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1.  Age- and Sex-related Risk Factors for Influenza-associated Mortality in the United States Between 1997–2007 
American Journal of Epidemiology  2013;179(2):156-167.
Limited information on age- and sex-specific estimates of influenza-associated death with different underlying causes is currently available. We regressed weekly age- and sex-specific US mortality outcomes underlying several causes between 1997 and 2007 to incidence proxies for influenza A/H3N2, A/H1N1, and B that combine data on influenzalike illness consultations and respiratory specimen testing, adjusting for seasonal baselines and time trends. Adults older than 75 years of age had the highest average annual rate of influenza-associated mortality, with 141.15 deaths per 100,000 people (95% confidence interval (CI): 118.3, 163.9), whereas children under 18 had the lowest average mortality rate, with 0.41 deaths per 100,000 people (95% CI: 0.23, 0.60). In addition to respiratory and circulatory causes, mortality with underlying cancer, diabetes, renal disease, and Alzheimer disease had a contribution from influenza in adult age groups, whereas mortality with underlying septicemia had a contribution from influenza in children. For adults, within several age groups and for several underlying causes, the rate of influenza-associated mortality was somewhat higher in men than in women. Of note, in men 50–64 years of age, our estimate for the average annual rate of influenza-associated cancer mortality per 100,000 persons (1.90, 95% CI: 1.20, 2.62) is similar to the corresponding rate of influenza-associated respiratory deaths (1.81, 95% CI: 1.42, 2.21). Age, sex, and underlying health conditions should be considered when planning influenza vaccination and treatment strategies.
doi:10.1093/aje/kwt235
PMCID: PMC3873104  PMID: 24190951
age; influenza; mortality; sex; underlying cause
2.  Global Seasonality of Rotavirus Disease 
Background
A substantial number of surveillance studies have documented rotavirus prevalence among children admitted for dehydrating diarrhea. We sought to establish global seasonal patterns of rotavirus disease before widespread vaccine introduction.
Methods
We reviewed studies of rotavirus detection in children with diarrhea published since 1995. We assessed potential relationships between seasonal prevalence and locality by plotting the average monthly proportion of diarrhea cases positive for rotavirus according to geography, country development, and latitude. We used linear regression to identify variables that were potentially associated with the seasonal intensity of rotavirus.
Results
Among a total of 99 studies representing all six geographical regions of the world, patterns of year-round disease were more evident in low- and low-middle income countries compared with upper-middle and high income countries where disease was more likely to be seasonal. The level of country development was a stronger predictor of strength of seasonality (P=0.001) than geographical location or climate. However, the observation of distinctly different seasonal patterns of rotavirus disease in some countries with similar geographical location, climate and level of development indicate that a single unifying explanation for variation in seasonality of rotavirus disease is unlikely.
Conclusion
While no unifying explanation emerged for varying rotavirus seasonality globally, the country income level was somewhat more predictive of the likelihood of having seasonal disease than other factors. Future evaluation of the effect of rotavirus vaccination on seasonal patterns of disease in different settings may help understand factors that drive the global seasonality of rotavirus disease.
doi:10.1097/INF.0b013e31827d3b68
PMCID: PMC4103797  PMID: 23190782
rotavirus; seasonality; season; diarrhea; global; surveillance
3.  Differing Epidemiological Dynamics of Influenza B Virus Lineages in Guangzhou, Southern China, 2009-2010 
Journal of Virology  2013;87(22):12447-12456.
The epidemiological and evolutionary dynamics of the two cocirculating lineages of influenza B virus, Victoria and Yamagata, are poorly understood, especially in tropical or subtropical areas of Southeast Asia. We performed a phylogenetic analysis of the hemagglutinin (HA) and neuraminidase (NA) sequences of influenza B viruses isolated in Guangzhou, a southern Chinese city, during 2009 to 2010 and compared the demographic and clinical features of infected patients. We identified multiple viral introductions of Victoria strains from both Chinese and international sources, which formed two phylogenetically and antigenically distinct clades (Victoria 1 and 2), some of which persisted between seasons. We identified one dominant Yamagata introduction from outside China during 2009. Our phylogenetic analysis reveals the occurrence of reassortment events among the Victoria and Yamagata lineages and also within the Victoria lineage. We found no significant difference in clinical severity by influenza B lineage, with the exceptions that (i) the Yamagata lineage infected older people than either Victoria lineage and (ii) fewer upper respiratory tract infections were caused by the Victoria 2 than the Victoria 1 clade. Overall, our study reveals the complex epidemiological dynamics of different influenza B lineages within a single geographic locality and has implications for vaccination policy in southern China.
doi:10.1128/JVI.01039-13
PMCID: PMC3807886  PMID: 24027322
4.  Improving the estimation of influenza-related mortality over a seasonal baseline 
Epidemiology (Cambridge, Mass.)  2012;23(6):829-838.
