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Immunostimulants for preventing respiratory tract infection in children: A systematic review and meta-analysis

Open AccessPublished:September 14, 2022DOI:https://doi.org/10.1016/j.waojou.2022.100684

      Abstract

      Childhood acute respiratory tract infections (ARTIs) are a significant cause of morbidity and mortality, so, immunostimulants have been used as a preventative measure. Despite this, there is no updated evidence regarding the safety and efficacy of immunostimulant drugs for this purpose. This study aimed to determine the effectiveness and safety of immunostimulants in preventing ARTIs in children based on the most recent scientific evidence. Data sources such as PubMed, Cochrane Central Register of Controlled Trials, Embase, Google Scholar, and Scopus were searched from 1965 to 10 January 2022 to identify randomized controlled trials (RCTs) comparing immunostimulants administered by any method, with placebo to prevent ARTIs on children under 18 years of age without immunodeficiencies, anatomical, genetic, or allergic conditions. In order to analyze data from the studies, we used Review Manager 5.4 (The Cochrane Collaboration, 2020), assessed the certainty of the evidence with Grading of Recommendations, Assessment, Development and Evaluations (GRADE), and assessed the quality and risk of bias of the studies using the RoB tool 1.0. Further, outcomes were combined and analyzed using meta-analysis, subgroup analysis, and sensitivity analysis. Throughout the review, we included 72 placebo-controlled clinical trials involving 12,229 children. The meta-analyses, however, included only 38 studies (52.8%) with 4643 children (38% of the total) with data on mean number of ARTIs. These studies demonstrated a reduction in the ARTIs (MD –1.12 [95%CI –1.39 to −0.85]) and ratio of means of ARTIs (0.61 [95%CI 0.54–0.69]), corresponding to a percentage reduction of 39% (95%CI, 46%–31%) with moderate-quality data. Nevertheless, since there was considerable to substantial heterogeneity and bias was unclear in all domains in 32 out of 72 trials, the quality of the evidence for efficacy was deemed low. Only 14 trials reported adverse events.
      The review indicates that immunostimulants reduce the incidence of ARTIs by 40% on average in susceptible children, despite low-quality evidence, heterogeneity, and the possibility of publication bias. However, further studies are needed to establish immunostimulants' safety and efficacy profiles.
      This review was conducted without the support of any funding and has no registered number.

      Keywords

      Introduction

      Most acute respiratory tract infections (ARTIs) are caused by viruses.
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      • et al.
      Viruses associated with acute respiratory infection in a community-based cohort of healthy New Zealand children.
      Nevertheless, it is not possible to develop vaccines for each of the hundreds of possible pathogenic agents. As a result, specific immunization may not be the best method for preventing ARTIs. A good example is the introduction of the pneumococcal conjugate vaccine, which led to a decrease in carriage and invasive infections due to the vaccine serotypes. Still, some non-vaccine serotypes are becoming antibiotic-resistant.
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      • et al.
      Effect of pneumococcal conjugate vaccine on pneumococcal meningitis.
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      • et al.
      Continued impact of pneumococcal conjugate vaccine on carriage in young children.
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      • Sahm D.F.
      The impact of the pneumococcal conjugate vaccine on antimicrobial resistance in the United States since 1996: evidence for a significant rebound by 2007 in many classes of antibiotics.
      The Immunology Study Group of the Italian Paediatric Society defined recurrent respiratory infections based on local epidemiological studies. The following criteria required the absence of any underlying pathological condition (primary or secondary immunodeficiency, cystic fibrosis, malformations of the airways, immotile-cilia syndrome) explaining recurrent respiratory tract infections and the presence of 1 of the following 3 conditions: having more than 6 respiratory infections per year; having more than 1 respiratory infection during the autumn and winter seasons (from September to March in the northern hemisphere); and/or having more than 3 lower respiratory tract infections per year. Additionally, the study group considered the possibility that repeat infections are caused in part by social and environmental factors, such as daycare attendance, family size, air pollution, parental smoking, and dampness in the home.
      • de Martino M.
      • Ballotti S.
      The child with recurrent respiratory infections: normal or not?.
      Thus, several clinical trials have studied non-specific measures for preventing ARTIs, including nutritional supplements such as vitamin A,
      • Imdad A.
      • Mayo-Wilson E.
      • Herzer K.
      • Bhutta Z.A.
      Vitamin A supplementation for preventing morbidity and mortality in children from six months to five years of age.
      vitamin C,
      • Hemilä H.
      • Chalker E.
      Vitamin C for preventing and treating the common cold.
      vitamin D,
      • Martineau A.R.
      • Jolliffe D.A.
      • Hooper R.L.
      • et al.
      Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data.
      and trace elements;
      • Lassi Z.S.
      • Moin A.
      • Bhutta Z.A.
      Zinc supplementation for the prevention of pneumonia in children aged 2 months to 59 months.
      preventive antibiotics;
      • Onakpoya I.J.
      • Hayward G.
      • Heneghan C.J.
      Antibiotics for preventing lower respiratory tract infections in high-risk children aged 12 years and under.
      herbal extracts;
      • Su G.
      • Chen X.
      • Liu Z.
      • et al.
      Oral Astragalus (Huang qi) for preventing frequent episodes of acute respiratory tract infection in children.
      xylitol;
      • Azarpazhooh A.
      • Lawrence H.P.
      • Shah P.S.
      Xylitol for preventing acute otitis media in children up to 12 years of age.
      and the use of immunostimulants from synthetic sources
      • Esposito S.
      • Soto-Martinez M.E.
      • Feleszko W.
      • Jones M.H.
      • Shen K.L.
      • Schaad U.B.
      Nonspecific immunomodulators for recurrent respiratory tract infections, wheezing and asthma in children: a systematic review of mechanistic and clinical evidence.
      ,
      • Ferrario B.E.
      • Garuti S.
      • Braido F.
      • Canonica G.W.
      Pidotimod: the state of art.
      or of bacterial origin.
      • Esposito S.
      • Soto-Martinez M.E.
      • Feleszko W.
      • Jones M.H.
      • Shen K.L.
      • Schaad U.B.
      Nonspecific immunomodulators for recurrent respiratory tract infections, wheezing and asthma in children: a systematic review of mechanistic and clinical evidence.
      ,
      • Bellanti J.A.
      • Settipane R.A.
      Bacterial vaccines and the innate immune system: a journey of rediscovery for the allergist-immunologist and all health care providers.
      ,
      • Del-Rio-Navarro B.
      • Becerril-Ngeles M.
      • Berber A.
      Eficacia del inmunoestimulante OM-BV85 en la prevención de infecciones respiratorias [Efficacy of the immunoestimulant OM-BV85 in the prevention of respiratory infections].
      In addition, bacterial extracts and synthetic compo-unds are currently used in Europe and Latin America to prevent ARTIs.
      Since there is information concerning the effects of immunostimulants, this review and meta-analysis aimed to evaluate and update (since 2006) the evidence regarding the efficacy and safety profile of immunostimulants as preventives for ARTIs in children based on scientific evidence by addressing the following PICOST: Population (children aged under 18 years of age susceptible to acute respiratory tract infections); Intervention (any immunostimulants); Comparison (placebo); Outcome (number of ARTIs per treatment group during the study period); Study (randomized controlled trials); and Time (Trials of 3–12 months duration published from January 1965 to January 10, 2022).

      Materials and methods

      Selecting criteria

      Types of studies

      We evaluated randomized controlled trials (RCTs) in which immunostimulants (administered by any method) were compared to a placebo to prevent ARTIs. The study excluded trials involving interferon inducers, vitamins, homeopathic and traditional remedies, and nutritional supplements.

      Types of participants

      Children under age of 18 were included. Children with immunodeficiencies, anatomical alterations, genetic conditions, asthma, allergies, atopy, or chronic respiratory diseases were excluded; asthma and allergic conditions were not included because their symptoms could be confounded with ARTIs.

      Types of interventions

      Any method of administering an immunostimulant to prevent ARTIs was investigated. It was considered that immunostimulants could be administered in the presence of active ARTI and concomitant therapies such as antipyretics and antibiotics.

