Cochrane inmunoestimulantes

EVIDENCE-BASED CHILD HEALTH: A COCHRANE REVIEW JOURNAL

Evid.-Based Child Health 7:2: 629–717 (2012)

Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ebch.1833

Immunostimulants for preventing respiratory tract infection

in children (Review)

Del-Rio-Navarro BE, Espinosa-Rosales FJ, Flenady V, Sienra-Monge JJL

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2011, Issue 6

http://www.thecochranelibrary.com

Immunostimulants for preventing respiratory tract infection in children (Review)

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.


T A B L E O F C O N T E N T S

631HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .631ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .632PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .632SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .635BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .637OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .637METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 639Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 640Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642

642RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 646Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 647Figure 7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 648Figure 8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 648

649DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .651AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .651ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .652REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .661CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .693DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Any IS compared with placebo, Outcome 1 Mean number of ARTIs. . . . . . . . 695Analysis 1.2. Comparison 1 Any IS compared with placebo, Outcome 2 Percent difference in ARTIs. . . . . . . 697Analysis 2.1. Comparison 2 Bacterial IS compared with placebo, Outcome 1 Mean number of ARTIs. . . . . . 699Analysis 2.2. Comparison 2 Bacterial IS compared with placebo, Outcome 2 Percent difference in ARTIs. . . . . 700Analysis 3.1. Comparison 3 Bacterial IS trials with n equal to or greater than 40 compared with placebo, Outcome 1 Mean

number of ARTIs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 701Analysis 3.2. Comparison 3 Bacterial IS trials with n equal to or greater than 40 compared with placebo, Outcome 2

Percent difference in ARTIs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 702Analysis 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. . . . . . . . . . . . . . . . . . . . . . . . 704Analysis 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. . . . . . . . . . . . . . . . . . . . . . 705Analysis 5.1. Comparison 5 Adverse events, Outcome 1 Gastrointestinal adverse events. . . . . . . . . . . 706Analysis 5.2. Comparison 5 Adverse events, Outcome 2 Skin adverse events. . . . . . . . . . . . . . . 707Analysis 6.1. Comparison 6 OM-85 trials, Outcome 1 Mean number of ARTIs. . . . . . . . . . . . . . 708Analysis 6.2. Comparison 6 OM-85 trials, Outcome 2 Percent difference in ARTIs. . . . . . . . . . . . . 709Analysis 7.1. Comparison 7 D53 trials, Outcome 1 Mean number of ARTIs. . . . . . . . . . . . . . . 710Analysis 7.2. Comparison 7 D53 trials, Outcome 2 Percent difference in ARTIs. . . . . . . . . . . . . . 711

711ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .713APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .716WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .716HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .716CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .716DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .717SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .717INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

630Immunostimulants for preventing respiratory tract infection in children (Review)



[Intervention Review]

Immunostimulants for preventing respiratory tract infectionin children

Blanca Estela Del-Rio-Navarro1, Francisco J Espinosa-Rosales2, Vicki Flenady3, Juan JL Sienra-Monge1

1Department of Allergy and Immunology, Hospital Infantil de México “Federico Gómez”, Mexico City, Mexico. 2Department ofImmunology, Instituto Nacional de Pediatría (National Institute of Pediatrics), México D.F., Mexico. 3 Translating Research Into Practice(TRIP) Centre - Mater Medical Research Institute, Mater Health Services, Woolloongabba, Australia

Contact address: Blanca Estela Del-Rio-Navarro, Department of Allergy and Immunology, Hospital Infantil de México “Fed-erico Gómez”, Dr. Marquez 162, Colonia de los Doctores, Mexico City, DF, CP 06720, Mexico. [email protected]@yahoo.com.mx.

Editorial group: Cochrane Acute Respiratory Infections Group.Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 6, 2011.Review content assessed as up-to-date: 3 March 2011.

Citation: Del-Rio-Navarro BE, Espinosa-Rosales FJ, Flenady V, Sienra-Monge JJL. Immunostimulants for preventing res-piratory tract infection in children. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD004974. DOI:10.1002/14651858.CD004974.pub2.


A B S T R A C T

Background

Acute respiratory tract infections (ARTIs) are a major cause of childhood morbidity and mortality. Immunostimulants (IS) may reducethe incidence of ARTIs.

Objectives

To determine the efficacy and safety of IS in preventing ARTIs in children.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) 2011, issue 1, which contains the Acute RespiratoryInfections Group’s Specialised Register, MEDLINE (1966 to February week 4, 2011), EMBASE (1990 to February 2011), GoogleScholar (2009 to February 2011), Scopus (2009 to February 2011), PASCAL (1990 to February 2010), SciSearch (1990 to February2010) and IPA (1990 to February 2010).

Selection criteria

We included all comparative randomized controlled trials (RCTs) which enrolled participants less than 18 years of age. The interventionwas IS medication, administered by any method, compared to placebo to prevent ARTIs.

Data collection and analysis

We analyzed the outcome on ARTIs both as the mean number of ARTIs by group and as a percent change in the rate of ARTIs. Weundertook meta-analyses using a random-effects model and presented results as mean differences (MD) with 95% confidence intervals(CI). Two review authors independently assessed the search results and risk of bias, and extracted data. A funnel plot suggested theremay be publication bias in the identified trials.




Main results

Thirty-five placebo-controlled trials (4060 participants) provided data in a form suitable for inclusion in the meta-analyses. Whencompared with placebo, the use of IS was shown to reduce ARTIs measured as the total numbers of ARTIs (MD -1.24; 95% CI -1.54to -0.94) and the difference in ARTI rates (MD -38.84%; 95% CI -46.37% to -31.31%). Trial quality was generally poor and a highlevel of statistical heterogeneity was evident. The subgroup analysis of bacterial IS, D53 and OM-85 studies produced similar results,with lower heterogeneity. No difference in adverse events was evident between the placebo and IS groups.

Authors’ conclusions

This review shows that IS reduce the incidence of ARTIs by 40% on average in susceptible children. Studies in healthy children are notavailable. Although the safety profile in the studies was good, some IS may be unsafe. ARTI-susceptible children may benefit from IStreatment. Further high-quality trials are needed and we encourage national health authorities to conduct large, multicentre, double-blind, placebo-controlled RCTs on the role of IS in preventing ARTIs in children.

P L A I N L A N G U A G E S U M M A R Y

Immunostimulants to prevent acute respiratory tract infections in children

Acute respiratory tract infections (ARTIs) are responsible for 19% of all deaths in children younger than five years of age, mainly in low-income countries in Africa, Asia and Latin America. In high-income countries ARTIs are among the most frequent illnesses, leadingto 20% of medical consultations, 30% of days lost from work and 75% of antibiotic prescriptions. In the USA the total cost of non-influenza-related viral ARTIs is around $40 billion annually, while the corresponding cost for influenza is US $87.1 billion. The mainsigns and symptoms of ARTIs include sneezing, runny nose, sore throat, cough and malaise. Children living in rural communities, notattending daycare centres, suffer about seven ARTI episodes in the first year of life; eight ARTIs per year from the ages of one to four;six per year aged five to nine; and five per year aged 10 to 19. Children exposed to risks factors, such as attendance at daycare centres,overcrowding, contact with older siblings, smoking at home and lack of breast feeding, may suffer more ARTIs.

Several treatments have been used to reduce the incidence of ARTIs (vitamin A, vitamin C, zinc, antibiotics). Among them areimmunostimulants (herbal extracts, bacterial extracts, synthetic compounds), which aim to increase the immune defences of therespiratory tract. We searched for clinical trials of immunostimulants to prevent ARTIs in children compared to placebo. Our reviewincludes 35 studies with 4060 participants. However, the quality of many of the studies was poor and the results were very diverse.

By combining results, immunostimulants reduced 1.24 ARTIs in a six-month period, equivalent to a 39% reduction in ARTIs comparedto the placebo group. Only 20 studies provided adequate data on adverse events: the most frequent were rash, nausea, vomiting,abdominal pain and diarrhea. The main limitations of this review were the poor methodological quality and diverse trial results.We conclude that ARTI-susceptible children may benefit from immunostimulants, but more high-quality studies are needed. Wesuggest that national health authorities conduct high-quality randomized controlled trials to assess the true effects of immunostimulantpreparations.



Evid.-BasedChild

Health

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(2012)

S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

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 con-

trol 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)

⊕⊕⊕

moderate1The 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)

⊕⊕⊕

moderate1,2

Incidence of gastrointestinal

adverse events

21 per 1000 30 per 1000 (11 to 50 per

1000)

1457

(10 studies)

⊕⊕

low1,3

Incidence of skin adverse

events

3 per 1000 7 per 1000 (-8 to 14 per 1000) 1469

(10 studies)

⊕⊕

low1,3

*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

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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 IS2 Heterogenity decreased with calculation of percent difference ARTIs.3 Adverse events were reported only in 10 trials; selective outcome reporting

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Evid.-Based Child Health 7:2: 629–717 (2012)B A C K G R O U N D

Description of the condition

In 1998 the World Health Organization (WHO) considered acuterespiratory tract infections (ARTIs) to be “the forgotten pandemic”as ARTIs caused 19% of all deaths in children younger than fiveyears and 8.2% of all disabilities and premature mortality (WHO1998). In 2000, 1.9 million (95% confidence interval (CI) 1.6 to2.2 million) children died from ARTIs worldwide, with 70% ofthe deaths in Africa and South-East Asia (Williams 2002). AR-TIs are the leading cause of morbidity in high-income countries(USA, Canada, Western Europe) and account for 20% of medicalconsultations, 30% of days lost from work and 75% of antibi-otic prescriptions (WHO 1998). ARTIs are responsible for mostsick days amongst school children (Haskins 1986) and parentalabsenteeism from work (Bell 1989). The cost of ARTIs in high-income countries is significant. For example, between 2000 and2002 there were approximately 500 million non-influenza-relatedviral ARTI episodes in the USA per year; the total economic im-pact of these episodes was around $40 billion annually (direct costsof $17 billion per year and indirect costs of $22.5 billion per year)(Fendrick 2003). Based on the 2003 US population, it has beencalculated that the total economic burden of annual influenza epi-demics in the USA was $87.1 billion US dollars ($47.2 to $149.5)(Molinari 2007). Risk factors for ARTIs in childhood include at-tendance at daycare centres (Schwartz 1994), overcrowding (Bell1989; Selwyn 1990), contact with elder siblings (Selwyn 1990),male gender (Monto 2002), smoking at home (Jin 1993) and lackof breast feeding (Wright 1989).Community health studies in high-income countries have pro-vided basic information on the incidence of ARTIs in children.In the Cleveland Family Study, 100 families were visited weeklyby nurses during 1948 to 1957. The annual frequency of respi-ratory illness was 6.72 in children less than one year old; 7.95 inchildren aged one to four years; 6.21 in children aged five to nineyears; 5.02 in children aged 10 to 14 years; and 4.71 in 15 to 19-year olds (Monto 2002). In the first phase of the Tecumseh study,from 1965 to 1971, 4905 residents registered their incidence ofARTIs for the six-year period. In the first report the residents hadsuffered approximately 14,600 ARTIs. The annual incidence ofARTIs per person was 6.1 in children less than one year old; 5.7 inchildren aged one to two years; 4.7 in children aged three to fouryears; 3.5 in children aged five to nine years; 2.7 in children aged10 to 14 years old; and 2.4 in 15 to 19-year olds (Monto 1974).In the second report of the Tecumseh study, which covered twophases comprising a total of 11 years (1965 to 1971 and 1976 to1981), the mean annual number of ARTIs was 4.9 in the groupaged from zero to four years; and 2.8 in the group aged five to 19years (Monto 1993). In both phases of the study viruses were themost common agents causing ARTIs.During the 1980s, the Board on Science and Technology for In-ternational Development (BOSTID) undertook a co-ordinated

effort to establish the aetiology and epidemiology of ARTIs inchildren in high-income countries. The project was carried outin populations from 0 to 59 months of age in Africa, Asia andLatin America. The incidence rate in six community-based stud-ies ranged from 12.7 to 16.8 ARTIs per 100 child-weeks and theincidence of lower ARTIs was from 0.2 to 0.4 per 100 child-weeks. The children studied spent from 21.7% to 40.1% of theobserved weeks with ARTIs and from 1% to 14.4% of the ob-served weeks with lower ARTIs. Viral agents were more frequentlyrecovered than bacterial agents; respiratory syncytial virus (RSV)was the most frequent virus (Selwyn 1990). In Mexico, a studyassessing the effect of daycare centres on ARTI incidence followed144 children (aged 43 days to 4 months at entry) at home for oneyear. The study found that these children had six ARTIs each year,with a median of 40 sick days in a year (Flores-Hernandez1999).Viruses were the main aetiological agents for ARTIs in childrenat daycare centres (Denny 1986) and in the community (Monto1993). The most common virus isolates are rhinovirus, respiratorysyncytial virus, parainfluenza virus and adenovirus. Lower ARTIsare also frequently associated with viral infections, but bacterialagents may be found in 4.5% to 40% of the cases (Selwyn 1990).Up to 50% of children admitted to hospital with proven bacte-rial ARTIs also have evidence of concurrent or recent viral ARTIs(Campbell 1995). The damage caused by viruses to epithelial cellsin the airways may increase the adherence of bacteria and lead toa bacterial superinfection (Hament 1999).History of respiratory infections in the first 12 years among chil-dren was established in a cohort of German children living in ur-ban areas. The mean cumulative number of ARTIs in the 12 yearswas 21.9 (standard deviation (SD) 9.0) episodes; the mean annualnumber was 1st year, 3.1 (2.1) episodes; 2nd year, 3.2 (2.5); 3rdyear, 2.1 (2.0); 4th year, 2.3 (2.1); 5th year, 1.8 (1.6); 7th throughto the 9th year, 1.1 (1.0) episodes; 10th year through 12th year,1.0 (0.9) episodes (Grüber 2008). The frequency of ARTIs in thisstudy was about a half of the classic Monto studies (Monto 1974;Monto 1993). The authors regarded incidence above the twofoldstandard deviation as clinically relevant; more than seven episodesin the 1st year of life, more than eight episodes in year two, morethan six episodes in year three and year four more than five episodesin year five, more than four episodes in year six, and more thanthree episodes from year seven onwards.In a healthy population without any special risk factors or immun-odeficiencies, there is a subgroup of people with a higher incidenceof ARTIs. A cohort of children from Nijmegen, Netherlands wasfollowed for 21 years to register the occurrence of ARTIs. Thenumber of respiratory infections was assessed at the ages of two,four, eight and 21. It was considered that a person had a recurrentinfection if the number of ARTIs was above 75th percentile of thedistribution of respiratory infection at each assessment. Twenty-three percent of the people had recurrent respiratory infection intwo or more assessments and 1% suffered from recurrent infectionin the four assessments (Rovers 2006).




Recent influenza epidemics have increased interest in effective un-specific measures to protect the global population, outside the pro-duction of appropriate vaccines which could take more than sixto nine months to be ready for use. These unspecific measures in-clude physical methods to reduce the spread of respiratory virusessuch as hand washing, wearing masks, gloves and gowns (Jefferson2009). In military populations, reported additional measures toprevent respiratory tract infections include reducing contact be-tween units, reducing crowding, installing cloth barriers betweenbeds, indoor air dilution and ventilation, dust suppression andair sterilisation (Lee 2005). Other measures include vitamin andmineral supplementation, such as vitamin A (Chen 2008a), vita-min C (Hemilä 2010), vitamin D (Yamshchikov 2009) and zinc(Aggarwal 2007). Interventions which stimulate the immune sys-tem (immunostimulants) have been proposed as effective measuresto reduce ARTIs.Some years ago, the idea that bacterial lysates, plant extracts orimidazole compounds, could induce unspecific immunity againstviruses and distinct bacteria was not very solid. However, the re-cent discovery of Toll-like-receptors (TLRs) supports the possiblemechanism of action of immunostimulants (Krieg 2003). TLRswere discovered in the 1990s and their importance on immunitywas found later, see How the intervention might work below. Infact, there is evidence that two bacterial lysates may act on TLR2(Alyanakian 2006; Nikolova 2009), as well as levamisole (Chen2008b).

Description of the intervention

The main way to prevent ARTI complications is to prevent theseinfections and administer early antibiotic treatment when bac-terial ARTIs are diagnosed (Heikkinen 1999; Henderson 1982;WHO 1998). Non-specific preventative measures for ARTIs stud-ied in clinical trials include general hygiene methods in childrenattending daycare centres (CDCIDSG 1984); the administrationof nutritional supplements such as vitamin A to malnourishedchildren (Barreto 1994), vitamin C to normal and malnourishedchildren (Hemila 1997; Jefferson 2001) and trace elements tomalnourished and susceptible children (Sazawal 1998); preven-tive antibiotics (Dajani 1995); administration of gamma glob-ulins (Nydahl-Persson 1995); nasal spray of immunoglobulins(Heikkinen 1998); herbal extracts (Grimm 1999); xylitol sugarsyrup or chewing gum (Uhari 1998); and the use of immunos-timulants (IS) from different sources. The sources are synthetic(Passali 1994a); thymic extracts or factors (De Mattia 1993); or ofbiological origin such as Klebsiella extracts containing lipopolysac-charide (Dahan 1986) and mixtures of bacterial extracts (Berber1996).

How the intervention might work

The actual mechanism of IS is not yet fully understood. Currentlythe mechanisms of action are known for only two synthetic IS,tucaresol and imiquimod. The mechanism of tucaresol is to form acomplex on the surface of T cells (a Schiff reaction with the amines,probably on CD2). This complex provides an additional stimu-lant which facilitates the activation of the T cells (a co-stimula-tory signal activating the MAPK ERK2 pathway) (Rhodes 1995).Imiquimod and other related molecules activate the immune cellsby binding to the receptor for the bacterial products that activatethe unspecific defence mechanism and promote the immune re-sponse; they bind to the Toll-like receptor 7 (TLR7) activating theMyD88-dependent signalling pathway (Hemmi 2002).It may be postulated that products with IS properties activate theimmune cells using the receptors that recognise common bacte-rial products or receptors that provide additional stimulation foractivation. For instance, Toll-like receptors (TLR) recognise com-ponents common to a range of bacteria, so-called pathogen-as-sociated molecular patterns (PAMPs) such as lipopolysaccharide,peptidoglycan, lipoteichoic acid, lipoarabinomannan, un-methy-lated DNA with CpG motif and bacterial lipoproteins which ac-tivate the innate immune responses. The innate immune responseis responsible for the early mechanisms of defence against infec-tion; for instance the phagocytosis and neutralisation of bacte-ria entering the body. The mechanisms that enhance the innateimmune responses (cytokines and chemokines) also stimulate theadaptive immune response (production of specific antibodies andreproduction of specific T cells) (Hoffmann 1999; Schnare 2001;Takeuchi 2001). In fact, there is evidence that two bacterial lysatesmay act on TLR2 (Alyanakian 2006; Nikolova 2009), as well aslevamisole (Chen 2008b).

Why it is important to do this review

Most ARTIs are caused by viruses, hundreds of which may causethis type of infection. It would be impractical, therefore, to havea vaccine for each possible pathogenic agent. Therefore, spe-cific immunisation may not be the ultimate solution to preventARTIs. The introduction of the pneumococcal conjugate vac-cine decreased carriage and invasive infections due to the vaccineserotypes, but it has been replaced by other non-vaccine serotypesthat are becoming antibiotic resistance (Hsu 2009; Huang 2009;Mera 2009).IS could provide an alternative to vaccines for preventing AR-TIs but the efficacy of these medications is controversial (Collet1992; Valleron 1992). Several bacterial extracts and synthetic com-pounds are used in Europe and the Americas to prevent ARTIs.However, the evidence of the safety and efficacy of this approachis unclear. A systematic review of immunostimulation for the pre-vention of ARTIs in children is required to enable a robust ap-praisal of the current evidence on the safety and efficacy of thisapproach and to provide clues for the development of new IS.




