Beyond Zika: The threat of diseases spread by Aedes mosquitoes

The rapid emergence of Zika virus, particularly as it pertains to the risk for microcephaly in children, led WHO to declare a Public Health Emergency of International Concern and the CDC to warn pregnant women against traveling to endemic areas. Zika, however, is not the only mosquito-borne disease that should concern travelers. Dengue and chikungunya viruses are rampant in the Americas and cause symptoms that are often debilitating. All three diseases share a common vector — the Aedes mosquito, an aggressive daytime biter.

Photo by Mike Saunders, BUSPH Communications Multimedia Director.

Headlines about Zika have overshadowed recent outbreaks of dengue and chikungunya in the Americas. However, the attention on Zika also may be helpful in the fight against those diseases, according to Annelies Wilder-Smith, MD, PhD, MIH, professor of infectious diseases at Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, and president of the International Society of Travel Medicine.

“Their commonalities around geographic locations and transmission by the same vectors mean that research on Zika, in particular improved vector control measures, will benefit all three,” Wilder-Smith said in an interview.

Infectious Disease News spoke with numerous ID and travel medicine experts about the threats posed by Zika, dengue and chikungunya, how international travelers can protect themselves against these diseases, and what is being done to stop their spread.

‘Breakbone fever’ and an overlooked epidemic

Dengue is the world’s most common arbovirus, with yearly global infections reaching an estimated 390 million. The virus is primarily spread by the Aedes aegypti mosquito, according to WHO, although it also is transmitted to a lesser extent by A. albopictus. A. aegypti, a likely vector in urban areas, prefers biting humans and is commonly found indoors, according to the CDC, while A. albopictus is an aggressive biter more commonly found outdoors. Both mosquitoes can be identified by the white stripes on their black legs.

“Globally, dengue is far more frequent than Zika and chikungunya combined,” Wilder-Smith said.

Symptoms of dengue range from a high fever to severe headache and pain in the muscles and joints. It is seldom fatal, but can be severely painful. The disease occasionally develops into severe dengue — or dengue hemorrhagic fever — a more lethal stage of the disease, according to WHO.

“Dengue is called ‘breakbone fever’ because it can cause such severe myalgia and bone pain,” Angelle Desiree LaBeaud, MD, MS, associate professor of pediatrics and infectious disease at the Lucile Salter Packard Children’s Hospital, Stanford School of Medicine, told Infectious Disease News.

While the global incidence of dengue has risen dramatically in recent decades to the point where it is estimated that about half of the world’s population is at risk, those numbers still may be underreported, according to WHO.

Dengue typically occurs in tropical and subtropical climates, mostly in urban and semi-urban areas, according to WHO. Recently, Hawaii experienced its first cluster of locally acquired dengue since 2011. In February, the mayor of Hawaii’s Big Island declared a state of emergency to stop the acceptance of tires at county landfills — a breeding ground for mosquitoes — after the number of confirmed cases of dengue reached more than 250. However, the disease is more widespread in Latin America, where severe dengue has become a leading cause of hospitalization and death among children, WHO reported.

Improved surveillance and eradication measures have done a better job at halting the spread of dengue in the United States, according to Davidson H. Hamer, MD, professor of global health and medicine at Boston University School of Public Health and School of Medicine.

“There’s been some smoldering outbreak of dengue in the [Florida] Keys, in Key West and so forth, and then along the border of Texas and Mexico,” Hamer told Infectious Disease News. “But it really hasn’t established a major foothold in the U.S.”

Chikungunya also can cause debilitating pain, and it can persist for months or even years, although most patients fully recover, according to WHO. Travelers in certain groups may be at a higher risk for chikungunya, including those aged older than 65 years and people with conditions such as arthritis, hypertension, heart disease and diabetes, according to the CDC. Its primary vectors are A. aegypti and A. albopictus.

In the Americas, the first indigenous outbreak of chikungunya began on the Caribbean island of Saint Martin in 2013 and has spread to more than 43 countries and territories, according to WHO. Local transmission of the disease has been reported in many popular destinations for travelers, including the Bahamas, the U.S. and British Virgin Islands, Dominican Republic, Jamaica and Puerto Rico, according to the CDC.

