Influenza-associated Disease Research Articles

Acute inflammatory asthma protects influenza infected mice from bacterial superinfection (P3065)

Abstract The Centers of Disease Control identified asthmatics to suffer more severe morbidity from influenza during the 2009 pandemic. However, our data indicate that pre-existing allergic inflammation during viral infection is protective against influenza associated disease in mice. Since bacterial super-infections during influenza increase morbidity and mortality, we hypothesized that acute inflammatory asthma promotes bacterial colonization of the lungs after influenza infection thereby leading to a more severe outcome. We created a triple variant model system by infecting Aspergillus fumigatus sensitized and challenged mice with 1000 TCID50/ml of A/CA/4/2009 virus a week after the last fungal challenge. Mice were co-infected with 600 cfu of Streptococcus pneumoniae strain A66.1 a week later and monitored for six days. Mice with allergic asthma lost less weight after co-infection, had less airway resistance after methacholine challenge, and had at least a 50% reduction in mortality compared to non-asthmatic controls. Fewer inflammatory cells were recruited into the airways of allergic mice after co-infection. Allergic asthma delayed S. pneumoniae colonization in the airways and lungs but not blood compared to co-infection alone. Mice in the asthma and co-infection model had less normal flora outgrowth in the airways, lungs, and blood compared to those in the co-infection model. Allergic asthma protects against, or delays, bacterial super-infection after influenza challenge.

Modeling Host Genetic Regulation of Influenza Pathogenesis in the Collaborative Cross

Genetic variation contributes to host responses and outcomes following infection by influenza A virus or other viral infections. Yet narrow windows of disease symptoms and confounding environmental factors have made it difficult to identify polymorphic genes that contribute to differential disease outcomes in human populations. Therefore, to control for these confounding environmental variables in a system that models the levels of genetic diversity found in outbred populations such as humans, we used incipient lines of the highly genetically diverse Collaborative Cross (CC) recombinant inbred (RI) panel (the pre-CC population) to study how genetic variation impacts influenza associated disease across a genetically diverse population. A wide range of variation in influenza disease related phenotypes including virus replication, virus-induced inflammation, and weight loss was observed. Many of the disease associated phenotypes were correlated, with viral replication and virus-induced inflammation being predictors of virus-induced weight loss. Despite these correlations, pre-CC mice with unique and novel disease phenotype combinations were observed. We also identified sets of transcripts (modules) that were correlated with aspects of disease. In order to identify how host genetic polymorphisms contribute to the observed variation in disease, we conducted quantitative trait loci (QTL) mapping. We identified several QTL contributing to specific aspects of the host response including virus-induced weight loss, titer, pulmonary edema, neutrophil recruitment to the airways, and transcriptional expression. Existing whole-genome sequence data was applied to identify high priority candidate genes within QTL regions. A key host response QTL was located at the site of the known anti-influenza Mx1 gene. We sequenced the coding regions of Mx1 in the eight CC founder strains, and identified a novel Mx1 allele that showed reduced ability to inhibit viral replication, while maintaining protection from weight loss.

An evaluation of the emerging vaccines against influenza in children

BackgroundInfluenza is an under-appreciated cause of acute lower respiratory infections (ALRI) in children. It is estimated to cause approximately 20 million new episodes of ALRI in children annually, 97% of these occurring in developing countries. It is also estimated to result in 28000 to 112000 deaths annually in young children. Apart from hospitalisations and deaths, influenza has significant economic consequences. The current egg-based inactivated influenza vaccines have several limitations: annual vaccination, high production costs, and cannot respond adequately to meet the demand during pandemics.MethodsWe used a modified CHNRI methodology for setting priorities in health research investments. This was done in two stages. In Stage I, we systematically reviewed the literature related to emerging cross-protective vaccines against influenza relevant to several criteria of interest: answerability; cost of development, production and implementation; efficacy and effectiveness; deliverability, affordability and sustainability; maximum potential impact on disease burden reduction; acceptability to the end users and health workers; and effect on equity. In Stage II, we conducted an expert opinion exercise by inviting 20 experts (leading basic scientists, international public health researchers, international policy makers and representatives of pharmaceutical companies). They answered questions from the CHNRI framework and their “collective optimism” towards each criterion was documented on a scale from 0 to 100%.ResultsThe experts expressed very high level of optimism for deliverability, impact on equity, and acceptability to health workers and end users. However, they expressed concerns over the criteria of answerability, low development cost, low product cost, low implementation cost, affordability and, to a lesser extent sustainability. In addition they felt that the vaccine would have higher efficacy and impact on disease burden reduction on overall influenza-associated disease rather than specifically influenza-associated pneumonia.ConclusionAlthough the landscape of emerging influenza vaccines shows several promising candidates, it is unlikely that the advancements in the newer vaccine technologies will be able to progress through to large scale production in the near future. The combined effects of continued investments in researching new vaccines and improvements of available vaccines will hopefully shorten the time needed to the development of an effective seasonal and pandemic influenza vaccine suitable for large scale production.

