Ebook One health: The Human– Animal–Environment interfaces in emerging infectious diseases (Part 2)

(BQ) Part 2 book “One health: The Human– Animal–Environment interfaces in emerging infectious diseases” has contents: Cost estimate of bovine tuberculosis to Ethiopia, Cysticercosis and Echinococcosis, H5N1 highly pathogenic avian influenza in Indonesia - retrospective considerations,… and other contents.

Part II Examples of Health approach to specific

diseases from the field

The Application of One Health

Approaches to Henipavirus Research

David T S Hayman, Emily S Gurley, Juliet R C Pulliam

and Hume E Field

Abstract Henipaviruses cause fatal infection in humans and domestic animals.Transmission from fruit bats, the wildlife reservoirs of henipaviruses, is putativelydriven (at least in part) by anthropogenic changes that alter host ecology Humanand domestic animal fatalities occur regularly in Asia and Australia, but recentfindings suggest henipaviruses are present in bats across the Old World tropics Wereview the application of the One Health approach to henipavirus research in three

Department of Biology, Colorado State University,

Fort Collins, CO 80523, USA

e-mail: davidtshayman@gmail.com

E S Gurley

icddr, b (International Centre for Diarrheal Diseases Research, Bangladesh),

68 Shaheed Tajuddin Ahmed Sharani, Mohakhali, 1212 Dhaka, Bangladesh

Queensland Centre for Emerging Infectious Diseases,

Department of Agriculture, Fisheries & Forestry,

39 Kessels Rd, Brisbane, QLD 4108, Australia

e-mail: Hume.Field@deedi.qld.gov.au

DOI: 10.1007/82_2012_276

 Springer-Verlag Berlin Heidelberg 2013

Published Online: 17 November 2012

locations: Australia, Malaysia and Bangladesh We propose that by recognising and addressing the complex interaction among human, domestic animal and wildlife systems, research within the One Health paradigm will be more successful

in mitigating future human and domestic animal deaths from henipavirus infection than alternative single-discipline approaches

Contents

1 Introduction 156

2 Hendra Virus in Australia 157

3 Nipah Virus in Malaysia 161

4 Nipah Virus in Bangladesh 162

5 Expanding the One Health Paradigm for Henipavirus Research 164

5.1 Geographic Expansion 164

5.2 Disciplinary Expansion 166

6 Conclusions 167

References 167

1 Introduction

Henipaviruses infect wildlife, domestic animals and humans and their emergence has been linked to anthropogenic activities Henipaviruses, therefore, provide a useful lens through which to view the development and implementation of the One Health paradigm, which strives for optimal human, animal and environmental health through collaborative multi-disciplinary work Furthermore, henipavirus outbreaks have occurred in countries as economically and culturally distinct as Australia and Bangladesh, providing opportunity for comparative approaches and cross-fertilisation of ideas that enhance understanding of the common processes that underlie cross-species transmission in these different settings To date, the One Health approach to henipavirus research has largely focused on integrating human and veterinary health; however, the continued transmission of Hendra virus (HeV) from bats to horse populations in Australia and Nipah virus (NiV) from bats to humans in Bangladesh indicates the challenges and complexity of preventing henipavirus spillover, and the need for further enhancement of the One Health approach In particular, additional integration of the social sciences to henipavirus research will be essential to identify locally acceptable and feasible interventions

to promote behavioural changes to reduce the risk of cross-species infection Here,

we review the history of henipavirus research since the first recognised outbreaks

of HeV in Australia in 1994 We argue that the integration of human and veteri-nary medicine, ecology and epidemiology has been an important step in henipa-virus control, but may prove inadequate in settings where ‘‘top-down’’ intervention, such as changes to policies and regulations, is less effective, as is

often the case when infrastructure and resources are limited, or where individuals

do not perceive themselves as being at risk (Spiegel et al 2011) Finally, wediscuss recent findings from Africa that suggest henipaviruses are present in batsacross the Old World tropics and how lessons from Australia and Asia can beapplied to the development of a One Health approach to henipavirus research inother regions

2 Hendra Virus in Australia

HeV emergence, its zoonotic consequences, and identification of fruit bats as itsreservoir prefaced the One Health approach to the investigation of emergingdiseases associated with bats In September 1994, a gravely ill horse was stabledfor veterinary care in the Brisbane suburb of Hendra, in the state of Queensland.This action inadvertently precipitated the first recognised and single largest out-break of HeV to date, resulting in 20 equine and two human cases (Fig.1a).Within 72 h of stabling the horse, two additional equine cases were evident and acascade of cases followed Thirteen horses died or were euthanised, a case fatality

of 65 % (Murray et al 1995) As the outbreak peaked, the treating veterinariannotified the state animal health authorities of the highly pathogenic novel syn-drome, prompting quarantine declarations, horse movement restrictions, andcancellation of race meetings in southeast Queensland Exotic infectious agents(e.g African horse sickness) and toxins were considered differential diagnoses, butwithin days, both the Queensland Animal Research Institute and the CSIROAustralian Animal Health Laboratory (AAHL) had isolated HeV (initially calledequine morbillivirus) AAHL subsequently conducted experimental infections inhorses and was able to reproduce the disease and re-isolate the virus (Murray et al

1995), fulfilling Koch’s postulates

Within a week of the first equine death, the horses’ trainer and a stable-handbecame ill with an influenza-like illness The trainer in particular had direct andrepeated contact with oro-nasal secretions as he endeavoured to force-feed theindex case The stable-hand recovered, but the trainer’s condition deteriorated Thedifferential diagnoses included glanders, the only known zoonotic equine disease(albeit exotic to Australia), indicating that medical authorities considered thepossibility that the human cases were related to the equine outbreak (Selvey et al

1995) The trainer subsequently died, and HeV was isolated from kidney tissue.Experimental studies later demonstrated HeV could infect multiple speciesincluding horses, cats, dogs, rabbits and laboratory rodents, although highlypathogenic disease was limited to horses and cats (Hooper et al 1997a, b;Westbury et al.1995,1996; Williamson et al.1998)

Subsequent retrospective investigations would show that the Brisbane outbreakdid not mark the first emergence of HeV A month earlier and 800 km north, twohorses on a stud farm near Mackay in Queensland died approximately a week apartafter acute illness, characterised respectively by respiratory and neurological

Fig 1 continued

symptoms (Baldock et al.1996) (Fig.1a) The veterinarian owner, assisted by herhusband, performed necropsies on both horses A definitive aetiology was notestablished The husband became ill shortly after with mild meningioencephalitis,but recovered after a short illness Cerebrospinal fluid analysis suggested a viralinfection (Allworth et al 1995) Fourteen months later he developed severeencephalitis which resulted in his death (O’Sullivan et al.1997) HeV genome wasretrospectively detected in samples from his initial illness and in samples from therelapsing illness, and matched sequences of HeV genome retrospectively detected

in the two horses

While the Brisbane outbreak precipitated an increased level of professionalinteraction between public and animal health authorities in Queensland, it wasarguably the Mackay incident that heralded a lasting change in the frequency and

in Australia (a) and Nipah virus (NiV) in Malaysia (b), Bangladesh (c) Arrows show which of the different disciplines required for a One Health approach are still being used; rectangles show studies that are not ongoing For brevity, disciplines such as microbiology, serology or the numerous branches of ecology are included in broad headings, such as veterinary (a focus on domestic animals), medical (a focus on humans), ecology (a focus on the host, host ecology and infection dynamics) and anthropology (a focus on human attitudes to disease, hosts and healthcare) Red–blue gradation indicates the extent to which the studies have been integrated Human and equine cases are given by H and EQ, respectively

nature of the inter-agency relationship Both authorities continued to operate asdiscrete agencies, but communication increased at the senior management,research and operational level (Fig.1a) When the next HeV incident occurred,strong cross-departmental linkages existed, facilitating communication and coor-dination of response activities The latter included case property visits, mediacommunication and cross-agency briefings/de-briefings A manifestation of thecross-agency approach has been the formation of a HeV inter-agency technicalworking group whose role is to provide current, science based, best practice inrelation to minimising HeV transmission that forms the basis of both animal andpublic health policy The inter-agency group includes public and animal health,workplace health and safety and industry representatives Information and riskmanagement protocols targeted to horse owners, veterinarians and medical prac-titioners are readily available online (Anonymous2011).

