EVIDENCE-BASED CHILD HEALTH: A COCHRANE REVIEW JOURNALEvid.-Based Child Health 7:2: 629–717 (2012)Published online in Wile...
Evid.-Based Child Health 7:2: 629–717 (2012)                                              TABLE OF CONTENTSHEADER . . . . ...
Evid.-Based Child Health 7:2: 629–717 (2012)[Intervention Review]Immunostimulants for preventing respiratory tract infecti...
Evid.-Based Child Health 7:2: 629–717 (2012)Main resultsThirty-five placebo-controlled trials (4060 participants) provided ...
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.Immunostimulants for preventing respirato...
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.Immunostimulants for preventing respirato...
Evid.-Based Child Health 7:2: 629–717 (2012)BACKGROUND                                                                    ...
Evid.-Based Child Health 7:2: 629–717 (2012)Recent influenza epidemics have increased interest in effective un-      The ac...
Evid.-Based Child Health 7:2: 629–717 (2012)OBJECTIVES                                                              Search...
Evid.-Based Child Health 7:2: 629–717 (2012)Searching other resources                                              Saracho...
Evid.-Based Child Health 7:2: 629–717 (2012)        Figure 1. Risk of bias graph: review authors’ judgements about each ri...
Evid.-Based Child Health 7:2: 629–717 (2012)   Figure 2. Risk of bias summary: review authors’ judgements about each risk ...
Evid.-Based Child Health 7:2: 629–717 (2012)                                                                      The way ...
Evid.-Based Child Health 7:2: 629–717 (2012)                                                                    Figure 4. ...
Evid.-Based Child Health 7:2: 629–717 (2012)authors or searching of trial registries. Of the references obtained,   the AR...
Evid.-Based Child Health 7:2: 629–717 (2012)and one dropped out due to a lack of confidence in the treatment).       tion s...
Evid.-Based Child Health 7:2: 629–717 (2012)The study protocols were not available. Sixty-one randomized,          non-ind...
Evid.-Based Child Health 7:2: 629–717 (2012)   Figure 5. Forest plot of comparison: Any IS compared with placebo, outcome:...
Evid.-Based Child Health 7:2: 629–717 (2012)    Figure 6. Forest plot of comparison: Any IS compared with placebo, outcome...
Evid.-Based Child Health 7:2: 629–717 (2012)number of ARTIs was MD -1.42 (95% CI -1.92 to -0.93); and            and the r...
Evid.-Based Child Health 7:2: 629–717 (2012)We did not perform the sub-analyses for good quality trials as onlytwo out of ...
Evid.-Based Child Health 7:2: 629–717 (2012)infants, toddlers, schoolboys and girls and adolescents without          ARTI ...
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  1. 1. EVIDENCE-BASED CHILD HEALTH: A COCHRANE REVIEW JOURNALEvid.-Based Child Health 7:2: 629–717 (2012)Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ebch.1833 Immunostimulants for preventing respiratory tract infection in children (Review) Del-Rio-Navarro BE, Espinosa-Rosales FJ, Flenady V, Sienra-Monge JJLThis is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2011, Issue 6 http://www.thecochranelibrary.comImmunostimulants for preventing respiratory tract infection in children (Review)Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  2. 2. Evid.-Based Child Health 7:2: 629–717 (2012) TABLE OF CONTENTSHEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 631ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 631PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 632SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . 632BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 635OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 637METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 637 Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 639 Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 640 Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641 Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642 Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 646 Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 647 Figure 7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 648 Figure 8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 648DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 649AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 651ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 651REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 652CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 661DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 693 Analysis 1.1. Comparison 1 Any IS compared with placebo, Outcome 1 Mean number of ARTIs. . . . . . . . 695 Analysis 1.2. Comparison 1 Any IS compared with placebo, Outcome 2 Percent difference in ARTIs. . . . . . . 697 Analysis 2.1. Comparison 2 Bacterial IS compared with placebo, Outcome 1 Mean number of ARTIs. . . . . . 699 Analysis 2.2. Comparison 2 Bacterial IS compared with placebo, Outcome 2 Percent difference in ARTIs. . . . . 700 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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 701 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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 702 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. . . . . . . . . . . . . . . . . . . . . . . . 704 Analysis 4.2. Comparison 4 Bacterial IS trials with n equal to or greater than 40 only OM-85 and BV D53 compared with placebo, Outcome 2 Percent difference in ARTIs. . . . . . . . . . . . . . . . . . . . . . 705 Analysis 5.1. Comparison 5 Adverse events, Outcome 1 Gastrointestinal adverse events. . . . . . . . . . . 706 Analysis 5.2. Comparison 5 Adverse events, Outcome 2 Skin adverse events. . . . . . . . . . . . . . . 707 Analysis 6.1. Comparison 6 OM-85 trials, Outcome 1 Mean number of ARTIs. . . . . . . . . . . . . . 708 Analysis 6.2. Comparison 6 OM-85 trials, Outcome 2 Percent difference in ARTIs. . . . . . . . . . . . . 709 Analysis 7.1. Comparison 7 D53 trials, Outcome 1 Mean number of ARTIs. . . . . . . . . . . . . . . 710 Analysis 7.2. Comparison 7 D53 trials, Outcome 2 Percent difference in ARTIs. . . . . . . . . . . . . . 711ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 711APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 713WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 716HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 716CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 716DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 716SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 717INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 717Immunostimulants for preventing respiratory tract infection in children (Review) 630Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  3. 3. Evid.-Based Child Health 7:2: 629–717 (2012)[Intervention Review]Immunostimulants for preventing respiratory tract infectionin childrenBlanca Estela Del-Rio-Navarro1 , Francisco J Espinosa-Rosales2 , Vicki Flenady3 , Juan JL Sienra-Monge11 Departmentof Allergy and Immunology, Hospital Infantil de México “Federico Gómez”, Mexico City, Mexico. 2 Department ofImmunology, Instituto Nacional de Pediatría (National Institute of Pediatrics), México D.F., Mexico. 3 Translating Research Into Practice(TRIP) Centre - Mater Medical Research Institute, Mater Health Services, Woolloongabba, AustraliaContact address: Blanca Estela Del-Rio-Navarro, Department of Allergy and Immunology, Hospital Infantil de México “Fed-erico Gómez”, Dr. Marquez 162, Colonia de los Doctores, Mexico City, DF, CP 06720, Mexico. blancadelrionavarro@gmail.com.blancadelrionavarro@yahoo.com.mx.Editorial group: Cochrane Acute Respiratory Infections Group.Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 6, 2011.Review content assessed as up-to-date: 3 March 2011.Citation: Del-Rio-Navarro BE, Espinosa-Rosales FJ, Flenady V, Sienra-Monge JJL. Immunostimulants for preventing res-piratory tract infection in children. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD004974. DOI:10.1002/14651858.CD004974.pub2.Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. ABSTRACTBackgroundAcute respiratory tract infections (ARTIs) are a major cause of childhood morbidity and mortality. Immunostimulants (IS) may reducethe incidence of ARTIs.ObjectivesTo determine the efficacy and safety of IS in preventing ARTIs in children.Search methodsWe searched the Cochrane Central Register of Controlled Trials (CENTRAL) 2011, issue 1, which contains the Acute RespiratoryInfections Group’s Specialised Register, MEDLINE (1966 to February week 4, 2011), EMBASE (1990 to February 2011), GoogleScholar (2009 to February 2011), Scopus (2009 to February 2011), PASCAL (1990 to February 2010), SciSearch (1990 to February2010) and IPA (1990 to February 2010).Selection criteriaWe included all comparative randomized controlled trials (RCTs) which enrolled participants less than 18 years of age. The interventionwas IS medication, administered by any method, compared to placebo to prevent ARTIs.Data collection and analysisWe analyzed the outcome on ARTIs both as the mean number of ARTIs by group and as a percent change in the rate of ARTIs. Weundertook meta-analyses using a random-effects model and presented results as mean differences (MD) with 95% confidence intervals(CI). Two review authors independently assessed the search results and risk of bias, and extracted data. A funnel plot suggested theremay be publication bias in the identified trials.Immunostimulants for preventing respiratory tract infection in children (Review) 631Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  4. 4. Evid.-Based Child Health 7:2: 629–717 (2012)Main resultsThirty-five placebo-controlled trials (4060 participants) provided data in a form suitable for inclusion in the meta-analyses. Whencompared with placebo, the use of IS was shown to reduce ARTIs measured as the total numbers of ARTIs (MD -1.24; 95% CI -1.54to -0.94) and the difference in ARTI rates (MD -38.84%; 95% CI -46.37% to -31.31%). Trial quality was generally poor and a highlevel of statistical heterogeneity was evident. The subgroup analysis of bacterial IS, D53 and OM-85 studies produced similar results,with lower heterogeneity. No difference in adverse events was evident between the placebo and IS groups.Authors’ conclusionsThis review shows that IS reduce the incidence of ARTIs by 40% on average in susceptible children. Studies in healthy children are notavailable. Although the safety profile in the studies was good, some IS may be unsafe. ARTI-susceptible children may benefit from IStreatment. Further high-quality trials are needed and we encourage national health authorities to conduct large, multicentre, double-blind, placebo-controlled RCTs on the role of IS in preventing ARTIs in children.PLAIN LANGUAGE SUMMARYImmunostimulants to prevent acute respiratory tract infections in childrenAcute respiratory tract infections (ARTIs) are responsible for 19% of all deaths in children younger than five years of age, mainly in low-income countries in Africa, Asia and Latin America. In high-income countries ARTIs are among the most frequent illnesses, leadingto 20% of medical consultations, 30% of days lost from work and 75% of antibiotic prescriptions. In the USA the total cost of non-influenza-related viral ARTIs is around $40 billion annually, while the corresponding cost for influenza is US $87.1 billion. The mainsigns and symptoms of ARTIs include sneezing, runny nose, sore throat, cough and malaise. Children living in rural communities, notattending daycare centres, suffer about seven ARTI episodes in the first year of life; eight ARTIs per year from the ages of one to four;six per year aged five to nine; and five per year aged 10 to 19. Children exposed to risks factors, such as attendance at daycare centres,overcrowding, contact with older siblings, smoking at home and lack of breast feeding, may suffer more ARTIs.Several treatments have been used to reduce the incidence of ARTIs (vitamin A, vitamin C, zinc, antibiotics). Among them areimmunostimulants (herbal extracts, bacterial extracts, synthetic compounds), which aim to increase the immune defences of therespiratory tract. We searched for clinical trials of immunostimulants to prevent ARTIs in children compared to placebo. Our reviewincludes 35 studies with 4060 participants. However, the quality of many of the studies was poor and the results were very diverse.By combining results, immunostimulants reduced 1.24 ARTIs in a six-month period, equivalent to a 39% reduction in ARTIs comparedto the placebo group. Only 20 studies provided adequate data on adverse events: the most frequent were rash, nausea, vomiting,abdominal pain and diarrhea. The main limitations of this review were the poor methodological quality and diverse trial results.We conclude that ARTI-susceptible children may benefit from immunostimulants, but more high-quality studies are needed. Wesuggest that national health authorities conduct high-quality randomized controlled trials to assess the true effects of immunostimulantpreparations.Immunostimulants for preventing respiratory tract infection in children (Review) 632Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  5. 5. Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.Immunostimulants for preventing respiratory tract infection in children (Review) Evid.-Based Child Health 7:2: 629–717 (2012) S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation] Any immunostimulant (IS) compared with placebo for preventing respiratory tract infection in children Patient or population: children (age <18 years) susceptible to acute respiratory tract infections (ARTIs) Settings: outpatient Intervention: any IS Comparison: placebo Outcomes Illustrative comparative risks’ (95% CI) No of participants (studies) Quality of the evidence Comments (GRADE) Assumed risk Corresponding risk Placebo Any IS Number of ARTIs The range of ARTIs in the con- The mean Number of ARTIs in 4060 ⊕⊕⊕ The effect depends on the trol group was 0.92 to 6.2 the intervention groups was (35 studies) moderate1 number of ARTIs in the control 1.24 lower (0.94 to 1.54 group lower) Percent difference in ARTIs The mean Percent difference 4060 ⊕⊕⊕ in ARTIs in the intervention (35 studies) moderate1,2 groups was 39 lower (31.31 to 46.37 lower) Incidence of gastrointestinal 21 per 1000 30 per 1000 (11 to 50 per 1457 ⊕⊕ adverse events 1000) (10 studies) low1,3 Incidence of skin adverse 3 per 1000 7 per 1000 (-8 to 14 per 1000) 1469 ⊕⊕ events (10 studies) low1,3 *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio; OR: odds ratio 633
  6. 6. Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.Immunostimulants for preventing respiratory tract infection in children (Review) Evid.-Based Child Health 7:2: 629–717 (2012) GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate. 1 Funnel plot shows possible publication bias, risk of bias in the studies moderate, and high heterogeneity among studies. A group of six studies with good quality point to the benefit of IS 2 Heterogenity decreased with calculation of percent difference ARTIs. 3 Adverse events were reported only in 10 trials; selective outcome reporting xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 634
  7. 7. Evid.-Based Child Health 7:2: 629–717 (2012)BACKGROUND effort to establish the aetiology and epidemiology of ARTIs in children in high-income countries. The project was carried outDescription of the condition in populations from 0 to 59 months of age in Africa, Asia and Latin America. The incidence rate in six community-based stud-In 1998 the World Health Organization (WHO) considered acute ies ranged from 12.7 to 16.8 ARTIs per 100 child-weeks and therespiratory tract infections (ARTIs) to be “the forgotten pandemic” incidence of lower ARTIs was from 0.2 to 0.4 per 100 child-as ARTIs caused 19% of all deaths in children younger than five weeks. The children studied spent from 21.7% to 40.1% of theyears and 8.2% of all disabilities and premature mortality (WHO observed weeks with ARTIs and from 1% to 14.4% of the ob-1998). In 2000, 1.9 million (95% confidence interval (CI) 1.6 to served weeks with lower ARTIs. Viral agents were more frequently2.2 million) children died from ARTIs worldwide, with 70% of recovered than bacterial agents; respiratory syncytial virus (RSV)the deaths in Africa and South-East Asia (Williams 2002). AR- was the most frequent virus (Selwyn 1990). In Mexico, a studyTIs are the leading cause of morbidity in high-income countries assessing the effect of daycare centres on ARTI incidence followed(USA, Canada, Western Europe) and account for 20% of medical 144 children (aged 43 days to 4 months at entry) at home for oneconsultations, 30% of days lost from work and 75% of antibi- year. The study found that these children had six ARTIs each year,otic prescriptions (WHO 1998). ARTIs are responsible for most with a median of 40 sick days in a year (Flores-Hernandez1999).sick days amongst school children (Haskins 1986) and parental Viruses were the main aetiological agents for ARTIs in childrenabsenteeism from work (Bell 1989). The cost of ARTIs in high- at daycare centres (Denny 1986) and in the community (Montoincome countries is significant. For example, between 2000 and 1993). The most common virus isolates are rhinovirus, respiratory2002 there were approximately 500 million non-influenza-related syncytial virus, parainfluenza virus and adenovirus. Lower ARTIsviral ARTI episodes in the USA per year; the total economic im- are also frequently associated with viral infections, but bacterialpact of these episodes was around $40 billion annually (direct costs agents may be found in 4.5% to 40% of the cases (Selwyn 1990).of $17 billion per year and indirect costs of $22.5 billion per year) Up to 50% of children admitted to hospital with proven bacte-(Fendrick 2003). Based on the 2003 US population, it has been rial ARTIs also have evidence of concurrent or recent viral ARTIscalculated that the total economic burden of annual influenza epi- (Campbell 1995). The damage caused by viruses to epithelial cellsdemics in the USA was $87.1 billion US dollars ($47.2 to $149.5) in the airways may increase the adherence of bacteria and lead to(Molinari 2007). Risk factors for ARTIs in childhood include at- a bacterial superinfection (Hament 1999).tendance at daycare centres (Schwartz 1994), overcrowding (Bell History of respiratory infections in the first 12 years among chil-1989; Selwyn 1990), contact with elder siblings (Selwyn 1990), dren was established in a cohort of German children living in ur-male gender (Monto 2002), smoking at home (Jin 1993) and lack ban areas. The mean cumulative number of ARTIs in the 12 yearsof breast feeding (Wright 1989). was 21.9 (standard deviation (SD) 9.0) episodes; the mean annualCommunity health studies in high-income countries have pro- number was 1st year, 3.1 (2.1) episodes; 2nd year, 3.2 (2.5); 3rdvided basic information on the incidence of ARTIs in children. year, 2.1 (2.0); 4th year, 2.3 (2.1); 5th year, 1.8 (1.6); 7th throughIn the Cleveland Family Study, 100 families were visited weekly to the 9th year, 1.1 (1.0) episodes; 10th year through 12th year,by nurses during 1948 to 1957. The annual frequency of respi- 1.0 (0.9) episodes (Grüber 2008). The frequency of ARTIs in thisratory illness was 6.72 in children less than one year old; 7.95 in study was about a half of the classic Monto studies (Monto 1974;children aged one to four years; 6.21 in children aged five to nine Monto 1993). The authors regarded incidence above the twofoldyears; 5.02 in children aged 10 to 14 years; and 4.71 in 15 to 19- standard deviation as clinically relevant; more than seven episodesyear olds (Monto 2002). In the first phase of the Tecumseh study, in the 1st year of life, more than eight episodes in year two, morefrom 1965 to 1971, 4905 residents registered their incidence of than six episodes in year three and year four more than five episodesARTIs for the six-year period. In the first report the residents had in year five, more than four episodes in year six, and more thansuffered approximately 14,600 ARTIs. The annual incidence of three episodes from year seven onwards.ARTIs per person was 6.1 in children less than one year old; 5.7 in In a healthy population without any special risk factors or immun-children aged one to two years; 4.7 in children aged three to four odeficiencies, there is a subgroup of people with a higher incidenceyears; 3.5 in children aged five to nine years; 2.7 in children aged of ARTIs. A cohort of children from Nijmegen, Netherlands was10 to 14 years old; and 2.4 in 15 to 19-year olds (Monto 1974). followed for 21 years to register the occurrence of ARTIs. TheIn the second report of the Tecumseh study, which covered two number of respiratory infections was assessed at the ages of two,phases comprising a total of 11 years (1965 to 1971 and 1976 to four, eight and 21. It was considered that a person had a recurrent1981), the mean annual number of ARTIs was 4.9 in the group infection if the number of ARTIs was above 75th percentile of theaged from zero to four years; and 2.8 in the group aged five to 19 distribution of respiratory infection at each assessment. Twenty-years (Monto 1993). In both phases of the study viruses were the three percent of the people had recurrent respiratory infection inmost common agents causing ARTIs. two or more assessments and 1% suffered from recurrent infectionDuring the 1980s, the Board on Science and Technology for In- in the four assessments (Rovers 2006).ternational Development (BOSTID) undertook a co-ordinatedImmunostimulants for preventing respiratory tract infection in children (Review) 635Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  8. 8. Evid.-Based Child Health 7:2: 629–717 (2012)Recent influenza epidemics have increased interest in effective un- The actual mechanism of IS is not yet fully understood. Currentlyspecific measures to protect the global population, outside the pro- the mechanisms of action are known for only two synthetic IS,duction of appropriate vaccines which could take more than six tucaresol and imiquimod. The mechanism of tucaresol is to form ato nine months to be ready for use. These unspecific measures in- complex on the surface of T cells (a Schiff reaction with the amines,clude physical methods to reduce the spread of respiratory viruses probably on CD2). This complex provides an additional stimu-such as hand washing, wearing masks, gloves and gowns (Jefferson lant which facilitates the activation of the T cells (a co-stimula-2009). In military populations, reported additional measures to tory signal activating the MAPK ERK2 pathway) (Rhodes 1995).prevent respiratory tract infections include reducing contact be- Imiquimod and other related molecules activate the immune cellstween units, reducing crowding, installing cloth barriers between by binding to the receptor for the bacterial products that activatebeds, indoor air dilution and ventilation, dust suppression and the unspecific defence mechanism and promote the immune re-air sterilisation (Lee 2005). Other measures include vitamin and sponse; they bind to the Toll-like receptor 7 (TLR7) activating themineral supplementation, such as vitamin A (Chen 2008a), vita- MyD88-dependent signalling pathway (Hemmi 2002).min C (Hemilä 2010), vitamin D (Yamshchikov 2009) and zinc It may be postulated that products with IS properties activate the(Aggarwal 2007). Interventions which stimulate the immune sys- immune cells using the receptors that recognise common bacte-tem (immunostimulants) have been proposed as effective measures rial products or receptors that provide additional stimulation forto reduce ARTIs. activation. For instance, Toll-like receptors (TLR) recognise com-Some years ago, the idea that bacterial lysates, plant extracts or ponents common to a range of bacteria, so-called pathogen-as-imidazole compounds, could induce unspecific immunity against sociated molecular patterns (PAMPs) such as lipopolysaccharide,viruses and distinct bacteria was not very solid. However, the re- peptidoglycan, lipoteichoic acid, lipoarabinomannan, un-methy-cent discovery of Toll-like-receptors (TLRs) supports the possible lated DNA with CpG motif and bacterial lipoproteins which ac-mechanism of action of immunostimulants (Krieg 2003). TLRs tivate the innate immune responses. The innate immune responsewere discovered in the 1990s and their importance on immunity is responsible for the early mechanisms of defence against infec-was found later, see How the intervention might work below. In tion; for instance the phagocytosis and neutralisation of bacte-fact, there is evidence that two bacterial lysates may act on TLR2 ria entering the body. The mechanisms that enhance the innate(Alyanakian 2006; Nikolova 2009), as well as levamisole (Chen immune responses (cytokines and chemokines) also stimulate the2008b). 