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Background The severity of influenza disease can range from mild symptoms to severe respiratory failure and can partly be explained by host genetic factors that predisposes the host to severe influenza. Here, we aimed to summarize the current state of evidence that host genetic variants play a role in the susceptibility to severe influenza infection by conducting a systematic review and performing a meta-analysis for all markers with at least three or more data entries. Results A total of 34 primary human genetic association studies were identified that investigated a total of 20 different genes. The only significant pooled ORs were retrieved for the rs12252 polymorphism: an overall OR of 1.52 (95% CI [1.06–2.17]) for the rs12252-C allele compared to the rs12252-T allele. A stratified analysis by ethnicity revealed opposite effects in different populations. Conclusion With exception for the rs12252 polymorphism, we could not identify specific genetic polymorphisms to be associated with severe influenza infection in a pooled meta-analysis. This advocates for the use of large, hypothesis-free, genome-wide association studies that account for the polygenic nature and the interactions with other host, pathogen and environmental factors.

The COVID-19 pandemic has caused us all to stop our normal activities and consider how we can safely return to caring for our patients. There are many common practices (such as an increased use of personal protective equipment) which we are all familiar with that can be easily incorporated into our daily routines. Other actions, such as cleaning more surfaces with solutions such as dilute povidone iodine or changing the air filtration systems used within operating room theaters, may require more extensive efforts on our behalf. In this article, we have attempted to highlight some of the changes that arthroplasty surgeons may need to instigate when we are able to resume elective joint arthroplasty procedures in an effort to disrupt the chain of pathogen transfer.

International audience; BACKGROUND: The global impact of the 2009 influenza A(H1N1) pandemic (H1N1pdm) is not well understood. OBJECTIVES: We estimate overall and age-specific prevalence of cross-reactive antibodies to H1N1pdm virus and rates of H1N1pdm infection during the first year of the pandemic using data from published and unpublished H1N1pdm seroepidemiological studies.METHODS: Primary aggregate H1N1pdm serologic data from each study were stratified in standardized age groups and evaluated based on when sera were collected in relation to national or subnational peak H1N1pdm activity. Seropositivity was assessed using well-described and standardized hemagglutination inhibition (HI titers ≥ 32 or ≥ 40) and microneutralization (MN ≥ 40) laboratory assays. The prevalence of cross-reactive antibodies to the H1N1pdm virus was estimated for studies using sera collected prior to the start of the pandemic (between 2004 and April 2009); H1N1pdm cumulative incidence was estimated for studies in which collected both pre- and post-pandemic sera; and H1N1pdm seropositivity was calculated from studies with post-pandemic sera only (collected between December 2009-June 2010).RESULTS: Data from 27 published/unpublished studies from 19 countries/administrative regions - Australia, Canada, China, Finland, France, Germany, Hong Kong SAR, India, Iran, Italy, Japan, Netherlands, New Zealand, Norway, Reunion Island, Singapore, United Kingdom, United States, and Vietnam - were eligible for inclusion. The overall age-standardized pre-pandemic prevalence of cross-reactive antibodies was 5% (95%CI 3-7%) and varied significantly by age with the highest rates among persons ≥ 65 years old (14% 95%CI 8-24%). Overall age-standardized H1N1pdm cumulative incidence was 24% (95%CI 20-27%) and varied significantly by age with the highest in children 5-19 (47% 95%CI 39-55%) and 0-4 years old (36% 95%CI 30-43%).CONCLUSIONS: Our results offer unique insight into the global impact of the H1N1 pandemic and highlight the need for standardization of seroepidemiological studies and for their inclusion in pre-pandemic preparedness plans. Our results taken together with recent global pandemic respiratory-associated mortality estimates suggest that the case fatality ratio of the pandemic virus was approximately 0.02%.

Background Recent studies suggest an association between the Interferon Inducible Transmembrane 3 (IFITM3) rs12252 variant and the course of influenza infection. However, it is not clear whether the reported association relates to influenza infection severity. The aim of this study was to estimate the hospitalization risk associated with this variant in Influenza Like Illness (ILI) patients during the H1N1 pandemic influenza. Methods A case-control genetic association study was performed, using nasopharyngeal/oropharyngeal swabs collected during the H1N1 pandemic influenza. Laboratory diagnosis of influenza infection was performed by RT-PCR, the IFITM3 rs12252 was genotyped by RFLP and tested for association with hospitalization. Conditional logistic regression was performed to calculate the confounder-adjusted odds ratio of hospitalization associated with IFITM3 rs12252. Results We selected 312 ILI cases and 624 matched non-hospitalized controls. Within ILI Influenza A(H1N1)pdm09 positive patients, no statistical significant association was found between the variant and the hospitalization risk (Adjusted OR: 0.73 (95% CI: 0.33-1.50)). Regarding ILI Influenza A(H1N1) pdm09 negative patients, CT/CC genotype carriers had a higher risk of being hospitalized than patients with TT genotype (Adjusted OR: 2.54 (95% CI: 1.54-4.19)). Conclusions The IFITM3 rs12252 variant was associated with respiratory infection hospitalization but not specifically in patients infected with Influenza A(H1N1) pdm09. publishersversion published

