The impact of neuraminidase inhibitors on influenza transmission: a systematic review PROTOCOL

Transcription

1 The impact of neuraminidase inhibitors on influenza transmission: a systematic review (A project commissioned by the World Health Organization Global Influenza Programme) PROTOCOL Prepared by: Dr. George N. Okoli, Miss Harmony E. Otete, Dr. Charles R. Beck Senior Supervisor: Professor Jonathan S. Nguyen- Van- Tam Project lead: Dr. George N. Okoli Health Protection and Influenza Research Group (HPIRG) Division of Epidemiology and Public Health Clinical Sciences Building Nottingham City Hospital Hucknall Road, Nottingham NG5 1PB, United Kingdom George.Okoli@nottingham.ac.uk Document date: 7 th January 2014 Project funding: World Health Organization Global Influenza Programme The impact of neuraminidase inhibitors on influenza transmission: a systematic review Page 1

2 TABLE OF CONTENTS 1.0 Background.. Pages Review questions. Pages Study selection.. Pages Assessment of risk of bias and data extraction.. Pages Data synthesis Pages Dissemination. Page Resource implications.. Page References Pages Appendix 1: Literature search strategy. Pages Appendix 2: Example search output Pages Appendix 3: Data extraction information Page The impact of neuraminidase inhibitors on influenza transmission: a systematic review Page 2

3 Background Influenza causes substantial disease burden globally through seasonal epidemics and occasional pandemics caused by novel strains. 1 Most influenza outbreaks among humans are caused by transmission and spread of the virus from person to person primarily through virus- laden particles released when an infected person coughs or sneezes near an uninfected or susceptible person. 2, 3 The incubation period for influenza averages two days, ranging one to four days. 4 Infected persons produce virus- laden respiratory particles during virus shedding, a stage of the infection which is usually equated to maximal infectivity. 5 A recent report from the World Health Organization (WHO) concluded that influenza virus shedding can be detected one to two days before clinical onset, and that it peaks during the first 24 hours of illness although some persons, particularly children and immunocompromised persons may shed virus for longer periods. 6 The mean interval between onsets of illness in two successive persons in a chain of transmission is two to four days. 7 These factors contribute to the ability of influenza to spread rapidly through communities. Reducing viral shedding may reduce infectivity and thereby make onward transmission of the virus less likely; it has been suggested that if this phenomenon occurs in a widespread fashion, this may produce a slowing of community transmission. 8 Thus it is argued that treatment of cases, and prophylaxis of contacts with antiviral drugs will reduce infectiousness and susceptibility to influenza infection respectively, thus reducing transmission and spread. 9 Measures to reduce the spread of influenza within a given population, based on treatment or prophylaxis with antiviral medications is considered important to reducing transmissibility, 10 and form the basis of the current WHO Rapid Contain Strategy. 11 Some studies suggest that early treatment with neuraminidase inhibitors may reduce the quantity of influenza virus released from an infected person and may shorten the duration of viral shedding Inconclusive findings have also been reported 15. Reduced secondary household transmission has been reported but it is not clear if this is the same at community level, thus suggesting the need for comprehensive assessment of the impact of neuraminidase inhibitors on influenza transmission at population level, as this will contribute to informing policy on the The impact of neuraminidase inhibitors on influenza transmission: a systematic review Page 3

4 treatment, and the prevention of the spread of influenza. The objective of this protocol is to describe the methodology for undertaking a systematic review to assess the impact of treatment and prophylaxis with neuraminidase inhibitors on influenza transmission. The systematic review will be conducted and reported according to the requirements of the Preferred Reporting Items for Systematic Review and Meta- Analyses (PRISMA) statement. 19 This protocol will be registered with the international prospective register of systematic reviews (PROSPERO) before the literature search strategy is executed. Review questions The objective for the systematic review is to assess the impact of neuraminidase inhibitors on influenza transmission. The review will aim to assess whether treatment of confirmed cases of influenza, and prophylaxis of exposed persons, with neuraminidase inhibitors, will reduce transmission. The review question is: 1. What is the evidence in humans that treatment and prophylaxis of, respectively, confirmed cases and contacts reduces community transmission, compared with no treatment, placebo, or sham treatment? The Population, Intervention, Comparators, and Outcomes (PICO) framework to inform the review objectives are as follows: Population Persons of any age with laboratory confirmed influenza infection, whether of seasonal, pandemic or avian origin; or persons of any age with symptomatic Influenza- like illness (ILI), and persons of any age considered to have had close contact with any of the above persons. Close contact will be defined according to WHO definition 20 as having cared for, lived with, or had direct contact with respiratory or body fluids of person or persons with laboratory confirmed influenza infection or symptomatic ILI. Laboratory confirmation of influenza will also be The impact of neuraminidase inhibitors on influenza transmission: a systematic review Page 4

