Nosocomial acquisition of influenza is associated with significant morbidity and mortality: Results of a prospective observational study.

BACKGROUND: Nosocomial acquisition of influenza is known to occur but the risk after exposure to a known case and the outcomes after acquisition are poorly defined. METHODS: Prospective observational study of patients exposed to influenza from another patient in a multi-site healthcare organisation, with follow-up of 7 days or until discharge, and PCR-confirmation of symptomatic disease. Multivariable analysis was used to investigate association of influenza acquisition with high dependency unit/intensive care unit (HDU/ITU) admission and in-hospital mortality. RESULTS: 23/298 (7.7%) contacts of 11 cases were subsequently symptomatic and tested influenza-positive during follow-up. HDU/ITU admission was significantly higher in these secondary cases (6/23, 26%) compared to flu-negative contacts (20/275, 7.2%; p = 0.002). In-hospital mortality was significantly higher in secondary cases (5/23, 21.7%) compared to flu-negative contacts (11/275, 4%; p < 0.001). In multivariable analysis, age (OR 1.25 95% CI: 1.01-1.54, p = 0.02) and being a secondary case (OR 4.77, 95% CI: 1.63-13.9, p = 0.008) were significantly associated with HDU/ITU admission in contacts. Age (OR 1.00, 95% CI: 0.93-1.00, p = 0.02), being a secondary case after exposure to influenza (OR 3.81, 95% CI 1.09-13.3, p = 0.049) and co-morbidity (OR 1.29 per unit increment in the Charlson score, 95% CI 1.02-1.61, p = 0.03) were significantly associated with in-hospital mortality in contacts. CONCLUSIONS: Nosocomial acquisition of influenza was significantly associated with increased risk of HDU/ITU admission and in-hospital mortality.

Self-sampling for community respiratory illness: a new tool for national virological surveillance.

This report aims to evaluate the usefulness of self-sampling as an approach for future national surveillance of emerging respiratory infections by comparing virological data from two parallel surveillance schemes in England. Nasal swabs were obtained via self-administered sampling from consenting adults (≥ 16 years-old) with influenza symptoms who had contacted the National Pandemic Flu Service (NPFS) health line during the 2009 influenza pandemic. Equivalent samples submitted by sentinel general practitioners participating in the national influenza surveillance scheme run jointly by the Royal College of General Practitioners (RCGP) and Health Protection Agency were also obtained. When comparable samples were analysed there was no significant difference in results obtained from self-sampling and clinician-led sampling schemes. These results demonstrate that self-sampling can be applied in a responsive and flexible manner, to supplement sentinel clinician-based sampling, to achieve a wide spread and geographically representative way of assessing community transmission of a known organism.

Effectiveness of trivalent seasonal influenza vaccine in preventing laboratory-confirmed influenza in primary care in the United Kingdom: 2012/13 end of season results.

The effectiveness of the 2012/13 trivalent seasonal influenza vaccine (TIV) was assessed using a test-negative case-control study of patients consulting primary care with influenza-like illness in the United Kingdom. Strain characterisation was undertaken on selected isolates. Vaccine effectiveness (VE) against confirmed influenza A(H3N2), A(H1N1) and B virus infection, adjusted for age, sex, surveillance scheme (i.e. setting) and month of sample collection was 26% (95% confidence interval (CI): -4 to 48), 73% (95% CI: 37 to 89) and 51% (95% CI: 34 to 63) respectively. There was an indication, although not significant, that VE declined by time since vaccination for influenza A(H3N2) (VE 50% within three months, 2% after three months, p=0.25). For influenza A(H3N2) this is the second season of low VE, contributing to the World Health Organization (WHO) recommendation that the 2013/14 influenza vaccine strain composition be changed to an A(H3N2) virus antigenically like cell-propagated prototype 2012/13 vaccine strain (A/Victoria/361/2011). The lower VE seen for type B is consistent with antigenic drift away from the 2012/13 vaccine strain. The majority of influenza B viruses analysed belong to the genetic clade 2 and were antigenically distinguishable from the 2012/13 vaccine virus B/Wisconsin/1/2010 clade 3. These findings supported the change to the WHO recommended influenza B vaccine component for 2013/14.

Y155H amino acid substitution in influenza A(H1N1)pdm09 viruses does not confer a phenotype of reduced susceptibility to neuraminidase inhibitors.

The Y155H amino acid substitution in the neuraminidase gene (NA) has previously been associated with highly reduced inhibition by neuraminidase inhibitors in the seasonal H1N1 influenza A virus which circulated in humans before the 2009 pandemic. During the 2012/13 epidemic season in Spain, two A(H1N1) pdm09 viruses bearing the specific Y155H substitution in the NA were detected and isolated from two patients diagnosed with severe respiratory syndrome and pneumonia requiring admission to the intensive care unit. Contrary to what was observed in the seasonal A(H1N1) viruses, neither of the Y155H A(H1N1) pdm09 viruses described here showed a phenotype of reduced inhibition by NAIs as determined by the neuraminidase enzyme inhibition assay (MUNANA). High-throughput sequencing of the NA of both Y155H viruses showed that they were composed to >99% of H155 variants. We believe that this report can contribute to a better understanding of the biological significance of amino acid substitutions in the neuraminidase protein with regard to susceptibility of influenza viruses to neuraminidase inhibitors. This is of critical importance for optimal management of influenza disease patients.