Syndromic and virological data are routinely collected by many countries and are often the only information available in real time. The analysis of surveillance data poses many statistical challenges that have not yet been addressed. For instance, the fraction of cases that seek healthcare and are thus detected is often unknown. Here, we propose a general statistical framework that explicitly takes into account the way the surveillance data are generated. Our approach couples a deterministic mathematical model with a statistical description of the reporting process and is applied to surveillance data collected in Italy during the 2009–2010 A/H1N1 influenza pandemic. We estimate that the reproduction number R was initially into the range 1.2–1.4 and that case detection in children was significantly higher than in adults. According to the best fit models, we estimate that school-age children experienced the highest infection rate overall. In terms of both estimated peak-incidence and overall attack rate, according to the Susceptibility and Immunity models the 5–14 years age-class was about 5 times more infected than the 65+ years old age-group and about twice more than the 15–64 years age-class. The multiplying factors are doubled using the Baseline model. Overall, the estimated attack rate was about 16% according to the Baseline model and 30% according to the Susceptibility and Immunity models.

Serologic studies for swine influenza viruses (SIVs) in humans with occupational exposure to swine have been reported from the Americas but not from Europe. We compared levels of neutralizing antibodies against 3 influenza viruses--pandemic (H1N1) 2009, an avian-like enzootic subtype H1N1 SIV, and a 2007-08 seasonal subtype H1N1--in 211 persons with swine contact and 224 matched controls in Luxembourg. Persons whose profession involved contact with swine had more neutralizing antibodies against SIV and pandemic (H1N1) 2009 virus than did the controls. Controls also had antibodies against these viruses although exposure to them was unlikely. Antibodies against SIV and pandemic (H1N1) 2009 virus correlated with each other but not with seasonal subtype H1N1 virus. Sequential exposure to variants of seasonal influenza (H1N1) viruses may have increased chances for serologic cross-reactivity with antigenically distinct viruses. Further studies are needed to determine the extent to which serologic responses correlate with infection.

This study was designed to identify the optimal dose of an MF59-adjuvanted, monovalent, A/H1N1 influenza vaccine in healthy paediatric subjects.Subjects aged 3-8 years (n=194) and 9-17 years (n=160) were randomized to receive two primary doses of A/H1N1 vaccine containing either 3.75 μg antigen with half a standard dose of MF59 adjuvant, 7.5 μg antigen with a full dose of MF59, or (children 3-8 years only), a non-adjuvanted 15 μg formulation. A booster dose of MF59-adjuvanted seasonal influenza vaccine including homologous A/H1N1 strain was given one year after priming. Immunogenicity was assessed by haemagglutination inhibition (HI) and microneutralization assays. Vaccine safety was assessed throughout the study (up to 18 months).A single priming dose of either MF59-adjuvanted formulation was sufficient to meet the European licensure criteria for pandemic influenza vaccines (HI titres ≥1:4070%; seroconversion40%; and GMR2.5). Two non-adjuvanted vaccine doses were required to meet the same licensure criteria. After first and second doses, percentage of subjects with HI titres ≥1:40 were between 97% and 100% in the adjuvanted vaccine groups compared with 68% and 91% in the non-adjuvanted group, respectively. Postvaccination seroconversion rates ranged from 91% to 98% in adjuvanted groups and were 68% (first dose) and 98% (second dose) in the non-adjuvanted group. HI titres ≥1:330 after primary doses were achieved in 69% to 90% in adjuvanted groups compared with 41% in the non-adjuvanted group. Long-term antibody persistence after priming and a robust antibody response to booster immunization were observed in all vaccination groups. All A/H1N1 vaccine formulations were generally well tolerated. No vaccine-related serious adverse events occurred, and no subjects were withdrawn from the study due to an adverse event.An MF59-adjuvanted influenza vaccine containing 3.75 μg of A/H1N1 antigen was well tolerated and sufficiently immunogenic to meet all the European licensure criteria after a single dose in healthy children 3-17 years old.

