epidemiology

The Nipah riddle

Print edition : July 20, 2018

Collection of sweet date palm sap, West Bengal (Source: https://en.wikipedia.org/wiki/Date_palm).

The glaring difference between the Bangladesh and West Bengal outbreaks is certainly curious and should be of epidemiological interest. Is it a case of poor surveillance and monitoring or under-reporting, or both?

IN the context of the recent Nipah virus (NiV) outbreak in Kerala (now largely contained and localised in its spread to the region around Kozhikode), it is of interest to look at the Nipah disease outbreaks in the Indian subcontinent since it spread to this part of South Asia after it first broke out in Malaysia and Singapore during 1998-99 (see table). The virus, which belongs to the Paramyxoviridae family, was first isolated from a patient from Sungai Nipah in Malaysia and is, therefore, named after the village.

Looking at the table, one is bound to be struck by the skewed distribution of the outbreaks. The glaring difference in outbreaks between Bangladesh and West Bengal is certainly curious and should be of epidemiological interest. Since 2001, when it surfaced in Meherpur, Bangladesh, that country has been reporting Nipah outbreaks practically every year. In contrast, prior to the present Kerala outbreak, only two outbreaks were reported in West Bengal—once in 2001 in Siliguri (in which 66 people were infected and 45 died), and then in 2007 in an isolated incident limited to one family in Nadia district (in which five were infected and all five died). Siliguri is about 15 kilometres from the northern West Bengal-Bangladesh border; Belechupara in Nadia district is also very close to the border.

Fruit bats belonging to the Pteropodidae family are a natural reservoir for the virus; large fruit bats of the genus Pteropus have been implicated as the primary source of the virus in these outbreaks. While in Malaysia and Singapore the transmission was through the “spillover” of the virus from bats of the species P. vampyrus and P. hypomelanus (primary hosts) into pigs (intermediary hosts), and then from pigs to humans (via pig-rearing farms and related commercial activities) followed by human-to-human transmission, the source of the virus in both the Bangladesh and West Bengal outbreaks was the species P. giganteus (the Indian flying fox). But unlike the Malaysia-Singapore outbreaks, the transmission here has been direct from the primary hosts to humans.

India shares a nearly 4,100-km-long border with Bangladesh, the longest among the borders with its neighbours. Of the Indian States that share their borders with Bangladesh, West Bengal, which lies to the west of Bangladesh, shares the longest, about 2,216 km. Since bats do not recognise national boundaries and fruit bats can fly hundreds of kilometres—they can traverse up to 2,000 km in a year—the reach of the species would naturally cover the entire region of Bangladesh and its border States, enabling the cross-border spread of the Nipah virus. The West Bengal-Bangladesh border is also known to be quite porous, which could facilitate human-to-human transmission. The population densities in the districts on both sides of the border are also quite similar.

Raw date sap consumption

The identified risky behaviour of the index cases—the first in the chain of human-to-human transmission—in the Bangladesh outbreaks as well as in the Nadia episode is the consumption of raw date palm sap which could have been contaminated by the virus shed by bats through saliva and urine. The timing of the outbreaks corroborates that. Date palm sap is extracted during the months of December to March. A portion of the tree bark is removed, a tap is cut into the trunk there, and sap is allowed to flow slowly—usually through a bamboo duct—into an unprotected wide-mouthed clay pot that is hung from the tree (Pic. 1). Bats feed on the sap thus collected in the pot (Pic. 2) and can contaminate the sap with saliva and urine, which may have the virus shed by the bats. NiV can survive for days on sugar-rich sap. The practice of making jaggery from date palm sap is prevalent on both sides of the border—khejurer gur and sweets made from it are popular all over Bengal—and so would be the corollary risky behaviour of consuming fresh sap, which is considered a delicacy. It is usually consumed within hours of its collection and before it is boiled to turn it into molasses; the process of heating to high temperature would destroy the virus.

The geographical distribution of the Bangladesh outbreaks is also interesting. All the affected districts (except for the single case of Comilla district during the 2011 outbreak) lie in the western half of Bangladesh—that is, towards West Bengal—and that too mainly in the west central and north-western parts. This may be an indication that date palm sap extraction for producing jaggery and raw sap consumption is more prevalent in western Bangladesh (and thus also in West Bengal) than in eastern Bangladesh, and this may be epidemiologically significant. And yet, we have seen only two Nipah outbreaks in West Bengal compared with 18 in Bangladesh in the past 18 years, which range from single sporadic cases to outbreaks with cluster events.

A picture taken by infrared night observation showing a small fruit bat (in circle) licking sap from the shaved surface of a date palm tree in Bangladesh without any intervention during the winter of 2010. Source: A Randomized Controlled Trial of Interventions to Impede Date Palm Sap Contamination by Bats to Prevent Nipah Virus Transmission in Bangladesh; M. Salah Uddin et. al. PLoS One, Vol 7, Issue 8, August 2012.

