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Background: Although asthma does not appear to be a risk factor for severe coronavirus disease 2019 (COVID-19), outcomes could vary for patients with different asthma subtypes. The objective of this analysis was to compare COVID-19 outcomes in real-world cohorts in the United States among patients with asthma, with or without evidence of allergy.Methods: In a retrospective analysis of the COVID-19 Optum electronic health record dataset (February 20, 2020-January 28, 2021), patients diagnosed with COVID-19 with a history of moderate-to-severe asthma were divided into 2 cohorts: those with evidence of allergic asthma and those without (nonallergic asthma). After 1:1 propensity score matching, in which covariates were balanced and potential bias was removed, COVID-19 outcomes were compared between cohorts.Results: From a COVID-19 population of 591,198 patients, 1595 patients with allergic asthma and 8204 patients with nonallergic asthma were identified. After propensity score matching (n = 1578 per cohort), risk of death from any cause after COVID-19 diagnosis was significantly lower for patients with allergic vs nonallergic asthma (hazard ratio, 0.48; 95% CI 0.28-0.83; P = 0.0087), and a smaller proportion of patients with allergic vs nonallergic asthma was hospitalized within - 7 to + 30 days of COVID-19 diagnosis (13.8% [n = 217] vs 18.3% [n = 289]; P = 0.0005). Among hospitalized patients, there were no significant differences between patients with allergic or nonallergic asthma in need for intensive care unit admission, respiratory support, or COVID-19 treatment.Conclusions: Asthma subtype may influence outcomes after COVID-19; patients with allergic asthma are at lower risk for hospitalization/death than those with nonallergic asthma. [ABSTRACT FROM AUTHOR]

Background/aim: The differences in molecular mechanisms during a stable period and the changes in the inflammatory responses during exacerbations between distinct severe asthma phenotypes remain unclear. In this study, we aimed to characterize stable and exacerbation period serum cytokine and periostin levels of 5 different predefined severe asthma phenotypes with real-life data. Changes in the viral infection-induced exacerbations were also analyzed. Materials and methods: Serum levels of 8 cytokines and periostin were measured from the sera obtained from the adult patients with five different severe asthma phenotypes based on the presence/absence of aeroallergen sensitivity, peripheral eosinophilia and chronic rhinosinusitis with nasal polyposis (CRSwNP) during stable and exacerbation periods, and from the matched controls. Results: Serum IL-13, IL-25, TSLP, and periostin levels were similar between the patient and the control groups during stable and exacerbation periods. Serum IL-25 and TSLP levels, and peripheral eosinophil count and periostin level showed a strong correlation. Stable period periostin levels were significantly higher in eosinophilic patients, and eosinophilic patients without long-term systemic steroid therapy had higher IL-13 levels. Compared to stable period, exacerbation period serum periostin levels found significantly lower [5853 (2309-8427) pg/mL vs. 4479 (2766-6495) pg/mL; p = 0.05] and periostin levels were much lower in viral infection-induced exacerbations [2913 (893-4770) pg/mL vs. 7094 (4782-9596) pg/mL; p = 0.022]. Conclusion: Our study showed that serum periostin levels were decreased in viral infection-induced exacerbations and increased in the presence of eosinophilia independent from atopy and it can help to differentiate eosinophilia even if the patient is under long-term systemic steroid therapy. Also, serum IL-13 levels may reflect peripheral eosinophilia in patients without long-term systemic steroid use. [ABSTRACT FROM AUTHOR]

Asthma is a common and debilitating chronic airway disease that affects people and horses of all ages worldwide. While asthma in humans most commonly involves an excessive type 2 immune response and eosinophilic inflammation, neutrophils have also been recognized as key players in the pathophysiology of asthma, including in the severe asthma phenotype where neutrophilic inflammation predominates. Severe equine asthma syndrome (sEAS) features prominent neutrophilic inflammation and has been increasingly used as a naturally occurring animal model for the study of human neutrophilic asthma. This comparative review examines the recent literature in order to explore the role of neutrophil inflammatory functions in the pathophysiology and immunology of asthma in humans and horses. [ABSTRACT FROM AUTHOR]