      Types of outcome measures

      In a broader sense, ARTI was defined as the occurrence of several specific conditions, such as colds, influenza, tonsillitis, pharyngitis, bronchitis, and otitis media. We also considered physician diagnosis of ARTI and adverse events.
      Since aetiological agents were not considered, there was no distinction between bacterial and viral ARTIs.

      Primary and secondary outcomes

      To assess efficacy, the primary outcome was the number of ARTIs per treatment group during the study period.
      Secondary outcomes were the ratio of means of ARTIs by treatment group and the incidence of adverse events.

      Search methods

      Electronic searches

      Our search was conducted on the Cochrane Central Register of Controlled Trials (CENTRAL) 2021, Issue 12, a part of the Cochrane Library, www.thecochranelibrary.com (accessed on 10 January 2022), which includes the ARI Group's Specialized Register, Pubmed (2011–10 January 2022), Embase (Elsevier) (2011–10 January 2022), Google Scholar (2011–10 January 2022), and Scopus (Elsevier) (2011–10 January 2022). A search for previous versions of this work covered a period from 1965 to 2006.
      • Del-Rio-Navarro B.E.
      • Espinosa Rosales F.
      • Flenady V.
      • Sienra-Monge J.J.
      Immunostimulants for preventing respiratory tract infection in children.

      Searching other resources

      Citation searches in Google Scholar and Scopus were conducted using identified articles as references. To identify additional studies, we searched the bibliographies of all included trials and those of relevant reviews. No language or publication restrictions were imposed. We also searched the WHO ICTRP website (http://www.who.int/ictrp/en/) and the National Institutes of Health's ClinicalTrials.gov site (http://www.ClinicalTrials.gov/.)

      Data collection and analysis

      Selection of studies

      The review's authors (AB, BEDRN, JJLSM) independently searched for trials for inclusion and resolved differences through discussion. The screening process was duplicated without any pre-calibration. The data collected were extracted independently and duplicated by 2 review authors (BEDRN, JJLSM). Potential disagreements were resolved by reviewing the papers collectively. The review's authors were able to read Spanish and English papers, as well as retrieve data from German, French, and other Romance languages. Several studies reported the number of infections and the standard deviation (SD) or standard error (SE).
      Review Manager 5.4 (Review Manager [RevMan] [Computer program] Version 5.4 of The Cochrane Collaboration, 2020) was used for data input and analysis.

      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 for each included trial a quality rating as high risk, low risk, or uncertain risk for the above domains, using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions.

      Pre-specified harms outcomes

      It was determined that the intervention had the potential to cause harm by increasing the incidence of adverse reactions and ARTIs.

      Data synthesis

      Across the studies, outcomes were combined and analyzed using meta-analysis, subgroup analysis, and sensitivity analysis. Variables included in the subgroup analyses were bacterial immunostimulants and the trials with a sample size of more than 40. A priori, subgroup analyses were performed as they were relevant in previous versions of the present meta-analysis.
      • Del-Rio-Navarro B.E.
      • Espinosa Rosales F.
      • Flenady V.
      • Sienra-Monge J.J.
      Immunostimulants for preventing respiratory tract infection in children.
      Initially, the protocol was published in the Cochrane Database of Systematic Reviews 2004,
      • Berber A.
      • Del-Rio-Navarro B.E.
      • Flenady V.
      • Sienra-Monge J.J.L.
      Immunostimulants for preventing respiratory tract infection in children [Protocol].
      which did not include a simple pooled analysis, allowing us to consider the characteristics of subgroups and individual studies and avoid the appearance of spurious or counterintuitive results. For the sensitivity analyses, the type of immunostimulants (D53, levamisole, OM-85, RU40171, and Thymomodulin), as well as the number of ARTIs in the control group as <2; 2 to <4; ≥4; ≥4 without the outlier were considered. Finally, homogeneity was assessed using the I2 test.

      GRADE and "summary of findings table"

      In order to create a summary of the findings table, we used the following outcomes: number of ARTIs, the ratio of means of ARTIs, and adverse events experienced. We used the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) criteria (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the certainty of the evidence related to the studies that contributed data to the meta-analyses, and assessed the quality and risk of bias of individual studies using the RoB tool 1.0.
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      • et al.
      Grading quality of evidence and strength of recommendations.
      The method and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions
      were applied using GRADEpro GDT software (GRADEpro GDT [Computer program]. Version accessed on 13 July 2020. Hamilton, ON: McMaster University [developed by Evidence Prime], 2020. Available at gradepro.org.).

      Results

      Description of studies

      Results of the search

      After searching electronic databases, we identified 798 references. However, only 124 studies were considered potentially relevant (see Fig. 1 “screening section” and supplementary material 1 and 2). No other potentially eligible studies were found through contact with trial authors or searches of trial registries.
      Fig. 1
      Fig. 1PRISMA flow diagram for search results and study selection

      Source of data

      The data were obtained from the original research papers. Exceptions to this were data from OM-85 studies in Mexico;
      • Del-Río-Navarro B.E.
      • Luis Sienra-Monge J.J.
      • Berber A.
      • Torres-Alcántara S.
      • Avila-Castañón L.
      • Gómez-Barreto D.
      Use of OM-85 BV in children suffering from recurrent respiratory tract infections and subnormal IgG subclass levels.
      • Gómez Barreto D.
      • De la Torre C.
      • Alvarez A.
      • Faure A.
      • Berber A.
      Seguridad y eficacia de OM-85-BV más amoxicilina/clavulanato en el tratamiento de la sinusitis subaguda y prevención de infecciones recurrentes en niños [Safety and efficacy of OM-85-BV plus amoxicillin/clavulanate in the treatment of subacute sinusitis and the prevention of recurrent infections in children].
      • Gutiérrez-Tarango M.D.
      • Berber A.
      Safety and efficacy of two courses of OM-85 BV in the prevention of respiratory tract infections in children during 12 months.
      • Jara-Pérez J.V.
      • Berber A.
      Primary prevention of acute respiratory tract infections in children using a bacterial immunostimulant: a double-masked, placebo-controlled clinical trial.
      data from Schaad et al,
      • Schaad U.B.
      • Mütterlein R.
      • Goffin H.
      BV-Child Study Group
      Immunostimulation with OM-85 in children with recurrent infections of the upper respiratory tract: a double-blind, placebo-controlled multicenter study.
      which were obtained from the review;
      • Steurer-Stey C.
      • Lagler L.
      • Straub D.A.
      • Steurer J.
      • Bachmann L.M.
      Oral purified bacterial extracts in acute respiratory tract infections in childhood: a systematic quantitative review.
      and data from D53 studies.
      • Bellanti J.
      • Olivieri D.
      • Serrano E.
      Ribosomal immunostimulation: assessment of studies evaluating its clinical relevance in the prevention of upper and lower respiratory tract infections in children and adults.
      • Garabedian E.N.
      • Dubreuil C.
      • Triglia J.C.
      Effectiveness and Tolerance of Ribomunyl Tablets in Preventing Middle Ear Infections in Children Affected by S.O.M..
      • Haguernauer J.P.
      Prevention of the ENT repeating infectious episodes by D53 tablets in children of less than 5 years [Prévention des épisodes infectieux récidivants de la sphére ORL par D53 comimés chez lénfant de moins de 5 ans].
      • Hüls P.
      • Welbers P.
      • Lindemann H.
      Immunotherapy of children with the help of a multibacterial ribosomal preparation [Immuntherapie bei kindern mit hilfe eines multibakteriellen ribosomenpräparates].
      • Lacomme Y.
      • Narcy P.
      Prevention of the repeating episodes of ENT superinfection by ribosomal immunotherapy in the child. Clinical results of a multicenter study [Prévention par immunothérapie ribosomale des épisodes de superinfection récidivantes de la sphére ORL chez l'enfant. Résultats cliniques d'une étude multicentrique].

      Included studies

      A total of 72 placebo-controlled trials involving 12 229 children were included. There were diverse interventions, number of ARTIs in placebo groups, and outcomes reported in the included studies. We were only able to meta-analyze 38 studies (52.8% of the total) with 4643 children (38% of the total).

      Population

      In the included trials, participants ranged in age from 6 months to 18 years. The majority of the studies (n = 45) included children with recurrent ARTIs. Other trial participants (n = 4) had chronic or recurrent ARTIs. In some studies, participants were described as healthy or as having no significant health problems (n = 7). The rest of the studies included patients with acute and chronic infections or did not specify the patients' health status.

