"I hope India will set up a long-term surveillance programme on Nipah"
Dr Emily S Gurley has worked in public health research in Bangladesh since 2003 and spent 12 years at the ICDDR-B (International Center for Diarrheal Diseases Research, Bangladesh) where she led the Surveillance and Outbreak Investigation Unit and served as Director of the Program on Emerging Infections. She worked closely with the US CDC and the Government of Bangladesh to establish national surveillance for meningoencephalitis, respiratory infections, acute gastroenteritis, acute hepatitis, and hospital-acquired infections, with a focus on developing junior scientists. Dr Gurley leads multi-disciplinary studies on the transmission, burden and epidemiology of a variety of emerging and established diseases, taking into account the ecological context in which human disease occurs. She has been working on describing the ecology and epidemiology of Nipah virus since 2004, including identifying transmission pathways and drivers of person-to-person transmission, and designing and testing interventions to prevent human infection. She currently serves on WHO’s Nipah Virus Taskforce, advising on the research and development of medical countermeasures. Her research adopts a One Health approach to the study and prevention of Infectious Disease, taking into account the ecological context in which human disease occurs. Emily is the lead for the Bangladesh component of Preventing Emerging Pathogenic Threats (PREEMPT) program to study henipaviruses in bats, and the Co-Director for the Child Health and Mortality Prevention Surveillance (CHAMPS) site in Bangladesh, which aims to determine the aetiology of and prevent child deaths.
The AMJ: Where did it all begin, your association with the Nipah outbreak in Bangladesh?
Dr Gurley: The first time that I moved to Bangladesh I was 11 years old. It was 1986. It’s been like a second home for me. I moved there again in 2003, and that’s when I first began working at the ICDDR-B, an international health re- search organization located in Dhaka. And at that time, I was a young public health researcher starting to work in infectious diseases. It was in January 2004, right after I began, that one of the early outbreaks in Bangladesh was identified, and that was the first outbreak of Nipah that was investigated in real time. I remember it was a very traumatic community event, traumatic to bear witness to the destruction of this Disease. It is a terribly compel- ling Disease. After the first outbreak, it was clear to me that I would be studying that disease for a long time, so, I’ve been working on it since 2004 in Bangladesh, and I lived there for most of that time. I came back to the US for my doctoral studies and then went back to Bangladesh. I relocated to Baltimore in 2016 after the terrorist attack in Dhaka, but my work is still there. I’m usually in Dhaka every three months.
The AMJ: The first outbreak in India was close to the Nipah belt of Bangladesh, but Kerala is much further from the Nipah Belt. It came as a surprise to the majority of the people in Kerala, so what might have caused a spillover event in the Kerala outbreak?
Dr Gurley: I know many people found this shocking or surprising. How do we have Nipah when the other outbreaks are so far away? Also, we are far from West Bengal, so why is it here? This is very surprising.We know that the bats that carry this virus are all over India, around South Asia, Madagascar, Ghana, and throughout Southeast Asia. So, if we know that the bats are there and they have the virus, why would we be surprised that humans are infected? Sometimes we con- fuse the absence of observing something with the absence of it happening. If you have a surveillance system in place and you are testing everyone for Nipah, and no case were reported for five years and all of a sudden, a case occurs, that would be surprising. But if you’ve never tested anyone before yet the reservoir species exists in the region then why would you be surprised to find it if you start looking?
How can you tell if it’s Nipah or not unless you are doing a diagnostic test? If there is a major outbreak, you ask some questions and you do more testing. All these years it could have been misdiagnosed as Japanese Encephalitis (JE). In fact, in Malaysia, the whole outbreak was misdiagnosed as JE for many months before they found the new virus. That’s often the case, then as we have seen in Kerala, we have a doctor saying “wait a minute, this doesn’t seem right. I need to investigate. I need to do something more”.
“Only 10 per cent of Nipah patients in Bangladesh have ever transmitted the virus to someone else.”
AMJ: How do you compare and contrast the spillover dynamics and transmission pathways of the Kerala and Bangladesh outbreaks?
Dr Gurley: Each time a bat virus infects a human, we call this a spillover event. It’s a new chance for that virus to adapt to a new host, to try that species and see if it can do well in that species. So, if you look at the example of Malaysia, how were humans affected? Through infected pigs. The evidence suggests that there were one or two spillover events from bats to pigs.
In commercial pig farming, many new piglets come in all the time, meaning the outbreak was able to be sustained within the pigs, then that virus causing an outbreak in the pigs also infected the people. So, it was really one virus that took off in pigs and then infected people. That’s our best understanding of Malaysia.
