Daniel Ramalho/For The Globe and Mail
As the virus ravages Brazil, leaving at least 580 babies with devastated brains, researchers are painstakingly trying to unspool a medical mystery that some say is reminiscent of the early study of the AIDS virus. And as they discover more, the picture becomes increasingly alarming.
South America bureau chief Stephanie Nolen in Campina Grande, Brazil speaks with the remarkable doctors who have been at the centre of the outbreak since its earliest hints, and with mothers trying to cope with their afflicted children
When her last patient had left, Dr. Adriana Melo sat in her quiet clinic on a Friday night last October and stared at the fetal ultrasound images on her screen. The baby's brain – it made no sense. It had atrophied in the two weeks since she last scanned the patient. The fetus was missing a piece of its cerebellum, as if there were a genetic abnormality. Yet, the brain showed the splotches of calcification, typically a sign of infection.
In 17 years of practising fetal medicine, Dr. Melo had never seen anything like it. She went home and began to make arrangements to get her pregnant patient every possible test – and then the screen of her cellphone flashed with a message on WhatsApp. She glanced at it and had a sudden, horrible suspicion that she knew what was wrong with the fetus.
That night, Dr. Melo plunged into a medical mystery that has left her wrung out and devastated, groping for increasingly scarce words of encouragement for her patients. A health crisis, centred on the supposedly benign Zika virus and babies with devastated brains, has unfolded swiftly in Brazil in the past five months. The scientific response has raced at an equally dizzying speed.
And as each day brings new findings, Dr. Melo's anxiety deepens. Like many of her colleagues in a hastily formed network of doctors and researchers studying Zika, she has a growing sense that the news is going to get much, much worse before it ever gets better.
"This is the same as AIDS," Dr. Melo said one night this past week, slumped in the glow of the ultrasound screen. "It's just the same."
It is not the same virus, of course. But many people working on the Zika emergency have begun to make the comparison with 1981, when young gay men in the United States started dying. A tiny group of patients – at least at first; terrible, painful ailments that frighten both patients and clinicians; a mystery cause: It's hauntingly familiar to people who have been in the trenches of epidemiology for a while.
The human immunodefiency virus (HIV), which causes AIDS, has gone on to kill 42 million people. Known deaths from Zika, at this point, number no more than 110, the number collated by Brazil's Ministry of Health of babies who die shortly after birth or are stillborn. No one is suggesting mass fatalities. But when something is as fast, as weird and as brutal as Zika is here, the mystery is perhaps its most critical aspect.
"This is the most important public-health challenge since HIV," said Dr. Paulo Gadelha, president of the Oswaldo Cruz Foundation (FioCruz), the flagship Brazilian public-health research facility that has mobilized a vast team to respond to Zika. "Of course, the world is facing other challenges, like Ebola and influenza. But we know those diseases. We know what they do."
The key difference from the first days of the AIDS crisis is that HIV was an unknown. Although the syndrome had been killing people in Africa for 80 years at that point, no one had identified the virus that caused it. The culprit in Brazil, however, was identified quickly: As Dr. Melo's tests helped show, the severe damage to the brains of babies (about 580, in the latest count from the Ministry of Health) is related to the Zika virus.
And that's the last solid fact in this story.
"We don't know anything at all about this virus," said Dr. Ana Maria Bispo, a virologist who heads the FioCruz laboratory for flaviviruses – a family of mosquito-borne viruses that includes dengue, West Nile, yellow fever and Zika. It was Dr. Bispo to whom Dr. Melo turned for help when she was trying to prove her hunch about her patient's fetus.
"We're beginning from zero," Dr. Bispo said.
Here is just a slice of what is on the list of unknowns: Why do some women in Brazil who were infected with Zika while pregnant have babies with brain defects and others don't? How could a Brazilian woman who gave birth to twins have one affected and the other just fine? How many Zika-affected pregnancies are ending in miscarriages?
What's the chance of infection from each single mosquito bite? Is the virus being spread by more than one species? Is it living in other animals? If you get Zika once, are you immune? How long does it stay in the body? What is the effect on the central nervous system of children who get it? And adults? Will a lingering effect show up in six months or a year?
If Zika can wreak this kind of destruction on fetal brains, what else can it do?