      Settings

      The most of the studies were conducted in paediatric practices, paediatric clinics, or subspecialty paediatric clinics. In 5 trials, schools or pre-schools were used as the setting.
      • Andrianova I.V.
      • Sobenin I.A.
      • Sereda E.V.
      • Borodina L.I.
      • Studenikin M.I.
      Vliianie chesnochnykh tabletok prolongirovannogo deĭstviia "allikor" na zabolevaemost' ostrymi respiratornymivirusnymi infektsiiami u deteĭ [Effect of long-acting garlic tablets "allicor" on the incidence of acute respiratory viral infections in children].
      • Iuldashev A.K.
      • Slepushkin A.N.
      • Khodzhaeva M.A.
      • Schastnyĭ E.I.
      • Kamilov FKh
      Izuchenie profilakticheskoĭ éffektivnosti reaferona pri virusnom gepatite A i ostrykh respiratornykh infektsiiakh u deteĭ [Prophylactic efficacy of reaferon in viral hepatitis A and acute respiratory infections in children].
      • Padayachee Y.
      The Efficacy of Linctagon® Syrup in the Prevention of Colds and Influenza in Pre-school Children [Doctoral Dissertation].
      • Souza F.C.
      • Mocellin M.
      • Ongaratto R.
      • et al.
      OM-85 BV for primary prevention of recurrent airway infections: a pilot randomized, double-blind, placebo-controlled study.
      • Srámek J.
      • Josífko M.
      • Helcl J.
      • et al.
      Bacterial lysate (I.R.S. 19) applied intranasally in the prevention of acute respiratory diseases in children: a randomized double-blind study.
      Other trials were conducted to some extent in nurseries or day-care centres (n = 3)
      • Collet J.P.
      • Ducruet T.
      • Kramer M.S.
      • et al.
      Stimulation of nonspecific immunity to reduce the risk of recurrent infections in children attending day-care centers. The Epicrèche Research Group.
      • Fiocchi A.
      • Omboni S.
      • Mora R.
      • et al.
      Efficacy and safety of ribosome-component immune modulator for preventing recurrent respiratory infections in socialized children.
      • Martin du Pan R.E.
      • Martin du Pan R.C.
      Etude clinique de prévention des infections des voies respiratoires supérieures de l'enfant de l'âge préscolaire [Clinical study concerning the prevention of infections of the upper respiratory tract of preschool children].
      In one study, participants lived in an orphanage (200 girls).
      • Jara-Pérez J.V.
      • Berber A.
      Primary prevention of acute respiratory tract infections in children using a bacterial immunostimulant: a double-masked, placebo-controlled clinical trial.
      The setting was not well defined or described in the remaining studies.

      Interventions

      Twenty-eight studies lasted less than 6 months, 37 studies lasted 6 months, and only 7 studies lasted more than 6 months. D53 trials lasted for less than 6 months in 5 cases, and 6 months in 15 cases. In the OM-85 trials, there was 1 study that lasted less than 6 months, 14 OM-85 trials lasted 6 months, and 2 trials lasted longer than 6 months. There was a lack of clarity regarding the methodology in all D53 trials, and they used different administration routes (orally or nasally).

