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JAMA Intern Med. 03/2013; 173(5):380-2.
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Canadian Medical Association Journal 02/2013; 185(2):150. · 8.22 Impact Factor
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ABSTRACT: To explore the structure and content of a non-random sample of clinical study reports (CSRs) to guide clinicians and systematic reviewers.
We searched public sources and lodged Freedom of Information requests for previously confidential CSRs primarily written by the industry for regulators.
CSRs reporting sufficient information for extraction ('adequate').
Presence and length of essential elements of trial design and reporting and compression factor (ratio of page length for CSRs compared to its published counterpart in a scientific journal).
Data were extracted on standard forms and crosschecked for accuracy.
We assembled a population of 78 CSRs (covering 90 randomised controlled trials; 144 610 pages total) dated 1991-2011 of 14 pharmaceuticals. Report synopses had a median length of 5 pages, efficacy evaluation 13.5 pages, safety evaluation 17 pages, attached tables 337 pages, trial protocol 62 pages, statistical analysis plan 15 pages and individual efficacy and safety listings had a median length of 447 and 109.5 pages, respectively. While 16 (21%) of CSRs contained completed case report forms, these were accessible to us in only one case (765 pages representing 16 individuals). Compression factors ranged between 1 and 8805.
Clinical study reports represent a hitherto mostly hidden and untapped source of detailed and exhaustive data on each trial. They should be consulted by independent parties interested in a detailed record of a clinical trial, and should form the basic unit for evidence synthesis as their use is likely to minimise the problem of reporting bias. We cannot say whether our sample is representative and whether our conclusions are generalisable to an undefined and undefinable population of CSRs.
BMJ open. 01/2013; 3(2).
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Drug Safety 12/2012; 35(12):1187-8. · 3.63 Impact Factor
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ABSTRACT: Peter Doshi and colleagues describe their experience trying and failing to access clinical study reports from the manufacturer of Tamiflu and challenge industry to defend their current position of RCT data secrecy.
PLoS Medicine 04/2012; 9(4):e1001201. · 16.27 Impact Factor
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BMJ (Clinical research ed.). 01/2012; 344:d7898.
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Journal of the Royal Society of Medicine 01/2012; 105(1):35-40. · 1.41 Impact Factor
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ABSTRACT: The consequences of influenza in children and adults are mainly absenteeism from school and work. However, the risk of complications is greatest in children and people over 65 years of age.
To appraise all comparative studies evaluating the effects of influenza vaccines in healthy children, assess vaccine efficacy (prevention of confirmed influenza) and effectiveness (prevention of influenza-like illness (ILI)) and document adverse events associated with influenza vaccines.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 3) which includes the Acute Respiratory Infections Group's Specialised Register, OLD MEDLINE (1950 to 1965), MEDLINE (1966 to November 2011), EMBASE (1974 to November 2011), Biological Abstracts (1969 to September 2007), and Science Citation Index (1974 to September 2007).
Randomised controlled trials (RCTs), cohort and case-control studies of any influenza vaccine in healthy children under 16 years of age.
Four review authors independently assessed trial quality and extracted data.
We included 75 studies with about 300,000 observations. We included 17 RCTs, 19 cohort studies and 11 case-control studies in the analysis of vaccine efficacy and effectiveness. Evidence from RCTs shows that six children under the age of six need to be vaccinated with live attenuated vaccine to prevent one case of influenza (infection and symptoms). We could find no usable data for those aged two years or younger.Inactivated vaccines in children aged two years or younger are not significantly more efficacious than placebo. Twenty-eight children over the age of six need to be vaccinated to prevent one case of influenza (infection and symptoms). Eight need to be vaccinated to prevent one case of influenza-like-illness (ILI). We could find no evidence of effect on secondary cases, lower respiratory tract disease, drug prescriptions, otitis media and its consequences and socioeconomic impact. We found weak single-study evidence of effect on school absenteeism by children and caring parents from work. Variability in study design and presentation of data was such that a meta-analysis of safety outcome data was not feasible. Extensive evidence of reporting bias of safety outcomes from trials of live attenuated influenza vaccines (LAIVs) impeded meaningful analysis. One specific brand of monovalent pandemic vaccine is associated with cataplexy and narcolepsy in children and there is sparse evidence of serious harms (such as febrile convulsions) in specific situations.
