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1.  Real-time characterization of risks of death associated with the Middle East respiratory syndrome (MERS) in the Republic of Korea, 2015 
BMC Medicine  2015;13:228.
An outbreak of the Middle East respiratory syndrome (MERS), comprising 185 cases linked to healthcare facilities, occurred in the Republic of Korea from May to July 2015. Owing to the nosocomial nature of the outbreak, it is particularly important to gain a better understanding of the epidemiological determinants characterizing the risk of MERS death in order to predict the heterogeneous risk of death in medical settings.
We have devised a novel statistical model that identifies the risk of MERS death during the outbreak in real time. While accounting for the time delay from illness onset to death, risk factors for death were identified using a linear predictor tied to a logit model. We employ this approach to (1) quantify the risks of death and (2) characterize the temporal evolution of the case fatality ratio (CFR) as case ascertainment greatly improved during the course of the outbreak.
Senior persons aged 60 years or over were found to be 9.3 times (95 % confidence interval (CI), 5.3–16.9) more likely to die compared to younger MERS cases. Patients under treatment were at a 7.8-fold (95 % CI, 4.0–16.7) significantly higher risk of death compared to other MERS cases. The CFR among patients aged 60 years or older under treatment was estimated at 48.2 % (95 % CI, 35.2–61.3) as of July 31, 2015, while the CFR among other cases was estimated to lie below 15 %. From June 6, 2015, onwards, the CFR declined 0.3-fold (95 % CI, 0.1–1.1) compared to the earlier epidemic period, which may perhaps reflect enhanced case ascertainment following major contact tracing efforts.
The risk of MERS death was significantly associated with older age as well as treatment for underlying diseases after explicitly adjusting for the delay between illness onset and death. Because MERS outbreaks are greatly amplified in the healthcare setting, enhanced infection control practices in medical facilities should strive to shield risk groups from MERS exposure.
PMCID: PMC4588253  PMID: 26420593
Case fatality ratio; Fatal outcome; Middle East respiratory syndrome; Risk factors; Statistical model; South Korea
2.  Transmission characteristics of MERS and SARS in the healthcare setting: a comparative study 
BMC Medicine  2015;13:210.
The Middle East respiratory syndrome (MERS) coronavirus has caused recurrent outbreaks in the Arabian Peninsula since 2012. Although MERS has low overall human-to-human transmission potential, there is occasional amplification in the healthcare setting, a pattern reminiscent of the dynamics of the severe acute respiratory syndrome (SARS) outbreaks in 2003. Here we provide a head-to-head comparison of exposure patterns and transmission dynamics of large hospital clusters of MERS and SARS, including the most recent South Korean outbreak of MERS in 2015.
To assess the unexpected nature of the recent South Korean nosocomial outbreak of MERS and estimate the probability of future large hospital clusters, we compared exposure and transmission patterns for previously reported hospital clusters of MERS and SARS, based on individual-level data and transmission tree information. We carried out simulations of nosocomial outbreaks of MERS and SARS using branching process models rooted in transmission tree data, and inferred the probability and characteristics of large outbreaks.
A significant fraction of MERS cases were linked to the healthcare setting, ranging from 43.5 % for the nosocomial outbreak in Jeddah, Saudi Arabia, in 2014 to 100 % for both the outbreak in Al-Hasa, Saudi Arabia, in 2013 and the outbreak in South Korea in 2015. Both MERS and SARS nosocomial outbreaks are characterized by early nosocomial super-spreading events, with the reproduction number dropping below 1 within three to five disease generations. There was a systematic difference in the exposure patterns of MERS and SARS: a majority of MERS cases occurred among patients who sought care in the same facilities as the index case, whereas there was a greater concentration of SARS cases among healthcare workers throughout the outbreak. Exposure patterns differed slightly by disease generation, however, especially for SARS. Moreover, the distributions of secondary cases per single primary case varied highly across individual hospital outbreaks (Kruskal–Wallis test; P < 0.0001), with significantly higher transmission heterogeneity in the distribution of secondary cases for MERS than SARS. Simulations indicate a 2-fold higher probability of occurrence of large outbreaks (>100 cases) for SARS than MERS (2 % versus 1 %); however, owing to higher transmission heterogeneity, the largest outbreaks of MERS are characterized by sharper incidence peaks. The probability of occurrence of MERS outbreaks larger than the South Korean cluster (n = 186) is of the order of 1 %.
Our study suggests that the South Korean outbreak followed a similar progression to previously described hospital clusters involving coronaviruses, with early super-spreading events generating a disproportionately large number of secondary infections, and the transmission potential diminishing greatly in subsequent generations. Differences in relative exposure patterns and transmission heterogeneity of MERS and SARS could point to changes in hospital practices since 2003 or differences in transmission mechanisms of these coronaviruses.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-015-0450-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4558759  PMID: 26336062
Coronavirus; Exposure pattern; Hospital transmission; MERS; Middle East; Nosocomial; Reproduction number; SARS; South Korea
3.  The Western Africa Ebola Virus Disease Epidemic Exhibits Both Global Exponential and Local Polynomial Growth Rates 
PLoS Currents  2015;7:ecurrents.outbreaks.8b55f4bad99ac5c5db3663e916803261.
