Expression of toll-like receptors 2 and 4 in subjects with asthma by total serum IgE level.

BACKGROUND: Emerging data suggest that innate immunity may play a role in asthma, particularly the toll-like receptors (TLRs). Some studies pointed to an involvement of TLRs 2 and 4 in the pathogenesis of allergic asthma, and other studies related TLRs to IgE. However, there are not any studies that have comprehensively evaluated the expression of TLRs 2 and 4 in inflammatory cells, in peripheral blood and induced sputum specimens from asthmatic patients, according to their total serum IgE. METHODS: We studied 44 asthmatic patients (15 with high total serum IgE and 29 with normal total serum IgE). On a single visit, all patients underwent: induced sputum, pulmonary function tests, determination of exhaled nitric oxide fraction, venipuncture for blood analysis and skin prick allergy tests. The induced sputum cellularity was analyzed by flow cytometry, where expression of TLRs 2 and 4 was studied using fluorochrome-conjugated monoclonal antibodies. RESULTS: Asthmatic patients with high total serum IgE showed, a higher percentage of macrophages expressing TLR4 (42.99 % ± 22.49) versus asthmatic patients with normal total serum IgE (28.84 % ± 15.16) (P = 0.048). Furthermore, we observed a correlation (but weak) between the percentage of macrophages expressing TLR4 in induced sputum and the total serum IgE level (R = 0.314; P = 0.040). CONCLUSION: Asthmatic subjects with high total serum IgE show increased macrophage expression of TLR4 in induced sputum. This outcome may result from a link between innate immunity and IgE-mediated, adaptive immune responses in asthma, and point to TLR4 as a potential therapeutic target.

Clinical and inflammatory features of asthma with dissociation between fractional exhaled nitric oxide and eosinophils in induced sputum.

BACKGROUND: Measurement of the fractional exhaled nitric oxide (FeNO) and eosinophils in induced sputum are noninvasive markers for assessing airway inflammation in asthma. The clinical usefulness of the correlation between raised FeNO and sputum eosinophilia is controversial. We aimed to examine dissociation between FeNO and sputum eosinophils in a clinical series of asthma patients and to determine whether dissociation between these noninvasive markers was associated with clinical and inflammatory differences in these patients. METHODS AND FINDINGS: A total of 110 patients with asthma were included in a cross-sectional study. All of them were on maintenance treatment for asthma. All patients underwent the following on the same day: FeNO, induced sputum, spirometry, serum total IgE levels and skin prick test. The level of asthma control was determined by the Asthma control Test Questionnaire. In 46 (41.8%) patients, a discrepancy between FeNO and sputum eosinophil count was observed, of those, 34 (73.9%) had a FeNO <50 ppb and high eosinophil count, and were characterized by having a predominance of nonallergic asthma with bronchial eosinophilic inflammatory phenotype. Also, 12 (26.1%) patients had FeNO ≥50 ppb and sputum eosinophilia within the normal reference values, and were characterized by having a predominance of atopy with a paucigranulocytic inflammatory phenotype. CONCLUSIONS: A high percentage of patients with dissociation between results of FeNO and sputum eosinophils was observed. These patients showed differential clinical and inflammatory features.

A repeated short educational intervention improves asthma control and quality of life.

We assessed the effectiveness of an asthma educational programme based on a repeated short intervention (AEP-RSI) to improve asthma control (symptom control and future risk) and quality of life. A total of 230 adults with mild-to-moderate persistent uncontrolled asthma participated in a 1-year cluster randomised controlled multicentre study. The AEP-RSI was given in four face-to-face sessions at 3-month intervals, and included administration of a written personalised action plan and training on inhaler technique. Centres were randomised to the AEP-RSI (intervention) group or usual clinical practice group. Specialised centres using a standard educational programme were the gold standard group. A significant improvement in the Asthma Control Test score was observed in all three groups (p<0.001), but improvements were higher in the intervention and gold standard groups than in the usual clinical practice group (p=0.042), which also showed fewer exacerbations (mean±sd; 1.20±2.02 and 0.56±1.5 versus 2.04±2.72, respectively) and greater increases in the Mini Asthma Quality of Life Questionnaire scores (0.95±1.04 and 0.89±0.84 versus 0.52±0.97, respectively). The AEP-RSI was effective in improving asthma symptom control, future risk and quality of life.

