Results
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).
Characteristics of included
studies
Of the 12 studies included, eleven 16–26 investigated
the role of influenza co-infection with SARS-CoV-2 in the outcomes of
interest, and three 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 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 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 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.
Co-infection and risk of need or use of supplemental
oxygen
Four studies16,22,25,26 reported the
need or use of supplemental oxygen
as an outcome (four on influenza and one 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 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 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 22 had available data on SARS-CoV-2
co-infection with RSV; however, none of the included patients in that
study required supplemental oxygen.
Co-infection and risk of mechanical
ventilation
Six studies17,19,22,24,25,27 reported mechanical ventilation as
an outcome (all but one 27 on influenza and two
studies 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 19,25using multivariable models were consistent with our meta-estimates
although another high-quality study 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 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-quality22 study reported no patients receiving mechanical
ventilation in either group.
Co-infection and risk of admission to intensive care unit
(ICU)
Six studies18,19,22,24,25,27compared the utilisation of
intensive care between mono-infection and co-infection (all but one27 on influenza and two 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 19,25 were
in accordance with the meta-analysis results.
Two studies 22,27 investigated the SARS-CoV-2
co-infection with RSV. One moderate-quality study 27found 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 22 reported no patients being
admitted to ICU.
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 27 on influenza and three22,23,27 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 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 19 reported increased risk of death (OR:
2.27,95% CI: 1.23-4.19); in addition, another two studies24,25 (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 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).