Background: While many infectious disease epidemics are initially characterized by an exponential growth in time, we show that district-level Ebola virus disease (EVD) outbreaks in West Africa follow slower polynomial-based growth kinetics over several generations of the disease. Methods: We analyzed epidemic growth patterns at three different spatial scales (regional, national, and subnational) of the Ebola virus disease epidemic in Guinea, Sierra Leone and Liberia by compiling publicly available weekly time series of reported EVD case numbers from the patient database available from the World Health Organization website for the period 05-Jan to 17-Dec 2014. Results: We found significant differences in the growth patterns of EVD cases at the scale of the country, district, and other subnational administrative divisions. The national cumulative curves of EVD cases in Guinea, Sierra Leone, and Liberia show periods of approximate exponential growth. In contrast, local epidemics are asynchronous and exhibit slow growth patterns during 3 or more EVD generations, which can be better approximated by a polynomial than an exponential function. Conclusions: The slower than expected growth pattern of local EVD outbreaks could result from a variety of factors, including behavior changes, success of control interventions, or intrinsic features of the disease such as a high level of clustering. Quantifying the contribution of each of these factors could help refine estimates of final epidemic size and the relative impact of different mitigation efforts in current and future EVD outbreaks.
PMCID: PMC4322058  PMID: 25685633
4.  Is West Africa Approaching a Catastrophic Phase or is the 2014 Ebola Epidemic Slowing Down? Different Models Yield Different Answers for Liberia 
PLoS Currents  2014;6:ecurrents.outbreaks.b4690859d91684da963dc40e00f3da81.
An unprecedented epidemic of Zaire ebolavirus (EBOV) has affected West Africa since approximately December 2013, with intense transmission on-going in Guinea, Sierra Leone and Liberia and increasingly important international repercussions. Mathematical models are proving instrumental to forecast the expected number of infections and deaths and quantify the intensity of interventions required to control transmission; however, calibrating mechanistic transmission models to an on-going outbreak is a challenging task owing to limited availability of epidemiological data and rapidly changing interventions. Here we project the trajectory of the EBOV epidemic in Liberia by fitting logistic growth models to the cumulative number of cases. Our model predictions align well with the latest epidemiological reports available as of October 23, and indicates that the exponential growth phase is over in Liberia, with an expected final attack rate of ~0.1-0.12%. Our results indicate that simple phenomenological models can provide complementary insights into the dynamics of an outbreak and capture early signs of changes in population behavior and interventions. In particular, our results underscore the need to treat the effective size of the susceptible population as a dynamic variable rather than a fixed quantity, due to reactive changes in transmission throughout the outbreak. We show that predictions from the logistic model are more variable in the earlier stages of an epidemic (such as the EBOV epidemics in Sierra Leone and Guinea). More research is warranted to compare the performances of mechanistic and phenomenological approaches for disease forecasts, before such predictions can be fully used by public health authorities.
PMCID: PMC4318911  PMID: 25685615
5.  Accounting for behavioral responses during a flu epidemic using home television viewing 
Theory suggests that individual behavioral responses impact the spread of flu-like illnesses, but this has been difficult to empirically characterize. Social distancing is an important component of behavioral response, though analyses have been limited by a lack of behavioral data. Our objective is to use media data to characterize social distancing behavior in order to empirically inform explanatory and predictive epidemiological models.
We use data on variation in home television viewing as a proxy for variation in time spent in the home and, by extension, contact. This behavioral proxy is imperfect but appealing since information on a rich and representative sample is collected using consistent techniques across time and most major cities. We study the April-May 2009 outbreak of A/H1N1 in Central Mexico and examine the dynamic behavioral response in aggregate and contrast the observed patterns of various demographic subgroups. We develop and calibrate a dynamic behavioral model of disease transmission informed by the proxy data on daily variation in contact rates and compare it to a standard (non-adaptive) model and a fixed effects model that crudely captures behavior.
We find that after a demonstrable initial behavioral response (consistent with social distancing) at the onset of the outbreak, there was attenuation in the response before the conclusion of the public health intervention. We find substantial differences in the behavioral response across age subgroups and socioeconomic levels. We also find that the dynamic behavioral and fixed effects transmission models better account for variation in new confirmed cases, generate more stable estimates of the baseline rate of transmission over time and predict the number of new cases over a short horizon with substantially less error.
Results suggest that A/H1N1 had an innate transmission potential greater than previously thought but this was masked by behavioral responses. Observed differences in behavioral response across demographic groups indicate a potential benefit from targeting social distancing outreach efforts.
