Respiratory virus infection and risk of invasive meningococcal disease in central Ontario, Canada.
ABSTRACT: BACKGROUND: In temperate climates, invasive meningococcal disease (IMD) incidence tends to coincide with or closely follow peak incidence of influenza virus infection; at a seasonal level, increased influenza activity frequently correlates with increased seasonal risk of IMD. METHODS: We evaluated 240 cases of IMD reported in central Ontario, Canada, from 2000 to 2006. Associations between environmental and virological (influenza A, influenza B and respiratory syncytial virus (RSV)) exposures and IMD incidence were evaluated using negative binomial regression models controlling for seasonal oscillation. Acute effects of weekly respiratory virus activity on IMD risk were evaluated using a matched-period case-crossover design with random directionality of control selection. Effects were estimated using conditional logistic regression. RESULTS: Multivariable negative binomial regression identified elevated IMD risk with increasing influenza A activity (per 100 case increase, incidence rate ratio?=?1.18, 95% confidence interval (CI): 1.06, 1.31). In case-crossover models, increasing weekly influenza A activity was associated with an acute increase in the risk of IMD (per 100 case increase, odds ratio (OR) ?=?2.03, 95% CI: 1.28 to 3.23). Increasing weekly RSV activity was associated with increased risk of IMD after adjusting for RSV activity in the previous 3 weeks (per 100 case increase, OR?=?4.31, 95% CI: 1.14, 16.32). No change in disease risk was seen with increasing influenza B activity. CONCLUSIONS: We have identified an acute effect of influenza A and RSV activity on IMD risk. If confirmed, these finding suggest that influenza vaccination may have the indirect benefit of reducing IMD risk.
Project description:<h4>Background</h4>There is limited information on influenza and respiratory syncytial virus (RSV) seasonal patterns in tropical areas, although there is renewed interest in understanding the seasonal drivers of respiratory viruses.<h4>Methods</h4>We review geographic variations in seasonality of laboratory-confirmed influenza and RSV epidemics in 137 global locations based on literature review and electronic sources. We assessed peak timing and epidemic duration and explored their association with geography and study settings. We fitted time series model to weekly national data available from the WHO influenza surveillance system (FluNet) to further characterize seasonal parameters.<h4>Results</h4>Influenza and RSV activity consistently peaked during winter months in temperate locales, while there was greater diversity in the tropics. Several temperate locations experienced semi-annual influenza activity with peaks occurring in winter and summer. Semi-annual activity was relatively common in tropical areas of Southeast Asia for both viruses. Biennial cycles of RSV activity were identified in Northern Europe. Both viruses exhibited weak latitudinal gradients in the timing of epidemics by hemisphere, with peak timing occurring later in the calendar year with increasing latitude (P<0.03). Time series model applied to influenza data from 85 countries confirmed the presence of latitudinal gradients in timing, duration, seasonal amplitude, and between-year variability of epidemics. Overall, 80% of tropical locations experienced distinct RSV seasons lasting 6 months or less, while the percentage was 50% for influenza.<h4>Conclusion</h4>Our review combining literature and electronic data sources suggests that a large fraction of tropical locations experience focused seasons of respiratory virus activity in individual years. Information on seasonal patterns remains limited in large undersampled regions, included Africa and Central America. Future studies should attempt to link the observed latitudinal gradients in seasonality of viral epidemics with climatic and population factors, and explore regional differences in disease transmission dynamics and attack rates.
Project description:INTRODUCTION:Fine-grained influenza surveillance data are lacking in the US, hampering our ability to monitor disease spread at a local scale. Here we evaluate the performances of high-volume electronic medical claims data to assess local and regional influenza activity. MATERIAL AND METHODS:We used electronic medical claims data compiled by IMS Health in 480 US locations to create weekly regional influenza-like-illness (ILI) time series during 2003-2010. IMS Health captured 62% of US outpatient visits in 2009. We studied the performances of IMS-ILI indicators against reference influenza surveillance datasets, including CDC-ILI outpatient and laboratory-confirmed influenza data. We estimated correlation in weekly incidences, peak timing and seasonal intensity across datasets, stratified by 10 regions and four age groups (<5, 5-29, 30-59, and 60+ years). To test IMS-Health performances at the city level, we compared IMS-ILI indicators to syndromic surveillance data for New York City. We also used control data on laboratory-confirmed Respiratory Syncytial Virus (RSV) activity to test the specificity of IMS-ILI for influenza surveillance. RESULTS:Regional IMS-ILI indicators were highly synchronous with CDC's reference influenza surveillance data (Pearson correlation coefficients rho?0.89; range across regions, 0.80-0.97, P<0.001). Seasonal intensity estimates were weakly correlated across datasets in all age data (rho?0.52), moderately correlated among adults (rho?0.64) and uncorrelated among school-age children. IMS-ILI indicators were more correlated with reference influenza data than control RSV indicators (rho?=?0.93 with influenza v. rho?=?0.33 with RSV, P<0.05). City-level IMS-ILI indicators were highly consistent with reference syndromic data (rho?0.86). CONCLUSION:Medical claims-based ILI indicators accurately capture weekly fluctuations in influenza activity in all US regions during inter-pandemic and pandemic seasons, and can be broken down by age groups and fine geographical areas. Medical claims data provide more reliable and fine-grained indicators of influenza activity than other high-volume electronic algorithms and should be used to augment existing influenza surveillance systems.
