On the Zika trail

Where did the Zika virus come from, and after Brazil, where will it go?

The other evening, at a talk about my recent book on plague, I mentioned a curious happenstance. On the day the book was released, The New York Times ran the story about a recent attempt to “type” that city’s genomic profile by examining swabs from public places.

If it seems curious that a city can claim a genome, think awhile—what better way to understand the various forms of life it contains? These researchers were looking out for DNA evidence of the common microbes in places with dense human contact. One microbe they found in plenty wasYersinia pestis, the plague germ. Does New York have the plague? Far from it. The study elucidates a different truth: Bacteria and viruses are part of the landscape no matter where we live on the planet. We coexist until something tips the balance and makes us enemies.

“Then why, suddenly, do we have Zika?” a voice rang out.

Many things happened at that moment, as if the room had been seized by a poltergeist. The overhead fan whipped up hurricane velocity. Spectral flashes of static crackled as electric tennis rackets were conjured up and slapped around wildly. People rushed in all directions to shut doors and windows.

The motive force for this frenzy was already among us. A baby had entered the room. He gurgled approvingly at all this excitement. It seemed a familiar scenario, and the necklace of red wheals visible beneath his curls quite justified it.

A 3-month-old baby born with microcephaly is examined by a neurologist at a hospital in Paraiba. Photo: Felipe Dana/AP

A 3-month-old baby born with microcephaly is examined by a neurologist at a hospital in Paraiba. Photo: Felipe Dana/AP

“Did I hear you say Zika?” his mother wailed. “I’m going there next week!”

“Where’s there?” I asked, unwilling to believe she was off to trek in the Zika forest.

It turned out she wasn’t going to Uganda, or to Latin America either. California was her destination, and they don’t have mosquitoes, do they?

I was forced to disillusion her. California has an abundance of diphtheria.

She asked, “It won’t affect baby, will it?”

The room stilled as if the very air depended on my answer, and what could I possibly say? The Zika virus might have zipped across the planet unnoticed, but for the circumstantial evidence of a cluster of babies born with microcephaly in Brazil.

The baby began to cry, upset by the morose company.

I assured his mother he was safe.

But I did tell her the health warning could not be ignored. Travel to the affected areas was hazardous: Pregnant mothers infected with the Zika virus could transmit the infection to the foetus. And it wasn’t yet certain that all the babies in the news had developed small heads because of the Zika virus.

I sounded as lame as the reports I had been reading.

What do we know, really? Every iteration in the press raises panic on a seismic scale. The overall picture is terrifying: An entire generation of babies likely to be born with a disastrous abnormality.

What abnormality, exactly?

Microcephaly is just posh for small head. It is not a disease. It is a clinical finding. In mild cases, it is easily missed. Head measurements are skull measurements, and the development of the skull in foetal life is dictated by the development of the brain.

In microcephaly, the measurement of the head from the occiput (at the back) to the frontal bone is less than expected for the baby’s gestational age, gender and weight. Every paediatrician in every part of the world has seen the odd case or two.

Let’s take a closer look at these babies from Brazil.

Between the final months of 2015 and the end of January, 4,783 newborns were diagnosed as “microcephalic”.

Of these, 1,103 have been investigated, and 404 validated as microcephalic—the rest were normal. Among those validated, brain abnormalities were detected in 387. The Zika virus was isolated in 17 babies, and in two foetuses that miscarried.

Two pregnant mothers in whom ultrasonography revealed microcephalic foetuses underwent amniotic fluid testing. The Zika virus RNA was found in both cases. The virus has also been isolated from two microcephalic infants who died at birth.

zika-virus

That was the data at the end of January.

What’s the background?

The first question that comes to mind is: How common is microcephaly in this population? It is an important question because when head diameters are not measured as routine evaluation, the visual appraisal of an “odd head” can be fuzzy.

The world incidence of microcephaly is 1-2 cases per 10,000 live births. Before 2015, the incidence in Brazil was 0.5 cases per 10,000 live births. A recent report challenges this. A network of paediatric cardiologists in Paraiba, Brazil, has maintained a surveillance on heart defects in newborns since 2012. In light of the present panic, they mined their data on 16,208 babies for head measurements, and found the numbers for microcephaly higher than expected, peaking in mid-2014.(1)

Did the mothers report illness during pregnancy? Hindsight is not very reliable. Most mothers may not recall a casual fever or rash, and many more might dredge up a memory by suggestion. But it’s certain these births occurred in an area where the Zika virus is prevalent.