PMCID: PMC4304633  PMID: 25616673
Epidemic model; Social distancing; A/H1N1; Influenza; SIR
6.  Characterizing the Transmission Dynamics and Control of Ebola Virus Disease 
PLoS Biology  2015;13(1):e1002057.
Carefully calibrated transmission models have the potential to guide public health officials on the nature and scale of the interventions required to control the ongoing Ebola virus disease epidemic in West Africa.
Carefully calibrated transmission models have the potential to guide public health officials on the nature and scale of the interventions required to control epidemics. In the context of the ongoing Ebola virus disease (EVD) epidemic in Liberia, Drake and colleagues, in this issue of PLOS Biology, employed an elegant modeling approach to capture the distributions of the number of secondary cases that arise in the community and health care settings in the context of changing population behaviors and increasing hospital capacity. Their findings underscore the role of increasing the rate of safe burials and the fractions of infectious individuals who seek hospitalization together with hospital capacity to achieve epidemic control. However, further modeling efforts of EVD transmission and control in West Africa should utilize the spatial-temporal patterns of spread in the region by incorporating spatial heterogeneity in the transmission process. Detailed datasets are urgently needed to characterize temporal changes in population behaviors, contact networks at different spatial scales, population mobility patterns, adherence to infection control measures in hospital settings, and hospitalization and reporting rates.
PMCID: PMC4301953  PMID: 25607595
7.  Theoretical perspectives on the infectiousness of Ebola virus disease 
Ebola virus disease (EVD) has generated a large epidemic in West Africa since December 2013. This mini-review is aimed to clarify and illustrate different theoretical concepts of infectiousness in order to compare the infectiousness across different communicable diseases including EVD.
We employed a transmission model that rests on the renewal process in order to clarify theoretical concepts on infectiousness, namely the basic reproduction number, R0, which measures the infectiousness per generation of cases, the force of infection (i.e. the hazard rate of infection), the intrinsic growth rate (i.e. infectiousness per unit time) and the per-contact probability of infection (i.e. infectiousness per effective contact).
Whereas R0 of EVD is similar to that of influenza, the growth rate (i.e. the measure of infectiousness per unit time) for EVD was shown to be comparatively lower than that for influenza. Moreover, EVD and influenza differ in mode of transmission whereby the probability of transmission per contact is lower for EVD compared to that of influenza.
The slow spread of EVD associated with the need for physical contact with body fluids supports social distancing measures including contact tracing and case isolation. Descriptions and interpretations of different variables quantifying infectiousness need to be used clearly and objectively in the scientific community and for risk communication.
PMCID: PMC4430046  PMID: 25566687
8.  Lessons learned from case fatality risk estimates of 2009 pandemic influenza 
Epidemiology (Cambridge, Mass.)  2013;24(6):842-844.
PMCID: PMC3927950  PMID: 24076991
9.  Death Patterns during the 1918 Influenza Pandemic in Chile 
Emerging Infectious Diseases  2014;20(11):1803-1811.
Death rates varied by region, but not age group, and peaked during July–August 1919.
The 1918 Influenza Pandemic in Chile
Scarce information about the epidemiology of historical influenza pandemics in South America prevents complete understanding of pandemic patterns throughout the continent and across different climatic zones. To fill gaps with regard to spatiotemporal patterns of deaths associated with the 1918 influenza pandemic in Chile, we reviewed archival records. We found evidence that multiple pandemic waves at various times of the year and of varying intensities occurred during 1918–1921 and that influenza-related excess deaths peaked during July–August 1919. Pandemic-associated mortality rates were elevated for all age groups, including for adults >50 years of age; elevation from baseline was highest for young adults. Overall, the rate of excess deaths from the pandemic was estimated at 0.94% in Chile, similar to rates reported elsewhere in Latin America, but rates varied ≈10-fold across provinces. Patterns of death during the pandemic were affected by variation in host-specific susceptibility, population density, baseline death rate, and climate.
PMCID: PMC4214284  PMID: 25341056
1918 influenza pandemic; Chile; Concepción; age-specific mortality; geography; population density; latitudinal gradient; viruses; influenza
10.  Transmission dynamics and control of Ebola virus disease (EVD): a review 
BMC Medicine  2014;12:196.
The complex and unprecedented Ebola epidemic ongoing in West Africa has highlighted the need to review the epidemiological characteristics of Ebola Virus Disease (EVD) as well as our current understanding of the transmission dynamics and the effect of control interventions against Ebola transmission. Here we review key epidemiological data from past Ebola outbreaks and carry out a comparative review of mathematical models of the spread and control of Ebola in the context of past outbreaks and the ongoing epidemic in West Africa. We show that mathematical modeling offers useful insights into the risk of a major epidemic of EVD and the assessment of the impact of basic public health measures on disease spread. We also discuss the critical need to collect detailed epidemiological data in real-time during the course of an ongoing epidemic, carry out further studies to estimate the effectiveness of interventions during past outbreaks and the ongoing epidemic, and develop large-scale modeling studies to study the spread and control of viral hemorrhagic fevers in the context of the highly heterogeneous economic reality of African countries.
