The Pandemic Century

by The Pandemic Century- One Hundred Years of Panic, Hysteria

  BY APRIL 2015 Brito and Luz were becoming increasingly convinced that Zika was responsible for the spate of rashes and fevers in the northeast, but in order to convince the Pernambuco health authorities and Brazil’s Ministry of Health that these were not “dengue light” cases, they needed hard laboratory evidence. Unfortunately, antibodies to Zika cross-react with those of dengue and other flaviviruses, so conventional serological testing using ELISA or immunofluorescence would not be sufficient. To be certain that Zika was the cause, positive results would have to be obtained by the detection of viral nucleic acids using RT-PCR. Accordingly, in April, Luz sent serum samples from twenty-one suspected cases to Claudia Nunes Duarte dos Santos, a virologist at the Carlos Chagas Institute in Curitiba in Paraná. Eight of the patients, seven of whom were women, tested positive for Zika by RT-PCR. All lived in Natal and all had relatives with the same symptoms. At around the same time, another group of virologists based at the Federal University of Bahia in Salvador also detected the presence of Zika RNA in seven cases from Camacari, 650 miles to the south. There could now be no doubt, and on May 14 the Ministry of Health released a statement confirming that Zika was circulating in Brazil. However, while the statement prompted PAHO to issue an epidemiological alert, no further action was forthcoming, and the announcements prompted little alarm among Brazilian physicians or the wider global health community. By now, however, Brito had read up on the Guillain-Barré cases in French Polynesia and had issued an alert to members of the WhatsApp group warning them to look out for neurological symptoms. That’s how he came to learn about a group of patients being treated by Lucia Brito (no relation), the head of neurology at the Hospital da Restauração in Recife. Some had inflammation of the optic nerve, others of the brain and spinal cord, and several had Guillain-Barré syndrome.

  As yet, the link between Zika and Guillain-Barré was unproven—it was merely a temporal association and could have been a coincidence. To show the two were causally connected, a virologist would need to test the cerebrospinal fluid (CSF) of patients with Guillain-Barré for Zika virus—something that had not happened during the outbreak in French Polynesia. In short, Brito needed a microbiologist to help him connect the dots. Fortunately, Brito knew the perfect person: Ernesto Marques, the head of virology at Fiocruz in Recife and an expert on dengue.

  The grandson of a pharmacist from Recife, Marques was raised in Recife and has long felt a duty to use his knowledge to serve the people of his home town. That sense of purpose took Marques to medical school in Recife and, after graduation, to Johns Hopkins to study for a PhD in pharmacology. Drawn to research with practical applications for health problems, he decided to specialize in dengue, developing a tool to help doctors predict the health outcomes of patients infected with the virus. On obtaining his doctorate in 1999, Marques was offered a prestigious faculty research position, but he knew that in order to study dengue and other mosquito-borne diseases he needed to be close to the people most affected, so in 2006 he left Baltimore and returned to Recife to head up Fiocruz’s virology department at the Instituto Aggeu Magalhães (IAM). Among his first cohort of research students was Brito. While Brito was interested in the clinical symptoms of dengue, Marques was interested in mapping the T cells involved in clearing the virus with a view to identifying segments on the surface of the virus known as epitopes to which antibodies bind and that might be relevant to vaccine design. The two men soon became close friends, discovering in the process that they shared an enthusiasm for medical detection.

  In 2009, Marques was offered an associate professorship at the University of Pittsburgh’s Graduate School of Public Health, and began dividing his time between Pittsburgh and Recife. However, he and Brito stayed in touch, swapping notes and helping to recruit patients for Fiocruz’s ongoing research into dengue. The result was that when Marques first heard about the outbreak in Recife, he assumed the mysterious disease was mild dengue. Even when in late April, Brito visited Fiocruz with a list of candidate viruses, including Zika, and raised the possibility of a connection with Guillain-Barré, Marques, who watched the meeting on a videolink from his office in Pittsburgh, saw little reason to alter his opinion. Nevertheless, he agreed to order reagents to conduct tests for Zika and instructed his laboratory to concentrate on patients recently diagnosed with Guillain-Barré. Not long after, the laboratory took delivery of samples from thirty of Lucia Brito’s patients. By May Brito and Marques had their answer. Zika was present in the blood of seven of the patients. Not only that, but CSF from some of the same patients also tested positive—strong evidence of a causal link with Guillain-Barré.

