Exacerbations Among Patients With Asthma Are Largely Dependent on the Presence of Multimorbidity.

BACKGROUND AND OBJECTIVE: Comorbidities can influence asthma control and promote asthma exacerbations (AEs). However, the impact of multimorbidity in AEs, assessed based on long-term follow-up of patients with asthma of different degrees of severity, has received little attention in real-life conditions. To describe the epidemiological and clinical characteristics and predictors of AEs in patients who had presented at least 1 AE in the previous year in the MEchanism of Genesis and Evolution of Asthma (MEGA) cohort. METHODS: The work-up included a detailed clinical examination, pulmonary function testing, fractional exhaled nitric oxide (FeNO), blood counts, induced sputum, skin prick-tests, asthma questionnaires, and assessment of multimorbidity. The number of moderate-severe AEs in the preceding year was registered for each patient. RESULTS: The study population comprised 486 patients with asthma (23.7% mild, 35% moderate, 41.3% severe). Disease remained uncontrolled in 41.9%, and 47.3% presented ≥1 moderate-severe AE, with a mean (SD) annual exacerbation rate of 0.47 (0.91) vs 2.11 (2.82) in mild and severe asthma, respectively. Comorbidity was detected in 56.4% (66.6% among those with severe asthma). Bronchiectasis, chronic rhinosinusitis with nasal polyps, atopy, psychiatric illnesses, hyperlipidemia, and hypertension were significantly associated with AEs. No associations were found for FeNO, blood eosinophils, or total serum IgE. Sputum eosinophilia and a high-T2 inflammatory pattern were significantly associated with AEs. Multivariable regression analysis showed a significant association with asthma severity, uncontrolled disease, and low prebronchodilator FEV1/FVC. CONCLUSION: Our study revealed a high frequency of AE in the MEGA cohort. This was strongly associated with multimorbidity, asthma severity, poor asthma control, airflow obstruction, higher sputum eosinophils, and a very high-T2 inflammatory pattern.

Improvement in Olfaction in Patients With CRSwNP and Severe Asthma Taking Anti-IgE and Anti-IL-5 Biologics: A Real-Life Study.

BACKGROUND AND OBJECTIVES: Chronic rhinosinusitis with nasal polyps (CRSwNP), which is characterized by partial loss of smell (hyposmia) or total loss of smell (anosmia), is commonly associated with asthma and/or nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD). CRSwNP worsens disease severity and quality of life. The objective of this real-world study was to determine whether biological treatments prescribed for severe asthma can improve olfaction in patients with CRSwNP. A further objective was to compare the improvement in in olfaction in N-ERD and non-N-ERD subgroups. METHODS: We performed a multicenter, noninterventional, retrospective, observational study of 206 patients with severe asthma and CRSwNP undergoing biological treatment (omalizumab, mepolizumab, benralizumab, or reslizumab). RESULTS: Olfaction improved after treatment with all 4 monoclonal antibodies (omalizumab [35.8%], mepolizumab [35.4%], reslizumab [35.7%], and benralizumab [39.1%]), with no differences between the groups. Olfaction was more likely to improve in patients with atopy, more frequent use of short-course systemic corticosteroids, and larger polyp size. The proportion of patients whose olfaction improved was similar between the N-ERD (37%) and non-N-ERD (35.7%) groups. CONCLUSIONS: This is the first real-world study to compare improvement in olfaction among patients undergoing long-term treatment with omalizumab, mepolizumab, reslizumab, or benralizumab for severe asthma and associated CRSwNP. Approximately 4 out of 10 patients reported a subjective improvement in olfaction (with nonsignificant differences between biologic drugs). No differences were found for improved olfaction between the N-ERD and non-N-ERD groups.

Immunological Mechanisms in Allergic Diseases and Allergen Tolerance: The Role of Treg Cells.