A new laboratory-based surveillance system (Respiratory DataMart System) for influenza and other respiratory viruses in England: results and experience from 2009 to 2012.

During the 2009 influenza A(H1N1) pandemic, a new laboratory-based virological sentinel surveillance system, the Respiratory DataMart System (RDMS), was established in a network of 14 Health Protection Agency (now Public Health England (PHE)) and National Health Service (NHS) laboratories in England. Laboratory results (both positive and negative) were systematically collected from all routinely tested clinical respiratory samples for a range of respiratory viruses including influenza, respiratory syncytial virus (RSV), rhinovirus, parainfluenza virus, adenovirus and human metapneumovirus (hMPV). The RDMS also monitored the occurrence of antiviral resistance of influenza viruses. Data from the RDMS for the 2009­2012 period showed that the 2009 pandemic influenza virus caused three waves of activity with different intensities during the pandemic and post pandemic periods. Peaks in influenza A(H1N1)pdm09 positivity (defined as number of positive samples per total number of samples tested) were seen in summer and autumn in 2009, with slightly higher peak positivity observed in the first post-pandemic season in 2010/2011. The influenza A(H1N1)pdm09 virus strain almost completely disappeared in the second postpandemic season in 2011/2012. The RDMS findings are consistent with other existing community-based virological and clinical surveillance systems. With a large sample size, this new system provides a robust supplementary mechanism, through the collection of routinely available laboratory data at minimum extra cost, to monitor influenza as well as other respiratory virus activity. A near real-time, daily reporting mechanism in the RDMS was established during the London 2012 Olympic and Paralympic Games. Furthermore, this system can be quickly adapted and used to monitor future influenza pandemics and other major outbreaks of respiratory infectious disease, including novel pathogens.

Effectiveness of seasonal 2012/13 vaccine in preventing laboratory-confirmed influenza infection in primary care in the United Kingdom: mid-season analysis 2012/13.

The early experience of the United Kingdom (UK) is that influenza B has dominated the influenza 2012/13 season. Overall trivalent influenza vaccine (TIV) adjusted vaccine effectiveness (VE) against all laboratory-confirmed influenza in primary care was 51% (95% confidence interval (CI): 27% to 68%); TIV adjusted VE against influenza A alone or influenza B alone was 49% (95% CI: -2% to 75%) and 52% (95% CI: 23% to 70%) respectively. Vaccination remains the best protection against influenza.

Evaluation of influenza virus antiviral susceptibility testing in Europe: results from the first external quality assessment exercise.

BACKGROUND: The first antiviral susceptibility testing external quality assessment (EQA) was held for European influenza reference laboratories during winter 2010/11. OBJECTIVES: To assess European network influenza antiviral susceptibility testing capability and provide participants with an independent performance evaluation. STUDY DESIGN: The EQA panel contained ten coded specimens of inactivated human influenza A and B viruses with reduced susceptibility to neuraminidase inhibitors (NAI), or adamantanes. Twenty-four laboratories from 19 member states of the WHO European region analysed the panel using phenotypic (determination of 50% inhibitory concentration (IC(50)) values by neuraminidase (NA) enzyme inhibition assay) and/or genotypic methods. RESULTS: All 24 laboratories returned genotypic data for A(H1N1)pdm09 influenza virus, 18 (75%) for former seasonal A(H1N1), 16 (67%) for A(H3N2) and 15 (63%) for influenza B virus, correctly identifying NAI or adamantane reduced susceptibility-associated substitutions in the NA (mean 84%; range 52-100%) or M2 (mean 85%; range 73-94%), respectively. Thirteen laboratories (54%) returned phenotypic NAI susceptibility data. Despite inter-laboratory and inter-assay IC(50) value variation, all 13 laboratories correctly identified oseltamivir reduced susceptibility/resistance in pure preparations of A(H1N1) oseltamivir-resistant viruses. However, only 11 (85%) identified oseltamivir reduced susceptibility/resistance in a mixture of A(H1N1)pdm09 oseltamivir-sensitive/-resistant viruses. Furthermore, 3 laboratories (23%) considered oseltamivir-sensitive influenza B virus reduced susceptible/resistant. CONCLUSIONS: Detection of NA-H275Y in A(H1N1) viruses was achieved by most laboratories. IC(50) values and interpretation thereof varied for a sensitive/resistant virus mixture and for influenza B virus. The results of this exercise will assist harmonisation of antiviral susceptibility testing, interpretation and reporting within the European network through targeted training.

Continued emergence and changing epidemiology of oseltamivir-resistant influenza A(H1N1)2009 virus, United Kingdom, winter 2010/11.

