Anyone living in Trinidad and Tobago could not have failed to notice that dengue is a major and all too often overwhelming problem for our region. Each year, millions of people in the Americas experience the debilitating and, in some cases, life-threatening effects of dengue virus infection. A very conservative estimate suggests that dengue costs the Caribbean about US$321 million annually. This does not even consider the costs of surveillance, mosquito control and public education programmes or the impact of disruption to the rest of the healthcare system when an outbreak occurs.
Dengue has a long history in the Americas, with accounts of dengue-like illness as early as 1780 in Philadelphia, USA. However, outbreaks of the disease were few and far between up until the 1960s and ’70s, when large epidemics of dengue fever swept through the region. In the 1980s outbreaks with large numbers of cases of the more severe and life-threatening forms of dengue first appeared. Since then the size, frequency and severity of outbreaks in the Caribbean and the wider Americas have been increasing steadily. This trend is expected to continue and to be exacerbated by climate change.
It is cold comfort to learn that we are not alone in this regard. Dengue, which is caused by any one of four types of dengue virus (i.e. dengue virus serotypes 1, 2, 3 and 4), is the most rapidly spreading mosquito-borne viral disease and currently one of the most important emerging diseases. Prior to the 1950s, dengue as a major public health problem was effectively restricted to Asia. Today, the four dengue viruses and Aedes aegypti (the main mosquito species involved in transmitting the viruses from person to person) are found throughout the tropics. Recent estimates published in the journal Nature, suggest that about 390 million people around the world are infected by dengue viruses annually. Approximately 75% of these infections result in no symptoms, or symptoms so mild that they go unnoticed. However, for about 96 million people, disease is apparent. It may range from a mild, non-specific febrile syndrome to classic dengue fever (characterized by fever, headache, rash and severe muscle and joint pains), to life-threatening dengue haemorrhagic fever and dengue shock syndrome.
So why did dengue suddenly emerge in the Americas? Where did it come from? Why has the disease pattern changed, and what can we expect in the future?
Research has shown that dengue viruses originated in the forests of the Old World where up to today, in West Africa and South East Asia, a sylvatic or wild form of the virus is transmitted between non-human primates (monkeys and apes) by forest dwelling mosquitoes. Although humans are not their preferred host, given the opportunity, some of these mosquito species will feed on humans. Hence, humans living in forest fringe regions can occasionally become infected with sylvatic dengue viruses. These “spillover” events do not usually result in sustained onward transmission of sylvatic dengue viruses in human populations. However, analysis of the evolutionary relationship between currently circulating sylvatic and human dengue viruses indicates that this has happened at least four times (most likely in South East Asia) giving rise to the four known human dengue serotypes. While another Aedes species of mosquito was likely the original vector for human dengue, sustained transmission of dengue in human populations is undoubtedly a consequence of the subsequent involvement of A. aegypti, which prefers feeding on humans and breeding around man-made environments.
The earliest evidence of a disease with symptoms consistent with dengue is of “water poison,” documented in China during the Jin Dynasty over 1500 years ago. Dengue virus eventually spread to Africa and then to the Americas during the Atlantic Slave Trade. However, the dramatic global expansion of dengue virus out of Asia, beginning in the 1950s, has been attributed to troop movements and population displacement at the end of World War II. Expansion of the airline industry, increasing human population sizes and urbanization further facilitated global dissemination. These factors provided opportunities for rapid, long-distance movement of infected humans and mosquitoes into high-density human populations and conditions that favour the creation of breeding sites suitable for A. aegypti. As a consequence, in the Americas where for almost 200 years only dengue virus serotype 2 existed, within 18 years (from 1963) the three other dengue virus serotypes were introduced from Asia and very rapidly spread throughout the Americas. New strains of existing serotypes have continued to appear.