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 lysatesDescription of the intervention may act on TLR2 (Alyanakian 2006; Nikolova 2009), as well as levamisole (Chen 2008b).The main way to prevent ARTI complications is to prevent theseinfections and administer early antibiotic treatment when bac-terial ARTIs are diagnosed (Heikkinen 1999; Henderson 1982;WHO 1998). Non-specific preventative measures for ARTIs stud- Why it is important to do this reviewied in clinical trials include general hygiene methods in childrenattending daycare centres (CDCIDSG 1984); the administration Most ARTIs are caused by viruses, hundreds of which may causeof nutritional supplements such as vitamin A to malnourished this type of infection. It would be impractical, therefore, to havechildren (Barreto 1994), vitamin C to normal and malnourished a vaccine for each possible pathogenic agent. Therefore, spe-children (Hemila 1997; Jefferson 2001) and trace elements to cific immunisation may not be the ultimate solution to preventmalnourished and susceptible children (Sazawal 1998); preven- ARTIs. The introduction of the pneumococcal conjugate vac-tive antibiotics (Dajani 1995); administration of gamma glob- cine decreased carriage and invasive infections due to the vaccineulins (Nydahl-Persson 1995); nasal spray of immunoglobulins serotypes, but it has been replaced by other non-vaccine serotypes(Heikkinen 1998); herbal extracts (Grimm 1999); xylitol sugar that are becoming antibiotic resistance (Hsu 2009; Huang 2009;syrup or chewing gum (Uhari 1998); and the use of immunos- Mera 2009).timulants (IS) from different sources. The sources are synthetic IS could provide an alternative to vaccines for preventing AR-(Passali 1994a); thymic extracts or factors (De Mattia 1993); or of TIs but the efficacy of these medications is controversial (Colletbiological origin such as Klebsiella extracts containing lipopolysac- 1992; Valleron 1992). Several bacterial extracts and synthetic com-charide (Dahan 1986) and mixtures of bacterial extracts (Berber pounds are used in Europe and the Americas to prevent ARTIs.1996). However, the evidence of the safety and efficacy of this approach is unclear. A systematic review of immunostimulation for the pre- vention of ARTIs in children is required to enable a robust ap-How the intervention might work praisal of the current evidence on the safety and efficacy of this approach and to provide clues for the development of new IS.Immunostimulants for preventing respiratory tract infection in children (Review) 636Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  9. 9. Evid.-Based Child Health 7:2: 629–717 (2012)OBJECTIVES Search methods for identification of studiesTo assess the safety and efficacy of immunostimulants (IS) admin-istered to children to prevent ARTIs when compared with placebo,in terms of frequency of these infections and reported adverse ef- Electronic searchesfects. Trials comparing two IS were also included. For this update we searched the Cochrane Central Register of Con- trolled Trials (CENTRAL) 2011, issue 1, which contains the Acute Respiratory Infections Group’s Specialised Register, MEDLINEMETHODS (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). De-Criteria for considering studies for this review tails 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 strat-Types of studies egy with the Cochrane Highly Sensitive Search Strategy for identi-Randomised controlled trials (RCTs) comparing IS, administered fying randomized trials in MEDLINE: sensitivity- and precision-by any method, to placebo to prevent ARTIs. Trials referring to maximising version (2008 revision); Ovid format (Lefebvre 2009).interferon inducers, vitamins and nutritional supplements were The search strategy was adapted for EMBASE (see Appendix 2).not included. Details of the PASCAL, SciSearch, IPA and previous Embase search are in Appendix 3. MEDLINE (Ovid)Types of participants 1 exp Respiratory Tract Infections/ 2 (respiratory adj5 infection*).tw.Participants younger than 18 years of age. We did not include trials 3 1 or 2that included participants who suffered from asthma, allergy and 4 exp Adjuvants, Immunologic/atopy, or chronic respiratory diseases. 5 immunostimulant*.tw,nm. 6 immunomodulat*.tw,nm. 7 immunoadjuvant*.tw,nm.Types of interventions 8 immunologic adjuvant*.tw,nm.The use of an IS administered by any method to prevent ARTIs. 9 (immunobalt or lw50020 or luivac or paspat or munos-Administration of IS could begin in the presence of active ARTI. tin).tw,nm.We considered trials utilising concomitant therapies such as an- 10 (om-85 bv or om85bv or om 85 bv).tw,nm.tipyretics or antibiotics for inclusion. 11 (bronchovaxom or broncho-vaxom or broncho vaxom).tw,nm. 12 (pulmonar-om or pulmonar om).tw,nm. 13 d53.tw,nm.Types of outcome measures 14 (ribomunyl or ribovac or immucytal).tw,nm.A broad definition of ARTI was accepted and included using differ- 15 Lipopolysaccharides/ent specific diagnoses, such as cold, influenza, tonsillitis, pharyngi- 16 lipopolysaccharide*.tw,nm.tis, bronchitis and otitis media. Aetiological agents were not stud- 17 (ru41740 or ru-41740 or ru 41740 or biostim).tw,nm.ied and no distinction was made between bacterial and viral AR- 18 Thymus Extracts/TIs. Physician diagnosis of ARTI and adverse events was accepted. 19 thymus extract*.tw,nm. 20 (thymic extract* or thymomodulin*).tw,nm. 21 Pelargonium/Primary outcomes 22 (pelargonium* or umckaloabo).tw,nm. 23 (am3 or imunoferon or immunoferon or inmunoferon).tw,nm.The number of ARTIs in children suffered during the study period. 24 glycophosphopep*.tw,nm. 25 (pidotimod or adimod).tw,nm. 26 Levamisole/Secondary outcomes 27 levamisole.tw,nm. 1. The percentage of ARTIs. 28 or/4-27 2. The incidence of adverse events. 29 3 and 28Immunostimulants for preventing respiratory tract infection in children (Review) 637Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  10. 10. Evid.-Based Child Health 7:2: 629–717 (2012)Searching other resources Saracho-Weber 2001 (co-worker Vázquez-Ramos); Schaad 1986;We used identified articles as references for a Science Citation Schaad 2002). However, no additional data were provided. A fur-Index search. We searched bibliographies of all included trials as ther 11 trial authors were contacted by Dr Berber without responsewell as those of relevant reviews to identify additional studies. (Aymard 1994; Careddu 1994a; Careddu 1994b; Fiocchi 1986;Finally, we sent a letter to all first authors, as well as pharma- Fiocchi 1988; Fiocchi 1989; Fiocchi 1990; Motta 1994; Paupeceutical companies that manufacture immunostimulant drugs, re- 1986; Rutishauser 1998 (co-worker Grevers); Valleron 1992). Dr.questing data and references for any relevant published and un- Arturo Berber provided the database for OM-85 trials from Mex-published trials. There were no language or publication restric- ico. In 2010, we made attempts to contact the following au-tions. We also searched for studies in the trial registration web thors: Joseph Bellanti, Jean Bousquet, Herman A. Cohen, Craigsite: metaRegister of Controlled Trials (http://www.controlled- I Coleman, Jean Paul Collet, Alessandro Fiocchi, Sergio Mar-trials.com/mrct/). We searched for IS trial registries in the U.S. cassa, Renzo Mora, RJ Riedl-Seifert, Urs B. Schaad, DragankaNational Institutes of Health in http://www.ClinicalTrials.gov. Stankulova, Claudia Steurer-Stey and James A. Taylor, and manu- facturers 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 inData collection and analysis name of OM Pharma) replied; no information regarding new stud- ies was obtained.Selection of studiesTwo review authors (BN, JSM) independently searched for trials Assessment of risk of bias in included studiesfor inclusion and risk of bias assessment. We resolved differencesby discussion. We measured trial quality using seven domains. 1. Random sequence generation (selection bias). 2. Allocation concealment (selection bias).Data extraction and management 3. Blinding (performance bias and detection bias).We analyzed and managed data using Review Manager (RevMan 4. Blinding of participants and personnel (performance bias).2008). Two authors (BN, JSM) independently extracted data. We 5. Blinding of outcome assessment (detection bias).sought missing data from investigators of individual trials, as nec- 6. Incomplete outcome data (attrition bias).essary, in order to perform analyses on an intention-to-treat (ITT) 7. Selective reporting (reporting bias).basis. We assigned a quality rating for above domains for each includedDr Arturo Berber contacted trial authors to request unpublished trial using the criteria outlined in the Cochrane Handbook for Sys-data. Responses were received from 10 trial authors (Arroyave tematic Reviews of Interventions (Higgins 2011) as high risk, low1999; Collet 1993; Gómez-Barreto 1998; Gutiérrez-Tarango risk or uncertain risk . Figure 1 and Figure 2 shows the results of2001; Jara-Pérez 2000; Karam-Bechara 1995; Paupe 1991; risk of bias assessment for the seven domains.Immunostimulants for preventing respiratory tract infection in children (Review) 638Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  11. 