What are the cost-savings and health benefits of improving detection and management for six high cardiovascular risk conditions in England? An economic evaluation.

OBJECTIVES: To estimate the cost savings and health benefits of improving detection of individuals at high risk of cardiovascular disease (CVD) in England, to determine to which patient subgroups these benefits arise, and to compare different strategies for subsequent management. DESIGN: An economic analysis using the School for Public Health Research CVD Prevention Model. SETTING: England 2018. PARTICIPANTS: Adults aged 16 and older with one or more high cardiovascular risk conditions, including hypertension, diabetes, non-diabetic hyperglycaemia, atrial fibrillation, chronic kidney disease and high cholesterol. INTERVENTIONS: Detection of 100% of individuals with CVD high risk conditions compared with current levels of detection in England. Detected individuals are assumed to be managed either according to current levels of care or National Institute of Health and Care Excellence (NICE) guidelines. MAIN OUTCOME MEASURES: Incremental and cumulative costs, savings, quality adjusted life years (QALYs), CVD cases, and net monetary benefit, from a UK NHS and Personal Social Services perspective. RESULTS: £68 billion could be saved, 4.9 million QALYs gained and 3.4 million cases of CVD prevented over 25 years if all individuals in England with the six CVD high risk conditions were diagnosed and subsequently managed at current levels. Additionally, if all detected individuals were managed according to NICE guidelines, total savings would be £61 billion, 8.1 million QALYs would be gained and 5.2 million CVD cases prevented. Most benefits come from detection of high cholesterol in the short term and diabetes in the long term. CONCLUSIONS: Substantial cost savings and health benefits would accrue if all individuals with conditions that increase CVD risk could be diagnosed, with detection of undiagnosed diabetes producing greatest benefits. Ensuring all conditions are managed according to NICE guidelines would further increase health benefits. Projected cost-savings could be invested in developing acceptable and cost-effective solutions for improving detection and management.

Denosumab, raloxifene, romosozumab and teriparatide to prevent osteoporotic fragility fractures: a systematic review and economic evaluation.

BACKGROUND: Fragility fractures are fractures that result from mechanical forces that would not ordinarily result in fracture. OBJECTIVES: The objectives were to evaluate the clinical effectiveness, safety and cost-effectiveness of non-bisphosphonates {denosumab [Prolia®; Amgen Inc., Thousand Oaks, CA, USA], raloxifene [Evista®; Daiichi Sankyo Company, Ltd, Tokyo, Japan], romosozumab [Evenity®; Union Chimique Belge (UCB) S.A. (Brussels, Belgium) and Amgen Inc.] and teriparatide [Forsteo®; Eli Lilly and Company, Indianapolis, IN, USA]}, compared with each other, bisphosphonates or no treatment, for the prevention of fragility fracture. DATA SOURCES: For the clinical effectiveness review, nine electronic databases (including MEDLINE, EMBASE and the World Health Organization International Clinical Trials Registry Platform) were searched up to July 2018. REVIEW METHODS: A systematic review and network meta-analysis of fracture and femoral neck bone mineral density were conducted. A review of published economic analyses was undertaken and a model previously used to evaluate bisphosphonates was adapted. Discrete event simulation was used to estimate lifetime costs and quality-adjusted life-years for a simulated cohort of patients with heterogeneous characteristics. This was done for each non-bisphosphonate treatment, a strategy of no treatment, and the five bisphosphonate treatments previously evaluated. The model was populated with effectiveness evidence from the systematic review and network meta-analysis. All other parameters were estimated from published sources. An NHS and Personal Social Services perspective was taken, and costs and benefits were discounted at 3.5% per annum. Fracture risk was estimated from patient characteristics using the QFracture® (QFracture-2012 open source revision 38, Clinrisk Ltd, Leeds, UK) and FRAX® (web version 3.9, University of Sheffield, Sheffield, UK) tools. The relationship between fracture risk and incremental net monetary benefit was estimated using non-parametric regression. A probabilistic sensitivity analysis and scenario analyses were used to assess uncertainty. RESULTS: Fifty-two randomised controlled trials of non-bisphosphonates were included in the clinical effectiveness systematic review and an additional 51 randomised controlled trials of bisphosphonates were included in the network meta-analysis. All treatments had beneficial effects compared with placebo for vertebral, non-vertebral and hip fractures, with hazard ratios varying from 0.23 to 0.94, depending on treatment and fracture type. The effects on vertebral fractures and the percentage change in bone mineral density were statistically significant for all treatments. The rate of serious adverse events varied across trials (0-33%), with most between-group differences not being statistically significant for comparisons with placebo/no active treatment, non-bisphosphonates or bisphosphonates. The incremental cost-effectiveness ratios were > £20,000 per quality-adjusted life-year for all non-bisphosphonate interventions compared with no treatment across the range of QFracture and FRAX scores expected in the population eligible for fracture risk assessment. The incremental cost-effectiveness ratio for denosumab may fall below £30,000 per quality-adjusted life-year at very high levels of risk or for high-risk patients with specific characteristics. Raloxifene was dominated by no treatment (resulted in fewer quality-adjusted life-years) in most risk categories. LIMITATIONS: The incremental cost-effectiveness ratios are uncertain for very high-risk patients. CONCLUSIONS: Non-bisphosphonates are effective in preventing fragility fractures, but the incremental cost-effectiveness ratios are generally greater than the commonly applied threshold of £20,000-30,000 per quality-adjusted life-year. STUDY REGISTRATION: This study is registered as PROSPERO CRD42018107651. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 29. See the NIHR Journals Library website for further project information.

