by The Pandemic Century- One Hundred Years of Panic, Hysteria
However, for all that van der Linden was concerned, the twin was just one of hundreds of children delivered in Recife hospitals every month. Then, two weeks later, while doing her usual maternity rounds, she came across three more babies with microcephaly, and the following week two more. At a loss to explain the pattern of neurological damage, she shared her concern with her mother, Ana van der Linden, also a pediatrician. “Hà algo errado,” she told her. “There is something very wrong.” Her mother agreed, informing her that she had seen seven similar cases. Soon, the van der Lindens had identified fifteen cases in hospitals in Recife. In a normal year, physicians in Pernambuco might see five cases across the whole state. It could not be a coincidence.
The van der Lindens immediately informed the Pernambuco Health Department and asked them to check for reports of other cases of neurological malformations in newborns. In all, fifty-eight had been registered in hospitals across the state, most of them within the space of four weeks. In addition to rubella, syphilis, and toxoplasmosis, tests had been run for cytomegalovirus, HIV, and parvovirus, but they had all been negative. At a loss to explain the pattern, the Pernambuco Health Department did the only thing it could: it called a disease detective, Carlos Brito.
A slim man with wiry hair, Brito is constantly in motion. Trained as an infectious disease clinician, he seems never happier than when parsing epidemiological data or tapping furiously at his laptop. Brito’s first experience of outbreak control came in 1991 when Brazil’s Ministry of Health invited him to draw up diagnostic guidelines for physicians during a cholera epidemic. Since then he has consulted on several outbreaks in Brazil including, most notably, those caused by the arboviruses dengue and chikungunya, and he works closely with the Osvaldo Cruz Foundation (Fiocruz), Brazil’s premier public health and medical research organization. In August 2014, shortly after the FIFA World Cup final, Brito was summoned to Bahia, a state adjacent to Pernambuco famed for its coconut-fringed beaches and agreeable climate. A few weeks earlier an epidemic of chikungunya had broken out in Feira de Santana, a city sixty miles north of Salvador, Bahia’s populous capital. The Ministry of Health was concerned that physicians needed better guidelines to help them diagnose and recognize the mosquito-borne disease. As it turned out, this experience would make Brito the ideal person to investigate the mysterious cases of microcephaly in Pernambuco two years later.
ARBOVIRUSES (short for arthropod-borne viruses) are endemic to South America. The deadliest arbovirus, yellow fever, was most likely introduced to Brazil in the late seventeenth century when slave ships from West Africa began arriving at Recife and other coastal ports with slave laborers for the sugar plantations. Those ships also brought the Aedes aegypti mosquito, the main vector of yellow fever, dengue, and chikungunya. A small, dark mosquito with white lyre-shaped markings and banded legs, A. aegypti is extremely common in areas lacking regular public water services and adequate sanitation systems. Virtually eradicated from Brazil in the 1950s with DDT and other pesticides, in the 1970s the mosquito launched a comeback, gradually colonizing Brazil’s fast-growing cities and, in particular, urban slums and favelas. The result is that today A. aegypti is ubiquitous in Recife and other Brazilian cities, and in far greater densities than in the past.
The mosquito prefers to lay its eggs in fresh water (during the slave trade, the Aedes larvae would have bred in the casks of drinking water kept below decks, next to the slaves whose chains made them sitting targets for the mature mosquitoes). Ideally, Aedes looks for a shady uncovered container with a wide opening, but it is not fussy and its larvae have been found in everything from flowerpots to water bowls, to car tires and discarded plastic bottles. While the male mosquitoes feed exclusively on nectar, the females need blood to produce their eggs and are extremely active in the two hours after sunrise and at dusk. Their preferred mode of attack is to sneak up from behind and insert their sharply pointed proboscises into ankles or elbows, though knees will also do. The bad news is that one bite is usually sufficient to transmit whatever virus the mosquito happens to be harboring. Unlike other types of mosquitoes, such as Culex, Aedes is also a “sip” feeder, meaning it likes to bite again and again. But perhaps Aedes’s most important characteristic is that it is a house-haunting mosquito that seldom leaves any dwelling where it has once fed.
