Inmunoestimulantes 2012

EVIDENCE-BASED CHILD HEALTH: A COCHRANE REVIEW JOURNAL
Evid.-Based Child Health 7:2: 629717 (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 Library
2011, 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.

TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 1.
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Figure 2.
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Figure 3.
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Figure 4.
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RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 5.
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Figure 6.
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Figure 7.
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Figure 8.
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DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ACKNOWLEDGEMENTS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Any IS compared with placebo, Outcome 1 Mean number of ARTIs. . . . . . . .
Analysis 1.2. Comparison 1 Any IS compared with placebo, Outcome 2 Percent difference in ARTIs. . . . . . .
Analysis 2.1. Comparison 2 Bacterial IS compared with placebo, Outcome 1 Mean number of ARTIs. . . . . .
Analysis 2.2. Comparison 2 Bacterial IS compared with placebo, Outcome 2 Percent difference in ARTIs. . . . .
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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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. . . . . . . . . . . . . . . . . . . . . . . .
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. . . . . . . . . . . . . . . . . . . . . .
Analysis 5.1. Comparison 5 Adverse events, Outcome 1 Gastrointestinal adverse events. . . . . . . . . . .
Analysis 5.2. Comparison 5 Adverse events, Outcome 2 Skin adverse events. . . . . . . . . . . . . . .
Analysis 6.1. Comparison 6 OM-85 trials, Outcome 1 Mean number of ARTIs. . . . . . . . . . . . . .
Analysis 6.2. Comparison 6 OM-85 trials, Outcome 2 Percent difference in ARTIs. . . . . . . . . . . . .
Analysis 7.1. Comparison 7 D53 trials, Outcome 1 Mean number of ARTIs. . . . . . . . . . . . . . .
Analysis 7.2. Comparison 7 D53 trials, Outcome 2 Percent difference in ARTIs. . . . . . . . . . . . . .
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
INDEX TERMS
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631
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632
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637
637
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641
642
642
646
647
648
648
649
651
651
652
661
693
695
697
699
700

630
701
702
704
705
706
707
708
709
710
711
711
713
716
716
716
716
717
717

[Intervention Review]
Immunostimulants for preventing respiratory tract infection

in children
Blanca Estela Del-Rio-Navarro1 , Francisco J Espinosa-Rosales2 , Vicki Flenady3 , Juan JL Sienra-Monge1
1 Department
of Allergy and Immunology, Hospital Infantil de Mxico Federico Gmez, Mexico City, Mexico. 2 Department of
Immunology, Instituto Nacional de Pediatra (National Institute of Pediatrics), Mxico 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 Mxico Federico Gmez, Dr. Marquez 162, Colonia de los Doctores, Mexico City, DF, CP 06720, Mexico. [email protected].
[email protected].
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 respiratory tract infection in children. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD004974. DOI:
10.1002/14651858.CD004974.pub2.
ABSTRACT
Background
Acute respiratory tract infections (ARTIs) are a major cause of childhood morbidity and mortality. Immunostimulants (IS) may reduce
the incidence of ARTIs.
Objectives
To determine the efcacy 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 Respiratory
Infections Groups Specialised Register, MEDLINE (1966 to February week 4, 2011), EMBASE (1990 to February 2011), Google
Scholar (2009 to February 2011), Scopus (2009 to February 2011), PASCAL (1990 to February 2010), SciSearch (1990 to February
2010) 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 intervention
was 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. We
undertook meta-analyses using a random-effects model and presented results as mean differences (MD) with 95% condence intervals
(CI). Two review authors independently assessed the search results and risk of bias, and extracted data. A funnel plot suggested there
may be publication bias in the identied trials.
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Main results
Thirty-ve placebo-controlled trials (4060 participants) provided data in a form suitable for inclusion in the meta-analyses. When
compared with placebo, the use of IS was shown to reduce ARTIs measured as the total numbers of ARTIs (MD -1.24; 95% CI -1.54
to -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 high
level 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 not
available. Although the safety prole in the studies was good, some IS may be unsafe. ARTI-susceptible children may benet from IS
treatment. Further high-quality trials are needed and we encourage national health authorities to conduct large, multicentre, doubleblind, placebo-controlled RCTs on the role of IS in preventing ARTIs in children.
PLAIN LANGUAGE SUMMARY

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 ve years of age, mainly in lowincome countries in Africa, Asia and Latin America. In high-income countries ARTIs are among the most frequent illnesses, leading
to 20% of medical consultations, 30% of days lost from work and 75% of antibiotic prescriptions. In the USA the total cost of noninuenza-related viral ARTIs is around $40 billion annually, while the corresponding cost for inuenza is US $87.1 billion. The main
signs and symptoms of ARTIs include sneezing, runny nose, sore throat, cough and malaise. Children living in rural communities, not
attending daycare centres, suffer about seven ARTI episodes in the rst year of life; eight ARTIs per year from the ages of one to four;
six per year aged ve to nine; and ve 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 are
immunostimulants (herbal extracts, bacterial extracts, synthetic compounds), which aim to increase the immune defences of the
respiratory tract. We searched for clinical trials of immunostimulants to prevent ARTIs in children compared to placebo. Our review
includes 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 compared
to 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 benet from immunostimulants, but more high-quality studies are needed. We
suggest that national health authorities conduct high-quality randomized controlled trials to assess the true effects of immunostimulant
preparations.

632
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
Number of ARTIs
Illustrative comparative risks (95% CI)
Assumed risk
Corresponding risk
Placebo
Any IS
No of participants (studies) Quality of

(GRADE)
The range of ARTIs in the con- The mean Number of ARTIs in 4060
trol group was 0.92 to 6.2
the intervention groups was
(35 studies)
1.24 lower (0.94 to 1.54
lower)
moderate1
Percent difference in ARTIs
The mean Percent difference 4060

in ARTIs in the intervention (35 studies)
groups was
39 lower (31.31 to 46.37
lower)
moderate1,2
Incidence of gastrointestinal 21 per 1000

adverse events
30 per 1000 (11 to 50 per 1457

1000)
(10 studies)
low1,3
Incidence of skin adverse 3 per 1000

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

(10 studies)
low1,3
the
evidence Comments

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]
The effect depends on the

number of ARTIs in the control
group
*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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1 Funnel

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.
plot shows possible publication bias, risk of bias in the studies moderate, and high heterogeneity among studies. A group of six studies with good quality point to the benefit of IS
Heterogenity decreased with calculation of percent difference ARTIs.
3 Adverse events were reported only in 10 trials; selective outcome reporting
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2
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BACKGROUND
Description of the condition

In 1998 the World Health Organization (WHO) considered acute
respiratory tract infections (ARTIs) to be the forgotten pandemic
as ARTIs caused 19% of all deaths in children younger than ve
years and 8.2% of all disabilities and premature mortality (WHO
1998). In 2000, 1.9 million (95% condence interval (CI) 1.6 to
2.2 million) children died from ARTIs worldwide, with 70% of
the deaths in Africa and South-East Asia (Williams 2002). ARTIs are the leading cause of morbidity in high-income countries
(USA, Canada, Western Europe) and account for 20% of medical
consultations, 30% of days lost from work and 75% of antibiotic prescriptions (WHO 1998). ARTIs are responsible for most
sick days amongst school children (Haskins 1986) and parental
absenteeism from work (Bell 1989). The cost of ARTIs in highincome countries is signicant. For example, between 2000 and
2002 there were approximately 500 million non-inuenza-related
viral ARTI episodes in the USA per year; the total economic impact of these episodes was around $40 billion annually (direct costs
of $17 billion per year and indirect costs of $22.5 billion per year)
(Fendrick 2003). Based on the 2003 US population, it has been
calculated that the total economic burden of annual inuenza epidemics in the USA was $87.1 billion US dollars ($47.2 to $149.5)
(Molinari 2007). Risk factors for ARTIs in childhood include attendance at daycare centres (Schwartz 1994), overcrowding (Bell
1989; Selwyn 1990), contact with elder siblings (Selwyn 1990),
male gender (Monto 2002), smoking at home (Jin 1993) and lack
of breast feeding (Wright 1989).
Community health studies in high-income countries have provided basic information on the incidence of ARTIs in children.
In the Cleveland Family Study, 100 families were visited weekly
by nurses during 1948 to 1957. The annual frequency of respiratory illness was 6.72 in children less than one year old; 7.95 in
children aged one to four years; 6.21 in children aged ve to nine
years; 5.02 in children aged 10 to 14 years; and 4.71 in 15 to 19year olds (Monto 2002). In the rst phase of the Tecumseh study,
from 1965 to 1971, 4905 residents registered their incidence of
ARTIs for the six-year period. In the rst report the residents had
suffered approximately 14,600 ARTIs. The annual incidence of
ARTIs per person was 6.1 in children less than one year old; 5.7 in
children aged one to two years; 4.7 in children aged three to four
years; 3.5 in children aged ve to nine years; 2.7 in children aged
10 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 two
phases comprising a total of 11 years (1965 to 1971 and 1976 to
1981), the mean annual number of ARTIs was 4.9 in the group
aged from zero to four years; and 2.8 in the group aged ve to 19
years (Monto 1993). In both phases of the study viruses were the
most common agents causing ARTIs.
During the 1980s, the Board on Science and Technology for International Development (BOSTID) undertook a co-ordinated
effort to establish the aetiology and epidemiology of ARTIs in

children in high-income countries. The project was carried out
in populations from 0 to 59 months of age in Africa, Asia and
Latin America. The incidence rate in six community-based studies ranged from 12.7 to 16.8 ARTIs per 100 child-weeks and the
incidence of lower ARTIs was from 0.2 to 0.4 per 100 childweeks. The children studied spent from 21.7% to 40.1% of the
observed weeks with ARTIs and from 1% to 14.4% of the observed weeks with lower ARTIs. Viral agents were more frequently
recovered than bacterial agents; respiratory syncytial virus (RSV)
was the most frequent virus (Selwyn 1990). In Mexico, a study
assessing the effect of daycare centres on ARTI incidence followed
144 children (aged 43 days to 4 months at entry) at home for one
year. 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 children
at daycare centres (Denny 1986) and in the community (Monto
1993). The most common virus isolates are rhinovirus, respiratory
syncytial virus, parainuenza virus and adenovirus. Lower ARTIs
are also frequently associated with viral infections, but bacterial
agents may be found in 4.5% to 40% of the cases (Selwyn 1990).
Up to 50% of children admitted to hospital with proven bacterial ARTIs also have evidence of concurrent or recent viral ARTIs
(Campbell 1995). The damage caused by viruses to epithelial cells
in the airways may increase the adherence of bacteria and lead to
a bacterial superinfection (Hament 1999).
History of respiratory infections in the rst 12 years among children was established in a cohort of German children living in urban areas. The mean cumulative number of ARTIs in the 12 years
was 21.9 (standard deviation (SD) 9.0) episodes; the mean annual
number was 1st year, 3.1 (2.1) episodes; 2nd year, 3.2 (2.5); 3rd
year, 2.1 (2.0); 4th year, 2.3 (2.1); 5th year, 1.8 (1.6); 7th through
to the 9th year, 1.1 (1.0) episodes; 10th year through 12th year,
1.0 (0.9) episodes (Grber 2008). The frequency of ARTIs in this
study was about a half of the classic Monto studies (Monto 1974;
Monto 1993). The authors regarded incidence above the twofold
standard deviation as clinically relevant; more than seven episodes
in the 1st year of life, more than eight episodes in year two, more
than six episodes in year three and year four more than ve episodes
in year ve, more than four episodes in year six, and more than
three episodes from year seven onwards.
In a healthy population without any special risk factors or immunodeciencies, there is a subgroup of people with a higher incidence
of ARTIs. A cohort of children from Nijmegen, Netherlands was
followed for 21 years to register the occurrence of ARTIs. The
number of respiratory infections was assessed at the ages of two,
four, eight and 21. It was considered that a person had a recurrent
infection if the number of ARTIs was above 75th percentile of the
distribution of respiratory infection at each assessment. Twentythree percent of the people had recurrent respiratory infection in
two or more assessments and 1% suffered from recurrent infection
in the four assessments (Rovers 2006).

