Australian Bat Lyssavirus

Monograph
Tables
What's New
Reviews
History

Virology

Australian bat lyssavirus (ABLV) is a member of the Lyssavirus genus of the family Rhabdoviridae. Lyssaviruses are enveloped single stranded negative sense RNA viruses. There are 14 known species of lyssaviruses segregated into three phylogroups. Phylogroup I is the largest and consists of the type species rabies virus (RABV), along with Duvenhage virus (DUVV), European bat lyssaviruses 1 and 2 (EBLV 1 and 2), Australian bat lyssavirus, Aravan virus (ARAV), Khujand virus (KHUV), Irkut virus (IRKV) and finally Bokeloh bat lyssavirus (BBLV) (2). Phylogroup II consists of Lagos bat virus (LBV) and Mokola virus (MOKV) (4). Phylogroup III includes West Caucasian bat virus (WCBV), Shimoni bat virus, (SHIBV) and Ikoma lyssavirus (IKOV). The recently discovered tentative lyssavirus, Lleida bat lyssavirus (LLEBV), remains to be classified (17). Analysis of the ABLV genome shows that it is distinct from the other lyssaviruses (7).

Epidemiology

Australian bat lyssavirus is the first endemic Lyssavirus found in Australia, first identified from brain material from a fruit bat (Pteropus alecto) in New South Wales in May 1996 (6). This was closely followed by the first of 3 reported human cases in November that same year in Rockhampton, Queensland (1). This patient had a history of caring for flying foxes in the 2 to 4 weeks prior to the onset of her rabies like illness, reportedly receiving multiple scratches but no bites (1). A history of a bat bite 27 months prior to development of rabies like symptoms was obtained from the second patient in Mackay, Queensland in 1998 (8). The third reported case is the first reported in a child and occurred in an 8 year old boy from a Queensland regional island who received a scratch from a bat approximately 8 weeks prior to presentation (5). The first reported spillover of ABLV into a species other than bats and humans was reported in 2 horses in May 2013 in the Southern Downs area of Queensland (14).

Australian bat lyssavirus has been detected from all four species of flying foxes on mainland Australia, with a combined host range therefore extending from the west coast of Western Australia, through the Northern Territory, Queensland, New South Wales and Victoria. Serological evidence of Australian bat lyssavirus (or similar) infection has also been found in six different bat species in the Philippines (3).

The prevalence of Australian bat lyssavirus in bats is difficult to determine and variable amongst species as well as dependent on symptoms. Early reports demonstrated a seroprevalence of 6% amongst 366 sick, injured or displaced bats in Queensland (11). In healthy bats the prevalence is likely to be less than 1%. Sick, injured and/or orphaned spectacled flying foxes demonstrate an antigen positivity rate of approximately 1% whereas in similar cohorts of little red flying foxes positivity rates approach 17%. Flying foxes with central nervous system signs have the highest rates of Australian bat lyssavirus positivity at approximately 60% (18).

Clinical Manifestations

The clinical presentations and fatal outcomes of all three reported Australian bat lyssavirus cases is consistent with infection with other members of the Lyssavirus genus including classic rabies virus. In the first case in 1996 a 39 year old female developed weakness of one arm followed by progressive neurological symptoms and signs, bulbar palsy and death within 21 days (1). In 1998 a 37 year old female developed a rapidly progressive neurological illness similar to rabies from which she ultimately succumbed (8). In the first reported pediatric case in 2013 an 8 year old boy presented with fever, anorexia and abdominal pain. He developed central nervous system signs including distress, abnormal behavior and aggression followed by muscle spasms. Hydrophobia was not described but copious oral secretions were reported (5).

Laboratory Diagnosis

Definitive diagnosis of Australian bat lyssavirus infection is based on molecular identification by polymerase chain reaction (PCR) on saliva, cerebrospinal fluid or neural tissue (15). Viral culture of the brain is also diagnostic but a lengthy process. Histopathological examination and immunoperoxidase staining of neural tissue are useful in diagnosing lyssavirus infection but cannot differentiate genotypes (9). Serological testing using immunofluorescence and enzyme-linked immunosorbent assay can also be helpful although these tests cannot distinguish lyssavirus genotypes and there may be a delay in the appearance of antibody – 10 days following salivary PCR positivity in one case (15). These investigations are carried out at the laboratories of Queensland Health Scientific Services (Cooper’s Plains, Queensland, Australia), the Australian Animal Health laboratory (Geelong, Victoria, Australia) and the Centers for Disease Control (Atlanta, Georgia, USA).