O B J E C T I V E S

To assess the safety and efficacy of immunostimulants (IS) admin-istered to children to prevent ARTIs when compared with placebo,in terms of frequency of these infections and reported adverse ef-fects. Trials comparing two IS were also included.

M E T H O D S

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) comparing IS, administeredby any method, to placebo to prevent ARTIs. Trials referring tointerferon inducers, vitamins and nutritional supplements werenot included.

Types of participants

Participants younger than 18 years of age. We did not include trialsthat included participants who suffered from asthma, allergy andatopy, or chronic respiratory diseases.

Types of interventions

The use of an IS administered by any method to prevent ARTIs.Administration of IS could begin in the presence of active ARTI.We considered trials utilising concomitant therapies such as an-tipyretics or antibiotics for inclusion.

Types of outcome measures

A broad definition of ARTI was accepted and included using differ-ent specific diagnoses, such as cold, influenza, tonsillitis, pharyngi-tis, bronchitis and otitis media. Aetiological agents were not stud-ied and no distinction was made between bacterial and viral AR-TIs. Physician diagnosis of ARTI and adverse events was accepted.

Primary outcomes

The number of ARTIs in children suffered during the study period.

Secondary outcomes

1. The percentage of ARTIs.2. The incidence of adverse events.

Search methods for identification of studies

Electronic searches

For this update we searched the Cochrane Central Register of Con-trolled Trials (CENTRAL) 2011, issue 1, which contains the AcuteRespiratory Infections Group’s Specialised Register, MEDLINE(1966 to February week 4, 2011), EMBASE (1990 to February2011), Google Scholar (2009 to February 2011), Scopus (2009to February 2011), PASCAL (1990 to February 2010), SciSearch(1990 to February 2010) and IPA (1990 to February 2010). De-tails of the previous searches are in Appendix 1.We used the following search strategy to search MEDLINE andCENTRAL. To search MEDLINE, we combined the search strat-egy with the Cochrane Highly Sensitive Search Strategy for identi-fying randomized trials in MEDLINE: sensitivity- and precision-maximising version (2008 revision); Ovid format (Lefebvre 2009).The search strategy was adapted for EMBASE (see Appendix 2).Details of the PASCAL, SciSearch, IPA and previous Embasesearch are in Appendix 3.MEDLINE (Ovid)

1 exp Respiratory Tract Infections/2 (respiratory adj5 infection*).tw.3 1 or 24 exp Adjuvants, Immunologic/5 immunostimulant*.tw,nm.6 immunomodulat*.tw,nm.7 immunoadjuvant*.tw,nm.8 immunologic adjuvant*.tw,nm.9 (immunobalt or lw50020 or luivac or paspat or munos-tin).tw,nm.10 (om-85 bv or om85bv or om 85 bv).tw,nm.11 (bronchovaxom or broncho-vaxom or broncho vaxom).tw,nm.12 (pulmonar-om or pulmonar om).tw,nm.13 d53.tw,nm.14 (ribomunyl or ribovac or immucytal).tw,nm.15 Lipopolysaccharides/16 lipopolysaccharide*.tw,nm.17 (ru41740 or ru-41740 or ru 41740 or biostim).tw,nm.18 Thymus Extracts/19 thymus extract*.tw,nm.20 (thymic extract* or thymomodulin*).tw,nm.21 Pelargonium/22 (pelargonium* or umckaloabo).tw,nm.23 (am3 or imunoferon or immunoferon or inmunoferon).tw,nm.24 glycophosphopep*.tw,nm.25 (pidotimod or adimod).tw,nm.26 Levamisole/27 levamisole.tw,nm.28 or/4-2729 3 and 28




Searching other resources

We used identified articles as references for a Science CitationIndex search. We searched bibliographies of all included trials aswell as those of relevant reviews to identify additional studies.Finally, we sent a letter to all first authors, as well as pharma-ceutical companies that manufacture immunostimulant drugs, re-questing data and references for any relevant published and un-published trials. There were no language or publication restric-tions. We also searched for studies in the trial registration website: metaRegister of Controlled Trials (http://www.controlled-trials.com/mrct/). We searched for IS trial registries in the U.S.National Institutes of Health in http://www.ClinicalTrials.gov.

Data collection and analysis

Selection of studies

Two review authors (BN, JSM) independently searched for trialsfor inclusion and risk of bias assessment. We resolved differencesby discussion.

Data extraction and management

We analyzed and managed data using Review Manager (RevMan2008). Two authors (BN, JSM) independently extracted data. Wesought missing data from investigators of individual trials, as nec-essary, in order to perform analyses on an intention-to-treat (ITT)basis.Dr Arturo Berber contacted trial authors to request unpublisheddata. Responses were received from 10 trial authors (Arroyave1999; Collet 1993; Gómez-Barreto 1998; Gutiérrez-Tarango2001; Jara-Pérez 2000; Karam-Bechara 1995; Paupe 1991;

Saracho-Weber 2001 (co-worker Vázquez-Ramos); Schaad 1986;Schaad 2002). However, no additional data were provided. A fur-ther 11 trial authors were contacted by Dr Berber without response(Aymard 1994; Careddu 1994a; Careddu 1994b; Fiocchi 1986;Fiocchi 1988; Fiocchi 1989; Fiocchi 1990; Motta 1994; Paupe1986; Rutishauser 1998 (co-worker Grevers); Valleron 1992). Dr.Arturo Berber provided the database for OM-85 trials from Mex-ico. In 2010, we made attempts to contact the following au-thors: Joseph Bellanti, Jean Bousquet, Herman A. Cohen, CraigI Coleman, Jean Paul Collet, Alessandro Fiocchi, Sergio Mar-cassa, Renzo Mora, RJ Riedl-Seifert, Urs B. Schaad, DragankaStankulova, Claudia Steurer-Stey and James A. Taylor, and manu-facturers Luipold (luivac), OM Pharma (broncho-vaxom), PierreFabre (ribomunyl) and Polichem (adimod). Only Sergio Marcassa,Renzo Mora, RJ Riedl-Seifert, Urs B. Schaad (by himself and inname of OM Pharma) replied; no information regarding new stud-ies was obtained.

Assessment of risk of bias in included studies

We measured trial quality using seven domains.1. Random sequence generation (selection bias).2. Allocation concealment (selection bias).3. Blinding (performance bias and detection bias).4. Blinding of participants and personnel (performance bias).5. Blinding of outcome assessment (detection bias).6. Incomplete outcome data (attrition bias).7. Selective reporting (reporting bias).

We assigned a quality rating for above domains for each includedtrial using the criteria outlined in the Cochrane Handbook for Sys-tematic Reviews of Interventions (Higgins 2011) as high risk, lowrisk or uncertain risk . Figure 1 and Figure 2 shows the results ofrisk of bias assessment for the seven domains.




Figure 1. Risk of bias graph: review authors’ judgements about each risk of bias item presented as

percentages across all included studies.




Figure 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included

study.




Measures of treatment effect

We reported the mean differences (MD) (and 95% confidenceintervals (CI)) for the meta-analysis of data measured on a contin-uous scale. We assessed heterogeneity by visual inspection of theoutcomes tables and by using two statistics of heterogeneity (Hand I2 statistic) (Higgins 2003). Due to the observed statisticalheterogeneity, we used the random-effects model.

Unit of analysis issues

Regarding the trials with a description of randomisation and al-location, the unit of randomisation was the individual subject(Cohen 2004; Collet 1993; Del-Rio-Navarro 2003; Gutiérrez-Tarango 2001; Jara-Perez 2000; Taylor 2003).

Dealing with missing data

The studies only analyse the available data, ignoring the missingdata.

Assessment of heterogeneity

The way in which the outcomes were reported varied widely acrossthe trials. We decided to use the mean number of ARTIs and itsstandard deviation (SD) as the outcome as it allows the use of para-metric statistical methods that provide more power to the tests. Weassumed that the number of ARTIs in the IS-treated group wouldbe comparable to the number of ARTIs in the placebo group; andboth of these would depend on the susceptibility of the children(determined by age, duration of trial and seasons of the year dur-ing the trial). Consequently we expected to have heterogeneity inthe mean number of ARTIs. Therefore, we decided to standardisethe results using the percentage of infections considering the meannumber of infections in the placebo group as 100%.

Assessment of reporting biases

We assessed publication bias using a funnel plot (Egger 1997). Theresults indicated possible publication bias. The funnel plot for thenumber of ARTIs was asymmetrical with a large base skewed tothe left and narrower distribution at the top; the funnel plot forthe percentage of ARTIs was more symmetrical but the most ofthe points were on the left side. Figure 3 and Figure 4 are funnelplots showing the differences in the number of ARTIs and thepercentage of ARTIs.

Figure 3.




Figure 4.

Data synthesis

Due to the heterogeneity of the results we selected the random-effects model of meta-analysis.

Subgroup analysis and investigation of heterogeneity

We also conducted bivariate correlation as well as linear regressionand sensitivity analyses of subgroups to investigate the sources ofstatistical heterogeneity (please refer to Results section).

Sensitivity analysis

To determine whether conclusions were robust, we performedanalyses of different set of studies as follows: any IS; bacterial IS;bacterial IS trials with the total sample size of equal to or greaterthan 40; bacterial IS trials with total sample size equal to or greater

than 40 including only OM-85 and BV D53 and OM-85 aloneand D53 alone.

R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of excludedstudies.

Results of the search

The electronic search produced 764 references. No other poten-tially eligible studies were found as a result of contact with the trial




authors or searching of trial registries. Of the references obtained,we identified 93 studies as potentially eligible.

Included studies

We included 61 placebo-controlled clinical trials involving 4149participants. The studies were very heterogenous in the interven-tions studied, the number of ARTIs in the placebo groups and inthe reporting of outcomes.

Population

The participants enrolled in the included trials were children rang-ing from six months to 18 years of age. The echinacea trials differedin the selection criteria of participants as they used children with-out a significant health problem and without a history of recurrentARTI. The remainder of the trials included a history of recurrentARTIs in the inclusion criteria. All the trials were conducted inthe Northern (boreal) hemisphere except Fukuda’s (Fukuda 1999).Fall and winter seasons referred to the months from Septemberto January. The year of the trial was not specified in most of thestudies.

Interventions

Forty studies used bacterial products, four studies used herbal ex-tracts (echinacea and garlic), 11 studies used synthetic compounds,five studies used thymic extracts (thymomodulin) and one studyused a synthetic interferon. All trials used a placebo control. Thecommon names of the medications are in Table 1.Twenty-two studies had a duration shorter than six months, 33studies had a duration of six months and only six studies had aduration longer than six months. The duration of seven D53 trialswas less than six months and nine D53 trials had a duration of sixmonths. In all D53 trials the description of the methodology wasnot clear and different routes of administration were used (nasalspray or by mouth). Ten OM-85 BV trials lasted six months; twotrials had a duration of longer than six months.

Outcomes

Only 35 of the 61 included studies reported the mean and SDof the incidence of respiratory infections or provided data to cal-culate these measure, allowing their inclusion in the meta-analy-sis (Ahrens 1984; Arroyave 1999; Careddu 1994a; Clerici 1988;Cohen 2004; De Loore 1979; Del-Rio-Navarro 2003; Fiocchi1986; Garabedian 1990; Gutiérrez-Tarango 2001; Gómez-Barreto1998; Hauguenauer 1987; Hüls 1995; Jara-Pérez 2000; Karam-Bechara 1995; Lacomme 1985; Litzman 1999; Maestroni 1984;Motta 1994; Paupe 1986; Pech 1987; Piquett 1986; RB10 1994;RB17 1988; RB21 1988; RB22 1990; RB24 1990; RB25 1990;Saracho-Weber 2001; Schaad 1986; Schaad 2002; Van Eygen1976; Van Eygen 1979; Vautel 1993; Zagar 1988). In these studies

the ARTIs were defined by the presence of respiratory signs andsymptoms.The remaining 24 studies reported a variety of end points: symp-toms, clinical scales or presence or absence of respiratory infec-tions. Some trials reported the frequency of ARTIs as either equalto or more than one infection (Burgio 1994; Careddu 1994b;Fukuda 1999; Mora 2010a; Paupe 1991; Rutishauser 1998; Taylor2003; Wahl 2008); equal to or more than two infections (Mora2007); equal to or more than three infections (Collet 1993); thetotal number of ARTIs; mean number of ARTIs (Caramia 1994;Chen 2004; Dils 1979; Fiocchi 1988; Longo 1988; Passali 1994;Pozzi 2004; Riedl-Seifert 1995; Sramek 1986); or reduction inthe number of ARTIs (Andrianova 2003; Iuldashev 1988). Othersmeasured the severity of symptoms using clinical scales that werenot validated (Fiocchi 1989; Giovannini 2000; Mora 2002; Renzo2004) or as days suffering symptoms (Martin du Pan 1982).

Excluded studies

We excluded 36 studies: 32 did not comply with the selectioncriteria; two compared several IS treatments without a placebogroup; and two were duplicate reports of trials already included.See Characteristics of excluded studies table.

Risk of bias in included studies

The description of the methodology was not clear in most ofthe studies. Only 17.1% (6 out of 35) studies reported adequaterandomisation and blinding (participants and treating physicianswere blinded) (Cohen 2004; Collet 1993; Del-Rio-Navarro 2003;Gutiérrez-Tarango 2001; Jara-Perez 2000; Taylor 2003) (Figure1). Using the quality rating criteria (Higgins 2011), the quality ofthe rest of the trials (28 out of 34 (82.4%)) was B; randomisationand follow through of participants was unclear. See Table 2 for adescription of the quality of the trials.Only 17.1% (6 out of 35) studies reported on the number ofparticipants lost to follow up (Cohen 2004; Collet 1993; Del-Rio-Navarro 2003; Gutiérrez-Tarango 2001; Jara-Perez 2000; Taylor2003). Of these, five studies reported losses. While losses wereminimal, 0.5% to 7% in three studies, two studies reported aloss of 18% and 24%. As additional data were not obtained fromthe investigators on the outcomes of participants who were lostto follow up an intention-to-treat (ITT) analysis could not beundertaken. The numbers lost to follow up are explained in furtherdetail.In the Cohen 2004 trial, 160 out of 215 in the IS group com-pleted the trial (27 dropped out because the medication had anunpleasant taste, 24 due to non-compliance which was not fullyexplained, four dropped out due to a lack of confidence in thetreatment); and 168 out of 215 of the placebo group completedthe trial (22 dropped out because the placebo had an unpleasanttaste, 21 due to non-compliance which was not fully explained,




and one dropped out due to a lack of confidence in the treatment).A total of 24% were lost to follow up.In the Del-Rio-Navarro 2003 trial, 20 out of 25 in the IS groupcompleted the trial. Five children were lost to follow up. Twentyout of 24 in the placebo group completed the trial. Two childrenwere lost to follow up (the parents of one participant withdrewconsent for their child to continue in the trial and one left becausethe trial medication caused the child to have diarrhea). A total of18% were lost to follow up.In the Collet 1993 trial, 199 out of 210 in the IS group and 196out of 213 placebo group completed the trial. For both groups,the 28 lost to follow up were related either to the parents movingto a different location or the mothers stopped working and nolonger took their children to the daycare centres where the trialswere being held. A total of 7% were lost to follow up.In the Taylor 2003 trial, 242 out of 263 in the IS group completedthe trial (six withdrew before the first ARTI, five changed theirminds about participating, one never received the study medica-tion, five withdrew during the first ARTI, three refused the studymedication, one was concerned about the effect on their immunesystem, for one the protocol was too complicated, six log bookswere never received, four were lost to follow up); 244 out of 261in the placebo group completed the trial (three withdrew beforethe first ARTI, two changed their minds about participating, onewas excluded for taking another medication, one withdrew duringthe first ARTI, nine log books were never received and four werelost to follow up). A total of 7% were lost to follow up.In the Jara-Pérez 2000 trial, 99 out of 100 in the IS group com-pleted the trial. The case report from one child was lost. One hun-dred out of 100 in the placebo group completed the trial. A totalof 0.5% were lost to follow up.In the Gutiérrez-Tarango 2001 trial, outcomes were reported forall enrolled children. All the participants completed the trial.The outcome assessor was blinded to the treatment allocation in8.8% (three out of 34) of the studies (Cohen 2004; Collet 1993;Taylor 2003). Only 14.7% (five out of 34) of studies (Cohen 2004;Collet 1993; Del-Rio-Navarro 2003; Gutiérrez-Tarango 2001;Taylor 2003) were considered of quality A (Higgins 2011). Therest of the studies were of poor quality.

Allocation

In the studies with a proper description of randomisation andallocation (Cohen 2004; Collet 1993; Del-Rio-Navarro 2003;Gutiérrez-Tarango 2001; Jara-Perez 2000; Taylor 2003), the im-plementation of the random sequence of the treatments was re-ported. In Cohen 2004 active medication and the placebo weresupplied directly by the manufacturer and all randomisation lotswere stored in a sealed envelope at the pharmacy of the company,to be opened only in the event of an emergency. In Collet 1993participants were allocated to IS or placebo according to a pro-gram for remote data entry (Minitel a national telecommunica-

tion system network in France). Additionally, randomisation wasalso stratified by study centre and blocked for every four children.In the studies by Del-Rio-Navarro 2003 and Gutiérrez-Tarango2001 consecutive numbered study medication boxes, as well as aclosed opaque envelope describing the treatment, were supplieddirectly by the manufacturer; participants received a patient num-ber coincident with treatment number when the selection criteriawere completed. In the Jara-Perez 2000 study consecutive num-bered study medication boxes, as well as a closed opaque enve-lope describing the treatment, were supplied directly by the man-ufacturer; participants received a patient number corresponding atreatment according to an alphabetical name list. In Taylor 2003,each study centre had a supply of study medication (active medi-cation and placebo) in consecutively numbered bottles that wereidentical in appearance, contents of each bottle were randomlydetermined using a computer-generated randomisation list, andrandomisation was stratified by site and in blocks of 10. Enrolledchildren were assigned a unique study number corresponding tothe numbers on the bottles of study medication. Figure 1 showsthe review authors’ judgement of the risk of bias related to allo-cation concealment presented as percentages across all includedstudies and Figure 2shows the risk for each included study.

Blinding

Six studies (Cohen 2004; Collet 1993; Del-Rio-Navarro 2003;Gutiérrez-Tarango 2001; Jara-Perez 2000; Taylor 2003) claimedthat IS and placebo treatment had identical appearance and thatthe taste of both were similar. Investigators and participants werenot aware of the received treatment.

Incomplete outcome data

Only six studies (Cohen 2004; Collet 1993; Del-Rio-Navarro2003; Gutiérrez-Tarango 2001; Jara-Perez 2000; Taylor 2003) re-ported the number of patients lost to follow up. All used only theavailable data for the analyses. No imputation for the incompletedata were intended.Cohen 2004 had a total of 24% lost to follow up; the frequenciesand causes of it were similar in active and placebo groups. Inthe Del-Rio-Navarro 2003 trial 18% of participants were lost tofollow up; more children in the active group were lost (5/25 inactive group versus 2/25 in the placebo group). In the Collet 1993trial, 7% of participants were lost to follow up; in both groups therates and the reasons were similar. In the Taylor 2003 trial, 7% ofparticipants were lost to follow up; in both groups the rates andthe reasons were similar. In the Jara-Pérez 2000 trial only the dataof one participant on IS was lost. In the Gutiérrez-Tarango 2001trial, all the participants completed the trial.