Background
Existing methods for estimation of mortality attributable to influenza are limited by methodological and data uncertainty. We have used proxies for disease incidence of the three influenza co-circulating subtypes (A/H3N2, A/H1N1 and B) that combine data on influenza-like illness consultations and respiratory specimen testing to estimate influenza-associated mortality in the US between 1997 and 2007.
Methods
Weekly mortality rate for several mortality causes potentially affected by influenza was regressed linearly against subtype-specific influenza incidence proxies, adjusting for temporal trend and seasonal baseline, modeled by periodic cubic splines.
Results
Average annual influenza-associated mortality rates per 100,000 individuals were estimated for the following underlying causes of death: for pneumonia and influenza, 1.73 (95% confidence interval= 1.53 to 1.93); for chronic lower respiratory disease, 1.70 (1.48 to 1.93); for all respiratory causes, 3.58 (3.04 to 4.14); for myocardial infarctions, 1.02 (0.85 to 1.2); for ischemic heart disease, 2.7 (2.23 to 3.16); for heart disease, 3.82 (3.21 to 4.4); for cerebrovascular deaths, 0.65 (0.51 to 0.78); for all circulatory causes, 4.6 (3.79 to 5.39); for cancer, 0.87 (0.68 to 1.05); for diabetes, 0.33 (0.26 to 0.39); for renal disease, 0.19 (0.14 to 0.24); for Alzheimer disease, 0.41 (0.3 to 0.52); and for all causes, 11.92 (10.17 to 13.67). For several underlying causes of death, baseline mortality rates changed after the introduction of the pneumococcal conjugate vaccine.
Conclusions
The proposed methodology establishes a linear relation between influenza incidence proxies and excess mortality, rendering temporally consistent model fits, and allowing for the assessment of related epidemiologic phenomena such as changes in mortality baselines.
doi:10.1097/EDE.0b013e31826c2dda
PMCID: PMC3516362  PMID: 22992574
5.  Reassessing Google Flu Trends Data for Detection of Seasonal and Pandemic Influenza: A Comparative Epidemiological Study at Three Geographic Scales 
PLoS Computational Biology  2013;9(10):e1003256.
The goal of influenza-like illness (ILI) surveillance is to determine the timing, location and magnitude of outbreaks by monitoring the frequency and progression of clinical case incidence. Advances in computational and information technology have allowed for automated collection of higher volumes of electronic data and more timely analyses than previously possible. Novel surveillance systems, including those based on internet search query data like Google Flu Trends (GFT), are being used as surrogates for clinically-based reporting of influenza-like-illness (ILI). We investigated the reliability of GFT during the last decade (2003 to 2013), and compared weekly public health surveillance with search query data to characterize the timing and intensity of seasonal and pandemic influenza at the national (United States), regional (Mid-Atlantic) and local (New York City) levels. We identified substantial flaws in the original and updated GFT models at all three geographic scales, including completely missing the first wave of the 2009 influenza A/H1N1 pandemic, and greatly overestimating the intensity of the A/H3N2 epidemic during the 2012/2013 season. These results were obtained for both the original (2008) and the updated (2009) GFT algorithms. The performance of both models was problematic, perhaps because of changes in internet search behavior and differences in the seasonality, geographical heterogeneity and age-distribution of the epidemics between the periods of GFT model-fitting and prospective use. We conclude that GFT data may not provide reliable surveillance for seasonal or pandemic influenza and should be interpreted with caution until the algorithm can be improved and evaluated. Current internet search query data are no substitute for timely local clinical and laboratory surveillance, or national surveillance based on local data collection. New generation surveillance systems such as GFT should incorporate the use of near-real time electronic health data and computational methods for continued model-fitting and ongoing evaluation and improvement.
Author Summary
In November 2008, Google Flu Trends was launched as an open tool for influenza surveillance in the United States. Engineered as a system for early detection and daily monitoring of the intensity of seasonal influenza epidemics, Google Flu Trends uses internet search data and a proprietary algorithm to provide a surrogate measure of influenza-like illness in the population. During its first season of operation, the novel A/H1N1-pdm influenza virus emerged, heterogeneously causing sporadic outbreaks in the spring and summer of 2009 across many parts of the United States. During the autumn 2009 pandemic wave, Google updated their model with a new algorithm and case definition; the updated model has run prospectively since. Our study asks whether Google Flu Trends provides accurate detection and monitoring of influenza at the national, regional and local geographic scales. Reliable local surveillance is important to reduce uncertainty and improve situational awareness during seasonal epidemics and pandemics. We found substantial flaws with the original and updated Google Flu Trends models, including missing the emergence of the 2009 pandemic and overestimating the 2012/2013 influenza season epidemic. Our work supports the development of local near-real time computerized syndromic surveillance systems, and collaborative regional, national and international networks.
doi:10.1371/journal.pcbi.1003256
PMCID: PMC3798275  PMID: 24146603
6.  Influenza-Related Mortality Among Adults Aged 25–54 Years With AIDS in South Africa and the United States of America 
In the absence of highly active therapy antiretroviral (HAART), adults with AIDS experience substantially elevated influenza-associated mortality in South Africa and the United States. This elevated mortality risk declined with widespread HAART introduction in the United States but did not disappear entirely. These data support increased access to HAART and influenza vaccination for human immunodeficiency virus–infected adults globally.
