Managing Nipah

WITH the sudden outbreak of the deadly Nipah viral infection, whose origin is still unknown, Kerala’s stressed health care system had to learn quite a few hard lessons before it could declare that the “first wave” of the rare infection in the State was more or less under control.

It was on May 19 that the Nipah infection was first reported from Kozhikode district. By May 28, 16 people in Kozhikode and Malappuram districts were confirmed as having contracted the disease, which causes severe respiratory infection and fatal encephalitis in humans and animals. By May 30, 15 persons had died. Some 149 people suspected to have come in contact with those who had the infection tested negative in examinations conducted at the National Virology Institute, Pune.

After a high-level review meeting in Kozhikode, the epicentre of the Nipah occurrence, Health Minister K.K. Shailajah announced on May 28 that the Nipah infection was under control. “It has been established that all Nipah cases reported so far are connected to a single source. But as a matter of precaution, we should be prepared to prevent chances of a second wave of infection,” the Minister said. Kerala was praised for quickly identifying the virus and promptly initiating containment measures. The virus was identified in the second person it was known to have infected in the State.

In contrast, in the previous reported occurrence in India 17 years earlier at Siliguri in West Bengal, 45 people died within weeks of the outbreak, which went undetected for a long time. The majority of the dead were hospital workers or those who had come in contact with patients in hospitals. Similarly, in Bangladesh in 2011, 40 of the 44 people who contracted the infection died, according to the World Health Organisation (WHO).

Early detection It was thus a major achievement for Kerala to have identified the virus early, thanks mainly to Dr A.S. Anoop Kumar and his fellow doctors at the critical care unit of the Baby Memorial Hospital in Kozhikode. It was sheer skill and dedication that made them look a bit more closely at a young man who came to the hospital early in the morning on May 17 with a lot of “breathing difficulty” and “altered consciousness”.

The patient was soon admitted in the closed multidisciplinary intensive care unit (ICU), where doctors first considered it a case of encephalitis. “He was showing signs of encephalitis, but unlikely features as well, such as very high blood pressure and heart rate and severe inflammation of the heart muscles, what we call myocarditis,” Dr Anoop Kumar told Frontline .

“Irrespective of all the organ support measures that were provided, his condition kept deteriorating. When we asked for his history, the relatives told us that his brother too had died on May 5, at the Kozhikode Medical College Hospital [MCH], reportedly of encephalitis, and that there were two other members in the family who were similarly ill. We asked them to be brought to the hospital and their condition, too, was bad and deteriorating. We then thought it could be a case of accidental poisoning but soon veered around to the view that it was some kind of unusual but severe viral infection.

“Samples were sent to an expert virologist, Dr Arun Kumar of the Manipal Virology Institute [about 300 kilometres away], the same day. The first patient had become extremely sick by then, and our neurology team led by Dr Jayakrishnan suggested for the first time that it could be a case of Nipah virus encephalitis. But by then the young man had died, and we convinced the relatives of the need for a pathological autopsy, and organ samples, too, were sent to Manipal.”

Dr Anoop Kumar added: “We were soon informed that it was a deadly virus with high infectivity and were asked to tighten infection control measures at the hospital. The government was alerted and a meeting was organised to discuss preventive measures, even though it took two more days for the formal announcement to be made based on conformation from the National Virology Institute, Pune. Within 36 hours of admission of the young man, we could find out the cause of the infection.”

Government officials inspecting a well in Kozhikode district on May 21 to catch bats.

Kerala is known for its preparedness in dealing with outbreaks but in this case, the State’s early response was not robust, health officials said. For instance, although the second case was detected promptly in a private hospital, the health authorities are worried that a government medical college hospital failed to detect the first case, that of the young man from the same family who died there as early as May 5.