Daniel Ramalho/For The Globe and Mail
Zika was well-known
When HIV was confirmed as the cause of AIDS in 1984, it was something totally new. Zika, on the other hand, is well-known. It was identified in Uganda in 1947. Just 14 cases of Zika were registered by the World Health Organization from then until 2007. But antibody studies show that the virus was circulating in Africa and, since the 1960s, in Asia. And it was no big deal: It caused a mild fever, itchy red rash, sometimes a little joint pain. Its close cousins – dengue and chikungunya – were a far greater concern.
Then in 2007, the virus reached the island of Yap in Micronesia and provoked a large outbreak: 185 cases in a population of just 11,250. In 2013, Zika turned up in French Polynesia and three other groups of Pacific islands. It was the Zika virus that hit French Polynesia, we now know, that first made the jump from mild cousin to something new and terrifying.
Dr. Gadelha said it was no surprise to anyone at FioCruz that Zika came to Brazil; they were expecting it, as it made its way east, but no one was overly concerned. "Our big worry was chikungunya," he noted with a dark laugh. (Chikungunya is another mosquito-borne virus that has been spreading rapidly in the Americas in recent years.)
The first Zika cases in Brazil were reported in May of 2015; the precise timeline is now among the many things that researchers are trying to reconstruct. Did it arrive with kids who came to Rio from around the world to see the Pope on World Youth Day in 2013? Or competitors in a canoe race in August, 2014 – many of them were from Oceania – or soccer fans who came to the 2014 World Cup?
It is not clear how long it takes the virus to get established in a new mosquito population; Zika could have been in Brazil for more than a year before there was any hint of a problem. Certainly, by late 2014, Zika was moving swiftly through the country. About 1.5 million people are believed to have been infected so far.
Zika thrived in the places where Brazil is weakest: The highest infection rates are in northeastern cities where waste water runs in open canals, in neighbourhoods where the windows of small houses are left open all night for hints of breeze.
Then Zika ran up against one of the ways Brazil is strongest. Starting in September, doctors began to see a surge in babies with microcephaly (an abnormally small head) – a sign that their brains had failed to develop properly. They traded the puzzling observations on WhatsApp and began to talk to researchers. Word soon reached FioCruz. In less-connected countries or in a country that does not have as strong a health-surveillance system or the same depth of medical expertise, the trend might have gone unnoticed for months or years.
In late October, the Health Department in the state of Pernambuco issued an alert to doctors, reporting 60 babies with microcephaly born to mothers with suspected Zika infection. That's what flashed across Dr. Melo's phone.
Snatching it up, she dialled her patient. Why yes, the woman said, she had had Zika. Nothing serious, just a few days of aches and spots, when she was about two months pregnant. By then, Dr. Melo had booked tests of amniotic fluid for genetic conditions, but she told her patient that she was cancelling them. "I said, 'Wait until I figure out where I can send a sample to be analyzed for Zika.'"
She called lab after lab, but no one was equipped to analyze amniotic fluid for Zika. Finally, a friend mentioned Dr. Bispo, whom he had seen deliver a presentation on flaviviruses a few weeks before. Dr. Melo tracked her down and the two women talked for two hours late one night. ("It was my birthday," Dr. Melo said with a half-smile – that's how totally Zika has consumed her life.)
Dr. Melo dispatched blood, urine and amniotic-fluid samples from that patient and another of the women with affected fetuses who had been turning up each day at her practice.
Dr. Bispo gathered her team in the flavivirus lab at FioCruz in Rio, and began to check the samples for Zika and any other possible infectious agent. (Microcephaly can be caused by infections such as rubella and syphillis, as well as non-infectious issues such as maternal malnutrition.) The urine was negative, the blood was negative. But in the amniotic fluid, she found Zika virus fragments – so many that she was sure that she was somehow making a mistake, and asked her colleagues to run another protocol, and another. There was nothing else. "Just so much Zika."
She called Dr. Melo – and the federal Ministry of Health. "This was huge: Everyone was lost, and here, finally, was some direction."
She and her team worked straight through the next three days, and by Sunday night they had sequenced part of the virus genome. They drew other Zika samples from the international genome bank to compare, and soon knew that the virus in Brazil was the Asian strain, and the same genotype as that in French Polynesia.
