Risk of lung disease in the PI*SS genotype of alpha-1 antitrypsin: an EARCO research project.

BACKGROUND: The PI*S variant is one of the most prevalent mutations within alpha-1 antitrypsin deficiency (AATD). The risk of developing AATD-related lung disease in individuals with the PI*SS genotype is poorly defined despite its substantial prevalence. Our study aimed to characterize this genotype and its risk for lung disease and compare it with the PI*ZZ and PI*SZ genotypes using data from the European Alpha-1 antitrypsin Deficiency Research Collaboration international registry. METHOD: Demographic, clinical, functional, and quality of life (QoL) parameters were assessed to compare the PI*SS characteristics with the PI*SZ and PI*ZZ controls. A propensity score with 1:3 nearest-neighbour matching was performed for the most important confounding variables. RESULTS: The study included 1007 individuals, with PI*SS (n = 56; 5.6%), PI*ZZ (n = 578; 57.4%) and PI*SZ (n = 373; 37.0%). The PI*SS population consisted of 58.9% men, with a mean age of 59.2 years and a mean FEV1(% predicted) of 83.4%. Compared to PI*ZZ individuals they had less frequent lung disease (71.4% vs. 82.2%, p = 0.037), COPD (41.4% vs. 60%, p = 0.002), and emphysema (23.2% vs. 51.9%, p < 0.001) and better preserved lung function, fewer exacerbations, lower level of dyspnoea, and better QoL. In contrast, no significant differences were found in the prevalence of lung diseases between PI*SS and PI*SZ, or lung function parameters, exacerbations, dyspnoea, or QoL. CONCLUSIONS: We found that, as expected, the risk of lung disease associated with the PI*SS genotype is significantly lower compared with PI*ZZ, but does not differ from that observed in PI*SZ individuals, despite having higher serum AAT levels. TRIAL REGISTRATION: www. CLINICALTRIALS: gov (ID: NCT04180319).

Impact of family socioeconomic position on childhood asthma outcomes, severity, and specialist referral - a Danish nationwide study.

BACKGROUND: Asthma is the most common chronic illness in children, carrying a major burden. Socioeconomic position (SEP) affects adult asthma outcomes, but its impact on childhood asthma, particularly in primary versus specialist care, has not been studied thoroughly. METHODS: In a Danish cohort consisting of all children aged 2-17 years redeeming inhaled corticosteroids in 2015, parental SEP impact on asthma outcomes was investigated. Workforce attachment, income, education, and metropolitan residence were chosen as covariates in logistic regression. Outcomes were uncontrolled (excessive use of short-acting beta2-agonists), exacerbating (oral corticosteroid use or hospitalization), and severe asthma (according to GINA 2020). RESULTS: The cohort comprised 29,851 children (median age 8.0, 59% boys). 16% had uncontrolled asthma, 8% had ≥1 exacerbation. Lower income and metropolitan residence correlated with higher odds of poor control, exacerbations, and severe asthma. Lower education correlated with worse asthma outcomes. Education and income were protective factors in primary care, but not in specialist care. Metropolitan residence was the sole factor linked to specialist care referral for severe asthma. CONCLUSION: Low parental SEP and metropolitan residence associated with poor asthma outcomes. However, specialist care often mitigated these effects, though such care was less likely for at-risk children in non-metropolitan areas.

Psychiatric Adverse Effects of Montelukast-A Nationwide Cohort Study.

