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Readmission rate for acute exacerbation of chronic obstructive pulmonary disease: A systematic review and meta-analysis

  • Huanrong Ruan
    Affiliations
    Co-construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases by Henan & Education Ministry of PR China, Henan University of Chinese Medicine, Zhengzhou, Henan, 450046, PR China

    Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Henan University of Chinese Medicine, Zhengzhou, Henan, 450046, PR China
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  • Hailong Zhang
    Correspondence
    Corresponding author. The First Affiliated Hospital of Henan University of Chinese Medicine, No. 19, Renmin Road, Jinshui District, Zhengzhou, Henan, 450003, PR China.
    Affiliations
    Co-construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases by Henan & Education Ministry of PR China, Henan University of Chinese Medicine, Zhengzhou, Henan, 450046, PR China

    Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Henan University of Chinese Medicine, Zhengzhou, Henan, 450046, PR China

    Department of Respiratory Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, 450003, PR China
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  • Jiajia Wang
    Affiliations
    Co-construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases by Henan & Education Ministry of PR China, Henan University of Chinese Medicine, Zhengzhou, Henan, 450046, PR China

    Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Henan University of Chinese Medicine, Zhengzhou, Henan, 450046, PR China

    Department of Respiratory Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, 450003, PR China
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  • Hulei Zhao
    Affiliations
    Co-construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases by Henan & Education Ministry of PR China, Henan University of Chinese Medicine, Zhengzhou, Henan, 450046, PR China

    Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Henan University of Chinese Medicine, Zhengzhou, Henan, 450046, PR China

    Department of Respiratory Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, 450003, PR China
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  • Weihong Han
    Affiliations
    Co-construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases by Henan & Education Ministry of PR China, Henan University of Chinese Medicine, Zhengzhou, Henan, 450046, PR China

    Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Henan University of Chinese Medicine, Zhengzhou, Henan, 450046, PR China
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  • Jiansheng Li
    Affiliations
    Co-construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases by Henan & Education Ministry of PR China, Henan University of Chinese Medicine, Zhengzhou, Henan, 450046, PR China

    Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Henan University of Chinese Medicine, Zhengzhou, Henan, 450046, PR China

    Department of Respiratory Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, 450003, PR China
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Open AccessPublished:December 12, 2022DOI:https://doi.org/10.1016/j.rmed.2022.107090

      Highlights

      • This study is the first to summarize COPD readmission rates for acute exacerbations within 30, 60, 90, 180, and 365 days.
      • We performed a meta-analysis of risk factors for readmission due to acute exacerbation of COPD.
      • Patients with COPD had higher readmission rates for acute exacerbations and potential risk factors were identified.

      Abstract

      Background

      The readmission rate following hospitalization for chronic obstructive pulmonary disease (COPD) exacerbations is extremely high and has become a common and challenging clinical problem. This study aimed to systematically summarize COPD readmission rates for acute exacerbations and their underlying risk factors.

      Methods

      A comprehensive search was performed using PubMed, Embase, Cochrane Library, and Web of Science, published from database inception to April 2, 2022. Methodological quality was evaluated using the Newcastle-Ottawa Scale (NOS). We used a random-effects model or a fixed-effects model to estimate the pooled COPD readmission rate for acute exacerbations and underlying risk factors.

      Results

      A total of 46 studies were included, of which 24, 7, 17, 7, and 20 summarized the COPD readmission rates for acute exacerbations within 30, 60, 90, 180, and 365 days, respectively. The pooled 30-, 60-, 90-, 180-, and 365-day readmission rates were 11%, 17%, 17%, 30%, and 37%, respectively. The study design type, age stage, WHO region, and length of stay (LOS) were initially considered to be sources of heterogeneity. We also identified potential risk factors for COPD readmission, including male sex, number of hospitalizations in the previous year, LOS, and comorbidities such as heart failure, tumor or cancer, and diabetes, whereas obesity was a protective factor.

      Conclusions

      Patients with COPD had a high readmission rate for acute exacerbations, and potential risk factors were identified. Therefore, we should propose clinical interventions and adjust or targeted the control of avoidable risk factors to prevent and reduce the negative impact of COPD readmission.

      Systematic review registration

      PROSPERO, identifier CRD42022333581.

      Keywords

      Abbreviations:

      COPD (chronic obstructive pulmonary disease), AECOPD (acute exacerbation of COPD), NOS (Newcastle-Ottawa Scale), MOOSE (Meta-analysis of Observational Studies in Epidemiology), MeSH (Medical Subject Headings), LOS (length of stay), OR (odds ratio), CI (confidence interval), R (retrospective), P (prospective), NI (no information), Ref (reference)

      1. Introduction

      Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality globally, imposing a massive socioeconomic burden on the global healthcare system [
      GBD Chronic Respiratory Disease Collaborators
      Prevalence and attributable health burden of chronic respiratory diseases, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017.
      ,
      • López-Campos J.L.
      • Tan W.
      • Soriano J.B.
      Global burden of COPD.
      ,
      • Rehman A.U.
      • Ahmad Hassali M.A.
      • Muhammad S.A.
      • Shah S.
      • Abbas S.
      • Hyder Ali I.A.B.
      • et al.
      The economic burden of chronic obstructive pulmonary disease (COPD) in the USA, Europe, and Asia: results from a systematic review of the literature.
      ]. Moderate or severe COPD affects more than 65 million people worldwide and causes more than three million deaths annually [
      World Health Organization
      Burden of chronic obstructive pulmonary disease.
      ]. It is estimated that by 2030, more than 4.5 million people will die from COPD and related comorbidities every year [
      World Health Organization
      Projections of mortality and causes of death, 2015 and 2030.
      ], accounting for approximately 8.6% of global deaths [
      • Mathers C.D.
      • Loncar D.
      Projections of global mortality and burden of disease from 2002 to 2030.
      ]. Patients with COPD often experience episodes of exacerbation that usually require admission and readmission. Among the patients who survive hospitalization for COPD, readmission due to acute exacerbation within a short time after discharge remains a great intractable problem. Therefore, the early identification of relevant factors affecting readmission is critical.
      COPD has become one of the diseases with the highest readmission rate within 30 days, which is equivalent to pneumonia and heart failure [
      • Shams I.
      • Ajorlou S.
      • Yang K.
      A predictive analytics approach to reducing 30-day avoidable readmissions among patients with heart failure, acute myocardial infarction, pneumonia, or COPD.
      ]. Research on readmission rates and risk factors after discharge has been reported in recent years [
      • Sharif R.
      • Parekh T.M.
      • Pierson K.S.
      • Kuo Y.F.
      • Sharma G.
      Predictors of early readmission among patients 40 to 64 years of age hospitalized for chronic obstructive pulmonary disease.
      ,
      • Njoku C.M.
      • Alqahtani J.S.
      • Wimmer B.C.
      • Peterson G.M.
      • Kinsman L.
      • Hurst J.R.
      • et al.
      Risk factors and associated outcomes of hospital readmission in COPD: a systematic review.
      ,
      • Jo Y.S.
      • Rhee C.K.
      • Kim K.J.
      • Yoo K.H.
      • Park Y.B.
      Risk factors for early readmission after acute exacerbation of chronic obstructive pulmonary disease.
      ,
      • Fernández-García S.
      • Represas-Represas C.
      • Ruano-Raviña A.
      • Mouronte-Roibás C.
      • Botana-Rial M.
      • Ramos-Hernández C.
      • et al.
      Social and clinical predictors of short- and long-term readmission after a severe exacerbation of copd.
      ]. A study from the USA demonstrated that readmission rates for acute exacerbations at 30, 90, 180, and 365 days after discharge were 25%, 43%, 63%, and 87%, respectively. Among them, one readmission accounted for 44%, two for 21%, and three for 23%, respectively [
      • Bhatt S.P.
      • Khandelwal P.
      • Nanda S.
      • Stoltzfus J.C.
      • Fioravanti G.T.
      Serum magnesium is an independent predictor of frequent readmissions due to acute exacerbation of chronic obstructive pulmonary disease.
      ]. The COPD readmission rate is so high that it is associated with a higher risk of death and a significant financial burden. As is well known, in the US and UK, the Medicare and Medicaid Service Center has penalized hospitals with high readmission rates, attempting to reduce readmission rates and enhance nursing care quality. Globally, the prevention and reduction of readmission have been recognized as high-priority management strategies.
      Readmission is considered a catastrophic event in the clinical process for COPD patients. At present, there have been reports of systematic reviews and meta-analyses of risk factors for all-cause readmission, and a review of risk factors for readmission due to acute exacerbation. However, there has been no systematic review and meta-analysis of readmission rates for acute exacerbations and risk factors. Therefore, this study aimed to summarize and evaluate the readmission rate and identify potential risk factors, with a view to providing a reference for the post-discharge management of patients with COPD as well as contributing to clinical practice and public health policy.