The alignment of animal and public health authorities, however, represents anarrow definition of One Health, and the identification of fruit bats as the HeVreservoir promised a third perspective (Young et al 1996, Halpin et al 2000)

As broader research increasingly identified the association between changes inland use practices and disease emergence from wildlife, an ecological perspective

on the possible underlying drivers for HeV spillovers seemed relevant Thisoccurred quite early at a research level, but involvement by environmentalagencies at a broader level has been slower The reasons for this are unclear, butenvironmental agencies had a primary focus on wildlife management, and hadlimited expertise in relation to infectious diseases Thus, in an era of competingdemands, an emerging zoonosis involving horses may not have been viewed as apriority However, it is now recognised by health authorities that consideration ofecological factors that contribute to HeV spillover events are fundamental toeffective risk mitigation, and this perspective informs and complements the riskmanagement and response perspectives of the other agencies Environmentalagencies now contribute equally with animal and public health authorities at thepolicy and research levels, evident in the formation of an interstate and interagencyHendra Taskforce following 18 separate spillover incidents in 2011 The absence

of human cases in 2011 suggests effective progress in risk communication;however, the unprecedented cluster of equine cases indicates that the drivers forHeV spillover are incompletely understood To minimise the risk to human andanimal health, authorities have undertaken extensive interaction with key horseowner and veterinary stakeholders, fostering risk management strategies,proposing risk-mitigating on-farm animal and landscape management practicesand supporting the development of an effective equine vaccine This combination

of strategic policy and management at the government level and implemented mitigation efforts likely offers the most effective risk mitigationoutcome Whichever approach or combination of approaches are applied,Australia, because of its advantageous socioeconomic status, is better positionedfor success than countries that are less well resourced

3 Nipah Virus in Malaysia

The second virus in the genus Henipavirus, NiV, was recognised about 5 yearsafter the discovery of HeV in Australia (Fig.1b) The first ProMED report on whatwas eventually recognised as an ongoing outbreak of NiV encephalitis in pigs andpeople in Malaysia was published on November 24, 1998, under the heading

‘‘Japanese encephalitis, suspected—Malaysia’’ (ProMed 1998) This report tained information on control measures taken at that time, which included vac-cination of pig farm workers in Perak State against Japanese encephalitis virus(JEV) and insecticide fogging, intended to reduce mosquito populations, andtherefore transmission of JEV via infected mosquitoes When these measuresfailed to contain the outbreak, pigs were also vaccinated against JEV

con-Thus, from the outset—even before the correct aetiology of the disease wasidentified—efforts to control the outbreak of encephalitis in people took a multi-disciplinary approach, coordinated jointly by the Ministry of Health and theDepartment of Veterinary Services in the Ministry of Agriculture, and drew fromveterinary medicine and environmental health, as well as human medicine.However, the lack of early collaboration with epidemiologists more experienced indetecting and managing epidemic JEV may have delayed the recognition that theoutbreak was caused by a novel agent The discovery of a novel virus as the cause

of the outbreak was made by a medical virologist working outside the scope of themain investigation and response, and by the time the finding was confirmed inMarch 1999 (Chua2004; Chua et al.2000), the virus had spread to new areas andcaused more than 130 cases in Malaysia and Singapore (Anonymous1999).Once the cause of the outbreak was recognised as a novel paramyxovirus, and

in particular a HeV-like agent, international involvement was requested WorldHealth Organisation, Centers for Disease Control and Prevention and others sentteams to Malaysia that included experts in epidemiology, clinical microbiology,human and veterinary medicine, reservoir ecology, crisis management and logis-tics (Fig.1b) At this stage, the response to the NiV outbreak became recognisable

as what would now be considered a One Health approach, which not only involvedmultiple disciplines but reflected a coordinated, collaborative effort workingtowards a common set of goals The outbreak was brought under control within amatter of weeks when the national government decided to cull infected andneighbouring pig farms, along with mandating increased used of personal pro-tective equipment for those involved in the investigation and control efforts.Epidemiological teams worked to identify factors that contributed to the spread ofthe outbreak as well as identify individual and farm-level risk factors for infection(Lam and Chua2002; Parashar et al.2000) Due to its close relationship with HeV,once NiV was identified as the aetiological agent of the epidemic, pteropid batswere rapidly identified as the likely reservoir of the virus (Yob et al 2001)(Fig.1b) Investigations considered domestic animals (other than pigs) as potentialintermediate hosts (Mills et al.2009), and retrospectively identified the occurrence

of human cases on the outbreak’s index farm as early as January 1997 (Arif and

Nipah Virus Study Group1999) The practice of planting fruit trees adjacent topigsties was identified as the epidemiological link between flying foxes anddomestic pigs (Chua et al.2002) Further outbreaks have likely been prevented by

a regulation made in 1999, prohibiting fruit trees being grown near livestockenclosures to prevent domestic animals having contact with potentially infectiousbat fluids, such as urine or saliva on contaminated fruit

Following the NiV outbreak in 1998–1999, there was substantial interest in thecauses of viral emergence, which prompted a retrospective, multidisciplinaryinvestigation to examine the process and drivers of emergence Serological sur-veillance of flying fox populations and characterisation of their movements withinMalaysia through satellite tracking has indicated that the reservoir population ishighly mobile and well connected, with near-ubiquitous presence of NiV anti-bodies (Epstein et al.2009; Pulliam et al.2012), providing evidence that the viruscirculates widely Monitoring of captive bats has also highlighted difficulties ofinterpretation of serological data from the field and challenged assumptionsrelating to infection dynamics within the host (Rahman et al.2010; Sohayati et al

2011) The research team particularly focused on what factors influenced thetiming and extent of the outbreak that triggered international attention This effortendeavoured to identify aspects of the emergence event that would inform pre-vention and surveillance efforts These investigations suggested that agriculturalintensification was a major driver of emergence, both through the increasedpotential for ecological overlap between wildlife and domestic animals thatresulted from dual-use agricultural practices, and through the intense management

of commercial pig populations This intensive pig management ultimately allowedNiV to persist within the index farm (Pulliam et al.2012)

4 Nipah Virus in Bangladesh

Soon after the discovery of NiV in Malaysia, NiV was recognised as a cause ofsevere acute meningoencephalitis in Bangladesh in 2001 (Fig.1c) Much of what weknow regarding NiV in Bangladesh comes from investigating and responding tooutbreaks of human disease, including the risk factors for human disease, and localefforts to develop and implement public health interventions to prevent futureoutbreaks draw heavily from finding these investigations In contrast to HeV andNiV outbreaks in Australia, Malaysia and Singapore, human NiV infections inBangladesh appear to result primarily from indirect bat-human contact, without

an intermediate host, or through person-to-person transmission (Luby et al.2006,

2009) Thus, human health remains as the primary focus in Bangladesh theless, lessons learnt from Australia and Malaysia illustrated the importance ofinvestigating NiV transmission across the human–animal interface, and a OneHealth approach has been used in Bangladesh since the first outbreak was identified(Fig.1c)

Currently, there are two passive and two active surveillance activities foroutbreaks of NiV encephalitis in humans in Bangladesh First, physicians inBangladesh are encouraged to report clusters of severe disease to the Institute ofEpidemiology Disease Control and Research (IEDCR) at the Ministry of Healthand Family Welfare Likewise, IEDCR reviews media reports on a daily basis tolook for outbreaks suggestive of NiV In addition, active surveillance for clusters

of encephalitis is conducted in six government hospitals Surveillance physicianslist patients meeting an encephalitis case definition and determine whether or notthey cluster in time and space with other admitted encephalitis cases In three ofthese hospitals, any patient admitted with encephalitis has serum collected for NiVantibody testing during the season (January–March) that NiV infections in humanshave been most frequently identified Physicians in Bangladesh, particularly in thearea where NiV infections commonly occur, have learned from governmentcommunication messages that humans are frequently infected through drinkingdate palm sap which has been contaminated by fruit bats Therefore, physicians inthese parts of the country often investigate wildlife exposures among patientsadmitted with encephalitis and ask about date palm sap consumption Patients withencephalitis and a history of drinking date palm sap are considered likely to haveNiV and physicians often notify local health authorities when any case meetingthese criteria are identified

Once a human case of NiV infection is reported, intensive investigations ensue

to evaluate the role of livestock or wildlife in transmission The investigation teamvisits the locality where the cases reside and enquires about any recent animalillnesses or deaths Sick animals are examined by veterinarians and specimens arecollected for laboratory diagnosis Recently, deceased animals may also beexhumed for examination and specimen collection Additionally, case-patientexposures to animals in the 2 weeks prior to illness onset are systematicallyinvestigated through interviews with family members Due to the high case fatality

of NiV ([70 %), most case-patients are not able to provide the informationthemselves Epidemiologic studies compare these exposures among cases to those

of controls from the same neighbourhood to determine if contact with animals, orany animal in particular, is associated with having NiV infection Despite thedirect relationship between a livestock outbreak and human illness in Malaysia andSingapore, a domestic or peri-domestic animal has never been identified with NiVinfection during an outbreak in Bangladesh However, during two outbreaks in