Yellow fever is the most feared virus transmitted by A. aegypti. Though most people will experience little more than a mild headache, fever, and nausea, in something like one-fifth of cases patients enter a highly toxic phase with ghastly symptoms characterized by high fever, severe jaundice (hence its name “yellow fever”), bleeding from the mouth and gums, and the retching of black vomit (“vomito negro” in Spanish) due to the hemorrhaging of the stomach lining. In such cases, the disease is nearly always fatal. The good news is that there is a vaccine against yellow fever and one shot offers protection for life. This is not the case with dengue, a painful and debilitating disease caused by one of four closely related serotypes, or chikungunya. For both diseases there are, as yet, no vaccines approved for general use, nor are there any cures.
In the case of dengue, symptoms usually appear three to seven days after infection. Most patients experience a high fever, intense headaches, and severe joint and muscle pains. It can feel as if someone has taken a sledgehammer to your arms, legs, and neck; hence the common name for the disease, “breakbone fever.” Sometimes, patients will also develop a rash on the face and limbs two to five days after the onset of fever. After a period of four to seven weeks of illness, most patients will recover. However, some may go on to develop dengue hemorrhagic fever, a rare complication characterized by high fever, bleeding from the nose and gums, and failure of the circulatory system. In the worst cases of all, these symptoms may terminate in massive internal hemorrhaging, shock, and death.
The symptoms of chikungunya are almost identical, the main difference being that the virus is very rarely fatal and has a longer incubation period (one to twelve days). In addition, the characteristic rash of the disease usually appears within forty-eight hours of the onset of symptoms, and can be found practically anywhere on the body (the trunk, limbs, face, palms, or feet). Whereas with dengue the pains tend to be muscular, with chikungunya the pain is located in the joints and there may be noticeable swelling or edema in the morning. These joint pains may become chronic, particularly in the case of the elderly or those with underlying medical conditions.
Dengue has been a recurrent problem in Brazil since 1981, when an epidemic broke out unexpectedly in the state of Roraima. In 1986, and again in 1990, there were significant outbreaks in Rio de Janeiro, and by 2002 dengue was being reported in sixteen states, including in São Paolo, the most populous city in the Americas. Since 2008, when Brazil recorded 734,000 suspected cases and 225 deaths, and 2010, when cases exceeded one million for the first time, these epidemics have been growing in severity. Most worrying of all, there is now active circulation of all four serotypes with outbreaks of one or sometimes two or more dengue serotypes simultaneously every two to three years (while patients infected with one serotype enjoy lifelong immunity, cross-immunity to other serotypes is partial and temporary, and subsequent infections with other serotypes increase the risk of the hemorrhagic form of the disease). Little wonder then that the Pan American Health Organization (PAHO) has made the control of dengue a regional priority and that the WHO has been urging the uptake of an experimental vaccine developed by Sanofi Pasteur in areas of endemic transmission.
It was against this background of growing concern about dengue and the spread of arboviruses generally, that Brito was dispatched to Bahia to take stock of the chikungunya outbreak in Feira de Santana. There he was introduced to another physician, Kleber Luz, who specialized in arbovirus infections. Based in Natal, the state capital of Rio Grande de Norte, two hundred miles north of Recife, Luz had recently returned from Martinique, the site of a recent large chikungunya outbreak, so was well versed in differential diagnosis of the disease—the pro
cess of distinguishing a disease or condition from one with which it shares similar signs or symptoms. By the end of September, Feira de Santana had seen more than 4,000 cases, and Luz feared that chikungunya was primed to spread to neighboring states and cities, including Natal (chikungunya would eventually spark 20,000 infections across Brazil in 2015). However, when patients began turning up at clinics in Natal complaining of fever, rashes, and itchy red eyes the following January, Luz decided their symptoms did not fit either chikungunya or dengue, and shared his concerns with Brito. “These patients had mild fevers, but with dengue the fever is usually very high,” Brito explained. “About forty percent of the patients complained of joint pains, but unlike with chikungunya the pains were not severe. By contrast, there was a very high frequency of rashes, something you see infrequently in dengue and which is not all that important in chikungunya.” It was at this point that Brito and Luz made a crucial decision. Rather than writing a report and waiting for it to be circulated to interested parties, they decided to make use of the social messaging service, WhatsApp, so that they could share their thoughts instantly with other like-minded physicians. Inspired by the example of the early Jesuit missionaries to Brazil, they named their WhatsApp group, “Chikungunya: The Mission.”
