Nipah Viruses from Malaysia and Bangladesh: Two of a Kind?

Bronwyn A Clayton & Glenn A Marsh. Future Virology. Volume 9, Issue 11. November 2014.

Background


Zoonotic viruses represent a substantial, global threat to human health. Nipah (NiV) and Hendra viruses (HeV); highly pathogenic avian influenza viruses; severe acute respiratory syndrome and Middle East respiratory syndrome coronaviruses; and Marburg and Ebola viruses are all prominent examples of viral zoonoses that have emerged since the late 20th century and caused outbreaks of human disease. In addition to the immediate threat to human health posed by novel viral zoonoses, emergent agents may undergo host adaptations that give rise to the establishment of new pathogens within human populations. A momentous example of such an event is the emergence of HIV, which has resulted in an ongoing global human health crisis of unprecedented proportions.

NiV: History of Emergence—A Social & Global Context


Nipah virus and the closely related HeV are zoonotic agents harboured by flying foxes and have caused outbreaks of human disease, characterized by high fatality rates, in both the developed and developing world. NiV and HeV are classified in the genus Henipavirus within the family Paramyxoviridae, which includes a number of viruses that cause significant human disease, for example croup, measles and mumps (outlined in a review by Virtue et al). Human infection with NiV and HiV results in generalized vasculitis with multiple organ involvement and typically manifests as a febrile, predominantly neurological syndrome with varying degrees of concurrent respiratory involvement. The following perspective focuses specifically on NiV, which has caused human disease in Malaysia, Singapore, India and Bangladesh.

NiV emerged in 1998 in Malaysia, causing an outbreak of respiratory and neurological disease in commercially farmed pigs and, following pig-to-human transmission, an outbreak of febrile encephalitis in people that spread south to Singapore following the trade of infected pigs. The final documented number of human NiV encephalitis cases in Malaysia was 283, of which 109 were fatal. In Singapore, the total number of documented NiV infection cases was 22; 12 of these cases were symptomatically infected, one fatally so. NiV re-emerged in 2001 in outbreaks of human disease in India and Bangladesh. Since then, NiV has caused outbreaks of human disease with almost annual frequency in Bangladesh; a second outbreak in India was reported in 2007. All told, NiV has infected more than 500 people in Malaysia, Singapore, India and Bangladesh and caused the deaths of over 300 people. Survivors of acute infection live with the largely undefined risk of relapsing or late-onset central nervous system disease as a result of persistent infection, and may suffer from ongoing neurological sequelae to infection that impact negatively on their wellbeing and livelihood.

The emergence of NiV in Malaysia and resultant disease outbreak of people and pigs caused nationwide public fear. The 2001 outbreak in India forced the closure of a number of healthcare facilities in the affected area and caused tremendous public fear. In Bangladesh, NiV continues to raise acute concern and carry significant social consequences in affected villages where the ultra-poor, who comprise approximately 20% of the Bangladeshi population, are especially vulnerable to the income-erosion effects of ill-health. Natural infections of pigs—and onward transmission to people—highlight implications for adverse economical and human and animal health impacts of NiV within livestock and food production industries. In addition to considerations of animal health and welfare in the context of animal production industries, the social impact of NiV outbreaks can be further appreciated in cases of natural infections of dogs, cats and horses, domesticated species that hold a significant place in human culture and society, and for which human-animal bonds are unique and longstanding.

One Health & NiV


In consideration of the above points, NiV is a pathogen to which the 'One Health' paradigm—for the development of disease management strategies that marry human and veterinary medicine with ecosystem health and wildlife conservation—truly applies. NiV is an agent of significant concern to human health not only as the cause of severe and fatal infections in people, but also by the following considerations:

  • The wildlife reservoir, the flying fox, represents an ongoing potential source of spillover and transmission from bats to humans has been demonstrated;

  • Domestic animals, as intermediate hosts, represent a significant source of infection of people;

  • Person-to-person transmission has occurred in some outbreaks and the pandemic potential of future emergent henipavirus species or strains is undefined;

  • The recognized global range of henipaviruses and related paramyxoviruses continues to grow with expanding surveillance of bat populations; in at least one case, spillover of an uncharacterized novel henipa-like pathogen to domestic animals has been demonstrated (in pigs in Ghana);

  • The classification of NiV as a biosafety level 4 agent presents logistical challenges to the study of this and related agents, which is limited to a small number of laboratories around the world, and to the rapid development of effective therapeutic modalities for human henipavirus infection.

