Individualised treatment of COPD exacerbations using biomarkers.

This review highlights key aspects of treating chronic obstructive pulmonary disease (COPD) exacerbation, focusing on the optimisation of systemic corticosteroid and antibiotic use through personalised treatment using biomarkers. Eosinophil-guided therapy reduces corticosteroid usage which might reduce side effects, while procalcitonin-guided therapy contributes to reduced antibiotic consumption. These approaches, documented through well-conducted randomized controlled trials, suggest the possibility of enhancing COPD exacerbation management, reducing potential side effects, and addressing concerns related to antibiotic resistance.

Risk of Mortality and Cardiovascular Events in Patients with Chronic Obstructive Pulmonary Disease Treated with Azithromycin, Roxithromycin, Clarithromycin, and Amoxicillin.

Background: Prior research has raised concerns regarding the use of macrolides and their association with an increased risk of cardiovascular events. Methods: We conducted a cohort study, where we explored the cardiovascular risks associated with the treatment of COPD patients using macrolide antibiotics-namely azithromycin, clarithromycin, and roxithromycin-with amoxicillin serving as a reference. The study focused on COPD patients in an outpatient setting and included a thorough 3-year follow-up. Patients were categorized into four groups based on their treatment. The primary analysis utilized an adjusted Cox model, supplemented by sensitivity analysis through inverse probability of treatment weighting. Results: No significant differences were found in major adverse cardiovascular events (MACE-stroke, acute myocardial infarction, cardiovascular death) between the macrolide groups, and the amoxicillin/hazard ratios (HR) were azithromycin HR = 1.01, clarithromycin HR = 0.99, and roxithromycin HR = 1.02. Similarly, sensitivity analysis showed no disparities in all-cause mortality and cardiovascular death among the groups. Conclusions: Overall, the study revealed no evidence of increased risk of MACE, all-cause mortality, or cardiovascular death in COPD patients treated with these macrolides compared to amoxicillin over a 3-year period.

Effects of high-dose versus standard-dose quadrivalent influenza vaccine among patients with diabetes: A post-hoc analysis of the DANFLU-1 trial.

AIM: High-dose quadrivalent influenza vaccine (QIV-HD) has been shown to be more effective than standard-dose (QIV-SD) in reducing influenza infection, but whether diabetes status affects relative vaccine effectiveness (rVE) is unknown. We aimed to assess rVE on change in glycated haemoglobin [HbA1c (∆HbA1c)], incident diabetes, total all-cause hospitalizations (first + recurrent), and a composite of all-cause mortality and hospitalization for pneumonia or influenza. METHODS: DANFLU-1 was a pragmatic, open-label trial randomizing adults (65-79 years) 1:1 to QIV-HD or QIV-SD during the 2021/22 influenza season. Cox proportional hazards regression was used to estimate rVE against incident diabetes and the composite endpoint, negative binomial regression to estimate rVE against all-cause hospitalizations, and ANCOVA when assessing rVE against ∆HbA1c. RESULTS: Of the 12 477 participants, 1162 (9.3%) had diabetes at baseline. QIV-HD, compared with QIV-SD, was associated with a reduction in the rate of all-cause hospitalizations irrespective of diabetes [overall: 647 vs. 742 events, incidence rate ratio (IRR): 0.87, 95% CI (0.76-0.99); diabetes: 93 vs. 118 events, IRR: 0.80, 95% CI (0.55-1.15); without diabetes: 554 vs. 624 events, IRR: 0.88, 95% CI (0.76-1.01), pinteraction = 0.62]. Among those with diabetes, QIV-HD was associated with a lower risk of the composite outcome [2 vs. 11 events, HR: 0.18, 95% CI (0.04-0.83)] but had no effect on ∆HbA1c; QIV-HD adjusted mean difference: ∆ + 0.2 mmol/mol, 95% CI (-0.9 to 1.2). QIV-HD did not affect the risk of incident diabetes [HR 1.18, 95% CI (0.94-1.47)]. CONCLUSIONS: In this post-hoc analysis, QIV-HD versus QIV-SD was associated with an increased rVE against the composite of all-cause death and hospitalization for pneumonia/influenza, and the all-cause hospitalization rate irrespective of diabetes status.

Clinical Outcomes With Electronic Nudges to Increase Influenza Vaccination : A Prespecified Analysis of a Nationwide, Pragmatic, Registry-Based, Randomized Implementation Trial.