Project description:BACKGROUND:Few studies describe the respiratory syncytial virus (RSV) burden in African populations, and most have utilized hospital-based surveillance. In Mali, no community-based studies exist of the incidence or epidemiology of RSV infection. This study provides the first estimates of RSV incidence in Mali. METHODS:In a cohort of infants enrolled in a clinical trial of maternal influenza vaccination, we estimate incidence of RSV-associated febrile illness in the first 6 months of life and identify risk factors for RSV infection and progression to severe disease. Infants (N = 1871) were followed from birth to 6 months of age and visited weekly to detect pneumonia and influenza-like illness. Baseline covariates were explored as risk factors for RSV febrile illness and RSV pneumonia or hospitalization. RESULTS:Incidence of RSV illness was estimated at 536.8 per 1000 person-years, and 86% (131/153) of RSV illness episodes were positive for RSV-B. RSV illness was most frequent in the fifth month of life and associated with having older mothers and with lower parity. The incidence of RSV-associated hospitalizations was 45.6 per 1000 person-years. Among infants with RSV illness, males were more likely to be hospitalized. The incidence of RSV pneumonia was 29 cases per 1000 person-years. CONCLUSIONS:In the first 6 months of life, Malian infants have a high incidence of RSV illness, primarily caused by RSV-B. Prevention of early RSV will require passive protection via maternal immunization in pregnancy. Mali is the first country where RSV-B has been identified as the dominant subtype, with potential implications for vaccine development.
Project description:Background:Estimates of influenza- and respiratory syncytial virus (RSV)-associated mortality burden are important to guide policy for control. Data are limited on the contribution of out-of-hospital deaths to this mortality. Methods:We modeled excess mortality attributable to influenza and RSV infection by applying regression models to weekly deaths from national vital statistics from 2009 through 2013, using influenza and RSV laboratory surveillance data as covariates. We fitted separate models for in- and out-of-hospital deaths. Results:There were 509791 average annual deaths in South Africa, of which 44% (95% confidence interval [CI] 43%-45%) occurred out-of-hospital. Seasonal influenza and RSV all-cause mortality rates were 23.0 (95% CI 11.0-30.6) and 13.2 (95% CI 6.4-33.8) per 100000 population annually (2.3% [95%CI 2.3%-2.4%] and 1.3% [95% CI 1.2%-1.4%] of all deaths respectively). The peak mortality rate was in individuals aged ?75 years (386.0; 95% CI 176.5-466.3) for influenza and in infants (143.4; 95% CI 0-194.8) for RSV. Overall, 63% (95% CI 62%--65%) of seasonal influenza and 48% (95% CI 47%-49%) of RSV-associated deaths occurred out-of-hospital. Among children aged <5 years, RSV-associated deaths were more likely to occur in-hospital, whereas influenza-associated deaths were more likely to occur out-of-hospital. The mortality rate was 6.7 (95% CI 6.4-33.8) in the first influenza A(H1N1)pdm09 wave in 2009 and 20.9 (95% CI 6.4-33.8) in the second wave in 2011, with 30% (95% CI 29%-32%) of A(H1N1)pdm09-associated deaths in 2009 occurring out-of-hospital. Discussion:More than 45% of seasonal influenza- and RSV-associated deaths occur out-of-hospital in South Africa. These data suggest that hospital-based studies may substantially underestimate mortality burden.