The immune system regulates itself to establish an appropriate immune response to potentially harmful pathogens while tolerating harmless environmental antigens and self-antigens. A central role in this balance is played by regulatory T cells (Tregs) through various ways of actions. By means of molecule secretion and cell-cell contact mechanisms, Tregs may have the capacity to modulate effector T cells and suppress the action of proinflammatory cytokines across a broad range of cell types. As a result, abnormal regulatory T cell function has been pointed as a main cause in the development of allergic diseases, a major public health problem in industrialized countries, with a high socioeconomic impact. This prevalence and impact have created an international interest in improving the allergy diagnosis and therapy. Additionally, research has sought to gain a better understanding of the molecular mechanisms underlining this kind of disease, in order to a better management. At this respect, the role of Treg cells is one of the most promising areas of research, mainly because of their potential use as new immunotherapeutical approaches. Therefore, the aim of this review is to update the existing knowledge of the role of Tregs in this pathology deepening in their implication in allergen-specific therapy (AIT).

Differential gene-expression analysis defines a molecular pattern related to olive pollen allergy.

Analysis of gene-expression profiles by microarrays is useful for characterization of candidate genes, key regulatory networks, and to define phenotypes or molecular signatures which improve the diagnosis and/or classification of the allergic processes. We have used this approach in the study of olive pollen response in order to find differential molecular markers among responders and non-responders to this allergenic source. Five clinical groups, non-allergic, asymptomatic, allergic but not to olive pollen, untreated-olive-pollen allergic patients and olive-pollen allergic patients (under specific-immunotherapy), were assessed during and outside pollen seasons. Whole-genome gene expression analysis was performed in RNAs extracted from PBMCs. After assessment of data quality and principal components analysis (PCA), differential gene-expression, by multiple testing and, functional analyses by KEGG, for pathways and Gene-Ontology for biological processes were performed. Relevance was defined by fold change and corrected P values (less than 0.05). The most differential genes were validated by qRT-PCR in a larger set of individuals. Interestingly, gene-expression profiling obtained by PCA clearly showed five clusters of samples that correlated with the five clinical groups. Furthermore, differential gene expression and functional analyses revealed differential genes and pathways in the five clinical groups. The 93 most significant genes found were validated, and one set of 35 genes was able to discriminate profiles of olive pollen response. Our results, in addition to providing new information on allergic response, define a possible molecular signature for olive pollen allergy which could be useful for the diagnosis and treatment of this and other sensitizations.

Modelling diseases: the allergens of Olea europaea pollen.

This study analyzes the influence of the IgE response to certain olive pollen allergens in the modulation of the different clinical phenotypes of allergic disease and their relationship with the level of exposure to pollen and genetic factors. Patients from high-exposure areas had a complex IgE antibody response to allergens of Olea euroapea, which included 3 or more allergens in 75% of cases. The majority allergens were Ole e 1, Ole e 2 (profilin), Ole e 7 (lipid transporting protein), Ole e 9 (glucanase), and Ole e 10. The existence of the antigen HLA-DR2 (15) led to a higher risk of sensitization to Ole e 10 and a greater trend towards the development of severe asthma, which increased in the presence of an anti-profilin IgE. Thirty percent of patients suffering from pollinosis simultaneously presented allergy to vegetable foods. Anti-Ole e 7 IgE was significantly associated with fruit anaphylaxis and anti-profilin IgE was detected in 90% of patients with oral syndrome. Finally, we analyzed the role of glucanase and Ole e 10 as causes of the pollen-latex-fruit syndrome.

Modulation of allergic response by gene-environment interaction: olive pollen allergy.

This article summarizes the most important advances of recent years in the field of gene-environment interaction in allergic response. It specifically examines sensitization to olive pollen as an example of one of the main causes of allergic disease in the Mediterranean area. The presence of at least 20 proteins with allergic activity has been demonstrated in olive pollen, and 10 of these have been characterized (Ole e 1 to Ole e 10). Ole e 1, which is considered to be the majority allergen (causing sensitization in more than 70% of patients), has been the subject of many studies looking for risk factors and ways to protect against sensitization. Markers of the major histocompatibility complex and other genetic loci associated with the allergic response have been analyzed using population-based, family-based, and functional approaches, which have revealed the involvement of genetic regulation in this type of response. Furthermore, evaluation of environmental factors and their relationship with genetic factors is essential when attempting to understand this type of disease. In this review, we provide examples of how exposure to high doses of olive pollen allergen in a specific genetic context can trigger different allergic conditions (from asthma to nonresponse). We stress the importance of evaluating these factors in order to modulate this response correctly.

