Targeted AntiBiotics for Chronic pulmonary diseases (TARGET ABC): can targeted antibiotic therapy improve the prognosis of Pseudomonas aeruginosa-infected patients with chronic pulmonary obstructive disease, non-cystic fibrosis bronchiectasis, and asthma? A multicenter, randomized, controlled, open-label trial.

BACKGROUND: Pseudomonas aeruginosa infection is seen in chronic pulmonary disease and is associated with exacerbations and poor long-term prognosis. However, evidence-based guidelines for the management and treatment of P. aeruginosa infection in chronic, non-cystic fibrosis (CF) pulmonary disease are lacking. The aim of this study is to investigate whether targeted antibiotic treatment against P. aeruginosa can reduce exacerbations and mortality in patients with chronic obstructive pulmonary disease (COPD), non-CF bronchiectasis, and asthma. METHODS: This study is an ongoing multicenter, randomized, controlled, open-label trial. A total of 150 patients with COPD, non-CF bronchiectasis or asthma, and P. aeruginosa-positive lower respiratory tract samples will be randomly assigned with a 1:1 ratio to either no antibiotic treatment or anti-pseudomonal antibiotic treatment with intravenous beta-lactam and oral ciprofloxacin for 14 days. The primary outcome, analyzed with two co-primary endpoints, is (i) time to prednisolone and/or antibiotic requiring exacerbation or death, in the primary or secondary health sector, within days 20-365 from study allocation and (ii) days alive and without exacerbation within days 20-365 from the study allocation. DISCUSSION: This trial will determine whether targeted antibiotics can benefit future patients with chronic, non-CF pulmonary disease and P. aeruginosa infection in terms of reduced morbidity and mortality, thus optimizing therapeutic approaches in this large group of chronic patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT03262142 . Registered on August 25, 2017.

Use of inhaled corticosteroids and risk of acquiring Pseudomonas aeruginosa in patients with chronic obstructive pulmonary disease.

BACKGROUND: Inhaled corticosteroids (ICS) are commonly used to treat COPD and are associated with increased risk of pneumonia. The aim of this study was to assess if accumulated use of ICS is associated with a dose-dependent risk of a positive airway culture with Pseudomonas aeruginosa in patients with COPD. METHODS: We conducted a multiregional epidemiological cohort study including Danish COPD patients followed in outpatient clinics during 2010-2017. ICS use was categorised based on accumulated prescriptions redeemed 365 days prior to cohort entry. Cox proportional hazard regression model was used to estimate the risk of acquiring P. aeruginosa. Propensity score matched models were used as sensitivity analyses. RESULTS: A total of 21 408 patients were included in the study, of which 763 (3.6%) acquired P. aeruginosa during follow-up. ICS use was associated with a dose-dependent risk of P. aeruginosa (low ICS dose: HR 1.38, 95% CI 1.03 to 1.84, p=0.03; moderate ICS dose: HR 2.16, 95% CI 1.63 to 2.85, p<0.0001; high ICS dose: HR 3.58, 95% CI 2.75 to 4.65, p<0.0001; reference: no ICS use). A propensity matched model confirmed the results (high ICS dose compared with no/low/moderate ICS dose: HR 2.05, 95% CI 1.76 to 2.39, p p<0.0001). CONCLUSION: Use of ICS in patients with COPD followed in Danish outpatient clinics was associated with a substantially increased and dose-dependent risk of acquiring P. aeruginosa. Caution should be taken when administering high doses of ICS in severely ill patients with COPD. These results should be confirmed in comparable cohorts and other settings.

Azithromycin and hydroxychloroquine in hospitalised patients with confirmed COVID-19: a randomised double-blinded placebo-controlled trial.