PMCID: PMC4207625  PMID: 25300956
Ebola Virus Disease; Transmission model; Control interventions; Basic reproduction number; West Africa; Incubation; Serial interval; Case fatality ratio; Isolation; Behavior change
11.  Merging Economics and Epidemiology to Improve the Prediction and Management of Infectious Disease 
Ecohealth  2014;11(4):464-475.
Mathematical epidemiology, one of the oldest and richest areas in mathematical biology, has significantly enhanced our understanding of how pathogens emerge, evolve, and spread. Classical epidemiological models, the standard for predicting and managing the spread of infectious disease, assume that contacts between susceptible and infectious individuals depend on their relative frequency in the population. The behavioral factors that underpin contact rates are not generally addressed. There is, however, an emerging a class of models that addresses the feedbacks between infectious disease dynamics and the behavioral decisions driving host contact. Referred to as “economic epidemiology” or “epidemiological economics,” the approach explores the determinants of decisions about the number and type of contacts made by individuals, using insights and methods from economics. We show how the approach has the potential both to improve predictions of the course of infectious disease, and to support development of novel approaches to infectious disease management.
PMCID: PMC4366543  PMID: 25233829
economic epidemiology; epidemiological economics; incentives; infectious disease
12.  Time-Specific Ecologic Niche Models Forecast the Risk of Hemorrhagic Fever with Renal Syndrome in Dongting Lake District, China, 2005–2010 
PLoS ONE  2014;9(9):e106839.
Hemorrhagic fever with renal syndrome (HFRS), a rodent-borne infectious disease, is one of the most serious public health threats in China. Increasing our understanding of the spatial and temporal patterns of HFRS infections could guide local prevention and control strategies.
Methodology/Principal Findings
We employed statistical models to analyze HFRS case data together with environmental data from the Dongting Lake district during 2005–2010. Specifically, time-specific ecologic niche models (ENMs) were used to quantify and identify risk factors associated with HFRS transmission as well as forecast seasonal variation in risk across geographic areas. Results showed that the Maximum Entropy model provided the best predictive ability (AUC = 0.755). Time-specific Maximum Entropy models showed that the potential risk areas of HFRS significantly varied across seasons. High-risk areas were mainly found in the southeastern and southwestern areas of the Dongting Lake district. Our findings based on models focused on the spring and winter seasons showed particularly good performance. The potential risk areas were smaller in March, May and August compared with those identified for June, July and October to December. Both normalized difference vegetation index (NDVI) and land use types were found to be the dominant risk factors.
Our findings indicate that time-specific ENMs provide a useful tool to forecast the spatial and temporal risk of HFRS.
PMCID: PMC4153722  PMID: 25184252
13.  Spatial-temporal excess mortality patterns of the 1918–1919 influenza pandemic in Spain 
BMC Infectious Diseases  2014;14:371.
The impact of socio-demographic factors and baseline health on the mortality burden of seasonal and pandemic influenza remains debated. Here we analyzed the spatial-temporal mortality patterns of the 1918 influenza pandemic in Spain, one of the countries of Europe that experienced the highest mortality burden.
We analyzed monthly death rates from respiratory diseases and all-causes across 49 provinces of Spain, including the Canary and Balearic Islands, during the period January-1915 to June-1919. We estimated the influenza-related excess death rates and risk of death relative to baseline mortality by pandemic wave and province. We then explored the association between pandemic excess mortality rates and health and socio-demographic factors, which included population size and age structure, population density, infant mortality rates, baseline death rates, and urbanization.
Our analysis revealed high geographic heterogeneity in pandemic mortality impact. We identified 3 pandemic waves of varying timing and intensity covering the period from Jan-1918 to Jun-1919, with the highest pandemic-related excess mortality rates occurring during the months of October-November 1918 across all Spanish provinces. Cumulative excess mortality rates followed a south–north gradient after controlling for demographic factors, with the North experiencing highest excess mortality rates. A model that included latitude, population density, and the proportion of children living in provinces explained about 40% of the geographic variability in cumulative excess death rates during 1918–19, but different factors explained mortality variation in each wave.
A substantial fraction of the variability in excess mortality rates across Spanish provinces remained unexplained, which suggests that other unidentified factors such as comorbidities, climate and background immunity may have affected the 1918–19 pandemic mortality rates. Further archeo-epidemiological research should concentrate on identifying settings with combined availability of local historical mortality records and information on the prevalence of underlying risk factors, or patient-level clinical data, to further clarify the drivers of 1918 pandemic influenza mortality.
PMCID: PMC4094406  PMID: 24996457
1918–1919 influenza pandemic; Spain; Spanish influenza; Spring-summer wave; Excess death rates; Relative risk of death; Transmissibility; Provinces; Geography; Spatial heterogeneity
14.  Rates of Influenza-like Illness and Winter School Breaks, Chile, 2004–2010 
Emerging Infectious Diseases  2014;20(7):1195-1199.
