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Confidential

The Hendra Virus Report Chapter 4: Hendra virus in humans

This chapter discusses the nature of Hendra virus in humans.
4.1 Description of Hendra virus in humans

There have been seven recorded cases of Hendra virus in humans.56 In all cases
infection resulted from close contact with the bodily fluids of infected horses. Of the
seven cases, five people are believed to have been exposed to the virus while
performing autopsies, nasal lavages or endoscopies, while the other two had close
contact with a dying horse. Hendra virus was not a confirmed or suspected diagnosis
in any of these cases at the time of contact with the horse.
Of the seven recorded human infections, there have been four deaths. One of those
deaths occurred 13 months after the initial infection. The remaining three persons did
not survive their initial infections.
The first known human case of the virus occurred in the Brisbane suburb of Hendra
in 1994, where two people were infected. A horse trainer died from the virus, while a
stable worker survived an influenza-like illness that was later identified as Hendra
virus.
The second death occurred in Mackay in 1995, when a male person developed
severe encephalitis. It was later found that he had been exposed to Hendra virus
during the autopsy of two horses 13 months earlier. At the time, the cause of death of
the horses was unknown.57 The male person had been hospitalised with aseptic
meningitis shortly after the autopsies but his illness was not identified as Hendra
virus at that time.
The next human case of Hendra virus occurred in North Queensland in 2004, where
a private veterinarian performed an autopsy on a horse. She developed a mild
influenza-like illness approximately seven days later, and recovered. This illness was
subsequently diagnosed as Hendra virus, and the deceased horse was assumed to
be a Hendra virus case.
The most recent human cases of Hendra virus infection occurred during the 2008
Redlands incident (two people) and the 2009 Cawarral incident (one person).
In the Redlands incident, a private veterinarian and a veterinary nurse employed at
the same veterinary clinic developed acute influenza-like illnesses followed by
encephalitis. They had both performed a nasal cavity lavage on a seemingly well
horse in the days before it developed clinical signs of Hendra virus. The veterinarian,
Dr Cunneen, had also performed an autopsy on another horse that was later found to
have died of Hendra virus.58 Dr Cunneen passed away five weeks later. The
veterinary nurse survived the infection but continues to experience significant ill-
effects.
56 There have been no confirmed reports of Hendra virus in humans arising from the 2011 Hendra virus incidents. 57 The horse deaths in Mackay occurred before the Hendra incident in 1994, which was when Hendra virus was first identified. 58 QH Guidelines for Public Health Units, Hendra Virus Infection (formerly Equine Morbillivirus Infection) [accessed at on 1 April 2011]. Chapter 4: Hendra virus in humans The most recent human case of Hendra virus occurred during the 2009 Cawarral incident. Dr Rodgers passed away after contracting Hendra virus during an endoscopy on a sick horse that was later diagnosed with Hendra virus. 4.1.1 Human-to-human transmission
The clinical notification criteria for Hendra virus in humans are listed in the QH document Hendra Virus Infection - Queensland Health Guidelines for Public Health Units (QH Guideline). Although not previously available to the public, the QH Guideline is now available on the QH website.59 The current QH Guideline states: Acute illness following exposure to horses with suspected or confirmed Hendra virus infection. Infection in humans has included:  self-limiting influenza-like illness (two cases) influenza-like illness complicated by severe pneumonic illness contributing to death (one case) aseptic meningitis with apparent recovery, then death from encephalitis 13 months later (one case) acute influenza-like illness followed by encephalitis at seroconversion, followed by recovery (one case) and death (two cases). However, the QH Guideline notes that the full spectrum of human clinical infection is unknown. The incubation period for Hendra virus in humans is estimated as between five and 16 days, but could be up to 21 days. The current QH Guideline states that there is no evidence of human-to-human transmission of Hendra virus, and notes that: … Hendra virus does not appear to be very contagious. Serological testing in a large number of human contacts of the first three human cases was completely negative and serological testing of people who have close contact with bats has also failed to provide any evidence of infection. All human infections have been acquired through close contact with the body fluid (especially respiratory secretions and blood) of Hendra virus infected horses. Direct contact with respiratory secretions or blood of infected animals seems to be necessary for transmission, although droplet transmission cannot be discounted. There has been no evidence of person-to-person or bat-to-person transmission. Nevertheless, the QH Guideline advises that ‗it is desirable to avoid close contact with body fluids/secretions of a symptomatic human case.‘60 Consequently, the QH Guideline advises that ‗standard‘, ‗droplet‘ and ‗contact‘ precautions should be taken against human-to-human transmission.61 59 Refer http://www.health.qld.gov.au/cdcg/index/hendra.asp. 60 QH Guidelines for Public Health Units, Hendra Virus Infection (formerly Equine Morbillivirus Infection) accessed at on 1 April 2011]. 61 I note that such precautions are relatively standard for preventing the transmission of many diseases. A description of these precautions can be found a[accessed on 15 June 2011]. The Hendra Virus Report Standard precautions involve hand-washing, protection from contact with the blood or body fluids of a person who is, or is suspected to be, infected (for example, by wearing gloves and masks), and routine environmental cleaning. In addition to standard precautions, droplet precautions involve isolation, the routine use of surgical masks by staff, and the use of surgical masks by patients while they are in transit. Where Hendra virus is confirmed or highly suspected in a person, the current QH Guideline also advises that the person avoid close contact with horses. These precautions are only recommended where a person has had contact with a suspected or known Hendra-positive horse and shows signs of illnesses associated with Hendra virus. The QH Guideline does not recommend that any specific precautions be taken where a person has had contact with a suspected or known Hendra-positive horse but does not show any signs of illness. 4.2 Testing for Hendra virus in humans

