Immunostimulating agents for the prevention of acute otitis media (Protocol)

Rowe CE, Felber SA, Muttiah CK, van Driel ML, Del Mar CB

This is a reprint of a Cochrane protocol, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2011, Issue 7 http://www.thecochranelibrary.com

Immunostimulating agents for the prevention of acute otitis media (Protocol) Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. TABLE OF CONTENTS HEADER...... 1 ABSTRACT ...... 1 BACKGROUND ...... 2 OBJECTIVES ...... 2 METHODS ...... 3 ACKNOWLEDGEMENTS ...... 5 REFERENCES ...... 5 WHAT’SNEW...... 6 HISTORY...... 6 CONTRIBUTIONSOFAUTHORS ...... 7 DECLARATIONSOFINTEREST ...... 7 SOURCESOFSUPPORT ...... 7 NOTES...... 7

Immunostimulating agents for the prevention of acute otitis media (Protocol) i Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. [Intervention Protocol] Immunostimulating agents for the prevention of acute otitis media

Catherine E Rowe1, Saul A Felber1, Christine K Muttiah1, Mieke L van Driel1,2, Chris B Del Mar1

1Faculty of Health Sciences and Medicine, Bond University, Gold Coast, Australia. 2Department of General Practice and Primary Health Care, Ghent University, Ghent, Belgium

Contact address: Catherine E Rowe, Faculty of Health Sciences and Medicine, Bond University, University Drive, Robina, Gold Coast, Queensland, 4229, Australia. [email protected].

Editorial group: Cochrane Acute Respiratory Infections Group. Publication status and date: Amended to reflect a change in scope (see ’What’s new’), published in Issue 7, 2011.

Citation: Rowe CE, Felber SA, Muttiah CK, van Driel ML, Del Mar CB. Immunostimulating agents for the prevention of acute otitis media. Cochrane Database of Systematic Reviews 2011, Issue 7. Art. No.: CD004880. DOI: 10.1002/14651858.CD004880.pub3.

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the effectiveness of immunostimulants or ’biological response modifiers’, agents that stimulate a non-specific immune response (listed below) to prevent AOM in children.

