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\begin{document}

\title{The role of respiratory co-infection with influenza or respiratory
syncytial virus in the clinical severity of COVID-19 patients: a
systematic review and meta-analysis}



\author[1]{bingbng cong}%
\author[1]{shuyu deng}%
\author[1]{xin wang}%
\author[1]{You Li}%
\affil[1]{Nanjing Medical University}%


\vspace{-1em}



  
  \date{May 27, 2024}


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\selectlanguage{english}
\begin{abstract}
Aim: To understand the impact of influenza/RSV co-infection on clinical
disease severity among COVID-19 patients. Methods: We conducted a
systematic literature review of publications comparing the clinical
severity between the co-infection group (i.e., influenza/RSV with
SARS-CoV-2) and mono-infection group (i.e., SARS-CoV-2), using the
following four outcomes: need or use of supplemental oxygen, intensive
care unit (ICU) admission, mechanical ventilation and deaths. We
summarized the results by clinical outcome and conducted random-effect
meta-analyses, where applicable. Results: Twelve studies reporting a
total of 7862 COVID-19 patients were included in the review. Influenza
and SARS-CoV-2 co-infection was found to be associated with a higher
risk of ICU admission (5 studies, OR: 2.09, 95\% CI: 1.64-2.68) and
mechanical ventilation (5 studies, OR: 2.31, 95\% CI: 1.10-4.85). No
significant association was found between influenza co-infection and
need/use of supplemental oxygen or deaths among COVID-19 patients (4
studies, OR: 1.04, 95\% CI: 0.37-2.95; 11 studies, OR: 1.41, 95\% CI:
0.65-3.08, respectively). For RSV co-infection, data were only
sufficient to allow for analyses for the outcome of deaths, and no
significant association was found between RSV co-infection and deaths
among COVID-19 patients (3 studies, OR: 5.27, 95\% CI: 0.58-47.87).
Conclusions: Existing evidence suggests that co-infection with influenza
might be associated with a 2-fold increase in the risk for ICU admission
and for mechanical ventilation among COVID-19 patients whereas evidence
is limited on the role of RSV co-infection. Co-infection with influenza
does not increase the risk of death in COVID-19 patients.%
\end{abstract}%



\sloppy


\section*{Introduction}

{\label{introduction}}

Coronavirus disease 2019 (COVID-19), caused by the severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global
pandemic and public health concern \textsuperscript{1}. Despite the
rollout of vaccination programs and implementation of non-pharmaceutical
interventions (NPIs), the number of infected cases kept rising rapidly
particularly after the emergence of the delta variant and recently, the
emergence of the omicron variant. Globally, as of March 17, 2022, there
have been over 460 million COVID-19 cases and over 6 million deaths
\textsuperscript{2}.

Both influenza and respiratory syncytial virus (RSV) are the most common
respiratory viruses mainly affecting young children and older adults,
especially in low and middle income countries
(LMICs)\textsuperscript{3--7}. Globally, it is estimated that in the
year of 2016, influenza and RSV were associated with 39 and 25 million
acute lower respiratory infection episodes, and 58,000 and 77,000
deaths, respectively \textsuperscript{8}. In most temperate regions,
influenza and RSV normally circulates in autumn and winter
months\textsuperscript{9}. During the COVID-19 pandemic, the activity of
both viruses was low early on due to the large-scale implementation of
NPIs but then the resurgence of RSV epidemic was observed in a number of
countries globally since late 2020\textsuperscript{10}, followed by the
resurgence of influenza epidemic in the winter of 2021
\textsuperscript{11}. While there is no doubt that the comeback of
influenza and RSV will pose greater pressures on health-care providers
who are already over-stretched in response to the COVID-19 pandemic, it
is not yet known for individual COVID-19 patients, whether co-infection
of influenza or RSV could further increase their clinical severity.

In the present study, we aimed to systematically and critically review
the existing evidence on the impact of co-infection with influenza or
RSV on disease severity in COVID-19 patients.