BACKGROUND: In the NUDGE-FLU (Nationwide Utilization of Danish Government Electronic letter system for increasing inFLUenza vaccine uptake) trial, electronic letters incorporating cardiovascular (CV) gain-framing and repeated messaging increased influenza vaccination by approximately 1 percentage point. OBJECTIVE: To evaluate the effects of the successful nudging interventions on downstream clinical outcomes. DESIGN: Prespecified exploratory analysis of a nationwide randomized implementation trial. (ClinicalTrials.gov: NCT05542004). SETTING: The 2022 to 2023 influenza season. PARTICIPANTS: 964 870 Danish citizens aged 65 years or older. INTERVENTION: Usual care or 9 different electronically delivered behavioral nudging letters. MEASUREMENTS: Cardiovascular, respiratory, and other clinical end points during follow-up from intervention delivery (16 September 2022) through 31 May 2023. RESULTS: The analysis set included 691 820 participants. Hospitalization for pneumonia or influenza occurred in 3354 of 346 327 (1.0%) participants in the usual care group, 396 of 38 586 (1.0%) in the CV gain-framing group (hazard ratio [HR], 1.06 [95% CI, 0.95 to 1.18]; versus usual care), and 403 of 38 231 (1.1%) in the repeated letter group (HR, 1.09 [CI, 0.98 to 1.21]; versus usual care). In the usual care group, 44 682 (12.9%) participants were hospitalized for any cause, compared with 5002 (13.0%) in the CV gain-framing group (HR, 1.00 [CI, 0.97 to 1.03]; versus usual care) and 4965 (13.0%) in the repeated letter group (HR, 1.01 [CI, 0.98 to 1.04]; versus usual care). A total of 6341 (1.8%) participants died in the usual care group, compared with 721 (1.9%) in the CV gain-framing group (HR, 1.02 [CI, 0.94 to 1.10]; versus usual care) and 646 (1.7%) in the repeated letter group (HR, 0.92 [CI, 0.85 to 1.00]; versus usual care). LIMITATION: Prespecified but exploratory analysis, potential misclassification of events in routinely collected registry data, and results may not be generalizable to other health systems or countries with other racial compositions and/or cultural or societal norms. CONCLUSION: In a prespecified exploratory analysis, modest increases in influenza vaccination rates seen with electronic nudges did not translate into observable improvements in clinical outcomes. Seasonal influenza vaccination should remain strongly recommended. PRIMARY FUNDING SOURCE: Sanofi.

Inhaled corticosteroids and Stenotrophomonas maltophilia in outpatients with chronic obstructive pulmonary disease: a retrospective cohort study.

OBJECTIVES: Inhaled corticosteroids (ICS) are widely used in patients with chronic obstructive pulmonary disease (COPD). However, ICS are associated with an increased risk of adverse effects.We aimed to determine whether an association between a lower respiratory tract culture with Stenotrophomonas maltophilia and increasing ICS dosing in patients with COPD exists. DESIGN: An observational cohort study of outpatients with COPD in Denmark between 2010 and 2018.ICS exposure was categorised into four groups based on average daily consumption 1 year prior to inclusion: no use, low ICS dose (≤400 µg), moderate ICS dose (400-800 µg) and high ICS dose (>800 µg). Dose-response relationship was investigated by a multivariable Cox proportional hazards regression. RESULTS: Of the total 22 689 patients, 459 had lower respiratory tract cultures positive for S. maltophilia. The HR of S. maltophilia increased with increasing daily ICS dose: low ICS dose HR 2.6 (95% CI 1.6 to 4.0), moderate ICS dose HR 3.0 (95% CI 1.9 to 4.6) and high ICS dose HR 5.7 (95% CI 3.8 to 8.5). CONCLUSIONS: We found that ICS was associated with a high, dose-dependent increased hazard of S. maltophilia in outpatients with COPD. High dose users had a nearly six times increased hazard compared with non-users of ICS. When appropriate, attempts at de-escalating ICS treatment should be made.

Rationale and design of NUDGE-FLU-CHRONIC and NUDGE-FLU-2: Two nationwide randomized trials of electronic nudges to increase influenza vaccination among patients with chronic diseases and older adults during the 2023/2024 influenza season.