5 defined according to WHO definition 20 as a positive result of respiratory specimen tested for influenza virus by reverse transcriptase- polymerase chain reaction (RT- PCR) or viral culture. Symptomatic ILI will be defined based on WHO criteria 21 ; however, fever of 37.5 o C with cough or sore throat, with or without other respiratory symptoms will also be considered as symptomatic ILI. Interventions Neuraminidase inhibitors (oseltamivir, zanamivir, laninamivir) administration as capsules, suspensions, or by oral inhalation (Peramivir is not of interest in this study because it is an intravenously administered drug so considered unsuitable for community level intervention) Comparators No antivirals, placebo, or sham antivirals (Studies with no comparators will still be considered and compared with other studies where there is a comparator arm) Outcomes Community transmission; defined as epidemiologically linked cases in any settings other than hospitals, care homes, nursing homes, boarding schools, places of detention. The impact of neuraminidase inhibitors on influenza transmission: a systematic review Page 5

6 Study selection The study eligibility (inclusion and exclusion) criteria are as follows: Inclusion criteria Experimental and observational studies reporting data on neuraminidase inhibitors, and household/community influenza transmission Experimental and observational studies reporting data from controls with no influenza antiviral treatment, placebo, or sham treatment (where available) Experimental and observational studies without restriction on dose, and treatment/prophylaxis duration of neuraminidase inhibitors Experimental and observational studies in households, schools (excluding boarding schools), offices, and military barracks, that meet the other inclusion criteria Systematic reviews with or without meta- analysis, reporting data on the efficacy and effectiveness of neuraminidase inhibitors Studies in any language, which meet the above criteria Exclusion criteria Studies in hospitals, care homes, nursing homes, places of detention Studies comparing influenza vaccination against no vaccination, placebo, or sham vaccination Studies reporting data on the association between influenza vaccines and household or community transmission of influenza Studies on adverse effects of antivirals Any experimental and observational studies which does not provide information on the required outcome measures One reviewer will conduct the literature search (see Appendix 1: Literature search strategy). Identified literature will be screened by two reviewers, applying the eligibility criteria using a three stage sifting approach to review literature title, abstract and the full text. Following initial screening, the number of screened out literature will be recorded at each stage. A PRISMA diagram will be produced and The impact of neuraminidase inhibitors on influenza transmission: a systematic review Page 6

7 reasons for exclusion will be recorded when sifting at the full text stage. Any disagreement between the two reviewers will be discussed and resolved with the involvement of a third reviewer. Assessment of risk of bias and data extraction The risk of bias in the study and outcome level of selected studies will be assessed using the Cochrane Collaboration tool 22 for assessing risk of bias in experimental and prospective cohort studies. Other identified observational studies will be assessed for risk of bias using the Newcastle Ottawa scale. 23 In addition to assessing the risk of bias in non- randomised studies, the Cochrane Collaboration recommends the assessment of confounding due to the potential risk of selection bias in these studies, and importance in contributing towards heterogeneity between studies. Systematic reviews that meet the eligibility criteria for inclusion will be assessed for risk of bias using the United States Agency for Healthcare Research and Quality domain and element- based evaluation instrument. 24 Outcome reporting bias will be assessed within each study using the above quality assessment tools. The result of each assessment will be presented per domain or question since both the Cochrane Collaboration and PRISMA statement recommend against the use of summary scores for describing an overall risk of bias. Abstracts that are assessed to meet the study eligibility criteria for inclusion will be subject to data extraction only and not assessment for risk of bias. Reviewers will be required to identify the confounding factors stated in each study, describe the methodology used to measure them, and state how selection bias was controlled through any study design specific features and methods of statistical analysis. In compliance with the Cochrane collaboration, potential confounding factors anticipated to be of importance in the review are: Demography of the study population Settings from which study population has been sampled Prior vaccination of persons among study population The impact of neuraminidase inhibitors on influenza transmission: a systematic review Page 7