Influenza vaccines are efficacious in preventing cases of influenza in children older than two years of age, but little evidence is available for children younger than two years of age. There was a difference between vaccine efficacy and effectiveness, partly due to differing datasets, settings and viral circulation patterns. No safety comparisons could be carried out, emphasising the need for standardisation of methods and presentation of vaccine safety data in future studies. In specific cases, influenza vaccines were associated with serious harms such as narcolepsy and febrile convulsions. It was surprising to find only one study of inactivated vaccine in children under two years, given current recommendations to vaccinate healthy children from six months of age in the USA, Canada, parts of Europe and Australia. If immunisation in children is to be recommended as a public health policy, large-scale studies assessing important outcomes, and directly comparing vaccine types are urgently required. The degree of scrutiny needed to identify all global cases of potential harms is beyond the resources of this review. This review includes trials funded by industry. An earlier systematic review of 274 influenza vaccine studies published up to 2007 found industry-funded studies were published in more prestigious journals and cited more than other studies independently from methodological quality and size. Studies funded from public sources were significantly less likely to report conclusions favourable to the vaccines. The review showed that reliable evidence on influenza vaccines is thin but there is evidence of widespread manipulation of conclusions and spurious notoriety of the studies. The content and conclusions of this review should be interpreted in the light of this finding.
Cochrane database of systematic reviews (Online) 01/2012; 8:CD004879. · 5.72 Impact Factor
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ABSTRACT: Planning for outbreaks of influenza is a high priority public health issue for national governments. Neuraminidase inhibitors (NIs) are thought to help reduce the symptoms of influenza with several possible mechanisms proposed. NIs have been stockpiled with a view to their widespread use in the event of a pandemic. However, the evidence base for this class of agents remains a source of debate. In a previous review we have documented substantial risks of publication bias of trials of NIs for influenza (60% of patient data from phase III treatment trials of oseltamivir have never been published) and reporting bias in the published trials. Our confidence in the conclusions of previous versions of this review has been subsequently undermined. Since we have become aware of a large number of unpublished trials of NIs in the management of influenza, this review updates and merges existing reviews in this area.
To review clinical study reports of placebo-controlled randomised trials, regulatory comments and reviews ('regulatory information') of the effects of the NIs oseltamivir and zanamivir for influenza in all age groups and appraise trial programmes, rather than single studies.Clinical study reports are very detailed, unpublished clinical trial data containing in-depth descriptions of protocol rationale, methods analysis plans, trial results and organisational documents (such as contracts). A series of clinical studies designed and conducted by one sponsor represents a trial programme of a drug indication (for example treatment of influenza).
We searched trial registries, cross-referencing published and unpublished sources and corresponded with manufacturers and regulators. We searched the archives of the US Food and Drug Administration (FDA) and European and Japanese regulators. The evidence in this review reflects searches to obtain relevant information up to 12 April 2011.
We included regulatory information based on assessments of randomised controlled trials (RCTs) conducted in people of any age who had either confirmed or suspected influenza, or who had been exposed to influenza in the local community or place of residence. We included information which had been made available by our deadline.
We indexed regulatory information in two purpose-built instruments and reconstructed trials using CONSORT statement-based templates. To progress to Stage 2 (full analysis) we sought manufacturer explanations of discrepancies in the data. GlaxoSmithKline (GSK) offered us individual patient data and responded to our queries, but Roche did not provide us with complete clinical study reports. In Stage 2 we intended to analyse trials with validated data (i.e. assuming our validation questions aimed at clarifying omissions and discrepancies were resolved). No studies progressed to Stage 2. We carried out analyses of the effects of oseltamivir on time to first alleviation of symptoms and hospitalisations using the intention-to-treat (ITT) population and tested five hypotheses generated post-protocol publication.