BACKGROUND: Yearly influenza vaccination is strongly recommended for older adults and patients with chronic diseases including cardiovascular disease (CVD); however, vaccination rates remain suboptimal, particularly among younger patients. Electronic letters incorporating behavioral nudges are highly scalable public health interventions which can potentially increase vaccination, but further research is needed to determine the most effective strategies and to assess effectiveness across different populations. The purpose of NUDGE-FLU-CHRONIC and NUDGE-FLU-2 are to evaluate the effectiveness of electronic nudges delivered via the Danish governmental electronic letter system in increasing influenza vaccination among patients with chronic diseases and older adults, respectively. METHODS: Both trials are designed as pragmatic randomized implementation trials enrolling all Danish citizens in their respective target groups and conducted during the 2023/2024 influenza season. NUDGE-FLU-CHRONIC enrolls patients aged 18-64 years with chronic diseases. NUDGE-FLU-2 builds upon the NUDGE-FLU trial conducted in 2022/2023 and aims to expand the evidence by testing both previously successful and new nudges among adults ≥65 years during a subsequent influenza season. Persons with exemptions from the electronic letter system are excluded from both trials. In both trials, participants are randomized in a 2.45:1:1:1:1:1:1 ratio to either receive no electronic letter (usual care) or to receive one of 6 different behaviorally informed electronic letters. NUDGE-FLU-CHRONIC has randomized 299,881 participants with intervention letters delivered on September 24, 2023, while NUDGE-FLU-2 has randomized 881,373 participants and delivered intervention letters on September 13, 2023. Follow-up is currently ongoing. In both trials, the primary endpoint is receipt of influenza vaccination on or before January 1, 2024, and the secondary endpoint is time to vaccination. Clinical outcomes including respiratory and cardiovascular hospitalizations, all-cause hospitalization, and mortality are included as prespecified exploratory endpoints. Prespecified individual-level pooled analyses will be conducted across NUDGE-FLU, NUDGE-FLU-CHRONIC, and NUDGE-FLU-2. DISCUSSION: NUDGE-FLU-CHRONIC is the first nationwide randomized trial of electronic nudges to increase influenza vaccination conducted among 18-64-year-old high-risk patients with chronic diseases. NUDGE-FLU-2 will provide further evidence on the effectiveness of electronic nudges among older adults ≥65 years. Collectively, the NUDGE-FLU trials will provide an extensive evidence base for future public health communications. TRIAL REGISTRATION: NUDGE-FLU-CHRONIC: Clinicaltrials.gov: NCT06030739, registered September 11, 2023, https://clinicaltrials.gov/study/NCT06030739. NUDGE-FLU-2: Clinicaltrials.gov: NCT06030726, registered September 11, 2023, https://clinicaltrials.gov/study/NCT06030726.

Thrombelastography and Conventional Coagulation Markers in Chronic Obstructive Pulmonary Disease: A Prospective Paired-Measurements Study Comparing Exacerbation and Stable Phases.

Chronic Obstructive Pulmonary Disease (COPD) exacerbation is known for its substantial impact on morbidity and mortality among affected patients, creating a significant healthcare burden worldwide. Coagulation abnormalities have emerged as potential contributors to exacerbation pathogenesis, raising concerns about increased thrombotic events during exacerbation. The aim of this study was to explore the differences in thrombelastography (TEG) parameters and coagulation markers in COPD patients during admission with exacerbation and at a follow-up after discharge. This was a multi-center cohort study. COPD patients were enrolled within 72 h of hospitalization. The baseline assessments were Kaolin-TEG and blood samples. Statistical analysis involved using descriptive statistics; the main analysis was a paired t-test comparing coagulation parameters between exacerbation and follow-up. One hundred patients participated, 66% of whom were female, with a median age of 78.5 years and comorbidities including atrial fibrillation (18%) and essential arterial hypertension (45%), and sixty-five individuals completed a follow-up after discharge. No significant variations were observed in Kaolin-TEG or conventional coagulation markers between exacerbation and follow-up. The Activated Partial Thromboplastin Clotting Time (APTT) results were near-significant, with p = 0.08. In conclusion, TEG parameters displayed no significant alterations between exacerbation and follow-up.

Long-term cognitive and pulmonary functions following a lower versus a higher oxygenation target in the HOT-ICU and HOT-COVID trials: A protocol update.

BACKGROUND: The Handling Oxygenation Targets in the Intensive Care Unit (HOT-ICU) trial was a multicentre, randomised, parallel-group trial of a lower oxygenation target (arterial partial pressure of oxygen [PaO2 ] = 8 kPa) versus a higher oxygenation target (PaO2 = 12 kPa) in adult ICU patients with acute hypoxaemic respiratory failure; the Handling Oxygenation Targets in coronavirus disease 2019 (HOT-COVID) tested the same oxygenation targets in patients with confirmed COVID-19. In this study, we aim to evaluate the long-term effects of these oxygenation targets on cognitive and pulmonary function. We hypothesise that a lower oxygenation target throughout the ICU stay may result in cognitive impairment, whereas a higher oxygenation target may result in impaired pulmonary function. METHODS: This is the updated protocol and statistical analysis plan of two pre-planned secondary outcomes, the long-term cognitive function, and long-term pulmonary function, in the HOT-ICU and HOT-COVID trials. Patients enrolled in both trials at selected Danish sites and surviving to 1 year after randomisation are eligible to participate. A Repeatable Battery for the Assessment of Neuropsychological Status score and a full-body plethysmography, including diffusion capacity for carbon monoxide, will be obtained. The last patient is expected to be included in the spring of 2024. CONCLUSION: This study will provide important information on the long-term effects of a lower versus a higher oxygenation target on long-term cognitive and pulmonary functions in adult ICU patients with acute hypoxaemic respiratory failure.