Immunostimulating agents for the prevention of acute otitis media (Protocol) 1 Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. BACKGROUND sponse involving IgA when lyophilised bacterial extracts of Kleb- siella as well as other pathogens are presented directly to the up- per respiratory and gastrointestinal mucosae. Other immunos- Description of the condition timulants (for example, pidotimod) may stimulate a neutrophil/ Acute otitis media (AOM) is inflammation of the middle ear, the macrophage response. The recurrent nature and serious long-term space directly behind the ear drum. It is clinically characterised by effects from AOM outweigh the risks associated with the use of a sudden painful onset and illness lasting one to 10 days. By the immunoglobulins so it would seem appropriate to administer im- age of two, approximately half of all children will have had their munoglobulins to all individuals rather than only those at risk of first ear infection and more than 80% by the age of three (Kvaerner AOM. 1997; Teele 1989). The chances of subsequent ear infections are high: 5% of all children suffer six or more recorded episodes and 10% meet the definition or recurrent AOM, i.e. three episodes Why it is important to do this review of AOM within six months, or four episodes within one year Antibiotics have been the traditional first-line treatment for AOM (Ingvarsson 1990; Pichichero 2000). The prevalence of recurrent and currently are the most common reason for antibiotics to be otitis media may be increasing (Hoberman 2002). prescribed in children (Nelson 1987). However, they show only AOM is defined in this review pragmatically: when the primary modest benefits (Rosenfeld 2000; Sanders 2010) from the use of care clinician makes the diagnosis of AOM after eliciting sudden antibiotics and one of the most significant features of pain asso- onset of illness with fever and/or earache, with signs of middle ciated with AOM was not improved by use of antibiotics. They ear effusion and inflammation. In children too young to verbalise have significant disadvantages when prescribed for the recurrent any symptoms, AOM is likely to present with an irritable, lethar- otitis media (Little 2001). Antibiotic resistance to Streptococcus gic, anorexic child. Prevention of attacks of AOM is defined as pneumoniae (S. pneumoniae), which is the most common bacte- preventing any new or subsequent episode four weeks after a pri- rial ear pathogen, is emerging because of frequent and prolonged mary or index episode. We will exclude other diagnostic groups, community prescribing of antibiotics. including chronic suppurative otitis media and cholesteatoma (a Preventive approaches fall into medical and surgical categories, benign growth of skin in an abnormal location such as middle ear, with the former dividing into vaccine and non-vaccine approaches. where it can cause dangerous destruction of tissue) and children at The use of pneumococcal vaccine in recurrent otitis media is the special risk from AOM due to cleft palate and immune deficiency topic of another Cochrane Review (Jansen 2009). A range of other syndromes. vaccines is also being developed (Klein 2001). It is unclear whether the use of such vaccines is justified, with current vaccination sched- ules for infants and young children already well subscribed and Description of the intervention delineated. Surgery is also being evaluated for recurrent AOM and the related condition of otitis media with effusion (OME), a This review evaluates immunostimulants (also called ’biological condition characterised by inflammation and liquid in the middle response modifiers’). These are agents that stimulate a non-specific ear, but in which the signs and symptoms of acute infection are immune response, with the result that the body generates a gen- absent. It is thought these two conditions may be aetiologically eral immune response to defend the body against the pathogens linked, particularly in younger children. The Cochrane Review on responsible for AOM. As with conventional vaccines, immunos- grommets for OME excluded recurrent AOM cases (Lous 2004), timulants would need to be given many times, as opposed to only but another review for preventing recurrent AOM with grommets needing one dose to ensure continuing stimulation of the immune includes both AOM and OME cases (Rosenfeld 1994). system. They include a wide range of oral or intranasally admin- Immunostimulants have been investigated in their role of signifi- istered vaccines and adjuvants, such as bacterial extracts (for ex- cantly reducing the occurrence of acute respiratory tract infections ample, ribomunyl and OM-85 BV), synthetic chemicals (for ex- in children by 40%. Although their mechanism of action is not ample, pidotimod) and others (for example, those documented in entirely clear, it is likely that their mechanism would also be of the protege -2000 Class Immunostimulant list, Project NCI On- benefit in AOM as similar pathogens and defence mechanisms are cology http://www.mindswap.org/2003/CancerOncology/ involved (Del Rio 2006). htmhttp://www.mindswap.org/2003/CancerOncology/htmls/ Immunistimulant.htmlls/Immunistimulant.html).

OBJECTIVES How the intervention might work To assess the effectiveness of immunostimulants or ’biological re- The possible mechanisms of action for immunostimulants are di- sponse modifiers’, agents that stimulate a non-specific immune verse. One example would be the production of an immune re- response (listed below) to prevent AOM in children.

Immunostimulating agents for the prevention of acute otitis media (Protocol) 2 Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. METHODS 5. Incidence of hearing loss. 6. Subsequent episodes of OME. 7. Other respiratory infections, for example, upper respiratory Criteria for considering studies for this review tract infections (URTI), coryza, rhinitis, sinusitis, sore throat/ tonsillitis, lower respiratory tract infections (LRTI). 8. Days off school (if appropriate) Types of studies 9. Time off work for carers looking after the affected child. Randomised controlled trials (RCTs) of immunostimulating 10. Timing to outcomes will include short (up to one month), agents to prevent AOM in children that incorporate defined intermediate (three to six months) and long-term (six to 12 episodes of AOM as an outcome. Randomised, double-blind trials months) outcomes and will be followed up one year after with an untreated or placebo-controlled arm will be eligible. We randomisation. will exclude crossover studies. 11. Cost of the immunostimulating agent.