Each spillover event is a risk and carries a risk in it- self. In Bangladesh, we see multiple spillovers every year. There are many more viruses spilling over into people, and there’s diversity even among those viruses within Bangladesh. Considering the potential for a new virus to emerge that is more transmissible, that’s our biggest fear for Nipah viruses.
In Kerala, there were only two outbreaks until now, and we don’t know how the index cases were infected. We have hypotheses but we do not know, and probably will never know. And then you had the propagation of person to person transmission. The outbreak in Kerala looks very similar to the first outbreak identified in Siliguri, India during 2001, and it seemed very similar to the large 2004 outbreaks seen in Faridpur, Bangladesh. In many ways, it is a stereotypical super-spreader out- break and super-spreaders as first outbreaks are very common because those outbreaks are hard to miss.
AMJ: What was the nature of the transmission in Bangladesh? I believe, after the first major outbreak in 2004 in Fardipur, most of the outbreaks were smaller in scale?
Dr Gurley: In Bangladesh, our goal was to find the occurrence of singular cases, but we don’t see them unless we’re testing for Nipah. Since most cases don’t cause a major outbreak, we set up surveillance systems to test every individual patient who comes to the hospital with certain symptoms during the Nipah season. From this study, areas with higher risk can be identified. We found that almost all of the patients happened to be singular cases. Only 10 per cent of Nipah patients in Bangladesh ever transmitted the virus to someone else.
Case-control studies can be done with individual cases to find out how they are different from other people in their village who did not get Nipah, to identify how the virus is spilling over. This information is crucial. We have published a paper in the New England Journal of Medicine in May 2019, which is a comprehensive view of person to person transmission in Bangladesh. It’s a report of 14 years of investigation and that may be useful if you want to read up more about that.
I would say my guess is that the same thing is happening in Kerala – that there are more frequent spill- over events occurring, with only a few leading to larger outbreaks. There’s no reason to think this wouldn’t be the case. Based on our experience in Bangladesh, it is very unlikely that a single spillover led to this large out- break in 2018. It’s probably still present with a lower level transmission, but is not being recognized. So, with improved surveillance, I expect that you will continue to find cases.
The AMJ: To what extent do bat biology and immunology drive spillover dynamics in Nipah spillovers from bats to humans? Are there any environmental factors triggering or influencing these dynamics? Is there any active research to understand this?
Dr Gurley: There is an ongoing global study in collaboration with researchers in many other countries. I’m leading the efforts for Bangladesh. There are also field studies in Australia, Ghana and Madagascar. The overarching goal of that work is to understand when and where these bats shed Henipaviruses. We have very good evidence from Australia that the bats which carry the viruses tolerate the infections well. Sometimes when they shed these viruses, it seems that antibody levels can wane in the bats and they can become reinfected or start shedding the virus again. It is an interesting biological system of infection, and it looks different than other diseases that we study in humans. We’re trying to understand what’s going on with the bats and how they get infected and how they transmit the virus to each other.
In Australia, they have good evidence about what they call shedding pulses. There are certain times of the year when the bats are shedding more of these viruses than usual; they call it a shedding pulse. They have very good data to suggest that this happens when their immune systems are stressed due to the unavailability of high-quality food sources. So, their understanding is that in times and places where bats don’t have good food, their immune systems are suppressed, and that’s when they shed these viruses.
In Australia, it also happens to be the time when they move into more urban areas looking for food, because they don’t have enough food. In fact, last year, based on this information, they were able to predict when bats were going to be shedding Hendra virus, and their prediction was correct. In public health, when you’re able to predict when and where something is going to happen, it is very powerful because that allows you to put in interventions to try and stop transmission.
The goal of our study is to see if the same thing is true in other countries. To find the same kind of shedding pulse as is described in Australia with the same type of ecological predictors of those pulses is the first thing. The second part is to see if all these different Henipaviruses have the same or diverse genetic characteristics of the viruses. And how do those genetic characteristics translate into clinical disease? We often do this using animal models.
Ultimately, we want to predict when and where the bats are going to be shedding. Are there vaccines we could design to keep the bats from shedding? Using rabies as one example where we often vaccinate wild animals to protect human health, could we do the same in the Henipavirus system? Could we give bats better food sources? Could we have an ecological intervention to improve their habitat, so they don’t shed the viruses as much? There’s a lot of scientific work we have to do first to understand the process.
