at 6 and 24 hours. Results: Dramatic increases in the numbers of 2D7+ cells and in tissue staining by 2D7+ were observed 6 hours after allergen challenge compared with buffer challenge. Histamine levels in skin chamber fluid varied with 2D7+ cell concentrations. By 24 hours, 2D7+ cells and tissue staining appeared to diminish but were still detectable in the allergen-challenged sites. Basophils localized primarily in and around blood vessels, whereas mast cells remained mostly in the superficial dermis. Mast cells were 2D7− in both the allergen- and buffer-challenged skin. Metachromatic staining of 2D7 basophils with toluidine blue was absent in these tissue sections. Conclusions: The 2D7 monoclonal antibody provides a more sensitive and precise marker than histochemical staining for human basophil involvement during the late-phase response to an allergen challenge. Basophil infiltration was observed at 6 hours only after allergen challenge and persisted at similar levels by 24 hours. (J Allergy Clin Immunol 1998;101:354-62.)

Biomarkers of disease activity have come into wide use in the study of mechanisms of human disease and in clinical medicine to both diagnose and predict disease course; as well as to monitor response to therapeutic intervention. Here we review biomarkers of the involvement of mast cells, basophils, and eosinophils in human allergic inflammation. Included are surface markers of cell activation as well as specific products of these inflammatory cells that implicate specific cell types in the inflammatory process and are of possible value in clinical research as well as within decisions made in the practice of allergy-immunology.

4q12 Tricolor Orange/Green/Aqua rearrangement probe). Automated image analysis of the esophageal epithelium was performed (Ikoniskope Digital Microscopy System) to quantify the number of diseased vs normal nuclei in each of the study groups. Results: A total of 29 subjects (mean age 33 yrs; 16 male; 24 Caucasian) were identified (8 normal, 6 GERD, and 15 EoE (5 steroid refractory); see Table). The maximum eosinophil count was 0, 1, and 75, in the normal, GERD, and EoE groups, respectively. A median of 171, 171, and 139 nuclei could be assessed in the normal, GERD, and EoE groups. Overall, there was no difference in the proportion of normal nuclei in the normal, GERD, and EoE groups (98 vs 99 vs 99%; p=0.42). In the subgroup of steroid-refractory EoE patients, the F-P gene was also not detected; 99% of the nuclei in this group were normal. Conclusions: In this pilot study, the presence of the FIP1L1PDGFRα fusion gene was not detected with increased frequency in EoE as compared to GERD or normal controls, even when the analysis was limited to steroid-refractory EoE patients. The F-P fusion gene does not appear to be a pathogenic mechanism in EoE. Characteristics of the study population and results of FISH for the F-P fusion gene

Rationale Eosinophilic esophagitis is an entity characterized by episodes of dysphagia and eosinophilic infiltration of the esophageal squamous epithelium on biopsy, with or without food sensitization. Treatment usually involves a combination of food avoidance and systemic corticosteroids, and more recently, use of oral corticosteroid inhalers. We report a case of eosinophilic esophagitis that was responsive to treatment with budesonide inhaler. Methods A seven year old male presented with a two year history of abdominal pain, dysphagia, and choking when eating solid foods. He also had a past medical history of atopic dermatitis and asthma. Allergy skin testing revealed sensitization to multiple foods, although the only food the patient was actively avoiding was peanuts. An open label food challenge with cow's milk was negative. Additional laboratory tests revealed mild peripheral blood eosinophilia (absolute eosinophil count 1,100/mm 3 ), peanut RAST of 6.7 IU/mL (Class 4), and an IgE level of 212 IU/mL. A barium swallow showed narrowing in the upper thoracic esophagus. Endoscopy revealed friable mucosa with exudates and a stiff esophagus. Histopathological examination demonstrated eosinophilia with >20 eosinophils/hpf. The patient was treated with budesonide turbuhaler two inhalations BID. Results Budesonide therapy resulted in dramatic improvement in his dysphagia within one week. Repeat endoscopy performed ten weeks later showed improvement in mucosal appearance and motility, and normal histopathology without eosinophilia. A repeat barium swallow was normal. Conclusions This case demonstrates the effectiveness of topical corticosteroid therapy in the treatment of eosinophilic esophagitis in a child.

Rationale To examine the safety of budesonide inhalation suspension (BIS) in infants. Methods A 12-week, double-blind, placebo-controlled, parallel-group study was conducted in infants aged 6-12 months with mild to moderate asthma or recurrent wheeze who were randomized to once-daily BIS 0.5 or 1.0 mg, or placebo. Safety was assessed by adverse events (AEs), changes from baseline in vital signs, physical examinations, oropharyngeal and nasal fungal cultures, and laboratory results. Analysis included all patients who received ≥1 dose and had ≥1 observation (n=141). Results The majority of AEs were mild to moderate; 43 (97.7%), 43 (89.6%), and 43 (87.8%) patients receiving BIS 1 mg, 0.5 mg, and placebo had ≥1 AE, respectively. Five patients receiving BIS experienced serious AEs (2 aggravated asthma, 1 pneumonia, 1 respiratory and 1 viral infection) that were considered unrelated to treatment; 2 of these patients discontinued early. One patient receiving BIS 0.5 mg also discontinued prematurely because of a facial/neck rash. No serious AEs were reported for placebo. Changes in vital signs and laboratory results were comparable among groups. Although difficult to assess over a 12-week period, body length increased in all groups, with mean values of 3.1, 3.5, and 3.7 cm in the infants receiving BIS 1.0 mg, BIS 0.5 mg, and placebo, respectively ( P >0.5). No significant differences between groups in baseline-adjusted oropharyngeal or nasal fungal cultures occurred. Conclusions Consistent with long-term safety of BIS in older pediatric patients, once-daily BIS in infants aged 6 to 12 months was well tolerated and comparable with placebo.