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      The Impact of the Demographic Transition on Dengue in Thailand: Insights from a Statistical Analysis and Mathematical Modeling

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          Abstract

          Analyzing data from Thailand's 72 provinces, Derek Cummings and colleagues find that decreases in birth and death rates can explain the shift in age distribution of dengue hemorrhagic fever.

          Abstract

          Background

          An increase in the average age of dengue hemorrhagic fever (DHF) cases has been reported in Thailand. The cause of this increase is not known. Possible explanations include a reduction in transmission due to declining mosquito populations, declining contact between human and mosquito, and changes in reporting. We propose that a demographic shift toward lower birth and death rates has reduced dengue transmission and lengthened the interval between large epidemics.

          Methods and Findings

          Using data from each of the 72 provinces of Thailand, we looked for associations between force of infection (a measure of hazard, defined as the rate per capita at which susceptible individuals become infected) and demographic and climactic variables. We estimated the force of infection from the age distribution of cases from 1985 to 2005. We find that the force of infection has declined by 2% each year since a peak in the late 1970s and early 1980s. Contrary to recent findings suggesting that the incidence of DHF has increased in Thailand, we find a small but statistically significant decline in DHF incidence since 1985 in a majority of provinces. The strongest predictor of the change in force of infection and the mean force of infection is the median age of the population. Using mathematical simulations of dengue transmission we show that a reduced birth rate and a shift in the population's age structure can explain the shift in the age distribution of cases, reduction of the force of infection, and increase in the periodicity of multiannual oscillations of DHF incidence in the absence of other changes.

          Conclusions

          Lower birth and death rates decrease the flow of susceptible individuals into the population and increase the longevity of immune individuals. The increase in the proportion of the population that is immune increases the likelihood that an infectious mosquito will feed on an immune individual, reducing the force of infection. Though the force of infection has decreased by half, we find that the critical vaccination fraction has not changed significantly, declining from an average of 85% to 80%. Clinical guidelines should consider the impact of continued increases in the age of dengue cases in Thailand. Countries in the region lagging behind Thailand in the demographic transition may experience the same increase as their population ages. The impact of demographic changes on the force of infection has been hypothesized for other diseases, but, to our knowledge, this is the first observation of this phenomenon.

          Please see later in the article for the Editors' Summary

          Editors' Summary

          Background

          Every year, dengue infects 50–100 million people living in tropical and subtropical areas. The four closely related viruses that cause dengue are transmitted to people through the bites of female Aedes aegypti mosquitoes, which acquire dengue virus by feeding on the blood of an infected person. Although some people who become infected with dengue virus have no symptoms, many develop dengue fever, a severe, flu-like illness that lasts for a few days. Other people—more than half a million a year—develop dengue hemorrhagic fever, which causes bleeding from the gums and nose and bruising, or dengue shock syndrome in which circulatory failure also occurs. Both these potentially fatal conditions are associated with sequential infections with dengue virus—nonfatal infection with dengue virus of one type provides lifelong immunity against that type but only temporary protection against infection with dengue viruses of other types. There is no vaccine to prevent dengue and no specific treatment for the disease. However, standard medical care—in particular, replacement of lost fluids—can prevent most deaths from dengue.

          Why Was This Study Done?

          Historically, dengue has mainly affected young children but, recently, its age distribution has shifted towards older age groups in several Southeast Asian countries, including Thailand. In addition, the interval between large increases in incidence (epidemics) of dengue hemorrhagic fever has lengthened. It is important to know why these changes are happening because they could affect how dengue infections are dealt with in these countries. One idea is that an ongoing shift towards lower birth and death rates (the demographic transition; this occurs as countries move from a pre-industrial to an industrial economy) is reducing dengue transmission rates by reducing the “force of infection” (the rate at which susceptible individuals become infected). As birth and death rates decline, immune individuals account for more of the population so mosquitoes are more likely to bite an immune individual, which reduces the force of infection. Similarly, because susceptible individuals enter the population by being born, changing the birth rate alters the interval between epidemics. In this study, the researchers test whether the demographic transition might be responsible for the changing pattern of dengue infection in Thailand.

          What Did the Researchers Do and Find?

          The researchers retrieved data on dengue infection, demographic data (the population's age structure and birth and death rates), socioeconomic data, and climatic data for Thailand from 1980 to 2005 from various sources. They then fitted the data on dengue cases to several mathematical models to estimate the force of infection for each year. This analysis suggested that the force of infection has declined by 2% every year since the early1980s. Next, the researchers used statistical methods to show that the strongest predictor of this decline is the increase in the median age of the population (a measure of the average age of the population). Finally, using mathematical simulations of dengue transmission, they showed that a reduced birth rate and a shift in the population's age structure are sufficient to explain the recent shift in the age distribution of dengue cases, the reduction of the force of infection, and the increased interval between epidemics of dengue hemorrhagic fever.

          What Do These Findings Mean?