Effectiveness of high-dose versus standard-dose quadrivalent influenza vaccine against recurrent hospitalizations and mortality in relation to influenza circulation: A post-hoc analysis of the DANFLU-1 randomized clinical trial.

OBJECTIVES: To evaluate the relative effectiveness of high-dose quadrivalent influenza vaccine (QIV-HD) versus standard-dose quadrivalent influenza vaccine (QIV-SD) against recurrent hospitalizations and its potential variation in relation to influenza circulation. METHODS: We did a post-hoc analysis of a pragmatic, open-label, randomized trial of QIV-HD versus QIV-SD performed during the 2021-2022 influenza season among adults aged 65-79 years. Participants were enrolled in October 2021-November, 2021 and followed for outcomes from 14 days postvaccination until 31 May, 2022. We investigated the following outcomes: Hospitalizations for pneumonia or influenza, respiratory hospitalizations, cardio-respiratory hospitalizations, cardiovascular hospitalizations, all-cause hospitalizations, and all-cause death. Outcomes were analysed as recurrent events. Cumulative numbers of events were assessed weekly. Cumulative relative effectiveness estimates were calculated and descriptively compared with influenza circulation. The trial is registered at Clinicaltrials.gov: NCT05048589. RESULTS: Among 12,477 randomly assigned participants, receiving QIV-HD was associated with lower incidence rates of hospitalizations for pneumonia or influenza (10 vs. 33 events, incidence rate ratio [IRR] 0.30 [95% CI, 0.14-0.64]; p 0.002) and all-cause hospitalizations (647 vs. 742 events, IRR 0.87 [95% CI, 0.76-0.99]; p 0.032) compared with QIV-SD. Trends favouring QIV-HD were consistently observed over time including in the period before active influenza transmission; i.e. while the first week with a ≥10% influenza test positivity rate was calendar week 10, 2022, the first statistically significant reduction in hospitalizations for pneumonia or influenza was already observed by calendar week 3, 2022 (5 vs. 15 events, IRR 0.33 [95% CI, 0.11-0.94]; p 0.037). DISCUSSION: In a post-hoc analysis, QIV-HD was associated with lower incidence rates of hospitalizations for pneumonia or influenza and all-cause hospitalizations compared with QIV-SD, with trends evident independent of influenza circulation levels. Our exploratory results correspond to a number needed to treat of 65 (95% CI 35-840) persons vaccinated with QIV-HD compared with QIV-SD to prevent one additional all-cause hospitalization per season. Further research is needed to confirm these hypothesis-generating findings.

COPD: pulmonary vascular volume associated with cardiac structure and function.

BACKGROUND: Early recognition of cardiac dysfunction in patients with chronic obstructive pulmonary disease (COPD) may prevent future cardiac impairment and improve prognosis. Quantitative assessment of subsegmental and segmental vessel volume by Computed Tomographic (CT) imaging can provide a surrogate of pulmonary vascular remodeling. We aimed to examine the relationship between lung segmental- and subsegmental vessel volume, and echocardiographic measures of cardiac structure and function in patients with COPD. METHODS: We studied 205 participants with COPD, included in a large cohort study of cardiovascular disease in COPD patients. Participants had an available CT scan and echocardiogram. Artificial intelligence (AI) algorithms calculated the subsegmental vessel fraction as the vascular volume in vessels below 10 mm2 in cross-sectional area, indexed to total intrapulmonary vessel volume. Linear regressions were conducted, and standardized ß-coefficients were calculated. Scatterplots were created to visualize the continuous correlations between the vessel fractions and echocardiographic parameters. RESULTS: We found that lower subsegmental vessel fraction and higher segmental vessel volume were correlated with higher left ventricular (LV) mass, LV diastolic dysfunction, and inferior vena cava (IVC) dilatation. Subsegmental vessel fraction was correlated with right ventricular (RV) remodeling, while segmental vessel fraction was correlated with higher pulmonary pressure. Measures of LV mass and right atrial pressure displayed the strongest correlations with pulmonary vasculature measures. CONCLUSION: Pulmonary vascular remodeling in patients with COPD, may negatively affect cardiac structure and function. AI-identified remodeling in pulmonary vasculature may provide a tool for early identification of COPD patients at higher risk for cardiac impairment.