BACKGROUND: Fragility fractures are fractures that result from mechanical forces that would not ordinarily result in fracture, known as low-level (or 'low-energy') trauma. Some people are at particularly high risk of fragility fractures. The first treatment used is often a bisphosphonate, but non-bisphosphonate treatments are alternatives. AIMS: We aimed to determine how effective non-bisphosphonates {denosumab [Prolia®; Amgen Inc., Thousand Oaks, CA, USA], raloxifene [Evista®; Daiichi Sankyo Company, Ltd, Tokyo, Japan], romosozumab [Evenity®; Union Chimique Belge (UCB) S.A. (Brussels, Belgium) and Amgen Inc.] and teriparatide [Forsteo®; Eli Lilly and Company, Indianapolis, IN, USA]} are at preventing fractures, whether or not treatment has any risks for patients and whether or not the clinical benefits are achieved at a reasonable cost. METHODS: We have systematically identified and examined trials that assessed the clinical effects of non-bisphosphonates. For each clinical outcome, we have combined data from multiple trials to estimate the clinical effectiveness of each non-bisphosphonate treatment. We combined data from published sources in an economic model to estimate lifetime costs and clinical benefits for each non-bisphosphonate and compared these with the estimated costs and clinical outcomes for untreated patients and patients treated with bisphosphonates. RESULTS: All non-bisphosphonates reduced the risk of vertebral fractures compared with no treatment. For fractures at the hip or at any non-vertebral site, all of the non-bisphosphonates reduced the average number of fractures, but, for some non-bisphosphonates, we could not exclude the possibility that this was a chance finding. The chance of patients experiencing serious side effects was generally similar regardless of whether patients took non-bisphosphonates, bisphosphonates or placebo (a dummy pill). Blood clots were more common in patients taking raloxifene than in those taking placebo, but these were still a rare outcome (fewer than 1 in 100). The benefits of denosumab, teriparatide and romosozumab are few compared with their costs. For raloxifene, the risks generally outweigh the benefits. Treatment with bisphosphonates is likely to represent better value for money than treatment with non-bisphosphonates.

Clinical and Economic Impact of a Two-layer Compression System for the Treatment of Venous Leg Ulcers: A Systematic Review.

OBJECTIVE: This study evaluates the clinical and cost effectiveness of a 2-layer compression system (2LBA; 3M Coban Two-Layer Compression System; 3M, St Paul, MN) compared with other 2-layer (2LB) and 4-layer (4LB) compression systems in patients with noninfected venous leg ulcers (VLUs). METHODS: The MEDLINE, EMBASE, CINAHL, Cochrane Library, National Health Service (NHS) Economic Evaluation, and EconLit databases were searched from inception up to January 2017. The MEDLINE search was updated on March 31, 2017. Study selection, quality assessment, and data synthesis were undertaken in accordance with recommended standards. Findings were presented narratively. RESULTS: In total, 5 studies (N = 1509 patients) of mixed methodological quality were included. At 6 months, 2LBA achieved better ulcer healing in comparison with 2LBB (odds ratio [OR], 1.57; 95% confidence interval [CI], 1.10-2.24; P = .03) and 4LBA (OR, 1.93, 95% CI, 1.26-2.97; P = .05) in patients with newly diagnosed ulcers only. For a combined population with newly diagnosed and existing VLUs, healing outcomes were OR, 2.87; 95% CI, 1.06-7.77; P = .04, and OR, 16.51; 95% CI, 2.08-131.37; P = .008, for 2LBs and 4LBs, respectively. Results on slippage were inconclusive. Adverse events were infrequent and did not differ significantly between interventions. Lower 6-month NHS costs for the combined population (£2413 vs. £2707 or £2648) and for newly diagnosed patients (£3045 vs. £3842 or £4480) were observed comparing 2LBA with 2LBB or 4LBA. Also, 2LBA was associated with better health-related quality of life (HRQoL) at 6 months. CONCLUSIONS: Based on these findings, 2LBA may result in lower treatment costs and better ulcer healing and HRQoL compared with other multicomponent therapies, especially in patients with newly diagnosed VLUs. However, further high-quality research is needed, especially for outcomes such as slippage and bandage wear time.

