Cochrane Review: Immunostimulants for preventing respiratory tract infection in children

Authors


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 efficacy and safety of IS in preventing ARTIs in children.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) 2011, issue 1, which contains the Acute Respiratory Infections Group's 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% confidence 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 identified trials.

Main results

Thirty-five 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 profile in the studies was good, some IS may be unsafe. ARTI-susceptible children may benefit from IS treatment. Further high-quality trials are needed and we encourage national health authorities to conduct large, multicentre, double-blind, placebo-controlled RCTs on the role of IS in preventing ARTIs in children.

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 five years of age, mainly in low-income countries in Africa, Asia and Latin America. In high-income countries ARTIs are among the most frequent illnesses, leading to 20% of medical consultations, 30% of days lost from work and 75% of antibiotic prescriptions. In the USA the total cost of non-influenza-related viral ARTIs is around $40 billion annually, while the corresponding cost for influenza is US $87.1 billion. The 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 first year of life; eight ARTIs per year from the ages of one to four; six per year aged five to nine; and five per year aged 10 to 19. Children exposed to risks factors, such as attendance at daycare centres, overcrowding, contact with older siblings, smoking at home and lack of breast feeding, may suffer more ARTIs.

Several treatments have been used to reduce the incidence of ARTIs (vitamin A, vitamin C, zinc, antibiotics). Among them 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 benefit 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.

Summary of findings for the main comparison [Explanation]

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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 five years and 8.2% of all disabilities and premature mortality (WHO 1998). In 2000, 1.9 million (95% confidence 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 high-income countries is significant. For example, between 2000 and 2002 there were approximately 500 million non-influenza-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 influenza 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 five to nine years; 5.02 in children aged 10 to 14 years; and 4.71 in 15 to 19-year olds (Monto 2002). In the first phase of the Tecumseh study, from 1965 to 1971, 4905 residents registered their incidence of ARTIs for the six-year period. In the first 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 five 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 five 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 child-weeks. 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, parainfluenza 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 first 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 (Grüber 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 five episodes in year five, 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 immunodeficiencies, 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. Twenty-three 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).

Recent influenza epidemics have increased interest in effective unspecific 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 unspecific 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 (Hemilä 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 unspecific 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-specific 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 unspecific 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 specific antibodies and reproduction of specific 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, specific 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 efficacy 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 efficacy 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 efficacy of this approach and to provide clues for the development of new IS.

Objectives

To assess the safety and efficacy 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 definition of ARTI was accepted and included using different specific diagnoses, such as cold, influenza, 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 Group's 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 precision-maximising version (2008 revision); Ovid format (Lefebvre 2009). The search strategy was adapted for EMBASE (see Appendix 2). Details of the PASCAL, SciSearch, IPA and previous 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

Searching other resources

We used identified 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 first 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.controlled-trials.com/mrct/). We searched for IS trial registries in the U.S. National Institutes of Health in http://www.ClinicalTrials.gov.

Data collection and analysis

Selection of studies

Two review authors (BN, JSM) independently searched for 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; Gómez-Barreto 1998; Gutiérrez-Tarango 2001; Jara-Pérez 2000; Karam-Bechara 1995; Paupe 1991; Saracho-Weber 2001 (co-worker Vázquez-Ramos); Schaad 1986; Schaad 2002). However, no additional data were provided. A 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.

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.

Figure 1.

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

Figure 2.

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

Measures of treatment effect

We reported the mean differences (MD) (and 95% confidence 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; Gutiérrez-Tarango 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.
Figure 4.

Data synthesis

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

Subgroup analysis and investigation of heterogeneity

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

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

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

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

Included studies

We included 61 placebo-controlled clinical trials involving 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 significant 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 Fukuda's (Fukuda 1999). Fall and winter seasons referred to the months from September to January. The year of the trial was not specified in most of the studies.

Interventions

Forty studies used bacterial products, four studies used herbal extracts (echinacea and garlic), 11 studies used synthetic compounds, five 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.