  When other laboratories in Brazil had first reported the presence of Zika in dengue light patients, Marques had shared the news with his Pittsburgh colleagues, including Donald Burke, the dean of the Graduate School of Public Health and an expert on arboviruses (it was Burke who had written the chapter on arboviruses in the textbook that Luz had consulted in March). Although at this stage it was assumed that such infections were largely benign, with Marques’s input Burke agreed to draft an email to a former colleague in the Biological Threats Department of the White House. The email read: “If Zika is in fact spreading in Brazil, it is of concern for several reasons. 1. It will cause confusion about what is dengue and what is Zika, and what will be vaccine preventable. 2. It could spread more widely in the Americas. 3. There may be surprising interactions of Zika and dengue.” The email concluded by urging the implementation of surveillance for Zika “as soon as possible.” Now, with hard evidence of a causal link between Zika and Guillain-Barré, and possibly other neurological conditions as well, the case for surveillance was even more urgent. At the very least, Marques expected Fiocruz to issue an announcement about their findings. Instead, as Brito briefed the press, officials at Fiocruz urged caution, then issued a statement denying the reports. Marques was furious, but in the meantime he had filed a report to the Ministry of Health, so he knew it was only a matter of time before the truth came out.

  Events now moved quickly. When van der Linden began noticing the cases of microcephaly, one of the first persons she shared her concern with was Marques, her old medical school classmate. Soon Brito was also on the case. His first move was to gather together sixteen women who had recently given birth to babies with microcephaly at the Instituto Materno Infantil de Pernambuco (IMIP) and distribute detailed questionnaires asking whether they had recently experienced a rash, conjunctivitis, or edema. “Because of the discovery of Zika virus in cerebrospinal fluid and the neurological conditions seen in previous outbreaks, he was already thinking Zika,” said Marques when I met him at his office at IAM.

  As Brito expanded his inquiries, circulating questionnaires to women at other maternity wards, his conviction grew that he was on the right track. All the women had tested negative for the common causes of microcephaly, and all had experienced a rash and a fever during the first trimester of pregnancy. Besides, the dispersal was too extensive. “It could not be an outbreak transmitted by saliva, such as rubella, or a sudden decline in immunity that would allow the spread of cytomegalovirus,” says Brito. “It needed a vector.” However, although Brito was enthused by the thought that he might be on the brink of solving the mystery, his excitement was tempered by sadness. Many of the women he spoke to were as young as fourteen and barely out of childhood. “It was their first child and when they burst into tears it was hard for me not to cry too.”

  By now Luz had also identified several women in Natal who had given birth to microcephalic babies and had experienced symptoms characteristic of Zika early in their pregnancies. Increasingly convinced that Zika was responsible for the increase in microcephaly cases, in October Brito presented his findings to the Ministry of Health and the Pernambuco health authorities. At this juncture, 141 cases of microcephaly had been detected in Pernambuco (by comparison, in 2014 Pernambuco had registered 12 cases). Similar increases in microcephaly and other peculiar neurological malformations were being reported in Rio Gra
nde do Norte and other nearby states, and although the authorities were reluctant to accept that Zika was to blame, it was obvious there was a problem. Accordingly, on November 11 the Ministry of Health declared a national public health emergency and the Pernambuco Health Department issued an order requiring the compulsory notification of all microcephalic births.