BACKGROUND: Combining the antibiotic azithromycin and hydroxychloroquine induces airway immunomodulatory effects, with the latter also having in vitro antiviral properties. This may improve outcomes in patients hospitalised for coronavirus disease 2019 (COVID-19). METHODS: Placebo-controlled double-blind randomised multicentre trial. Patients aged ≥18 years, admitted to hospital for ≤48 h (not intensive care) with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcription PCR test were recruited. The intervention was 500 mg daily azithromycin for 3 days followed by 250 mg daily azithromycin for 12 days combined with 200 mg twice-daily hydroxychloroquine for all 15 days. The control group received placebo/placebo. The primary outcome was days alive and discharged from hospital within 14 days (DAOH14). RESULTS: After randomisation of 117 patients, at the first planned interim analysis, the data and safety monitoring board recommended stopping enrolment due to futility, based on pre-specified criteria. Consequently, the trial was terminated on 1 February 2021. 61 patients received the combined intervention and 56 patients received placebo. In the intervention group, patients had a median (interquartile range) 9.0 (3-11) DAOH14 versus 9.0 (7-10) DAOH14 in the placebo group (p=0.90). The primary safety outcome, death from all causes on day 30, occurred for one patient in the intervention group versus two patients receiving placebo (p=0.52), and readmittance or death within 30 days occurred for nine patients in the intervention group versus six patients receiving placebo (p=0.57). CONCLUSIONS: The combination of azithromycin and hydroxychloroquine did not improve survival or length of hospitalisation in patients with COVID-19.

Dysfunctional Bronchial Cilia Are a Feature of Chronic Obstructive Pulmonary Disease (COPD).

Impaired mucociliary clearance may increase COPD exacerbation risk. We aimed to compare bronchial ciliary function and epithelial ultrastructure of COPD patients to healthy controls and explore its relationship to exacerbator phenotypes (frequent [FE] and infrequent [IFE] exacerbator). In this cross-sectional study, 16 COPD patients and 12 controls underwent bronchial brushings. Ciliary beat frequency (CBF) and dyskinesia index (DI; % of dyskinetic cilia) were assessed using digital high-speed video microscopy, and epithelial ultrastructure using transmission electron microscopy (TEM). Bronchial epithelium in COPD showed lower CBF and higher DI, compared to controls (median [IQR] CBF: 6.8 (6.1-7.2) Hz vs 8.5 (7.7-8.9) Hz, p<0.001 and DI: 73.8 (60.7-89.8) % vs 14.5 (11.2-16.9) %, p<0.001, respectively). This was true for FE and IFE phenotypes of COPD, which were similar in terms of bronchial CBF or DI. Subgroup analyses demonstrated lower CBF and higher DI in FE and IFE COPD phenotypes compared to controls, irrespective of smoking status. TEM showed more loss of cilia, extrusion of cells, cytoplasmic blebs and dead cells in COPD patients versus controls. Profound dysfunction of bronchial cilia is a feature of COPD irrespective of exacerbation phenotype and smoking status, which is likely to contribute to poor mucus clearance in COPD.Supplemental data for this article is available online at https://doi.org/10.1080/15412555.2021.1963695 .

Corticosteroid Resistance in Smokers-A Substudy Analysis of the CORTICO-COP Randomised Controlled Trial.

The CORTICO-COP trial showed that eosinophil-guided corticosteroid-sparing treatment for acute exacerbation of chronic obstructive pulmonary disease was non-inferior to standard of care and decreased the accumulated dose of systemic corticosteroids that patients were exposed to by approximately 60%. Smoking status has been shown to affect corticosteroid responsiveness. This post hoc analysis investigated whether eosinophil-guided treatment is non-inferior to conventional treatment in current smokers. The main analysis of current smokers showed no significant difference in the primary endpoint, days alive, and out of hospital within 14 days between the control group (mean, 9.8 days; 95% confidence interval (CI), 8.7-10.8) and the eosinophil-guided group (mean, 8.7 days; 95% CI, 7.5-9.9; p = 0.34). Secondary analyses of the number of exacerbations or deaths, the number of intensive care unit admissions or deaths, lung function improvement, and change in health-related quality of life also showed no significant differences between the two groups. The results of a sensitivity analysis of ex-smokers are consistent with the main analysis. Our results suggest that eosinophil-guided treatment is non-inferior to standard of care in current smokers and ex-smokers. Because data on the impact of smoking status on eosinophil-guided treatments are sparse, more randomised trials are needed to confirm our results.

