Emergence of Zika compounds the global burden of mosquito-borne viruses

Brazilian officials estimate that there have been at least 1.5 million cases of Zika virus infection since the current outbreak began in May 2015, according to WHO.

This dramatic increase in Brazil — and throughout the Americas — coupled with the now-confirmed association between the virus and microcephaly forced the CDC to issue a travel warning advising pregnant women to avoid travel to most of South America and the Caribbean, and ultimately prompted WHO to declare a global health emergency.

Photo courtesy of Saint Louis University.

The rapid emergence of Zika in the Western Hemisphere, along with the continued spread of dengue and chikungunya, highlight the delicate state of international health relations between the United States and its neighbors in Central America, South America and the Caribbean. To better understand the threat posed by these viruses, Infectious Diseases in Children spoke with several infectious disease and travel medicine experts about the rise of Zika virus, its relationship to chikungunya and dengue virus, the implications of its association with microcephaly, and possible solutions to this emerging global health crisis.

Arrival of Zika

Through a common vector, the Aedes mosquito, Zika adds to the threat already posed by other prominent tropical diseases currently endemic in the Western Hemisphere, such as chikungunya and dengue virus. Furthermore, rising global temperatures and the ease of international travel threaten to increase the potential area of burden for these viruses by enabling them to spread farther than ever.

“The problem area is getting very big, very fast,” 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, told Infectious Disease in Children in an interview. “We’re talking 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 really figure out what the limits are on this epidemic and where it is heading.”

While Zika has been known to exist for more than half a century, the virus was not able to get a foothold and become endemic until relatively recently, according to Hotez.

“It was first identified in Africa — in Uganda, in the Zika forest in 1947,” Hotez said. “The virus was isolated in 1952. The first human infection with Zika was reported in Nigeria in 1954. It appears to have made a major jump in 2007 when it appeared on Yap Island in Micronesia in the Pacific where it affected more than three-quarters of the population. Then it really appeared in Brazil, in May 2015, where it spread across the population, especially in the northeastern region.”

Several factors may be responsible for the sudden prevalence of Zika virus in South America. According to Angelle Desiree LaBeaud, MD, MS, an associate professor of pediatrics and infectious diseases at the Lucile Salter Packard Children’s Hospital, Stanford School of Medicine, the increasing ease of global travel may play a role in spreading Zika and other viruses.

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

According to Susan L.F. McLellan, MD, MPH, clinical associate professor of tropical medicine at Tulane University, conditions related to climate control and urban density may have played a part in allowing the disease to establish a foothold.

LaBeaud agreed that the emergence of Zika could be due to urban density; however, she also suggested that global climate change is playing a part in creating more habitable environments for mosquitoes to live and thrive.

“The world is warming,” LaBeaud said. “We have a lot of very good habitats for this vector —Aedes aegypti — so if people travel knowingly or unknowingly with the virus, they are then able to infect vectors in the new place they arrive. Also, just the fact that the world has become more urban facilitates this. Aedes aegypti has evolved with us for centuries. They are a very urban mosquito that likes to live in and around our human habitations. It is a perfect storm for these types of infections to emerge.”

While there have yet to be any cases of locally transmitted Zika virus in the U.S., CDC officials said the potential for limited outbreaks is sufficient. According to Alexander Garza, MD, MPH, associate dean for public health practice at Saint Louis University, the fact that there has been no local transmission of Zika in the U.S. is a sign that living conditions in North America make it more difficult for the disease to propagate.

“The mere fact that we don’t have the virus existing in the United States right now outside of those isolated cases where people have traveled from other countries shows that the environment for spread of the disease in North America is much different than the environment for spread in South America,” Garza said in an interview. “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.”

A ‘game-changer’

Zika is closely related to other tropical viruses, which have been plaguing the same region of the Americas for years, specifically dengue and chikungunya virus, according to LaBeaud. These three viruses have a number of characteristics in common, making their combined presence in the region a global health concern.