      Outcomes

      Multiple outcome data

      Primary endpoints of the trials were diverse. The number of ARTIs, the percentage of children suffering more than one ARTI, the severity of the infection, and the number of days that the child had been ill were all included. Reports on these trials did not provide definitions of the end-points and the scales were not validated or consistent across authors. Consequently, we determined a priori that ARTIs, expressed as mean and standard deviation (SD), were the most appropriate choice for evaluating studies, as specified in the protocol and previous review.
      • Berber A.
      • Del-Rio-Navarro B.E.
      • Flenady V.
      • Sienra-Monge J.J.L.
      Immunostimulants for preventing respiratory tract infection in children [Protocol].
      Studies reporting ARTIs as mean and SD also reported on other variables (eg, sick days, school absences, number of antibiotic treatments), which mirrored and were dependent upon the number of ARTIs.
      The clinical scale results were not considered suitable for meta-analysis because the scales used were diverse, poorly described, and not validated.
      Among the 72 included studies, only 38 reported the mean and SD of ARTIs or provided data to calculate these measures, allowing them to be included in the meta-analysis. These studies defined ARTIs based on respiratory symptoms and signs. The number of ARTIs during the longest observation period available was used. The remaining studies reported a variety of endpoints, including symptoms, clinical scale scores, or the presence and/or absence of respiratory infections (see Table 1).
      Table 1Description of studies not included in the meta-analysis according to the report of their results.
      Characteristics of studies with median or mean number of ARTIs without SD or SE or a difference between them
      AuthorSettingHealth statusInterventionOutcomesTreatmentControlReported PFavored
      Caramia 1994Hospital-ClinicRecurrent ARTIsPidotimodMean number of relapsesn = 60, 0.67n = 60, 2.48<0.001Treatment
      Carriere-Roussel 2017Not specifiedRecurrent ARTIsD53Median difference of ARTIsn = 122, median difference −0.31 95% CI –0.18, −0.8n = 132<0.05Treatment
      Chen 2004Paediatric Clinical CentreRecurrent ARTIsLantigen BMedian of ARTIsn = 37, 3n = 37, 40.002Treatment
      Dils 1979Not availableChronic or recurrent ARTIsLevamisoleMean number of ARTIsn = 45, 0.98n = 41, 1.93<0.001Treatment
      Fiocchi 1988Paediatric Clinical CentreRecurrent ARTIsD53Mean number of ARTIsn = 30, 2.7n = 30, 3.13Not availableNot available
      Longo 1988Peadiatric Clinical CentreRecurrent ARTIsThymomodulinMean number of ARTIsn = 21, 1.24n = 19, 3.79<0.0002Treatment
      Passali 1994aENT centresHistory tonsillitis or pharyngitisPidotimodMean number of ARTIsn = 205, 1.54n = 211, 2.63<0.001Treatment
      Pozzi 2004Not availableRecurrent ARTIsLantigen BMean number of ARTIsn = 47, 1.211n = 47, 1.643Not availableNot available
      Riedl-Seifert 1995Paediatric Clinical CentreRecurrent ARTIsLW50020Mean number of ARTIsn = 99, 0.15n = 108, 0.270.026Treatment
      Schaad 2010bNot availableRecurrent ARTIsOM-85Mean number of ARTIsn = 198, 1.97n = 198, 2.420.0016Treatment
      Characteristics of the studies reporting clinical scores
      Fiocchi 1989Paediatric clinical centreRecurrent ARTIsD53Clinical scoren = 60, 4.2 ± 2.6n = 58, 8.0 ± 4.3<0.05Treatment
      Giovannini 2000Paediatric clinical centreChronic or acute ARTIsD53Clinical scoren = 45, 0.46n = 42, 0.76<0.01Treatment
      Mora 2002Not availableRecurrent ARTIsD53Clinical scoren = 41, not clearn = 40, not clearNot availableNot available
      Mora 2007ENT clinicRecurrent ARTIsD53Clinical scoren = 80, 1.9n = 80, 3.1Not availableNot available
      Renzo 2004Not availableChronic or recurrent ARTIsD53Clinical scoren = 36, 1.7n = 36, 2.4Not availableNot available
      Characteristics of the studies reporting the presence or absence of ARTIs or Symptoms
      Burgio 1994Not availableRecurrent ARTIsPidotimodPresence respiratory symptoms18%, 9/5062.5%, 25/400.000Treatment
      Careddu 1994bNot availableRecurrent ARTIsPidotimodPresence of ARTIs32%, 8/2591.7%, 22/240.000Treatment
      Göhring 2017Not availableRecurrent ARTIsOM-85Presence of ARTIs84.6% 165/19584.6% 170/2010.889No difference
      Fukuda 1999ENT clinicRecurrent ARTIsThymomodulinPresence of ARTIs44.4%, 4/980%, 8/100.17No difference
      Mora 2010aNot availableRecurrent ARTIsD53Presence of >1 acute adenoiditis6.67%, 2/3060%, 18/300.000Treatment
      Padayachee 2014Pre-school children facilitiesHealthyPelagoniumPresence of ARTIs46.7%, 7/1513.3%, 2/150.109No difference
      Paupe 1991ClinicsRecurrent ARTIsOM-85Presence of ARTIs60.7%, 37/6183.7%, 46/550.011Treatment
      Rutishauser 1998Not availableRecurrent ARTIsLW50020Presence of ARTIs24.8%, 29/11745.8%, 33/720.005Treatment
      Santamaria 2019Paediatric pulmonology Clinics and paediatric officeRecurrent ARTIsPidotimodSymptom days, % of total daysN = 13, 31%N = 16, 56%0.003Treatment
      Taylor 2003Paediatric private practicesNo significant health problemsEchinaceaPresence of >1 ARTIs55.8%, 112/20069.2%, 143/2070.009Treatment
      Wahl 2008Paediatric clinics and practicesRecurrent ARTIsEchinaceaPresence of acute otitis65%, 29/4441%, 19/460.022Control
      Characteristics of the Studies Reporting Diverse Outcomes
      Andrianova 2003SchoolsNot definedAllicorARTI morbidityn = 42, reduced ARTI morbidity 1.7 fold compared to placebon = 41<0.05Treatment
      Collet 1993Day care centresHealthy attending day care centreOM-85Presence of >4 upper ARTIs26.7% 56/210 participants33.8%, 72/213 with placebo0.136No difference
      Espinosa Rosales 2009Not availableRecurrent ARTIsPulmonaromIL10 levelsn = 26, constant levelsn = 26, decreasing levels0.034Treatment
      Fiocchi 2012Day care centres/ENT clinicAttending or to attend day-care-centreD53ARTI duration in daysn = 81, 3.6 ± 2.0n = 77, 4.7 ± 2.50.04Treatment; only a subgroup
      Iuldashev 1988Pre-school children institutionsHealthy childrenInterferonInfection rate of ARTIsn = 1100, 1.3 fewer ARTIs than the placebo group.n = 10780.05Treatment subgroup
      Mameli 2015Family paediatriciansHealthy entering day-care, kinderpidotimodInfection rate of ARTIsn = 29, 1.9 (95% CI 1.3 to 2.4)n = 28, 2.4 (95% CI 1.8 to 3.0)0.211No difference
      Martin du Pan 1982Day nurseries, private practiceDay care attendance, susceptible to ARTTIsOM-85Days suffering purulent rhinorr-hoean = 36, 265/3660 days (7.24%)n = 34, 569/3530 days (16.12%)0.000Treatment
      Sramek 1986Maternity SchoolHealthy and recurrent ARTIsIRS19ARTIs per 1000 persons daysn = 416, 7.79n = 409, 7.43>0.05No difference
      Twenty-two studies without sufficient data for meta-analysis supported immunostimulant treatment (including 2 studies that supported a subgroup treated with immunostimulant),
      • Caramia G.
      • Clemente E.
      • Solli R.
      • et al.
      Efficacy and safety of pidotimod in the treatment of recurrent respiratory infections in children.
      • Carrier-Roussel E.
      Clinical efficacy and safety of J022X ST in the prevention of recurrent upper-respiratory tract infections (RURTI) in children with a high risk of recurrence.
      • Chen A.H.
      • Chen R.C.
      • Zhang C.Q.
      • et al.
      [Efficacy of sublingual polyvalent bacterial vaccine (Lantigen B) in children with recurrent respiratory infection: a randomized double-blind controlled clinical trial].
      • Dils F.
      A placebo controlled, double-blind evaluation of levamisole in the reduction of the frequency, duration and severity of attacks in children suffering from recurrent upper respiratory tract infections.
      • Longo F.
      • Lepore L.
      • Agosti E.
      • Panizon F.
      Valutazione dell'efficacia della timomodulina in bambini con infezioni respiratorie ricorrenti [Evaluation of the effectiveness of thymomodulin in children with recurrent respiratory infections].
      • Passali D.
      • Calearo C.
      • Conticello S.
      Pidotimod in the management of recurrent pharyngotonsillar infections in childhood.
      • Riedl-Seifert R.J.
      • van Aubel A.
      • Kammereit A.
      • Elsasser U.
      Reduction of the number and severity of respiratory tract infections in children by oral immunostimulation.
      • Schaad U.B.
      • Principi N.
      European OM-85 Study Group
      Double-blind, placebo-controlled, randomised multicentre study of OM-85 (Broncho-Vaxom®), an immunostimulant, in paediatric recurrent upper respiratory tract infections. Poster 718.
      • Fiocchi A.
      • Borella E.
      • Riva E.
      • et al.
      A double-blind clinical trial for the evaluation of the therapeutical effectiveness of a calf thymus derivative (thymomodulin) in children with recurrent respiratory infections.
      • Giovannini M.
      • Fiocchi A.
      • Sala M.
      • et al.
