One year into the Zika outbreak: how an obscure disease became a global health emergency
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A "mild" illness takes off
In early February 2015, doctors in the impoverished northeastern part of Brazil noticed a surge in the number of people complaining about a mild illness, with and without fever, characterized by rash, fatigue, joint pains, and red eyes. The illness was brief and recovery was spontaneous. A mild form of dengue, a mosquito-borne disease hyperendemic throughout the country, was initially suspected, but tests were negative in the vast majority of samples. Chikungunya, another mosquito-borne disease first detected in Africa in 1952, had hopped to Brazil in September 2014 and was likewise suspected. Again, tests results were negative.
At the end of March, Brazil informed WHO that nearly 7,000 cases of an illness characterized by skin rash had been reported in six northeastern states. Laboratories had performed a battery of tests on more than 400 blood samples. 13% of the samples were positive for dengue, but negative for several other viruses known to cause skin rash. The causative agent remained elusive.
The first promising clue came in late April from a laboratory in Bahia State where researchers began to suspect that the disease might be spread by the area’s ubiquitous and dense mosquito population. On a long shot, they tested for Zika, an exotic and poorly understood virus, carried by mosquitoes, that had never been seen in the Americas. Though the results were positive, doubts remained. Testing for Zika is technically challenging as the virus cross-reacts immunologically with dengue and chikungunya viruses, both present in Brazil at that time.
A week later, on 7 May, tests conducted at Brazil’s national reference laboratory conclusively identified Zika in several samples. A new mosquito-borne disease had indeed arrived in the Americas, though no one knew what that might mean.
Mixed reviews
The finding was startling, yet difficult to interpret. The appearance of a virus in a new geographical area is always cause for concern, as the population will have no pre-existing immunity to slow the virus down. Spread can be explosive, quickly flooding health services with the sick and the worried well. As another concern, viruses in the same flavivirus family as Zika are known to undergo small genetic changes as they sweep through a vulnerable population that help them acquire epidemic potential. Though the changes are small and their significance is poorly understood, epidemic strains can deliver surprises as an outbreak evolves, sometimes behaving in previously unexpected ways.
On balance, though, the long history of Zika virus disease was reassuring. The virus was first detected in 1947 in a sentinel monkey, identified as Rhesus 776, in Uganda’s Zika forest as part of a research project on jungle yellow fever. Over the next six decades, only 14 naturally occurring human cases were identified, by virus isolation, worldwide, all in a narrow equatorial band stretching across Africa and Asia [table 1]. Two additional cases were reported: one in a European volunteer who was experimentally infected in Nigeria and a second in a laboratory worker in Portugal. All illnesses were mild and brief, followed by full and uneventful recovery.
A small group of dedicated scientists continued to conduct Zika experiments aimed at assessing the potential risk to the African people and, possibly, to the world at large. As far back as 1952, they speculated that Zika and other newly discovered African viruses might have effects on the central nervous system or produce congenital changes in the foetus if pregnant women were infected. But that was pure speculation. For all practical purposes, Zika looked like a medical curiosity that posed little, if any, threat to public health.
In Africa, researchers believed that transmission was largely confined to jungles and forests where canopy-dwelling mosquitoes preferred to draw their blood meals from monkeys. Human infections were incidental to this dominant transmission pattern. If the virus had any epidemic potential whatsoever, no one noticed.
The first outbreaks
After six decades of apparent slumber, the virus broke out of oblivion in 2007 when it caused its first outbreak on Yap Island in the Federated States of Micronesia. The outbreak was surprising, but ultimately reassuring. Although an estimated 5,000 people were infected, representing more than 70% of the island’s tiny population, no one was hospitalized and no one died. The outbreak was brief, lasting just three months. At that time, researchers speculated that a new virus strain, with greater fitness and epidemic potential, had likely emerged, as happened with the related dengue virus when it hopped among the Pacific Islands during the 1970s.