Our typical understanding of the way infectious dis- eases work is that, for example from the perspective of measles in humans, there can only be three states - a human can be susceptible to measles, or the person is infected, and then they recover and become immune for the rest of their life. You are never going to be infected again. You are never going to be susceptible again. We often think about infectious diseases in that way, and if we consider it in sort of conceptual model of how infections work, you can think about a bat being susceptible or infected and shedding or immune.
In the case of measles, who are the most susceptible to measles? It’s babies after maternal antibodies wane, and the same is true for bats. When they are born, they have some antibodies against the Nipah virus, usually. Those antibodies wane, and then the new juvenile bats are susceptible to infection. Those new susceptible bats could be playing a role in outbreaks in bats. However, unlike measles in humans, bats who have been infected with Nipah may be immune for some time, but then they lose their immune status, and can lose their anti- bodies. They can become reinfected or shed the virus again. So, you have this scenario where the new juvenile bats are susceptible to infection, and the adult bats can also become susceptible again. The bats don’t become sick, but can shed the viruses more than once.The second paradigm is that these viruses look more like herpes virus in humans, so let’s think about that model system when many people are infected with herpes viruses, Herpes Simplex Virus – Type1. The person is infected early in life and is infected for the rest of their life. However, the person is not always shedding that virus. You are shedding it when your immune system is down for some other reason, then you’ll get a cold sore.Another example of infections that don’t cause illness in wildlife could be pathogenic influenza viruses in wild ducks. They typically don’t make ducks sick at all, but they can infect poultry and make all the poultry die. They can be pathogenic for people, but the ducks are fine. The short answer is, it’s complicated. Both of these dynamics are probably happening, and it’s just going to take us some more time to figure it out.
The AMJ: Is there any evidence suggesting that the frequency of transmission changes over time, or is it linked to the strain of the virus?
Dr Gurley: Almost every outbreak at some point will stop, even without any intervention. Sometimes we try to over-interpret and say that the virus has changed and is not as infectious, but often what we’re seeing is just the normal process of an infectious disease. I don’t want to over-interpret, and again I would say that in our experience in Bangladesh, only one out of every 10 Nipah patients will infect someone else. Let’s take this outbreak in Kerala last year as an example. There was one super spreader. These are outliers. But then, among the patients that he infected, only maybe two or three infected someone else. Approximately 10 per cent of those patients affected someone else. So, it’s true to our experience that among those infected, few new people were affected. So if only 10 per cent are going to infect someone else and you have less than ten, you may not see an onward transmission. Our prior experience would tell you that you wouldn’t expect to see on average any more transmission events after that, and it doesn’t have anything to do with that attenuation of the virus, it’s just what we expect, that only 10 per cent will transmit.
Now if we have good data on the viruses through each transmission chain, and we found differences in the genetics of those viruses, and we could show through laboratory experiments that those genetic changes also cause some kind of attenuation in the ability of the virus to transmit to others, that would give us some strong evidence. But, we don’t have any- thing like that so far, the outbreaks that have happened including last year in Kerala have behaved precisely as we would predict without any changes in virus strains.
The AMJ: To what extent are ecological factors and climate change contributing to these zoonotic spillovers?
Dr Gurley: For one spillover event to happen, many different things have to align. Not only do you have to have shedding in the reservoir species, but that virus has to survive long enough outside the reservoir species or in fluids or something else on order to infect another species, and the virus has to get access to the right cells where it can bind. It has to be able to replicate. It has to overcome the innate immune response of that animal. If this is very swift and identifies this virus quickly to shut it down, you’re not going to have an active infection in the new host. So, all of these things have to line up. Once a virus has spilt over, there is something that may be unique about that virus that means it was able to create that spillover.
Some people like to think that spillovers are the fault of the bats. I think it’s the fault of humans. We’re creating new transmission pathways, for example, with the Nipah virus in Bangladesh. The major pathway of transmission is through consumption of date palm sap. This is an agricultural product. If humans weren’t shaving and tapping these trees, the bats would not have access to the sap. The only way they can drink it is if humans are making it available. Humans are the ones that are generating this transmission pathway.
We know that before the Malaysian outbreak, there had been a massive expansion of the commercial pig raising industry, and there was deforestation to help to accommodate that. If you have destroyed part of the bat habitat, then they have to go and live somewhere else. If you have destroyed the trees where they prefer to feed, they need to go somewhere else to look for food. We have seen this in Australia. They actually have very good data going back more than 30 years now where they show that the destruction of natural bat habitats has led to bats relying more on food sources around human settlements.
The AMJ: Are there lessons from Bangladesh that you would like India to follow in implementing a Nipah surveillance plan?
