Paul Reiter

Dengue and dengue haemorrhagic fever

Summary The incidence and geographical distribution of dengue have greatly increased in recent years. Dengue is an acute mosquito-transmitted viral disease characterised by fever, headache, muscle and joint pains, rash, nausea, and vomiting. Some infections result in dengue haemorrhagic fever (DHF), a syndrome that in its most severe form can threaten the patients life, primarily through increased vascular permeability and shock. The case fatality rate in patients with dengue shock syndrome can be as high as 44%. For decades, two distinct hypotheses to explain the mechanism of DHF have been debated—secondary infection or viral virulence. However, a combination of both now seems to be the plausible explanation. The geographical expansion of DHF presents the need for well-documented clinical, epidemiological, and virological descriptions of the syndrome in the Americas. Biological and social research are essential to develop effective mosquito control, medications to reduce capillary leakage, and a safe tetravalent vaccine.

Climate variability and change in the United States: potential impacts on vector- and rodent-borne diseases.

Diseases such as plague, typhus, malaria, yellow fever, and dengue fever, transmitted between humans by blood-feeding arthropods, were once common in the United States. Many of these diseases are no longer present, mainly because of changes in land use, agricultural methods, residential patterns, human behavior, and vector control. However, diseases that may be transmitted to humans from wild birds or mammals (zoonoses) continue to circulate in nature in many parts of the country. Most vector-borne diseases exhibit a distinct seasonal pattern, which clearly suggests that they are weather sensitive. Rainfall, temperature, and other weather variables affect in many ways both the vectors and the pathogens they transmit. For example, high temperatures can increase or reduce survival rate, depending on the vector, its behavior, ecology, and many other factors. Thus, the probability of transmission may or may not be increased by higher temperatures. The tremendous growth in international travel increases the risk of importation of vector-borne diseases, some of which can be transmitted locally under suitable circumstances at the right time of the year. But demographic and sociologic factors also play a critical role in determining disease incidence, and it is unlikely that these diseases will cause major epidemics in the United States if the public health infrastructure is maintained and improved.

Texas Lifestyle Limits Transmission of Dengue Virus

Urban dengue is common in most countries of the Americas, but has been rare in the United States for more than half a century. In 1999 we investigated an outbreak of the disease that affected Nuevo Laredo, Tamaulipas, Mexico, and Laredo, Texas, United States, contiguous cities that straddle the international border. The incidence of recent cases, indicated by immunoglobulin M antibody serosurvey, was higher in Nuevo Laredo, although the vector, Aedes aegypti, was more abundant in Laredo. Environmental factors that affect contact with mosquitoes, such as air-conditioning and human behavior, appear to account for this paradox. We conclude that the low prevalence of dengue in the United States is primarily due to economic, rather than climatic, factors.

Vector Competence of Some French Culex and Aedes Mosquitoes for West Nile Virus

To identify the mosquito species able to sustain the transmission of West Nile Virus (WNV) in the Camargue region (the main WNV focus of southern France), we assessed the vector competence of Culex modestus and Culex pipiens, the most abundant bird-feeders, and Aedes caspius, the most abundant mammophilic species occasionally found engorged with avian blood. Female mosquitoes were exposed to the infectious meal (10(10.3) plaque forming units (PFU)/mL) by membrane feeding, and hold at 26 degrees C. After the incubation period, disseminated infection was assessed by WNV detection using an indirect fluorescent antibody assay (IFA) on head squashes, and the transmission rate was assessed by the presence of WNV RNA in salivary secretions with a real-time reverse transcriptase-polymerase chain reaction (RT-PCR). After 14 incubation days, the disseminated infection and the transmission rates were 89.2% and 54.5% for Cx. modestus, 38.5% and 15.8% for Cx. pipiens, and 0.8% and 0 for Ae. caspius. Culex modestus was found to be an extremely efficient laboratory WNV vector and could thus be considered the main WNV vector in wetlands of the Camargue. Culex pipiens was a moderately efficient laboratory WNV vector, but in dry areas of the region it could play the main role in WNV transmission between birds and from birds to mammals. Aedes caspius was an inefficient vector of WNV in the laboratory, and despite its high densities, its role in WNV transmission may be minor in southern France.