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Recent inuenza epidemics have increased interest in effective unspecic measures to protect the global population, outside the production of appropriate vaccines which could take more than six
to nine months to be ready for use. These unspecic measures include physical methods to reduce the spread of respiratory viruses
such as hand washing, wearing masks, gloves and gowns (Jefferson
2009). In military populations, reported additional measures to
prevent respiratory tract infections include reducing contact between units, reducing crowding, installing cloth barriers between
beds, indoor air dilution and ventilation, dust suppression and
air sterilisation (Lee 2005). Other measures include vitamin and
mineral supplementation, such as vitamin A (Chen 2008a), vitamin C (Hemil 2010), vitamin D (Yamshchikov 2009) and zinc
(Aggarwal 2007). Interventions which stimulate the immune system (immunostimulants) have been proposed as effective measures
to reduce ARTIs.
Some years ago, the idea that bacterial lysates, plant extracts or
imidazole compounds, could induce unspecic immunity against
viruses and distinct bacteria was not very solid. However, the recent discovery of Toll-like-receptors (TLRs) supports the possible
mechanism of action of immunostimulants (Krieg 2003). TLRs
were discovered in the 1990s and their importance on immunity
was found later, see How the intervention might work below. In
fact, there is evidence that two bacterial lysates may act on TLR2
(Alyanakian 2006; Nikolova 2009), as well as levamisole (Chen
2008b).
Description of the intervention

The main way to prevent ARTI complications is to prevent these
infections and administer early antibiotic treatment when bacterial ARTIs are diagnosed (Heikkinen 1999; Henderson 1982;
WHO 1998). Non-specic preventative measures for ARTIs studied in clinical trials include general hygiene methods in children
attending daycare centres (CDCIDSG 1984); the administration
of nutritional supplements such as vitamin A to malnourished
children (Barreto 1994), vitamin C to normal and malnourished
children (Hemila 1997; Jefferson 2001) and trace elements to
malnourished and susceptible children (Sazawal 1998); preventive antibiotics (Dajani 1995); administration of gamma globulins (Nydahl-Persson 1995); nasal spray of immunoglobulins
(Heikkinen 1998); herbal extracts (Grimm 1999); xylitol sugar
syrup or chewing gum (Uhari 1998); and the use of immunostimulants (IS) from different sources. The sources are synthetic
(Passali 1994a); thymic extracts or factors (De Mattia 1993); or of
biological origin such as Klebsiella extracts containing lipopolysaccharide (Dahan 1986) and mixtures of bacterial extracts (Berber
1996).
How the intervention might work
The actual mechanism of IS is not yet fully understood. Currently

the mechanisms of action are known for only two synthetic IS,
tucaresol and imiquimod. The mechanism of tucaresol is to form a
complex on the surface of T cells (a Schiff reaction with the amines,
probably on CD2). This complex provides an additional stimulant which facilitates the activation of the T cells (a co-stimulatory signal activating the MAPK ERK2 pathway) (Rhodes 1995).
Imiquimod and other related molecules activate the immune cells
by binding to the receptor for the bacterial products that activate
the unspecic defence mechanism and promote the immune response; they bind to the Toll-like receptor 7 (TLR7) activating the
MyD88-dependent signalling pathway (Hemmi 2002).
It may be postulated that products with IS properties activate the
immune cells using the receptors that recognise common bacterial products or receptors that provide additional stimulation for
activation. For instance, Toll-like receptors (TLR) recognise components common to a range of bacteria, so-called pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide,
peptidoglycan, lipoteichoic acid, lipoarabinomannan, un-methylated DNA with CpG motif and bacterial lipoproteins which activate the innate immune responses. The innate immune response
is responsible for the early mechanisms of defence against infection; for instance the phagocytosis and neutralisation of bacteria entering the body. The mechanisms that enhance the innate
immune responses (cytokines and chemokines) also stimulate the
adaptive immune response (production of specic antibodies and
reproduction of specic T cells) (Hoffmann 1999; Schnare 2001;
Takeuchi 2001). In fact, there is evidence that two bacterial lysates
may act on TLR2 (Alyanakian 2006; Nikolova 2009), as well as
levamisole (Chen 2008b).
Why it is important to do this review

Most ARTIs are caused by viruses, hundreds of which may cause
this type of infection. It would be impractical, therefore, to have
a vaccine for each possible pathogenic agent. Therefore, specic immunisation may not be the ultimate solution to prevent
ARTIs. The introduction of the pneumococcal conjugate vaccine decreased carriage and invasive infections due to the vaccine
serotypes, but it has been replaced by other non-vaccine serotypes
that are becoming antibiotic resistance (Hsu 2009; Huang 2009;
Mera 2009).
IS could provide an alternative to vaccines for preventing ARTIs but the efcacy of these medications is controversial (Collet
1992; Valleron 1992). Several bacterial extracts and synthetic compounds are used in Europe and the Americas to prevent ARTIs.
However, the evidence of the safety and efcacy of this approach
is unclear. A systematic review of immunostimulation for the prevention of ARTIs in children is required to enable a robust appraisal of the current evidence on the safety and efcacy of this
approach and to provide clues for the development of new IS.

636

OBJECTIVES
To assess the safety and efcacy of immunostimulants (IS) administered to children to prevent ARTIs when compared with placebo,
in terms of frequency of these infections and reported adverse effects. Trials comparing two IS were also included.
METHODS
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs) comparing IS, administered
by any method, to placebo to prevent ARTIs. Trials referring to
interferon inducers, vitamins and nutritional supplements were
not included.
Types of participants
Participants younger than 18 years of age. We did not include trials
that included participants who suffered from asthma, allergy and
atopy, 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 antipyretics or antibiotics for inclusion.
Types of outcome measures

A broad denition of ARTI was accepted and included using different specic diagnoses, such as cold, inuenza, tonsillitis, pharyngitis, bronchitis and otitis media. Aetiological agents were not studied and no distinction was made between bacterial and viral ARTIs. 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 Controlled Trials (CENTRAL) 2011, issue 1, which contains the Acute
Respiratory Infections Groups Specialised Register, MEDLINE
(1966 to February week 4, 2011), EMBASE (1990 to February
2011), Google Scholar (2009 to February 2011), Scopus (2009
to February 2011), PASCAL (1990 to February 2010), SciSearch
(1990 to February 2010) and IPA (1990 to February 2010). Details of the previous searches are in Appendix 1.
We used the following search strategy to search MEDLINE and
CENTRAL. To search MEDLINE, we combined the search strategy with the Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE: sensitivity- and precisionmaximising 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 Embase
search are in Appendix 3.
MEDLINE (Ovid)
1 exp Respiratory Tract Infections/
2 (respiratory adj5 infection*).tw.
3 1 or 2
4 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 munostin).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/4-27
29 3 and 28

637

Searching other resources
We used identied articles as references for a Science Citation
Index search. We searched bibliographies of all included trials as
well as those of relevant reviews to identify additional studies.
Finally, we sent a letter to all rst authors, as well as pharmaceutical companies that manufacture immunostimulant drugs, requesting data and references for any relevant published and unpublished trials. There were no language or publication restrictions. We also searched for studies in the trial registration web
site: metaRegister of Controlled Trials (http://www.controlledtrials.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
Saracho-Weber 2001 (co-worker Vzquez-Ramos); Schaad 1986;

Schaad 2002). However, no additional data were provided. A further 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; Paupe
1986; Rutishauser 1998 (co-worker Grevers); Valleron 1992). Dr.
Arturo Berber provided the database for OM-85 trials from Mexico. In 2010, we made attempts to contact the following authors: Joseph Bellanti, Jean Bousquet, Herman A. Cohen, Craig
I Coleman, Jean Paul Collet, Alessandro Fiocchi, Sergio Marcassa, Renzo Mora, RJ Riedl-Seifert, Urs B. Schaad, Draganka
Stankulova, Claudia Steurer-Stey and James A. Taylor, and manufacturers Luipold (luivac), OM Pharma (broncho-vaxom), Pierre
Fabre (ribomunyl) and Polichem (adimod). Only Sergio Marcassa,
Renzo Mora, RJ Riedl-Seifert, Urs B. Schaad (by himself and in
name of OM Pharma) replied; no information regarding new studies was obtained.
Selection of studies
Two review authors (BN, JSM) independently searched for trials
for inclusion and risk of bias assessment. We resolved differences
by discussion.
Data extraction and management
We analyzed and managed data using Review Manager (RevMan
2008). Two authors (BN, JSM) independently extracted data. We
sought missing data from investigators of individual trials, as necessary, in order to perform analyses on an intention-to-treat (ITT)
basis.
Dr Arturo Berber contacted trial authors to request unpublished
data. Responses were received from 10 trial authors (Arroyave
1999; Collet 1993; Gmez-Barreto 1998; Gutirrez-Tarango
2001; Jara-Prez 2000; Karam-Bechara 1995; Paupe 1991;
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 included
trial using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) as high risk, low
risk or uncertain risk . Figure 1 and Figure 2 shows the results of
risk of bias assessment for the seven domains.

638

Figure 1. Risk of bias graph: review authors judgements about each risk of bias item presented as
percentages across all included studies.

639

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

640
Measures of treatment effect

We reported the mean differences (MD) (and 95% condence
intervals (CI)) for the meta-analysis of data measured on a continuous scale. We assessed heterogeneity by visual inspection of the
outcomes tables and by using two statistics of heterogeneity (H
and I2 statistic) (Higgins 2003). Due to the observed statistical
heterogeneity, we used the random-effects model.
Unit of analysis issues

Regarding the trials with a description of randomisation and allocation, the unit of randomisation was the individual subject
(Cohen 2004; Collet 1993; Del-Rio-Navarro 2003; GutirrezTarango 2001; Jara-Perez 2000; Taylor 2003).
Dealing with missing data

The studies only analyse the available data, ignoring the missing
data.
Assessment of heterogeneity
The way in which the outcomes were reported varied widely across
the trials. We decided to use the mean number of ARTIs and its
standard deviation (SD) as the outcome as it allows the use of parametric statistical methods that provide more power to the tests. We
assumed that the number of ARTIs in the IS-treated group would
be comparable to the number of ARTIs in the placebo group; and
both of these would depend on the susceptibility of the children
(determined by age, duration of trial and seasons of the year during the trial). Consequently we expected to have heterogeneity in
the mean number of ARTIs. Therefore, we decided to standardise
the results using the percentage of infections considering the mean
number of infections in the placebo group as 100%.
Assessment of reporting biases

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

641
Figure 4.
Data synthesis
than 40 including only OM-85 and BV D53 and OM-85 alone

and D53 alone.
Due to the heterogeneity of the results we selected the randomeffects model of meta-analysis.
Subgroup analysis and investigation of heterogeneity
RESULTS
We also conducted bivariate correlation as well as linear regression

and sensitivity analyses of subgroups to investigate the sources of
statistical heterogeneity (please refer to Results section).
Description of studies
See: Characteristics of included studies; Characteristics of excluded
studies.
Sensitivity analysis
To determine whether conclusions were robust, we performed
analyses of different set of studies as follows: any IS; bacterial IS;
bacterial IS trials with the total sample size of equal to or greater
than 40; bacterial IS trials with total sample size equal to or greater
Results of the search