To determine effects of school breaks on influenza virus transmission in the Southern Hemisphere, we analyzed 2004–2010 influenza-like–illness surveillance data from Chile. Winter breaks were significantly associated with a two-thirds temporary incidence reduction among schoolchildren, which supports use of school closure to temporarily reduce illness, especially among schoolchildren, in the Southern Hemisphere.
PMCID: PMC4073857  PMID: 24963800
Influenza-like illness; Chile; age-specific incidence rates; incidence ratio; influenza; viruses
15.  Assessing the impact of public health interventions on the transmission of pandemic H1N1 influenza a virus aboard a Peruvian navy ship 
Limited data exist on transmission dynamics and effectiveness of control measures for influenza in confined settings.
To investigate the transmission dynamics of a 2009 pandemic H1N1 influenza A outbreak aboard a Peruvian Navy ship and quantify the effectiveness of the implemented control measures.
We used surveillance data and a simple stochastic epidemic model to characterize and evaluate the effectiveness of control interventions implemented during an outbreak of 2009 pandemic H1N1 influenza A aboard a Peruvian Navy ship.
The serological attack rate for the outbreak was 49·1%, with younger cadets and low-ranking officers at greater risk of infection than older, higher-ranking officers. Our transmission model yielded a good fit to the daily time series of new influenza cases by date of symptom onset. We estimated a reduction of 54·4% in the reproduction number during the period of intense control interventions.
Our results indicate that the patient isolation strategy and other control measures put in place during the outbreak reduced the infectiousness of isolated individuals by 86·7%. Our findings support that early implementation of control interventions can limit the spread of influenza epidemics in confined settings.
PMCID: PMC4181484  PMID: 24506160
Disease outbreak; influenza; military personnel; Peru; ships; transmission
16.  Substantial Morbidity and Mortality Associated with Pandemic A/H1N1 Influenza in Mexico, Winter 2013-2014: Gradual Age Shift and Severity 
PLoS Currents  2014;6:ecurrents.outbreaks.a855a92f19db1d90ca955f5e908d6631.
Background: A recrudescent wave of pandemic influenza A/H1N1 is underway in Mexico in winter 2013-14, following a mild 2012-13 A/H3N2 influenza season. Mexico previously experienced several waves of pandemic A/H1N1 activity in spring, summer and fall 2009 and winter 2011-2012, with a gradual shift of influenza-related hospitalizations and deaths towards older ages. Here we describe changes in the epidemiology of the 2013-14 A/H1N1 influenza outbreak, relative to previous seasons dominated by the A/H1N1 pandemic virus. The analysis is intended to guide public health intervention strategies in near real time. Methods: We analyzed demographic and geographic data on hospitalizations with severe acute respiratory infection (SARI), laboratory-confirmed A/H1N1 influenza hospitalizations, and inpatient deaths, from a large prospective surveillance system maintained by the Mexican Social Security medical system during 01-October 2013 to 31-Jan 2014. We characterized the age and regional patterns of influenza activity relative to the preceding 2011-2012 A/H1N1 influenza epidemic. We also estimated the reproduction number (R) based on the growth rate of daily case incidence by date of symptoms onset. Results: A total of 7,886 SARI hospitalizations and 529 inpatient-deaths (3.2%) were reported between 01-October 2013 and 31-January 2014 (resulting in 3.2 laboratory-confirmed A/H1N1 hospitalizations per 100,00 and 0.52 laboratory-confirmed A/H1N1-positive deaths per 100,000). The progression of daily SARI hospitalizations in 2013-14 exceeded that observed during the 2011-2012 A/H1N1 epidemic. The mean age of laboratory-confirmed A/H1N1 patients in 2013-14 was 41.1 y (SD=20.3) for hospitalizations and 49.2 y (SD=16.7) for deaths. Rates of laboratory-confirmed A/H1N1 hospitalizations and deaths were significantly higher among individuals aged 30-59 y and lower among younger age groups for the ongoing 2013-2014 epidemic, compared to the 2011-12 A/H1N1 epidemic (Chi-square test, P<0.001). The reproduction number of the winter 2013-14 wave in central Mexico was estimated at 1.3-1.4 which is slightly higher than that reported for the 2011-2012 A/H1N1 epidemic. Conclusions: We have documented a substantial and ongoing increase in the number of A/H1N1-related hospitalizations and deaths during the period October 2013-January 2014 and a proportionate shift of severe disease to middle aged adults, relative to the preceding A/H1N1 2011-2012 epidemic in Mexico. In the absence of clear antigenic drift in globally circulating A/H1N1 viruses in the post-pandemic period, the gradual change in the age distribution of A/H1N1 infections observed in Mexico suggests a slow build-up of immunity among younger populations, reminiscent of the age profile of past pandemics.