Global warming and malaria:a call for accuracy

For more than a decade, malaria has held a prominent place in speculations on the impacts of global climate change. Mathematical models that “predict” increases in the geographic distribution of malaria vectors and the prevalence of the disease have received wide publicity. Efforts to put the issue into perspective1–5 are rarely quoted and have had little influence on the political debate. The model proposed by Frank C Tanser and colleagues6 in The Lancet and the accompanying Commentary by Simon Hales and Alistair Woodward7 are typically misleading examples. The relation between climate and malaria transmission is complex and varies according to location,2 yet Tanser et al base their projections on thresholds derived from a mere 15 African locations. Slight adjustments of values assigned to such thresholds and rules can influence spatial predictions strongly.8 The authors invest considerable effort in assessing the sensitivity of their model to climate change scenarios but do not report the internal sensitivities to thresholds and rules. The predictive skill of their model is low (63% sensitivity, 95% CI 61–65%) but they consider projections acceptable if prevalence is projected “to within a month” (presumably +/− 1 month?), thereby biasing their model towards success. A model covering an entire year in a parasite-positive site would always be correct, although in such areas it would be relatively insensitive to climate. By contrast, sites in which transmission is seasonal would provide a more reliable test of accuracy, but estimation is more difficult because climate sensitivity is greater. Furthermore, because parasite clearance in communities is not instantaneous,9 spot samples of parasitaemia on survey dates are not a suitable indicator of the duration of the transmission season. Lastly, “person/months” are unsuitable as a measure of transmission: an extension of season from 1 to 4 months will have more impact than from 10 to 12 months. According to their model, an extension of transmission from 11 to 12 months results in 106 more person/months in a population of 106 people, whereas an extension from 1 to 5 months gives the same increase in a population of 250 000. What Tanser and colleagues have modelled is merely the duration of the transmission season, which they interpret as “heightened transmission” and increased incidence. A greater failing is their reliance on “parasite-ratio studies”. The relations between transmission season and parasite prevalence, and parasite prevalence and clinical disease, are unclear but unlikely to be linear. Moreover, they use 1995 data for human populations, although these are projected to double by 2030. In addition, the proportion living in urban areas—with a specific climate10 and orders of magnitude less malaria transmission11,12—is projected to rise from 37% to 53%.13 For all these reasons, we do not accept the model as a “baseline against which interventions can be planned”. It is regrettable that many involved in this debate ignore the rich heritage of literature on the subject. For example, in 1937, in his classic textbook,14 L W Hackett stated: “Everything about malaria is so moulded and altered by local conditions that it becomes a thousand different diseases and epidemiological puzzles. Like chess, it is played with a few pieces, but is capable of an infinite variety of situations”. A pressing question in Hackett’s time was the changing distribution of the disease in Europe. On the role of climate, he wrote: “Certainly, climate lays down the broad lines of malaria distribution … Nevertheless, although this is a very simple and plausible explanation … even the early malariologists felt that there was something unsatisfactory about it … malaria has not so much receded as it has contracted, oftentimes toward the north … Thus in Germany it is the northern coast which is still malarious, the south is free … There is, therefore, no climatic reason why (malaria) should have abandoned south Germany or the French Riviera”. We quote Hackett because we feel that the classic components of science—unbiased observation and systematic experimentation—cannot be sidestepped with models that omit many of his chess pieces. Yet Hales and Woodward7 begin by stating: “The present geographical distribution of malaria is explained by a combination of environmental factors (especially climate) and social factors (such as disease-control measures)”. In our opinion, “even the early malariologists” would surely disagree: much of the decline of malaria in Europe took place without control measures during a period when the climate was warming. The text by Hales and Woodward that follows displays a lack of knowledge. Thus, “Most people at risk of malaria live in areas of stable transmission … ” is simply wrong. It is true that in many parts of the world malaria is termed “stable” because transmission remains relatively constant from year to year, the disease is endemic, the collective immunity is high, and epidemics are uncommon. However, in many other regions, the disease is endemic but “unstable” because annual transmission varies considerably, and the potential for epidemics is great. Climatic factors, particularly rainfall, are sometimes, but by no means always, relevant.15 Again, “On the fringes of endemic zones, where transmission is limited by rainfall … there are strong seasonal patterns, and occasional major epidemics” is also wrong. In many regions, far from any “fringes”, malaria is endemic, stable, but highly seasonal. For example, in semi-arid regions of Mali, transmission is restricted to the rainy season, from July to September. The same 3 months constituted the transmission season for Plasmodium falciparum in Italy before it was eliminated.16 Paradoxically, in parts of the Sudan, rainfall is restricted to a month at most, but malaria is transmitted throughout the year. Female Anopheles gambiae survive drought and heat by resting in dwellings and other sheltered places.17 Blood feeding and transmission continue, but the mosquitoes do not develop eggs until the rains return. This phenomenon, termed gonotrophic dissociation, is remarkably similar to the winter survival strategy of Anopheles atroparvus, the principal vector of malaria in Holland until the mid 20th century.16 By contrast, malaria is unstable in many regions that normally have abundant rainfall, and epidemics occur during periods of drought. An illustrative example is the catastrophic 1934–35 epidemic in Ceylon (now Sri Lanka), estimated to have killed 100 000 people.18 Worst hit was the south-western quadrant of the country, where average annual rainfall is greater than 250 cm, and malaria was endemic, but unstable and relatively infrequent. The dominant vector, Anopheles culicifacies, breeds along the banks of rivers and tends to be scarce in normal years. In the years 1928–33 there was abundant rainfall, river flow was high, A culicifacies was rare, and the human population was exceptionally malaria-free. However, after failure of two successive monsoons, the drying rivers produced colossal numbers of A culicifacies, and the resulting epidemic was exacerbated by the low collective immunity. In the drier parts of the island, where A culicifacies was dominant but transmission was more stable, immunity protected the population from the worst ravages of the disease. Hales and Woodward state that “the underlying problem” of the future “extension of seasonality” of malaria is “pollution of the atmosphere”, and call for rich countries to “recognise their obligations to the poorest by substantially reducing fossil-fuel consumption”. We understand public anxiety about climate change, but are concerned that many of these much-publicised predictions are ill informed and misleading. We urge those involved to pay closer attention to the complexities of this challenging subject.

