Body + Brain

19
Feb

Stealthy, Debilitating Disease Is Poised to Sweep the United States

Tourists have long flocked to the Caribbean for its white sandy beaches, turquoise waters, and year-round warm temperatures and sunshine. With so many people coming and going, it’s no surprise that the area has also been home to a variety of hitchhikers. Some of these globe-trotting stowaways are human, sneaking in on boats and planes. More common are plants and animals. But in recent years, officials in the Caribbean islands have been on the alert for much smaller and potentially more pernicious vagabonds—infectious diseases.

The island of Saint Martin—popular with tourists—has been hit hard by an outbreak of a mosquito-borne illness.

So when Sylvie Cassadou, an epidemiologist on the islands of Guadaloupe, St. Bartholomew, and St. Martin, received the phone call in November that residents in the French Quarter of Marigot on St. Martin were complaining of fever, rash, and joint pain, she wasn’t terribly surprised. Both the World Health Organization and the Pan-American Health Organization had warned her to be on the lookout for this cluster of symptoms, signs of a strangely named, peripatetic virus called chikungunya. Originally from southeastern Africa, the mosquito-borne virus has been slinking around the world for the past decade, leaving a trail of outbreaks in its wake.

Since December, just after Cassadou was first alerted to the presence of chikungunya on St. Martin, over 1,446 of cases have been identified on islands throughout the Caribbean—411 of which popped up between February 3–7. Chikungunya’s appearance in the Caribbean—a tourist hub that draws vacationers from around the world—has epidemiologists particularly concerned.

“There is a lot of airplane traffic in the Caribbean, which gives the virus the opportunity to spread elsewhere,” Cassadou says.

Given high rates of travel to the area, officials at the Centers for Disease Control and Prevention are growing increasingly concerned about the possibility of chikungunya arriving in the United States. “The more travelers coming back from an area with chikungunya,” says Ann Powers, chief of the arbovirus disease branch at the CDC, “the higher the risk of an infected person coming back infected and starting an outbreak here.”

Chikungunya Packs Its Suitcases

Despite its recent arrival to newspaper headlines, chikungunya is not a new virus. For centuries, it lived quietly in southeastern Africa, jumping between primates, humans, and local Aedes mosquitoes. The virus rarely caused outbreaks of note. Unlike other arthropod-borne viruses (arboviruses) like dengue and yellow fever, chikungunya didn’t immediately move out of Africa with the slave trade or later with globalized travel. As far as anyone knows, the virus stayed local until the 1960s.

In the language of the Makonde people in Africa, “chikungunya” means “that which bends over,” a testament to the extreme joint pain caused by the virus, which can leave sufferers unable to sit up for weeks. It rarely kills, but the infected are often debilitated and unable to work for several months. Chikungunya is transmitted primarily by two species of mosquito: the tropical Aedes aegypti—which also transmits yellow fever and dengue—and the more temperate Aedes albopictus, better known as the Asian tiger mosquito. Both flying insects have made themselves at home in the United States, which raises the specter of chikungunya doing the same.

When chikungunya first packed its bags for adventures on a foreign shore, it hitched a ride to India and Southeast Asia in an infected person or mosquito in the early 1960s. Residents in nearby Cambodia and Thailand soon began complaining of severe joint pain, too. By the end of the decade, the virus had caused epidemics throughout Southeast Asia.

Aedes albopictus
Aedes albopictus, the Asian tiger mosquito

As travel changes so many of us humans, it also changed chikungunya. Its first sojourn out of rural Africa to the urban wilds of Asia had subtle effects on how the virus was transmitted. Instead of cycling between humans, primates, and mosquitoes, the virus cycled back and forth between humans and the tropical mosquito Ae. aegypti.

Scott Weaver, an arbovirus expert at the University of Texas Medical Branch (UTMB) in Galveston, says dengue and yellow fever had followed similar paths in their round-the-world journey. “All of these viruses evolved in forests, and they all adapted to city life through the urban Aedes aegypti,” he says.

