The 64-Year Hunt For The Origins of The Kyasanur Forest Disease

11/19/2016 The 64Year Hunt for the Origins of the Kyasanur Forest Disease
FE ATURE D
The Seven-Decade
Transnational Hunt
for the Origins of a
Strange Disease in
Karnataka
BY NIT HY ANAND R AO ON 19/11/20 16 • LEAVE A COMMENT
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
http://thewire.in/81210/kyasanurkfdrajagopalanboshell/ 1/26
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, twentyseven 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 wellbeing 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 yellowfever 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.
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
typhoidlike 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”.
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
VRC field investigators on platforms erected around trees.
Credit: P.K. Rajagopalan
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 arthropodborne virus,
classified today in the family flaviviridae, to which the yellowfever,
dengue, Japaneseencephalitis 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 springSummer encephalitis, a tickborne
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
(http://www.annualreviews.org/doi/abs/10.1146/annurev.en.11.010166.001401) “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 flareups in 19821984. Over
six decades, it has killed more than 500
(http://www.thehindu.com/news/national/karnataka/vaccinationdriveagainst
kyasanurforestdiseasefromtoday/article7939157.ece) 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 (http://dx.doi.org/10.3201/eid1909.121884)
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
(http://dx.doi.org/10.1016/j.ttbdis.2016.09.010) by more than 100 human
infections in an adivasi community in Wayanad, of whom 11 died. It
also emerged in Goa (http://timesofindia.indiatimes.com/city/goa/Rare
monkeyfeverbehindPallivillagersfallingsick/articleshow/46925148.cms), where
up to 50 were infected and five died. And this year, it was reported
(http://timesofindia.indiatimes.com/city/pune/Monkeyfeverjabforhighrisk
groupthiswintertocounterspread/articleshow/53349272.cms) in Sindhudurg,
Maharashtra, infecting up to a hundred and killing seven. This caused
“a public health alert”, according
(http://niv.co.in/annual_reports/Annual_Report_15_16/Director_desk.pdf) to the
National Institute of Virology, the successor institute to the VRC. In
Goa, which has become a new epicentre, 264 cases
(http://www.navhindtimes.in/monkeyfevercasesundercontrolfornow/) have
been reported this year, with three deaths. Meanwhile, the virus
continues to haunt (http://www.thehindu.com/news/national/karnataka/30
dengueand12kfdpositivecasesreportedinshivamogga
district/article8518663.ece) 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 (http://www.jstor.org/stable/648544) of the flareup in
1982 put it, “is truly a bhumi dosha, a trouble of the land.”
“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 selfinflicted 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 bloodengorged 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 firstclass, 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
postmortem.”
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 everyday 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 (https://books.google.co.in/books?
id=JnBpAgAAQBAJ&pg=PR11&lpg=PR11&dq=rockefeller+jorge+boshell&source=bl&
ots=NmTofSfng5&sig=NWPcVjfBCvauMxR8bx6d3eBDS9s&hl=en&sa=X&ved=0ahUK
Ewj2o9mw
uXOAhUcT48KHQtRCMkQ6AEIKjAD#v=onepage&q=rockefeller%20jorge%20boshell
&f=false), “but it is also a sterling metaphor for human selfinflicted
impact through disturbance of nature.” A virologist visiting
Villavicencio in 1963 found a brass plate on a tree
(https://ia802604.us.archive.org/19/items/virologistnatura00johnrich/virologistnat
ura00johnrich.pdf) 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?
“These
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
questions are far from academic,” wrote Boshell in a prescient 1969
paper (http://www.ajtmh.org/content/18/1/67.full.pdf+html), 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 springsummer 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
(http://www.jstor.org/stable/4412243), 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 groundforaging birds
such as the jungle fowl.
So, the virus had to be indigenous.