\section*{Methods}

{\label{methods}}

\subsection*{Search strategy and selection
criteria}

{\label{search-strategy-and-selection-criteria}}

This systematic review was reported according to the Preferred Reporting
Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline (Text
S1) and Synthesis without meta-analysis in systematic reviews (SWiM)
reporting guideline (Text S2). The protocol of this review was
registered in International Prospective Register of Systematic Review
(PROSEPRO) with registration number CRD42021283045. We searched the
following electronic databases: MEDLINE, EMBASE, Web of Science, the WHO
COVID-19 Global literature on coronavirus disease database, China
National Knowledge Infrastructure (CNKI), WanFang, CqVip, and Sinomond
for relevant publications from January 1, 2020 to December 31, 2021
using a tailored search strategy (Text S3). No restrictions on language
were applied. The reference lists of eligible studies were also examined
for eligibility. The following selection criteria were applied.

\subsubsection*{Inclusion criteria}

{\label{inclusion-criteria}}

Population-based studies reporting any laboratory-confirmed
co-infections with influenza or RSV in COVID-19 patients; AND

At least one of the following outcomes should be reported separately in
co-infection group (i.e., SARS-CoV-2 and influenza / RSV) and
mono-infection group (i.e., SARS-CoV-2): need or use of supplemental
oxygen, ICU admission, mechanical ventilation (including invasive and
non-invasive ventilation) and deaths.

\subsubsection*{Exclusion criteria}

{\label{exclusion-criteria}}

\begin{itemize}
\tightlist
\item
  Studies that focused on reporting nosocomial infections; OR
\item
  Studies that only included patients with comorbidities (e.g., patients
  with chronic obstructive pulmonary disease, or patients infected with
  human immunodeficiency virus) OR
\item
  Reviews or studies reporting data that were previously reported by
  another study (in which case only the primary studies were considered
  for inclusion).
\end{itemize}

\subsection*{Systematic literature
review}

{\label{systematic-literature-review}}

Two reviewers (BC and SD) independently screened titles, abstracts and
full-texts of the retrieved records from the literature search, and
extracted data using tailored data extraction template. The data
extraction template consisted of two parts: the first part collected
study-level characteristics such as the study location, period, number
of subjects, age of subjects, statistical method, disease severity
outcomes reported, clinical specimens, viral diagnostic techniques and
so on; the second part collected data on the clinical outcomes by mono-
infection group and co-infection group. Any discrepancies during data
screening and extraction were resolved among YL, BC and SD.

\subsection*{Quality assessment}

{\label{quality-assessment}}

Quality assessment was conducted for all included studies independently
by two reviewers (BC and SD). The questionnaire used for the quality
assessment was modified based on the Critical Appraisal Skills Programme
(CASP) checklist for cohort studies\textsuperscript{12}. The modified
questionnaire contained the following seven questions: 1. Did the study
address a clearly focused issue?, 2. Were the subjects recruited in an
acceptable way?, 3. Was the exposure accurately measured to minimize
bias?, 4. Was the outcome accurately measured to minimize bias?, 5. Have
the authors used multivariable analysis method to adjust for
confounders?, 6. Can the results be applied to the local population?, 7.
Do the results of this study fit with other available evidence? The
questionnaire contained seven questions and answer to each of the
questions could be ``Yes'', ``No'', or ``Can't tell'', corresponding to
1, 0 and 0 points, respectively. We calculated the overall score for
each study after assessing each criterion as listed above. Studies with
7, 5-6 and [?]4 points were defined as ``high quality'', ``moderate
quality'' and ``low quality'', respectively. Any discrepancies during
quality assessment were resolved among YL, BC and SD.