Incidence of bacterial respiratory infection and pneumonia in people with HIV with and without airflow limitation.

OBJECTIVES: We aimed to determine the incidence rate, pathogen composition, and risk factors, particularly airflow limitation, associated with bacterial respiratory infection and pneumonia in a prospective cohort of well-treated people with HIV (PWH) between 2015-2021. METHODS: We included 1007 PWH from the Copenhagen Comorbidity in HIV infection (COCOMO) study. Spirometry was performed at inclusion. Microbiology samples were collected prospectively. Cumulative incidence was determined by the Aalen-Johansen estimator. Cox proportional hazard models were used to calculate risk factors, adjusted for traditional and HIV-specific variables. RESULTS: The incidence rates of first bacterial respiratory infection and pneumonia were 12.4 (95% CI 9.7-15.5) and 5.5 (95% CI: 3.8-7.7) per 1000 person-years, respectively. The cumulative incidence of pneumonia was four times higher in PWH with airflow limitation (11.8% vs 3.2%, P <0.001). Risk factors for bacterial respiratory infection were airflow limitation (hazard ratio [HR] 2.9, [95% CI: 1.7-5.1], P <0.001), smoking (HR 2.3, [95% CI: 1.4-3.8], P <0.001), and previous AIDS-defining event (HR 2.0, [95% CI: 1.2-3.3], P = 0.009). For pneumonia, airflow limitation (HR 2.7, [95% CI: 1.2-6.3], P = 0.016), smoking (HR 2.5, [95% CI: 1.2-5.4], P = 0.016), and older age (HR 1.5, [95% CI: 1.1-2.1], P = 0.015) were identified as risk factors. CONCLUSIONS: Increased emphasis on airflow limitation prevention, including smoking cessation, may reduce the burden of bacterial respiratory infection and pneumonia in PWH.

Electronically Delivered Nudges to Increase Influenza Vaccination Uptake in Older Adults With Diabetes: A Secondary Analysis of the NUDGE-FLU Trial.

Importance: Influenza vaccination is associated with a reduced risk of mortality in patients with diabetes, but vaccination rates remain suboptimal. Objective: To assess the effect of electronic nudges on influenza vaccination uptake according to diabetes status. Design, Setting, and Participants: The NUDGE-FLU (Nationwide Utilization of Danish Government Electronic Letter System for Increasing Influenza Vaccine Uptake) trial was a nationwide clinical trial of Danish citizens 65 years or older that randomized participants at the household level to usual care or 9 different electronic nudge letters during the 2022 to 2023 influenza season. End of follow-up was January 1, 2023. This secondary analysis of the NUDGE-FLU trial was performed from May to July 2023. Intervention: Nine different electronic nudge letters designed to boost influenza vaccination were sent in September to October 2022. Effect modification by diabetes status was assessed in a pooled analysis of all intervention arms vs usual care and for individual letters. Main Outcomes and Measures: The primary end point was receipt of a seasonal influenza vaccine. Results: The trial included 964 870 participants (51.5% female; mean [SD] age, 73.8 [6.3] years); 123 974 had diabetes. During follow-up, 83.5% with diabetes vs 80.2% without diabetes received a vaccine (P < .001). In the pooled analysis, nudges improved vaccination uptake in participants without diabetes (80.4% vs 80.0%; difference, 0.37 percentage points; 99.55% CI, 0.08 to 0.66), whereas there was no evidence of effect in those with diabetes (83.4% vs 83.6%; difference, -0.19 percentage points; 99.55% CI, -0.89 to 0.51) (P = .02 for interaction). In the main results of NUDGE-FLU, 2 of the 9 behaviorally designed letters (cardiovascular benefits letter and a repeated letter) significantly increased uptake of influenza vaccination vs usual care; these benefits similarly appeared attenuated in participants with diabetes (cardiovascular gain letter: 83.7% vs 83.6%; difference, 0.04 percentage points; 99.55% CI, -1.52 to 1.60; repeated letter: 83.5% vs 83.6%; difference, -0.15 percentage points; 99.55% CI, -1.71 to 1.41) vs those without diabetes (cardiovascular gain letter: 81.1% vs 80.0%; difference, 1.06 percentage points; 99.55% CI, 0.42 to 1.70; repeated letter: 80.9% vs 80.0%; difference, 0.87 percentage points; 99.55% CI, 0.22 to 1.52) (P = .07 for interaction). Conclusions and Relevance: In this exploratory subgroup analysis, electronic nudges improved influenza vaccination uptake in persons without diabetes, whereas there was no evidence of an effect in persons with diabetes. Trials are needed to investigate the effect of digital nudges specifically tailored to individuals with diabetes. Trial Registration: ClinicalTrials.gov Identifier: NCT05542004.

