Health

The Seven-Decade Transnational Hunt for the Origins of a Strange Indian Disease

Zeroing in on the genesis of the Kyasanur forest disease was, at one point, called “possibly the most dramatic epidemiological detective story of our time.” This is that story.

All the places where the disease has emerged lie along the Western Ghats. Credit: timjblack/Flickr, CC BY 2.0

All the places where the disease has emerged lie along the Western Ghats. Credit: timjblack/Flickr, CC BY 2.0

Rajagopalan climbed to the top of the tree and brought the carcass of the dead langur down. Placing it on the forest floor, he studied the body and found nothing remarkable on the surface. Then, unaware or unmindful of the dangers, he opened up the dead monkey. It appeared to have suffered a haemorrhage. He removed its kidney, liver, spleen and brain, collected tissue and blood samples and deposited them all in separate containers packed with dry ice, ready to be dispatched to the Virus Research Centre (VRC) in Pune. Elsewhere in the forest, his fellow team members were doing the same.

Only a few days ago, he had been living on a boat on the Godavari river in Andhra Pradesh, collecting mosquitoes and bird blood. There, he and the others were part of a field team from the VRC investigating if migrant birds were responsible for bringing Japanese encephalitis to India. It had been only four years since he had joined the VRC after a master’s degree in zoology, and he was still only a research assistant. But Rajagopalan, twenty-seven and a bachelor, had a thirst to make something of his life and was quite willing to take risks. That was why he had been summoned here to the evergreen forest known as Kyasanur, in the taluks of Sagar and Sorab in Shimoga district, Karnataka, in early April 1957.

The field investigators from VRC were following up on the mysterious deaths of dozens of monkeys in these parts. The first reports had reached Pune on March 23. More alarming was the accompanying news that people in villages near the forests were falling ill with puzzling symptoms – continuous high fever, lasting for up to two weeks, body pain, headache, vomiting and diarrhoea, sometimes with blood in the stool. Tellingly, the villagers had noted that it was those who had gone into the forest and “seen” or “smelt” dead monkeys who were falling sick. There was only one known disease which killed monkeys in the forest and took down humans too: the dreaded yellow fever.

The Rockefeller Foundation, which had established the VRC in 1952, knew all about yellow fever, a disease carried by mosquitoes that had killed tens of thousands, particularly in South America and Africa. Their health programme, aiming for “the well-being of mankind throughout the world”, had the eradication of yellow fever as one of its first goals, supporting virus research labs in Brazil, Colombia, Nigeria and Uganda. They pioneered research on yellow fever and developed a vaccine, but at a great cost: five of the 67 staff members of the foundation who participated in their yellow-fever programme had died of the disease.

The foundation pulled out of yellow fever research and eradication efforts in the 1930s but their interest in viruses carried by arthropods – such as mosquitoes – continued. In 1951, the foundation embarked on a worldwide programme to discover and catalogue arthropod-transmitted viruses. For a period of 15 to 20 years, they supported labs around the world – in Trinidad, Brazil, South Africa, Colombia, Nigeria – funding them, sending researchers from their headquarters, training researchers in the host nations. And that was how they were in India, too, setting up the VRC in Pune in 1952. Scientists at the foundation’s labs isolated hundreds of viruses by inoculating infant mice with samples that their scientists at field stations around the world had collected. They had wondered why yellow fever appeared to be absent in India. Now, it seemed, they would find out.

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The Kyasanur forest disease “is truly a bhumi dosha, a trouble of the land”.

When Rajagopalan and his fellow field investigators arrived in the forest on April 2, they had no trouble finding monkey carcasses, some freshly dead while others were in various stages of decomposition. The villagers told them that monkeys had been dying since January that year and that a similar episode, on a smaller scale, had occurred a year earlier, too. They were able to confirm this from the Mysore Department of Health, which had records of people falling ill with a typhoid-like illness dubbed “enteric fever”. Some had experienced drowsiness and “mental confusion”. Over 500 fell ill and 70 died of the new disease in 1957. Locals began calling it the “monkey fever”.

VRC field investigators on platforms erected around trees. Credit: P.K. Rajagopalan

VRC field investigators on platforms erected around trees. Credit: P.K. Rajagopalan

There was no time to waste. If this was indeed yellow fever, the numbers of forest mosquitoes which carried it could fluctuate rapidly. The very next day, the team of around a dozen people set to work. They started collecting mosquitoes, day and night, from varying heights in the forest by setting up platforms on the trees. However, unlike in South America, they could find no distinctive forest canopy mosquito in Shimoga. Other puzzles soon presented themselves. They couldn’t find many mosquitoes that bit humans during daytime, which was when the villagers would go into the forest and presumably get bitten. “Only a single mosquito,” noted an early paper [1] presenting their work, “was collected attacking a quiescent human subject during three hours.”

