Immunostimulants for preventing respiratory tract infection in children

Blanca Estela Del‐Rio‐Navarro; Francisco J Espinosa‐Rosales; Vicki Flenady; Juan JL Sienra‐Monge

doi:10.1002/14651858.CD004974.pub2

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Figure 1

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 3

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Figure 4

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Figure 5

Forest plot of comparison: Any IS compared with placebo, outcome: 1.1 Mean number of ARTIs.

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Figure 6

Forest plot of comparison: Any IS compared with placebo, outcome: 1.2 Per cent difference in ARTIs.

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Figure 7

Forest plot of comparison: OM‐85 trials, outcome: 6.2 Per cent difference in ARTIs.

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Figure 8

Forest plot of comparison: D53 trials, outcome: 7.2 Per cent difference in ARTIs.

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Analysis 1.1

Comparison 1 Any IS compared with placebo, Outcome 1 Mean number of ARTIs.

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Analysis 1.2

Comparison 1 Any IS compared with placebo, Outcome 2 Percent difference in ARTIs.

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Analysis 2.1

Comparison 2 Bacterial IS compared with placebo, Outcome 1 Mean number of ARTIs.

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Analysis 2.2

Comparison 2 Bacterial IS compared with placebo, Outcome 2 Percent difference in ARTIs.

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Analysis 3.1

Comparison 3 Bacterial IS trials with n equal to or greater than 40 compared with placebo, Outcome 1 Mean number of ARTIs.

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Analysis 3.2

Comparison 3 Bacterial IS trials with n equal to or greater than 40 compared with placebo, Outcome 2 Percent difference in ARTIs.

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Analysis 4.1

Comparison 4 Bacterial IS trials with n equal to or greater than 40 only OM‐85 and BV D53 compared with placebo, Outcome 1 Mean number of ARTIs.

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Analysis 4.2

Comparison 4 Bacterial IS trials with n equal to or greater than 40 only OM‐85 and BV D53 compared with placebo, Outcome 2 Percent difference in ARTIs.

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Analysis 5.1

Comparison 5 Adverse events, Outcome 1 Gastrointestinal adverse events.

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Analysis 5.2

Comparison 5 Adverse events, Outcome 2 Skin adverse events.

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Analysis 6.1

Comparison 6 OM‐85 trials, Outcome 1 Mean number of ARTIs.

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Analysis 6.2

Comparison 6 OM‐85 trials, Outcome 2 Percent difference in ARTIs.

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Analysis 7.1

Comparison 7 D53 trials, Outcome 1 Mean number of ARTIs.

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Analysis 7.2

Comparison 7 D53 trials, Outcome 2 Percent difference in ARTIs.

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Summary of findings for the main comparison. Summary of findings table

Any immunostimulant (IS) compared with placebo for preventing respiratory tract infection in children
Patient or population: children (age < 18 years) susceptible to acute respiratory tract infections (ARTIs) Settings: outpatient Intervention: any IS Comparison: placebo
Outcomes	Illustrative comparative risks' (95% CI)		No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Any IS
Number of ARTIs	The range of ARTIs in the control group was 0.92 to 6.2	The mean Number of ARTIs in the intervention groups was 1.24 lower (0.94 to 1.54 lower)	4060 (35 studies)	⊕⊕⊕⊖ moderate¹	The effect depends on the number of ARTIs in the control group
Percent difference in ARTIs		The mean Percent difference in ARTIs in the intervention groups was 39 lower (31.31 to 46.37 lower)	4060 (35 studies)	⊕⊕⊕⊖ moderate^1,2
Incidence of gastrointestinal adverse events	21 per 1000	30 per 1000 (11 to 50 per 1000)	1457 (10 studies)	⊕⊕⊖⊖ low^1,3
Incidence of skin adverse events	3 per 1000	7 per 1000 (‐8 to 14 per 1000)	1469 (10 studies)	⊕⊕⊖⊖ low^1,3
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio; OR: odds ratio
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.
¹Funnel plot shows possible publication bias, risk of bias in the studies moderate, and high heterogeneity among studies. A group of six studies with good quality point to the benefit of IS. ² Heterogenity decreased with calculation of percent difference ARTIs. ³ Adverse events were reported only in 10 trials; selective outcome reporting

Summary of findings for the main comparison. Summary of findings table

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Table 1. Trade and common names of IS used for prevention of ARIs

Trade name	Common name	Active ingredient
Adimod	Pidotimod	Pidotimod
Allicor	Not available	Garlic extract
Biostim	RU41740	Glycoprotein and membranes of Klebsiella pneumoniae
Broncho‐Vaxom, Broncho‐Munal, Ommunal	OM‐85 or OM‐85 BV	Lyophilised bacterial lysates
Chizukit	Not available	Preparation of Echinacea purpurea, propolis and vitamin C
Decaris	Levamisole	Levamisole
Echinacea	Echinacea purpurea	Extract of Echinacea purpurea
Immunoferon, Inmunol	AM3	Glycophosphopeptical
IRS 19	Not available	Bacterial lysates
Ismigen	Not available	Bacterial lysates
Lantigen B	Not available	Bacterial antigens
Leucotrofina, Leucogen	Thymomodulin	Thymus extract
Luivac	LW50020	Bacterial antigens
Munostin	Not available	Bacterial corpses and lysates
Not available	SL04	Bacterial extracts
Paspat	Not available	Autolysate mixture of bacterial antigens for parenteral application
Prasosine	Isoprinosine	Isoprinosine
Pulmotabs	Not available	Bacterial lysates
Pulmonarom	Not available	Bacterial lysates
Reaferon	Not available	Analogue of human interferon 2 obtained by genetic engineering
Respivax	Not available	Bacterial lysates
Ribovac, Ribomunyl, Immucithal	D53	Proteoglycans of K. pneumoniae plus bacterial ribosomes
TFX	Thymus extract	Thymus extract
Umckaloabo	Pelargonium sidoides	Alcohol extract from the roots of Pelargonium sidoides