The next surprise was more ominous. Having demonstrated its ability to spark an outbreak, Zika did so again in French Polynesia from 2013-2014, causing an estimated 30,000 infections. During and after the outbreak, the virus spread to an additional seven island nations, though the outbreaks were much smaller. Again, no deaths were reported, but the disease had established a strong foothold in the Pacific and no longer looked so harmless.
As the outbreak in French Polynesia evolved, doctors began seeing usually rare neurological complications, including 42 cases of Guillain-Barré syndrome, a severe neurological disorder that required long hospital stays for several patients, with 12 needing respiratory assistance. For the 16 patients admitted to intensive care, the median duration of hospital stay was 51 days. Three months after hospital discharge, only 24 patients (57%) were able to walk without assistance. If Zika was indeed linked to the syndrome, the burden on health services would be considerable.
The number of cases of the syndrome was striking, representing a 20-fold increase over previous years. But the concomitant presence of dengue, which had been previously linked to the syndrome, precluded any firm conclusions about a causative role for Zika. Nonetheless, the possible association with neurological complications changed the image of Zika from a benign disease to one with more sinister potential.
Some virologists argued that a more virulent strain of the virus emerged as the outbreak swept through French Polynesia. Others were more sceptical: since Guillain-Barré syndrome was so rare, an outbreak with a large number of cases was needed to detect it. In their view, it was the numbers, and not an altered virus, that explained the presumed association of Zika with neurological complications.
The virus reaches Brazil
The virus was almost certainly brought to Brazil by a traveller from French Polynesia, as molecular studies showed that viruses from the two countries were virtually identical, and clearly from the Asian, not the African, lineage. Researchers looking at flight patterns initially suspected that the 2014 World Cup soccer competition, held in Brazil from June to July 2014, was the seminal event, but no teams from countries with a Zika outbreak attended that event. Researchers now believe the virus was introduced during the August 2014 World Sprint Championship canoe race, held in Rio de Janeiro, which attracted participants from four Pacific Island nations, including French Polynesia, with active Zika transmission.
Retrospective investigations show that the virus was already causing illness in the northeastern part of Brazil near the end of 2014. Cases were retrospectively identified in Rio de Janeiro as early as January 2015. Research published in late April 2016 indicates that Zika was causing cases in Haiti as early as December 2014, though the outbreak was not detected and reported until January 2016. Comparisons of viruses suggest that the virus from French Polynesia first stopped on Easter Island before entering the Americas.
Once established in Brazil, Zika spread explosively within the country and then throughout Latin America and the Caribbean. Within a year, the virus had been detected in nearly every country or territory infested with Aedes aegypti, the principal mosquito species that transmits Zika, dengue, and chikungunya. Two factors favoured explosive spread: the lack of population immunity and the behaviour of the mosquito.
Ae. aegypti is the ultimate “citified” mosquito, having adapted to thrive in tropical areas that have undergone rapid, sprawling urban growth. The mosquitos flourish in the litter, open ditches, clogged drains, containers for water storage, old tyre dumps, and crowded flimsy dwellings typically seen in urban and periurban areas where population growth has outstripped the capacity to construct essential infrastructure, like piped water and sanitation.
Ae. aegypti mosquitoes are exquisitely adapted to city life. They like humans best, live with people in their homes, bite aggressively during the day, don’t mind stagnant water, and prefer to breed in artificial containers. Even something as small as a bottle cap or a discarded plastic wrapper will do.
Fondly known to some entomologists as the “gothic cockroaches” of the mosquito world, these mosquitoes are attracted to black things, like suitcases piled on closets or used tyres dumped in vacant lots. Inside homes, they hide in shadowy places, inside closets, under beds, and beneath sinks. They can breed in toilet tanks, flower vases, and water dishes for pets. The difficulty of their control makes the diseases they spread, including Zika, a much larger menace.