Table 1. Trade and common names of IS used for prevention of ARIs
Trade nameCommon nameActive ingredient
Adimod Pidotimod Pidotimod
Allicor Not available Garlic extract
Biostim RU41740 Glycoprotein and membranes of Klebsiella pneumoniae
Broncho-Vaxom, Broncho-Munal, Ommunal OM-85 or OM-85 BV Lyophilised bacterial lysates
Chizukit Not available Preparation of Echinacea purpurea, propolis and vitamin C
Decaris Levamisole Levamisole
Echinacea Echinacea purpurea Extract of Echinacea purpurea
Immunoferon, Inmunol AM3 Glycophosphopeptical
IRS 19 Not available Bacterial lysates
Ismigen Not available Bacterial lysates
Lantigen B Not available Bacterial antigens
Leucotrofina, Leucogen Thymomodulin Thymus extract
Luivac LW50020 Bacterial antigens
Munostin Not available Bacterial corpses and lysates
Not available SL04 Bacterial extracts
Paspat Not available Autolysate mixture of bacterial antigens for parenteral application
Prasosine Isoprinosine Isoprinosine
Pulmotabs Not available Bacterial lysates
Pulmonarom Not available Bacterial lysates
Reaferon Not available Analogue of human interferon 2 obtained by genetic engineering
Respivax Not available Bacterial lysates
Ribovac, Ribomunyl, Immucithal D53 Proteoglycans of K. pneumoniae plus bacterial ribosomes
TFX Thymus extract Thymus extract
Umckaloabo Pelargonium sidoides Alcohol extract from the roots of Pelargonium sidoides

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; Gutiérrez-Tarango 2001; Gómez-Barreto 1998; Hauguenauer 1987; Hüls 1995; Jara-Pérez 2000; Karam-Bechara 1995; Lacomme 1985; Litzman 1999; Maestroni 1984; Motta 1994; Paupe 1986; Pech 1987; Piquett 1986; RB10 1994; RB17 1988; RB21 1988; RB22 1990; RB24 1990; RB25 1990; Saracho-Weber 2001; Schaad 1986; Schaad 2002; Van Eygen 1976; Van Eygen 1979; Vautel 1993; Zagar 1988). In these studies the ARTIs were defined 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.

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; Gutiérrez-Tarango 2001; Jara-Perez 2000; Taylor 2003) (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.

Table 2. Description of the studies
Immunostimulantnn analysis dataDuration < 6 monthsDuration 6 monthsDuration > 6 monthsQuality AQuality BQuality CQuality D
D53 18 11 7 11 - - 18 - -
IRS19 1 0 - 1 - - - 1 -
Lantigen B 2 0 - 2 - - 2 - -
LW50020 2 0 2 - - - 2 - -
OM-85 BV 12 9 - 10 2 4 8 - -
RU41740 5 5 - 3 2 - 5 - -
Total bacterial 40 25 9 27 4 4 35 1 -
Herbal (echinacea/garlic) 4 1 2 1 1 2 2 - -
Isoprinosine 1 1 - 1 - - 1 - -
Levamisole 4 3 2 2 - - 4 - -
Pidotimod 6 2 6 - - - 6 - -
Total synthetic 11 6 8 3 - - 11 - -
Thymic extract 5 3 4 - 1 - 5 - -
Synthetic interferon 1 0 1 - - - 1 - -
Grand total 61 35 24 31 6 6 53 2 -

Only 17.1% (6 out of 35) studies reported on the number of participants lost to follow up (Cohen 2004; Collet 1993; Del-Rio-Navarro 2003; Gutiérrez-Tarango 2001; Jara-Perez 2000; Taylor 2003). Of these, five 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 confidence 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, and one dropped out due to a lack of confidence in the treatment). A total of 24% were lost to follow up.

In the Del-Rio-Navarro 2003 trial, 20 out of 25 in the IS 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 first ARTI, five changed their minds about participating, one never received the study medication, five withdrew during the first 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 first ARTI, two changed their minds about participating, one was excluded for taking another medication, one withdrew during the first 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-Pérez 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 Gutiérrez-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% (five out of 34) of studies (Cohen 2004; Collet 1993; Del-Rio-Navarro 2003; Gutiérrez-Tarango 2001; Taylor 2003) were considered of quality A (Higgins 2011). 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; Gutiérrez-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 telecommunication system network in France). Additionally, randomisation was also stratified by study centre and blocked for every four children. In the studies by Del-Rio-Navarro 2003 and Gutiérrez-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 stratified 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 2 shows the risk for each included study.