When Weaver first began this study of chikungunya’s travels in the early 2000s, it seemed like little more than a quaint area of study. The African and Asian lineages had the same symptoms and same severity of illness—in other words, it wasn’t a particularly alluring disease, at least from a virologist’s perspective. Still, Weaver knew that arboviruses liked to globetrot, and he had a hunch that it was just a matter of time before chikungunya reappeared on the world map. Neither he nor anyone else in the public health community, however, could predict when.

After chikungunya’s first jump across the Indian Ocean, the Asian strain of the virus never returned to Africa. The two strains had gone their separate ways. Both viruses continued to be transmitted, but at very low levels. Many of the symptoms closely resembled the difficulties of life in the developing world, so they didn’t stand out. As a result, they weren’t noted by infectious disease experts. In a world fighting dengue and malaria, chikungunya seemed like a relatively minor concern. Then drought struck.

Stamps in the Passport

Summer in sub-Saharan Africa is generally hot and humid, with drenching monsoon rains arriving in March and April. The spring of 2004 was different. The heat came, but the rains didn’t. Farmers in Kenya watched their normally green fields wither and turn brown. Rivers began drying up. Women who normally hauled water in small jugs back to their homes from nearby streams had to trek many miles to get their family’s water. Instead of getting water as they needed it, the woman started to store the water in large containers near their homes to save their aching feet and backs.

These containers provided a perfect breeding ground for Ae. aegypti. When the mosquitoes hatched, they were also close to the humans that are a favorite food source for the mosquitos. Chikungunya, which had been smoldering in the region for decades, began to spread like wildfire. A person who is infected with chikungunya can carry the virus in their bloodstream for up to a week. This means that they can spread the virus to any Ae. aegypti mosquito that bites them during this time.

Once the mosquito drinks the blood containing chikungunya, the virus replicates in the mosquito’s gut. From there, it rapidly spreads to the salivary glands where it remains for the rest of the mosquito’s life. When the mosquito bites another human for its next meal, it injects a small amount of saliva into the bite to keep the blood from clotting. For mosquitoes infected with chikungunya, this dollop of virus-infused spit enters the bloodstream of the waiting human. Once it is back in a human, the virus begins its cycle of replication all over again. After two to seven days, the newly infected person has high levels of virus in the bloodstream, and the cycle can restart.

Mtwara Tanzania
Chikungunya was first noticed by epidemiologists following a 1952 outbreak in the region that straddles the current border between Tanzania and Mozambique.

Because chikungunya must successfully infect both mosquitoes and humans to complete its life cycle, the right mosquito species must be present for an outbreak to occur. Besides several species of Aedes mosquitoes present only in southeastern Africa, Ae. aegypti was the only species of mosquito known to transmit chikungunya. When residents of the island of La Reunión, a French protectorate 1,300 miles to the east of Kenya, first heard about the chikungunya, they breathed a sigh of relief. Their island didn’t have any Ae. aegypti mosquitoes, only the closely related Asian tiger mosquito (Ae. albopictus), which wasn’t known to transmit chikungunya. Public health officials were expecting to get a few cases from travelers, but nothing more.

So when the virus began ravaging the island in 2005, scientists couldn’t figure out what was happening. Without any Ae. aegypti, the virus shouldn’t have found a suitable home on La Reunión. But it did anyway. In the 18 months that the virus swept through the 920-square-mile island, over 200,000 of the island’s 750,000 residents were sickened.

“What you need for an outbreak of chikungunya is the virus, humans without immunity, and the right species of mosquito,” says Olivier Schwartz, a virologist at the Pasteur Institute in France and a member of the task force created to control the outbreak on La Reunión. The island had two of the three, but appeared to be missing the right species of mosquito. Something must have changed to create an outbreak on this scale, though no one could figure out what. Stephen Higgs, then a colleague of Weaver’s at UTMB, set out to solve this mystery.

He began by comparing the genome of several known samples of the chikungunya virus, including older samples from the 1950s and 60s, as well as more recent ones from the Kenyan outbreak in 2005, from early victims of the La Reunión epidemic, and from humans who had become infected later in the outbreak. There, buried deep in the genome of the virus from the La Reunión outbreak, was Higgs’ answer: the virus had mutated. Only one single nucleotide had changed—the 226th position on gene E1—but it was enough to allow the virus to be transmitted by the Asian tiger mosquito rather than Ae. aegypti.

