Nipah virus (NiV) has resurfaced in Kerala exactly a year after its first-ever outbreak, leaving open several puzzling questions.
It was in May 2018 that this southern state of India reported its first confirmed case of NiV infection. The infection, which started off as a cluster outbreak in a small village in the northern district of Kozhikode, ended up killing 21 out of the total 23 it touched, marking one of the worst fatalities in the history of NiV outbreaks.
A highly fatal infection, characterised by acute respiratory distress and encephalitis, the disease was first identified in Malaysia in 1998. Named after Sungai Nipah, a Malaysian village, NiV outbreaks have been reported in Singapore, Philippines and Bangladesh, with fatality rates ranging from 50-75%.
Antibodies against this emerging infectious agent have also been detected in flying bats in Thailand and Timor-Leste.
NiV is suspected to have entered India from Bangladesh through West Bengal, which shares its boundaries with the south Asian country.
In India, an outbreak was first reported in 2001 in Siliguri, West Bengal. A subsequent outbreak occurred in 2007 in Nadia, another district in the same state. Fifty people died out of the 71 cases reported in the two outbreaks, demonstrating a mortality rate of 70%, according to the figures available with WHO.
Another place; another mode
At 91%, the rate of fatality in the first recorded outbreak in Kerala was unquestionably the highest. The average rate of fatality, estimated by WHO from various NiV outbreaks, is 74.5%, even though the fatality rate of NiV encephalitis ranges from 0-100.
The transmission of the virus occurred mostly in three hospitals in the Kozhikode district, which were forced to deal with a disease that was hitherto unheard of in the region. Nine people contracted the virus from the index (first infected) case in the hospital where he was first rushed to. The infected comprised immediate family members, neighbouring patients, companions of patients admitted in the ward and caregivers. 10 more people contracted the virus while the index case was in the second hospital. The people who got infected from the index case at the second hospital were patients or companions/caregivers who were present in the emergency department or in the corridor outside the CT room during the period when the index case was waiting to undergo CT.
Another three secondary cases contracted the disease at hospital 2 and hospital 3 after primary cases sought care there, according to a report titled Outbreak Investigation of Nipah Virus Disease in Kerala, India, 2018, published in The Journal of Infectious Disease.
“NiV is primarily a respiratory virus. From the respiratory tract it gets into the central nervous system. The primary mode of transmission of NiV is through droplet infection though contact with body fluids may also transmit,” says Prof Arunkumar Govindakarnavar, the lead author of the study.
Respiratory symptoms like cough were persistently high in the patients, paving the way for more aggressive transmission of the virus to unprotected victims, notes Prof Arunkumar, who is also the Director, Manipal Institute of Virology, Manipal Academy of Higher Education (Deemed University).
On the contrary, in the lone confirmed case reported from Kochi in 2019, the respiratory symptoms were markedly less. Probably, this was also among the reasons for the non-transmission of the disease from the patient to others, he explains, comparing the two outbreaks.
In this year’s outbreak, nobody got infected from the index patient, who presented with acute encephalitis/cerebellitis at Government Medical College Hospital, Kalamassery, Kochi.
Typically, the disease spreads through direct contact with the infected source. Transmission from infected animals to humans — one of the three modes of transmission — was established in the large outbreak that occurred in Malaysia. Most patients had physical contact with sick pigs or had been in close association with infected patients, and then presented primarily with encephalitis during the Malaysian outbreak.
Close contact with imported pigs from Malaysia was identified as the reason for developing the infection in abattoir workers in Singapore during March 1999. In the Philippines, horses infected with the virus were found to be the source of infection.
The route of infection was different in Bangladesh. There was no involvement of pigs or any other animal that acted as an intermediary in NiV transmission. There, people started showing symptoms following consumption of raw date palm sap contaminated by flying bats.
As far as the outbreaks in Kerala are concerned, no conclusive evidence about the source of infection could be ascertained as yet.
Researchers who carried out the investigations believe that the index case in 2018 outbreak may have come into contact with an NiV-infected baby bat. They support the theory based on the timing of the outbreak, which coincides with the breeding season for bats, a known zoonotic reservoir for the virus.
Investigators are still looking for a clue as to how the 2019 index patient contracted the infection.