Does not that seem strange? It does. Of course, it is known that bats do not shed the virus easily. Though fruit bats are asymptomatic carriers of the virus, the viremia phase in them occurs during hormonal changes caused by stress or pregnancy. So, in a population of one lakh bats, four or five might be in that phase. That is why there have been no outbreaks in other South Asian countries such as Thailand and Cambodia even though fruit bats there have been found to harbour the Nipah virus. This may be because the practice of raw date palm sap consumption is not prevalent there. But in regions where raw date palm sap is consumed, given that bat habitats are large colonies and bats do feed on sap, the probability of them contaminating it with the virus would still be significant, as it has been seen in Bangladesh with multiple Nipah outbreaks. So the West Bengal situation does look like an epidemiological oddity.

Virologists and epidemiologists are still to gain a full understanding of the spread of the virus and the transmission of this emerging zoonotic disease in animals and humans. “The exact Nipah virus transmission process from bats to humans as a whole has not yet been completely unravelled,” pointed out a virologist from the National Institute of High Security Animal Diseases (NIHSAD) in Bhopal.

Often the diagnosis happens only retrospectively, and given that the disease is an evolving one, its early symptoms can be confused with that of other diseases. In fact, the 2001 outbreak in Siliguri (which actually preceded the 2001 Bangladesh outbreak in Meherpur in west-central Bangladesh by a couple of months) was identified as a Nipah outbreak more than two years later. At the time of the outbreak, it was declared as a measles variant virus, and it was only two years later that clinical material from the outbreak was sent to the Centres for Disease Control and Prevention (CDC), Atlanta, and was confirmed to be infected with Nipah, though the source of the virus in the index case did not get established. The first publication about the Nipah outbreak in Siliguri was, therefore, only in 2006. So, actually, the Nipah virus arrived in India, in Siliguri, before it did in Bangladesh. While the coincidental timing of these two first outbreaks in the Indian subcontinent may have epidemiological significance, they are unlikely to be linked otherwise. 

Distinct genetic lineages

There are two distinct genetic lineages of the Nipah virus circulating in the region, with Pteropus bats serving as the natural reservoir: NiV-Malaysia (NiV-MY) and NiV-Bangladesh (NiV-BD). A study published in 2009 by Stephen Luby and associates in the journal Emerging Infections observes: “The diversity of NiV strains recovered from Bangladesh… supports multiple introduction of the virus from bats into human population even within a single year. Among 4 NiV isolates from human NiV cases in 2004, …the isolates differed by 0.9 per cent in nucleotide homology in contrast to the sequences obtained from all the human cases in Malaysia, which were nearly identical to each other.”

Sequencing of isolates from both the West Bengal outbreaks has shown that they are much closer to the Bangladesh strains than the Malaysian strain. A full genomic sequencing of the isolate from the samples of the 2007 outbreak in Nadia district by V. Arankalle and others from the National Institute of Virology (NIV), Pune, a constituent laboratory of the Indian Council of Medical Research (ICMR), in 2011 had shown over 99 per cent similarity with an isolate from the 2004 Bangladesh outbreak.

Researchers at the NIV have also conclusively established that Pteropus bats in West Bengal are indeed the carriers of the Nipah virus. A survey of Pteropus bats in West Bengal in 2011 and during 2015-16 revealed the presence of the virus in P. giganteus bats. During 2009-10, an NIV survey captured 140 bats of three species: P. giganteus, Cynopterus sphinx and Megaderma Iyra from Maharashtra and West Bengal. Of the 140 bat specimens, viral RNA was detected from a liver sample of P. giganteus bat from Maynaguri near Siliguri. Serum sample from the same bat also tested positive for Nipah virus specific (IgG) antibodies.

“Nipah viral RNA and IgG positivity in Pteropus bat from West Bengal prove that this species is a potential reservoir [for the virus]… and raise an alarm for monitoring of this disease in the State which has gone through two outbreaks,” says the 2011-12 annual report of the NIV. Similarly, liver, spleen and kidney samples from 62 P. giganteus bats (39 from Cooch Behar and six from Jalpaiguri in West Bengal and 17 from Dhubri in Assam) were tested for the presence of the virus. Of these, seven were found to be positive for Nipah. Of the 35 serum samples from these bats that were tested for anti-Nipah IgG antibodies, two samples of P. giganteus tested positive, according to the 2016-17 annual report of the institute. (If NiV could not be found in fruit bats around the outbreak region in Kerala, it does not mean that they are not the source of the virus. Given the low chance of the bats being in viremia and shedding the virus, a survey over a much larger sample is needed to detect the virus.)

Workers of Kerala’s Health Department with protective gear at the Government Medical College, Kozhikode, on June 2.   -  K. Ragesh

The nucleotide and amino acid sequencing of these isolates from the NIV surveys, too, have shown that the virus strain in circulation in West Bengal is genetically closer to the NiV-BD lineage than the NiV-MY lineage. In fact, limited sequence analyses by the NIV of isolates from human samples in the recent Kerala outbreak have also shown similarity to the Bangladesh strains from the 2004, 2008 and 2010 strains and the Nadia strain, according to D.T. Mourya, Director of the NIV. According to a news report of 2013, the NIV had also embarked on a sero-surveillance programme—detection of antibodies to the virus in normal healthy people—in the State. Results of this programme are not, however, available in the annual reports.