Delivering Influenza Vaccine to High-Risk Adults

Influenza is responsible for significant morbidity and mortality in the United States. Despite long-standing national recommendations, only 47% of adults with a high-risk condition received the influenza vaccine in 2009-2010. Subspecialty practices provide a significant portion of ambulatory care visits for high-risk adults and understanding their role in the immunization infrastructure may increase immunization rates, decrease public health burden, and reduce influenza-associated disease. A cross-sectional survey of cardiology, pulmonology, and obstetrics/gynecology practices was conducted to assess influenza vaccination practices, plans, patient acceptance, frustrations, and reasons for not vaccinating. It was found that 51% of respondents planned to vaccinate patients. Plans differed significantly by practice type. Practices that do not vaccinate generally recommend vaccination and refer patients to public health clinics, primary care, and pharmacies. Administrative and patient-related barriers affected most practices, but practices that vaccinate were able to overcome these barriers. Improvements in vaccination may be addressed by adapting practice support services for subspecialty practices.

Model Selection in Time Series Studies of Influenza-Associated Mortality

BackgroundPoisson regression modeling has been widely used to estimate influenza-associated disease burden, as it has the advantage of adjusting for multiple seasonal confounders. However, few studies have discussed how to judge the adequacy of confounding adjustment. This study aims to compare the performance of commonly adopted model selection criteria in terms of providing a reliable and valid estimate for the health impact of influenza.MethodsWe assessed four model selection criteria: quasi Akaike information criterion (QAIC), quasi Bayesian information criterion (QBIC), partial autocorrelation functions of residuals (PACF), and generalized cross-validation (GCV), by separately applying them to select the Poisson model best fitted to the mortality datasets that were simulated under the different assumptions of seasonal confounding. The performance of these criteria was evaluated by the bias and root-mean-square error (RMSE) of estimates from the pre-determined coefficients of influenza proxy variable. These four criteria were subsequently applied to an empirical hospitalization dataset to confirm the findings of simulation study.ResultsGCV consistently provided smaller biases and RMSEs for the influenza coefficient estimates than QAIC, QBIC and PACF, under the different simulation scenarios. Sensitivity analysis of different pre-determined influenza coefficients, study periods and lag weeks showed that GCV consistently outperformed the other criteria. Similar results were found in applying these selection criteria to estimate influenza-associated hospitalization.ConclusionsGCV criterion is recommended for selection of Poisson models to estimate influenza-associated mortality and morbidity burden with proper adjustment for confounding. These findings shall help standardize the Poisson modeling approach for influenza disease burden studies.

Mucosal antibody responses are directed by viral burden in children with acute influenza infection

Please cite this paper as: He et al. (2012) Mucosal antibody responses are directed by viral burden in children with acute influenza infection. Influenza and Other Respiratory Viruses DOI: 10.1111/j.1750‐2659.2012.00346.x. Background Influenza infection causes excess hospitalizations and deaths in younger patients, but susceptibility to severe disease is poorly understood. While mucosal antibodies can limit influenza‐associated infection and disease, little is known about acute mucosal antibody responses to influenza infection. Objectives These studies characterize mucosal antiviral antibody production in children during lower respiratory infection (LRI) with H1N1 influenza versus other viral LRI and examine the relationship between mucosal antiviral antibodies and protection against severe disease. Methods B lymphocytes were assessed by immunohistochemistry in lung tissue from infants with fatal acute seasonal influenza infection. Nasopharyngeal secretions (NPS) were obtained at presentation from children with acute respiratory illness, including H1N1 (2009) influenza infection. Total and antiviral antibodies, and inflammatory and immune mediators, were quantified by ELISA. Neutralizing activity in NPS was detected using a pseudotyped virus assay. Viral burden was assessed by qPCR. Results and conclusions B lymphocytes were abundant in lung tissue of infants with fatal acute influenza LRI. Among surviving children with H1N1 infection, only a small subset (11%) demonstrated H1N1 neutralizing activity in NPS. H1N1 neutralizing activity coincided with high local levels of antiviral IgM, IgG and IgA, greater detection of inflammatory mediators, and higher viral burden (P = 0·016). Patients with mucosal antiviral antibody responses demonstrated more severe respiratory symptoms including greater hypoxia (P = 0·0018) and pneumonia (P = 0·038). These patients also trended toward younger age, longer duration of illness and longer hospital stays. Prophylaxis strategies that heighten neutralizing antibody production in the mucosa are likely to benefit both older and younger children.

