Disease

SYSTEMS AND DISEASE

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C o p y r i g h t 2 0 1 6 . 5 m P u b l i s h i n g .

A l l r i g h t s r e s e r v e d . M a y n o t b e r e p r o d u c e d i n a n y f o r m w i t h o u t p e r m i s s i o n f r o m t h e p u b l i s h e r , e x c e p t f a i r u s e s p e r m i t t e d u n d e r U . S . o r a p p l i c a b l e c o p y r i g h t l a w .

EBSCO Publishing : eBook Collection (EBSCOhost) - printed on 3/22/2023 12:15 PM via UNIVERSITY OF MARYLAND GLOBAL CAMPUS AN: 1510846 ; Susan Cork, David Hall, Karen Liljebjelke.; One Health Case Studies : Addressing Complex Problems in a Changing World Account: s4264928.main.eds

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chapter 2 One Health approaches to rabies

control in Bali, Indonesia

David C. Hall, Anak Agung Gde Putra, Iwan Willyanto and Edi Basuno

2.1 Introduction

Rabies is one of the first reported diseases in written history. As early as 2200 bce, writings from Mesopotamia link dog bites with ill- ness in humans exhibiting rage-like symptoms (Adamson, 1977; Theodorides, 1974; Pritchard, 1955). In the eighth century bce, Homer wrote in The Iliad of ‘menin’ to describe the rage of Achilles and ‘lyssa’ in reference to Achilles’ rage, from which we derive the words meningitis1 and lys- savirus.2 By the sixth century bce, rabies was in China and thought to have expanded into Asia. More than four millennia after the first writings on canine rabies and despite development of a

vaccine by Pasteur and Roux in 1885, rabies is still a major disease burden for many parts of the world, causing not just death but also economic stress on health systems where post-exposure prophylaxis (PEP) treatment and vector control campaigns are mobilized. This chapter explores an epidemic of rabies in Bali, Indonesia, and examines elements of a One Health approach used in the epidemic and the impact of that approach.

The island of Bali is known for its beautiful beaches, Hindu culture and temples, and ter- raced rice fields amid integrated agricultural communities. Prior to late 2008, unlike most of Indonesia, there was no record of rabies in

Abstract

In 2008, Bali, Indonesia saw its first case of rabies. Initially the response was to cull unconfined dogs with limited vaccination, a response that did not control the epidemic. Following engage- ment with villagers, epidemiologists, ecologists and NGOs, and with assistance from the FAO and international researchers, a One Health approach was adopted focusing on understanding the complexity of dog ecology in Bali, community engagement and improved communication. The current approach follows a capture, vaccination, collar and release plan for unconfined dogs. Domesticated dogs are vaccinated and sterilization encouraged. At least half of all dogs on Bali are thought to have been vaccinated, and cases of human rabies have declined since 2010, although the epidemic continues.

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14 David C. Hall, Anak Agung Gde Putra, Iwan Willyanto and Edi Basuno

Bali. However, in November 2008 the death two months earlier of 46-year-old Putu Linda was diagnosed as being a result of rabies, probably brought to the island several months before that on a fishing boat from neighbouring Flores (Putra, 1998; Putra and Gunata, 2009).

The response to controlling the rabies epi- demic in Bali presents a compelling case study for supporting a One Health approach to health management. All six of the classic pillars of ecohealth are present, briefly identified here. Understanding the complexity of the epidemiol- ogy of the rabies epidemic has required learning about canine ecology on the island as well as the social and cultural importance of the dog in Bali society. Consideration of various alternative strategies to control the spread of the disease has taught that community participation is essential, particularly for sustainability of con- trol. Social inequity plays a role where members of lower-income communities are less likely to have attained higher levels of formal education allowing clearer understanding of the etiology of rabies and the importance of rapid post- exposure treatment to dog bites. Finally, learning from past efforts can inform local and national rabies policy, particularly with respect to how to engage with communities in order to foster sustainable approaches to control.

This chapter will briefly explain the history of the rabies epidemic in Bali, the approaches to control used thus far, and recommendations for furthering a One Health sustainable approach to managing control and local elimination of rabies in Bali and neighbouring islands in Indonesia.

2.2 Rabies in Bali – an outline of the epidemic

Until 2008, Bali was known as one of the very few Indonesian provinces that had never seen a case of rabies, in part due to the fact it is an island but also due to strict quarantine measures

for dogs brought onto the island. Although the latter control measure was generally respected by fishermen who travelled with their dogs as companions between the islands in the area, the index case of canine rabies was most likely in a dog brought to Bali by a fisherman probably from neighbouring Flores Island, where rabies was known to exist. This is supported by phy- logenetic analysis of the rabies strain in Bali (Mahardika et al., 2014), which is a descendent of the Kalimantan 00-18 strain, correspondingly an ancestor of the Flores and Sulawesi strains. By November 2008, two villagers had died of clinical signs consistent with rabies, and on 30 November, the governor of Bali declared rabies present on the island.