Pathogenesis

The pathogenesis of Australian bat lyssavirus infection is similar to that of other Lyssaviruses including rabies. Inoculation is likely to occur from saliva of an infected bat following a bite or scratch. Following entry into the peripheral motor neurons via the neuromuscular junction, the virus is transported centrally to the brain and then to other tissues. Experimental inoculation of bats revealed an incubation period of 15 to 24 days (12). Longer incubation periods have been demonstrated for 2 of the 3 human infections (5,8). Histological examination of inoculated flying foxes has demonstrated nonsuppurative meningoencephalitis and ganglioneuritis (9).

SUSCEPTIBILITY IN VITRO AND IN VIVO

There are no in vitro or in vivo studies on drug susceptibility.

ANTIVIRAL THERAPY

There are no clinical reports on antiviral therapy.

ADJUNCTIVE THERAPY

Supportive and symptomatic therapy is indicated for convulsions, impaired consciousness and other neurological manifestations. In the third reported case the Milwaukee Protocol was utilized which includes induction of mild hypernatremia and sedation with ketamine and benzodiazepines (5) however subsequently it has been suggested by some that the use of this protocol should be discontinued (10).

ENDPOINTS FOR MONITORING THERAPY

No therapeutic endpoints have been established, there have been no survivors from ABLV infection.

VACCINES

There are no studies on the efficacy of rabies vaccine in prevention of ABLV infection but the genotypic relatedness of these two viruses makes it likely that a significant degree of protection would result.

Indications

Pre-exposure prophylaxis is recommended in people with a high risk of potential exposure to bats including bat handlers, veterinarians and wildlife workers in any country including Australia. Post-exposure prophylaxis is recommended following a bite, scratch or significant salivary exposure to a bat particularly in eastern Australia. Initial management should include wound cleansing with soap and water or antiseptic solution and rabies immunoglobulin (RIG) should also be used (13). The indications and regimens are similar to those used for rabies. There is no defined period following exposure to a bat when Australian bat lyssavirus is not likely to occur.

Doses, Schedules

The dose of human diploid cell or purified chick embryo cell rabies vaccine is 1 ml intramuscularly. For pre-exposure prophylaxis doses are given at days 0, 7 and 28. For post-exposure prophylaxis doses are given at days 0, 3, 7, and 14. The previously recommended fifth dose is no longer recommended in immunocompetent individuals based on evidence that antibody responses were similar after the 4th and 5th dose and both were several orders of magnitude higher than the recommended cutoff (16).

Rabies immunoglobulin (20 IU/kg; 150 IU/ml) should be given no later than 7 days after the first dose of vaccine; as much as possible should be infiltrated around the wound site and the remainder given intramuscularly. In people who have received pre-exposure prophylaxis a modified post-exposure regimen is recommended, with vaccine dosing at days 0 and 3 and omission of rabies immunoglobulin (16).

Adverse Effects

The most common side effects of vaccination or rabies immunoglobulin are sore arm (15-25%), headache (5-8%), malaise or nausea (2-5%) and allergic oedema (0.1%). These reactions are not more common in children. More severe allergic reactions are rare – estimated at 1 per 10,000 vaccines, but are more likely with booster doses. These usually occur 2-21 days after injection, may consist of urticaria, fever, vomiting or arthralgia and are very rarely life-threatening. The potential severity of ABLV infection mandates that prophylactic regimens should not be interrupted unless severe reactions occur (16).

PREVENTION OR INFECTION CONTROL MEASURES

Prevention depends on avoidance of exposure to bats, particularly if they are unwell or behaving unusually. If an exposure is likely then prior vaccination is recommended or if an exposure occurs then post exposure prophylaxis with rabies vaccine is indicated as outlined above. Human to human transmission has not been documented and standard infection control measures are recommended when looking after infected patients.