All but six U.S. states cited new cases of the virus in 2015, the CDC reported. However, all 679 cases reported last year — including 176 in California, the state most heavily affected — occurred in travelers returning from areas with active chikungunya transmission.

The outbreak is thought to have infected more than 1.6 million people in the Americas, according to the Pan American Health Organization. Meanwhile, outbreaks of other diseases have received more attention, LaBeaud said.

“What happened was, chikungunya emerged, and then Ebola happened. Chikungunya finally got back in the spotlight for a second and then Zika hit, so poor chikungunya — it never gets the limelight,” she said.

 

The codistribution of dengue and chikungunya in certain areas means coinfection and misidentification are possible, according to a recent study. Evidence of coinfection of chikungunya and dengue was observed in patients in 13 of the 98 countries or territories that reported both diseases. Most cases of coinfection were seen in Africa and Asia, but there also were 16 in Saint Martin in 2013-2014. The diseases have similar symptoms; thus, they can be misdiagnosed, leading to potential risks for patients, including delays in proper treatment.

About 75% of all dengue cases may be asymptomatic, according to the CDC. Chikungunya may not present with symptoms in approximately 3% to 28% of cases. Comparatively, WHO estimates that 80% of Zika virus infections are asymptomatic. While Zika goes unnoticed in most of the people infected by it, there still are concerns about the disease’s effects — chiefly among pregnant women and their fetuses.

Researchers from three U.S. universities recently exhibited the first evidence of a likely biological link between Zika and microcephaly by showing the virus directly targeted and infected cells involved in the brain’s development. In another study, researchers used data from the 2013-2014 Zika outbreak in French Polynesia to estimate the risk for microcephaly to be approximately 1 in 100 women infected by the virus during the first trimester.

Zika may cause other possible grave outcomes for fetuses, including fetal death, placental insufficiency and central nervous system injury, according to a study published in the New England Journal of Medicine. It has been transmitted primarily by A. aegypti, which is less widespread in the U.S. than A. albopictus.

“Zika is probably the mildest of the three on a population basis [but is] the most neurotropic of all,” Wilder-Smith said. “It has the capability of invading the nervous system, thereby causing neurological complications such as Guillain-Barré syndrome in about 24 out of 100,000 Zika infections, according to the latest study. But our main fear for Zika is its teratogenic effects during pregnancy.”

According to Peter J. Hotez, MD, PhD, chair of tropical pediatrics at Texas Children’s Hospital and dean of the National School of Tropical Medicine at Baylor College of Medicine, the problem area for Zika is increasing quickly.

“We’re talking about most of Latin America and the Caribbean, and we could be talking about the Gulf Coast of the U.S. as well. This is going to be a very challenging year, trying to figure out what the limits are on this epidemic and where it is heading,” he said during an interview with Infectious Disease News.

Hamer advised against pregnant women traveling to areas with ongoing Zika transmission.

“Beyond that,” he said, “it’s hard to block people from traveling to places where dengue and chikungunya occur.”

A ‘connected’ — and warming — world

The ease of global travel plays a significant role in spreading viruses like those transmitted by Aedes mosquitoes, according to LaBeaud.

“It has a lot to do with the fact that we have a very connected world right now,” she said. “There is a lot of travel between places, so people are able to bring these infections with them when they travel.”

Global climate change and the urbanization of the human population also play parts in creating more habitable environments in which mosquitoes can thrive, according to LaBeaud.

“It is a perfect storm for these types of infections to emerge,” she said.

The spread of A. aegypti and A. albopictus, aided by international trade and travel, will increase as the Earth warms, according to Donald Kaye, MD, professor of medicine at Drexel University College of Medicine and Infectious Disease News Editorial Board member, and Thomas Yuill, PhD, professor emeritus in the department of pathobiological sciences and the department of forest and wildlife ecology at the University of Wisconsin-Madison.

“International trade helped spread the vectors with survival of their eggs in used tires and other items,” Kaye and Yuill told Infectious Disease News. “International travel brings viremic tourists to the mosquitoes waiting to transmit these three and other viruses. Aedes aegypti occurs in the Southeastern states across to southern Texas, New Mexico, Arizona and in Southern California. Aedes albopictus is widespread in the U.S. With global warming their ranges will increase.”