Usefulness of the Exhaled Breath Temperature Plateau in Asthma Patients.

BACKGROUND: Exhaled breath temperature (EBT) has recently been proposed as a noninvasive marker of bronchial inflammation in patients with asthma. However, the usefulness of EBT in everyday clinical practice is not well established. Results to date are contradictory and are mainly derived from small, pediatric populations. A comparison of results is further complicated by the use of different equipment and measurements. OBJECTIVE: We performed a comprehensive study to determine whether EBT is related to asthma control, disease severity, bronchial obstruction, or bronchial inflammation. METHODS: Sixty-nine patients on maintenance treatment for asthma were included in a cross-sectional study. At the same visit, we measured the EBT plateau (EBTp) using an X-halo Breath Thermometer (Delmedica, Singapore), the fraction of exhaled nitric oxide (FeNO), spirometry, and inflammatory cell count in induced sputum, and we administered the Asthma Control Test questionnaire. RESULTS: No significant differences were found between EBTp measurements and the level of asthma control, disease severity, bronchial obstruction, FeNO levels, or inflammatory asthma phenotypes. We found a significant difference between EBTp and gender. The EBTp was 34.07°C (SD 0.74) in women and 34.38°C (0.46) in men (p = 0.038). We also found a significant correlation between EBTp measurements and the induced sputum eosinophil count (R = -0.348, p = 0.003). CONCLUSIONS: The results of this study do not support the usefulness of the EBTp in asthma management in routine clinical practice. Further research using standardized methods is needed to determine the potential use of the EBTp measurement in asthma management.

Total and specific immunoglobulin E in induced sputum in allergic and non-allergic asthma.

BACKGROUND: Most patients with nonallergic asthma have normal serum immunoglobulin E (IgE) levels. Recent reports suggest that total and aeroallergen-specific IgE levels in induced sputum may be higher in nonallergic asthmatics than in healthy controls. Our objective is to compare total and dust-mite specific (Der p 1) IgE levels in induced sputum in allergic and nonallergic asthmatics and healthy controls. METHODS: Total and Der p 1-specific IgE were measured in induced sputum (ImmunoCAP immunoassay) from 56 age- and sex-matched asthmatics (21 allergic, 35 nonallergic) and 9 healthy controls. Allergic asthma was defined as asthma with a positive prick test and/or clinically-significant Der p 1-specific serum IgE levels. RESULTS: Patients with allergic asthma presented significantly higher total and Der p 1-specific serum IgE levels. There were no significant between-group differences in total sputum IgE. However, Der p 1-specific sputum IgE levels were significantly higher (p = 0.000) in the allergic asthmatics, but without differences between the controls and nonallergic asthmatics. Serum and sputum IgE levels were significantly correlated, both for total IgE (rho = 0.498; p = 0.000) and Der p 1-specific IgE (rho, 0.621; p = 0001). CONCLUSIONS: Total IgE levels measured in serum and induced sputum are significantly correlated. No significant differences were found between the differents groups in total sputum IgE. Nevertheless, the levels of Der p 1-specific sputum IgE levels were significantly higher in the allergic asthmatics, but without differences between the controls and nonallergic asthmatics. Probably due to the lack of sensitivity of the test used, but with the growing evidence for local allergic reactions better methods are need to explore its presence. The Clinical Trials Identifier for this project is NCT03640936.

[Knowledge of and attitudes and adherence to the Spanish Guidelines for Asthma Management (GEMA) among Spanish health care professionals: the GEMA test Project]. / Opinión, conocimientos y grado de seguimiento referidos por los profesionales sanitarios españoles de la Guía Española para el Manejo del Asma (GEMA). Proyecto GEMA-TEST.