The ongoing study of NiV and related henipaviruses, development of suitable prophylactic and therapeutic modalities to mitigate human disease and the design of effective outbreak prevention and management strategies will be critical to minimizing impacts to human and animal health of future henipavirus outbreak events.

Differences in Epidemiological Features Between Outbreaks of NiVs from Malaysia & Bangladesh


Differences in Transmission


Outbreaks of human disease caused by NiV isolated from Malaysia (NiV-MY) and NiV isolated from Bangladesh (NiV-BD) have been associated with considerable differences in epidemiological features. A key to obtaining the objectives mentioned above is the determination of risk factors for person-to-person NiV transmission, as well as viral characteristics that may contribute to observed differences in the rates of person-to-person transmission events associated with different NiV outbreaks.

Isolation and sequence comparison of NiV isolates obtained from pigs, bats and humans in Malaysia indicated that a single introduction of infection from bats to pigs precipitated the 1998-1999 outbreak of infection of people. Importantly, pig-to-human transmission accounted for the vast majority of documented human cases of disease in Malaysia, and bat-to-human transmission was not identified as a pathway for infection of people. In contrast, bat-to-human transmission appears to have played a significant role in the epidemiology of NiV outbreak events in Bangladesh. There appear to have been numerous introductions into the human population of NiV circulating in different colonies of flying foxes in Bangladesh; one study identified 20 such putative bat-to-human NiV transmission events since 2001. Bat-to-human NiV transmission is discussed in further detail later.

The most compelling epidemiological difference between NiV disease outbreaks in Malaysia and Bangladesh is the observed increased incidence of human-to-human transmission associated with outbreaks of NiV in Bangladesh. Human-to-human transmission of NiV in Bangladesh accounted for 51% of recognized cases of human NiV infection between 2001-2007 and played a significant role in the spread of disease in the Indian outbreak of 2001. Factors associated with increased risk of onward NiV transmission in Bangladesh were associated with close contact with infected patients and included living with or caring for clinically unwell persons and contact with secretions from infected people. More specifically, activities marked by contact with respiratory secretions or urine of patients, for example, receiving a cough or sneeze from an ill patient directly to the face, were associated with an increased risk of onward NiV transmission. Hand washing, and avoiding contact with infected individuals, have been negatively associated with infection. One study identified the practice of spoon-feeding of patients, requiring close physical contact with patients who were often in the terminal stages of their illness, as an activity carrying the highest risk of onward transmission in one study cohort. Human-to-human transmission was also observed in NiV outbreaks in India, where nosocomial transmission was a major pathway for human infection and resulted in the infection of medical, paramedical and nursing personnel. Transmission was attributed to failure to use personal protective equipment during contact with infected patients and exposure to respiratory secretions during procedures such as intubation of patients. A single probable case of nosocomial transmission has also been described in Bangladesh. In Malaysia, a survey of over 300 healthcare personnel involved with the care of patients during the NiV outbreak did not reveal evidence for person-to-person transmission and the risk of infection from hospitalized patients was concluded to be very low. There have been two cases of NiV infection in Malaysia, both retrospectively identified, which have been attributed to possible person-to-person transmission; these cases will be discussed in further detail later. Taken together, these data indicate that onward transmission of NiV infection of people in Malaysia was a rare event.

Differences in Clinical Features of Disease


Fatality rates associated with outbreaks in India and Bangladesh were typically higher than the 38.5% rate reported for the Malaysian outbreak: of 206 documented cases across a number of human NiV outbreaks in Bangladesh and India between 2001-2008, an overall fatality rate of 73% was recorded. The increased prevalence and severity of respiratory disease observed for NiV-BD cases during human outbreaks of disease has been identified as the primary difference in disease phenotype between NiV from Malaysia and Bangladesh, and appears to underlie an increased propensity for person-to-person transmission in the case of NiV in Bangladesh. Overall, 14-29% of patients in Malaysia showed some degree of respiratory involvement. Respiratory involvement was a far more predominant feature of infection in Bangladesh and India, occurring in approximately 60-75% of patients overall in Bangladesh and 51% of patients during the 2001 outbreak in India. Acute respiratory distress syndrome characterized by cough and difficulty breathing was diagnosed based on clinical presentation and radiographic findings and was feature of infection with NiV from Bangladesh that was not described for human cases of NiV infection in Malaysia. Patients in Bangladesh presenting with respiratory signs during NiV infection were significantly more likely to transmit infection to other in-contact individuals than those who did not present with a respiratory syndrome These findings indicate human-to-human transmission of NiV in Bangladesh occurred largely via infectious respiratory secretions and provide a possible explanation for a propensity for onward transmission of NiV in Bangladesh.