In recent years, several new asthma therapeutics have been developed. Although many of these agents show promise in treating allergic asthma, they are less effective against nonallergic forms of asthma. The gut microbiome has important roles in human health and disease, and a growing body of evidence indicates a link between the gut microbiome and asthma.Here, we review those data focusing on the role of themicrobiome inmouse models of nonallergic asthma including obese asthma and asthma triggered by exposure to air pollutants. We describe the impact of antibiotics, diet, and early life events on airway responses to the air pollutant ozone, including in the setting of obesity.We also review potential mechanisms responsible for gut--lung interactions focusing on bacterial-derived metabolites, the immune system, and hormones. Finally, we discuss future prospects for gut microbiome--targeted therapies such as fecal microbiome transplantation, prebiotics, probiotics, and prudent use of antibiotics. Better understanding of the role of the microbiome in airway responses may lead to exploration of new microbiometargeted therapies to control asthma, especially nonallergic forms of asthma. [ABSTRACT FROM AUTHOR]

Background: Asthma is heterogeneous disease with different phenotypes, endotypes and severities. Definition of these subgroups requires the identification of biomarkers in biological samples, and serum proteomics is a useful and minimally invasive method for this purpose. Therefore, the aim of this study was to detect serum proteins whose abundance is distinctively associated with different asthma phenotypes (allergic vs nonallergic) or severities. Methods: For each group of donors (32 healthy controls, 43 allergic rhinitis patients and 192 asthmatics with different phenotypes and severities), we generated two pools of sera that were analysed by a shotgun MS approach based on combinatorial peptide ligand libraries and iTRAQ‐LC‐MS/MS. Results: MS analyses identified 18 proteins with a differential abundance. Functional/network study of these proteins identified key processes for asthma pathogenesis, such as complement activation, extracellular matrix organization, platelet activation and degranulation, or post‐translational protein phosphorylation. Furthermore, our results highlighted an enrichment of the "Regulation of Insulin‐like Growth Factor (IGF) transport and uptake by Insulin‐like Growth Factor Binding Proteins (IGFBPs)" route in allergic asthma and the lectin pathway of complement activation in nonallergic asthma. Thus, several proteins (eg IGFALS, HSPG2, FCN2 or MASP1) displayed a differential abundance between the different groups of donors. Particularly, our results revealed IGFALS as a useful biomarker for moderate‐severe allergic asthma. Conclusion: Our data suggest a set of serum biomarkers, especially IGFALS, capable of differentiating allergic from nonallergic asthma. These proteins reveal different pathophysiological mechanisms and may be useful in the future for diagnosis, prognosis or targeted therapy purposes. [ABSTRACT FROM AUTHOR]

Asthma is a complex and heterogeneous respiratory disorder characterized by chronic airway inflammation. It has generally been associated with allergic mechanisms related to type 2 airway inflammation. Nevertheless, between 10 and 33% of asthmatic individuals have nonallergic asthma (NA). Several targeted treatments are in clinical development for patients with Th2 immune response, but few biomarkers are been defined for low or non-Th2-mediated inflammation asthma. We have recently defined by gene expression a set of genes as potential biomarkers of NA, mainly associated with disease severity: IL10, MSR1, PHLDA1, SERPINB2, CHI3L1, IL8, and PI3. Here, we analyzed their protein expression and specificity using sera and isolated peripheral blood mononuclear cells (PBMCs). First, protein quantification was carried out using ELISA (in sera) or Western blot (proteins extracted from PBMCs by Trizol procedure), depending on the biomarker in 30 healthy controls (C) subjects and 30 NA patients. A receiver operating characteristic curve analysis was performed by using the R program to study the specificity and sensitivity of the candidate biomarkers at a gene- and protein expression level. Four kinds of comparisons were performed: total NA group vs C group, severe NA patients vs C, moderate–mild NA patients vs C, and severe NA patients vs moderate–mild NA patients. We found that all the single genes showed good sensitivity vs specificity for some phenotypic discrimination, with CHI3L1 and PI3 exhibiting the best results for C vs NA: CHI3L1 area under the curve (AUC) (CI 95%): 0.95 (0.84–1.00) and PI3 AUC: 0.99 (0.98–1.00); C vs severe NA: PI3 AUC: 1 (0.99–1.00); and C vs moderate–mild NA: CHI3L1 AUC: 1 (0.99–1.00) and PI3 AUC: 0.99 (0.96–1.00). However, the results for discriminating asthma disease and severity with protein expression were better when two or three biomarkers were combined. In conclusion, individual genes and combinations of proteins have been evaluated as reliable biomarkers for classifying NA subjects and their severity. These new panels could be good diagnostic tests.