Background. Data are limited on human immunodeficiency virus (HIV)–associated influenza burden in sub-Saharan Africa and the impact of highly active antiretroviral therapy (HAART). We compared influenza-related mortality in adults with AIDS in South Africa and the United States in the pre-HAART era and evaluated mortality trends after HAART introduction in the United States.
Methods. Monthly all-cause and pneumonia and influenza (P&I) mortality rates were compiled for adults with AIDS aged 25–54 years in South Africa (1998–2005) and the United States (pre-HAART era, 1987–1994; HAART era, 1997–2005). We estimated influenza-related deaths as excess mortality above a model baseline during influenza epidemic periods. Influenza-related mortality rates in adults with AIDS were compared with rates for age peers in the general population and adults ≥65 years old.
Results. In the United States before HAART, influenza-related mortality rates in adults with AIDS were 150 (95% confidence interval [CI], 49–460) and 208 (95% CI, 74–583) times greater than in the general population for all-cause and P&I deaths, respectively, and 2.5 (95% CI, 0.9–7.2) and 4.1 (95% CI, 1.4–13) times higher than in elderly adults. After HAART introduction , influenza-related mortality in adults with AIDS dropped 3–6-fold but remained elevated compared with the general population (all-cause relative risk [RR], 44 [95% CI, 16–121]); P&I RR, 73 [95% CI, 47–113]). Influenza-related mortality in South African adults with AIDS in recent years was similar to that in the United States in the pre-HAART era.
Conclusions. Adults with AIDS experience substantially elevated influenza-associated mortality, which declines with widespread HAART introduction but does not disappear. These data support increased access to HAART and influenza vaccination for HIV-infected adults.
doi:10.1093/cid/cis549
PMCID: PMC3657519  PMID: 22715173
7.  PLOS Currents: Outbreaks --- For findings that the world just can't wait to see 
PLoS Currents  2013;5:ecurrents.outbreaks.8ed218c079fbded60c505f025ed45f67.
doi:10.1371/currents.outbreaks.8ed218c079fbded60c505f025ed45f67
PMCID: PMC3712484  PMID: 23872871
8.  Hospitalizations Associated With Influenza and Respiratory Syncytial Virus in the United States, 1993–2008 
Influenza and respiratory syncytial virus (RSV) infections each resulted in approximately 60 US hospitalizations per 100000 persons annually during 1993–2008. RSV was associated with 16 times more hospitalizations than influenza in children aged <1 year, whereas influenza caused 8 times more hospitalizations in persons aged >5 years.
Background. Age-specific comparisons of influenza and respiratory syncytial virus (RSV) hospitalization rates can inform prevention efforts, including vaccine development plans. Previous US studies have not estimated jointly the burden of these viruses using similar data sources and over many seasons.
Methods. We estimated influenza and RSV hospitalizations in 5 age categories (<1, 1–4, 5–49, 50–64, and ≥65 years) with data for 13 states from 1993–1994 through 2007–2008. For each state and age group, we estimated the contribution of influenza and RSV to hospitalizations for respiratory and circulatory disease by using negative binomial regression models that incorporated weekly influenza and RSV surveillance data as covariates.
Results. Mean rates of influenza and RSV hospitalizations were 63.5 (95% confidence interval [CI], 37.5–237) and 55.3 (95% CI, 44.4–107) per 100000 person-years, respectively. The highest hospitalization rates for influenza were among persons aged ≥65 years (309/100000; 95% CI, 186–1100) and those aged <1 year (151/100000; 95% CI, 151–660). For RSV, children aged <1 year had the highest hospitalization rate (2350/100000; 95% CI, 2220–2520) followed by those aged 1–4 years (178/100000; 95% CI, 155–230). Age-standardized annual rates per 100000 person-years varied substantially for influenza (33–100) but less for RSV (42–77).