Global respiratory syncytial virus-associated mortality in young children (RSV GOLD): a retrospective case series.

BACKGROUND: Respiratory syncytial virus (RSV) infection is an important cause of pneumonia mortality in young children. However, clinical data for fatal RSV infection are scarce. We aimed to identify clinical and socioeconomic characteristics of children aged younger than 5 years with RSV-related mortality using individual patient data. METHODS: In this retrospective case series, we developed an online questionnaire to obtain individual patient data for clinical and socioeconomic characteristics of children aged younger than 5 years who died with community-acquired RSV infection between Jan 1, 1995, and Oct 31, 2015, through leading research groups for child pneumonia identified through a comprehensive literature search and existing research networks. For the literature search, we searched PubMed for articles published up to Feb 3, 2015, using the key terms "RSV", "respiratory syncytial virus", or "respiratory syncytial viral" combined with "mortality", "fatality", "death", "died", "deaths", or "CFR" for articles published in English. We invited researchers and clinicians identified to participate between Nov 1, 2014, and Oct 31, 2015. We calculated descriptive statistics for all variables. FINDINGS: We studied 358 children with RSV-related in-hospital death from 23 countries across the world, with data contributed from 31 research groups. 117 (33%) children were from low-income or lower middle-income countries, 77 (22%) were from upper middle-income countries, and 164 (46%) were from high-income countries. 190 (53%) were male. Data for comorbidities were missing for some children in low-income and middle-income countries. Available data showed that comorbidities were present in at least 33 (28%) children from low-income or lower middle-income countries, 36 (47%) from upper middle-income countries, and 114 (70%) from high-income countries. Median age for RSV-related deaths was 5·0 months (IQR 2·3-11·0) in low-income or lower middle-income countries, 4·0 years (2·0-10·0) in upper middle-income countries, and 7·0 years (3·6-16·8) in high-income countries. INTERPRETATION: This study is the first large case series of children who died with community-acquired RSV infection. A substantial proportion of children with RSV-related death had comorbidities. Our results show that perinatal immunisation strategies for children aged younger than 6 months could have a substantial impact on RSV-related child mortality in low-income and middle-income countries. FUNDING: Bill & Melinda Gates Foundation.

The Relationship between Hospital or Surgeon Volume and Outcomes in Lower Limb Vascular Surgery in the United Kingdom and Europe.

BACKGROUND: Peripheral vascular disease is a major cause of death and disability. The extent to which volume influences outcome of lower limb (LL) vascular surgery remains unclear. This review evaluated the relationship between hospital/surgeon volume and outcome in LL surgery. METHODS: Electronic databases-MEDLINE, Embase, the Cochrane Library Databases, Science Citation Index, and CINAHL-proceedings from conferences, citations, and references of included studies were searched. Studies from Europe, of adults undergoing LL vascular surgery reporting outcomes by hospital or surgeon volume were included. The quality of studies was assessed using a modified Cochrane Risk Of Bias Assessment Tool: for Non-Randomized Studies of Interventions (Robins1) tool. The association between hospital/surgeon volume and outcome was summarized using tables. RESULTS: Nine studies from different European countries, comprising 67,445 patients who had undergone diverse LL surgeries were included. The increase in hospital/surgeon volume was associated with a decrease in post-operative amputations (hospital at 30 days [odds ratio {OR}: 0.20, 95% confidence interval {CI} 0.29-0.45, P = 0.01; OR: 0.67, 95% CI 0.44-0.9, P = 0.05; OR: 0.96, 95% CI 0.92-1.00, P = 0.06], at 1 year [OR: 0.96, 95% CI 0.93-0.98, P = 0.002; OR: 0.66, 95% CI 0.52-0.84, P < 0.001; OR: 2.05, 95% CI 1.24-3.42, P = 0.01], surgeon at 30 days [OR: 0.53, 95% CI 0.36-0.87, P = 0.01; OR: 0.40, 95% CI 0.18-0.91, P = 0.03; OR: 0.41, 95% CI 0.24-0.69, P = 0.0006]). The evidence on an association between hospital/surgeon volume and mortality was contradictory, but mortality and amputations may covary by hospital volume. There were an insufficient number of studies reporting on the other variables to draw firm conclusions, but their results suggest that high-volume hospitals may undertake more repeated surgeries/revascularizations and limb salvage. The impact of hospital/surgical volume on adverse events and length of hospitalization could not be determined. CONCLUSIONS: High-volume hospitals/surgeons may undertake fewer amputations and mortality and amputations may covary. The finding that hospital and surgeon volume affected the number of secondary amputations has implications on reorganization of vascular surgery services. However, due to the small number and poor quality of some of the included studies, decisions on reorganization of LL vascular surgery services should be supplemented by results from clinical audits. There is need for standardization of definition of volume stratification of outcomes by patient's clinical conditions.

