Table 1. Summary of findings for the severity of clinical disease of children with viral co-infections versus single respiratory acute illnesses.

Outcomes	Illustrative comparative risks (95% CI)		Relative effect (95%)	N of Participants (studies)	Quality of the evidence (GRADE)
	Assumed risk (Control group)	Corresponding risk (with viral co-infections)
Length of hospital stay			−0.20 days (−0.94 to 0.53)	2153 (11)	lowa , b , c , d
Oxygen requirements	319 per 1000	316 per 1000 (249 to 402 per 1000)	RR 0.99 (0.78 to 1.26)	1926 (8)	moderatee , f , g , h
ICU admission	158 per 1000	114 per 1000 (63 to 202 per 1000)	RR 0.72 (0.40 to 1.28)	1093 (7)	lowi , j , k , l
Mortality	74 per 1000	181 per 1000 (64 to 511)	RR 2.44 (0.86 to 6.91)	796 (5)	lowm , n , o
Mechanical Ventilation	472 per 1000	746 per 1000 (288 to 1000)	RR 1.58 (0.61 to 4.13)	285 (3)	lowp , q , r , s

Note: N = number, CI = confidence interval, GRADE [31] = Grading of Recommendations Assessment, Development and Evaluation, RR = risk ratio, SD = standard deviation, CI = confidence interval.

GRADE Working Group grades of evidence.

High quality: Further research is very unlikely to change our confidence in the estimate of effect.

Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Very low quality: We are very uncertain about the estimate.

^aSerious design limitations: Eight [15], [19], [21], [32], [22], [35], [23] [24] of the eleven studies had serious design limitations including the absence of notification or adjustment for important prognostic factors and the absence of evidence provided on the similarity of co-interventions between both groups.

^bSerious Inconsistency: There was high statistical heterogeneity (I² = 72%, p<0.001), which was not explained on further subgroup analysis.

^cSerious indirectness of the comparison: Only three [33] [19] [24] of the eleven studies focused primarily on the comparison of disease severity between single vs viral co-infections.

^dNo serious imprecision: The assumption of our a priori hypothesis of no difference was met. Cumulative sample size was appropriate. The optimal information size to detect a 1-day difference in LOS (alpha 0.05, 90% power) assuming a mean of 4 days (standard deviation 2 days) was 85 subjects per group. The number of subject exceeded this number. The 95% CI interval was narrow and it did not cross the minimally important difference of 1 day although it included the null effect.

^eSerious limitations in design. All the eight studies had serious design limitations including the absence of notification or adjustment for important prognostic factors and the absence of evidence provided on the similarity of co-interventions between both groups.

^fModerate inconsistency: There was moderate statistical heterogeneity (I² = 47%, p = 0.06), which was not explained on further subgroup analysis.

^gNo serious indirectness: Three [21] [15] [23] of the eight studies included did not focus primarily on the comparison of disease severity between single vs viral co- infections.

^hNo serious imprecision: Cumulative sample size was appropriate. The 95% CI interval was narrow and included the null effect as predicted in our a priori hypothesis.

ⁱSerious design limitations: All but one [34] of the seven studies of had very serious design limitations including the absence of notification or adjustment for important prognostic factors and the absence of evidence provided on the similarity of co-interventions between both groups.

^jSerious inconsistency: There was high statistical heterogeneity (I² = 53%, p = 0.05), which was not explained on further subgroup analysis.

^kNo serious indirectness: Three [21] [23] [24] of the seven studies included did not focus primarily on the comparison of disease severity between single vs viral co-infections.

^lNo serious imprecision: Cumulative sample size was appropriate. The 95% CI interval was narrow and included the null effect as predicted in our a priori hypothesis.

^mSerious design limitation: all five studies had serious design limitations including the absence of notification or adjustment for important prognostic factors and the absence of evidence provided on the similarity of co-interventions between both groups.

ⁿSerious indirectness: Two [16] [15] of the five studies included did not focus primarily on the comparison of disease severity between single vs viral co-infections.

^oThere was no serious imprecision: Adequate cumulative sample size, the 95%CI included the null effect as predicted in our a priori hypothesis although the 95%CI were wide.

^pSerious design limitations: Two of the three studies [17] [23] had serious design limitations including the absence of notification or adjustment for important prognostic factors and the absence of evidence provided on the similarity of co-interventions between both groups.

^qSerious Inconsistency: There was high statistical heterogeneity (I² = 75%, p = 0.05), which was not explained on further subgroup analysis.

^rSerious indirectness as two [34] [23] of the three studies did not primarily focus on the comparison between single vs viral co-infections.

^sSerious imprecision: Although the a priori hypothesis of no effect was met, serious imprecision was attributed to the inadequate cumulative sample size and large CI.