But what had happened to make Zika so vicious here? By the end of January, Dr. Bispo's lab had sequenced the entire genome of the Brazilian virus and identified a deletion, a mutation in which part of a sequence of RNA was lost during replication.
"The deletion is the most likely explanation for how infectious it is," Dr. Bispo said. And somehow that missing splinter of RNA has given the virus the power to demolish the brains of developing fetuses and to cause the neuroparalytic disorder Guillain-Barré syndrome in a tiny number of the adults who get it.
Scientists in French Polynesia have now gone back through medical records searching for pregnant women infected with Zika in the 2013 outbreak and have found 17 cases of babies with neurological damage now believed to be related to Zika – a connection no one made at the time. (Abortion is legal in French Polynesia, and researchers speculate that a number of women carrying fetuses with catastrophic brain damage may have chosen to terminate their pregnancies.)
It's all profoundly weird from an evolutionary perspective, pointed out Dr. Eduardo Massad, an epidemiologist at the University of Sao Paulo and a member of the Zika network. This mutation seems to have made Zika more transmissible than other strains – sexually, and perhaps also in urine and saliva – and that's a win for the virus. But it also causes brain damage, at least some of the time. "And that's a dead end: Anything that causes neurological or other kinds of problems is a dead end for the parasite. It's not an evolutionary advantage," Dr. Massad said. So this devastation of babies? "It's a side effect of the process of maximizing transmissibility – it's an accident of the virus."
All together, it's a scientific mystery of the first order, Dr.
said. "We are like paleontologists in the desert who have found one tooth, and we have to reconstruct the whole skeleton." But the peculiar dual nature of this mutation suggests that the
crisis could go in either direction, he said. "
will either [burn out], the way
did not turn out to be the huge disaster people were anticipating," he said, "or else it's the Godzilla of infections. There is nothing in-between."
Daniel Ramalho/For The Globe and Mail
'A daring move'
While Dr. Bispo and her team were working through the weekend to analyze the amniotic fluid last November, Dr. Melo, by coincidence, was headed to a conference on fetal brains in Sao Paulo.
She sent ahead images of the fetus in her first patient and another she had identified, and asked if she could bring the women themselves. Soon, they were on examination tables in front of the country's top neurologists.
"People were doubtful that the virus could cause such a violent destruction in the brain," Dr. Melo recalled. "They didn't believe it was the virus. … And I told them that on Monday I would send the result of tests. Because I was sure.
"And then it started: the battle to convince the rest of the world that this was not a joke."
On Nov. 11, Brazil declared a public-health emergency – a spike in babies born with microcephaly believed to be related to Zika infection in their mothers. At first, it seemed that tiny heads and sloping foreheads were characteristic of the disease, but the abnormal head size is only a symptom of the brain damage, and the definition of the problem has shifted to congenital Zika infection.
It was the first health emergency declared in Brazil since the Spanish flu epidemic nearly 100 years ago, and Dr. Gadelha called it "a daring move" on the part of government.
This country is deep in the throes of a massive political and economic crisis; the President is under threat of impeachment and the government's popularity rating does not exceed single digits. "There was the risk that everyone would say, 'The government is trying to find a diversion.' I think it was very brave to do this," Dr. Gadelha said.
The epidemic also raised a new shadow over what was meant to be one of Brazil's few bright spots this year, the Olympic Games in Rio in August.
Dr. Bruce Aylward, executive director of emergencies and outbreaks for the WHO, said there was skepticism last October, when his team first began to raise the subject of the strange thing going on in Brazil. Dr. Aylward, an epidemiologist from Newfoundland, was busy overseeing the set-up of new systems after the WHO was widely slated for its bungled response to the West African Ebola outbreak. And suddenly there was a new emergency, this one in the Americas – with a proposed cause that seemed difficult to credit.
"But even then … you've been through this enough times that all the alarm bells are going off. In the back of your mind you want to go, 'It could be all those other things!' But we've had them all along. Something has happened with Zika," Dr. Aylward said.
The WHO declared a public-health emergency on Feb. 1 for the "cluster of microcephaly and other neurological disorders" with no confirmed cause.