We included and analysed data from 25 studies (15 oseltamivir and 10 zanamivir studies). We could not use data from a further 42 studies due to insufficient information or unresolved discrepancies in their data. The included trials were predominantly conducted in adults during influenza seasons in both hemispheres. A small number of studies were conducted in older people residing in care homes and in people with underlying respiratory diseases. The studies had adequate randomisation and blinding procedures, but imbalances in the analysis populations available (ITT influenza-infected) left many of the studies at risk of attrition bias. All the studies were sponsored by manufacturers of NIs. Time to first alleviation of symptoms in people with influenza-like illness symptoms (i.e. ITT population) was a median of 160 hours (range 125 to 192 hours) in the placebo groups and oseltamivir shortened this by around 21 hours (95% confidence interval (CI) -29.5 to -12.9 hours, P < 0.001; five studies) but there was no evidence of effect on hospitalisations based on seven studies with a median placebo group event rate of 0.84% (range 0% to 11%): odds ratio (OR) 0.95; 95% CI 0.57 to 1.61, P = 0.86). These results are based on the comprehensive ITT population data and are unlikely to be biased. A post-protocol analysis showed that participants randomised to oseltamivir in treatment trials had a reduced odds being diagnosed with influenza (OR 0.83; 95% CI 0.73 to 0.94, P = 0.003; eight studies), probably due to an altered antibody response. Zanamivir trials showed no evidence of this. Due to limitations in the design, conduct and reporting of the trial programme, the data available to us lacked sufficient detail to credibly assess a possible effect of oseltamivir on complications and viral transmission. We postponed analysis of zanamivir evidence because of the offer of individual patient data (IPD) from its manufacturer. The authors have been unable to obtain the full set of clinical study reports or obtain verification of data from the manufacturer of oseltamivir (Roche) despite five requests between June 2010 and February 2011. No substantial comments were made by Roche on the protocol of our Cochrane Review which has been publicly available since December 2010.
We found a high risk of publication and reporting biases in the trial programme of oseltamivir. Sub-population analyses of the influenza infected population in the oseltamivir trial programme are not possible because the two arms are non-comparable due to oseltamivir's apparent interference with antibody production. The evidence supports a direct oseltamivir mechanism of action on symptoms but we are unable to draw conclusions about its effect on complications or transmission. We expect full clinical study reports containing study protocol, reporting analysis plan, statistical analysis plan and individual patient data to clarify outstanding issues. These full clinical study reports are at present unavailable to us.
Cochrane database of systematic reviews (Online) 01/2012; 1:CD008965. · 5.72 Impact Factor
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Tom Jefferson,
Chris B Del Mar,
Liz Dooley,
Eliana Ferroni,
Lubna A Al-Ansary,
Ghada A Bawazeer,
Mieke L van Driel,
Sreekumaran Nair,
Mark A Jones,
Sarah Thorning,
John M Conly
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ABSTRACT: Viral epidemics or pandemics of acute respiratory infections like influenza or severe acute respiratory syndrome pose a global threat. Antiviral drugs and vaccinations may be insufficient to prevent their spread.
To review the effectiveness of physical interventions to interrupt or reduce the spread of respiratory viruses.
We searched The Cochrane Library, the Cochrane Central Register of Controlled Trials (CENTRAL 2010, Issue 3), which includes the Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to October 2010), OLDMEDLINE (1950 to 1965), EMBASE (1990 to October 2010), CINAHL (1982 to October 2010), LILACS (2008 to October 2010), Indian MEDLARS (2008 to October 2010) and IMSEAR (2008 to October 2010).
In this update, two review authors independently applied the inclusion criteria to all identified and retrieved articles and extracted data. We scanned 3775 titles, excluded 3560 and retrieved full papers of 215 studies, to include 66 papers of 67 studies. We included physical interventions (screening at entry ports, isolation, quarantine, social distancing, barriers, personal protection, hand hygiene) to prevent respiratory virus transmission. We included randomised controlled trials (RCTs), cohorts, case-controls, before-after and time series studies.
We used a standardised form to assess trial eligibility. We assessed RCTs by randomisation method, allocation generation, concealment, blinding and follow up. We assessed non-RCTs for potential confounders and classified them as low, medium and high risk of bias.
We included 67 studies including randomised controlled trials and observational studies with a mixed risk of bias. A total number of participants is not included as the total would be made up of a heterogenous set of observations (participant people, observations on participants and countries (object of some studies)). The risk of bias for five RCTs and most cluster-RCTs was high. Observational studies were of mixed quality. Only case-control data were sufficiently homogeneous to allow meta-analysis. The highest quality cluster-RCTs suggest respiratory virus spread can be prevented by hygienic measures, such as handwashing, especially around younger children. Benefit from reduced transmission from children to household members is broadly supported also in other study designs where the potential for confounding is greater. Nine case-control studies suggested implementing transmission barriers, isolation and hygienic measures are effective at containing respiratory virus epidemics. Surgical masks or N95 respirators were the most consistent and comprehensive supportive measures. N95 respirators were non-inferior to simple surgical masks but more expensive, uncomfortable and irritating to skin. Adding virucidals or antiseptics to normal handwashing to decrease respiratory disease transmission remains uncertain. Global measures, such as screening at entry ports, led to a non-significant marginal delay in spread. There was limited evidence that social distancing was effective, especially if related to the risk of exposure.
Simple and low-cost interventions would be useful for reducing transmission of epidemic respiratory viruses. Routine long-term implementation of some measures assessed might be difficult without the threat of an epidemic.