      Immucytal ® in the prevention and treatment of recurrent upper respiratory tract infections in children: a randomized, placebo-controlled, double-blind study.
      • Burgio G.R.
      • Marseglia G.L.
      • Severi F.
      • et al.
      Immunoactivation by pidotimod in children with recurrent respiratory infections.
      • Careddu P.
      • Mei V.
      • Venturoli V.
      • Corsini A.
      Pidotimod in the treatment of recurrent respiratory infections in paediatric patients.
      • Mora R.
      • Dellepiane M.
      • Crippa B.
      • Guastini L.
      • Santomauro V.
      • Salami A.
      Ribosomal therapy in the treatment of recurrent acute adenoiditis.
      • Paupe J.
      Immunotherapy with an oral bacterial extract (OM-85 BV) for upper respiratory infections.
      • Rutishauser M.
      • Pitzke P.
      • Grevers G.
      • van Aubel A.
      • Elsasser U.
      • Kammereit A.
      Use of a polyvalent bacterial lysate in patients with recurrent respiratory tract infections: results of a prospective, placebo-controlled, randomized, double-blind study.
      • Santamaria F.
      • Montella S.
      • Stocchero M.
      • et al.
      Effects of pidotimod and bifidobacteria mixture on clinical symptoms and urinary metabolomic profile of children with recurrent respiratory infections: a randomized placebo-controlled trial.
      • Taylor J.A.
      • Weber W.
      • Standish L.
      • et al.
      Efficacy and safety of echinacea in treating upper respiratory tract infections in children: a randomized controlled trial.
      • Andrianova I.V.
      • Sobenin I.A.
      • Sereda E.V.
      • Borodina L.I.
      • Studenikin M.I.
      [Effect of long-acting garlic tablets "allicor" on the incidence of acute respiratory viral infections in children].
      • Espinosa-Rosales F.
      Prospective, pivotal unicentre, randomized double-blind, placebo-controlled study, to evaluate efficacy and safety of Bacterial Lysates (Pulmonarom®) in the prevention of respiratory tract infections.
      • Martin du Pan R.E.
      • Martin du Pan R.C.
      [Clinical study concerning the prevention of infections of the upper respiratory tract of preschool children].
      • Fiocchi A.
      • Omboni S.
      • Mora R.
      • et al.
      Efficacy and safety of ribosome-component immune modulator for preventing recurrent respiratory infections in socialized children.
      • Iuldashev A.K.
      • Slepushkin A.N.
      • Khodzhaeva M.A.
      • Schastnyi E.I.
      • Kamilov F.K.
      [Prophylactic efficacy of reaferon in viral hepatitis A and acute respiratory infections in children].
      6 studies showed no difference between immunostimulant and placebo groups,
      • Fiocchi A.
      • Zuccotti G.
      • Rottoli A.
      • et al.
      [Treatment with immucytal in recidivant respiratory infection in the pediatric age] Rivista di Pediatria.
      • Pozzi E.
      • Serra C.
      Efficacy of Lantigen B in the prevention of bacterial respiratory infections.
      • Mora R.
      • Barbieri M.
      • Passali G.C.
      • Sovatzis A.
      • Mora F.
      • Cordone M.P.
      A preventive measure for otitis media in children with upper respiratory tract infections.
      • Mora R.
      • Dellepiane M.
      • Crippa B.
      • Salami A.
      Ribosomal therapy in the prophylaxis of recurrent pharyngotonsillitis in children.
      • Renzo M.
      • Giovanni R.
      • Maria P.F.
      • et al.
      Short ribosomal prophylaxis in the prevention of clinical recurrences of chronic otitis media in children.
      • Göhring U.M.
      Double-Blind, placebo-controlled, randomised clinical study of broncho-vaxom® in children suffering from recurrent upper respiratory tract infections.
      and 5 studies did not explicitly report a statistical difference or superiority between groups.
      • Padayachee Y.
      The Efficacy of Linctagon® Syrup in the Prevention of Colds and Influenza in Pre-school Children [Doctoral Dissertation].
      ,
      • Fukuda Y.
      • Jordão-Neves B.M.
      • da-Cunha J.
      • Mangabeira Albernaz P.L.
      [Assessment of efficacy and safety of thymomodulin (Leucogen®) in the prevention of recurrent otitis media and recurrent tonsilitis].
      • Collet J.P.
      • Ducruet T.
      • Kramer M.S.
      • et al.
      Stimulation of nonspecific immunity to reduce the risk of recurrent infections in children attending day-care centers. The Epicreche Research Group.
      • Mameli C.
      • Pasinato A.
      • Picca M.
      • Bedogni G.
      • Pisanelli S.
      • Zuccotti G.V.
      AX-Working Group
      Pidotimod for the prevention of acute respiratory infections in healthy children entering into daycare: a double blind randomized placebo-controlled study.
      • Sramek J.
      • Josifko M.
      • Helcl J.
      • et al.
      Bacterial lysate (I.R.S. 19) applied intranasally in the prevention of acute respiratory diseases in children: a randomized double-blind study.
      • Wahl R.A.
      • Aldous M.B.
      • Worden K.A.
      • Grant K.L.
      Echinacea purpurea and osteopathic manipulative treatment in children with recurrent otitis media: a randomized controlled trial.
      Only 1 study reported an increased incidence of ARTIs or related outcomes in immunostimulant-treated patients,
      • Cohen H.A.
      • Varsano I.
      • Kahan E.
      • Sarrell E.M.
      • Uziel Y.
      Effectiveness of an herbal preparation containing echinacea, propolis, and vitamin C in preventing respiratory tract infections in children: a randomized, double-blind, placebo-controlled, multicenter study.
      as indicated in Table 1.
      A total of 52 studies were excluded: 50 failed to meet the selection criteria, and 2 compared several immunostimulant treatments without a placebo group (see Table 2).
      Table 2Excluded studies the meta-analysis
      Author, yearReasons for their exclusion
      Almeida, 1999Participants with asthma were included
      Banovcin, 1992The trial was not double-blind or placebo-controlled
      Barr, 1965Trial with asthmatic children
      Barrett, 2010Children and adults were included
      Braido 2014Clinical trial with adults
      Carlone, 2014Clinical trial with adults
      Colombo, 2014Not a placebo-controlled trial
      Das, 2000Participants' ages were not specified
      Doody-Oppikofer, 1998The study examined only the acute phase of infection
      Erman, 2009A poorly defined homeopathic treatment
      Fintelmann, 2012Clinical trial with adults
      Fontana, 1965Clinical trial with children and adults
      Graubaum, 2012Clinical trial with adults
      Grimfeld, 2004An antihistamine was used in the trial
      Grimm, 1999Children and adults were not separated in the results
      Heinz, 2010Clinical trial with adults
      Herrera-Basto, 1998Researchers compared the effect of pidotimod only during the acute phase of ARTI
      Jawad, 2012Clinical trial with adults
      Jesenak, 2013Trials comparing vitamin C with placebo
      Kondrat'eva, 2009A poorly defined homeopathic treatment
      Kozhukharova, 1987The trial was not double-blind or placebo-controlled
      Kudin, 2009A poorly defined homeopathic treatment
      Lauriello, 1990Researchers compared the effect of the intervention only during the acute phase of ARTI
      Lee, 2012Clinical trial with adults
      Licari, 2014The trial was not double-blind or placebo-controlled
      Luchikhin, 2000The trial was not double-blind or placebo-controlled
      Ma, 1994The trial was not double-blind or placebo-controlled
      Macchi, 2005Clinical trial with adults
      Makovetskaya, 2001The trial was not double-blind or placebo-controlled
      Mohammadi, 2014Not a placebo-controlled trial
      Mora, 2010bA trial without the prevention approach for acute respiratory tract infections
      Mueller, 1969Participants with asthma were included
      Namazova-Baranova, 2015Not a placebo-controlled trial
      Nespoli, 1992Not a placebo-controlled trial
      Obrosova-Serova, 1972The trial was not double-blind or placebo-controlled
      Oggiano, 1985Open trial with children
      Oldini, 1990Children and adults were not separated in the results
      Ortega del Alamo, 2005Researchers compared the effect of the intervention only during the acute phase of ARTI
      Predy, 2005Clinical trial with adults
      Prusek, 1987Not a placebo-controlled trial
      Razi, 2010Participants with asthma were included
      Rosaschino, 2004Open trial
      Rossi, 2004Clinical trial with adults
      Ruah, 2001Not a placebo-controlled trial
      Rytel, 1974Clinical trial with adults
      Scotti, 1987Not a placebo-controlled trial
      Sly PD, 2019Only related to lower respiratory tract infections.
      Steinsbekk, 2005A poorly defined homeopathic treatment
      Tiralongo, 2012Clinical trial with adults
      Vascotto, 1985Not a placebo-controlled trial
      Yale, 2004Clinical trial with adults
      Zagólski, 2015Not a placebo-controlled trial