Changes in Control Status of COPD Over Time and Their Consequences: A Prospective International Study / Cambios en el estado de control de la EPOC a lo largo del tiempo y sus consecuencias: un estudio internacional prospectivo

INTRODUCTION: Control status may be a useful tool to assess response to treatment at each clinical visit in COPD. Control status has demonstrated to have long-term predictive value for exacerbations, but there is no information about the short-term predictive value of the lack of control and changes in control status over time. METHOD: Prospective, international, multicenter study aimed at describing the short-term (6 months) prognostic value of control status in patients with COPD. Patients with COPD were classified as controlled/uncontrolled at baseline and at 3,6-month follow-up visits using previously validated criteria of control. Moderate and severe exacerbation rates were compared between controlled and uncontrolled visits and between patients persistently controlled, uncontrolled and those changing control status over follow-up. RESULTS: A total of 267 patients were analyzed: 80 (29.8%) were persistently controlled, 43 (16%) persistently uncontrolled and 144 (53.7%) changed control status during follow-up. Persistently controlled patients were more frequently men, with lower (not increased) body mass index and higher FEV1(%). During the 6 months following an uncontrolled patient visit the odds ratio (OR) for presenting a moderate exacerbation was 3.41 (95% confidence interval (CI) 2.47-4.69) and OR = 4.25 (95%CI 2.48-7.27) for hospitalization compared with a controlled patient visit. CONCLUSIONS: Evaluation of control status at each clinical visit provides relevant prognostic information about the risk of exacerbation in the next 6 months. Lack of control is a warning signal that should prompt investigation and action in order to achieve control status

INTRODUCCIÓN: El estado de control de la enfermedad puede ser una herramienta útil para evaluar la respuesta al tratamiento de la EPOC en cada asistencia a consulta. El estado de control de la enfermedad ha demostrado tener valor predictivo a largo plazo para las exacerbaciones, pero no existe información sobre el valor predictivo a corto plazo de la falta de control de la EPOC y los cambios en dicho control a lo largo del tiempo. MÉTODO: Estudio prospectivo, internacional, multicéntrico enfocado en describir el valor pronóstico a corto plazo (6 meses) del estado de control de la enfermedad en pacientes con EPOC. Los pacientes con EPOC se clasificaron como con enfermedad controlada/sin controlar al inicio del estudio y en las 3 visitas de seguimiento separadas 6 meses, utilizando criterios de control previamente validados. Se compararon las tasas de exacerbación moderada y grave entre visitas en las que la enfermedad estaba controlada y aquellas en las que no y entre pacientes con control persistente de la enfermedad, pacientes sin control de la enfermedad y aquellos cuyo estado de control cambió durante el seguimiento. RESULTADOS: Se analizó a un total de 267 pacientes: 80 (29,8%) presentaron control persistente de la enfermedad, 43 (16%) permanecieron con enfermedad no controlada de manera persistente y 144 (53,7%) presentaron un cambio en el estado de control de su EPOC durante el seguimiento. Los pacientes con control persistente de su enfermedad fueron con mayor frecuencia hombres, con un índice de masa corporal más bajo (no elevado) y un FEV1 (%) más alto. Durante los 6 meses posteriores a una visita en la que la enfermedad del paciente no estaba controlada, la odds ratio (OR) para presentar una exacerbación moderada fue de 3,41 (intervalo de confianza [IC] del 95%: 2,47 a 4,69) y la OR = 4,25 (IC del 95%: 2,48 a 7,27) para la hospitalización, en comparación con una visita en la que la EPOC estaba controlada. CONCLUSIONES: La evaluación del estado de control de la EPOC en cada asistencia a consulta proporciona información pronóstica relevante sobre el riesgo de exacerbación en los próximos 6 meses. La falta de control es una señal de alarma que debe motivar la investigación y la acción para lograr el control de la enfermedad

Changes in Control Status of COPD Over Time and Their Consequences: A Prospective International Study.

INTRODUCTION: Control status may be a useful tool to assess response to treatment at each clinical visit in COPD. Control status has demonstrated to have long-term predictive value for exacerbations, but there is no information about the short-term predictive value of the lack of control and changes in control status over time. METHOD: Prospective, international, multicenter study aimed at describing the short-term (6 months) prognostic value of control status in patients with COPD. Patients with COPD were classified as controlled/uncontrolled at baseline and at 3,6-month follow-up visits using previously validated criteria of control. Moderate and severe exacerbation rates were compared between controlled and uncontrolled visits and between patients persistently controlled, uncontrolled and those changing control status over follow-up. RESULTS: A total of 267 patients were analyzed: 80 (29.8%) were persistently controlled, 43 (16%) persistently uncontrolled and 144 (53.7%) changed control status during follow-up. Persistently controlled patients were more frequently men, with lower (not increased) body mass index and higher FEV1(%). During the 6 months following an uncontrolled patient visit the odds ratio (OR) for presenting a moderate exacerbation was 3.41 (95% confidence interval (CI) 2.47-4.69) and OR=4.25 (95%CI 2.48-7.27) for hospitalization compared with a controlled patient visit. CONCLUSIONS: Evaluation of control status at each clinical visit provides relevant prognostic information about the risk of exacerbation in the next 6 months. Lack of control is a warning signal that should prompt investigation and action in order to achieve control status.