  Still, rumors abounded. Some people speculated that the supposed increase in microcephaly cases could be an artifact of Brazil’s live-birth reporting system and better surveillance. Others clung to the theory that it was a bad batch of rubella vaccine or the fault of insecticides and larvicides. What scientists needed was live virus from a pregnant woman. But the Zika virus is typically detectable only in the first two to five days after the onset of symptoms, after which it usually disappears from the blood.‡ Because no one in Brazil was aware of the threat posed by Zika in the early part of the year, presumably the most common time when pregnant women had contracted the disease, no one had thought to test their blood for the virus during this critical period. Nor could they have—even as late as December 2015, when epidemiologists began to study the microcephaly births intensively, there was no routine diagnostic test available for Zika, and PCR was only available in specialist labs such as Marques’s. Of course, antibodies to Zika might still be detectable, but such antibodies could have been produced during prior exposures and were not evidence that the women had been infected with Zika during their pregnancies. The only possibility was to look for the virus in the amniotic fluid of a pregnant woman. The question was, where could such a candidate be found?

  Unbeknownst to Brito and Marques, while they were puzzling over these questions, Adrian Melo, a researcher in fetal medicine in Paraíba specializing in high-risk pregnancies, was treating two women whose sonograms showed unusual fetal brain development. The first woman had developed a rash, followed by fever and myalgia at eighteen weeks of gestation, and had been prescribed intravenous cortisone. She recovered, and at sixteen weeks her ultrasound was normal, but further ultrasounds at twenty-one and twenty-seven weeks indicated fetal microcephaly (the woman would eventually give birth to a baby with a head circumference of 30 cm). The second woman had similarly suffered Zika-like symptoms during pregnancy—in this case, at the tenth gestational week—with an ultrasound at twenty-five weeks also indicating fetal microcephaly. What particularly concerned Melo was that both fetuses had marked deformations of their cerebellum, the part of the brain that controls muscular movement, hearing, and eyesight, something that was not usual in microcephaly.§ A few days later, Melo received a text about the suspected link between neurological malformations in newborns and Zika. That’s when it hit home. “It was the only possible explanation,” she said.

  In early November Melo succeeded in making contact with a researcher at Fiocruz in Rio de Janeiro and arranged for amniotic fluid to be drawn from the women at twenty-eight weeks. Both samples tested positive for Zika virus. It was exactly the proof Brito needed, but still the Ministry of Health hesitated. Only when on November 28 another research group in the state of Pará announced it had also isolated the virus, this time from the brain of a stillborn baby with microcephaly and other congenital abnormalities, did the ministry agree to issue a statement confirming the findings. It was official: something as innocuous as a mosquito bite might be causing severe neurological damage in newborns across Brazil, the most populous country in South America; and pregnant women exposed to Zika, especially during their first trimester, should be presumed to be at risk of microcephaly. On December 1, with nine other countries in South America, including Venezuela, Colombia, and Mexico, reporting transmission of Zika, PAHO also fell into line, issuing an alert warning member states about the virus and advising them to prepare health centers and antenatal centers for a “possible increase in demand . . . for neurological syndromes.” At this point, Brazil was investigating 1,248 cases of microcephaly, including seven deaths, in fourteen states. That gave a prevalence of 99.7 microcephaly cases per 100,000 live births—a twentyfold increase over the 2010 rate. The question was how much of this increase was down to Zika, as opposed to heightened awareness of microcephaly and the efficiency of Brazil’s live births information system. Were other countries in Latin America experiencing similar increases? As 2015 drew to a close, no one knew the answers to those questions, least of all the WHO’s then–director-general Margaret Chan, to whom it now fell to assess the level of the threat and whether it constituted a public health emergency of international concern (pheic).

  IN A FILING CABINET somewhere at WHO headquarters in Geneva is a document listing the world’s leading infectious disease threats. Only to be referred to in the event of an emergency, the document, known as a “decision instrument,” provides a step-by-step guide for assessing outbreaks that may pose a “serious” threat to public health. At the top of that list are smallpox, polio, pandemic influenza, and SARS. Outbreaks of any of these pathogens automatically trigger a pheic. In second place come cholera, pneumonic plague, and viral hemorrhagic fevers such as Ebola and Marburg. Yellow fever, dengue, and West Nile, another arbovirus, also make the list, but in 2015 there was no mention of Zika. This is not because the virus was unknown to public health experts—it had first been identified in 1947—but because until the outbreak in Brazil no one had imagined it might pose a threat to expectant mothers and their babies, let alone require a coordinated international response.