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

642

authors or searching of trial registries. Of the references obtained,
we identied 93 studies as potentially eligible.
Included studies
We included 61 placebo-controlled clinical trials involving 4149
participants. The studies were very heterogenous in the interventions studied, the number of ARTIs in the placebo groups and in
the reporting of outcomes.
Population
The participants enrolled in the included trials were children ranging from six months to 18 years of age. The echinacea trials differed
in the selection criteria of participants as they used children without a signicant health problem and without a history of recurrent
ARTI. The remainder of the trials included a history of recurrent
ARTIs in the inclusion criteria. All the trials were conducted in
the Northern (boreal) hemisphere except Fukudas (Fukuda 1999).
Fall and winter seasons referred to the months from September
to January. The year of the trial was not specied in most of the
studies.
the ARTIs were dened by the presence of respiratory signs and

symptoms.
The remaining 24 studies reported a variety of end points: symptoms, clinical scales or presence or absence of respiratory infections. Some trials reported the frequency of ARTIs as either equal
to or more than one infection (Burgio 1994; Careddu 1994b;
Fukuda 1999; Mora 2010a; Paupe 1991; Rutishauser 1998; Taylor
2003; Wahl 2008); equal to or more than two infections (Mora
2007); equal to or more than three infections (Collet 1993); the
total 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 in
the number of ARTIs (Andrianova 2003; Iuldashev 1988). Others
measured the severity of symptoms using clinical scales that were
not validated (Fiocchi 1989; Giovannini 2000; Mora 2002; Renzo
2004) or as days suffering symptoms (Martin du Pan 1982).
Excluded studies
We excluded 36 studies: 32 did not comply with the selection
criteria; two compared several IS treatments without a placebo
group; and two were duplicate reports of trials already included.
See Characteristics of excluded studies table.
Interventions
Forty studies used bacterial products, four studies used herbal extracts (echinacea and garlic), 11 studies used synthetic compounds,
ve studies used thymic extracts (thymomodulin) and one study
used a synthetic interferon. All trials used a placebo control. The
common names of the medications are in Table 1.
Twenty-two studies had a duration shorter than six months, 33
studies had a duration of six months and only six studies had a
duration longer than six months. The duration of seven D53 trials
was less than six months and nine D53 trials had a duration of six
months. In all D53 trials the description of the methodology was
not clear and different routes of administration were used (nasal
spray or by mouth). Ten OM-85 BV trials lasted six months; two
trials had a duration of longer than six months.
Outcomes
Only 35 of the 61 included studies reported the mean and SD

of the incidence of respiratory infections or provided data to calculate these measure, allowing their inclusion in the meta-analysis (Ahrens 1984; Arroyave 1999; Careddu 1994a; Clerici 1988;
Cohen 2004; De Loore 1979; Del-Rio-Navarro 2003; Fiocchi
1986; Garabedian 1990; Gutirrez-Tarango 2001; Gmez-Barreto
1998; Hauguenauer 1987; Hls 1995; Jara-Prez 2000; KaramBechara 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 Eygen
1976; Van Eygen 1979; Vautel 1993; Zagar 1988). In these studies
Risk of bias in included studies

The description of the methodology was not clear in most of
the studies. Only 17.1% (6 out of 35) studies reported adequate
randomisation and blinding (participants and treating physicians
were blinded) (Cohen 2004; Collet 1993; Del-Rio-Navarro 2003;
Gutirrez-Tarango 2001; Jara-Perez 2000; Taylor 2003) (Figure
1). Using the quality rating criteria (Higgins 2011), the quality of
the rest of the trials (28 out of 34 (82.4%)) was B; randomisation
and follow through of participants was unclear. See Table 2 for a
description of the quality of the trials.
Only 17.1% (6 out of 35) studies reported on the number of
participants lost to follow up (Cohen 2004; Collet 1993; Del-RioNavarro 2003; Gutirrez-Tarango 2001; Jara-Perez 2000; Taylor
2003). Of these, ve studies reported losses. While losses were
minimal, 0.5% to 7% in three studies, two studies reported a
loss of 18% and 24%. As additional data were not obtained from
the investigators on the outcomes of participants who were lost
to follow up an intention-to-treat (ITT) analysis could not be
undertaken. The numbers lost to follow up are explained in further
detail.
In the Cohen 2004 trial, 160 out of 215 in the IS group completed the trial (27 dropped out because the medication had an
unpleasant taste, 24 due to non-compliance which was not fully
explained, four dropped out due to a lack of condence in the
treatment); and 168 out of 215 of the placebo group completed
the trial (22 dropped out because the placebo had an unpleasant
taste, 21 due to non-compliance which was not fully explained,

643

and one dropped out due to a lack of condence 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 group
completed the trial. Five children were lost to follow up. Twenty
out of 24 in the placebo group completed the trial. Two children
were lost to follow up (the parents of one participant withdrew
consent for their child to continue in the trial and one left because
the trial medication caused the child to have diarrhea). A total of
18% were lost to follow up.
In the Collet 1993 trial, 199 out of 210 in the IS group and 196
out of 213 placebo group completed the trial. For both groups,
the 28 lost to follow up were related either to the parents moving
to a different location or the mothers stopped working and no
longer took their children to the daycare centres where the trials
were being held. A total of 7% were lost to follow up.
In the Taylor 2003 trial, 242 out of 263 in the IS group completed
the trial (six withdrew before the rst ARTI, ve changed their
minds about participating, one never received the study medication, ve withdrew during the rst ARTI, three refused the study
medication, one was concerned about the effect on their immune
system, for one the protocol was too complicated, six log books
were never received, four were lost to follow up); 244 out of 261
in the placebo group completed the trial (three withdrew before
the rst ARTI, two changed their minds about participating, one
was excluded for taking another medication, one withdrew during
the rst ARTI, nine log books were never received and four were
lost to follow up). A total of 7% were lost to follow up.
In the Jara-Prez 2000 trial, 99 out of 100 in the IS group completed the trial. The case report from one child was lost. One hundred out of 100 in the placebo group completed the trial. A total
of 0.5% were lost to follow up.
In the Gutirrez-Tarango 2001 trial, outcomes were reported for
all enrolled children. All the participants completed the trial.
The outcome assessor was blinded to the treatment allocation in
8.8% (three out of 34) of the studies (Cohen 2004; Collet 1993;
Taylor 2003). Only 14.7% (ve out of 34) of studies (Cohen 2004;
Collet 1993; Del-Rio-Navarro 2003; Gutirrez-Tarango 2001;
Taylor 2003) were considered of quality A (Higgins 2011). The
rest of the studies were of poor quality.
Allocation
In the studies with a proper description of randomisation and
allocation (Cohen 2004; Collet 1993; Del-Rio-Navarro 2003;
Gutirrez-Tarango 2001; Jara-Perez 2000; Taylor 2003), the implementation of the random sequence of the treatments was reported. In Cohen 2004 active medication and the placebo were
supplied directly by the manufacturer and all randomisation lots
were stored in a sealed envelope at the pharmacy of the company,
to be opened only in the event of an emergency. In Collet 1993
participants were allocated to IS or placebo according to a program for remote data entry (Minitel a national telecommunica-
tion system network in France). Additionally, randomisation was

also stratied by study centre and blocked for every four children.
In the studies by Del-Rio-Navarro 2003 and Gutirrez-Tarango
2001 consecutive numbered study medication boxes, as well as a
closed opaque envelope describing the treatment, were supplied
directly by the manufacturer; participants received a patient number coincident with treatment number when the selection criteria
were completed. In the Jara-Perez 2000 study consecutive numbered study medication boxes, as well as a closed opaque envelope describing the treatment, were supplied directly by the manufacturer; participants received a patient number corresponding a
treatment according to an alphabetical name list. In Taylor 2003,
each study centre had a supply of study medication (active medication and placebo) in consecutively numbered bottles that were
identical in appearance, contents of each bottle were randomly
determined using a computer-generated randomisation list, and
randomisation was stratied by site and in blocks of 10. Enrolled
children were assigned a unique study number corresponding to
the numbers on the bottles of study medication. Figure 1 shows
the review authors judgement of the risk of bias related to allocation concealment presented as percentages across all included
studies and Figure 2shows the risk for each included study.
Blinding
Six studies (Cohen 2004; Collet 1993; Del-Rio-Navarro 2003;
Gutirrez-Tarango 2001; Jara-Perez 2000; Taylor 2003) claimed
that IS and placebo treatment had identical appearance and that
the taste of both were similar. Investigators and participants were
not aware of the received treatment.
Incomplete outcome data

Only six studies (Cohen 2004; Collet 1993; Del-Rio-Navarro
2003; Gutirrez-Tarango 2001; Jara-Perez 2000; Taylor 2003) reported the number of patients lost to follow up. All used only the
available data for the analyses. No imputation for the incomplete
data were intended.
Cohen 2004 had a total of 24% lost to follow up; the frequencies
and causes of it were similar in active and placebo groups. In
the Del-Rio-Navarro 2003 trial 18% of participants were lost to
follow up; more children in the active group were lost (5/25 in
active group versus 2/25 in the placebo group). In the Collet 1993
trial, 7% of participants were lost to follow up; in both groups the
rates and the reasons were similar. In the Taylor 2003 trial, 7% of
participants were lost to follow up; in both groups the rates and
the reasons were similar. In the Jara-Prez 2000 trial only the data
of one participant on IS was lost. In the Gutirrez-Tarango 2001
trial, all the participants completed the trial.
Selective reporting

644

The study protocols were not available. Sixty-one randomized,
placebo-controlled clinical trials were identied. Only 35 studies reported the mean and SD of the incidence of respiratory
infections or provided data to calculate these measure (Ahrens
1984; Arroyave 1999; Careddu 1994a; Clerici 1988; Cohen
2004; De Loore 1979; Del-Rio-Navarro 2003; Fiocchi 1986;
Garabedian 1990; Gutirrez-Tarango 2001; Gmez-Barreto 1998;
Hauguenauer 1987; Hls 1995; Jara-Prez 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 Eygen
1976; Van Eygen 1979; Vautel 1993; Zagar 1988). Seven trials
reported the frequency of ARTIs (Burgio 1994; Careddu 1994b;
Collet 1993; Fukuda 1999; Paupe 1991; Rutishauser 1998; Taylor
2003). The rest of the studies did not use outcome measures relevant to the prevention of respiratory infections.
Other potential sources of bias

In 29 out of the 35 included studies, the process of randomisation
and allocation was not described. Additionally, the disposition of
participants and reasons for withdrawals were not reported.
Funnel plots of IS effects have a considerable asymmetry, indicating 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 Summary
of ndings table
Effect of immunostimulants (IS) on acute respiratory

tract infections (ARTIs)
Of the 61 included studies only 35 provided data in a form suitable
for inclusion in the meta-analysis for this outcome. All 35 trials
compared IS with a placebo.
Twenty-four out of 35 studies showed a reduction of ARTIs, both
as total numbers and as a percentage reduction of ARTIs (considering the mean number of ARTIs in the placebo group as 100%).
In the meta-analysis the use of IS was shown to reduce the total
number of ARTIs (mean difference (MD) -1.24 95% CI -1.54
to -0.94) as well as producing a percentage change in the rate of
ARTIs (MD -38.84%; 95% CI -46.37% to -31.31%). The total
number of ARTIs outcome showed high heterogeneity (I2 statistic
= 94.0%, Chi2 test = 582.02, P < 0.00001); the use of percentage change in the rate of ARTIs reduced the heterogeneity but
it remained very high (I2 statistic = 83.0%, Chi2 test = 195.07,
P < 0.00001). Therefore, we decided to use the random-effects
model with MD to calculate the global effect of immunostimulants (Figure 5; Figure 6).