2001 and 2003, epidemiologic studies showed that cases were more likely to havehad contact with livestock than controls (Hsu et al.2004) In addition, one childwith NiV reported exposure to goats who had died from apparent neurologicalillness, but these animals were not available for exam during the investigation(Luby et al.2009)

Investigations into the role of wildlife during human outbreaks have focused onthe local reservoir host, Pteropus giganteus Initial studies that sampled wildlifemore broadly found no evidence of other wildlife infected, so investigationsremain focused on Pteropus bats (icddr, b2004) Wildlife ecologists and veteri-narians working with the outbreak team routinely capture and collect specimens

from P giganteus located in and around outbreak localities to determine the NiVseroprevalence and frequency of NiV shedding Case-patients are also systemat-ically surveyed about exposure to fruit bats, including catching and consumingbats, living near or under roosts and consuming foods that may be contaminated.Based on the presumed pathway of transmission from bats to pigs in Malaysiathrough bat-bitten (or otherwise contaminated) dropped fruits (Chua et al.2002;Pulliam et al 2012), investigations of humans in Bangladesh have consistentlyqueried case-patients about their consumption of fruit with evidence of animalbites Although consumption of animal-bitten fruits is frequently reported by case-patients, they have been no more likely to report this exposure than controls fromthe same community Conversely, consumption of date palm sap has beenrepeatedly associated with NiV in humans (Luby et al.2006,2009; Rahman et al.

2012) Based on these findings, further wildlife studies have been conducted toobserve how bats contaminate the sap (Khan et al 2010), and interventions toprevent bats’ access to the sap are one current focus of interventions underdevelopment to prevent NiV in Bangladesh (Nahar et al.2010)

A key to utilising the One Health approach in outbreak investigation isassembling a research team with the requisite skills and experiences Over the pastdecade, the outbreak investigation team in Bangladesh has evolved to includephysicians, epidemiologists, veterinarians, wildlife ecologists, virologists andanthropologists Dedicated efforts have been made to bring together governmentcollaborators from the Ministry of Health and Family Welfare, as well as theMinistry of Fisheries and Livestock and the Ministry of Environment and Forests

to investigate zoonotic diseases in Bangladesh Working across disciplines andministries is not simple and building and maintaining these relationships takestime and attention However, once built, the One Health approach to investigatingNiV in Bangladesh has been an invaluable template for the response to otheroutbreaks of zoonotic origin The use of qualitative anthropological studies toinvestigate the exposures associated with NiV risk, and in understanding factorsimportant for outbreak control in Bangladesh, such as rejection of biomedicalrecommendations (Blum et al.2009), is particularly well developed in Bangladesh

In Australia and Malaysia anthropological studies have been neglected, perhapsbecause domestic animals have acted as intermediate or amplification hosts andchanges to national policies and regulations to prevent transmission to domesticanimals have been successful in reducing risk

5 Expanding the One Health Paradigm for Henipavirus

integration between disciplines Such approaches developed on a somewhat ad hocbasis starting in Australia, and better integration of multi-disciplinary research hasbeen achieved with time There is, however, an urgent need to apply the OneHealth approach to investigating henipaviruses in other places like India, whererepeated outbreaks of NiV encephalitis have been reported in humans In Siliguri,West Bengal, cases were diagnosed retrospectively by testing serum samplesfrom patients from 2001 for anti-NiV IgM antibodies, with subsequent detection

of NiV RNA in patient urine (Chadha et al.2006) A second outbreak in India in

2007 also occurred in West Bengal (Arankalle et al 2011), a state that bordersBangladesh Seroprevalence studies of pteropid bats in India show that henip-aviruses likely circulate commonly among these animals (Epstein et al 2008)and the geographic proximity of Indian outbreaks to the Bangladesh bordersuggest that similar ecological factors and cultural practices may be contributing

to outbreaks in both countries Additional research on NiV in India and border collaborations with Bangladesh would likely improve our understanding

cross-of NiV transmission and result in a more effective public health response inSouth Asia

In the One Health examples presented in this chapter, research initiatives beganonce human and/or domestic animal infections were found However, in somecountries, research has started with investigations of wildlife and possible heni-pavirus reservoir hosts For example, recent serological and virological findingssuggest henipaviruses occur in African bats, perhaps even originating in Africanbats (Drexler et al 2009, 2012; Hayman et al 2008a) However, it is unclearwhether the absence of human and livestock infections reported from these areas isdue to a lack of surveillance or a lack of transmission since human and animalsurveillance systems are poor over much of geographic areas where risk theoret-ically exists Serological surveys suggest pigs in Ghana may have been exposed to

a henipavirus-like infection (Hayman et al 2011), but there are no active veillance systems for henipavirus infections in these countries The only henipa-virus reservoir identified in Africa to date, Eidolon helvum, is both geneticallyclose and behaviourally similar to pteropid bats (including roosting in closeproximity to man), and the application of a One Health approach to henipaviruses

sur-in Africa would provide an sur-interestsur-ing opportunity for comparative studies acrosscontinents that may help elucidate the drivers for spillover in general Forexample, in Africa, Asia and Australasia, Pteropus and Eidolon species have beenfound to be long distance migrants (Breed et al.2010; Epstein et al.2009; Richterand Cumming 2008) The highly mobile nature of the reservoir species poseschallenges, because transborder studies may be necessary to understand processesdriving ecological changes, which may in turn affect spillover potential (Plowright

et al.2011) The collaborative nature of the One Health paradigm may also help inthe development of the needed transborder approaches, especially if comple-mentary expertise is leveraged from within each stakeholder country

large-Understanding people’s interaction with bats and their motivation for seekingthis contact can be useful for designing interventions to reduce risk of diseasetransmission and mitigate possible harm to bat populations from human activities.The response to NiV in Bangladesh, where contamination of fresh date palm sap isthought to be the primary mechanism for NiV transmission to humans, is the oneexample where anthropological studies have been integrated into the response tohenipavirus spillover Interventions in Bangladesh developed with communityinput, thus enhancing the likelihood of community acceptability and increasing thefeasibility of the interventions A local practice of covering sap collection potswith bamboo skirts was identified by researchers as a potential intervention toreduce spillover risk In regions where the bamboo skirts were used, the origin ofthe practice was to prevent the contamination of palm sap (Nahar et al 2010),enabling the harvest of ‘‘clean’’, better quality palm sap, rather than to prevent NiVtransmission.

Increased use of anthropological studies may be useful throughout the pavirus range to better understand the cultural context within which human–batcontact occurs For example, populations in Africa and Asia hunt bats potentiallyinfected with henipaviruses (Epstein et al.2009; Kamins et al.2011; Struebig et al

heni-2007), but the motivations for hunting these bats are not well described Huntedspecies may provide extra income, be a source of protein, or be culturallyimportant for human populations that hunt them These factors may affect people’sperceptions of the value of bats and their willingness to comply with proposedspillover mitigation measures

In Accra, Ghana, for example, local legend is that bats arrived in the city with alocal chief (of Kibi), who died at the hospital in Accra, and the bats have remainedthere ever since E helvum bats now roost in trees on hospital grounds, inmunicipal areas and around military barracks The military made a recent attempt

to control the bats, including removal of trees to prevent them roosting in, anddefecating and urinating on, public areas and military barracks; however, the movewas prevented by the Wildlife Division of the Ghanaian Forestry Commission,whose aim is to protect Ghanaian wildlife (Hayman, personal observation) Theremoval of trees and the bats roosted in was also unpopular among the public, who

seek shelter under the trees and hunt the bats for food (Hayman et al 2008b;Kamins et al.2011) These mixed responses to urban-dwelling bats and the localfolklore in Ghana suggest that locally sensitive methods of minimising contactmay be required, if African henipaviruses cause infection in humans and domesticanimals.

6 Conclusions

In summary, we propose that a One Health approach offers a more completeunderstanding of the complex drivers of henipavirus transmission between species,along with the most appropriate ways to mitigate this transmission This is par-ticularly important for henipaviruses because both human and domestic animalhealth are affected, sometimes dramatically, and because spillover is driven byinteractions between human behaviour and host ecology Ecological changes due

to agriculture and other factors may affect human–bat contact, domestic animal–bat contact and the infection dynamics within the bat populations themselves(Plowright et al 2011; Pulliam et al 2012) A One Health approach, like alleffective collaboration, requires mutual respect, trust and acknowledgement of thecomplementary skills of all parties We believe that increasing the effectiveinvolvement of ecologists and social scientists, such as medical anthropologists,with virological, veterinary, medical and epidemiologic studies is necessary forspillover to be understood and for appropriate locally sensitive control measures to

be implemented Appropriate integration of social scientists will be particularlyimportant in areas where top-down control from government agencies may beineffective or unaffordable, such as in Bangladesh In each case study presented,however, we have seen increasing collaboration between disciplines and anincreasing recognition that no single discipline can address all the questions Theprogress that has been made developing and implementing the One Healthapproach to henipavirus research provides a good general model for those con-ducting research on other zoonotic infections and emerging diseases of wildlifeorigin

Foundation through a David H Smith Fellowship in Conservation Research DTSH, ESG, JRCP are supported by the Research and Policy for Infectious Disease Dynamics (RAPIDD) pro- gramme of the Science and Technology Directorate (U.S Department of Homeland Security) and the Fogarty International Center (NIH) HEF acknowledges support from the Queensland and Australian Governments, and from EcoHealth Alliance, USA.