The virus, in its first run through the Americas, profited greatly from the demise of the massive mosquito control programmes of the 1940s and 1950s that virtually eliminated yellow fever from the western hemisphere. As so often happens in public health, when a disease subsides the control programme dies. In addition, options for control shrank dramatically as more and more mainstay insecticides were rendered useless as mosquitoes developed resistance.
The outbreak in Brazil also carried a high risk of exported cases, with around 10 million travellers departing each year for international destinations. Although several hundred imported cases have been reported worldwide, none is known to have sparked an outbreak. This is likely more a matter of luck than evidence of little potential for spread, as most cases were exported to countries during a season of no or low mosquito activity.
A dramatic new profile for a “harmless” old disease
In mid-July 2015, Brazil informed WHO of an uptick in the detection of neurological disorders, including Guillain-Barré syndrome, mainly from the northeastern state of Bahia, an early epicentre of Zika virus transmission. That finding was later repeated in other countries with large outbreaks, including Colombia, Dominican Republic, El Salvador, Honduras, Suriname, and Venezuela. In most of these countries, the syndrome was detected about three months after virus circulation was confirmed. A link with Zika was strongly suspected.
The most riveting news emerged at the end of October 2015, when Brazil informed WHO that 54 cases of microcephaly among newborns had been detected since August. The possibility that a mosquito bite during pregnancy could be linked to severe brain abnormalities in newborns alarmed the public and astonished scientists. Though evidence was scant, paediatric neurologists in Brazil were convinced that the brain abnormalities were linked to Zika. Subsequent findings would prove them right.
The detection of microcephaly in Brazil prompted a retrospective investigation of the outbreak in French Polynesia. The results, communicated to WHO in November 2015, identified at least 17 newborns with different severe brain malformations, including microcephaly and neonatal brainstem dysfunction.
In late January 2016, a second report from French Polynesia informed WHO that further research had now convincingly linked Zika to the surge in cases of Guillain-Barré syndrome.
On 1 February 2016, WHO declared that the association between Zika and the cluster of microcephaly cases and other neurologic disorders reported in Brazil, following a similar cluster in French Polynesia, constituted a Public Health Emergency of International Concern.
A flurry of studies followed, as newborns, miscarriages, and stillbirths with brain abnormalities and their mothers were investigated. Zika was detected in amniotic fluid, the placenta, the umbilical cord, fetal blood, and fetal brain tissue. In one case of severe brain malformations, live Zika virus was cultured from fetal brain tissue.
Many of these studies excluded co-infection with dengue and chikungunya and eliminated other known infectious causes of microcephaly, strengthening the evidence of causality. Further evidence came from laboratory studies demonstrating that Zika is neurotropic, meaning that it preferentially affects brain cells.
Some of the foetuses studied were consistent with the so-called “fetal brain disruption sequence”, an extreme form of microcephaly in which the fetal brain stops growing, the skull partially collapses, and excess scalp skin shows distinctive folds. The concept of a “congenital Zika syndrome” emerged as a typical pattern including severe microcephaly, brain calcifications, and other brain anomalies, sometimes accompanied by impaired eyesight and hearing loss.
In children and adults, the full spectrum of effects on the central nervous system is likely yet to be discovered, as hinted by case reports of inflammation of the spinal cord, and cases consistent with a syndrome involving inflammation of the spinal cord and brain that resembles multiple sclerosis. For newborns, many experts believe that a virus capable of causing such severe abnormalities is likely to cause additional neurological problems as children develop.
Based on these and other studies, WHO concluded at the end of March 2016 that there is scientific consensus that Zika virus is a cause of microcephaly and Guillain-Barré syndrome. At that time, cases of microcephaly had been reported in Brazil, Cabo Verde, Colombia, Martinique, and Panama as well as French Polynesia.
A subsequent paper by scientists from the US Centers for Disease Control and Prevention, published in April 2016 in the New England Journal of Medicine, put to rest remaining doubts about the causal association between Zika infection during pregnancy and microcephaly in newborns.