\subsection*{Data analysis}

{\label{data-analysis}}

A narrative synthesis was conducted for all outcomes of interest. The
outcomes were compared between the mono-infection group and the
co-infection group. A random-effect meta-analysis of the corresponding
odds ratios was conducted if three or more studies were available per
comparison (i.e., influenza and SARS-CoV-2 co-infection vs SARS-CoV-2
mono-infection, and RSV and SARS-CoV-2 co-infection vs SARS-CoV-2
mono-infection). The choice of conducting a random-effect meta-analysis
(rather than fixed-effect meta-analysis) was based on the anticipation
that populations included in the studies differed by region, age, study
period (in relation to the COVID-19 pandemic), clinical specimens and
diagnostic methods. We applied a continuity correction of 0.5 if no one
had severity outcomes in any group \textsuperscript{13}. This allowed
calculation of an OR for these instances, and enabled inclusion within
subsequent meta--analyses. When odds ratios could be obtained both from
univariate analysis and multivariate analysis in a report, the one from
the multivariate analysis was included in the meta-analysis. For
influenza and SARS-CoV-2 co-infection, the subgroup analysis was
conducted by influenza type (i.e., influenza A and influenza B) if data
allowed. Sensitivity analyses excluding studies with small sample sizes
(defined as [?] 5 subjects in any of the mono-infection and co-infection
groups) and excluding those low-quality studies were performed. Symmetry
of funnel plot and Egger's regression method were used to evaluate the
presence of small study effects \textsuperscript{14}. Heterogeneity was
evaluated by I\textsuperscript{2} values; I\textsuperscript{2} value of
\textgreater{}50\% and \textgreater{}75\% suggested moderate and high
heterogeneity, respectively \textsuperscript{15}. All statistical
analyses and data visualizations were performed with R version 4.1.0.

\section*{Results}

{\label{results}}

\subsection*{Review process}

{\label{review-process}}

After elimination of duplicates, 1591 records were assessed by title and
abstract, of which 164 records were further assessed by full-text.
Finally, a total of 12 studies were included (Figure 1).

\subsection*{Characteristics of included
studies}

{\label{characteristics-of-included-studies}}

Of the 12 studies included, eleven \textsuperscript{16--26} investigated
the role of influenza co-infection with SARS-CoV-2 in the outcomes of
interest, and three \textsuperscript{22,23,27} investigated the role of
RSV co-infection with SARS-CoV-2. The included studies represented 955
laboratory-confirmed COVID-19 patients coinfected with influenza or RSV
and 6907 patients infected with SARS-CoV-2 mono-infection. All studies
reported deaths as one of the outcomes of interest; four, six and six
studies reported the outcomes of need or use of supplemental oxygen,
mechanical ventilation and ICU admission, respectively.

All studies were conducted in inpatient settings except one study
\textsuperscript{19} with mixed settings (i.e., inpatients, emergence
department and outpatients). Subject age varied greatly across the
included studies and was reported in various statistical forms (e.g.,
frequency by age group, mean and standard deviation, median, etc.). The
total number of SARS-CoV-2 coinfected with influenza/RSV and
mono-infected patients per study ranged from 22 to 4501. The included
studies were mainly conducted in Asia (9/10), among which six
\textsuperscript{16,17,21--23,25} were from China. For viral detection
method, SARS-CoV-2 was detected using PCR for all studies whereas
influenza and / or RSV co-infection was confirmed by PCR, serological
testing or antigen assays. The quality assessment of included studies is
provided in Table S1. Four studies \textsuperscript{16,17,19,25} were
assessed as high-quality and they used multivariate statistical methods
to account for common confounders such as age, sex, and comorbidities.
The basic characteristics of the included studies are available in Table
1.

\subsection*{Co-infection and risk of need or use of supplemental
oxygen}

{\label{co-infection-and-risk-of-need-or-use-of-supplemental-oxygen}}

Four studies\textsuperscript{16,22,25,26} reported the need or use of
supplemental oxygen as an outcome (four on influenza and one
\textsuperscript{22} on RSV co-infection).