Blinding

Six studies (Cohen 2004; Collet 1993; Del-Rio-Navarro 2003; Gutiérrez-Tarango 2001; Jara-Perez 2000; Taylor 2003) 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; Gutiérrez-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-Pérez 2000 trial only the data of one participant on IS was lost. In the Gutiérrez-Tarango 2001 trial, all the participants completed the trial.

Selective reporting

The study protocols were not available. Sixty-one randomized, placebo-controlled clinical trials were identified. Only 35 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; Gutiérrez-Tarango 2001; Gómez-Barreto 1998; Hauguenauer 1987; Hüls 1995; Jara-Pérez 2000; Karam-Bechara 1995; Lacomme 1985; Litzman 1999; Maestroni 1984; Motta 1994; Paupe 1986; Pech 1987; Piquett 1986; RB10 1994; RB17 1988; RB21 1988; RB22 1990; RB24 1990; RB25 1990; Saracho-Weber 2001; Schaad 1986; Schaad 2002; Van 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 findings 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).

Figure 5.

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

Figure 6.

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

We investigated heterogeneity by bivariate correlation as well 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 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.

We did not perform the sub-analyses for good quality trials as only two out of five trials provided data as mean and SD (Del-Rio-Navarro 2003; Gutiérrez-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 confirmed 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 significant 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; Bánovein 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; Gómez-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-Pérez 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 beneficial 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 benefits 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 efficacy 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 significant 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 sufficient to reproduce parametric and non-parametric statistical tests or carry out meta-analysis;

  • 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 definition of ARTI and other end points or used non validated scales;

  • misused statistical tests, especially the use of Student's t test for data under suspicion of non-normal distribution (SD > mean/2 or mean - SD < 0);

  • under reported adverse events or did not report them at all;

  • did not report the power of the statistical tests in trials without significant difference;

  • did not report or explain the flow chart and attrition of the participants and the statistical methods did not consider the data from missing participants (censored data);

  • published articles in low impact journals;

  • included heterogeneous groups of children comprising 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-Pérez 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 significance of the findings 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; Gutiérrez-Tarango 2001; Jara-Pérez 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 first 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 identified. 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).

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; Gutiérrez-Tarango 2001; Jara-Perez 2000; Taylor 2003).

Due to the above and the classification 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 confidence 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 confidence 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 findings 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.

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 OM-85 BV-treated population, 32% had three or more ARTIs in six months, against 58.2% in the placebo-treated population. The reduction with OM-85 was -1.21 (95% CI -1.39 to -1.03), which is similar to the findings in this review.

The results of this review do not agree with the review by Steurer-Stey (Steurer-Stey 2007) which pooled two OM-85 studies 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 benefits of IS in toddlers (two to five 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 profile 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

Further high-quality trials are required to confirm 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 benefits 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 first 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.