Yellow fever in South America was more prevalent during the rainy season because that’s when mosquitoes were most abundant. In Shimoga, however, all known human – and most of the monkey – infections were reported after the monsoons. And why did the disease not affect monkeys and humans outside Shimoga? The villages affected in 1957, they learned, were mostly the same that had been affected the previous year. Surely mosquitoes were capable of flying into other districts, too? Yellow fever would have raced a hundred miles in a year.

By the middle of April, they heard back from Pune. The samples they sent had been tested. It was indeed an arthropod-borne virus, classified today in the family flaviviridae, to which the yellow-fever, dengue, Japanese-encephalitis and Zika viruses also belong. Human blood samples confirmed the result. The VRC reassigned more insect-collecting teams to Shimoga from Vellore and Pune.

But they could find no virused in the mosquitoes collected. It was clear something else was at work. The samples had been sent to the Rockefeller Foundation’s labs in New York as well. And those results bore a surprise: the virus wasn’t yellow fever. It was, instead, found to be related to the Russian spring-Summer encephalitis, a tick-borne virus prevalent in Russia.

By now, the researchers had noticed that monkey carcasses almost always had large numbers of ticks on them. So they started dragging “flags” of cotton flannel, a square meter across, over the forest floor to collect ticks. They found plenty.

On 17 April, the third day after they had started collecting ticks, two of the team members fell sick. Fearing the worst, work was immediately suspended. Within two weeks, a third man fell ill. The virus was found in all their blood samples.

The great American entomologist Harry Hoogstraal called it “possibly the most dramatic epidemiological detective story of our time.” And it was just beginning.

For half a century, the Kyasanur forest disease (KFD) was confined to five districts of Karnataka: Shimoga, Chikkamagalur, Uttara Kannada, Dakshina Kannada and Udupi. It smouldered quietly most of the time, but there had been major flare-ups in 1982-1984. Over six decades, it has killed more than 500 in Karnataka with a fatality rate of about 5%. In 2006, the first human case outside this endemic area was reported in Gulbarga district that borders Maharashtra. In 2012, six people who handled dead monkeys in the Bandipur National Park, bordering Kerala and Tamil Nadu, fell ill. In 2013, monkeys in neighbouring Nilgiri district, in Tamil Nadu, were found dead and tested positive for the KFD virus.

In the same year, the first human infection was reported from Kerala, in Wayanad district, which borders Bandipur. In 2014, the virus infected adivasis in Nilambur, in Malappuram district in Kerala. In 2015, monkey deaths were followed by more than 100 human infections in an adivasi community in Wayanad, of whom 11 died. It also emerged in Goa, where up to 50 were infected and five died. And this year, it was reported in Sindhudurg, Maharashtra, infecting up to a hundred and killing seven. This caused “a public health alert”, according to the National Institute of Virology, the successor institute to the VRC. In Goa, which has become a new epicentre, 264 cases have been reported this year, with three deaths. Meanwhile, the virus continues to haunt Shimoga, which has had 12 cases and a death this year.

All the places where the disease has emerged lie along the Western Ghats. And therein lies the clue to the case of KFD, which, as an ethnological study of the flare-up in 1982 put it, “is truly a bhumi dosha, a trouble of the land.”

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“That was a brilliant example of the prepared mind and the central importance of field biology, but it is also a sterling metaphor for human self-inflicted impact through disturbance of nature.”

In August 2016, I met Payyalore Krishnaier Rajagopalan at his home in Chennai, a few hundred metres from the sea in a quiet neighbourhood. At 86, he keeps himself occupied by writing on a variety of topics and corresponding with scientists in India and around the world. He points me to the desktop wallpaper on his computer – a blood-engorged Aedes aegypti mosquito, the vector for many flaviviruses such as dengue, chikungunya, Zika and yellow fever. “A beautiful photo,” he tells me.

Rajagopalan shows me other photos as well. “Here’s me with a useless first-class, M.Sc. Zoology degree,” pointing to photos of himself while working as part of the VRC’s team in Shimoga in 1957. He stayed in the KFD area in a field research station for close to 13 years. That is where he says his education really began. One of the tasks he was assigned in the early days was transporting patients, and sometimes dead bodies, from the villages to the hospitals. He recalls how he was chased by a mob on one such occasion and had to run for his life. “Nobody likes their relatives to be cut apart and subjected to post-mortem.”