Snowbirds and infection--new phenomena in pneumonia and influenza hospitalizations from winter migration of older adults: A spatiotemporal analysis

BackgroundDespite advances in surveillance and prevention, pneumonia and influenza (P&I) remain among the leading causes of mortality in the United States. Elderly adults experience the most severe morbidity from influenza-associated diseases, and have the highest rates of seasonal migration within the U.S. compared to other subpopulations. The objective of this study is to assess spatiotemporal patterns in influenza-associated hospitalizations in the elderly, by time, geography, and intensity of P&I. Given the high seasonal migration of individuals to Florida, this state was examined more closely using harmonic regression to assess spatial and temporal patterns of P&I hospitalizations by state of residence.MethodsData containing all Medicare-eligible hospitalizations in the United States for 1991-2006 with P&I (ICD-9-CM codes 480-487) were abstracted for the 65+ population. Hospitalizations were classified by state of residence, provider state, and date of admissions, specifically comparing those admitted between October and March to those admitted between April and September. We then compared the hospitalization profile data of Florida residents with that of out-of-state residents by state of primary residence and time of year (in-season or out-of-season).ResultsWe observed distinct seasonal patterns of nonresident P&I hospitalizations, especially comparing typical winter destination states, such as California, Arizona, Texas, and Florida, to other states. Although most other states generally experienced a higher proportion of non-resident P&I during the summer months (April-September), these states had higher nonresident P&I during the traditional peak influenza season (October-March).ConclusionsThis study is among the first to quantify spatiotemporal P&I hospitalization patterns in the elderly, focusing on the change of patterns that are possibly due to seasonal population migration. Understanding migration and influenza-associated disease patterns in this vulnerable population is critical to prepare for and potentially prevent influenza outbreaks in this vulnerable population.

Validation of Statistical Models for Estimating Hospitalization Associated with Influenza and Other Respiratory Viruses

BackgroundReliable estimates of disease burden associated with respiratory viruses are keys to deployment of preventive strategies such as vaccination and resource allocation. Such estimates are particularly needed in tropical and subtropical regions where some methods commonly used in temperate regions are not applicable. While a number of alternative approaches to assess the influenza associated disease burden have been recently reported, none of these models have been validated with virologically confirmed data. Even fewer methods have been developed for other common respiratory viruses such as respiratory syncytial virus (RSV), parainfluenza and adenovirus.Methods and FindingsWe had recently conducted a prospective population-based study of virologically confirmed hospitalization for acute respiratory illnesses in persons <18 years residing in Hong Kong Island. Here we used this dataset to validate two commonly used models for estimation of influenza disease burden, namely the rate difference model and Poisson regression model, and also explored the applicability of these models to estimate the disease burden of other respiratory viruses. The Poisson regression models with different link functions all yielded estimates well correlated with the virologically confirmed influenza associated hospitalization, especially in children older than two years. The disease burden estimates for RSV, parainfluenza and adenovirus were less reliable with wide confidence intervals. The rate difference model was not applicable to RSV, parainfluenza and adenovirus and grossly underestimated the true burden of influenza associated hospitalization.ConclusionThe Poisson regression model generally produced satisfactory estimates in calculating the disease burden of respiratory viruses in a subtropical region such as Hong Kong.

Characteristic findings of pediatric inpatients with pandemic (H1N1) 2009 virus infection among severe and nonsevere illnesses

We analyzed the clinical features of inpatients at a Japanese pediatric department who were infected with pandemic (H1N1) 2009 virus. Study participants included 46 children hospitalized from July 2009 to January 2010. Infection with the virus was confirmed using real-time reverse transcriptase polymerase chain reaction (RT-PCR). The epidemic month was October 2009; 34 patients were boys, and median age was 7 years. Pandemic influenza-associated respiratory diseases included pneumonia (n = 42), bronchitis (n = 3), and pharyngitis (n = 1). The median time from onset to admission was 3 days. Children were divided into those with severe (n = 32) versus nonsevere illnesses (n = 14) according to Japanese guidelines. Significant features in the severe group were younger age, previous asthmatic attack, exacerbation of asthma, decreased oxygen saturation, elevated white blood cell/neutrophil counts and serum lactate dehydrogenase, and longer times from admission to being afebrile and discharged. Both groups showed lymphopenia at admission. Additional infection with Streptococcus pneumoniae was frequent in the severe group. Whereas 44 patients received antiviral therapy (median times from onset to initiation 2 days), 32 received antibiotics (median duration 7 days). All children recovered, with a median hospital stay of 8 days. Our observations suggest that history of asthma and preschool age might be risk factors for severe illness. Prompt initiation of antiviral and antibiotic treatments should be considered to prevent development of severe illness.