Rajeev Sadanandan, Additional Chief Secretary (Health), told Frontline : “Nipah infection mimics the symptoms of encephalitis. So, those States that have prevalence of other forms of encephalitis could mistake Nipah infection for some other form of encephalitis. In Siliguri they mistook it for Japanese encephalitis. That is why there was delay there and there were so many deaths. In the case of Kerala, these kinds of encephalitis are very rare. Like malaria, for instance, which too is rare. So, whenever such cases arise, we tend to investigate it deeply. But we failed to do it this time.”

He added: “The first case of a 26-year-old man was referred to the Kozhikode Medical College Hospital, where we failed to identify the real cause of death. Had they been able to identify the virus correctly, many lives could have been saved and we would have had a real good head start.”

But on May 17, the very next case at the Baby Memorial Hospital was identified correctly owing to the diagnostic skills and timely efforts of the team of doctors.

Once the infection was identified, the State government machinery began its emergency drill in right earnest. It started tracing all those who had come in contact with the patients or otherwise had any possibility of exposure to the virus. On the basis of the universally accepted method of contact tracing, as on May 28, samples from 149 people were sent for tests, but only 16 tested positive for the virus.

“We went back to the basics. Every case was reviewed and their contacts were identified, put on observation, quarantined and tracked and on the first sign of infection shifted to hospital care. That is how we believe we were able to contain it,” a Health Department official said.

“Field staff were put on constant watch. Dedicated ambulances were kept ready to bring suspected cases directly to the Kozhikode Medical College Hospital. We sought out each person in the contacts list, meticulously took their history for the previous 25 days, took notes on where they went, who they met and the latter became the next contact for us to trace. Thus, we prepared a list of 826 people, our target list in what we describe as the ‘first wave’. What we are most happy about is that all the cases that tested positive were there on our list (except one, who later died in a private hospital). So we are reasonably confident that our strategy has worked well, even allowing for some gaps,” the official added.

The State authorities decided to expand their inquiries further after two deaths were reported on May 30 of people who were already under treatment and who were either not on the original list or were from places where Nipah was originally not reported.

According to the WHO’s surveillance and outbreak alert of Nipah virus encephalitis in Kerala, it is an emerging infectious disease spread by secretions of infected bats. It can spread to humans through contaminated fruit, infected animals or close contact with infected humans.

The WHO Nipah fact sheet says that fruit bats of the Pteropodidae family are the natural host of the Nipah virus. It can be transmitted to humans from animals such as bats or pigs or contaminated foods and can also be transmitted directly from humans.

The virus infection in humans causes a range of clinical presentations, from asymptomatic infection to acute respiratory infection and fatal encephalitis. The case fatality rate is estimated at 40-75 per cent. This rate can vary depending on local capabilities for epidemiological surveillance and clinical management.

Over the years, the Nipah virus has shown a tendency to be increasingly fatal in human beings. The fatality rate in the first series of outbreaks in Malaysia and Singapore, where transmission had occurred from bats to humans through an intermediary host, mainly pigs, was relatively low. But in the later outbreaks, in Bangladesh and India from 2001, where transmission was more from bats to humans and between humans who had come in close contact with each other, especially in hospital settings, the fatality rate was reported to be as high as 75 per cent or more.

In India, according to WHO figures, the fatality rate in Kerala was above 82.5 per cent as on May 28, while those reported in Siliguri in February 2001 and Nadia, also in West Bengal, in April 2007 were 68 per cent and 100 per cent respectively.

Increased human-to-human transmission is a feature of many recent Nipah outbreaks. The virus is highly virulent and lethal and there are no medicines or vaccines. Hospitals can only provide intensive supportive care, mostly to treat severe respiratory and neurological complications.

The chances of infection from fruit bats, the natural reservoirs of this virus found throughout South Asia, and for human-to-human transmission have also increased in recent times. Experts said that the former was because of the widespread destruction of natural habitats of the bats, while the latter was because of late detection and inadequate safety precautions while dealing with infected persons, especially in hospitals.

The virus is known to be present in the wild, in bat urine, and potentially bat faeces, saliva and birthing fluids.