Later, he himself contracted KFD and began throwing up blood. However, the infection was mild and he recovered. He suspects this is because he had, over the course of his work in Africa and the US where the Rockefeller Foundation sent him, received vaccinations for several related viruses, including yellow fever. But the infection did end up weakening his eyesight. “The Rockefeller Foundation treated my absence as if I was on tour,” he says. “They were great people.”

He also fondly recalls his colleagues at the foundation. Among them was the man he describes as one of his gurus: Jorge Boshell-Manrique, a Colombian physician and epidemiologist. When Boshell arrived in Pune in 1960, Rajagopalan was back from Berkeley where he had been sent for a degree in public health after his initial work in Shimoga.

“For Boshell,” Rajagopalan recalls, “visiting the forest and studying its denizens and their surroundings every day was a must.” That was Boshell’s habit and it was how he had discovered the jungle cycle of yellow fever, a disease that was believed to be spread only by the ubiquitous Aedes aegypti, a very urban mosquito. It was thought that humans played an important role in keeping the virus in circulation by inadvertently helping A. aegypti thrive. Through the Rockefeller Foundation’s efforts, A. aegypti, and thus yellow fever, had been eradicated in South America.

But they did not know that the virus was enzootic, that it was silently circulating in the forests where it was killing howler monkeys. Until, that is, Boshell happened upon woodcutters felling a tree in Villavicencio, Colombia, and watched as they were surrounded by a great number of a hitherto unknown species of mosquito. He had discovered how the virus jumped from mosquitoes, which lived in the forest canopy and infected monkeys, to humans on the forest floor a hundred feet below. “That was a brilliant example of the prepared mind and the central importance of field biology,” a colleague of Boshell wrote later, “but it is also a sterling metaphor for human self-inflicted impact through disturbance of nature.” A virologist visiting Villavicencio in 1963 found a brass plate on a tree commemorating this discovery.

In the Kyasanur forest, Boshell always walked with a machete in his hand to clear the undergrowth, with an eager Rajagopalan behind him. In the five years that they were together at the VRC’s field research station in Shimoga, Rajagopalan scarcely missed an opportunity to listen to Boshell tell stories of his field work all over the world. Boshell too fell ill with KFD, but recovered and spent five years in India before returning to South America. “He was like a walking university,” Rajagopalan says.

Together, they had many mysteries to unravel, now that it had become clear that the virus was not yellow fever. Nevertheless, was it something that had arrived in Shimoga from elsewhere? Migratory birds, for instance, might carry ticks and viruses. But why would they let go of their cargo only in Shimoga? And why now? On the other hand, if the virus was indigenous, why the sudden outbreak? Did this mean the virus had always been enzootic, silently present in the wild? But that led to the same questions: Why only Shimoga? And why now?

A blood sample being taken from a patient with acute fever in a village in Shimoga, c. 1962. P.K. Rajagopalan is the bespectacled person on the extreme right. Credit NIV

A blood sample being taken from a patient with acute fever in a village in Shimoga, c. 1962. P.K. Rajagopalan is the bespectacled person on the extreme right. Credit NIV

“These questions are far from academic,” wrote Boshell in a prescient 1969 paper, collecting the results of years of field work by the VRC. He knew that the way the puzzle unfolded would determine whether KFD would emerge – become epizootic – in new areas in subsequent decades.

Because the Rockefeller Lab in New York had found the KFD virus to be related to that of the Russian spring-summer encephalitis, the possibility arose that this was a virus that had somehow arrived from Russia. As it happened, the ornithologist Salim Ali had a longstanding interest in studying migratory birds by banding them – capturing and attaching small metal tags to the birds – and recapturing them elsewhere, thus tracking their migration. But he hadn’t been able to find funds for such a project. He sensed an opportunity and convinced the WHO that he could study the origins of KFD by collecting ticks and blood samples from the birds arriving from Central Asia. The WHO agreed in 1960 and this became the Bird Migration Project of the Bombay Natural History Society.

KFD, however, did not emerge in new areas immediately after the initial outbreak. The WHO stopped funding but the Smithsonian Institution and the Migratory Animals Pathological Survey (MAPS) programme of the US Army Medical Research Unit – a larger bird-banding project in Southeast Asia to study Japanese encephalitis, among other infectious diseases – started funding Ali instead, in 1964. The full MAPS programme, from 1963 to 1975, banded some 1.2 million birds. Ali agreed to share data and samples with the larger project. Soviet scientists were also involved in Ali’s project and data and samples were sent to their labs. Despite that, a controversy erupted over the American army funding the project with a possible eye on biological weapons. Knowing bird migration routes, critics felt, could open the door to their usage for the delivery of viruses across international borders.