Bat-To-Human NiV Transmission in Bangladesh


Sporadic cases of NiV infection featuring isolated or small clusters of human cases have been attributed to bat-to-human transmission in Bangladesh, and index cases in a number of larger outbreaks have been attributed to infection of people by bats. Bat-to-human NiV transmission in Bangladesh has been largely attributed to food-borne transmission via date palm sap. Fresh date palm sap is consumed as a national delicacy by the people of Bangladesh, and outbreaks of human NiV infection associated with bat-to-human spillover events occur with a temporal pattern that corresponds to the seasonal date palm sap harvest period. Harvesting practices give rise to the opportunity for access to date palm sap collection pots by foraging flying foxes and subsequent contamination of sap with bat saliva, urine or feces.

Features of NiV infection and shedding in pteropid bats have not been characterized for viral isolates from Bangladesh and surveillance data on the prevalence of NiV infections in Pteropus giganteus populations in India and Bangladesh are limited. However, studies of viral shedding of NiV isolated from Malaysia as well as HeV in flying foxes suggest that shedding by infected bats occurs sporadically at low levels, and that opportunities for spillover from bats are infrequent. No evidence has been found for bat-to-human NiV transmission in Malaysia and the risk of infection of people by NiV spillover from bats in Malaysia has been determined to be low.

The most plausible explanation for the continued and frequent introduction of NiV into the human population by transmission from bats in Bangladesh is that consumption of date palm juice represents a unique bat-to-human interface not described in Malaysia, and one that allows adequate exposure of people to infectious secretions from bats to occur, increasing opportunities for bat-to-human NiV transmission. Thus, while the risk of bat to human transmission of NiV isolates from Bangladesh has not been defined at the level of viral shedding by the reservoir host, it is likely that bat-to-human transmission events in Bangladesh are driven by human social and environmental factors, and not by features of NiV infection and shedding in flying fox hosts that differ between reservoir species in Malaysia and those in Bangladesh.

Although consumption of date palm sap is an activity that is restricted geographically, bat-to-human interactions that may represent increased opportunities for the emergence of henipaviruses by direct bat-to-human transmission do exist in other parts of the world. In Africa, henipavirus RNA has been detected in tissues of bats hunted and butchered for human consumption. In Cambodia, wild-caught pteropid bats intended for human consumption had serological evidence of infection with NiV- and HeV-like viruses; NiV has been isolated from Cambodian flying foxes. The risk of zoonotic infection associated with these specific bat-to-human interactions remains undefined at this point in time.

NiVs from Malaysia & Bangladesh: How Different Are They?


At the molecular level, human isolates of NiV from Malaysia and Bangladesh share 91.8% nucleotide homology across the entire genome. The 8% heterogeneity observed between the viral isolates is distributed across the genome, although the majority map to untranslated regions flanking each of the viral gene open reading frames and the predicted amino acid identity of the viral proteins is considerably greater than observed sequence differences at the nucleotide level. The greatest level of nucleotide heterogeneity between the Malaysia and Bangladesh NiV isolates is observed in the P gene. In addition to encoding the viral phosphoprotein (P), the P gene employs a number of transcription strategies to encode accessory proteins V, W and C. These accessory proteins have roles in antagonizing host innate immune responses to henipavirus infection, in particular by abrogating the function of STAT1 in the interferon (IFN) pathway. Recombinant Malaysia NiV C- and V-depleted mutants demonstrated marked reductions in virulence in infected hamsters, despite retaining strong interferon antagonism in vitro, suggesting these P gene products are important determinants of NiV pathogenicity during infection. Comparative studies of Malaysia and Bangladesh NiV isolates in primary human respiratory epithelial cell lines have demonstrated differences in the induction of host immune genes as well as the level to which STAT1 activation is blocked, which is presumed to be a key component of the ability of the henipaviruses to abrogate the host immune response. In baby hamster kidney cells, infection with the Malaysia NiV isolate induced earlier and more extensive cytopathology, compared with the Bangladesh isolate. The interpretation of these observed differences in vitro, in light of infection outcomes in the human host, is not clear. Similarly, the biological relevance of observed sequence divergence in NiV isolates remains to be defined. Heterogeneity between NiV strains across the untranslated regions of the genome may well give rise to differential regulation of viral gene transcriptional and translational efficiency and influence virulence and disease phenotype, as has been described for other paramyxoviruses. In particular, sequence divergence within the P gene may have a role in differential production and function of accessory viral proteins that interact with host innate immune pathways. However, these possibilities have not been explored in vitro. Nor has the significance on host cell receptor affinity and viral infection and budding of variation in predicted G protein glycosylation sites between NiV isolated from Malaysia and Bangladesh.

