DOI: 10.5061/dryad.m63xsj3zd
title: Effectiveness of steroid therapy on pneumonic chronic obstructive pulmonary disease exacerbation: a multi-centred retrospective cohort study

description: Background To date, no consensus exists on the effects of steroid use on
 pneumonic chronic obstructive pulmonary disease (COPD) owing to trial
 design issues in previous trials involving these conditions. Therefore, we
 aimed to evaluate steroid effectiveness in pneumonic COPD exacerbation
 patients. Methods This multi-centred, retrospective, observational study
 was conducted across five acute general hospitals in Japan. We analysed
 the association between parenteral/oral steroid therapy and time to
 clinical stability in pneumonic COPD exacerbation. We used a validated
 algorithm derived from the 10th revision of the International
 Classification of Diseases and Related Health Problems (ICD-10) to include
 pneumonic COPD exacerbation patients. We excluded patients with other
 hypoxia causes (asthma exacerbation, pneumothorax, heart failure) and
 complicated pneumonia (obstructive pneumonia, empyema), those who required
 tracheal intubation/vasopressors, and those who were clinically stable on
 the admission day. The primary outcome was time to clinical stability.
 Multiple imputation was used for missing data. Propensity scores within
 each imputed dataset were calculated using potential confounding factors.
 The Fine and Gray model was used within each dataset to account for the
 competing risk of death and hospital discharge without clinical stability,
 and we combined the results. Results Altogether, 1237 patients were
 included. The pooled estimated subdistribution hazard ratio of time to
 clinical stability in steroid versus non-steroid users was 0.89 (95%
 confidence interval, 0.78 to 1.03). However, there were potentially
 unmeasured confounders, and we could not assess longer-term outcomes.
 Conclusions The current study recommends that steroid therapy should not
 be used routinely for pneumonic COPD exacerbation.
description: <b>Study design and
 participants</b> This retrospective cohort study
 was conducted across five acute general hospitals in Japan: Kameda Medical
 Center, Hyogo Prefectural Amagasaki General Medical Center, Awa Regional
 Medical Center, Saiseikai Yokohamashi Tobu Hospital, and Ichinomiyanishi
 Hospital. Kameda Medical Center and Hyogo Prefectural Amagasaki General
 Medical Center are tertiary care hospitals while Awa Regional
 Medical Center, Saiseikai Yokohamashi Tobu Hospital, and Ichinomiyanishi
 Hospital are secondary care hospitals. These hospitals cover a wide
 medical area in Honshu, the main island in Japan. The study protocol
 adhered to the Declaration of Helsinki. Additionally, this project was
 approved by the institutional review board of each hospital, and the need
 for written informed consent was waived by the institutional review board
 of Kameda Medical Center because of the study’s retrospective nature
 (approval number, 19-076).  We analysed
 the association between steroid therapy and the clinical important
 outcomes among patients with pneumonic COPD exacerbation. Each hospital
 included patients who were treated during the following different time
 periods because the hospitals had different storage terms for their
 electronic medical records: Kameda Medical Center, April 1, 2008–March 31,
 2019; Hyogo Prefectural Amagasaki General Medical Center, July 1,
 2015–August 31, 2019; Awa Regional Medical Center, April 1, 2010–August
 31, 2019; Saiseikai Yokohamashi Tobu Hospital, April 1, 2009–August 31,
 2019; and Ichinomiyanishi Hospital, June 1, 2014–August 31, 2019. The
 inclusion criteria were patients who were 40 years or older and who were
 hospitalized for both pneumonia and COPD exacerbation. We used a modified
 version of the patient selection algorithm based on the 10th revision of
 the International Statistical Classification of Diseases and Related
 Health Problems (ICD-10), as described in a previous article. To validate
 the patient selection algorithm, we conducted a validation study at Kameda
 Medical Center between October 1, 2018 and March 31, 2019 using the chart
 review results of all the patients who were hospitalized in the Department
 of Internal Medicine and Pulmonology as a reference standard. We made a
 clinical diagnosis of pneumonic COPD exacerbation at the time of admission
 based on previous diagnostic criteria for each disease [6, 7]. For
 admission, we used either criteria (ⅰ) or (ⅱ) as follows: (ⅰ)
 admission-precipitating the diagnosis of pneumonia (ICD-10 codes; J12,
 J13, J14, J15, J16, J18, J69, and P23) with comorbidities present at the
 time of admission for COPD (ICD-10 codes; J44.1 and J44.9) and (ⅱ)
 admission-precipitating the diagnosis of COPD exacerbation (ICD-10 code;
 J44.1) with comorbidities present at the time of admission for pneumonia
 (ICD-10 code; J12, J13, J14, J15, J18, J69, and P23). By reviewing patient
 charts, we excluded those who had the following conditions at the time of
 admission: hypoxia caused by other respiratory diseases (asthma
 exacerbation, pneumothorax, or heart failure), complicated pneumonia
 (obstructive pneumonia or empyema), severe cardiopulmonary conditions
 (patients who needed tracheal intubation or vasopressors on the day of
 admission), or conditions requiring daily steroid use. We also excluded