It was in this period that Rajagopalan did his PhD work with Salim Ali, collecting ticks from migratory birds arriving in Shimoga. He found that the birds did not carry any foreign ticks, much less ones carrying viruses. The only birds which appeared to be capable of distributing ticks, though only locally, were ground-foraging birds such as the jungle fowl.

So, the virus had to be indigenous.

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If the VRC researchers wanted to study ticks in the area, they first had to collect them. One way to track down ‘pools’ of ticks in the forest was to go to a village where a human KFD infection had recently been reported and try to reconstruct where the patient had been in the days before they started showing symptoms of the disease. This was difficult, not least because the villagers tended to travel all over the forest in search of firewood or for grazing their cattle. It was easier with children, especially girls who visited the forest rarely and therefore remembered more clearly. These were girls who had gone into the forest to gather twigs or to find jackfruit or flowers for making garlands and had ended up bitten by ticks.

Once they had identified promising areas, the field investigators dragged flags across the forest floor to collect ticks. They would then pick them off using tweezers. This couldn’t be done during the monsoon, so the ticks had to be picked off by hand from under the surfaces of leaves. After sorting the ticks by sex and species, they were put in glass tubes and sent to the VRC lab in Pune for testing. The ticks were indeed carrying the KFD virus.

From the thousands of tick pools collected, a pattern emerged. At the centre was Haemaphysalis spinigera, a tick that infested monkeys and bit human beings. Its larvae start building up in numbers in September after the monsoon. They start reaching their adolescent – or nymphal – stage in November or December, feeding on multiple hosts, becoming capable of transmitting the KFD virus. The nymphs peak in numbers in February or March, maturing into adults with the onset of the monsoon in June. It became clear that the period of nymphal activity coincided with the season of monkey and human infections.

Credit: Ita Mehrotra (KFD)

Credit: Ita Mehrotra

But there was a puzzle, too: tick pools from which the KFD virus had been isolated were often surrounded by other pools not far away from which no virus was found. Such isolated foci of infected ticks had to mean that there was an amplifying factor acting locally: there must be some animal that could circulate the virus in large quantities in its blood, infecting many ticks.

Monkeys were the obvious suspects, but this had to be confirmed. So the researchers captured some, tied belts to their waists, attached a stick to the belt and walked them around the forest to see if they picked up ticks. “After initials fits of rebellion,” reported a paper [2] that resulted, “they submitted and trotted wherever directed.” The monkeys were then taken to a lab in the field research station and placed in cages over water pans. The researchers counted the ticks that dropped from the monkeys after their bloodmeal. In the forest, the ticks drop wherever the monkeys rested or died, explaining the isolated foci.

But were the monkeys really dying of the KFD virus acquired from tick bites? And what was the virus doing to them? To find out, the researchers set up a monitoring system to obtain information about monkey deaths, one that we would today call “crowdsourcing”, complete with rewards. They were not surprised to find that more monkeys died in February and March than in any other month. Over the next seven years, the field team investigated over a thousand monkey deaths and autopsied around 400, the majority of which were langurs. If they found a monkey sick and moribund, it would be transported to the field laboratory or chloroformed on the spot and autopsied – but not before collecting the ticks it hosted and drawing blood from its femoral vein. If the monkey was found dead, they drew blood straight from its heart. Only a few showed anything unusual externally, such as blood clots on the anal sphincter or a slight swelling in the region of the kidneys.

The researchers collected organs – brain, lung, liver, spleen, kidney – from the monkeys, but soon found only the brain and lung were necessary to isolate the virus. These were dispatched weekly by rail to Pune on wet ice. Or, in later years, to the Virus Diagnostic Laboratory in Shimoga. Examination of the liver revealed an abundance of Kupffer cells, which are immune cells that ingest foreign substances and cellular debris, some of which were huge and in the process of dividing. In the brain, they found dying neurons surrounded by microglial cells, which are the brain’s immune cells. “These alterations are not by themselves in any way specific,” noted a paper [3], “and could be part of any general toxemic or infective fever.”


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There were more puzzles: The monkeys were dying in different areas each year, though the total affected area did not expand much. Was the virus moving on after depleting the monkey population in an area? Were the surviving monkeys immune? In any case, monkeys weren’t dying throughout the year. And their heavy mortality meant they couldn’t be the ‘reservoir hosts’ for the virus. Besides, the new generation of tick larvae emerging each season weren’t infected. Both ticks and monkeys were acquiring the virus from somewhere.

Zoonotic viruses, in order to survive, must find a way go back and forth between a vector and a reservoir organism, a relationship that must have co-evolved over millions of years. “Each virus is a zoological entity unto itself,” wrote the virologist Wilbur Downs, “with its own narrowly defined determinants for its continued successful existence.”