However, Dr. Aylward is urging caution, and plays down the comparison with the early days of HIV. "You can't get too hysterical," he said in a telephone interview from Geneva. With Zika, like most viruses, the ill effects are most likely to be associated with the acute phase of infection, rather than turn up much later. "There is nothing from Zika historically to suggest that. We're 10 years out from the Yap outbreak and we don't have people saying, 'We have post-Zika arthritis.' So you want to narrow your scope of concern."
Trish McAlaster and Carrie Cockburn/The GlobE and Mail / Source: World Health Organization
But he admitted that Zika now keeps him up at night. What haunts him is a vision of three overlapping maps. The first shows the 34 countries that are currently experiencing Zika outbreaks. The second shows the countries that have a serious burden of dengue fever, a disease that claims 22,000 lives globally, costs billions in lost productivity and strains health systems in developing countries. Its infection rates climb each year. And the third? The third shows where the Aedes aegypti mosquito, the presumed vector for Zika, lives. The mosquito is in the Southern United States now. With climate change, its territorial map gets a little wider every day.
"Is this virus going to continue to move this way? Are we going to see something worse in places with even less capacity to manage it? You're heading into countries with potentially very high vulnerability – they have the vector, and their health systems are in rough shape."
And we aren't even sure what they need to watch for.
Daniel Ramalho/For The Globe and Mail
'I know what's wrong'
When Aldayanne Alves da Silva was five months pregnant, she began to bleed heavily and she was sent for an ultrasound. The doctor told her that her baby had something badly wrong with her brain. She went to follow-up appointments for the next few weeks. "At each one, the doctor said, 'Her heart is beating now, but I can't tell you it will be beating the next time you come,'" Ms. da Silva recalls. "So I just stopped going."
Her baby might not survive, but hearing this kind of news every week was making her crazy, and since the doctors couldn't do anything for her, she decided to try a series of churches instead.
When Ester Sophia was born four months ago, she was taken to intensive care, where doctors did an ultrasound and concluded that she was missing a piece of her brain. They asked Ms. da Silva if she had had Zika while pregnant. "I said no. I didn't know what it was."
So then there was more speculation and dark predictions. But Ester Sophia looked normal and seemed fine, so Ms. da Silva, weary of more pessimistic doctors, took her home. It was weeks later that her mother, Roberta, saw a news report about Zika and microcephaly and called her daughter, shrieking, "I know what's wrong with Ester Sophia!"
At that point, Ms. da Silva recalled a strange fever and rash she had had early in her pregnancy. She thought that it was an allergy, but now knows the symptoms are part of the classic profile of Zika.
(Because the virus so rarely causes serious illness, few people who have it see a doctor. There is no test available yet to show Zika infection unless the person is at the height of her illness. So the great majority of cases were like Ms. da Silva, women who felt unwell for a day or two, and then thought no more about it.)
Ms. da Silva took Ester Sophia to the doctor at the government health clinic in her down-at-the-heels neighbourhood, and he measured the baby's head – 32 centimetres, the cut-off point for microcephaly – and sent her to the clinic at the local hospital that Dr. Melo and colleagues had set up for congenital Zika cases, in utero or out.
"I got a shock the first time I went to the clinic and saw a microcephaly baby," Ms. da Silva confided. Those babies with the tiny heads look like something is terribly wrong with them – not like Ester Sophia.
Ms. da Silva, 21, who is raising two children on help from her parents and the $50 a month her former partner sends from his grocery store checkout job, spends her days taking the baby to physiotherapy and working to get her to clap, to wave, to sit up on her own. She is confident that her dark-haired, bow-lipped little girl will catch up.
But the CT scan images she keeps bundled up in a plastic bag tell another story. It's a dark twist in an already bleak tale, Dr. Melo pointed out, that the babies who look the most normal are typically the most badly affected. In the microcephaly babies who were spotted first, their brain development is arrested and their skull has not grown. But in other babies, such as Ester Sophia, the brain did not develop but the space filled with fluid, which pushed the skull to a normal size.