Conclusions. Overall US hospitalization rates for influenza and RSV are similar; however, their age-specific burdens differ dramatically. Our estimates are consistent with those from previous studies focusing either on influenza or RSV. Our approach provides robust national comparisons of hospitalizations associated with these 2 viral respiratory pathogens by age group and over time.
doi:10.1093/cid/cis211
PMCID: PMC3334364  PMID: 22495079
9.  Recrudescent wave of pandemic A/H1N1 influenza in Mexico, winter 2011-2012: Age shift and severity 
PLoS Currents  2012;4:RRN1306.
Background
A substantial recrudescent wave of pandemic influenza A/H1N1 that began in December 2011 is ongoing and has not yet peaked in Mexico, following a 2-year period of sporadic transmission. Mexico previously experienced three pandemic waves of A/H1N1 in 2009, associated with higher excess mortality rates than those reported in other countries, and prompting a large influenza vaccination campaign. Here we describe changes in the epidemiological patterns of the ongoing 4th pandemic wave in 2011-12, relative to the earlier waves in 2009. The analysis is intended to guide public health intervention strategies in near real time.
Methods
We analyzed demographic and geographic data on all hospitalizations with acute respiratory infection (ARI) and laboratory-confirmed A/H1N1 influenza, and inpatient deaths, from a large prospective surveillance system maintained by the Mexican Social Security medical system during 01-April 2009 to 10-Feb 2012. We characterized the age and regional patterns of A/H1N1-positive hospitalizations and inpatient-deaths relative to the 2009 A/H1N1 influenza pandemic. We also estimated the reproduction number (R) based on the growth rate of the daily case incidence by date of symptoms onset.
Results
A total of 5,795 ARI hospitalizations and 186 inpatient-deaths (3.2%) were reported between 01-December 2011 and 10-February 2012 (685 A/H1N1-positive inpatients and 75 A/H1N1-positive deaths). The nationwide peak of daily ARI hospitalizations in early 2012 has already exceeded the peak of ARI hospitalizations observed during the major fall pandemic wave in 2009. The mean age was 34.3 y (SD=21.3) among A/H1N1 inpatients and 43.5 y (SD=21) among A/H1N1 deaths in 2011-12. The proportion of laboratory-confirmed A/H1N1 hospitalizations and deaths was higher among seniors >=60 years of age (Chi-square test P<0.001) and lower among younger age groups (Chi-square test, P<0.03) for the 2011-2012 pandemic wave, compared to the earlier waves in 2009. The reproduction number of the winter 2011-12 wave in central Mexico was estimated at 1.2-1.3, similar to that reported for the fall 2009 wave, but lower than that of spring 2009.
Conclusions
We have documented a substantial and ongoing increase in the number of ARI hospitalizations during the period December 2011-February 2012 and an older age distribution of laboratory-confirmed A/H1N1 influenza hospitalizations and deaths, relative to 2009 A/H1N1 pandemic patterns. The gradual change in the age distribution of A/H1N1 infections in the post-pandemic period is reminiscent of historical pandemics and indicates either a gradual drift in the A/H1N1 virus, and/or a build-up of immunity among younger populations.
doi:10.1371/currents.RRN1306
PMCID: PMC3286879  PMID: 22485199
10.  Recrudescent wave of pandemic A/H1N1 influenza in Mexico, winter 2011-2012: Age shift and severity 
PLoS Currents  2012;4:RRN1306.
Background
A substantial recrudescent wave of pandemic influenza A/H1N1 that began in December 2011 is ongoing and has not yet peaked in Mexico, following a 2-year period of sporadic transmission. Mexico previously experienced three pandemic waves of A/H1N1 in 2009, associated with higher excess mortality rates than those reported in other countries, and prompting a large influenza vaccination campaign. Here we describe changes in the epidemiological patterns of the ongoing 4th pandemic wave in 2011-12, relative to the earlier waves in 2009. The analysis is intended to guide public health intervention strategies in near real time.
Methods
We analyzed demographic and geographic data on all hospitalizations with acute respiratory infection (ARI) and laboratory-confirmed A/H1N1 influenza, and inpatient deaths, from a large prospective surveillance system maintained by the Mexican Social Security medical system during 01-April 2009 to 10-Feb 2012. We characterized the age and regional patterns of A/H1N1-positive hospitalizations and inpatient-deaths relative to the 2009 A/H1N1 influenza pandemic. We also estimated the reproduction number (R) based on the growth rate of the daily case incidence by date of symptoms onset.
Results
A total of 5,795 ARI hospitalizations and 186 inpatient-deaths (3.2%) were reported between 01-December 2011 and 10-February 2012 (685 A/H1N1-positive inpatients and 75 A/H1N1-positive deaths). The nationwide peak of daily ARI hospitalizations in early 2012 has already exceeded the peak of ARI hospitalizations observed during the major fall pandemic wave in 2009. The mean age was 34.3 y (SD=21.3) among A/H1N1 inpatients and 43.5 y (SD=21) among A/H1N1 deaths in 2011-12. The proportion of laboratory-confirmed A/H1N1 hospitalizations and deaths was higher among seniors >=60 years of age (Chi-square test P<0.001) and lower among younger age groups (Chi-square test, P<0.03) for the 2011-2012 pandemic wave, compared to the earlier waves in 2009. The reproduction number of the winter 2011-12 wave in central Mexico was estimated at 1.2-1.3, similar to that reported for the fall 2009 wave, but lower than that of spring 2009.