Rajagopalan and his fellow researchers suspected the various smaller mammals roaming about on the forest floor – rodents and shrews. They set up Sherman traps along forest interfaces, in the undergrowth, in the entrances of holes in the ground and outside hollow trunks. Within these traps, they placed an enticing bait: “a spiced split-pea paste mixed with onion and fried in oil”. [4] In other words, a pakoda. The animals were indeed hosting ticks, of several species, and many were infected with the KFD virus. These small mammals were keeping the virus alive during the monsoon, between infection seasons, hosting both H. spinigera and other genera of ticks, mainly Ixodes, which are also vectors for the KFD virus. In turn, the quick population turnover of these animals ensures that there’s always a good number of susceptible hosts for the virus. “In three or four months, another batch comes,” Rajagopalan told me, snapping his fingers.

They found, however, that the number of infected animals was a small proportion of the total population. Of those, only some circulated the virus in their blood and became capable of infecting ticks. What had caused the virus to break out of this enzootic cycle and infect humans?

Rajagopalan likes to refer to the confluence of factors responsible as “Boshell’s cup of coffee”. First, one must have quality coffee seeds – the virus. “Then,” he says, “it must be freshly roasted.” A susceptible population of animals. The roasted seeds must be freshly ground; the climate and environment must be suitable. There must be a thick decoction, meaning the presence of large number of vectors, the ticks. Add to this fresh cream or milk – susceptible monkeys. He recalls what Boshell liked to say: “If all these are present in the right proportions,” as in a good cup of Chikkamagalur coffee, “you get a human KFD case.”

An illustration of Boshell's cup of coffee. Credit: Ita Mehrotra (KFD)

An illustration of Boshell’s cup of coffee. Credit: Ita Mehrotra

All these factors were at play in Shimoga. The forest was not unbroken; it was interspersed with fields where rice, sugarcane, arecanut and other crops were cultivated. And the villages were on the edges of these forests. Domestic cattle, though not themselves infected, hosted adult ticks, amplified their population and distributed them. The region had witnessed a doubling of its human population in ten years from 1951 to 1961. This was accompanied by an increase in the cultivated area, with clearing of forests.

Boshell reported in his paper that the interface between forest and cultivated area or open grassland, areas where original forests had been destroyed, was often occupied by an invasive weed called Lantana camara, which grew in thickets up to three metres high. Lantana had made its way to India from Sri Lanka, where it had arrived from Central America. “It is a fact of daily observation, for instance,” noted Boshell, “that the last refuge of the hard-pressed jungle fowl is the impenetrable lantana thicket.” Other invasive weeds linked to abundant tick populations include Eupatorium and Chromolaena odorata. Small mammals would spend time in this dense undergrowth, shedding ticks that could then be picked up by monkeys forced to spend more time on the ground. As they retreated to the forest, the monkeys would shed ticks wherever they rested. Moreover, monkeys infected with KFD have high viremia, circulating the virus in their blood in large quantities, thus infecting ticks that bite them.

Such transition zones, where animals that normally have different habitats mix, are a known risk factor for spillover of wild pathogens. Lower biodiversity can make this worse because the disease vectors would be forced to more frequently parasitise their primary hosts. Perhaps a species that hosted the vectors, but had low viremia, is now disappearing and the vectors infest high viremia species instead. This has the effect of amplifying the proportion of those hosts and vectors that are infected with a pathogen. A higher biodiversity would mean the vectors can feed on a wider range of hosts, some of which might not be good reservoirs for the pathogen.

A good example is the case of Lyme disease in the US, caused by bacteria and carried by Ixodes ticks found on deer. In forests with a smaller diversity of vertebrates, the tick population was found to be larger. Moreover, a larger proportion of the tick population was found to be infected with the bacterium. Another example is the protozoan that causes Chagas disease, whose prevalence in small mammals in fragmented forests was found to be higher than in contiguous forests.

It is notable that no such detailed ecological studies have been carried out for any zoonotic pathogen in India, including the KFD virus, since the 1970s, when the Rockefeller Foundation pulled out and closed their field research stations. This is made worse by poor knowledge of zoonotic pathogens in India’s wildlife. Worldwide, an estimated 75% of emerging pathogens are zoonotic.

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Review papers have noted how virtually everything that is known about KFD comes from studies in the late 1950s and early 1960s.

After the initial outbreak in 1957, the places where KFD flared-up shifted from year to year but slowly. In 1964, a dam constructed for a hydroelectric power project on the river Sharavathi, which runs through Shimoga and neighbouring districts, caused “submersion of a large area along with loss of biodiversity”, according to an impact assessment. Then, in the early 1970s, there were outbreaks in four districts that neighbour Shimoga. There was a major flare-up in 1982-1984 when more than a thousand people were infected, a tenth of whom died. This was preceded by a deforestation for export-oriented cashew plantations financed by the World Bank. The area under cashew cultivation had quadrupled in Dakshina Kannada district in the preceding years. Several papers have noted how KFD has appeared in areas where forests have been cleared for ‘monocultures’ such as teak, eucalyptus or cashew plantations.

