Continuing Education Activity

Nipah virus infection is caused by the Nipah virus (NiV) and occurs as outbreaks in South and Southeast Asia. It is a zoonotic disease with bats being the reservoir host. Transmission can occur from bat to humans or through pigs which are the intermediate hosts. NiV presents as two distinct clinical syndromes as encephalitis or with predominantly respiratory involvement based on the strain of the virus and has a high mortality rate. This activity reviews the clinical evaluation of Nipah virus infection and explains the role of an inter-professional team in coordinating the care of this disease.

Objectives:

• Review how Nipah virus infection is acquired.
• Describe the history and physical exam of a patient with Nipah virus infection.
• Summarize the treatment of Nipah virus infection.
• Explain modalities to improve the care coordination between inter-professional team members to improve outcomes for patients affected by Nipah virus infection.

Introduction

Nipah virus (NiV) is an RNA virus that belongs to the family of Paramyxoviridae and Henipavirus genus, which also consists of Hendra virus (HeV) as well as the Cedar virus. NiV was first identified in Malaysia in 1998 and has since caused numerous outbreaks in and around South and Southeast Asia. NiV is a WHO priority pathogen due to its propensity for causing outbreaks.[1] 

NiV is a zoonotic disease, with the reservoir of NiV being the Pteropus fruit bat from which spillover likely happened to pigs and subsequently humans. NiV is considered a Biological safety level 4 (BSL 4) pathogen due to the unavailability of effective treatment or vaccination against it.[2] As it is a zoonotic disease, a One Health approach involving humans, animals, and the environment is necessary to prevent further spillovers.

Etiology

Nipah virus is a paramyxovirus belonging to the Henipavirus genus, the Paramyxovirinae subfamily, the Paramyxoviridae family, and the Mononegavirales order. NiV is a negative sense, single-stranded, enveloped RNA virus. The reservoir host of NiV is the Pteropus fruit bat, and NiV has a half-life of 18 hours in the urine of the bats.[3]

NiV transmission happens through three transmission pathways, including the consumption of contaminated foods, contact with infected human or animal body fluids, and droplet or aerosol exposure. The risk factors for acquiring the infection include close proximity with an infected person. Contaminated food can include fruits and date palm sap contaminated by the bat’s bodily fluids.

Epidemiology

The first case of NiV infection was reported near the city of Ipoh in Perak, Malaysia, in 1998.[2] In March 1999, NiV was isolated for the first time from a patient’s cerebrospinal fluid (CSF) from the Sungai Nipah village, thereby obtaining its name from the village.[1] In 1999, another outbreak involving 11 cases and one death occurred in Singapore.[4]

In Bangladesh, the epidemiology of NiV differed, starting with an outbreak of encephalitis in Meherpur in 2001. The primary difference included the absence of pigs being involved in the outbreak, as pig farming was not being practiced in Bangladesh, which is a predominantly Muslim country. Following this, multiple seasonal outbreaks have occurred, each of which is thought to be separate spillover events.[2] 

In 2001, an outbreak of encephalitis was reported in Siliguri, West Bengal, India, which is geographically adjacent to Bangladesh. This is now retrospectively thought to have been an outbreak of Nipah.[5] Hence, in Bangladesh and the Siliguri outbreak, the consumption of fresh date palm sap is thought to be responsible for a direct spillover of NiV from bat to humans.[6]

In 2014, an outbreak was reported in the Philippines where NiV transmission occurred by exposure to infected horses, similar to the Hendra virus infections in Australia.[2][7] In 2018 and 2019, the southern state of Kerala in India reported two discrete NiV outbreaks where fruit bats were once again implicated in the spillover events.[8][9]

Pathophysiology

Flying foxes (Pteropus giganteus) are the reservoirs of the Nipah virus in Bangladesh and India.[10][11] Pteropus species of bats in other countries (Cambodia, Thailand, Indonesia, and Madagascar) have anti–Nipah virus antibodies.[12][13][14][15] Rarely non-Pteropus species of bats can be reservoirs.[13][16][17] Pigs acted as intermediate hosts of the Nipah virus during the initial outbreak in Malaysia and Singapore and horses during the outbreak in the Philippines.[18] 

Transmission of the Nipah virus can occur from direct contact with infected animals (bats, pigs, horses) or their body fluids (blood, urine, or saliva), consuming contaminated food products (palm sap or fruit), or close contact with an infected person or their body fluids (nasal or respiratory droplets, urine, or blood).

NiV enters through the oro-nasal route into humans and other hosts. High concentrations of antigen in the lymphoid and respiratory tissue suggest that these are the probable sites of initial replication. NiV infects the epithelium of the respiratory tract and induces inflammatory cytokines, leading to the development of an acute respiratory distress syndrome-like disease.[19] Other than the lungs, the kidneys, spleen, and the brain may be involved, leading to multiple organ failure.[3]

History and Physical

The incubation period ranges between 4 days to 2 weeks.[20] The presentation may be encephalitis, respiratory involvement, or asymptomatic infection in a small proportion of patients. A difference is noted between the clinical features between the Malaysian and Indian variants of NiV, with the respiratory illness being encountered in almost 70% of patients in India and Bangladesh. Still, no significant respiratory involvement was noted in Malaysia.[21][5]