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H5N1 Highly Pathogenic Avian Influenza

of this disease in Indonesia, the virus that causes it and the control and preventivemeasures introduced, focusing on the successes and shortcomings of veterinaryand One Health approaches Indonesia provides many examples of situationswhere this latter approach has been successful, and others where further work is

Disease Investigation Center (DIC), Balai Besar Veteriner (BBVet) Maros,

JaIan DR Samratulangi Maros Kt., Pos 322 Makassar, Sulawesi Selatan 90001, Indonesia

L D Sims

Asia Pacific Veterinary Information Services Pty Ltd, 55 Montmorency 3094, Australia

DOI: 10.1007/82_2012_265

 Springer-Verlag Berlin Heidelberg 2013

Published Online: 6 September 2012

needed to maximize the benefits from coordinated responses to this disease leading

to effective management of the risk to human health

Contents

1 Background 172

2 Early Responses 173

2.1 Delays in Initiating Control Efforts 173

2.2 Adoption of a Whole of Government Approach 174

2.3 Early Logistical and Technical Challenges to the Animal Health Sector to Respond Comprehensively: Successes and Ongoing Issues 174

2.4 The Understanding of the Natural History of the H5N1 Virus in Indonesia that has Emerged 177

3 Endemnicity and the Continuing ‘‘One Health’’ Threat 178

3.1 Understanding the Indonesian Poultry Production and Marketing Sector 179

3.2 Understanding the Disease in Humans 180

4 Other Current and Future Requirements 180

4.1 Virus Sharing 180

4.2 Vaccination of Poultry 181

5 Conclusions 182

References 182

1 Background

H5N1 HPAI was first recognized as being more than just an important avian disease

in 1997, when severe disease occurred in both poultry and humans in Hong Kong SAR Poultry were demonstrated to be a direct source of influenza virus infection for humans, creating international alarm over the potential for emergence of a severe human influenza pandemic with a potentially high case-fatality rate The strain of H5N1 HPAI virus that caused this zoonotic disease was eliminated from Hong Kong through a series of determined measures, including the destruction of all commercial poultry in Hong Kong and cessation of trade in live poultry for a 7-week period This allowed time for thorough cleaning and disinfection of existing markets and farms and the introduction of changes to the way poultry were reared, transported, and marketed, including mandatory enhanced hygiene measures The package of measures was monitored by a comprehensive surveillance program supported by reliable laboratory diagnostic testing (Sims et al.2003)

The Hong Kong SAR outbreak and the way it was managed demonstrated the importance of a One Health approach to the control and prevention of this disease

It involved close cooperation between animal health and human health authorities and understanding of the factors that allowed the disease to emerge and be transmitted (Sims and Peiris2012) These lessons have been well recognized but have been much harder to replicate in countries with much larger and more complex poultry production systems, with less well-resourced veterinary services

and governance systems, less able to effectively implement policy along the farm

to consumer supply chain (FAO2011a)

Although the strain of H5N1 HPAI virus detected in Hong Kong SAR wasalmost certainly eliminated, other H5N1 HPAI viruses continued to circulate andevolve in mainland China (Li et al.2004; Chen et al 2006) The significance ofcontinuing circulation of these viruses became apparent in late 2003 and early

2004 when eight countries (including China) reported outbreaks of disease ciated with H5N1 HPAI viruses in poultry, in some countries with accompanyinghuman cases In rapid succession, Japan, the Republic of Korea, Vietnam,Thailand, Indonesia, Cambodia, China, and Lao PDR all reported disease inpoultry The outbreak strains of virus all formed part of a lineage extending back to

asso-a virus first detected in geese in Guasso-angdong province in 1996 (Li et asso-al.2004).Although these reports were received almost simultaneously by the internationalcommunity, it soon became evident that the time of reporting did not coincide withthe time of virus introduction for a number of these countries In Indonesia, viruswas probably introduced in the first half of 2003 and by the time it was reported, ithad become well entrenched and widespread As a result, attempts to eliminate thevirus using standard methods based around early detection and stamping out weredestined to fail, except in some of the more remote provinces and islands where thevirus had been recently introduced and the poultry density was relatively low

2 Early Responses

2.1 Delays in Initiating Control Efforts

Details of the early phases of the H5N1 outbreak in poultry in Indonesia have beenpublished in the Indonesian literature (Wiyono et al 2004a; Damayanti et al

2004a, b; Dharmayanti et al 2004; Indriani et al 2004), and reviewed by theDirectorate General of Livestock and Animal Health Services (DGLAHS)(Wiyono 2004b) The first recognized case was in August 2003 in Central Java,with progressive spread to both West and East Java in subsequent months and withwidespread infection across the whole island of Java by January 2004 Infectionspread to Bali in October 2003, with disease being reported across the whole island

by February 2004 The southern parts of the islands of Sumatera and Kalimantanbecame infected in November 2003 Nationally it was estimated that by April

2004, 7.5 million poultry had died and another 2.75 million depopulated.Unfortunately, it was not until 2 February 2004 that the disease was formallyrecognized and reported to OIE, a necessary trigger to allow publically commu-nicated initiation of control measures However by this time, the infection wasbeing actively transmitted in at least four major islands in Indonesia with the mostnumerous and densely-packed poultry populations and with a human population inexcess of 150 million people Any prospect of a rapid response to contain thespread of the disease had long disappeared

An important lesson is for countries to be systematically sensitized to andprepared for the possibility of EID outbreaks Departments with technicalresponsibilities, such as in agriculture and public health, must have a clearlydefined legal basis for dealing with such disease outbreaks and clear communi-cation and agreement with the political arms of government that early diagnosisand reporting is essential and to be applauded A political expectation should bedeveloped that responsible departments will deliver rapid diagnosis and gainfavorable recognition for such discoveries.

2.2 Adoption of a Whole of Government Approach

Following confirmation of the H5N1 outbreak in poultry and the diagnosis ofhuman cases, the government of Indonesia quickly recognized that an integrated,whole of government approach was needed for coordination of response activities.Human cases were not reported until 2005, with 20 cases leading to 13 deathsrecognized that year (WHO2012a)

Nationally it was recognized that the control of infection in people depended onthe control of the disease in poultry Accordingly, an HPAI campaign managementunit (CMU) was established in the Ministry of Agriculture to coordinate veterinaryinputs, including liaising with the Ministry of Health Donor coordination in theagricultural sector also became an important role of the CMU

The National Committee for Avian Influenza Control and Pandemic InfluenzaPreparedness (KOMNAS FBPI) was subsequently formed to provide a whole ofgovernment approach and operated from 2006 until 2010 Having strong technicaland political connections it provided effective communication with the seniorlevels of the government and provided international agencies with a single focalpoint for developing national support programs The usefulness of the committeehas been recognized through its being expanded in scope to include other diseases:KOMNAS Pengendalian Zoonosis (The National Committee for Zoonosis

also recommended that control of infectious disease outbreaks also be under thesupervision of the National Disaster Management Agency (BNPB) Hence,important principles were recognized

2.3 Early Logistical and Technical Challenges to the Animal Health Sector to Respond Comprehensively: Successes and Ongoing Issues

The control of infectious disease requires the breaking of the chain of sion, which Hong Kong SAR was able to achieve with comprehensive measuresincluding the destruction of all poultry as outlined in the background section ofthis chapter The veterinary services in Indonesia, in the broadest sense includingtheir relationships with poultry keepers, their operational capacity, and their

resourcing by government, were unable to comprehensively detect cases,quarantine cases or infected areas, or to stamp out foci of infection Attempts todevelop a system of compensation for poultry owners for birds compulsorilydestroyed, to facilitate stamping out, were not convincingly implemented Fundswere inadequate and a ‘‘social contract’’, which would simultaneously managesuspicions and opportunism and lead to constructive engagement with the poultryowners, was not able to be developed.