There are few reported in vivo comparisons of NiV from Malaysia and Bangladesh. In a study of NiV infection of ferrets, we observed that, following oronasal exposure of animals to comparable infectious virus doses of either NiV from Malaysia or from Bangladesh, ferrets infected with the Bangladesh isolate had significantly higher levels of viral RNA recoverable from oral secretions over the course of infection. These findings suggest that differences between viral isolates—specifically in their ability to infect and replicate within tissues of the respiratory tract—may be reflected by higher levels of viral shedding of the Bangladesh strain. However, we did not observe differences in the distribution or severity of viral replication and infection-induced lesions within the respiratory tract, nor did we observe any appreciable difference in the level of respiratory disease in the clinical presentation of infections of ferrets with either viral strain. In contrast, in hamsters inoculated with NiV via the intraperitoneal route, the Malaysia isolate caused more rapid and severe lung pathology when compared with hamsters exposed to the Bangladesh isolate, and differential upregulation of host inflammatory genes was observed in various tissues between hamsters exposed to the two isolates. Observations in the hamster model for infection are perhaps difficult to interpret in light of the observed increased level of respiratory involvement reported for human cases of infection with NiV in Bangladesh, compared with those in Malaysia. Additionally, the intraperitoneal route of exposure of hamsters may not reflect biologically relevant routes of infection of people with NiV. Furthermore, transmission of NiV from Malaysia has been demonstrated to occur from experimentally exposed hamsters to na├»ve cage mates. More recently, a comparison of infection of mice with NiV isolates from Malaysia and Bangladesh was reported; infection in this model, however, was characterized by self-limiting, localized viral replication in the lower respiratory tract in the absence of clinical disease, and is thus not reflective of features of human infections.

In consideration of the above, it seems entirely plausible that differences between NiV isolates at the nucleotide level, particularly within the P gene, may have functional significance in viral pathogenesis and replicative ability in mammalian hosts, leading to differences in outcomes of infection as reported for in vitro and in vivo comparative studies to date. However, the interpretation of observed differences between NiV isolates in vitro as well as meaningful comparisons of features of infection in different animal models, in light of an observed increased propensity for person-to-person transmission of NiV in Bangladesh, remain unclear. Overall, the significance of the 8% level of genetic variation observed between NiV isolates from Malaysia and Bangladesh, and the level to which this variation may contribute to differences in outcomes of infection in people observed during natural outbreaks of disease, remain largely undefined at this time.

Overlooked Transmission Events in Malaysia: What About the Other 8%?


In a study of 110 patients from the Malaysia outbreak defined as positive for NiV infection, 8% of cases had atypical epidemiological features—specifically, these patients reported limited or no contact with pigs during the outbreak period. A number of these cases were attributed to possible transmission from other intermediate animal hosts. However, there are two cases reported in the literature that suggest person-to-person transmission of NiV did occur during the Malaysia outbreak. In one case, a healthcare worker who tended to patients infected with NiV demonstrated seroconversion and magnetic resonance imaging brain lesions consistent with undiagnosed, asymptomatic NiV infection; this patient had no history of contact with pigs. More recently, an individual who had shown no previous clinical signs of disease was reported to have developed late-onset NiV encephalitis. This patient also had no history of contact with pigs, and infection in this case was attributed to contact with infected relatives at the time of the outbreak. Specific features of the exposure history of these two cases have not been reported. While the 8% of patients who had no reported history of contact with pigs were considered to have acquired their infections through transmission events that were atypical epidemiological features of the outbreak, these two cases highlight the fact that opportunities for onward NiV transmission in people did occur during the Malaysia outbreak. The fact remains that person-to-person transmission of NiV in Malaysia was a rare event, but this in turn raises the question: what are the possible driving forces for onwards transmission of NiV that may have differed in Malaysia and Bangladesh, beyond a difference at the level of genetic variation between viral isolates? While human-to-human transmission accounted for a major pathway for spread of NiV infection in Bangladesh and India, it appears that only a small number of infected patients actually transmitted their infection to other in-contact individuals. In Siliguri, India, less than 6% of cases transmitted infection to other people; in Bangladesh, of 122 cases identified from 2001 to 2007, 7% of infected people transmitted virus.