Our meta-analysis results showed that SARS-CoV-2 co-infection with
influenza did not seem to be associated with increased need or use of
supplemental oxygen compared with SARS-CoV-2 mono-infections (OR=1.04,
95\% CI: 0.37-2.95) (Figure 2, panel A). When excluding studies with
small sample size or low-quality studies, the meta-estimates did not
differ substantially from the main analyses (Figure S1, panel A; Figure
S2, panel A). SARS-CoV-2 co-infection with influenza A virus was also
not observed to be associated with increased need or use of supplemental
oxygen (OR=1.28, 95\% CI: 0.36-4.53) (Figure 2, panel B). Two
high-quality studies showed contrasting findings: one study
\textsuperscript{16} showed SARS-CoV-2 co-infection with influenza A
virus was associated with decreased need or use of supplemental oxygen
(OR=0.61, 95\% CI: 0.48-0.76) whereas no such difference was observed on
SARS-CoV-2 co-infection with influenza B virus (OR=0.97, 95\% CI:
0.56-1.67); the other study \textsuperscript{25} showed that SARS-CoV-2
co-infection with influenza was associated with increased need or use of
supplemental oxygen (OR=2.47, 95\%CI: 1.04-5.86).

Only one study \textsuperscript{22} had available data on SARS-CoV-2
co-infection with RSV; however, none of the included patients in that
study required supplemental oxygen.

\subsection*{Co-infection and risk of mechanical
ventilation}

{\label{co-infection-and-risk-of-mechanical-ventilation}}

Six studies\textsuperscript{17,19,22,24,25,27} reported mechanical
ventilation as an outcome (all but one \textsuperscript{27} on influenza
and two studies \textsuperscript{22,27} on RSV co-infection).

Based on the meta-analysis results, SARS-CoV-2 co-infection with
influenza was found to be associated with a higher risk of mechanical
ventilation as compared to SARS-CoV-2 mono-infection (OR=2.31, 95\% CI:
1.10-4.85) (Figure 3, panel A). SARS-CoV-2 co-infection with influenza A
virus was also associated with a higher risk mechanical ventilation
(OR=5.04, 95\% CI: 2.19-11.62) (Figure 3, panel B). After excluding
low-quality studies, a similar meta-estimate was observed (Figure S2,
panel B). Results from two high-quality studies
\textsuperscript{19,25}using multivariable models were consistent with
our meta-estimates although another high-quality study
\textsuperscript{17} showed no significant difference in receiving
mechanical ventilation between the two groups.

Regarding the SARS-CoV-2 co-infection with RSV, one moderate-quality
study \textsuperscript{27} indicated that the co-infection was not
associated with increased risk of mechanical ventilation (OR=5.00, 95\%
CI: 0.27-93.96) in children under two years old. The other
low-quality\textsuperscript{22} study reported no patients receiving
mechanical ventilation in either group.

\subsection*{Co-infection and risk of admission to intensive care unit
(ICU)}

{\label{co-infection-and-risk-of-admission-to-intensive-care-unit-icu}}

Six studies\textsuperscript{18,19,22,24,25,27}compared the utilisation
of intensive care between mono-infection and co-infection (all but
one\textsuperscript{27} on influenza and two \textsuperscript{22,27} on
RSV co-infection).

Based on the meta-analysis results, SARS-CoV-2 co-infection with
influenza was associated with a higher risk of ICU admission compared
with SARS-CoV-2 mono-infection (OR=2.09, 95\% CI: 1.64-2.68) (Figure 4,
panel A). Sensitivity analysis revealed a similar meta-estimate when
excluding low-quality studies (Figure. S2, panel C). SARS-CoV-2
co-infection with influenza A virus was also associated with a higher
risk of ICU admission (OR=2.11, 95\% CI: 1.61-2.76) (Figure 4, panel B).
Results from the two high-quality studies \textsuperscript{19,25} were
in accordance with the meta-analysis results.

Two studies \textsuperscript{22,27} investigated the SARS-CoV-2
co-infection with RSV. One moderate-quality study
\textsuperscript{27}found no significant difference in ICU admission
(OR: 2.40, 95\% CI: 0.18-31.88) between mono- and co-infection groups.
Another one low-quality study \textsuperscript{22} reported no patients
being admitted to ICU.

\subsection*{Co-infection and risk of
death}

{\label{co-infection-and-risk-of-death}}

All studies included in our review reported the proportion of deaths in
mono- and co-infection groups (all but one \textsuperscript{27} on
influenza and three\textsuperscript{22,23,27} on RSV co-infection).