645

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

646

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 as

by linear regression. The variables considered were total number
of children in the study, duration of the trial, mean number of
ARTIs in the control group versus the mean difference in number
of ARTIs and mean difference in the percentage of ARTIs. The
main source of heterogeneity was the mean number of ARTIs in
the control group, using the mean difference in number of ARTIs
(linear regression model correlation - 0.672, P < 0.001). Using
the mean difference in the percentage of ARTIs, the source of
heterogeneity was related to the mean difference in the number of
ARTIs and mean number of ARTIs in the control group (linear
regression model correlation 0.834, P < 0.001). The age of the
participants in each trial could be another important source of
variation in the number of ARTIs, as younger children would
suffer more ARTIs. Yet the age in each trial was diverse, including
enrolled preschool children, school-aged children and adolescents.
This made the exploration of this potential source of variation
problematic. In general, the net reduction in the number of ARTIs
was dependent on the background rate of ARTIs.
Another potential source of heterogeneity was the type of IS. We

decided to investigate this source of heterogeneity by performing
sub-analyses as follows.
1. Including the bacterial IS studies data (and excluding the
Saracho-Weber 2001 trial because it was the only trial with more
ARTIs in the IS group than in the placebo group, probably due
to a clerical mistake inverting ARTI incidences). The number of
trials was 24; total number of participants was 2154, the number
of IS participants was 1091 and the number of placebo
participants was 1063. The reduction in the total number of
ARTIs was MD -1.41 (95% CI -1.85 to -0.98); the reduction in
the 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-Weber
2001) with a total number of participants of at least 40. The
number of trials was 19; the total number of participants was
2009, the number of IS participants was 1019 and the number
of placebo participants was 990. The reduction in the total

647

number of ARTIs was MD -1.42 (95% CI -1.92 to -0.93); and
the 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 of
participants was more than 40 (including D53 and OM-85 BV).
The number of trials was 16; the total number of participants
was 1811, the number of IS participants was 921 and the
number of placebo participants was 890. The reduction in the
total 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 was

MD -36.16 (95% CI -44.51 to -27.80).
4. Only OM-85 studies. The number of trials was nine; total
number of participants was 852, the number of IS participants
was 437 and the number of placebo participants was 415. The
reduction 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 a
percentage was MD -35.90 (95% CI -49.46 to -22.35) (Figure
7).
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; total

number of participants was 852, the number of IS participants
was 437 and the number of placebo participants was 415. The
reduction 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 a
percentage was MD -43.47 (95% CI -53.22 to -33.72) (Figure
8).
Figure 8. Forest plot of comparison: D53 trials, outcome: 7.2 Per cent difference in ARTIs.

648

We did not perform the sub-analyses for good quality trials as only
two out of ve trials provided data as mean and SD (Del-RioNavarro 2003; Gutirrez-Tarango 2001). The selection of bacterial
IS studies reduced the heterogeneity of the percentage difference
outcome 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 analysis
for all sub-analyses. The reduction of the I2 statistic when only
the bacterial IS were analyzed conrmed that the different kinds
of IS were another major source of heterogeneity. The combined
analysis of percentage difference outcome of D53 and OM-85 had
an I2 statistic of 65%; D53 alone 55%; OM-85 alone 75%.
Adverse effects
Twenty studies provided data on adverse events in a form suitable for inclusion in the meta-analysis. The most frequent events
were skin and gastrointestinal effects (nausea, vomiting, abdominal pain and diarrhea). No statistically signicant difference was
shown in these adverse events when comparing IS with a placebo.
A summary of the reported safety data for each trial is noted in the
outcome section of the Characteristics of included studies table.
In 22 studies, authors did not report the presence or absence of
adverse events (Andrianova 2003; Bnovein 1992; Clerici 1988;
Fiocchi 1986; Fiocchi 1988; Garabedian 1990; Giovannini 2000;
Hauguenauer 1987; Iuldashev 1988; Longo 1988; Maestroni
1984; Martin du Pan 1982; Piquett 1986; Prusek 1987; RB10
1994; RB17 1988; RB21 1988; RB22 1990; RB24 1990; RB25
1990; Saracho-Weber 2001; Sramek 1986). In eight studies, trial
authors claimed that no adverse event were observed (Chen 2004;
De Loore 1979; Dils 1979; Karam-Bechara 1995; Mora 2007
Renzo 2004; Van Eygen 1976; Zagar 1988). In four studies no adverse events were observed in the immunostimulant group (Burgio
1994; Fiocchi 1989; Lacomme 1985; Schaad 1986). Five studies
reported a single case of adverse events in the IS group (Fukuda
1999; Gmez-Barreto 1998; Paupe 1986; Paupe 1991; Van Eygen
1979). One study reported only two adverse events (Wahl 2008).
In three studies no adverse events related to administration of the
trial medications were reported (Arroyave 1999; Jara-Prez 2000;
Mora 2010a).
DISCUSSION
Summary of main results
This review shows that IS reduce the incidence of ARTIs by about
40% on average (from 35 trials with a total of 4060 participants).
However, due to the poor quality of the included trials this may be
an overestimate of the true effect of IS. Most of the trials reported
a low incidence of adverse events or no adverse events. The most
frequent adverse events were gastrointestinal complaints such as
nausea, vomiting, abdominal pain and diarrhea; and skin disorders

such as rash, urticaria and pruritus.
The possible benecial effects of immunostimulants in the prevention of ARTIs, cancers, AIDS/HIV infections, tuberculosis etc.
have been awaited expectantly by many clinicians and medical
researchers. One of the main indications of registered IS is the
prevention of ARTIs in children, as they are more susceptible to
ARTIs. IS use is common in some countries in Europe and in the
Americas as result of the demand to reduce the incidence of ARTIs
in children.
While the use of IS is currently controversial and is viewed with
skepticism by many physicians, there have been several clinical trials supporting their use as ancillary treatment and in the prevention of ARTIs. Yet their mechanism of action and possible benets and risks are not well known. The aim of this review was to
synthesise all the evidence currently available from trials on this
topic to enable a more robust, unbiased assessment of the role of
efcacy and safety of IS to prevent ARTIs in children.
After reviewing all available IS studies on the prevention of ARTIs
in children, we empathise with the skepticism of many physicians.
This review has a number of limitations due to the quality and
reporting of the trials on this topic, the heterogeneity of the included trials and the possibility of publication bias. Few papers
complied with standards for methodological quality and reporting
of clinical trials, with the majority having signicant deviations
from these standards. In addition, the lack of detail in many of the
trial publications limited the quality of this review.
The most common problems with the included trials were that
they:
did not report data on ARTIs sufcient to reproduce
parametric and non-parametric statistical tests or carry out metaanalysis;
did not establish the normal incidence of ARTIs in the local
population 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 denition of ARTI and other end
points or used non validated scales;
misused statistical tests, especially the use of Students 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 signicant difference;
did not report or explain the ow chart and attrition of the
participants and the statistical methods did not consider the data
from missing participants (censored data);
published articles in low impact journals;
included heterogeneous groups of children comprising

649

infants, toddlers, schoolboys and girls and adolescents without
considering the incidence of ARTIs in each group;
did not control for or report on confounding factors (that is
to say, age groups, concomitant asthma or allergy, number of
siblings, 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 herbal
supplements (Wolsko 2005) and bacterial extracts.
All the trials were conducted in populations of highly susceptible
children (secondary prevention) except Collet 1993 and Jara-Prez
2000, which studied children over-exposed to ARTIs due to the
fact that they attended daycare centres and an orphanage, respectively, and Martin du Pan 1982 which included a subgroup from
daycare centres. In contrast, the echinacea trials were carried out in
populations without a history of recurrent ARTIs (Cohen 2004;
Taylor 2003).
The lack of signicance of the ndings of some trials could be
ascribed to small sample size, duration of the intervention, season
of intervention, broad participant selection criteria (mainly diverse
age groups) and low incidence of ARTIs in the studied population
(caused by an over-reporting of previous ARTIs or reduction of
incidence as children grew older).
Thymic extracts have been withdrawn from sale in several countries, due to the possible prion contamination and consequent
risk of bovine spongiform encephalopathy (WHO 2005). The use
of levamisole is restricted because of the risk of agranulocytosis,
neurologic disease (Symoens 1978) and leukoencephalopathy (Xu
2009).
The overall effect of IS was a reduction in the total number of
ARTIs (MD -1.24; 95% CI -1.54 to -0.94) but the individual
size of the effect in each trial depended on the number of ARTIs
in the control group. The size of the effect could seem small but
expressing the reduction of ARTIs as a percentage indicates a good
effect, about 40% (MD -38.84%; 95% CI -46.37 to -31.31). The
results indicate that the reduction in the incidence of ARTIs is a
real possibility but as the net effect depends on the background rate
of ARTIs the effect would only be noticeable when the number of
infections to be reduced is higher than the normal incidence for
a given age group. Therefore, the use of IS for the prevention of
ARTIs must be limited to children with proven high susceptibility
to ARTIs or over-exposed children who are over-exposed to ARTIs
because they are in daycare centres, orphanages, kindergarten or
elementary school.
Sub-analysis of studies with available databases (Del-Rio-Navarro
2003; Gutirrez-Tarango 2001; Jara-Prez 2000) have shown that
IS are not very effective in the prevention of one ARTI but are in
the prevention of recurrent infections (that is, two or three). This
may be the reason why echinacea trials fail to show protection to
the rst infection but had some effect on the second infection. In
addition, the participants had no history of increased incidence
of ARTI. In a re-analysis of one study (Taylor 2003) it was found
that 69.2% of the children treated with placebo had a second
ARTI while only 55.8% of children on echinacea had a second

infection (P = 0.01). However, this effect could not be explored
in this review.
In all meta-analyses it is important to consider the presence and
possible effect of publication bias; that is, the selective publication
of trials with positive results. The funnel plot demonstrated considerable asymmetry, indicating possible publication bias. Other
types of bias that could affect the funnel plot are the language bias
(publication in languages other than English and publication in
non-indexed, small, local journals), poor methodological design,
inadequate analysis and inadequate presentation of the results. In
only one study (Saracho-Weber 2001) the treated group had an
increase in ARTIs and, therefore, a positive difference.
The high heterogeneity limits the external validity of the analyses
with all the studies. However, when we selected only the studies
on bacterial IS (particularly those of D53 and OM-85 BV), and
used percentage of ARTIs, the heterogeneity could be regarded
as acceptable. It is important to note that the size of the effects
is similar in the different sub-analyses, supporting the external
validity of the conclusions.
On the basis of the asymmetry shown in the funnel plot, the heterogeneity of the trials and the low quality of many included trials,
the possibility of bias (resulting in an overestimation of the true
effects of IS on ARTIs) should be considered as high. Therefore,
caution needs to be applied when interpreting the possible advantages of IS shown in this review. However, the results of this review
provide a reference to the probable effect of IS in the prevention of
ARTIs in children and point to the need for further clinical trials.
Further trials on IS must follow the established guidelines (Collet
1992; Moher 2001; Valleron 1992), estimate sample size according
to realistic incidence of ARTI and control for confounding factors.
Multivariable analysis should be used when confounding factors
are identied. Reports of such trials must include enough data to
replicate non-parametric statistical tests (for instance, frequency
of ARTIs at the end point) and include statistical analysis dealing
with censored data (Mahe 1999). Registration of all the protocols
and ongoing trials would be desirable to obtain all the possible
outcomes. It would be necessary to conduct trials on otitis and
lower ARTIs with large numbers of highly susceptible children.
Considering the present review, the prevention of ARTIs using
IS may be possible. Larger clinical trials, adequately powered for
important population groups, sponsored by health authorities,
would be desirable to establish the true effects of IS and the effect
of individual IS preparations.
Overall completeness and applicability of

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

650

Quality of the evidence
Although the global quality of the trials was poor, a group of
studies comply with the quality standards (Cohen 2004; Collet
1993; Del-Rio-Navarro 2003; Gutirrez-Tarango 2001; Jara-Perez
2000; Taylor 2003).
Due to the above and the classication of the studies with the
GRADEpro tool, the global quality of the evidence on the effect of
immunostimulants to reduce the incidence of ARTIs is regarded
as moderate. Additional research is likely to have an impact on our
condence in the estimate of effect and may change the estimate.
Meanwhile, the evidence of the incidence of adverse events is considered as low. Further research is very likely to have an important
impact on our condence in the estimate of effect and is likely
to change the estimate, as the incidence of adverse events was not
properly reported in most of the studies. See Summary of ndings
for the main comparison.
Potential biases in the review process

We consider the risk of biases in the review process minimal, as
the plausible sources of information have been consulted and the
authors and manufactures were contacted. Additionally, no external funding was provided for this review.
reduction with OM-85 was -1.21 (95% CI -1.39 to -1.03), which

is similar to the ndings in this review.
The results of this review do not agree with the review by SteurerStey (Steurer-Stey 2007) which pooled two OM-85 studies to
calculate the risk of fewer than three infections over six months of
follow up in children not in daycare (RR 0.82; 95% CI 0.65 to
1.02).
AUTHORS CONCLUSIONS
Implications for practice
This review indicates that IS reduce the incidence of ARTIs by 40%
on average in susceptible children. The trials have shown benets
of IS in toddlers (two to ve years), school boys (six to 12 years)
and children with a high incidence of ARTIs, for example children
attending daycare and children living in orphanages. Studies in
healthy children are not available. Although the safety prole in the
studies was good, some IS may be unsafe. For instance, levamisole
has been related to agranulocytosis and neurologic disease, and
thymic extracts introduce the risk of prion contamination and
therefore the risk of bovine spongiform encephalopathy.
Implications for research