Selective reporting




The study protocols were not available. Sixty-one randomized,placebo-controlled clinical trials were identified. Only 35 stud-ies reported the mean and SD of the incidence of respiratoryinfections or provided data to calculate these measure (Ahrens1984; Arroyave 1999; Careddu 1994a; Clerici 1988; Cohen2004; De Loore 1979; Del-Rio-Navarro 2003; Fiocchi 1986;Garabedian 1990; Gutiérrez-Tarango 2001; Gómez-Barreto 1998;Hauguenauer 1987; Hüls 1995; Jara-Pérez 2000; Karam-Bechara1995; Lacomme 1985; Litzman 1999; Maestroni 1984; Motta1994; Paupe 1986; Pech 1987; Piquett 1986; RB10 1994;RB17 1988; RB21 1988; RB22 1990; RB24 1990; RB25 1990;Saracho-Weber 2001; Schaad 1986; Schaad 2002; Van Eygen1976; Van Eygen 1979; Vautel 1993; Zagar 1988). Seven trialsreported the frequency of ARTIs (Burgio 1994; Careddu 1994b;Collet 1993; Fukuda 1999; Paupe 1991; Rutishauser 1998; Taylor2003). The rest of the studies did not use outcome measures rele-vant to the prevention of respiratory infections.

Other potential sources of bias

In 29 out of the 35 included studies, the process of randomisationand allocation was not described. Additionally, the disposition ofparticipants and reasons for withdrawals were not reported.Funnel plots of IS effects have a considerable asymmetry, indicat-ing possible publication bias, i.e. publishing only positive results(see Assessment of reporting biases). Language bias is also possible(publication in languages other than English and publication in

non-indexed, small, local journals).

Effects of interventions

See: Summary of findings for the main comparison Summaryof findings table

Effect of immunostimulants (IS) on acute respiratory

tract infections (ARTIs)

Of the 61 included studies only 35 provided data in a form suitablefor inclusion in the meta-analysis for this outcome. All 35 trialscompared IS with a placebo.Twenty-four out of 35 studies showed a reduction of ARTIs, bothas total numbers and as a percentage reduction of ARTIs (consid-ering the mean number of ARTIs in the placebo group as 100%).In the meta-analysis the use of IS was shown to reduce the totalnumber of ARTIs (mean difference (MD) -1.24 95% CI -1.54to -0.94) as well as producing a percentage change in the rate ofARTIs (MD -38.84%; 95% CI -46.37% to -31.31%). The totalnumber of ARTIs outcome showed high heterogeneity (I2 statistic= 94.0%, Chi2 test = 582.02, P < 0.00001); the use of percent-age change in the rate of ARTIs reduced the heterogeneity butit remained very high (I2 statistic = 83.0%, Chi2 test = 195.07,P < 0.00001). Therefore, we decided to use the random-effectsmodel with MD to calculate the global effect of immunostimu-lants (Figure 5; Figure 6).




Figure 5. Forest plot of comparison: Any IS compared with placebo, outcome: 1.1 Mean number of ARTIs.




Figure 6. Forest plot of comparison: Any IS compared with placebo, outcome: 1.2 Per cent difference in

ARTIs.

We investigated heterogeneity by bivariate correlation as well asby linear regression. The variables considered were total numberof children in the study, duration of the trial, mean number ofARTIs in the control group versus the mean difference in numberof ARTIs and mean difference in the percentage of ARTIs. Themain source of heterogeneity was the mean number of ARTIs inthe control group, using the mean difference in number of ARTIs(linear regression model correlation - 0.672, P < 0.001). Usingthe mean difference in the percentage of ARTIs, the source ofheterogeneity was related to the mean difference in the number ofARTIs and mean number of ARTIs in the control group (linearregression model correlation 0.834, P < 0.001). The age of theparticipants in each trial could be another important source ofvariation in the number of ARTIs, as younger children wouldsuffer more ARTIs. Yet the age in each trial was diverse, includingenrolled preschool children, school-aged children and adolescents.This made the exploration of this potential source of variationproblematic. In general, the net reduction in the number of ARTIswas dependent on the background rate of ARTIs.

Another potential source of heterogeneity was the type of IS. Wedecided to investigate this source of heterogeneity by performingsub-analyses as follows.

1. Including the bacterial IS studies data (and excluding theSaracho-Weber 2001 trial because it was the only trial with moreARTIs in the IS group than in the placebo group, probably dueto a clerical mistake inverting ARTI incidences). The number oftrials was 24; total number of participants was 2154, the numberof IS participants was 1091 and the number of placeboparticipants was 1063. The reduction in the total number ofARTIs was MD -1.41 (95% CI -1.85 to -0.98); the reduction inthe number of ARTIs as a percentage was MD -41.21 (95% CI -49.10 to -33.31).

2. Only bacterial IS studies data (excluding Saracho-Weber2001) with a total number of participants of at least 40. Thenumber of trials was 19; the total number of participants was2009, the number of IS participants was 1019 and the numberof placebo participants was 990. The reduction in the total




number of ARTIs was MD -1.42 (95% CI -1.92 to -0.93); andthe reduction in the number of ARTIs as a percentage was MD -38.44 (95% CI -47.25 to -29.63).

3. Only bacterial IS studies where the total number ofparticipants was more than 40 (including D53 and OM-85 BV).The number of trials was 16; the total number of participantswas 1811, the number of IS participants was 921 and thenumber of placebo participants was 890. The reduction in thetotal number of ARTIs was MD -1.17 (95% CI -1.56 to -0.78);

and the reduction in the number of ARTIs as a percentage wasMD -36.16 (95% CI -44.51 to -27.80).

4. Only OM-85 studies. The number of trials was nine; totalnumber of participants was 852, the number of IS participantswas 437 and the number of placebo participants was 415. Thereduction in the total number of ARTIs was MD -1.20 (95% CI-1.75 to -0.66) and the reduction in the number of ARTIs as apercentage was MD -35.90 (95% CI -49.46 to -22.35) (Figure7).

Figure 7. Forest plot of comparison: OM-85 trials, outcome: 6.2 Per cent difference in ARTIs.

1. Only D53 studies. The number of trials was 11; totalnumber of participants was 852, the number of IS participantswas 437 and the number of placebo participants was 415. Thereduction in the total number of ARTIs was MD -1.32 (95% CI-1.86 to -0.79); and the reduction in the number of ARTIs as apercentage was MD -43.47 (95% CI -53.22 to -33.72) (Figure8).

Figure 8. Forest plot of comparison: D53 trials, outcome: 7.2 Per cent difference in ARTIs.



Evid.-Based Child Health 7:2: 629–717 (2012)We did not perform the sub-analyses for good quality trials as onlytwo out of five trials provided data as mean and SD (Del-Rio-Navarro 2003; Gutiérrez-Tarango 2001). The selection of bacterialIS studies reduced the heterogeneity of the percentage differenceoutcome from very high (I2 statistic > 75) to moderate (I2 statistic <75) (Higgins 2003). However, the percentage differences and 95%CI in the total number of ARTIs were similar to the overall analysisfor all sub-analyses. The reduction of the I2 statistic when onlythe bacterial IS were analyzed confirmed that the different kindsof IS were another major source of heterogeneity. The combinedanalysis of percentage difference outcome of D53 and OM-85 hadan I2 statistic of 65%; D53 alone 55%; OM-85 alone 75%.

Adverse effects

Twenty studies provided data on adverse events in a form suit-able for inclusion in the meta-analysis. The most frequent eventswere skin and gastrointestinal effects (nausea, vomiting, abdomi-nal pain and diarrhea). No statistically significant difference wasshown in these adverse events when comparing IS with a placebo.A summary of the reported safety data for each trial is noted in theoutcome section of the Characteristics of included studies table.In 22 studies, authors did not report the presence or absence ofadverse events (Andrianova 2003; Bánovein 1992; Clerici 1988;Fiocchi 1986; Fiocchi 1988; Garabedian 1990; Giovannini 2000;Hauguenauer 1987; Iuldashev 1988; Longo 1988; Maestroni1984; Martin du Pan 1982; Piquett 1986; Prusek 1987; RB101994; RB17 1988; RB21 1988; RB22 1990; RB24 1990; RB251990; Saracho-Weber 2001; Sramek 1986). In eight studies, trialauthors claimed that no adverse event were observed (Chen 2004;De Loore 1979; Dils 1979; Karam-Bechara 1995; Mora 2007Renzo 2004; Van Eygen 1976; Zagar 1988). In four studies no ad-verse events were observed in the immunostimulant group (Burgio1994; Fiocchi 1989; Lacomme 1985; Schaad 1986). Five studiesreported a single case of adverse events in the IS group (Fukuda1999; Gómez-Barreto 1998; Paupe 1986; Paupe 1991; Van Eygen1979). One study reported only two adverse events (Wahl 2008).In three studies no adverse events related to administration of thetrial medications were reported (Arroyave 1999; Jara-Pérez 2000;Mora 2010a).

D I S C U S S I O N

Summary of main results

This review shows that IS reduce the incidence of ARTIs by about40% on average (from 35 trials with a total of 4060 participants).However, due to the poor quality of the included trials this may bean overestimate of the true effect of IS. Most of the trials reporteda low incidence of adverse events or no adverse events. The mostfrequent adverse events were gastrointestinal complaints such as

nausea, vomiting, abdominal pain and diarrhea; and skin disorderssuch as rash, urticaria and pruritus.The possible beneficial effects of immunostimulants in the pre-vention of ARTIs, cancers, AIDS/HIV infections, tuberculosis etc.have been awaited expectantly by many clinicians and medicalresearchers. One of the main indications of registered IS is theprevention of ARTIs in children, as they are more susceptible toARTIs. IS use is common in some countries in Europe and in theAmericas as result of the demand to reduce the incidence of ARTIsin children.While the use of IS is currently controversial and is viewed withskepticism by many physicians, there have been several clinical tri-als supporting their use as ancillary treatment and in the preven-tion of ARTIs. Yet their mechanism of action and possible bene-fits and risks are not well known. The aim of this review was tosynthesise all the evidence currently available from trials on thistopic to enable a more robust, unbiased assessment of the role ofefficacy and safety of IS to prevent ARTIs in children.After reviewing all available IS studies on the prevention of ARTIsin children, we empathise with the skepticism of many physicians.This review has a number of limitations due to the quality andreporting of the trials on this topic, the heterogeneity of the in-cluded trials and the possibility of publication bias. Few paperscomplied with standards for methodological quality and reportingof clinical trials, with the majority having significant deviationsfrom these standards. In addition, the lack of detail in many of thetrial publications limited the quality of this review.The most common problems with the included trials were thatthey:

• did not report data on ARTIs sufficient to reproduceparametric and non-parametric statistical tests or carry out meta-analysis;

• did not establish the normal incidence of ARTIs in the localpopulation and the number of infections in susceptible children,therefore, endpoint changes were not properly established;

• did not identify the possible causes of recurrent ARTIs;• did not try to isolate or identify the causative pathogen;• did not calculate the sample size required;• used small sample sizes;• did not include a clinical definition of ARTI and other end

points or used non validated scales;• misused statistical tests, especially the use of Student’s t test

for data under suspicion of non-normal distribution (SD >mean/2 or mean - SD < 0);

• under reported adverse events or did not report them at all;• did not report the power of the statistical tests in trials

without significant difference;• did not report or explain the flow chart and attrition of the

participants and the statistical methods did not consider the datafrom missing participants (censored data);

• published articles in low impact journals;• included heterogeneous groups of children comprising




infants, toddlers, schoolboys and girls and adolescents withoutconsidering the incidence of ARTIs in each group;

• did not control for or report on confounding factors (that isto say, age groups, concomitant asthma or allergy, number ofsiblings, smokers at home, birth weight, seasons during the study,time and timing of attendance at daycare centre or school).

• did not report the quality and standardisation of the herbalsupplements (Wolsko 2005) and bacterial extracts.

All the trials were conducted in populations of highly susceptiblechildren (secondary prevention) except Collet 1993 and Jara-Pérez2000, which studied children over-exposed to ARTIs due to thefact that they attended daycare centres and an orphanage, respec-tively, and Martin du Pan 1982 which included a subgroup fromdaycare centres. In contrast, the echinacea trials were carried out inpopulations without a history of recurrent ARTIs (Cohen 2004;Taylor 2003).The lack of significance of the findings of some trials could beascribed to small sample size, duration of the intervention, seasonof intervention, broad participant selection criteria (mainly diverseage groups) and low incidence of ARTIs in the studied population(caused by an over-reporting of previous ARTIs or reduction ofincidence as children grew older).Thymic extracts have been withdrawn from sale in several coun-tries, due to the possible prion contamination and consequentrisk of bovine spongiform encephalopathy (WHO 2005). The useof levamisole is restricted because of the risk of agranulocytosis,neurologic disease (Symoens 1978) and leukoencephalopathy (Xu2009).The overall effect of IS was a reduction in the total number ofARTIs (MD -1.24; 95% CI -1.54 to -0.94) but the individualsize of the effect in each trial depended on the number of ARTIsin the control group. The size of the effect could seem small butexpressing the reduction of ARTIs as a percentage indicates a goodeffect, about 40% (MD -38.84%; 95% CI -46.37 to -31.31). Theresults indicate that the reduction in the incidence of ARTIs is areal possibility but as the net effect depends on the background rateof ARTIs the effect would only be noticeable when the number ofinfections to be reduced is higher than the normal incidence fora given age group. Therefore, the use of IS for the prevention ofARTIs must be limited to children with proven high susceptibilityto ARTIs or over-exposed children who are over-exposed to ARTIsbecause they are in daycare centres, orphanages, kindergarten orelementary school.Sub-analysis of studies with available databases (Del-Rio-Navarro2003; Gutiérrez-Tarango 2001; Jara-Pérez 2000) have shown thatIS are not very effective in the prevention of one ARTI but are inthe prevention of recurrent infections (that is, two or three). Thismay be the reason why echinacea trials fail to show protection tothe first infection but had some effect on the second infection. Inaddition, the participants had no history of increased incidenceof ARTI. In a re-analysis of one study (Taylor 2003) it was foundthat 69.2% of the children treated with placebo had a second

ARTI while only 55.8% of children on echinacea had a secondinfection (P = 0.01). However, this effect could not be exploredin this review.In all meta-analyses it is important to consider the presence andpossible effect of publication bias; that is, the selective publicationof trials with positive results. The funnel plot demonstrated con-siderable asymmetry, indicating possible publication bias. Othertypes of bias that could affect the funnel plot are the language bias(publication in languages other than English and publication innon-indexed, small, local journals), poor methodological design,inadequate analysis and inadequate presentation of the results. Inonly one study (Saracho-Weber 2001) the treated group had anincrease in ARTIs and, therefore, a positive difference.The high heterogeneity limits the external validity of the analyseswith all the studies. However, when we selected only the studieson bacterial IS (particularly those of D53 and OM-85 BV), andused percentage of ARTIs, the heterogeneity could be regardedas acceptable. It is important to note that the size of the effectsis similar in the different sub-analyses, supporting the externalvalidity of the conclusions.On the basis of the asymmetry shown in the funnel plot, the het-erogeneity of the trials and the low quality of many included trials,the possibility of bias (resulting in an overestimation of the trueeffects of IS on ARTIs) should be considered as high. Therefore,caution needs to be applied when interpreting the possible advan-tages of IS shown in this review. However, the results of this reviewprovide a reference to the probable effect of IS in the prevention ofARTIs in children and point to the need for further clinical trials.Further trials on IS must follow the established guidelines (Collet1992; Moher 2001; Valleron 1992), estimate sample size accordingto realistic incidence of ARTI and control for confounding factors.Multivariable analysis should be used when confounding factorsare identified. Reports of such trials must include enough data toreplicate non-parametric statistical tests (for instance, frequencyof ARTIs at the end point) and include statistical analysis dealingwith censored data (Mahe 1999). Registration of all the protocolsand ongoing trials would be desirable to obtain all the possibleoutcomes. It would be necessary to conduct trials on otitis andlower ARTIs with large numbers of highly susceptible children.Considering the present review, the prevention of ARTIs usingIS may be possible. Larger clinical trials, adequately powered forimportant population groups, sponsored by health authorities,would be desirable to establish the true effects of IS and the effectof individual IS preparations.

Overall completeness and applicability ofevidence

According to the funnel plots, it is possible that some trials withnegative results have not been published (Figure 3 and Figure 4).




Quality of the evidence

Although the global quality of the trials was poor, a group ofstudies comply with the quality standards (Cohen 2004; Collet1993; Del-Rio-Navarro 2003; Gutiérrez-Tarango 2001; Jara-Perez2000; Taylor 2003).Due to the above and the classification of the studies with theGRADEpro tool, the global quality of the evidence on the effect ofimmunostimulants to reduce the incidence of ARTIs is regardedas moderate. Additional research is likely to have an impact on ourconfidence in the estimate of effect and may change the estimate.Meanwhile, the evidence of the incidence of adverse events is con-sidered as low. Further research is very likely to have an importantimpact on our confidence in the estimate of effect and is likelyto change the estimate, as the incidence of adverse events was notproperly reported in most of the studies. See Summary of findingsfor the main comparison.

Potential biases in the review process

We consider the risk of biases in the review process minimal, asthe plausible sources of information have been consulted and theauthors and manufactures were contacted. Additionally, no exter-nal funding was provided for this review.

Agreements and disagreements with otherstudies or reviews

The present review is in agreement with a previous meta-analysison the effect of IS showing a percent decrease in ARTIs of -42.64%(95% CI -45.19% to -40.08%) (Berber 2001).Another review on the effect of D53 in the incidence of ARTIsshowed a reduction of child ear, nose and throat (ENT) infec-tions of 27% to 68%, and a decrease in child ENT and bron-chopulmonary infections of 32% to 61% compared with placebo(Bellanti 2003). This concurs with the effect of D53 shown in thisreview.Other meta-analyses on the effect of individual IS report an effectas a percent reduction of -31.86% (95% CI -34.32 to -29.40) forD53, and a corresponding reduction of -39.28% (95% CI -52.58to -25.98) for OM-85 (De-La-Torre-Gonzalez 2005). Both CIsare in agreement with those in this review.Schaad (Schaad 2010) in a meta-analysis reported that in an OM-85 BV-treated population, 32% had three or more ARTIs in sixmonths, against 58.2% in the placebo-treated population. The

reduction with OM-85 was -1.21 (95% CI -1.39 to -1.03), whichis similar to the findings in this review.The results of this review do not agree with the review by Steurer-Stey (Steurer-Stey 2007) which pooled two OM-85 studies tocalculate the risk of fewer than three infections over six months offollow up in children not in daycare (RR 0.82; 95% CI 0.65 to1.02).

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

This review indicates that IS reduce the incidence of ARTIs by 40%on average in susceptible children. The trials have shown benefitsof IS in toddlers (two to five years), school boys (six to 12 years)and children with a high incidence of ARTIs, for example childrenattending daycare and children living in orphanages. Studies inhealthy children are not available. Although the safety profile in thestudies was good, some IS may be unsafe. For instance, levamisolehas been related to agranulocytosis and neurologic disease, andthymic extracts introduce the risk of prion contamination andtherefore the risk of bovine spongiform encephalopathy.

Implications for research

Further high-quality trials are required to confirm the true effectof IS and individual IS preparations in the prevention of ARTIs.We encourage national health authorities to conduct large, mul-ticentre, double-blind, placebo-controlled studies to establish theprecise benefits and risks for using IS to prevent ARTIs. It is nec-essary to conduct more studies on the number and frequency ofARTIs and the physiological and immunological basis of recurrentARTIs.

