Zika (13 page)

10

The Proof

O
N
F
EBRUARY 1,
2016, when the WHO declared its emergency based on the
possibility
that Zika caused microcephaly, reporters asked WHO officials exactly what evidence was needed to be sure it did.

Initially, both Dr. Bruce Aylward, who was in charge of the response, and Dr. Heymann, the advisory committee chairman, gave the same answer: a large case-control study.

Scientists in Latin America, they said, were already recruiting pregnant women into one. They had signed up about 5,000, mostly in Colombia, some in Brazil, some elsewhere; they had to be pregnant and to have come up positive on tests for the virus. Those were the “cases.” They were also signing up “controls”: a roughly equal number of pregnant women who did not have Zika. They would try to match the two cohorts as closely as possible: same ages, same races, same neighborhoods, same income levels, same medical histories, especially regarding previous dengue or chikungunya infections. (Obviously, if a woman in the control group got Zika during the study, she would be shifted to the case group.)

They would monitor the two groups until their babies were born, and compare the results. If the Zika group had far more babies with microcephaly than the control group, they could definitively say Zika was the cause.

This was a “prospective cohort study,” the gold standard in epidemiology. The women enrolled first were due to start giving birth in May and June, Dr. Aylward said, so final proof would have to wait until that data was ready.

In fact, the science moved forward much faster.

On March 31, without any fanfare, the WHO made a subtle but important change to one sentence on the face of its weekly Zika situation report. It read:

“Based on observational, cohort and case-control studies there is strong scientific consensus that Zika virus is a cause of GBS, microcephaly and other neurological disorders.”

“Strong scientific consensus” marked a shift from previous reports, which said it was “highly likely” Zika was a cause.

Then on April 13, the CDC made it definitive. Its director, Dr. Frieden, scheduled an afternoon press conference with the leaders of his Zika team and declared unequivocally, “It is now clear: the CDC has concluded that Zika
does
cause microcephaly.”

It was “an unprecedented association” in medicine, he added. “Never before in history has there been a situation where a bite from a mosquito can result in a devastating malformation.”

What led the agencies to change their minds about waiting for the big study?

A series of small studies.

The number of cases of confirmed microcephaly in Brazil had just kept growing. Before the CDC announcement, it had passed the 1,000 mark, with nearly 900 clustered in the northeast.

Microcephalic babies were by then being born not just in Brazil but in Colombia, in Panama, in Martinique, and in the Cape Verde Islands, not to mention the cluster discovered retrospectively in French Polynesia. Each cluster had followed a Zika outbreak about nine months earlier.

Separate teams of doctors—in Brazil, in the United States, even in Slovenia—had found Zika virus in the brain tissue or amniotic fluid of babies who had been born with microcephaly, had died in the womb with microcephaly, or had been aborted because microcephaly was detected on ultrasound.
One particularly grim case was described in the
New England Journal of Medicine
on March 30. It involved a 33-year-old newly pregnant Finnish woman living in Washington, DC, who had taken a quick trip through Belize, Guatemala, and Mexico over Thanksgiving 2015. She had a routine sonogram on December 5, and her baby was fine. But she was having odd symptoms—a rash, eye pain, and a fever. Over New Year's, she was in Finland—presumably home for Christmas—and she must have read the news about Zika, which was just emerging then, and recognized her symptoms. She had a blood test and an ultrasound there. The ultrasound was normal. But her blood was positive for Zika virus. She went back to the United States and had the same two tests on January 5. Same results. Then, over the next three weeks, two things happened. Her blood remained positive for the virus, which was abnormal. And, horribly, her baby's brain began to dissolve. On her next MRI and ultrasound, at 19 and 20 weeks, the skull is the right size, but the surface of the brain has thinned out, the hollow spaces in the frontal lobes are larger than they should be, and the white matter that connects the two hemispheres is far smaller than it should be. At week 21, she decided to terminate the pregnancy. On autopsy, the brain was found to be teeming with viral particles. That was solid evidence.

There was also “biological plausibility,” the CDC said. Biologists at Florida State University had tested the virus in several types of fetal cells that grow into the various parts of a baby. It barely infected some, such as the prekidney cells. But it homed in on the neural progenitor cells—the ones that ultimately turn into the brain—and destroyed them.

(Also, in results that were then still unpublished, when injected into immune-deficient mice, the virus did not kill adults but did kill fetal ones, and it was found in their brains.)

But the most convincing and most frightening piece of evidence was a miniature case-control study published by the
New England Journal of Medicine
on March 4. It was done by doctors at the Cruz Foundation in Rio working with a team from the David Geffen School of Medicine at UCLA. They described a group of 88 pregnant women whom they had started to enroll in September 2015, when the reports of microcephaly began coming out of the northeast. (Although the epidemic's initial epicenter was in that region, there was a simultaneous smaller outbreak in some parts of the Rio region.) The researchers were already in the middle of a dengue study, and they had noticed a few months earlier that they were getting many patients with fevers and rashes who tested negative for dengue. So they started testing them for Zika, and then began a substudy that looked just at the pregnant ones.

The study wasn't nearly over when they published the results. They had rushed it into print because what they were finding was so alarming that it needed to serve as a warning.