REFERENCES

1. Allworth A, Murray K, Morgan J. A human case of encephalitis due to a Lyssavirus recently identified in fruit bats. Communicable Disease Intelligence 1996;20:504.

2. Arai YT, Kuzmin IV, Kameoka Y, Botvinkin AD. New lyssavirus genome from the Lesser Mouse-eared bat (Myotis blythi), Kyrghyzstan. Emerging Infectious Diseases 2003;9:333-7. [PubMed]

3. Arguin PM, Murray-Lillibridge K, Miranda ME, Smith JS, Calaor AB, Rupprecht CE. Serological evidence of Lyssavirus infections among bats, the Philippines. Emerging Infectious Diseases 2002;8:258-62. [PubMed]

4. Badrane H, Bahloul C, Perrin P, Tordo N. Evidence of two Lyssavirus phylogroups with distinct pathogenicity and immunogenicity. Journal of Virology 2001;75:3268-76. [PubMed]

5. Francis JR, Nourse C, Vaska VL, Calvert S, Northill JA, McCall B, Mattke AC. Australian Bat Lyssavirus in a Child: The First Reported Case. Pediatrics. 2014;133:e1063–e1067. [PubMed]

6. Fraser GC, Hooper PT, Lunt RA, Gould AR, Gleeson LJ, Hyatt AD, Russell GM, Kattenbelt JA. Encephalitis caused by a Lyssavirus in fruit bats in Australia. Emerging infectious diseases. 1996;2:327. [PubMed]

7. Gould AR, Hyatt AD, Lunt R, Kattenbelt JA, Hengstberger S, Blacksell SD. Characterisation of a novel lyssa virus isolated from Pteropid bats in Australia. Virus Research 1998;54:165-87. [PubMed]

8. Hanna JN, Carney IK, Smith GA, Tannenberg AE, Deverill JE, Botha JA, Serafin IL, Harrower BJ, Fitzpatrick JW. Australian bat lyssa virus infection: a second human case, with a long incubation period. Medical Journal of Australia 2000;172:597-9. [PubMed]

9. Hooper PT, Fraser GC, Foster RA, Storie GJ. Histopathology and immunocytochemistry of bats infected by Australian bat lyssavirus. Australian Veterinary Journal 1999;77:595-9. [PubMed]

10. Jackson AC. Current and future approaches to the therapy of human rabies. Antiviral research. 2013;99:61–7. [PubMed]

11. McCall BJ, Epstein JH, Neill AS, Heel K, Field H, Barrett J, Smith GA, Selvey LA, Rodwell B, Lunt R. Potential exposure to Australian bat lyssa virus, Queensland, 1996-1999. Emerging Infectious Diseases 2000;6:259-64. [PubMed] McCormack JG, Allworth AM. Emerging viral infections in Australia. Medical Journal of Australia 2002;177:45-9. [PubMed]

12. McColl KA, Chamberlain T, Lunt RA, Newberry KM, Middleton D, Westbury HA. Pathogenesis studies with Australian bat lyssavirus in grey-headed flying foxes (Pteropus poliocechalus). Australian Veterinary Journal 2002;80:636-41. [PubMed]

13. McCormack JG, Allworth AM. Emerging viral infections in Australia. Medical Journal of Australia 2002;177:45-9. [PubMed]

14. Roth, I. CVO Bulletin to NSW Veterinarians regarding Australian Bat Lyssavirus (ABLV);Bulletin Number 20130529; Veterinary Practitioners Board of New South Wales: Mascot, Australia, 29 May 2013.

15. Smith IL, Northill JA, Harrower BJ, Smith GA. Detection of Australian bat lyssavirus using a fluorogenic probe. Journal of Clinical Virology 2002;25:285-91. [PubMed]

16. The Australian Immunisation Handbook. National Health and Medical Research Council, Australia. National Capital printing, Canberra. 8th edition, 2003.

17. Virus Taxonomy: 2013 release. Available online: http://www.ictvonline.org/virusTaxonomy.asp (accessed on 13 June 2014).

18. Weir DL, Annand EJ, Reid PA, Broder CC. Recent observations on Australian bat lyssavirus tropism and viral entry. Viruses 2014;6:909–26. [PubMed]