At this point, chikungunya had evolved into three separate strains—the original in Africa, the earlier Ae. aegypti transmitted strain that traveled to Asia, and E1-226V, the newest variant that can be carried by the Asian tiger mosquito.

“The protein that replicates the genetic material in chikungunya isn’t very accurate, which means there are lots of mistakes and mutations. If one of these mutations provides an advantage, it can easily sweep through the population,” Schwartz says. Which is exactly what happened on La Reunión.

Eye of the Tiger

The Asian tiger mosquito has raised serious public health concerns in recent years. Nicknamed the “Asian tiger” both for its striped appearance and its ferocious bite, the mosquito began its own travels in the 1980s. Trade in used tires and bamboo plants transported the Asian tiger mosquito from its native home in Southeast Asia to North America, Europe, Australia, and elsewhere by the late 1990s.

Since the Asian tiger mosquito can live in climates where the tropical Ae. aegypti would freeze, it brings the prospect of tropical diseases to more temperate climates, Weaver says. Diseases that were once limited to equatorial regions could now spread throughout North America and Europe. Chikungunya was among the first to come knocking.

After burning through La Reunión, chikungunya continued its trek eastward, landing next in India. Then the virus veered off its expected path and headed for Italy. It didn’t take much for that to happen, Schwartz says. “Scientists traced it back to just one person.”

Chikungunya had hitchhiked aboard an older man visiting India from his home in a small town on Italy’s Adriatic coast. In June 2007, he began to feel feverish, achy, and tired. Later that month, he stopped at his cousin’s house in the neighboring town of Castiglione di Cervia. While there, the man was bitten by an Asian tiger mosquito. That same mosquito seems to have bitten his cousin, too, because on July 4, his cousin reported similar symptoms. It started with one bite from one mosquito, but it was enough.

Soon, more people around Castiglione began reporting symptoms similar to the traveler’s: fever, rash, and extreme joint pain. Public health officials first suspected dengue, which has nearly identical symptoms and is also transmitted by mosquito. When dengue tests came back negative, epidemiologists widened their search for what was causing this mysterious outbreak. Their tests revealed it was chikungunya. In three months, over 200 people were infected with the virus. One man reported he was in such pain that he couldn’t even sit up for more than a month. Without any drugs to help fight chikungunya infections, doctors could only tell their patients to get plenty of rest, drink lots of fluids, and take pain relievers and fever reducers as needed. The outbreak only stopped after aggressive mosquito control measures by the Italian government.

The appearance of a sustained chikungunya outbreak set the world’s health organizations on edge. The United States was especially worried. The Asian tiger mosquito’s rapidly expanding range currently spans the southern half of the continental U.S., and the West Nile Virus outbreaks of 2001 and 2002 revealed just how disruptive a mosquito-borne virus could be.

At the Gates

In the immediate aftermath of the Italy outbreak, however, chikungunya remained in the Eastern Hemisphere. A few cases popped up in southeastern France, but the virus remained mostly confined to Asia. Chikungunya swept through India, sickening millions throughout 2006 and 2007. It also spread to other parts of the continent, including Malaysia, Indonesia, Singapore, and the Philippines.

Although some of these cases were clearly caused by the E1-226V strain, it’s also likely that the older, Asian strain of the virus was also actively circulating. Epidemiologists had missed ongoing chikungunya transmission because it wasn’t causing any major outbreaks, and, without advanced medical testing, chikungunya is often difficult to distinguish from dengue. With all eyes on the more established dengue, the transmission of chikungunya was largely ignored.

“Some of these strains have been circulating for years, we just didn’t notice that they were there,” says Powers, the arborovirus chief at the CDC. “Only once we became aware of the other outbreaks did we think to start looking.”

From a clinical standpoint, identifying the different strains of chikungunya is an academic exercise. The symptoms of the two present the same symptoms. But from a public health perspective, knowing which strain you’re dealing with is extremely important. Each has peculiarities which can affect their transmission—the African strain has shown a predilection for mutation, the strain that made it to Asia in the 1960s is much less adaptable, and the recent E1-226V strain opened up Asian tiger mosquitoes as a vector. Knowing which one is responsible helps epidemiologists predict when and where chikungunya could pop up next.