Ill-prepared to cope
The emergence of Zika in the Americas surprised a world that was ill-prepared to cope, especially with the heart-breaking neurological abnormalities in newborns. With no vaccines, clinicians can offer women of child-bearing age little protection beyond advice to avoid mosquito bites, delay pregnancy, or refrain from travel to areas with ongoing transmission.
Concerned pregnant women also get little reassurance. Apart from impeding disease investigations, the lack of reliable and widely available diagnostic tests means that pregnant women possibly exposed to Zika are left to worry about the consequences for their unborn babies, especially since ultrasound can detect brain abnormalities only in the third trimester of pregnancy.
The fact that sexual transmission of Zika is more common than previously thought further complicates advice to couples planning their families. During the first year of the outbreak, sexual transmission was documented in nine countries: Argentina, Canada, Chile, France, Italy, New Zealand, Peru, Portugal, and the United States of America.
Few countries in the outbreak zone offer universal access to sexual and family planning services. According to a recent study, countries in Latin America and the Caribbean have the highest proportion, at 56%, of unintended pregnancies anywhere in the world.
In Brazil, many women giving birth to babies with microcephaly are young and poor. In a rich country, like the US, the costs of caring for a single child with microcephaly have been estimated to be as high as $10 million. In a poor country, the burden of care will largely fall on mothers, who may have to give up salaried work or have difficulty finding the time and the transportation to access support from health and social services.
The burden of Zika falls on the poor for other reasons as well. In tropical cities throughout the developing world, the poor cannot afford air-conditioning, window screens, or even insect repellents. With no piped water and poor sanitation, they are forced to store water in containers, providing ideal conditions for the proliferation of mosquitoes.
Perhaps the greatest failure of coping capacity comes from the complacency that set in after the spectacularly successful mosquito control campaigns in the 1940s and 1950s. During the 1960s, with yellow fever vanquished, funding for mosquito control dried up, control programmes were largely dismantled, and entomologists vanished. The response to the infectious disease threat shifted from building basic public health infrastructures and capacities for prevention as the first line of defence to the use of surveillance to pick up early signals of an outbreak and then mount an emergency response.
The weaknesses of such a stop-gap approach have been demonstrated by the dramatic resurgence of dengue, the recent emergence of chikungunya as a significant threat to health, the delayed detection and subsequent exponential spread of Ebola in West Africa, and this year’s return of urban yellow fever to Africa. Zika seems destined to make these weaknesses even more explicit.
The burning question: are populations in Africa and Asia protected by immunity?
Although the re-profiling of Zika from a benign disease to a global health emergency stimulated a flurry of research, the disease remains poorly understood at levels ranging from its virology and epidemiology to the clinical spectrum of complications it can cause. No one can answer questions about further international spread with certainty, though theories abound.
As the virus has been detected in parts of Asia and Africa for several decades, some level of endemicity is assumed, though no one knows whether presence of the virus over time has resulted in widespread or low-level immune protection or possibly no protection at all.
In Africa, the ancestral transmission pattern is a sylvatic cycle, involving mosquitoes in forest canopies that preferentially feed on monkeys. This pattern may have historically restricted human cases to very small numbers, or cases may simply have been missed during low levels of “silent” transmission. The vast majority of Zika infections produce no symptoms at all. When symptoms do occur, they are mild and mimic those seen in dozens of other viral infections common in the tropics.
Moreover, microcephaly and Guillain-Barré syndrome are low-frequency events that are easily missed. In Asia and Africa, surveillance systems set up to detect polio-associated paralysis might pick up some cases of GBS, but this surveillance is geared towards detection in young children whereas GBS tends to affect older adults.
Other researchers, pointing to differences in the African and Asian lineages of the virus, note that the African lineage has never been known to cause an outbreak. The outbreak in Cabo Verde, which began in October 2015 and caused more than 7,000 cases, remains a puzzle. Sampling and transportation problems have delayed sequencing of the virus.