A C K N O W L E D G E M E N T S

We especially acknowledged the great editorial work of Liz Doo-ley. We thank Arturo Berber for his contribution to the protocol.The authors also wish to thank the following people for comment-ing on the draft review of the first version: Chanpen Choprapa-won, Ville Peltola, Richard Shoemaker and Ludovic Reveiz; andto Anne Lyddiatt, Ville Peltola, Sree Nair and Ludovic Reveiz forthe comments on the updated draft review.




R E F E R E N C E S

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Vautel 1993 {published data only}



Therapy 2003;17:355–67.∗ Vautel JM, Cauquil J, Perruchet AM, Thomas AM.Prevention of recurrent ear, nose, and throat infections inyoung children with Ribomunyl, double-blind, placebo-controlled study. Current Therapeutic Research, Clinical and

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∗ Indicates the major publication for the study




C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Ahrens 1984

Methods Double-blind, placebo-controlled, multicentre trial

Participants Paediatric participants (1 to 19 years) suffering from chronic obstructive disease of res-piratory tract, or those who received treatment for at least 1 ARTI during the autumnand winter seasons in the last year. 87 participants received OM-85 BV and 77 placebo

Interventions Participants received either 1 capsule of 3.5 mg of OM-85 BV or placebo a day by 10days per month during 3 monthsParticipants were followed for another 3 months for a total study period of 6 months

Outcomes During the study 83 participants with OM-85 BV had 3.75 ± 3.42 (mean ± SD) ARTIsand 72 participants with placebo had 5.04 ± 4.04 ARTIsTwo participants in the OM-85 BV had adverse events, 1 presented abdominal painand diarrhea and the other gastrointestinal distress. Six placebo participants had adverseevents with 2 cases of folliculitis

Notes It is not stated that the trial is randomizedSelection criteria of the participants allows the inclusion of non-susceptible participantsThe reason for excluding participants from the analysis are givenThe trial was conducted in GermanyThe trial took place over the 4 seasons of the year

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

High risk

Allocation concealment (selection bias) High risk

Blinding (performance bias and detectionbias)All outcomes

High risk

Blinding of participants and personnel(performance bias)All outcomes

High risk

Blinding of outcome assessment (detectionbias)All outcomes

High risk




Ahrens 1984 (Continued)


High risk

Incomplete outcome data (attrition bias)All outcomes

High risk

Selective reporting (reporting bias) High risk

Andrianova 2003

Methods Double-blind, placebo-controlled trial

Participants Participants from 6 to 11 years attending school

Interventions In the first part of the study 172 students received Allicor (300 mg of garlic extract) and 468 students received placeboonce a day for 5 monthsIn the second part of the study, 42 students had Allicor, 41 students had placebo and 73 students had dibazol for 5months

Outcomes In the first part of the study Allicor diminished the rate of ARTIs from 28.5% to 9.5%. During this phase there wasa case of atopyIn the second phase of the study Allicor subjects had 1.7 fewer infections than those in the placebo group and 2.4fewer infections than those in the dibazol group

Notes It is not stated that the trial is randomizedSelection criteria of the participants allows the inclusion of non-susceptible participantsThe trial was conducted in Russia

Arroyave 1999


Participants Children from 1 to 6 years with history of more than 6 ARTIs during the last year

Interventions One capsule with 1 mg of Klebsiella products (RU41740) or placebo once a day for 8 days per month for 3 months,plus a follow up for 15 months

Outcomes During 12 months of the trial 42 RU41740 participants had 2.8 ± 1.3 (mean ± SD) ARTIs and 44 placebo participantshad 8.4 ± 1.9 ARTIsNo adverse events related to the trial medications were reported

Notes It is not stated that the trial was randomizedFlow of patient numbers and drop-outs were not clearSD was obtained from the reported varianceThis is the greatest reduction in the treatment group regarding the placebo groupThe trial was conducted in Mexico




Arroyave 1999 (Continued)

The trial was run over the 4 seasons of the year

Burgio 1994

Methods Randomised, double-blind, placebo-controlled, multicentre trial

Participants Children from 2 to 13 years with history of recurrent ARTIs. 101 participants were randomized

Interventions Pidotimod 400 mg or placebo by mouth once a day by 60 days plus a follow up of 60 days

Outcomes After the treatment, during the follow up, 18% of 50 participants treated with pidotimod suffered respiratorysymptoms and this happened in 62.5% of 40 placebo participantsThere was no adverse events in the pidotimod group while 2 adverse events were reported in the placebo group

Notes Flow of patient numbers and drop-outs are given. Most of the pidotimod papers were published in a single supplementissue of a German magazineThe trial was conducted in ItalyThere were no data about the seasons during the trial

Caramia 1994


Participants Participants from 2 to 8 years with history of 6 ARTIs in the 6 months before the trial with at least 3 antibioticcourses with current hospitalization because of relapse of ARTI (active infection) and deficit of at least 1 parameterof immune system120 children were randomized

Interventions Pidotimod 400 mg or placebo twice a day for 15 days; followed by pidotimod 400 mg or placebo once a day by 60days plus a follow-up period of 3 months

Outcomes During the follow up 60 pidotimod participants had 40 relapses and 60 placebo participants had 149 relapses5 pidotimod participants and 7 placebo participants suffered from adverse events, mainly gastrointestinal complaints

Notes Drop-outs were not reported. Only total numbers of relapses were reported. Most of the pidotimod papers werepublished in a single supplement issue of a German magazineThe trial was conducted in ItalyThere were no data about the seasons during the trial

Careddu 1994a


Participants Participants from 3 to 14 years who had suffered more than 6 ARTIs in the autumn-winter period before the trial,with at least 3 courses of antibiotics




Careddu 1994a (Continued)

Interventions Pidotimod 400 mg daily or placebo for 60 days and a follow-up period of 90 days for a total study period of 150 days

Outcomes 329 pidotimod participants had 0.75 ± 0.99 (mean ± SD) ARTIs during the trial period, and 342 placebo participantshad 1.03 ± 1.0 ARTIsThere were 22 adverse events in the pidotimod group and 15 in the placebo group, mainly gastrointestinal complaints

Notes Number of screened participants and analyzed participants are given but there is no report of drop-outs during thetrial. The mean number of ARTIs in the placebo group is rather low. Most of the pidotimod papers were publishedin a single supplement issue of a German magazineThe trial was conducted in ItalyThere were no data about the seasons during the trial

Careddu 1994b

Methods Randomised, double-blind, placebo-controlled trial

Participants Children with mean age of 4.8 years with history of recurrent ARTI in the fall-winter period before the trial. 50participants were randomized

Interventions Pidotimod 400 mg or placebo per os twice a day by 20 days and an additional follow-up period of 60 days

Outcomes After the treatment during the follow up 100% of 25 pidotimod participants were without infection, while 4.35%of 24 placebo participants were without infection.Only 3 participants in the pidotimod group presented skin rash

Notes The reason for 1 drop-out is given. Most of the pidotimod papers were published in a single supplement issue of aGerman magazineThe trial was conducted in ItalyThere were no data about the seasons during the trial

Chen 2004


Participants Children from 2 to 12 years

Interventions 43 children had sublingual Lantigen B (bacterial antigen suspension) and there were 43 placebo participants inperiods of 4 and 2 weeks with an interval of 2 weeks. They were followed up for 6 months

Outcomes Children with Lantigen B had 3 (1 to 5) (mean and interval) ARTIs and children with placebo had 4 (1 to 10) ARTIsSix participants in the Lantigen B group and 6 in the control group were lost to follow upNo adverse events were observed

Notes The study was conducted in China. No information on the seasons during the trial was provided




Clerici 1988


Participants Children aged 4.7 ± 1.1 years (mean ± SD) with history of 6 ARTIs in the last year

Interventions A vial (liquid form) with thymomodulin 60 mg or placebo twice a day for 3 months. There was not additional followup

Outcomes During the trial 20 thymomodulin participants had 2.55 ± 0.6 (mean ± SD) ARTIs and 20 placebo participants had4.60 ± 0.6 ARTIsThe adverse events were not reported

Notes Flow diagram of participants and drop-outs is not given. It is not stated that the trial is randomizedThe trial was conducted in Italy in autumn-winter seasons

Cohen 2004


Participants Children from 1 to 5 years, without clinical alterations

Interventions Participants received Chizukit (preparation of Echinacea purpurea, propolis and vitaminC) or placebo for 12 weeks. Children from 1 to 3 years had 5 ml twice a day and thosefrom 4 to 5 years had 7.5 ml twice a day. During ARTIs participants had the respectivedosage 4 times a day

Outcomes 160 Chizukit participants had 0.9 ± 1.1 (mean ± SD) ARTIs and 168 placebo participantshad 1.8 ±1.3 ARTIs. Nine participants in the verum group and 7 in the placebo grouphad adverse events, all gastrointestinal and palatability symptoms

Notes A flow diagram of the participants was provided. Trial was conducted in winter in Israel

Risk of bias



Low risk

Allocation concealment (selection bias) Low risk


Low risk


Low risk




Cohen 2004 (Continued)


Low risk


Low risk


Low risk

Selective reporting (reporting bias) Low risk

Collet 1993


Participants Children older than 6 months attending daycare centres423 children were randomized

Interventions Participants received either 1 capsule of 3.5 mg of OM-85 BV or placebo a day by 10days per month during 3 months. Participants were followed up after 4.5 months for atotal study period of 7.5 months

Outcomes 26.7% of 210 participants with OM-85 BV and 33.8% of 213 with placebo had morethan 4 infections in the 7.5 month periodOM-85 BV participants had 17 adverse events the most frequent were eczema (n = 3)and adenoidectomy (n = 2); placebo participants had 19 adverse event the most frequentwere tympanocentesis (n = 3) and adenoidectomy (n = 2)

Notes Flow diagram and drop-outs are given. Sub-analysis for different age groups and for thetreatment period are givenThe trial was conducted in France during boreal autumn-winter seasons

Risk of bias



Low risk



Low risk




Collet 1993 (Continued)


Low risk


Low risk


Low risk


Low risk


De Loore 1979


Participants Children suffering from chronic or recurrent upper ARTIs with history of 4 ARTIs the last winter

Interventions Participants had levamisole tablets (50 mg) or placebo tabletsDosage: participants under 15 kg had half a tablet; participants from 15 to 30 kg had a tablet; participants over 30kg had 2 tablets. Participants were given a weekly dose for 4 months

Outcomes After 4 months, 15 levamisole participants had 1.3 ± 1.2 (mean ± SD) ARTIs; 17 placebo participants had 2.3 ± 1.7. Authors reported that no adverse event occurred

Notes A levamisole drop-out is explained. The trial was conducted in Belgium during autumn and winter

Del-Rio-Navarro 2003


Participants Participants from 3 to 6 years with at least 3 ARTIs during the previous 6 months. 54children were randomized

Interventions Participants received either 1 capsule of 3.5 mg of OM-85 BV or placebo a day by 10days per month during 3 monthsParticipants were followed up for 3 months for a total study period of 6 months

Outcomes After 6 months participants in the OM-85 group (n = 20) had 2.8 ± 1.4 (mean ± SD)ARTIs, while participants in the placebo group (n = 20) had 5.2 ± 1.5 ARTIs. Eightparticipants in the OM-85 BV group had 10 adverse events; only 3 gastrointestinal eventswere related to drug administration. Nine participants with placebo had 10 adverse




Del-Rio-Navarro 2003 (Continued)

events; 4 were related to the administration of placebo

Notes Flow of patient numbers and drop-outs are given. The trial was conducted in MexicoThe trial was conducted over the 4 seasons. Changes in the levels of IgG subclasses wereinvestigated; only the OM-85 BV group presented significant reduction in the IgG4levels

Risk of bias



Low risk



Low risk


Low risk


Low risk


Dils 1979


Participants Children from 2.5 to 17 years suffering chronic or recurrent RTIs with at least 4 infections from October to Februaryin the last year

Interventions Participants had levamisole tablets (50 mg) or placebo tabletsDosage: participants under 15 kg had half a tablet; participants from 15 to 30 kg had 1 tablet; participants over 30kg had 2 tablets. Participants had 1 dose 1 day per week after supper

Outcomes After 4 months, 45 children in levamisole group had 44 episodes of infection while 41 children in placebo group had79 ARTIsAuthor claimed that no side effects were reported

Notes No flow diagram nor drop-outs are providedThere are no data on the dispersion of ARTIsThe study was conducted in Belgium during autumn and winter




Fiocchi 1986

Methods Double-blind, placebo-controlled clinical trial

Participants Participants from 4 to 14 years with more than 6 ARTIs in the last fall-winter period with at least 3 antibiotic courses.16 participants were included

Interventions Thymomodulin 3 mg/kg/day or placebo by 3 months. There was no additional follow up

Outcomes During the 3-month period, 8 thymomodulin participants had 0.53 ± 0.11 (mean ± SD) ARTIs, and 8 placeboparticipants had 0.82 ± 0.12 ARTIsThe adverse events were not reported

Notes The sample size is clearly insufficientThe number of ARTIs in the placebo group was rather lowIt is not stated that the trial is randomizedThe trial was conducted in Italy during boreal autumn-winter seasons

Fiocchi 1988

Methods Randomised double-blind, placebo-controlled clinical trial

Participants Participants from 3 to 12 years with a clinical score more than 30 in a clinical scale for ARTIs

Interventions Participants received ribosomal extract spray (D53) or placebo, 1 puff in the nose and 1 in pharynx 3 times a dayby 2 weeks; this schedule was repeated another 2 times with intervals of 1 week between the puff administrations.Additionally participants had 1 subcutaneous injection in the weeks 2, 5 and 8Participants were followed up for 6 months

Outcomes After 6 months 30 participants in the D53 group had 36 upper ARTIs and 45 lower ARTIs, while 30 participantsin the placebo group had 43 upper ARTIs and 51 lower ARTIsAdverse events were not reported

Notes Flow of participants is not reported. The number of lower ARTIs is extremely high. Trial was conducted in Italyduring autumn-winter seasonsIt was not possible to identify this study in the Bellanti review

Fiocchi 1989

Methods Randomised, double-blind, placebo-controlled clinical trial

Participants Children from 2 to 15 years suffering recurrent ARTIs defined as 30 points in a clinical scale and more than 5 ARTIsin the last 6 months120 participants were included

Interventions Placebo or ribosomal extract spray (D53); 1 puff in each nostril plus 1 puff in the oropharyngeal cavity 3 times a dayaccording to the following schedule; 2 weeks treatment, 1 week washout and 1 week treatment in the first month;2 week treatment and 2 week washout in the second, third and fourth months. Total duration of the study was 4months




Fiocchi 1989 (Continued)

Outcomes Monthly clinical score by month 4 was 4.2 ± 2.6 in 60 D53 participants and 8.0 ± 4.3 in 58 placebo participants.One child in the placebo group had a headache and was withdrawn

Notes Two drop-outs in the placebo group are explainedThe main outcome is a non-validated clinical scoreThe trial was conducted during boreal winter-spring seasons in ItalyIt was not possible to identify this study in the Bellanti review

Fukuda 1999


Participants Participants from 8 months to 7 years with recurrent acute otitis and repetitive tonsillitis. At baseline, there were 18participants in the thymomodulin group and 17 in the placebo group

Interventions Thymomodulin 4 mg/kg/day divided in 2 doses a day for 3 months or the corresponding placebo

Outcomes 55.5% of children on thymomodulin group (n = 9) and only 20% of children on placebo (n = 10) group were freefrom infections after the end of medicationOne patient in the thymomodulin group had nausea and vomiting

Notes The sample size is clearly insufficientIt is not stated that the trial is randomizedThe trial was conducted in BrazilThere is no indication of the season during the trial

Garabedian 1990

Methods Double-blind, placebo-controlled, multicentre clinical trial

Participants Participants with a mean age of 3.8 years

Interventions Participants had D53 or placebo

Outcomes In a period of 3 months 75 D53 participants had 0.73 ± 0.1 (mean ± SE) ARTIs and 69 placebo participants had 1.5 ± 0.2 ARTIs

Notes The trial was conducted in FranceData were obtained from Boyle 2000 and Bellanti 2003 (trial RB13)




Giovannini 2000

Methods Randomised, double-blind, placebo-controlled clinical trial

Participants Children from 3 to 14 years with recurrent ARTI symptoms in the last 2 years who had also suffered from at least 5ARTIs requiring medical care in the last winter. 114 children were included

Interventions Participants had a tablets of 0.525 mg of ribosomal extracts (D53) or placebo daily by 4 days per week for the first 3weeks and then 1 tablet 4 consecutive days per month for the following 5 months

Outcomes 45 in D53 group and 42 in placebo group finished the trial. A clinical score for upper ARTIs was 0.46 in the D53group and 0.76 in the placebo group

Notes Drop-outs are explained, but adverse event description is not clear. Primary endpoint is a non-validated clinical score.There are no data on the dispersion of the variable. Trial was conducted in autumn, winter and spring in Italy

Gutiérrez-Tarango 2001


Participants Participants from 1 to 12 years with at least 3 ARTIs during the previous 6 months. 54children were randomized

Interventions At the beginning participants received either 1 capsule of 3.5 mg of OM-85 BV orplacebo a day by 10 days per month during 3 months. The treatment was repeated 6months after the beginningParticipants were followed for a total study period of 12 months

Outcomes During the trial the OM-85 BV group (n = 26) had 5.04 ± 1.99 (mean ± SD) ARTIswhile the placebo group (n = 28) had 8.0 ± 2.55Four OM-85 BV participants had 5 adverse events and 6 placebo participants had 6adverse events

Notes Flow of patient numbers and drop-outs are givenThe trial was conducted in MexicoThe trial was conducted during the 4 seasons

Risk of bias



Low risk



Low risk




Gutiérrez-Tarango 2001 (Continued)


Low risk


Low risk


Gómez-Barreto 1998


Participants Participants from 1.5 to 9 years suffering subacute sinusitis (lasting more than 60 days and less than 90 days)26 participants with OM-85 BV and 30 with placebo were included

Interventions Participants received either 1 capsule of 3.5 mg of OM-85 BV or placebo a day by 10 days per month during 3monthsBoth groups received amoxicillin/ clavulanate at entry; 40/10 mg/kg a day, divided in 3 doses, by 21 daysParticipants were followed up for 3 months for a total study period of 6 months

Outcomes During the study 26 participants with OM-85 BV had 1.56 ± 1.55 ARTIs and 30 participants with placebo had 2.22 ± 2.37 ARTIsA patient in the OM-85 BV presented rash and withdrew from the trial

Notes Definitions of subacute sinus and its cure are given. A sub-analysis for children under 6 years was includedDrop-outs are reported. But the flow of participants is not clearThe trial was conducted over the 4 seasons in Mexico

Hauguenauer 1987


Participants Participants aged less than 5 years with at least 3 ARTI treated with antibiotics in the last year

Interventions Participants had D53 or placebo. During the first month they had 3 weeks with 3 tablets per day for 4 days per week.The next 5 months they had a week per month with 3 tablets a day for 4 days

Outcomes In a period of 6 months 45 D53 participants had 3.24 ± 2.1 (mean ± SD) ARTIs and 42 placebo participants had4.9 ± 4.3 ARTIsThere were no adverse events

Notes The trial was conducted in FranceFlow of patient numbers is not clear. The trial was conducted from January to JuneARTIs data were obtained from Boyle 2000 and Bellanti 2003 (trial RB12)




