D. Sunitha1*, P. Anusri2, M. Sudhakar3
1Department of Pharmaceutical Chemistry, Malla Reddy College of Pharmacy, Maisammaguda, Secunderabad, Osmania University, Telangana, India.
2Pharm D, Malla Reddy College of Pharmacy, Maisammaguda, Secunderabad,
Osmania University, Telangana, India.
3Department of Pharmaceutics, Malla Reddy College of Pharmacy, Maisammaguda, Secunderabad,
Osmania University, Telangana, India.
Nipah virus disease is an emerging infectious disease spread by secretions of infected bats. It can spread to humans through contaminated fruit, infected animals, or through close contact with infected humans. In infected people, it causes a range of illnesses from asymptomatic (subclinical) infection to acute respiratory illness and fatal encephalitis. The virus can also cause severe disease in animals such as pigs, resulting in significant economic losses for farmers.
Nipah virus (NiV) was first detected during a major infectious disease outbreak in Malaysia in 1998-99 and the virus was named after the Sungai Nipah village on the banks of Nipah River in Malaysia. NiV belongs to a genus of paramyxo viruses (Henipa virus), including the highly pathogenic Hendra virus found in Australia that can cause acute respiratory distress and encephalitis with mortality rates in excess of 70%1.
Since its first detection in Malaysia, a closely related Nipah virus has emerged in Bangladesh/India region since 2001. The Nipah Bangladesh strain (Nipah virus-BD) is approximately 91% identical in genome sequence to the Nipah Malaysia strain (Nipah virus-MY).
In 2015, there was a Nipah virus outbreak in the Philippines which affected 17 individuals with a case mortality reaching 80% for those developing neurological symptoms. Preliminary serological and molecular data indicated it was caused by the Nipah virus-MY strain or a closely related virus.
Pteropus bats (fruit eating bats) are likely the main animal reservoir for Nipah virus, although there is evidence suggesting that other bat species are also susceptible to Nipah virus infection in nature. Various bat species ranging from Australia to West Africa can carry viruses genetically closely related to henipaviruses.
Studies from the known human infection outbreaks in Australia, Malaysia, Singapore, Bangladesh, India, and the Philippines, show that the virus can be transmitted to human by three different routes:
1) From bats to humans who come in contact with virus contaminated material (e.g., date palm sap);
2) From intermediate hosts such as pigs and horses; and
3) From infected humans.
There is also epidemiological evidence that companion animals (including dogs and cats) can be infected with these viruses and they can in theory transmit viruses to humans as well. There are currently no effective therapeutics, and supportive care and prevention are the mainstays of management1.
Nipah Virus outbreak in Bangladesh:
Possible contamination by bats in the clay pot collecting date palm sap
A new outbreak of Nipah virus has been reported in Bangladesh in 2013, with 24 cases and 21 deaths till 02 April 2013. Fourteen districts have been affected. The virus is believed to have been transmitted by the drinking of Nipah-contaminate raw date palm sap in all these cases. Human Nipah virus infection is an emerging zoonotic disease spread from fruit bats. In South-East Asia Region, the disease has been reported in Bangladesh and India.
Nipah virus outbreaks in the WHO South-East Asia Region:
Nipah virus (NiV) encephalitis is an emerging infectious disease of public health importance in the WHO South-East Asia Region. Bangladesh and India have reported human cases of Nipah virus encephalitis. Indonesia, Thailand and Timor-Leste have identified antibodies against NiV in the bat population and the source of the virus has been isolated. The status of NiV infection in other SEAR countries is not known although flying bats are found throughout the region.
The first identification of Nipah virus as a cause of an outbreak of encephalitis was reported in 2001 in Meherpur district of Bangladesh. Since then, outbreaks of Nipah virus encephalitis have been reported almost every year in selected districts of Bangladesh. The Nipah outbreaks have been identified in Naogoan (2003), Rajbari and Faridpur (2004), Tangail (2005), Thakurgaon, Kushtia and Naogaon (2007), Manikgonj and Rajbari (2008), Rangpur and Rajbari (2009), Faridpur, Rajbari and Madaripur (2010) and Lalmohirhat, Dinajpur, Rangpur and Comilla (2011) and Joypurhat, Rajshahi, Rajbari and Natore (2012). Repeated outbreaks of Nipah virus encephalitis were established in some districts. Sporadic cases of Nipah virus encephalitis have been reported, mostly from the west and north-western regions of Bangladesh almost every year, with high mortality and constituting a public health threat. Up to March 31, 2012 a total of 209 human cases of NiV infection in Bangladesh were reported; 161 (77%) of them died.
India reported two outbreaks of Nipah virus encephalitis in the eastern state of West Bengal, bordering Bangladesh, in 2001 and 2007. Seventy one cases with 50 deaths (70% of the cases) were reported in two outbreaks. During January and February 2001, an outbreak of febrile illness with neurological symptoms was observed in Siliguri, West Bengal. Clinical material obtained during the Siliguri outbreak was retrospectively analyzed for evidence of NiV infection. Nipah virus-specific immunoglobulin M(IgM) and IgG antibodies were detected in 9 out of 18 patients. Reverse transcription-polymerase chain reaction (RT-PCR) assays detected RNA from NiV in urine samples from 5 patients. A second outbreak was reported in 2007 in Nadia district of West Bengal. Thirty cases of fever with acute respiratory distress and/or neurological symptoms were reported and five cases were fatal. All five fatal cases were found to be positive for NiV by RT-PCR.