Agreements and disagreements with other
studies or reviews
The present review is in agreement with a previous meta-analysis
on 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 ARTIs
showed a reduction of child ear, nose and throat (ENT) infections of 27% to 68%, and a decrease in child ENT and bronchopulmonary infections of 32% to 61% compared with placebo
(Bellanti 2003). This concurs with the effect of D53 shown in this
review.
Other meta-analyses on the effect of individual IS report an effect
as a percent reduction of -31.86% (95% CI -34.32 to -29.40) for
D53, and a corresponding reduction of -39.28% (95% CI -52.58
to -25.98) for OM-85 (De-La-Torre-Gonzalez 2005). Both CIs
are in agreement with those in this review.
Schaad (Schaad 2010) in a meta-analysis reported that in an OM85 BV-treated population, 32% had three or more ARTIs in six
months, against 58.2% in the placebo-treated population. The
Further high-quality trials are required to conrm the true effect

of IS and individual IS preparations in the prevention of ARTIs.
We encourage national health authorities to conduct large, multicentre, double-blind, placebo-controlled studies to establish the
precise benets and risks for using IS to prevent ARTIs. It is necessary to conduct more studies on the number and frequency of
ARTIs and the physiological and immunological basis of recurrent
ARTIs.
ACKNOWLEDGEMENTS
We especially acknowledged the great editorial work of Liz Dooley. We thank Arturo Berber for his contribution to the protocol.
The authors also wish to thank the following people for commenting on the draft review of the rst version: Chanpen Choprapawon, Ville Peltola, Richard Shoemaker and Ludovic Reveiz; and
to Anne Lyddiatt, Ville Peltola, Sree Nair and Ludovic Reveiz for
the comments on the updated draft review.

651

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Immunopharmacology 2001;1:62535.
Uhari 1998
Uhari M, Kontiokari T, Niemel M. A novel use of xylitol
sugar in preventing acute otitis media. Pediatrics 1998;102
(4 Pt 1):87984. [MEDLINE: 9755259]
Valleron 1992
Valleron AJ, Grimeld A. Evaluation of clinical trials
of immunomodulators for prevention of recurrent
respiratory infections in children. Developments in Biological
Standardization 1992;77:14958. [MEDLINE: 1426656]
WHO 1998
WHO. Acute respiratory infections: the forgotten
pandemic. Bulletin of the World Health Organization 1998;
76(1):1013. [MEDLINE: 9615503]
WHO 2005
World Health Organization. Fact Sheet 113. Bovine
spongiform encephalopathy. http://www.who.int/
mediacentre/factsheets/fs113/en/print.html (accessed 20
July 2005) 2005.
Williams 2002
Williams BG, Gouws E, Boschi-Pinto C, Bryce J, Dye C.
Estimates of world-wide distribution of child deaths from
acute respiratory infections. Lancet Infectious Diseases 2002;
2:2532.
Wolsko 2005
Wolsko PM, Solondz DK, Phillips RS, Schachter SC,
Eisenberg DM. Lack of herbal supplement characterization
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16194636]
Wright 1989
Wright AL, Holberg CJ, Martinez FD, Morgan WJ, Taussig
LM. Breast feeding and lower respiratory tract illness
in the rst year of life. BMJ 1989;299(6705):9469.
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Xu 2009
Xu N, Zhou W, Li S, Zhou G, Zhang N, Liang
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Yamshchikov AV, Desai NS, Blumberg HM, Ziegler TR,
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References to other published versions of this review

Del-Rio-Navarro 2006
Del-Rio-Navarro BE, Espinosa Rosales F, Flenady V,
Sienra-Monge JJL. Immunostimulants for preventing
respiratory tract infection in children. Cochrane Database
14651858.CD004974.pub2]
Indicates the major publication for the study

661

CHARACTERISTICS OF STUDIES
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 respiratory tract, or those who received treatment for at least 1 ARTI during the autumn
and 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 10

days per month during 3 months
Participants 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) ARTIs
and 72 participants with placebo had 5.04 4.04 ARTIs
Two participants in the OM-85 BV had adverse events, 1 presented abdominal pain
and diarrhea and the other gastrointestinal distress. Six placebo participants had adverse
events with 2 cases of folliculitis
Notes
It is not stated that the trial is randomized

Selection criteria of the participants allows the inclusion of non-susceptible participants
The reason for excluding participants from the analysis are given
The trial was conducted in Germany
The trial took place over the 4 seasons of the year
Risk of bias
Bias
Authors judgement
Support for judgement
Random sequence generation (selection High risk

bias)
Allocation concealment (selection bias)
High risk
Blinding (performance bias and detection High risk

bias)
All outcomes
Blinding of participants and personnel High risk
(performance bias)
All outcomes
Blinding of outcome assessment (detection High risk
bias)
All outcomes

662

Ahrens 1984
(Continued)

bias)
All outcomes
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 rst part of the study 172 students received Allicor (300 mg of garlic extract) and 468 students received placebo
once a day for 5 months
In the second part of the study, 42 students had Allicor, 41 students had placebo and 73 students had dibazol for 5
months
Outcomes
In the rst part of the study Allicor diminished the rate of ARTIs from 28.5% to 9.5%. During this phase there was
a case of atopy
In the second phase of the study Allicor subjects had 1.7 fewer infections than those in the placebo group and 2.4
fewer infections than those in the dibazol group
Notes

The trial was conducted in Russia
Arroyave 1999
Methods
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 participants
had 8.4 1.9 ARTIs
No adverse events related to the trial medications were reported
Notes
It is not stated that the trial was randomized

Flow of patient numbers and drop-outs were not clear
SD was obtained from the reported variance
This is the greatest reduction in the treatment group regarding the placebo group
The trial was conducted in Mexico

663

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 respiratory
symptoms and this happened in 62.5% of 40 placebo participants
There 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 supplement
issue of a German magazine
The trial was conducted in Italy
There were no data about the seasons during the trial
Caramia 1994
Methods
Participants
Participants from 2 to 8 years with history of 6 ARTIs in the 6 months before the trial with at least 3 antibiotic
courses with current hospitalization because of relapse of ARTI (active infection) and decit of at least 1 parameter
of immune system
120 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 60
days 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 relapses
5 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 were
published in a single supplement issue of a German magazine
Careddu 1994a
Methods
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

664

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 participants
had 1.03 1.0 ARTIs
There 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 the
trial. The mean number of ARTIs in the placebo group is rather low. Most of the pidotimod papers were published
in a single supplement issue of a German magazine
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. 50
participants 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 a
German magazine
Chen 2004
Methods
Participants
Children from 2 to 12 years
Interventions
43 children had sublingual Lantigen B (bacterial antigen suspension) and there were 43 placebo participants in
periods 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) ARTIs
Six participants in the Lantigen B group and 6 in the control group were lost to follow up
No adverse events were observed
Notes
The study was conducted in China. No information on the seasons during the trial was provided

665

Clerici 1988
Methods
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 follow
up
Outcomes
During the trial 20 thymomodulin participants had 2.55 0.6 (mean SD) ARTIs and 20 placebo participants had
4.60 0.6 ARTIs
The adverse events were not reported
Notes
Flow diagram of participants and drop-outs is not given. It is not stated that the trial is randomized
The trial was conducted in Italy in autumn-winter seasons
Cohen 2004
Methods
Participants
Children from 1 to 5 years, without clinical alterations
Interventions
Participants received Chizukit (preparation of Echinacea purpurea, propolis and vitamin

C) or placebo for 12 weeks. Children from 1 to 3 years had 5 ml twice a day and those
from 4 to 5 years had 7.5 ml twice a day. During ARTIs participants had the respective
dosage 4 times a day
Outcomes
160 Chizukit participants had 0.9 1.1 (mean SD) ARTIs and 168 placebo participants
had 1.8 1.3 ARTIs. Nine participants in the verum group and 7 in the placebo group
had adverse events, all gastrointestinal and palatability symptoms
Notes
A ow diagram of the participants was provided. Trial was conducted in winter in Israel
Risk of bias
Bias
Authors judgement
Random sequence generation (selection Low risk

bias)
Low risk
Blinding (performance bias and detection Low risk

bias)
All outcomes
Blinding of participants and personnel Low risk
(performance bias)
All outcomes

666

Cohen 2004
(Continued)
Blinding of outcome assessment (detection Low risk

bias)
All outcomes
bias)
All outcomes
All outcomes
Low risk
Low risk
Collet 1993
Methods
Participants
Children older than 6 months attending daycare centres

423 children were randomized
Interventions

days per month during 3 months. Participants were followed up after 4.5 months for a
total study period of 7.5 months
Outcomes
26.7% of 210 participants with OM-85 BV and 33.8% of 213 with placebo had more
than 4 infections in the 7.5 month period
OM-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 frequent
were tympanocentesis (n = 3) and adenoidectomy (n = 2)
Notes
Flow diagram and drop-outs are given. Sub-analysis for different age groups and for the
treatment period are given
The trial was conducted in France during boreal autumn-winter seasons
Risk of bias
Bias
Authors judgement

bias)
Low risk

bias)
All outcomes

667

Collet 1993
(Continued)

(performance bias)
All outcomes
bias)
All outcomes
bias)
All outcomes
All outcomes
Low risk
Low risk
De Loore 1979
Methods
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 tablets

Dosage: participants under 15 kg had half a tablet; participants from 15 to 30 kg had a tablet; participants over 30
kg 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
Methods
Participants
Participants from 3 to 6 years with at least 3 ARTIs during the previous 6 months. 54
children were randomized
Interventions

days per month during 3 months
Participants 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. Eight
participants in the OM-85 BV group had 10 adverse events; only 3 gastrointestinal events
were related to drug administration. Nine participants with placebo had 10 adverse

668

(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 Mexico
The trial was conducted over the 4 seasons. Changes in the levels of IgG subclasses were
investigated; only the OM-85 BV group presented signicant reduction in the IgG4
levels
Risk of bias
Bias
Authors judgement

bias)
Low risk

bias)
All outcomes
(performance bias)
All outcomes
All outcomes
Low risk
Low risk
Dils 1979
Methods
Participants
Children from 2.5 to 17 years suffering chronic or recurrent RTIs with at least 4 infections from October to February
in the last year
Interventions
Participants had levamisole tablets (50 mg) or placebo tablets

Dosage: participants under 15 kg had half a tablet; participants from 15 to 30 kg had 1 tablet; participants over 30
kg 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 had
79 ARTIs
Author claimed that no side effects were reported
Notes
No ow diagram nor drop-outs are provided

There are no data on the dispersion of ARTIs
The study was conducted in Belgium during autumn and winter

669

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 placebo
participants had 0.82 0.12 ARTIs
Notes
The sample size is clearly insufcient

The number of ARTIs in the placebo group was rather low
The 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 day
by 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 8
Participants 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 participants
in the placebo group had 43 upper ARTIs and 51 lower ARTIs
Adverse events were not reported
Notes
Flow of participants is not reported. The number of lower ARTIs is extremely high. Trial was conducted in Italy
during autumn-winter seasons
It 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 dened as 30 points in a clinical scale and more than 5 ARTIs
in the last 6 months
Interventions
Placebo or ribosomal extract spray (D53); 1 puff in each nostril plus 1 puff in the oropharyngeal cavity 3 times a day
according to the following schedule; 2 weeks treatment, 1 week washout and 1 week treatment in the rst month;
2 week treatment and 2 week washout in the second, third and fourth months. Total duration of the study was 4
months

670

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 explained

The main outcome is a non-validated clinical score
The trial was conducted during boreal winter-spring seasons in Italy
It was not possible to identify this study in the Bellanti review
Fukuda 1999
Methods
Participants
Participants from 8 months to 7 years with recurrent acute otitis and repetitive tonsillitis. At baseline, there were 18
participants 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 free
from infections after the end of medication
One patient in the thymomodulin group had nausea and vomiting
Notes
The sample size is clearly insufcient