To predict the virus’s next steps, Cassadou and other epidemiologists in the Caribbean and the Western Hemisphere are carefully examining the genome of the strain of chikungunya that had recently arrived on St. Martin. Preliminary sequencing data reported on Pro-MED Mail, a worldwide electronic reporting system for infectious diseases, indicated that the Asian strain of virus is responsible for the Caribbean outbreak, not E1-226V.

Powers says the strain in the Caribbean most closely matches samples of chikungunya isolated in China and on the island of Yap in Micronesia. How the virus made the long trans-Pacific voyage is unclear, as none of the initial victims on St. Martin had any history of travel to areas with known chikungunya outbreaks. Cassadou says it still isn’t clear whether another traveler with milder symptoms might have brought the virus into the country, or whether the virus was transported by an infected mosquito.

Regardless of how the virus arrived in the Caribbean, chikungunya has gone about island-hopping like any bona fide tourist and has made itself right at home. The trickle of cases that Cassadou initially saw in her Guadaloupe office has become a flood. The outbreak is looking like it might have the same destructive potential as the one on La Reunión, where nearly one-third of the population was sickened. “We don’t know how far this outbreak will spread or how many people it will affect,” Schwartz says.

“We have the right mosquito here, and no one is immune to chikungunya,” Cassadou says. “These are the factors that can create a big epidemic.”

Future Travel

With chikungunya’s propensity for travel, Powers and other epidemiologists have begun identifying areas where the restless virus might arrive next. With flights crisscrossing the Caribbean on their way to North, Central, and South America, it seems almost certain that chikungunya won’t be contained to a few islands for long. Several cases have already been reported in French Guiana on the South American mainland.

“We expect that this outbreak will spread to more hard-core urban areas that also have problems with dengue,” says Weaver, the UTMB arbovirus expert. “For all we know, the virus might already be there, only it’s being confused with dengue and no one’s doing the right testing to identify it.”

The virus’ potential spread to North America is less certain. If the Asian strain of the virus is responsible for the cases currently being reported in the Caribbean, as preliminary evidence suggests, the United States may have dodged a bullet. The Asian strain relies on Ae. aegypti, which is only lives in the Southeast. That would greatly limit the potential for an American outbreak. But if E1-226V arrives on U.S. shores, it could be a very different story. The strain can be carried by the Asian tiger mosquito, which lives as far north as southern New England.

Entomologists at Cornell University and Colorado State University recently calculated the likelihood of a chikungunya outbreak in the U.S., assuming the E1-226V strain pops up in one of three American cities: New York, Atlanta, and Miami. Since the Asian tiger mosquito is prominent in all three, arrival of the virus has the potential to spark an epidemic in any of these locations, the researchers concluded in an article in PLoS Neglected Tropical Diseases. Chikungunya outbreaks are most likely in New York during the height of summer when mosquitos are active and biting. Atlanta’s warmer climate lengthens the risk period, while Miami is balmy enough that mosquitoes can generally bite year-round, making an epidemic possible at any time.

“All we need is one tourist arriving with virus in their blood to be bitten by a mosquito. If the right circumstances are present, that could start an outbreak,” says Kenneth Olson, a professor of virology at Colorado State University.

If the E1-226V strain does come to the U.S., Weaver expects that the epidemic will look similar to West Nile Virus: an explosion of cases as the virus sweeps across the nation, followed by ongoing, low-level transmission. It’s what happened on La Reunión, and what Weaver thinks will happen in the Caribbean and possibly the U.S. “I think that chikungunya is here to stay,” he says.

The CDC has reported several cases of chikungunya imported after American tourists returned home, but so far, no sustained transmission of the virus has occurred. Weaver doesn’t expect that luck to last forever, though. With no vaccine available, immunity to chikungunya can only occur by becoming infected. “The introduction of chikungunya to the U.S. is probably inevitable, and virtually everyone is susceptible.”