8 Influenza infection type Comorbidities Comparative intervention(s) received by control group(s) Neuraminidase inhibitor type, dosing and form Consistency of laboratory confirmatory test for influenza (differences in labs and scientists) Definition of contact and contact tracing Methodology used to assess study outcome measures Data will be collected according to the PICO framework as already explained. Data extraction (see appendix 3) and quality assessments will be conducted by one reviewer and then reviewed by a second reviewer. Any disagreements will be recorded and resolved with the involvement of a third reviewer (Project Supervisor). Data synthesis A narrative approach will be used to synthesise quality assessments and extract data according to the following framework described by the Economic and social research council and recommended by the University of York Centre for Review and Dissemination. 25 Develop a theory of how the intervention works, why and for whom Develop a preliminary synthesis of findings of included studies Exploring relationships within and between studies Assessing the robustness of the synthesis Study specific characteristics and outcome measures will be tabulated to aid narrative synthesis. Subgroup analyses will be used to describe differences between (1) Post Exposure Prophylaxis (PEP) without treatment of index case; PEP with treatment of index case; Treatment of index case only; Pre exposure prophylaxis. (2) Seasonal, pandemic and avian influenza, (3) neuraminidase inhibitor type, and (4) studies at low risk of bias. Meta- analyses will be conducted using appropriate The impact of neuraminidase inhibitors on influenza transmission: a systematic review Page 8

9 extracted data and statistical analyses will then be performed where feasible to produce a meta- analysis of pooled estimates of effect size (including 95% confidence intervals), test for heterogeneity, and sensitivity analyses. Publication bias will be assessed for each outcome measure studied using funnel plots of effect size versus sample size for each included study. Dissemination It is anticipated that an oral presentation of the systematic review may be delivered to WHO Global Influenza Programme (GIP) at the Technical Working Group Meeting on Influenza Severity Assessment in Collaboration with the Peer Review Group for the Revised Pandemic Preparedness Guidance in April An abstract of the systematic review may be submitted for presentation at Options for the Control of influenza conference, scheduled for September 2013 or for other appropriate infectious diseases or health protection conferences during the year. A manuscript will be prepared for publication in an appropriate peer- reviewed journal and the final version of the manuscript will be submitted to WHO GIP as the deliverable of the Agreement for Performance of Work (APW). Resource implications The Senior Supervisor will collaborate with the WHO GIP office to define the review questions. The WHO GIP office will facilitate access to necessary unpublished literature, and translation of non- English literature. The Senior Supervisor will agreed timescales and key milestones for the systematic review with the WHO GIP office, and the office will be provided with updates as the review progresses. The impact of neuraminidase inhibitors on influenza transmission: a systematic review Page 9

10 References 1. Nicholson, K. G., Wood, J. M., Zambon, M. (2003). Influenza. Lancet vol. 362 pp World Health Organization (2007). Infection prevention and control of epidemic and pandemic- prone acute respiratory diseases in health care. WHO Interim Guidelines; Available [online] from: Accessed 1 February Centers for Disease Control and Prevention (2009). Clinical Signs and Symptoms of Influenza. Influenza Prevention and Control Recommendations. Available [online] from: Accessed 6 February World Health Organization (2008). Pandemic influenza preparedness and mitigation in refugee and displaced populations. WHO guidelines for humanitarian agencies (2 nd Ed). Geneva 5. Carrat, F., Vergu, E., Ferguson, N. M., Lemaitre, M., Cauchemez, S., Leach, S. and Valleron, A. (2008). Time Lines of Infection and Disease in Human Influenza: A Review of Volunteer Challenge Studies. American Journal of Epidemiology vol. 167 (7) pp Bell, D. M. (2006). Non- Pharmaceutical interventions for pandemic influenza, international measures. Emerging Infectious Diseases vol. 12 pp Donnelly, C. A., Finelli, L., Cauchemez, S., Olsen, S. J., Doshi, S., Jackson, M. L., Kennedy, E. D., Kamimoto, L., Marchbanks, T. L., Morgan, O. W., Patel, M., David, L. S. and Ferguson, N. M. (2011). Serial Intervals and the Temporal Distribution of Secondary Infections within Households of 2009 Pandemic Influenza A (H1N1): Implications for Influenza Control Recommendations. Clinical Infectious Diseases vol. 52 (1) pp. S123 S Ng, S., Cowling, B. J., Fang, V. J., Chan, K. H., Dennis, K. M., Cheng, C. K. Y., Uyeki, T. M., Houck, P. M., Peiris Malik, J. S., and Leung, G. M. (2010). Effects of Oseltamivir The impact of neuraminidase inhibitors on influenza transmission: a systematic review Page 10