Up pops the question: Since when has Zika been prevalent there?

A certain date does loom: 12 June-13 July 2014, the Fifa World Cup in Brazil.

Again, where’s the proof?

In medical jargon, the label “autochthonous transmission” is used to describe the spread of a disease within the area under discussion, and the first such report on the Zika virus in Brazil was published in June 2015, a few months before the microcephaly story broke.(2)

The authors reported on a “dengue-like illness” that tested negative for dengue. Chikungunya? The Aedes mosquito is a vector for both viruses, after all. Negative again. Aedes also carries Zika, but nobody had thought of looking for it till now—and there it was!

So, how did the Zika virus get to Brazil? Why did anybody get to Brazil in 2014? Blame it on the World Cup.

It is a starting point, anyway.

Is it? Then what caused all those microcephalic births before the World Cup?

Zika must have come from somewhere, or it couldn’t erupt suddenly in Brazil, is the general outcry. What if the Zika was part of Brazil’s landscape all along, flourishing in peaceful anonymity, like the plague bacillus in the New York subway? Which begs the question: What made it turn virulent and cause disease?

Let’s take a look at the known origins of the Zika virus. It was discovered in a forest, in the year of India’s independence, although the findings were not reported till 1952. And where exactly was this forest of the night?

I could point to Uganda on the map, but the voice of discovery is so much more thrilling.

“About 7 miles north-east is a forested area called Zika. This area of forest consists of a narrow, dense belt of high but broken canopy growth with clumps of large trees. It lies along the edge of a long arm of Lake Victoria, from which it is separated by a papyrus swamp. The greater part of the forest runs parallel with the Entebbe-Kampala road; there is a narrow stretch of grassland between the forest and the road. At no place is the forest more than 500 yards wide. It is about 1 mile in length and is almost continuous with scattered forest which in turn joins the forest at Bujuko on the Kampala-Fort Portal road.”(3)

In April 1947, three scientists, G.W.A. Dick, S.F. Kitchen and A.J. Haddow, were investigating yellow fever. Although the disease was endemic in that area, rhesus monkeys seemed immune to it. So a number of monkeys were chained on high platforms beneath the tree canopy as bait for the forest’s teeming mosquitoes.

The picture is disquieting as night falls on these unresisting captives waiting to get sick.

On 19 April, one monkey recorded a fever. Rhesus 766 was quickly taken off his lonely perch and rushed to the laboratory. His blood was sampled the next day, and the serum was separated and injected into mice.

The monkey recovered in a few days. The mice died. A filterable transmissible agent was isolated from the brains of these sick mice. Voila!

A month later, Rhesus 766 showed antibodies to the original serum. The finding was replicated in another monkey.

The researchers named the new virus after the forest. The Zika virus, they concluded, induced a mild illness in monkeys and made them quickly immune to a second infection.

Rhesus 766 had been chained to his platform as mosquito bait. So did the mosquito transmit the Zika virus? Subsequent experiments with the local mosquito Aedes africanus proved that it did.

What of the human population around the forest?

Antibodies were present in 6.1% of 99 samples of human serum collected from the Zika area, indicating that these people, all in good health, had been infected with the Zika virus at some point. Several “human volunteers” exposed themselves to Aedes africanus bites and to injections of serum; they developed a mild fever, and showed antibodies to the virus a month later.

The Zika virus, then, could infect humans, but one didn’t really get sick from it. Nobody considered it virulent enough to cause an epidemic—until 2007, when there was an outbreak of fever on the island of Yap.

It’s difficult to locate Yap on the map. It’s a dot in the spatter of islands in the Pacific that make up the Federated States of Micronesia. It shouldn’t take long to circumambulate, the island is just 15x9km: by Indian standards, a lonesome place—with just about 7,000 inhabitants. In May 2007, many of them fell sick.

The illness was mild—fever, joint pains, conjunctivitis. None of the patients on Yap tested positive for dengue viral RNA, though many had antibodies against this disease. This meant that they had been exposed to dengue earlier, but their present illness was something different. What could it be? The answer was not long in coming. Many patients showed up the viral RNA of the Zika virus.

In immunological terms, Yap was a “naïve” population that had not been exposed to the Zika virus before. There were 12 mosquito species on the island, the predominant beingAedes hensilli, but no Zika virus was isolated from the insects collected. Where had the virus come from?