Cochrane database of systematic reviews (Online) 01/2011; · 5.72 Impact Factor
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ABSTRACT: During the autumn-winter months (influenza seasons), influenza circulates more frequently, causing a greater proportion of influenza-like illness and sometimes serious seasonal epidemics. The incidence of symptoms related to influenza as well as influenza-like illness depends on the underlying immunity of the population. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of vaccines to prevent influenza? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2011 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 9 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
In this systematic review we present information relating to the effectiveness and safety of the following interventions: vaccines in adults, children, and older people.
Clinical evidence 01/2011; 2011.
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ABSTRACT: To identify studies of influenza vaccination of HCWs and influenza in elderly residents in long-term care facilities.
We searched seven electronic databases for randomised controlled trials (RCTs) and non-RCTs. Two reviewers independently extracted data and assessed trial quality.
The key outcomes are serologically proven influenza, pneumonia, and deaths from pneumonia, and pooled data from three C-RCTs showed no effect. Pooled data from three C-RCTs showed lower resident all-cause mortality, but as influenza constituted less than 10% of all deaths even in epidemic years we question the appropriateness of this outcome measure. Pooled data from three C-RCTs showed vaccination of HCWs reduced ILI and data from one C-RCT that HCW vaccination reduced GP consultations for ILI, but as influenza constitutes less than 25% of ILI and we did not show that HCW influenza vaccination reduced serologically proven influenza we question whether this effect is due to confounding.
Vaccine 10/2010; 29(2):344-56. · 3.77 Impact Factor
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BMJ (Clinical research ed.). 01/2010; 340:c3455.
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BMJ (Clinical research ed.). 01/2010; 340:c3461.
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ABSTRACT: Healthcare workers' (HCWs) influenza rates are unknown, but may be similar to the general public and they may transmit influenza to patients.
To identify studies of vaccinating HCWs and the incidence of influenza, its complications and influenza-like illness (ILI) in individuals >/= 60 in long-term care facilities (LTCFs).
We searched CENTRAL (The Cochrane Library 2009, issue 3), which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to 2009), EMBASE (1974 to 2009) and Biological Abstracts and Science Citation Index-Expanded.
Randomised controlled trials (RCTs) and non-RCTs of influenza vaccination of HCWs caring for individuals >/= 60 in LTCFs and the incidence of laboratory-proven influenza, its complications or ILI.
Two authors independently extracted data and assessed risk of bias.
We identified four cluster-RCTs (C-RCTs) (n = 7558) and one cohort (n = 12742) of influenza vaccination for HCWs caring for individuals >/= 60 in LTCFs. Pooled data from three C-RCTs showed no effect on specific outcomes: laboratory-proven influenza, pneumonia or deaths from pneumonia. For non-specific outcomes pooled data from three C-RCTs showed HCW vaccination reduced ILI; data from one C-RCT that HCW vaccination reduced GP consultations for ILI; and pooled data from three C-RCTs showed reduced all-cause mortality in individuals >/= 60.
No effect was shown for specific outcomes: laboratory-proven influenza, pneumonia and death from pneumonia. An effect was shown for the non-specific outcomes of ILI, GP consultations for ILI and all-cause mortality in individuals >/= 60. These non-specific outcomes are difficult to interpret because ILI includes many pathogens, and winter influenza contributes < 10% to all-cause mortality in individuals >/= 60. The key interest is preventing laboratory-proven influenza in individuals >/= 60, pneumonia and deaths from pneumonia, and we cannot draw such conclusions.The identified studies are at high risk of bias.Some HCWs remain unvaccinated because they do not perceive risk, doubt vaccine efficacy and are concerned about side effects. This review did not find information on co-interventions with HCW vaccination: hand washing, face masks, early detection of laboratory-proven influenza, quarantine, avoiding admissions, anti-virals, and asking HCWs with ILI not to work. We conclude there is no evidence that vaccinating HCWs prevents influenza in elderly residents in LTCFs. High quality RCTs are required to avoid risks of bias in methodology and conduct, and to test these interventions in combination.
Cochrane database of systematic reviews (Online) 01/2010; · 5.72 Impact Factor
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BMJ (Clinical research ed.). 01/2010; 340:c2994.
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ABSTRACT: Vaccines have been the main global weapon to minimise the impact of influenza in the elderly for the last four decades and are recommended worldwide for individuals aged 65 years or older. The primary goal of influenza vaccination in the elderly is to reduce the risk of complications among persons who are most vulnerable.