Rather than test all their subjects, they had chosen rashes as the recruitment factor. Whenever they saw a pregnant woman with a rash, they asked whether she would agree to participate. Eighty-eight had said yes. Of those 88, 72 tested positive for Zika. The other 16 became the “controls.” Of the 72, 2 had miscarriages almost immediately. That didn't necessarily mean anything—miscarriages in early pregnancy are common. Of the 70 left, 42 agreed to have ultrasounds every few weeks. The other 28 refused. Some said the ultrasound clinic was too far away. But some “declined because of fear of abnormalities.” That is, they preferred not to know whether their babies were deformed. They would find out at birth.

By the time the authors published their preliminary results, 12 of the 42 mothers having ultrasounds were showing evidence of “grave outcomes.” Two babies had had normal ultrasounds, and then had suddenly died in the womb. Both of those mothers had been infected late in their pregnancies, not in the first trimester. The rest had ultrasounds revealing serious defects: some had microcephaly, some had white spots—brain calcifications—suggesting inflammation or cell death, some babies were much too small for their gestational age, some had almost no blood flow in their umbilical cords. By the time the study was published, 8 of the women had given birth, and the ultrasounds had proven accurate.

Twelve damaged babies out of 42 was a 29 percent “grave outcome” rate. The 16 Zika-free women acting as controls had zero problems. A difference of 29 percent versus 0 percent is more than “statistically significant.” It's overwhelming. Among other things, those results forced experts to stop saying that the danger was all in the first trimester. Clearly, Zika could kill babies at any point.

“We were just blown away by that,” Dr. Karin Nielsen-Saines, one of the authors, said. “We weren't expecting to find problems in all trimesters.”

(A study done by the CDC that came out later, on May 25, in the
New England Journal of Medicine
looked at Brazil's northeastern Bahia state during the height of its epidemic and found that a Zika-infected woman's risk of having a microcephalic child was between one and 13 percent.)

The stack of evidence piled up by all these disparate studies, the CDC said, fulfilled “Shepard's criteria.” That was a set of conditions published in 1994 by a professor of pediatrics at the University of Washington, Dr. Thomas H. Shepard, for determining whether a particular insult to a fetus caused a particular birth defect. (They were different from Koch's postulates, a better-known set of criteria published by the pioneering German microbiologist Robert Koch in 1890. But Koch's postulates are for concluding whether a particular germ causes a particular disease. Shepard's criteria relate to birth defects and incorporate nondisease causes like poisons or radiation.)

Dr. Bruce Aylward of the WHO was very pleased about the CDC's timing, even if it jumped the gun on waiting for results from the large study. It was both good science and “really responsible public health,” he said.

It was good public health policy because many people in the Americas still doubted that Zika was the cause of microcephaly and were not taking precautions against it. As a result, babies would die. “If you're going to prevent disease, you've got to change behavior today,” he said. “Not when it's too late.”

By this point, the flurry of denial rumors had diminished, at least as far as I could tell. I was no longer getting emails about them. They had faded from social media, and the mainstream press was no longer repeating them. I wrote to Dr. Powell to ask whether his mind had changed. He replied that he was “becoming convinced there may be a causative connection between Zika infection and microcephaly.” He did add that he was “less sure that mosquitoes are the sole culprit”—about which he was right, since sex clearly played a role, too.

Questions remained: Was the silence because of widespread acceptance? Or widespread indifference? And even if women accepted it, were they going to do anything about it? And what exactly
could
they do?

11

Delaying Pregnancy

W
EEK AFTER WEEK,
as the epidemic pressed outward from its Brazilian epicenter and more and more women fell within its orbit, one thing became clearer and clearer:

Nothing was stopping this virus. Not one country—not even one city or one island—was claiming that its babies were safe.

None of the vigorous mosquito-control efforts, none of the constant reminders to women to wear repellent and long sleeves, appeared to be winning. None of the calls to deploy genetically modified mosquitoes or bring back DDT were making any difference.

Much of that was wishful thinking anyway.

Oxitec, which bred GM mosquitos, was still in the field trial stage. The company would have needed thousands of insect hatcheries scattered all over the Americas to raise enough males to make a dent in the epidemic.

The spray trucks featured in so much television footage from South America were largely useless publicity ploys. Governments liked them because people found them reassuring. But against
Aedes aegypti
mosquitoes, relying heavily on street fogging was almost counterproductive: they bred near houses and slipped indoors as soon as they could, following the carbon dioxide vapor trail of human breath. As the trucks drove by, people closed their windows, thereby protecting the mosquitoes. TV footage of soldiers emptying standing water was also good publicity; but as soon as it rained, neighborhoods were back to square one.

And few of those calling for DDT to be revived seemed to realize that it would be a waste of time. Latin American governments had used it so intensely from 1947 to 1962 that they
almost
wiped out
Aedes aegypti
on the continent. In doing so, they
almost
eradicated yellow fever. But almost counts only in horseshoes and hand grenades. The genetic mutation that confers DDT resistance had emerged in Venezuela and had became fixed in the species before it spread outward from there. More than 50 years later,
Aedes aegypti
in the Americas still had the resistance gene. DDT was useless against it.