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
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 coevolved over millions of years. “Each virus is a
zoological entity unto itself,” wrote
(http://www.annualreviews.org/doi/abs/10.1146/annurev.me.33.020182.000245)
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 splitpea 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
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 hardpressed
jungle fowl is the impenetrable lantana thicket.” Other invasive
weeds linked to abundant tick populations include Eupatorium
(http://ces.iisc.ernet.in/envis/sdev/etr16.pdf) and Chromolaena odorata
(http://timesofindia.indiatimes.com/city/goa/KFDoutbreaklinkedtoforest
degradation/articleshow/50875364.cms). 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
(http://www.pnas.org/cgi/doi/10.1073/pnas.1208059110) 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
(http://dx.doi.org/10.1016/j.actatropica.2014.06.009) of zoonotic pathogens in
India’s wildlife. Worldwide, an estimated 75%
(http://dx.doi.org/10.1098/rstb.2001.0888) of emerging pathogens are
zoonotic.
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 flaredup
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
(http://ces.iisc.ernet.in/energy/water/paper/rvp/rvp_right_down_sa.htm). Then,
in the early 1970s, there were outbreaks in four districts that
neighbour Shimoga. There was a major flareup in 19821984 when
more than a thousand people were infected, a tenth of whom died.
This was preceded by a deforestation for exportoriented cashew
plantations (https://books.google.co.in/books?id=fX
PvR86gD8C&pg=PA256&lpg=PA256&dq=kyasanur+sri+lanka&source=bl&ots=_b
jPg718n&sig=qSMCLJgwzs_FiyhE32DEt
RYyBA&hl=en&sa=X&ved=0ahUKEwjo99yd0pXOAhWDpo8KHZ5PD7wQ6AEIYTAJ
#v=onepage&q=kyasanur%20sri%20lanka&f=false) financed by the World
Bank. The area under cashew cultivation had quadrupled
(https://books.google.co.in/books?
id=Afm3YbD_TV0C&pg=PA115&lpg=PA115&dq=cashew+plantation+world+bank+da
kshina+kannada&source=bl&ots=99c6V5bHUA&sig=xStzwE3XOMIWIB6XUkwp1vkb
8EY&hl=en&sa=X&ved=0ahUKEwjDlsuE78LOAhWIto8KHVIxCSAQ6AEIHTAA#v=o
nepage&q&f=false) in Dakshina Kannada district in the preceding years.
Several papers have noted (https://books.google.co.in/books?id=fX
PvR86gD8C&pg=PA256&lpg=PA256&dq=kyasanur+sri+lanka&source=bl&ots=_b
jPg718n&sig=qSMCLJgwzs_FiyhE32DEt
RYyBA&hl=en&sa=X&ved=0ahUKEwjo99yd0pXOAhWDpo8KHZ5PD7wQ6AEIYTAJ
#v=onepage&q=kyasanur%20sri%20lanka&f=false) 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 tickborne flaviviruses.
“KFDV is an interesting virus because it behaves somewhat
differently from other related tickborne flaviviruses,” says Michael
Holbrook of the National Institute of Allergy and Infectious Diseases,
US. Unlike for other tickborne flaviviruses, he 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 nonhuman primates?”
According to him, 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
(http://www.icmr.nic.in/pinstitute/niv/KYASANUR%20FOREST%20DISEASE.pdf)
KFD a “complete success story from detection of virus to the
development of killed vaccine”. But a 2016 paper acknowledged
(http://dx.doi.org/10.1016/j.ijid.2014.05.013) 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 (http://dx.doi.org/10.1002/rmv.495). Annual
rounds of vaccination have been carried out
(http://dx.doi.org/10.1371/journal.pntd.0002025) in the affected areas since
1990. However, this is confined to villages within a fivekilometre
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 (http://dx.doi.org/10.3201/eid2101.141227) 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
(http://dx.doi.org/10.1007/s4047501600671) in Gulbarga district bordering
Maharashtra. After modern diagnostic tests were developed
(http://dx.doi.org/10.1016/j.jviromet.2012.07.019) 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 (http://timesofindia.indiatimes.com/city/goa/KFDhasSattari
cashewfarmersinatightspot/articleshow/51162409.cms) at greater risk. In
both Goa (http://timesofindia.indiatimes.com/city/goa/Soonmonkeystobe
declaredverminGoaCM/articleshow/50562690.cms) and Wayanad
(http://www.thehindu.com/news/national/kerala/nomoremonkeying
around/article8039204.ece), there is a clamour for monkeys to be declared
“vermin”. And in both places, tribal communities are the ones
affected and have reportedly (http://www.ndtv.com/indianews/villagersin
goarefusevaccinationagainstraredisease764662) been refusing vaccination.