BACKGROUND: Recent observational studies suggest that the leukotriene receptor antagonist montelukast may have neuropsychiatric adverse effects; however, results are conflicting. OBJECTIVE: To assess whether montelukast exposure in adults with asthma is associated with onset of neuropsychiatric adverse events using data from the Danish nationwide health registers. METHODS: Individuals 18 years old or older with either 1 or more prescription redemption of inhaled corticosteroids or with at least 1 hospital contact with asthma as the main diagnosis between January 1, 2011, and December 31, 2018, were included. Montelukast exposure was assessed as a time-dependent variable. The 2 outcomes of interest were use of neuropsychiatric medicine including antidepressants, antipsychotics, anxiolytics, lithium, and medication used for attention-deficit/hyperactivity disorder (outcome 1), and hospital contacts with a neuropsychiatric diagnosis (outcome 2), within 90 days of exposure to montelukast. RESULTS: Initiation of montelukast was significantly associated with outcome 1: use of neuropsychiatric medicine (hazard ratio [95% confidence interval]) 1.14 [1.08-1.20]; P < .0001). In the assessment of outcome 2: hospital contacts with a neuropsychiatric diagnosis, a significant risk associated with montelukast initiation was found only in the youngest age groups (hazard ratio [95% confidence interval] 1.28 [1.12-1.47], P < .001 and 1.16 [1.02-1.31]; P < .05, for age group 18-29 y and 30-44 y, respectively). Age-stratified analyses showed that the risk of both outcomes increased with decreasing age, with the highest risk seen in patients aged 18 to 29 years. CONCLUSIONS: Among younger individuals, montelukast use was significantly associated with an increased risk of neuropsychiatric events such as use of neuropsychiatric medicine and hospital treatment. Clinicians should increase awareness of such adverse effects when prescribing montelukast.

Hospitalization for chronic obstructive pulmonary disease and pneumonia: association with the dose of inhaled corticosteroids. A nation-wide cohort study of 52 100 outpatients.

OBJECTIVES: International guidelines only advocate the use of inhaled corticosteroids (ICSs) in patients with chronic obstructive pulmonary disease (COPD) experiencing recurring exacerbations and eosinophilic inflammation. However, ICSs are commonly used in patients with COPD and without exacerbations and signs of eosinophilic inflammation, thus possibly increasing the risk of hospitalization for pneumonia. Thus, we aimed to determine the risk of hospitalization for pneumonia associated with increasing cumulated ICS doses among patients with COPD to establish whether there is dose dependency. METHODS: A retrospective cohort study included all patients with COPD treated at a respiratory outpatient clinic in Denmark. The patients were divided into four groups based on their average daily ICS exposure. The dose-response relationship was investigated using a multivariable Cox proportional hazard regression analysis. RESULTS: In total, 52 100 patients were included, who were divided into the no-use (n = 15 755), low-dose (n = 12 050), moderate-dose (n = 12 488), and high-dose (n = 11 807) groups. ICS use was strongly associated with hospitalization for pneumonia (hazard ratio [HR], 1.3; CI, 1.2-1.3) (ICS vs. no ICS). The risk of hospitalization for pneumonia increased with every dosing group step: low dose: HR, 1.1 (CI, 1.0-1.2); moderate dose: HR, 1.2 (CI, 1.1-1.3), and high dose: HR, 1.5 (CI, 1.4-1.6); "no use" was the reference. Sensitivity analyses confirmed these findings. CONCLUSIONS: In the dose-response relationship analysis, ICS dose were associated with a substantially increased risk of hospitalization for pneumonia of up to 50%. Our data support that ICSs should be administered at the lowest possible dose and only to patients with COPD who have a documented need.

The Impact of Social Distancing in 2020 on Admission Rates for Exacerbations in Asthma: A Nationwide Cohort Study.

BACKGROUND: Social distancing measures introduced during the coronavirus disease 2019 pandemic have reduced admission rates for various infectious and noninfectious respiratory diseases. We hypothesized that rates of asthma exacerbations would decline following the national lockdown in Denmark. OBJECTIVE: To determine weekly rates of in- and out-of-hospital asthma exacerbations before and during the social distancing intervention implemented on March 12, 2020. METHODS: All individuals older than 18 years with at least 1 outpatient hospital contact with asthma as the main diagnosis from January 1, 2013, to December 31, 2017, were included. Weekly asthma exacerbation rates from January 1, 2018, to May 22, 2020, were calculated. An interrupted time-series model with the lockdown on March 12, 2020, as the point of interruption was used. RESULTS: A total of 38,225 patients with asthma were identified. The interrupted time-series model showed no immediate fall in exacerbation rates during the first week after March 12, 2020. However, there was a significant decline in weekly exacerbation rates in the following 10 weeks (change in trend for exacerbations requiring hospitalization: -0.75 [95% CI, -1.39 to -0.12]; P < .02 and in all asthma exacerbations: -12.2 [95% CI, -19.1 to -5.4; P < .001), amounting to a reduction of approximately 1 and 16.5 exacerbations per year per 100 patients in the cohort, respectively. CONCLUSIONS: The introduction of the social distancing measures in Denmark did not lead to an immediate reduction in asthma exacerbation rates; however, a gradual decline in exacerbation rates during the following 10-week period was observed.