The trial was conducted in Brazil
There 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 France

Data were obtained from Boyle 2000 and Bellanti 2003 (trial RB13)

671

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 5
ARTIs 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 rst 3
weeks and then 1 tablet 4 consecutive days per month for the following 5 months
Outcomes
45 in D53 group and 42 in placebo group nished the trial. A clinical score for upper ARTIs was 0.46 in the D53
group 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
Gutirrez-Tarango 2001
Methods
Participants
Participants from 1 to 12 years with at least 3 ARTIs during the previous 6 months. 54
children were randomized
Interventions
At the beginning participants received either 1 capsule of 3.5 mg of OM-85 BV or

placebo a day by 10 days per month during 3 months. The treatment was repeated 6
months after the beginning
Participants 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) ARTIs
while the placebo group (n = 28) had 8.0 2.55
Four OM-85 BV participants had 5 adverse events and 6 placebo participants had 6
adverse events
Notes
Flow of patient numbers and drop-outs are given

The trial was conducted during the 4 seasons
Risk of bias
Bias
Authors judgement

bias)
Low risk

bias)
All outcomes

672

Gutirrez-Tarango 2001
(Continued)

(performance bias)
All outcomes
All outcomes
Low risk
Low risk
Gmez-Barreto 1998
Methods
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 3
months
Both groups received amoxicillin/ clavulanate at entry; 40/10 mg/kg a day, divided in 3 doses, by 21 days
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 ARTIs
A patient in the OM-85 BV presented rash and withdrew from the trial
Notes
Denitions of subacute sinus and its cure are given. A sub-analysis for children under 6 years was included
Drop-outs are reported. But the ow of participants is not clear
The trial was conducted over the 4 seasons in Mexico
Hauguenauer 1987
Methods
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 rst 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 had
4.9 4.3 ARTIs
There were no adverse events
Notes

Flow of patient numbers is not clear. The trial was conducted from January to June
ARTIs data were obtained from Boyle 2000 and Bellanti 2003 (trial RB12)

673

Hls 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 consecutive
weeks. 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 ARTIs
Three participants in the D53 group had aggressiveness, cough and headache respectively; 2 placebo participants
presented fever and exudative erythema respectively
Notes
It was conducted in Germany during boreal autumn-winter seasons

This study is cited by Boyle, and it corresponds to RB14 in Bellantis review
Iuldashev 1988
Methods
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 in
0.5 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 did
not have statistically signicant improvement
Notes

The study was conducted from September to October in the former USSR
Jara-Prez 2000
Methods
Participants
Girls from 6 to 13 years suffering more than 3 ARTI during fall and winter seasons
before the trial, living in an orphanage
200 girls entered the trial
Interventions
Participants received either 1 capsule of 3.5 mg of OM-85 BV or placebo once daily for
10 days per month for 3 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 related
to the trial medications were reported

674

Jara-Prez 2000
(Continued)
Notes
The reason for excluding 1 participants from the analysis is given

Confounders are well controlled as all the participants had the same background and
lived in the same place under the same conditions
The trial was conducted during the boreal autumn-winter seasons
Risk of bias
Bias
Authors judgement

bias)
Low risk

bias)
All outcomes
(performance bias)
All outcomes
All outcomes
Low risk
Low risk
Karam-Bechara 1995
Methods
Participants
Children from 3 to 12 years suffering recurrent bronchitis with 6 episodes probed by the physician prescriptions in
the 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 follow
up
Outcomes
During the trial 33 thymomodulin participants had 1.59 1.98 (mean SD) ARTIs and 39 placebo participants
had 2.61 3.04 ARTIs
Participants did not present adverse events
Notes
Drop-outs are explained


675

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 rst 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 had
5.38 3.7 ARTIs
There was no adverse event in the D53 group, while there were 6 cases of digestive adverse events in the placebo
group
Notes
The trial was conducted in France. There are no data about the seasons during the trial
ARTIs data were obtained from Boyle 2000 and Bellanti 2003 (trial RB11)
Litzman 1999
Methods
Participants
Children from 4 to 8 years with at least 5 documented respiratory tract infections during the last autumn-winter
seasons
Interventions
Participants had placebo or isoprinosine, 50 mg/kg per day divided in 4 to 6 doses for a period of 6 weeks and then
50 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 placebo
A isoprinosine patient and a placebo patient had transit increase in antinuclear antibodies and 1 placebo participant
had 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
Methods
Participants
Children from 3.5 to 9 years with history of recurrent ARTI in the last fall-winter period with more than 1 fever
episode by month
Interventions
Participants were followed by 1 year before the beginning of study medication

Participants 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 in
the 19 placebo participants

676

Longo 1988
(Continued)
Notes
Flow of patient numbers and drop-outs are not given

Maestroni 1984
Methods
Participants
Children from 1 to 16 years who were susceptible to upper ARTIs

Interventions
Participants received either 1 capsule of 3.5 mg of OM-85 BV or placebo a day by 10 days per month during 3
months
Outcomes
During the study 11 participants receiving OM-85 BV had 2.0 2.05 (mean SD) ARTIs and 9 participants with
placebo had 5.55 5.36 ARTIs
Notes
Inclusion criteria are not clear

It is not stated that the trial is randomized; the sample size is clearly insufcient
The trial was conducted in Switzerland
Martin du Pan 1982

Methods
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 months
Participants 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 from
purulent rhinorrhea, while 34 placebo participants had 569/3530 days (16.12%) suffering from purulent rhinorrhea
Notes
The participants participated in a previous trial 1 year before comparing the effect of a syrup with yeast extract versus
a placebo syrup
Flow of patient numbers and drop-outs are not given. Sub-analyses for the children attending the daycare centres
and private practice are provided
The trial was conducted in Switzerland during autumn-winter seasons

677

Mora 2002
Methods
Participants
Children from 4 to 14 years with history of otitis and recurrent ARTIs by more than 2 years, with 3 ARTIs requiring
medical 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 rst 3 weeks and
then 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 nished the 6-month trial. There were greater improvements
in D53 group regarding incidence of infections, otitis, fever and duration of antibiotic and ancillary treatments. One
D53 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 denition of otitis.
Primary end points are a non-validated clinical scores given as ranks. To express a signicant difference P > is used;
for instance P > 0.02.
Trial was conducted in autumn, winter and spring in Italy
It 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 1
and 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 ow diagram of the number of participants
is 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 dened as more than 4 episodes of acute
adenoiditis during a 6-month period. Acute adenoiditis was dened as mouth breathing, nasal obstruction, body
temperature 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 placebo
in 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

678

Mora 2010a
Notes
(Continued)
Levels of IgE, IgA, IgG, and IgM were investigated, as well as tympanometry, rhinomanometry, and symptom visual
analogue scale by the parents. Only 60 participants completed the trial, the lost of participants are explained
Motta 1994
Methods
Participants
Children from 3 to 14 years with history of recurrent tonsillitis with at least 8 episodes in the last 2 years, who had
suffered 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 day
by 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 participants
had 3.12 2.45 ARTIs
11 pidotimod participants had 15 adverse events, while 12 placebo participants had 18 adverse events, mainly
gastrointestinal complaints
Notes
Flow diagram of participants and drop-outs are not given. Number of infections per group was reconstructed from
the reported frequencies
Most of the pidotimod papers were published in a single supplement issue of a German magazine
Passali 1994a
Methods
Participants
Children from 3 to 14 years with history of tonsillitis or pharyngitis in the previous autumn-winter seasons
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 186
and 129 in the 205 pidotimod participants, while for the same periods the number of ARTIs were 278 and 276 in
216 placebo participants
There 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 given

Only the total number of ARTIs per group is reported
Most of the pidotimod papers were published in a single supplement issue of a German magazine

679

Paupe 1986
Methods
Participants
Children from 1 to 13 years with history of recurrent rhinopharyngeal infection with at least 3 infections of this kind
during 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 weeks
The 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 placebo
participants 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 from
Paupe
Paupe 1991
Methods
Participants
Participants from 0.5 to 19 years, with history of more than 3 ARTIS in the last 6 months. 127 participants were
randomized
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 months
Outcomes
During the study 34% of 61 participants with OM-85 BV and 3.5% of 55 participants with placebo had no infection
One patient with OM-85 BV, 2 with placebo had diarrhea
Notes
The reasons for excluding participants from the analysis are given
Pech 1987
Methods
Participants
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 weeks

680

Pech 1987
(Continued)
Outcomes
In RU41740 group 1 patient presented dry cough and another had difculties in swallowing
Notes
ARTI data were obtained from a paper by Reinert 1995

The number of ARTIs in the placebo group is low
Piquett 1986
Methods
Participants
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 weeks
Outcomes
Adverse events report is not available
Notes
ARTI data were obtained from a paper by Reinert 1995

The number of ARTIs in the placebo group is low
Pozzi 2004
Methods
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 placebo
participants had 1.643. The number but not the kind of adverse events are reported
Notes
Drop-outs are explained

Dispersion of the mean number of ARTIs (SD) is not provided
A group of adults was also included in the trial
There were no data on the seasons during the trial

681

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. No
adverse event report is provided
Notes
Available data are from the Bellanti review. It was not possible to establish if this trial corresponds to any other
published trial
RB17 1988
Methods
Double blind, placebo-controlled trial
Participants
Children
Interventions
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
published trial
The number of ARTIs is extremely high
RB21 1988
Methods
Participants
Children
Interventions
Outcomes
Notes
published trial

682

RB22 1990
Methods
Double blind placebo-controlled trial
Participants
Children
Interventions
Outcomes
20 D53 participants had 3.0 1.0 (mean SD) ARTIs and 20 placebo participants had 6.2 1.4 ARTIs. No adverse
event report is provided
Notes
published trial
The number of ARTIs is extremely high
RB24 1990
Methods
Participants
Children
Interventions
Outcomes
Notes
published trial
RB25 1990
Methods
Participants
Children
Interventions
Outcomes
Notes
published trial

683

Renzo 2004
Methods
Participants
Children from 6 to 14 years with history of recurrent or chronic ARTIs for more than 2 years and at least 5 ARTIs
in 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 nished the 6-month trial. There were greater improvements in D53 group regarding
incidence of infections, otitis, fever, and duration of antibiotic and ancillary treatments. According to the authors
there was no adverse event
Notes
Drop-outs are explained. There is no clinical denition of otitis. Primary endpoints are a non-validated clinical scores
given as ranks. To express a signicant difference P > is used; for instance P > 0.02
Trial was conducted in autumn, winter and spring in Italy
It is not possible to establish if this trial correspond to any study cited by Bellanti in his review
Riedl-Seifert 1995
Methods
Participants
Children from 4 to 9 years, with history of 10 ARTIs in the last year

Children from 4 to 6 years must have 8 severe ARTIs lasting more than 2 weeks in this period
Children from 7 to 9 years must have 4 severe ARTIs lasting more than 2 weeks in this period
115 children had LW50020 and 118 had placebo
Interventions
Dosage is not specied. Total follow up of 14 weeks
Outcomes
During the study period 99 participants with LW50020 had 15 ARTIs and 108 participants with placebo had 29
ARTIs data dispersion is not specied
10.4% of participants with LW50020 experienced adverse events versus 5.1% in the placebo group. The adverse
events were mainly gastrointestinal complaints
Notes
The reasons for participants exclusion from analysis are given. The intervention is not well dened
The trial was conducted in Germany
Rutishauser 1998
Methods
Participants
Children from 4 to 11 years with history of recurrent ARTIs; children from 4 to 6 years with more than 10 ARTIs
in the last year, those from 7 to 11 with more than 8 ARTIs in the last year. 200 children were included
Participants suffering 4 ARTIs lasting more than 2 weeks were included too
124 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 once
a day); 4-week follow up; 4-week treatment (same schedule); and 4-week follow up

