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1.  Multiyear Persistence of 2 Pandemic A/H1N1 Influenza Virus Lineages in West Africa 
The Journal of Infectious Diseases  2014;210(1):121-125.
Our understanding of the global ecology of influenza viruses is impeded by historically low levels of viral surveillance in Africa. Increased genetic sequencing of African A/H1N1 pandemic influenza viruses during 2009–2013 revealed multiyear persistence of 2 viral lineages within West Africa, raising questions about the roles of reduced air traffic and the asynchrony of seasonal influenza epidemics among West African countries in the evolution of independent lineages. The potential for novel influenza virus lineages to evolve within Africa warrants intensified influenza surveillance in Africa and other understudied areas.
doi:10.1093/infdis/jiu047
PMCID: PMC4162001  PMID: 24446525
human influenza A virus; pandemic; phylogenetic analysis; Africa
2.  Influenza seasonality in Madagascar: the mysterious African free-runner 
Background
The seasonal drivers of influenza activity remain debated in tropical settings where epidemics are not clearly phased. Antananarivo is a particularly interesting case study because it is in Madagascar, an island situated in the tropics and with quantifiable connectivity levels to other countries.
Objectives
We aimed at disentangling the role of environmental forcing and population fluxes on influenza seasonality in Madagascar.
Methods
We compiled weekly counts of laboratory-confirmed influenza-positive specimens for the period 2002 to 2012 collected in Antananarivo, with data available from sub-Saharan countries and countries contributing most foreign travelers to Madagascar. Daily climate indicators were compiled for the study period.
Results
Overall, influenza activity detected in Antananarivo predated that identified in temperate Northern Hemisphere locations. This activity presented poor temporal matching with viral activity in other countries from the African continent or countries highly connected to Madagascar excepted for A(H1N1)pdm09. Influenza detection in Antananarivo was not associated with travel activity and, although it was positively correlated with all climatic variables studied, such association was weak.
Conclusions
The timing of influenza activity in Antananarivo is irregular, is not driven by climate, and does not align with that of countries in geographic proximity or highly connected to Madagascar. This work opens fresh questions regarding the drivers of influenza seasonality globally particularly in mid-latitude and less-connected regions to tailor vaccine strategies locally.
doi:10.1111/irv.12308
PMCID: PMC4415694  PMID: 25711873
Influenza; Madagascar; population connectivity; seasonality; time series; viral migration
3.  Deaths Associated with Respiratory Syncytial and Influenza Viruses among Persons ≥5 Years of Age in HIV-Prevalent Area, South Africa, 1998–20091 
Emerging Infectious Diseases  2015;21(4):600-608.
Mortality rates were higher among HIV-positive persons and older persons who had influenza.
Deaths Associated with Respiratory Viruses in HIV-Prevalent Area
We estimated deaths attributable to influenza and respiratory syncytial virus (RSV) among persons >5 years of age in South Africa during 1998–2009 by applying regression models to monthly deaths and laboratory surveillance data. Rates were expressed per 100,000 person-years. The mean annual number of seasonal influenza–associated deaths was 9,093 (rate 21.6). Persons >65 years of age and HIV-positive persons accounted for 50% (n = 4,552) and 28% (n = 2,564) of overall seasonal influenza-associated deaths, respectively. In 2009, we estimated 4,113 (rate 9.2) influenza A(H1N1)pdm09–associated deaths. The mean of annual RSV-associated deaths during the study period was 511 (rate 1.2); no RSV-associated deaths were estimated in persons >45 years of age. Our findings support the recommendation for influenza vaccination of older persons and HIV-positive persons. Surveillance for RSV should be strengthened to clarify the public health implications and severity of illness associated with RSV infection in South Africa.
doi:10.3201/eid2104.141033
PMCID: PMC4378466  PMID: 25811455
Influenza; viruses; respiratory syncytial virus; RSV; HIV; human immunodeficiency virus; mortality rates; deaths; South Africa
4.  Introductions and Evolution of Human-Origin Seasonal Influenza A Viruses in Multinational Swine Populations 
Journal of Virology  2014;88(17):10110-10119.
ABSTRACT
The capacity of influenza A viruses to cross species barriers presents a continual threat to human and animal health. Knowledge of the human-swine interface is particularly important for understanding how viruses with pandemic potential evolve in swine hosts. We sequenced the genomes of 141 influenza viruses collected from North American swine during 2002 to 2011 and identified a swine virus that possessed all eight genome segments of human seasonal A/H3N2 virus origin. A molecular clock analysis indicates that this virus—A/sw/Saskatchewan/02903/2009(H3N2)—has likely circulated undetected in swine for at least 7 years. For historical context, we performed a comprehensive phylogenetic analysis of an additional 1,404 whole-genome sequences from swine influenza A viruses collected globally during 1931 to 2013. Human-to-swine transmission occurred frequently over this time period, with 20 discrete introductions of human seasonal influenza A viruses showing sustained onward transmission in swine for at least 1 year since 1965. Notably, human-origin hemagglutinin (H1 and H3) and neuraminidase (particularly N2) segments were detected in swine at a much higher rate than the six internal gene segments, suggesting an association between the acquisition of swine-origin internal genes via reassortment and the adaptation of human influenza viruses to new swine hosts. Further understanding of the fitness constraints on the adaptation of human viruses to swine, and vice versa, at a genomic level is central to understanding the complex multihost ecology of influenza and the disease threats that swine and humans pose to each other.
IMPORTANCE The swine origin of the 2009 A/H1N1 pandemic virus underscored the importance of understanding how influenza A virus evolves in these animals hosts. While the importance of reassortment in generating genetically diverse influenza viruses in swine is well documented, the role of human-to-swine transmission has not been as intensively studied. Through a large-scale sequencing effort, we identified a novel influenza virus of wholly human origin that has been circulating undetected in swine for at least 7 years. In addition, we demonstrate that human-to-swine transmission has occurred frequently on a global scale over the past decades but that there is little persistence of human virus internal gene segments in swine.
doi:10.1128/JVI.01080-14
PMCID: PMC4136342  PMID: 24965467
5.  Eight challenges in phylodynamic inference 
Epidemics  2015;10:88-92.
Highlights
•We outline core challenges in phylodynamic inference.•Evolutionary challenges include selection and recombination.•Epidemiological challenges include population structure and stochasticity.•Methodological challenges include sampling bias and computational complexity.
The field of phylodynamics, which attempts to enhance our understanding of infectious disease dynamics using pathogen phylogenies, has made great strides in the past decade. Basic epidemiological and evolutionary models are now well characterized with inferential frameworks in place. However, significant challenges remain in extending phylodynamic inference to more complex systems. These challenges include accounting for evolutionary complexities such as changing mutation rates, selection, reassortment, and recombination, as well as epidemiological complexities such as stochastic population dynamics, host population structure, and different patterns at the within-host and between-host scales. An additional challenge exists in making efficient inferences from an ever increasing corpus of sequence data.
doi:10.1016/j.epidem.2014.09.001
PMCID: PMC4383806  PMID: 25843391
Phylodynamics; Coalescent models; Selection; Recombination
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  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
18.  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
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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