Factors that may contribute to the likelihood of a NiV-infected person with respiratory disease transmitting virus have not been characterized, and data on viral shedding during human infection with NiV are lacking. However, importantly, NiV has been isolated from urine and respiratory secretions of infected patients in both Malaysia and Bangladesh. In the ferret model for acute NiV infection, the mammalian model that perhaps best recapitulates features of human NiV infections, the following similarities have been observed between infections caused by NiV isolates from Malaysia and Bangladesh:

  • Oronasal exposure resulted in infections characterized by acute, rapidly fatal disease with similar incubation periods for both viral isolates;

  • Viremia with systemic, multiorgan infection and vasculitis were the hallmarks of advanced infection;

  • Virus was isolated from nasal and oropharyngeal secretions, and evidence for viral shedding was detected prior to the onset of clinical disease in some cases;

  • Viral loads in respiratory secretions increased over time and were highest at the point of advanced, severe clinical disease;

  • Virus replication was observed throughout the upper and lower respiratory tract and virus was recovered from upper airway tissues and lungs of infected animals;

  • Acute bronchoalveolitis with associated viral antigen was the predominant lung lesion.

These findings represent similarities in viral infectivity, tissue tropism following infection, patterns of viral shedding and clinical outcomes of disease, in the ferret model, between NiV isolates from Malaysia and Bangladesh.

Controlling Human Outbreaks: Focusing on the Forest or the Trees?


The use of animal models to accurately determine the relative contribution of viral factors to the transmissibility of particular NiV isolates, with an adequate level of statistical power, is hampered by the logistical limitations to carrying out large-scale transmission studies at biosafety level 4. However, we have observed that isolates of NiV from Malaysia are transmissible in the ferret model, when exposure events are characterized by direct mucous membrane exposure of in-contact ferrets to respiratory secretions from experimentally infected ferrets. Transmission of NiV from Malaysia has also been observed between experimentally exposed hamsters and their uninfected cage mates. Critically, this demonstrates that transmission of NiV from Malaysia occurs under certain exposure conditions in mammalian models for human infection. In light of this, we propose the following: first, that environmental (nonviral) factors are the major drivers of onward transmission of NiV during certain outbreaks of human disease; second, the social and cultural milieu within which each NiV outbreak occurs is critical in determining outcomes of infection and transmission in people; and, last, consideration and understanding of the context within which human outbreaks of NiV occur will be crucial in the future development of management strategies.

One example that perhaps best illustrates some important elements of the cultural and social framework that may be driving onward transmission of NiV among people in Bangladesh, is further discussed here; this description has been adapted from. The case occurred during an outbreak in the Faridpur district of Bangladesh in 2004. A large number of human infections during this outbreak were attributed to person-to-person transmission, and one particular individual transmitted NiV infection to 22 other people. This patient was the religious leader of an Islamic sect and had high social standing within his community. He had travelled to the village of a family member who was infected with NiV and ministered to her during her illness. He had close physical contact with that person, holding her hands, feeding her water and reciting excerpts from the Koran into her ear. Upon returning to his own village, he became ill and subsequently died of NiV infection. On the night of his death, family members—including some who had traveled from other villages—and members of his congregation held a vigil by his bedside, touching him and feeding him liquids from a glass and solids by hand. Caregivers rested his head in their laps and massaged his body with oil to comfort him, and leant close to his face to whisper blessings in his ear. The patient had a severe cough and frequently spat fluid from his mouth. A total of 22 people developed NiV infection following close contact with this man; two of these cases spread infection to other people. The fact that so many of the religious leader's family and followers became ill was attributed by many unaffected members of his community to divine retribution, as the religious sect he led was considered to engage in practices that contradicted orthodox teachings of Islamic faith.