11. Evid.-Based Child Health 7:2: 629–717 (2012) Figure 1. Risk of bias graph: review authors’ judgements about each risk of bias item presented as percentages across all included studies.Immunostimulants for preventing respiratory tract infection in children (Review) 639Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  12. 12. Evid.-Based Child Health 7:2: 629–717 (2012) Figure 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included study.Immunostimulants for preventing respiratory tract infection in children (Review) 640Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  13. 13. Evid.-Based Child Health 7:2: 629–717 (2012) The way in which the outcomes were reported varied widely acrossMeasures of treatment effect the trials. We decided to use the mean number of ARTIs and itsWe reported the mean differences (MD) (and 95% confidence standard deviation (SD) as the outcome as it allows the use of para-intervals (CI)) for the meta-analysis of data measured on a contin- metric statistical methods that provide more power to the tests. Weuous scale. We assessed heterogeneity by visual inspection of the assumed that the number of ARTIs in the IS-treated group wouldoutcomes tables and by using two statistics of heterogeneity (H be comparable to the number of ARTIs in the placebo group; andand I2 statistic) (Higgins 2003). Due to the observed statistical both of these would depend on the susceptibility of the childrenheterogeneity, we used the random-effects model. (determined by age, duration of trial and seasons of the year dur- ing the trial). Consequently we expected to have heterogeneity in the mean number of ARTIs. Therefore, we decided to standardiseUnit of analysis issues the results using the percentage of infections considering the meanRegarding the trials with a description of randomisation and al- number of infections in the placebo group as 100%.location, the unit of randomisation was the individual subject(Cohen 2004; Collet 1993; Del-Rio-Navarro 2003; Gutiérrez-Tarango 2001; Jara-Perez 2000; Taylor 2003). Assessment of reporting biases We assessed publication bias using a funnel plot (Egger 1997). The results indicated possible publication bias. The funnel plot for theDealing with missing data number of ARTIs was asymmetrical with a large base skewed toThe studies only analyse the available data, ignoring the missing the left and narrower distribution at the top; the funnel plot fordata. 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 theAssessment of heterogeneity percentage of ARTIs. Figure 3.Immunostimulants for preventing respiratory tract infection in children (Review) 641Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  14. 14. Evid.-Based Child Health 7:2: 629–717 (2012) Figure 4. than 40 including only OM-85 and BV D53 and OM-85 aloneData synthesis and D53 alone.Due to the heterogeneity of the results we selected the random-effects model of meta-analysis.Subgroup analysis and investigation of heterogeneity RESULTSWe also conducted bivariate correlation as well as linear regressionand sensitivity analyses of subgroups to investigate the sources of Description of studiesstatistical heterogeneity (please refer to Results section). See: Characteristics of included studies; Characteristics of excluded studies.Sensitivity analysisTo determine whether conclusions were robust, we performedanalyses of different set of studies as follows: any IS; bacterial IS; Results of the searchbacterial IS trials with the total sample size of equal to or greater The electronic search produced 764 references. No other poten-than 40; bacterial IS trials with total sample size equal to or greater tially eligible studies were found as a result of contact with the trialImmunostimulants for preventing respiratory tract infection in children (Review) 642Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  15. 15. Evid.-Based Child Health 7:2: 629–717 (2012)authors or searching of trial registries. Of the references obtained, the ARTIs were defined by the presence of respiratory signs andwe identified 93 studies as potentially eligible. symptoms. The remaining 24 studies reported a variety of end points: symp- toms, clinical scales or presence or absence of respiratory infec-Included studies tions. Some trials reported the frequency of ARTIs as either equalWe included 61 placebo-controlled clinical trials involving 4149 to or more than one infection (Burgio 1994; Careddu 1994b;participants. The studies were very heterogenous in the interven- Fukuda 1999; Mora 2010a; Paupe 1991; Rutishauser 1998; Taylortions studied, the number of ARTIs in the placebo groups and in 2003; Wahl 2008); equal to or more than two infections (Morathe reporting of outcomes. 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;Population Pozzi 2004; Riedl-Seifert 1995; Sramek 1986); or reduction inThe participants enrolled in the included trials were children rang- the number of ARTIs (Andrianova 2003; Iuldashev 1988). Othersing from six months to 18 years of age. The echinacea trials differed measured the severity of symptoms using clinical scales that werein the selection criteria of participants as they used children with- not validated (Fiocchi 1989; Giovannini 2000; Mora 2002; Renzoout a significant health problem and without a history of recurrent 2004) or as days suffering symptoms (Martin du Pan 1982).ARTI. The remainder of the trials included a history of recurrentARTIs in the inclusion criteria. All the trials were conducted inthe Northern (boreal) hemisphere except Fukuda’s (Fukuda 1999). Excluded studiesFall and winter seasons referred to the months from September We excluded 36 studies: 32 did not comply with the selectionto January. The year of the trial was not specified in most of the criteria; two compared several IS treatments without a placebostudies. group; and two were duplicate reports of trials already included. See Characteristics of excluded studies table.InterventionsForty studies used bacterial products, four studies used herbal ex- Risk of bias in included studiestracts (echinacea and garlic), 11 studies used synthetic compounds,five studies used thymic extracts (thymomodulin) and one study The description of the methodology was not clear in most ofused a synthetic interferon. All trials used a placebo control. The the studies. Only 17.1% (6 out of 35) studies reported adequatecommon names of the medications are in Table 1. randomisation and blinding (participants and treating physiciansTwenty-two studies had a duration shorter than six months, 33 were blinded) (Cohen 2004; Collet 1993; Del-Rio-Navarro 2003;studies had a duration of six months and only six studies had a Gutiérrez-Tarango 2001; Jara-Perez 2000; Taylor 2003) (Figureduration longer than six months. The duration of seven D53 trials 1). Using the quality rating criteria (Higgins 2011), the quality ofwas less than six months and nine D53 trials had a duration of six the rest of the trials (28 out of 34 (82.4%)) was B; randomisationmonths. In all D53 trials the description of the methodology was and follow through of participants was unclear. See Table 2 for anot clear and different routes of administration were used (nasal description of the quality of the trials.spray or by mouth). Ten OM-85 BV trials lasted six months; two Only 17.1% (6 out of 35) studies reported on the number oftrials had a duration of longer than six months. 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 wereOutcomes minimal, 0.5% to 7% in three studies, two studies reported aOnly 35 of the 61 included studies reported the mean and SD loss of 18% and 24%. As additional data were not obtained fromof the incidence of respiratory infections or provided data to cal- the investigators on the outcomes of participants who were lostculate these measure, allowing their inclusion in the meta-analy- to follow up an intention-to-treat (ITT) analysis could not besis (Ahrens 1984; Arroyave 1999; Careddu 1994a; Clerici 1988; undertaken. The numbers lost to follow up are explained in furtherCohen 2004; De Loore 1979; Del-Rio-Navarro 2003; Fiocchi detail.1986; Garabedian 1990; Gutiérrez-Tarango 2001; Gómez-Barreto In the Cohen 2004 trial, 160 out of 215 in the IS group com-1998; Hauguenauer 1987; Hüls 1995; Jara-Pérez 2000; Karam- pleted the trial (27 dropped out because the medication had anBechara 1995; Lacomme 1985; Litzman 1999; Maestroni 1984; unpleasant taste, 24 due to non-compliance which was not fullyMotta 1994; Paupe 1986; Pech 1987; Piquett 1986; RB10 1994; explained, four dropped out due to a lack of confidence in theRB17 1988; RB21 1988; RB22 1990; RB24 1990; RB25 1990; treatment); and 168 out of 215 of the placebo group completedSaracho-Weber 2001; Schaad 1986; Schaad 2002; Van Eygen the trial (22 dropped out because the placebo had an unpleasant1976; Van Eygen 1979; Vautel 1993; Zagar 1988). In these studies taste, 21 due to non-compliance which was not fully explained,Immunostimulants for preventing respiratory tract infection in children (Review) 643Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  16. 