      Risk of bias in included studies

      In 32 studies, bias risks were unclear in all domains. Allocation bias (selection bias) was low in 7 studies;
      • Del-Río-Navarro B.E.
      • Luis Sienra-Monge J.J.
      • Berber A.
      • Torres-Alcántara S.
      • Avila-Castañón L.
      • Gómez-Barreto D.
      Use of OM-85 BV in children suffering from recurrent respiratory tract infections and subnormal IgG subclass levels.
      ,
      • Gutiérrez-Tarango M.D.
      • Berber A.
      Safety and efficacy of two courses of OM-85 BV in the prevention of respiratory tract infections in children during 12 months.
      ,
      • Jara-Pérez J.V.
      • Berber A.
      Primary prevention of acute respiratory tract infections in children using a bacterial immunostimulant: a double-masked, placebo-controlled clinical trial.
      ,
      • Collet J.P.
      • Ducruet T.
      • Kramer M.S.
      • et al.
      Stimulation of nonspecific immunity to reduce the risk of recurrent infections in children attending day-care centers. The Epicrèche Research Group.
      ,
      • Taylor J.A.
      • Weber W.
      • Standish L.
      • et al.
      Efficacy and safety of echinacea in treating upper respiratory tract infections in children: a randomized controlled trial.
      ,
      • Cohen H.A.
      • Varsano I.
      • Kahan E.
      • Sarrell E.M.
      • Uziel Y.
      Effectiveness of an herbal preparation containing echinacea, propolis, and vitamin C in preventing respiratory tract infections in children: a randomized, double-blind, placebo-controlled, multicenter study.
      ,
      • Mameli C.
      • Pasinato A.
      • Picca M.
      • et al.
      Pidotimod for the prevention of acute respiratory infections in healthy children entering into daycare: a double blind randomized placebo-controlled study.
      blinding bias (performance bias and detection bias) was low in 8 studies;
      • Del-Río-Navarro B.E.
      • Luis Sienra-Monge J.J.
      • Berber A.
      • Torres-Alcántara S.
      • Avila-Castañón L.
      • Gómez-Barreto D.
      Use of OM-85 BV in children suffering from recurrent respiratory tract infections and subnormal IgG subclass levels.
      • Gómez Barreto D.
      • De la Torre C.
      • Alvarez A.
      • Faure A.
      • Berber A.
      Seguridad y eficacia de OM-85-BV más amoxicilina/clavulanato en el tratamiento de la sinusitis subaguda y prevención de infecciones recurrentes en niños [Safety and efficacy of OM-85-BV plus amoxicillin/clavulanate in the treatment of subacute sinusitis and the prevention of recurrent infections in children].
      • Gutiérrez-Tarango M.D.
      • Berber A.
      Safety and efficacy of two courses of OM-85 BV in the prevention of respiratory tract infections in children during 12 months.
      • Jara-Pérez J.V.
      • Berber A.
      Primary prevention of acute respiratory tract infections in children using a bacterial immunostimulant: a double-masked, placebo-controlled clinical trial.
      ,
      • Collet J.P.
      • Ducruet T.
      • Kramer M.S.
      • et al.
      Stimulation of nonspecific immunity to reduce the risk of recurrent infections in children attending day-care centers. The Epicrèche Research Group.
      ,
      • Taylor J.A.
      • Weber W.
      • Standish L.
      • et al.
      Efficacy and safety of echinacea in treating upper respiratory tract infections in children: a randomized controlled trial.
      ,
      • Cohen H.A.
      • Varsano I.
      • Kahan E.
      • Sarrell E.M.
      • Uziel Y.
      Effectiveness of an herbal preparation containing echinacea, propolis, and vitamin C in preventing respiratory tract infections in children: a randomized, double-blind, placebo-controlled, multicenter study.
      ,
      • Mameli C.
      • Pasinato A.
      • Picca M.
      • et al.
      Pidotimod for the prevention of acute respiratory infections in healthy children entering into daycare: a double blind randomized placebo-controlled study.
      incomplete outcome bias (attrition bias) was low in 5 studies;
      • Del-Río-Navarro B.E.
      • Luis Sienra-Monge J.J.
      • Berber A.
      • Torres-Alcántara S.
      • Avila-Castañón L.
      • Gómez-Barreto D.
      Use of OM-85 BV in children suffering from recurrent respiratory tract infections and subnormal IgG subclass levels.
      ,
      • Gutiérrez-Tarango M.D.
      • Berber A.
      Safety and efficacy of two courses of OM-85 BV in the prevention of respiratory tract infections in children during 12 months.
      ,
      • Jara-Pérez J.V.
      • Berber A.
      Primary prevention of acute respiratory tract infections in children using a bacterial immunostimulant: a double-masked, placebo-controlled clinical trial.
      ,
      • Cohen H.A.
      • Varsano I.
      • Kahan E.
      • Sarrell E.M.
      • Uziel Y.
      Effectiveness of an herbal preparation containing echinacea, propolis, and vitamin C in preventing respiratory tract infections in children: a randomized, double-blind, placebo-controlled, multicenter study.
      ,
      • Taylor J.A.
      • Weber W.
      • Standish L.
      • et al.
      Efficacy and safety of echinacea in treating upper respiratory tract infections in children: a randomized controlled trial.
      and selective reporting (reporting bias) was low in 3 studies.
      • Del-Río-Navarro B.E.
      • Luis Sienra-Monge J.J.
      • Berber A.
      • Torres-Alcántara S.
      • Avila-Castañón L.
      • Gómez-Barreto D.
      Use of OM-85 BV in children suffering from recurrent respiratory tract infections and subnormal IgG subclass levels.
      ,
      • Gutiérrez-Tarango M.D.
      • Berber A.
      Safety and efficacy of two courses of OM-85 BV in the prevention of respiratory tract infections in children during 12 months.
      ,
      • Cohen H.A.
      • Varsano I.
      • Kahan E.
      • Sarrell E.M.
      • Uziel Y.
      Effectiveness of an herbal preparation containing echinacea, propolis, and vitamin C in preventing respiratory tract infections in children: a randomized, double-blind, placebo-controlled, multicenter study.
      (See Fig. 2 and Supplementary material 3a,3b).
      Fig. 2
      Fig. 2Summary of risk of bias in included studies according to GRADE

      Primary outcome

      As the primary outcome of the study was the number of ARTIs in children during the study period, comparing the use of immunostimulants with placebos showed to reduce the number of ARTIs with a mean difference (MD) of −1.12, 95% confidence interval (95%CI) −0.85, −1.39), see Fig. 3. The corresponding heterogeneity was I2 = 94%, Tau
      • Hsu H.E.
      • Shutt K.A.
      • Moore M.R.
      • et al.
      Effect of pneumococcal conjugate vaccine on pneumococcal meningitis.
       = 0.55; Chi
      • Hsu H.E.
      • Shutt K.A.
      • Moore M.R.
      • et al.
      Effect of pneumococcal conjugate vaccine on pneumococcal meningitis.
       = 617.59 and df = 37 (p < 0.00001). GRADE certainty of evidence (CoE) was moderate, but it was downgraded to low due to high bias and heterogeneity, so the quality of evidence was lower than expected. In addition, most studies failed to accurately report the incidence of adverse events. This led to an inadequate understanding of the safety profile of the intervention. See Table 3.
      Fig. 3
      Fig. 3Mean difference of ARFs between the use of immunostimulants compared to placebo. Measures of heterogeneity (Tau2 and I2 statistics) and prediction intervals are also presented for the 38 studies analysis
      Table 3Certainty of the evidence in the GRADE assessment of the effect of immunostimulant compared with placebo for preventing respiratory tract infection in children by the number of ARTIs, SD and incidence of adverse events.
      Patient or population: children aged under 18 years of age susceptible to acute respiratory tract infections from clinics, private practices, hospital departments, schools, orphanages, etc.

      Intervention: Any immunostimulant with a trial period of 3–12 months.

      Comparison: Placebo

      O: Number of ARTIs per treatment group during the study period

      S: Randomized controlled trials

      T: Trials of 3–12 months duration published from January 1965 to January 10, 2022).
      OutcomesIllustrative comparative risks' (95% CI)Number of participants (studies)Quality of the evidence (GRADE)Comments
      Assumed riskCorresponding risk
      PlaceboAny immuno-stimulant
      Number of ARTIsThe range of ARTIs in the control group was 0.64–8.4The mean number of ARTIs in the intervention groups was 1.12 lower (0.85–1.39 lower)4643 (38 studies)⊕⊕⊖⊖ low
      Heterogeneity was from considerable to substantial; the risk of bias was unclear for all the domains in 32 out of 72 trials. The quality of the evidence was downgraded from moderate to low.
      The heterogeneity depends on the number of ARTIs in the control group
      Ratio of Means ARTIsRatio of means was 0.61 (95% CI 0.54, 0.69) corresponding to percentual reductions in ARTIS of 39% (31%–46%).4643 (38 studies)⊕⊕⊖⊖ low
      Heterogeneity was from considerable to substantial; the risk of bias was unclear for all the domains in 32 out of 72 trials. The quality of the evidence was downgraded from moderate to low.
      Incidence of gastrointestinal adverse events198/1276 (15.5%)The odds ratio of adverse events regarding the intervention group was 0.93 (95% CI 0.65 to 1.33)2565 (14 studies)⊕⊖⊖⊖ very low
      Adverse events were reported only in 14 trials implying selective outcome reporting. The quality of the evidence was downgraded from low to very low
      Only 14 trials have a proper report of adverse events
      Incidence of skin adverse events28/1276 (2.2%)The odds ratio of adverse events regarding the intervention group was 1.79 (95% CI 1.11 to 12.90)2565 (14 studies)⊕⊖⊖⊖ very low
      Adverse events were reported only in 14 trials implying selective outcome reporting. The quality of the evidence was downgraded from low to very low
      Only 14 trials have a proper report of adverse events
      ∗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% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
      CI: confidence interval; RR: risk ratio; OR: odds ratio.
      GRADE Working Group grades of evidence.
      High quality: Further research is improbable 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.
      a Heterogeneity was from considerable to substantial; the risk of bias was unclear for all the domains in 32 out of 72 trials. The quality of the evidence was downgraded from moderate to low.
      b Adverse events were reported only in 14 trials implying selective outcome reporting. The quality of the evidence was downgraded from low to very low

      Secondary outcomes

      • 1.
        The ratio of means of ARTIs
      ARTIs ratio mean was 0.61, (95% C,I 0.54–0.69), reflecting a percentual reduction of 39% (95%CI, 31–46) in the number of ARTIs. Heterogeneity: Tau2 = 0.13; Chi2 = 414.90, df = 37 (p = 0.00001) and I2 = 91%. GRADE CoE was moderate, but it was downgraded to low due to high bias and heterogeneity. See Fig. 4.
      • 2.
        The incidence of adverse events
      Fig. 4
      Fig. 4Rate radio of ARFs between the use of immunostimulants compared to placebo. Measures of heterogeneity (Tau2 and I2 statistics) and prediction intervals are also presented for the 38 studies analysis
      In total, 14 studies included in this meta-analysis reported adverse events, setting 2565 participants (1289 in the active treatment groups and 1276 in the placebo groups) for the gastrointestinal adverse events synthesis (nausea, vomiting, abdominal pain, and diarrhea) and 2565 participants (1289 in the active groups and 1276 in the placebo groups) for the skin adverse events synthesis. These were the most frequently reported adverse events (see supplemental material 2, “adverse events section”). The odds ratio for gastrointestinal adverse events was 0.93 (95% CI 0.65, 1.33). Heterogeneity: Tau2 = 0.07; Chi2 = 12.17, df = 9 (p = 0.20) and I2 = 26%. Test of overall effect: Z = 0.39 (p = 0.69) did not reveal a significant difference between groups. The odds ratio for adverse skin events was 1.79 (95% CI 1.11, 2.90). Heterogeneity: Tau2 = 0.00; Chi2 = 3.36, df = 6 (p = 0.76) and I2 = 0%. Test for overall effect: Z = 2.37 (p = 0.02) had a significant difference between groups, with more skin adverse events in the treatment group. GRADE CoE was low, but it was downgraded to very low as a result of inadequate reporting of adverse events in most of the trials.

