Identification of Asthma Phenotypes in the Spanish MEGA Cohort Study Using Cluster Analysis

Introduction: The definition of asthma phenotypes has not been fully established, neither there are cluster studies showing homogeneous results to solidly establish clear phenotypes. The purpose of this study was to develop a classification algorithm based on unsupervised cluster analysis, identifying clusters that represent clinically relevant asthma phenotypes that may share asthma-related outcomes. Methods: We performed a multicentre prospective cohort study, including adult patients with asthma (N=512) from the MEGA study (Mechanisms underlying the Genesis and evolution of Asthma). A standardised clinical history was completed for each patient. Cluster analysis was performed using the kernel k-groups algorithm. Results: Four clusters were identified. Cluster 1 (31.5% of subjects) includes adult-onset atopic patients with better lung function, lower BMI, good asthma control, low ICS dose, and few exacerbations. Cluster 2 (23.6%) is made of adolescent-onset atopic asthma patients with normal lung function, but low adherence to treatment (59% well-controlled) and smokers (48%). Cluster 3 (17.1%) includes adult-onset patients, mostly severe non-atopic, with overweight, the worse lung function and asthma control, and receiving combination of treatments. Cluster 4 (26.7%) consists of the elderly-onset patients, mostly female, atopic (64%), with high BMI and normal lung function, prevalence of smokers and comorbidities. Conclusion: We defined four phenotypes of asthma using unsupervised cluster analysis. These clusters are clinically relevant and differ from each other as regards FEV1, age of onset, age, BMI, atopy, asthma severity, exacerbations, control, social class, smoking and nasal polyps. (AU)

Identification of Asthma Phenotypes in the Spanish MEGA Cohort Study Using Cluster Analysis.

INTRODUCTION: The definition of asthma phenotypes has not been fully established, neither there are cluster studies showing homogeneous results to solidly establish clear phenotypes. The purpose of this study was to develop a classification algorithm based on unsupervised cluster analysis, identifying clusters that represent clinically relevant asthma phenotypes that may share asthma-related outcomes. METHODS: We performed a multicentre prospective cohort study, including adult patients with asthma (N=512) from the MEGA study (Mechanisms underlying the Genesis and evolution of Asthma). A standardised clinical history was completed for each patient. Cluster analysis was performed using the kernel k-groups algorithm. RESULTS: Four clusters were identified. Cluster 1 (31.5% of subjects) includes adult-onset atopic patients with better lung function, lower BMI, good asthma control, low ICS dose, and few exacerbations. Cluster 2 (23.6%) is made of adolescent-onset atopic asthma patients with normal lung function, but low adherence to treatment (59% well-controlled) and smokers (48%). Cluster 3 (17.1%) includes adult-onset patients, mostly severe non-atopic, with overweight, the worse lung function and asthma control, and receiving combination of treatments. Cluster 4 (26.7%) consists of the elderly-onset patients, mostly female, atopic (64%), with high BMI and normal lung function, prevalence of smokers and comorbidities. CONCLUSION: We defined four phenotypes of asthma using unsupervised cluster analysis. These clusters are clinically relevant and differ from each other as regards FEV1, age of onset, age, BMI, atopy, asthma severity, exacerbations, control, social class, smoking and nasal polyps.

Clinical and inflammatory characteristics of patients with asthma in the Spanish MEGA project cohort.

INTRODUCTION: The MEGA (MEchanism underlying the Genesis and evolution of Asthma) project is a multicenter cohort study carried out in eight Spanish hospitals, gathering clinical, physiological, and molecular data from patients with asthma and multimorbidities in order to gain insight into the different physiopathological mechanisms involved in this disorder. MATERIAL AND METHODS: We report the baseline clinical and physiological characteristics and biomarker measures of adult participants in the project with the aim of better understanding the natural history and underlying mechanisms of asthma as well as the associated multimorbidities across different levels of severity. We carried out a detailed clinical examination, pulmonary function testing, measurement of fractional exhaled nitric oxide (FeNO), blood counts, induced sputum, skin prick tests, chest computed tomography scan, asthma questionnaires, and multimorbidity assessment in 512 asthmatic patients. RESULTS: When compared to patients with milder disease, severe asthmatic patients showed greater presence of symptoms, more exacerbations, lower asthma control, increased airflow obstruction, and higher frequency of chronic rhinosinusitis with nasal polyps, severe rhinitis, anxiety and depression, gastroesophageal reflux, and bronchiectasis. CONCLUSION: The MEGA project succeeded in recruiting a high number of asthma patients, especially those with severe disease, who showed lower control and higher frequency of multimorbidities.