Ole e 2 and Ole e 10: new clinical aspects and genetic restrictions in olive pollen allergy.

BACKGROUND: The clinical characteristics in olive pollen allergy are dependent on the antigenic load, the allergens profile, and the genetic restrictions. Our objective was to determine specific response pattern in Ole e 2 and Ole e 10 sensitization at those levels. METHODS: We studied 146 patients with seasonal rhinitis and/or asthma and positive prick test to Olea europaea pollen. IgE against Ole e 2 and Ole e 10 were detected by skin prick test and ELISA. HLA-DRB1 and HLA-DQB1 loci were typed by polymerase chain reaction sequence-specific primers method. RESULTS: A total of 102 (69.9%) and 79 (54.0%) patients showed significant IgE antibody response against Ole e 2 and Ole e 10, respectively. There was a significant association between Ole e 2 (OR 2.2, P = 0.04) and Ole e 10 reactivities (OR 2.8, P = 0.007) with asthma. In addition, total and specific IgE antibody levels significantly correlated with asthma (P < 0.05). Patients who reacted to both allergens reached the highest asthma risk factor (OR 4.3, P = 0.002). Phenotypic frequency of DR7 (OR 5.4, Pc = 0.003) and DQ2 (OR 3.6, Pc = 0.02) were increased in positive Ole e 2 patients compared with control subjects. DR2(15) phenotypic frequency was significantly increased (OR 5.6, Pc = 0.02) in positive Ole e 10 patients compared with control subjects. CONCLUSIONS: Our data suggest an association of Ole e 2 and Ole e 10 with bronchial asthma. Also, we found a genetic control of Ole e 2 and Ole e 10 IgE-specific responses that could be relevant to clinical disease in olive pollen allergy.

Immunological studies in a case of hydrochlorothiazide-induced pulmonary edema.

A case of acute onset non-cardiogenic pulmonary edema induced by hydrochlorothiazide (HCT) is presented. Rapid recovery was obtained with supportive therapy. Leukopenia was evident during the acute phase, with rapid recovery parallel to the clinical improvement, suggesting pulmonary sequestration of granulocytes. Immunological studies including lymphocyte stimulation test with HCT and measurement of specific IgG and IgE to HCT elicited negative results. The pathogenesis of this type of reaction remains to be elucidated.

Allergy to dermatophagoides in a group of Spanish gypsies: genetic restrictions.

BACKGROUND: Spanish gypsies have traditionally lived as nomads, a reason why few epidemiological studies were done in this ethnic group. However, the high prevalence of asthmatic diseases demonstrated in a population residing in the North of Spain induces us to analyse whether it was due to the influence of genetic loci previously implicated in other population studies as causing the disorders. METHODS: DRB1* and DQB1* HLA class II, TCR-Valpha8.1, FcepsilonRI-beta Rsa I exon 7 and intron 2, TNF-beta (LTalpha-Nco I) and CD14, were tested for association with asthma and atopy by multiple regression analysis, in 5 families comprising 87 individuals. RESULTS: Significant associations were found with DQB1*02 (p = 0.02) and DQB1*0301 (p = 0.008) and elevated levels of total serum IgE. A negative association (p = 0.02) was found between total serum IgE and DRB1*14. FcepsilonRI-beta Rsa I-In2 allele 1 was associated with high levels of total serum IgE (p = 0.04). Levels of Der p 1 IgE antibodies were negatively associated with DRB1*11-DQB1*0301 (p = 0.007), and positively with TCR Valpha-8 allele 1 (p = 0.04) and with FcepsilonRI-beta Rsa I-In2 allele 1 (p = 0.009). CONCLUSIONS: Our results do not show any association between asthma and the genetic loci studied although they do suggest the existence of multiple genetic influences on the allergic response in these families.

Molecular cloning of major allergen from Cupressus arizonica pollen: Cup a 1.