So far, NiV has infected 263 people and resulting in 196 deaths since 2001. The case fatality rate of Nipah virus encephalitis ranges from 0-100 and average case fatality rate is 74.5%. The case fatality rate has remained high during 2008 – 2012 despite a public awareness campaign and establishment of a referral system for better treatment and nursing care of patients in potential outbreak areas in Bangladesh.
There was no involvement of pigs in NiV transmission as was observed in Malaysia during an outbreak in 1998-99. Consumption of raw date palm sap contaminated by flying bats was the primary source of human NiV infection in Bangladesh.
Nipah cases tend to occur in a cluster or as an outbreak, although 18% of cases in Bangladesh were isolated. Strong evidence indicative of human-to-human transmission of NiV was found in Siliguri (India) in 2001 and in Bangladesh in 2004.
Outbreaks of Nipah in South-East Asia have a strong seasonal pattern and a limited geographical range. All the outbreaks occurred during winter and spring. This could be associated with several factors like the breeding season of the bats, increased shedding of virus by the bats and the date palm sap harvesting season.
First outbreak of Nipah virus in Malaysia and Singapore:
Nipah virus infection was first recognized in a large outbreak of 265 suspected cases in peninsular Malaysia during September 1998 to April 1999. Most patients had contact with sick pigs or had been in close physical contact with Nipah virus infected patients and then presented primarily with encephalitis. The outbreak was initially thought to be due to Japanese encephalitis, but it was later identified as Nipah virus encephalitis. This outbreak caused widespread panic and fear in Malaysia leading to considerable social disruptions and tremendous economic loss because of the mass culling of over one million pigs. In addition, eleven abattoir workers in Singapore developed a febrile illness caused by Nipah virus during March 1999 following close contact with imported pigs from Malaysia. The presentation of Nipah virus infection has been variable, ranging from the high mortality observed in the original Malaysian outbreak to an outbreak of low mortality disease among abattoir workers in Singapore, which presented as neurological illness and atypical pneumonia. No new outbreaks have been reported from these countries since May 1999. Bangladesh have identified consumption of fresh date palm sap as the primary route of bat-to-human transmission. Outbreaks have continued to occur in Bangladesh and India on an almost annual basis since 20012.
2018 Nipah virus outbreak in Kerala:
People are believed to have caught the infection after consuming date palm sap, which could have been licked or partially eaten by infected fruit bats. It was first alerted when three members of a family, two brothers (age 26 and 28) and their aunt (age 50), died on May 5th, May 18th, and May 19th, respectively, in the private Baby Memorial Hospital (Kozhikode district, Kerala). They died with signs of viral encephalitis. Laboratory testing was initially conducted at the Manipal Centre for Viral Research using blood and fluid samples from this patient. The etiologic cause of their death due to Nipah virus encephalitis was confirmed by the National Institute of Virology in Pune.
· The father of the two siblings died on May 24 after fighting for his life for about three weeks. In total, four family members died in this “index case” cluster.
· As the incubation period of Nipah virus infection varies from 4 to 14 days3, it was difficult to definitively determine who the true “index case” was and how the infection was acquired.
· Although more studies are required to prove or disprove that all the human cases are related and resulted from a single spill over event, early genetic analysis seems to indicate that the outbreak was caused by a virus closely related to the Nipah virus-BD strain.
· It is interesting to note that the distance from Kerala to the known “Nipah belt” in western/north western Bangladesh and the bordering areas of west Bengal is ~2,600 km (1600 miles).
· Sun May 27, there are 17 confirmed cases with 14 deaths giving a presumptive mortality rate of ~80%. Dozens of samples remain to be tested.
· At least 31 species of bats have been documented in Kerala (including 5 species of fruit bats)4 .
· The recent report that 21 samples of bats and pigs from the affected area tested negative for Nipah Virus should be interpreted with caution with regards to expected reservoir.
· The sample size is too small and the quality of the specimen (especially those from the dead bats in the well near the “index case” cluster) might also be an issue. Contrary to local news reports, it is impossible to rule out bats as a reservoir species based on these 21 samples.
· As a reservoir species, bats are not supposed to be affected, much less killed by the virus.
· The bats tested so far are insectivorous bats. A fruit bat colony 4-5 km from the site of the outbreak has yet to be tested.
· Longitudinal studies of Hendra virus in Australia revealed that the viral load in the bat population could go through short periods of “spikes”. As the timing of the assumed initial spill over event could not be conclusively determined, it is also possible that the viral load in the bat population has dropped recently, hence leading to negative findings.
· There is a vast literature showing that bats are the natural reservoirs for henipaviruses.