Under-reporting of cases?

So, given that the virus is in circulation in the region, West Bengal in particular, one needs to understand why, besides the two outbreaks, no cases have shown up. Is it a case of poor surveillance and monitoring or under-reporting, or both? “Yes, I feel that India is under-reporting the cases,” Mourya said. “This needs active surveillance programme for monitoring the cases,” he added.

“I agree that surveillance may be incomplete, but it has improved considerably in the past few years. Fever surveillance set up in many States at [the] PHC [primary health centre] level has demonstrated the value of diagnostics in identifying causes of fever,” said Soumya Swaminathan, former ICMR Director General, in an email message.

“It is very likely that cases are being missed,” pointed out G. Arunkumar, head of the Manipal Centre for Virus Research (MCVR) of Manipal University, the key man behind the identification of the Nipah outbreak in Kerala. “We need better surveillance that does not rely on symptoms of encephalitis and the central nervous system [CNS] as indicators for Nipah. The surveillance strategy has to be different,” he said. “Nipah is primarily a respiratory virus and the disease is primarily respiratory; every case is not encephalitis. In Bangladesh also, over 50 per cent of the cases had only respiratory symptoms. If we just look at cerebro- spinal fluid [CSF], we may not detect the virus. Early on it will be negative. In Nipah the fever is localised. In the later stages, some viruses spread to other organs and may go to the brain. Therefore, blood and CSF samples are not enough for detecting Nipah; testing throat secretions is a sensitive tool and it is important for any surveillance programme. We need very good surveillance with a good laboratory back-up,” he added.

Talking about human-to-human transmission, Arunkumar said: “In India, the respiratory route has been primarily responsible for human-to-human transmission. The chance of transmission is very high when the patient develops cough. Patients develop heavy cough during the later stages of the disease. The index case in Kerala, for example, developed cough only in the last two days even as there were other respiratory symptoms early on. Unlike Ebola, body-fluid-mediated transmission is very low in Nipah. In Kerala we have seen that only those in the direct line of cough got infected.”

In this context the observations made in the 2009 study by Luby and others in Emerging Infections are pertinent. “The clinical presentation of NiV infection in Bangladesh,” the study said, “differed from Malaysia. In Bangladesh, severe respiratory disease is more common, with 62 per cent of cases having cough, 69 per cent developing respiratory difficulty, and available chest radiographs showing diffuse bilateral opacities covering the majority of lung fluids. By contrast, in Malaysia, 14 per cent of patients had a non-productive cough on presentation; only 6 per cent of chest radiographs were abnormal and these abnormalities were mild and focal.”

The study also noted that, in the Bangladesh outbreaks, respiratory secretions were particularly important for person-to-person transmission of NiV, and the virus was readily identified in the saliva of patients. “Across all recognised outbreaks in Bangladesh from 2001 through 2007, Nipah patients with respiratory symptoms were more likely to transmit Nipah,” the study said. Given this, and given that the social setting on both sides of the border is similar, the observation made by Arunkumar assumes significance from an epidemiological as well as surveillance strategy perspective.

Luby and co. also posed an interesting question in their 2009 study: “Why is respiratory disease and person-to-person transmission more common among human NiV infection in Bangladesh [and India] compared to Malaysia? Are certain strains of [the] virus more likely to cause respiratory tract disease in humans or might the different clinical syndromes in Bangladesh and Malaysia reflect differences in host susceptibility from malnutrition or other causes?” According to Arunkumar, contact tracing in the current Kerala outbreak has so far linked all but one person to the first index case, which is indicative of the importance of person-to-person transmission and relative unimportance of the secondary cases becoming transmitters of the virus. (In the Kerala outbreak over 2,600 people [both direct and distant] have been tested as part of contact tracing so far.) Considering that the West Bengal strains (and the Kozhikode strain) are closer to the Bangladesh strains, the question assumes importance from a research point of view.

Returning to our original poser, except for the two outbreaks, why have no Nipah cases been picked up in West Bengal so far despite all conditions being seemingly conducive to the disease striking the population? The surveillance programme should not just be limited to testing for the virus but also go into prevalent social practices, feels Arunkumar. According to him, Bangladesh has a fairly good surveillance programme, which is now very well evolved and robust. The Indian surveillance has definitely got to improve and maybe there is a case here for collaboration with Bangladesh. Nipah is not yet part of the Infectious Disease Surveillance programme of the government. At least now, in the wake of the Kerala outbreak, one hopes that it is included and a more intensive and robust Nipah surveillance programme gets established. Of course, this means substantial investment. “With much improved molecular techniques now available, we should be able to identify hot spots for the disease if we have a good comprehensive programme,” says Arunkumar.

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