 patients who fulfilled the clinical stability criteria outlined below on
 the day of admission. <b>Data
 extraction</b> The patients’ medical records
 provided the following data: age, sex, types of inhalers used for COPD
 (inhaled corticosteroid, long-acting beta-agonist, and long-acting
 muscarinic antagonist), use of steroid treatment for pneumonic COPD
 exacerbation, use of home oxygen therapy, activity of daily living (full
 assistance or not), blood test (white blood cell counts, eosinophil
 counts, and urea nitrogen) results on admission, information regarding
 wheezing lung sounds, and tracheal intubation. <b>Exposure</b> Treatments of interest included systemic steroid therapy versus no steroid therapy. Steroid therapy was defined as oral or parenteral administration of steroids after hospitalization regardless of the doses or timings.    <b>Outcomes</b> The primary outcome was time to clinical stability. The definition of clinical stability that we used is outlined in a previous RCT. Patients were determined to be clinically stable when they met all the following criteria: temperature ≤ 37.2°C, heart rate ≤ 100 beats/minute, systolic blood pressure ≥ 90 mmHg, arterial oxygen tension ≥ 60 mmHg, or blood oxygen saturation level (SpO2) ≥ 90% in ambient air or with the preadmission oxygen flow. The secondary outcomes were time to hospital discharge, time to in-hospital death, number of clinically diagnosed patients with delirium, number of new insulin users, and number of tracheal intubated patients following day 2 of hospitalization. We selected patients with delirium and new insulin users based on the chart review that included medical records written by doctors, charts filled in by nurses, and patients’ drug prescriptions during hospitalization. <b>Covariates</b> The potential confounding factors were age, sex, use of home oxygen therapy, activity of daily living, respiratory rate, altered mental status, heart rate, and blood urea nitrogen. We selected these variables as confounding factors based on previously reported prognostic factors for pneumonia and COPD exacerbation [9, 10]. As patients admitted to the same hospital may have received similar treatments, we considered each hospital as a cluster. <b>Statistical analysis</b> The participants’ baseline characteristics were summarized as proportions for categorical variables and as means with standard deviations for continuous variables. We compared the differences between the treatment groups (steroid users vs. non-steroid users).               We used multiple imputation and propensity score analysis for assessing the time to clinical stability, time to hospital discharge, and time to in-hospital death. Missing data were imputed by 100 complete datasets with multiple imputation by chained equations on the assumption of data missing at random. We used potential confounders and outcome variables for estimating the missing data. The propensity score was calculated for each imputed dataset, and patients who were steroid users were matched to steroid non-users in a 1:1 ratio without replacement based on the propensity score. The nearest neighbour technique was used with a calliper of width equal to 0.2 of pooled standard deviation of the logit of propensity score. Disparities in baseline characteristics between the two groups were assessed with the standardized mean difference. Then, we used the survival analysis within each dataset for comparing the event rates based on the treatment group. Regarding time to clinical stability and time to hospital discharge, we estimated the cumulative incidence of patients who reached each event. We calculated the subdistribution hazard ratio (sHR) using the Fine and Gray model by adjusting for potential confounding factors to account for the competing risk of death and hospital discharge without clinical stability [11]. Regarding time to in-hospital death, we used the Cox proportional hazards model. Finally, we averaged with Rubin’s rule over datasets to estimate the treatment effects
description: <strong>variables'
 information</strong> id: anonimized
 patients' ID, age: patients' age on hospitalization, gender:
 1=male, 2=female, steroid: steroid use (0=not, 1=steroid use), hospital:
 categorized hospital name (1=Kameda Medical Center, 2=Awa Regional,
 3=Hyogo Prefectural Amagasaki General Medical Center, 4=Saiseikai
 Yokohamashi Tobu Hospital, 5=Ichinomiyanishi hospital), adl: activity
 daily living before hospitalization (0: full support, 1: not full
 support), wheeze: wheezing lung sound on admission (0:not, 1:wheezing lung
 sound), bun: blood urea nitrogen (mg/dL), rr: respiratory rate (/minute),
 ams: altered mental status (0=not, 1=altered mental status),  hr: heart
 rate (/minute), hot: home oxygen therapy use before hospitalization
 (0=not, 1=users), insulin: new insuline users during hospitalization
 (0=not, 1=new users), delirium: clinical diagnosis of delirium during
 hospitalization (0=not, 1=delirium), stability: reaching the clinical
 stability (0=not, 1=reached clinical stability), time_to_stability: time
 to clinical stability (days), death: in-hospital death,
 non-informative_censoring: non-informative censoring (0=not,
 1=non-informative censoring), discharge (0=not, 1=discharged patients),
 intubation: tracheal intubation during hospitalization (0=not,
 1=intubated), hospitalization=length of stay (days)