Certolizumab Pegol for Treating Rheumatoid Arthritis Following Inadequate Response to a TNF-α Inhibitor: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of its single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (UCB Pharma) of certolizumab pegol (CZP; Cimzia®) to submit evidence of its clinical and cost effectiveness for the treatment of rheumatoid arthritis (RA) following inadequate response to a tumour necrosis factor-α inhibitor (TNFi). The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a detailed review of the evidence for the clinical and cost effectiveness of the technology, based upon the company's submission to NICE. The clinical effectiveness evidence in the company's submission for CZP was based predominantly on six randomised controlled trials (RCTs) comparing the efficacy of CZP against placebo. The clinical effectiveness review identified no head-to-head evidence on the efficacy of CZP against the comparators within the scope; therefore, the company performed a network meta-analysis (NMA). The company's NMA concluded that CZP had a similar efficacy to that of its comparators. The company submitted a Markov model that assessed the incremental cost effectiveness of CZP versus comparator biologic disease-modifying antirheumatic drugs (bDMARDs) for the treatment of RA from the perspective of the National Health Service for three decision problems, each of which followed an inadequate response to a TNFi. These were (1) a comparison against rituximab (RTX) in combination with methotrexate (MTX); (2) a comparison against bDMARDs when RTX was contraindicated or withdrawn due to an adverse event; and (3) a comparison against bDMARDs when MTX was contraindicated or withdrawn due to an adverse event. Results from the company's economic evaluation showed that CZP resulted in a similar number of quality-adjusted life years (QALYs) produced at similar or lower costs compared with comparator bDMARDs. The commercial-in-confidence patient access schemes for abatacept and tocilizumab could not be incorporated by the company, but were incorporated by the ERG in a confidential appendix for the NICE Appraisal Committee (AC). The company estimated that the addition of CZP before RTX in a sequence for patients who could receive MTX produced more QALYs at an increased cost, with a cost per QALY of £33,222. Following a critique of the model, the ERG undertook exploratory analyses that did not change the conclusions reached based on the company's economic evaluation in relation to the comparison with bDMARDs. The ERG estimated that where CZP replaced RTX, CZP was dominated, as it produced fewer QALYs at an increased cost. The AC concluded that there was little difference in effectiveness between CZP and comparator bDMARDs and that equivalence among bDMARDs could be accepted. The AC consequently recommended CZP plus MTX for people for whom RTX is contraindicated or not tolerated and CZP monotherapy for people for whom MTX is contraindicated or not tolerated. The AC concluded that CZP plus MTX could not be considered a cost-effective use of National Health Service resources when RTX plus MTX is a treatment option.

A systematic review and economic evaluation of bisphosphonates for the prevention of fragility fractures.