      2. Materials and methods

      2.1 Search strategy

      We followed the Meta-analysis of Observational Studies in Epidemiology (MOOSE) [
      • Stroup D.F.
      • Berlin J.A.
      • Morton S.C.
      • Olkin I.
      • Williamson G.D.
      • Rennie D D.
      • et al.
      Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of Observational Studies in Epidemiology (MOOSE) group.
      ] for this study. The detailed steps are provided in Supplement A. A literature search was performed using four databases, including PubMed, Embase, Cochrane Library, and Web of Science, from their inception to April 2, 2022. We adopted the search pattern of Medical Subject Headings (MeSH) combined with free terms and formulated detailed search strategies for each database. The search terms were adjusted appropriately according to the diverse databases to identify all eligible studies. The search strategies were related to “chronic obstructive pulmonary disease,” “readmission,” and “risk factors.” The detailed search strategies are provided in the Supplement B.

      2.2 Inclusion and exclusion criteria

      We included studies that met the following criteria:
      • Population: Participants were diagnosed with COPD according to any accepted clinical guidelines or criteria and hospitalized due to acute exacerbation of COPD (AECOPD) (as inpatients, excluding emergency department visits), regardless of sex and race.
      • Outcomes: COPD readmission for acute exacerbation within 30, 60, 90,180, or 365 days; risk factors for readmission. It was clearly defined as readmission due to COPD or an exacerbation of COPD after discharge, where COPD was the primary diagnosis for readmission.
      We excluded studies that met the following criteria:
      • All-cause readmission that did not regard COPD as the primary diagnosis.
      • The interventions or programs go beyond conventional care.
      • Studies that were published in any language other than English.
      • Duplicate publications, conference abstract and studies with incomplete or inaccessible data.

      2.3 Literature selection

      All the retrieved literature was imported into the Endnote X8 software, and repeated records were removed. Two investigators independently screened for potential eligible studies by scanning titles and abstracts. After obtaining and reviewing the full-text articles, studies that met the inclusion criteria were identified. Admittedly, a third researcher served as an arbitrator to resolve any disagreements through consensus.

      2.4 Quality assessment

      The Newcastle-Ottawa Scale (NOS) was used by two researchers to independently assess the methodological quality of the included studies [
      • Wells G.A.
      • Shea B.
      • O'Connell D.
      • Robertson J.
      • Peterson J.
      • Welch V.
      • et al.
      The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses.
      ]. It includes three aspects: population selection, comparability, and exposure or result evaluation, with a total of nine stars for eight items. Scores of 7–9 were defined as “good,” 4–6 as “fair,” and 1–3 as “poor.” Any inconsistencies in quality assessments were resolved by consensus.

      2.5 Data extraction

      We constructed a standardized form for data extraction using Microsoft Excel 2019, and the data extraction was performed independently by two reviewers. The form contained the characteristics of the included studies, such as title, first author, publication year, country, age, sample size, study design, readmission rate, risk factors, and quality assessment of the included studies. Arguments were arbitrated by a third reviewer to reach a consensus or resolved by team discussion.

      2.6 Statistical analysis

      To measure the overall readmission rate, we performed a single-proportion meta-analysis using the metaprop procedure [
      • Nyaga V.N.
      • Arbyn M.
      • Aerts M.
      Metaprop: a Stata command to perform meta-analysis of binomial data.
      ] in STATA 15.1. This procedure was typically used to pool proportions, using a binomial distribution to simulate variability within the study or allowing Freeman-Tukey double arcsine transformations to stabilize the variance. We choose a random-effects model to estimate the overall readmission rate. Heterogeneity between studies was assessed using Cochran's Q test and I2 test statistics. I2>50% was defined as substantial heterogeneity. Sensitivity analysis was performed by iteratively excluding one study at a time to assess the impact on the overall readmission rate and judge the robustness of the results. Publication bias was assessed by Begg's and Egger's tests. Subgroup analysis based on the study design type, age stage, and WHO region was conducted. In addition, we performed meta-regression to assess subgroup differences and further examine whether the estimates were influenced by study-level covariates.
      Considering that the risk factors reported by different studies were inconsistent, and that two or more studies reported the same risk factor for readmission and they were obtained by using a multivariate model, we performed a meta-analysis. Risk factors were estimated using odds ratio (OR) with 95% confidence interval (CI), and I2>50% was defined as substantial heterogeneity. If there was significant heterogeneity in the included studies, we used a random-effects model; otherwise, we used a fixed-effects model. In this study, differences were considered statistically significant at P < 0.05.

      3. Results

      3.1 Study search and selection

      A total of 3903 studies were retrieved using the specific search strategy of each database. One thousand two hundred and sixty-four duplicate studies were excluded, 2530 were excluded after scanning titles and abstracts, and 63 were excluded after reviewing the full-text articles. Finally, 46 studies were included and extracted for further analysis. The selection procedure is illustrated in Fig. 1.