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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias) High risk  
Allocation concealment (selection bias) High risk  
Blinding (performance bias and detection bias) All outcomes High risk  
Blinding of participants and personnel (performance bias) All outcomes High risk  
Blinding of outcome assessment (detection bias) All outcomes High risk  
Blinding of outcome assessment (detection bias) All outcomes High risk  
Incomplete outcome data (attrition bias) All outcomes High risk  
Selective reporting (reporting bias) High risk  
Andrianova 2003
Methods Double-blind, placebo-controlled trial
Participants Participants from 6 to 11 years attending school
Interventions In the first part of the study 172 students received Allicor (300 mg of garlic extract) and 468 students received 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 first 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 It is not stated that the trial is randomized Selection criteria of the participants allows the inclusion of non-susceptible participants The trial was conducted in Russia
Arroyave 1999
Methods Double-blind, placebo-controlled trial
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 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 Randomised, double-blind, placebo-controlled, multicentre trial
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 deficit 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 The trial was conducted in Italy There were no data about the seasons during the trial
Careddu 1994a
Methods Randomised, double-blind, placebo-controlled, multicentre trial
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
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 The trial was conducted in Italy There were no data about the seasons during the trial
Careddu 1994b
Methods Randomised, double-blind, placebo-controlled trial
Participants Children with mean age of 4.8 years with history of recurrent ARTI in the fall-winter period before the trial. 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 The trial was conducted in Italy There were no data about the seasons during the trial
Chen 2004
Methods Randomised, double-blind, placebo-controlled trial
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
Clerici 1988
Methods Double-blind, placebo-controlled trial
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 Randomised, double-blind, placebo-controlled, multicentre trial
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 flow diagram of the participants was provided. Trial was conducted in winter in Israel
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias) Low risk  
Allocation concealment (selection bias) Low risk  
Blinding (performance bias and detection bias) All outcomes Low risk  
Blinding of participants and personnel (performance bias) All outcomes Low risk  
Blinding of outcome assessment (detection bias) All outcomes Low risk  
Blinding of outcome assessment (detection bias) All outcomes Low risk  
Incomplete outcome data (attrition bias) All outcomes Low risk  
Selective reporting (reporting bias) Low risk  
Collet 1993
Methods Randomised, double-blind, placebo-controlled, multicentre trial
Participants Children older than 6 months attending daycare centres 423 children were randomized
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 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias) Low risk  
Allocation concealment (selection bias) Low risk  
Blinding (performance bias and detection bias) All outcomes Low risk  
Blinding of participants and personnel (performance bias) All outcomes Low risk  
Blinding of outcome assessment (detection bias) All outcomes Low risk  
Blinding of outcome assessment (detection bias) All outcomes Low risk  
Incomplete outcome data (attrition bias) All outcomes Low risk  
Selective reporting (reporting bias) Low risk  
De Loore 1979
Methods Double-blind, placebo-controlled trial
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
Del-Rio-Navarro 2003
Methods Randomised, double-blind, placebo-controlled trial
Participants Participants from 3 to 6 years with at least 3 ARTIs during the previous 6 months. 54 children were randomized
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 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 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 significant reduction in the IgG4 levels
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias) Low risk  
Allocation concealment (selection bias) Low risk  
Blinding (performance bias and detection bias) All outcomes Low risk  
Blinding of participants and personnel (performance bias) All outcomes Low risk  
Incomplete outcome data (attrition bias) All outcomes Low risk  
Selective reporting (reporting bias) Low risk  
Dils 1979
Methods Double-blind, placebo-controlled trial
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 flow 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
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 The adverse events were not reported
Notes The sample size is clearly insufficient The number of ARTIs in the placebo group was rather low It is not stated that the trial is randomized 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 defined as 30 points in a clinical scale and more than 5 ARTIs in the last 6 months 120 participants were included
Interventions Placebo or ribosomal extract spray (D53); 1 puff in each nostril plus 1 puff in the oropharyngeal cavity 3 times a day according to the following schedule; 2 weeks treatment, 1 week washout and 1 week treatment in the first month; 2 week treatment and 2 week washout in the second, third and fourth months. Total duration of the study was 4 months
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 Double-blind, placebo-controlled clinical trial
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 insufficient It is not stated that the trial is randomized 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)
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 first 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 finished 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
Gutiérrez-Tarango 2001
Methods Randomised, double-blind, placebo-controlled trial
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 in Mexico The trial was conducted during the 4 seasons
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias) Low risk  
Allocation concealment (selection bias) Low risk  
Blinding (performance bias and detection bias) All outcomes Low risk  
Blinding of participants and personnel (performance bias) All outcomes Low risk  
Incomplete outcome data (attrition bias) All outcomes Low risk  
Selective reporting (reporting bias) Low risk  
Gómez-Barreto 1998
Methods Randomised, double-blind, placebo-controlled trial
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 Participants were followed up for 3 months for a total study period of 6 months
Outcomes During the study 26 participants with OM-85 BV had 1.56 ± 1.55 ARTIs and 30 participants with placebo had 2.22 ± 2.37 ARTIs A patient in the OM-85 BV presented rash and withdrew from the trial