BACKGROUND: Fragility fractures are fractures that result from mechanical forces that would not ordinarily result in fracture. OBJECTIVES: To evaluate the clinical effectiveness and safety of bisphosphonates [alendronic acid (Fosamax® and Fosamax® Once Weekly, Merck Sharp & Dohme Ltd), risedronic acid (Actonel® and Actonel Once a Week®, Warner Chilcott UK Ltd), ibandronic acid (Bonviva®, Roche Products Ltd) and zoledronic acid (Aclasta®, Novartis Pharmaceuticals UK Ltd)] for the prevention of fragility fracture and to assess their cost-effectiveness at varying levels of fracture risk. DATA SOURCES: For the clinical effectiveness review, six electronic databases and two trial registries were searched: MEDLINE, EMBASE, The Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, Web of Science and BIOSIS Previews, Clinicaltrials.gov and World Health Organization International Clinical Trials Registry Platform. Searches were limited by date from 2008 until September 2014. REVIEW METHODS: A systematic review and network meta-analysis (NMA) of effectiveness studies were conducted. A review of published economic analyses was undertaken and a de novo health economic model was constructed. Discrete event simulation was used to estimate lifetime costs and quality-adjusted life-years (QALYs) for each bisphosphonate treatment strategy and a strategy of no treatment for a simulated cohort of patients with heterogeneous characteristics. The model was populated with effectiveness evidence from the systematic review and NMA. All other parameters were estimated from published sources. A NHS and Personal Social Services perspective was taken, and costs and benefits were discounted at 3.5% per annum. Fracture risk was estimated from patient characteristics using the QFracture® (QFracture-2012 open source revision 38, Clinrisk Ltd, Leeds, UK) and FRAX® (web version 3.9, University of Sheffield, Sheffield, UK) tools. The relationship between fracture risk and incremental net benefit (INB) was estimated using non-parametric regression. Probabilistic sensitivity analysis (PSA) and scenario analyses were used to assess uncertainty. RESULTS: Forty-six randomised controlled trials (RCTs) were included in the clinical effectiveness systematic review, with 27 RCTs providing data for the fracture NMA and 35 RCTs providing data for the femoral neck bone mineral density (BMD) NMA. All treatments had beneficial effects on fractures versus placebo, with hazard ratios varying from 0.41 to 0.92 depending on treatment and fracture type. The effects on vertebral fractures and percentage change in BMD were statistically significant for all treatments. There was no evidence of a difference in effect on fractures between bisphosphonates. A statistically significant difference in the incidence of influenza-like symptoms was identified from the RCTs for zoledronic acid compared with placebo. Reviews of observational studies suggest that upper gastrointestinal symptoms are frequently reported in the first month of oral bisphosphonate treatment, but pooled analyses of placebo-controlled trials found no statistically significant difference. A strategy of no treatment was estimated to have the maximum INB for patients with a 10-year QFracture risk under 1.5%, whereas oral bisphosphonates provided maximum INB at higher levels of risk. However, the PSA suggested that there is considerable uncertainty regarding whether or not no treatment is the optimal strategy until the QFracture score is around 5.5%. In the model using FRAX, the mean INBs were positive for all oral bisphosphonate treatments across all risk categories. Intravenous bisphosphonates were estimated to have lower INBs than oral bisphosphonates across all levels of fracture risk when estimated using either QFracture or FRAX. LIMITATIONS: We assumed that all treatment strategies are viable alternatives across the whole population. CONCLUSIONS: Bisphosphonates are effective in preventing fragility fractures. However, the benefit-to-risk ratio in the lowest-risk patients may be debatable given the low absolute QALY gains and the potential for adverse events. We plan to extend the analysis to include non-bisphosphonate therapies. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013006883. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Clinical effectiveness of bisphosphonates for the prevention of fragility fractures: A systematic review and network meta-analysis.

OBJECTIVES: To assess the relative efficacy of bisphosphonates (alendronate, risedronate, ibandronate and zoledronic acid) for the treatment of osteoporosis using network meta-analysis (NMA). METHODS: A systematic review of the literature was conducted using PRISMA guidelines. A network meta-analysis was used to determine the relative efficacy of treatments on four fracture outcomes (vertebral, non-vertebral, hip and wrist) and percentage change in femoral neck bone mineral density (BMD). Treatment effects were modelled using an exchangeable treatment effects model. Heterogeneity in treatment effects was explored by considering potential treatment effect modifiers using meta-regression. Where appropriate, inconsistency between direct and indirect evidence was assessed using node-splitting. RESULTS: 46 randomised controlled trials (RCTs) were identified. Twenty seven RCTs provided fracture data and 35 RCTs provided BMD data for analysis. Zoledronic acid was associated with the greatest treatment effect on vertebral fractures (HR 0.41, 95% CrI: 0.28, 0.56) and percentage change in BMD (3.21, 95%: CrI 2.52, 3.86) compared to placebo. The greatest treatment effect on non-vertebral and wrist fractures was given by risedronate (HR 0.72, 95%: CrI 0.53, 0.89 and HR 0.77, 95%: CrI 0.44, 1.24, respectively). For hip fractures the greatest treatment effect was given by alendronate (HR 0.78, 95% CrI: 0.44, 1.30). CONCLUSIONS: All treatments examined were associated with beneficial effects on fractures and femoral neck BMD relative to placebo. For vertebral fractures and percentage change in femoral neck BMD the treatment effects were statistically significant for all treatments. Pairwise comparisons between treatments indicated that no active treatment was statistically significantly more effective than any other active treatment for fracture outcomes. There was some heterogeneity in treatment effects between studies suggesting differential treatment effects according to study characteristics; however, there was no evidence of differential treatment effects with respect to gender and age.