The Nipah virus infection is classified under zoonoses, or diseases naturally transmitted between humans and vertebrate animals. According to one estimate, of the approximate 180 emerging or re-emerging pathogens in the past 30 years, 130 are known to be zoonotic, with a disproportionate number of the new zoonoses being caused by RNA viruses, similar to the Nipah virus, which have the potential for high rates of mutations.

Nipah and the closely related Hendra virus are also significant in that they are listed as “Category C biothreat agents” because they can be isolated from their natural reservoir, easily grown to large amounts in laboratories and transmitted through easy means.

Incubation period The virus does not become infectious immediately after it enters a host body. Its incubation period is said to be between four and 18 days. However, according to Health Department officials, the mean incubation period in the latest infection was 9.6 days; the minimum was eight days and the maximum 17 days, the latter an outlier (the patient died subsequently on May 30).

Except for the family that first contracted the infection, most of the others, including hospital staff, got it from hospitals. The State managed to implement proper screening procedure and foolproof isolation care units only much later, when the “first wave” of infection was tapering off.

Rajeev Sadanandan said: “Had we been a little more careful, we would have used the Ebola experience to better design the care centre in Kozhikode. But that was a gap we plugged by May 28. We identified two separate buildings at the Kozhikode Medical College. All patients suspected of having Nipah infection would bypass the rest of the Medical College wings and would be brought to this care centre. They would first enter a preliminary screening area. Inside, we have separate areas for housing patients with low probability of Nipah as well as high probability cases. Then [there is] another area for patients with Nipah. We have a separate entry area for health care personnel, where they put on their protective gear and another exit area where they remove their gear. Both these are very important when it comes to controlling Nipah infection. We also learned that it was important that we set up only one well-equipped hospital centre at each location for handling such outbreaks.”

There was also a lot of confusion after it became known that samples taken from bats inside a well belonging to the family that first contracted the infection and from other animals in the area proved negative for the Nipah virus in tests done by the Southern Regional Disease Diagnostic Laboratory in Bengaluru.

The Health Secretary said that his department still believed the source of the infection was definitely a bat, irrespective of other opinions, “because the virus is always present inside these bats.”

He added: “Most of the time they will be present in very low concentrations. When hormonal changes occur in bats, there is a probability for the virus to shoot up. Experts call it a ‘spike’. Only then will the excretions become infectious. That is the time when they infect other bats also. Because bats live so close to each other and have sex with each other, a large number of fruit bats may get infected. So, irrespective of the number of bats you catch, unless you catch the ones having the spike, the tests will show a negative result.”

He also said that the tests could have turned negative because there was a failure to catch the right species of fruit bats—which are known to live on trees than inside wells—or because the bats had been caught when the virus concentration in them was low, or because appropriate serological tests were not used.

But if the virus is in circulation, it can come back in later years. The State government is therefore undertaking “a proper study of the bat population in Kerala” and the prevalence of the virus among the bat population.

“We are trying to involve some of the best experts in Asia to work with us. We are also asking the ICMR [Indian Council for Medical Research] to join us. Or we will do it ourselves,” Rajeev Sadanandan said.

Kerala was lucky in that it faced only one episode of Nipah outbreak, unlike multiple episodes as had happened in Malaysia several years earlier. The current episode was confined to one location where the public health facilities were among the best in the State.

Migrants not the source The Kerala government has scotched all rumours that the large population of migrant labourers could have been the source of the outbreak. “We can rule out the migrant labour route because had such a person been the source of infection, others too would have got it by now because they live in overcrowded quarters and we would have seen hordes of people infected and dying of the disease. But not one of them has been infected. So, by inference the infection has not been carried into Kerala by migrant labourers. The concern is whether some of them will get the infection from here,” Rajeev Sadanandan said.

