Approach

Patients with Hendra virus (HeV) or Nipah virus (NiV) infection present predominantly with neurological and/or respiratory complaints. Practitioners in non-endemic countries should be alert to the possibility of patients presenting with these viruses, particularly in light of almost annual outbreaks of NiV in Bangladesh.

Diagnosis of these rare but emerging infections requires a high index of suspicion in a patient with a suggestive clinical presentation, together with appropriate travel history and exposure risk. Confirmation of diagnosis is through serology testing and/or reverse transcription-polymerase chain reaction (RT-PCR).

History

A thorough history in relation to travel, diet, occupation, and exposure to sick animals or humans is crucial in considering and subsequently identifying henipavirus infections.

Outbreaks of NiV appear in Bangladesh almost annually, particularly in winter months.[5] Other countries where NiV outbreaks have occurred include Singapore and Malaysia (where the virus was first discovered in 1998-1999), India,and the Philippines (probable).[7][8][11][9] Therefore, NiV should be in the differential list for returning travellers from these destinations with an appropriate clinical picture. However, given the widespread geographical distribution of the Pteropus bats, the natural hosts for these viruses, there is potential for other countries to have outbreaks too.

Important risk factors in relation to NiV are:

  • Contact with relevant animals (bats, pigs, and horses)[9][19][26]

  • Contact with known or suspected human cases of NiV,[9][24] and

  • Consumption of any food products that may have been contaminated by bat secretions, such as date palm sap.[20]

HeV outbreaks have only occurred in Australia, with a total of 7 human infections (as of July 2016) since its emergence in 1994, all involving direct contact with horses.[13] Again, given the widespread distribution of Pteropus bats, outbreaks may occur elsewhere, but the risk of this appears to be less than with NiV given that no direct bat-to-human or human-to-human transmission has been known to have occurred with HeV so far.[13]

Clinical presentation

NiV may be asymptomatic, but more often causes acute encephalitis, with symptoms including fever, altered mental status, headache, myalgia, weakness/lethargy, dizziness, nausea, and vomiting.[5][22][36] Seizures and other neurological manifestations may occur. Clinical signs may include areflexia, hypotonia, prominent autonomic disturbance, and segmental myoclonus.[22][36] Respiratory signs and symptoms, including cough, dyspnoea, and acute respiratory distress syndrome (ARDS), may occur with or without an encephalitic syndrome.[37]

The incubation period for NiV is on average 4 to 18 days, but may be up to 2 months.[1][23] After contact with an infected human case, incubation periods of 6 to 11 days have been reported.[37]

Nipah encephalitis may ‘relapse’ months after apparent resolution or may even present for the first time many months after an initial non-neurological presentation, termed ‘late-onset’ encephalitis.[36] Therefore, clinicians need to be alert to any acute neurological presentation in a patient who may have previously been infected with NiV.

HeV infection can present as an influenza-like illness with fever, headache, and myalgia, which can be complicated by severe pneumonic illness or encephalitis. One case had a mild meningoencephalitis with apparent recovery, but then relapsed with encephalitis a year later and died. Incubation period for HeV infection is estimated to be between 5 and 21 days.[13]

Initial investigations

Routine biochemistry and haematology blood tests should be carried out, including FBC, LFTs, urea and electrolytes, and clotting profiles. However, the laboratory abnormalities seen in henipavirus infections are non-specific. More is known about NiV, in which thrombocytopenia and raised transaminases are often seen.[22][23] Leukocyte counts are usually within the normal range, but may show a leukopenia.[22][23] In the few cases of HeV, thrombocytopenia and neutropenia have been reported.[29]

On chest imaging, consolidation and/or reticular changes may be seen.[23] Diffuse bilateral opacities consistent with ARDS were reported in Bangladesh and Indian NiV outbreaks.[37][38]

Thick and thin blood films for malaria and blood/urine cultures should be requested in order to exclude other potential aetiologies.

A diagnosis of henipavirus infection requires confirmatory laboratory tests. The choice of assay depends on local availability. The reference standard for laboratory confirmation is serum neutralisation tests. However, these are not performed in most laboratories since NiV and HeV are category 4 pathogens and handling live virus needs to be done under biosafety level 4 conditions.[17][39] Neutralisation tests using pseudotyped viruses bearing HeV glycoproteins have been developed to avoid the need to handle live virus.[9][40][41] In practice, however, confirmation is most commonly through:

  • Enzyme-linked immunosorbent assay on serum or cerebrospinal fluid (CSF) to demonstrate the presence of specific NiV or HeV antibodies, and/or

  • Detection of NiV- or HeV-RNA via RT-PCR assays.

Serum/CSF serological assays may be negative very early in the course of the illness; therefore, PCR is most useful at this stage.[31] For NiV, IgM has been reported to be positive in two-thirds of cases by day 4 and 100% of cases by day 12, whereas it takes until day 26 for 100% of cases to be IgG positive.[36][42] IgG appears to remain positive persistently, whereas IgM starts to become undetectable after 3 months (although it can persist for longer than 7 months in some patients).[43][42] By contrast, diagnostic sensitivity of serological tests is less well established in HeV.[36]

All patients presenting with neurological symptoms should have a lumbar puncture performed (if not contraindicated). CSF abnormalities are commonly seen, with a lymphocytic pleocytosis and raised protein but normal glucose levels (as seen with other viral encephalitides).[22][36]

CSF PCR tests for other viral encephalitides (e.g., herpes simplex virus, varicella zoster virus) should be ordered depending on clinical presentation, and other serologies/assays should be requested dependent of geographical exposure in order to exclude other potential aetiologies (e.g., dengue, Japanese encephalitis).

Other investigations

EEGs may be helpful for monitoring progression of the disease. Diffuse polymorphic slow waves are non-specific, but correlate well with severity of illness.[44]

MRI brain is the neurological imaging modality of choice, useful in both acute and relapsed/late-onset neurological presentations.[45] Multiple discrete hyperintense lesions in subcortical and deep white matter have been reported (in Malaysian NiV outbreaks), representing widespread micro-infarctions consistent with central nervous system vasculitis.[36][45] More confluent cortical changes have been reported in Bangladesh NiV outbreaks.[36][46] 

Consistent with the imaging, histopathological analyses of brain tissue samples have been reported to show vasculitis of medium- to small-sized blood vessels with resultant disseminated micro-infarctions, as well as direct neuronal invasion by the virus.[23][27][36]

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