          The findings of all modeling studies depend on how the mathematical models are built and the accuracy of the data fed into them. Nevertheless, these findings suggest that recent changes in birth and death rates in Thailand are sufficient to produce the observed changes in the age distribution of dengue and periodicity of dengue outbreaks. One implication of these findings is that other countries in Southeast Asia that follow Thailand in the demographic transition may experience similar shifts in the pattern of dengue infections as the age structure of their populations changes. This means that clinical guidelines for the management of dengue infections in Southeast Asia will need to be adjusted to allow for the increasing age of dengue cases. Finally, although the researchers' calculations show the force of infection has fallen substantially over the past two decades, they also show that when a dengue vaccine becomes available, it will still be necessary to vaccinate most of the population to halt dengue transmission.

          Additional Information

          Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000139

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          Most cited references21

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          A simple model for complex dynamical transitions in epidemics.

          Dramatic changes in patterns of epidemics have been observed throughout this century. For childhood infectious diseases such as measles, the major transitions are between regular cycles and irregular, possibly chaotic epidemics, and from regionally synchronized oscillations to complex, spatially incoherent epidemics. A simple model can explain both kinds of transitions as the consequences of changes in birth and vaccination rates. Measles is a natural ecological system that exhibits different dynamical transitions at different times and places, yet all of these transitions can be predicted as bifurcations of a single nonlinear model.
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            Ecological and immunological determinants of dengue epidemics.

            The management of infectious diseases is an increasingly important public health issue, the effective implementation of which is often complicated by difficulties in teasing apart the relative roles of extrinsic and intrinsic factors influencing transmission. Dengue, a vector-borne strain polymorphic disease, is one such infection where transmission dynamics are affected by environmental variables as well as immune-mediated serotype interactions. To understand how alternative hypotheses concerning dengue infection and transmission may explain observed multiannual cycles in disease incidence, we adopt a theoretical approach that combines both ecological and immunological mechanisms. We demonstrate that, contrary to perceived wisdom, patterns generated solely by antibody-dependent enhancement or heterogeneity in virus virulence are not consistent with serotype-specific notification data in important ways. Furthermore, to generate epidemics with the characteristic signatures observed in data, we find that a combination of seasonal variation in vector demography and, crucially, a short-lived period of cross-immunity is sufficient. We then show how understanding the persistence and eradication of dengue serotypes critically depends on the alternative assumed mechanisms.
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              Serotype-specific dengue virus circulation and dengue disease in Bangkok, Thailand from 1973 to 1999.

              Dengue virus circulation and association with epidemics and severe dengue disease were studied in hospitalized children with suspected dengue at the Queen Sirikit National Institute of Child Health in Bangkok, Thailand, from 1973 to 1999. Dengue serology was performed on all patients and viral isolation attempted on laboratory-confirmed patients. Acute dengue was diagnosed in 15,569 children and virus isolated from 4,846. DEN-3 was the most frequent serotype in primary dengue (49% of all isolates), DEN-2 in secondary and in dengue hemorrhagic fever (37% and 35%, respectively). The predominant dengue serotype varied by year: DEN-1 from 1990-92, DEN-2 from 1973-86 and 1988-89; DEN-3 in 1987 and 1995-99; and DEN-4 from 1993-94. Only DEN-3 was associated with severe outbreak years. Our findings illustrate the uniqueness of each serotype in producing epidemics and severe disease and underscore the importance of long-term surveillance of dengue serotypes in understanding the epidemiology of these viruses.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS Med
                PLoS
                plosmed
                PLoS Medicine
                Public Library of Science (San Francisco, USA )
                1549-1277
                1549-1676
                September 2009
                September 2009
                1 September 2009
                : 6
                : 9
                : e1000139
                Affiliations
                [1 ]Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America
                [2 ]Bureau of Epidemiology, Ministry of Public Health, Nonthaburi, Thailand
                [3 ]Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America
                [4 ]Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand
                [5 ]Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
                Oxford University Clinical Research Unit, Viet Nam
                Author notes

                ICMJE criteria for authorship read and met: DC SI JL AM RP AN RGJ DSB RVG. Agree with the manuscript's results and conclusions: DC SI JL AM RP AN RGJ DSB RVG. Designed the experiments/the study: DC AM RGJ RVG. Analyzed the data: SI AM RGJ RVG. Collected data/did experiments for the study: DC AN RGJ. Wrote the first draft of the paper: DC RVG. Contributed to the writing of the paper: DC SI JL RGJ DSB RVG. Involved in the discussions and analysis plans for the paper from its inception, including the idea of the analysis: RVG.

                Article
                08-PLME-RA-2115R3
                10.1371/journal.pmed.1000139
                2726436
                19721696
                cd85612b-88f3-4b0f-8fac-f5e196c71c98
                This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
                History
                : 30 July 2008
                : 17 July 2009
                Page count
                Pages: 10
                Categories
                Research Article
                Ecology/Population Ecology
                Ecology/Theoretical Ecology
                Infectious Diseases/Epidemiology and Control of Infectious Diseases
                Infectious Diseases/Neglected Tropical Diseases
                Infectious Diseases/Viral Infections
                Public Health and Epidemiology/Epidemiology
                Public Health and Epidemiology/Infectious Diseases

                Medicine
                Medicine

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