Enhanced surveillance of infections due to the pandemic A(H1N1) influenza virus, which included monitoring for antiviral resistance, was carried out in the Netherlands from late April 2009 through late May 2010. More than 1100 instances of infection with the pandemic A(H1N1) influenza virus from 2009 and 2010 [A(H1N1) 2009] distributed across this period were analyzed. Of these, 19 cases of oseltamivir-resistant virus harboring the H275Y mutation in the neuraminidase (NA) were detected. The mean 50% inhibitory concentration (IC50) levels for oseltamivir- and zanamivir-susceptible A(H1N1) 2009 viruses were 1.4-fold and 2-fold, respectively, lower than for the seasonal A(H1N1) influenza viruses from 2007/2008: for oseltamivir-resistant A(H1N1)2009 virus the IC50 was 2.9-fold lower. Eighteen of the 19 patients with oseltamivir-resistant virus showed prolonged shedding of the virus and developed resistance while on oseltamivir therapy. Sixteen of these 18 patients had an immunodeficiency, of whom 11 had a hematologic disorder. The two other patients had another underlying disease. Six of the patients who had an underlying disease died; of these, five had received cytostatic or immunosuppressive therapy. No indications for onward transmission of resistant viruses were found. This study showed that the main association for the emergence of cases of oseltamivir-resistant A(H1N1) 2009 virus was receiving antiviral therapy and having drug-induced immunosuppression or an hematologic disorder. Except for a single case of a resistant virus not linked to oseltamivir therapy, the absence of detection of resistant variants in community specimens and in specimens from contacts of cases with resistant virus suggested that the spread of resistant A(H1N1) 2009 virus was limited. Containment may have been the cumulative result of impaired NA function, successful isolation of the patients, and prophylactic measures to limit exposure. (C) 2011 Elsevier B.V. All rights reserved.

Influenza vaccines have been in use for more than 60 years and have proven to be efficacious in protecting from influenza infections during epidemics and the recent H1N1 pandemic. The development of influenza vaccines has so far been largely based on empirical grounds, which leaves room for vaccine improvement by implementation of recent insights in innate and adaptive immunity. Also, evaluation and approval of new vaccines rely on rather broad correlates of protection such as the hemagglutination inhibition titre, thereby neglecting qualitative aspects of the immune response. Here we discuss how current inactivated influenza vaccine formulations differ in the type of immune response they elcit, their protective capacity, and what causes these differences. Finally, we will discuss how this knowledge can guide the development of new adjuvants that optimize the protective efficacy of influenza vaccines.

Background One pathway through which pandemic influenza strains might emerge is reassortment from coinfection of different influenza A viruses. Seasonal influenza vaccines are designed to target the circulating strains, which intuitively decreases the prevalence of coinfection and the chance of pandemic emergence due to reassortment. However, individual-based analyses on 2009 pandemic influenza show that the previous seasonal vaccination may increase the risk of pandemic A(H1N1) pdm09 infection. In view of pandemic influenza preparedness, it is essential to understand the overall effect of seasonal vaccination on pandemic emergence via reassortment. Methods and Findings In a previous study we applied a population dynamics approach to investigate the effect of infection-induced cross-immunity on reducing such a pandemic risk. Here the model was extended by incorporating vaccination for seasonal influenza to assess its potential role on the pandemic emergence via reassortment and its effect in protecting humans if a pandemic does emerge. The vaccination is assumed to protect against the target strains but only partially against other strains. We find that a universal seasonal vaccine that provides full-spectrum cross-immunity substantially reduces the opportunity of pandemic emergence. However, our results show that such effectiveness depends on the strength of infection-induced cross-immunity against any novel reassortant strain. If it is weak, the vaccine that induces cross-immunity strongly against non-target resident strains but weakly against novel reassortant strains, can further depress the pandemic emergence; if it is very strong, the same kind of vaccine increases the probability of pandemic emergence. Conclusions Two types of vaccines are available: inactivated and live attenuated, only live attenuated vaccines can induce heterosubtypic immunity. Current vaccines are effective in controlling circulating strains; they cannot always help restrain pandemic emergence because of the uncertainty of the oncoming reassortant strains, however. This urges the development of universal vaccines for prevention of pandemic influenza.