11 treatment on duration of clinical illness, and viral shedding and household transmission of influenza virus. Clinical Infectious Diseases vol. 50 pp Centers for Disease Control and Prevention (2011). Antiviral agents for the treatment and chemoprophylaxis of influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP) 60 (RR01) pp Centers for Disease Control and Prevention (CDC) Interim Guidance on Infection Control Measures for 2009 H1N1 Influenza in Healthcare Settings, Including Protection of Healthcare Personnel. Available [online] from: Accessed 31 March World Health Organization (2007). WHO Interim Protocol: Rapid operations to contain the initial emergence of pandemic influenza. Available [online] from: Accessed 11 February Hayden, F. G., Treanor, J. J., Scott Fritz, R., Lobo, M., Betts, R. F., Miller, M., Kinnersley, N., Mills, R. G., Ward, P. and Straus, S. E. (1999). Use of the oral neuraminidase inhibitors oseltamivir in Experimental Human influenza: Randomized Controlled Trials for Prevention and Treatment. JAMA. Vol. 282(13) pp Hayden, F. G., Treanor, J. J., Betts, R. F., Lobo, M, Esinhart, J. D. and Hussey, E. K. (1996). Safety and efficacy of the neuraminidase inhibitor GG167 in experimental human influenza. JAMA vol. 275 pp Ling, L. M., Chow, A. L., Lye, D. C., Tan, A. S., Krishnan, P., Cui, L., Win, N. N., Chan, M., Lim, P. L., Lee, C. C. and Leo, Y. S. (2010). Effects of Early Oseltamivir Therapy on Viral Shedding in 2009 Pandemic Influenza A (H1N1) Virus Infection. Clinical Infectious Diseases vol. 50 pp Sato, M., Hosoya, M., Kato, K. and Suzuki, H. (2005). Viral shedding in children with influenza virus infections treated with neuraminidase inhibitors. Journal of Pediatric Infectious Diseases vol. 24 pp Welliver, R., Monto, A. S., Carewicz, O., Schatteman, E., Hassman, M., Hendrick, J., The impact of neuraminidase inhibitors on influenza transmission: a systematic review Page 11

12 Jackson, H. C., Huson, L., Ward, P., Oxford, J. S. (2001). Effectiveness of oseltamivir in preventing influenza in household contacts: a randomized controlled trial. JAMA vol. 285 pp Hayden, F. G., Belshe, R., Villanueva, C., Lanno, R., Hughes, C., Small, I., Dutkowski, R., Ward, P. and Carr, J. (2004) Management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without post exposure prophylaxis. Journal of Infectious Diseases vol. 189 pp Monto, A. S., Pichichero, M. E., Blanckenberg, S. J., Ruuskanen, O., Cooper, C., Fleming, D. M. and Kerr, C. (2002). Zanamivir Prophylaxis: An Effective Strategy for the Prevention of Influenza Types A and B within Households. Journal of Infectious Diseases vol. 186 pp Moher, D., Liberati, A., Tetzlaff, J., Altman, D. G. (2009). Preferred Reporting Items for Systematic Reviews and Meta- analyses: the PRISMA statement. BMJ vol. 339 p World Health Organization (2009). Interim WHO guidance for the surveillance of human infection with swine influenza A (H1N1) virus. Available [online] from: Accessed 6 February World Health Organization (2011). WHO Regional Office for Europe guidance for sentinel influenza surveillance in humans. Available [online] from: data/assets/pdf_file/0020/90443/e92738.pdf Accessed 4 February Higgens, J. and Green, S. (Eds) (2009). Cochrane Handbook for Systematic Reviews of Interventions. Version The Cochrane Collaboration 23. Wells, G. A., Shea, B., O Connell, D., Peterson, J., Welch, V., Losos, M. and Tugwell, P. (2008). The Newcastle- Ottawa Scale (NOS) for assessing the quality of non- randomised studies in meta- analyses. Available [online] from: Accessed 12 The impact of neuraminidase inhibitors on influenza transmission: a systematic review Page 12

13 24. Agency for Healthcare Research and Quality (2002). Systems to rate the strength of scientific evidence. Evidence report/technology appraisal No. 47. Available [online] from: Accessed 6 February Centre for Reviews and Dissemination (2008). Systematic reviews. CRD s guidance for undertaking reviews in health care. York: Centre for Reviews and Dissemination, University of York The impact of neuraminidase inhibitors on influenza transmission: a systematic review Page 13