For SARS-CoV-2 co-infection with influenza, the meta-analysis results
showed that the co-infection was not associated with increased risk of
death compared with SARS-CoV-2 mono-infection (OR=1.41, 95\% CI:
0.65-3.08) (Figure 5, panel A). Sensitivity analyses that excluded
studies with small sample size and low-quality studies showed similar
meta-estimates (Figure S1, panel B; Figure S2, panel D). Similar results
were also found in subgroup analysis by co-infection of influenza A and
B virus (Figure 5, panel B, C). Findings from high-quality studies
showed contrasting results: two studies \textsuperscript{16,17} reported
decreased risk of death in co-infection group (OR=0.51, 95\% CI:
0.36-0.73; OR=0.26, 95\% CI: 0.07-0.95, respectively) whereas another
study \textsuperscript{19} reported increased risk of death (OR:
2.27,95\% CI: 1.23-4.19); in addition, another two
studies\textsuperscript{24,25} (moderate-quality and high-quality,
respectively) reported no differences in risk of death between the two
groups (OR=4.61,95\% CI: 0.98-21.67; OR=21.09, 95\% CI: 0.84-527.66,
respectively).

With respect to SARS-CoV-2 co-infection with RSV, three lower-quality
studies \textsuperscript{22,23,27} reported very small number of
coinfected patients (range: 1-6). Our meta-analysis results suggested
that no significant association was found between the co-infection
status and death (OR=5.27, 95\% CI: 0.58-47.87) (Figure 5, panel D).

\section*{Discussion}

{\label{discussion}}

In this systematic review and meta-analysis, we included 955
laboratory-confirmed COVID-19 patients coinfected with influenza or RSV
and 6907 patients infected with SARS-CoV-2 alone from 12 retrospective
observational studies. We found that co-infection with influenza was
associated with a 2-fold increase in the risk for ICU admission and for
mechanical ventilation among COVID-19 patients whereas evidence was
limited on the role of RSV co-infection. Co-infection with influenza did
not seem to increase the risk of death in COVID-19 patients.

The 2-fold increase in the risk of ICU admission and receiving
mechanical ventilation in COVID-19 patients coinfected with influenza
could have important implications for the clinical management. COVID-19
patients who received influenza positive tests before or upon admission
might benefit from early interventions that could prevent or slow
disease deterioration. This also highlights the importance of influenza
vaccination program that might have been suspended because of the
COVID-19 pandemic\textsuperscript{28}.

Earlier systematic reviews that compared co-infections of any viruses
(rather than co-infection of influenza as used in this study) with
mono-infection among COVID-19 patients did not observe any statistical
differences in ICU admission between the co-infection and mono-infection
groups \textsuperscript{29--31}. This suggests that the increased risk
of ICU admission in the co-infection group observed in our study was
likely to be influenza-specific. One of the possible explanations is
that influenza co-infection could predispose patients to secondary
bacterial infections, which could lead to more severe clinical
outcomes\textsuperscript{32,33}. This explanation is supported by a
recently published study in Israel that observed substantial reductions
in pneumococcal diseases in young children during the COVID-19 pandemic;
the authors showed that the reductions in pneumococcal and
pneumococcus-associated diseases were not predominantly related to
reduced pneumococcal carriage and density but were strongly associated
with the disappearance of specific respiratory viruses such as
influenza\textsuperscript{34}. The role of influenza co-infection in the
increased severity of COVID-19 patients was also supported by influenza
probe studies. In a large Brazilian cohort study of over 53,000 COVID-19
patients, those who received a recent influenza vaccine had 7\% lower
risks of requiring intensive care treatment (95\% CI: 2\% to 13\%) and
17\% lower risks of requiring invasive respiratory support (95\% CI:
12\% to 23\%)\textsuperscript{35}. Moreover, a recently published animal
model study found that simultaneous or sequential co-infection by
SARS-CoV-2 and the influenza A(H1N1)pdm09 strain caused more severe
disease than mono-infection by either virus in hamsters
\textsuperscript{36}.

