title: Clinical determinants of the severity of Middle East respiratory syndrome (MERS): a systematic review and meta-analysis.
abstract: While the risk of severe complications of Middle East respiratory syndrome (MERS) and its determinants have been explored in previous studies, a systematic analysis of published articles with different designs and populations has yet to be conducted. The present study aimed to systematically review the risk of death associated with MERS as well as risk factors for associated complications.
  
  
  
  PubMed and Web of Science databases were searched for clinical and epidemiological studies on confirmed cases of MERS. Eligible articles reported clinical outcomes, especially severe complications or death associated with MERS. Risks of admission to intensive care unit (ICU), mechanical ventilation and death were estimated. Subsequently, potential associations between MERS-associated death and age, sex, underlying medical conditions and study design were explored.
  
  
  
  A total of 25 eligible articles were identified. The case fatality risk ranged from 14.5 to 100%, with the pooled estimate at 39.1%. The risks of ICU admission and mechanical ventilation ranged from 44.4 to 100% and from 25.0 to 100%, with pooled estimates at 78.2 and 73.0%, respectively. These risks showed a substantial heterogeneity among the identified studies, and appeared to be the highest in case studies focusing on ICU cases. We identified older age, male sex and underlying medical conditions, including diabetes mellitus, renal disease, respiratory disease, heart disease and hypertension, as clinical predictors of death associated with MERS. In ICU case studies, the expected odds ratios (OR) of death among patients with underlying heart disease or renal disease to patients without such comorbidities were 0.6 (95% Confidence Interval (CI): 0.1, 4.3) and 0.6 (95% CI: 0.0, 2.1), respectively, while the ORs were 3.8 (95% CI: 3.4, 4.2) and 2.4 (95% CI: 2.0, 2.9), respectively, in studies with other types of designs.
  
  
  
  The heterogeneity for the risk of death and severe manifestations was substantially high among the studies, and varying study designs was one of the underlying reasons for this heterogeneity. A statistical estimation of the risk of MERS death and identification of risk factors must be conducted, particularly considering the study design and potential biases associated with case detection and diagnosis.
authors.affiliation: Graduate School of Medicine, Hokkaido University, Kita 15 Jo Nishi 7 Chome, Kita-ku, Sapporo, 060-8638, Japan.|CREST, Japan Science and Technology Agency, 4-1-8, Honcho, Kawaguchi-shi, Saitama, 332-0012, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Matsuyama
authors.affiliation: Graduate School of Medicine, Hokkaido University, Kita 15 Jo Nishi 7 Chome, Kita-ku, Sapporo, 060-8638, Japan. nishiurah@med.hokudai.ac.jp.|CREST, Japan Science and Technology Agency, 4-1-8, Honcho, Kawaguchi-shi, Saitama, 332-0012, Japan. nishiurah@med.hokudai.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishiura
authors.affiliation: Disease Control and Prevention Center, National Center for Global Health and Medicine Hospital, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kutsuna
authors.affiliation: Disease Control and Prevention Center, National Center for Global Health and Medicine Hospital, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Hayakawa
authors.affiliation: Disease Control and Prevention Center, National Center for Global Health and Medicine Hospital, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Ohmagari
mesh_terms: D015897:Comorbidity; D018352:Coronavirus Infections / Q000453:epidemiology* / Q000401:mortality; D016208:Databases, Factual; D014943:Global Health; D006801:Humans; D016017:Odds Ratio; D012307:Risk Factors; D012720:Severity of Illness Index
keywords: Ascertainment bias; Case fatality ratio; Comorbidity; Middle East respiratory syndrome