16. Evid.-Based Child Health 7:2: 629–717 (2012)and one dropped out due to a lack of confidence in the treatment). tion system network in France). Additionally, randomisation wasA total of 24% were lost to follow up. also stratified by study centre and blocked for every four children.In the Del-Rio-Navarro 2003 trial, 20 out of 25 in the IS group In the studies by Del-Rio-Navarro 2003 and Gutiérrez-Tarangocompleted the trial. Five children were lost to follow up. Twenty 2001 consecutive numbered study medication boxes, as well as aout of 24 in the placebo group completed the trial. Two children closed opaque envelope describing the treatment, were suppliedwere lost to follow up (the parents of one participant withdrew directly by the manufacturer; participants received a patient num-consent for their child to continue in the trial and one left because ber coincident with treatment number when the selection criteriathe trial medication caused the child to have diarrhea). A total of were completed. In the Jara-Perez 2000 study consecutive num-18% were lost to follow up. bered study medication boxes, as well as a closed opaque enve-In the Collet 1993 trial, 199 out of 210 in the IS group and 196 lope describing the treatment, were supplied directly by the man-out of 213 placebo group completed the trial. For both groups, ufacturer; participants received a patient number corresponding athe 28 lost to follow up were related either to the parents moving treatment according to an alphabetical name list. In Taylor 2003,to a different location or the mothers stopped working and no each study centre had a supply of study medication (active medi-longer took their children to the daycare centres where the trials cation and placebo) in consecutively numbered bottles that werewere being held. A total of 7% were lost to follow up. identical in appearance, contents of each bottle were randomlyIn the Taylor 2003 trial, 242 out of 263 in the IS group completed determined using a computer-generated randomisation list, andthe trial (six withdrew before the first ARTI, five changed their randomisation was stratified by site and in blocks of 10. Enrolledminds about participating, one never received the study medica- children were assigned a unique study number corresponding totion, five withdrew during the first ARTI, three refused the study the numbers on the bottles of study medication. Figure 1 showsmedication, one was concerned about the effect on their immune the review authors’ judgement of the risk of bias related to allo-system, for one the protocol was too complicated, six log books cation concealment presented as percentages across all includedwere never received, four were lost to follow up); 244 out of 261 studies and Figure 2shows the risk for each included study.in the placebo group completed the trial (three withdrew beforethe first ARTI, two changed their minds about participating, onewas excluded for taking another medication, one withdrew during Blindingthe first ARTI, nine log books were never received and four were Six studies (Cohen 2004; Collet 1993; Del-Rio-Navarro 2003;lost to follow up). A total of 7% were lost to follow up. Gutiérrez-Tarango 2001; Jara-Perez 2000; Taylor 2003) claimedIn the Jara-Pérez 2000 trial, 99 out of 100 in the IS group com- that IS and placebo treatment had identical appearance and thatpleted the trial. The case report from one child was lost. One hun- the taste of both were similar. Investigators and participants weredred out of 100 in the placebo group completed the trial. A total not aware of the received treatment.of 0.5% were lost to follow up.In the Gutiérrez-Tarango 2001 trial, outcomes were reported forall enrolled children. All the participants completed the trial. Incomplete outcome dataThe outcome assessor was blinded to the treatment allocation in Only six studies (Cohen 2004; Collet 1993; Del-Rio-Navarro8.8% (three out of 34) of the studies (Cohen 2004; Collet 1993; 2003; Gutiérrez-Tarango 2001; Jara-Perez 2000; Taylor 2003) re-Taylor 2003). Only 14.7% (five out of 34) of studies (Cohen 2004; ported the number of patients lost to follow up. All used only theCollet 1993; Del-Rio-Navarro 2003; Gutiérrez-Tarango 2001; available data for the analyses. No imputation for the incompleteTaylor 2003) were considered of quality A (Higgins 2011). The data were intended.rest of the studies were of poor quality. 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 toAllocation follow up; more children in the active group were lost (5/25 inIn the studies with a proper description of randomisation and active group versus 2/25 in the placebo group). In the Collet 1993allocation (Cohen 2004; Collet 1993; Del-Rio-Navarro 2003; trial, 7% of participants were lost to follow up; in both groups theGutiérrez-Tarango 2001; Jara-Perez 2000; Taylor 2003), the im- rates and the reasons were similar. In the Taylor 2003 trial, 7% ofplementation of the random sequence of the treatments was re- participants were lost to follow up; in both groups the rates andported. In Cohen 2004 active medication and the placebo were the reasons were similar. In the Jara-Pérez 2000 trial only the datasupplied directly by the manufacturer and all randomisation lots of one participant on IS was lost. In the Gutiérrez-Tarango 2001were stored in a sealed envelope at the pharmacy of the company, trial, all the participants completed the trial.to be opened only in the event of an emergency. In Collet 1993participants were allocated to IS or placebo according to a pro- Selective reportinggram for remote data entry (Minitel a national telecommunica-Immunostimulants for preventing respiratory tract infection in children (Review) 644Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  17. 17. Evid.-Based Child Health 7:2: 629–717 (2012)The study protocols were not available. Sixty-one randomized, non-indexed, small, local journals).placebo-controlled clinical trials were identified. Only 35 stud-ies reported the mean and SD of the incidence of respiratoryinfections or provided data to calculate these measure (Ahrens Effects of interventions1984; Arroyave 1999; Careddu 1994a; Clerici 1988; Cohen2004; De Loore 1979; Del-Rio-Navarro 2003; Fiocchi 1986; See: Summary of findings for the main comparison SummaryGarabedian 1990; Gutiérrez-Tarango 2001; Gómez-Barreto 1998; of findings tableHauguenauer 1987; Hüls 1995; Jara-Pérez 2000; Karam-Bechara1995; Lacomme 1985; Litzman 1999; Maestroni 1984; Motta Effect of immunostimulants (IS) on acute respiratory1994; Paupe 1986; Pech 1987; Piquett 1986; RB10 1994; tract infections (ARTIs)RB17 1988; RB21 1988; RB22 1990; RB24 1990; RB25 1990; Of the 61 included studies only 35 provided data in a form suitableSaracho-Weber 2001; Schaad 1986; Schaad 2002; Van Eygen for inclusion in the meta-analysis for this outcome. All 35 trials1976; Van Eygen 1979; Vautel 1993; Zagar 1988). Seven trials compared IS with a placebo.reported the frequency of ARTIs (Burgio 1994; Careddu 1994b; Twenty-four out of 35 studies showed a reduction of ARTIs, bothCollet 1993; Fukuda 1999; Paupe 1991; Rutishauser 1998; Taylor as total numbers and as a percentage reduction of ARTIs (consid-2003). The rest of the studies did not use outcome measures rele- ering the mean number of ARTIs in the placebo group as 100%).vant to the prevention of respiratory infections. 