OBJECTIVE: Health care professionals' adherence to asthma guidelines is believed to be low. The aim of the present study was to determine the knowledge, attitudes, and adherence of Spanish health care professionals with respect to the Spanish Guidelines for Asthma Management (GEMA). MATERIAL AND METHODS: A multiple choice test with 15 questions was constructed. Items assessed knowledge of and opinions and adherence to asthma guidelines in general and the GEMA in particular. Test completion was voluntary, individual, and anonymous. RESULTS: A total of 1,066 physicians and nurses took the test. The sample consisted of 241 (22.6%) respiratory medicine specialists and 244 (22.9%) nurses from the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR), 221 (20.7%) pediatric pulmonologists from the Spanish Society of Pediatric Pulmonology (SENP), 220 (20.6%) general practitioners from the Spanish Society of Family and Community Medicine (semFYC), 181 (17%) general practitioners from the Spanish Society of Rural and General Medicine (SEMERGEN), and 38 (3.6%) others. Asthma guidelines were considered useful or very useful by 805 (76%), and 771 (72%) stated they were familiar with the GEMA. However, 388 (36%) admitted that they followed guidelines seldom or never. The level of adherence to the GEMA was poor for 243 (30.3%) respondents. The multivariate analysis revealed that low adherence was associated with the following characteristics: coming from the geographic center or south of Spain; being a primary care physician, unfamiliar with guidelines, or unconvinced of their utility; and not being a user of spirometry. CONCLUSIONS: Even though the majority of Spanish health care professionals surveyed seem to know of the GEMA, their adherence to those guidelines is very low. Educational programs that seek to improve knowledge of asthma guidelines should consider the profile of professionals with low adherence to the GEMA so as to include educational strategies that target them specifically.

The MEGA Project: A Study of the Mechanisms Involved in the Genesis and Disease Course of Asthma. Asthma Cohort Creation and Long-Term Follow-Up. / Estudio de los mecanismos implicados en la génesis y evolución del asma (proyecto MEGA): creación y seguimiento a largo plazo de una cohorte de pacientes asmáticos.

The general aim of this study is to create a cohort of asthma patients with varying grades of severity in order to gain greater insight into the mechanisms underlying the genesis and course of this disease. The specific objectives focus on various studies, including imaging, lung function, inflammation, and bronchial hyperresponsiveness, to determine the relevant events that characterize the asthma population, the long-term parameters that can determine changes in the severity of patients, and the treatments that influence disease progression. The study will also seek to identify the causes of exacerbations and how this affects the course of the disease. Patients will be contacted via the outpatient clinics of the 8 participating institutions under the auspices of the Spanish Respiratory Diseases Networking System (CIBER). In the inclusion visit, a standardized clinical history will be obtained, a clinical examination, including blood pressure, body mass index, complete respiratory function tests, and FENO will be performed, and the Asthma Control Test (ACT), Morisky-Green test, Asthma Quality of Life Questionnaire (Mini AQLQ), the Sino-Nasal Outcome Test 22 (SNOT-22), and the Hospital Anxiety and Depression scale (HADS) will be administered. A specific electronic database has been designed for data collection. Exhaled breath condensate, urine and blood samples will also be collected. Non-specific bronchial hyperresponsiveness testing with methacholine will be performed and an induced sputum sample will be collected at the beginning of the study and every 24 months. A skin prick test for airborne allergens and a chest CT will be performed at the beginning of the study and repeated every 5 years.

Asthma with bronchial hypersecretion: expression of mucins and toll-like receptors in sputum and blood.