  By any measure Zika’s rise through the microbial threat rankings had been astonishing. In the corridors of the WHO some officials were suggesting it might even constitute a bigger health risk than Ebola. The timing was particularly unwelcome for Chan. After she had weathered months of criticism over her handling of the Ebola epidemic and stinging reports questioning her leadership abilities, the epidemic was finally over and officials were returning from West Africa to enjoy Christmas with their families. In the closing months of the outbreak, the WHO had even scored a significant victory, supervising the trial of an experimental vaccine that, according to preliminary data, conferred complete protection against Ebola. Now, with just eighteen months of her term as director-general left to serve, Chan was faced with another critical decision, one that could forever define her stewardship of the WHO as a success or failure. She could not afford to make another wrong call. But in the case of Zika, it was by no means clear what was the right thing to do. As yet, there was no proof the virus caused birth defects—it was simply an association in time and space. Moreover, any suggestion that there might be a causal relationship risked needlessly panicking expectant mothers. There was another consideration, too: the Olympic torch was on its way to Rio ready for the official launch of the Summer Games on August 5. The Olympics would bring thousands of spectators and tourists flocking to Brazil. As few of them would have been exposed to Zika before, few would possess immunity, risking further outbreaks and the introduction of the virus to their home countries once the games were over. Finally, there were the athletes and the Brazilian economy to consider. The Olympics was a mega-event, one in which the Brazilian government and corporate sponsors had invested millions. Stadium construction was already behind schedule, and with the government facing growing criticism over its clearance of urban slums and other favela “beautification” measures, there was a risk athletes might withdraw rather than risk exposing themselves and their families to Zika.

  When faced with a tricky decision there is nothing like safety in numbers. In weighing whether or not to announce a pheic for Ebola, Chan had taken advice from thirteen experts. In the case of the Zika emergency committee Chan recruited eighteen experts and invited David Heymann to chair their deliberations. It was a shrewd choice. Heymann had been a key architect of the 2005 revisions to the International Health Regulations and one of those who, behind the scenes, had criticized Chan’s handling of Ebola, believing she had been too slow to challenge claims by WHO’s Africa office and member states that they had the outbreak under control. After leaving WHO’s Communicable Dis
ease Division, Heymann had taken up a position as professor of infectious disease epidemiology at the London School of Hygiene and Tropical Medicine and accepted the chairmanship of Public Health England, an executive agency of Britain’s Department of Health and Social Care tasked with the surveillance and control of contagious disease outbreaks. A regular contributor to The Lancet and the New England Journal of Medicine, he also headed Chatham House’s Center on Global Health Security, giving him a powerful platform to expound on global health issues and network with other key opinion makers.

  From Heymann’s point of view, chairmanship of the emergency committee would give him a chance to push for the sort of systems that had proved so successful during SARS when the WHO had put its faith in virtual networks of experts and allowed them the space and security to collaborate and share confidential research data. Still, it must have come as a shock when four days before the committee was due to meet, Heymann got the call to say he had been selected as chair.

  In the case of Ebola, once an emergency committee had been convened, the determination of a pheic had been relatively easy. After all, by August 2015 Ebola had killed thousands of people in West Africa and was known to be highly virulent. But in the case of Zika there was so much that was not known about the virus and its pathology, and although it was clear that transmission was widespread and likely to affect other countries in the Americas, it was unclear to what extent Zika posed an ongoing health threat, let alone a “serious” one, which is the first test of a pheic. Another problem was that although the relationship between Zika and microcephaly was unknown, the virus was not: on the contrary, it had first been described in 1947 only to be dismissed by experts as a virological curiosity (in epistemological terms this made it an “unknown known”). Nor was it possible to say whether Zika’s emergence in Brazil was truly “unexpected” or “unusual”—the other tests of a pheic—or simply an artifact of better surveillance. Adding to the pressure on Heymann and other committee members were the heartbreaking pictures of babies with tiny heads that were beginning to fill the morning news shows and Twitter feeds and a recent travel advisory from the CDC recommending that pregnant women consider postponing travel to Brazil and twelve other countries with Zika transmission.