Dr Gurley: I had the opportunity to be a part of a team that worked to build the first Nipah surveillance plat- form in Bangladesh. I’m only one part of that team, and many other dedicated, talented people working in Bangladesh worked for many years to maintain that plat- form and continue to do so now. It’s run in collaboration with the Institute of Epidemiological Disease Control and Research, which is part of the Directorate General of Health Services and the Ministry of Health, in collaboration with ICDDR -B and also with support from the U.S. Centers for Disease Control and Prevention.
I think we do have one major lesson that I hope we can disseminate far and wide, and this lesson is that systematic surveillance is essential for monitoring this virus. The closer you look, the more cases you find, and the faster you can be in responding to outbreaks. Imagine in Kerala if they had found the first case and they had put him into isolation, would you have seen the super-spreading effect? It could have been mitigated somehow.
With viruses like Nipah, it’s crucial to think about transmission over multiple years. This is possible if you have surveillance in place as we have had in Bangladesh since 2007, with the same three hospitals testing every patient during NIPAH season. It is seasonal in Bangladesh because of the spillover pathway. It spills over because humans and bats share date palm sap, and that’s a very seasonal activity. So, in the Nipah season, we test every patient.
It’s a huge activity. Only 1 per cent of all the patients we test have Nipah. It’s a small proportion, but partly because we do that, and every time we find a case, we go back to the village to look for other cases. We do contact tracing as a routine activity, so even if there was a larger outbreak, there wouldn’t be such big re- ports, because we’re investigating this as a routine thing. What this allows us to do is to track the important epidemiologic characteristics of the virus over time. Since 2007 every year, we can see how incidence and mortality changes. Does the person to person transmission change? Does the geography of these spillover events change? Does the number of spillover events each season change? Unless you have the same systematic surveillance over decades, you cannot do that, you can’t make any sense of the patterns.
The AMJ: The count of lives that the Nipah virus has claimed so far, from the first outbreak to the last outbreak in India, is less than 400 worldwide. However, WHO has classified Nipah as a priority pathogen, which can potentially cause large outbreaks or even a pandemic — are we becoming overcautious?
Dr Gurley: There are many health problems in India. There are many health problems in Bangladesh. Did more people die last year in India from Nipah or Japanese Encephalitis or from traffic accidents? Nipah does not kill more people than these other diseases. However, from a global health perspective, the reason why we care about Nipah is that we have a fear that a strain could emerge that is more easily transmissible between people, and this could cause a massive outbreak or even a pandemic. So, the outbreaks themselves are devastating for a particular community, but the global interest in Nipah is not in those individual outbreaks, it is in the emergence of a more transmissible strain.
The only thing that we know for sure is that we will have more pandemics. If you ask which Disease is going to cause it, we have no idea. But this I want to emphasize, just be- cause we don’t exactly know which one it will be, does not give us an excuse for inaction.
What does this mean? It means that we have to address the emerging pathogens that give us the best reason to believe they could cause a pandemic or a massive outbreak. Nipah is on that list. SARS is on that list. We have to focus on the ones we know are causing problems. It also means that we have to constantly be vigilant and be looking for the next emerging disease. Twenty years ago we didn’t know about Nipah. Does that mean that Nipah was not there? There is no reason to believe that there haven’t been cases, but we just didn’t see them.
How do we know if a more transmissible strain is emerging, or if we’re seeing changes in epidemiology over time that suggest it’s becoming worse? You can only do this through this systematic surveillance. That’s why systematic surveillance is so important. We can look at changes in those vital epidemiologic parameters over time and it will help us to be smarter. Imagine there is an outbreak next year in a different country, Not India or Malaysia, but another place where bats live. The clinicians there are not familiar with Nipah. They don’t have any experience to draw upon, but if we have some data over time from other places, we can give them our advice, and they can start to build on their own experience.
Right now, Bangladesh is the only place with this long-term surveillance experience, but I hope that India will take this up and they will set up similar long-term surveillance platforms so that we can see if we are finding the same things. Bangladesh is just one place, and we don’t know if that place represents what’s happening in other locations. I hope that more places will take up this responsibility to set up surveillance and report the results. I have been so impressed with India’s transparency on this issue, and as I mentioned to you earlier, this is essential for our Global Public Health good.
Lastly, I don’t think it’s a coincidence that the out- break in India was diagnosed in an Indian state that already had a very well-developed healthcare system and a scientific community. Kerala found and diagnosed the outbreak so quickly. Why? Because you have an excellent medical system. You have well-trained clinicians. You have the capability to find it.