Hüls 1995

Methods Randomised, double-blind, placebo-controlled, multicentre clinical trial

Participants Participants with a mean age from 3 to 12 years with at least 3 severe ARTIs in the last year

Interventions Participants had 3 tablets of 0.25 mg of D53 or placebo in the morning for 4 consecutive days a week for 3 consecutiveweeks. The following 5 months they had a 1 week cycle per month

Outcomes In a period of 6 months 78 D53 participants had 1.7 ± 0.16 (mean ± SE) ARTIs and 78 placebo participants had 2.5 ± 0.2 ARTIsThree participants in the D53 group had aggressiveness, cough and headache respectively; 2 placebo participantspresented fever and exudative erythema respectively

Notes It was conducted in Germany during boreal autumn-winter seasonsThis study is cited by Boyle, and it corresponds to RB14 in Bellanti’s review

Iuldashev 1988


Participants Healthy children from 2 to 6 years

Interventions 1100 children received Reaferon (an analogue of human interferon 2 obtained by genetic engineering) 1106 IU in0.5 ml of water orally twice a week for 2 months. 1078 received 0.5 ml of water as placebo

Outcomes Children from 2 to 3 years treated with Reaferon had 1.3 less ARTIs than the placebo group. Children > 3 years didnot have statistically significant improvement

Notes It is not stated that the trial is randomizedSelection criteria of the participants allows the inclusion of non-susceptible participantsThe study was conducted from September to October in the former USSR

Jara-Pérez 2000


Participants Girls from 6 to 13 years suffering more than 3 ARTI during fall and winter seasonsbefore the trial, living in an orphanage200 girls entered the trial

Interventions Participants received either 1 capsule of 3.5 mg of OM-85 BV or placebo once daily for10 days per month for 3 monthsParticipants were followed up for 3 months for a total study period of 6 months

Outcomes During the study period 99 OM-85 BV participants had 1.43 ± 0.94 (mean ± SD)ARTIs and 100 placebo participants had 2.99 ± 0.81 ARTIs. No adverse events relatedto the trial medications were reported




Jara-Pérez 2000 (Continued)

Notes The reason for excluding 1 participants from the analysis is givenConfounders are well controlled as all the participants had the same background andlived in the same place under the same conditionsThe trial was conducted in MexicoThe trial was conducted during the boreal autumn-winter seasons

Risk of bias



Low risk



Low risk


Low risk


Low risk


Karam-Bechara 1995


Participants Children from 3 to 12 years suffering recurrent bronchitis with 6 episodes probed by the physician prescriptions inthe last year with 3 antibiotic courses.80 participants were randomized

Interventions A vial (liquid form) with thymomodulin 3 mg/kg or placebo once a day by 3 months. There was no additional followup

Outcomes During the trial 33 thymomodulin participants had 1.59 ± 1.98 (mean ± SD) ARTIs and 39 placebo participantshad 2.61 ± 3.04 ARTIsParticipants did not present adverse events

Notes Drop-outs are explainedThe trial was conducted in MexicoThere were no data about the seasons during the trial




Lacomme 1985

Methods Double-blind, placebo-controlled, multicentre clinical trial

Participants Participants aged from 2 to 15 years with 5 to 7 ARTIs and 5 antibiotic courses during the last year

Interventions Participants had D53 or placebo. During the first month they had 3 weeks of 3 tablets a day for 4 days per week.The next 5 months they had a week per month with 3 tablets a day for 4 days

Outcomes In a period of 6 months 47 D53 participants had 4.04 ± 4.2 (mean ± SD) ARTIs and 40 placebo participants had5.38 ± 3.7 ARTIsThere was no adverse event in the D53 group, while there were 6 cases of digestive adverse events in the placebogroup

Notes The trial was conducted in France. There are no data about the seasons during the trialARTIs data were obtained from Boyle 2000 and Bellanti 2003 (trial RB11)

Litzman 1999


Participants Children from 4 to 8 years with at least 5 documented respiratory tract infections during the last autumn-winterseasons

Interventions Participants had placebo or isoprinosine, 50 mg/kg per day divided in 4 to 6 doses for a period of 6 weeks and then50 mg/kg per day twice a week during 6 weeks

Outcomes During the 6-month study period, 43 isoprinosine participants had 3.3 ± 1.9 (mean ± SD) ARTIs and 41 placeboparticipants had 3.9 ± 2.0 ARTIsA isoprinosine patient and a placebo patient had transit increase in antinuclear antibodies and 1 placebo participanthad an increase in the rheumatoid factor

Notes Reasons for drop-out are provided. Trial was conducted during autumn and winter in the Czech Republic

Longo 1988


Participants Children from 3.5 to 9 years with history of recurrent ARTI in the last fall-winter period with more than 1 feverepisode by month

Interventions Participants were followed by 1 year before the beginning of study medicationParticipants took thymomodulin 30 mg or placebo twice a day by 4 months plus a follow up of 8 months

Outcomes During 12 months the total number of infections was 26 in 21 participants treated with thymomodulin and 72 inthe 19 placebo participantsThe adverse events were not reported




Longo 1988 (Continued)

Notes Flow of patient numbers and drop-outs are not givenThe trial was conducted in ItalyThe trial was conducted during the 4 seasons

Maestroni 1984


Participants Children from 1 to 16 years who were susceptible to upper ARTIs20 participants were included

Interventions Participants received either 1 capsule of 3.5 mg of OM-85 BV or placebo a day by 10 days per month during 3monthsParticipants were followed up for 3 months for a total study period of 6 months

Outcomes During the study 11 participants receiving OM-85 BV had 2.0 ± 2.05 (mean ± SD) ARTIs and 9 participants withplacebo had 5.55 ± 5.36 ARTIsThe adverse events were not reported

Notes Inclusion criteria are not clearIt is not stated that the trial is randomized; the sample size is clearly insufficientThe trial was conducted in SwitzerlandThere were no data about the seasons during the trial

Martin du Pan 1982


Participants Children from 8 months to 5 years attending to daycare centres or those highly susceptible to ARTI

Interventions One capsule of 3.5 mg of OM-85 BV or placebo once a day for 10 days per month for 3 monthsParticipants were followed for a further 3 months for a total study period of 6 months

Outcomes During the 6-month study period 36 participants with OM-85 BV had 265/3660 days (7.24%) suffering frompurulent rhinorrhea, while 34 placebo participants had 569/3530 days (16.12%) suffering from purulent rhinorrheaThe adverse events were not reported

Notes The participants participated in a previous trial 1 year before comparing the effect of a syrup with yeast extract versusa placebo syrupFlow of patient numbers and drop-outs are not given. Sub-analyses for the children attending the daycare centresand private practice are providedThe trial was conducted in Switzerland during autumn-winter seasons




Mora 2002


Participants Children from 4 to 14 years with history of otitis and recurrent ARTIs by more than 2 years, with 3 ARTIs requiringmedical care the last winter. 84 children were included

Interventions Participants had a tablets of ribosomal extracts (D53) or placebo daily for 4 days per week for the first 3 weeks andthen 1 tablet for 4 consecutive days per month for the following 5 months

Outcomes 41 children in the D53 group and 40 in placebo group finished the 6-month trial. There were greater improvementsin D53 group regarding incidence of infections, otitis, fever and duration of antibiotic and ancillary treatments. OneD53 patient has dysuria and another 2 heartburn; 1 placebo patient had somnolence and another 1 had heartburn

Notes It was not established if trial was randomized. Drop-outs are explained. There is no clinical definition of otitis.Primary end points are a non-validated clinical scores given as ranks. To express a significant difference “P >” is used;for instance “P > 0.02”.Trial was conducted in autumn, winter and spring in ItalyIt is not possible to establish if this trial corresponds to any study cited by Bellanti in his review

Mora 2007

Methods Double-blind, placebo-controlled

Participants 160 participants from 5 to 14 years with recurrent pharyngotonsillitis

Interventions Participants had D53 or placebo 1 tablet a day, 8 days a month for 3 months plus 3 months of follow up

Outcomes The number of ARTIs was reported as an ordinal categorical scale (1, 2 or > 2). By the end of trial D53 score was 1and placebo 2 (no dispersion is reported). A clinical scale score was 1.9 in D53 group and 3.1 in placebo group

Notes The clinical scale was not described. The study was conducted in Italy. The flow diagram of the number of participantsis not included. Authors claimed that no participant experienced side effects from the treatment

Mora 2010a

Methods Randomised, double-blind, placebo-controlled

Participants 80 children aged between 6 and 14 years with recurrent acute adenoiditis defined as more than 4 episodes of acuteadenoiditis during a 6-month period. Acute adenoiditis was defined as mouth breathing, nasal obstruction, bodytemperature higher than 38 C, mucoid anterior nasal discharge, postnasal drip, otitis media and snoring

Interventions Group A children had D53 (Immucytal) 1 tablet daily, 8 days a month for 3 months; group B children had placeboin the same way. Both groups were followed 3 extra months

Outcomes After 3 months 2/30 in the D53 group and 12/30 in the placebo group had more than 1 acute episode of adenoiditis.After 6 months 2/30 in the D53 group and 18/30 in the placebo group had more than 1 acute episode of adenoiditis




Mora 2010a (Continued)

Notes Levels of IgE, IgA, IgG, and IgM were investigated, as well as tympanometry, rhinomanometry, and symptom visualanalogue scale by the parents. Only 60 participants completed the trial, the lost of participants are explained

Motta 1994


Participants Children from 3 to 14 years with history of recurrent tonsillitis with at least 8 episodes in the last 2 years, who hadsuffered tonsillitis 10 days before the enrolment to the trial

Interventions Pidotimod 400 mg (liquid form) or placebo twice a day by 15 days; then pidotimod 400 mg or placebo once a dayby 45 days. Participants were followed up for another 90 days

Outcomes During the trial 117 pidotimod participants had 1.96 ± 1.80 (mean ± SD) ARTIs and the 118 placebo participantshad 3.12 ± 2.45 ARTIs11 pidotimod participants had 15 adverse events, while 12 placebo participants had 18 adverse events, mainlygastrointestinal complaints

Notes Flow diagram of participants and drop-outs are not given. Number of infections per group was reconstructed fromthe reported frequenciesMost of the pidotimod papers were published in a single supplement issue of a German magazineThe trial was conducted in ItalyThere were no data about the seasons during the trial

Passali 1994a


Participants Children from 3 to 14 years with history of tonsillitis or pharyngitis in the previous autumn-winter seasons429 participants were randomized

Interventions Pidotimod 400 mg or placebo once a day for 2 months plus a follow-up period of 3 months

Outcomes Total number of infections during the treatment period of 2 months and the follow up period of 3 months were 186and 129 in the 205 pidotimod participants, while for the same periods the number of ARTIs were 278 and 276 in216 placebo participantsThere were 5 adverse events in the pidotimod group and 10 in the placebo group, mainly gastrointestinal complaints

Notes Flow of patient numbers and drop-outs are givenOnly the total number of ARTIs per group is reportedMost of the pidotimod papers were published in a single supplement issue of a German magazineThe trial was conducted in ItalyThere were no data about the seasons during the trial




Paupe 1986


Participants Children from 1 to 13 years with history of recurrent rhinopharyngeal infection with at least 3 infections of this kindduring the year before the study

Interventions 2 capsules with 1 mg of Klebsiella products (RU41740) or placebo once a day for 8 days; 3 weeks without treatment;then 1 capsule a day for 8 days per month for 2 months; plus an additional follow up period of 21 weeksThe total period of the study was 6 months

Outcomes During the study period 21 participants with RU41740 had 1.57 ± 1.60 (mean ± SD) ARTIs and 22 placeboparticipants had 2.41 ± 2.59 ARTIs. There was 1 case of diarrhea and 1 of urticaria in the RU41740 group

Notes ARTI data were obtained from a paper by Reinert 1995 as he reported the data as mean ± SD. Safety data are fromPaupeThe trial was conducted in FranceThere were no data about the seasons during the trial

Paupe 1991


Participants Participants from 0.5 to 19 years, with history of more than 3 ARTIS in the last 6 months. 127 participants wererandomized

Interventions Participants received either 1 capsule of 3.5 mg of OM-85 BV or placebo a day for 10 days per month for 3 monthsParticipants were followed for another 3 months for a total study period of 6 months

Outcomes During the study 34% of 61 participants with OM-85 BV and 3.5% of 55 participants with placebo had no infectionOne patient with OM-85 BV, 2 with placebo had diarrhea

Notes The reasons for excluding participants from the analysis are givenThe trial was conducted in FranceThere were no data about the seasons during the trial

Pech 1987



Interventions 2 capsules with 1 mg of Klebsiella products (RU41740) or placebo once a day by 8 days; 3 weeks without treatment;then a capsule once a day for 8 days per month for 2 months; plus an additional follow-up period of 21 weeksThe total period of the study was 6 months




Pech 1987 (Continued)

Outcomes During the study period 35 participants with RU41740 had 1.11 ± 1.16 (mean ± SD) ARTIs and 34 placeboparticipants had 1.88 ± 1.43 ARTIsIn RU41740 group 1 patient presented dry cough and another had difficulties in swallowing

Notes ARTI data were obtained from a paper by Reinert 1995The number of ARTIs in the placebo group is lowThe trial was conducted in FranceThere were no data about the seasons during the trial

Piquett 1986



Interventions 2 capsules with 1 mg of Klebsiella products (RU41740) or placebo once a day by 8 days; 3 weeks without treatment;then a capsule a day by 8 days per month by 2 months; plus an additional follow-up period of 21 weeksThe total period of the study was 6 months

Outcomes During the study period 17 participants with RU41740 had 1.35 ± 1.41 (mean ± SD) ARTIs and 20 placeboparticipants had 1.35 ± 1.46 ARTIsAdverse events report is not available

Notes ARTI data were obtained from a paper by Reinert 1995The number of ARTIs in the placebo group is lowThe trial was conducted in FranceThere were no data about the seasons during the trial

Pozzi 2004


Participants Children with recurrent ARTIs from 1.5 to 15.2 years

Interventions The participants had bacterial lysate (Lantigen B) or placebo. Participants received 7 to 8 drops twice a day during:weeks 1, 2, 3 and 4 of the second month; weeks 3 and 4 of the third month; weeks 3 and 4 of the fourth month;weeks 1 and 2 of the sixth month; weeks 1 and 2 of the seventh month

Outcomes During the 6-month period 47 Lantigen B participants had a mean number of ARTIS of 1.211 while 47 placeboparticipants had 1.643. The number but not the kind of adverse events are reported

Notes Drop-outs are explainedDispersion of the mean number of ARTIs (SD) is not providedA group of adults was also included in the trialThere were no data on the seasons during the trial




RB10 1994

Methods Double blind, placebo-controlled trial

Participants Children

Interventions D53 or placebo for 6 months

Outcomes 153 D53 participants had 1.13 ± 1.2 (mean ± SD) ARTIs and 161 placebo participants had 1.32 ± 1.4 ARTIs. Noadverse event report is provided

Notes Available data are from the Bellanti review. It was not possible to establish if this trial corresponds to any otherpublished trial

RB17 1988

Methods Double blind, placebo-controlled trial



Outcomes By the third month, 15 D53 participants had 1.2 ± 0.86 (mean ± SD) ARTIs and 15 placebo participants had 3.73± 2.05 ARTIs. No adverse event report was provided

Notes Available data are from the Bellanti review. It was not possible to establish if this trial corresponds to any otherpublished trialThe number of ARTIs is extremely high

RB21 1988









RB22 1990

Methods Double blind placebo-controlled trial



Outcomes 20 D53 participants had 3.0 ± 1.0 (mean ± SD) ARTIs and 20 placebo participants had 6.2 ± 1.4 ARTIs. No adverseevent report is provided

Notes Available data are from the Bellanti review. It was not possible to establish if this trial corresponds to any otherpublished trialThe number of ARTIs is extremely high

RB24 1990






RB25 1990









Renzo 2004


Participants Children from 6 to 14 years with history of recurrent or chronic ARTIs for more than 2 years and at least 5 ARTIsin the last years or suffering otitis media by more than 3 months. 72 children were included

Interventions Ribosomal extracts (D53) or placebo, 1 tablet daily in the morning 8 days per month for 3 consecutive months

Outcomes 36 children in each group finished the 6-month trial. There were greater improvements in D53 group regardingincidence of infections, otitis, fever, and duration of antibiotic and ancillary treatments. According to the authorsthere was no adverse event

Notes Drop-outs are explained. There is no clinical definition of otitis. Primary endpoints are a non-validated clinical scoresgiven as ranks. To express a significant difference “P >” is used; for instance “P > 0.02”Trial was conducted in autumn, winter and spring in ItalyIt is not possible to establish if this trial correspond to any study cited by Bellanti in his review

Riedl-Seifert 1995


Participants Children from 4 to 9 years, with history of 10 ARTIs in the last yearChildren from 4 to 6 years must have 8 severe ARTIs lasting more than 2 weeks in this periodChildren from 7 to 9 years must have 4 severe ARTIs lasting more than 2 weeks in this period115 children had LW50020 and 118 had placebo

Interventions Dosage is not specified. Total follow up of 14 weeks

Outcomes During the study period 99 participants with LW50020 had 15 ARTIs and 108 participants with placebo had 29ARTIs data dispersion is not specified10.4% of participants with LW50020 experienced adverse events versus 5.1% in the placebo group. The adverseevents were mainly gastrointestinal complaints

Notes The reasons for participants’ exclusion from analysis are given. The intervention is not well definedThe trial was conducted in GermanyThere were no data about the seasons during the trial

Rutishauser 1998


Participants Children from 4 to 11 years with history of recurrent ARTIs; children from 4 to 6 years with more than 10 ARTIsin the last year, those from 7 to 11 with more than 8 ARTIs in the last year. 200 children were includedParticipants suffering 4 ARTIs lasting more than 2 weeks were included too124 children had LW50020 and 76 had placebo

Interventions The total duration of the trial was 16 weeks: 4-week treatment (a tablet with 3 mg of bacterial lysates or placebo oncea day); 4-week follow up; 4-week treatment (same schedule); and 4-week follow up




Rutishauser 1998 (Continued)

Outcomes Considering only children. During the study period 75% of 117 participants with LW50020 had no infection and54% of 72 placebo participants had no infectionConsidering children and adults, 62 participants had 101 adverse events in the LW50020 group, while 26 participantshad 38 adverse events in the placebo group

Notes The reason for excluding participants from the analysis are not givenBeside the children group, the trial included a group of adolescents and adultsThe trial was conducted in SwitzerlandThe trial was conducted during the 4 seasons

Saracho-Weber 2001


Participants Children older than 2 years and younger than 18 years currently suffering acute orchronic ARTIs and history of 3 ARTIs the last year

Interventions 135 participants had RU 41740 (1 mg of klebsiella glycoproteins by tablet) and 117placebo. Participants had 1 tablet OD for 8 consecutive days per month, for 3 consecutivemonthsThe total period of the study was 12 months

Outcomes Participants with RU 41740 had 8.0 ± 3.4 (mean ± SD) ARTIs and placebo participants7.2 ± 3.2. Yet authors claimed that RU 41740 participants experienced clinical improve-mentAuthors did not describe the adverse events

Notes There is no flow diagram of the study, nor explanation of drop-outs. This is the onlystudy where the active treatment participants had a higher ARTIs number, probably aclerical mistake

Risk of bias



High risk

Schaad 1986


Participants Participants from 8 months to 12 years with who had recurrent ARTIs during fall and winter seasons in the last year45 participants received OM-85 BV and 49 placebo

Interventions One capsule of 3.5 mg of OM-85 BV or placebo a day by 10 days per month during 3 monthsParticipants were followed up for 3 months for a total study period of 6 months