      Other sub-group analyses

      Several subgroup analyses were realized considering factors that could influence the results:
      • 1.
        It included the data from bacterial immunostimulant studies (excluding the Saracho Weber trial,
        • Saracho-Weber F.
        • Vázquez-Ramos V.
        • Ayala-Barajas C.
        Evaluation of glycoprotein of Klebsiella pneumoniae efficacy in recurrent infections [Evaluación de la eficacia de glucoproteínas de Klebsiella pneumoniae en infecciones recurrentes].
        which was the only trial with more ARTIs in the immunostimulants group than the placebo group, possibly as a result of a clerical error inverting the ARTI incidences). In total, 27 trials were conducted with 2737 children, of whom 1400 received active treatment and 1337 received placebo treatment. ARTIs were reduced by MD -1.22 (95%CI -0.84,-1.60). Heterogeneity: Tau2 = 0.83; Chi2 = 448.97, df = 26 (p < 0.00001) and I2 = 94%. The ratio of means of ARTIs was 0.60 (95%CI 0.51, 0.71). Heterogeneity: Tau2 = 0.15; Chi2 = 280.62, df = 26 (p < 0.00001) and I2 = 91%.
      • 2.
        Data from studies that involved at least 40 children and used bacterial immunostimulants (excluding the Saracho-Weber trial
        • Saracho-Weber F.
        • Vázquez-Ramos V.
        • Ayala-Barajas C.
        Evaluation of glycoprotein of Klebsiella pneumoniae efficacy in recurrent infections [Evaluación de la eficacia de glucoproteínas de Klebsiella pneumoniae en infecciones recurrentes].
        ). Twenty-two trials were conducted, involving 2592 children, with 1328 receiving immunostimulants and 1264 receiving placebo. The reduction in the total number of ARTIs was MD –1.19 (95% CI –0.77, −1.61). Heterogeneity: Tau2 = 0.83; Chi2 = 390.02, df = 21 (p < 0.00001); I2 = 95%. The ratio of means of ARTIs was 0.64 (95% CI 0.54, 0.75). Heterogeneity: Tau2 = 0.14; Chi2 = 225.36, df = 21 (p < 0.00001) and I2 = 91%.
      • 3.
        Data from bacterial immunostimulants D53 and OM85 studies conducted with at least 40 children. There were 19 trials with 2394 participants, 1230 of whom received immunostimulants and 1164 took placebo. The reduction in the total number of ARTIs was MD –0.94 (95% CI –0.61, −1.28). Heterogeneity: Tau2 = 0.41; Chi2 = 190.38, df = 18 (p < 0.00001) and I2 = 91%. The ratio of means of ARTIs was 0.66 (95% CI 0.57, 0.77). Heterogeneity: Tau2 = 0.10; Chi2 = 146.91, df = 18 (p < 0.00001) and I2 = 88%.

      Sensitivity analyses

      According to the Cochrane Manual:

      Deeks JJ, Higgins JPT, Altman DG. Chapter 9: Analysing data and undertaking meta-analyses. In: Higgins JP, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, Available from handbook.cochrane.org.

      “A sensitivity analysis is a repeat of the primary analysis or meta-analysis, substituting alternative decisions or ranges of values for decisions that were arbitrary or unclear” and “some sensitivity analyses involve restricting the analysis to a subset of the totality of studies.” In addition to the subanalyses, the sensitivity analyses included the reduction in the total number of ARTIs considering the type of immunostimulants (D53, levamisole, OM-85, RU40171 and Thymomodulin), as well as the number of ARTIs in the control group (<2; 2 to <4; ≥4; ≥4 without the outliers) in all the subgroups (type of immunostimulant and the number of infections in the control group). The results for the difference in the mean number of ARTIs were similar, with the 95% CI overlapping (not statistically significant differences), except for the group with less than 2 ARTIs in the control group with lesser size of effect, indicating the robustness of the meta-analysis (see supplementary material 2).

      Discussion

      Products with immunostimulant properties have been reported to activate immune cells with receptors that recognize common bacterial products or to provide additional stimulation to activate them.
      • Alyanakian M.A.
      • Grela F.
      • Aumeunier A.
      • et al.
      Transforming growth factor-beta and natural killer T-cells are involved in the protective effect of a bacterial extract on type 1 diabetes.
      For instance, 2 bacterial lysates have been shown to activate TLR2,
      • Nikolova M.
      • Stankulova D.
      • Taskov H.
      • Nenkov P.
      • Maximov V.
      • Petrunov B.
      Polybacterial immunomodulator Respivax restores the inductive function of innate immunity in patients with recurrent respiratory infections.
      ,
      • Chen L.Y.
      • Lin Y.L.
      • Chiang B.L.
      Levamisole enhances immune response by affecting the activation and maturation of human monocyte-derived dendritic cells.
      and levamisole may do the same.
      • Luan H.
      • Zhang Q.
      • Wang L.
      • et al.
      OM85-BV induced the productions of IL-1β, IL-6, and TNF-α via TLR4- and TLR2-mediated ERK1/2/NF-κB pathway in RAW264.7 cells.
      In another study, OM-85 induced interleukin-1beta, IL-6, and tumor necrosis factor alpha (TNF-α) in murine macrophages by activating TLR4 and TLR2 via the ERK1/2/NF kappa B pathway.
      • Luan H.
      • Zhang Q.
      • Wang L.
      • et al.
      OM85-BV induced the productions of IL-1β, IL-6, and TNF-α via TLR4- and TLR2-mediated ERK1/2/NF-κB pathway in RAW264.7 cells.
      Recent research suggests that OM-85 induces proIL-1 beta and proIL-1 alpha levels in bone marrow-derived dendritic cells without activating the inflammasome.
      • Dang A.T.
      • Pasquali C.
      • Ludigs K.
      • Guarda G.
      OM-85 is an immunomodulator of interferon-β production and inflammasome activity.
      On the other hand, the activation of the PI3K/Akt signaling pathway via the CXC Chemokine Receptor 3A (CXCR3A) isoform receptor is required for the adhesion and chemotaxis of monocytes induced by pidotimod, as well as the migration of activated T cells induced by IL-2.
      • Caccuri F.
      • Bugatti A.
      • Corbellini S.
      • et al.
      The synthetic dipeptide pidotimod shows a chemokine-like activity through CXC chemokine receptor 3 (CXCR3).

      Summary of main results

      A relatively small number of papers met the standards for methodological quality and clinical trial reporting and the majority deviated significantly from these standards. Additionally, many of the trial publications lacked clarity, reducing the quality of the information.
      Based on the current review, immunostimulants may be able to prevent ARTI. To establish the actual effects of immunostimulants and the effects of individual immunostimulant preparations, more extensive clinical trials should be conducted, with adequate power for important population groups and sponsored by health authorities.

      Overall completeness and applicability of evidence

      It is possible that some studies with negative results have not been published due to the positive outcome results bias.
      • Del-Rio-Navarro B.E.
      • Espinosa Rosales F.
      • Flenady V.
      • Sienra-Monge J.J.
      Immunostimulants for preventing respiratory tract infection in children.
      In addition, the risk of bias is unclear for 32 studies in all domains, 34 studies had high risks for reporting bias, and 8 studies had low risks in some bias domains (see supplementary material 4).