Types of participants Search methods for identification of studies We will include children aged over six months to 16 years in any healthcare setting (for example, primary or secondary care populations). We will exclude children under six months of age, as Electronic searches they have not fully developed their immune system, are considered to be in an immunocompromised state and have a higher frequency We will search The Cochrane Library, Cochrane Central Register of secondary complications. We will exclude individuals of any age of Controlled Trials (CENTRAL latest issue), which contains the on oral corticosteroids or with a documented immune deficiency, Cochrane Acute Respiratory Infections Group’s Specialised Reg- as they are also immunocompromised. ister, MEDLINE (January 1966 to present), EMBASE (January 1990 to present), LILACS (1985 to present) and Current Con- tents (1985 to present). Types of interventions We will use the following search strategy to search MEDLINE Immunostimulanting agents that stimulate a non-specific immune and CENTRAL. We will combine the MEDLINE search with response. They include a wide range of oral or intranasally ad- the Cochrane Highly Sensitive Search Strategy for identifying ran- ministered vaccines and adjuvants, such as bacterial extracts (for domized trials in MEDLINE (Lefebvre 2011). We will adapt the example, ribomunyl and OM-85 BV), synthetic chemicals (for search strategy to search EMBASE, LILACS and Current Con- example, pidotimod), and others (for example, those documented tents. in the protege -2000 Class Immunostimulant list, Project NCI 1 exp Otitis Media/ Oncology http://www.mindswap.org/2003/CancerOncology/ 2 otitis media.tw. htmhttp://www.mindswap.org/2003/CancerOncology/ 3 (OM or OME or AOM).tw. htmls/Immunistimulant.htmlls/Immunistimulant.html). We will 4 upper respiratory tract infection*.tw. exclude conventional vaccines inducing a specific immune re- 5 upper respiratory infection*.tw. sponse. 6 urti.tw. 7 ((middle ear) adj3 (infect* or inflam*)).tw 8 or/1-7 Types of outcome measures 9 exp Immunologic Factors/ 10 biological response modifier*.tw. Primary outcomes 11 biomodulat*.tw. The number of reported clinical episodes of AOM at one month, 12 immunomodulat*.tw. three to six months and six to 12 months follow-up. 13 immunostimul*.tw. 14 (extract* adj3 bacteria*).tw. 15 Klebsiella pneumoniae/ Secondary outcomes 16 klebsiella*.tw,nm. 1. Days with illness. 17 (om-85bv or om85-bv or om-85-bv).tw,nm. 2. Antibiotic use. 18 (bronchovaxom* or broncho-vaxom*).tw,nm. 3. Number of ear, nose and throat (ENT) specialist referrals. 19 (lw50020 or lw-50020).tw,nm. 4. Side effects and adverse events of therapy, for example, 20 (immocur* or luivac* or bacterial ribosomal extract* or ri- gastrointestinal (GI) side effects including nausea, vomiting, bosomal immunotherap* or ribomunyl* or immucytal* or ribo- diarrhea as well as rashes. vac*).tw,nm.