In the case described above, the patient was cared for in his own home by family members. This typified the care received by the majority of NiV-infected patients in Bangladesh, where rural residents are underrepresented in their utilization of hospital services and have limited access to tertiary healthcare. Bangladeshi social norms dictate that the role of caregiver is ascribed to female family members. Within the hospital environment, elements critical to the provision of nursing care for patients are in conflict with Bangladeshi sociocultural customs, religious beliefs and perceptions of gender roles. Trained nurses adopted a largely 'hands off' approach during patient care and skilled interventions were often performed by untrained hospital support staff. Thus, even within the hospital setting it was considered vital for family member caregivers to stay with patients and provide care. The outcome of these considerations was that virtually all hands-on contact with NiV patients during their illnesses was provided by people who had little or no training in, or understanding of, infection control.

The intense physical interactions between caregivers and the ill patient in this case were also typical for those observed in cases where person-to-person NiV transmission was documented. In Bangladesh, family members and loved ones maintained close physical contact and hands-on care with sick patients to demonstrate the importance of the ill person; this need for physical contact intensified as patients became more ill. Family and friends of patients traveled to visit them, contributing to the spread of infection between communities.

Demonstrations of affectation demanded by this particular individual's religious standing within the community underscore the importance of religious and spiritual belief in Bangladeshi constructs of disease causality, which do not encompass the concepts of infectiousness and contagiousness but commonly attribute serious illness to divine or supernatural causal elements. Among the rural poor in Bangladesh, the first line response to illness is typically sought from spiritual or herbal healers with little or no formal medical training. Worsening clinical disease in patients who were hospitalized or received allopathic therapies for their illness were interpreted by family members as evidence that such modes of care were either ineffective or were actually contributing to illness, reinforcing suspicions and fears of biomedical treatment and the belief that the observed illness had a supernatural cause. Models of communicative disease largely fail to fit within the Bangladeshi cultural framework, even among doctors and nurses involved in the outbreaks.

The importance of religious beliefs in contributing to attitudes toward infectious disease and infection risks can also be appreciated in the observation of corpse-to-human transmission of NiV in Bangladesh during one outbreak, in which the likely means of infection of a number of individuals were either embracing the corpse of a patient shortly following his death, or participation in the Muslim practice of ritual purification of the patient's body for burial. The practice involved cleaning the anus, urethra and oral and nasal cavities with ungloved hands and bathing the corpse in water, activities that plausibly brought these individuals into contact with infectious secretions from the dead patient, as well as potentially generating aerosols or large droplets of infectious material, contributing to an increased risk of infection. Conversely, in Malaysia, the incidence of NiV infection among the Muslim population was low; an observation attributed largely to Muslims shunning contact with pigs in line with their religious doctrines.

Conclusion & Future Perspective


In the argument presented above we have made the case for focusing on nonviral factors in understanding and predicting drivers for person-to-person transmission of NiV. However, the further elucidation of differences between NiV strains in vitro, examining viral replication, transcription or translational efficiency at the molecular level, remains important. The biological significance of differences between NiV isolates at a molecular level remain largely undefined and their contribution to outcomes of infection remains, at this point, an open question. Identifying underlying mechanisms for differential upregulation of innate immune factors during infections between NiV-MY and NiV-BD may very well lead to the identification of novel targets for therapeutic intervention, with the aim to limit viral replication at sites relevant to NiV transmission. The isolation and characterization of Cedar virus, a henipavirus that is nonpathogenic in animal models examined to date, will be an invaluable tool in dissecting mechanisms of pathogenesis of the henipaviruses. We anticipate that future studies will utilize reverse genetics techniques to compare viral elements of Cedar viruswith pathogenic henipaviruses, to determine viral factors that drive infection outcomes in vivo. This will be of particular value in the characterization of newly emergent henipa- or henipa-like viruses, as current sequence data supports the possibility that many as-yet unidentified viruses related to NiV may circulate in bat populations in various parts of the world.

A further consideration for future studies of NiV is the comparison of isolates from outbreaks in Bangladesh in which human-to-human transmission was a major pathway for infection, and those for which bat-to-human transmission was the only source of infection of people. All reported studies to date have utilized a human isolate of NiV from Bangladesh that, while obtained from respiratory secretions of a clinically infected patient, was not associated with person-to-person transmission.

