Diseases transmitted by arthropods (e.g. mosquitoes and ticks) are very common in areas with warmer climates such as Central and South America, Africa and Asia. These diseases, which include malaria, dengue fever, and Chikungunya, are classified as endemic, with outbreaks occurring seasonally, yearly or every few years. In these areas, medical resources are often scarce and/or easily overwhelmed, leading to challenges in the diagnosis and treatment of these diseases. In response, the World Health Organization has made simpler and cheaper diagnostics, as well as new approaches to vaccines, a large priority in an effort to combat arthropod-borne diseases. In this article, we will use dengue fever as a case study to identify challenges in diagnosis and treatment in resource-limited settings and examine new developments in diagnostics and prevention methods.
Dengue: an important vector-borne disease
Dengue (den-gee) fever is caused by the dengue virus, a member of the Flavivirus family, which also includes West Nile and yellow fever viruses. As the incidence of dengue fever has increased a whopping 30-fold in the past fifty years, the disease has become a major health concern. It is estimated that 40% of the world’s population lives in regions where dengue is endemic, meaning that the disease is continually present in that region .
Dengue fever falls under the umbrella category of vector-borne diseases. These diseases are transmitted by animals, most commonly mosquitoes, ticks and fleas, to the human population. In the United States, the most common vector-borne diseases include Lyme disease, West Nile Virus, and Rocky Mountain spotted fever . Globally, vector-borne diseases account for a significant disease burden in tropical and subtropical regions, including South America, Africa and Southeast Asia. These common diseases also include the parasitic infection malaria and the viral infection Chikungunya .
Many tropical and subtropical regions burdened by vector-borne disease also lack adequate health care funds and infrastructure and are thus designated “resource-limited environments” . The resulting morbidity (poor health/disability), mortality (death), and economic costs are significant and illustrate the importance of controlling vector-borne diseases. To explore the implications of vector-borne disease in the developing world, we will use dengue fever as an example. This case study will enable us to consider the challenges of diagnosis and disease management in resource-limited environments, as well as new efforts in the treatment and prevention of vector-borne diseases in general.
Dengue fever: disease course and treatment
Dengue fever cases vary widely; some individuals may show no symptoms at all, but 5-10% of patients progress to severe dengue . The mortality rate for severe dengue ranges from <0.1-10% depending on the quality of care . This contrasts sharply with viruses like Ebola, which cause severe disease in almost all infected individuals. The dengue virus consists of 5 closely related serotypes or strains, any of which can infect an individual. The first time a person is infected with dengue, he/she may have only a slight fever, or show no symptoms at all! As a result of the primary infection, the individual becomes immune to that serotype. However, if this individual should later become infected with a different dengue serotype, for instance during the next summer, that secondary infection is much more likely to result in severe disease.
The rapid increase in dengue cases worldwide is at least partially attributed to a growing risk of secondary infections. Recent years have witnessed a significant expansion in the geographic range and overlap of dengue serotypes (Figure 1) . Urbanization and globalization are partially responsible for these increased ranges; the mosquitoes that transmit dengue thrive in urban areas, and travelers can bring dengue with them when they return home, exposing mosquitoes around them to new dengue serotypes.
Figure 1 The incidence and distribution of dengue serotypes have increased rapidly over the last fifty years. Countries with reported dengue cases during 1970-1979 (a) or 2000-2013 (b) are colored in pink. Serotypes present in these regions in 1970 (c) or 2004 (d) are listed. Figures adapted from [5,6].
The dengue infections that do manifest symptoms follow a stereotypical course. After a 3-7 day incubation period, the individual develops a high fever (101-104 °F) Other symptoms include headache, rash, and muscle and joint pain. This pain can be very intense (one nickname for dengue is “breakbone fever”). Most patients recover without complications; however, about 5-10% of patients develop severe dengue and enter a critical phase of infection. In this phase, the blood vessels can become leaky, causing fluid loss, which decreases the blood flow to vital organs and can lead to death. In the final, recovery phase, lost fluid is reabsorbed and symptoms begin to resolve; however, fatigue may be present in individuals for weeks post-infection .
There is no vaccine or antiviral treatment for dengue fever; rather, treatment focuses on managing the patient’s pain level and monitoring their fluid status. Clinicians must not only diagnose a case of dengue fever, but, more importantly, determine which cases of dengue fever will progress to severe dengue. In treating a case of severe dengue, the patient must be administered fluid to counteract fluid loss from blood vessels, but must not be fluid overloaded, as too much reabsorption during the recovery phase will lead to additional complications . Predicting the course of dengue disease is therefore an important challenge, especially in resource-limited environments where there may be fewer hospital or clinic beds than dengue patients.
Figure 2. The progression of dengue fever. 3-7 days after being bitten by an infected mosquito, patients develop a high fever of 101-104 °F. Most patients recover, but 5-10% develop symptoms of severe dengue, which include bleeding and fluid loss. Multiple factors can put individuals at greater risk for developing severe dengue. For instance, we know that secondary dengue infections are more likely to progress to severe dengue. Individuals who are young or have chronic conditions are also at elevated risk. Information compiled from [1-4].