Immunostimulating agents for the prevention of acute otitis media (Protocol) 3 Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 21 pidotimod*.tw,nm. will obtain the full articles for those selected trials. We will resolve 22 “pgt/1a”.tw,nm. disagreements by consensus or by involving a third review author 23 ams.tw,nm. as arbiter (MLVD). 24 forphenicinol.tw,nm. 25 Thymus Extracts/ Data extraction and management 26 (thymic extract* or thymus extract* or thymomod- ulin*).tw,nm. Two review authors (CR, CM) will independently extract data 27 (agatolimod sodium or alpha galactosylceramide or ammo- from all included trials using a standardised data extraction form. nium trichlorotellurate or anti-cd37 single-chain polypeptide tru- We will contact trial authors to request important missing data. 016 or arginine butyrate or atvogen or avridine or azimexon or bcg solution or bci immune activator or beta alethine or beta-glu- Assessment of risk of bias in included studies can or betulinic acid or bropirimine or carbetimer or cl 246738 Two review authors (SF, MLVD) will assess the risk of bias of the or copovithane or cpg-28 oligodeoxynucleotide or cya 246 or de- included trials. We will use the risk of bias assessment as outlined fensins or dinitrochlorobenzene or diphencyprone or ditiocarb or in the Cochrane Handbook of Systematic Reviews of Interventions etiocholanolone or forfenimex or gm-csf-encoding oncolytic her- (Higgins 2011) and resolve differences by discussion or with a pes simplex virus or histamine dihydrochloride or hyb2055 or third review author as arbiter (CDM). imp321 or imreg-1 or imuvert or inosine pranobex or iss 1018 cpg oligodeoxynucleodide or keyhole limpet hemocyanin or kleb- siella pneumoniae glycoprotein or mgn3 or mifamurtide or mixed Measures of treatment effect bacteria vaccine or muramyl dipeptide or mycobacterial cell wall- We will report dichotomous outcomes as proportions with 95% dna complex or oligofructose-enriched inulin or pgg beta-glucan confidence interval (CI) and continuing variables as means with or pidotimod or poly au or poly ic or poly iclc or polysaccharide- standard deviations. We aim to calculate a pooled estimate of the k or purified protein derivative of tuberculin or roquinimex or treatment effect for each outcome across trials using the odds ratio sinomenine or sivifene or sotrimod or spirogermanium or staphage (OR) when dealing with dichotomous outcome measures. We lysate or synthetic peptide-based erythropoiesis stimulating agent plan to record either mean change from baseline for each group or talactoferin or theramide or thymopentin or thymotrinan or or mean post-intervention values and standard deviation (SD) for tiprotimod or tlr* agonist or tricom or ubenimex or virulizin or each group for continuous outcomes. We will calculate a pooled vitespen).tw,nm. estimate of treatment effect by calculating the mean difference 28 or/9-27 where appropriate. 29 8 and 28

Unit of analysis issues Searching other resources We will use individual participants in the clinical trials as the We will search www.clinicaltrials.gov and other appropriate trials unit of analysis. We will adjust the effect estimates by using the registers. We will contact drug manufacturers and active research methods outlined in the Cochrane Handbook for Systematic Reviews groups, including complementary and alternative medicine man- of Interventions (Higgins 2011) in the case of cluster RCTs, where ufacturers, for details of any published or unpublished trials. We the unit of randomisation is not the same as the unit of analysis. will search abstracts of specialised conferences and scrutinise bibli- ographies of other published systematic reviews and meta-analyses for additional trial references, as well as bibliographies of identified Dealing with missing data trials. We will check all the references cited in articles to identify We will follow recommendations in the Handbook (Higgins 2011) any other relevant or missed articles. There will be no language or regarding strategies for dealing with missing data. We will contact publication restrictions. trial authors to request missing data. We will use an intention- to-treat (ITT) analysis whenever available to account for missing data in the pooled analyses. Data collection and analysis Assessment of heterogeneity We will assess the presence of heterogeneity in two steps. First, we Selection of studies will assess obvious heterogeneity at face value by comparing pop- Two review authors (CR, CM) will obtain the abstracts for all ulations, settings, interventions and outcomes. Second, we will trials identified as eligible from the searches and independently assess statistical heterogeneity by means of the I2 statistic (Higgins assess them to identify which trials meet the inclusion criteria. We 2011). Thresholds for the interpretation of the I2 statistic can be

Immunostimulating agents for the prevention of acute otitis media (Protocol) 4 Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. misleading, since the importance of inconsistency depends on sev- model for calculations of summary estimates (summary weighted eral factors. We plan to use the guide to interpretation as outlined OR and 95% CI for dichotomous outcomes or mean difference in the Handbook (Higgins 2011): 0% to 40%: might not be impor- with SD for continuous outcomes). We will use a random-effects tant; 30% to 60%: may represent moderate heterogeneity; 50% model if heterogeneity is present, as outlined above. We will un- to 90%: may represent substantial heterogeneity; 75% to 100%: dertake ITT analyses. considerable heterogeneity. We will use a fixed-effect model to pool data in the absence of het- Subgroup analysis and investigation of heterogeneity erogeneity (Higgins 2011). We will explore the potential sources of heterogeneity when important heterogeneity is present and either We will perform subgroup analyses on the basis of types of inter- not pool the studies or use a random-effects model (DerSimonian ventions (i.e. type of immunostimulants according to proposed 1986). mechanism of action) and different age groups (younger versus older children).