With full awareness of the importance of a rapid response to the introduction of this fatal zoonotic disease, in December 2008 the provin- cial government of Bali began a two-pronged approach to rabies control: (1) culling of uncon- fined dogs in the rabies confirmed regencies of Denpasar and Badung with the use of strychnine bait and blow-dart methods; and (2) vaccina- tion of dogs at selected locations with a locally produced vaccine that required a booster three months after first vaccination. From a survey of dog owners in Badung Peninsula (Putra et al., 2011), it was estimated that up to 40 per cent of all known dogs in Badung and Denpasar were vaccinated by March 2009; of those, slightly more than half received a booster vaccination by June 2009, suggesting effective protection of about one quarter of the owned dog population.

The low coverage of vaccination combined with other factors to suggest this approach would not be successful. For example, dog density is about one in eight in Denpasar, and most dogs are communally owned, fed and free- roaming (Morters et al., 2014), meaning human/ dog encounters resulting in bites from unvac- cinated dogs would not be uncommon. By September 2010, rabies was confirmed present in 221 or one-third of all villages in Bali. It was

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One Health approaches to rabies control in Bali, Indonesia 15

accepted that the rapid response had failed to control the rabies epidemic.

Involvement of NGOs and outside agencies

By 2010, a number of charitable organizations as well as outside government aid agencies had begun to participate in the efforts to reduce rabies in Bali. These included the Bali Animal Welfare Association (BAWA), the World Society for the Protection of Animals (WSPA, now called World Animal Protection), the Australian govern- ment (AusAID), the United States government

(USAID), the International Development Research Centre of Canada (IDRC) and the Food and Agriculture Organization of the United Nations (FAO). BAWA and AusAID led the charge in late 2010 to use vaccination (as well as sterilization) rather than culling as the sole tactic in the rabies containment and elimination strategy for Bali. This was through a Memorandum of Understanding developed in agreement with the governor of Bali and most regencies of Bali, indicating an early will- ingness of key stakeholders to discuss and agree on approaches for control, particularly when it included funding support for costly vaccines.

The strategy developed in late 2010 included several components that can be seen as incorpo-

Table 2.1 Timeline of rabies in Bali, Indonesia

Jan–May 2008 Rabies probably arrives via a dog from a neighbouring island (e.g., Flores Island); settles in Ungasan Village, Bukit Peninsula, Bali.

Jul 2008 Dog from Flores, normally placid, bites owner (Mr TA) and is claimed to have bitten a friend in August; this is thought to be the first human infection with rabies in Bali.

6 Sep 2008 Female child (Miss L) bitten in Ungasan village.

9 Sep 2008 Male adult (Mr MA, aged 32) bitten.

16 Sep 2008 Male adult (Mr KW, aged 28) bitten in Ungasan village.

17 Sep 2008 Miss L dies (thought to be first human death of rabies in Bali).

Sep 2008 Ms Putu Linda (aged 46) dies of rabies, diagnosed on post-mortem examination.

19 Oct 2008 Muhammad Oktav Rhamana Putra (male, aged 3) in Ungasan Village bitten by stray dog; PEP denied at Sanglah Hospital, Denpasar, Bali due to presumed absence of rabies on Bali.

14 Nov 2008 Mr MA dies.

21 Nov 2008 Muhammad Oktav dies after exhibiting clinical signs consistent with rabies.

23 Nov 2008 Mr KW dies.

24 Nov 2008 Regent of Badung requests rabies vaccines be sent to Bali.

26 Nov 2008 Human bitten in Kedonganan by a dog that later dies and is diagnosed positive for rabies using fluorescent antibody technique.

30 Nov 2008 Indonesian Department of Agriculture declares rabies present on Bali.

Dec 2008 Provincial government of Bali launches canine cull and vaccination campaigns.

16 Jan 2009 Mr TA dies (six months post-infection).

Apr 2013 130 people reported dead from rabies; PEP administered to more than 130,000 people following dog bites.

July 2015 Rabies deaths in humans has started to rise again; one in 2013 to 12 by July 2015.