Risks of wide spread transmission:
· From past Nipah virus outbreaks, the R0 was estimated to be ~0.45. R0 is mathematical term quantifying the average number of new infections that one infected individual can generate, in an otherwise naive population. For an infection to spread through a population, R0 needs to >1. When R0 is <1, the infection will eventually die out.
· Human-to-human transmission requires intimate contact with high levels of bodily secretions (respiratory secretions, saliva, urine, etc.). The risk of wide-spread transmission is therefore low. This is also reflected in estimated R0 ~0.4 for Nipah virus.
· The current outbreak appears to be small, and the appropriate public health measures have been rapidly implemented to contain its spread. To put the current Nipah virus outbreak in context, consider the following two vignettes:
· The 2001 outbreak in Siliguri, India, involved 66 people. The index case transmitted the virus to 11 additional patients at the hospital. These secondarily infected patients were transferred to other facilities – in two facilities, subsequent transmission involved 25 staff and 8 visitors6. This was likely before the implementation of universal precautions— personal protective equipment (PPE) such as gloves, masks and/or face shields.
· 50% of Pteropus bats sampled in an outbreak area (Thakurgaon district) in Northwest Bangladesh were seropositive for Nipah virus antibodies7. Yet transmission is still very sporadic. Thus, the drivers of virus spillover remain relatively unknown (other than drinking of virus contaminated date palm sap).
Measures to reduce the infection:
· Quarantining of suspect cases are effective forms of infection control and containment. These have been appropriately implemented by the responsible government agencies responding to this outbreak in Kerala.
· Educational efforts combined with preventive measures appear to be effective. Examples include:
· The use of universal precautions and appropriate PPE (gloves, masks and/or face shield) is sufficient to limit the spread of Nipah virus to patient caretakers including family relatives and healthcare workers.
· Funeral practices that avoid direct contact with the deceased can cut the train of transmission.
· Avoiding direct contact with bodily fluids, especially respiratory secretions of infected individuals.
· Counsel relatives to avoid prolonged close contact with the infected individual (e.g. sleeping beside patient, sharing of foods, etc.).
All the above require culturally sensitive educational campaigns targeted to the affected community.
There is evidence that Nipah virus RNA patients are more likely to contaminate towels, bedsheets, and bed rails8. A previous study also showed that Nipah virus RNA could also be detected on the surrounding walls and bedframe of a deceased Nipah virus infected patient9. Thus, infection controls should target hospital surfaces, which will reduce the risk of formite transmission.
Diagnosis, Treatment and Prevention:
· Clinical symptoms include fever and headaches, which can progress to drowsiness, disorientation, mental confusion, and finally encephalitis (brain swelling) in less than a week.
· Molecular tests (both qPCR and next generation sequencing) are the most rapid and accurate tools available to confirm Nipah virus infection. Acute-phase serum, CSF, throat swabs, saliva, and urine can be used for these tests.
Initial signs and symptoms of Nipah virus infection are nonspecific, and the diagnosis is often not suspected at the time of presentation. Nipah virus infection can be diagnosed with clinical history during the acute and convalescent phase of the disease. The main tests used are real time polymerase chain reaction (RT-PCR) from bodily fluids and antibody detection via enzyme-linked immunosorbent assay (ELISA). There is also an IgM ELISA test based on whole viral antigen.
· Live virus isolation should be conducted in a high level biocontainment facility.
Prevention and control:
· Ribovirin was used during the Nipah virus outbreak in Malaysia, but its effect is non-conclusive. A targeted recombinant human monoclonal antibody therapy has proven to be effective in animal models and has passed Phase I clinical trial.
· There are several forms of recombinant vaccines proven to be effective in animal models. These include a recombinant G-protein based vaccine and viral vector-delivered vaccines. The recombinant G-protein vaccine has been licensed for use in horses. With the founding from the Coalition for Pandemics Preparedness Innovations (CEPI), there is an effort to fast track the development of a Nipah virus vaccine for human use.
· As treatment options are less, focus on NiV management should be on prevention. Preventive strategies include interventions to prevent farm animals from acquiring NiV by eating fruit contaminated by bats. Farms should be designed to reduce overcrowding to avoid rapid spread of disease between animals and should not be near fruit trees that attract bats. Consumption of contaminated sap should be avoided10.
Intensive supportive care is recommended to treat severe respiratory and neurologic complications. The initial measures consisted of fogging to kill mosquitoes and stepping up of JE immunization11.
A number of vaccine candidates have been found to be capable of complete protection against NiV disease in preclinical studies of small animal and nonhuman primate models. Candidate vaccines using a vesicular stomatitis virus vector are the most advanced, having demonstrated protection in hamsters, ferrets, and African green monkeys12.
Nipah virus emerged as a new virus 20 years ago only, causing severe morbidity and mortality in both humans and animals and destroyed the pig-farming industry in Malaysia, and it continues to cause outbreaks in Bangladesh and India. As the reservoir host Pteropus bat is widespread, and Nipah virus has been found in bats in various countries, the potential for outbreaks to occur in new regions remains significant. Care must be taken to completely eradicate this disease by taking the necessary preventive measures.
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Received on 11.08.2019 Accepted on 20.09.2019
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Asian J. Pharm. Res. 2019; 9(4):307-311.