Guideline for the management of COVID-19 patients during hospital admission in a non-intensive care setting.

INTRODUCTION: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has presented health-care systems worldwide with novel challenges and experiences and evidence is emerging during the pandemic. Patients requiring hospitalization frequently suffer from respiratory failure of different severities. AIM: The aim of this guideline is the treatment of patients with SARS CoV-2 (COVID-19) in hospital; in particular, it addresses the treatment of respiratory failure treated in general Internal Medical- and Pulmonary Medical wards. RESULTS: Elderly patients and patients with chronic disease are particularly vulnerable to COVID-19. Target oxygen saturation should be between 92% and 96% in patients without chronic lung diseases. Treatment with >5 L oxygen/min should be in close collaboration with intensive care colleagues and >15 l/min preferably in intensive care units. High-flow nasal canula (HFNC) and long-term Continuous Positive Airway Pressure (CPAP) are recommended for patients not responding to conventional oxygen therapy. Non-invasive ventilation (NIV) is only recommended for selected patients, such as those with a ceiling of treatment or patients presenting with hypercapnic failure. With the use of humidification protective equipment as FFP2-3 masks should be used. Nebulized medication should be avoided, and spacers should be used instead. CONCLUSION: Respiratory failure is frequently the cause of hospitalization in patients with COVID-19 and should be monitored closely.

Chronic rhinosinusitis in COPD: A prevalent but unrecognized comorbidity impacting health related quality of life.

INTRODUCTION: Unified airway disease where upper respiratory tract inflammation including chronic rhinosinusitis (CRS) affects lower airway disease is known from asthma, bronchiectasis, cystic fibrosis and primary ciliary dyskinesia but little is known about CRS and health related quality of life in COPD. We investigate firstly, the prevalence of CRS in COPD. Secondly the impact of CRS on HRQoL. Thirdly, risk factors for CRS in COPD. METHODS: cross-sectional study of CRS in 222 COPD patients from 2017 to 2019 according to EPOS2012/2020 and GOLD2019 criteria. Patients completed the COPD assessment test (CAT), Medical Research Council dyspnea scale and Sinonasal outcome test 22 (SNOT22) and questions on CRS symptoms. They then had a physical examination including flexible nasal endoscopy, CT-sinus scan and HRCT-thorax. RESULTS: 22.5% of COPD patients had CRS and 82% of these were undiagnosed prior to the study. HRQoL (CAT, SNOT22 and the SNOT22-nasal symptom subscore) was significantly worse in COPD patients with CRS compared with those without CRS and healthy controls. Multiple logistic regression analysis suggests that the most likely candidate for having CRS was a male COPD patient who actively smoked, took inhaled steroids, had a high CAT and SNOT22_nasal symptom subscore. DISCUSSION: the largest clinical study of CRS in COPD and the only study diagnosing CRS according to EPOS and GOLD. This study supports unified airway disease in COPD. The SNOT22_nasal symptoms subscore is recommended as a standard questionnaire for COPD patients and patients at risk should be referred to an otorhinolaryngologist.