      3.2 Characteristics of included studies

      A total of 46 studies [
      • Lau A.C.
      • Yam L.Y.
      • Poon E.
      Hospital re-admission in patients with acute exacerbation of chronic obstructive pulmonary disease.
      ,
      • Sin D.D.
      • Tu J.V.
      Inhaled corticosteroids and the risk of mortality and readmission in elderly patients with chronic obstructive pulmonary disease.
      ,
      • González C.
      • Servera E.
      • Ferris G.
      • Blasco M.L.
      • Marín J.
      Risk factors of readmission in acute exacerbation of moderate-to-severe chronic obstructive pulmonary disease.
      ,
      • Gudmundsson G.
      • Gislason T.
      • Janson C.
      • Lindberg E.
      • Hallin R.
      • Ulrik C.S.
      • et al.
      Risk factors for rehospitalisation in COPD: role of health status, anxiety and depression.
      ,
      • Almagro P.
      • Barreiro B.
      • de Echaguen A.O.
      • Quintana S.
      • Carballeira M.R.
      • Heredia J.L.
      • et al.
      Risk factors for hospital readmission in patients with chronic obstructive pulmonary disease.
      ,
      • McGhan R.
      • Radcliff T.
      • Fish R.
      • Sutherland E.R.
      • Welsh C.
      • Make B.
      Predictors of rehospitalization and death after a severe exacerbation of COPD.
      ,
      • Wong A.W.
      • Gan W.Q.
      • Burns J.
      • Sin D.D.
      • van Eeden S.F.
      Acute exacerbation of chronic obstructive pulmonary disease: influence of social factors in determining length of hospital stay and readmission rates.
      ,
      • González C.
      • Servera E.
      • Marín J.
      Importance of noninvasively measured respiratory muscle overload among the causes of hospital readmission of COPD patients.
      ,
      • Eriksen N.
      • Vestbo J.
      Management and survival of patients admitted with an exacerbation of COPD: comparison of two Danish patient cohorts.
      ,
      • Coventry P.A.
      • Gemmell I.
      • Todd C.J.
      Psychosocial risk factors for hospital readmission in COPD patients on early discharge services: a cohort study.
      ,
      • Chan F.W.
      • Wong F.Y.
      • Yam C.H.
      • Cheung W.L.
      • Wong E.L.
      • Leung M.C.
      • et al.
      Risk factors of hospitalization and readmission of patients with COPD in Hong Kong population: analysis of hospital admission records.
      ,
      • Barba R.
      • de Casasola G.G.
      • Marco J.
      • Emilio Losa J.
      • Plaza S.
      • Canora J.
      • et al.
      Anemia in chronic obstructive pulmonary disease: a readmission prognosis factor.
      ,
      • Nantsupawat T.
      • Limsuwat C.
      • Nugent K.
      Factors affecting chronic obstructive pulmonary disease early rehospitalization.
      ,
      • Zapatero A.
      • Barba R.
      • Ruiz J.
      • Losa J.E.
      • Plaza S.
      • Canora J.
      • et al.
      Malnutrition and obesity: influence in mortality and readmissions in chronic obstructive pulmonary disease patients.
      ,
      • Johannesdottir S.A.
      • Christiansen C.F.
      • Johansen M.B.
      • Olsen M.
      • Xu X.
      • Parker J.M.
      • et al.
      Hospitalization with acute exacerbation of chronic obstructive pulmonary disease and associated health resource utilization: a population-based Danish cohort study.
      ,
      • Baker C.L.
      • Zou K.H.
      • Su J.
      Risk assessment of readmissions following an initial COPD-related hospitalization.
      ,
      • Ozyilmaz E.
      • Kokturk N.
      • Teksut G.
      • Tatlicioglu T.
      Unsuspected risk factors of frequent exacerbations requiring hospital admission in chronic obstructive pulmonary disease.
      ,
      • Lin J.
      • Xu Y.Z.
      • Wu X.M.
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      • Lin L.
      • Gong L.Y.
      • et al.
      Risk factors associated with chronic obstructive pulmonary disease early readmission.
      ,
      • Chang C.
      • Zhu H.
      • Shen N.
      • Han X.
      • Chen Y.H.
      • He B.
      Utility of the combination of serum highly-sensitive C-reactive protein level at discharge and a risk index in predicting readmission for acute exacerbation of COPD.
      ,
      • Quintana J.M.
      • Esteban C.
      • Garcia-Gutierrez S.
      • Aguirre U.
      • Gonzalez N.
      • Lafuente I.
      • et al.
      Predictors of hospital admission two months after emergency department evaluation of COPD exacerbation.
      ,
      • Crisafulli E.
      • Torres A.
      • Huerta A.
      • Méndez R.
      • Guerrero M.
      • Martinez R.
      • et al.
      C-reactive protein at discharge, diabetes mellitus and ≥ 1 hospitalization during previous year predict early readmission in patients with acute exacerbation of chronic obstructive pulmonary disease.
      ,
      • Candrilli S.D.
      • Dhamane A.D.
      • Meyers J.L.
      • Kaila S.
      Factors associated with inpatient readmission among managed care enrollees with COPD.
      ,
      • Gavish R.
      • Levy A.
      • Dekel O.K.
      • Karp E.
      • Maimon N.
      The association between hospital readmission and pulmonologist follow-up visits in patients with COPD.
      ,
      • Hartl S.
      • Lopez-Campos J.L.
      • Pozo-Rodriguez F.
      • Castro-Acosta A.
      • Studnicka M.
      • Kaiser B.
      • et al.
      Risk of death and readmission of hospital-admitted COPD exacerbations: European COPD Audit.
      ,
      • de Miguel-Díez J.
      • Jiménez-García R.
      • Hernández-Barrera V.
      • Carrasco-Garrido P.
      • Puente Maestu L.
      • Ramírez García L.
      • et al.
      Readmissions following an initial hospitalization by COPD exacerbation in Spain from 2006 to 2012.
      ,
      • Guerrero M.
      • Crisafulli E.
      • Liapikou A.
      • Huerta A.
      • Gabarrús A.
      • Chetta A.
      • et al.
      Readmission for acute exacerbation within 30 Days of discharge is associated with a subsequent progressive increase in mortality risk in COPD patients: a long-term observational study.
      ,
      • Iyer A.S.
      • Bhatt S.P.
      • Garner J.J.
      • Wells J.M.
      • Trevor J.L.
      • Patel N.M.
      • et al.
      Depression is associated with readmission for acute exacerbation of chronic obstructive pulmonary disease.
      ,
      • Roberts M.H.
      • Clerisme-Beaty E.
      • Kozma C.M.
      • Paris A.
      • Slaton T.
      • Mapel D.W.
      A retrospective analysis to identify predictors of COPD-related rehospitalization.
      ,
      • Lau C.S.
      • Siracuse B.L.
      • Chamberlain R.S.
      Readmission after COPD Exacerbation Scale: determining 30-day readmission risk for COPD patients.
      ,
      • Bishwakarma R.
      • Zhang W.
      • Kuo Y.F.
      • Sharma G.
      Long-acting bronchodilators with or without inhaled corticosteroids and 30-day readmission in patients hospitalized for COPD.
      ,
      • Harries T.H.
      • Thornton H.
      • Crichton S.
      • Schofield P.
      • Gilkes A.
      • White P.T.
      Hospital readmissions for COPD: a retrospective longitudinal study.
      ,
      • Al Aqqad S.M.H.
      • Tangiisuran B.
      • Hyder Ali I.A.
      • Md Kassim R.M.N.
      • Wong J.L.
      • Tengku Saifudin T.I.
      Hospitalisation of multiethnic older patients with AECOPD: exploration of the occurrence of anxiety, depression and factors associated with short-term hospital readmission.
      ,
      • Couillard S.
      • Larivée P.
      • Courteau J.
      • Vanasse A.
      Eosinophils in COPD exacerbations are associated with increased readmissions.
      ,
      • Fuhrman C.
      • Moutengou E.
      • Roche N.
      • Delmas M.C.
      Prognostic factors after hospitalization for COPD exacerbation.
      ,
      • Epstein D.
      • Nasser R.
      • Mashiach T.
      • Azzam Z.S.
      • Berger G.
      Increased red cell distribution width: a novel predictor of adverse outcome in patients hospitalized due to acute exacerbation of chronic obstructive pulmonary disease.
      ,
      • Gershon A.S.
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      • Aaron S.
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      • Vozoris N.
      • Tan W.C.
      • et al.
      Socioeconomic status (SES) and 30-day hospital readmissions for chronic obstructive pulmonary (COPD) disease: a population-based cohort study.
      ,
      • Hegewald M.J.
      • Horne B.D.
      • Trudo F.
      • Kreindler J.L.
      • Chung Y.
      • Rea S.
      • et al.
      Blood eosinophil count and hospital readmission in patients with acute exacerbation of chronic obstructive pulmonary disease.
      ,
      • Cavailles A.
      • Melloni B.
      • Motola S.
      • Dayde F.
      • Laurent M.
      • Le Lay K.
      • et al.
      Identification of patient profiles with high risk of hospital Re-admissions for acute COPD exacerbations (AECOPD) in France using a machine learning model.
      ,
      • Jacobsen P.A.
      • Kragholm K.H.
      • Torp-Pedersen C.
      • Janssen D.J.A.
      • Spruit M.A.
      • Weinreich U.M.
      Employment status, readmission and mortality after acute exacerbation of COPD.
      ,
      • Kim T.W.
      • Choi E.S.
      • Kim W.J.
      • Jo H.S.
      The association with COPD readmission rate and access to medical institutions in elderly patients.
      ,
      • Meeraus W.H.
      • Mullerova H.
      • El Baou C.
      • Fahey M.
      • Hessel E.M.
      • Fahy W.A.
      Predicting Re-exacerbation timing and understanding prolonged exacerbations: an analysis of patients with COPD in the ECLIPSE cohort.
      ,
      • Zhou Y.Q.
      • Thanathi Mohamed Ameen M.N.A.
      • Li W.J.
      • Feng D.Y.
      • Yang H.L.
      • Zou X.L.
      • et al.
      Main pulmonary artery enlargement predicts 90-day readmissions in Chinese COPD patients.
      ,
      • Peng J.N.
      • Yu Q.
      • Fan S.L.
      • Chen X.R.
      • Tang R.
      • Wang D.X.
      • et al.
      High blood eosinophil and YKL-40 levels, as well as low CXCL9 levels, are associated with increased readmission in patients with acute exacerbation of chronic obstructive pulmonary disease.
      ,
      • Wu Y.K.
      • Lan C.C.
      • Tzeng I.S.
      • Wu C.W.
      The COPD-readmission (CORE) score: a novel prediction model for one-year chronic obstructive pulmonary disease readmissions.
      ,
      • Njoku C.M.
      • Wimmer B.C.
      • Peterson G.M.
      • Kinsman L.
      • Bereznicki B.J.
      Hospital readmission due to chronic obstructive pulmonary disease: a longitudinal study.
      ,
      • Quintana J.M.
      • Anton-Ladislao A.
      • Orive M.
      • Aramburu A.
      • Iriberri M.
      • Sánchez R.
      • et al.
      Predictors of short-term COPD readmission.
      ] were included, of which 21, 9, 13, 2, and 1 were conducted in European region, Western Pacific region, Americas region, Eastern Mediterranean region, and Non-member observer country or region, respectively, based on the WHO regions. The included studies were published from 2001 to 2022, with 19 prospective and 27 retrospective studies. Among the retrospective studies, there were 26 cohort studies and only one case-control study. The sample size ranged from 79 to 339389 individuals, with an average age of 54.0–76.8 years old. Detailed characteristics of the included studies are presented in Table 1 and Supplement C.
      Table 1Characteristics of included studies.
      ReferencesCountryStudy designSample sizeMale/Female (%)Age (years)ReferencesCountryStudy designSample sizeMale/Female (%)Age (years)
      Lau et al. [
      • Lau A.C.
      • Yam L.Y.
      • Poon E.
      Hospital re-admission in patients with acute exacerbation of chronic obstructive pulmonary disease.
      ]
      ChinaR551426 (77.3%)/125 (22.7%)73.75 ± 8.59Barba [
      • Barba R.
      • de Casasola G.G.
      • Marco J.
      • Emilio Losa J.
      • Plaza S.
      • Canora J.
      • et al.
      Anemia in chronic obstructive pulmonary disease: a readmission prognosis factor.
      ]
      SpainR275521192865 (70.0%)/82656 (30.0%)72.3 ± 15.9
      Sin et al. [
      • Sin D.D.
      • Tu J.V.
      Inhaled corticosteroids and the risk of mortality and readmission in elderly patients with chronic obstructive pulmonary disease.
      ]
      CanadaP2262012770 (56.5%)/9850 (43.5%)75.1Nantsupawat [
      • Nantsupawat T.
      • Limsuwat C.
      • Nugent K.
      Factors affecting chronic obstructive pulmonary disease early rehospitalization.
      ]
      USAR8148 (46.9%)/43 (53.1%)73.9
      Gonzalez [
      • González C.
      • Servera E.
      • Ferris G.
      • Blasco M.L.
      • Marín J.
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      AustriaP1601610865 (67.8%)/5151 (32.2%)70.8 ± 10.8Gershon [
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      SpainR301794(85.96%)/(14.04%)74.8 ± 10.0Hegewald [
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      USAR24451205 (49.3%)/1240 (50.7%)68.4 ± 11.6
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      FranceR14300688280 (62.1%)/54186 (37.9%)73.9 ± 12.2
      Iyer [
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      Footnote: R retrospective; P prospective; NI no information.

