Edward Goka

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

Please cite this paper as: Goka et al. (2013) Influenza A viruses dual and multiple infections with other respiratory viruses and risk of hospitalisation and mortality. Influenza and Other Respiratory Viruses 7(6), 1079–1087.

Single, dual and multiple respiratory virus infections and risk of hospitalization and mortality.

Respiratory virus infections cause a significant number of hospitalization and deaths globally. This study investigated the association between single and multiple respiratory virus infections and risk of admission to a general ward, intensive care unit or death in patients aged 0-105 years (mean ± s.d. = 24·4 ± 24·1 years), from North West England, that were tested for respiratory virus infections between January 2007 and June 2012. The majority of infections were in children aged ⩽5 years. Dual or multiple infections occurred in 10·4% (1214/11 715) of patients, whereas single infection occurred in 89·6% (10 501/11 715). Rhinovirus was the most common co-infecting virus (occurring in 69·5%; 844/1214 of co-infections). In a multivariate logistic regression model, multiple infections were associated with an increased risk of admission to a general ward [odds ratio (OR) 1·43, 95% confidence interval (CI) 1·2-1·7, P < 0·0001]. On the other hand, patients with respiratory syncytial virus (RSV) and human parainfluenza virus types 1-3 (hPIV1-3), as a single infection, had a higher risk of being admitted to a general ward (OR 1·49, 95% CI 1·28-1·73, P < 0·0001 and OR 1·34, 95% CI 1·003-1·8, P = 0·05, respectively); admitted to an intensive-care unit or dying (OR 1·5, 95% CI 1·20-2·0, P = 0·001 and OR 1·60, 95% CI 1·02-2·40, P = 0·04, respectively). This result emphasizes the importance of RSV, hPIV and mixed infections and calls for research on vaccines, drugs and diagnostic tests targeting these respiratory viruses.

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

Abstract 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.

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

Summary 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.

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.

Systematic review of carotid artery procedures and the volume–outcome relationship in Europe

Hospitals that conduct more procedures on the carotid arteries may achieve better outcomes. In the context of ongoing reconfiguration of UK vascular services, this systematic review was conducted to evaluate the relationship between the volume of carotid procedures and outcomes, including mortality and stroke.

Systematic Review of Carotid Artery Procedures and the Volume-Outcome Relationship in Europe

Study design: This study was a search of studies that reported the effect of hospital or clinician volume on carotid endarterectomy (CEA) and stenting (CAS) outcomes restricted to European populations using MEDLINE, Embase, the Cochrane Library, Science Citation Index, and CINAHL from December 2014 to June 2016. Key findings: Eleven eligible studies were identified (233,411 participants): 5 from the UK, 2 from Sweden, 1 each from Germany, Finland, and Italy, and a combinedGerman,Austrian, andSwiss population. Two large studies (179,736patients) suggested an inverse relationshipbetweenhospital volumeandmortalityandcombinedmortality andstroke followingCEA.An inverse relationshipwasalso identifiedby2of3 small studiesofCEA.Theevidencewas lessclear for CAS;multiple analyses in three studiesdidnot identify convincingevidenceof anassociation. Limiteddata areavailableon the relationshipbetweenclinician volume and outcome in CAS. Conclusion: The evidence from the largest and highest-quality studies included in this review support the centralization of CEA. Commentary: Althoughmany studies have showna correlationbetweenhospital procedure volumeandoutcomes,manyhave also shown that themore important factor is thevolumeof the individual surgeonor interventionalist. Thisassociationmakes senseparticularly forCEA,where itwouldnotbesurprising that an outstanding vascular surgeon performing these operations at a small hospital where no one else performs CEAs obtained excellent results. Itmay be that the large-volumehospitalsdrawexcellentsurgeonsandthehospital itselfhas little impactonoutcomes.Theothervariable thathasbeenshowntohavea strong impact on CEA outcomes is the specialist performing the surgery. Several past studies have shown that vascular surgeons have better outcomes than general surgeons or neurosurgeons when performing CEA. The results of the current study are not surprising, but the plea for centralization of CEAsmakes senseonly if the surgeons at aparticular hospital havebeen shown toobtainexcellent results. On the otherhand, itmaybedifficult to expect a surgeon, especially a board-certified vascular surgeon, to tell patients to travel 2 hours, or even to go across town, to a hospital that doesmore CEAs than his or her hospital does, when that individual has tracked his or her own results andmet accepted standards in terms of low stroke andmortality rates.

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

Abstract 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.

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.