As of now, two major strains – NiV-Malaysia (NiV-M) and NiV-Bangladesh (NiV-B), have been isolated. The virus has also been isolated from the uterine fluids and tissue samples of fruit bats. NiV can persist on surfaces, posing a further risk for fomite borne NiV transmission, studies show.
In Kozhikode, a strain of NiV which is very similar to the one implicated in the outbreak in Bangladesh was detected in 19% of the samples collected from fruit bats captured from the area where the disease broke out in 2018.
“At 99.7%–100%, we found the highest similarity between human NiV complete sequences from Kerala and NiV N gene sequences from Pteropus spp. fruit bats, compared with NiV sequences reported from Malaysia, Cambodia, and Bangladesh (85.14%–96.15%). This finding indicates that Pteropus spp. bats were most likely the source for human infection in this outbreak,” writes authors of another recently published study titled Nipah Virus Sequences from Humans and Bats During Nipah Outbreak, Kerala, India, 2018.
During 2019 investigations, as many as 33% of the bat samples tested positive for NiV in qRT-PCR analysis.
So, the question arises as to whether the index case in Kerala contracted the NiV disease through direct contact with the reservoir of the virus. Answer is probably yes. But it is difficult to make a definitive conclusion because there are not many instances available to corroborate the evidence, experts say.
The involvement of an additional animal has been found unlikely, however.
Migrants theory debunked
Naturally, questions arise about the route of transmission of the virus to the bat population of a new geographical region, such as Kerala. No outbreak has been reported from West Bengal for more than a decade now. The virus has to traverse several states to reach Kerala.
Could the bats in the region have been harbouring the virus for some time?
“I personally believe that the bat population not only in Kerala, but across the states may have been carrying the virus for quite some time. I would not be surprised if an NiV infection gets reported from any of the neighbouring states,” contents Dr Anoop Kumar AS, Chief of Critical Care Medicine at Baby Memorial Hospital, Kozhikode.
All encephalitic diseases present with a more or less similar symptoms, which are not always easy to distinguish. NiV infection typically presents as acute encephalitis or pneumonia, and can be difficult to single out from other illnesses having similar symptoms, remarks Dr Anoop, who was instrumental in pinpointing the first-ever NiV infection in Kozhikode.
“ How will we know Nipah cases have not occurred in some other place this season?” asks Prof Arunkumar concurring with the view.
It is not possible to know this for sure because every encephalitis case is not reported, and every death is not investigated. What we know about Nipah is that every case may not lead to human-to-human transmission or result in a cluster. So, if there is not a cluster or outbreak, it is very unlikely to get identified, he says.
In fact, it would have taken much longer if the cluster infection had not happened in the family in Kozhikode. It is the cluster of encephalitis in the family that alerted the whole system about the disease.
According to him, NiV is likely to be detected if a test is conducted for the virus elsewhere in the country where fruit bats are present. There is ample proof that NiV antibodies have been detected in the states of Haryana, and NiV RNA has been detected in bats from West Bengal, Assam and Kerala. But no cluster outbreak has been reported from Haryana or Assam so far. There may be a few cases there, but so far, we have not been able to detect any.
Interestingly, the virus detected in West Bengal was also the one that caused the disease outbreak in Bangladesh. Even as the virus isolated from the Kerala outbreak belonged to the Bangladesh (NiV-B) lineage, it was not the strain that is circulating in Bangladesh. This finding has been used to debunk the theory that the virus may have been brought to Kerala by migrant labourers from Bengal. The virus likely came from natural sources within Kerala.
Relapse of NiV encephalitis & recrudescence
Disturbingly, NiV infection can also have longer term consequences. In rare cases, it can relapse after initial infection in certain susceptible survivors. In such cases, individuals can undergo a process called recrudescence of virus replication in the central nervous system, causing a relapse of encephalitis.
Approximately 20% of encephalitis survivors sustain neurological dysfunction, including persistent seizures, disabling fatigue and behavioural abnormalities. NiV infection can persist as non-encephalitic as well, without any symptoms. Similarly, late-onset encephalitis and relapses can occur for months following initial recovery, studies show.