That means that, potentially, an unknown number of babies who were born with normal-looking heads were sent home with their condition undetected. If their mothers did not have ultrasounds in pregnancy (one exam at around 22 weeks is standard in the public system, but not all women have them), or if they were infected with Zika after that exam, there could be no sign that the baby was affected until it stopped meeting development milestones. Some of the babies with normal heads in the clinic here have ocular or audio deficits, and some have muscular or skeletal problems. But not all.
It doesn't really matter if they don't get detected right away, Dr. Melo noted bleakly, since there is really nothing to be done for the affected children in any case. There is no treatment for brain atrophy or microcephaly. But it matters for science. It is critical to know what percentage of babies born to mothers who had Zika are actually affected.
Daniel Ramalho/For The Globe and Mail
A haunted look
The pediatricians of Paraiba and other northeastern states get a similar haunted look when they talk about the brain scans they see these days. They describe brains that are largely water; brains that are as smooth as well-worn beach rocks, without a single ridge; brains that are tiny and entombed in a crust of calcification; brains that are missing pieces; and brains that simply aren't there at all.
"For us, it's a very big challenge … because answers from science come slower than the immediate response a mother demands," said Dr. Bruno Leandro de Souza, a pediatrician and the technical director of the maternity hospital in the state capital, Joao Pessoa, that has registered the bulk of Paraiba's cases.
He rubbed his hands briefly across his face and slouched back in his chair. "A mother with a child in her womb, suddenly she knows she has a problem, and she says, 'What now? What can you tell me about this?' And we don't have a concrete answer. I don't know what's going to happen to her child, I don't know how it will develop. If it will develop. If it will survive. I don't know. It's very disturbing."
On Thursday, scientists from Yale University and Hospital Geral Roberto Santos in Bahia said a stillborn baby born there in January had signs of severe tissue swelling as well as central nervous system defects that caused a near-complete loss of brain tissue – the first time congenital Zika infection was associated with damage to tissues outside the central nervous system.
Yale epidemiologist Albert Ko and colleagues said the case suggests that congenital Zika may also be linked to hydrops fetalis (abnormal accumulation of fluid in fetal compartments), hydranencephaly (almost complete loss of brain tissue) and fetal demise (stillbirth).
"There is a huge range in the impact – in the ones that survive," Dr. Melo said. That is one of the key puzzles, why the virus's attack on the developing nervous system seems to produce such diverse effects.
And there so many other mysteries. Most critically, this: Why do only some of the pregnant women who get infected have affected babies?
It is not yet peer-reviewed research, but Dr. Melo said she is seeing congenital Zika in the fetuses of one in every 17 women who had symptoms of the virus.
This past week, Brazil's Ministry of Health and the U.S. Centers for Disease Control launched the first major effort to dig into some of this, setting out to identify and study 100 women in Paraiba who have babies with microcephaly and 300 women who gave birth at the same time to normal babies.
In addition to tracking Zika, they are looking at everything from what medications the women took in pregnancy to how much fish they eat to whether there is livestock in their home environment to what pesticides they might have been exposed to. It's an effort to find additional evidence that Zika is the primary cause, and to find "influencing factors."
There is also a hunt for genetic susceptibility in the mothers whose babies are affected. And increasingly the virologists are honing in on dengue, wondering if a co-infection or a previous infection with dengue is the thing that is making some women's babies susceptible.
"We think maybe dengue antibodies can cross-react with Zika and, instead of neutralizing the virus, they turn it into a sort of Trojan horse – and carry it into the placenta – so that when it reaches the fetus, it is still active," Dr. Bispo explained.
Also on the research list: Scour the body for Zika. "Does it stay hiding [in reservoirs] like herpes? That's a thing we need to know," Dr. Bispo added.
And what has happened to rates of miscarriage? " Microcephalic is the tip of iceberg," the WHO's Dr. Aylward said. "There may be huge fetal loss problem that we're not even seeing clearly yet."
On WhatsApp, Brazilian doctors are now trading reports of surprising neurological problems in young adults. There is no confirmed association with Zika, just a sense of heightened awareness and anxiety.
Daniel Ramalho/For The Globe and Mail
Wipe out the mosquito
And then, critically, there is the transmission. The focus of response in Brazil today is "vector control" – wiping out the mosquito. The government has deployed the armed forces and saturated the media with a public information campaign about where Aedes aegypti can breed.