To assess the effectiveness of vaccines in preventing influenza, influenza-like illness (ILI), hospital admissions, complications and mortality in the elderly. To identify and appraise comparative studies evaluating the effects of influenza vaccines in the elderly. To document types and frequency of adverse effects associated with influenza vaccines in the elderly.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Acute Respiratory Infections (ARI) Group's Specialised Register (The Cochrane Library 2009, issue 4); MEDLINE (January 1966 to October Week 1 2009); EMBASE (1974 to October 2009) and Web of Science (1974 to October 2009).
Randomised controlled trials (RCTs), quasi-RCTs, cohort and case-control studies assessing efficacy against influenza (laboratory-confirmed cases) or effectiveness against influenza-like illness (ILI) or safety. Any influenza vaccine given independently, in any dose, preparation or time schedule, compared with placebo or with no intervention was considered.
We grouped reports first according to the setting of the study (community or long-term care facilities) and then by level of viral circulation and vaccine matching. We further stratified by co-administration of pneumococcal polysaccharide vaccine (PPV) and by different types of influenza vaccines. We analysed the following outcomes: influenza, influenza-like illness, hospital admissions, complications and deaths.
We included 75 studies. Overall we identified 100 data sets. We identified one RCT assessing efficacy and effectiveness. Although this seemed to show an effect against influenza symptoms it was underpowered to detect any effect on complications (1348 participants). The remainder of our evidence base included non-RCTs. Due to the general low quality of non-RCTs and the likely presence of biases, which make interpretation of these data difficult and any firm conclusions potentially misleading, we were unable to reach clear conclusions about the effects of the vaccines in the elderly.
The available evidence is of poor quality and provides no guidance regarding the safety, efficacy or effectiveness of influenza vaccines for people aged 65 years or older. To resolve the uncertainty, an adequately powered publicly-funded randomised, placebo-controlled trial run over several seasons should be undertaken.
Cochrane database of systematic reviews (Online) 01/2010; · 5.72 Impact Factor
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ABSTRACT: Different types of influenza vaccines are currently produced worldwide. Healthy adults are presently targeted mainly in North America.
Identify, retrieve and assess all studies evaluating the effects of vaccines against influenza in healthy adults.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2010, issue 2), MEDLINE (January 1966 to June 2010) and EMBASE (1990 to June 2010).
Randomised controlled trials (RCTs) or quasi-RCTs comparing influenza vaccines with placebo or no intervention in naturally-occurring influenza in healthy individuals aged 16 to 65 years. We also included comparative studies assessing serious and rare harms.
Two review authors independently assessed trial quality and extracted data.
We included 50 reports. Forty (59 sub-studies) were clinical trials of over 70,000 people. Eight were comparative non-RCTs and assessed serious harms. Two were reports of harms which could not be introduced in the data analysis. In the relatively uncommon circumstance of vaccine matching the viral circulating strain and high circulation, 4% of unvaccinated people versus 1% of vaccinated people developed influenza symptoms (risk difference (RD) 3%, 95% confidence interval (CI) 2% to 5%). The corresponding figures for poor vaccine matching were 2% and 1% (RD 1, 95% CI 0% to 3%). These differences were not likely to be due to chance. Vaccination had a modest effect on time off work and had no effect on hospital admissions or complication rates. Inactivated vaccines caused local harms and an estimated 1.6 additional cases of Guillain-Barré Syndrome per million vaccinations. The harms evidence base is limited.
Influenza vaccines have a modest effect in reducing influenza symptoms and working days lost. There is no evidence that they affect complications, such as pneumonia, or transmission.WARNING: This review includes 15 out of 36 trials funded by industry (four had no funding declaration). An earlier systematic review of 274 influenza vaccine studies published up to 2007 found industry funded studies were published in more prestigious journals and cited more than other studies independently from methodological quality and size. Studies funded from public sources were significantly less likely to report conclusions favorable to the vaccines. The review showed that reliable evidence on influenza vaccines is thin but there is evidence of widespread manipulation of conclusions and spurious notoriety of the studies. The content and conclusions of this review should be interpreted in light of this finding.
Cochrane database of systematic reviews (Online) 01/2010; · 5.72 Impact Factor
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ABSTRACT: Viral epidemics or pandemics of acute respiratory infections like influenza or severe acute respiratory syndrome pose a world-wide threat. Antiviral drugs and vaccinations may be insufficient to prevent catastrophe.
