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.

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.

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.

Fibrin degradation products and survival in patients with chronic obstructive pulmonary disease: a protocolized prospective observational study.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) have a high incidence of cardiovascular disease including thromboembolisms. Fibrin degradation products, like D-dimer, have been associated with death from all causes in healthy individuals and COPD patients. We aimed to determine the (i) association between D-dimer levels and all-cause mortality and time being alive and out of a hospital, (ii) possible modifying effect of anticoagulant treatment,, and (iii) distribution of D-dimer in patients with moderate to severe COPD. METHODS: Results of routinely measured stable phase D-dimer samples from COPD-outpatients at Copenhagen University Hospital - Herlev and Gentofte, COPD-outpatient clinic were collected using the Danish registries. These were used to examine whether COPD-patients with a D-dimer level in the upper quartile, had a higher risk of death from all causes within 365 days. RESULTS: In the unadjusted Cox proportional hazards regression we found an association between high D-dimer and all-cause mortality: Hazard ratio (HR): 2.3 (95% Confidence Interval (CI) 1.1-4.7). In the fully adjusted regression, the HR was 1.8 (CI 0.8-3.9). We did not find any interaction between D-dimer and anticoagulant or antiplatelet therapy. For the secondary outcome, proportion of days alive and out of hospital in 365 days (pDAOH), the unadjusted multiple linear regression had an association between high D-dimer level and pDAOH: -2.7% points (pp) (CI -3.9 pp - -1.5 pp), which was attenuated to -1,7pp (-2.9pp - -0.4pp) in the fully adjusted regression. CONCLUSIONS: In patients with moderate to severe COPD, patients with a high level of D-dimer were more likely to die; however, the signal was not strong in the adjusted analyses and our results do not support unselected risk stratification with D-dimer in COPD-outpatients.

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.

Biomarkers of Clot Activation and Degradation and Risk of Future Major Cardiovascular Events in Acute Exacerbation of COPD: A Cohort Sub-Study in a Randomized Trial Population.

Cardiovascular diseases are common in patients with chronic obstructive pulmonary disease (COPD). Clot formation and resolution secondary to systemic inflammation may be a part of the explanation. The aim was to determine whether biomarkers of clot formation (products of von Willebrand Factor formation and activation) and clot resolution (product of fibrin degeneration) during COPD exacerbation predicted major cardiovascular events (MACE). The cohort was based on clinical data and biobank plasma samples from a trial including patients admitted with an acute exacerbation of COPD (CORTICO-COP). Neo-epitope biomarkers of formation and the activation of von Willebrand factor (VWF-N and V-WFA, respectively) and cross-linked fibrin degradation (X-FIB) were assessed using ELISAs in EDTA plasma at the time of acute admission, and analyzed for time-to-first MACE within 36 months, using multivariable Cox proportional hazards models. In total, 299/318 participants had samples available for analysis. The risk of MACE for patients in the upper quartile of each biomarker versus the lower quartile was: X-FIB: HR 0.98 (95% CI 0.65-1.48), VWF-N: HR 1.56 (95% CI 1.07-2.27), and VWF-A: HR 0.78 (95% CI 0.52-1.16). Thus, in COPD patients with an acute exacerbation, VWF-N was associated with future MACE and warrants further studies in a larger population.

Severe acute hepatitis E infection presenting with acute abdomen and meningoencephalitis.

We present a case of a 50-year-old man admitted due to acute abdomen, icterus and fever. The patient had a history of sufficiently treated type 2 diabetes and a high daily alcohol consumption, no recent travel history and had a strictly heterosexual and monogamous way of living. A full blood count displayed severe elevated liver enzymes. A CT of the abdomen was performed and revealed steatosis but no acute abdominal pathology. During admission, the patient developed signs of meningoencephalitis. A lumbar puncture was performed, and the cerebrospinal fluid revealed lymphocytic pleocytosis consistent with mild inflammation. Furthermore, hepatitis E was found in the blood and the definitive diagnosis was established. The patient gradually recovered and was discharged within 8 days of admission. To the best of our knowledge, we present the second case describing concomitant hepatitis and meningoencephalitis, resolving spontaneously and not giving rise to sequelae.