Background: Metabolic conditions may worsen asthma. There is a need to define a composite biomarker of metabolic dysfunction that has relevance to asthma outcomes., Objective: To determine the association of the triglyceride-glucose index (TyG), a biomarker of metabolic syndrome and insulin resistance, with risk of severe asthma exacerbation., Methods: A 5-year retrospective cohort of patients with asthma receiving health care from the US Veterans Health Administration from January 1, 2015, to December 31, 2019, was constructed. Fasting TyG values were extracted. Patients were followed for a severe asthma exacerbation, defined as an asthma-related corticosteroid prescription fill or an emergency encounter or hospitalization for asthma. Adjusted models estimated the relative hazard of exacerbation associated with elevated TyG, accounting for known exacerbation risk factors., Results: A total of 108,219 patients fulfilled study criteria. Over 286,343 person-years of follow-up, 21,467 exacerbations were identified, corresponding to a crude rate of 7.5 exacerbations/100 person-years. In exploratory analysis, we found a threshold effect at a TyG of 8.3, which was defined as elevated. In a fully adjusted model, patients with an elevated TyG had a 6% (95% CI, 3%-10%) higher hazard for severe asthma exacerbation, independent of eosinophil count, smoking, obesity, and asthma treatment intensity., Conclusions: Elevated TyG is a risk factor for severe asthma exacerbation independent of conventional predictors. Elevated TyG may identify patients who warrant more intensive asthma treatment and who are candidates for future clinical trials of metabolic intervention for purposes of improving asthma morbidity., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Objectives: This study investigated comorbidity in chemical intolerance (CI) and building- related intolerance (BRI) with (i) chronic sinusitis, chronic obstructive pulmonary disease, allergic and nonallergic asthma and allergic rhinitis, and (ii) airway inflammatory symptoms. Methods: Data from two population-based questionnaire surveys, the Västerbotten and Österbotten Environmental Health Studies, were used. The participants were categorized as CI or BRI and referents, and binary logistic regression analysis was applied. Results: Prevalence rates for the case groups were 7.2% to 40.0%for diseases and 24.3% to 68.9% for symptoms, whereas adjusted odds ratios (ORs) were 3.4 to 26.1 for diseases and 3.3 to 17.0 for symptoms, all being significantly higher than unity. Prevalence rates and ORs were in general higher in BRI than in CI. Conclusion: Inflammatory airway diseases and symptoms are associated with CI and BRI, which encourages further research regarding underlying mechanisms and treatments. [ABSTRACT FROM AUTHOR]

Background: Omalizumab in treating persistent moderate to severe asthma is clearly documented in patients difficult to control, reducing morbidity and absenteeism. Objective: To describe the clinical efficacy of omalizumab in patients older than 18 years with phenotype allergic and non-allergic asthma, poorly controlled symptoms, FEV1 less than 80%, IgE between 30 and 700 IU/mL and testing skin positive or negative in two referral hospitals in the city of Puebla, Mexico. Material and method: A prospective observational study with patients who were treated with omalizumab in asthma allergic indication or no moderate to severe persistent allergic from January 2014 to January 2015. Age, sex, weight, and IgE reactivity were recorded in vitro to perennial allergens, FEV1, basic treatment, asthma exacerbations and the need for systemic corticosteroids or revenue emergencies, symptoms daytime or nighttime awakenings originated at the beginning of treatment and at 8, 16, 32 and 52 weeks. Side effects and changes in base treatment were collected. Results: 35 patients with a mean weight of 67.3 kg (89-55 kg). The baseline IgE before the start of omalizumab was 202.5 IU/mL (10-564 IU/mL); 35 patients had reduced lung function with a FEV1 at baseline average of 67% (54-78%). FEV1 at 8 weeks was 67.5% (55-79%) and FEV1 at 52 weeks was 73% (70-80%). The mean dose of omalizumab administered every 30 days was 222.8 mg (150-450). Adverse reactions were observed in 7 patients, none required discontinuation of therapy; 23 patients had positive skin tests and 12 patients had negative skin tests. At the end of follow-up period 20 patients had decreased control treatment (11 patients with allergic asthma and 9 non-allergic asthma patients); 28 patients showed overall improvement, 18 patients in the context of allergic asthma and 10 patients in the context of non-allergic asthma. Conclusion: Omalizumab produced improvement in non-allergic phenotype (via dendritic cells). In both groups it was observed decreased number of exacerbations and emergency room visits; 93% of patients had overall improvement by clinical criteria and not statistically significant in FEV1 changes were observed, thus, it is concluded that improvement is given in the clinical setting and the quality of life of patients. [ABSTRACT FROM AUTHOR]