PMCID: PMC3967911  PMID: 24744975
A/H1N1; Influenza; Mexico; Pandemic
17.  Heat-Related Deaths in Hot Cities: Estimates of Human Tolerance to High Temperature Thresholds 
In this study we characterized the relationship between temperature and mortality in central Arizona desert cities that have an extremely hot climate. Relationships between daily maximum apparent temperature (ATmax) and mortality for eight condition-specific causes and all-cause deaths were modeled for all residents and separately for males and females ages <65 and ≥65 during the months May–October for years 2000–2008. The most robust relationship was between ATmax on day of death and mortality from direct exposure to high environmental heat. For this condition-specific cause of death, the heat thresholds in all gender and age groups (ATmax = 90–97 °F; 32.2‒36.1 °C) were below local median seasonal temperatures in the study period (ATmax = 99.5 °F; 37.5 °C). Heat threshold was defined as ATmax at which the mortality ratio begins an exponential upward trend. Thresholds were identified in younger and older females for cardiac disease/stroke mortality (ATmax = 106 and 108 °F; 41.1 and 42.2 °C) with a one-day lag. Thresholds were also identified for mortality from respiratory diseases in older people (ATmax = 109 °F; 42.8 °C) and for all-cause mortality in females (ATmax = 107 °F; 41.7 °C) and males <65 years (ATmax = 102 °F; 38.9 °C). Heat-related mortality in a region that has already made some adaptations to predictable periods of extremely high temperatures suggests that more extensive and targeted heat-adaptation plans for climate change are needed in cities worldwide.
PMCID: PMC3987036  PMID: 24658410
apparent temperature; climate; gender; heat-related deaths; hot climate; hot cities; temperature threshold
18.  A Data-Driven Mathematical Model of CA-MRSA Transmission among Age Groups: Evaluating the Effect of Control Interventions 
PLoS Computational Biology  2013;9(11):e1003328.
Community associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has become a major cause of skin and soft tissue infections (SSTIs) in the US. We developed an age-structured compartmental model to study the spread of CA-MRSA at the population level and assess the effect of control intervention strategies. We used Monte-Carlo Markov Chain (MCMC) techniques to parameterize our model using monthly time series data on SSTIs incidence in children (≤19 years) during January 2004 -December 2006 in Maricopa County, Arizona. Our model-based forecast for the period January 2007–December 2008 also provided a good fit to data. We also carried out an uncertainty and sensitivity analysis on the control reproduction number, which we estimated at 1.3 (95% CI [1.2,1.4]) based on the model fit to data. Using our calibrated model, we evaluated the effect of typical intervention strategies namely reducing the contact rate of infected individuals owing to awareness of infection and decolonization strategies targeting symptomatic infected individuals on both and the long-term disease dynamics. We also evaluated the impact of hypothetical decolonization strategies targeting asymptomatic colonized individuals. We found that strategies focused on infected individuals were not capable of achieving disease control when implemented alone or in combination. In contrast, our results suggest that decolonization strategies targeting the pediatric population colonized with CA-MRSA have the potential of achieving disease elimination.
Author Summary
Community associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is a bacteria that causes skin infections in the US. We developed a mathematical model of CA-MRSA transmission among different age groups at the population level. We parameterized the model using monthly time series data on number of SSTIs in children during the period January 2004–December 2006 in Maricopa County, Arizona. Our model-based forecast to additional time series data covering the period 2007–2008 yielded a good fit to data. Using our calibrated model, we calculated that an infected individual generates on average 1.3 infected people in a totally susceptible population in the study area. We assessed the impact of intervention strategies including reductions in contact rates between infected and non-infected individuals and the effect of decolonization strategies aimed at infected individuals by drug treatment, and found that neither of the two strategies when implemented alone or in combination were able to control the disease. In contrast, we found that decolonization strategies targeting the pediatric population colonized with CA-MRSA have the potential of achieving disease elimination.
PMCID: PMC3836697  PMID: 24277998
19.  Epidemiological Characterization of a Fourth Wave of Pandemic A/H1N1 Influenza in Mexico, Winter 2011–2012: Age Shift and Severity 
Archives of medical research  2012;43(7):563-570.
Background and Aims
A substantial recrudescent wave of pandemic influenza A/H1N1 affected the Mexican population from December 1, 2011–March 20, 2012 following a 2-year period of sporadic transmission.
We analyzed demographic and geographic data on all hospitalizations with severe acute respiratory infection (SARI) and laboratory-confirmed A/H1N1 influenza, and inpatient deaths, from a large prospective surveillance system maintained by a Mexican social security medical system during April 1, 2009– March 20, 2012. We also estimated the reproduction number (R) based on the growth rate of the daily case incidence by date of symptoms onset.
A total of 7569 SARI hospitalizations and 443 in-patient deaths (5.9%) were reported between December 1, 2011, and March 20, 2012 (1115 A/H1N1-positive inpatients and 154 A/H1N1-positive deaths). The proportion of laboratory-confirmed A/H1N1 hospitalizations and deaths was higher among subjects ≥60 years of age (χ2 test, p <0.0001) and lower among younger age groups (χ2 test, p <0.04) for the 2011–2012 pandemic wave compared to the earlier waves in 2009. The reproduction number of the winter 2011–2012 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.
