Static lung volumes and diffusion capacity in adults 30 years after being diagnosed with asthma.

BACKGROUND: Long-term follow-up studies of adults with well-characterized asthma are sparse. We aimed to explore static lung volumes and diffusion capacity after 30 + years with asthma. METHODS: A total of 125 adults with an objectively verified diagnosis of asthma between 1974-1990 at a Danish respiratory outpatient clinic completed a follow-up visit 2017-19. All participants (age range 44-88 years) completed a comprehensive workup and were, based on these assessments, classified as having either active asthma or being in complete remission. The examination program included measurements of static lung volumes and diffusion capacity. RESULTS: Participants with active asthma were hyperinflated (residual volume/total lung capacity ratio 0.43, 95% CI 0.41-0.45) (RV/TLC ratio) compared with those in remission (RV/TLC ratio 0.38, 95% CI 0.36-0.41) (p < 0.03). A tendency towards higher diffusion capacity per liter lung volume was seen in participants with active asthma (KCO 100% predicted, 95% CI 97-104) compared with those in remission (KCO 94% pred., 95% CI 89-99) (P = 0.10). Longer asthma duration was associated with a higher KCO 0.47% pred./year (95% CI 0.14-0.80), adjusted for age and smoking. Patients on GINA step 4 and 5 treatment were more hyperinflated ([Formula: see text] RV 14% pred., 95% CI 3-27) and had higher airway resistance (mean 53% pred., 95% CI 9-97) than participants on lower GINA steps. Patients with uncontrolled disease had substantially higher airway resistance (72% pred. 95% CI 20-124) than well-controlled patients. CONCLUSION: Thirty years after a confirmed diagnosis of asthma, those continuing to have active asthma and those having severe asthma, have higher diffusion capacity and more hyperinflation than patients in remission.

Demographic, lifestyle and comorbid risk factors for all-cause mortality in a Danish cohort of middle-aged adults with incident asthma.

OBJECTIVE: We aimed to identify factors associated with all-cause mortality in adults with incident asthma. DESIGN AND SETTING: Cross-sectional cohort study, in the metropolitan areas of Copenhagen and Aarhus, Denmark. PARTICIPANTS: Adults aged 50-64 years enrolled in the Danish Diet, Cancer, and Health cohort were followed up from baseline (1993-1997) in the National Patients Registry for first-time admissions for asthma and vital status. We defined incident asthma as at least one first-time hospital admission with asthma as the primary registered diagnosis between baseline and end of follow-up (2013) in participants without previously known asthma. Among the cohort comprising 57 053 individuals, we identified 785 adults (aged 50-64) with incident asthma, of whom 76 died during follow-up. PRIMARY AND SECONDARY OUTCOME MEASURES: Baseline reported socioeconomic and lifestyle traits, and comorbidities associated with all-cause mortality. RESULTS: Self-reported leisure-time physical activity was associated with a substantial reduction in risk with an HR of 0.53 (95% CI 0.33 to 0.85). Being male, single and having a diagnosis of hypertension or diabetes were associated with an increased risk of all-cause mortality with an HR of 1.83 (95% CI 1.14 to 2.38), 2.16 (95% CI 2.06 to 4.40), 2.47 (95% CI 1.54 to 3.95) and of 2.42 (95% CI 0.96 to 6.11), respectively. CONCLUSIONS: This long-term study of adults with hospital contacts for incident asthma revealed that self-reported leisure-time physical activity is associated with an approximately 50% reduction in all-cause mortality. In contrast, both hypertension and diabetes were associated with a higher risk of mortality.

Long-term predictors of severe exacerbations and mortality in a cohort of well-characterised adults with asthma.

BACKGROUND: We aimed to explore long-term predictors of severe exacerbations and mortality in adults with well-characterised asthma. STUDY DESIGN AND METHODS: Adults (aged ≥ 15) with an objectively verified diagnosis of asthma were recruited from a Danish respiratory outpatient clinic between 1974 and 1990. All individuals were followed in Danish registries for vital status, hospital admissions for asthma and cause of death until end of 2017. Predictors of exacerbations were obtained from a repeated measures model. Standardised mortality rates (SMR) for all-causes were compared with the Danish background population. Hazard ratios for mortality were obtained from a cox proportional hazards model in a two-step process. RESULTS: At baseline, the cohort comprised 1071 patients (mean age 38, SD 16, 61% women), of whom 357 (33%) died during follow-up, with 93 (26%) dying from asthma (primary diagnosis). We found an SMR of 1.24 (95% CI 1.11-1.37, p < 0.001) for all-cause mortality. Baseline predictors for asthma-related death and repeated severe exacerbations were increasing age, ever smoker, FEV1 < 80% pred., high blood eosinophils, longer duration of symptoms and use of SABA > twice daily. Being non-atopic, having a positive histamine challenge test and symptoms more than twice a week were also predictors of repeated exacerbations. CONCLUSIONS: Markers of poor asthma control, including high use of SABA, are predictors of long-term exacerbation rate and mortality over 30 years in patients with well-characterised asthma. Improving asthma control, including lung function and reducing use of reliever medication, is vital for improving the long-term outcome of asthma.

Remission and Changes in Severity Over 30 Years in an Adult Asthma Cohort.