By now similar cases were appearing in Recife. Then in March came reports of further outbreaks in Salvador and Fortaleza, another city in the northeast, prompting journalists to begin talking about the “doença exantemática misteriosa”—the “mysterious disease with a rash.” Frantically, Luz and Brito began searching the medical literature for clues. Eventually, in the medical textbook Fields Virology, under the section on arboviruses, Luz found a brief report of a virus whose symptoms seemed to fit the pattern of illness he had observed in patients in Natal. The virus was called Zika and had last been associated with an outbreak in 2013 in French Polynesia in the South Pacific, five thousand miles from the coast of Chile. As in Natal, patients presented with a mild fever, an itchy pink rash, bloodshot eyes, headaches, and joint pains. In all, 18 percent of the population of French Polynesia had been affected, but no one had died and the outbreak had been rapidly forgotten. Could this be the mysterious disease?
With growing conviction, Luz sent Brito a message on WhatsApp. It read: “Isso deve sere Zika virus. Veja. Aqui esta todo munde doente . . . vai ter que dar Zika virus.” (“This must be Zika virus. Look. Here everyone is sick . . . it can only be Zika virus”). The date stamp read 21:19 on March 28, 2015. Brito, who admits he had never heard of Zika, recalls the moment clearly as he was in a restaurant having dinner with his family at the time and immediately typed “Zika” into a search engine, coming up with several references to the outbreak in French Polynesia, as well as another smaller outbreak that had occurred in Micronesia in 2007. Although Micronesia is in the western Pacific and even further from South America than French Polynesia, Brito was intrigued. “I will begin working on it first thing tomorrow,” he replied, toasting Luz with a glass of wine.
Brito was not the only person who had never heard of Zika. Except for a handful of arbovirus experts, no one had. Rarely diagnosed, most Zika infections are mild and even fewer require hospitalization. Certainly, in the seventy years since the first description of the virus, no one had recorded a fatality from the disease. Worse, Zika lacked a reliable animal model. The only way to study the virus’s properties was to passage it repeatedly through mice specially adapted for the purpose, but in so doing the risk was that the virus would cease to bear much resemblance to the pathogen seen in nature. In short, as the New York Times’s Science correspondent Donald McNeil put it: “In the hunt for research funding, a virologist specializing in Zika would struggle to get grants.”
Indeed, as he delved into Zika’s history, it became apparent to Brito that knowledge of Zika was largely a by-product of historical research into yellow fever and laboratory studies that focused on the Aedes mosquito. In 1942 Alexander Haddow, a Scottish-educated zoologist with an interest in mosquito-borne diseases, had moved to Africa to work as an entomologist at the Rockefeller Foundation’s Yellow Fever Research Institute in Entebbe, Uganda (now the Uganda Virus Research Institute). There, he teamed up with another Rockefeller researcher, Stuart F. Kitchen, and George W. A. Dick from the UK’s National Institute for Medical Research, and began looking for a suitable site to trap mosquitoes. They found it in the Zika forest, a swampy inlet of Lake Victoria adjacent to the Entebbe-Kampala highway which was home to several species of Aedes, including A. africanus, the vector of yellow fever in Uganda. Placing traps on steel towers that rose forty meters above the forest floor, they began by measuring the density of mosquitoes at different levels of the tree canopy and the times they were most active. Next, they placed monkeys in cages at the elevations where they knew there were a lot of Aedes and allowed them to be bitten repeatedly. Afterwards, they checked the monkeys’ temperatures and, if they were sick, took a blood sample to see whether they were infected with yellow fever or some other virus. It was from one of these monkeys that, in April 1947, Haddow and his colleagues succeeded in isolating the Zika virus for the first time. Nine months later, they also isolated the virus from an A. africanus mosquito, though it would take five more years for them to prove that mosquito and monkey were infected with one and the same virus and that it had an affinity for nerve tissue.