Conclusions
We have documented a substantial and ongoing increase in the number of ARI hospitalizations during the period December 2011-February 2012 and an older age distribution of laboratory-confirmed A/H1N1 influenza hospitalizations and deaths, relative to 2009 A/H1N1 pandemic patterns. The gradual change in the age distribution of A/H1N1 infections in the post-pandemic period is reminiscent of historical pandemics and indicates either a gradual drift in the A/H1N1 virus, and/or a build-up of immunity among younger populations.
doi:10.1371/currents.RRN1306
PMCID: PMC3286879  PMID: 22485199
11.  Prioritization of Influenza Pandemic Vaccination to Minimize Years of Life Lost 
The Journal of infectious diseases  2008;198(3):305-311.
Background
How to allocate limited vaccine supplies in the event of an influenza pandemic is currently under debate. Conventional vaccination strategies focus on those at highest risk for severe outcomes, including seniors, but do not consider (1) the signature pandemic pattern in which mortality risk is shifted to younger ages, (2) likely reduced vaccine response in seniors, and (3) differences in remaining years of life with age.
Methods
We integrated these factors to project the age-specific years of life lost (YLL) and saved in a future pandemic, on the basis of mortality patterns from 3 historical pandemics, age-specific vaccine efficacy, and the 2000 US population structure.
Results
For a 1918-like scenario, the absolute mortality risk is highest in people <45 years old; in contrast, seniors (those ⩾65 years old) have the highest mortality risk in the 1957 and 1968 scenarios. The greatest YLL savings would be achieved by targeting different age groups in each scenario; people <45 years old in the 1918 scenario, people 45–64 years old in the 1968 scenario, and people >45 years old in the 1957 scenario.
Conclusions
Our findings shift the focus of pandemic vaccination strategies onto younger populations and illustrate the need for real-time surveillance of mortality patterns in a future pandemic. Flexible setting of vaccination priority is essential to minimize mortality.
doi:10.1086/589716
PMCID: PMC3206321  PMID: 18558871
12.  The early diversification of influenza A/H1N1pdm 
PLoS Currents  2009;1:RRN1126.
Background Since its initial detection in April 2009, the A/H1N1pdm influenza virus has spread rapidly in humans, with over 5,700 human deaths. However, little is known about the evolutionary dynamics of H1N1pdm and its geographic and temporal diversification.
Methods Phylogenetic analysis was conducted upon the concatenated coding regions of whole-genome sequences from 290 H1N1pdm isolates sampled globally between April 1 – July 9, 2009, including relatively large samples from the US states of Wisconsin and New York.
Results At least 7 phylogenetically distinct viral clades have disseminated globally and co-circulated in localities that experienced multiple introductions of H1N1pdm. The epidemics in New York and Wisconsin were dominated by two different clades, both phylogenetically distinct from the viruses first identified in California and Mexico, suggesting an important role for founder effects in determining local viral population structures.
Conclusions Determining the global diversity of H1N1pdm is central to understanding the evolution and spatial spread of the current pandemic, and to predict its future impact on human populations. Our results indicate that H1N1pdm has already diversified into distinct viral lineages with defined spatial patterns.
doi:10.1371/currents.RRN1126
PMCID: PMC2773564  PMID: 20029664
13.  Phylogeography of the Spring and Fall Waves of the H1N1/09 Pandemic Influenza Virus in the United States▿ §  
Journal of Virology  2010;85(2):828-834.
Spatial variation in the epidemiological patterns of successive waves of pandemic influenza virus in humans has been documented throughout the 20th century but never understood at a molecular level. However, the unprecedented intensity of sampling and whole-genome sequencing of the H1N1/09 pandemic virus now makes such an approach possible. To determine whether the spring and fall waves of the H1N1/09 influenza pandemic were associated with different epidemiological patterns, we undertook a large-scale phylogeographic analysis of viruses sampled from three localities in the United States. Analysis of genomic and epidemiological data reveals distinct spatial heterogeneities associated with the first pandemic wave, March to July 2009, in Houston, TX, Milwaukee, WI, and New York State. In Houston, no specific H1N1/09 viral lineage dominated during the spring of 2009, a period when little epidemiological activity was observed in Texas. In contrast, major pandemic outbreaks occurred at this time in Milwaukee and New York State, each dominated by a different viral lineage and resulting from strong founder effects. During the second pandemic wave, beginning in August 2009, all three U.S. localities were dominated by a single viral lineage, that which had been dominant in New York during wave 1. Hence, during this second phase of the pandemic, extensive viral migration and mixing diffused the spatially defined population structure that had characterized wave 1, amplifying the one viral lineage that had dominated early on in one of the world's largest international travel centers.
doi:10.1128/JVI.01762-10
PMCID: PMC3020026  PMID: 21068250
14.  Excess Mortality Associated with Influenza Epidemics in Portugal, 1980 to 2004 
PLoS ONE  2011;6(6):e20661.