A complicating factor in the case of Indonesia was inexperience in managing apolitical system with devolved responsibilities to deliver a coordinated nationalresponse to a national threat such as an emerging infectious disease The opera-tional arms of the veterinary services were managed at the provincial and districtlevel, with no line of command from the national to the local level Hence, theresponse at each level of government was potentially subject to a variety ofconflicting local priorities A point for future consideration would be the devel-opment of systems across the various levels of government to deal with declarednational emergencies in a uniform manner

Perhaps associated with the issue of coordination of jurisdictional bilities was an inability in the early years of the outbreak to modify the marketchain, a highly traditional, deeply embedded social activity not directly under theresponsibility of the veterinary services Potentially infected poultry continued tomove through marketing systems, spreading infection It should be appreciatedthat the Indonesian poultry population is huge DGLS figures in 2004 were 1.2billion broilers, 80 million layers, 295 million native chickens, and 45 millionother poultry (Wiyono 2004b) Managing this number of birds in an essentiallyunregulated industry has obvious challenges, with enormous resistance to change.Under these circumstances solutions were sought separately to various aspects

responsi-of the problem that could be implemented with the objective responsi-of contributing to animproved situation without being the whole solution A vaccination program wasintroduced, systems for surveillance and improved laboratory diagnosis wereestablished, and depopulation with a compensation budget was trialled Studieswere also initiated to identify major pathways of transmission of H5N1 in poultry

to allow support to be developed for intervention measures in the marketing chain

2.3.1 Surveillance

In 2005, a system of disease detection and control at the village level calledparticipatory disease surveillance and response (PDSR) was initiated for trial(Azhar et al.2010) Working at the village level was considered important because

of the importance of village poultry in society The weak links between ment and the large commercial sector were not adequately addressed, and thisissue remains a weakness PDSR evolved to incorporate small-scale farmsespecially those with relatively weak biosecurity systems

govern-Under the PDSR system teams of mostly veterinary paraprofessionals undertookregular village surveillance using participatory techniques leading to heightened

community awareness, and to their then being called to villages to investigateapparent outbreaks of disease and conduct on-site testing with rapid tests Goodinformation on village level prevalence of disease resulted in the areas covered, andnationally it can be expected that Indonesia has reasonable information of ongoingdisease in small-holder poultry A parallel benefit of the PDSR was the training infield investigations and response for hundreds of animal health workers Howeverthe scheme suffered from not being adequately funded to implement effectivecontrol measures Another problem was its being unsustainable in its initial formbecause it was supported by donor funding and included remuneration packages forthe workers involved greater than remuneration for government employees.

A transition from donor support to sustainable mechanisms is being trialled, but theongoing sustainability of the approach is yet to be demonstrated However withinIndonesia, the PDSR system, with its networks, is believed to be useful not only fordetection of H5N1 infections but also for helping manage other EID outbreaks such

as the recent rabies outbreak in Bali In the context of One Health, PDSR is working

in collaboration with DSO from Public Health

2.3.2 Laboratory Services and Diagnosis

Laboratory capacity building in support of diagnosis, and subsequently in thefurther characterization of viruses, has been a markedly successful aspect of theIndonesian response (Damayanti et al 2004a, b; Dharmayanti et al 2004 andWiyono et al.2004a,b) Biosafety considerations demanded an alternative diag-nostic approach to virus isolation as the standard diagnostic approach Real-timePCR, supported by proficiency testing and trouble shooting support, has seen thetechnique successfully established in all national government laboratories andmore broadly However nationally, there has not been full and effective use of thiscapability The flow of specimens to laboratories has been less than that consideredoptimal More submissions from the larger commercial poultry operators to thegovernment laboratory system are necessary to allow for an ongoing compre-hensive monitoring of the national situation

Importantly, laboratory biosafety issues have been addressed to the extentpossible with available facilities Laboratory-acquired human infections have notbeen reported Initial molecular analyses of isolates (Smith et al.2006) and analyses

to the present time (WHO/OIE/FAO2012) provide evidence that Indonesia sufferedonly one introduction of H5N1 infection and that therefore national quarantineprocedures and supporting biosafety communications have been effective

2.3.3 Donor Support and Coordination

From 2004 to 2009, some $175 million was pledged to Indonesia for the controland prevention of avian influenza including bilateral support from individualcountries, the international financial institutions, and FAO, OIE, WHO, UNICEF,

and a range of civil society agencies Never before has there been a program such

as this that crossed the boundaries of human and animal health and delivered somuch support in such a short time period This has resulted in some issues withabsorptive capacity It will be a point of future analysis whether the assistance wastargeted to the best advantage, and coordinated optimally in spite of thecomprehensive efforts of KOMNAS FBPI In such analyses, it should beremembered that neither the assistance nor the advice that accompanied it wasavailable or identified at a single, early point in time, nor did these contributionscome from a single source Many different donors earmarked their funding tospecific areas of activity It will likely be assessed that the Indonesia governmentprovided structured coordination across the public and animal health sectors in acrisis situation

An important outcome will be whether Indonesia has been able to translatethese experiences in coordination into a risk analysis based national contingencyplan for managing not only the ongoing H5N1 situation but other national orregional emerging infectious disease incidents or global pandemic situations

2.4 The Understanding of the Natural History of the H5N1 Virus

in Indonesia that has Emerged

The origin and route of introduction of the Indonesian H5N1 virus remain unclear.Molecular evidence suggests that the precursor to the Indonesian outbreak strainwas present in Hunan province in China in late 2002 and early 2003 (Wang et al

2008) As stated above, there is no evidence that new strains of virus have beenintroduced into Indonesia after 2003 (Smith et al.2006; WHO/OIE/FAO 2012).Instead the virus introduced in 2003 has persisted and evolved forming a number

of subclades Conversely, since 2003, no Clade 2.1 viruses or derivatives havebeen found in other countries (WHO/OIE /FAO 2012), indicating that this virushas not spread out of Indonesia

A possible mode of introduction was through the illegal introduction of infectedlive poultry or fomite transfer of the virus However, potential trade or industrylinks between Indonesia and the relevant Chinese province have not been formallyidentified or reported Since the data indicate a single introduction of virus in 2003,

it follows that there is no evidence of repeated waves of introduction over time ofH5N1 via long-range bird migration (Smith et al.2006)

A One Health success story of the H5N1 HPAI outbreak in Indonesia has beenthe application of molecular epidemiological techniques as an aid in understandingthe evolution and spread of the various strains of viruses Hundreds of isolatesfrom Indonesia (of avian and human origin, and occasionally of other species)have been sequenced either partially or fully and the results made available foranalysis through genetic databases and international organisations

The original Indonesian H5N1 influenza viruses fell within what became known

as Clade 2.1 Since then Clade 2.1 has diverged to form three third-order clades2.1.1, 2.1.2, and 2.1.3 Fourth-order clades have now been recognized in Clade2.1.3 (WHO/OIE/FAO2012) This work has allowed the evolution of viruses to beviewed in close to real time and allows comparison of isolates from differentepidemiological situations and links to be made between viruses within animal andhuman populations and within different poultry production sectors

Much of the active surveillance in Indonesia has targeted small holders and less

is known about the viruses in the larger commercial farms One Health approachesrequire all players to be closely involved in information sharing and while therehas been some sharing, full transparency has not been achieved

3 Endemnicity and the Continuing ‘‘One Health’’ Threat

FAO has reviewed the circumstances leading to H5N1’s becoming endemic, or

"entrenched’’, in certain countries (FAO2011a) Three factors were identified.The structure of the poultry sector is a key determinant Endemically infectedcountries generally have complex production and market chains that are poorlyintegrated, with a large demand for locally produced poultry and poultry prod-ucts A high proportion of poultry are reared and sold under conditions thatafford little protection from influenza viruses, production systems that result inminimal or no farm gate biosecurity The situation is complicated by a signifi-cant proportion of poultry not displaying clinical signs at the times transmission.This may occur in the relatively unmanaged production and marketing chains,such as via domestic ducks or poultry transacted relatively quickly in infectedmarkets and collector yards

Overseeing the unstructured poultry sector are frequently relatively weak publicand private veterinary and animal production services, which have limited or nocapacity to identify and respond to all cases of infection and hence cannot fullyunderstand the drivers of transmission of infection in value chains Such veterinaryservices have been unable to implement needed changes to production and mar-keting systems

But the management of infectious disease ultimately depends on an effectivewhole of society response Endemically infected countries simply do not display

by their actions an adequate level of commitment within the poultry sector,governments, and by the public toward the elimination of H5N1 HPAI viruses.The fear of H5N1 HPAI has not translated into determined action for virus controland elimination Support for the type of measures needed to eliminate H5N1 HPAI

is likely to be half-hearted until most farmers regard H5N1 HPAI as a seriousthreat to their livelihoods and well-being Strong public support is a prerequisitefor the elimination of the virus from endemically infected countries

