Respiratory viral co-infections in patients with COVID-19 and associated outcomes: A systematic review and meta-analysis

Abstract

The aim of this systematic review and meta-analysis was to critically assess the published literature related to community-acquired viral co-infections and COVID-19 and to evaluate the prevalence, most identified co-pathogens, and relevant risk factors. Furthermore, we aimed to examine the clinical features and outcomes of co-infected compared to mono-infected COVID-19 patients. We systematically searched PubMed, Web of Science, Embase, Scopus, and The Cochrane Library for studies published from 1 November 2019 to 13 August 2021. We included patients of all ages and any COVID-19 severity who were screened for respiratory viral co-infection within 48 h of COVID-19 diagnosis. The main outcome was the proportion of patients with a respiratory viral co-infection. The systematic review was registered to PROSPERO (CRD42021272235). Out of 6053 initially retrieved studies, 59 studies with a total of 16,643 SARS-CoV-2 positive patients were included. The global pooled prevalence was 5.01% (95% CI 3.34%-7.27%; I² = 95%) based on a random-effects model, with Influenza Viruses (1.54%) and Enteroviruses (1.32%) being the most prevalent pathogens. Subgroup analyses showed that co-infection was significantly higher in paediatric (9.39%) than adult (3.51%) patients (p-value = 0.02). Furthermore, co-infected patients were more likely to be dyspnoeic and the odds of fatality (OR = 1.66) were increased. Although a relatively low proportion of COVID-19 patients have a respiratory viral co-infection, our findings show that multiplex viral panel testing may be advisable in patients with compatible symptoms. Indeed, respiratory virus co-infections may be associated with adverse clinical outcomes and therefore have therapeutic and prognostic implications.

Keywords: COVID-19; SARS-CoV-2; co-infection; meta-analysis; respiratory viruses.

FIGURE 1

PRISMA flow diagram indicating the screening process to identify studies reporting on respiratory viral co‐infection rates in COVID‐19 patients. Abbreviations: SARS‐CoV‐2: severe acute respiratory syndrome‐related coronavirus 2; RT PCR: reverse‐transcription polymerase chain reaction (RT‐PCR) test; Ag RDT: antigen rapid diagnostic tests; COVID‐19: coronavirus disease 2019

FIGURE 2

Forest plot of pooled prevalence of respiratory viral co‐infections (RVCI) among COVID‐19 patients according to the random effects approach. Each included study is presented by the first author and year of publication. Abbreviation: CI, confidence interval

FIGURE 3

Meta‐analysis of respiratory viral co‐infection prevalence among COVID‐19 subgroups (Figure S2–S6). Abbreviations: CI, confidence interval; SARS‐CoV‐2, Severe acute respiratory syndrome‐related coronavirus. ^aPatients under the age of 18 years. ^bSize of SARS‐CoV‐2 positive patients tested for co‐infection. ^cContinents Africa and Oceania are not demonstrated, since only one study was identified for each of them, . ^dSummer is not showed, since studies that screened COVID‐19 patients for co‐infections during the summer months overlap with the Spring or Autumn season. Studies from tropical geographic regions (N = 2 ²⁹ , ³⁰ ) have been left out because they only experience a dry and a wet season.

FIGURE 4

Prevalence and proportion of each respiratory virus identified in COVID‐19 patients. (a), Pooled prevalence of each respiratory virus identified in co‐infected COVID‐19 patients based on the number of tests performed for each pathogen. Each line segment's midpoint exhibited the prevalence estimation; the line segment length presents 95% confidence intervals. (b), Number of respiratory viral pathogens detected in COVID‐19 patients, as a proportion of the total number of detections (N = 749). Abbreviations: FLU, Human influenza virus; FLUA, Human influenza virus A; FLUB, Human influenza virus B; HPIV, Human parainfluenza virus; HPIV‐1, Human parainfluenza virus 1; HPIV‐2, Human parainfluenza virus 2; HPIV‐3, Human parainfluenza virus 3; HPIV‐4, Human parainfluenza virus 4; HCoV, Human respiratory coronavirus; HCoV‐229E, Human respiratory coronavirus 229E strain; HCoV‐NL63, Human respiratory coronavirus NL63 strain; HCoV‐OC43, Human respiratory coronavirus OC43 strain; HCoV‐HKU1, Human respiratory coronavirus HKU1 strain; HAdV, Human adenovirus; HRSV, Human respiratory syncytial virus; RV, Human rhinovirus; EV, Human enterovirus; HBoV, Human bocavirus; HMPV, Human metapneumovirus; MERS‐CoV, Middle East respiratory syndrome‐related coronavirus; HPeV, Human parechovirus