Background
Influenza epidemics have a substantial impact on human health, by increasing the mortality from pneumonia and influenza, respiratory and circulatory diseases, and all causes. This paper provides estimates of excess mortality rates associated with influenza virus circulation for 7 causes of death and 8 age groups in Portugal during the period of 1980–2004.
Methodology/Principal Findings
We compiled monthly mortality time series data by age for all-cause mortality, cerebrovascular diseases, ischemic heart diseases, diseases of the respiratory system, chronic respiratory diseases, pneumonia and influenza. We also used a control outcome, deaths from injuries. Age- and cause-specific baseline mortality was modelled by the ARIMA approach; excess deaths attributable to influenza were calculated by subtracting expected deaths from observed deaths during influenza epidemic periods. Influenza was associated with a seasonal average of 24.7 all-cause excess deaths per 100,000 inhabitants, approximately 90% of which were among seniors over 65 yrs. Excess mortality was 3–6 fold higher during seasons dominated by the A(H3N2) subtype than seasons dominated by A(H1N1)/B. High excess mortality impact was also seen in children under the age of four years. Seasonal excess mortality rates from all the studied causes of death were highly correlated with each other (Pearson correlation range, 0.65 to 0.95, P<0.001) and with seasonal rates of influenza-like-illness (ILI) among seniors over 65 years (Pearson correlation rho>0.64, P<0.05). By contrast, there was no correlation with excess mortality from injuries.
Conclusions/Significance
Our excess mortality approach is specific to influenza virus activity and produces influenza-related mortality rates for Portugal that are similar to those published for other countries. Our results indicate that all-cause excess mortality is a robust indicator of influenza burden in Portugal, and could be used to monitor the impact of influenza epidemics in this country. Additional studies are warranted to confirm these findings in other settings.
doi:10.1371/journal.pone.0020661
PMCID: PMC3119666  PMID: 21713040
15.  Absolute Humidity and the Seasonal Onset of Influenza in the Continental US 
PLoS Currents  2010;2:RRN1138.
Much of the observed wintertime increase of mortality in temperate regions is attributed to seasonal influenza. A recent re-analysis of laboratory experiments indicates that absolute humidity strongly modulates the airborne survival and transmission of the influenza virus. Here we extend these findings to the human population level, showing that the onset of increased wintertime influenza-related mortality in the United States is associated with anomalously low absolute humidity levels during the prior weeks. We then use an epidemiological model, in which observed absolute humidity conditions temper influenza transmission rates, to successfully simulate the seasonal cycle of observed influenza-related mortality. The model results indicate that direct modulation of influenza transmissibility by absolute humidity alone is sufficient to produce this observed seasonality. These findings provide epidemiological support for the hypothesis that absolute humidity drives seasonal variations of influenza transmission in temperate regions.
doi:10.1371/currents.RRN1138
PMCID: PMC2803311  PMID: 20066155
16.  Projection of seasonal influenza severity from sequence and serological data 
PLoS Currents  2010;2:RRN1200.
Severity of seasonal influenza A epidemics is related to the antigenic novelty of the predominant viral strains circulating each year. Support for a strong correlation between epidemic severity and antigenic drift comes from infectious challenge experiments on vaccinated animals and human volunteers, field studies of vaccine efficacy, prospective studies of subjects with laboratory-confirmed prior infections, and analysis of the connection between drift and severity from surveillance data. We show that, given data on the antigenic and sequence novelty of the hemagglutinin protein of clinical isolates of H3N2 virus from a season along with the corresponding data from prior seasons, we can accurately predict the influenza severity for that season. This model therefore provides a framework for making projections of the severity of the upcoming season using assumptions based on viral isolates collected in the current season. Our results based on two independent data sets from the US and Hong Kong suggest that seasonal severity is largely determined by the novelty of the hemagglutinin protein although other factors, including mutations in other influenza genes, co-circulating pathogens and weather conditions, might also play a role. These results should be helpful for the control of seasonal influenza and have implications for improvement of influenza surveillance.
doi:10.1371/currents.RRN1200
PMCID: PMC2998708  PMID: 21152078
17.  Preliminary Estimates of Mortality and Years of Life Lost Associated with the 2009 A/H1N1 Pandemic in the US and Comparison with Past Influenza Seasons 
PLoS Currents  2010;2:RRN1153.