BACKGROUND: Long-term follow-up studies of adults with well-characterized asthma are sparse. OBJECTIVE: We aimed to examine long-term remission and change in disease severity over 30 years in adults with asthma. METHODS: A total of 125 individuals diagnosed with asthma between 1974 and 1990 at a Danish respiratory and allergy clinic, based on history and objective assessments, were included. At follow-up (2017-2019), participants completed questionnaires and had spirometry, bronchodilator reversibility, airway responsiveness, and blood biomarkers measured. Based on these assessments, participants were classified as having either active asthma, clinical remission (no symptoms or prescribed asthma medication within the last year), or complete remission (fractional exhaled nitric oxide <50 parts per billion, no bronchodilator reversibility, no airway hyperresponsiveness, and no airflow limitation). Changes in severity were determined according to Global Initiative for Asthma guidelines based on symptom control and currently prescribed medication. RESULTS: At follow-up, 25% (n = 31) and 15% (n = 19), respectively, had clinical and complete remission. Our analyses showed that a longer duration of symptoms before the initial assessment (odds ratio, 0.86; 95% confidence interval, 0.75-0.98) was associated with a lower chance of asthma remission. At follow-up, 30% had well-controlled asthma compared with none at baseline. Female sex, previous severe exacerbation(s), and older age at baseline were associated with uncontrolled asthma at follow-up. Blood-eosinophil count (≥0.3 × 109/L) and prescribed inhaled corticosteroid (ICS) at baseline were associated with being prescribed medium/high-dose ICS at follow-up. CONCLUSION: Despite 30 years of follow-up, asthma rarely remits in adults, especially in individuals with longer duration and presumably more severe disease. Initial signs of pronounced disease activity were associated with uncontrolled asthma at follow-up.

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).

Opportunistic screening for COPD in primary care: a pooled analysis of 6,710 symptomatic smokers and ex-smokers.

Objective: To investigate the prevalence and predictors of COPD in a large cohort of symptomatic smokers and ex-smokers in a primary care setting. Methods: General practitioners (n=390) consecutively recruited individuals ≥35 years, with current or previous tobacco exposure, at least one respiratory symptom, and no previous diagnosis of obstructive airways disease; and obtained data on tobacco exposure, body mass index (BMI), and dyspnea (Medical Research Council dyspnea scale). All individuals with airflow obstruction, ie, FEV1/FVC <0.70 at initial lung function test, had diagnostic spirometry, including bronchodilator reversibility test. COPD was defined as respiratory symptom(s), tobacco exposure, and nonreversible airflow limitation. Results: Of the 6,710 at-risk individuals screened with spirometry (52% male sex, mean age 58 years [SD 10.9]), 1,185 were diagnosed with COPD (17.7%). Apart from age and pack-years, multivariate logistics regression analysis, adjusted for FEV1, revealed that BMI <25 kg/m2 (OR 4.2, 95% CI 3.0-5.9, p<0.001), BMI 35+ kg/m2 (OR 1.6, 95% CI 1.2-2.3), self-reported dyspnea (OR 1.2, 95% CI 1.1-14, p=0.04), wheeze (OR 1.3, 95% CI 1.1-1.6, p=0.001), phlegm (OR 1.4, 95% CI 1.1-1.6, p<0.001), and MRC ≥3 (OR 1.6, 95% CI 1.2-2.0, p=0.001) were associated with a significantly higher likelihood of being diagnosed with COPD. No association was found between sex, cough, and recurrent respiratory tract infections and a diagnosis of COPD. Conclusion: The prevalence of COPD is high among smokers and ex-smokers with one or more respiratory symptoms seen in primary care, and the presence of wheeze, phlegm and dyspnea, together with both low BMI and obesity identify a subgroup with an even higher likelihood of COPD.

Predictors of COPD in symptomatic smokers and ex-smokers seen in primary care.

Even in subjects at high risk of chronic obstructive pulmonary disease (COPD), the diagnosis is often missed due to lack of awareness of symptoms and risk factors. The objective of this study was to identify predictors of a diagnosis of COPD in symptomatic current and ex-smokers seen in a primary care setting. General practitioners ( n = 241) consecutively recruited subjects ≥ 35 years, with tobacco exposure, at least one respiratory symptom (i.e. cough, sputum, wheeze, dyspnoea and/or recurrent lower respiratory tract infections), and no previous diagnosis of obstructive airways disease. Information on age, smoking status, body mass index (BMI) and dyspnoea (Medical Research Council (MRC) dyspnoea scale) was obtained. Individuals with airway obstruction (i.e. forced expiratory volume in 1 second (FEV1)/forced vital capacity ratio (FVC) < 0.70) at initial spirometry had a diagnostic spirometry after administration of a bronchodilator. COPD was defined as the presence of symptoms, tobacco exposure and persistent airflow limitation. The most prevalent symptoms were cough (72%) and dyspnoea (48%). Of 3875 (50% females, mean age 57 years) subjects screened, 700 (18.1%) were diagnosed with COPD. Multivariate logistic regression analysis revealed that increasing age 50-59 years (OR 2.4, 95% CI 1.8-3.3), 60-69 years (OR 4.1, 95% CI 3.1-5.5), ≥70 years (OR 5.7, 95% CI 4.2-7.8), BMI < 25 (OR 2.3, 95% CI 1.9-2.7), being current smoker (OR 1.2, 95% CI 1.01-1.5), self-reported dyspnoea (OR 1.7, 95% CI 1.4-2.0), wheeze (OR 1.9, 95% CI 1.5-2.3) and sputum (OR 1.4, 95% CI 1.1-1.7) were associated with a significantly higher risk of being diagnosed with COPD. No association was found between gender, cough and recurrent respiratory tract infections and a diagnosis of COPD. Among symptomatic smokers and ex-smokers seen in primary care, self-reported sputum production, wheeze, dyspnoea and low BMI identify a subgroup with a higher likelihood of COPD.