Chronic exposure to farm environments is a risk factor for nonallergic lung disease. In contrast to allergic asthma, in which type 2 helper T cell (Th2) activation is dominant, exposure to farm dust extracts (FDE) induces Th1/Th17 lung inflammation, associated with neutrophil infiltration. Macrophage influx is a common feature of both types of lung inflammation, allergic and nonallergic. However, macrophage functions and phenotypes may vary according to their polarized state, which is dependent on the cytokine environment. In this study, we aimed to characterize and quantify the lung macrophage populations in two established murine models of allergic and nonallergic lung inflammation by means of fluorescence-activated cell sorting and immunohistochemistry. We demonstrated that, whereas in allergic asthma M2-dominant macrophages predominated in the lungs, in nonallergic inflammation M1-dominant macrophages were more prevalent. This was confirmed in vitro using a macrophage cell line, where FDE exerted a direct effect on macrophages, inducing M1-dominant polarization. The polarization of macrophages diverged depending on the exposure and inflammatory status of the tissue. Interfering with this polarization could be a target for treatment of different types of lung inflammation. [ABSTRACT FROM AUTHOR]

Background: T lymphocytes are involved in the pathogenesis of nonallergic asthma. The objective of this study was to characterize the subset distribution and pattern of chemokine receptor expression in circulating T lymphocyte subsets from nonallergic asthma patients. Methods: Forty stable nonallergic asthma patients and 16 sex- and age-matched healthy donors were studied. Twelve patients did not receive inhaled steroids (untreated patients), 16 received 50-500 μg b.i.d. of inhaled fluticasone propionate (FP) (standard-dose patients), and 12 received over 500 μg b.i.d. of inhaled FP (high-dose patients) for at least 12 months prior to the beginning of this study and were clinically well controlled. Flow cytometry was performed using a panel of monoclonal antibodies (4 colors). Results: Nonallergic asthma patients treated with high doses of inhaled FP showed a significant reduction in the percentages of CD3+ T lymphocytes compared to healthy controls. Untreated patients showed a significant increase in CCR6 expression in CD8+CD25+ and CD8+CD25+bright T cells compared to healthy controls. The results were similar for CXCR3 and CCR5 expression. In patients treated with standard doses of FP, CCR5 expression was significantly increased in CD3+ T lymphocytes relative to healthy controls. Conclusions: The different groups of clinically stable nonallergic asthmatic patients showed distinct patterns of alterations in subset distribution as well as CCR6, CXCR3, and CCR5 expression on circulating T lymphocytes. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Asthma is a chronic inflammatory disorder of the airways resulting physiologically in hyperreactivity and clinically in recurrent episodes of wheezing, chest tightness, or coughing. Airway inflammation, smooth muscle contraction, epithelial sloughing, mucous hypersecretion, bronchial hyperresponsiveness, and mucosal edema contribute to the underlying pathophysiology of asthma. Diagnostic tests such as methacholine or mannitol challenges or spirometry (pre- and postbronchodilator responses) help to identify such underlying pathophysiology via assessments of bronchial hyperreactivity and lung mechanics but are imperfect and ultimately must be viewed in the context of a patient's clinical presentation including response to pharmacotherapy. The National Asthma Education and Prevention Program Expert Panel Report (2007) classifies asthma into either intermittent or persistent, and the latter is either mild, moderate, or severe. Some patients change in either direction from intermittent to persistent asthma. In addition, patients with asthma may be classified as allergic (IgE mediated), nonallergic (often triggered by viral upper respiratory tract infections or no apparent cause), occupational, aspirin-exacerbated respiratory disease, potentially (near) fatal, exercise induced, and cough variant asthma. In the latter, the patients have a nonproductive cough that responds to treatment for asthma but not with antibiotics, expectorants, mucolytics, antitussives, beta2-adrenergic agonists, treatment for acid reflux, or rhinosinusitis. Thus, cough variant asthma is in the differential diagnosis of chronic cough. [ABSTRACT FROM AUTHOR]