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 ofOther potential sources of bias ARTIs (MD -38.84%; 95% CI -46.37% to -31.31%). The totalIn 29 out of the 35 included studies, the process of randomisation number of ARTIs outcome showed high heterogeneity (I2 statisticand allocation was not described. Additionally, the disposition of = 94.0%, Chi2 test = 582.02, P < 0.00001); the use of percent-participants and reasons for withdrawals were not reported. age change in the rate of ARTIs reduced the heterogeneity butFunnel plots of IS effects have a considerable asymmetry, indicat- it remained very high (I2 statistic = 83.0%, Chi2 test = 195.07,ing possible publication bias, i.e. publishing only positive results P < 0.00001). Therefore, we decided to use the random-effects(see Assessment of reporting biases). Language bias is also possible model with MD to calculate the global effect of immunostimu-(publication in languages other than English and publication in lants (Figure 5; Figure 6).Immunostimulants for preventing respiratory tract infection in children (Review) 645Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  18. 18. Evid.-Based Child Health 7:2: 629–717 (2012) Figure 5. Forest plot of comparison: Any IS compared with placebo, outcome: 1.1 Mean number of ARTIs.Immunostimulants for preventing respiratory tract infection in children (Review) 646Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  19. 19. Evid.-Based Child Health 7:2: 629–717 (2012) Figure 6. Forest plot of comparison: Any IS compared with placebo, outcome: 1.2 Per cent difference in ARTIs.We investigated heterogeneity by bivariate correlation as well asby linear regression. The variables considered were total number Another potential source of heterogeneity was the type of IS. Weof children in the study, duration of the trial, mean number of decided to investigate this source of heterogeneity by performingARTIs in the control group versus the mean difference in number sub-analyses as follows.of ARTIs and mean difference in the percentage of ARTIs. The 1. Including the bacterial IS studies data (and excluding themain source of heterogeneity was the mean number of ARTIs in Saracho-Weber 2001 trial because it was the only trial with morethe control group, using the mean difference in number of ARTIs ARTIs in the IS group than in the placebo group, probably due(linear regression model correlation - 0.672, P < 0.001). Using to a clerical mistake inverting ARTI incidences). The number ofthe mean difference in the percentage of ARTIs, the source of trials was 24; total number of participants was 2154, the numberheterogeneity was related to the mean difference in the number of of IS participants was 1091 and the number of placeboARTIs and mean number of ARTIs in the control group (linear participants was 1063. The reduction in the total number ofregression model correlation 0.834, P < 0.001). The age of the ARTIs was MD -1.41 (95% CI -1.85 to -0.98); the reduction inparticipants in each trial could be another important source of the number of ARTIs as a percentage was MD -41.21 (95% CI -variation in the number of ARTIs, as younger children would 49.10 to -33.31).suffer more ARTIs. Yet the age in each trial was diverse, including 2. Only bacterial IS studies data (excluding Saracho-Weberenrolled preschool children, school-aged children and adolescents. 2001) with a total number of participants of at least 40. TheThis made the exploration of this potential source of variation number of trials was 19; the total number of participants wasproblematic. In general, the net reduction in the number of ARTIs 2009, the number of IS participants was 1019 and the numberwas dependent on the background rate of ARTIs. of placebo participants was 990. The reduction in the totalImmunostimulants for preventing respiratory tract infection in children (Review) 647Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  20. 20. Evid.-Based Child Health 7:2: 629–717 (2012)number of ARTIs was MD -1.42 (95% CI -1.92 to -0.93); and and the reduction in the number of ARTIs as a percentage wasthe reduction in the number of ARTIs as a percentage was MD - MD -36.16 (95% CI -44.51 to -27.80).38.44 (95% CI -47.25 to -29.63). 4. Only OM-85 studies. The number of trials was nine; total 3. Only bacterial IS studies where the total number of number of participants was 852, the number of IS participantsparticipants was more than 40 (including D53 and OM-85 BV). was 437 and the number of placebo participants was 415. TheThe number of trials was 16; the total number of participants reduction in the total number of ARTIs was MD -1.20 (95% CIwas 1811, the number of IS participants was 921 and the -1.75 to -0.66) and the reduction in the number of ARTIs as anumber of placebo participants was 890. The reduction in the percentage was MD -35.90 (95% CI -49.46 to -22.35) (Figuretotal number of ARTIs was MD -1.17 (95% CI -1.56 to -0.78); 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; totalnumber of participants was 852, the number of IS participantswas 437 and the number of placebo participants was 415. Thereduction in the total number of ARTIs was MD -1.32 (95% CI-1.86 to -0.79); and the reduction in the number of ARTIs as apercentage was MD -43.47 (95% CI -53.22 to -33.72) (Figure8). Figure 8. Forest plot of comparison: D53 trials, outcome: 7.2 Per cent difference in ARTIs.Immunostimulants for preventing respiratory tract infection in children (Review) 648Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  21. 21. Evid.-Based Child Health 7:2: 629–717 (2012)We did not perform the sub-analyses for good quality trials as onlytwo out of five trials provided data as mean and SD (Del-Rio- nausea, vomiting, abdominal pain and diarrhea; and skin disordersNavarro 2003; Gutiérrez-Tarango 2001). The selection of bacterial such as rash, urticaria and pruritus.IS studies reduced the heterogeneity of the percentage difference The possible beneficial effects of immunostimulants in the pre-outcome from very high (I2 statistic > 75) to moderate (I2 statistic < vention of ARTIs, cancers, AIDS/HIV infections, tuberculosis etc.75) (Higgins 2003). However, the percentage differences and 95% have been awaited expectantly by many clinicians and medicalCI in the total number of ARTIs were similar to the overall analysis researchers. One of the main indications of registered IS is thefor all sub-analyses. The reduction of the I2 statistic when only prevention of ARTIs in children, as they are more susceptible tothe bacterial IS were analyzed confirmed that the different kinds ARTIs. IS use is common in some countries in Europe and in theof IS were another major source of heterogeneity. The combined Americas as result of the demand to reduce the incidence of ARTIsanalysis of percentage difference outcome of D53 and OM-85 had in children.an I2 statistic of 65%; D53 alone 55%; OM-85 alone 75%. While the use of IS is currently controversial and is viewed with skepticism by many physicians, there have been several clinical tri- als supporting their use as ancillary treatment and in the preven-Adverse effects tion of ARTIs. Yet their mechanism of action and possible bene-Twenty studies provided data on adverse events in a form suit- fits and risks are not well known. The aim of this review was toable for inclusion in the meta-analysis. The most frequent events synthesise all the evidence currently available from trials on thiswere skin and gastrointestinal effects (nausea, vomiting, abdomi- topic to enable a more robust, unbiased assessment of the role ofnal pain and diarrhea). No statistically significant difference was efficacy and safety of IS to prevent ARTIs in children.shown in these adverse events when comparing IS with a placebo. After reviewing all available IS studies on the prevention of ARTIsA summary of the reported safety data for each trial is noted in the in children, we empathise with the skepticism of many physicians.outcome section of the Characteristics of included studies table. This review has a number of limitations due to the quality andIn 22 studies, authors did not report the presence or absence of reporting of the trials on this topic, the heterogeneity of the in-adverse events (Andrianova 2003; Bánovein 1992; Clerici 1988; cluded trials and the possibility of publication bias. Few papersFiocchi 1986; Fiocchi 1988; Garabedian 1990; Giovannini 2000; complied with standards for methodological quality and reportingHauguenauer 1987; Iuldashev 1988; Longo 1988; Maestroni of clinical trials, with the majority having significant deviations1984; Martin du Pan 1982; Piquett 1986; Prusek 1987; RB10 from these standards. In addition, the lack of detail in many of the1994; RB17 1988; RB21 1988; RB22 1990; RB24 1990; RB25 trial publications limited the quality of this review.1990; Saracho-Weber 2001; Sramek 1986). In eight studies, trial The most common