Human testing for Hendra virus is conducted by QHFSS. Further testing on human
samples may also be conducted by AAHL.
4.2.1 Nature of tests
QH has provided information to the general public about testing for Hendra virus in humans. I have commented on this further in chapter 13. Generally, a combination of PCR and serological tests are used to test for Hendra virus in humans. As discussed in section 3.2.1, PCR tests aim to identify the presence of virus matter. These tests are used where a person who has been exposed or potentially exposed to Hendra virus is unwell. A positive PCR test is considered by QH to be a conclusive indicator that a person has been infected with Hendra virus. QHFSS also uses techniques to isolate the virus in human samples; however, because this process can take some weeks it is of limited use. As with horses, serological testing examines a person‘s antibody response to Hendra virus. The Indirect ELISA test used for horses is not species specific and can also be used for human testing. However, this test is known for producing relatively high numbers of false positives and is therefore no longer used by QHFSS for human testing. Instead, human-specific serology tests are used to detect antibodies to Hendra virus in human samples (microsphere immunoassay, confirmed by specific immunofluorescent assay). Chapter 4: Hendra virus in humans Where a positive serological result is obtained, this is considered to be a conclusive indicator of infection. Supplementary testing including a VNT test may be conducted by AAHL, as QHFSS does not conduct VNT testing. The test involves introducing the virus into the human blood sample and the amount of virus remaining after incubation shows whether antibodies are present. Alternatively, if an unknown virus is detected in the blood sample, the virus can be incubated in the presence of virus specific antibodies to determine the nature of the particular virus. The current QH case definition for Hendra virus requires only one of the following for a diagnosis of Hendra virus to be confirmed in a human:  isolation of the virus a positive PCR test detection of antibodies to Hendra virus by microsphere immunoassay, confirmed by specific immunofluorescent assay. 4.2.2 When testing is carried out
Initial tests62 on persons who have been exposed to an infected or potentially infected horse are generally carried out soon after a Hendra virus incident is identified, and usually involve only serological testing to detect antibodies to the virus. When conducted in the first few days after possible infection, serology test results are expected to be negative. The results of an initial serology test may be useful to aid interpretation of later serological tests, but are not essential. Further serology tests will generally be carried out three and six weeks after exposure. However, not all people will require this course of testing, and QH will have regard to the timing of the first and second rounds of tests or any subsequent re-exposure by a person to an infected or potentially infected horse. A person would only be expected to be positive to a PCR test during the initial stages of acute infection. For this reason, PCR testing is usually only conducted on people who are showing clinical signs of Hendra virus, as in the absence of clinical signs a person would be expected to be negative to this test. People who have contracted Hendra virus have all become unwell. VNT or isolation testing is not considered necessary for a confirmed result in a human case, and is not carried out by QHFSS. Such additional testing may be carried out by AAHL if requested. Neither a single negative serology test nor a single negative PCR test conducted early during the possible incubation period is conclusive evidence of a lack of Hendra virus infection. On the other hand, a single positive PCR test or a single positive serology test (microsphere immunoassay, confirmed by specific immunofluorescent assay) will be sufficient evidence of infection. Because the incubation period for Hendra virus in humans could be as high as 21 days, testing may be done at both 21 days (three weeks) and approximately 42 days (six weeks) after exposure (two incubation periods). 62 Often referred to as ‗baseline tests‘. The Hendra Virus Report Finally, it is important to note that this information refers to approximate testing timeframes which are subject to change as QH gathers further information about Hendra virus. The timeframes are only guidelines and may vary depending on an individual‘s circumstances and level of risk. 4.2.3 Testing procedure
There is no QH policy specifically relating to testing, and the only procedures for testing are set out in the QH Guideline. The current QH Guideline states: Human testing should be on the basis of exposure to known or suspected equine cases, or for a compatible human illness in consultation with an infectious diseases physician. Testing is not routinely recommended for those with nil or negligible exposures. … There have been no positive nucleic acid tests or seroconversions demonstrated in any asymptomatic human contacts followed up as part of any outbreak investigations to date. This last paragraph explains that no person has tested positive to a PCR or serological test without showing clinical signs of Hendra virus. The current QH Guideline also states: Commence investigation immediately on notification of a confirmed human or equine case, or where notified by Biosecurity Queensland of heightened suspicion of infection in a horse on clinical/ epidemiological grounds. Attempt to verify case(s) and establish time-line for results of laboratory testing if results are still pending. … The urgent priorities are to obtain a spreadsheet of all people who may have been in contact with the infectious horse/s (it is best to refer to horses by their common name/s to minimise confusion), then to: conduct assessment of exposure and current health status of those people provide information about Hendra virus counsel about risk provide advice about health monitoring refer any symptomatic people to appropriate care and facilitate recommended testing as indicated by level of risk. There is no suggestion that people who have been in contact with the horse will be tested while awaiting the results of the tests on the horse. The current QH Guideline also provides that testing is not routinely recommended for those with nil or negligible exposures, but may have to be undertaken in such situations so as to manage extreme anxiety. Furthermore: Chapter 4: Hendra virus in humans For those with low exposures, the decision to test should be based on an understanding of what testing is (eg baseline screening is not proof of ‗clearance‘) and that there have been no previous examples of asymptomatic seroconversion.63 Testing does not take the place of self-monitoring for symptoms and appropriate investigation of illness. I understand that QH‘s current position is that testing will be arranged for anyone exposed to a Hendra virus infected horse who wishes to be tested, whatever their level of exposure. 4.2.4 Testing fees
Human testing for Hendra virus is only available where requested by a medical practitioner. QH does not charge a fee for human testing for Hendra virus where requested by a medical practitioner. Prioritisation of testing (that is, whether routine or urgent) occurs, informed by the QH Guideline. 4.2.5 Treatment for Hendra virus