There is currently no cure for dengue, although early detection and appropriate management of individuals who show warning signs of developing severe dengue can reduce case fatality rates from 10% to as low as 1%. Several vaccines are currently in clinical trials, but none is yet approved for use. In the absence of a cure or a vaccine, reducing dengue virus transmission depends entirely on reducing mosquito populations and breeding sites, and interrupting contact between humans and mosquitoes, but these interventions must be well targeted. Access to accurate and timely information on the number and distribution of dengue cases is critical. Unfortunately, this is not as straightforward as it sounds because a large proportion of dengue virus infections occur without symptoms. Even when individuals show signs or symptoms of the disease dengue can only be confirmed by laboratory testing since it is generally clinically indistinguishable from a range of other flu-like illnesses. Determining how much dengue is around and where it is, is further complicated in settings such as ours, where reporting systems tend to be slow and inefficient, where regulatory and quality control on diagnostic laboratories are variable and where the public health infrastructure is easily and often overwhelmed.
Fortunately, while we humans have been struggling to obtain and document this type of information, dengue viruses (like all other organisms) have been doing a good job of keeping a record of their own past imprinted in their genetic material. Using our knowledge of how viruses evolve (i.e. how their genetic material changes over time), it is possible to estimate when and where a given epidemic began or particular strains of a virus arose, the order and timing of transmission events, how virus population size has changed over time and even the patterns and rates of virus movement between geographic regions. The genetic material required for these types of analyses may be relatively easily obtained from patients’ blood or from infected mosquitoes.
Researchers at The UWI, St Augustine have been using this type of “molecular phylogenetic” approach to reconstruct the histories of the four dengue virus serotypes in the Americas (including when and where each serotype was first introduced) and to investigate how factors such as patterns of human movement between countries, the size of human populations and the geographic distances between countries and major population centres influence the rates and directions of movement amongst countries. Our results suggest a significant time lag between the arrival of each of the serotypes to our region and when it was first reported. This indicates that for some time after arriving viruses remain below our detection threshold (which may be quite high due to poor surveillance in many countries in the Americas). We have also found that dengue virus in a given location is more likely to move to a nearby and larger human population than to a smaller or more distant population. However, while most of the strongest links (in terms of dengue virus movement) are between neighbouring countries, there are a few countries (including T&T) that act as major hubs for virus dispersal throughout the region. Presumably, this reflects human movement patterns, which would be expected to play a more significant role in dispersal of dengue on a regional scale than movement of infected mosquitoes. Investigations continue into whether airline traffic patterns can predict dengue virus spread within the Americas.
This molecular phylogenetic approach cannot replace good epidemiological data. However, it complements traditional approaches and provides insights into the evolutionary dynamics underlying how epidemics behave. It can contribute towards improved surveillance and development of models to predict the spread of viruses, particularly when coupled with other sensitive and specific molecular tools for rapid detection of both known and unknown viruses. Work in this area (funded by the UWI-Trinidad and Tobago Research and Development Impact Fund) is currently underway at The UWI. The aims are to determine the rate of dengue virus infection among patients who present with fevers at selected healthcare institutions in T&T, to identify viruses associated with those cases that cannot be attributed to dengue virus, and to identify factors that best explain the behaviour of dengue virus outbreaks within T&T. The overall goal is to facilitate improved surveillance and develop models to predict (and ideally prevent) the spread of dengue in T&T.
The World Health Organisation’s recently published strategic plan for dengue prevention and control aims to reduce morbidity and mortality by at least 25% and 50% respectively by 2020. They believe that these targets are achievable using already existing tools. However, they emphasise that research “continue(s) to play an important role in reversing the trend in dengue...” As the cost and time required to retrieve and analyse genetic data continue to decline, one can envisage a time in the not too distant future when real-time analysis of genetic, clinical and demographic data from patient specimens collected at the “point-of-care” will be routinely incorporated into surveillance strategies for dengue and other viruses.
Christine Carrington is Professor of Molecular Genetics and Virology, based at the Department of Preclinical Sciences, UWI St. Augustine.