This coincides with reports from Goa of a shortage
(http://timesofindia.indiatimes.com/city/goa/450registerforKFDimmunization
inSattari/articleshow/51466957.cms) of vaccines. And earlier this year,
some people in Wayanad resorted to setting forest undergrowth on
fire (http://timesofindia.indiatimes.com/city/kozhikode/Fightingmanmadefires
onforestdepartmentslistthisyear/articleshow/51385847.cms) in an effort to
kill ticks, reportedly on the suggestion of health workers.
G.
Arunkumar
of the
Manipal
Centre for
Virus
Research
acknowledges
the need for a
better
vaccine. He
Ticks being picked off (the person in this image is not P.K.
Rajagopalan). Credit: P.K. Rajagopalan
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
(http://dx.doi.org/10.1002/rmv.495) 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 (http://www.navhindtimes.in/kyasnur
forestdiseaserediscoveredingoa/) 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 (http://dx.doi.org/10.1016/j.ttbdis.2016.09.010) 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 (http://dx.doi.org/10.1371/journal.pntd.0001352) (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 (http://dx.doi.org/10.1371/journal.pntd.0001352)
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
(http://dx.doi.org/10.3201/eid1509.080759). The history of the virus remains
a mystery for now – along with other questions, some more pressing.
“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 mammalHaemaphysalissmall mammal’ chain
and the ‘small mammalIxodessmall 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
Haemaphysalismonkey’ chain. Finally, the ‘monkeytickman’
chain.” He also suspects there must be a ‘battickbat’ 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 mammaltickmonkey’ 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 (http://dx.doi.org/10.1007/s104930129615
0) require very specific conditions of rainfall, humidity and
temperature for their survival.
In Turkey, for example, the risk of occurrence of the CrimeanCongo
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 climatechangeinduced 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 (http://dx.doi.org/10.1016/j.antiviral.2012.10.005)
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
(http://www.jstor.org/stable/1722721) 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 vectorborne 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
(http://www.frontline.in/thenation/ailingresearch/article6951366.ece) 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
(http://www.annualreviews.org/doi/abs/10.1146/annurev.me.33.020182.000245) of
the Rockefeller Foundation’s virus research programme that
“financing of field epidemiological studies does not receive high
priority in today’s laboratoryoriented 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] BoshellManrique, Jorge, P.K. Rajagopalan, M.K. Goverdhan, and
K.M. Pavri. “The Isolation of Kyasanur Forest Disease Virus from
Small Mammals of the SagarSorab Forests.” Indian Journal of
Medical Research 56.4 (1968): 56972. Web. 19 Nov. 2016.
[2] BoshellManrique, 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): 57388. 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): 27686. Web. 19 Nov.
2016.
[4] BoshellManrique, Jorge, P.K. Rajagopalan, M.K. Goverdhan, and
K.M. Pavri. “The Isolation of Kyasanur Forest Disease Virus from
Small Mammals of the SagarSorab Forests, Mysore State, India:
19611964.” Indian Journal of Medical Research 56.4 (1968): 56972.
Web. 19 Nov. 2016.
Nithyanand Rao is a freelance science journalist in Bengaluru.
Copy editor: Thomas Manuel
Editor: Vasudevan Mukunth (mailto:mukunth@thewire.in)
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