Once a human is infected with the virus, it can take anywhere from two days to a week for the symptoms to show up. Apart from the continuous high fever and body pain, diarrhoea and vomiting is common – as is an extreme sensitivity to light, abnormal red blood cells and a reduction in platelet count. However, there are variations, too. Most cases are not haemorrhagic but of those that are, bleeding has been observed from the nose, gums and intestines. Some people recover after two weeks of persistent symptoms. A few, after a week or so of no symptoms, relapse – this time with neurological symptoms.

This biphasic nature of the illness remains a puzzle. Most patients recover completely but remain weak for months. In these and other aspects, the KFD virus – classified as Biosafety Level 4, the most dangerous class of pathogens – was found to closely resemble Omsk Haemorrhagic Fever, found in Siberia, and which also belongs to the family of tick-borne flaviviruses.

“KFDV is an interesting virus because it behaves somewhat differently from other related tick-borne flaviviruses,” says a researcher who did not want to be named. Unlike for other tick-borne flaviviruses, she says, monkeys play an important part in the transmission. There are more specific questions having to do with what the virus does once inside the body. “What is the immune response following KFD virus infection? Does the virus regulate components of the immune response? What are the target cells for the virus? How does the virus get into the brain? What does the disease process look like in non-human primates?”

According to her, these questions are important because, once someone is infected, “you are often dealing with the immune response or other repercussions of the virus infection rather than the virus itself.”

As recently as 2004, India’s National Institute of Virology (NIV) had declared KFD a “complete success story from detection of virus to the development of killed vaccine”. But a 2016 paper acknowledged that “human infections have reached an alarming level in spite of the availability of a vaccine”. The vaccine for KFD was developed in the 1960s based on a strain isolated during the early research. Annual rounds of vaccination have been carried out in the affected areas since 1990. However, this is confined to villages within a five-kilometre radius of areas where infections had been reported in the previous year.

The vaccine also has a cumbersome protocol: two doses spaced one month apart, with a booster after six to nine months. This has to be followed by another booster at the end of one year, repeated yearly for the next four years. The vaccine is limited to those between the ages of 7 and 65 on the grounds that only they are likely to be exposed to the forest – which is another oddity because 17% of infections in a study fell outside this age group. Further, in 2005–2010, 52% of the eligible population did not receive the vaccine. Of those who did receive, some who had received two doses and a booster were infected, too.

In 2006, the first human case outside this endemic area was reported in Gulbarga district bordering Maharashtra. After modern diagnostic tests were developed at NIV, unexplained fevers in other places began to be screened for KFD. Since 2012, more than a hundred cases and twenty deaths have been reported from districts that border Karnataka in the neighbouring states of Kerala, Tamil Nadu, Goa and Maharashtra. In Goa, workers at cashew plantations appear to be at greater risk. In both Goa and Wayanad, there is a clamour for monkeys to be declared “vermin”. And in both places, tribal communities are the ones affected and have reportedly been refusing vaccination.

This coincides with reports from Goa of a shortage of vaccines. And earlier this year, some people in Wayanad resorted to setting forest undergrowth on fire in an effort to kill ticks, reportedly on the suggestion of health workers.

Ticks being picked off (the person in this image is not P.K. Rajagopalan). Credit: P.K. Rajagopalan

Ticks being picked off (the person in this image is not P.K. Rajagopalan). Credit: P.K. Rajagopalan

G. Arunkumar of the Manipal Centre for Virus Research acknowledges the need for a better vaccine. He believes KFD has always been misdiagnosed in the new areas because its symptoms resemble that of dengue or that of any other illness causing an acute fever. “There is no reason to believe that it has emerged now. It was always there,” he says. “All our disease surveillance efforts till 2012 were limited only to the Shimoga area. But when we at Manipal Centre for Virus Research started active fever surveillance along Western Ghats, the disease was detected in other areas, too.”

Serological surveys had indeed uncovered the presence of antibodies in animals and humans in places far removed from Shimoga and as far back as 1952. But if modern diagnostic tests and surveillance are the reasons for KFD’s apparent emergence in recent years, it only pushes further back in time the question of when and how it becomes epizootic in these areas. In fact, there are claims that KFD has been infecting people in Goa from the 1980s. But several questions remain: Why are monkeys dying in noticeable numbers now? Why these and not other places along the Western Ghats? And what factors are amplifying the tick population in these new areas?