Influenza Mortality in the United States, 2009 Pandemic: Burden, Timing and Age Distribution Ann M. Nguyen 1 , Andrew Noymer 2 * 1 Palomar Health, Escondido, California, United States of America, 2 Department of Population Health and Disease Prevention, University of California Irvine, Irvine, California, United States of America Abstract Background: In April 2009, the most recent pandemic of influenza A began. We present the first estimates of pandemic mortality based on the newly-released final data on deaths in 2009 and 2010 in the United States. Methods: We obtained data on influenza and pneumonia deaths from the National Center for Health Statistics (NCHS). Age- and sex-specific death rates, and age-standardized death rates, were calculated. Using negative binomial Serfling-type methods, excess mortality was calculated separately by sex and age groups. Results: In many age groups, observed pneumonia and influenza cause-specific mortality rates in October and November 2009 broke month-specific records since 1959 when the current series of detailed US mortality data began. Compared to the typical pattern of seasonal flu deaths, the 2009 pandemic age-specific mortality, as well as influenza-attributable (excess) mortality, skewed much younger. We estimate 2,634 excess pneumonia and influenza deaths in 2009–10; the excess death rate in 2009 was 0.79 per 100,000. Conclusions: Pandemic influenza mortality skews younger than seasonal influenza. This can be explained by a protective effect due to antigenic cycling. When older cohorts have been previously exposed to a similar antigen, immune memory results in lower death rates at older ages. Age-targeted vaccination of younger people should be considered in future pandemics. Citation: Nguyen AM, Noymer A (2013) Influenza Mortality in the United States, 2009 Pandemic: Burden, Timing and Age Distribution. PLoS ONE 8(5): e64198. doi:10.1371/journal.pone.0064198 Editor: Benjamin J. Cowling, University of Hong Kong, Hong Kong Received December 2, 2012; Accepted April 9, 2013; Published May 22, 2013 Copyright: s 2013 Nguyen, Noymer. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The authors have no support or funding to report. Competing Interests: Ann M. Nguyen works for Palomar Health, a public health district in San Diego County, California, USA. Palomar Health is not a commercial entity, and therefore no commercial competing interests exist. None of the data analyzed in the article come from Palomar Health. * E-mail: noymer@uci.edu together [16]. Age-specific mortality burden estimates can aid pandemic planning. Introduction In April 2009, a novel strain of influenza A/H1N1 emerged in Mexico, rapidly spreading to the United States [1] and then worldwide. On 11 June 2009, the World Health Organization declared a pandemic [2], which eventually caused an estimated 284,500 deaths worldwide [3]. The pandemic was declared over on 10 August 2010 [4]. Approximately 20% of the US population contracted influenza during the pandemic [5,6]. In 2009, there were 53,692 pneumonia and influenza deaths, making this combination the eighth leading cause of death [7]; in 2010 there were 50,003 pneumonia and influenza deaths (ninth leading cause) [8]. Overall, the pandemic case fatality rate was low, and attack rates were higher among children and young adults [9]. The sparing of adults 65 and older is thought to be due to immunity from previous exposure to antigenically-similar H1N1 strains [10– In this article, we analyze final mortality data for the United States which were released in August 2012. This is the first analysis of the complete mortality record of influenza for 2009 and 2010. Our age- and sex-specific analysis incorporates data from 1959– 2010, and pneumonia and influenza deaths were analyzed PLOS ONE | www.plosone.org Materials and Methods All the data used in this study are fully in the public domain. We obtained data on number of deaths, by cause, from the mortality detail files of the National Center for Health Statistics (NCHS) [17]. Deaths were stratified by age, sex, month, and underlying cause. We extracted data on influenza and pneumonia deaths from January 1959 to December 2010. As shown in table 1, this period spans four revisions of the International Classification of Diseases (ICD 7–10). To ensure comparability, all data were converted to ICD-10 using the published crossover tables [18–20]. Prior to 1959, no detailed mortality data (i.e., simultaneously disaggregated by age, sex, month, and cause) are available. Final mortality data for 2009 and 2010 were released in 2012. Rates (per 100,000) were calculated using these death counts in the numerator, and exposure data (person-years at risk) from the Human Mortality Database [21] in the denominator. The age-specific exposure data were interpolated to monthly units to match the death counts. Variable days per month, including leap years, were used in the monthly exposure interpolation. May 2013 | Volume 8 | Issue 5 | e64198

Objectives, To report a prospective epidemiological, virological and serological investigation of a SARS-CoV-2 outbreak in a primary school., Methods, As part of a longitudinal, prospective, school-based surveillance study, this investigation involved repeated testing of 73 pupils, 9 teachers, 13 non-teaching staff and 26 household members of participants who tested positive, with rapid antigen tests and/or RT-PCR (Day 0-2 and Day 5-7), serologies on dried capillary blood samples (Day 0-2 and Day 30), contact tracing interviews and SARS-CoV-2 whole genome sequencing., Results, We identified 20 children (aged 4 to 6 years from 4 school classes), 2 teachers and a total of 4 household members who were infected by the Alpha variant during this outbreak. Infection attack rates were between 11.8 and 62.0% among pupils from the 4 school classes, 22.2% among teachers and 0% among non-teaching staff. Secondary attack rate among household members was 15.4%. Symptoms were reported by 63% of infected children, 100% of teachers and 50% of household members. All analysed sequences but one showed 100% identity. Serological tests detected 8 seroconversions unidentified by SARS-CoV-2 virological tests., Conclusions, This study confirmed child-to-child and child-to-adult SARS-CoV-2 transmission and introduction into households. Effective measures to limit transmission in schools have the potential to reduce the overall community circulation.