The on-going debate about the health burden of the 2009 influenza pandemic and discussions about the usefulness of vaccine recommendations has been hampered by an absence of directly comparable measures of mortality impact. Here we set out to generate an "apples-to-apples" metric to compare pandemic and epidemic mortality. We estimated the mortality burden of the pandemic in the US using a methodology similar to that used to generate excess mortality burden for inter-pandemic influenza seasons. We also took into account the particularly young age distribution of deaths in the 2009 H1N1 pandemic, using the metric "Years of Life Lost" instead of numbers of deaths. Estimates are based on the timely pneumonia and influenza mortality surveillance data from 122 US cities, and the age distribution of laboratory-confirmed pandemic deaths, which has a mean of 37 years. We estimated that between 7,500 and 44,100 deaths are attributable to the A/H1N1 pandemic virus in the US during May-December 2009, and that between 334,000 and 1,973,000 years of life were lost. The range of years of life lost estimates includes in its lower part the impact of a typical influenza epidemic dominated by the more virulent A/H3N2 subtype, and the impact of the 1968 pandemic in its upper bound. We conclude that the 2009 A/H1N1 pandemic virus had a substantial health burden in the US over the first few months of circulation in terms of years of life lost, justifying the efforts to protect the population with vaccination programs. Analysis of historic records from three other pandemics over the last century suggests that the emerging pandemic virus will continue to circulate and cause excess mortality in unusually young populations for the next few years. Continuing surveillance for indicators of increased mortality is of key importance, as pandemics do not always cause the majority of associated deaths in the first season of circulation.
doi:10.1371/currents.RRN1153
PMCID: PMC2843747  PMID: 20352125
18.  Absolute Humidity and the Seasonal Onset of Influenza in the Continental US 
PLoS Currents  2009;1:RRN1138.
Much of the observed wintertime increase of mortality in temperate regions is attributed to seasonal influenza. A recent re-analysis of laboratory experiments indicates that absolute humidity strongly modulates the airborne survival and transmission of the influenza virus. Here we extend these findings to the human population level, showing that the onset of increased wintertime influenza-related mortality in the United States is associated with anomalously low absolute humidity levels during the prior weeks. We then use an epidemiological model, in which observed absolute humidity conditions temper influenza transmission rates, to successfully simulate the seasonal cycle of observed influenza-related mortality. The model results indicate that direct modulation of influenza transmissibility by absolute humidity alone is sufficient to produce this observed seasonality. These findings provide epidemiological support for the hypothesis that absolute humidity drives seasonal variations of influenza transmission in temperate regions.
doi:10.1371/currents.RRN1138
PMCID: PMC2803311  PMID: 20066155
19.  Nontuberculous Mycobacteria–associated Lung Disease in Hospitalized Persons, United States, 1998–2005 
Emerging Infectious Diseases  2009;15(10):1562-1569.
This bacterium is an underappreciated cause of lung disease and infection rates appear to be increasing.
The prevalence and trends of pulmonary nontuberculous mycobacteria (NTM)–associated hospitalizations in the United States were estimated using national hospital discharge data. Records were extracted for all persons with a pulmonary NTM International Classification of Diseases code (031.0) hospitalized in the 11 states with continuous data available from 1998 through 2005. Prevalence was calculated using US census data. Pulmonary NTM hospitalizations (031.0) increased significantly with age among both sexes: relative prevalence for persons 70–79 years of age compared with those 40–49 years of age was 15/100,000 for women (9.4 vs. 0.6) and 9/100,000 for men (7.6 vs. 0.83). Annual prevalence increased significantly among men and women in Florida (3.2%/year and 6.5%/year, respectively) and among women in New York (4.6%/year) with no significant changes in California. The prevalence of pulmonary NTM–associated hospitalizations is increasing in selected geographic areas of the United States.
doi:10.3201/eid1510.090196
PMCID: PMC2866394  PMID: 19861046
Mycobacteria; atypical; nontuberculous mycobacteria; tuberculosis and other mycobacteria; prevalence; hospitalizations; United States; research
20.  Mortality and morbidity burden associated with A/H1N1pdm influenza virus 
PLoS Currents  2009;1:RRN1013.
Here we use lessons from past influenza pandemics and recent information about the H1N1pdm pandemic to discuss variations in H1N1pdm disease burden with age, underlying risk factors, and geography.
doi:10.1371/currents.RRN1013
PMCID: PMC2762375  PMID: 20029607
21.  Mortality and morbidity burden associated with A/H1N1pdm influenza virus 
PLoS Currents  2009;1:RRN1013.