      3.3 Quality assessment of included studies

      We assessed the quality of the included studies using the NOS scale, and the overall quality was good, with scores ranging from five to nine. Only three studies were judged fair, of which two had six points and one had five points. Considering that the comparability of cohorts is not entirely clear, some studies did not specify the relevant variables that they controlled. The results of the methodological assessment of the included studies are presented in Table 1.

      3.4 Readmission rate for COPD

      The COPD readmission rate for acute exacerbations ranged from 6% to 24% within 30 days after discharge in 24 studies, 7%–39% within 60 days in 7 studies, 10%–41% within 90 days in 17 studies, 18%–50% within 180 days in 7 studies, and 18%–76% within 365 days in 20 studies. The pooled 30-, 60-, 90-, 180-, and 365-day readmission rates were 11% (95% CI: 0.09–0.13; I2 = 99.94%), 17% (95% CI: 0.10–0.25; I2 = 98.61%), 17% (95% CI: 0.15–0.19; I2 = 98.60%), 30% (95% CI: 0.25–0.35; I2 = 99.38%), and 37% (95% CI: 0.34–0.40; I2 = 99.08%), respectively (Fig. 2, Fig. 3, Fig. 4, Fig. 5, Fig. 6).
      Fig. 2
      Fig. 2Forest plot of 30-day readmission rate for COPD.
      Fig. 3
      Fig. 3Forest plot of 60-day readmission rate for COPD.
      Fig. 4
      Fig. 4Forest plot of 90-day readmission rate for COPD.
      Fig. 5
      Fig. 5Forest plot of 180-day readmission rate for COPD.
      Fig. 6
      Fig. 6Forest plot of 365-day readmission rate for COPD.

      3.5 Sensitivity analysis

      Sensitivity analysis demonstrated that there were no abnormal values in the results of the COPD readmission rate for acute exacerbations within 30, 60, 90, and 365 days after excluding one study at a time, which confirmed the robustness of our results. However, one study interfered with the results of the estimated pooled readmission rate within 180 days by 5%, indicating that this study was a source of heterogeneity (Supplement D).

      3.6 Subgroup analysis

      In terms of study design type, subgroup analysis showed that the COPD readmission rates for acute exacerbations in the prospective studies within 30, 60, 90, 180, and 365 days were 13% (95% CI: 0.09–0.18), 25% (95% CI: 0.17–0.33), 23% (95% CI: 0.19–0.26), 39% (95% CI: 0.22–0.57), and 41% (95% CI: 0.37–0.45), respectively. The readmission rates in those retrospective studies were 11% (95% CI: 0.09–0.13), 8% (95% CI: 0.07–0.20), 14% (95% CI: 0.12–0.16), 22% (95% CI: 0.19–0.26), and 34% (95% CI: 0.29–0.40), respectively (Table 2, Table 3, Table 4).
      Table 2Subgroup analysis of the COPD readmission rate within 30 and 60 days and subgroup differences.
      SubgroupReadmission rate within 30 daysUnivariate meta regression (P)Readmission rate within 60 daysUnivariate meta regression (P)
      Heterogeneity test results (I2, P)ES (95% CI)Heterogeneity test results (I2, P)ES (95% CI)
      Study design type
      Prospective94.25%0.000.13 (0.09–0.18)0.81696.61%0.000.25 (0.17–0.33)0.029
      Retrospective99.95%0.000.11 (0.09–0.13)Ref72.85%0.030.08 (0.07–0.10)Ref
      Age stage
      <70 years old95.35%0.000.07 (0.06–0.07)Ref96.88%0.000.17 (0.08–0.29)Ref
      ≥70 years old99.88%0.000.13 (0.11–0.15)0.01098.66%0.000.17 (0.09–0.27)0.858
      WHO region
      European Region99.82%0.000.13 (0.11–0.15)0.00996.61%0.000.25 (0.17–0.33)0.189
      Western Pacific Region99.71%0.000.15 (0.07–0.26)0.0180.07 (0.05–0.09)
      Americas Region99.82%0.000.08 (0.06–0.09)Ref0.08 (0.07–0.09)Ref
      Eastern Mediterranean Region0.11 (0.08–0.14)
      Comorbidities: Heart failure
      Yes99.94%0.000.10 (0.08–0.13)0.33498.61%0.000.19 (0.12–0.28)0.324
      No99.94%0.000.12 (0.08–0.17)Ref0.07 (0.05–0.06)Ref
      Comorbidities: Diabetes
      Yes99.90%0.000.10 (0.08–0.12)0.21396.00%0.000.18 (0.09–0.19)0.094
      No99.94%0.000.12 (0.09–0.16)Ref0.00%0.25 (0.23–0.26)Ref
      LOS
      <7 days54.95%0.080.07 (0.06–0.07)Ref0.00%0.18 (0.16–0.20)Ref
      ≥7 days99.85%0.000.14 (0.11–0.16)0.0300.07 (0.05–0.09)0.465
      Footnote: LOS length of stay; CI confidence interval; Ref reference.
      Table 3Subgroup analysis of the COPD readmission rate within 90 and 180 days and subgroup differences.
      SubgroupReadmission rate within 90 daysUnivariate meta regression (P)Readmission rate within 180 daysUnivariate meta regression (P)
      Heterogeneity test results (I2, P)ES (95% CI)Heterogeneity test results (I2, P)ES (95% CI)
      Study design type
      Prospective97.52%0.000.23 (0.19–0.26)0.01898.58%0.000.39 (0.22–0.57)0.092
      Retrospective98.44%0.000.14 (0.12–0.16)Ref99.03%0.000.22 (0.19–0.26)Ref
      Age stage
      <70 years old97.83%0.000.16 (0.14–0.19)Ref99.60%0.000.35 (0.12–0.61)Ref
      ≥70 years old95.76%0.000.17 (0.15–0.19)0.67299.13%0.000.26 (0.21–0.30)0.429
      WHO region
      European Region98.08%0.000.19 (0.17–0.22)0.08499.57%0.000.31 (0.25–0.38)0.690
      Western Pacific Region94.52%0.000.20 (0.11–0.31)0.517
      Americas Region80.80%0.000.12 (0.11–0.13)Ref0.00%0.18 (0.17–0.20)Ref
      Eastern Mediterranean Region0.18 (0.13–0.25)0.432
      Comorbidities: Heart failure
      Yes98.21%0.000.16 (0.12–0.20)0.78099.59%0.000.31 (0.13–0.51)0.834
      No98.89%0.000.18 (0.15–0.20)Ref99.10%0.000.27 (0.23–0.33)Ref
      Comorbidities: Diabetes
      Yes98.10%0.000.18 (0.14–0.22)0.80699.55%0.000.27 (0.18–0.38)0.645
      No98.97%0.000.17 (0.14–0.19)Ref93.23%0.000.34 (0.21–0.48)Ref
      LOS
      <7 days93.40%0.000.16 (0.13–0.21)Reference0.39 (0.30–0.49)Reference
      ≥7 days96.39%0.000.17 (0.15–0.20)0.15999.36%0.000.25(0.20–0.30)0.433
      Footnote: LOS length of stay; CI confidence interval; Ref reference.
      Table 4Subgroup analysis of the COPD readmission rate within 365 days and subgroup differences.
      SubgroupReadmission rate within 365 daysUnivariate meta regression (P)
      Heterogeneity test results (I2, P)ES (95% CI)
      Study design type
      Prospective99.14%0.000.41 (0.37–0.45)0.299
      Retrospective99.11%0.000.34 (0.29–0.40)Ref
      Age stage
      <70 years old98.36%0.000.35 (0.31–0.39)Ref
      ≥70 years old98.96%0.000.39 (0.35–0.43)0.659
      WHO region
      European Region98.95%0.000.41 (0.37–0.45)0.045
      Western Pacific Region98.88%0.000.44 (0.23–0.66)0.047
      Americas Region94.78%0.000.25 (0.23–0.27)Ref
      Non-member State or Region0.60 (0.56–0.63)0.002
      Comorbidities: Heart failure
      Yes99.18%0.000.38 (0.31–0.46)0.976
      No99.07%0.000.36 (0.33–0.40)Ref
      Comorbidities: Diabetes
      Yes99.00%0.000.38 (0.33–0.42)0.945
      No98.87%0.000.36 (0.32–0.40)Ref
      LOS
      <7 days0.24 (0.22–0.26)Ref
      ≥7 days98.78%0.000.47 (0.42–0.52)0.151
      Footnote: LOS length of stay; CI confidence interval; Ref reference.
      Subgroup analysis regarding the age stage, the COPD readmission rates with aged <70 years old were 7% (95% CI: 0.06–0.07) within 30 days, 17% (95% CI: 0.08–0.29) within 60 days, 16% (95% CI: 0.14–0.19) within 90 days, 35% (95% CI: 0.12–0.61) within 180 days, and 35% (95% CI: 0.31–0.39) within 365 days. In those aged ≥70 years old were 13% (95% CI: 0.11–0.15), 17% (95% CI: 0.09–0.27), 17% (95% CI: 0.15–0.19), 26% (95% CI: 0.21–0.30), and 39% (95% CI: 0.35–0.43), respectively (Table 2, Table 3, Table 4).
      The regional readmission rates within 30, 60, 90, 180, and 365 days were 13% (95% CI: 0.11–0.15), 25% (95% CI: 0.17–0.33), 19% (95% CI: 0.17–0.22), 31% (95% CI: 0.25–0.38), and 41% (95% CI: 0.37–0.45) in the European region, respectively, and 8% (95% CI: 0.06–0.09), 8% (95% CI: 0.07–0.09), 12% (95% CI: 0.11–0.13), 18% (95% CI: 0.17–0.20), and 25% (95% CI: 0.23–0.27) in the Americas region, respectively. In the Western Pacific region, the 30-, 60-, 90-, and 365-day readmission rate were 15% (95% CI: 0.07–0.26), 7% (95% CI: 0.05–0.09), 20% (95% CI: 0.11–0.31), and 44% (95% CI: 0.23–0.66), respectively. The 60- and 90-day readmission rates were 11% (95% CI: 0.08–0.14) and 18% (95% CI: 0.13–0.25) in the Eastern Mediterranean region. The 365-day readmission rate was 60% (95% CI: 0.56–0.63) in the Non-member state or region (Table 2, Table 3, Table 4).
      The subgroup analysis of heart failure and diabetes indicated that readmission rates within 30 days were 10% (95% CI: 0.08–0.13) and 10% (95% CI: 0.08–0.12), 19% (95% CI: 0.12–0.28) and 18% (95% CI: 0.09–0.19) within 60 days, 16% (95% CI: 0.12–0.20) and 18% (95% CI: 0.14–0.22) within 90 days, 31% (95% CI: 0.13–0.51) and 27% (95% CI: 0.18–0.38) within 180 days, and 38% (95% CI: 0.31–0.46) and 38% (95% CI: 0.33–0.42) within 365 days. The subgroup results without comorbidities were 12% (95% CI: 0.08–0.17) and 12% (95% CI: 0.09–0.16), 7% (0.05–0.06) and 25% (95% CI: 0.23–0.26), 18% (95% CI: 0.15–0.20) and 17% (95% CI: 0.14–0.19), 27% (95% CI: 0.23–0.33) and 34% (95% CI: 0.21–0.48), and 36% (95% CI: 0.33–0.40) and 36% (95% CI: 0.32–0.40), respectively (Table 2, Table 3, Table 4).
      In terms of length of stay (LOS), the 30-, 60-, 90-, 180-, and 365-day COPD readmission rates with LOS <7 days were 7% (95% CI: 0.06–0.07), 18% (95% CI: 0.16–0.20), 16% (95% CI: 0.13–0.21), 39% (95% CI: 0.30–0.49), and 24% (95% CI: 0.22–0.26), respectively. In those LOS ≥7 days were 14% (95% CI: 0.11–0.16), 7% (95% CI: 0.05–0.09), 17% (95% CI: 0.15–0.20), 25% (95% CI: 0.20–0.30), and 47% (95% CI: 0.42–0.52), respectively (Table 2, Table 3, Table 4).