“Nobody has looked at it. We worked because of the Rockefeller Foundation. Those scientists were dedicated people. If we were purely under the [Indian Council of Medical Research] we would also not have done anything,” says Rajagopalan. The council has been running NIV after the Rockefeller Foundation’s support ended in 1967.

A recent paper on the Kerala outbreaks reported that although people living in the affected areas had been bitten by ticks even in previous years, it was only in 2014-2015 that they fell ill. If this is true, then it suggests that KFD has become epizootic in these areas only now. Arunkumar, however, dismissed this as “baseless”.

Meanwhile, in 1994, a butcher in Makkah, Saudi Arabia fell ill with symptoms similar to KFD. The virus in his blood was found to be closely related to the KFD virus. Cases of the Alkhurma haemorrhagic fever (AHFV) have since turned up in other parts of Saudi Arabia over the years and with a fatality rate similar to KFD. In 2010, it surfaced near the Egypt-Sudan border. It was found that this fever was also carried by ticks of Ornithodoros and other genera and which parasitise sheep and camels.

It was initially thought that the KFD virus had been somehow introduced to Saudi Arabia in the recent past. Genetic analysis of the KFD and AHFV viruses, however, revealed that they diverged around 700 years ago. The Karshi and Farm Royal viruses in Uzbekistan and Afghanistan, respectively, have also been found to be related to the KFD virus. A paper noted that this “raises the possibility of closely related but undiscovered virus variants existing in the regions between Saudi Arabia and India.”

There is speculation that the ancestor of all these viruses may have travelled along the Silk Road, between China and Europe, presumably on camels carrying ticks. A related virus was believed to have been found in China but this has since been contested. The history of the virus remains a mystery for now – along with other questions, some more pressing.

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“We worked because of the Rockefeller Foundation. Those scientists were dedicated people. If we were purely under the ICMR we would not have done anything.”

Rajagopalan likes to refer to the pioneering Soviet entomologist and disease ecologist Yevgeny Pavlovsky’s concept of the “nidality” of a disease. Just as animals have their natural habitats, Pavlovsky argued, so does a disease. A zoonotic disease exists under certain environmental conditions in which the pathogen, its vectors and its reservoir hosts have a relationship that is defined by the geography they find themselves in. When they penetrate this web of interrelationships, humans can inadvertently cause the nidus, or focus, of the disease to shift.

“There are wheels within wheels,” Wilbur Downs had written, referring to the intricate mechanisms a virus has to find over aeons to keep itself alive, flitting from species to species in the wild through various chains of infections that may or may not overlap.

“There is the ‘small mammal-Haemaphysalis-small mammal’ chain and the ‘small mammal-Ixodes-small mammal’ chain,” Rajagopalan told me, referring to the two genera to which ticks found to carry the KFD virus belong. “Then there is the ‘small mammal-Haemaphysalis-monkey’ chain. Finally, the ‘monkey-tick-man’ chain.” He also suspects there must be a ‘bat-tick-bat’ zoonotic cycle in nature, based on work he did just before the field research station in Shimoga was closed. It is not known if such a cycle feeds into the ‘small mammal-tick-monkey’ chain.

Although ticks have been found to transmit the virus from one generation to the next in the lab, Rajagopalan believes this is not an important mechanism for keeping the virus in circulation between infection seasons. Researchers in the 1960s had found infected Haemaphysalis nymphs and adults that survived the dry season preceding the monsoon, overlapping the next generation of ticks that started appearing after the monsoon. Further, shrews are parasitised by both the Haemaphysalis and Ixodes ticks, perhaps facilitating transfer of infection from one to the other. This is important because Ixodes ticks are more numerous during the monsoon.

If ticks are present in unusually large numbers, as was found in Wayanad and Malappuram districts of Kerala, it means that there is an abundance of appropriate hosts. What these hosts are in the new areas where KFD has emerged remains unknown in the absence of detailed field investigations. When they’re not attached to a host and feeding, the ticks are known to require very specific conditions of rainfall, humidity and temperature for their survival.

In Turkey, for example, the risk of occurrence of the Crimean-Congo haemorrhagic fever in new regions has been modelled statistically, based on knowledge of where the relevant tick species was already present, and on climatic conditions and ecological interface zones. Worldwide, a climate-change-induced shift of the abundance and distribution of many tick species has been noted over the last three decades. Increasing mean temperatures have been associated with shorter development cycles in ticks. In fact, the VRC researchers had noted that after an abnormally brief monsoon season in 1965, when it stopped raining abruptly in the middle of August, nymphs had started appearing a month early in October. Whether the emergence of KFD in new areas is in any way linked to climate change is unknown and has also remained unexplored.