Optimal duration of allergen immunotherapy in children with dust mite respiratory allergy.

BACKGROUND: Subcutaneous immunotherapy (SCIT) discontinuation data in children remain scarce. OBJECTIVE: We sought for differences in the clinical efficacy of 3 vs. 5 yr of SCIT in children with dust mite respiratory allergy. METHODS: We performed a 5-yr, phase IV prospective study. After the first year, the patients were randomized to 3 (IT3) or 5 yr of treatment (IT5). Efficacy was assessed at 3rd and 5th year by symptom and medication scores and visual analog scales (VAS). Skin tests with common allergens and in vitro assessments were also performed. RESULTS: Eighty-one children (mean age: 9 yr) were randomly assigned to 3 (IT3: 41) or 5 yr (IT5: 40) of immunotherapy. After 3 years, rhinitis global scores decreased in IT3 (44%; p = 0.002) and in IT5 (50%; p = 0.001). Asthma global, symptom and medication scores decreased by 100% in IT3 (p = 0.001) and IT5 (p = 0.001). VAS scores also diminished significantly (IT3: 70%, p = 0.001; IT5: 62.5%; p = 0.001). At 5th year, global rhinitis scores were reduced an additional 30% in IT5 children. Comparisons between both groups did not show differences in rhinitis (p = 0.055), asthma global scores (p = 0.948) or VAS scores at 5th year. Twenty percent of IT5 (p = 0.002) and 7% of IT3 children (p = 0.705) developed new sensitizations. At 5th year, sIgG4 determinations decreased in IT3 without significant variations in IT5. CONCLUSIONS: Three years of SCIT induced significant improvement in children with dust mite respiratory allergy, but a 5-yr course added clinical improvement in rhinitis.

[Physiology and physiopathology of the distal airways in asthma]. / Fisiología y fisiopatología de la vía aérea pequeña en el asma.

The small airways are those with an internal diameter of less than 2 mm. The contribution of these airways to total airflow resistance is small in healthy individuals but can represent 50-90 % of total airflow resistance in asthmatics. Suspicion of small airways disease has been based on reduction of midexpiratory and instantaneous flows, although wide variability in their values and the absence of a sufficiently validated cut-off point has limited their clinical application. Static pulmonary volumes can provide indirect evidence of the state of the most distal airways, revealing two effects of their alteration: air trapping and dynamic hyperinflation. While determination of airway resistance by plethysmography and of respiratory system resistance measured by flow interruption are highly non-specific, the forced oscillation technique allows obstruction of the small airways to be distinguished from that of medium-caliber airways. The characteristic pattern of peripheral obstruction includes a decrease in frequency-dependent resistance, reduced reactivity and an increase in resonance frequency. Single-or multiple-breath nitrogen washout can also provide specific information on the small airways, although the apparatus required is less frequently available. Analysis through bicompartmental models of exhaled nitric oxide allows alveolar nitric oxide concentrations to be determined, which seems to provide information on inflammatory activity in the small airways.

Fisiología y fisiopatología de la vía aérea pequeña en el asma / Physiology and physiopathology of the distal airways in asthma

Las vías aéreas pequeñas (VAP) son aquellas que tienen un diámetro interno menor de 2 mm. Aunque en sujetossanos su contribución a la resistencia total al flujo aéreo es discreta, en asmáticos podrían ser responsablesdel 50-90 % de la resistencia total al flujo aéreo.La reducción de los flujos mesoespiratorios e instantáneos ha constituido el principal instrumento para sospecharenfermedad de la VAP, aunque su notable variabilidad y la ausencia de un punto de corte suficientementevalidado le resta aplicación clínica.Los volúmenes pulmonares estáticos pueden aportar información indirecta sobre el estado de las vías aéreasmás distales evidenciando dos consecuencias de su alteración: el atrapamiento aéreo y la hiperinsuflacióndinámica.Mientras que la determinación de las resistencias de las vías aéreas por pletismografía y de las resistencias delsistema respiratorio por interrupción al flujo resultan muy inespecíficas, la técnica de la oscilación forzadapermite discriminar obstrucción de las VAP frente a las de mediano calibre. El patrón característico de obstrucciónperiférica comprende el descenso de la resistencia dependiente de la frecuencia, la disminución dela reactancia y el incremento de la frecuencia de resonancia.El lavado de nitrógeno mediante respiración única o por reinhalación múltiple también proporciona informaciónespecífica de las VAP, aunque la disponibilidad de este tipo de equipos es menor.El análisis mediante modelos bicompartimentales del óxido nítrico exhalado permite la determinación dela concentración alveolar de óxido nítrico, que parece aportar información sobre la actividad inflamatoria enla VAP(AU)

