Putting the Brakes on Break-bone Fever (Dengue)

“How to spell Aedes aegypti, the world’s one-stop, viral-disease-transmitting mosquito: T-R-O-U-B-L-E.” T.K. Naliaka, author

“It [Wolbachia-infected mosquito deployment] has the potential to revolutionize mosquito control.” Oliver Brady, PhD, assistant professor and dengue expert, London School of Hygiene and Tropical Medicine

Two articles on dengue in the June 10, 2021 issue of the New England Journal of Medicine caught my eye. One described the exciting results of a randomized trial in Yogyakarta, Indonesia of the release of Wolbachia-infected Aedes aegypti mosquitoes to control this viral disease. The other was far more somber; it reported a fatal case of dengue in a woman in her 30s who was living in Miami, Florida. Thus it seemed to me like a good time for a Germ Gems post on recent developments in the control of dengue—a disease that, according to the World Health Organization (WHO), now endangers about half of the world’s population.

What is dengue? Dengue is an acute viral infection that is transmitted to humans by the bite of one of two mosquito species that harbor the dengue virus (DENV): A. aegypti, or less commonly A. albopictus. The disease has been around for centuries. The first case of what was probably dengue is recorded in a Chinese medical encyclopedia from the Jin Dynasty (265-420). In North America, the first confirmed case was reported in 1789 by Dr. Benjamin Rush, a signer of the U.S. Declaration of Independence, who coined the term “break-bone fever,” referring to the severe muscle, bone, and joint pains associated with dengue. Other common symptoms include sudden high fever, headaches, pain behind the eyes, nausea and vomiting.

About 80% of infected people are asymptomatic or have only mild symptoms. But as many as 5% of all patients develop severe life-threatening dengue hemorrhagic fever, characterized by leakage of plasma from blood vessels or severe bleeding from the gastrointestinal tract resulting in shock. To date there is no specific antiviral therapy, therefore supportive care in an intensive care unit is crucial for those with severe disease. The risk of death among those with severe disease is 0.8% to 2.5%, but with adequate treatment it is less than 1%.

Dengue is widespread throughout the tropics affecting 129 countries. The WHO considers dengue to be one of the top ten global health threats. The number of dengue cases reported to the WHO increased more than 8-fold over the past two decades. One modeling estimate indicates that about 100 million cases of clinically manifest infections occur globally per year, with over 20,000 fatalities. Today, the impact of severe dengue is seen mostly in Asian and Latin American countries, where it has become a leading cause of hospitalization and death among children and adults.

The culprit. There are four types of closely related DENVs (DENV-1, DENV-2, DENV-3, and DENV-4) which all cause the same symptoms. It is possible, however, to be immune to one form of dengue yet vulnerable to the others. And strangely, if you’ve already had infection by one type of DENV and you become infected with another, the earlier infection increases your risk of developing severe illness. This phenomenon complicates vaccine development for dengue.

The vector. Of the over 3,000 mosquito species in the world, just 200 bite humans and only two species, A. aegypti and the Asian tiger mosquito (scientific name A. albopictus), carry DENV. Only the female Aedes mosquito, however, poses a risk of transmitting DENV (males don’t have a proboscis). These females bite because their eggs require a protein in blood for development.

Like many mosquito species, A. aegypti and A. albopictus prefer tropical and subtropical areas of the world; they can’t survive in the cold temperatures. But global warming and increased precipitation associated with climate change is fueling the geographic spread of all mosquitoes, and along with them pathogens, such as, DENV. In 2019, the year when the fatal case of dengue mentioned above occurred in Miami, there were 413 dengue cases of dengue reported in Florida. These included 14 cases of severe dengue. As dengue continues to expand outside the tropics, more frequent importations and local transmissions of DENV are predicted.

Deployment of Wolbachia-infected mosquitoes (a form of germ warfare). Wolbachia is an intracellular bacterium that is thought by some experts to be the most successful bacterial parasite on Earth. It doesn’t infect humans. But it does infect an estimated 40% to 60% of all inspect species, including 51% of mosquito species. It is a master manipulator of the sex life of its hosts; it both feminizes and kills off males. Wolbachia therefore has a potential use in limiting the transmission of dengue and other mosquito-borne viruses.

The exact mechanism whereby Wolbachia makes A. aegypti mosquitoes less susceptible to DENV has been under investigation for some time yet still is not understood. But we may be getting closer. The New England Journal of Medicine recently published “Efficacy of Wolbachia-Infected Mosquito Deployments for the Control of Dengue.” (The Atlantic also featured this study on June 10, 2021 in the article “A Pivotal Mosquito Experiment Could Not Have Gone Better” by staff writer Ed Yong.) Building upon promising results of smaller studies in Australia and elsewhere, this study showed that Wolbachia had a protective efficacy of 77% against all four DENV serotypes. This is considered a potential game-changer in mosquito control.

Use of genetically modified mosquitoes. Oxitech, a British-based biotechnology firm, is pioneering another strategy aimed at the mosquito vector for controlling dengue: genetically modified mosquitos. On May 10, 2021, Oxitech, along with the Florida Keys Mosquito Control District, launched for the first time in the U.S. a pilot study of genetically modified mosquitoes in the Florida Keys aimed at A. aegypti. As only female mosquitoes bite and spread disease, Oxitec created males that pass on a gene that kills female offspring before they mature. Their male offspring then continue mating and passing on the altered gene. The company has run similar projects in other countries such as Brazil, Panama, the Cayman Islands, and Malaysia and reports a success rate of over a 90%.

Dengue vaccine. Development of dengue vaccines has been in the works since the 1920s, but as of 2021, only one version, made by Sanofi Pasteur, is commercially available. Sold under the brand name Dengvaxia, the vaccine is only recommended for those who previously had dengue or for populations in which most people have been previously infected.

In May 2019, Dengvaxia was approved in the U.S. as the first vaccine for prevention of dengue caused by all four DENV serotypes in people ages nine through 16 who have laboratory-confirmed evidence of previous dengue infection and who live in endemic areas (territories of American Samoa, Guam, Puerto Rico, and the U.S. Virgin Islands). The value of the vaccine is limited, however, by the fact that it may actually increase the risk of severe dengue in those who have not been previously infected.

What you need to do when traveling in dengue-laden countries. When traveling in the tropics, one often thinks that a net covered bed can provide protection against any and all diseases where the mosquito is a vector. Pyrethrin-impregnated bed nets are very effective in controlling Anopholes mosquitoes, the vector of plasmodia, the parasite that causes malaria. But they are of little value in fighting Aedes mosquitoes, a species that bites during the day.

Therefore, until a highly effective and safe vaccine is available, here are a few simple precautions you should take when traveling to any of the 100+ countries where dengue is a problem:

1. Use mosquito repellent—one containing 20% to 30% DEET (Lemon eucalyptus or picardin also work);

2. Wear long-sleeved shirts and pants with legs—especially during the day when Aedes mosquitoes feed;

3. Use screens in all windows and doorways; and

4. Remove all containers that can hold water (even bottle caps), because mosquitoes may breed in them.

The bottom line: Do whatever you can while traveling to protect yourself from A. aegypti and A. albopictus. These mosquito species transmit not only DENV, but they also serve as vectors for viruses that cause other serious diseases like Zika, chikungunya, yellow fever, St. Louis encephalitis, Eastern and Western equine encephalitis, and California encephalitis. They are two mosquito species that Homo sapiens can clearly live better without. I think even animals that feed on mosquitoes wouldn’t miss them that much, as there would still be at least another 2998 species upon which to dine.