problems with the included trials were thatauthors claimed that no adverse event were observed (Chen 2004; they:De Loore 1979; Dils 1979; Karam-Bechara 1995; Mora 2007 • did not report data on ARTIs sufficient to reproduceRenzo 2004; Van Eygen 1976; Zagar 1988). In four studies no ad- parametric and non-parametric statistical tests or carry out meta-verse events were observed in the immunostimulant group (Burgio analysis;1994; Fiocchi 1989; Lacomme 1985; Schaad 1986). Five studies • did not establish the normal incidence of ARTIs in the localreported a single case of adverse events in the IS group (Fukuda population and the number of infections in susceptible children,1999; Gómez-Barreto 1998; Paupe 1986; Paupe 1991; Van Eygen therefore, endpoint changes were not properly established;1979). One study reported only two adverse events (Wahl 2008). • did not identify the possible causes of recurrent ARTIs;In three studies no adverse events related to administration of the • did not try to isolate or identify the causative pathogen;trial medications were reported (Arroyave 1999; Jara-Pérez 2000; • did not calculate the sample size required;Mora 2010a). • 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 >DISCUSSION mean/2 or mean - SD < 0); • under reported adverse events or did not report them at all;Summary of main results • did not report the power of the statistical tests in trials without significant difference;This review shows that IS reduce the incidence of ARTIs by about • did not report or explain the flow chart and attrition of the40% on average (from 35 trials with a total of 4060 participants). participants and the statistical methods did not consider the dataHowever, due to the poor quality of the included trials this may be from missing participants (censored data);an overestimate of the true effect of IS. Most of the trials reported • published articles in low impact journals;a low incidence of adverse events or no adverse events. The most • included heterogeneous groups of children comprisingfrequent adverse events were gastrointestinal complaints such asImmunostimulants for preventing respiratory tract infection in children (Review) 649Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  22. 22. Evid.-Based Child Health 7:2: 629–717 (2012)infants, toddlers, schoolboys and girls and adolescents without ARTI while only 55.8% of children on echinacea had a secondconsidering the incidence of ARTIs in each group; infection (P = 0.01). However, this effect could not be explored • did not control for or report on confounding factors (that is in this review.to say, age groups, concomitant asthma or allergy, number of In all meta-analyses it is important to consider the presence andsiblings, smokers at home, birth weight, seasons during the study, possible effect of publication bias; that is, the selective publicationtime and timing of attendance at daycare centre or school). of trials with positive results. The funnel plot demonstrated con- • did not report the quality and standardisation of the herbal siderable asymmetry, indicating possible publication bias. Othersupplements (Wolsko 2005) and bacterial extracts. types of bias that could affect the funnel plot are the language bias (publication in languages other than English and publication inAll the trials were conducted in populations of highly susceptible non-indexed, small, local journals), poor methodological design,children (secondary prevention) except Collet 1993 and Jara-Pérez inadequate analysis and inadequate presentation of the results. In2000, which studied children over-exposed to ARTIs due to the only one study (Saracho-Weber 2001) the treated group had anfact that they attended daycare centres and an orphanage, respec- increase in ARTIs and, therefore, a positive difference.tively, and Martin du Pan 1982 which included a subgroup from The high heterogeneity limits the external validity of the analysesdaycare centres. In contrast, the echinacea trials were carried out in with all the studies. However, when we selected only the studiespopulations without a history of recurrent ARTIs (Cohen 2004; on bacterial IS (particularly those of D53 and OM-85 BV), andTaylor 2003). used percentage of ARTIs, the heterogeneity could be regardedThe lack of significance of the findings of some trials could be as acceptable. It is important to note that the size of the effectsascribed to small sample size, duration of the intervention, season is similar in the different sub-analyses, supporting the externalof intervention, broad participant selection criteria (mainly diverse validity of the conclusions.age groups) and low incidence of ARTIs in the studied population On the basis of the asymmetry shown in the funnel plot, the het-(caused by an over-reporting of previous ARTIs or reduction of erogeneity of the trials and the low quality of many included trials,incidence as children grew older). the possibility of bias (resulting in an overestimation of the trueThymic extracts have been withdrawn from sale in several coun- effects of IS on ARTIs) should be considered as high. Therefore,tries, due to the possible prion contamination and consequent caution needs to be applied when interpreting the possible advan-risk of bovine spongiform encephalopathy (WHO 2005). The use tages of IS shown in this review. However, the results of this reviewof levamisole is restricted because of the risk of agranulocytosis, provide a reference to the probable effect of IS in the prevention ofneurologic disease (Symoens 1978) and leukoencephalopathy (Xu ARTIs in children and point to the need for further clinical trials.2009). Further trials on IS must follow the established guidelines (ColletThe overall effect of IS was a reduction in the total number of 1992; Moher 2001; Valleron 1992), estimate sample size accordingARTIs (MD -1.24; 95% CI -1.54 to -0.94) but the individual to realistic incidence of ARTI and control for confounding factors.size of the effect in each trial depended on the number of ARTIs Multivariable analysis should be used when confounding factorsin the control group. The size of the effect could seem small but are identified. Reports of such trials must include enough data toexpressing the reduction of ARTIs as a percentage indicates a good replicate non-parametric statistical tests (for instance, frequencyeffect, about 40% (MD -38.84%; 95% CI -46.37 to -31.31). The of ARTIs at the end point) and include statistical analysis dealingresults indicate that the reduction in the incidence of ARTIs is a with censored data (Mahe 1999). Registration of all the protocolsreal possibility but as the net effect depends on the background rate and ongoing trials would be desirable to obtain all the possibleof ARTIs the effect would only be noticeable when the number of outcomes. It would be necessary to conduct trials on otitis andinfections to be reduced is higher than the normal incidence for lower ARTIs with large numbers of highly susceptible children.a given age group. Therefore, the use of IS for the prevention of Considering the present review, the prevention of ARTIs usingARTIs must be limited to children with proven high susceptibility IS may be possible. Larger clinical trials, adequately powered forto ARTIs or over-exposed children who are over-exposed to ARTIs important population groups, sponsored by health authorities,because they are in daycare centres, orphanages, kindergarten or would be desirable to establish the true effects of IS and the effectelementary school. of individual IS preparations.Sub-analysis of studies with available databases (Del-Rio-Navarro2003; Gutiérrez-Tarango 2001; Jara-Pérez 2000) have shown thatIS are not very effective in the prevention of one ARTI but are inthe prevention of recurrent infections (that is, two or three). Thismay be the reason why echinacea trials fail to show protection tothe first infection but had some effect on the second infection. In Overall completeness and applicability ofaddition, the participants had no history of increased incidence evidenceof ARTI. In a re-analysis of one study (Taylor 2003) it was found According to the funnel plots, it is possible that some trials withthat 69.2% of the children treated with placebo had a second negative results have not been published (Figure 3 and Figure 4).Immunostimulants for preventing respiratory tract infection in children (Review) 650Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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