684

Rutishauser 1998
(Continued)
Outcomes
Considering only children. During the study period 75% of 117 participants with LW50020 had no infection and
54% of 72 placebo participants had no infection
Considering children and adults, 62 participants had 101 adverse events in the LW50020 group, while 26 participants
had 38 adverse events in the placebo group
Notes
The reason for excluding participants from the analysis are not given
Beside the children group, the trial included a group of adolescents and adults
The trial was conducted in Switzerland
Saracho-Weber 2001
Methods
Participants
Children older than 2 years and younger than 18 years currently suffering acute or
chronic ARTIs and history of 3 ARTIs the last year
Interventions
135 participants had RU 41740 (1 mg of klebsiella glycoproteins by tablet) and 117

placebo. Participants had 1 tablet OD for 8 consecutive days per month, for 3 consecutive
months
Outcomes
Participants with RU 41740 had 8.0 3.4 (mean SD) ARTIs and placebo participants
7.2 3.2. Yet authors claimed that RU 41740 participants experienced clinical improvement
Authors did not describe the adverse events
Notes
There is no ow diagram of the study, nor explanation of drop-outs. This is the only
study where the active treatment participants had a higher ARTIs number, probably a
clerical mistake
Risk of bias
Bias
Authors judgement

All outcomes
High risk
Schaad 1986
Methods
Participants
Participants from 8 months to 12 years with who had recurrent ARTIs during fall and winter seasons in the last year
45 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 months

685

Schaad 1986
(Continued)
Outcomes
During the study 45 OM-85 BV participants had 2.89 1.77 (mean SD) ARTIs and 49 placebo participants had
2.98 1.56 ARTIs
Only 1 patient in the placebo group had urticaria
Notes
It is not stated that the trial is randomized. Flow diagram of participants is not provided
The trial was conducted in Germany during autumn-winter seasons
Schaad 2002
Methods
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 months
120 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-85
BV. 88 participants with OM-85 BV had 456 adverse events and 76 placebo participants had 379 events. Most of
the adverse events were gastrointestinal and respiratory
Notes
There is no ow diagram of the study, nor explanation of drop-outs. This trial was conducted in Germany and
Switzerland 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 school

1203 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 of

participants (327) did not receive any medication, the total duration of the follow up is
variable (about 6 months)
Outcomes
The number of ARTIs as cases per 1000 persons days was IRS19 7.79, placebo 7.43,
and no-treatment 8.04
Adverse events were not reported
Notes
Randomisation was unblinded ascribing children to 1 of 2 medication batches or left

without treatment
Reasons for drop-outs are not specied
Only ARTIs associated with school absenteeism were considered. Tonsillitis, sinusitis
and otitis media were not considered. There is a bias to consider only severe infections
The trial was conducted in the former Czechoslovakia
The trial was conducted during autumn-winter seasons

686

Sramek 1986
(Continued)
Risk of bias
Bias
Authors judgement
Random sequence generation (selection High risk

bias)
High risk
Blinding (performance bias and detection High risk

bias)
All outcomes
Blinding of participants and personnel High risk
(performance bias)
All outcomes
bias)
All outcomes
bias)
All outcomes
All outcomes
High risk
High risk
Taylor 2003
Methods
Participants
Children from 2 to 11 years without signicant health problems
Interventions
Participants had a preparation of Echinacea purpurea or placebo. Children from 2 to 5

years had 3.75 ml twice a day and children from 6 to 11 years had 5 ml twice a day
during ARTIs (up to 3 ARTIs, during a maximum of 10 days each). The study period
was 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 more
than 1 ARTI
Echinacea and placebo. Participants had 152 and 146 adverse events respectively. Most
of the adverse events were cutaneous and gastrointestinal

687

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
Bias
Authors judgement

bias)
Low risk

bias)
All outcomes
(performance bias)
All outcomes
bias)
All outcomes
bias)
All outcomes
All outcomes
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 ARTIs
Authors claim that no adverse event were observed
Notes
Apparently, there were no drop-outs. The trial was conducted in Belgium during autumn and winter

688

Van Eygen 1979
Methods
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 a
day 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 1.89
ARTIs
Only 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
Methods
Participants
Children aged 2.98 0.17 years (mean SE) with history of 5 ARTIs during the last 12 months or with 3 ARTIs
during the last 3 months
Interventions
D53 or placebo 3 tablets daily taken as a single dose 4 days per week for the rst 3 weeks and then 4 consecutive days
per 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 participants
had 5.56 0.39 ARTIs
Regarding adverse events D53 participants had 3 cases of rhinitis and placebo participants had 3 cases of rhinitis, 1
of 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 practice
Potential ARTIs were reported as adverse events
There 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, dened as 3 or more separate episodes of acute otitis
media (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 manipulative treatment (OMT), true OMT (including cranial manipulation) plus placebo echinacea, or true echinacea
plus OMT. An alcohol extract of Echinacea purpurea roots and seeds (or placebo) was administered for 10 days at the
rst sign of each common cold. Five OMT visits (or sham treatments) were offered over 3 months

689

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
Methods
Participants
Children from 4 to 12 years, suffering from chronic rhino-sinusitis during a symptomatic episode of the disease
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 1
capsule 1 day for 10 days per month for 3 months. Participants received antibiotics at the beginning of the trial. The
total 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 placebo
had 1.09 0.65 ARTIs
Participants did not present adverse events
Notes
Clinical denitions of chronic sinusitis and its cure are not provided
The reasons for excluding participants from the analysis are not given. The number of ARTIs is rather low
The trial was conducted in the former Yugoslavia
The trial was conducted during autumn-winter seasons
ARTI = acute respiratory tract infection

RTIs = respiratory tract infections
SD = standard deviation
COPD = chronic obstructive airways disease
iv = intravenously
n = number
IgG = immunoglobulin G
OD = 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 Collets study. Yet, it is a good paper and it is the only one showing prevention of
viral ARTIs proved with viral test

690

(Continued)
Barr 1965
It was a trial on asthmatic children
Bnovein 1992
Comparison between IS without placebo group
Das 2000
The age of the participants is not specied
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
Ma 1994
Macchi 2005
Open trial in adults
Makovetskaya 2001
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
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

691

(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

692

DATA AND ANALYSES
Comparison 1. Any IS compared with placebo
Outcome or subgroup title
No. of
studies
No. of
participants
1 Mean number of ARTIs

2 Percent difference in ARTIs
35
35
4060
4060
Statistical method
Mean Difference (IV, Random, 95% CI)
Effect size
-1.24 [-1.54, -0.94]
-38.84 [-46.37, -31.
31]
Comparison 2. Bacterial IS compared with placebo
No. of
studies
No. of
participants

24
24
2154
2154
Statistical method
Effect size
-1.41 [-1.85, -0.98]
-41.21 [-49.10, -33.
31]
Comparison 3. Bacterial IS trials with n equal to or greater than 40 compared with placebo
No. of
studies
No. of
participants

19
19
2009
2009
Statistical method
Effect size
-1.42 [-1.92, -0.93]
-38.44 [-47.25, -29.
63]
Comparison 4. Bacterial IS trials with n equal to or greater than 40 only OM-85 and BV D53 compared with
placebo
No. of
studies
No. of
participants

16
16
1811
1811
Statistical method

Effect size
-1.17 [-1.56, -0.78]
-36.16 [-44.51, -27.
80]
693

Comparison 5. Adverse events
No. of
studies
No. of
participants
10
10
1457
1469
No. of
studies
No. of
participants

9
9
852
852
No. of
studies
No. of
participants

11
11
1067
1067

1 Gastrointestinal adverse events
2 Skin adverse events
Statistical method
Risk Difference (M-H, Fixed, 95% CI)
Risk Difference (M-H, Fixed, 95% CI)
Effect size
0.01 [-0.01, 0.03]
0.00 [-0.01, 0.01]
Comparison 6. OM-85 trials
Statistical method
Effect size
-1.20 [-1.75, -0.66]
-35.90 [-49.46, -22.
35]
Comparison 7. D53 trials
Statistical method

Effect size
-1.32 [-1.86, -0.79]
-43.47 [-53.22, -33.
72]
694

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(SD)
Mean(SD)
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 ]
20
2.8 (1.4)
20
5.2 (1.5)
2.7 %
-2.40 [ -3.30, -1.50 ]
0.53 (0.11)
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)
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 ]
Fiocchi 1986
IV,Random,95% CI
Mean Difference
-4
-2
Favours immunostimulant

IV,Random,95% CI
Favours control
(Continued . . . )
695
Study or subgroup
Immunostimulant
Control
Mean Difference
Weight
Mean(SD)
Mean(SD)
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 ]
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 ]
Saracho-Weber 2001
Total (95% CI)
2042
IV,Random,95% CI
(. . . Continued)
Mean Difference
IV,Random,95% CI
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

Favours control
696

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

Outcome: 2 Percent difference in ARTIs
Study or subgroup
Immunostimulant
Control
Mean Difference
Weight
Mean(SD)
Mean(SD)
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 ]
20
53.85 (26.92)
20
100 (28.85)
3.4 %
-46.15 [ -63.44, -28.86 ]
64.63 (13.41)
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 ]
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)
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 ]
Fiocchi 1986
IV,Random,95% CI
Mean Difference
-50
-25

25
IV,Random,95% CI
50
Favours control
(Continued . . . )
697
Study or subgroup
Immunostimulant
Control
Mean Difference
Weight
Mean(SD)
Mean(SD)
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 ]
135 111.11 (47.22)
117
100 (44.44)
3.8 %
11.11 [ -0.22, 22.44 ]
Saracho-Weber 2001
IV,Random,95% CI
(. . . Continued)
Mean Difference
IV,Random,95% CI
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

25
50
Favours control
698

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

Study or subgroup
Immunostimulant
Control
Mean Difference
Weight
Mean(SD)
Mean(SD)
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 ]
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 ]
26
5.04 (1.99)
28
8 (2.55)
3.6 %
-2.96 [ -4.18, -1.74 ]
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)
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
IV,Random,95% CI
Mean Difference
IV,Random,95% CI
1063
100.0 % -1.41 [ -1.85, -0.98 ]

-2
-1

Favours control
699

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

Study or subgroup
Immunostimulant
Control
Mean Difference
Weight
Mean(SD)
Mean(SD)
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 ]
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 ]
26
63 (24.88)
28
100 (31.88)
5.7 %
-37.00 [ -52.20, -21.80 ]
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)
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
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
59.04 (61.7)
IV,Random,95% CI
Mean Difference
IV,Random,95% CI
1063
100.0 % -41.21 [ -49.10, -33.31 ]

-100
-50

50
100
Favours control
(Continued . . . )
700
Study or subgroup
Immunostimulant
N
Control
Mean(SD)
Mean Difference
Mean(SD)
Weight
IV,Random,95% CI
(. . . Continued)
Mean Difference
IV,Random,95% CI

-100
-50
50
100
Favours control
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.
Review:
Comparison: 3 Bacterial IS trials with n equal to or greater than 40 compared with placebo
Study or subgroup
Immunostimulant
Control
Mean Difference
Weight
IV,Random,95% CI
Mean Difference
Mean(SD)
Mean(SD)
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 ]
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 ]
26
5.04 (1.99)
28
8 (2.55)
4.5 %
-2.96 [ -4.18, -1.74 ]
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

IV,Random,95% CI
Favours control
(Continued . . . )
701
Study or subgroup
Immunostimulant
Control
Mean Difference
Weight
Mean(SD)
Mean(SD)
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
IV,Random,95% CI
(. . . Continued)
Mean Difference
IV,Random,95% CI
990
100.0 % -1.42 [ -1.92, -0.93 ]

-4
-2
Favours control
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.
Review:
Comparison: 3 Bacterial IS trials with n equal to or greater than 40 compared with placebo
Study or subgroup
Immunostimulant
Control
Mean Difference
Weight
Mean(SD)
Mean(SD)
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 ]
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 ]
26
63 (24.88)
28
100 (31.88)
6.6 %
-37.00 [ -52.20, -21.80 ]
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
IV,Random,95% CI
Mean Difference
-50
50
IV,Random,95% CI
100
Favours control
(Continued . . . )