The small airways are those with an internal diameter of less than 2 mm. The contribution of these airways tototal airflow resistance is small in healthy individuals but can represent 50-90 % of total airflow resistance inasthmatics. Suspicion of small airways disease has been based on reduction of midexpiratory andinstantaneous flows, although wide variability in their values and the absence of a sufficiently validatedcut-off point has limited their clinical application. Static pulmonary volumes can provide indirect evidence ofthe state of the most distal airways, revealing two effects of their alteration: air trapping and dynamichyperinflation. While determination of airway resistance by plethysmography and of respiratory systemresistance measured by flow interruption are highly non-specific, the forced oscillation technique allowsobstruction of the small airways to be distinguished from that of medium-caliber airways. The characteristicpattern of peripheral obstruction includes a decrease in frequency-dependent resistance, reduced reactivityand an increase in resonance frequency. Single-or multiple-breath nitrogen washout can also provide specificinformation on the small airways, although the apparatus required is less frequently available. Analysisthrough bicompartmental models of exhaled nitric oxide allows alveolar nitric oxide concentrations to bedetermined, which seems to provide information on inflammatory activity in the small airways(AU)

Three years of specific immunotherapy may be sufficient in house dust mite respiratory allergy.

BACKGROUND: Specific immunotherapy (SIT) duration for respiratory allergy is currently based on individual decisions. OBJECTIVE: To evaluate the differences in clinical efficacy of SIT as a result of the duration between the current recommended limits (3-5 years). METHODS: A 5-year prospective, controlled clinical trial of SIT blind until the first year and randomization to a 3-year (IT3) or 5-year (IT5) course was conducted. Of the 239 patients with respiratory allergy caused by D pteronyssinus initially included, 142 completed 3 years of SIT with good compliance. Twenty-seven controls were included at the third year. Efficacy of SIT after 3 (T3) and 5 (T5) years was assessed by using clinical scores, visual analog scales (VASs), rhinitis (RQLQ) and asthma (AQLQ) quality of life questionnaires, skin tests, and serum immunoglobulins. RESULTS: At T3, significant reductions were observed in rhinitis (44% in IT3 and 50% in IT5; P < .001), asthma (80.9 % in IT3 and 70.9% in IT5; P < .001) scores, VAS (P < .001 in both), RQLQ (P < .001 in both) and AQLQ (P < .001 in both). At T5, the clinical benefit was maintained in both groups, and IT5 patients presented additional decreases (19%; P = .019) in rhinitis scores. At Tf, specific IgG(4) measurements were lower in IT3 (P = .03) without detecting differences in IT5. An increase in asthma score of 133% was the only difference observed in controls. CONCLUSION: Clinical improvement is obtained with 3 years of D pteronyssinus SIT. Two additional years of SIT add clinical benefit in rhinitis only.

Is exhaled nitric oxide a useful adjunctive test for assessing asthma?

RATIONALE: To determine the general utility of clinical (Asthma Control Test) and physiologic (forced expiratory volume in the first second of exhalation [FEV(1)] and fractionated exhaled nitric oxide level [FeNO]) parameters for characterizing asthma patients. METHODS: Two cross-sectional independent studies simultaneously enrolled 100 patients in the US and 109 patients in Spain > or = 18 years of age with a physician-diagnosis of asthma and confirmed by a > or = 12% improvement in FEV(1) after bronchodilators or the presence of airway hyperresponsiveness, a central feature of asthma, as measured by methacholine challenge (PC(20) < 10 mg/mL). There was no restriction on asthma severity or treatment. Patients were excluded if they had a diagnosis of chronic obstructive pulmonary disease and/or were current cigarette smokers. Statistical analyses were performed to compare ACT, FeNO, and spirometry within and between sites. RESULTS: Population characteristics revealed significant differences in distributions of age, percent-predicted FEV(1) (%FEV(1)), FeNO, inhaled corticosteroid usage, and atopy between the two populations. The Spain site enrolled younger patients with milder asthma, based on higher %FEV(1) values and less frequent treatment with inhaled corticosteroids. At each site, mean FeNO levels decreased as asthma control categories increased, and means were lower in the US. There was a negative correlation between ACT and FeNO that was statistically significant for Spain patients not treated with inhaled corticosteroids. CONCLUSIONS: The results of this study support the use of FeNO as an adjunctive tool for assessing asthma primarily in mild inhaled corticosteroid (ICS)-naïve asthma patients. The lack of correlation of ACT with FeNO in this and other studies across the entire population appears to reflect the heterogeneity of asthma patients who have an admixture of asthma severity and treatment regimens making it very difficult to appreciate the nuances of sensitive tests like FeNO.