During the winter period 2010/11 27 epidemiologically unlinked, confirmed cases of oseltamivir-resistant influenza A(H1N1)2009 virus infection have been detected in multiple, geographically dispersed settings. Three of these cases were in community settings, with no known exposure to oseltamivir. This suggests possible onward transmission of resistant strains and could be an indication of a possibility of changing epidemiology of oseltamivir-resistant influenza A(H1N1)2009 virus.

Virological analysis of fatal influenza cases in the United Kingdom during the early wave of influenza in winter 2010/11.

The 2010/11 winter influenza season is underway in the United Kingdom, with co-circulation of influenza A(H1N1)2009 (antigenically similar to the current 2010/11 vaccine strain), influenza B (mainly B/Victoria/2/87 lineage, similar to the 2010/11 vaccine strain) and a few sporadic influenza A(H3N2) viruses. Clinical influenza activity has been increasing. Severe illness, resulting in hospitalisation and deaths, has occurred in children and young adults and has predominantly been associated with influenza A(H1N1)2009, but also influenza B viruses.

Influenza antiviral susceptibility monitoring activities in relation to national antiviral stockpiles in Europe during the winter 2006/2007 season.

Due to the influenza pandemic threat, many countries are stockpiling antivirals in the hope of limiting the impact of a future pandemic virus. Since resistance to antiviral drugs would probably significantly alter the effectiveness of antivirals, surveillance programmes to monitor the emergence of resistance are of considerable importance. During the 2006/2007 influenza season, an inventory was conducted by the European Surveillance Network for Vigilance against Viral Resistance (VIRGIL) in collaboration with the European Influenza Surveillance Scheme (EISS) to evaluate antiviral susceptibility testing by the National Influenza Reference Laboratories (NIRL) in relation to the national antiviral stockpile in 30 European countries that are members of EISS. All countries except Ukraine had a stockpile of the neuraminidase inhibitor (NAI) oseltamivir. Additionally, four countries had a stockpile of the NAI zanamivir and three of the M2 ion channel inhibitor rimantadine. Of 29 countries with a NAI stockpile, six countries' NIRLs could determine virus susceptibility by 50% inhibitory concentration (IC50) and in 13 countries it could be done by sequencing. Only in one of the three countries with a rimantadine stockpile could the NIRL determine virus susceptibility, by sequencing only. However, including the 18 countries that had plans to introduce or extend antiviral susceptibility testing, the NIRLs of 21 of the 29 countries with a stockpile would be capable of susceptibility testing appropriate to the stockpiled drug by the end of the 2007/2008 influenza season. Although most European countries in this study have stockpiles of influenza antivirals, susceptibility surveillance capability by the NIRLs appropriate to the stockpiled antivirals is limited.

NS1 proteins of avian influenza A viruses can act as antagonists of the human alpha/beta interferon response.

Many viruses, including human influenza A virus, have developed strategies for counteracting the host type I interferon (IFN) response. We have explored whether avian influenza viruses were less capable of combating the type I IFN response in mammalian cells, as this might be a determinant of host range restriction. A panel of avian influenza viruses isolated between 1927 and 1997 was assembled. The selected viruses showed variation in their ability to activate the expression of a reporter gene under the control of the IFN-beta promoter and in the levels of IFN induced in mammalian cells. Surprisingly, the avian NS1 proteins expressed alone or in the genetic background of a human influenza virus controlled IFN-beta induction in a manner similar to the NS1 protein of human strains. There was no direct correlation between the IFN-beta induction and replication of avian influenza viruses in human A549 cells. Nevertheless, human cells deficient in the type I IFN system showed enhanced replication of the avian viruses studied, implying that the human type I IFN response limits avian influenza viruses and can contribute to host range restriction.

Variation in the ability of human influenza A viruses to induce and inhibit the IFN-beta pathway.

We investigated the ability of a selection of human influenza A viruses, including recent clinical isolates, to induce IFN-beta production in cultured cell lines. In contrast to the well-characterized laboratory strain A/PR/8/34, several, but not all, recent isolates of H3N2 viruses resulted in moderate IFN-beta stimulation. Through the generation of recombinant viruses, we were able to show that this is not due to a loss of the ability of the NS1 genes to suppress IFN-beta induction; indeed, the NS1 genes behaved similarly with respect to their abilities to block dsRNA signaling. Interestingly, replication of A/Sydney/5/97 virus was less susceptible to pre-treatment with IFN-alpha than the other viruses. In contrast to the universal effect on dsRNA signaling, we noted differences in the effect of NS1 proteins on expression of interferon stimulated genes and also genes induced by a distinct pathway. The majority of NS1 proteins blocked expression from both IFN-dependent and TNF-dependent promoters by an apparent post-transcriptional mechanism. The NS1 gene of A/PR/8/34 NS1 did not confer these blocks. We noted striking differences in the cellular localization of different influenza A virus NS1 proteins during infection, which might explain differences in biological activity.