We documented a substantial increase in the number of SARI hospitalizations during the period December 2011–March 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 consistent with a build-up of immunity among younger populations.
PMCID: PMC3545473  PMID: 23079035
A/H1N1 influenza pandemic; Hospitalizations; Deaths; Age distribution; Transmissibility
20.  Transmission potential of influenza A/H7N9, February to May 2013, China 
BMC Medicine  2013;11:214.
On 31 March 2013, the first human infections with the novel influenza A/H7N9 virus were reported in Eastern China. The outbreak expanded rapidly in geographic scope and size, with a total of 132 laboratory-confirmed cases reported by 3 June 2013, in 10 Chinese provinces and Taiwan. The incidence of A/H7N9 cases has stalled in recent weeks, presumably as a consequence of live bird market closures in the most heavily affected areas. Here we compare the transmission potential of influenza A/H7N9 with that of other emerging pathogens and evaluate the impact of intervention measures in an effort to guide pandemic preparedness.
We used a Bayesian approach combined with a SEIR (Susceptible-Exposed-Infectious-Removed) transmission model fitted to daily case data to assess the reproduction number (R) of A/H7N9 by province and to evaluate the impact of live bird market closures in April and May 2013. Simulation studies helped quantify the performance of our approach in the context of an emerging pathogen, where human-to-human transmission is limited and most cases arise from spillover events. We also used alternative approaches to estimate R based on individual-level information on prior exposure and compared the transmission potential of influenza A/H7N9 with that of other recent zoonoses.
Estimates of R for the A/H7N9 outbreak were below the epidemic threshold required for sustained human-to-human transmission and remained near 0.1 throughout the study period, with broad 95% credible intervals by the Bayesian method (0.01 to 0.49). The Bayesian estimation approach was dominated by the prior distribution, however, due to relatively little information contained in the case data. We observe a statistically significant deceleration in growth rate after 6 April 2013, which is consistent with a reduction in A/H7N9 transmission associated with the preemptive closure of live bird markets. Although confidence intervals are broad, the estimated transmission potential of A/H7N9 appears lower than that of recent zoonotic threats, including avian influenza A/H5N1, swine influenza H3N2sw and Nipah virus.
Although uncertainty remains high in R estimates for H7N9 due to limited epidemiological information, all available evidence points to a low transmission potential. Continued monitoring of the transmission potential of A/H7N9 is critical in the coming months as intervention measures may be relaxed and seasonal factors could promote disease transmission in colder months.
PMCID: PMC3851127  PMID: 24083506
Influenza A/H7N9; Transmissibility; Reproduction number; Spillover; Animal reservoir; Emerging infection; Influenza A/H5N1; Swine influenza; Transmission potential; China; Real-time estimation
21.  Climate change and influenza: the likelihood of early and severe influenza seasons following warmer than average winters 
PLoS Currents  2013;5:ecurrents.flu.3679b56a3a5313dc7c043fb944c6f138.
The 2012-13 influenza season had an unusually early and severe start in the US, succeeding the record mild 2011-12 influenza season, which occurred during the fourth warmest winter on record. Our analysis of climate and past US influenza epidemic seasons between 1997-98 to present indicates that warm winters tend to be followed by severe epidemics with early onset, and that these patterns are seen for both influenza A and B. We posit that fewer people are infected with influenza during warm winters, thereby leaving an unnaturally large fraction of susceptible individuals in the population going into the next season, which can lead to early and severe epidemics. In the event of continued global warming, warm winters such as that of 2011-12 are expected to occur more frequently. Our results thus suggest that expedited manufacture and distribution of influenza vaccines after mild winters has the potential to mitigate the severity of future influenza epidemics.
PMCID: PMC3770759  PMID: 24045424
22.  A Population Based Study of Seasonality of Skin and Soft Tissue Infections: Implications for the Spread of CA-MRSA 
PLoS ONE  2013;8(4):e60872.
Methicillin resistant Staphylococcus aureus (MRSA) is currently a major cause of skin and soft tissue infections (SSTI) in the United States. Seasonal variation of MRSA infections in hospital settings has been widely observed. However, systematic time-series analysis of incidence data is desirable to understand the seasonality of community acquired (CA)-MRSA infections at the population level. In this paper, using data on monthly SSTI incidence in children aged 0–19 years and enrolled in Medicaid in Maricopa County, Arizona, from January 2005 to December 2008, we carried out time-series and nonlinear regression analysis to determine the periodicity, trend, and peak timing in SSTI incidence in children at different age: 0–4 years, 5–9 years, 10–14 years, and 15–19 years. We also assessed the temporal correlation between SSTI incidence and meteorological variables including average temperature and humidity. Our analysis revealed a strong annual seasonal pattern of SSTI incidence with peak occurring in early September. This pattern was consistent across age groups. Moreover, SSTIs followed a significantly increasing trend over the 4-year study period with annual incidence increasing from 3.36% to 5.55% in our pediatric population of approximately 290,000. We also found a significant correlation between the temporal variation in SSTI incidence and mean temperature and specific humidity. Our findings could have potential implications on prevention and control efforts against CA-MRSA.