“Dengue, chikungunya, and Zika are all mosquito-borne viruses,” LaBeaud said. “Dengue and Zika are both flaviviruses ... so, they are more closely related evolutionarily, while chikungunya is an alphavirus. However, they are all spread by Aedes aegypti and Aedes albopictus mosquitoes.”

According to Davidson Hamer, MD, a professor of global health and medicine at Boston University School of Public Health and School of Medicine, the viruses also all share very similar symptom profiles, making it harder for clinicians to make a differential diagnosis when presented with symptomatic patients.

“Clinically, when diagnosing chikungunya, there is overlap with both dengue and Zika, so it can be tricky,” Hamer told Infectious Diseases in Children. “The challenges are the tests available. For chikungunya, they’re more readily available. However, Zika is a challenge, because the serology can cross-react with dengue because they’re both flaviviruses. Therefore, if it’s the first week after infection, you might be able to do a PCR and have an answer that way. But, if it’s later, you need to do more specific antibody tests, and those are not widely available.”

According to LaBeaud, however, Zika infection results in the least amount of sequelae, for the individual infected, when compared with dengue and chikungunya. Furthermore, according to WHO, an estimated 80% of Zika virus infections are asymptomatic.

“Zika is almost like a ‘dengue light,’ ” LaBeaud said. “It results in fever that isn’t that high for a few days, an itchy red rash, red eyes — and usually people get better within about a week. Dengue can cause an infection that presents in the same way, but patients can progress to severe dengue, which can result in vascular leak, hemorrhagic disease and shock. Dengue is called “break bone fever” because it can cause such severe myalgia and bone pain. But unlike dengue and Zika, the acute febrile illness caused by chikungunya is often manifested by arthritis and arthralgia and sometimes that’s the tip-off. Unfortunately, with chikungunya, patients can end up with severe arthritis or arthralgia for several years after the acute onset disease is finished.”

LaBeaud said there are a small percentage of patients who develop Guillain-Barré syndrome as a result of Zika infection, but that the condition is common among these types of infections.

In November, Brazilian health officials alerted WHO of an increase in cases of microcephaly and quickly discovered a possible association with Zika virus infection. Microcephaly is a condition that affects newborns, in which the occipitofrontal circumference is smaller than average. The condition is diagnosed in children with a head circumference of two standard deviations below the mean compared with similarly aged children. According to WHO, there have been more than 400 confirmed cases of Zika associated-microcephaly, while more than 3,600 cases remain under investigation. Zika is thought to threaten the fetal development of women who become infected with Zika during their first trimester of pregnancy.

“Microcephaly is the concern,” McLellan said. “Zika is not much more frightening than the common cold in a sense. But, that was before there were enough cases to pick up an association between an outbreak of this disease and the increased rate of significant congenital defects.”

According to the CDC, Zika has been found in the brain tissue and placental tissue of newborn infants and miscarried fetuses. While the association has been confirmed, the mechanisms for how Zika attacks the brain and causes neurological damage remains unclear.

“The main event is the fact that the virus affects women who are pregnant,” Hotez said. “The virus is going from the woman’s bloodstream to the placenta, where it is entering the baby and causing massive neurologic destruction, leading to abnormal brain formation and microcephaly — and now we think many cases of stillbirth as well.”

Garza said the global burden of massive amounts of children being born with microcephaly, as a result of widespread Zika, could be devastating in the long term as well.

“It is not just a burden at the moment of birth, it is also a burden throughout that child’s entire life span,” Garza said. “This is a large group of children now that are going to need a whole spectrum of needs ... the majority of them are going to require some intensive resources in order to be able to get along in their life span. In a way that also plays into some of the policy decisions now being advocated for, particularly in South and Central America.”

The CDC recently determined the virus also can be acquired through sexual contact. These findings are supported by two previously published case studies. According to LaBeaud, this development is another characteristic unique to Zika virus.

“The challenge with sexual transmission is if males are returning from endemic areas back to the United States, and then having intercourse with their partners back in the United States, which is not endemic, and particularly if their partner is pregnant,” Garza said. “The majority of people that are infected with the Zika are completely asymptomatic, so someone could theoretically go down to an endemic area, become infected, come back home and have absolutely no symptoms and have intercourse with their pregnant partner and potentially spread the virus.”