      3.7 Subgroup differences and meta-regression

      For the COPD readmission rate for acute exacerbations within 30 days, subgroup differences were found in age stage (P = 0.010), WHO region (P = 0.009 and P = 0.018) and LOS (P = 0.030) (Table 2). Subgroup differences in readmission rate within 60 and 90 days were demonstrated by study design type (P = 0.029 and P = 0.018) (Table 2, Table 3). We observed the WHO regions were related to the 365-day readmission rate, which were Europe region, Western Pacific region, Non-member state or region versus Americas region (P = 0.045, P = 0.047, and P = 0.002), respectively (Table 4). No subgroup differences in 180-day readmission rate were found.

      3.8 Publication bias

      Neither begg's nor egger's tests indicated significant publication bias in COPD readmission rates within 30 days (P = 0.097 and P = 0.612), within 60 days (P = 1.000 and P = 0.620), within 90 days (P = 0.537 and P = 0.058), within 180 days (P = 0.764 and P = 0.098), and within 365 days (P = 0.381 and P = 0.053). (Supplement E).

      3.9 Risk factors for COPD readmission

      The meta-analysis indicated that male sex (OR: 1.33; 95% CI: 1.23–1.42; P = 0.000), heart failure (OR: 1.06; 95% CI: 1.05–1.08; P = 0.000), cancer or tumor (OR: 1.45; 95% CI: 1.34–1.58; P = 0.000), diabetes (OR: 1.08; 95% CI: 1.04–1.13; P = 0.000), malnutritionn (OR: 1.42; 95% CI: 1.19–1.70; P = 0.000), and LOS (OR: 1.01; 95% CI: 1.01–1.01; P = 0.000) were the major risk factors for 30-day readmission, whereas obesity was a protective factor (OR: 0.84; 95% CI: 0.78–0.90; P = 0.000). The number of hospitalizations in the previous year (OR: 2.47; 95% CI: 2.30–2.66; P = 0.000) was associated with an increased risk of 90-day readmission. The main risk factors for 365-day readmission were the number of hospitalizations in the previous year (OR: 2.42; 95%CI: 1.20–4.87; P = 0.013) and asthma (OR: 1.17; 95% CI: 1.01–1.36; P = 0.035). However, the pooled analysis results of comorbidities such as depression, anemia, and pneumonia were not statistically significant (P > 0.05) (Table 5).
      Table 5Meta-analysis of risk factors for COPD readmission within 30, 90 and 365 days.
      Risk factorsStudiesHeterogeneity testEffect modelOR (95% CI)P
      I2P
      Risk factors of readmission within 30 dayss
      Gender7 [
      • Chan F.W.
      • Wong F.Y.
      • Yam C.H.
      • Cheung W.L.
      • Wong E.L.
      • Leung M.C.
      • et al.
      Risk factors of hospitalization and readmission of patients with COPD in Hong Kong population: analysis of hospital admission records.
      ,
      • Barba R.
      • de Casasola G.G.
      • Marco J.
      • Emilio Losa J.
      • Plaza S.
      • Canora J.
      • et al.
      Anemia in chronic obstructive pulmonary disease: a readmission prognosis factor.
      ,
      • de Miguel-Díez J.
      • Jiménez-García R.
      • Hernández-Barrera V.
      • Carrasco-Garrido P.
      • Puente Maestu L.
      • Ramírez García L.
      • et al.
      Readmissions following an initial hospitalization by COPD exacerbation in Spain from 2006 to 2012.
      ,
      • Lau C.S.
      • Siracuse B.L.
      • Chamberlain R.S.
      Readmission after COPD Exacerbation Scale: determining 30-day readmission risk for COPD patients.
      ,
      • Gershon A.S.
      • Thiruchelvam D.
      • Aaron S.
      • Stanbrook M.
      • Vozoris N.
      • Tan W.C.
      • et al.
      Socioeconomic status (SES) and 30-day hospital readmissions for chronic obstructive pulmonary (COPD) disease: a population-based cohort study.
      ,
      • Kim T.W.
      • Choi E.S.
      • Kim W.J.
      • Jo H.S.
      The association with COPD readmission rate and access to medical institutions in elderly patients.
      ,
      • Njoku C.M.
      • Wimmer B.C.
      • Peterson G.M.
      • Kinsman L.
      • Bereznicki B.J.
      Hospital readmission due to chronic obstructive pulmonary disease: a longitudinal study.
      ]
      96.00.000Random1.33 (1.23–1.42)0.000
      Heart failure4 [
      • Barba R.
      • de Casasola G.G.
      • Marco J.
      • Emilio Losa J.
      • Plaza S.
      • Canora J.
      • et al.
      Anemia in chronic obstructive pulmonary disease: a readmission prognosis factor.
      ,
      • Zapatero A.
      • Barba R.
      • Ruiz J.
      • Losa J.E.
      • Plaza S.
      • Canora J.
      • et al.
      Malnutrition and obesity: influence in mortality and readmissions in chronic obstructive pulmonary disease patients.
      ,
      • Lau C.S.
      • Siracuse B.L.
      • Chamberlain R.S.
      Readmission after COPD Exacerbation Scale: determining 30-day readmission risk for COPD patients.
      ,
      • Gershon A.S.
      • Thiruchelvam D.
      • Aaron S.
      • Stanbrook M.
      • Vozoris N.
      • Tan W.C.
      • et al.
      Socioeconomic status (SES) and 30-day hospital readmissions for chronic obstructive pulmonary (COPD) disease: a population-based cohort study.
      ]
      44.10.147Fixed1.06 (1.05–1.08)0.000
      Cancer/tumor4 [
      • Barba R.
      • de Casasola G.G.
      • Marco J.
      • Emilio Losa J.
      • Plaza S.
      • Canora J.
      • et al.
      Anemia in chronic obstructive pulmonary disease: a readmission prognosis factor.
      ,
      • Zapatero A.
      • Barba R.
      • Ruiz J.
      • Losa J.E.
      • Plaza S.
      • Canora J.
      • et al.
      Malnutrition and obesity: influence in mortality and readmissions in chronic obstructive pulmonary disease patients.
      ,
      • Baker C.L.
      • Zou K.H.
      • Su J.
      Risk assessment of readmissions following an initial COPD-related hospitalization.
      ,
      • Hegewald M.J.
      • Horne B.D.
      • Trudo F.
      • Kreindler J.L.
      • Chung Y.
      • Rea S.
      • et al.
      Blood eosinophil count and hospital readmission in patients with acute exacerbation of chronic obstructive pulmonary disease.
      ]
      86.10.000Random1.45 (1.34–1.58)0.000
      Diabetes3 [
      • Barba R.
      • de Casasola G.G.
      • Marco J.
      • Emilio Losa J.
      • Plaza S.
      • Canora J.
      • et al.
      Anemia in chronic obstructive pulmonary disease: a readmission prognosis factor.
      ,
      • Roberts M.H.
      • Clerisme-Beaty E.
      • Kozma C.M.
      • Paris A.
      • Slaton T.
      • Mapel D.W.
      A retrospective analysis to identify predictors of COPD-related rehospitalization.
      ,
      • Lau C.S.
      • Siracuse B.L.
      • Chamberlain R.S.
      Readmission after COPD Exacerbation Scale: determining 30-day readmission risk for COPD patients.
      ]
      60.90.077Random1.08 (1.04–1.13)0.000
      Malnutritionn3 [
      • Barba R.
      • de Casasola G.G.
      • Marco J.
      • Emilio Losa J.
      • Plaza S.
      • Canora J.
      • et al.
      Anemia in chronic obstructive pulmonary disease: a readmission prognosis factor.
      ,
      • Zapatero A.
      • Barba R.
      • Ruiz J.
      • Losa J.E.
      • Plaza S.
      • Canora J.
      • et al.
      Malnutrition and obesity: influence in mortality and readmissions in chronic obstructive pulmonary disease patients.
      ,
      • de Miguel-Díez J.
      • Jiménez-García R.
      • Hernández-Barrera V.
      • Carrasco-Garrido P.
      • Puente Maestu L.
      • Ramírez García L.
      • et al.
      Readmissions following an initial hospitalization by COPD exacerbation in Spain from 2006 to 2012.
      ]
      95.10.000Random1.42 (1.19–1.70)0.000