These considerations set the scene for understanding the H5N1 situation inIndonesia

3.1 Understanding the Indonesian Poultry Production and

Marketing Sector

In a One Health approach, a most important aspect is to understand the drivers ofdisease emergence and persistence, including human behaviors, motivations, andincentives Central issues include the ways in which poultry are reared, trans-ported, and sold

Indonesia has a very complex poultry production system combining an sive industrialized poultry production subsector, mainly on the islands of Java andSumatra, thousands of medium-sized farms, millions of households rearing smallnumbers of poultry, and a small but significant duck and quail productionsubsector

inten-The response to the disease by the industrial sector was to tighten biosecuritymeasures and to implement vaccination Many smaller producers did not improvebiosecurity systems, presumably because the incentives to invest in biosecuritymeasures were limited (Sudarman et al.2010)

Massive movements of live poultry and poultry products occur throughcomplex value chains (see, for example, Sudarman et al.2010), especially into andaround the urban conglomerate of greater Jakarta with a human populationexceeding 25 million people and daily trade of approximately 1 million poultry(FAO2011b) Poorly controlled and possibly illegal movement of poultry fromJava to other islands also occur, facilitating the transmission of infection Thedifferent poultry production and marketing systems in some ways could seem to beseparate systems but are intertwined both at the production level, with limitedspatial separation between farms implementing divergent biosecurity measures,and at the marketing level, with poultry from different farm types sold through thesame market chains

Live poultry markets are clearly important from a One Health perspectivebecause these are places where humans and poultry in many urban areas come intocontact Certainly, market places have been shown to be common foci of infectionand hence of disease transmission in poultry (Indriani et al 2010) Marketstraditionally have also been a place to purchase live birds for stocking backyardoperations or for sale in other markets Although a start has been made on triallingmarket place reform, with some recommendations taken up but with resistanceencountered to other changes (Samaan et al.2012), the challenge of dealing withthis source of human and poultry infection has yet to be met as was done soeffectively in Hong Kong

It is likely that a shift away from trade in live poultry through markets andtraders’ yards would assist in the control and prevention of avian influenza, but inpractice it has been hard to achieve Broiler chickens are not sent directly toslaughterhouses but are predominantly sold through the live poultry markets.Delays have been encountered in the shift of such markets in Jakarta to theoutskirts of the city, a move that has been on the policy agenda for a number ofyears This reflects, in part, a reluctance by traders and consumers to the move

which the spectrum of relevant authorities has not been able to resolve Hence, it isnecessary to take a broad view of this disease that encompasses not only thepathogen but also the host and the environments in which the host is reared andsold As in so many animal health problems it is human behavior that is a keydeterminant in maintaining transmission of the disease.

3.2 Understanding the Disease in Humans

As of 2 May 2012, 189 human cases of Influenza A (H5N1) had been reported in

confirmed that Influenza A (H5N1) is largely a zoonotic disease with occasionallimited human-to-human transmission Prevention of the disease in humanstherefore depends on preventing and controlling infection in poultry

One aspect of zoonotic H5N1 infections of people that continues to raisequestions is the high reported case fatality rate Some hypothesize that there are alarge number of undetected human infections, which would bring the proportion ofdeaths relative to infections back to a level more closely resembling other humaninfluenzas More work could be directed toward addressing this issue, but to datethere is no evidence of widespread human exposures An integrated study that wasundertaken in Bali revealed no evidence of subclinical infection of people evenwhen high risk groups were tested (Santhia et al.2009)

A number of clusters of human cases have been reported (Kandun et al.2006)but sustained human-to-human transmission has not occurred (Aditama et al

2012) A One Health approach was adopted for these investigations to assess therole of poultry in the transmission of cases to humans In some cases, a clear link

to sick or dead poultry was evident, in one case contact with poultry manure couldnot be ruled out as a possible source and in some others no apparent poultrycontacts have been recorded (Sedyaningsih et al.2007)

4 Other Current and Future Requirements

4.1 Virus Sharing

The Indonesian agricultural sector, through participation in the internationalcollaborations with OFFLU (OFFLU2012; Wong et al.2012), has continued tomake H5N1 isolates available for international studies This is of critical impor-tance for these viruses are also analyzed from a One Health perspective throughthe formal activities of the WHO in its vaccine strain selection consultations twiceyearly The genetic and antigenic characterization of zoonotic influenza virusesand development of candidate vaccine viruses for pandemic preparedness (WHO

2012b), to identify whether antigenic drift is leading to strains against which the

antigens in the antigen panel for the selection of human vaccines may not beeffective, has become a standing item in these consultations, with substantialIndonesian contribution Development of some antiviral drug resistance has alsobeen monitored and reported (McKimm-Breschkin et al.2012).

The process of sharing isolates globally has not been without its complicationsespecially when concerns were raised about the benefits to Indonesia of sharinghuman isolates with foreign laboratories It is now believed that these issues havebeen explored in considerable detail and that the recently approved and published

provide a workable basis for continuing global One Health collaborations

4.2 Vaccination of Poultry

Where more direct measures to break the chain of transmission have not beensuccessfully implemented, vaccination appears an attractive option Primarily itprotects birds, and hence livelihoods, against disease and allows the commercialsector to function, fulfilling its role in national food security Conceptually,vaccination of poultry can be justified on One Health grounds, in that it can reducethe viral load in an otherwise contaminated environment and hence opportunitiesfor exposure of the human population Vaccination has been used as one of themeasures for control and prevention of HPAI in Indonesia (Domenech et al.2009;Swayne et al.2011)

However, mass vaccination at the village level was difficult to implementeffectively and ultimately was unsustainable because of costs and the high turnover

of poultry Hence, vaccination of village poultry was quickly dropped asIndonesian government policy The commercial sector, with controlled poultrypopulations in more biosecure facilities, continues to use vaccination, especially inlong-lived poultry such as breeder birds and layers

In Indonesia, a wide range of vaccines containing different antigens was usedbut concerns quickly arose as to the suitability and effectiveness of availableproducts An internationally supported investigation under OFFLU (FAO 2010)confirmed problems of efficacy with some products, developed antigenic mapping(antigenic cartography) as a tool for use with avian influenza and identified anti-genic drift in viruses isolated from both commercial and village poultry Indonesianow has the capability, with ongoing international collaborations, to identifyvaccine antigens matched to currently circulating field strains of H5N1 (Wong et

al.2012)

Several other One Health issues potentially arise from the use of vaccination.Consistent with the results on the antigenic cartography studies, evidence suggeststhat long-term vaccination of poultry against avian influenza virus will probably beassociated with development of antigenic variants This has implications forvaccine antigen selection not only for poultry vaccines but also for humanpandemic preparedness

Vaccination under field conditions does not necessarily prevent short-termlow-level virus shedding by infected, vaccinated poultry which will not showclinical disease Therefore, if the presence of poultry morbidity and mortality isused as a risk factor for investigating human cases, it is important to modify humancase definitions Note also that even without vaccination subclinical H5N1 HPAIinfection has been described in ducks.

5 Conclusions

Highly pathogenic avian influenza caused by viruses of the H5N1 subtypeemerged as a serious animal health and potential public health threat in Indonesia

in 2003, and as an actual public health threat with potential pandemic implications

in 2005 In retrospect there was a delayed response to the animal health gency, with an apparent reluctance to accept the diagnosis and consequentlydelayed reporting and implementation of control measures, allowing the infection

emer-to become widely distributed and entrenched in poultry, both commercial andvillage In retrospect it can be seen that this created the conditions for the publichealth aspects to emerge, a valuable lesson in the management of emerginginfectious diseases Rapid diagnosis and response while the problem may still becontained is critical, recognizing that this requires well-developed veterinarycapacity and reporting systems

Indonesia has made significant advances in the field and in the laboratory indeveloping tools to monitor the now endemic problem, but has not succeeded inmobilizing the types of whole of society responses that will be needed to eliminatethe infection by breaking the chains of transmission Since the country is anarchipelago, there may be strategic advantages in developing and trialling controlmeasures island by island Certainly, this aspect has led to one notable success,that molecular analyses clearly show there has been only the one breach ofnational quarantine, one introduction of the H5N1 virus The international com-munity should continue to assist Indonesia to build on this success with inter-ventions along the value chain from village and commercial poultry production,through improved marketing systems to consumers and a society much moreeducated in infectious disease control and in food safety

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Rabies in Asia: The Classical Zoonosis

Henry Wilde, Thiravat Hemachudha,

Supaporn Wacharapluesadee, Boonlert Lumlertdacha

and Veera Tepsumethanon

Abstract Rabies remains a constant threat to humans throughout much of Asia.The dog is the main reservoir and vector with wildlife playing a very minor role