Dengue diagnosis and management
As noted above, clinicians ask two key questions when faced with a possible dengue patient: Is this disease in fact dengue? And, if the patient has dengue, is it likely to progress to severe dengue?
To detect dengue infection, most tests identify one of the following: the virus itself, or the antibodies produced by the body in response to the virus. Viral material can be detected only in the active stage of disease, whereas the antibodies persist in the blood and can be used to monitor dengue status in a population.
Common dengue diagnostic tests fall into three groups: reverse-transcription polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assays (ELISA) and rapid diagnostic tests (RDTs). RT-PCR amplifies the viral genome and ELISAs can be used to detect viral proteins or antibody production. The relatively high cost, long processing time and scientific training necessary to conduct the tests have limited the effectiveness of these tests in resource-limited environments. These tests are conducted in larger urban centers and are primarily used to monitor the prevalence of dengue in a population rather than to confirm an individual diagnosis.
The ideal future diagnostics will be quick and easy to use, and will yield results before a patient leaves the clinic. Rapid diagnostic tests (RDTs) are simple to use and provide results within 15-90 minutes. Unfortunately, the trade-off for increased speed is decreased sensitivity; in a patient that has dengue, an ELISA is more likely to indicate a positive result than any currently available RDT kit . The ELISA/RDT comparison is emblematic of the larger issues in resource-limited environments. Due to limited funding and infrastructure, the sophisticated diagnostic methods and patient tracking that can be employed in high-resource Western countries are simply not feasible in resource-limited environments. The current solution to this problem is cheaper but less accurate testing methods, such as the RDTs, that do not require laboratory processing. This disparity contributes to the high burden of infectious disease in resource-limited environments.
After a clinician diagnoses dengue, the patient must be triaged based on the likelihood that he/she will develop severe dengue. To lower the increased mortality rate and medical costs associated with severe dengue, researchers are working to develop simple and inexpensive strategies to classify dengue patients, such as biomarkers or non-invasive tests. The Compensatory Reserve Index (CRI), an exciting new technique to measure changes in blood volume (which would indicate plasma leakage), is currently being tested in Southeast Asia. This simple test uses a finger pulse oximeter (a simple sensor placed on the finger to measure blood oxygen levels), which is both inexpensive and non-invasive, and can detect changes earlier than standard laboratory measures . Should this technique prove successful on a large scale, it would greatly improve dengue case management.
Current efforts in vaccine development and disease prevention
In 2012, the WHO announced the goal of reducing dengue mortality by 50% and morbidity by 25% by 2020 . To achieve this goal, we need better monitoring of outbreaks to facilitate the allocation of resources to the areas hardest hit by disease. In addition, improved triaging and monitoring of dengue patients would greatly reduce the human and economic costs associated with disease complications, as discussed above.
The development of an effective vaccine is the ultimate goal for prevention of an infectious disease. The Dengue Vaccine Initiative is working to stimulate development of a safe and effective dengue vaccine that would protect against all serotypes. There are five vaccine candidates currently being tested in humans, as well as other candidates in pre-clinical testing. Sanofi Pasteur’s vaccine candidate has shown protective effects against dengue infection; however, this protection is incomplete (~30-60%). The lack of good laboratory animal models to study dengue infection has hampered exploration of the complicated interactions of dengue and the human immune system ; increased research into this area could inform the development of more effective vaccines.
Traditional methods to control mosquito-borne disease have focused on direct control of the mosquito population, using a combination of pesticides and protective netting; however, these strategies have been ineffective at curbing the spread of dengue . More recently, genetic and biological strategies are being explored. One biological strategy for mosquito control uses the bacteria Wolbachia, which can shorten the mosquito lifespan and/or block viral transmission, essentially “vaccinating” the mosquito against dengue and preventing dengue transmission to humans . Another exciting approach is the sterile insect technique, in which genetically-modified male mosquitoes are bred in captivity and released in to the wild. When these males breed with females, the eggs hatch but never mature to the adult stage, thus reducing the number of biting mosquitoes in the next generation. Brazil is conducting a sterile insect trial in conjunction with the company Oxitec, and dengue experts are waiting to see the results .
The WHO ranks dengue fever as the most important mosquito-borne viral disease (remember, malaria is a parasitic disease), based on the high number of infections and wide geographic range of the virus. Dengue serves as a good model to explore the effects of infectious disease in resource-limited environments. In these locations, disease outbreaks can quickly overwhelm a healthcare system that lacks sophisticated testing and monitoring capabilities. Suboptimal disease management leads to costly complications and unnecessary mortality. It is only through increased research into the triad of disease prevention, diagnosis, and treatment that we can begin to lessen the burden of dengue and other vector-borne diseases.
Mary E. Gearing is a graduate student in the Biological and Biomedical Sciences Program at Harvard University.
Graphics by Kristen Seim.
Graphics by Kristen Seim.
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