There has been a global epidemic of asthma during the past half-century. More recently, the prevalence has leveled off or declined in many Western countries, whereas the prevalence in less affluent nations is still increasing. The reasons for this and the different geographical patterns of asthma prevalence remain unclear. This paper provides an epidemiologic perspective on whether allergen exposure and allergies can explain these trends. In particular, the paper discusses 1) geographical and temporal trends in asthma and the role of allergens and allergy, 2) the importance of nonallergic mechanisms, 3) nonallergenic exposures that may modify the risk of allergies and asthma, and 4) new and emerging risk and protective factors. Although allergy and asthma are closely related, allergen exposure and allergy alone cannot explain current time trends and geographical patterns of asthma. Population-based studies focusing on recently identified risk and protective factors may provide further insight. [ABSTRACT FROM AUTHOR]

Asthma and autoimmune diseases apparently have little to share except for the involvement of the immune system in both types of disorder. However, epidemiological studies have shown that asthma and Type 1 diabetes, a typical autoimmune disease, are associated at the population level, and some experimental findings have suggested that autoimmune mechanisms might be operating in asthma as well. Female preponderance, increased incidence of antinuclear autoantibodies and detection of autoantibodies against either bronchial epithelial antigens or endothelial antigens in patients with nonallergic asthma suggest that the disease may have an autoimmune basis. Approximately 50% of patients with nonallergic asthma react to intradermal injection of autologous serum, indicating the presence of circulating vasoactive factors and suggesting an autoreactive mechanism. Recent findings in experimental animals support the involvement of an autoreactive mechanism in allergic asthma as well, indicating that human a-nascent polypeptide-associated complex, identified as an IgE-reactive autoantigen, has the potential to sensitize and induce immediate skin reactions and airway inflammation. In summary, asthma is a heterogeneous disorder characterized by chronic inflammation of the respiratory airways that can be triggered by allergen exposure or by other mechanisms, possibly autoreactive/autoimmune. The autoimmune hypothesis is further, indirectly, supported by the response to immunosuppressive drugs. [ABSTRACT FROM AUTHOR]

This study was undertaken to investigate the association of Chlamydophila pneumoniae infection (CPI) with asthma and allergy. One hundred forty-one patients with asthma aged 3–21 years, 125 healthy controls aged 3–21 years, and 62 allergic but nonasthmatic patients aged 4–20 years participated in this study. C. pneumoniae–specific antibodies were measured by ELISA. There were no significant differences in the percentage of patients positive for C. pneumoniae–specific antibodies between the three groups. Significantly more allergic asthmatic patients were positive for C. pneumoniae–specific IgA and IgA + IgG than nonallergic asthmatic patients, and this difference remained significant after adjustment for age and gender: adjusted odds ratio (OR) 5.9 (1.7–26.2) and p = 0.01 for IgA, and OR 5.2 (1.6–25.8) and p = 0.02 for IgA + IgG. The prevalence of the C. pneumoniae–specific IgA and the IgA + IgG positivity also was significantly lower in the nonallergic asthmatic group than in the allergic and control groups (p < 0.005). No food/drug-allergic patient was positive for C. pneumoniae–specific IgA, whereas 41.6% of the inhalative-allergic patients were positive for this antibody (p = 0.002). In our population CPI does not associate directly with asthma and allergy, but chronic or recurrent infection is associated with allergic asthma and inhalative allergy as opposed to nonallergic asthma and noninhalative allergy. [ABSTRACT FROM AUTHOR]

The genome-wide linkage disequilibrium screen for loci associated with genetic difference between allergic and nonallergic asthma was conducted with 763 autosomal STR markers and included 190 asthmatic children. Evidence for association with differences between the two forms of asthma was observed for 36 STR markers. Marker-to-marker synergetic effect and by simulation resampling tests revealed D5S2011, D6S305, and D9S286 were important loci in allergic asthma while D6S1574, D8S1769, and D19S226 were important in nonallergic asthma. Our results show strong genetic evidence that these markers play an important role in defining allergic and nonallergic asthma and provides important candidates of susceptible genes in these two categories of asthma. This study further shows that asthma is, indeed, a heterogeneous group of underlying diseases and, although with similar clinical phenotypes, may have different clinical severities, outcomes, and need more tailor-made management. [ABSTRACT FROM AUTHOR]