However and interestingly, a systematic review and meta-analysis by Guan
and colleagues reported that influenza co-infection lowered the risk for
critical outcomes (composite outcomes including any of shock, being
admitted to ICU and requiring ventilatory support), with the pooled OR
of 0.64 (0.43 to 0.97) based on five studies \textsuperscript{37}. As
this was contrary to the findings of our study, we closely compared the
methodology and the extractions between our study and that by Guan and
colleagues; in addition to the use of the composite outcomes as
mentioned above that differed from our study, the meta-estimate by Guan
and colleagues was largely driven by a preprint that only had univariate
OR available for extraction. Moreover, there seemed to be a discrepancy
in the extracted OR in the study by Guan and colleagues --- one of the
included studies, by Stowe and colleagues, \textsuperscript{19} reported
that COVID-19 patients with influenza co-infection were around twice as
likely to be ventilated (OR 2.15, 1.20 to 3.84) or to be admitted to ICU
(OR 2.08, 1.17 to 3.70) through multivariate analysis whereas the OR was
extracted as 0.91 (0.41 to 2.02) in the report by Guan and colleagues.
After removing the preprint and correcting the extraction above from the
included studies by Guan and colleagues, the updated OR in their study
reversed --- 1.76 (1.06 to 2.92), which re-confirmed the robustness of
the meta-estimates in our study (details are provided in Figure S4).

Our meta-analysis revealed that co-infection with SARS-CoV-2 and
influenza had no observable effects on the overall mortality in both the
main and the two sensitivity analyses (i.e., excluding studies with
small sample size and excluding low-quality studies). Nonetheless, these
findings did not yet indicate that co-infection of influenza did not
increase the risks of mortality. We could not rule out type II error
(i.e., false negative) due to the limited statistical power; most
studies had less than 50 COVID-19 patients with co-infections and the
median number of deaths is 1 (IQR: 0-4). Moreover, the point estimates
from the main and sensitivity analyses were consistently above 1,
favouring the association between influenza co-infection and mortality.

Similar to influenza co-infection, no effects on the overall mortality
were observed for RSV co-infection but this was only based on three
small studies. Our review highlighted the gaps in the knowledge on the
role of RSV co-infection in COVID-19 disease severity. A retrospective
study among six children's hospitals in the United States revealed that
one in six COVID-19 inpatients under 18 years old had viral
co-infections, with two thirds of viral co-infections being RSV
co-infections; the proportion of viral co-infections was even higher in
infants under one year --- one in three infants hospitalized for
COVID-19 had viral co-infections, with almost three quarters of them
having RSV co-infections \textsuperscript{38}. The substantial
proportion of RSV co-infection among paediatric COVID-19 patients calls
for further research on the possible synergistic effects of the RSV and
SARS-CoV-2 in this vulnerable age group.

At the time of writing of this manuscript, a large-scale study from the
UK (including about 7000 COVID-19 patients) was published, which
reported that that influenza co-infection was associated with increased
odds of receiving invasive mechanical ventilation among COVID-19
patients (OR: 4.1, 2.0 to 8.5) in a multivariable regression analysis,
further confirming the findings of our study\textsuperscript{39}. The
authors of that study did not find any significant associations for
co-infection with other viruses including adenovirus and RSV, confirming
our speculation that the association on viral co-infection and COVID-19
clinical severity is specific to influenza. Ad-hoc inclusion of the
estimates from that study did not substantially change our
meta-estimates (Table S2).

We acknowledge some limitations of this study. Several factors could
contribute to heterogeneity in the findings of the studies, such as
study population (including age and sex), case definition, laboratory
method and statistical method; we were unable to explicitly account for
these variations. In the present review, there were only four studies
applying multivariate analyses to adjust for common confounders between
co-infections and severity outcomes. Although restricting to these
high-quality studies did not substantially change any of our findings,
this highlighted the lack of high-quality studies on the role of
co-infections and COVID-19 disease severity. We were also unable to
account for bacterial co-infection in the analysis due to the absence of
data that had reliable laboratory confirmation on viral and bacterial
infections. Compared with other outcomes, mortality as the proxy for
disease severity was more likely to be affected by variations in
clinical treatment, which could confound the estimates if treatment
differed by status of co-infection. All of the included studies were
conducted in 2020 when the activity of influenza and RSV was on the
course to gradual reduction; it remains unknown whether the resurgence
of influenza and RSV could modify the association reported in this
review.