Three treatments have been trialled with people exposed to Hendra virus; however,
because none has been registered for the purpose of preventing Hendra virus
infection, they are considered experimental. Treatment is only offered to those who
have had significant exposure to a horse known to have Hendra virus. The
treatments are ribavirin, chloroquine and monoclonal antibodies.
Ribavirin

Ribavirin is an antiviral drug commonly used to treat hepatitis C. A test-tube
laboratory study published in 2005 provided limited evidence suggesting that ribavirin
may have some effectiveness in preventing Hendra virus,64 and a preliminary clinical
study in 2001 had previously suggested some effectiveness against the related
Nipah virus.65 However, by late 2009 results from a further study suggested that
ribavirin may not be effective to treat Hendra virus in animals.66
Chloroquine

Chloroquine is a well-known anti-malarial drug. A single test-tube laboratory study in
2009 suggested that it may be effective against Nipah virus;67 however, a study later
that year questioned its effectiveness in responding to the related Nipah virus in
ferrets.68
63 Asymptomatic seroconversion refers to situations where a person‘s immune system creates antibodies in response to an infection without the person showing clinical signs. This has not been recorded in relation to Hendra virus. 64 Wright, P.J. et al. Archives of Virology 2005 Mar;150(3):521–32). 'RNA synthesis during infection by Hendra virus: an examination by quantitative real-time PCR of RNA accumulation, the effect of ribavirin and the attenuation of transcription'. 65 Chong, H.T. et al. Annals of Neurology 2001 Jun;49(6):810–3. 'Treatment of acute Nipah encephalitis with ribavirin'. 66 While this study had not yet been published, QH was aware of the results of the study. 67 Porotto, M. et al. Journal of Virology 2009; 83:5148–5155. 'Simulating henipavirus multicycle replication in a screening assay leads to identification of a promising candidate for therapy'. 68 Pallister, J. et al. Journal of Virology, November 2009;83(22):11979–11982. 'Chloroquine Administration Does Not Prevent Nipah Virus Infection and Disease in Ferrets'. The Hendra Virus Report Monoclonal antibodies

One specific monoclonal antibody has been shown to protect ferrets from serious
disease after exposure to Nipah virus.69 This treatment has not been the subject of
experimental trials on humans and is not registered in Australia. However, it may be
used in exceptional circumstances following appropriate consideration of the
potential risks and benefits and ethics committee approval.
Since at least 2008, some of these treatments have been offered, in varying
combinations, to those who had developed Hendra virus or were at high risk of doing
so. It is not known whether the treatments were effective in preventing or minimising
infection.
Following analysis of all studies to date, ribavirin and chloroquine are no longer
recommended by QH for treatment of persons at risk of developing Hendra virus
infection.
Presently, there is no human vaccine available for Hendra virus.
69 Bossart, K. et al. PLoS Pathogens October 2009:5(10):1–11. ‗A Neutralizing Human Monoclonal Antibody Protects against Lethal Disease in a New Ferret Model of Acute Nipah Virus Infection‘.

Source: http://www.ombudsman.qld.gov.au/Portals/0/docs/Publications/Inv_reports/Hendra/Hendra_S4.pdf