Project description:BACKGROUND: Influenza and respiratory syncytial virus (RSV) cause substantial mortality from respiratory and other causes in the USA, especially among people aged 65 and older. OBJECTIVES: We estimated the influenza-attributable mortality and RSV-attributable mortality in the USA, stratified by age and risk status, using outcome definitions with different sensitivity and specificity. METHODS: Influenza- and RSV-associated mortality was assessed from October 1997-March 2009 using multiple linear regression modeling on data obtained from designated government repositories. RESULTS: The main outcomes and measures included mortality outcome definitions-pneumonia and influenza, respiratory broad, and cardiorespiratory disease. A seasonal average of 10,682 (2287-16,363), 19,100 (4862-29,245), and 28,169 (6797-42,316) deaths was attributed to influenza for pneumonia and influenza, respiratory broad, and cardiorespiratory outcome definitions, respectively. Corresponding values for RSV were 6211 (4584-8169), 11,300 (8546-14,244), and 17,199 (13,384-21,891), respectively. A/H3N2 accounted for seasonal average of 71% influenza-attributable deaths; influenza B accounted for most (51-95%) deaths during four seasons. Approximately 70% influenza-attributable deaths occurred in individuals ?75 years, with increasing mortality for influenza A/H3N2 and B, but not A/H1N1. In children aged 0-4 years, an average of 97 deaths was attributed to influenza (A/H3N2 = 49, B = 33, A/H1N1 = 15) and 165 to respiratory broad outcome definition (RSV). Influenza-attributable mortality was 2.94-fold higher in high-risk individuals. CONCLUSIONS: Influenza-attributable mortality was highest in older and high-risk individuals and mortality in children was higher than reported in passive Centers for Disease Control and Prevention surveillance. Influenza B-attributable mortality was higher than A in four of 12 seasons. Our estimates represent an updated assessment of influenza-attributable mortality in the USA.
Project description:Growing evidence suggests respiratory syncytial virus (RSV) is an important cause of respiratory disease in adults. However, the adult burden remains largely uncharacterized as most RSV studies focus on children, and population-based studies with laboratory-confirmation of infection are difficult to implement. Indirect modelling methods, long used for influenza, can further our understanding of RSV burden by circumventing some limitations of traditional surveillance studies that rely on direct linkage of individual-level exposure and outcome data.Multiple linear time-series regression was used to estimate RSV burden in the United Kingdom (UK) between 1995 and 2009 among the total population and adults in terms of general practice (GP) episodes (counted as first consultation ?28 days following any previous consultation for same diagnosis/diagnostic group), hospitalisations, and deaths for respiratory disease, using data from Public Health England weekly influenza/RSV surveillance, Clinical Practice Research Datalink, Hospital Episode Statistics, and Office of National Statistics. The main outcome considered all ICD-listed respiratory diseases and, for GP episodes, related symptoms. Estimates were adjusted for non-specific seasonal drivers of disease using secular cyclical terms and stratified by age and risk group (according to chronic conditions indicating severe influenza risk as per UK recommendations for influenza vaccination). Trial registration NCT01706302 . Registered 11 October 2012.Among adults aged 18+ years an estimated 487,247 GP episodes, 17,799 hospitalisations, and 8,482 deaths were attributable to RSV per average season. Of these, 175,070 GP episodes (36 %), 14,039 hospitalisations (79 %) and 7,915 deaths (93 %) were in persons aged 65+ years. High- versus low-risk elderly were two-fold more likely to have a RSV-related GP episode or death and four-fold more likely be hospitalised for RSV. In most seasons since 2001, more GP episodes, hospitalisations and deaths were attributable to RSV in adults than to influenza.RSV is associated with a substantial disease burden in adults comparable to influenza, with most of the hospitalisation and mortality burden in the elderly. Treatment options and measures to prevent RSV could have a major impact on the burden of RSV respiratory disease in adults, especially the elderly.
Project description:The importance of bacterial infections following respiratory syncytial virus (RSV) remains unclear. We evaluated whether variations in RSV epidemic timing and magnitude are associated with variations in pneumococcal disease epidemics and whether changes in pneumococcal disease following the introduction of seven-valent pneumococcal conjugate vaccine (PCV7) were associated with changes in the rate of hospitalizations coded as RSV.We used data from the State Inpatient Databases (Agency for Healthcare Research and Quality), including >700,000 RSV hospitalizations and >16,000 pneumococcal pneumonia hospitalizations in 36 states (1992/1993-2008/2009). Harmonic regression was used to estimate the timing of the average seasonal peak of RSV, pneumococcal pneumonia, and pneumococcal septicemia. We then estimated the association between the incidence of pneumococcal disease in children and the activity of RSV and influenza (where there is a well-established association) using Poisson regression models that controlled for shared seasonal variations. Finally, we estimated changes in the rate of hospitalizations coded as RSV following the introduction of PCV7. RSV and pneumococcal pneumonia shared a distinctive spatiotemporal pattern (correlation of peak timing: ??=?0.70, 95% CI: 0.45, 0.84). RSV was associated with a significant increase in the incidence of pneumococcal pneumonia in children aged <1 y (attributable percent [AP]: 20.3%, 95% CI: 17.4%, 25.1%) and among children aged 1-2 y (AP: 10.1%, 95% CI: 7.6%, 13.9%). Influenza was also associated with an increase in pneumococcal pneumonia among children aged 1-2 y (AP: 3.2%, 95% CI: 1.7%, 4.7%). Finally, we observed a significant decline in RSV-coded hospitalizations in children aged <1 y following PCV7 introduction (-18.0%, 95% CI: -22.6%, -13.1%, for 2004/2005-2008/2009 versus 1997/1998-1999/2000). This study used aggregated hospitalization data, and studies with individual-level, laboratory-confirmed data could help to confirm these findings.These analyses provide evidence for an interaction between RSV and pneumococcal pneumonia. Future work should evaluate whether treatment for secondary bacterial infections could be considered for pneumonia cases even if a child tests positive for RSV. Please see later in the article for the Editors' Summary.