Notes Definitions of subacute sinus and its cure are given. A sub-analysis for children under 6 years was included Drop-outs are reported. But the flow of participants is not clear The trial was conducted over the 4 seasons in Mexico
Hauguenauer 1987
Methods Double-blind, placebo-controlled clinical trial
Participants Participants aged less than 5 years with at least 3 ARTI treated with antibiotics in the last year
Interventions Participants had D53 or placebo. During the first month they had 3 weeks with 3 tablets per day for 4 days per week. The next 5 months they had a week per month with 3 tablets a day for 4 days
Outcomes In a period of 6 months 45 D53 participants had 3.24 ± 2.1 (mean ± SD) ARTIs and 42 placebo participants had 4.9 ± 4.3 ARTIs There were no adverse events
Notes The trial was conducted in France 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)
Hüls 1995
Methods Randomised, double-blind, placebo-controlled, multicentre clinical trial
Participants Participants with a mean age from 3 to 12 years with at least 3 severe ARTIs in the last year
Interventions Participants had 3 tablets of 0.25 mg of D53 or placebo in the morning for 4 consecutive days a week for 3 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 Bellanti's review
Iuldashev 1988
Methods Double-blind, placebo-controlled trial
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 significant improvement
Notes It is not stated that the trial is randomized Selection criteria of the participants allows the inclusion of non-susceptible participants The study was conducted from September to October in the former USSR
Jara-Pérez 2000
Methods Randomised, double-blind, placebo-controlled trial
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 Participants were followed up for 3 months for a total study period of 6 months
Outcomes During the study period 99 OM-85 BV participants had 1.43 ± 0.94 (mean ± SD) ARTIs and 100 placebo participants had 2.99 ± 0.81 ARTIs. No adverse events related to the trial medications were reported
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 in Mexico The trial was conducted during the boreal autumn-winter seasons
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias) Low risk  
Allocation concealment (selection bias) Low risk  
Blinding (performance bias and detection bias) All outcomes Low risk  
Blinding of participants and personnel (performance bias) All outcomes Low risk  
Incomplete outcome data (attrition bias) All outcomes Low risk  
Selective reporting (reporting bias) Low risk  
Karam-Bechara 1995
Methods Randomised, double-blind, placebo-controlled trial
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 The trial was conducted in Mexico There were no data about the seasons during the trial
Lacomme 1985
Methods Double-blind, placebo-controlled, multicentre clinical trial
Participants Participants aged from 2 to 15 years with 5 to 7 ARTIs and 5 antibiotic courses during the last year
Interventions Participants had D53 or placebo. During the first month they had 3 weeks of 3 tablets a day for 4 days per week. The next 5 months they had a week per month with 3 tablets a day for 4 days
Outcomes In a period of 6 months 47 D53 participants had 4.04 ± 4.2 (mean ± SD) ARTIs and 40 placebo participants 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 Randomised, double-blind, placebo-controlled trial
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 participants had 3.9 ± 2.0 ARTIs 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 Double-blind, placebo-controlled trial
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 The adverse events were not reported
Notes Flow of patient numbers and drop-outs are not given The trial was conducted in Italy The trial was conducted during the 4 seasons
Maestroni 1984
Methods Double-blind, placebo-controlled trial
Participants Children from 1 to 16 years who were susceptible to upper ARTIs 20 participants were included
Interventions Participants received either 1 capsule of 3.5 mg of OM-85 BV or placebo a day by 10 days per month during 3 months Participants were followed up for 3 months for a total study period of 6 months
Outcomes During the study 11 participants receiving OM-85 BV had 2.0 ± 2.05 (mean ± SD) ARTIs and 9 participants with placebo had 5.55 ± 5.36 ARTIs The adverse events were not reported
Notes Inclusion criteria are not clear It is not stated that the trial is randomized; the sample size is clearly insufficient The trial was conducted in Switzerland There were no data about the seasons during the trial
Martin du Pan 1982
Methods Double-blind, placebo-controlled trial
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 The adverse events were not reported
Notes The participants participated in a previous trial 1 year before comparing the effect of a syrup with yeast extract 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
Mora 2002
Methods Double-blind, placebo-controlled trial
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 first 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 finished 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 definition of otitis. Primary end points are a non-validated clinical scores given as ranks. To express a significant difference “P >" is used; for instance “P > 0.02". Trial was conducted in autumn, winter and spring in 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 flow 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 defined as more than 4 episodes of acute adenoiditis during a 6-month period. Acute adenoiditis was defined 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
Notes 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 Randomised, double-blind, placebo-controlled, multicentre trial
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 The trial was conducted in Italy There were no data about the seasons during the trial
Passali 1994a
Methods Randomised, double-blind, placebo-controlled, multicentre trial
Participants Children from 3 to 14 years with history of tonsillitis or pharyngitis in the previous autumn-winter seasons 429 participants were randomized
Interventions Pidotimod 400 mg or placebo once a day for 2 months plus a follow-up period of 3 months
Outcomes Total number of infections during the treatment period of 2 months and the follow up period of 3 months were 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 The trial was conducted in Italy There were no data about the seasons during the trial
Paupe 1986
Methods Double-blind, placebo-controlled trial
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 The trial was conducted in France There were no data about the seasons during the trial
Paupe 1991
Methods Randomised, double-blind, placebo-controlled, multicentre trial
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 Participants were followed for another 3 months for a total study period of 6 months
Outcomes During the study 34% of 61 participants with OM-85 BV and 3.5% of 55 participants with placebo had no infection One patient with OM-85 BV, 2 with placebo had diarrhea
Notes The reasons for excluding participants from the analysis are given The trial was conducted in France There were no data about the seasons during the trial
Pech 1987
Methods Double-blind, placebo-controlled trial