Carmine (E-120)-induced occupational asthma revisited.

BACKGROUND: Occupational asthma (OA) caused by carmine (E-120) has been reported. OBJECTIVE: We sought to evaluate the prevalence of sensitization and OA at a natural dye processing factory in which 2 workers had been given a diagnosis of carmine-induced OA 6 years previously. METHODS: The 24 current employees and one worker who had recently left work because of asthma completed a questionnaire and underwent skin testing (carmine, cochineal, carminic acid, curcuma, annato, and chlorophyll), carmine IgE dot-blot analysis, and methacholine inhalation testing. Workers exhibiting positive occupational skin test responses, work-related asthma, or bronchial hyperresponsiveness underwent specific inhalation challenge and serial peak expiratory flow rate recording. RESULTS: Positive skin test responses to carmine (41.7%), cochineal (29.2%), and carminic acid (4.2%) were observed. Carmine IgE dot-blot results were positive in 4 subjects. No difference in atopy or smoking was observed between occupationally sensitized and nonsensitized subjects. Among the 5 employees reporting work-related asthma, 2 had positive skin test responses, and 4 had bronchial hyperresponsiveness. Five subjects underwent specific inhalation challenges: 2 workers had early asthma responses to carmine and cochineal challenges, and the remaining subjects did not have suggestive peak expiratory flow recordings. The subject who had left his job was given a diagnosis of carmine-induced OA. CONCLUSION: The prevalence of sensitization and OA caused by carmine was 41.6% and 8.3%, respectively. When the 3 workers who had left their jobs were included, the cumulative incidence of sensitization and OA was 48.1% and 18.5%, resembling the healthy worker effect. Prevention programs to establish the permissible levels of airborne allergen should be implemented.

Sputum eosinophilia and maximal airway narrowing in Dermatophagoides pteronyssinus allergic rhinitis patients: only rhinitis or rhinitis plus mild asthma?

STUDY OBJECTIVE: To study the existence of bronchial disease among rhinitis patients. To evaluate the laboratory test or set of tests (ie, symptoms, exposure, and sensitization to the allergen, and the provocative dose of methacholine [Mth] causing a 20% fall in FEV(1) [PD(20)] and the maximal response plateau [MRP] to Mth) that best identifies a case of mild asthma. DESIGN: Cross-sectional analysis in 52 Dermatophagoides pteronyssinus-monosensitized patients who were consulting a physician for perennial rhinitis. SETTING: Allergy Department, Hospital Doctor Negrín, Las Palmas, Grand Canary Island, Spain. INTERVENTIONS AND MEASUREMENTS: Patients filled out a standardized asthma symptom questionnaire, and underwent sputum induction and Mth challenge in which 40% falls in FEV(1) were attained. Dose-response curves were expressed in terms of both PD(20) values and the level of the MRP. D pteronyssinus allergen exposure was assessed in dust samples from patients' beds. RESULTS: No difference between patients who positively responded to the questionnaire and those who did not was observed. Mth-PD(20) values were not detected in 13% of the patients reporting bronchial symptoms, and an MRP was not identified in 59% of the subjects who did not respond positively. A higher degree of allergen sensitization (ascertained from skin test results, and total and specific serum IgE levels) and higher degree of sputum eosinophilia were detected in subjects in whom an MRP had not been identified. The presence of sputum eosinophilia provided the best differentiation between those patients who presented with an MRP and those who did not. CONCLUSION: The individual perception of bronchial symptoms is highly variable among perennial allergic rhinitis patients. The lack of a maximal airway-narrowing plateau is related to the presence of sputum eosinophilia, which might be useful in the detection of patients susceptible to anti-inflammatory therapy. Prospective studies evaluating whether these patients are more likely to develop symptomatic asthma in the future and if the early anti-inflammatory treatment prevents its development are needed.