Of course, observations made in nonhuman mammalian models are, by their nature, limited by the degree to which the model in question might reflect what occurs during natural infections of people. Although our conclusion is tentative, we would suggest that—given the current body of knowledge of NiV—viral factors at the level of differences in infection, replication and shedding between NiV isolates, are not pivotal determinants of onward NiV transmission. Moving forward, in determining the most effective means of preventing human-to-human NiV transmission events with the view to practical, achievable intervention strategies, we propose that the consideration of nonviral factors driving outbreaks of disease will be critical.

Despite observed differences between NiV from Malaysia and Bangladesh at the genetic level, it appears that the risks of bat-to-human and human-to-human transmission of NiV in Bangladesh are more plausibly underpinned by the cultural context within which each outbreak event occurs. This conclusion is consistent with our observation that exposure to NiV Malaysia and NiV Bangladesh have comparable outcomes of infection of ferrets within a controlled experimental system.

We anticipate that the paramyxoviruses will continue to be a family of viruses that pose an ongoing threat of emergent human disease. The wide distribution of bats that are known to harbor these viruses, and the detection of Nipah-like or henipa-like viruses, circulating in bat populations across the globe, will no doubt give rise to spillover opportunities for new outbreaks of animal and human disease in the future. Experimentally, the determination of the relative contribution of viral and nonviral factors to the transmissibility of certain isolates of NiV is challenging, based on the difficulty of accurately calculating relative transmissibility of NiV isolates using experimental systems, and the uncertainty of applying observations made in animal models to natural outbreaks of human disease. Having said this, in achieving the end goal of breaking chains of human NiV transmission, we would suggest that the future value of determining whether particular NiV isolates might have a relatively higher risk of transmission than others is largely academic. This suggestion is based on the following (all of which have been discussed herein):

  • NiV was isolated from respiratory secretions of patients infected in Malaysia;

  • There were at least two identified cases in Malaysia that were attributed to person-to-person transmission;

  • Only 7% of infected patients in Bangladesh transmit infection to other people;

  • NiV isolated from Malaysia transmits between animals under certain experimental exposure conditions.

The fact that outbreaks of NiV infection continue to occur within impoverished rural settings, in which patients have limited access to tertiary healthcare and within which societal constructs of disease causality typically fail to encompass concepts of disease transmissibility, will be a far greater hurdle to overcome in the control of NiV infection than the determination that one particular isolate of NiV might have increased transmissibility in humans. Furthermore, it seems unlikely that specific genetic signatures of newly emerged paramyxoviruses will alone be reliable indicators of which future emergent henipa- or henipa-like virus might have pandemic potential. On the other hand, identifying differences between Cedar virus and NiV and HeV, at a genetic level, may offer us valuable insights into genetic determinants of pathogenicity of henipaviruses in animal and human hosts that will enable us to perhaps predict whether henipaviruses circulating in wildlife reservoirs might have the potential to cause disease in other mammalian hosts, were spillover to occur.

We propose that reflections on patient management and care strategies specific to the Malaysia outbreak will allow us invaluable insights into how to better achieve effective management of future NiV outbreaks and prevent person-to-person transmission. In Malaysia, patients were hospitalized in the early stages of infection and remained hospitalized for the duration of their illnesses, where they received advanced tertiary supportive care within a developed healthcare system. Those with reduced neurological function consistently received mechanical ventilatory support, no doubt contributing to the lower observed mortality rate associated with the NiV-MY outbreak. Following the identification of NiV as the causative agent of the outbreak, protocols for rigorous barrier nursing were instituted to prevent person-to-person transmission.

In the above discussion, we have highlighted only a few considerations in the myriad challenges faced in delivering such interventions and management strategies to Bangladesh. These issues go beyond the enormous practical considerations of the cost and resources associated with redressing inequity in access to healthcare, increasing patient uptake of healthcare services and improving the quality of hospital care available in an impoverished setting such as rural Bangladesh. In order for measures for NiV outbreak control, preparedness and prevention to be effective, their development and implementation must be underpinned by an understanding and consideration of the social, cultural and religious frameworks within which outbreaks occur. An awareness of how such frameworks influence every facet of patient management and community response and awareness during outbreak events will be critical in directing the development and implementation of practical strategies for the prevention of human-to-human NiV transmission in future outbreak events.