There are other unknowns about the transmission of the KFD virus. Review papers have noted how virtually everything that is known about KFD comes from studies in the late 1950s and early 1960s. In this period, over 50 workers at the VRC lab in Pune were infected with the KFD virus. Some spilled infected fluids on their hands, but for others, the route of infection was less clear. Such infections raised the possibility that the virus could enter the body through inhalation of aerosols. After the Rockefeller Foundation pulled out in 1967, and the VRC became the NIV, lab work was discontinued. It only resumed in 2005 when the ‘Biosafety Level 4’ classification was established.

New studies will require not just money but also expertise in entomology, which Rajagopalan believes India lacks. He has written extensively in the context of vector-borne diseases as to why he believes entomologists are a dying race in India. Rajagopalan, who was awarded the Padma Shri in 1990, has been very critical of the ICMR, a body that he served for more than three decades before rising to become the founding director of the Vector Control Research Centre in Puducherry in 1975. “You ask them to live there in the forest,” he says, referring to scientists today. “He’s a scientist you know. Without white coat and an A/C room, he cannot work. Without a computer he cannot become a scientist.”

Back in 1982, Wilbur Downs had noted in a review of the Rockefeller Foundation’s virus research programme that “financing of field epidemiological studies does not receive high priority in today’s laboratory-oriented virus research world.” Rajagopalan concurs, and refers to field studies today as “safari research”. “One thing you must understand in India – as long as people die, everybody will be interested. If people don’t die anymore, nobody is interested.”


Citations of papers to which permalinks were not available:

[1] Boshell-Manrique, Jorge, P.K. Rajagopalan, M.K. Goverdhan, and K.M. Pavri. “The Isolation of Kyasanur Forest Disease Virus from Small Mammals of the Sagar-Sorab Forests.” Indian Journal of Medical Research 56.4 (1968): 569-72. Web. 19 Nov. 2016.

[2] Boshell-Manrique, Jorge, and P.K. Rajagopalan. “Observations on the Experimental Exposure of Monkeys, Rodents and Shrews to Infestation of Ticks in Forest in Kyasanur Forest Disease Area.” Indian Journal of Medical Research 56.4 (1968): 573-88. Web. 19 Nov. 2016.

[3] Iyer, C.G.S., T.H. Work, D.P. Narasimha Murthy, H. Trapido, and P.K. Rajagopalan. “Pathological Findings in Monkeys, Presbytis Entellus and Macaca Radiata, Found Dead in the Forest.” Indian Journal of Medical Research 48.3 (1960): 276-86. Web. 19 Nov. 2016.

[4] Boshell-Manrique, Jorge, P.K. Rajagopalan, M.K. Goverdhan, and K.M. Pavri. “The Isolation of Kyasanur Forest Disease Virus from Small Mammals of the Sagar-Sorab Forests, Mysore State, India: 1961-1964.” Indian Journal of Medical Research 56.4 (1968): 569-72. Web. 19 Nov. 2016.

Nithyanand Rao is a freelance science journalist in Bengaluru.

Copy editor: Thomas Manuel
Editor: Vasudevan Mukunth

  • Dr.K.SParthasarathy

    Very informative article

  • K SHESHU BABU

    Fascinating write-up on the tracking of a rare but dangerous disease . The hard work is commendable

  • binay panda

    sad to know that dedicated researchers have such low opinion on indian research organizations. we must thrive to change that.

  • Pratik Gupte

    This is a damn good piece!

  • Vaibhhav Sinha

    A thrilling read! Zoonotic viruses are always fascinating, but this was like a whodunnit within a whodunnit. It’s remarkable to see the kind of physical, cultural, and logistic challenges which had to be overcome to put all the pieces together. Great job connecting those dots for the piece.

  • Amit Misra

    Very well-written. Thank you so much for educating me about KFD, and even more for highlighting the importance of field biology. However, today it would be unthinkable for researchers to expose themselves to the kind of dangers that our seniors gladly faced in the 1950s-1990s. BSL4 containment of the forest floor is simply not an option, and regulations, ethics committees and funding agencies would not be in a position to allow and fund similar studies required for explication of mystery diseases prevalent in eastern UP, Bihar, Odisha, Himachal, you name the region…

  • Shirish Kavadi

    Thank you for a very interesting article. I am currently working on a book manuscript on the Rockefeller Foundation and Medicine in India:1947-1970 and have a chapter on the Virus Research Centre with a section on the VRC intervention in KFD. I have primarily relied on the RF archives in New York but found little at NIV here in Pune. I would be happy if anyone could direct me to some useful sources and share information they may have on the VRC and KFD in the 1950s and 1960s.