Symptoms start with fever, headache, dizziness, vomiting. This is followed by rapidly progressive encephalitis resulting in drowsiness, disorientation, confusion, and coma. Among CNS symptoms, decreased level of consciousness, brainstem dysfunction, myoclonus, areflexia, hypotonia, cerebellar signs are commonly observed. In fulminant illness, multiorgan dysfunction, gastrointestinal bleeding, and renal failure are seen. 69% of patients had respiratory difficulty in outbreaks in Bangladesh, and some cases led to acute respiratory distress syndrome.[20][22][23][21] 

Patients also have long-term neurologic effects from encephalitis, including fatigue, encephalopathy, ocular motor palsies, cervical dystonia, focal weakness, and facial paralysis. In a small proportion of patients, the onset of the illness may be delayed, and there may be relapses after recovery from the acute infection.[24]

Evaluation

Leukopenia, thrombocytopenia, and elevated levels of alanine aminotransferase and aspartate aminotransferase are commonly seen. CSF analysis in most patients showed elevated WBC count or protein level, or both.[20] In acute Nipah virus infection, virus-specific antibodies were present in the serum in more than 70% of samples but in less than one-third of CSF samples. The presence of the virus in CSF culture was strongly associated with mortality.[25] EEG in encephalitis shows bilateral temporal periodic complexes of sharp and slow waves occurring every 1 or 2 seconds.[26]

Typical MRI findings were multiple 2 to 7 mm lesions best visualized in the T2-weighted images in the subcortical & deep white matter of the cerebral hemispheres, periventricular areas, and the corpus callosum, without associated cerebral edema or mass effect. Few patients have leptomeningeal enhancement or parenchymal lesion enhancement.[20][27][28] Nipah virus can be detected from urine and respiratory secretions by culture and PCR. Real-time RT-PCR is more sensitive than conventional assay.[29][30][31][32][33] Serology is not helpful for acute infections but mostly useful for epidemiologic studies.[34]

Treatment / Management

Patients with NiV infection should be isolated with infection control practices in place. Treatment is primarily supportive. Ribavirin is an antiviral that is effective against other paramyxoviruses like respiratory syncytial virus. Reports on its efficacy are unclear, with conflicting reports showing a reduction in mortality and no effect. However, the Indian National Centre for Disease Control recommends the use of ribavirin in Nipah virus infections.[20][1][35] Acyclovir, chloroquine, and ephrin-B2 are under review as potential therapeutic options.[4][36][37] 

Favipiravir, which is licensed for the treatment of influenza in Japan, was shown to be effective in hamsters.[38] The human monoclonal antibody has been shown to be useful in ferrets and non-human primates.[39][40] Patients should be discharged only after a negative RT-PCR is performed on a throat swab. Discharged patients remain in isolation for 21 days following confirmation of the infection.[1]

Differential Diagnosis

Differential diagnosis involves any disease presenting with fever and encephalitis, and/or ARDS, but epidemiology, travel history, and ongoing outbreaks help differentiate the diagnosis. The common differentials in NiV infection can include:[41]

• Japanese encephalitis
• Measles
• Rabies
• Dengue encephalitis
• Cerebral malaria
• Scrub typhus
• Leptospirosis
• Herpes encephalitis
• Bacterial meningitis

Prognosis

The case fatality rates can range between 40% and 100%. Poor prognostic factors include old age and severe brain-stem involvement.[41] Prognosis and case fatality rates also depend on the strain of the virus, with the Malaysian variant showing lower rates.[42]

Complications

There may be residual neurological deficits in survivors, including behavioral change, cervical dystonia, ocular motor palsies, weakness, and facial paralysis. In a small proportion of patients, there may be relapses after recovery from the acute infection.[24]

Deterrence and Patient Education

Patient education is of extreme importance in preventing the disease, especially in the context of the lack of an effective treatment. Patient education should focus on efforts to prevent the contamination or consumption of date palm sap. The WHO also recommends avoiding exposure to bats and pigs and avoiding exposure to bat-bitten fruits or raw date palm sap. Protective clothing is recommended for people involved in the slaughter of animals. Human-to-human transmission during an outbreak can be contained by limiting exposure and the use of personal protective equipment. Contact tracing and quarantining potential contacts form a large part of an outbreak response.[1][9][43]

Pearls and Other Issues

Nipah virus infection is a highly lethal infection that adequate preventive measures can prevent. The diagnosis may be made based on RT-PCR in the clinical context of encephalitis or an ARDS-like picture. There are no effective treatment options available at present. Nipah virus has pandemic potential, and further research is warranted into its epidemiology and therapeutic options.

Enhancing Healthcare Team Outcomes

The management of Nipah virus infection is best accomplished via an inter-professional team approach that includes infectious disease specialists, clinicians, mid-level practitioners, and nursing staff. The infection has no cure, and treatment options are limited. The patient needs consultations from numerous specialists. Since no effective treatment exists, prevention is critical. This can be achieved by preventing exposure to bats, pigs, and bat-bitten fruits in addition to avoiding consumption of date palm sap. In the context of an outbreak, adequate infection control practices are necessary to prevent human-to-human transmission. The outcome for patients with NiV infection is guarded. In addition to infectious diseases clinicians, the involvement of a neurologist and subsequently a physiatrist may be required due to the residual neuropsychiatric deficits following recovery. [Level 4]

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Disclosure: Balram Rathish declares no relevant financial relationships with ineligible companies.

Disclosure: Kushal Vaishnani declares no relevant financial relationships with ineligible companies.