Assessment of reporting biases Sensitivity analysis We will assess any publication bias by using funnel plots if 10 or more studies have been included. We will use the Trim and Fill We will carry out sensitivity analyses if there are sufficient trials, method to assess the effect of asymmetry on the conclusions when to explore the effect of risk of bias on the review’s conclusions (for asymmetry is present (Sutton 2000). example, adding studies with a high risk of bias to the summary estimates for studies with low risk of bias).

Data synthesis We will include in the meta-analysis the results from studies that meet the inclusion criteria and report any of the selected outcomes. ACKNOWLEDGEMENTS When appropriate, we will perform meta-analyses by pooling trial data. We will extract the numbers reporting an outcome in each We would like to acknowledge Ian Williamson, Chris Del Mar, group in relation to the numbers at risk in each group for categor- Zoe Crosby and Paul Little who were authors of the withdrawn ical data (for example, proportion of participants with cure). We protocol (Williamson 2004). We also thank the following people will extract and pool the mean difference (MD) in each group for for commenting on this draft protocol: Anne Lyddiatt, Renzo continuous variables. As a general rule, we will use a fixed-effect Mora, Alessandro Fiocchi, Max Bulsara and Roger Damoiseaux.

REFERENCES

Additional references Ingvarsson 1990 Ingvarsson L, Lundgren K, Stenstrom C. Occurrence of acute otitis media in children: cohort studies in an urban Del Rio 2006 population. Annals of Otology, Rhinology and Laryngology Del-Rio-Navarro BE, Espinosa-Rosales FJ, Flenady V, 1990;149(Suppl):17–8. Sienra-Monge JJL. Immunostimulants for preventing respiratory tract infection in children. Cochrane Database Jansen 2009 of Systematic Reviews 2006, Issue 4. [DOI: 10.1002/ Jansen AGSC, Hak E, Veenhoven RH, Damoiseaux RAMJ, 14651858.CD004974.pub2] Schilder AGM, Sanders EAM. Pneumococcal conjugate vaccines for preventing otitis media. Cochrane Database DerSimonian 1986 of Systematic Reviews 2009, Issue 2. [DOI: 10.1002/ DerSimonian R, Laird N. Meta-analysis in clinical trials. 14651858.CD001480.pub3] Controlled Clinical Trials 1986;7(3):177–88.

Higgins 2011 Klein 2001 Higgins JPT, Green S (editors). Cochrane Handbook for Klein JO. The burden of otitis media. Vaccine 2001;19 Systematic Reviews of Interventions. Chichester: Wiley- (Suppl 1):52–8. Blackwell, 2011. Kvaerner 1997 Hoberman 2002 Kvaerner KJ, Mair IW. Acute and recurrent otitis media. Hoberman A, Marchant CD, Kaplan SL, Feldman S. Prevention and treatment in the light of current knowledge. Treatment of acute otitis media consensus recommendations. Tidsskrift for den Norske Laege forening 1997;117(28): Clinical Paediatrics 2002;41(6):373–90. 4096–8.