14 Appendix 1 Literature search strategy Search Terms Area MeSH thesaurus headings Free text persons patient* OR health* OR neonat* OR infant OR child* OR young OR adolescen* OR adult* OR elder* OR old* OR men OR women OR people OR person* OR subject* OR individual* disease disease* OR ill* OR risk Population pediatrics paediatr* OR pediatr* geriatrics geriatr* rt- pcr OR rtpcr OR (reverse AND polymerase chain reaction transcriptase AND polymerase AND chain AND reaction) OR (polymerase AND chain AND reaction) laboratory AND culture laboratory AND confirm* oseltamivir oseltamivir OR tamiflu zanamivir zanamivir OR relenza laninamivir OR inavir Intervention antiviral agents influenza- antiviral* OR flu- antiviral* OR (influenza AND antiviral*) OR (flu AND antiviral) neuraminidase AND inhibitor* Comparators Outcomes placebos disease transmission, infectious neuraminidase OR antiviral* AND (drug* OR therap* OR treat*) (no OR placebo* OR sham) AND (oseltamivir OR zanamivir OR laninamivir OR tamiflu OR relenza OR inavir OR influenza- antiviral* OR flu- antiviral* OR (influenza AND antiviral*) OR (neuraminidase AND inhibitor*) OR (neuraminidase OR antiviral*) AND (drug* OR therap* OR treat*)) transmi* OR spread OR infect* OR "person to person" OR "person- person" OR "person- to- person" OR house* OR communit* Influenza terms influenza, human influenza A virus influenza B virus influenza OR flu OR (influenza AND like) OR influenza- like OR (flu AND like) OR flu- like OR ILI The impact of neuraminidase inhibitors on influenza transmission: a systematic review Page 14

15 Search Sources Categories Healthcare databases Evidence based reviews Guidelines Grey Literature Hand searching of relevant journals Internet searching Referencing tracking Citation tracking Sources MEDLINE EMBASE CINAHL Cochrane Library PubMed WHO Global Index Medicus Bandolier Cochrane Library (CDSR, DARE, NHS HTA database) NHS Evidence (NHS Clinical Knowledge Summaries and the National Library of Guidelines) Web of Science NHS Evidence (drug information, evidence summaries, grey literature, health technology assessments, primary research, and systematic reviews) OpenSIGLE (System for information on grey literature in Europe) Neuraminidase inhibitors manufacturers (Roche, GlaxoSmithkline, Biota Scientific) IFPMA (International Federation of Pharmaceutical Manufacturers Associations, Geneva/Zurich) Journal of Infectious Diseases, Clinical Infectious Diseases Journal, British Medical Journal Reference list of all selected studies will be searched to identify further relevant studies Web of Science (Science Citation Index) Google Scholar The impact of neuraminidase inhibitors on influenza transmission: a systematic review Page 15

16 Search Limits Limit Category Languages Publication type Specified Limit All languages None Date of publication All publications up to the end of 2012 Study design Other limits Experimental, observational studies and systematic reviews Human data The above MeSH thesaurus headings and free text terms may be amended to maintain compatibility with databases which do not use MeSH or include non- English language studies. Search interfaces with limited functionality (example those which support single line searches only, small number of search terms etc.) may be initially searched using broad influenza specific terms followed by longer search strings. Conducted literature searches must be documented (including but not limited to the terms used, sources interrogated and hits identified) such that these may be replicated. The scope of each free text search will include the study title and abstract where available, when the search strategy is executed. Individual MeSH thesaurus headings and free text terms will be searched for within each group of PICO. Combinations of search terms across the PICO groups must be extracted separately to produce the final list of search hits from each database. All search hits will be imported into reference management software to collate the identified literature and remove duplicates entries prior to conducting the three- stage sifting process. Where search interfaces do not allow the export of search hits to reference management software, search hits may be sifted using alternative electronic or paper- based methods. The impact of neuraminidase inhibitors on influenza transmission: a systematic review Page 16

17 Appendix 2: Example search (MEDLINE) output Search Term Results 1 exp Persons/ exp Disease/ exp Pediatrics/ exp Geriatrics/ exp Polymerase Chain Reaction/ (patient* or health* or neonat* or infant or child* or young or adolescen* or adult* or elder* or old* or men or women or people or person* or subject* or individual*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (disease* or ill* or risk).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (paediatr* or pediatr*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] geriatr*.mp (rt- pcr or rtpcr or (reverse and transcriptase and polymerase and chain and reaction) or (polymerase and chain and reaction)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (laboratory and culture).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (laboratory and confirm*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] The impact of neuraminidase inhibitors on influenza transmission: a systematic review Page 17