Health officials in Cabo Verde believe the virus might be of the Asia lineage, given the country’s strong travel ties with Brazil where viruses from the Asian lineage are circulating. As an alternative theory, viruses from both lineages may have circulated during the outbreak. Of note, no cases of Guillain-Barré syndrome have been detected despite dedicated surveillance; two cases of microcephaly have been confirmed.
Some experts speculate about what might happen if the recently emerged epidemic strains of the Asian lineage begin to spread in the sprawling cities of tropical Africa and Asia, with their dense populations of people and mosquitoes and flimsy infrastructures. Others believe that infection with viruses from one lineage might provide at least some protection against infection with viruses from the other, but no one knows for sure.
Still others use statistical vulnerability to assess the theoretical threat: more than half the world’s population lives in areas infested with Ae. aegypti. In any event, research is now rapidly filling in the gaps left during the many decades when Zika looked like a harmless disease, unworthy of much attention.
Evidence suggesting at least some level of immune protection comes from two sources: older surveys that detected Zika antibodies in blood samples and recent case reports of travellers infected with Zika while visiting a country with no documented ongoing virus transmission.
Numerous surveys, conducted in Africa and Asia in the 1950s and 1960s, detected Zika antibodies in blood samples. However, the results need to be interpreted with caution, as the researchers used different detection methods with varying degrees of specificity. As researchers themselves noted at the time, the finding of antibody to a given virus in a single blood sample from a donor is not conclusive proof of either infection or protective immunity.
Because of immunological cross-reactions among related viruses, studies thought to have detected Zika may have detected antibodies to dengue or another similar virus that co-circulates with Zika and is carried by the same mosquito species. The occurrence of Zika cases in countries is ideally confirmed by PCR testing or by virus isolation.
Additional anecdotal evidence comes from travellers from Zika-free countries, like Australia, Canada, Finland, Germany, Japan, and the United States, who acquired PCR-confirmed Zika infection after visiting countries in Asia and Africa that had not detected recent virus transmission in their territories and were unaware of a potential outbreak [table 2].
In this case, immunologically naive travellers may have acted as sentinels for the detection of virus circulation that might otherwise be missed, possibly because widespread immunological protection limits the number of cases. Alternatively, the mild self-limiting nature of Zika infection, the absence of symptoms in the majority of infections, clinical symptoms of Zika that overlap those of dengue and chikungunya, the weakness of surveillance systems, and the difficulty of differential diagnosis may mean that Zika infections occur in these countries but are not being detected.
Experts who advise WHO and have closely followed the dramatic resurgence of dengue and the recent transformation of chikungunya into an international threat are reluctant to issue reassuring advice concerning the potential of epidemic Zika virus strains to spread beyond the Americas. Outbreaks of dengue are now recurring in countries at short intervals, suggesting it is unlikely that Zika will simply burn itself out and go away. Moreover, flaviviruses are well-equipped to adapt to ecological pressures and exploit opportunities to spread.
The latest “firsts” for the Zika virus in the Americas are not encouraging in terms of virus persistence and the potential for further spread. In April 2016, researchers in Ecuador and the northeastern part of Brazil reported the detection of Zika in monkeys, suggesting a new transmission cycle that could allow the virus to persist. In Brazil, the virus detected in monkeys was identical to the one circulating in humans.
At the end of that same month, researchers at a government laboratory in Mexico reported detection of the Zika virus in female Aedes albopictus mosquitoes collected in the wild, as opposed to experimentally infected – another first for the western hemisphere. Ae. albopictus, also known as the Asian tiger mosquito, is an invasive species that continues to expand geographically well beyond Asia and has adapted to flourish in a variety of habitats closely associated with humans. As the mosquito can survive the winter in temperate climates, its ability to carry the Zika virus could expand the map of areas at risk of Zika virus transmission significantly.
Most likely, Zika – now re-profiled as a serious disease – is on the move, and this virus has staying power.
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This page links to all WHO information to its response on the Public Health Emergency of International Concern. |
Related links
Zika virus disease
Microcephaly
Guillain–Barré syndrome