Proactive Prophylaxis With Azithromycin and HydroxyChloroquine in Hospitalised Patients With COVID-19 (ProPAC-COVID): A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: The aim of this randomised GCP-controlled trial is to clarify whether combination therapy with the antibiotic azithromycin and hydroxychloroquine via anti-inflammation/immune modulation, antiviral efficacy and pre-emptive treatment of supra-infections can shorten hospitalisation duration for patients with COVID-19 (measured as "days alive and out of hospital" as the primary outcome), reduce the risk of non- invasive ventilation, treatment in the intensive care unit and death. TRIAL DESIGN: This is a multi-centre, randomised, Placebo-controlled, 2-arm ratio 1:1, parallel group double-blind study. PARTICIPANTS: 226 participants are recruited at the trial sites/hospitals, where the study will take place in Denmark: Aalborg, Bispebjerg, Gentofte, Herlev, Hillerød, Hvidovre, Odense and Slagelse hospitals. INCLUSION CRITERIA: • Patient admitted to Danish emergency departments, respiratory medicine departments or internal medicine departments • Age≥ 18 years • Hospitalized ≤48 hours • Positive COVID-19 test / diagnosis during the hospitalization (confirmed). • Men or non-fertile women. Fertile women* must not be pregnant, i.e. negative pregnancy test must be available at inclusion • Informed consent signed by the patient *Defined as after menarche and until postmenopausal (no menstruation for 12 months) Exclusion criteria: • At the time of recruitment, the patient uses >5 LO2/min (equivalent to 40% FiO2 if measured) • Known intolerance/allergy to azithromycin or hydroxychloroquine or hypersensitivity to quinine or 4-aminoquinoline derivatives • Neurogenic hearing loss • Psoriasis • Retinopathy • Maculopathy • Visual field changes • Breastfeeding • Severe liver diseases other than amoebiasis (INR> 1.5 spontaneously) • Severe gastrointestinal, neurological and hematological disorders (investigator-assessed) • eGFR <45 ml/min/1.73 m2 • Clinically significant cardiac conduction disorders/arrhythmias or prolonged QTc interval (QTc (f) of> 480/470 ms). • Myasthenia gravis • Treatment with digoxin* • Glucose-6-phosphate dehydrogenase deficiency • Porphyria • Hypoglycaemia (Blood glucose at any time since hospitalization of <3.0 mmol/L) • Severe mental illness which significantly impedes cooperation • Severe linguistic problems that significantly hinder cooperation • Treatment with ergot alkaloids *The patient must not be treated with digoxin for the duration of the intervention. For atrial fibrillation/flutter, select according to the Cardiovascular National Treatment Guide (NBV): Calcium antagonist, Beta blocker, direct current (DC) conversion or amiodarone. In case of urgent need for digoxin treatment (contraindication for the aforementioned equal alternatives), the test drug should be paused, and ECG should be taken daily. INTERVENTION AND COMPARATOR: Control group: The control group will receive the standard treatment + placebo for both types of intervention medication at all times. If part or all the intervention therapy being investigated becomes standard treatment during the study, this may also be offered to the control group. Intervention group: The patients in the intervention group will also receive standard care. Immediately after randomisation to the intervention group, the patient will begin treatment with: Azithromycin: Day 1-3: 500 mg x 1 Day 4-15: 250 mg x 1 If the patient is unable to take the medication orally by themselves, the medication will, if possible, be administered by either stomach-feeding tube, or alternatively, temporary be changed to clarithromycin 500 mg x 2 (this only in agreement with either study coordinator Pradeesh Sivapalan or principal investigator Jens-Ulrik Stæhr Jensen). This will also be done in the control group if necessary. The patient will switch back to azithromycin when possible. Hydroxychloroquine: Furthermore, the patient will be treated with hydroxychloroquine as follows: Day 1-15: 200 mg x 2 MAIN OUTCOMES: • Number of days alive and discharged from hospital within 14 days (summarises both whether the patient is alive and discharged from hospital) ("Days alive and out of hospital") RANDOMISATION: The sponsor (Chronic Obstructive Pulmonary Disease Trial Network, COP:TRIN) generates a randomisation sequence. Randomisation will be in blocks of unknown size and the final allocation will be via an encrypted website (REDCap). There will be stratification for age (>70 years vs. <=70 years), site of recruitment and whether the patient has any of the following chronic lung diseases: COPD, asthma, bronchiectasis, interstitial lung disease (Yes vs. No). BLINDING (MASKING): Participants and study personnel will both be blinded, i.e. neither will know which group the participant is allocated to. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): This study requires 226 patients randomised 1:1 with 113 in each group. TRIAL STATUS: Protocol version 1.8, from April 16, 2020. Recruitment is ongoing (first patient recruited April 6, 2020; final patient expected to be recruited October 31, 2020). TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04322396 (registered March 26, 2020) FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Comparison of clinical baseline characteristics between Asian and Western COPD patients in a prospective, international, multicenter study.