According to Hamer, international travel increases the risk that all three viruses will become locally transmissible in the U.S.

“With all the travel back and forth to the Caribbean and Latin America, [there is a risk] for somebody to come back and be viremic and then have a local mosquito pick up the virus,” Hamer said.

However, living conditions in North America make it more difficult for these diseases to propagate, according to Alexander Garza, MD, MPH, associate dean for public health practice at Saint Louis University.

“The environment for spread ... in North America is much different than the environment for spread in South America,” Garza told Infectious Disease News. “We have much better mosquito control. ... By and large, most people have adequate housing in the United States. We have air conditioning, screened windows, etc.”

But mosquito control is not easy and is often done through abatement measures that vary in success, according to CDC Director Thomas R. Frieden, MD, MPH.

“For mosquito control, you need to have monitoring of both mosquito larvae and adult mosquitoes,” Frieden said during a recent teleconference with reporters. “That’s a labor-intensive, complex undertaking, and then you need to control mosquito larvae and adult mosquitoes, and that’s a labor-intensive and challenging area. We know from the experience with dengue, you have to get to very high levels of mosquito control to drive down the risk of dengue in the community.”

Preventive measures for travelers

Although the CDC confirmed that Zika can be spread through sexual contact, a bite by a female Aedes mosquito remains the primary cause of Zika, dengue and chikungunya.

To protect themselves, LaBeaud recommends that people visit their local travel clinic for advice about the types of infections they might acquire while abroad.

“I think that people should travel and experience the world and all it has to offer. They should just be smart about it,” she said. “I think not only do you get information about these sorts of mosquito-borne viral infections, but you also get information about safe foods and safe water, and sunscreen, and being safe in cars. ... But I would never say ‘no’ to travel.”

The risk associated with travel differs from patient to patient, according to Phyllis Kozarsky, MD, professor of medicine in the division of infectious diseases and medical director of the TravelWell Center at Emory University School of Medicine, which provides vaccinations and other health services for international travelers.

“For some, it may not be safe if they are already debilitated,” Kozarsky told Infectious Disease News. “Risk is something that each person has to evaluate for him or herself. The most common cause of preventable deaths in travelers is motor vehicle accidents. So, it just depends how the traveler perceives the risk.”

Wearing long sleeves, using effective insect repellent such as DEET, and remaining indoors and behind screens, if possible, are among the steps travelers can take to protect themselves against mosquito bites, Hamer said.

“The major thing is the mosquitoes that are transmitting all three of these [viruses] are daytime-biting ... especially early in the morning and then later in the afternoon. But it can be any time during the day,” Hamer said. “Sometimes, the other possibility is treating clothing with permethrin or some sort of insect repellent. If somebody is going to be working in an area outdoors where there are lots of mosquitoes, that’s an additional measure that can be helpful. But for the average person, that’s not necessary.”

From a public health standpoint, eliminating breeding sites for mosquitoes can be effective, according to Hamer.

“Small amounts of water, even the water at the base of a potted plant, a tire in the yard, almost any small volume of water is often sufficient for the mosquitoes to breed,” Hamer said. “So, trying to drain standing water is very important.”

Progress on vaccines

Although there are no available vaccines for Zika, dengue or chikungunya, researchers are working on all three.

Recently, researchers in the U.S. used a small-scale human challenge model to show that a dengue vaccine being developed by the NIH’s National Institute of Allergy and Infectious Diseases, or NIAID, was 100% effective in preventing dengue virus serotype 2 infection after 6 months.

Protecting against dengue has been challenging because an effective vaccine needs to be useful against all four serotypes. A partially effective vaccine is dangerous, putting patients who are infected with one serotype at risk for more serious symptoms if they are infected with another. The researchers said human challenge models may help identify promising vaccine candidates while weeding out poor ones before they reach much larger trials.

“There is an urgent need for a Zika vaccine,” study investigator Anna P. Durbin, MD, associate professor at Johns Hopkins University Bloomberg School of Public Health, said during a teleconference. “We are looking at strategies to really accelerate that time line, and we think that a Zika human challenge model could be useful in that endeavor.”