Significantly, he also said the government believed that there was a single source infection. The person who died at the medical college had come into contact with some sort of infected secretions from a bat. He added: “We can only conclude that people have died even earlier because of Nipah and we have failed to identify it properly. And the young man we know as the first casualty had got the infection from such a person. But almost all the cases that tested positive are linked to the first case in one way or the other. One patient alone is an exception. We have not been able to link it to the other cases; there is probably some link that we have missed.”

According to him, one positive factor is that the Nipah virus is usually found to be active between December and May. “So far we have seen no sign of more infections. So, the time for new infections hopefully is over.”

Doctors and other caregivers who spoke to Frontline said that fear was the dominant theme at the hospitals and isolation centres and the critical care units that handled suspected cases. The normally crowded Kozhikode Medical College premises have been largely deserted ever since the first cases were admitted. The hospital itself discharged several patients [suffering from other ailments] and advised them to seek care elsewhere. Nipah was declared the top priority. At Perambra village in Kozhikode district, where the family of four first contracted the disease, people were scared to come out and rumours spread more viciously than the virus itself. All public functions in Kozhikode and Malappuram districts were cancelled. Schools and colleges remained closed. People were reluctant even to shake hands with each other and generally preferred to stay indoors.

There were instances of government initiating action against some elements spreading rumours that the outbreak was the handiwork of pharma companies and circulating videos with mischievous footage. There were also reports of attempts to stigmatise patients and their families and caregivers who had interacted with them in hospitals.

But in general, the public, the media, the elected representatives and the State health personnel were supportive in the fight against the outbreak.

A family wearing protective masks at a hospital in Kozhikode on May 25.

What did Kerala learn from its first tryst with the Nipah virus? The answer was quick: “The message is clear. We have to be prepared for outbreaks of this type anytime; it could be anything, MERS, SARS, anything. So, we need to put in place facilities that can handle such emergencies. Two, we should have people working on the science behind such diseases, surveying our animal population, and so on, for which we need enormous funds. Three, it is essential that we observe sound infection control policies and put in place all precautionary measures if we are to avoid tragedies such as the death of a young nurse on duty at a hospital treating Nipah patients. We probably got lucky this time, but we need to gain more experience and expertise for managing emergency situations like this,” Rajeev Sadanandan said.

According to him, the State Health Department has already contacted a network of international experts and groups and is currently considering two molecules that have been found to be potentially effective against the Nipah virus. One is a human monoclonal antibody called “m102.4”, which proved successful against Nipah and Hendra viruses in animal tests; the other is “GS5734”, an experimental anti-viral drug being developed by the U.S. drugmaker Gilead Sciences.

The two molecules had already been identified by the Nipah Clinical Trial Working Group set up by the WHO Health Emergency Programme, which is currently working on the protocols for its use. Kerala has agreed to provide support if the ICMR decides to join hands with the Queensland (Australia) government in the research.

Among the key researchers the State government authorities are in touch with are Prof. Lin-Fa Wang, an international leader in the field of emerging zoonotic viruses, and Prof. Christopher C. Broder, director of the Emerging Infectious Diseases Graduate Program of the U.S. Uniformed Services University of the Health Sciences (USU), who has been involved in vaccines and antibody therapeutics development for the human immunodeficiency virus (HIV) and emerging zoonotic viruses, including the Nipah and Hendra viruses.

Prof. Wang, who is the director of the Emerging Infectious Diseases Programme at Duke-NUS Medical School, Singapore, has been studying bat-borne viruses for over two decades. He also co-led the development of a vaccine for horses to prevent transmission of the bat-borne Hendra virus to horses, which can prevent the infection from spreading from horses to humans.

Meanwhile, a Reuters report on May 24 said that the Coalition for Epidemic Preparedness Innovations (CEP), a global public-private body set up nearly a year ago with the aim of financing and coordinating the development of new vaccines to prevent and contain infectious disease epidemics, had announced that it had struck a $25 million deal with two U.S. biotech companies to accelerate work on a vaccine against the Nipah virus in the wake of the outbreak in Kerala.