Tracking the Zika virus was an occasional epidemiological sport before this recent outbreak, so we do have a timeline to follow:

Nigeria 1971 and 1975, Sierra Leone 1972, Gabon 1975, Uganda 1969 and 1970, Central African Republic 1979, Senegal 1988-91, Cote d’Ivoire 1999, Senegal 2011-12; Pakistan, Malaysia, Indonesia 1977-78, French Polynesia 2013.

So what is this traveller’s tale? How did the Zika virus find travel so easy? What were its adventures? These adventures can be tracked by tracing changes in the viral genome.(4)

Forty-three ZIKV (Zika virus) strains, sampled from 1947-2007 in Africa and Asia, reveal Zika’s hectic secret life. It emerged in Zika sometime between 1892 and 1943. It reached the west coast of Africa in two migrations from Uganda between 1935 and 1940. Another lineage departed Uganda for Malaysia in 1945 and made it into Micronesia in the 1960s, introducing the “Asian cluster”. Somewhere along its travels, genetic shuffling or recombination events took place. Perhaps as the virus changed hosts. Its presence in the wild (enzootic cycle) may not be restricted to the Zika forest: With urban encroachments into wooded areas, Zika’s habitat is growing, and so are its vectors, as local strains of Aedes co-opt the virus.

The question here is not how Zika travelled into Brazil, but why the disease emerged there. Brazil’s famed Nordeste has crowded cities within its Zona da Mata, the rainforest zone. The last few months must have set off an entomological frenzy to examine its mosquitoes for evidence of the virus.

At home, the scene is ripe for Zika in every Indian city where dengue and chikungunya have already established endemicity.

What else do we know about the Zika virus that alarms and terrifies?

Oh yes, the possibility of sexual transmission, based on the anecdote of the research worker whose joyous homecoming transmitted the virus to his wife.

A pamphlet to raise awareness in Rio de Janeiro about the Zika virus. Sergio Moraes/Reuters

A pamphlet to raise awareness in Rio de Janeiro about the Zika virus. Sergio Moraes/Reuters

Viruses display varied tropism, or affinity for selective tissues. The very first report on the Zika virus showed it to have a tropism for nervous tissue, and research in the 1970s confirmed that. The Guillain-Barré Syndrome (GBS), a transient paralysis which may be life-threatening, is an auto-immune response to many infections. The outbreak of the Zika virus in French Polynesia (2013) was associated with a few cases of GBS. Growing numbers are now being reported from Venezuela. However, so far, the most frightening of Zika’s neurological complications—microcephaly—has only been reported from Brazil.

Should we have anticipated these brain anomalies? Although intra-uterine infections have been known to cause defects in brain development for at least half a century, we’re only now beginning to understand the how and why of it.

Last week put an end to surmise. A case report in The New England Journal of Medicine completely documented foetal infection with the Zika virus.(5) At foetal autopsy, the small and severely deformed brain yielded the entire genome of the Zika virus. No other tissues of the foetus manifested the virus, proving that Zika is definitely neurotropic, showing a marked preference for nervous tissue.

We should be asking why the Zika virus caused microcephaly in Brazil and not elsewhere.




The human question torments us. Is Brazil—and perhaps the world—facing a sterile, even a celibate future? The TORCH group—Toxoplasmosis, Rubella, Cytomegalovirus, Herpes Simplex—are the usual suspects when maternal infections cross the placenta, damaging the developing foetus. That’s a presumption based on data from temperate countries. What about the tropics? We should long have examined the teratogenic potential of common tropical illnesses during pregnancy—at least, we must start now.

The Zika alarm taps into the most basic human right of all. Pregnancy and birth make up the rhythm of life, and society has always seized control of it. Pope Francis’ nod to contraception is heartening, but it stops short of the full measure of compassion. Denied the right to terminate an abnormal pregnancy, Brazil’s women are terrified by their helplessness. The impact of these tragedies can be understood only by the afflicted. Law and religion must step side. All they should offer is support.

“So, could we get Zika here, in Mumbai?”

The question was inescapable. Even more inescapable was the answer: We can’t tell.

Eena Meena Zika? Is it all white noise and nonsense? Yes, because we haven’t yet given a hearing to the only voice which can tell us the story, all of it.

It’s a small voice, quickly silenced. Science is the only democracy left on the planet, one where every voice counts.

We must listen, now, to the mosquito.

Ishrat Syed and Kalpana Swaminathan are surgeons who write together as Kalpish Ratna. Their most recent book isRoom 000: Narratives Of The Bombay Plague.




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