Immunostimulating agents for the prevention of acute otitis media (Protocol) 5 Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Lefebvre 2011 Rosenfeld 1994 Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching Rosenfeld RM, Vertrees JE, Carr J, Cipolle RJ, Uden DL, for studies. In: Higgins JPT, Green S editor(s). Cochrane Giebink GS, et al.Clinical efficacy of antimicrobial drugs Handbook forSystematic Reviews of Interventions Version for acute otitis media:meta analysis of 5400 children from 5.1.0 [updated March 2011]. The Cochrane Collaboration. 33 randomised trials. Journal of Pediatrics 1994;124(3): Available from www.cochrane-handbook.org. Chichester: 355–67. Wiley-Blackwell, 2011. Rosenfeld 2000 Little 2001 Rosenfeld RM. Surgical prevention of otitis media. Vaccine Little P, Gould C, Williamson I, Moore M, Warner G, 2000;19(Suppl 1):134–9. Dunleavey J. Pragmatic randomized controlled trial of two Sanders 2010 prescribing strategies for childhood acute otitis media. BMJ Sanders S, Glasziou PP,Del Mar C, Rovers MM. Antibiotics 2001;322(7282):336–42. for acute otitis media in children. Cochrane Database Lous 2004 of Systematic Reviews 2010, Issue 1. [DOI: 10.1002/ Lous J, Burton M, Felding JU, Ovesen T, Rovers MM, 14651858.CD000219.pub2] Wake M, et al.Grommets (ventilation tubes) for hearing Sutton 2000 loss associated with otitis media with effusion in children. Sutton AJ, Duval SJ, Tweedie RL, Abrams KR, Jones D. Cochrane Database of Systematic Reviews 2004, Issue 1. Empirical assessment of effect of publication bias on meta- [DOI: 10.1002/14651858.CD001801.pub2] analyses. BMJ 2000;320(7249):1574–7. Nelson 1987 Teele 1989 Nelson WI, Kuritsky JN, Kennedy DL, Lao CS. Out- Teele DW, Klein JO, Rosner B. Epidemiology of otitis patient pediatric antibiotic use in the US: trends and media during the first seven years of life in children in therapy for otitis media. Program and Abstracts of the Greater Boston: a prospective cohort study. Journal of 27th Inter-science conference on Antimicrobial agents and Infectious Diseases 1989;160(1):83–94. Chemotherapy. Washington DC: American Society for Microbiology. 1987. References to other published versions of this review Pichichero 2000 Pichichero ME, Reiner SA, Brook I, Gooch WM, Williamson 2004 Yaumachi T, Jenkins SG, et al.Controversies in the medical Williamson I, Del Mar C, Crosby Z, Little P. management of persistent and recurrent acute otitis media. Immunostimulating agents for the prevention of acute otitis Recommendations of a clinical advisory committee. Annals media. Cochrane Database of Systematic Reviews 2004, Issue of Otology, Rhinology and Laryngology 2000;183(Suppl): 3. [DOI: 10.1002/14651858.CD004880.pub2] 1–12. ∗ Indicates the major publication for the study

WHAT’S NEW

Date Event Description

3 February 2010 New citation required and major changes This formerly withdrawn protocol has been taken over by a new team of authors

Immunostimulating agents for the prevention of acute otitis media (Protocol) 6 Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. HISTORY Protocol first published: Issue 3, 2004

Date Event Description

14 May 2008 New citation required and major changes Converted to new review format.

CONTRIBUTIONSOFAUTHORS CR will obtain abstracts for all the trials identified and assess them, as well as independently extract data from all the included trials. SF will assess the risk of bias of the included trials. CM will obtain abstracts for all the trials identified and assess them, as well as independently extract data from all the included trials. MLVD will be a third review author to resolve any disagreements in assessing all the trials identified as eligible; will obtain abstracts for all the trials identified and assess them; and independently extract data from all the included trials. CDM will be a third review author to resolve any differences in the assessment of the risk of bias in included trials. All review authors contributed to the writing of the protocol.

DECLARATIONSOFINTEREST None known.

SOURCES OF SUPPORT

Internal sources • New Source of support, Not specified.

External sources • No sources of support supplied

NOTES This protocol was withdrawn from Issue 4, 2009 of The Cochrane Library as the original review authors were unable to write the review.

Immunostimulating agents for the prevention of acute otitis media (Protocol) 7 Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.