Project description:Morbidity and mortality resulting from influenza-like disease are a threat, especially for older adults. To improve case management, next-generation broad-spectrum antiviral therapeutics that are efficacious against major drivers of influenza-like disease, including influenza viruses and respiratory syncytial virus (RSV), are urgently needed. Using a dual-pathogen high-throughput screening protocol for influenza A virus (IAV) and RSV inhibitors, we have identified N4-hydroxycytidine (NHC) as a potent inhibitor of RSV, influenza B viruses, and IAVs of human, avian, and swine origins. Biochemical in vitro polymerase assays and viral RNA sequencing revealed that the ribonucleotide analog is incorporated into nascent viral RNAs in place of cytidine, increasing the frequency of viral mutagenesis. Viral passaging in cell culture in the presence of an inhibitor did not induce robust resistance. Pharmacokinetic profiling demonstrated dose-dependent oral bioavailability of 36 to 56%, sustained levels of the active 5'-triphosphate anabolite in primary human airway cells and mouse lung tissue, and good tolerability after extended dosing at 800 mg/kg of body weight/day. The compound was orally efficacious against RSV and both seasonal and highly pathogenic avian IAVs in mouse models, reducing lung virus loads and alleviating disease biomarkers. Oral dosing reduced IAV burdens in a guinea pig transmission model and suppressed virus spread to uninfected contact animals through direct transmission. Based on its broad-spectrum efficacy and pharmacokinetic properties, NHC is a promising candidate for future clinical development as a treatment option for influenza-like diseases.
Project description:Both influenza and respiratory syncytial virus (RSV) are active throughout the year in subtropical or tropical regions, but few studies have reported on age-specific seasonal patterns of these viruses. We examined the age-specific epidemic curves of laboratory-confirmed cases of influenza A (subtyped into seasonal A(H1N1), A(H3N2), and pandemic virus A(H1N1)pdm09), influenza B and respiratory syncytial virus (RSV), in subtropical city Hong Kong from 2004 to 2013. We found that different types and subtypes of influenza showed similar two-peak patterns across age groups, with one peak in winter and another in spring/summer. Age differences were found in epidemic onset time and duration, but none could reach statistical significance (p > 0.05). Age synchrony was found in epidemic peak time for both cool and warm seasons. RSV showed less clear seasonal patterns and non-synchronized epidemic curves across age. In conclusion, age synchrony was found in influenza seasonal epidemics and the 2009 pandemic, but not in RSV. None of the age groups consistently appear as the driving force for seasonal epidemics of influenza and RSV in Hong Kong.
Project description:BACKGROUND:Within-country differences in the timing of RSV and influenza epidemics have not been assessed in Argentina, the eighth largest country in the world by area. OBJECTIVE:We aimed to compare seasonality for RSV and influenza both nationally and in each of the five regions to inform Argentina's prevention and treatment guidelines. METHOD:The Argentine National Laboratories and Health Institutes Administration collected respiratory specimens from clinical practices, outbreak investigations, and respiratory virus surveillance in 2007-2016; these were tested using immunofluorescence or RT-PCR techniques. We calculated weekly percent positive (PP) and defined season onset as >2 consecutive weeks when PP exceeded the annual mean for the respective year and region. Median season measures (onset, offset and peak) and the established mean method were calculated for each virus. RESULTS:An annual median 59 396 specimens were tested for RSV and 60 931 for influenza; 21-29% tested positive for RSV and 2-7% for influenza. National RSV activity began in April; region-specific start weeks varied by 7 weeks. Duration of RSV activity did not vary widely by region (16-18 weeks in duration). National influenza activity started in June; region-specific start weeks varied by 3 weeks. Duration of influenza epidemic activity varied more by region than that of RSV (7-13 weeks in duration). CONCLUSION:In Argentina, RSV and influenza activity overlapped during the winter months. RSV season tended to begin prior to the influenza season, and showed more variation in start week by region. Influenza seasons tended to vary more in duration than RSV seasons.