      Quality of the evidence

      In 32 out of 72 trials, the risk of bias was unclear for all domains. The quality of the evidence for the safety of the intervention has been downgraded from low to very low because adverse events were reported in only 14 trials, suggesting selective reporting. This is summarized in Table 3.

      Agreements and disagreements with other studies or reviews

      This study supports a prior meta-analysis of the effects of immunostimulants, in which a percent decline in ARTIs was measured at 42.64% (95%IC, −40.08, −45.19).
      • Berber A.
      • Del-Rio-Navarro B.
      Compilation and meta-analysis of randomized placebo-controlled clinical trials on the prevention of respiratory tract infections in children using immunostimulants.
      In a review of D53's effectiveness in reducing the incidence of ARTIs among children, it was also found to decrease ENT bronchopulmonary infections by 32%–61% in comparison to a placebo,
      • Haguernauer J.P.
      Prevention of the ENT repeating infectious episodes by D53 tablets in children of less than 5 years [Prévention des épisodes infectieux récidivants de la sphére ORL par D53 comimés chez lénfant de moins de 5 ans].
      which is consistent with the effect of D53 shown in this review.
      Another meta-analysis of individual immunostimulants reports an ARTIs reduction of −31.86% (95%CI, −29.40, −34.32) for D53, and a corresponding reduction of −39.28% (95%CI, −25.98, −52.58) for OM-85.
      • de la Torre González C.
      • Pacheco Ríos A.
      • Escalante Domínguez A.J.
      • del Río Navarro B.E.
      Metaanálisis comparativo de los inmunoestimulantes utilizados en pediatría en México [Comparative meta-analysis of immunoestimulant agents used in pediatric patients in Mexico].
      Both CIs are in agreement with those in this study. Based on one meta-analysis,
      • de la Torre González C.
      • Pacheco Ríos A.
      • Escalante Domínguez A.J.
      • del Río Navarro B.E.
      Metaanálisis comparativo de los inmunoestimulantes utilizados en pediatría en México [Comparative meta-analysis of immunoestimulant agents used in pediatric patients in Mexico].
      32% of the OM-85 treated patients experienced three or more ARTIs in 6 months, compared to 58.2% of the placebo-treated patients. With OM-85, the reduction was −1.21 (95%CI, −1.03, −1.39), similar to those found in this study.
      This review's findings disagree with those published by Steurer-Stey,
      • Steurer-Stey C.
      • Lagler L.
      • Straub D.A.
      • Steurer J.
      • Bachmann L.M.
      Oral purified bacterial extracts in acute respiratory tract infections in childhood: a systematic quantitative review.
      who pooled two OM-85 studies to calculate the risk of fewer than 3 infections over 6 months of follow-up in children not in daycare (risk ratio = 0.82 [95%CI, 0.65,1.02]).
      In another meta-analysis, a single polyvalent mechanical bacterial lysate was examined. Multiple non-placebo studies in different age groups and indications were combined in this study. According to the results of a sub-analysis in three studies, which included 193 treated children and 153 untreated children, the ARTI rate was reduced by 2.2 (CI 95% 3.3 to 1.1).
      • Cazzola M.
      • Anapurapu S.
      • Page C.P.
      Polyvalent mechanical bacterial lysate for the prevention of recurrent respiratory infections: a meta-analysis.
      This is consistent with the findings of this study.
      An extensive review of the efficacy and safety of OM-85 in children included both placebo-controlled studies published internationally, and uncontrolled studies conducted in China. The study found a reduction in ARTIs of −2.33 (95%CI –1.90, −2.75), P = 0.00001. Despite the fact that efficacy was greater in this study, adverse event rates were higher (RR 1.39 [95%CI 1.02, 1.88]; P = 0.04).
      • Yin J.
      • Xu B.
      • Zeng X.
      • Shen K.
      Broncho-Vaxom in pediatric recurrent respiratory tract infections: a systematic review and meta-analysis.
      In China, a systematic review of pidotimod in children, including placebo and non-placebo-controlled trials, was conducted. In the review, 24 studies were considered; 1912 patients were assigned to the pidotimod group, and 1848 patients were assigned to the conventional treatment group. The outcome was the proportion of children experiencing a relapse of ARTIs with a score of 0, 1, or 2. The proportion of participants who took pidotimod had fewer infections; the relative risk was 1.59, (95%CI, 1.45–1.74), I2 = 51%, p = 0.00001 compared to those who took conventional treatment. It is not possible to compare these efficacy findings with those of other meta-analyses. Pidotimod did not appear to increase the risk of adverse events statistically significantly.
      • Niu H.
      • Wang R.
      • Jia Y.T.
      • Cai Y.
      Pidotimod, an immunostimulant in pediatric recurrent respiratory tract infections: a meta-analysis of randomized controlled trials.

      Limitations

      Using the most relevant databases, we identified and selected all potentially relevant references to other studies. We also examined articles citing all identified studies. Additionally, authors and manufacturers were contacted (see previous version of this review Del-Rio-Navarro 2012).
      • Del-Rio-Navarro B.
      • Becerril-Ngeles M.
      • Berber A.
      Eficacia del inmunoestimulante OM-BV85 en la prevención de infecciones respiratorias [Efficacy of the immunoestimulant OM-BV85 in the prevention of respiratory infections].
      However, this review has limitations because of the information quality, heterogeneity, and the possibility of publication bias.
      We may have missed some studies because they were never published, published in obscure locations, rarely cited, or incorrectly indexed in databases. The publication bias of neutral, negative, uninteresting, or unwanted results in studies sponsored by pharmaceutical companies must be taken into account.
      Although most of the studies (with ARTI as mean and dispersion) were integrated into the meta-analysis, other studies reporting different results were not included.

      Authors' conclusions

      According to this review, immunostimulants reduce the incidence of ARTIs by 40% on average among susceptible children. Trial studies have shown the benefits of immunostimulants in toddlers (2–5 years of age), schoolchildren (6–12 years of age), and children with high incidences of ARTIs, such as those in daycare centers or orphanages. A further high-quality trial is required to confirm the true effect of immunostimulants and individual immunostimulant preparations on the prevention of ARTIs. We encourage national health authorities to conduct large, multicenter, double-blinded, placebo-controlled studies to establish the precise benefits and risks of using immunostimulants to prevent ARTIs.

      Abbreviations

      ARTIs, acute respiratory tract infections; RCTs, randomized controlled trials; CI, confidence intervals; SD, standard deviation; MD, mean difference.

      Acknowledgments

      We would like to acknowledge especially the outstanding editorial work of Liz Dooley and Vicki Flenady. Vicki Flenady was a co-author of earlier versions of this systematic review and San Francisco Edit (https://www.sfedit.net/) edited and proofread it. Finally, we wish to thank Axel Arturo Berber-Del-Rio for proofreading the last version of the manuscript.

      Funding

      No financial support for this work that could have influenced its outcome.

      Availability of data and materials

      The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

      Contributors’ statement page

      Arturo Berber and Blanca Estela Del-Rio-Navarro: wrote the protocol, conducted the bibliographical search, extracted data for meta-analyses, realize the statistical analyses, and prepared the first draft, and final manuscript. She is the corresponding author.
      Nayely Reyes-Noriega: drafted and revised the final version of the systematic review. She also contributed to the development of the graphics and supplementary information of this revision, as well as the interpretation of the results of the meta-analysis, subanalysis, and sensitivity analysis.
      Juan José Luis Sienra-Monge: reviewed the protocol, conducted the bibliographical search, extracted data for meta-analyses and reviewed the final manuscript.
      All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

      Ethics approval and consent to participate

      The authors declare that all procedures were carried out in accordance with the ethical standards of the institutional committee on human investigation, the World Medical Association, and the Helsinki Declaration. Ethics committee review and patient consent were not required, as this was an investigation of the literature.

      Consent for publication

      All authors consent this article for publication.

      Declaration of competing interest

      The authors declare that they have no conflict of interest in relation to the methods or materials employed in this study.

      Cochrane registration

      Appendix A. Supplementary data

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