In November, it was announced that a chikungunya vaccine candidate, also being developed by NIAID, would undergo a phase 2 trial to evaluate its safety and efficacy. It previously demonstrated a robust immune response in 25 healthy volunteers during a phase 1 trial conducted in 2014.

The NIAID also is currently working on vaccine candidates to prevent Zika virus infection, and a phase 1 trial evaluating the safety and immunogenicity of one candidate is slated for the end of this summer or early fall, with results expected in early 2017, according to Anthony S. Fauci, MD, NIAID director.

According to LaBeaud, the reactive research approach to easily transmitted infectious diseases is ineffective.

“It is a very reactive climate right now when it comes to these infections, and they seem to be surprising us with their emergence,” LaBeaud said. “There are many other infections that have yet to emerge and could be the next Zika, or chikungunya, or West Nile virus, and I think it is important to realize how vulnerable we are. We need to figure out how we can be more proactive in these sorts of situations, because this reactiveness doesn’t seem to be working very well.”

The solution lies in international health investments, requiring diplomatic and humanitarian efforts to stop these viruses before they come to the U.S., according to Garza.

“We need to be investing in public health infrastructure overseas because they are typically the ones that have to deal with these problems first,” Garza said. “We should be investing globally in disease eradication and research efforts to understand what is going on in those communities.”

For now, the risk for acquiring an infectious disease from Aedes mosquitoes remains a reality for travelers.

“We are all at risk of dengue, chikungunya and Zika when traveling to areas where Aedes mosquitoes are present in combination with circulating viruses,” Wilder-Smith said. – by Gerard Gallagher and David Costill

• References:
• Brasil P, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1602412.
• Cauchemez S, et al. Lancet. 2016;doi:10.1016/S0140-6736(16)00651-6.
• CDC. Chikungunya in the Caribbean. 2015. http://wwwnc.cdc.gov/travel/notices/watch/chikungunya-caribbean. Accessed March 23, 2016.
• CDC. Table. Laboratory-confirmed chikungunya virus disease cases reported to ArboNET by state or territory — United States, 2015. http://www.cdc.gov/chikungunya/pdfs/2015table-011215.pdf. Accessed March 23, 2016.
• Furuya-Kanamori L, et al. BMC Infect Dis. 2016;doi:10.1186/s12879-016-1417-2.
• Kirkpatrick BD, et al. Sci Transl Med. 2016;doi:10.1126/scitranslmed.aaf1517.
• NIH. NIH-sponsored clinical trial of chikungunya vaccine opens. https://www.niaid.nih.gov/news/newsreleases/2015/Pages/ChikungunyaVaxTrial.aspx. Accessed March 15, 2016.
• Pan American Health Organization. More than 1.6 million cases of chikungunya reported in the Americas since first appearance of the virus in 2013. http://www.paho.org/hq/index.php?option=com_content&view=article&id=11329&Itemid=41586&lang=en. Accessed March 23, 2016.
• Tang H, et al. Cell Stem Cell. 2016;doi:10.1016/j.stem.2016.02.016.
• WHO. Chikungunya fact sheet. http://www.who.int/mediacentre/factsheets/fs327/en/. Updated May 2015. Accessed March 23, 2016.
• WHO. Dengue and severe dengue. http://www.who.int/mediacentre/factsheets/fs117/en/. Updated March 2016. Accessed March 23, 2016.

• For more information:
• Alexander Garza, MD, MPH, can be reached at Saint Louis University College for Public Health and Social Justice, Salus Center.
• Davidson H. Hamer, MD, can be reached at dhamer@bu.edu.
• Peter J. Hotez, MD, PhD, can be reached at hotez@bcm.edu.
• Phyllis Kozarsky, MD, can be reached at pkozars@emory.edu.
• Angelle Desiree LaBeaud, MD, MS, can be reached at dlabeaud@stanford.edu.
• Annelies Wilder-Smith, MD, PhD, MIH, can be reached at awilder-smith@ntu.edu.sg.

Disclosures: Fauci is director of the NIAID. Frieden is director of the CDC. Garza, Hamer, Hotez, Kaye, Kozarsky, LaBeaud, Wilder-Smith and Yuill report no relevant financial disclosures.