But the attack on the mosquito is all based on an assumption – on the fact that because it is this mosquito that carries the other flaviviruses here, and it has been shown to transmit Zika in a laboratory, most probably it's spreading Zika.
Constancia Ayres, an entomologist with FioCruz in Pernambuco, pointed out that not one single Zika-infected Aedes aegypti mosquito has been found in the wild in Brazil. She is capturing thousands of them to look, as are other researchers. But two weeks ago in an article in The Lancet, she wrote, "To assume that the main vector is A. aegypti in areas in which other mosquito species co-exist is naive, and could be catastrophic if other species are found to have important roles in Zika virus transmission."
Dr. Bispo is pushing to study other forms of transmission. "Zika circulated the whole of last winter, even though it was a very dry winter, and in my lab we were saying, 'Why is this virus circulating?' We need to check if this virus needs only the vector to transmit – it's strange. We started to collect saliva and urine."
In the past weeks, Zika has been found live in urine and saliva by other FioCruz researchers, and sexual transmission has been confirmed by scientists in the United States.
But Dr. Bispo is wondering about other sources. She noted that Zika is behaving somewhat like Japanese encephalitis, another flavivirus, which is associated with miscarriage and fetal malformation. "Japanese encephilatis is a neurotropic virus and it has a vector of pigs and birds," she observed. Could those or other species be acting as reservoirs of the virus? And could other mosquitoes be carrying it, such as the genus Culex, which is vastly more common in Brazil and thrives even in sewage? "If it's in Culex, we're lost," Dr. Bispo said. (Culex also happens to be found in Canada, where it transmits West Nile virus.)
The urgency of the mothers is acute, but science is slow, as Dr. Bruno de Souza noted. It will be at least mid-2016 before there are answers to even a few of these questions. Colombia will provide some: There, the mosquito season lags six months behind Brazil's, so the government was alerted in time to start tracking pregnant women. There are now more than 6,000 pregnant women with confirmed Zika infection registered there; the first case of a fetus with the defects was confirmed on Thursday. Already, the country has 86 reported cases of Guillain-Barré related to Zika.
"I don't wish this for Colombia – but it will be just like here," Dr. Bispo predicted.
The only public-health solution is a vaccine; at best, it is five or six years away, and all of these unknowns complicate the process of developing one. "We are trying to get in front of it with an R&D agenda, with vaccines and diagnostics that prevent some of the awful impact we saw, of things like rubella in earlier epidemics," Dr. Aylward said.
He is the man charged with making sure there is no repeat of the Ebola tragedy, and he understands that it is difficult to see Zika in the same light, when fewer than 1,000 people are affected so far. But an epidemiologist thinks about more than just mortality rates.
"I'm reading the stuff in the press – and it's valid – about there being more devastating diseases out there – malaria, influenza – that will ultimately have bigger mortality associated with them, but this is a different thing, an evolving situation. You don't know where it's going to land, you don't know everything about it, you don't understand the longer-term effects, you have very little predictive ability because it's all new. Those other diseases, we know them, we understand them, we understand the damage they can do. With this, we don't understand it at all."
Daniel Ramalho/For The Globe and Mail
'I want to donate his organs'
Jessica dos Santos, one of the two women for whom Dr. Melo tested amniotic fluid, had her baby in February. In addition to the catastrophic damage to his brain, the virus had left his limbs contracted and twisted. His dark eyes had a faraway look for his brief hours of life.
Dr. Melo was desperate to study him further. "But I didn't have the guts to ask her. I wouldn't have the courage, even though I knew it was important for us to have a brain to study, so we could understand many things," she said, adding softly, "Her pain was so great."
And then Ms. dos Santos, a 23-year-old from a low-income rural area who had limited education, made a request of the doctor.
"She said, 'I want to donate his organs.' She said that her son's last mission was that science understood this disease better, so many wouldn't go through what she did."
Dr. Melo accepted. The research is under way.
- With files from Manuela Andreoni
Editor's note: An earlier digital version of this story incorrectly stated the year of the Spanish flu epidemic. This version has been corrected.
A Saturday story on Zika referred to a deletion in the virus's DNA sequence. In fact, the mutation occurred in the virus's RNA.