Response to WHO to questions:
Who is likely to be infected and experience clinical symptoms with H1N1pdm 2009 pandemic virus ?
What is the expected death rate in developing and developed countries ?
doi:10.1371/currents.RRN1013
PMCID: PMC2762375  PMID: 20029607
22.  Adaptive vaccination strategies to mitigate pandemic influenza 
PLoS Currents  2009;1:RRN1004.
In this modeling work, we explore the effectiveness of various age-targeted vaccination strategies to mitigate hospitalization and mortality from pandemic influenza, assuming limited vaccine supplies. We propose a novel adaptive vaccination strategy in which vaccination is initiated during the outbreak and priority groups are identified based on real-time epidemiological data monitoring age-specific risk of hospitalization and death. We apply this strategy to detailed epidemiological and demographic data collected during the recent swine A/H1N1 outbreak in Mexico. We show that the adaptive strategy targeting age groups 6-59 years is the most effective in reducing hospitalizations and deaths, as compared with a more traditional strategy used in the control of seasonal influenza and targeting children under 5 and seniors over 65. Results are robust to a number of assumptions and could provide guidance to many nations facing a recrudescence of A/H1N1v pandemic activity in the fall and likely vaccine shortages.
doi:10.1371/currents.RRN1004
PMCID: PMC2762696  PMID: 20025196
23.  The genomic and epidemiological dynamics of human influenza A virus 
Nature  2008;453(7195):615-619.
The evolutionary interaction between influenza A virus and the human immune system, manifest as ‘antigenic drift’ of the viral haemagglutinin, is one of the best described patterns in molecular evolution. However, little is known about the genome-scale evolutionary dynamics of this pathogen. Similarly, how genomic processes relate to global influenza epidemiology, in which the A/H3N2 and A/H1N1 subtypes co-circulate, is poorly understood. Here through an analysis of 1,302 complete viral genomes sampled from temperate populations in both hemispheres, we show that the genomic evolution of influenza A virus is characterized by a complex interplay between frequent reassortment and periodic selective sweeps. The A/H3N2 and A/H1N1 subtypes exhibit different evolutionary dynamics, with diverse lineages circulating in A/H1N1, indicative of weaker antigenic drift. These results suggest a sink-source model of viral ecology in which new lineages are seeded from a persistent influenza reservoir, which we hypothesize to be located in the tropics, to sink populations in temperate regions.
doi:10.1038/nature06945
PMCID: PMC2441973  PMID: 18418375
24.  Trends in Intussusception Hospitalizations Among US Infants, 1993–2004: Implications for Monitoring the Safety of the New Rotavirus Vaccination Program 
Pediatrics  2008;121(5):e1125-e1132.
OBJECTIVES
In 2006, a new rotavirus vaccine was recommended for routine immunization of US infants. Because a previous rotavirus vaccine was withdrawn in 1999 after it was associated with intussusception, monitoring for this adverse event with the new vaccine is important. The objectives of this study were to assess intussusception hospitalizations trends among US infants for 1993 to 2004; provide estimates of hospitalization rates for intussusception for 2002–2004; and assess variations in background rates by age, race/ethnicity, and surgical management.
METHODS
By using the Healthcare Cost and Utilization Project’s State Inpatient Data-base that captures US hospital discharges from 16 states representing 49% of the birth cohort during 1993–2004 and from 35 states representing 85% of the birth cohort in 2002–2004, we examined hospitalizations among infants (<12 months of age) with an International Classification of Disease, Ninth Revision, Clinical Modification code for intussusception (560.0). Incidence rates were calculated by using census data, and rate ratios with 95% confidence intervals were calculated by using Poisson regression data.
RESULTS
Annual intussusception hospitalization rates declined 25% from 1993 to 2004 but have remained stable at ~35 cases per 100 000 infants since 2000. Rates were very low for infants younger than 9 weeks (<5 per 100 000) then increased rapidly, peaking at ~62 per 100 000 at 26 to 29 weeks, before declining gradually to 26 per 100 000 at 52 weeks. Compared with rates among non-Hispanic white infants (27 per 100 000), rates were greater among non-Hispanic black infants (37 per 100 000) and Hispanic infants (45 per 100 000); however, rates did not differ by race/ethnicity for infants who were younger than 16 weeks.
CONCLUSIONS
This assessment of US hospitalizations provides up-to-date and nationally representative prevaccine rates of intussusception. Because rates varied almost 12-fold by week of age and to a lesser extent by race/ethnicity during the age of vaccination, adjusting baseline rates to reflect the demographics of the vaccinated population will be crucial for assessing risk for intussusception after rotavirus vaccination.
doi:10.1542/peds.2007-1590
PMCID: PMC2680116  PMID: 18450856
intussusception; rotavirus vaccine; vaccine safety monitoring

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