No Asian country or region has been declared rabies free by WHO in over twodecades and there is evidence of canine rabies spread to new regions during thepast 10 years We now have the knowledge and technology to control caninerabies The main barrier in managing this costly endemic is lack of motivation byauthorities to address this issue along with regional inability of public health andlivestock (agriculture) officials to tackle this issue in cooperation and coordination.Rabies is one of the first recognized zoonoses and a model for a true ‘‘One Health’’management goal where human; veterinary, and government officials must worktogether in harmony to defeat this disease

5 Clinical Features, Diagnosis, and Management 193

6 Pre and Post-exposure Management 195 6.1 Post-Exposure Schedules 196 6.2 Pre-Exposure Schedules 196

7 Phylogency 198

Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand

e-mail: henrywilde27@gmail.com

Queen Saovhabha Memorial Institute, Rama IV Rd, Bangkok 10330, Thailand

DOI: 10.1007/82_2012_228

 Springer-Verlag Berlin Heidelberg 2013

Published Online: 8 June 2012

8 Control Management Strategies 198

9 Is Rabies an Ecosystem Problem? 199

10 Summary 199 References 200

1 Introduction

Concerns over newly emerging zoonotic diseases spreading from animals to man are

of increasing concern worldwide (Meslin1997a,b; Chomel and Sun2011) Rabieshas been known and feared since antiquity Over 4,000 years ago, the MesopotanianLegal Codex of Eshnuna (1930 BC) stated that the owner of a rabid dog that bit aperson who dies of rabies must pay a fine for not having killed the dog first The closeinteraction of man with dogs makes rabies a major concern This is particularly true

in regions with large unvaccinated canines Energetic dog population control andsustained rabies vaccination have virtually eliminated rabies in industrializedcountries This should be proof that rabies control of dogs is possible Asiandescriptions of ‘‘mad dogs’’ causing human deaths go back to hundreds of years In

1911, the dramatic case of a young princess, who was bitten by a dog at a time whenrabies vaccine was unavailable in Thailand, led to the founding of ‘‘Institute Pasteur’’

in Bangkok It later became the ‘‘Queen Saovabha Memorial Institute’’ Its missionwas to manufacture snake antivenins and Semple-type rabies vaccine French andBritish colonial powers established similar institutions even earlier in India and VietNam Thailand and much of Asia remain rabies endemic to this day (Fig.1).International travel and migration results in import of cases to rabies-freeregions (Smith et al.1991) Lack of awareness and experience with this diseasecaused misdiagnoses and inappropriate management (Bronnert et al.2007; Maier

et al.2010; Srinivasan et al.2005)

2 Emergence of Rabies in South and Southeast Asia

Dogs are the main vectors responsible for human rabies worldwide Rabies in Asia

is almost completely due to largely unvaccinated dog populations The estimatedhuman to dog ratio in Thailand is 1/10, in India 1/28, US 1/5, Canada 1/13, UK 1/9,and the global ratio is estimated at 1/16 (www.mapsofworld.com) With a humanpopulation of over 65 million, there are at least 6 million dogs in Thailand Only amodest number of this population receives sustained rabies vaccination The situ-ation is very similar in most of south and Southeast Asia (Hossain et al.2011; Meng

et al.2011; Meng et al.2010)

Cats are the second most common source of human rabies exposures in Asia(Fogelman et al.1993; Dodet et al.2008a,b) Virus samples collected from Asianrabid cats and other domestic animals revealed only canine street virus strains An

investigation in America was also unable to find evidence of sustained cat-to-cattransmission (Lumlertdacha et al.2006; Denduangboripant et al.2005; Fogelman

et al.1993)

Non-genotype 1 bat lyssavirus was identified by serological methods in land in 2001 (Lumlertdacha et al.2005) There are over 110 different species ofbats in this region and some harbor lyssaviruses Of 394 serum samples fromfrugivorous bats; Pteropus lylei (335), Eonycteris spelaea (45), and Rousettusleschennaulti (1), and insectivorous bats (Hipposideros armiger) (13), none hadevidence of neutralizing antibodies against rabies virus However, 16 samples;

Thai-P lylei (15) and E spelaea (1), had detectable neutralizing antibodies againstAravan virus, Khujand virus, Irkut virus, or Australian bat lyssavirus These resultsare consistent with the presence of naturally occurring viruses related to newputative lyssavirus genotypes No human case of bat derived rabies has, as yet,been identified in Thailand even though bats are often hunted and eaten by vil-lagers The situation appears no different in neighboring Asian countries Non-biteexposure via mucous membranes, respiratory, and alimentary routes is also pos-sible (Afshar1979) Bats are nocturnal and spend most of the day living in roosts

known and may well be virtually worldwide Other regions with wildlife rabies usually parallel those where canine rabies is also present Source adopted from WHO

Their habitats are caves, forest, buildings, and construction sites They areadaptive, resisting minor disturbances such as guano collection and the invasion ofcaves by tourists In certain areas where, bats are captured and eaten or otherwiseseriously disturbed, this may result in migration of entire colonies (Wanghongsaand Boongird 2005) The expansion of cities and use of toxic chemical in horti-culture and industry encourage migration (Clark 1988) Forest species are alsosensitive to exogenous changes Seasonal migration of bat colonies in Thailand hasbeen studied It was found that populations may vary up to 10-fold between hot,rainy, and cool seasons Male bats also migrate during mating and weaning periods

to avoid food scarcities and fighting The larger a bat population in a single colony,the broader will be the coverage area to hunt for food Results from a populationbiometric study revealed that insectivorous bats (Tadarida spp) have been found

30 km from their roost and that tagged Pteropid bats have been found in even moreremote locations (Wanghongsa and Boongird 2005) A telemetry study in flyingfox species found that they could fly between land and islands with a range of76–3011 km and the radial distance covering 17–245 km (Breed et al.2010) Thiscapacity to migrate over long distances increases the risk of spreading infectiousdiseases of concern to man Large fruit bats, found in south and Southeast Asia,harbor rabies and Nipah viruses and may well harbor other unknown ones Theyclearly represent public health potential risks Studies of bat viruses are difficultdue to financial and logistic constrains but there are also cultural and even legalbarriers to their collection and study (Wacharapluesadee and Hemachudha2010).Monkey rabies is rare, even though they often live in close proximity to manand dogs Monkey bites are not uncommon The Thai Red Cross animal bite clinicsees approximately 10 annual monkey bite cases (often in tourists) and considersthem potential rabies exposures The responsible monkey is usually not identified.However, no monkey origin human rabies cases have been reported from Thailandand India (GN Gongal, personal communication)

Thailand is populated by at least 21 species of rats with Rattus norwegicus andRattus rattus being the most common Many are field rats (Legakul B andMcNeely Legakul and McNeely1977) Bandicota rats (B indica or B savilei) areseen in rice fields and occasionally in some urban areas throughout Asia A layperson would find them virtually indistinguishable from common urban rats butrabit Bandicotas have been reported rabid from Sri Lanka and India (Wimalaratne

1997; Patabendige and Wimalaratne 2003) However, it is not known whetherthese cases are spillovers or independent vector reservoirs There are two reports

of rabid rats (species not identified but thought to have been urban) from Thailandduring the past 20 years (Kamoltham et al.2002) It is, however, accepted that ratsare not reservoirs of rabies but represent spillovers Asian rats are large enough tosurvive a dog or cat attack Thailand animal bite centers therefore provide post-exposure treatment for transdermal rat bites However, mongooses are consideredrabies vectors in Asia (Patabendige and Wimalaratne2003)

Cattle are occasional victims of rabies in Asian agricultural societies They aremost likely infected by dogs Table1shows the species distribution of laboratory

proven rabies cases in Thailand Similar findings can be expected from boring countries in south and Southeast Asia (Table2).

neigh-Rabies in elephants and other domestic and wild animals represents spillover andhas not generated self-sustaining new cycles (Wimalaratne and Kodikara1999)

3 Pathogenesis

Although rabies has long been considered invariably fatal, this is not entirely true.Dogs survived symptomatic infection at near 14 % in one large and well-designedexperiment at the Wistar Institute (Bear GM personal communication) Dogs, that hadnever received rabies vaccine, have been found with neutralizing rabies antibody Thishas also been reported from Ethiopia and Thailand (Fekadu and Baer1980; Yasmuth

et al.1983) It is virtually certain that they survived abortive infections Studies fromAmerica have also shown that raccoons can survive rabies and that may be the casewith other mammal (Bigler et al.1983) Neutralizing rabies antibodies were found in

an elderly Eskimo fox trapper, living on the banks of Alaska’s isolated KuskokwimRiver He had never received rabies vaccine but had trapped and skinned foxes withbare hands in a fox rabies endemic region for nearly 50 years (Follmann et al.1994).Low rabies antibody has also been reported among Canadian Inuit (Eskimo) hunters(Orr et al.1988) The existence of asymptomatic rare dog virus carriers has been thesubject of several controversial papers (Zhang et al.2008)

There have been very rare human rabies survivors with and without intensive caremanagement They were found to have high neutralizing and non-neutralizingantibodies in serum and spinal fluid shortly after onset of symptoms In none of thesewas it possible to isolate viable RNA from serum, spinal fluid, or tissues (Wilde et al

Source Department of Livestock Development, MOPH, Thailand

2008; Jackson2007,2010) Survival was almost certainly due to early mustering ofhumoral and cellular antibodies that eliminated the virus As these current cases wereassociated with bat variants, this may have been a factor in survival (Wilde et al.