The objective of the study was to compare triggers for asthma attacks in a group of intrinsic (IA) and extrinsic asthmatic (EA) subjects. We included 205 asthmatic patients divided, according to skin-prick tests, in a group (n=63) of IA and a group (n=142) of EA. The questionnaire provided information on associated conditions (nasal polyps and intolerance to aspirin) as well as on allergenic and nonallergenic triggers. Data analysis demonstrated that in IA, some airborne nonallergenic factors were significantly more often involved. In addition, this association did hold true when comparing subgroups of patients with normal baseline FEV[SUB1] values. For those subjects, PC[SUB20] and the slopes of the dose-response curves to metacholine were comparable. In conclusion, the higher sensitivity of a group IA subjects to some nonallergenic factors is not related to a lower baseline spirometric value in this subgroup. It may be hypothesized that, in these patients, sensitivity of airways irritant receptors might be increased. [ABSTRACT FROM AUTHOR]

In recent years, several new asthma therapeutics have been developed. Although many of these agents show promise in treating allergic asthma, they are less effective against nonallergic forms of asthma. The gut microbiome has important roles in human health and disease, and a growing body of evidence indicates a link between the gut microbiome and asthma. Here, we review those data focusing on the role of the microbiome in mouse models of nonallergic asthma including obese asthma and asthma triggered by exposure to air pollutants. We describe the impact of antibiotics, diet, and early life events on airway responses to the air pollutant ozone, including in the setting of obesity. We also review potential mechanisms responsible for gut-lung interactions focusing on bacterial-derived metabolites, the immune system, and hormones. Finally, we discuss future prospects for gut microbiome-targeted therapies such as fecal microbiome transplantation, prebiotics, probiotics, and prudent use of antibiotics. Better understanding of the role of the microbiome in airway responses may lead to exploration of new microbiome-targeted therapies to control asthma, especially nonallergic forms of asthma.

Background Allergic and nonallergic asthma severity in children can be affected by microbial exposures. Objective We sought to examine associations between exposures to household microbes and childhood asthma severity stratified by atopic status. Methods Participants (n = 196) were selected from a cohort of asthmatic children in Connecticut and Massachusetts. Children were grouped according to asthma severity (mild with no or minimal symptoms and medication or moderate to severe persistent) and atopic status (determined by serum IgE levels). Microbial community structure and concentrations in house dust were determined by using next-generation DNA sequencing and quantitative PCR. Logistic regression was used to explore associations between asthma severity and exposure metrics, including richness, taxa identification and quantification, community composition, and concentration of total fungi and bacteria. Results Among all children, increased asthma severity was significantly associated with an increased concentration of summed allergenic fungal species, high total fungal concentrations, and high bacterial richness by using logistic regression in addition to microbial community composition by using the distance comparison t test. Asthma severity in atopic children was associated with fungal community composition ( P = .001). By using logistic regression, asthma severity in nonatopic children was associated with total fungal concentration (odds ratio, 2.40; 95% CI, 1.06-5.44). The fungal genus Volutella was associated with increased asthma severity in atopic children ( P = .0001, q = 0.04). The yeast genera Kondoa might be protective; Cryptococcus species might also affect asthma severity. Conclusion Asthma severity among this cohort of children was associated with microbial exposure, and associations differed based on atopic status. [ABSTRACT FROM AUTHOR]

The definition of nonallergic asthma includes that subset of subjects with asthma and with whom allergic sensitization cannot be demonstrated. These individuals should have negative skin prick test or in vitro specific-IgE test to a panel of seasonal and perennial allergens. Nonallergic asthma occurs in 10% to 33% of individuals with asthma and has a later onset than allergic asthma, with a female predominance. Nonallergic asthma appears to be more severe than allergic asthma in many cases and may be less responsive to standard therapy. Although many of the immunopathologic features of nonallergic asthma are similar to those observed with allergic asthma, some differences have been described, including a higher expression of RANTES in mucosa and bronchoalveolar lavage fluid, as well as a higher GM-CSF receptor alpha expression. Unbiased statistical methods, such as cluster analysis and latent class analysis, indicate that the lack of atopy is not the most important defining factor in assigning an individual to many specific phenotypes but rather is more important in some phenotypes than others, and appears to modulate the clinical expression of the disease. Despite an appreciation of this clinical entity for many years, many of its clinical implications remain unclear., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)