18 13 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or exp Oseltamivir/ exp Zanamivir/ exp Antiviral Agents/ (oseltamivir or tamiflu).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (zanamivir or relenza).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (laninamivir or inavir).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (influenza- antiviral* or flu- antiviral* or (influenza and antiviral*) or (flu and antiviral)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (neuraminidase and inhibitor*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] ((neuraminidase or antiviral*) and (drug* or therap* or treat*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] or 15 or 16 or 17 or 18 or 19 or 20 or 21 or exp Placebos/ ((no or placebo* or sham) and ((oseltamivir or zanamivir or laninamivir or tamiflu or relenza or inavir or influenza- antiviral* or flu- antiviral* or (influenza and antiviral*) or (neuraminidase and inhibitor*) or (neuraminidase or antiviral*)) and (drug* or therap* or treat*))).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease The impact of neuraminidase inhibitors on influenza transmission: a systematic review Page 18

19 supplementary concept, unique identifier] or exp Disease Transmission, Infectious/ (transmi* or spread or infect* or "person to person" or "person- person" or "person- to- person" or house* or communit*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] or exp Influenza, Human/ exp Influenza A virus/ exp Influenza B virus/ (influenza or flu or (influenza and like) or influenza- like or (flu and like) or flu- like or ILI).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] or 31 or 32 or and 23 and and 23 and 26 and and and limit 37 to humans limit 38 to humans 646 The impact of neuraminidase inhibitors on influenza transmission: a systematic review Page 19

20 Appendix 3: Data extraction information A piloted form was used for the purpose of the data extraction. A study identification number was given to each included study. Identification was also given to each of the two reviewers involved in the data extraction. Data extracted from the studies using the extraction form were as follows: General study information The full citation Year of study Source of funding Study location i.e. the country in which study was conducted Study setting i.e. household, study centre, specific community, etc. Study design i.e. RCT, observational study type Study population Study sample size Breakdown of the sample size by age, gender and ethnicity Average age of participants Participants age range Participants influenza vaccination status Participants health status i.e. comorbidities Other information Influenza type i.e. seasonal, pandemic, avian Influenza virus strain Influenza transmission studied i.e. household transmission, transmission between individuals or within community Influenza infection confirmation method i.e. RT- PCR, culture etc. Intervention Neuraminidase inhibitor involved (type, brand name) Number of recipients Dose, form and route of administration of the neuraminidase inhibitor Duration of intervention with neuraminidase inhibitor The impact of neuraminidase inhibitors on influenza transmission: a systematic review Page 20

21 Comparator Comparator i.e. whether placebo, no treatment, shame treatment etc. Number of recipients Dose, form and route of administration of the comparator Duration of intervention with comparator Outcome Study focus example pre- or post- exposure prophylaxis, treatment of index case etc. Outcome measure compared between recipients of neuraminidase inhibitor and recipients of comparator i.e. protective efficacy, SAR, R0 etc. Risk of bias assessment Risk of bias assessments were captured in the data extraction form using validated tools For the risk of bias in experimental and prospective cohort studies using the Cochrane Collaboration tool, data assessed were as follows: Sequence generation Allocation concealment Blinding of participants and researchers Incomplete outcome data assessment Selective outcome reporting assessment Other sources of bias assessment For the risk of bias assessment in retrospective cohort and other studies using Newcastle Ottawa scale, data assessed were as follows: Representativeness of the exposed cohort Selection of the non- exposed cohort Ascertainment of exposures Demonstration that outcome of interest was not present at start of study Comparability of cohorts on the basis of the design or analysis Assessment of outcome Was follow- up long enough for outcomes to occur Adequacy of follow- up of cohorts The impact of neuraminidase inhibitors on influenza transmission: a systematic review Page 21

22 For the risk of bias assessment in systematic reviews using the United States Agency for Healthcare Research and Quality (AHRQ) domain and element- based evaluation instrument, data assessed were as follows: Study question Search strategy Inclusion and exclusion criteria Interventions Outcomes Data extraction Study quality and validity Data synthesis and analysis Results Discussions Funding or sponsorship The impact of neuraminidase inhibitors on influenza transmission: a systematic review Page 22