Table 1. Trade and common names of IS used for prevention of ARIs

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Table 2. Description of the studies

Immunostimulant	n	n analysis data	Duration < 6 months	Duration 6 months	Duration > 6 months	Quality A	Quality B	Quality C	Quality D
D53	18	11	7	11	‐	‐	18	‐	‐
IRS19	1	0	‐	1	‐	‐	‐	1	‐
Lantigen B	2	0	‐	2	‐	‐	2	‐	‐
LW50020	2	0	2	‐	‐	‐	2	‐	‐
OM‐85 BV	12	9	‐	10	2	4	8	‐	‐
RU41740	5	5	‐	3	2	‐	5	‐	‐
Total bacterial	40	25	9	27	4	4	35	1	‐
Herbal (echinacea/garlic)	4	1	2	1	1	2	2	‐	‐
Isoprinosine	1	1	‐	1	‐	‐	1	‐	‐
Levamisole	4	3	2	2	‐	‐	4	‐	‐
Pidotimod	6	2	6	‐	‐	‐	6	‐	‐
Total synthetic	11	6	8	3	‐	‐	11	‐	‐
Thymic extract	5	3	4	‐	1	‐	5	‐	‐
Synthetic interferon	1	0	1	‐	‐	‐	1	‐	‐
Grand total	61	35	24	31	6	6	53	2	‐

Table 2. Description of the studies

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Comparison 1. Any IS compared with placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mean number of ARTIs Show forest plot	35	4060	Mean Difference (IV, Random, 95% CI)	‐1.24 [‐1.54, ‐0.94]

2 Percent difference in ARTIs Show forest plot	35	4060	Mean Difference (IV, Random, 95% CI)	‐38.84 [‐46.37, ‐31.31]

Comparison 1. Any IS compared with placebo

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Comparison 2. Bacterial IS compared with placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mean number of ARTIs Show forest plot	24	2154	Mean Difference (IV, Random, 95% CI)	‐1.41 [‐1.85, ‐0.98]

2 Percent difference in ARTIs Show forest plot	24	2154	Mean Difference (IV, Random, 95% CI)	‐41.21 [‐49.10, ‐33.31]

Comparison 2. Bacterial IS compared with placebo

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Comparison 3. Bacterial IS trials with n equal to or greater than 40 compared with placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mean number of ARTIs Show forest plot	19	2009	Mean Difference (IV, Random, 95% CI)	‐1.42 [‐1.92, ‐0.93]

2 Percent difference in ARTIs Show forest plot	19	2009	Mean Difference (IV, Random, 95% CI)	‐38.44 [‐47.25, ‐29.63]

Comparison 3. Bacterial IS trials with n equal to or greater than 40 compared with placebo

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Comparison 4. Bacterial IS trials with n equal to or greater than 40 only OM‐85 and BV D53 compared with placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mean number of ARTIs Show forest plot	16	1811	Mean Difference (IV, Random, 95% CI)	‐1.17 [‐1.56, ‐0.78]

2 Percent difference in ARTIs Show forest plot	16	1811	Mean Difference (IV, Random, 95% CI)	‐36.16 [‐44.51, ‐27.80]

Comparison 4. Bacterial IS trials with n equal to or greater than 40 only OM‐85 and BV D53 compared with placebo

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Comparison 5. Adverse events

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Gastrointestinal adverse events Show forest plot	10	1457	Risk Difference (M‐H, Fixed, 95% CI)	0.01 [‐0.01, 0.03]

2 Skin adverse events Show forest plot	10	1469	Risk Difference (M‐H, Fixed, 95% CI)	0.00 [‐0.01, 0.01]

Comparison 5. Adverse events

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Comparison 6. OM‐85 trials

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mean number of ARTIs Show forest plot	9	852	Mean Difference (IV, Random, 95% CI)	‐1.20 [‐1.75, ‐0.66]

2 Percent difference in ARTIs Show forest plot	9	852	Mean Difference (IV, Random, 95% CI)	‐35.90 [‐49.46, ‐22.35]

Comparison 6. OM‐85 trials

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Comparison 7. D53 trials

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mean number of ARTIs Show forest plot	11	1067	Mean Difference (IV, Random, 95% CI)	‐1.32 [‐1.86, ‐0.79]

2 Percent difference in ARTIs Show forest plot	11	1067	Mean Difference (IV, Random, 95% CI)	‐43.47 [‐53.22, ‐33.72]

Comparison 7. D53 trials

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