Schaad 1986 (Continued)

Outcomes During the study 45 OM-85 BV participants had 2.89 ± 1.77 (mean ± SD) ARTIs and 49 placebo participants had2.98 ± 1.56 ARTIsOnly 1 patient in the placebo group had urticaria

Notes It is not stated that the trial is randomized. Flow diagram of participants is not providedThe trial was conducted in Germany during autumn-winter seasons

Schaad 2002


Participants Participants from 36 to 96 months with a history of recurrent ARTIs

Interventions One capsule of 3.5 mg of OM-85 BV or placebo once a day for 10 days per month for 3 monthsParticipants were followed for another 3 months for a total study period of 6 months120 participants had OM-85 BV and 100 placebo

Outcomes The mean cumulative difference of ARTIs between the groups was -0.4 or a reduction of 16%, favorable to OM-85BV. 88 participants with OM-85 BV had 456 adverse events and 76 placebo participants had 379 events. Most ofthe adverse events were gastrointestinal and respiratory

Notes There is no flow diagram of the study, nor explanation of drop-outs. This trial was conducted in Germany andSwitzerland during summer and autumn. There are no data on the dispersion of ARTIs (SD)A later review by the same author reported ARTIs; 2.12 ± 1.44 for OM-85 and 2.48 ± 1.63

Sramek 1986

Methods Double-blind, placebo-controlled, multicentre trial

Participants Children from 3 to 6 years attending school or maternal school1203 entered the trial, only 1152 completed the trial and their data were used for analysis

Interventions Spray application of IRS19 (n = 416) or placebo (n = 409) during 20 days, a group ofparticipants (327) did not receive any medication, the total duration of the follow up isvariable (about 6 months)

Outcomes The number of ARTIs as cases per 1000 persons days was IRS19 7.79, placebo 7.43,and no-treatment 8.04Adverse events were not reported

Notes Randomisation was unblinded ascribing children to 1 of 2 medication batches or leftwithout treatmentReasons for drop-outs are not specifiedOnly ARTIs associated with school absenteeism were considered. Tonsillitis, sinusitisand otitis media were not considered. There is a bias to consider only severe infectionsThe trial was conducted in the former CzechoslovakiaThe trial was conducted during autumn-winter seasons




Sramek 1986 (Continued)

Risk of bias



High risk

Allocation concealment (selection bias) High risk


High risk


High risk


High risk


High risk


High risk

Selective reporting (reporting bias) High risk

Taylor 2003


Participants Children from 2 to 11 years without significant health problems

Interventions Participants had a preparation of Echinacea purpurea or placebo. Children from 2 to 5years had 3.75 ml twice a day and children from 6 to 11 years had 5 ml twice a dayduring ARTIs (up to 3 ARTIs, during a maximum of 10 days each). The study periodwas 4 months

Outcomes 200 children with echinacea had 337 ARTIs and 207 with placebo had 370 ARTIs. 52.3% of the children with echinacea and 64.4% of the children with placebo had morethan 1 ARTIEchinacea and placebo. Participants had 152 and 146 adverse events respectively. Mostof the adverse events were cutaneous and gastrointestinal




Taylor 2003 (Continued)

Notes Flow diagram of participants is provided. Subject did not have history of recurrent ARTIs.The trial was conducted in the USA during autumn, winter and spring

Risk of bias



Low risk



Low risk


Low risk


Low risk


Low risk


Low risk


Van Eygen 1976

Methods Randomised, double-blind, placebo-controlled multicentre trial

Participants Children aged 1.8 to 14.5 years with history of relapsing upper ARTIs in winter

Interventions Participants had placebo or levamisole 1.25 mg/kg twice a day for 2 consecutive days every week for 6 months

Outcomes 38 levamisole participants had 1.6 ± 1.5 (mean ± SD) ARTIs while 32 placebo participants had 3.8 ± 2.0 ARTIsAuthors claim that no adverse event were observed

Notes Apparently, there were no drop-outs. The trial was conducted in Belgium during autumn and winter




Van Eygen 1979


Participants Children from 0.6 to 16 years suffering recurrent ARTIs

Interventions Participants had syrup with placebo or 5 mg of levamisole per ml. Participants had 5 ml of syrup per 5 kg twice aday for 2 consecutive days every week

Outcomes After 6 months 53 levamisole participants had 1.28 ± 1.49 (mean ± SD) ARTIs and the placebo group 3.07 ±1.89ARTIsOnly 1 patient with levamisole had stomach complaints

Notes Apparently, there were no drop-outs. The trial was conducted in Belgium during autumn and winter

Vautel 1993


Participants Children aged 2.98 ± 0.17 years (mean ± SE) with history of 5 ARTIs during the last 12 months or with 3 ARTIsduring the last 3 months

Interventions D53 or placebo 3 tablets daily taken as a single dose 4 days per week for the first 3 weeks and then 4 consecutive daysper month for the following 5 months

Outcomes During the 6-month period 32 D53 participants had 3.39 ± 0.38 (mean ± SE) ARTIs and 32 placebo participantshad 5.56 ± 0.39 ARTIsRegarding adverse events D53 participants had 3 cases of rhinitis and placebo participants had 3 cases of rhinitis, 1of pharyngitis, and 1 with abdominal pain

Notes Flow of number of participants and drop-out are not reported. The trial was conducted in the private practicePotential ARTIs were reported as adverse eventsThe trial was conducted in FranceThere were no data about the seasons during the trial. This trial corresponds to the study RB 15 in the Bellanti review

Wahl 2008

Methods Randomised, placebo-controlled, two-by-two factorial trial with 6-month follow up

Participants 90 children aged 12 to 60 months with recurrent otitis media, defined as 3 or more separate episodes of acute otitismedia (AOM) within 6 months, or at least 4 episodes in 1 year

Interventions Children were randomly assigned to 1 of 4 protocol groups: double placebo, echinacea plus sham osteopathic ma-nipulative treatment (OMT), true OMT (including cranial manipulation) plus placebo echinacea, or true echinaceaplus OMT. An alcohol extract of Echinacea purpurea roots and seeds (or placebo) was administered for 10 days at thefirst sign of each common cold. Five OMT visits (or sham treatments) were offered over 3 months




Wahl 2008 (Continued)

Outcomes As no interaction was found between echinacea and OMT, the results of echinacea versus placebo were presented;65% of children assigned to echinacea experienced AOM compared to 41% of children taking placebo (RR 1.59;95% CI 1.04 to 2.42)

Notes Only 62% of the participants completed the follow-up period of 6 months

Zagar 1988


Participants Children from 4 to 12 years, suffering from chronic rhino-sinusitis during a symptomatic episode of the disease55 participants were randomized

Interventions Participants received either 1 capsule of 3.5 mg of OM-85 BV or placebo once a day by 30 days. After 1 month 1capsule 1 day for 10 days per month for 3 months. Participants received antibiotics at the beginning of the trial. Thetotal period of the trial was 6 months

Outcomes During the study period 29 with OM-85 BV had 0.38 ± 0.26 (mean ± SD) ARTIs and 22 participants with placebohad 1.09 ± 0.65 ARTIsParticipants did not present adverse events

Notes Clinical definitions of chronic sinusitis and its cure are not providedThe reasons for excluding participants from the analysis are not given. The number of ARTIs is rather lowThe trial was conducted in the former YugoslaviaThe trial was conducted during autumn-winter seasons

ARTI = acute respiratory tract infectionRTIs = respiratory tract infectionsSD = standard deviationCOPD = chronic obstructive airways diseaseiv = intravenouslyn = numberIgG = immunoglobulin GOD = daily

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Almeida 1999 Only included participants with asthma

Aymard 1994 The trial was part of the Collet’s study. Yet, it is a good paper and it is the only one showing prevention ofviral ARTIs proved with viral test




(Continued)

Barr 1965 It was a trial on asthmatic children

Bánovein 1992 Comparison between IS without placebo group

Das 2000 The age of the participants is not specified

Fiocchi 1990 Unable to ascertain whether this was a subgroup of an included study Fiocchi 1989

Fontana 1965 It was a trial on asthmatic children

Grimfeld 2004 The trial used an antihistaminic

Grimm 1999 Results of children and adults are not separated

Heinz 2010 The trial was on adults

Herrera-Basto 1998 The results only compare the effect of pidotimod during the acute phase of ARTIs

Kozhukharova 1987 Trial was not double-blind, placebo-controlled

Lauriello 1990 It was a trial during the acute phase of respiratory infection in children

Luchikhin 2000 Trial was not double-blind, placebo-controlled

Ma 1994 Trial was not double-blind, placebo-controlled

Macchi 2005 Open trial in adults

Makovetskaya 2001 Trial was not double-blind, placebo-controlled

Mora 2010b Trial on acute adenoiditis not on prevention of acute respiratory tract infections

Mueller 1969 It was a study on asthmatic participants

Nespoli 1992 It was a randomized, multicentre trial - it did not include a placebo group but a group without treatment

Obrosova-Serova 1972 Trial was not double-blind, placebo-controlled

Oggiano 1985 It was an open trial on children

Oldini 1990 It was a Ribomunyl trial including adults and children without a separate analysis for each group

Ortega del 2005 It was an acute phase trial

Predy 2005 It is a trial in adults

Prusek 1987 Comparison between IS without placebo group




(Continued)

Razi 2010 The trial included children with asthma symptoms

Riedl-Seifert 1993 The report duplicates the results of Riedl-Seifert 1995

Rosaschino 2004 It was an open trial

Rossi 2004 It was an open trial in adults

Ruah 2001 Both study groups had immunostimulants

Rytel 1974 It was a trial in an adult population

Scotti 1987 It was an open trial in children without a control group

Steinsbekk 2005 The trial used a homeopathic medicine

Vascotto 1985 It was an open trial in children without a control group

Yale 2004 It was an acute phase trial in adults

IS = immunostimulants




D A T A A N D A N A L Y S E S

Comparison 1. Any IS compared with placebo

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Mean number of ARTIs 35 4060 Mean Difference (IV, Random, 95% CI) -1.24 [-1.54, -0.94]2 Percent difference in ARTIs 35 4060 Mean Difference (IV, Random, 95% CI) -38.84 [-46.37, -31.

31]

Comparison 2. Bacterial IS compared with placebo


studies

No. of



31]

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


studies

No. of



63]

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

placebo


studies

No. of



80]




Comparison 5. Adverse events


studies

No. of


1 Gastrointestinal adverse events 10 1457 Risk Difference (M-H, Fixed, 95% CI) 0.01 [-0.01, 0.03]2 Skin adverse events 10 1469 Risk Difference (M-H, Fixed, 95% CI) 0.00 [-0.01, 0.01]

Comparison 6. OM-85 trials


studies

No. of



35]

Comparison 7. D53 trials


studies

No. of



72]




Analysis 1.1. Comparison 1 Any IS compared with placebo, Outcome 1 Mean number of ARTIs.

Review: Immunostimulants for preventing respiratory tract infection in children

Comparison: 1 Any IS compared with placebo

Outcome: 1 Mean number of ARTIs

Study or subgroup Immunostimulant Control Mean Difference Weight Mean Difference

N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Ahrens 1984 83 3.75 (3.42) 72 5.04 (4.04) 2.3 % -1.29 [ -2.48, -0.10 ]

Arroyave 1999 42 2.8 (1.3) 44 8.4 (1.9) 3.0 % -5.60 [ -6.29, -4.91 ]

Careddu 1994a 329 0.75 (0.99) 342 1.03 (1) 3.6 % -0.28 [ -0.43, -0.13 ]

Clerici 1988 20 2.55 (0.6) 20 4.6 (0.6) 3.4 % -2.05 [ -2.42, -1.68 ]

Cohen 2004 160 0.9 (1.1) 168 1.8 (1.3) 3.5 % -0.90 [ -1.16, -0.64 ]

De Loore 1979 15 1.3 (1.2) 17 2.3 (1.7) 2.5 % -1.00 [ -2.01, 0.01 ]

Del-Rio-Navarro 2003 20 2.8 (1.4) 20 5.2 (1.5) 2.7 % -2.40 [ -3.30, -1.50 ]

Fiocchi 1986 8 0.53 (0.11) 8 0.82 (0.12) 3.6 % -0.29 [ -0.40, -0.18 ]

Garabedian 1990 75 0.73 (0.87) 69 1.5 (1.66) 3.3 % -0.77 [ -1.21, -0.33 ]

Guti?rrez-Tarango 2001 26 5.04 (1.99) 28 8 (2.55) 2.2 % -2.96 [ -4.18, -1.74 ]

G?mez-Barreto 1998 26 1.56 (1.55) 30 2.22 (2.37) 2.5 % -0.66 [ -1.70, 0.38 ]

Hauguenauer 1987 45 3.24 (2.1) 42 4.9 (4.3) 2.0 % -1.66 [ -3.10, -0.22 ]

H?ls 1995 78 1.7 (1.41) 78 2.5 (1.77) 3.3 % -0.80 [ -1.30, -0.30 ]

Jara-P?rez 2000 99 1.43 (0.94) 100 2.99 (0.81) 3.5 % -1.56 [ -1.80, -1.32 ]

Karam-Bechara 1995 33 1.59 (1.98) 39 2.61 (3.04) 2.3 % -1.02 [ -2.19, 0.15 ]

Lacomme 1985 47 4.04 (4.2) 40 5.38 (3.7) 1.7 % -1.34 [ -3.00, 0.32 ]

Litzman 1999 43 3.3 (1.9) 41 3.9 (2) 2.8 % -0.60 [ -1.44, 0.24 ]

Maestroni 1984 11 2 (2.05) 9 5.55 (5.36) 0.5 % -3.55 [ -7.26, 0.16 ]

Motta 1994 117 1.96 (1.8) 118 3.12 (2.45) 3.2 % -1.16 [ -1.71, -0.61 ]

Paupe 1986 21 1.57 (1.6) 22 2.41 (2.59) 2.2 % -0.84 [ -2.12, 0.44 ]

Pech 1987 35 1.11 (1.16) 34 1.88 (1.43) 3.1 % -0.77 [ -1.39, -0.15 ]

Piquett 1986 17 1.35 (1.41) 20 1.35 (1.46) 2.7 % 0.0 [ -0.93, 0.93 ]

RB10 1994 153 1.13 (1.2) 161 1.32 (1.4) 3.5 % -0.19 [ -0.48, 0.10 ]

RB17 1988 15 1.2 (0.86) 15 3.73 (2.05) 2.4 % -2.53 [ -3.66, -1.40 ]

RB21 1988 45 0.54 (0.6) 42 0.95 (0.5) 3.5 % -0.41 [ -0.64, -0.18 ]

RB22 1990 20 3 (1) 20 6.2 (1.4) 2.9 % -3.20 [ -3.95, -2.45 ]

-4 -2 0 2 4

Favours immunostimulant Favours control

(Continued . . . )




(. . . Continued)Study or subgroup Immunostimulant Control Mean Difference Weight Mean Difference


RB24 1990 16 0.36 (0.5) 17 0.92 (0.8) 3.3 % -0.56 [ -1.01, -0.11 ]

RB25 1990 13 1.31 (0.2) 12 3.25 (0.6) 3.4 % -1.94 [ -2.30, -1.58 ]

Saracho-Weber 2001 135 8 (3.4) 117 7.2 (3.2) 2.8 % 0.80 [ -0.02, 1.62 ]

Schaad 1986 45 2.89 (1.77) 49 2.98 (1.56) 3.0 % -0.09 [ -0.77, 0.59 ]

Schaad 2002 98 2.12 (1.44) 85 2.48 (1.63) 3.3 % -0.36 [ -0.81, 0.09 ]

Van Eygen 1976 38 1.6 (1.5) 32 3.8 (2) 2.8 % -2.20 [ -3.04, -1.36 ]

Van Eygen 1979 53 1.28 (1.49) 53 3.07 (1.89) 3.1 % -1.79 [ -2.44, -1.14 ]

Vautel 1993 32 3.39 (2.15) 32 5.56 (2.21) 2.5 % -2.17 [ -3.24, -1.10 ]

Zagar 1988 29 0.38 (0.26) 22 1.09 (0.65) 3.5 % -0.71 [ -1.00, -0.42 ]

Total (95% CI) 2042 2018 100.0 % -1.24 [ -1.54, -0.94 ]

Heterogeneity: Tau2 = 0.64; Chi2 = 582.02, df = 34 (P<0.00001); I2 =94%

Test for overall effect: Z = 8.18 (P < 0.00001)

Test for subgroup differences: Not applicable

-4 -2 0 2 4





Analysis 1.2. Comparison 1 Any IS compared with placebo, Outcome 2 Percent difference in ARTIs.


Comparison: 1 Any IS compared with placebo

Outcome: 2 Percent difference in ARTIs



Ahrens 1984 83 74.4 (67.86) 72 100 (80.16) 2.9 % -25.60 [ -49.18, -2.02 ]

Arroyave 1999 42 33.33 (15.48) 44 100 (22.62) 3.9 % -66.67 [ -74.83, -58.51 ]

Careddu 1994a 329 72.82 (96.12) 342 100 (97.09) 3.6 % -27.18 [ -41.80, -12.56 ]

Clerici 1988 20 55.43 (13.04) 20 100 (13.04) 3.9 % -44.57 [ -52.65, -36.49 ]

Cohen 2004 160 50 (61.11) 168 100 (72.22) 3.6 % -50.00 [ -64.45, -35.55 ]

De Loore 1979 15 56.62 (52.17) 17 100 (73.91) 1.7 % -43.38 [ -87.33, 0.57 ]

Del-Rio-Navarro 2003 20 53.85 (26.92) 20 100 (28.85) 3.4 % -46.15 [ -63.44, -28.86 ]

Fiocchi 1986 8 64.63 (13.41) 8 100 (14.63) 3.6 % -35.37 [ -49.12, -21.62 ]

Garabedian 1990 75 48.67 (58) 69 100 (110.67) 2.5 % -51.33 [ -80.56, -22.10 ]

Guti?rrez-Tarango 2001 26 63 (24.88) 28 100 (31.88) 3.5 % -37.00 [ -52.20, -21.80 ]

G?mez-Barreto 1998 26 70.27 (69.82) 30 100 (106.76) 1.6 % -29.73 [ -76.42, 16.96 ]

Hauguenauer 1987 45 66.12 (42.86) 42 100 (87.76) 2.5 % -33.88 [ -63.23, -4.53 ]

H?ls 1995 78 68 (56.4) 78 100 (70.8) 3.2 % -32.00 [ -52.09, -11.91 ]

Jara-P?rez 2000 99 47.83 (31.44) 100 100 (27.09) 3.9 % -52.17 [ -60.33, -44.01 ]

Karam-Bechara 1995 33 60.92 (75.86) 39 100 (116.48) 1.7 % -39.08 [ -83.87, 5.71 ]

Lacomme 1985 47 75.09 (78.07) 40 100 (68.77) 2.4 % -24.91 [ -55.77, 5.95 ]

Litzman 1999 43 84.62 (48.72) 41 100 (51.28) 3.1 % -15.38 [ -36.79, 6.03 ]

Maestroni 1984 11 36.04 (36.94) 9 100 (96.58) 1.0 % -63.96 [ -130.73, 2.81 ]

Motta 1994 117 62.82 (57.69) 118 100 (78.53) 3.4 % -37.18 [ -54.79, -19.57 ]

Paupe 1986 21 65.15 (66.39) 22 100 (107.47) 1.4 % -34.85 [ -87.98, 18.28 ]

Pech 1987 35 59.04 (61.7) 34 100 (76.06) 2.3 % -40.96 [ -73.69, -8.23 ]

Piquett 1986 17 100 (104.44) 20 100 (108.15) 0.9 % 0.0 [ -68.64, 68.64 ]

RB10 1994 153 85.61 (90.91) 161 100 (106.06) 3.1 % -14.39 [ -36.21, 7.43 ]

RB17 1988 15 32.17 (23.06) 15 100 (54.96) 2.5 % -67.83 [ -97.99, -37.67 ]

RB21 1988 45 56.84 (63.16) 42 100 (52.63) 2.9 % -43.16 [ -67.53, -18.79 ]

RB22 1990 20 48.39 (16.13) 20 100 (22.58) 3.7 % -51.61 [ -63.77, -39.45 ]

-50 -25 0 25 50


(Continued . . . )






RB24 1990 16 39.13 (54.35) 17 100 (86.96) 1.5 % -60.87 [ -110.04, -11.70 ]

RB25 1990 13 40.31 (6.15) 12 100 (18.46) 3.8 % -59.69 [ -70.66, -48.72 ]

Saracho-Weber 2001 135 111.11 (47.22) 117 100 (44.44) 3.8 % 11.11 [ -0.22, 22.44 ]

Schaad 1986 45 96.98 (59.4) 49 100 (52.35) 3.0 % -3.02 [ -25.74, 19.70 ]

Schaad 2002 98 85.48 (58.06) 85 100 (65.72) 3.3 % -14.52 [ -32.61, 3.57 ]

Van Eygen 1976 38 42.11 (39.47) 32 100 (52.63) 3.0 % -57.89 [ -80.03, -35.75 ]

Van Eygen 1979 53 41.69 (48.53) 53 100 (61.56) 3.1 % -58.31 [ -79.41, -37.21 ]

Vautel 1993 32 60.97 (38.67) 32 100 (39.75) 3.3 % -39.03 [ -58.24, -19.82 ]

Zagar 1988 29 34.86 (23.85) 22 100 (59.63) 2.7 % -65.14 [ -91.53, -38.75 ]

Total (95% CI) 2042 2018 100.0 % -38.84 [ -46.37, -31.31 ]




-50 -25 0 25 50





Analysis 2.1. Comparison 2 Bacterial IS compared with placebo, Outcome 1 Mean number of ARTIs.