We aimed to compare clinical characteristics between Asian and Western chronic obstructive pulmonary disease (COPD) patients. This was a sub-analysis of an international, multicenter, prospective cohort study. Asian patients were enrolled in Singapore and South Korea. Western patients were enrolled in Spain, Poland, Ireland, the United Kingdom, and Malta. A total of 349 patients were analyzed. Among them, 110 (32%) patients were Asian and 239 (68%) Western. Male sex was more predominant in Asian than in Western (95% versus 63%, respectively; P<0.01). Body mass index was significantly lower in Asian (23.5 versus 27.1; P<0.01). The proportion of patients with a history of exacerbation was lower in Asian (12% versus 64%; P<0.01). Although patients were enrolled by same inclusion criteria, there were several differences between Asian and Western COPD patients. Our study has shown unbiased real-world differences between Asian and Western COPD patients. Since prospective follow-up study is currently ongoing, the result of this study can be fundamental base of future analysis.

Impact of simulation training on performance and outcomes of endobronchial ultrasound-guided transbronchial needle aspiration performed by trainees in a tertiary academic hospital.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has a high diagnostic yield and low complication rate. Whilst it has been included in international guidelines for the diagnosis and staging of lung cancer, current results are mostly based on EBUS experts performing EBUS-TBNA in centres of excellence. The impact of simulation training on diagnostic yield, complications, scope damage and repair cost in a real-world teaching hospital is unclear. METHODS: A review of our hospital EBUS-TBNA registry from August 2008 to December 2016 was performed. A positive diagnosis was defined as a confirmed histological or microbiological diagnosis based on EBUS sampling. Complications were classified as major or minor according to the British Thoracic Society guidelines. In addition, we assessed the cost of repairs for scope damage before and after simulation training was implemented. Using CUSUM analysis, the learning curves of individual trainees and the institution were plotted. RESULTS: There were 608 EBUS-TBNA procedures included in the study. The number of procedures performed by trainees who underwent conventional training was 331 and those who underwent simulation training performed 277 procedures. Diagnostic yield for trainees without simulation training was 88.2% vs. 84.5% for trainees with simulation training (P=0.179). There was no statistical difference in the diagnostic yield between the groups of trainees (OR: 0.781, 95% CI: 0.418-1.460, P=0.438) after adjusting for risk factors. There was an increase in overall complications from 13.6% to 16.6% (OR: 2.247, 95% CI: 1.297-3.891, P=0.004) after introduction of the simulation training, but a trend to decrease in major complications 3.6% to 0.7% (P=0.112). The cost for scope repairs for the trainees without simulation training was SGD 413.88 per procedure vs. SGD 182.79 per procedure for the trainees with simulation training, with the mean difference being SGD 231.09 per procedure (95% CI: 178.40-640.60, P=0.268). CUSUM analysis showed an increasing learning curve for the trainees with simulation training after an initial competency period. CONCLUSIONS: There was no statistical difference in diagnostic yield from EBUS-TBNA and cost of scope damage after simulation training was introduced into our training program. Interestingly, there was an increase in minor complications. CUSUM analysis can provide additional information on institutional learning curves. The value of simulation training in EBUS-TBNA remains uncertain.

Evaluation of criteria for clinical control in a prospective, international, multicenter study of patients with COPD.

BACKGROUND: The concept of clinical control in COPD has been developed to help in treatment decisions, but it requires validation in prospective studies. METHOD: This international, multicenter, prospective study aimed to validate the concept of control in COPD [control = stability (no exacerbations or impairment in CAT scores) + low impact (low level of symptoms)]. Data from the screening visit was used to: investigate the level of control, compare characteristics of patients according to the control status, and perform a sensitivity analysis of the levels of control using either clinical criteria or questionnaires (COPD Assessment Test -CAT- or Clinical COPD Questionnaire -CCQ-). RESULTS: A total of 314 patients were analysed, mean age was 68.5 years and mean FEV1 was 52.6% of predicted. According to the prespecified criteria 21% of patients were classified as controlled, all of them with mild/moderate COPD (Body mass index, Obstruction, Dyspnea and Exacerbations, -BODEx-index <5). A high level of dyspnea, a high CAT score or an exacerbation in the previous 3 months were found, using univariate analysis, to be the main reasons for patients not being classified as controlled. Multivariate analysis showed that female sex, chronic bronchitis and having exacerbations in the previous year were associated with uncontrolled COPD. Changing the severity cut off of BODEx from 5 to 3 did not change significantly the percentage of patients fulfilling the criteria of control. CONCLUSIONS: The proposed criteria of control were only fulfilled by 21% of patients. The suggested cut offs and their predictive value for poor outcomes need to be refined in prospective studies.