Brain Health After COVID-19, Pneumonia, Myocardial Infarction, or Critical Illness.

Importance: Brain health is most likely compromised after hospitalization for COVID-19; however, long-term prospective investigations with matched control cohorts and face-to-face assessments are lacking. Objective: To assess whether long-term cognitive, psychiatric, or neurological complications among patients hospitalized for COVID-19 differ from those among patients hospitalized for other medical conditions of similar severity and from healthy controls. Design, Setting, and Participants: This prospective cohort study with matched controls was conducted at 2 academic hospitals in Copenhagen, Denmark. The case cohort comprised patients with COVID-19 hospitalized between March 1, 2020, and March 31, 2021. Control cohorts consisted of patients hospitalized for pneumonia, myocardial infarction, or non-COVID-19 intensive care-requiring illness between March 1, 2020, and June 30, 2021, and healthy age- and sex-matched individuals. The follow-up period was 18 months; participants were evaluated between November 1, 2021, and February 28, 2023. Exposures: Hospitalization for COVID-19. Main Outcomes and Measures: The primary outcome was overall cognition, assessed by the Screen for Cognitive Impairment in Psychiatry (SCIP) and the Montreal Cognitive Assessment (MoCA). Secondary outcomes were executive function, anxiety, depressive symptoms, and neurological deficits. Results: The study included 345 participants, including 120 patients with COVID-19 (mean [SD] age, 60.8 [14.4] years; 70 men [58.3%]), 125 hospitalized controls (mean [SD] age, 66.0 [12.0] years; 73 men [58.4%]), and 100 healthy controls (mean [SD] age, 62.9 [15.3] years; 46 men [46.0%]). Patients with COVID-19 had worse cognitive status than healthy controls (estimated mean SCIP score, 59.0 [95% CI, 56.9-61.2] vs 68.8 [95% CI, 66.2-71.5]; estimated mean MoCA score, 26.5 [95% CI, 26.0-27.0] vs 28.2 [95% CI, 27.8-28.6]), but not hospitalized controls (mean SCIP score, 61.6 [95% CI, 59.1-64.1]; mean MoCA score, 27.2 [95% CI, 26.8-27.7]). Patients with COVID-19 also performed worse than healthy controls during all other psychiatric and neurological assessments. However, except for executive dysfunction (Trail Making Test Part B; relative mean difference, 1.15 [95% CI, 1.01-1.31]), the brain health of patients with COVID-19 was not more impaired than among hospitalized control patients. These results remained consistent across various sensitivity analyses. Conclusions and Relevance: This prospective cohort study suggests that post-COVID-19 brain health was impaired but, overall, no more than the brain health of patients from 3 non-COVID-19 cohorts of comparable disease severity. Long-term associations with brain health might not be specific to COVID-19 but associated with overall illness severity and hospitalization. This information is important for putting understandable concerns about brain health after COVID-19 into perspective.

Incidence of community-acquired pneumonia hospitalisation in persons with bronchiectasis during the COVID-19 lockdown in Denmark: a retrospective cohort study.

BACKGROUND: Persons with bronchiectasis have a high risk of community-acquired pneumonia. Social distancing measures, implemented to prevent the spreading of SARS-CoV-2, could potentially reduce the incidence of other infectious diseases. RESEARCH QUESTION: Was the COVID-19 lockdown period, along with accompanying social distancing measures, associated with reduced hospital admissions for community-acquired pneumonia and decreased overall mortality rates among individuals with bronchiectasis? METHODS: Social distancing measures were introduced in Denmark by 12 March 2020 and were preserved until 20 May 2020 (social distancing period), after which the measures were gradually dismissed. The study included all adults (≥18 years) with bronchiectasis residing in Denmark. Confirmed cases of SARS-CoV-2 infection were excluded. We retrospectively investigated the incidence of community-acquired pneumonia hospital admission, death of all causes and respiratory antibiotic treatment in the 10-week social distancing period in 2020, compared with the same dates in 2019. 9344 persons were included in the study. RESULTS: In the social distancing period, the incidence rate of pneumonia-hospitalisation per 10 000 person-weeks was 9.2 compared with 13.8 in the reference period. This reduction corresponds to an incidence rate ratio (IRR) of 0.67 (95% CI 0.51 to 0.88, p<0.01). Mortality was unchanged (IRR 0.90, 95% CI 0.61 to 1.32, p=0.58). Fewer persons received respiratory antibiotics (IRR 0.85, 95% CI 0.78 to 0.94, p<0.001). CONCLUSION: The social distancing period was associated with a lower incidence of community-acquired pneumonia hospitalisations and respiratory antibiotic treatments in persons with bronchiectasis while all-cause mortality remained unchanged.