      Asthma2 [
      • Roberts M.H.
      • Clerisme-Beaty E.
      • Kozma C.M.
      • Paris A.
      • Slaton T.
      • Mapel D.W.
      A retrospective analysis to identify predictors of COPD-related rehospitalization.
      ,
      • Gershon A.S.
      • Thiruchelvam D.
      • Aaron S.
      • Stanbrook M.
      • Vozoris N.
      • Tan W.C.
      • et al.
      Socioeconomic status (SES) and 30-day hospital readmissions for chronic obstructive pulmonary (COPD) disease: a population-based cohort study.
      ]
      81.80.019Random1.25 (0.87–1.81)0.233
      LOS2 [
      • Barba R.
      • de Casasola G.G.
      • Marco J.
      • Emilio Losa J.
      • Plaza S.
      • Canora J.
      • et al.
      Anemia in chronic obstructive pulmonary disease: a readmission prognosis factor.
      ,
      • Zapatero A.
      • Barba R.
      • Ruiz J.
      • Losa J.E.
      • Plaza S.
      • Canora J.
      • et al.
      Malnutrition and obesity: influence in mortality and readmissions in chronic obstructive pulmonary disease patients.
      ]
      0.00.722Fixed1.01 (1.01–1.01)0.000
      Depression2 [
      • Iyer A.S.
      • Bhatt S.P.
      • Garner J.J.
      • Wells J.M.
      • Trevor J.L.
      • Patel N.M.
      • et al.
      Depression is associated with readmission for acute exacerbation of chronic obstructive pulmonary disease.
      ,
      • Lau C.S.
      • Siracuse B.L.
      • Chamberlain R.S.
      Readmission after COPD Exacerbation Scale: determining 30-day readmission risk for COPD patients.
      ]
      89.90.002Random2.00 (0.64–6.32)0.235
      Anemia2 [
      • Barba R.
      • de Casasola G.G.
      • Marco J.
      • Emilio Losa J.
      • Plaza S.
      • Canora J.
      • et al.
      Anemia in chronic obstructive pulmonary disease: a readmission prognosis factor.
      ,
      • Lau C.S.
      • Siracuse B.L.
      • Chamberlain R.S.
      Readmission after COPD Exacerbation Scale: determining 30-day readmission risk for COPD patients.
      ]
      98.20.000Random1.15 (0.97–1.36)0.119
      Obesity2 [
      • Zapatero A.
      • Barba R.
      • Ruiz J.
      • Losa J.E.
      • Plaza S.
      • Canora J.
      • et al.
      Malnutrition and obesity: influence in mortality and readmissions in chronic obstructive pulmonary disease patients.
      ,
      • de Miguel-Díez J.
      • Jiménez-García R.
      • Hernández-Barrera V.
      • Carrasco-Garrido P.
      • Puente Maestu L.
      • Ramírez García L.
      • et al.
      Readmissions following an initial hospitalization by COPD exacerbation in Spain from 2006 to 2012.
      ]
      85.00.010Random0.84 (0.78–0.90)0.000
      Risk factors of readmission within 90 days
      Number of hospitalizations in the previous year3 [
      • Gavish R.
      • Levy A.
      • Dekel O.K.
      • Karp E.
      • Maimon N.
      The association between hospital readmission and pulmonologist follow-up visits in patients with COPD.
      ,
      • Hartl S.
      • Lopez-Campos J.L.
      • Pozo-Rodriguez F.
      • Castro-Acosta A.
      • Studnicka M.
      • Kaiser B.
      • et al.
      Risk of death and readmission of hospital-admitted COPD exacerbations: European COPD Audit.
      ,
      • Al Aqqad S.M.H.
      • Tangiisuran B.
      • Hyder Ali I.A.
      • Md Kassim R.M.N.
      • Wong J.L.
      • Tengku Saifudin T.I.
      Hospitalisation of multiethnic older patients with AECOPD: exploration of the occurrence of anxiety, depression and factors associated with short-term hospital readmission.
      ]
      0.00.823Fixed2.47 (2.30–2.66)0.000
      Pneumonia2 [
      • Candrilli S.D.
      • Dhamane A.D.
      • Meyers J.L.
      • Kaila S.
      Factors associated with inpatient readmission among managed care enrollees with COPD.
      ,
      • Zhou Y.Q.
      • Thanathi Mohamed Ameen M.N.A.
      • Li W.J.
      • Feng D.Y.
      • Yang H.L.
      • Zou X.L.
      • et al.
      Main pulmonary artery enlargement predicts 90-day readmissions in Chinese COPD patients.
      ]
      70.00.068Random1.56 (0.67–3.95)0.304
      Risk factors of readmission within 365 days
      Number of hospitalizations in the previous year4 [
      • Almagro P.
      • Barreiro B.
      • de Echaguen A.O.
      • Quintana S.
      • Carballeira M.R.
      • Heredia J.L.
      • et al.
      Risk factors for hospital readmission in patients with chronic obstructive pulmonary disease.
      ,
      • McGhan R.
      • Radcliff T.
      • Fish R.
      • Sutherland E.R.
      • Welsh C.
      • Make B.
      Predictors of rehospitalization and death after a severe exacerbation of COPD.
      ,
      • Eriksen N.
      • Vestbo J.
      Management and survival of patients admitted with an exacerbation of COPD: comparison of two Danish patient cohorts.
      ,
      • Johannesdottir S.A.
      • Christiansen C.F.
      • Johansen M.B.
      • Olsen M.
      • Xu X.
      • Parker J.M.
      • et al.
      Hospitalization with acute exacerbation of chronic obstructive pulmonary disease and associated health resource utilization: a population-based Danish cohort study.
      ]
      96.90.000Random2.42 (1.20–4.87)0.013
      Depression2 [
      • Coventry P.A.
      • Gemmell I.
      • Todd C.J.
      Psychosocial risk factors for hospital readmission in COPD patients on early discharge services: a cohort study.
      ,
      • Iyer A.S.
      • Bhatt S.P.
      • Garner J.J.
      • Wells J.M.
      • Trevor J.L.
      • Patel N.M.
      • et al.
      Depression is associated with readmission for acute exacerbation of chronic obstructive pulmonary disease.
      ]
      84.40.011Random1.79 (0.89–3.61)0.104
      Eosinophils:≥200 cells/μL or 2% vs <200 cells/μL and 2%2 [
      • Couillard S.
      • Larivée P.
      • Courteau J.
      • Vanasse A.
      Eosinophils in COPD exacerbations are associated with increased readmissions.
      ,
      • Peng J.N.
      • Yu Q.
      • Fan S.L.
      • Chen X.R.
      • Tang R.
      • Wang D.X.
      • et al.
      High blood eosinophil and YKL-40 levels, as well as low CXCL9 levels, are associated with increased readmission in patients with acute exacerbation of chronic obstructive pulmonary disease.
      ]
      0.00.821Fixed3.38(1.90–6.02)0.000
      Eosinophils:≥300 cells/μL or 3% vs <300 cells/μL and 3%2 [
      • Couillard S.
      • Larivée P.
      • Courteau J.
      • Vanasse A.
      Eosinophils in COPD exacerbations are associated with increased readmissions.
      ,
      • Peng J.N.
      • Yu Q.
      • Fan S.L.
      • Chen X.R.
      • Tang R.
      • Wang D.X.
      • et al.
      High blood eosinophil and YKL-40 levels, as well as low CXCL9 levels, are associated with increased readmission in patients with acute exacerbation of chronic obstructive pulmonary disease.
      ]
      0.00.770Fixed2.93(1.58–5.42)0.001
      Asthma2 [
      • McGhan R.
      • Radcliff T.
      • Fish R.
      • Sutherland E.R.
      • Welsh C.
      • Make B.
      Predictors of rehospitalization and death after a severe exacerbation of COPD.
      ,
      • Johannesdottir S.A.
      • Christiansen C.F.
      • Johansen M.B.
      • Olsen M.
      • Xu X.
      • Parker J.M.
      • et al.
      Hospitalization with acute exacerbation of chronic obstructive pulmonary disease and associated health resource utilization: a population-based Danish cohort study.
      ]
      59.20.117Random1.17(1.01–1.36)0.035
      Footnote: LOS length of stay; OR odds ratio; CI confidence interval.