The family Cupressaceae is a relevant source of allergens that causes winter respiratory allergies. Cloning and sequencing the major antigen of Cupressus arizonica is important for a better diagnosis and treatment of sensitized patients. To obtain a full-length complementary DNA for Cup a 1, the major allergen of Cupressus arizonica pollen. It was cloned and sequenced and the recombinant protein was expressed. Messenger RNA from Cupressus arizonica pollen was obtained and the Cup a 1 sequence was established using a 3'-RACE system and primers based on the N-terminal amino acid sequence. Recombinant Cup a 1 was cloned in pBluescript and expressed in a glycosylated form in rabbit reticulocytes. The cDNA was subcloned in pGEX-5X-1 and expressed in Escherichia coli as a fusion protein with GST. Recombinant Cup a 1 is highly homologous with the major allergens of mountain cedar (Jun a 1), Japanese cypress (Cha o 1) and Japanese cedar (Cry j 1). Cup a 1 contains three potential N-glycosylation sites that are different from those found in Jun a 1 and Cry j 1. The cloned protein contains a pectate lyase active site identical to those of Cry j 1 and Jun a 1. The IgE from patients' sera recognizes recombinant Cup a 1, and this reactivity is higher with the glycosylated protein. Cup a 1 has been cloned and sequenced. As expected, the high degree of homology with Cha o 1, Jun a 1 and Cry j 1 explains the cross-reactivity of conifer pollens. Different IgE reactivity with the glycosylated and non-glycosylated protein suggests the importance of carbohydrate moieties in the IgE binding site.

Expression on human eosinophils of CD148: a membrane tyrosine phosphatase. Implications in the effector function of eosinophils.

The role of protein tyrosine phosphatases (PTP) is crucial in regulating the phosphorylation status of cells. CD148 is a recently described membrane-type PTP. In this study, we have demonstrated that this molecule is expressed on human eosinophils and eosinophilic cell line EoL-3. Interestingly, our data also showed that this molecule acts as a transduction molecule on these cells. Thus, the crosslinking of CD148 was able to induce the degranulation and the induction of superoxide anion generation. By using specific inhibitor and by western blotting, we have shown that tyrosine kinase activation is involved in this transduction pathway. In addition, we have shown the presence of a serine/threonine kinase activity associated with CD148. In conclusion, the activation capacity of CD148 on eosinophils suggests a potential role of this molecule on inflammatory diseases, such as allergic and parasitic diseases, associated with eosinophilia.

Molecular cloning and characterization of an IgE-reactive protein from Anisakis simplex: Ani s 1.

Ingestion of the parasitic nematode Anisakis simplex in undercooked fish can cause severe allergic reactions in some individuals. Using pooled human sera from sensitized patients we have probed an expression library for A. simplex antigens. One positive clone was found to encode a full length 21 kDa protein with strong homology to nematode troponins. The recombinant protein was expressed as a GST-fusion protein and found by immunoblot analysis to react with sera from 20% of allergic patients. The presence of functional EF-hand Ca(2+) binding motifs was demonstrated by gel-shift analysis.

DR2 antigens are associated with severity of disease in toxic oil syndrome (TOS).

Toxic oil syndrome (TOS) was an epidemic which broke out in Spain in 1981, caused by the ingestion of rapeseed oil denatured with 2% aniline and sold illegally as edible oil. More than 20,000 people were affected and mortality rate was 8.4%. Genetic susceptibility appears to be involved in the pathology of this disease. Several reports have described association between the chronic stage of the disease and DR-DQ antigens (DR3, DR4, DR2 and DQ8). In the present work, we have reassessed the HLA class II antigens in a well-designed case-control study. Triplets of subjects (n=265) composed by chronic patients (n=117), non-affected family members (n=71) and non-related controls (n=77) were studied. Also, HLA class II antigens were analyzed in patients who had died from TOS (n= 34) and in TOS control patients who died from other non-TOS related causes (n=13). Regarding surviving patients no significant association was found between HLA and disease. In contrast, an increase in phenotypic frequency of DR2 antigen, was found in patients who had died from TOS (73.5%) compared with the whole study group: TOS-affected alive patients (25.6%, corrected P<0.001), non-affected family members (28.5%, corrected P<0.001), non-related controls (23.9%, corrected P<0.001) and dead controls (38.4%, P=0.03).