The mechanism by which the pathogen survives the immune-mediated clearance and later causes a recrudescence of replication in the CNS is largely unknown.
Need to bolster surveillance
The only way to deal more effectively with possible NiV outbreaks is through increased surveillance and right protocols.
Currently, Encephalitis surveillance efforts are centered on Japanese encephalitis (JE). When a case of encephalitis occurs, the diagnosis is either JE or non-JE. Though there was an initiative to include diseases like dengue and scrub typhus into it, the routine surveillance was never extended beyond JE.
Since JE is vector-borne and vaccine preventable, the encephalitis surveillance programme focuses on vector control and vaccination. When WHO coined the term Acute Encephalitis Syndrome (AES) as part of the JE surveillance guideline, the idea was to increase the sensitivity of case detection by using a broad case definition to include all possible case of JE.
What happens in India is that if a case is found of AES, we test for JE virus. If it is non-JE, some laboratories may then test for dengue and or scrub typhus. It stops there. There is no effort to go down and clinically classify the syndrome to find whether it is really meningitis or encephalitis or encephalopathy or a febrile seizure.
“Things will start changing once we start classifying these diseases clinically. Then we›ll come to know that the encephalitic diseases happening in different parts of India are not the same,” says Prof Arunkumar. More thrust is required to classify the cases and investigate the problem. Such an understanding will help address the root cause rather than blindly doing something, he adds.
NiV disease, as observed, follows a seasonal pattern. Hence, the risk of recurrence or the reintroduction of the pathogen into an animal or a human cannot be managed without understanding the wildlife reservoir.
Even though the second outbreak was limited to a single case in Kerala, its seasonal presentation, that too in a different location, clearly indicates the region is an endemic zone and similar outbreaks cannot be ruled out in the future.
“The virus is there in Kerala. We don’t need any more proof. And this kind of natural spillover can happen and are bound to happen anywhere in Kerala and other parts of India where fruit bats are there,” explains Prof Arunkumar.
Nothing can be done with bats, the natural hosts. Therefore, bringing community-based infection to zero is not possible. All we can do to avoid a catastrophic outbreak is to equip our hospitals to prevent human to human transmission by strengthening the implementation of infection control practices.
Doing so will also prevent many other diseases which have an infectious nature. Infection control practices should be integrated in good clinical practices and audited regularly. This may include simple practices like providing a surgical mask to a coughing patient or wearing a mask while attending a coughing patient or doing a procedure which generates aerosol. This should become a culture with healthcare workers and should be an everyday practice in hospitals rather than a practice adopted only during outbreaks, he adds.
NiV surveillance has found evidence of infection in fruit bats across Southeast Asia, with seropositivity as far as West Africa and Brazil, in addition to the sporadic cases of human infection reported from Malaysia, Singapore, India and Bangladesh.
Education campaigns started by the state government may be helpful to increase awareness of the risk of NiV infection in the community and to promote appropriate care-seeking behaviour, besides maintaining vigilance for case identification.
Confirmation of NiV infection is usually performed by gold-standard seroneutralisation assays using live NiV, which requires a high-containment BSL-4 facility.
Kerala is yet to upgrade its recently set up virology centres to BSL-4. The state will soon have three virology institutes set up, according to KK Shylaja, health minister, Kerala. The ministry has got administrative sanctions for establishing the centres.
Setting up level 4 labs alone will not solve the problem. Having a facility does not mean that it is functional. You need to create volumes, quality control etc to get the required results. It is also not practical to have level 4 labs in every taluk, alert experts.
As BSL-4 facilities may be limited to the endemic settings, BSL-3 and BSL-2 facilities may be sufficient if the virus can be deactivated, following specimen collection. Virus particles designed not to cause infection are used in neutralisation assays under a BSL-2 environment.
The absence of clear data on the source of NiV infection is a major hindrance in disease prevention efforts. Lessons from Malaysia and Singapore show that it would be easier to avoid a potential infection and possibly avert a catastrophic outbreak if we can identify the source of the NiV infection.
Kerala’s example in controlling the 2018 outbreak is certainly worth emulating. However, to institutionalize this success, early detection and response to outbreaks, a culture of laboratory confirmation — including access to apex laboratories — and an improvement in infection control practices need to be implemented.