Lung ultrasound findings following COVID-19 hospitalization: A prospective longitudinal cohort study.

BACKGROUND: Lung ultrasound (LUS) is a useful tool for diagnosis and monitoring in patients with active COVID-19-infection. However, less is known about the changes in LUS findings after a hospitalization for COVID-19. METHODS: In a prospective, longitudinal study in patients with COVID-19 enrolled from non-ICU hospital units, adult patients underwent 8-zone LUS and blood sampling both during the hospitalization and 2-3 months after discharge. LUS images were analyzed blinded to clinical variables and outcomes. RESULTS: A total of 71 patients with interpretable LUS at baseline and follow up (mean age 64 years, 61% male, 24% with acute respiratory distress syndrome (ARDS)) were included. The follow-up LUS was performed a median of 72 days after the initial LUS performed during hospitalization. At baseline, 87% had pathologic LUS findings in ≥1 zone (e.g. ≥3 B-lines, confluent B-lines or subpleural or lobar consolidation), whereas 30% had pathologic findings at follow-up (p < 0.001). The total number of B-lines and LUS score decreased significantly from hospitalization to follow-up (median 17 vs. 4, p < 0.001 and 4 vs. 0, p < 0.001, respectively). On the follow-up LUS, 28% of all patients had ≥3 B-lines in ≥1 zone, whereas in those with ARDS during the baseline hospitalization (n = 17), 47% had ≥3 B-lines in ≥1 zone. CONCLUSION: LUS findings improved significantly from hospitalization to follow-up 2-3 months after discharge in COVID-19 survivors. However, persistent B-lines were frequent at follow-up, especially among those who initially had ARDS. LUS seems to be a promising method to monitor COVID-19 lung changes over time. GOV ID: NCT04377035.

Treatment Response Biomarkers in Asthma and COPD.

Chronic obstructive pulmonary disease (COPD) and asthma are two of the most common chronic diseases worldwide. Both diseases are heterogenous and complex, and despite their similarities, they differ in terms of pathophysiological and immunological mechanisms. Mounting evidence supports the presence of several phenotypes with various responses to treatment. A systematic and thorough assessment concerning the diagnosis of both asthma and COPD is crucial to the clinical management of the disease. The identification of different biomarkers can facilitate targeted treatment and monitoring. Thanks to the presence of numerous immunological studies, our understanding of asthma phenotypes and mechanisms of disease has increased markedly in the last decade, and several treatments with monoclonal antibodies are available. There are compelling data that link eosinophilia with an increased risk of COPD exacerbations but a greater treatment response and lower all-cause mortality. Eosinophilia can be considered as a treatable trait, and the initiation of inhaled corticosteroid in COPD patients with eosinophilia is supported in many studies. In spite of advances in our understanding of both asthma and COPD in terms pathophysiology, disease mechanisms, biomarkers, and response to treatment, many uncertainties in the management of obstructive airways exist.

Systemic Corticosteroids and the Risk of Venous Thromboembolism in Patients with Severe COPD: A Nationwide Study of 30,473 Outpatients.

Due to frequent exacerbations, many patients with chronic obstructive pulmonary disease (COPD) are exposed to oral corticosteroids (OCS), which may be thrombogenic. We evaluated the risk of hospitalisation with venous thromboembolism (VTE) and death in patients with acute exacerbation of COPD (AECOPD) treated with long and short OCS regimens. In this nationwide cohort study of 30,473 COPD outpatients treated for AECOPD, we compared the risk of VTE hospitalisation and all-cause mortality within 6 months in OCS dose of >250 mg vs. ≤250 mg. A multivariable Cox proportional hazard regression was used to estimate the risk. The incidence of VTE hospitalisations was 0.23%. A long OCS treatment course was associated with an increased risk of VTE compared to a short course (hazard ratio (HR) 1.69, [95% confidence interval (CI) 1.05 to 2.72], p < 0.031). A higher risk of all-cause mortality was seen in the group of COPD patients treated with a long OCS course (HR 1.71, [95% CI 1.63 to 1.79], p < 0.0001). The risk of reported VTE hospitalisation was higher among AECOPD patients treated with long courses of OCS, but the absolute risk was low, suggesting under-reporting of the condition.