Emergence of oseltamivir-resistant influenza A/H3N2 virus with altered hemagglutination pattern in a hematopoietic stem cell transplant recipient

Background Persistent influenza virus replication during antiviral therapy in patients undergoing hematopoietic stem cell transplantation (HSCT) could promote the emergence of antiviral drug resistance. Objectives To follow the viral genotypic and drug susceptibility changes in a patient who developed progressive influenza A/H3N2 pneumonia despite oseltamivir therapy after haploidentical HSCT. Study design Direct genotypic analysis of the neuraminidase (NA) and hemagglutinin (HA) genes in successive bronchoalveolar lavage specimens was employed in combination with hemagglutination and NA enzymatic activity assays of the corresponding viral isolates. Results The emergence of NA oseltamivir-resistance mutation R292K was detected by 12 days of oseltamivir treatment with 44,286-fold increase in oseltamivir IC 50. Resurgence of wild type viral population was identified by 7 days after cessation of oseltamivir. Sequential HA mutations R228S and A138S were identified and associated with a shift in the HA receptor binding pattern reflected by loss of the ability to agglutinate chicken erythrocytes. Conclusions These rapid evolutionary changes warrant close virologic monitoring of immunocompromised patients treated for influenza infection, and raise concern about the efficacy of mono-drug therapy for influenza-associated disease in HSCT recipients.

Impact of Influenza-Attributable Disease on Hospitalizations in Children Younger than 24 Months with Lower Respiratory Tract Infections (LRTI) in Subtropical Brazil: Tl 24

Top of pageAbstract Background: Influenzavirus (Flu) is associated with high morbidity in children less than 24-mo old, with high rates of hospitalization. Recommendation for annual influenza vaccination has been extended to this age group in the USA. Objective: We evaluated the proportion of Flu-attributable disease in children younger than 2 years, admitted to a tertiary care hospital for LRTI during the 2004 influenza seasonal outbreak in southeast Brazil. Methods: All samples submitted for respiratory virus detection were tested for Flu by immunofluorescence and/or RT-PCR. Influenza positive samples were used for viral isolation and identification. Patient records were reviewed for length of hospital stay (LOS), need for oxygen supplementation (OS) and clinical diagnosis. Results: From March to May 2004, 159 samples were collected and 17 (10.7%) were positive for influenza A. Influenza virus was isolated from 6 samples, all of them A/Korea (H3N2). Of the 17 positive samples, 8 (47%) were obtained in April. Patient records were available for review in 12 cases (7 boys). Of these, 10 (83%) were 6 days. OS was required by 58% (7/12) of the patients and 71% (5/7) required O2 for 6 or more days. Bronchodilators and antibiotics were the two most frequent treatments used (92% and 42%, respectively). Conclusions: During this outbreak in a subtropical region of Brazil, influenza associated disease represented 10.7% of all hospitalizations in children less than 24 months of age with LRTI, and the associated morbidity was responsible for prolonged LOS and requirement for OS. The impact of influenza-associated disease on pediatric hospitalization could be reduced by vaccination in this age group. Financial Support: FAPESP, CNPq and Sanofi -Pasteur

Wild-type and attenuated influenza virus infection of the neonatal rat brain.

Although influenza virus infection of humans has been associated with a wide spectrum of clinical neurological syndromes, the pathogenesis of influenza virus associated central nervous system (CNS) disease in humans remains controversial. To better study influenza virus neuropathogenesis, an animal model of influenza-associated CNS disease using human virus isolates without adaptation to an animal host was developed. This neonatal rat model of influenza virus CNS infection was developed using low-passage human isolates and shows outcomes in specific brain regions, cell types infected, and neuropathological outcomes that parallel the available literature on cases of human CNS infection. The degree of virus replication and spread in the rat brain correlated with the strains' neurotoxicity potential for humans. In addition, using sensitive neurobehavioral test paradigms, changes in brain function were found to be associated with areas of virus replication in neurons. These data suggest that further evaluation of this pathogenesis model may provide important information regarding influenza virus neuropathogenesis, and that this model may have possible utility as a preclinical assay for evaluating the neurological safety of new live attenuated influenza virus vaccine strains.