Participants Children from 1 to 12 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 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 The total period of the study was 6 months
Outcomes During the study period 35 participants with RU41740 had 1.11 ± 1.16 (mean ± SD) ARTIs and 34 placebo participants had 1.88 ± 1.43 ARTIs In RU41740 group 1 patient presented dry cough and another had difficulties in swallowing
Notes ARTI data were obtained from a paper by Reinert 1995 The number of ARTIs in the placebo group is low The trial was conducted in France There were no data about the seasons during the trial
Piquett 1986
Methods Double-blind, placebo-controlled trial
Participants Children from 1 to 12 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 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 The total period of the study was 6 months
Outcomes During the study period 17 participants with RU41740 had 1.35 ± 1.41 (mean ± SD) ARTIs and 20 placebo participants had 1.35 ± 1.46 ARTIs 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 The trial was conducted in France There were no data about the seasons during the trial
Pozzi 2004
Methods Randomised, double-blind, placebo-controlled, multicentre trial
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
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 D53 or placebo for 4 months
Outcomes By the third month, 15 D53 participants had 1.2 ± 0.86 (mean ± SD) ARTIs and 15 placebo participants had 3.73 ± 2.05 ARTIs. No adverse event report was provided
Notes Available data are from the Bellanti review. It was not possible to establish if this trial corresponds to any other published trial The number of ARTIs is extremely high
RB21 1988
Methods Double-blind, placebo-controlled trial
Participants Children
Interventions D53 or placebo for 6 months
Outcomes 45 D53 participants had 0.54 ± 0.6 (mean ± SD) ARTIs and 42 placebo participants had 0.95 ± 0.5 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
RB22 1990
Methods Double blind placebo-controlled trial
Participants Children
Interventions D53 or placebo for 3 months
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 Available data are from the Bellanti review. It was not possible to establish if this trial corresponds to any other published trial The number of ARTIs is extremely high
RB24 1990
Methods Double-blind, placebo-controlled trial
Participants Children
Interventions D53 or placebo for 6 months
Outcomes 16 D53 participants had 0.36 ± 0.5 (mean ± SD) ARTIs and 17 placebo participants had 0.92 ± 0.8 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
RB25 1990
Methods Double-blind, placebo-controlled trial
Participants Children
Interventions D53 or placebo for 3 months
Outcomes 13 D53 participants had 1.31 ± 0.2 (mean ± SD) ARTIs and 12 placebo participants had 3.25 ± 0.6 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
Renzo 2004
Methods Randomised, double-blind, placebo-controlled trial
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 finished 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 definition of otitis. Primary endpoints are a non-validated clinical scores given as ranks. To express a significant difference “P >" is used; for instance “P > 0.02" Trial was conducted in autumn, winter and spring in Italy It is not possible to establish if this trial correspond to any study cited by Bellanti in his review
Riedl-Seifert 1995
Methods Randomised, double-blind, placebo-controlled, multicentre trial
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 specified. Total follow up of 14 weeks
Outcomes During the study period 99 participants with LW50020 had 15 ARTIs and 108 participants with placebo had 29 ARTIs data dispersion is not specified 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 defined The trial was conducted in Germany There were no data about the seasons during the trial
Rutishauser 1998
Methods Randomised, double-blind, placebo-controlled, multicentre trial
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
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 The trial was conducted during the 4 seasons
Saracho-Weber 2001
Methods Randomised, double-blind, placebo-controlled, multicentre trial
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 The total period of the study was 12 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 flow 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
BiasAuthors' judgementSupport for judgement
Incomplete outcome data (attrition bias) All outcomes High risk  
Schaad 1986
Methods Double-blind, placebo-controlled trial
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 Participants were followed up for 3 months for a total study period of 6 months
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 Randomised, double-blind, placebo-controlled, multicentre trial
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 Participants were followed for another 3 months for a total study period of 6 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 flow 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 specified 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
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias) High risk  
Allocation concealment (selection bias) High risk  
Blinding (performance bias and detection bias) All outcomes High risk  
Blinding of participants and personnel (performance bias) All outcomes High risk  
Blinding of outcome assessment (detection bias) All outcomes High risk  
Blinding of outcome assessment (detection bias) All outcomes High risk  
Incomplete outcome data (attrition bias) All outcomes High risk  
Selective reporting (reporting bias) High risk  
Taylor 2003
Methods Randomised, double-blind, placebo-controlled, multicentre trial
Participants Children from 2 to 11 years without significant health problems
Interventions Participants had a preparation of Echinacea purpurea or placebo. Children from 2 to 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
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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias) Low risk  
Allocation concealment (selection bias) Low risk  
Blinding (performance bias and detection bias) All outcomes Low risk  
Blinding of participants and personnel (performance bias) All outcomes Low risk  
Blinding of outcome assessment (detection bias) All outcomes Low risk  
Blinding of outcome assessment (detection bias) All outcomes Low risk  
Incomplete outcome data (attrition bias) All outcomes Low risk  
Selective reporting (reporting bias) 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
Van Eygen 1979
Methods Randomised, double-blind, placebo-controlled trial
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 Randomised, double-blind, placebo-controlled trial
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 first 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 The trial was conducted in France 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, defined 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 first sign of each common cold. Five OMT visits (or sham treatments) were offered over 3 months
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
  1. ARTI = acute respiratory tract infection