However, according to McLellan, although the risk for sexual transmission is possible, it is not a significant risk factor at this time.

“It is very unlikely that sexual transmission is a significant means of transmission,” McLellan said. “Transmission is primarily going to be mosquito-borne. But, if we want to talk about splitting hairs and small possible risks, then that is one.”

Travel and prevention measures

Zika, dengue and chikungunya are currently locally transmissible in some of the most popular travel destinations in the country, including Hawaii, Puerto Rico, the U.S. Virgin Islands and many more. The presence of Zika in these areas has prompted the CDC to release a travel warning advising pregnant women to avoid travel to any country where Zika is currently endemic, sparking concern for travelers across the globe. This has forced many airlines and cruise lines to issue refunds to worried travelers who arranged travel in advance of the outbreak.

“Our ‘job’ is to facilitate travel and to make it as pleasant and safe as possible,” Phyllis Kozarsky, MD, a professor of medicine in the division of infectious diseases and medical director of TravelWell at Emory University School of Medicine, told Infectious Diseases in Children. “That isn’t to say that some should not go to a Zika-affected area; however, I believe that pregnant women or those trying to become pregnant would be safest not to travel to a Zika-affected area now.”

According to Harvey Rubin, MD, PhD, professor of infectious diseases at the Perelman School of Medicine at the University of Pennsylvania, the travel risk for men and nonpregnant women is very low.

“For the nonpregnant traveler, there is no recommendation to avoid traveling,” Rubin said. “With the caveat that personal protection is always important. The WHO did issue an international health emergency of international consequence, but that doesn’t require quarantining or not traveling.”

LaBeaud suggested that physicians should recommend that their patients get all the information they need before traveling to regions where tropical diseases are endemic.

“For non-pregnant individuals, I would not recommend to never travel,” LaBeaud said. “People just need to travel safe. They need to go and visit their local travel clinic and get travel advice about the types of infections you are at risk for in different places in the world and how to decrease that risk.”

According to Kozarsky, the risk associated with travel differs from patient to patient.

“For some, it may not be safe if they are already debilitated,” Kozarsky said. “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.”

The CDC recommends that travelers to Zika-endemic areas practice mosquito-prevention strategies, including the use of insect repellents containing DEET, picaridin and IR3535.

“If you are traveling to endemic areas, make sure you are taking precautions to reduce your risk of infection,” Garza said. “Sleeping under bed nets, staying in air conditioning, wearing long sleeve clothing and using mosquito repellent are some of the big things.”

However, Hotez questions the safety of the CDC’s recommendation for pregnant women to use insect repellents that contain DEET.

“There seems to be some disagreement about the safety of DEET,” Hotez said. “The CDC, on their website, is saying it is safe. However, I talked to a couple of obstetrician colleagues at Texas Children’s Hospital, which is one of the biggest OB services in Texas, and they said, ‘What? No, no, we don’t recommend that. Based on studies ... it does not appear necessarily to be safe.’ So, that’s got to be resolved.”

According to Hamer, the primary way to effectively reduce the risk for Zika infection is for personal and communitywide vector awareness and control habits.

“There are things that can be done from a public health standpoint,” Hamer said “One of them is to try and eliminate breeding sites around houses or neighborhoods. Small amounts of water, even the water at the base of a potted plant or a tire in the yard, are often sufficient for the mosquitoes to breed. So, trying to drain standing water is very important.”

Future research necessary

Lack of institutional knowledge regarding Zika virus has caused a surge of research interest to fill that gap, according to LaBeaud.

“Right now a lot of effort is focused on this infection,” LaBeaud said. “Usually these infections seem so far away, and then all of a sudden, they are at your backdoor, and people are always surprised that we don’t know everything about them.”

In order for clinicians to have the best information available to them, Rubin recommends staying up-to-date with all breaking recommendations regarding Zika and other tropical illnesses.