Asthma with bronchial hypersecretion is a type of asthma that is poorly studied. Its pathogenesis is not well understood, but is probably related to innate impaired immunity, particularly with toll-like receptors (TLRs) and secretory mucins (MUC). OBJECTIVES: 1) Define the clinical and inflammatory phenotype of asthma with bronchial hypersecretion of mucus. 2) Compare the type of mucin present in induced sputum (IS) of patients with and without bronchial hypersecretion. 3) Determine the expression of TLRs in IS and blood of asthmatics with and without bronchial hypersecretion. MATERIALS AND METHODS: Cross-sectional study which included 43 non-smoking asthmatic patients without bronchiectasis, 19 with bronchiectasis, and 24 without bronchial hypersecretion. All patients underwent the following: IS, spirometry, fractional exhaled nitric oxide, prick test, total immunoglobulin E (IgE), and blood albumin. Analysis of mucins was determined by ELISA and expression of TLR2 and TLR4 by flow cytometry. The level of asthma control was determined by the Asthma Control Test (ACT) questionnaire and quality of life was assessed by the reduced version of the Asthma Quality of Life Questionnaire (mini-AQLQ). RESULTS: Asthmatics with bronchial hypersecretion were significantly older (62.6 years vs 48.5 years; p=0.02); had greater severity (persistent severe asthma 94.7% vs 29.2%; p=0.000); a higher proportion of nasal polyposis (36.8% vs 8.3%; p=0.022); less control of asthma (73.7% vs 8.3%; p=0,000); a higher proportion of asthma with negative prick test (68.4% vs 16.6%; p=0.001), and lower levels of IgE (113.4 IU/mL vs 448 IU/mL; p=0.007), compared with asthmatics without bronchial hypersecretion. Significant differences were observed neither in the expression of TLRs 2 and 4 in inflammatory cells of IS or peripheral blood, nor in the expression of mucins between both groups. CONCLUSION: Asthma patients with bronchial hypersecretion have more severe and uncontrolled disease, with poor quality of life as well as a non-allergic inflammatory phenotype. Within the mechanisms involving these differences, it does not appear that mucins and TLRs play an important role.

[Swelling of the bronchial mucose and quickness of onset in acute asthma]. / Edema de la mucosa bronquial y rapidez de instauración de la crisis de asma.

BACKGROUND AND OBJECTIVE: The plasma protein leakage produced in the bronchial mucose of patients with acute asthma might be associated to the quickness of the onset exacerbation. The aim of this study was to study this association. PATIENTS AND METHOD: 22 patients with acute asthma were recruited, and the magnitude of plasma protein leakage was measured by the concentrations of albumin and alpha2-macroglobulin in sputum. RESULTS: Days of onset in acute asthma correlated negatively with albumin sputum concentration (r = -0.563; p = 0.006), alpha2-macroglobulin sputum concentration (r = -0.603; p = 0.003), and related relative coefficients of albumin sputum/serum (r = -0.538; p = 0.01) and alpha2-macroglobulin sputum/serum (r = -0.514; p = 0.014). When the sample was divided by the following daily cutoff: < or = 4, patients suffering from a shorter onset of acute asthma showed a higher concentration of alpha2-macroglobulin in sputum: mean (standard deviation) of 14.4 (18) versus 5.3 (5.4) (p = 0.028). CONCLUSIONS: Plasma protein leakage seems to play an important role in the inflammatory pathogenesis of asthma exacerbation. The quicker onset of asthma the more plasma protein extravasation to the bronchial lumen.

Utility of Induced Sputum in Routine Clinical Practice. / Utilidad del esputo inducido en la práctica clínica habitual.

OBJECTIVE: To determine the general and specific utility in diagnosis and/or treatment of induced sputum (IS) inflammatory cell counts in routine clinical practice. METHODS: Retrospective study of 171 patients referred for clinical sputum induction over a 1-year period in the pulmonology department of a referral hospital. Independent observers established whether the information provided by IS inflammatory cell count was useful for making diagnostic and therapeutic decisions. RESULTS: The most frequent reasons for determination of IS inflammatory cell count were: asthma 103 (59.20%); uncontrolled asthma 34 (19.54%); chronic cough 19 (10.9%), and gastroesophageal reflux 15 (8.6%). In 115 patients (67.3%) it was generally useful for diagnosis and/or treatment; in 98 patients (57.3%) it provided diagnostic information and in 85 patients (49.7%) it assisted in therapeutic decision-making. In asthma, uncontrolled asthma, chronic cough and gastroesophageal reflux, the results were useful in 71.8%, 67.6%, 47.4% and 60%, respectively. CONCLUSION: The information provided by IS inflammatory cell count is extremely useful in clinical practice, especially in asthma and chronic cough. These results may justify the inclusion of the IS technique in pulmonology departments and asthma units of referral centers.