Today Zika is classified as a flavivirus, from flavus, the Latin word for yellow (in the case of Zika the name is somewhat misleading as, unlike yellow fever, the virus rarely causes jaundice). Under an electron microscope both viruses look like twenty-sided polygons called icosahedrons, each containing a single strand of RNA. It is these strands that invade and hijack the machinery of animal cells, including human cells, and cause the characteristic symptoms of Zika: a raised red rash, headache, conjunctivitis, and myalgia.
In the 1950s, following reports of the first human infections, several researchers tried to show that A. africanus was not the only vector, but that A. aegypti, which thrives in urban environments, could also transmit the virus (they did this by infecting themselves with Zika and allowing A. aegypti to bite them on the arm repeatedly, something that would not be permitted by university ethics committees today). However, the experiments proved unsuccessful, and it was not until 1966 that the virus was isolated from A. aegypti for the first time. That this occurred in Malaysia, not Africa, should have rung alarm bells, indicating that the virus was on the move and might be capable of infecting people in urban areas. Indeed, by the early 1980s Zika had spread to India and other parts of equatorial Asia and was being reported as far west as Indonesia. However, since cases requiring medical attention were rare and seroprevalence studies showed there was wide population exposure, there was little concern. In retrospect, researchers suspect that the fact that just sixteen human Zika infections were recorded between 1947 and 2007 probably resulted from underreporting due to the disease’s similarity to dengue and chikungunya, and because 80 percent of people infected with Zika never develop symptoms and so do not seek medical attention.*
The first outbreak to make an impression on doctors and public health professionals came in 2007 when five hundred Yap islanders suddenly fell ill. At first the outbreak was mistaken for mild dengue, but when the CDC sent samples to the United States for testing, they turned out to be positive for Zika. This was a shock, as Yap is a long way from Africa and there were no monkeys present on the island. In theory, the virus could have been introduced by windblown mosquitoes from Indonesia. However, it is far more likely the virus was carried to Yap in the blood of an infected patient or by an Aedes mosquito that hitched a ride on a ship. Whatever the source, within five months more than two-thirds of the island’s 7,000 residents were infected.†
The next significant outbreak occurred in 2013 when physicians on Tahiti and other islands in French Polynesia reported an “eruption” of fevers, rashes, and bloodshot eyes. At first the French suspected dengue, but by the end of October half of the samples had tested
positive for Zika, and by December cases were being reported on all seventy-six islands that comprise the archipelago. In addition, patients began arriving at emergency rooms in varying degrees of paralysis, something that had not been noted or reported in previous Zika outbreaks. The cause of the paralysis was Guillain-Barré syndrome, a rare autoimmune condition that in the most extreme cases can result in permanent nerve and muscle damage and even death if the paralysis extends to the diaphragm. As fears of Guillain-Barré spread and the government stepped up mosquito spraying, rumors began to circulate that the insecticide, deltamethrin, was responsible. By the time the outbreak concluded the following April, 8,750 people had fallen sick and forty-two had been diagnosed with Guillain-Barré. Fortunately, most of these cases resolved with time, but if the world needed another wake-up call that Zika deserved to be taken seriously, this was it. That is not what happened, however. Instead, as Zika continued its westerly spread across the Pacific, reaching New Caledonia in March 2014 and Rapa Nui (Easter Island), a territory of Chile, soon after, the world’s attention was seized by a far more visible emerging disease threat: the Ebola outbreak in West Africa. The result was that when at some point in 2014 Zika arrived in Brazil, no one noticed.