DengueTools: innovative tools and strategies for the surveillance and control of dengue

Dengue fever is a mosquito-borne viral disease estimated to cause about 230 million infections worldwide every year, of which 25,000 are fatal. Global incidence has risen rapidly in recent decades with some 3.6 billion people, over half of the worlds population, now at risk, mainly in urban centres of the tropics and subtropics. Demographic and societal changes, in particular urbanization, globalization, and increased international travel, are major contributors to the rise in incidence and geographic expansion of dengue infections. Major research gaps continue to hamper the control of dengue. The European Commission launched a call under the 7th Framework Programme with the title of ‘Comprehensive control of Dengue fever under changing climatic conditions’. Fourteen partners from several countries in Europe, Asia, and South America formed a consortium named ‘DengueTools’ to respond to the call to achieve better diagnosis, surveillance, prevention, and predictive models and improve our understanding of the spread of dengue to previously uninfected regions (including Europe) in the context of globalization and climate change. The consortium comprises 12 work packages to address a set of research questions in three areas: Research area 1 Develop a comprehensive early warning and surveillance system that has predictive capability for epidemic dengue and benefits from novel tools for laboratory diagnosis and vector monitoring. Research area 2 Develop novel strategies to prevent dengue in children. Research area 3 Understand and predict the risk of global spread of dengue, in particular the risk of introduction and establishment in Europe, within the context of parameters of vectorial capacity, global mobility, and climate change. In this paper, we report on the rationale and specific study objectives of ‘DengueTools’. DengueTools is funded under the Health theme of the Seventh Framework Programme of the European Community, Grant Agreement Number: 282589 Dengue Tools.

Global warming and malaria: knowing the horse before hitching the cart.

Speculations on the potential impact of climate change on human health frequently focus on malaria. Predictions are common that in the coming decades, tens – even hundreds – of millions more cases will occur in regions where the disease is already present, and that transmission will extend to higher latitudes and altitudes. Such predictions, sometimes supported by simple models, are persuasive because they are intuitive, but they sidestep factors that are key to the transmission and epidemiology of the disease: the ecology and behaviour of both humans and vectors, and the immunity of the human population. A holistic view of the natural history of the disease, in the context of these factors and in the precise setting where it is transmitted, is the only valid starting point for assessing the likely significance of future changes in climate.

Field Investigations of an Outbreak of Ebola Hemorrhagic Fever, Kikwit, Democratic Republic of the Congo, 1995: Arthropod Studies

During the final weeks of a 6-month epidemic of Ebola hemorrhagic fever in Kikwit, Democratic Republic of the Congo, an extensive collection of arthropods was made in an attempt to learn more of the natural history of the disease. A reconstruction of the activities of the likely primary case, a 42-year-old man who lived in the city, indicated that he probably acquired his infection in a partly forested area 15 km from his home. Collections were made throughout this area, along the route he followed from the city, and at various sites in the city itself. No Ebola virus was isolated, but a description of the collections and the ecotopes involved is given for comparison with future studies of other outbreaks.

Dispersal and Survival of Male and Female Aedes albopictus (Diptera: Culicidae) on Réunion Island

ABSTRACT Mouse-baited traps were used to assess the longevity and dispersal of male and female Aedes albopictus by mark-release-recapture at two sites on La Réunion Island. Recapture rate was high, and mosquitoes of both sexes appeared up to 23 d after release. A daily survival probability of ≈0.95 for males and females, far higher than expected, was estimated from these results. There was evidence that both sexes prefer to follow corridors of vegetation rather than crossing open spaces. Populations of wild mosquitoes had parous and insemination rates indicative of a young population. These results are relevant to future attempts to control this species by sterile insect technology.

Fitness of Transgenic Mosquito Aedes aegypti Males Carrying a Dominant Lethal Genetic System

OX513A is a transgenic strain of Aedes aegypti engineered to carry a dominant, non-sex-specific, late-acting lethal genetic system that is repressed in the presence of tetracycline. It was designed for use in a sterile-insect (SIT) pest control system called RIDL® (Release of Insects carrying a Dominant Lethal gene) by which transgenic males are released in the field to mate with wild females; in the absence of tetracycline, the progeny from such matings will not survive. We investigated the mating fitness of OX513A in the laboratory. Male OX513A were as effective as Rockefeller (ROCK) males at inducing refractoriness to further mating in wild type females and there was no reduction in their ability to inseminate multiple females. They had a lower mating success but yielded more progeny than the wild-type comparator strain (ROCK) when one male of each strain was caged with a ROCK female. Mating success and fertility of groups of 10 males—with different ratios of RIDL to ROCK—competing for five ROCK females was similar, but the median longevity of RIDL males was somewhat (18%) lower. We conclude that the fitness under laboratory conditions of OX513A males carrying a tetracycline repressible lethal gene is comparable to that of males of the wild-type comparator strain.