To systematically review the effectiveness of physical interventions to interrupt or reduce the spread of respiratory viruses.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, issue 2); MEDLINE (1966 to May 2009); OLDMEDLINE (1950 to 1965); EMBASE (1990 to May 2009); and CINAHL (1982 to May 2009).
We scanned 2958 titles, excluded 2790 and retrieved the full papers of 168 trials, to include 59 papers of 60 studies. We included any physical interventions (isolation, quarantine, social distancing, barriers, personal protection and hygiene) to prevent transmission of respiratory viruses. We included the following study designs: randomised controlled trials (RCTs), cohorts, case controls, cross-over, before-after, and time series studies.
We used a standardised form to assess trial eligibility. RCTs were assessed by: randomisation method; allocation generation; concealment; blinding; and follow up. Non-RCTs were assessed for the presence of potential confounders, and classified into low, medium, and high risks of bias.
The risk of bias for the four RCTs, and most cluster RCTs, was high. The observational studies were of mixed quality. Only case-control data were sufficiently homogeneous to allow meta-analysis.The highest quality cluster RCTs suggest respiratory virus spread can be prevented by hygienic measures, such as handwashing, especially around younger children. Additional benefit from reduced transmission from children to other household members is broadly supported in results of other study designs, where the potential for confounding is greater. Six case-control studies suggested that implementing barriers to transmission, isolation, and hygienic measures are effective at containing respiratory virus epidemics. We found limited evidence that N95 respirators were superior to simple surgical masks, but were more expensive, uncomfortable, and caused skin irritation. The incremental effect of adding virucidals or antiseptics to normal handwashing to decrease respiratory disease remains uncertain. Global measures, such as screening at entry ports, were not properly evaluated. There was limited evidence that social distancing was effective especially if related to the risk of exposure.
Many simple and probably low-cost interventions would be useful for reducing the transmission of epidemic respiratory viruses. Routine long-term implementation of some of the measures assessed might be difficult without the threat of a looming epidemic.
Cochrane database of systematic reviews (Online) 01/2010; · 5.72 Impact Factor
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ABSTRACT: Neuraminidase inhibitors (NI) are recommended for use against influenza and its complications in inter-pandemic years and during pandemics.
To assess the effects of NIs in preventing and treating influenza, its transmission, and its complications in otherwise healthy adults, and to estimate the frequency of adverse effects.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, issue 3) which contains the Acute Respiratory Infections Group's Specialised Register, MEDLINE (1950 to August 2009) and EMBASE (1980 to August 2009).
Randomised controlled trials (RCTs) or quasi-randomised placebo-controlled trials of NIs in healthy adults exposed to naturally occurring influenza.
Two review authors independently applied inclusion criteria, assessed trial quality, and extracted data. We structured the comparisons into prophylaxis, treatment, and adverse events, with further subdivision by outcome and dose.
We identified four prophylaxis, 12 treatment and four post-exposure prophylaxis trials. In prophylaxis compared to placebo, NIs had no effect against influenza-like illnesses (ILI) (risk ratio (RR) ranging from 1.28 for oral oseltamivir 75 mg daily to 0.76 for inhaled zanamivir 10 mg daily). The efficacy of oral oseltamivir against symptomatic influenza was 76% (at 75 mg daily), and 73% (at 150 mg daily). Inhaled zanamivir 10 mg daily performed similarly. Neither NI had a significant effect on asymptomatic influenza. Oseltamivir induced nausea (odds ratio (OR) 1.79, 95% CI 1.10 to 2.93). Oseltamivir for post-exposure prophylaxis had an efficacy of 58% and 84% in two trials for households. Zanamivir performed similarly. The hazard ratios for time to alleviation of symptoms were in favour of the treated group 1.20 (1.06 to 1.35) for oseltamivir and 1.24 (1.13 to 1.36) for zanamivir. Because of the exclusion of a review of mainly unpublished trials of oseltamivir, insufficient evidence remained to reach a conclusion on the prevention of complications requiring antibiotics in influenza cases (RR 0.57, 95% CI 0.23 to 1.37). Analysis of the US FDA and Japan's PMDA regulators' pharmacovigilance dataset, revealed incomplete reporting and description of harms preventing us from reaching firm conclusions on the central nervous system toxicity of neuraminidase inhibitors.
Numerous inconsistencies detected in the available evidence, followed by an inability to adequately access the data, has undermined confidence in our previous conclusions for oseltamivir. Independent RCTs to resolve these uncertainties are needed.
Cochrane database of systematic reviews (Online) 01/2010; · 5.72 Impact Factor