Mortality and exacerbations associated with Stenotrophomonas maltophilia in chronic obstructive pulmonary disease. A regional cohort study of 22,689 outpatients.

OBJECTIVES: The clinical significance of Stenotrophomonas maltophilia in patients with COPD is poorly understood. We aimed to determine whether a lower respiratory tract culture positive for S. maltophilia in COPD patients was independently associated with increased risk of death and hospitalisation for exacerbation of COPD. METHODS: An observational cohort study following outpatients with COPD in Eastern Denmark between 2010 and 2018, with a follow-up period of five years. Presence of S. maltophilia was treated as a time-varying exposure, where patients were considered exposed at the time of the first isolation of S. maltophilia from the lower respiratory tract. The hazard ratio (HR) of death and hospitalisation for acute exacerbations of COPD was assessed using a Cox proportional hazards regression. RESULTS: Of the total 22,689 patients 459 (2.0%) had a lower respiratory sample positive for S. maltophilia. A total of 7,649 deaths (S. maltophilia positive: 243 (52.9%) and S. maltophilia negative: 7,406 (34.4%)) and 24,912 hospitalisations for exacerbation of COPD (S. maltophilia positive: 1,100 in 459 patients and S. maltophilia negative: 23,821 in 22,230 patients) were registered during the study period. We found that a lower respiratory tract culture positive for S. maltophilia was associated with both increased mortality: HR 3.3 (95% CI 2.6-4.3), and hospitalisation for exacerbation of COPD: HR 3.4 (95% CI 2.8-4.1). CONCLUSIONS: A lower respiratory tract culture positive for S. maltophilia in COPD patients was associated with a substantially increased mortality and hospitalisation for exacerbation of COPD. Randomised controlled trials are proposed to determine whether S. maltophilia should be the target of antibiotic treatment.

Long-term non-invasive ventilation for COPD patients following an exacerbation with acute hypercapnic respiratory failure: a randomized controlled trial.

Introduction: It remains unclear whether long-term non-invasive ventilation (LT-NIV) for patients with chronic obstructive pulmonary disease (COPD) improves survival and reduces admissions as results from randomized trials are inconsistent. We aim to determine whether LT-NIV initiated after an admission with acute hypercapnic respiratory failure (AHRF) can affect survival and admission rate in COPD patients. Methods: A randomized controlled open-label trial, allocating patients with COPD to LT-NIV or standard of care immediately after an admission with AHRF treated with acute NIV. LT-NIV was aimed to normalize PaCO2 using high-pressure NIV. Results: The study was discontinued before full sample size due to slow recruitment. 28 patients were randomized to LT-NIV and 27 patients to standard of care. 42% of patients had a history of ≥ 2 admissions with AHRF. Median IPAP was 24 cmH2O (IQR 20-28). The primary outcome, time to readmission with AHRF or death within 12 months, did not reach significance, hazard ratio 0.53 (95% CI 0.25-1.12) p = 0.097. In a competing risk analysis, adjusted for history of AHRF, the odds ratio for AHRF within 12 months was 0.30 (95% CI 0.11-0.87) p = 0.024. The LT-NIV group had less exacerbations (median 1 (0-1) vs 2 (1-4) p = 0.021) and readmissions with AHRF (median 0 (0-1) vs 1 (0-1) p = 0.016). Conclusion: The risk of the primary outcome, time to readmission with AHRF or death within 12 months was numerically smaller in the LT-NIV group, however, did not reach significance. Nevertheless, several secondary outcome analyses like risk of AHRF, number of episodes of AHRF and exacerbations were all significantly reduced in favour of high-pressure LT-NIV, especially in patients with frequent AHRF.

Inhalation devices and inhaled corticosteroids particle size influence on severe pneumonia in patients with chronic obstructive pulmonary disease: a nationwide cohort study.