702
Study or subgroup
Immunostimulant
N
Control
Mean(SD)
Mean Difference
Mean(SD)
Weight
IV,Random,95% CI
(. . . Continued)
Mean Difference
IV,Random,95% CI
Paupe 1986
21 65.15 (66.39)
22 100 (107.47)
2.1 %
-34.85 [ -87.98, 18.28 ]
Pech 1987
35
34
100 (76.06)
3.9 %
-40.96 [ -73.69, -8.23 ]
161 100 (106.06)
5.5 %
-14.39 [ -36.21, 7.43 ]
59.04 (61.7)
RB10 1994
153 85.61 (90.91)
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

50
100
Favours control
703

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.
Review:
Comparison: 4 Bacterial IS trials with n equal to or greater than 40 only OM-85 and BV D53 compared with placebo
Study or subgroup
Immunostimulant
Control
Mean Difference
Weight
Mean(SD)
Mean(SD)
Ahrens 1984
83
3.75 (3.42)
72
5.04 (4.04)
4.7 %
-1.29 [ -2.48, -0.10 ]
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 ]
26
5.04 (1.99)
28
8 (2.55)
4.6 %
-2.96 [ -4.18, -1.74 ]
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
IV,Random,95% CI
Mean Difference
IV,Random,95% CI
890
100.0 % -1.17 [ -1.56, -0.78 ]

-4
-2

Favours control
704

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.
Review:
Comparison: 4 Bacterial IS trials with n equal to or greater than 40 only OM-85 and BV D53 compared with placebo
Study or subgroup
Immunostimulant
Control
Mean Difference
Weight
IV,Random,95% CI
Mean Difference
Mean(SD)
Mean(SD)
IV,Random,95% CI
Ahrens 1984
83
74.4 (67.86)
72
100 (80.16)
5.8 %
-25.60 [ -49.18, -2.02 ]
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 ]
26
63 (24.88)
28
100 (31.88)
8.0 %
-37.00 [ -52.20, -21.80 ]
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 ]
161 100 (106.06)
6.2 %
-14.39 [ -36.21, 7.43 ]
RB10 1994
153 85.61 (90.91)
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

50
100
Favours control
705

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

Outcome: 1 Gastrointestinal adverse events
Study or subgroup
Immunostimulant
Control
n/N
n/N
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 ]
3/20
4/20
2.8 %
-0.05 [ -0.28, 0.18 ]
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 ]
744
713
100.0 %
0.01 [ -0.01, 0.03 ]
Total (95% CI)
Risk Difference
Weight
M-H,Fixed,95% CI
Risk Difference
M-H,Fixed,95% CI
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
0.1
0.2
Favours control

706

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

Outcome: 2 Skin adverse events
Study or subgroup
Immunostimulant
Control
n/N
n/N
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 ]
0/20
0/20
2.7 %
0.0 [ -0.09, 0.09 ]
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 ]
744
725
100.0 %
0.00 [ -0.01, 0.01 ]
Total (95% CI)
Risk Difference
Weight
M-H,Fixed,95% CI
Risk Difference
M-H,Fixed,95% CI
Total events: 5 (Immunostimulant), 2 (Control)

Heterogeneity: Chi2 = 4.08, df = 9 (P = 0.91); I2 =0.0%
-0.1
-0.05
0.05
0.1
Favours control

707

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

Study or subgroup
Experimental
Control
Mean Difference
Weight
Mean(SD)
Mean(SD)
Ahrens 1984
83
3.75 (3.42)
72
5.04 (4.04)
9.1 %
-1.29 [ -2.48, -0.10 ]
20
2.8 (1.4)
20
5.2 (1.5)
11.2 %
-2.40 [ -3.30, -1.50 ]
26
5.04 (1.99)
28
8 (2.55)
8.9 %
-2.96 [ -4.18, -1.74 ]
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)
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
IV,Random,95% CI
Mean Difference
IV,Random,95% CI
415
100.0 % -1.20 [ -1.75, -0.66 ]

-4
-2
Favours experimental

Favours control
708

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

Study or subgroup
Experimental
Control
Mean Difference
Weight
Mean(SD)
Mean(SD)
Ahrens 1984
83
74.4 (67.86)
72
100 (80.16)
11.4 %
-25.60 [ -49.18, -2.02 ]
20 53.85 (26.92)
20
100 (28.85)
13.5 %
-46.15 [ -63.44, -28.86 ]
26
28
100 (31.88)
14.3 %
-37.00 [ -52.20, -21.80 ]
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)
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)
63 (24.88)
437
IV,Random,95% CI
Mean Difference
IV,Random,95% CI
415
100.0 % -35.90 [ -49.46, -22.35 ]

-100
-50

50
100
Favours control
709

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

Study or subgroup
Experimental
Control
Mean Difference
Weight
Mean(SD)
Mean(SD)
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 ]
100.0 %
-1.32 [ -1.86, -0.79 ]
Total (95% CI)
539
IV,Random,95% CI
Mean Difference
IV,Random,95% CI
528

-4
-2

Favours control
710

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

Study or subgroup
Experimental
Control
Mean Difference
Weight
Mean(SD)
Mean(SD)
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
IV,Random,95% CI
Mean Difference
IV,Random,95% CI
528
100.0 % -43.47 [ -53.22, -33.72 ]

-100
-50
50
100
Favours control
ADDITIONAL TABLES
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- OM-85 or OM-85 BV

munal
Lyophilised bacterial lysates
Chizukit
Preparation of Echinacea purpurea, propolis and vitamin C
Not available

711

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
Leucotrona, Leucogen
Thymomodulin
Thymus extract
Luivac
LW50020
Bacterial antigens
Munostin
Not available
Bacterial corpses and lysates
Not available
SL04
Bacterial extracts
Paspat
Not available
Autolysate mixture of bacterial antigens for parenteral application
Prasosine
Isoprinosine
Isoprinosine
Pulmotabs
Not available
Bacterial lysates
Pulmonarom
Not available
Bacterial lysates
Reaferon
Not available
Analogue of human interferon 2 obtained by genetic engineering
Respivax
Not available
Bacterial lysates
Ribovac, Ribomunyl, Immucithal
D53
Proteoglycans of K. pneumoniae plus bacterial ribosomes
TFX
Thymus extract
Thymus extract
Umckaloabo
Pelargonium sidoides
Alcohol extract from the roots of Pelargonium sidoides

712

Table 2. Description of the studies
Immunos- n
timulant
n analysis Duration < Duration 6 Duration > Quality A

data
6 months
months
6 months
Quality B
Quality C
Quality D
D53
18
11
11
18
IRS19
Lantigen B 2
LW50020
OM-85
BV
12
10
RU41740
Total bac- 40
terial
25
27
35
Herbal
(echinacea/
garlic)
Isoprinosine
Levamisole
Pidotimod
Total syn- 11
thetic
11
Thymic
extract
Synthetic
interferon
35
24
31
53
Grand to- 61
tal

713

APPENDICES
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 January
2006); and IPA (up to January 2006) for reports of trials.
Trials were identied using the Cochrane methodology searches phase 1 and phase 2 (Dickersin 1994). The following search strategy
was 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$)
3 or/1-2
4 exp Adjuvants, Immunologic/
5 (immunostimulants$ or immunomodulator$)
6 Immunobalt
7 (LW50020 or Luivac or Paspat)
8 Munostin
9 (OM-85 BV or Broncho-Vaxom)
10 Pulmonar-OM
11 D53
12 Ribomunyl
13 Ribovac
14 Immucytal
15 exp Lipopolysaccharides/
16 lipopolysaccharid$
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 AM3
24 Inmunoferon
25 glycophosphopeptical
26 or/4-25
27 3 and 26
Identied articles were used as references for a Science Citation Index search. Bibliographies of all included trials as well as those of
relevant reviews were searched to identify additional studies. Finally, a letter was sent to all rst authors, as well as pharmaceutical
companies 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/).

714

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/exp
AND [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,ti
AND [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 from
2005 to March 2010, for the following interventions:
Immunostimulants OR immunomodulators
Bacterial lysates OR bacterial antigens OR bacterial extracts
LW50020 OR Luivac OR Paspat
OM-85 OR OM-85 BV OR Broncho-Vaxom
D53 OR Ribomunyl OR Ribovac OR Immucytal
RU 41740 OR Biostim
AM3 OR Inmunoferon OR glycophosphopeptical
Pidotimod
715

Levamisole
Echinacea
WHATS NEW
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 respiratory tract infections in Schaad 2002. We excluded six new trials (Grimfeld 2004;
Heinz 2010; Mora 2010b; Razi 2010; Riedl-Seifert 1993; Steinsbekk 2005). We
included sub-analyses on the efcacy of D53 and OM-85. The conclusions remain unchanged
HISTORY
Protocol rst published: Issue 4, 2004
Review rst 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.
CONTRIBUTIONS OF AUTHORS
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.

716

DECLARATIONS OF INTEREST
Dr Arturo Berber was the medical manager for OM-85 BV (Broncho-Vaxom) in Mexico for BASF Pharma Mexico (Qumica Knoll
de Mxico) from 1995 to 2001. He was also the contact author of the initial protocol until he graciously stepped down because of a
potential conict 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 respiratory
tract 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. Use
of 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 IV
trial in 587 children. Clinical Therapeutics 1996 Nov-Dec;18(6):1068-79.
SOURCES OF SUPPORT
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
INDEX TERMS
Medical Subject Headings (MeSH)
Adjuvants, Immunologic [ therapeutic use]; Adolescent; Randomized Controlled Trials as Topic; Respiratory Tract Infections
[ prevention & control]
MeSH check words

Child; Humans

717

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EVIDENCE-BASED CHILD HEALTH: A COCHRANE REVIEW JOURNAL

Evid.-Based Child Health 7:2: 629717 (2012)

Immunostimulants for preventing respiratory tract infection

Immunostimulants for preventing respiratory tract infection in children (Review)

Evid.-Based Child Health 7:2: 629717 (2012)

Immunostimulants for preventing respiratory tract infection in children (Review)

Evid.-Based Child Health 7:2: 629717 (2012)

Immunostimulants for preventing respiratory tract infection

Evid.-Based Child Health 7:2: 629717 (2012)

PLAIN LANGUAGE SUMMARY

Immunostimulants for preventing respiratory tract infection in children (Review)

Illustrative comparative risks (95% CI)

No of participants (studies) Quality of

Percent difference in ARTIs

The mean Percent difference 4060

Incidence of gastrointestinal 21 per 1000

30 per 1000 (11 to 50 per 1457

Incidence of skin adverse 3 per 1000

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

Evid.-Based Child Health 7:2: 629717 (2012)

Immunostimulants for preventing respiratory tract infection in children (Review)

The effect depends on the

Evid.-Based Child Health 7:2: 629717 (2012)

Immunostimulants for preventing respiratory tract infection in children (Review)

GRADE Working Group grades of evidence

Evid.-Based Child Health 7:2: 629717 (2012)

Description of the condition

effort to establish the aetiology and epidemiology of ARTIs in

Immunostimulants for preventing respiratory tract infection in children (Review)

Evid.-Based Child Health 7:2: 629717 (2012)

Description of the intervention

How the intervention might work

The actual mechanism of IS is not yet fully understood. Currently

Why it is important to do this review

Immunostimulants for preventing respiratory tract infection in children (Review)

Evid.-Based Child Health 7:2: 629717 (2012)

Criteria for considering studies for this review

Types of outcome measures

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

1. The percentage of ARTIs.

Search methods for identification of studies

Immunostimulants for preventing respiratory tract infection in children (Review)

Evid.-Based Child Health 7:2: 629717 (2012)

Data collection and analysis

Saracho-Weber 2001 (co-worker Vzquez-Ramos); Schaad 1986;

Assessment of risk of bias in included studies

Immunostimulants for preventing respiratory tract infection in children (Review)

Evid.-Based Child Health 7:2: 629717 (2012)

Immunostimulants for preventing respiratory tract infection in children (Review)

Evid.-Based Child Health 7:2: 629717 (2012)

Immunostimulants for preventing respiratory tract infection in children (Review)

Evid.-Based Child Health 7:2: 629717 (2012)

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of reporting biases

Immunostimulants for preventing respiratory tract infection in children (Review)

Evid.-Based Child Health 7:2: 629717 (2012)

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