  2. RTIs = respiratory tract infections

  3. SD = standard deviation

  4. COPD = chronic obstructive airways disease

  5. iv = intravenously

  6. n = number

  7. IgG = immunoglobulin G

  8. OD = daily

Methods Randomised, double-blind, placebo-controlled trial
Participants Children from 4 to 12 years, suffering from chronic rhino-sinusitis during a symptomatic episode of the disease 55 participants were randomized
Interventions Participants received either 1 capsule of 3.5 mg of OM-85 BV or placebo once a day by 30 days. After 1 month 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 definitions 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

Characteristics of excluded studies [ordered by study ID]

  1. IS = immunostimulants

Study Reason for exclusion
Almeida 1999 Only included participants with asthma
Aymard 1994 The trial was part of the Collet's study. Yet, it is a good paper and it is the only one showing prevention of viral ARTIs proved with viral test
Barr 1965 It was a trial on asthmatic children
Bánovein 1992 Comparison between IS without placebo group
Das 2000 The age of the participants is not specified
Fiocchi 1990 Unable to ascertain whether this was a subgroup of an included study Fiocchi 1989
Fontana 1965 It was a trial on asthmatic children
Grimfeld 2004 The trial used an antihistaminic
Grimm 1999 Results of children and adults are not separated
Heinz 2010 The trial was on adults
Herrera-Basto 1998 The results only compare the effect of pidotimod during the acute phase of ARTIs
Kozhukharova 1987 Trial was not double-blind, placebo-controlled
Lauriello 1990 It was a trial during the acute phase of respiratory infection in children
Luchikhin 2000 Trial was not double-blind, placebo-controlled
Ma 1994 Trial was not double-blind, placebo-controlled
Macchi 2005 Open trial in adults
Makovetskaya 2001 Trial was not double-blind, placebo-controlled
Mora 2010b Trial on acute adenoiditis not on prevention of acute respiratory tract infections
Mueller 1969 It was a study on asthmatic participants
Nespoli 1992 It was a randomized, multicentre trial - it did not include a placebo group but a group without treatment
Obrosova-Serova 1972 Trial was not double-blind, placebo-controlled
Oggiano 1985 It was an open trial on children
Oldini 1990 It was a Ribomunyl trial including adults and children without a separate analysis for each group
Ortega del 2005 It was an acute phase trial
Predy 2005 It is a trial in adults
Prusek 1987 Comparison between IS without placebo group
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