“I heartily recommend clinicians taking care of women and newborns to keep on top of the current recommendations,” Rubin said.

According to LaBeaud, one area of research in desperate need of advancements is diagnostics.

“We need to bring the diagnostic a lot closer to the patient,” LaBeaud said. “Right now for Zika, we’re having to send all our serology to the board of health and then on to the CDC. Really, we need good tests that are specific and sensitive that can be done close to the bedside at different hospitals around the world, so we know: ‘Is this Zika? Is this not Zika?’ Think of all those poor pregnant women out there who are concerned that they might have been exposed to a virus that harmed their baby somehow. It’s a lot of anxiety that could be abated if we could get our diagnostic situation resolved.”

During a CDC news conference, Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, said NIAID is currently working on vaccine candidates to prevent Zika virus infection.

“We already have existing vaccine platforms to use as a sort of jumping off point,” he said “First, a DNA-based vaccine using a strategy very similar to what we employed for ... the West Nile virus. This vaccine was found in a phase 1 trial to be both safe and immunogenic. Second, a live-attenuated vaccine building on similar and highly immunogenic approaches used for the closely related dengue virus.”

Fauci added that the media attention surrounding Zika is propelling pharmaceutical interests to support development of the vaccine.

“The reason why the West Nile virus phase 1 did not turn into a vaccine approved, produced and made widely available is we could not find pharmaceutical partners to partner with us to push it to the next stage of advanced development.” Fauci said. “I do not anticipate we’ll have any problem partnering with pharmaceutical companies now because of the extraordinary attention and interest that is now put into Zika.”

According to Hotez, accelerated research is currently needed because Zika poses a threat to the continental U.S., due to the risk associated with impoverished living conditions.

“It’s been such a problem in northeastern Brazil because it is one of the poorest parts of Brazil,” Hotez said. “People have no protection against mosquitoes living in poor-quality housing without window screens, uncollected garbage that fills with water and breeds mosquito larvae. So, poverty is a huge factor. We also have profound poverty on the Texas Gulf Coast. So, I think Houston and parts of South Texas are also vulnerable.”

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 that 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.”

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

“This is a classic example of how you ignore emerging infectious disease at your own peril,” Garza said. “It finds a way to become relevant. We need to be investing in public health infrastructure overseas because they are typically the ones that have to deal with these problems first. We should be investing globally in disease eradication and research efforts to understand what is going on in those communities.”

• References:
• Chen LH, et al. Ann Intern Med. 2016;doi:10.7326/M16-0150.
• Hamer DH, et al. Ann Intern Med. 2014;doi:10.7326/M14-1958.
• Martines RB, et al. MMWR Morb Mortal Wkly Rep. 2016;doi:10.15585/mmwr.mm6506e1.
• Mlakar J, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1600651.
• Petersen EE, et al. MMWR Morb Mortal Wkly Rep. 2016;doi:10.15585/mmwr.mm6502e1.
• Oduyebo, T, et al. MMWR Morb Mortal Wkly Rep. 2016;doi:10.15585/mmwr.mm6505e2e.Oster AM, et al. MMWR Morb Mortal Wkly Rep. 2016;doi:10.15585/mmwr.mm6505e1.
• WHO. Emergencies – Zika Situation Report. www.who.int/emergencies/zika-virus/situation-report/19-February-2016/en/. Accessed February 23, 2016.
• WHO. Dengue and severe dengue. www.who.int/mediacentre.factsheets/fs117/en/. Accessed February 23, 2016.

• For more information:
• Alexander Garza, MD, MPH, can be reached at SLU College for Public Health and Social Justice, Salus Center.
• Davidson 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.
• Susan L. F. McLellan, MD, MPH, can be reached at smclell@tulane.edu.
• Harvey Rubin, MD, PhD, can be reached at RubinH@mail.med.upenn.edu.

Disclosures: Garza, Hamer, Hotez, Kozarsky, LaBeaud, McLellan and Rubin report no relevant financial disclosures.