Authors' objectives

To compile and to perform a meta-analysis of the findings of randomised, placebo-controlled trials on the prevention of acute respiratory tract infections (ARTIs) in children, using immunostimulants.

Searching

The authors state that they searched for all the references of immunostimulants in the Mexican market (listed in the 'Specific Interventions' field), as they included the most popular and best-selling products worldwide and as they are also registered in Europe and South America.

MEDLINE and EMBASE were searched from 1960 to July 2000 for references containing the trade names, or the codes, of immunostimulants in any search field. In addition, references containing the terms 'bacterial lysates' or 'Klebsiella glycoprotein' and 'infection' were also checked. Additional references on immunostimulants were obtained from the special register of the Cochrane Acute Respiratory Infections Group. Papers in English, Spanish, French, Italian and German were included.

Study selection

Assessment of study quality

The quality of the papers was assessed according to the instrument of Jadad et al. (see Other Publications of Related Interest). The authors do not state who performed the quality assessment.

Data extraction

The authors do not state how the data were extracted for the review, or how many of the reviewers performed the data extraction.

Data were abstracted on the number of ARTIs during the study period; if these were unavailable, then data were abstracted on the total number of ARTIs during the follow-up period, or on the monthly ARTIs. The authors state that they preferred databases with the number of ARTIs from trials they had participated in or reconstructed databases from published data. If this was not possible, data were extracted on the mean ARTI (plus or minus the standard deviation, SD); failing this, the percentage of patients suffering certain frequencies of ARTIs (e.g. the number of patients without infection), the raw total number of infections per group, and the clinical scores or other measures (e.g. days suffering from a purulent rhinorrhoea) were used. Data were also extracted on the participants' ages and dose schedules.

Methods of synthesis

Results of the review

A total of 27 RCTs were included in the review. There were 2 studies (n=396) of LW 50020, 9 studies (n=1,184) of OM-85 BV, 6 studies (n=1,597) of pidotimod, 4 studies (n=235) of RU41740, 2 studies (n=184) of Ribomunyl, and 4 studies (n=168) of thymomodulin. Only 16 studies (n=1,908) reporting the mean (plus or minus SD) and/or dispersion were analysed.

Four of the 5 RCTs with a Jadad score of greater than 3 showed a significant reduction of ARTIs in immunostimulant groups. When only those trials reporting the mean plus or minus SDs and/or dispersion were included (n=16), the global weighted percentage effect of immunostimulants showed a change of -42.64% (95% confidence interval: -45.19, -40.08); the intervention group presented approximately 60% of the mean number of ARTIs in the placebo group.

Authors' conclusions

Immunostimulants are an effective treatment for the prevention of ARTIs.

CRD commentary

The review question was clear. The study selection criteria were stated clearly, although later in the data extraction and presentation of results sections, it was unclear which studies were actually included in the analysis. The literature search was reasonably comprehensive, with the reviewers checking the Cochrane Acute Respiratory Infection Group for references, although the restriction of electronic searches to MEDLINE and EMBASE may have resulted in some studies being missed. Similarly, the authors state that only medications registered in Mexico were included in the search, which may have meant that those not registered in Mexico were missed. However, language restrictions were not applied, and the dates for the searches were unrestricted. The authors provided no information on the methodology of the review, validation and the data extraction processes.

The statistical tests employed seem to have been appropriate for the analysis carried out. There was ample graphical presentation of these tests and the results were provided. However, as noted already, preference was clearly given to some studies in the analysis, despite the original stated inclusion criteria; this resulted in only 16 of the original 27 included studies, or the 5 RCTs with Jadad scores of greater than 3, being included for global analysis.

The authors' conclusions seem appropriate in the light of the findings of their meta-analysis, but since 11 studies originally to be included in the analysis were later excluded from the final global calculations owing to insufficient data, it is not possible to know how these would have altered the overall findings. Also, the methodological limitations noted by the review's authors (only 5 of the 27 trials scored more than 3 on the Jadad scale) would indicate that their conclusions should probably be more cautious. There is a possible conflict of interest in that one of the study's authors was the medical manager for OM-85 BV in Mexico between 1995 and 2000, and the study was sponsored by Quimica Knoll de Mexico, BASF Pharma who market OM-85 BV in Mexico.

Implications of the review for practice and research

Practice: The authors state that the use of immunostimulants for the prevention of ARTIs should be limited to children with proven high susceptibility, or to overexposed children attending day care centres, in orphanages, or entering kindergarten or elementary school.

Research: The authors state that further high-quality RCTs are required to confirm the effect and the size of effect of each individual immunostimulant.

Funding

Quimica Knol de Mexico, BASF Pharma.

Bibliographic details

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. Journal of Investigational Allergology and Clinical Immunology 2001; 11(4): 235-246. [PubMed: 11908811]

Other publications of related interest

Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1-12.

Indexing Status

Subject indexing assigned by NLM

MeSH

Adjuvants, Immunologic /therapeutic use; Adolescent; Child; Child, Preschool; Humans; Randomized Controlled Trials as Topic; Respiratory Tract Infections /prevention & control

AccessionNumber

12002000708

Database entry date

28/02/2003

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.