Comparison: 2 Bacterial IS compared with placebo




Ahrens 1984 83 3.75 (3.42) 72 5.04 (4.04) 3.7 % -1.29 [ -2.48, -0.10 ]

Arroyave 1999 42 2.8 (1.3) 44 8.4 (1.9) 4.5 % -5.60 [ -6.29, -4.91 ]

Del-Rio-Navarro 2003 20 2.8 (1.4) 20 5.2 (1.5) 4.2 % -2.40 [ -3.30, -1.50 ]

Garabedian 1990 75 0.73 (0.87) 69 1.5 (1.66) 4.8 % -0.77 [ -1.21, -0.33 ]


G?mez-Barreto 1998 26 1.56 (1.55) 30 2.22 (2.37) 3.9 % -0.66 [ -1.70, 0.38 ]

Hauguenauer 1987 45 3.24 (2.1) 42 4.9 (4.3) 3.3 % -1.66 [ -3.10, -0.22 ]

H?ls 1995 78 1.7 (1.41) 78 2.5 (1.77) 4.7 % -0.80 [ -1.30, -0.30 ]

Jara-P?rez 2000 99 1.43 (0.94) 100 2.99 (0.81) 5.0 % -1.56 [ -1.80, -1.32 ]

Lacomme 1985 47 4.04 (4.2) 40 5.38 (3.7) 2.9 % -1.34 [ -3.00, 0.32 ]

Maestroni 1984 11 2 (2.05) 9 5.55 (5.36) 1.1 % -3.55 [ -7.26, 0.16 ]

Paupe 1986 21 1.57 (1.6) 22 2.41 (2.59) 3.5 % -0.84 [ -2.12, 0.44 ]

Pech 1987 35 1.11 (1.16) 34 1.88 (1.43) 4.6 % -0.77 [ -1.39, -0.15 ]

Piquett 1986 17 1.35 (1.41) 20 1.35 (1.46) 4.1 % 0.0 [ -0.93, 0.93 ]

RB10 1994 153 1.13 (1.2) 161 1.32 (1.4) 5.0 % -0.19 [ -0.48, 0.10 ]

RB17 1988 15 1.2 (0.86) 15 3.73 (2.05) 3.8 % -2.53 [ -3.66, -1.40 ]

RB21 1988 45 0.54 (0.6) 42 0.95 (0.5) 5.0 % -0.41 [ -0.64, -0.18 ]

RB22 1990 20 3 (1) 20 6.2 (1.4) 4.4 % -3.20 [ -3.95, -2.45 ]

RB24 1990 16 0.36 (0.5) 17 0.92 (0.8) 4.8 % -0.56 [ -1.01, -0.11 ]

RB25 1990 13 1.31 (0.2) 12 3.25 (0.6) 4.9 % -1.94 [ -2.30, -1.58 ]

Schaad 1986 45 2.89 (1.77) 49 2.98 (1.56) 4.5 % -0.09 [ -0.77, 0.59 ]

Schaad 2002 98 2.12 (1.44) 85 2.48 (1.63) 4.8 % -0.36 [ -0.81, 0.09 ]

Vautel 1993 32 3.39 (2.15) 32 5.56 (2.21) 3.9 % -2.17 [ -3.24, -1.10 ]

Zagar 1988 29 0.38 (0.26) 22 1.09 (0.65) 5.0 % -0.71 [ -1.00, -0.42 ]

Total (95% CI) 1091 1063 100.0 % -1.41 [ -1.85, -0.98 ]




-2 -1 0 1 2





Analysis 2.2. Comparison 2 Bacterial IS compared with placebo, Outcome 2 Percent difference in ARTIs.


Comparison: 2 Bacterial IS compared with placebo




Ahrens 1984 83 74.4 (67.86) 72 100 (80.16) 4.4 % -25.60 [ -49.18, -2.02 ]

Arroyave 1999 42 33.33 (15.48) 44 100 (22.62) 6.8 % -66.67 [ -74.83, -58.51 ]

Del-Rio-Navarro 2003 20 53.85 (26.92) 20 100 (28.85) 5.4 % -46.15 [ -63.44, -28.86 ]

Garabedian 1990 75 48.67 (58) 69 100 (110.67) 3.6 % -51.33 [ -80.56, -22.10 ]


G?mez-Barreto 1998 26 70.27 (69.82) 30 100 (106.76) 2.1 % -29.73 [ -76.42, 16.96 ]

Hauguenauer 1987 45 66.12 (42.86) 42 100 (87.76) 3.6 % -33.88 [ -63.23, -4.53 ]

H?ls 1995 78 68 (56.4) 78 100 (70.8) 5.0 % -32.00 [ -52.09, -11.91 ]

Jara-P?rez 2000 99 47.83 (31.44) 100 100 (27.09) 6.8 % -52.17 [ -60.33, -44.01 ]

Lacomme 1985 47 75.09 (78.07) 40 100 (68.77) 3.4 % -24.91 [ -55.77, 5.95 ]

Maestroni 1984 11 36.04 (36.94) 9 100 (96.58) 1.2 % -63.96 [ -130.73, 2.81 ]

Paupe 1986 21 65.15 (66.39) 22 100 (107.47) 1.7 % -34.85 [ -87.98, 18.28 ]

Pech 1987 35 59.04 (61.7) 34 100 (76.06) 3.2 % -40.96 [ -73.69, -8.23 ]

Piquett 1986 17 100 (100.44) 20 100 (108.15) 1.2 % 0.0 [ -67.28, 67.28 ]

RB10 1994 153 85.61 (90.91) 161 100 (106.06) 4.7 % -14.39 [ -36.21, 7.43 ]

RB17 1988 15 32.17 (23.06) 15 100 (54.96) 3.5 % -67.83 [ -97.99, -37.67 ]

RB21 1988 45 56.84 (63.16) 42 100 (52.63) 4.3 % -43.16 [ -67.53, -18.79 ]

RB22 1990 20 48.39 (16.13) 20 100 (22.58) 6.2 % -51.61 [ -63.77, -39.45 ]

RB24 1990 16 39.13 (54.35) 17 100 (86.96) 1.9 % -60.87 [ -110.04, -11.70 ]

RB25 1990 13 40.31 (6.15) 12 100 (18.46) 6.4 % -59.69 [ -70.66, -48.72 ]

Schaad 1986 45 96.98 (59.4) 49 100 (52.35) 4.5 % -3.02 [ -25.74, 19.70 ]

Schaad 2002 98 85.48 (58.06) 85 100 (65.72) 5.3 % -14.52 [ -32.61, 3.57 ]

Vautel 1993 32 60.97 (38.67) 32 100 (39.75) 5.1 % -39.03 [ -58.24, -19.82 ]

Zagar 1988 29 34.86 (23.85) 22 100 (59.63) 4.0 % -65.14 [ -91.53, -38.75 ]

Total (95% CI) 1091 1063 100.0 % -41.21 [ -49.10, -33.31 ]

-100 -50 0 50 100


(Continued . . . )









-100 -50 0 50 100


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.


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




Ahrens 1984 83 3.75 (3.42) 72 5.04 (4.04) 4.6 % -1.29 [ -2.48, -0.10 ]

Arroyave 1999 42 2.8 (1.3) 44 8.4 (1.9) 5.5 % -5.60 [ -6.29, -4.91 ]

Del-Rio-Navarro 2003 20 2.8 (1.4) 20 5.2 (1.5) 5.1 % -2.40 [ -3.30, -1.50 ]

Garabedian 1990 75 0.73 (0.87) 69 1.5 (1.66) 5.9 % -0.77 [ -1.21, -0.33 ]


G?mez-Barreto 1998 26 1.56 (1.55) 30 2.22 (2.37) 4.9 % -0.66 [ -1.70, 0.38 ]

Hauguenauer 1987 45 3.24 (2.1) 42 4.9 (4.3) 4.1 % -1.66 [ -3.10, -0.22 ]

H?ls 1995 78 1.7 (1.41) 78 2.5 (1.77) 5.8 % -0.80 [ -1.30, -0.30 ]

Jara-P?rez 2000 99 1.43 (0.94) 100 2.99 (0.81) 6.1 % -1.56 [ -1.80, -1.32 ]

Lacomme 1985 47 4.04 (4.2) 40 5.38 (3.7) 3.7 % -1.34 [ -3.00, 0.32 ]

Paupe 1986 21 1.57 (1.6) 22 2.41 (2.59) 4.4 % -0.84 [ -2.12, 0.44 ]

Pech 1987 35 1.11 (1.16) 34 1.88 (1.43) 5.6 % -0.77 [ -1.39, -0.15 ]

RB10 1994 153 1.13 (1.2) 161 1.32 (1.4) 6.0 % -0.19 [ -0.48, 0.10 ]

RB21 1988 45 0.54 (0.6) 42 0.95 (0.5) 6.1 % -0.41 [ -0.64, -0.18 ]

RB22 1990 20 3 (1) 20 6.2 (1.4) 5.4 % -3.20 [ -3.95, -2.45 ]

-4 -2 0 2 4


(Continued . . . )






Schaad 1986 45 2.89 (1.77) 49 2.98 (1.56) 5.5 % -0.09 [ -0.77, 0.59 ]

Schaad 2002 98 2.12 (1.44) 85 2.48 (1.63) 5.9 % -0.36 [ -0.81, 0.09 ]

Vautel 1993 32 3.39 (2.15) 32 5.56 (2.21) 4.8 % -2.17 [ -3.24, -1.10 ]

Zagar 1988 29 0.38 (0.26) 22 1.09 (0.65) 6.0 % -0.71 [ -1.00, -0.42 ]

Total (95% CI) 1019 990 100.0 % -1.42 [ -1.92, -0.93 ]




-4 -2 0 2 4


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.


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




Ahrens 1984 83 74.4 (67.86) 72 100 (80.16) 5.2 % -25.60 [ -49.18, -2.02 ]

Arroyave 1999 42 33.33 (15.48) 44 100 (22.62) 7.7 % -66.67 [ -74.83, -58.51 ]

Del-Rio-Navarro 2003 20 53.85 (26.92) 20 100 (28.85) 6.2 % -46.15 [ -63.44, -28.86 ]

Garabedian 1990 75 48.67 (58) 69 100 (110.67) 4.3 % -51.33 [ -80.56, -22.10 ]


G?mez-Barreto 1998 26 70.27 (69.82) 30 100 (106.76) 2.5 % -29.73 [ -76.42, 16.96 ]

Hauguenauer 1987 45 66.12 (42.66) 42 100 (87.66) 4.3 % -33.88 [ -63.17, -4.59 ]

H?ls 1995 78 68 (56.4) 78 100 (70.8) 5.8 % -32.00 [ -52.09, -11.91 ]

Jara-P?rez 2000 99 47.83 (31.44) 100 100 (27.09) 7.7 % -52.17 [ -60.33, -44.01 ]

Lacomme 1985 47 75.09 (78.07) 40 100 (68.77) 4.1 % -24.91 [ -55.77, 5.95 ]

-100 -50 0 50 100


(Continued . . . )






Paupe 1986 21 65.15 (66.39) 22 100 (107.47) 2.1 % -34.85 [ -87.98, 18.28 ]

Pech 1987 35 59.04 (61.7) 34 100 (76.06) 3.9 % -40.96 [ -73.69, -8.23 ]

RB10 1994 153 85.61 (90.91) 161 100 (106.06) 5.5 % -14.39 [ -36.21, 7.43 ]

RB21 1988 45 56.84 (63.16) 42 100 (52.63) 5.0 % -43.16 [ -67.53, -18.79 ]

RB22 1990 20 48.39 (16.13) 20 100 (22.58) 7.1 % -51.61 [ -63.77, -39.45 ]

Schaad 1986 45 96.98 (59.4) 49 100 (52.35) 5.3 % -3.02 [ -25.74, 19.70 ]

Schaad 2002 98 85.48 (58.06) 85 100 (65.72) 6.1 % -14.52 [ -32.61, 3.57 ]

Vautel 1993 32 60.97 (38.67) 32 100 (39.75) 5.9 % -39.03 [ -58.24, -19.82 ]

Zagar 1988 29 34.86 (23.85) 22 100 (59.63) 4.7 % -65.14 [ -91.53, -38.75 ]

Total (95% CI) 1019 990 100.0 % -38.44 [ -47.25, -29.63 ]




-100 -50 0 50 100





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.


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




Ahrens 1984 83 3.75 (3.42) 72 5.04 (4.04) 4.7 % -1.29 [ -2.48, -0.10 ]

Del-Rio-Navarro 2003 20 2.8 (1.4) 20 5.2 (1.5) 5.8 % -2.40 [ -3.30, -1.50 ]

Garabedian 1990 75 0.73 (0.87) 69 1.5 (1.66) 7.5 % -0.77 [ -1.21, -0.33 ]


G?mez-Barreto 1998 26 1.56 (1.55) 30 2.22 (2.37) 5.2 % -0.66 [ -1.70, 0.38 ]

Hauguenauer 1987 45 3.24 (2.1) 42 4.9 (4.3) 3.9 % -1.66 [ -3.10, -0.22 ]

H?ls 1995 78 1.7 (1.41) 78 2.5 (1.77) 7.3 % -0.80 [ -1.30, -0.30 ]

Jara-P?rez 2000 99 1.43 (0.94) 100 2.99 (0.81) 8.0 % -1.56 [ -1.80, -1.32 ]

Lacomme 1985 47 4.04 (4.2) 40 5.38 (3.7) 3.3 % -1.34 [ -3.00, 0.32 ]

RB10 1994 153 1.13 (1.2) 161 1.32 (1.4) 7.9 % -0.19 [ -0.48, 0.10 ]

RB21 1988 45 0.54 (0.6) 42 0.95 (0.5) 8.1 % -0.41 [ -0.64, -0.18 ]

RB22 1990 20 3 (1) 20 6.2 (1.4) 6.3 % -3.20 [ -3.95, -2.45 ]

Schaad 1986 45 2.89 (1.77) 49 2.98 (1.56) 6.6 % -0.09 [ -0.77, 0.59 ]

Schaad 2002 98 2.12 (1.44) 85 2.48 (1.63) 7.5 % -0.36 [ -0.81, 0.09 ]

Vautel 1993 32 3.39 (2.15) 32 5.56 (2.21) 5.1 % -2.17 [ -3.24, -1.10 ]

Zagar 1988 29 0.38 (0.26) 22 1.09 (0.65) 7.9 % -0.71 [ -1.00, -0.42 ]

Total (95% CI) 921 890 100.0 % -1.17 [ -1.56, -0.78 ]




-4 -2 0 2 4





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.


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




Ahrens 1984 83 74.4 (67.86) 72 100 (80.16) 5.8 % -25.60 [ -49.18, -2.02 ]

Del-Rio-Navarro 2003 20 53.85 (26.92) 20 100 (28.85) 7.4 % -46.15 [ -63.44, -28.86 ]

Garabedian 1990 75 48.67 (58) 69 100 (110.67) 4.7 % -51.33 [ -80.56, -22.10 ]


G?mez-Barreto 1998 26 70.27 (69.82) 30 100 (106.76) 2.5 % -29.73 [ -76.42, 16.96 ]

Hauguenauer 1987 45 66.12 (42.86) 42 100 (87.76) 4.6 % -33.88 [ -63.23, -4.53 ]

H?ls 1995 78 68 (56.4) 78 100 (70.8) 6.7 % -32.00 [ -52.09, -11.91 ]

Jara-P?rez 2000 99 47.83 (31.44) 100 100 (27.09) 9.8 % -52.17 [ -60.33, -44.01 ]

Lacomme 1985 47 75.09 (78.07) 40 100 (68.77) 4.4 % -24.91 [ -55.77, 5.95 ]

RB10 1994 153 85.61 (90.91) 161 100 (106.06) 6.2 % -14.39 [ -36.21, 7.43 ]

RB21 1988 45 56.84 (63.16) 42 100 (52.63) 5.6 % -43.16 [ -67.53, -18.79 ]

RB22 1990 20 48.39 (16.13) 20 100 (22.58) 8.8 % -51.61 [ -63.77, -39.45 ]

Schaad 1986 45 96.98 (59.4) 49 100 (52.35) 6.0 % -3.02 [ -25.74, 19.70 ]

Schaad 2002 98 85.48 (58.06) 85 100 (65.72) 7.2 % -14.52 [ -32.61, 3.57 ]

Vautel 1993 32 60.97 (38.67) 32 100 (39.75) 6.9 % -39.03 [ -58.24, -19.82 ]

Zagar 1988 29 34.86 (23.85) 22 100 (59.63) 5.2 % -65.14 [ -91.53, -38.75 ]

Total (95% CI) 921 890 100.0 % -36.16 [ -44.51, -27.80 ]

Heterogeneity: Tau2 = 167.36; Chi2 = 43.08, df = 15 (P = 0.00015); I2 =65%



-100 -50 0 50 100





Analysis 5.1. Comparison 5 Adverse events, Outcome 1 Gastrointestinal adverse events.