2008) There was a recent report of abortive rabies in a 14-year-old girl with a batexposure She recovered without intensive care and also had mounted an earlyvigorous non-neutralizing antibody response without finding viable virus or viralRNA on extensive laboratory studies Another survivor in 201, with no knownexposure, also had non-neutralizing antibody in the serum with no recoverable virus

or RNA (Blanton et al.2011)

Rabies viruses are not hardy; subject to early inactivation by heat, chemicals,and desiccation They are unlikely to survive long in the environment Rabies virushas the unique, not yet fully understood, ability to suppress the host’s immuneresponse (Lafon2007) Infection is usually by bites from an infected mammal Thevirus enters the nervous system via attachment to acetylcholine receptors (AchR)

at the muscle where it remains dormant under control of muscle-specific oRNA This may explain long incubation periods It then gains access to peripheralnerve endings and moves slowly centrally The duration of the asymptomatic stagealso depends on the bite site, virus inoculums, density of nerve supply, and dis-tance from the central nervous system The virus transport time in peripheralnerves is thought to be 8–20 mm/day (Hemachudha et al 2005) There are nosymptoms or clinical signs during this time (Susan and Nadin2007) Once thevirus reaches the central nervous system symptoms appear Prodromes with itchingand pain, at or near bite sites, often come first and are soon followed by majorclinical manifestation and death (Laothamatas et al.2008)

micr-Shortly before onset of symptoms, virus disseminates peripherally to manyorgans, including salivary glands and myocardium It can then close a viral sur-vival cycle by infecting new victims Selective functional impairment of mid braincontributes to the unique aggressive behavior of the infected dogs (not always true,particularly in other species) which results in attacks Tepsumethanon demon-strated in a large study that rabid dogs and cats will all die within 10 days ofobservation after onset of symptoms if no life extending measures are applied(Tepsumethanon et al.2004a,b) The period prior to onset of symptoms in a dog orcat, when saliva is infective, is 2–3 days (Vaughn et al.1963,1965; Patabendigeand Wimalaratne2003; Wimalaratne1997; Fogelman et al.1993)

4 Spillover Transmission

Canine rabies probably originated in Africa and was introduced to America byEuropean invaders However, there is evidence suggesting that vampire bat rabieswas known to the Aztecs before arrival of Columbus (Vos et al 2011) Knownreservoir vectors are dogs, wolves, foxes, skunks, raccoons, raccoon dogs, mon-gooses, hyenas, bats, and coyotes They maintain their own cycle of infection andharbor individual virus variants (Hanlon et al.2007) Transmission from them to

other domestic and wild animals is by bites The newly infected mammal is theneither a spillover victim or, rarely, starts a new reservoir.

The most common risk factor for transmission is the presence of infectedcanines and, to a lesser extent, bats Bat rabies represents a lower risk to humanssince interaction with bats is less common Nevertheless, Australian bat lyssavirus(ABLV) has become the cause of an emerging disease with two human deaths(1996 and 1998) In Australia, the virus has been isolated from all four species offlying foxes found on the mainland (i.e., P alecto, P scapulatus, P poliocephalus,and P conspicillatus) as well as a single species of insectivorous bat (Saccolaimusflaviventris) Bat rabies can be transmitted to terrestrial animals (Kuzmin andRuppecht2007; Gibbons2002) Bats live near humans and in caves frequented byvillagers and tourists (Banyard et al.2011; Kuzmin and Ruppecht2007; Gibbons

2002) Small insectivorous species have needle-like teeth that can cause virtuallypainless bites (Banyard et al.2011; Gibbons2002) One publication showed air-borne transmission of rabies to animals caged in a bat cave (Constantine 1967).Thus, any close contact with bats may represent a rabies exposure (Kuzmin andRuppecht2007) Most bat species are migratory A rabid insectivorous bat, usuallyseen in the Pacific Northwest, was found in rabies-free southeast Alaska (Personalcommunication Alaska section of epidemiology, 2011) A large brown bat Ep-tesicus fuscus, native to the continental USA, came to rabies-free Hawaii in acontainer (Sasaki et al.1992) A bat, most likely from continental Europe, bit aman in rabies-free Scotland who died of rabies (Anon2011) Rabies viruses iso-lated in India were thought to be closely related to periarctic strains (Nadin-Davis

et al.2007) Rabies is a potentially worldwide threat and can spread over a widerange by migration and human assisted mechanisms It is then up to public healthauthorities to have contingency plans on how to rapidly isolate and eradicate a newoutbreak before it becomes established as is now happening on Indonesian islands.Infection of health care staff with rabies is possible but no deaths have beendocumented to the best of our knowledge The authors had one experience where

as many as 300 hospital employees had varying degrees of real or imaginedexposures to a rabies patient on a tertiary care surgical service (Kietdumrongwongand Hemachudha2005) Rare rabies deaths in veterinarians have become knowneven though pre-exposure vaccination of veterinary students is recommended.Most, if not all of these, were preventable by pre-exposure vaccination

Rabies can spread over long distances and across species barriers In order for anew zoonosis to establish itself, the infected mammal must be capable ofaggression and bites By transporting dogs, humans are often the conduits fortransfers to rabies-free regions Fisherman in south and Southeast Asia travel overwide ranges and often carry dogs for company and security They continue to beresponsible for new outbreaks on rabies free Pacific islands (Windiyaningsih et al

prophylaxis (Dacheux et al.2008; Prakrong and Wasi1990; Muller-Holve et al.

1979) We could only find one human transplacental transmission report fromTurkey The vaginally delivered baby died 40 h after birth of laboratory docu-mented rabies (Sipaioglu and Alpaud1985)

Laboratory rabies mishaps have been published but have not led to human deaths(Kaplan 1981) One scientist, who had pre-exposure vaccination, was infectedaccidentally and developed an attenuated form with partial recovery (Tillotson

1977) The authors experienced a student who had a centrifuge accident withdroplets of virus entering conjunctivae She had received pre-exposure vaccination

1 year previously Her eye was immediately irrigated with saline followed 2 h later

by diluted human rabies immunoglobulin She was given booster vaccination andsurvived symptom free having had a pre-booster antibody titer [0.5 IU and avigorous anamnestic response

Transmission by organ or tissue transplantation has been reported from Europe,America, and Asia (Bronnert et al.2007) The authors also know of one additionalunpublished case of corneal transplantation

Eating dogs and cats is common in many cultures Rabies transmission fromconsuming poorly cooked dog or cat meat has been reported from Asia, Africa,and South America Several humans have died from rabies after butchering andeating a rabid dog in Viet Nam and Philippines Infection may also have been frombutchering (Personal communication from Merrit C, ANIMAL PEOPLE (ClintonWashington, USA, Editorial2009)

A recent survey in Asia revealed inadequate understanding of rabies by thepublic and an urgent need for increasing awareness and for dog populationmanagement in canine rabies endemic countries Sadly, the Asian death toll fromrabies remains at over 31,000 annually of which 50 % are in children (Dodet et al

2008a,b; Robertson et al.2011)

5 Clinical Features, Diagnosis, and Management

The cardinal features of human rabies are well known, especially those ofaggression, hypersalivation, and phobic spasms (aero- and hydrophobia) Theymay, however, escape notice or are poorly expressed They may also not persistand disappear once the patient becomes comatose or absent altogether Patients areoften delivered to hospitals comatose with poor or no history The authors alsoexperienced one child diagnosed with rabies who was taken home and later, when

in respiratory distress, taken to another hospital without history of priorhospitalization and the rabies diagnosis Dozens of staff needed to receive post-exposure prophylaxis Awareness of unusual presentations and a good history areimportant The Guillain–Barre-like paralytic syndrome and atypical presentationsreminiscent of stroke or spinal cord disease in the forms of hemisensory-motordeficits and paraparesis have been recognized (Hemachudha et al.2005) They are