      4. Discussion

      Readmissions for acute exacerbations of COPD have brought about a significant epidemiological and economic burden, which has had a great impact on global public health healthcare systems. Therefore, this study is the first to systematically evaluate and summarize acute exacerbation readmission rates and risk factors for readmission in patients with COPD within 30, 60, 90, 180, and 365 days after discharge, respectively. The overall quality assessment of the 46 studies was good. Systematic evaluation and meta-analysis indicated that pooled COPD readmission rates within 30, 60, 90, 180, and 365 days were 11%, 17%, 17%, 30%, and 37%, respectively. At the same time, we also identified potential risk factors for COPD readmissions, mainly including being male, number of hospitalizations in the previous year, LOS, and comorbidities such as heart failure, cancer or tumor, diabetes, malnutrition, and so on.
      In recent years, a systematic review with similar criteria for the definition of readmission described the prevalence of COPD readmission for acute exacerbation as 2.6–82.2% at 30 days, 11.8–44.8% at 31–90 days, 17.9–63.0% at 180 days, and 25.0–87.0% at 365 days [
      • Njoku C.M.
      • Alqahtani J.S.
      • Wimmer B.C.
      • Peterson G.M.
      • Kinsman L.
      • Hurst J.R.
      • et al.
      Risk factors and associated outcomes of hospital readmission in COPD: a systematic review.
      ]. We observed that the summary results of our study at each time point were also within the range of readmission rates described in this review. And the other thing to point out is that the 60-day readmission rate was the same as that of the 90-day. Our preliminary considerations were as follows: Firstly, for the outcome of a 60-day readmission, only seven original studies were included, which were distributed in different regions and countries. Furthermore, one of the original studies had a smaller sample size with a high readmission rate variability of 39% [
      • Ozyilmaz E.
      • Kokturk N.
      • Teksut G.
      • Tatlicioglu T.
      Unsuspected risk factors of frequent exacerbations requiring hospital admission in chronic obstructive pulmonary disease.
      ]. Secondly, the interval between 60 and 90 days is relatively short. In addition, some studies have reported that exacerbations were not random events but clustered together in time, such that there was a high-risk period for recurrent exacerbations in the 8-week period after discharge [
      • Hurst J.R.
      • Donaldson G.C.
      • Quint J.K.
      • Goldring J.J.
      • Baghai-Ravary R.
      • Wedzicha J.A.
      Temporal clustering of exacerbations in chronic obstructive pulmonary disease.
      ].
      Subgroup analysis based on the study design type showed higher COPD readmission rates in the prospective studies than in the retrospective studies at different time points, and subgroup differences were found at 60 and 90 days, respectively (P < 0.05), indicating that the study design type was considered to be the cause of greater heterogeneity. This may also indirectly account for the differences in readmission rates reported by different types of studies. The outcomes of retrospective studies were mostly derived from medical records and related databases and were subject to the common limitations of their retrospective design, including selection bias, misclassification bias, and residual confounding. Therefore, estimates of readmission rates in retrospective studies are inevitably underestimated. The results of subgroup analysis based on different age stages demonstrated that the readmission rate of patients aged ≥70 years old was higher than that of patients aged <70 years old on the whole, and there was a significant difference at 30 days (P < 0.05), indicating that age stage may be the source of heterogeneity in readmission rate. The European audit of a prospective cohort study from 13 European countries indicated that older age was associated with the risk of readmission [
      • Fuhrman C.
      • Moutengou E.
      • Roche N.
      • Delmas M.C.
      Prognostic factors after hospitalization for COPD exacerbation.
      ]. However, age had little effect on the readmission rate at other time points in this study. This is an initial summary report. Some studies provided the median or mean age, and the age of the included subjects was not homogeneous, which may have affected the results to some extent.
      In addition, subgroup analysis reported a difference in the COPD readmission rate for acute exacerbations based on WHO regions. It is worth mentioning that there were differences between regional subgroups at 30 and 365 days (P < 0.05); that is, regional distribution may be the source of heterogeneity. The readmission rate varied by region, although no statistical differences were found between the subgroups at 60, 90, and 180 days. Potential geographical differences may exist in the 30, 90, and 365 days readmission rates in different countries: 5.11%, 10.06%, and 18.46% of AECOPD admissions were readmitted within 30, 90, and 365 days in the USA [
      • Hegewald M.J.
      • Horne B.D.
      • Trudo F.
      • Kreindler J.L.
      • Chung Y.
      • Rea S.
      • et al.
      Blood eosinophil count and hospital readmission in patients with acute exacerbation of chronic obstructive pulmonary disease.
      ], 6.7%, 12.2%, and 23.7% in Australian [
      • Njoku C.M.
      • Wimmer B.C.
      • Peterson G.M.
      • Kinsman L.
      • Bereznicki B.J.
      Hospital readmission due to chronic obstructive pulmonary disease: a longitudinal study.
      ], and 9.4%, 18.2%, and 37.0% in Denmark [
      • Johannesdottir S.A.
      • Christiansen C.F.
      • Johansen M.B.
      • Olsen M.
      • Xu X.
      • Parker J.M.
      • et al.
      Hospitalization with acute exacerbation of chronic obstructive pulmonary disease and associated health resource utilization: a population-based Danish cohort study.
      ], respectively. This phenomenon is consistent with our findings. After observation, compared with the Americas region, the readmission rate in European region revealed a higher trend at all time points. Simultaneously, the Western Pacific region had a higher readmission rate within 30, 90, and 365 days.
      In this study, subgroup analysis was performed on the comorbidities of patients with heart failure and diabetes; however, no difference was found in the subgroup results at each time point. In this regard, a key point to consider was that when we selected the subgroups, if a study did not report this comorbidity, it was classified into a group without comorbidity, which may cause some bias. In addition, the sample size of the original studies included at each time point was uneven and affected by differences in age, region, and nation, which may also explain the insignificant differences between subgroups. The average LOS for COPD was generally 7–10 days [
      • Ruparel M.
      • López-Campos J.L.
      • Castro-Acosta A.
      • Hartl S.
      • Pozo-Rodriguez F.
      • Roberts C.M.
      Understanding variation in length of hospital stay for COPD exacerbation: European COPD audit.
      ,
      • Harries T.H.
      • Thornton H.V.
      • Crichton S.
      • Schofield P.
      • Gilkes A.
      • White P.T.
      Length of stay of COPD hospital admissions between 2006 and 2010: a retrospective longitudinal study.
      ,
      • Germini F.
      • Veronese G.
      • Marcucci M.
      • Coen D.
      • Ardemagni D.
      • Montano N.
      • et al.
      COPD exacerbations in the emergency department: epidemiology and related costs. A retrospective cohort multicentre study from the Italian Society of Emergency Medicine (SIMEU).
      ]. Therefore, in combination with the LOS reported in the original studies we included, we used seven days as a grouping basis. Our study indicated that the 30-, 90-, and 365-day readmission rates of the LOS ≥7 days were slightly higher than those of LOS <7 days, and the difference in 30-day was statistically significant (P < 0.05). However, no differences between the groups were observed at the other time points. The readmission trends of the 60- and 180-day subgroups were opposite. The general explanation is that the studies that did not describe the LOS were not considered for grouping, resulting in a small number of original studies at these two time points, which would affect the reliability of the results. A meta-analysis by Wang et al. [
      • Wang Q.
      • Pei G.
      • Chen L.
      • He Z.
      Factors affecting the length of stay and hospital readmission rates after an acute exacerbation of chronic obstructive pulmonary disease: a systematic review and meta-analysis.
      ] showed no significant relationship between LOS and COPD readmission rate. This finding was consistent with our subgroup results and confirmed the reliability of our results.
      Our meta-analysis found that male sex and heart failure were potential risk factors for 30-day COPD readmission, which was consistent with the report of Alqahtani et al. [
      • Alqahtani J.S.
      • Njoku C.M.
      • Bereznicki B.
      • Wimmer B.C.
      • Peterson G.M.
      • Kinsman L.
      • et al.
      Risk factors for all-cause hospital readmission following exacerbation of COPD: a systematic review and meta-analysis.
      ]. Although the present study described female sex as a protective factor, and male sex as a risk factor in our study, the essence of the influencing factors was similiar. In addition, this study also found that the LOS and comorbidities such as cancer or tumor, diabetes, and malnutrition were closely related to readmissions. The differences between the two results were caused by different outcomes and inclusion criteria. Studies have demonstrated that the male sex, LOS, and comorbidities are associated with an increased risk of readmissions for COPD [
      • Candrilli S.D.
      • Dhamane A.D.
      • Meyers J.L.
      • Kaila S.
      Factors associated with inpatient readmission among managed care enrollees with COPD.
      ,
      • Kim T.W.
      • Choi E.S.
      • Kim W.J.
      • Jo H.S.
      The association with COPD readmission rate and access to medical institutions in elderly patients.
      ]. Compared to females, higher readmission rate in males was due to higher rates of smokers and lower adherence to medical advice. Compared with the LOS of 1–3 days, a longer LOS was associated with significantly greater odds of 30- and 90-day COPD readmission [
      • Candrilli S.D.
      • Dhamane A.D.
      • Meyers J.L.
      • Kaila S.
      Factors associated with inpatient readmission among managed care enrollees with COPD.
      ]. COPD is a chronic, consumptive disease that affects not only the lungs but also has a variety of extrapulmonary effects, such as impaired nutritional status or malnutrition [
      • Cavaillès A.
      • Brinchault-Rabin G.
      • Dixmier A.
      • Goupil F.
      • Gut-Gobert C.
      • Marchand-Adam S.
      • et al.
      Comorbidities of COPD.
      ,
      • Kaluźniak-Szymanowska A.
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      • Deskur-Śmielecka E.
      • Lewandowicz M.
      • Kaczmarek B.
      • Wieczorowska-Tobis K.
      Malnutrition, sarcopenia, and malnutrition-sarcopenia syndrome in older adults with COPD.
      ]. Malnutrition was an important factor affecting prognosis, which was associated with a significant increase in the risk of readmission in the 30 days following discharge [
      • Zapatero A.
      • Barba R.
      • Ruiz J.
      • Losa J.E.
      • Plaza S.
      • Canora J.
      • et al.
      Malnutrition and obesity: influence in mortality and readmissions in chronic obstructive pulmonary disease patients.
      ]. Previous reviews indicated that the history of hospitalization in the year prior to admission was a key predictor of COPD readmissions [36.38,39], which was consistent with the risk factors reported at 90 and 365 days in our review. However, no relevant factors affecting readmission were found at 60 and 180 day follow-up in this study. Our preliminary consideration was that the number of original studies was smaller, and the risk factors reported in different studies were different; therefore, it was not suitable for quantitative synthetic analysis. Studies on the influencing factors of readmission within 30, 90, and 365 days after discharge are generally concerning, but there are few studies on readmission within 60 and 180 days. The likelihood of recurrence within 60 days of discharge increased significantly [
      • Hurst J.R.
      • Donaldson G.C.
      • Quint J.K.
      • Goldring J.J.
      • Baghai-Ravary R.
      • Wedzicha J.A.
      Temporal clustering of exacerbations in chronic obstructive pulmonary disease.
      ,
      • Hurst J.R.
      • Vestbo J.
      • Anzueto A.
      • Locantore N.
      • Müllerova H.
      • Tal-Singer R.
      • et al.
      Susceptibility to exacerbation in chronic obstructive pulmonary disease.
      ]. Li et al. [
      • Li J.S.
      • Wang H.F.
      Sequential syndrome differentiation by eliminating pathogen and strengthening vital Qi on the basis of acute exacerbation of chronic obstructive pulmonary disease risk window.
      ] first proposed the concept of the “AECOPD risk window” in 2011. International studies have mentioned the existence of this phenomenon and its hazards. Therefore, it is urgent for clinical and scientific researchers to strengthen relevant research 60 days after discharge.
      Depression has been documented as a risk factor for readmission; however, this was not the case in this study. Among all the included studies, only three original studies reported depression as a risk factor, and their OR values were significantly different. Therefore, the CI of the summarized result was wide and no statistical difference was found. Obesity was identified as a protective factor identified in this study, which was in accordance with the inherent nature of the risk factors reported above, namely, low body weight due to malnutrition. Compared with normal-weight patients, obese COPD patients had a 13% lower risk of 30-day readmission and a 29% higher risk of readmission if malnutrition was present [
      • Zapatero A.
      • Barba R.
      • Ruiz J.
      • Losa J.E.
      • Plaza S.
      • Canora J.
      • et al.
      Malnutrition and obesity: influence in mortality and readmissions in chronic obstructive pulmonary disease patients.
      ]. It is recommended to supplement nutrition and increase body weight appropriately to delay the progression of COPD. With such a high readmission rate and more risk factors for COPD readmission, it is crucial to strengthen the follow-up management after discharge. As recommended by the GOLD and national guidelines, the follow-up plan may include regular symptom monitoring, reduction of exposure to risk factors, adjustment of controlled medications when necessary, and enhancement of information on compliance.