Data and analyses

Download statistical data

Table Comparison 1. Any IS compared with placebo
Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
1 Mean number of ARTIs 35 4060 Mean Difference (IV, Random, 95% CI) -1.24 [-1.54, -0.94]
2 Percent difference in ARTIs 35 4060 Mean Difference (IV, Random, 95% CI) -38.84 [-46.37, -31.31]
Figure Analysis 1.1.

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

Figure Analysis 1.2.

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

Table Comparison 2. Bacterial IS compared with placebo
Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
1 Mean number of ARTIs 24 2154 Mean Difference (IV, Random, 95% CI) -1.41 [-1.85, -0.98]
2 Percent difference in ARTIs 24 2154 Mean Difference (IV, Random, 95% CI) -41.21 [-49.10, -33.31]
Figure Analysis 2.1.

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

Figure Analysis 2.2.

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

Table Comparison 3. Bacterial IS trials with n equal to or greater than 40 compared with placebo
Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
1 Mean number of ARTIs 19 2009 Mean Difference (IV, Random, 95% CI) -1.42 [-1.92, -0.93]
2 Percent difference in ARTIs 19 2009 Mean Difference (IV, Random, 95% CI) -38.44 [-47.25, -29.63]
Figure 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.

Figure 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.

Table Comparison 4. Bacterial IS trials with n equal to or greater than 40 only OM-85 and BV D53 compared with placebo
Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
1 Mean number of ARTIs 16 1811 Mean Difference (IV, Random, 95% CI) -1.17 [-1.56, -0.78]
2 Percent difference in ARTIs 16 1811 Mean Difference (IV, Random, 95% CI) -36.16 [-44.51, -27.80]
Figure 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.

Figure 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.

Table Comparison 5. Adverse events
Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
1 Gastrointestinal adverse events 10 1457 Risk Difference (M-H, Fixed, 95% CI) 0.01 [-0.01, 0.03]
2 Skin adverse events 10 1469 Risk Difference (M-H, Fixed, 95% CI) 0.00 [-0.01, 0.01]
Figure Analysis 5.1.

Comparison 5 Adverse events, Outcome 1 Gastrointestinal adverse events.

Figure Analysis 5.2.

Comparison 5 Adverse events, Outcome 2 Skin adverse events.

Table Comparison 6. OM-85 trials
Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
1 Mean number of ARTIs 9 852 Mean Difference (IV, Random, 95% CI) -1.20 [-1.75, -0.66]
2 Percent difference in ARTIs 9 852 Mean Difference (IV, Random, 95% CI) -35.90 [-49.46, -22.35]
Figure Analysis 6.1.

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

Figure Analysis 6.2.

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

Table Comparison 7. D53 trials
Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
1 Mean number of ARTIs 11 1067 Mean Difference (IV, Random, 95% CI) -1.32 [-1.86, -0.79]
2 Percent difference in ARTIs 11 1067 Mean Difference (IV, Random, 95% CI) -43.47 [-53.22, -33.72]
Figure Analysis 7.1.

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

Figure Analysis 7.2.

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

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 identified 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

Identified 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 first 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/).

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

Levamisole

Echinacea

What's new

DateEventDescription
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 efficacy of D53 and OM-85. The conclusions remain unchanged.

History

Protocol first published: Issue 4, 2004

Review first published: Issue 4, 2006

DateEventDescription
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.

Declarations of interest

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

Dr Blanca Del Rio-Navarro and Dr Sienra-Monge were involved in the following IS trial: Del-Rio-Navarro BE, Luis Sienra-Monge JJ, Berber A, Torres-Alcantara S, Avila-Castanon L, Gomez-Barreto D. Use of OM-85 BV in children suffering from recurrent 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

Ancillary