Knowledge and Attitudes of Nurses in Spain about Inhaled Therapy: Results of a National Survey.

BACKGROUND: The main problem with inhalation therapy is incorrect use of inhalers. Nurses' limited knowledge may contribute to this situation. This study aimed to assess the level of knowledge and attitudes of respiratory nurses about inhaled therapy. METHODS: A 12-item multiple-choice questionnaire was sent to members in the Nursing Area of the Spanish Society of Pneumology and Thorax Surgery and to nurses working with respiratory patients using inhalers devices. The survey was voluntary, self-administered, and anonymous. It collected demographic characteristics, preferences, and knowledge and education about devices and inhalation technique. RESULTS: A total of 1496 nurses completed the questionnaire correctly. Results showed 65.4% preferred dry powder inhalers (DPI), 8.7% were familiar with all 12 devices listed, 59.6% identified "firing the device after beginning inspiration" as the most important step when using the pressurized metered dose inhaler (pMDI), 53.5% identified ''inhale deeply and forcefully'' as the most significant step using DPI, and 20.4% "always checked a patient's inhalation technique when a new inhaler was prescribed." A composite, variable, general inhaled therapy knowledge pooled the correct answers related to knowledge and showed only 14% of nurses had adequate knowledge of inhaled therapy. CONCLUSIONS: In spite of recent training activities, knowledge concerning use of inhaler devices among Spanish nurses managing patients with respiratory diseases continues to be poor. Improvements are also needed in patient education and follow-up of inhalation techniques. Undergraduate and postgraduate educational programs need to be further developed.

Variability in Asthma Inflammatory Phenotype in Induced Sputum. Frequency and Causes.

INTRODUCTION: Recent studies have found variability in asthma inflammatory phenotypes determined by the inflammatory cells in induced sputum (IS). The aim of this study was to determine the frequency and factors affecting inflammatory phenotype variability in IS. METHODS: Retrospective observational study that included 61 asthmatic patients who underwent at least two IS tests over a period of 5 years. They were classified according to their baseline inflammatory phenotype and subsequently grouped according to phenotype variability (persistent eosinophilic, persistent non-eosinophilic and intermittent eosinophilic). Demographic, clinical and functional data and factors potentially influencing IS variability were collected in all cases. RESULTS: Of the 61 patients, 31 (50.8%) had a change with respect to baseline inflammatory phenotype. Of these, 16 (51.6%) were eosinophilic, 5 (16.1%) neutrophilic, 1 (3.2%) mixed and 9 (29.1%) paucigranulocytic. According to phenotype variability, 18 patients (29.5%) were classified as persistent eosinophilic, 17 (27.9%) non-persistent eosinophilic, and 26 (42.6%) intermittent eosinophilic. Smoking and recent asthma exacerbation were significantly associated with increased risk of variability of the IS inflammatory phenotype (OR=6.44; p=.013; 95% CI=1.49-27.80 and OR=5.84; p=.022; 95% CI=1.29-26.37, respectively). CONCLUSION: Half of asthma patients, predominantly those with eosinophilic phenotype, present a change in IS inflammatory phenotype. This variability is associated with smoking and recent asthma exacerbation. Data suggest these factors can modify the classification of IS inflammatory phenotype in clinical practice.

Knowledge of their own allergic sensitizations in asthmatic patients and its impact on the level of asthma control.