Comparison: 5 Adverse events

Outcome: 1 Gastrointestinal adverse events

Study or subgroup Immunostimulant Control Risk Difference Weight Risk Difference

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Ahrens 1984 2/83 0/72 10.6 % 0.02 [ -0.02, 0.07 ]

Collet 1993 0/210 0/213 29.1 % 0.0 [ -0.01, 0.01 ]

Del-Rio-Navarro 2003 3/20 4/20 2.8 % -0.05 [ -0.28, 0.18 ]

Guti?rrez-Tarango 2001 0/26 0/28 3.7 % 0.0 [ -0.07, 0.07 ]

H?ls 1995 0/78 0/78 10.8 % 0.0 [ -0.02, 0.02 ]

Mora 2002 2/41 1/40 5.6 % 0.02 [ -0.06, 0.11 ]

Pech 1987 0/35 0/34 4.8 % 0.0 [ -0.05, 0.05 ]

Riedl-Seifert 1995 10/99 6/108 14.2 % 0.05 [ -0.03, 0.12 ]

Schaad 2002 6/120 0/100 15.0 % 0.05 [ 0.01, 0.09 ]

Vautel 1993 0/32 4/20 3.4 % -0.20 [ -0.38, -0.02 ]

Total (95% CI) 744 713 100.0 % 0.01 [ -0.01, 0.03 ]

Total events: 23 (Immunostimulant), 15 (Control)

Heterogeneity: Chi2 = 15.46, df = 9 (P = 0.08); I2 =42%

Test for overall effect: Z = 1.09 (P = 0.27)


-0.2 -0.1 0 0.1 0.2





Analysis 5.2. Comparison 5 Adverse events, Outcome 2 Skin adverse events.


Comparison: 5 Adverse events

Outcome: 2 Skin adverse events

Study or subgroup Immunostimulant Control Risk Difference Weight Risk Difference

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Ahrens 1984 0/83 2/72 10.5 % -0.03 [ -0.07, 0.02 ]

Collet 1993 3/210 0/213 28.9 % 0.01 [ 0.00, 0.03 ]

Del-Rio-Navarro 2003 0/20 0/20 2.7 % 0.0 [ -0.09, 0.09 ]

Guti?rrez-Tarango 2001 1/26 0/28 3.7 % 0.04 [ -0.06, 0.14 ]

H?ls 1995 0/78 0/78 10.6 % 0.0 [ -0.02, 0.02 ]

Mora 2002 0/41 0/40 5.5 % 0.0 [ -0.05, 0.05 ]

Pech 1987 0/35 0/34 4.7 % 0.0 [ -0.05, 0.05 ]

Riedl-Seifert 1995 0/99 0/108 14.1 % 0.0 [ -0.02, 0.02 ]

Schaad 2002 1/120 0/100 14.9 % 0.01 [ -0.02, 0.03 ]

Vautel 1993 0/32 0/32 4.4 % 0.0 [ -0.06, 0.06 ]

Total (95% CI) 744 725 100.0 % 0.00 [ -0.01, 0.01 ]

Total events: 5 (Immunostimulant), 2 (Control)

Heterogeneity: Chi2 = 4.08, df = 9 (P = 0.91); I2 =0.0%



-0.1 -0.05 0 0.05 0.1





Analysis 6.1. Comparison 6 OM-85 trials, Outcome 1 Mean number of ARTIs.


Comparison: 6 OM-85 trials


Study or subgroup Experimental Control Mean Difference Weight Mean Difference


Ahrens 1984 83 3.75 (3.42) 72 5.04 (4.04) 9.1 % -1.29 [ -2.48, -0.10 ]

Del-Rio-Navarro 2003 20 2.8 (1.4) 20 5.2 (1.5) 11.2 % -2.40 [ -3.30, -1.50 ]


G?mez-Barreto 1998 26 1.56 (1.55) 30 2.22 (2.37) 10.2 % -0.66 [ -1.70, 0.38 ]

Jara-P?rez 2000 99 1.43 (0.94) 100 2.99 (0.81) 15.7 % -1.56 [ -1.80, -1.32 ]

Maestroni 1984 11 2 (2.05) 9 5.55 (5.36) 1.9 % -3.55 [ -7.26, 0.16 ]

Schaad 1986 45 2.89 (1.77) 49 2.98 (1.56) 12.9 % -0.09 [ -0.77, 0.59 ]

Schaad 2002 98 2.12 (1.44) 85 2.48 (1.63) 14.6 % -0.36 [ -0.81, 0.09 ]

Zagar 1988 29 0.38 (0.26) 22 1.09 (0.65) 15.5 % -0.71 [ -1.00, -0.42 ]

Total (95% CI) 437 415 100.0 % -1.20 [ -1.75, -0.66 ]




-4 -2 0 2 4

Favours experimental Favours control




Analysis 6.2. Comparison 6 OM-85 trials, Outcome 2 Percent difference in ARTIs.


Comparison: 6 OM-85 trials




Ahrens 1984 83 74.4 (67.86) 72 100 (80.16) 11.4 % -25.60 [ -49.18, -2.02 ]

Del-Rio-Navarro 2003 20 53.85 (26.92) 20 100 (28.85) 13.5 % -46.15 [ -63.44, -28.86 ]


G?mez-Barreto 1998 26 70.27 (69.82) 30 100 (106.76) 5.7 % -29.73 [ -76.42, 16.96 ]

Jara-P?rez 2000 99 47.83 (31.44) 100 100 (27.09) 16.4 % -52.17 [ -60.33, -44.01 ]

Maestroni 1984 11 36.04 (36.94) 9 100 (96.58) 3.3 % -63.96 [ -130.73, 2.81 ]

Schaad 1986 45 96.98 (59.4) 49 100 (52.35) 11.7 % -3.02 [ -25.74, 19.70 ]

Schaad 2002 98 85.48 (58.06) 85 100 (65.72) 13.3 % -14.52 [ -32.61, 3.57 ]

Zagar 1988 29 34.86 (23.85) 22 100 (59.63) 10.5 % -65.14 [ -91.53, -38.75 ]

Total (95% CI) 437 415 100.0 % -35.90 [ -49.46, -22.35 ]




-100 -50 0 50 100





Analysis 7.1. Comparison 7 D53 trials, Outcome 1 Mean number of ARTIs.


Comparison: 7 D53 trials




Garabedian 1990 75 0.73 (0.87) 69 1.5 (1.66) 10.5 % -0.77 [ -1.21, -0.33 ]

Hauguenauer 1987 45 3.24 (2.1) 42 4.9 (4.3) 6.2 % -1.66 [ -3.10, -0.22 ]

H?ls 1995 78 1.7 (1.41) 78 2.5 (1.77) 10.3 % -0.80 [ -1.30, -0.30 ]

Lacomme 1985 47 4.04 (4.2) 40 5.38 (3.7) 5.4 % -1.34 [ -3.00, 0.32 ]

RB10 1994 153 1.13 (1.2) 161 1.32 (1.4) 10.9 % -0.19 [ -0.48, 0.10 ]

RB17 1988 15 1.2 (0.86) 15 3.73 (2.05) 7.5 % -2.53 [ -3.66, -1.40 ]

RB21 1988 45 0.54 (0.6) 42 0.95 (0.5) 11.1 % -0.41 [ -0.64, -0.18 ]

RB22 1990 20 3 (1) 20 6.2 (1.4) 9.2 % -3.20 [ -3.95, -2.45 ]

RB24 1990 16 0.36 (0.5) 17 0.92 (0.8) 10.4 % -0.56 [ -1.01, -0.11 ]

RB25 1990 13 1.31 (0.2) 12 3.25 (0.6) 10.8 % -1.94 [ -2.30, -1.58 ]

Vautel 1993 32 3.39 (2.15) 32 5.56 (2.21) 7.8 % -2.17 [ -3.24, -1.10 ]

Total (95% CI) 539 528 100.0 % -1.32 [ -1.86, -0.79 ]




-4 -2 0 2 4





Analysis 7.2. Comparison 7 D53 trials, Outcome 2 Percent difference in ARTIs.


Comparison: 7 D53 trials




Garabedian 1990 75 48.67 (58) 69 100 (110.67) 7.0 % -51.33 [ -80.56, -22.10 ]

Hauguenauer 1987 45 66.12 (42.86) 42 100 (87.76) 7.0 % -33.88 [ -63.23, -4.53 ]

H?ls 1995 78 68 (56.4) 78 100 (70.8) 10.5 % -32.00 [ -52.09, -11.91 ]

Lacomme 1985 47 75.09 (78.07) 40 100 (68.77) 6.5 % -24.91 [ -55.77, 5.95 ]

RB10 1994 153 85.61 (90.91) 161 100 (106.06) 9.7 % -14.39 [ -36.21, 7.43 ]

RB17 1988 15 32.17 (23.06) 15 100 (54.96) 6.7 % -67.83 [ -97.99, -37.67 ]

RB21 1988 45 56.84 (63.16) 42 100 (52.63) 8.7 % -43.16 [ -67.53, -18.79 ]

RB22 1990 20 48.39 (16.13) 20 100 (22.58) 14.6 % -51.61 [ -63.77, -39.45 ]

RB24 1990 16 39.13 (54.35) 17 100 (86.96) 3.3 % -60.87 [ -110.04, -11.70 ]

RB25 1990 13 40.31 (6.15) 12 100 (18.46) 15.2 % -59.69 [ -70.66, -48.72 ]

Vautel 1993 32 60.97 (38.67) 32 100 (39.75) 10.9 % -39.03 [ -58.24, -19.82 ]

Total (95% CI) 539 528 100.0 % -43.47 [ -53.22, -33.72 ]




-100 -50 0 50 100


A D D I T I O N A L T A B L E S

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, Om-munal

OM-85 or OM-85 BV Lyophilised bacterial lysates

Chizukit Not available Preparation of Echinacea purpurea, propolis and vitamin C




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

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 appli-cation

Prasosine Isoprinosine Isoprinosine

Pulmotabs Not available Bacterial lysates

Pulmonarom Not available Bacterial lysates

Reaferon Not available Analogue of human interferon 2 obtained by genetic engi-neering

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 2. Description of the studies

Immunos-

timulant

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-85BV

12 9 - 10 2 4 8 - -

RU41740 5 5 - 3 2 - 5 - -

Total bac-terial

40 25 9 27 4 4 35 1 -

Herbal(echi-nacea/garlic)

4 1 2 1 1 2 2 - -

Isoprino-sine

1 1 - 1 - - 1 - -

Lev-amisole

4 3 2 2 - - 4 - -

Pidotimod 6 2 6 - - - 6 - -

Total syn-thetic

11 6 8 3 - - 11 - -

Thymicextract

5 3 4 - 1 - 5 - -

Syntheticinterferon

1 0 1 - - - 1 - -

Grand to-tal

61 35 24 31 6 6 53 2 -




A P P E N D I C E S

Appendix 1. Previous searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 4, 2005); MEDLINE(January 1966 to January 2006); EMBASE (January 1990 to January 2006); PASCAL (up to January 2006); SciSearch (up to January2006); and IPA (up to January 2006) for reports of trials.Trials were identified using the Cochrane methodology searches phase 1 and phase 2 (Dickersin 1994). The following search strategywas combined with the highly sensitive search strategy used in MEDLINE and CENTRAL and adapted for EMBASE, PASCAL,SciSearch and IPA.MEDLINE (Ovid)

1 exp Respiratory Tract Infections/2 (respiratory tract infection$ or respiratory infection$)3 or/1-24 exp Adjuvants, Immunologic/5 (immunostimulants$ or immunomodulator$)6 Immunobalt7 (LW50020 or Luivac or Paspat)8 Munostin9 (OM-85 BV or Broncho-Vaxom)10 Pulmonar-OM11 D5312 Ribomunyl13 Ribovac14 Immucytal15 exp Lipopolysaccharides/16 lipopolysaccharid$17 (RU 41740 or Biostim)18 exp Thymus Extracts/19 calf thymus extract$20 (thymic extract$ or thymomodulin)21 exp Pelargonium/22 (Pelargonium sidoides or Umckaloabo)23 AM324 Inmunoferon25 glycophosphopeptical26 or/4-2527 3 and 26Identified articles were used as references for a Science Citation Index search. Bibliographies of all included trials as well as those ofrelevant reviews were searched to identify additional studies. Finally, a letter was sent to all first authors, as well as pharmaceuticalcompanies that manufacture immunostimulant drugs, requesting data and references for any relevant published and unpublished trials.There were no language restrictions. We also searched for studies in the trial registration web site: metaRegister of Controlled Trials(http://www.controlled-trials.com/mrct/).




Appendix 2. Embase search strategy

Embase.com (Elsevier)

(Search strategy used for January 2010 to March 2011 update)#29. #25 AND #28 400 3 Mar 2011#28. #26 OR #27 841,770 3 Mar 2011#27. random*:ab,ti OR placebo*:ab,ti OR factorial*:ab,ti OR crossover*:ab,ti OR ’cross over’:ab,ti OR ’cross-over’:ab,ti OR volunteer*:ab,ti OR assign*:ab,ti OR allocat*:ab,ti OR ((singl* OR doubl*) NEAR/1 blind*):ab,ti AND [embase]/lim 802,449 3 Mar 2011#26. ’randomized controlled trial’/exp OR ’single blind procedure’/exp OR ’double blind procedure’/exp OR ’crossover procedure’/expAND [embase]/lim 237,948 3 Mar 2011#25. #3 AND #24 3,234 3 Mar 2011#24. #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 114,581 3 Mar 2011#23. ’immunostimulating agent’/de OR ’immunomodulating agent’/de AND [embase]/lim 11,919 3 Mar 2011#22. levamisole:ab,ti AND [embase]/lim 3,610 3 Mar 2011#21. pidotimod:ab,ti OR adimod:ab,ti AND [embase]/lim 68 3 Mar 2011#20. glycophosphopep:ab,ti AND [embase]/lim 3 Mar 2011#19. am3:ab,ti OR imunoferon:ab,ti OR immunoferon:ab,ti OR inmunoferon:ab,ti AND [embase]/lim 144 3 Mar 2011#18. pelargonium*:ab,ti OR umckaloabo:ab,ti AND [embase]/lim 249 3 Mar 2011#17. ’pelargonium sidoides extract’/de AND [embase]/lim 98 3 Mar 2011#16. ’thymus extract’:ab,ti OR ’thymus extracts’:ab,ti OR ’thymic extract’:ab,ti OR ’thymic extracts’:ab,ti OR thymomodulin*:ab,tiAND [embase]/lim 556 3 Mar 2011#15. ’thymus extract’/de AND [embase]/lim 514 3 Mar 2011#14. ru41740:ab,ti OR ’ru-41740’:ab,ti OR ’ru 41740’:ab,ti OR biostim:ab,ti AND [embase]/lim 122 3 Mar 2011#13. lipopolysaccharide*:ab,ti AND [embase]/lim 48,375 3 Mar 2011#12. ’lipopolysaccharide’/exp AND [embase]/lim 53,723 3 Mar 2011#11. ribomunyl:ab,ti OR ribovac:ab,ti OR immucytal:ab,ti AND [embase]/lim 68 3 Mar 2011#10. d53:ab,ti AND [embase]/lim 40 3 Mar 2011#9. ’pulmonar-om’:ab,ti OR ’pulmonar om’:ab,ti AND [embase]/lim 1 3 Mar 2011#8. bronchovaxom:ab,ti OR ’broncho-vaxom’:ab,ti OR ’broncho vaxom’:ab,ti AND [embase]/lim 113 3 Mar 2011#7. ’om 85 bv’:ab,ti OR om85bv:ab,ti OR ’om-85 bv’:ab,ti AND [embase]/lim 51 3 Mar 2011#6. immunobalt:ab,ti OR lw50020:ab,ti OR luivac:ab,ti OR paspat:ab,ti OR munostin:ab,ti AND [embase]/lim 18 3 Mar 2011#5. immunostimulant*:ab,ti OR immunomodul*:ab,ti OR immunoadjuvant*:ab,ti OR (immuno* NEAR/1 adjuvant*):ab,ti AND[embase]/lim 30,022 3 Mar 2011#4. ’immunological adjuvant’/exp AND [embase]/lim 11,700 3 Mar 2011#3. #1 OR #2 158,887 3 Mar 2011#2. (respiratory NEAR/5 infection*):ab,ti AND 30,608 3 Mar 2011[embase]/lim#1. ’respiratory tract infection’/exp AND 149,401 3 Mar 2011 [embase]/lim

Appendix 3. Search terms used for searching other databases

Our library assistant searched for clinical trials on children with the term ’respiratory’ in EMBASE, PASCAL, SciSearch and IPA from2005 to March 2010, for the following interventions:Immunostimulants OR immunomodulatorsBacterial lysates OR bacterial antigens OR bacterial extractsLW50020 OR Luivac OR PaspatOM-85 OR OM-85 BV OR Broncho-VaxomD53 OR Ribomunyl OR Ribovac OR ImmucytalRU 41740 OR BiostimAM3 OR Inmunoferon OR glycophosphopepticalPidotimod




LevamisoleEchinacea

W H A T ’ S N E W

Last assessed as up-to-date: 3 March 2011.

Date Event Description

4 March 2011 New search has been performed Searches conducted. We included three new trials (Mora 2007; Mora 2010a;Wahl 2008) and the mean and standard deviation on the number of acute respira-tory tract infections in Schaad 2002. We excluded six new trials (Grimfeld 2004;Heinz 2010; Mora 2010b; Razi 2010; Riedl-Seifert 1993; Steinsbekk 2005). Weincluded sub-analyses on the efficacy of D53 and OM-85. The conclusions re-main unchanged

H I S T O R Y

Protocol first published: Issue 4, 2004

Review first published: Issue 4, 2006

Date Event Description

21 April 2008 Amended Converted to new review format.

24 January 2006 New search has been performed Searches conducted.

C O N T R I B U T I O N S O F A U T H O R S

Dr Blanca Estela Del-Rio-Navarro (BN) searched for papers, extracted the relevant data, analyzed data and co-wrote the review.

Dr Juan JL Sienra-Monge (JSM) searched for papers, extracted the relevant data and co-wrote the review.

Dr Francisco Espinosa-Rosales (FER) searched for papers, analyzed data and co-wrote the review.

Vicki Flenady (VF) co-wrote and made corrections to the review.




D E C L A R A T I O N S O F I N T E R E S T

Dr Arturo Berber was the medical manager for OM-85 BV (Broncho-Vaxom) in Mexico for BASF Pharma Mexico (Química Knollde México) from 1995 to 2001. He was also the contact author of the initial protocol until he graciously stepped down because of apotential conflict of interest.

Dr Blanca Del Rio-Navarro and Dr Sienra-Monge were involved in the following IS trial: Del-Rio-Navarro BE, Luis Sienra-Monge JJ,Berber A, Torres-Alcantara S, Avila-Castanon L, Gomez-Barreto D. Use of OM-85 BV in children suffering from recurrent respiratorytract infections and subnormal IgG subclass levels. Allergologia et Immunopathologia (Madrid) 2003 Jan-Feb;31(1):7-13.

Dr Blanca Del Rio-Navarro was involved in the following IS trials: Field J, Gomez-Barreto D, Del-Rio-Navarro BE, Berber A. Useof OM-85 BV in primary prevention of acute respiratory tract infections in children in orphanages Current Therapeutics Research,Clinical and Experimental 1998 59:6 (407-18); Berber AC, Del-Rio-Navarro BE. Use of Broncho-Vaxom in private practice: phase IVtrial in 587 children. Clinical Therapeutics 1996 Nov-Dec;18(6):1068-79.

S O U R C E S O F S U P P O R T

Internal sources

• Allergy and Clinical Immunolgy Service, Children Hospital of Mexico Federico Gomez, Mexico.The review was supported by the local institution

External sources

• No sources of support supplied

I N D E X T E R M S

Medical Subject Headings (MeSH)

Adjuvants, Immunologic [∗therapeutic use]; Adolescent; Randomized Controlled Trials as Topic; Respiratory Tract Infections[∗prevention & control]

MeSH check words

Child; Humans



Documents

Cochrane inmunoestimulantes