Single and multiple respiratory virus infections and severity of respiratory disease: a systematic review.

INTRODUCTION: There are suggestions that virus co-infections may influence the clinical outcome of respiratory virus illness. We performed a systematic review of the literature to summarise the evidence. METHODS: MEDLINE, EMBASE, Ovid and WEB of Science databases, major organisation websites and reference lists of published studies were searched. The quality of studies was assessed using the STROBE tool (von Elm et al., 1) Individual study data was analyzed using odds ratios and 95% confidence intervals as a measure of association between exposure (co-infection), patient outcome and results summarised using forest plots and tables RESULTS: Nineteen (19) studies from all over the world were identified and included in the review. Most of the studies 73.7% (14/19) recruited children ≤ 6 years old. Evidence on the role of co-infection in increasing disease severity was inconclusive. In five out of eight studies, co-infection significantly increased risk of admission to general ward (OR: 2.4, 95% CI: 1.3 - 4.4, p = 0.005; OR: 2.4, 95% CI: 1.1 - 7.7, P = 0.04; OR: 3.1, 95% CI: 2.0 - 5.1, p = <0.001; OR: 2.4, 95% CI: 1.7-3.4, p = <0.0001 and OR: 2.3, 95% CI: 1.1 - 5.1, p = 0.34), one found it did not (OR: 0.59, 95% CI: 0.4 - 0.9, p = 0.02) and the other 2 had insignificant results. Similarly on risk of admission to ICU, some studies found that co-infection significantly increased risk of admission to ICU (OR: 2.9, 95% CI: 1.4 - 5.9, p = 0.004 and OR: 3.0, 95% CI: 1.7 - 5.6, p = <0.0001), whereas others did not (OR: 0.18, 95% CI: 0.05 - 0.75, p = 0.02 and OR: 0.3, 95% CI: 0.2 - 0.6, p = <0.0001). There was no evidence for or against respiratory virus co-infections and risk of bronchiolitis or pneumonia. CONCLUSION: The influence of co-infections on severe viral respiratory disease is still unclear. The observed conflict in outcomes could be because they were conducted in different seasons and covered different years and periods. It could also be due to bias towards the null, especially in studies where only crude analysis was conducted. Future studies should employ stratified analysis.

Influenza A viruses dual and multiple infections with other respiratory viruses and risk of hospitalisation and mortality.

INTRODUCTION: Recent literature suggests that dual or multiple virus infections may affect disease severity. However, few studies have investigated the effect of co-infection with influenza A viruses. OBJECTIVES: To identify the association between influenza A and respiratory viruses co-infections with disease outcome. METHODOLOGY: Data for samples from North West England tested between January 2007 and June 2011 was analysed for patterns of co-infection between influenza A viruses and eight respiratory viruses. Risk of hospitalisation to ICU or general ward in single versus co-infections was assessed using logistic regression. RESULTS: Of the 25,596 samples analysed for respiratory viruses 40·7% (10,501) were positive for any virus. Co-infections were detected in 4·7% (137/2879) of all patients with influenza A(H1N1)pdm09, and 7·3% (57/779) of those with other influenza A virus infections. Co-infection between seasonal influenza A viruses and influenza B virus was associated with a significant increase in the risk of admission to ICU/death (OR: 22·0, 95% CI: 2·21-219·8, P=0·008). Respiratory syncytial virus/influenza A (RSV/Flu A) co-infection also increased this risk but was not statistically significant. For influenza A(H1N1)pdm09, RSV and AdV co-infection increased risk of hospitalisation to general ward whereas Flu B increased risk of admission to ICU, but none of these were statistically significant. CONCLUSION: Co-infection is a significant predictor of disease outcome; combined treatment, introduction of an integrated vaccine for all respiratory viruses and development of multi-target rapid diagnostic tests is recommended. Integration of respiratory viruses' co-infections into public health reports could also contribute to the accumulation of evidence.