PMCID: PMC3614932  PMID: 23565281
23.  Skip the Trip: Air Travelers' Behavioral Responses to Pandemic Influenza 
PLoS ONE  2013;8(3):e58249.
Theory suggests that human behavior has implications for disease spread. We examine the hypothesis that individuals engage in voluntary defensive behavior during an epidemic. We estimate the number of passengers missing previously purchased flights as a function of concern for swine flu or A/H1N1 influenza using 1.7 million detailed flight records, Google Trends, and the World Health Organization's FluNet data. We estimate that concern over “swine flu,” as measured by Google Trends, accounted for 0.34% of missed flights during the epidemic. The Google Trends data correlates strongly with media attention, but poorly (at times negatively) with reported cases in FluNet. Passengers show no response to reported cases. Passengers skipping their purchased trips forwent at least $50 M in travel related benefits. Responding to actual cases would have cut this estimate in half. Thus, people appear to respond to an epidemic by voluntarily engaging in self-protection behavior, but this behavior may not be responsive to objective measures of risk. Clearer risk communication could substantially reduce epidemic costs. People undertaking costly risk reduction behavior, for example, forgoing nonrefundable flights, suggests they may also make less costly behavior adjustments to avoid infection. Accounting for defensive behaviors may be important for forecasting epidemics, but linking behavior with epidemics likely requires consideration of risk communication.
PMCID: PMC3604007  PMID: 23526970
24.  A practical method to target individuals for outbreak detection and control 
BMC Medicine  2013;11:36.
Identification of individuals or subpopulations that contribute the most to disease transmission is key to target surveillance and control efforts. In a recent study in BMC Medicine, Smieszek and Salathé introduced a novel method based on readily available information about spatial proximity in high schools, to help identify individuals at higher risk of infection and those more likely to be infected early in the outbreak. By combining simulation models for influenza transmission with high-resolution data on school contact patterns, the authors showed that their proximity method compares favorably to more sophisticated methods using detailed contact tracing information. The proximity method is simple and promising, but further research is warranted to confront this method against real influenza outbreak data, and to assess the generalizability of the approach to other important transmission units, such as work, households, and transportation systems.
See related research article here
PMCID: PMC3606446  PMID: 23402649
contact network; hotspot; dynamic network; contact pattern; wireless sensing devices; collocation ranking; class schedule; high school; influenza; disease transmission.
25.  The age distribution of mortality due to influenza: pandemic and peri-pandemic 
BMC Medicine  2012;10:162.
Pandemic influenza is said to 'shift mortality' to younger age groups; but also to spare a subpopulation of the elderly population. Does one of these effects dominate? Might this have important ramifications?
We estimated age-specific excess mortality rates for all-years for which data were available in the 20th century for Australia, Canada, France, Japan, the UK, and the USA for people older than 44 years of age. We modeled variation with age, and standardized estimates to allow direct comparison across age groups and countries. Attack rate data for four pandemics were assembled.
For nearly all seasons, an exponential model characterized mortality data extremely well. For seasons of emergence and a variable number of seasons following, however, a subpopulation above a threshold age invariably enjoyed reduced mortality. 'Immune escape', a stepwise increase in mortality among the oldest elderly, was observed a number of seasons after both the A(H2N2) and A(H3N2) pandemics. The number of seasons from emergence to escape varied by country. For the latter pandemic, mortality rates in four countries increased for younger age groups but only in the season following that of emergence. Adaptation to both emergent viruses was apparent as a progressive decrease in mortality rates, which, with two exceptions, was seen only in younger age groups. Pandemic attack rate variation with age was estimated to be similar across four pandemics with very different mortality impact.
In all influenza pandemics of the 20th century, emergent viruses resembled those that had circulated previously within the lifespan of then-living people. Such individuals were relatively immune to the emergent strain, but this immunity waned with mutation of the emergent virus. An immune subpopulation complicates and may invalidate vaccine trials. Pandemic influenza does not 'shift' mortality to younger age groups; rather, the mortality level is reset by the virulence of the emerging virus and is moderated by immunity of past experience. In this study, we found that after immune escape, older age groups showed no further mortality reduction, despite their being the principal target of conventional influenza vaccines. Vaccines incorporating variants of pandemic viruses seem to provide little benefit to those previously immune. If attack rates truly are similar across pandemics, it must be the case that immunity to the pandemic virus does not prevent infection, but only mitigates the consequences.
PMCID: PMC3554498  PMID: 23234604
Pandemic influenza; mortality due to influenza; recycling; pandemic attack rates; vaccination; protective immunity

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