BACKGROUND: Inhaled corticosteroids (ICSs) are associated with an increased risk of pneumonia among patients with chronic obstructive pulmonary disease (COPD). The introduction of extrafine particle ICS has aimed to improve the distribution of medicine in the airways by altering deposition within the lungs, potentially affecting efficacy and side effects. It remains unclear if extrafine particle ICS administration alters the risk of pneumonia compared with standard particle size ICS. METHODS: An observational cohort study including all Danish COPD outpatients receiving ICS from 2010 to 2017. The primary outcome was pneumonia hospitalisation in the different ICS particle dosing regimens. The primary analysis was an adjusted Cox proportional hazards model. For sensitivity analysis, a subgroup analysis of patients receiving spray devices was done. Further, we created a propensity score matched cohort, in which we matched for the same covariates as adjusted for in the main analysis. RESULTS: A total of 35 691 patients were included of whom 1471 received extrafine particle ICS. Among these patients, 4657 were hospitalised due to pneumonia. Patients with COPD receiving extrafine particle ICS had a lower risk of hospitalisation due to pneumonia compared with patients receiving standard particle size ICS in our primary analysis (HR 0.75; 95% CI 0.63 to 0.89; p=0.002), subgroup analysis (HR 0.54; 95% CI 0.45 to 0.65; p<0.0001) and the propensity-matched population (HR 0.72; 95% CI 0.60 to 0.87; p=0.0006). INTERPRETATION: The use of extrafine particle ICS administration was associated with a lower risk of pneumonia hospitalisation in patients with COPD compared with those who received standard size treatment.

Existing Data Sources in Clinical Epidemiology: Database of Community Acquired Infections Requiring Hospital Referral in Eastern Denmark (DCAIED) 2018-2021.

Infectious diseases are major health care challenges globally and a prevalent cause of admission to emergency departments. Epidemiologic characteristics and outcomes based on population level data are limited. The Database of Community Acquired Infections in Eastern Denmark (DCAIED) 2018-2021 was established with the aim to explore and estimate the population characteristics, and outcomes of patients suffering from community acquired infections at the emergency departments in the Capital Region and the Zealand Region of Denmark using data from electronic medical records. Adult patients (≥18 years) presenting to the emergency department with suspected or confirmed infection are included in the cohort. Presence of sepsis and organ failure are assessed using modified criteria from the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). During the inclusion period from January 2018 to January 2022, 2,241,652 adult emergency department visits have been registered. Of these, 451,825 were unique encounters of which 60,316 fulfilled criteria of suspected infection and 28,472 fulfilled sepsis criteria and 8,027 were defined as septic shock. The database covers the entire Capital and Zealand Region of Denmark with an uptake area of 2.6 million inhabitants and includes demographic, laboratory and outcome indicators, with complete follow-up. The database is well-suited for epidemiological research for future national and international collaborations.

Sedating antihistamine treatment with promethazine in patients with severe COPD with and without asthma: death and severe exacerbations in a nationwide register study.

Background: Sedating antihistamines such as promethazine are used as anxiolytics and hypnotic agents for patients with chronic obstructive pulmonary disease (COPD) with and without asthma despite limited knowledge of its effects and side effects. We evaluated if treatment with promethazine had a lower risk of harmful outcome. Methods: Nationwide retrospective cohort study of Danish specialist diagnosed outpatients with COPD treated with promethazine or an active comparator (melatonin). Patients with collection of promethazine or melatonin were propensity score matched 1:1. The primary outcome was a composite of severe COPD exacerbations and death from all causes analyzed by Cox proportional hazards regression. We performed an interaction analysis for comorbid asthma. Results: In our registry of 56,523 patients with COPD, 5,661 collected promethazine (n = 3,723) or melatonin (n = 1,938). A cohort of 3,290 promethazine- or melatonin-treated patients matched 1:1 was available for the primary analysis.Within 1-year patients treated with promethazine were at higher risk of the primary outcome than matched controls with a Hazard Ratio (HR) of 1.42 (CI 1.27-1.58, p < 0.0001). Similarly, the risk of death was higher for promethazine-treated patients (HR 1.53, CI 1.32-1.77, p < 0.0001). An interaction analysis for comorbid asthma showed no interaction between comorbid asthma and the likelihood of a primary outcome when collecting promethazine (p = 0.19). Adjusted Cox analysis on the entire population indicated a further increased risk with more promethazine (HR for primary outcome among patients collecting ≥ 400 promethazine tablets/year=2.15, CI 1.94-2.38, p<0.0001). Conclusions: Promethazine-treated patients with COPD had a concerning excess risk of a composite outcome of severe exacerbations and death from all causes compared to melatonin.