Sensitization to Aspergillus species is associated with frequent exacerbations in severe asthma.

BACKGROUND: Severe asthma is a largely heterogeneous disease with varying phenotypic profiles. The relationship between specific allergen sensitization and asthma severity, particularly in Asia, remains unclear. We aim to study the prevalence of specific allergen sensitization patterns and investigate their association with outcomes in a severe asthma cohort in an Asian setting. METHODS: We conducted a cross-sectional study of patients receiving step 4 or 5 Global Initiative for Asthma treatment. Univariate and multivariate analyses were performed to assess the association between sensitization to a specific identifiable allergen by skin prick test (SPT) and uncontrolled asthma (defined in our study as the use of ≥2 steroid bursts or hospitalization in the past year, a history of near-fatal asthma or evidence of airflow obstruction on spirometry). RESULTS: Two hundred and six severe asthma patients (mean age 45±17 years, 99 [48.1%] male) were evaluated. Of them, 78.2% had a positive SPT to one or more allergens. The most common allergen to which patients were sensitized was house dust mites (Blomia tropicalis, Dermatophagoides pteronyssinus and Dermatophagoides farinae). Also, 11.7% were sensitized to Aspergillus species. On multivariate analysis, Aspergillus sensitization was associated with uncontrolled asthma (odds ratio 6.07, 95% confidence interval 1.80-20.51). In particular, Aspergillus sensitization was independently associated with the use of ≥2 steroid bursts in the past year (odds ratio 3.05, 95% confidence interval 1.04-8.95). No similar associations of uncontrolled asthma with sensitization to any other allergens were found. CONCLUSION: High allergen, specifically Aspergillus sensitization was observed in the Asian population with severe asthma by SPT. Aspergillus sensitization was specifically associated with frequent exacerbations and a greater corticosteroid requirement. An improved understanding of the severe asthma with Aspergillus sensitization phenotype is warranted, which is likely a subgroup of severe asthma with fungal sensitization.

Fixed airways obstruction among patients with severe asthma: findings from the Singapore General Hospital-Severe Asthma Phenotype Study.

BACKGROUND: A subset of severe asthma patients has fixed airways obstruction, which is characterized by incomplete reversibility to bronchodilator challenge. We aimed to elucidate the factors associated with fixed airways obstruction in a cohort of patients with severe asthma in Singapore. METHODS: 245 patients from the Singapore General Hospital-Severe Asthma Phenotype Study (SGH-SAPS) were screened. These patients fulfilled World Health Organization criteria for "treatment-resistant severe asthma" and were all on combination of high-dose inhaled corticosteroids and long-acting beta2 agonists. 76 patients had pre- and postbronchodilator lung function tests and were selected for analysis. They were divided into two groups based on postbronchodilator (Post BD) forced expiratory volume in one second, PostBDFEV1 % predicted: ≥70% (Non-Fixed Obs) and < 70% (Fixed Obs). We compared clinical and demographic parameters between the two groups. RESULTS: Patients in the Fixed Obs group were more frequently past or current smokers and had a higher pack-year smoking history. Overall, pack-year smoking history had a modest negative correlation with PostBDFEV1 % predicted. Atopy, allergen sensitization (type and numbers), comorbidities, symptoms, health care utilization and medication use did not differ between the two groups. The prebronchodilator FEV1 % predicted, FEV1/FVC and FVC % predicted were significantly lower in the Fixed Obs group. In addition, prebronchodilator FVC % predicted accounted for more variability than FEV1/FVC in predicting PostBDFEV1% predicted. CONCLUSION: Smoking is associated with fixed airways obstruction in patients with treatment-resistant severe asthma in Singapore. Furthermore, our results suggest that both small and large airways obstruction contribute independently to fixed airways obstruction in severe asthma.