Despite these limitations, this systematic review and meta-analysis
includes a comprehensive summary with extensive literature search, and
critical appraisal and synthesis of existing evidence on the role of
influenza and RSV co-infection in the clinical severity of COVID-19
patients. While our study highlights the gaps in research on this topic
particularly for RSV, existing evidence suggests that influenza
co-infection could increase the disease severity of COVID-19 patients,
which could have important implications for clinical management as well
as influenza vaccination campaign in the context of resurgence of
influenza among other respiratory viruses in the post-COVID-19 era.

\textbf{Competing interests:} YL reported grants from the World Health
Organization and Wellcome Trust, outside the submitted work. All other
authors declared that they have no competing interests.

\textbf{Funding:} This work receive1234-d support from the Nanjing
Medical University Talents Start-up Grants (NMUR20210008).

\textbf{Access to data:} The study data are available from the
corresponding author upon reasonable request.

\textbf{Authorship contribution:} BC -- led data extraction, analysis
and interpretation and wrote the manuscript;SD -- contributed to data
extraction and quality assessment; XW -- contributed to interpretation
and critically reviewed the manuscript; YL -- conceptualised the study,
provided critical oversight to data extraction, analysis and
interpretation and critically reviewed the manuscript. The corresponding
author (YL) had full access to all the data in the study and was
responsible for the decision to submit the manuscript for publication.

\textbf{ORCID:\emph{https://orcid.org/0000-0002-5929-7721}}

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\textbf{Figures and Tables:}

\par\null

Figure 1. PRISMA diagram for selection of studies.

Figure 2. Comparison of risk for need or use of supplemental oxygen
between SARS-CoV-2 co-infection with influenza and SARS-CoV-2
mono-infection. N-the total number of SARS-CoV-2 coinfected and
mono-infected patients; QA-the score of quality assessment.

Figure 3. Comparison of risk for mechanical ventilation between
SARS-CoV-2 co-infection with influenza and SARS-CoV-2 mono-infection.
N-the total number of SARS-CoV-2 coinfected and mono-infected patients;
QA-the score of quality assessment.

Figure 4. Comparison of risk for ICU admission between SARS-CoV-2
mono-infection and A) SARS-CoV-2 co-infection with influenza, B)
SARS-CoV-2 co-infection with influenza A virus. N-the total number of
SARS-CoV-2 coinfected and mono-infected patients; QA-the score of
quality assessment.

Figure 5. Comparison of risk for death between SARS-CoV-2 mono-infection
and A) SARS-CoV-2 co-infection with influenza, B) SARS-CoV-2
co-infection with influenza A virus, C) SARS-CoV-2 co-infection with
influenza B virus, D) SARS-CoV-2 co-infection with RSV. N-the total
number of SARS-CoV-2 coinfected and mono-infected patients; QA-the score
of quality assessment.

Table 1. Characteristics of included studies.

ER = emergency room; IP = inpatient; OP = outpatient; NPS=Nasopharyngeal
swab; OPS=Oropharyngeal swab; BLF=Bronchoalveolar lavage fluid;
BAF=bronchial aspiration fluid; NPS=nasopharyngeal aspirate; NA= not
available; RT-PCR = Reverse transcription polymerase chain reaction; DFA
= direct immunofluorescence assay; IFA = indirect immunofluorescence
assay; CL = chemiluminescence; CIA = chromatographic immunoassay; Number
of subjects = the total number of SARS-CoV-2 coinfected with
influenza/RSV and mono-infected patients; O2=oxygen; MV= mechanical
ventilation; ICU = intensive care unit; IQR = interquartile range; SD =
standard deviation; y=years; m=month.

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