      5. Limitations

      There are some limitations that need to be addressed. We included only studies published in English. Those in other languages were omitted, which may have affected the reliability of the results. We can not further analyze the impact of differences in mortality among patients who were died outside of hospitals (e.g., at home or at nursing homes) without readmitted on the results of our analysis. The included studies were highly heterogeneous, and subgroup analyses indicated that the study design type, age stage, WHO region, and LOS revealed the sources of heterogeneity. However, we only explored the important factors available from the studies and did not perform subgroup analysis on the severity of the disease, pulmonary function classification, or GOLD grouping of COPD, which may also account for the heterogeneity. Although we included heterogeneous studies, the results of the sensitivity analysis were stable; in addition, no publication bias was found, so the results were relatively reliable.

      6. Conclusions

      Patients with COPD had higher readmission rates for acute exacerbations within 30, 60, 90, 180, and 365 days after discharge, and older age, prospective design type, European region, and longer LOS were associated with higher readmission rates. Male sex, number of hospitalizations in the previous year, LOS, and comorbidities were the most common risk factors for readmission. Therefore, after the symptoms of acute exacerbation are relieved and the patient is discharged from hospital, relevant clinical interventions should be put forward to adjust or control the avoidable risk factors in a targeted manner to prevent and reduce the negative impact and heavy economic burden caused by readmission.

      Data availability statement

      All data generated or analyzed during the present study are included in this article and supplementary data.

      Funding sources

      This study was supported by the National Natural Science Foundation of China (81830116 and 81973781); Chinese Medicine Inheritance and Innovation “Hundred and Ten Million” Talent Project -- Chief Scientist of Qi-Huang Project ([2020] No. 219); Special Program for Scientific Research of Chinese Medicine from Henan Province, China (2019JDZX2004); Traditional Chinese Medicine Discipline Construction Project of Henan Province's Characteristic Backbone Discipline (STG-ZYXKY-2020007).

      Author contributions

      Jiansheng Li conceived and designed this study; Hailong Zhang provided study materials and administrative support; JiaJia Wang and Hulei Zhao evaluated the reporting quality; Weihong Han screened literatures and extracted data; Huanrong Ruan screened literatures, extracted data, conducted the data statistical analysis and interpretation; all authors were responsible for manuscript writing and final approval of manuscript.

      Declaration of competing interest

      No potential conflict of interest was reported by the authors.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:
      Supplement A. Moose checklist; Supplement B. Details of the literature search strategy; Supplement C. Characteristics of included studies; Supplement D. Sensitivity analysis of included studies on readmission rate for COPD; Supplement E. Publication bias of included studies on readmission rate for COPD.

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