BACKGROUND: Asthma guidelines recommend the adoption of allergen avoidance measures (AAM). To do so, patients need to know their own allergies. However, this degree of knowledge has not yet been assessed. The aims of this study were to determine, in allergic asthma patients: i)the degree of knowledge of their own allergic sensitizations; ii)the percentage of those who knew all their allergies and, in addition, adopted AAM against all of them, and iii)the possible impact of this degree of knowledge on the level of asthma control. PATIENTS AND METHODS: Descriptive, prospective and multicentre study, including 147patients from 9 Respiratory Medicine outpatient clinics. After confirming the previous allergic asthma diagnosis, a questionnaire was completed. It included asthma control and severity levels, results of previous allergy tests, and the description and number of allergic sensitizations known by the patients and AAM followed. RESULTS: Only 72 (49%) patients knew all their allergic sensitizations and only 48 (33%) were also following AAM against all the allergens to which they were allergic. No relationship was established between the degree of knowledge of their own allergies and the level of asthma control (P=.544). CONCLUSIONS: Overall knowledge about the allergic nature of their disease among asthmatic patients attending Spanish Respiratory Medicine Departments is inadequate. Furthermore, a higher degree of knowledge of their allergies does not seem to lead, by itself, to better asthma control. Both findings seem to question the effectiveness of current educational strategies in this field and consequently, they should be revised.

Bronchial inflammation, respiratory symptoms and lung function in Primary Sjögren's syndrome.

INTRODUCTION: There is no information available regarding the relationship between the respiratory symptoms or lung function and bronchial inflammation, measured by induced sputum. OBJECTIVES: Description of the clinical characteristics, radiographic images and lung function of patients suffering from Primary Sjögren Syndrome (PSS), and to assess the relationship with the inflammatory airway profile. METHODS: We analysed clinical, radiology, lung function tests, bronchial hyperresponsiveness and inflammatory data in the induced sputum from 36 consecutive patients with PSS. RESULTS: A total of 58% of patients had hoarseness and 42% had cough and dispnea. No lung dysfunction was observed, although 46% (n=16) had a positive bronchial response. Lymphocytosis >2.6% in induced sputum was observed in 69% of all sputa. There was chronic cough in 29% of patients with lymphocytosis (n=24), whereas 73% were normal (n=11) (P=.02). The duration time of cough was less for the former (P=.02). On the contrary a positive bronchial response was associated with lymphocytosis >2.6% (P=.02). Lipophages were present in 55% of pathological sputa (n=22) (index >15) versus 18% of the non-pathological ones (n=11) (P=.05). CONCLUSION: Hoarseness, cough and dyspnea are frequent respiratory symptoms in PSS, although there is a wide variation in the relationship with bronchial responsiveness and airway inflammation. Lymphocytosis in the airways is another site of the infiltrative process in PSS, and the induced sputum is a complementary tool in the identification of active inflammatory process.

[Inflammatory response of rapid onset asthma exacerbation]. / Respuesta inflamatoria de la exacerbación asmática de instauración rápida.

UNLABELLED: The association between onset of asthma exacerbation and the inflammatory response has not been sufficiently studied. OBJECTIVE: To determine the differential mechanisms of the rapid onset (RO) asthma exacerbation. METHODS: We designed a prospective, multicentre study that included 34 patients who suffered from asthma exacerbation. They were distributed into three groups of asthmatics, depending of the time of onset: from 0 to 24h, from 25 to 144h and more than 145h. We collected clinical data, sputum, blood and urine samples when first seen at the clinic and the next 24h later, and differential cell counts and biomarkers were determined RESULTS: The asthmatics who suffered a RO exacerbation showed a higher elastase concentration, (1.028±1.140; 310±364; 401±390ng/ml) (P<0.05) and albumin (46.2±4.3; 42±3.4; 39.9±4.8g/l) (P<0.05) in the blood sample. Neutrophils, eosinophils (blood or sputum), eosinophil cationic protein (ECP) (blood), interleukin 8 (IL(8)) (blood) and leukotriene E4 (LTE(4)) (urine) were high in the three groups (P>0.05). We demonstrated an association between the onset of exacerbation and the severity of obstruction (FEV(1)) (r=-0.360; P=0.037), eosinophils in sputum (r=-0.399; P=0.029), albumin (r=-0.442; P=0.013), and IL(8) in sputum (r=0.357; P=0.038). CONCLUSIONS: The results suggest a rapid inflammatory response, both neutrophilic and eosinophilic, in the asthmatic exacerbation. However, the swelling in the bronchi may play an important role in the initial inflammatory response in the exacerbations depending of time of onset.