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16 David C. Hall, Anak Agung Gde Putra, Iwan Willyanto and Edi Basuno

rating a One Health approach. These included a transdisciplinary approach to a vaccination strat- egy (dog ecology was recognized as important, as well as understanding the epidemiology of the disease and a communication plan) intend- ing to vaccinate 70 per cent of the dogs in Bali; a community education component, recognizing the importance of collaboration and community participation; and addressing equity by offer- ing free vaccination for those who could not afford to pay to vaccinate their dogs. As many as 239,000 of the more than 500,000 dogs in Bali were thought to have been vaccinated under this first stage of vaccination. A second stage was due to vaccinate 235,000 dogs, and a third round would cover 250,000 additional vaccinations. By the time of the second stage, responsibility for second implementation of the vaccination programme and subsequent phases had been assumed by the governments of Bali and Indonesia with strong technical coopera- tion assistance from FAO. Although a red collar programme existed, it was not possible to collar most free-roaming dogs (the majority of dogs in Bali) and thus it was not clear how many dogs were being revaccinated.

An additional element critical to surveillance for rabies was the integrated bite case man- agement (IBCM) system, generated through cooperation between animal and human health authorities and designed to improve both sur- veillance for rabies cases and medical response to human exposure. Bali is also home to a large number of chick hatcheries, and the ICBM sys- tem benefitted from Indonesia’s and Bali’s need for effective One Health surveillance experience with highly pathogenic avian influenza (HPAI), which resulted in several outbreaks in Bali as well as human illness and death. The experience with HPAI outbreaks led to development and col- laboration of a veterinary Participatory Disease Surveillance and Response (PDSR) programme and a human health District Surveillance Office (DSO) programme; it was around the experi-

ence and success of these HPAI surveillance and response programmes that the ICBM system was developed. An important part of the ICBM system has been a coordinated SMS messag- ing protocol used to communicate events and alert system members to possible rabies-linked events, accelerating response time and in order to ensure both animal and human health officials are aware of possible need for medical or other intervention.

Although the strategy was admirable in its efforts to bring together government, local and international agencies, and community mem- bers, the full logistics of the strategy were slow to roll out, delaying a second stage until May 2011. This difficulty in logistics (in hindsight, ‘operationalizing’ the One Health approach) may have been a costly opening in the vaccination coverage that began to roll out in 2010. From that point forward, the government of Bali with directive from the government of Indonesia and continuing input from FAO took charge of the rabies control campaign. Different stakeholders have varying views on reasons for this, but the summary conclusion seems to be concern on the part of the government that rabies cases were not decreasing rapidly enough under a vaccina- tion-only campaign, and it has since resorted to occasional sweeps of culling free-roaming dogs.

In hindsight, there was considerable prog- ress towards a 70 per cent coverage in several regencies by 2012 – including Denpasar, Badung, Gianyar and Bangli – which saw more than 235,000 dogs vaccinated in each of the two vaccination campaigns (Putra et al., 2013). However, it is impossible to say how many dogs were repeat vaccinates, how many escaped vac- cination altogether and how many were simply inaccessible, leaving the claim of 70 per cent total coverage on the island unclear. Further challenges in the 2010 and 2011 campaigns were cold chain management, varying access to and supply of vaccine, funding liquidity and data reporting and management.

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One Health approaches to rabies control in Bali, Indonesia 17

At time of writing, rabies remains in the dog population in Bali. By July 2015 there were 12 more human deaths from canine rabies and there continue to be human/dog confrontations with dog bites numbering around 150 a year (see Figure 2.1). As a result, the official target for freedom from rabies in Bali has been pushed out to 2016. The government of Bali continues to recognize vaccination and sterilization as valid options for rabies control but also actively and vigorously pursues culling of free-roaming dogs (Erviani, 2014), noting that in their opinion, control results from vaccination alone have been slow and not completely satisfactory.

2.3 Dogs in Bali

The dog plays an important cultural role in Balinese society, adding further complex- ity to the mix of dog ecology and stakeholder interaction that continues to be a part of the investigation of rabies epidemiology in Bali. The fact that most Balinese dogs are free-roaming further confounds the issue. Both the cultural

role and free-roaming as an issue for disease control are described here.

The dog has long been a part of community life in Bali, functioning as a guard dog for house and garden, a companion in hunting and fishing, and a pet (Putra et al., 2011). Most Balinese are Hindu; in Hindu culture, the dog is referred to as the guardian of Heaven and Hell. Caring for dogs is thus considered a conduit to Heaven, as well as a way to avert calamity (Lodrick, 2009). As well, certain colours of dogs are used in cultural ceremonies by the Balinese, who also believe dogs may cure certain diseases and prevent mis- fortune. Clearly, killing off all the dogs would not be a culturally respectful nor reasonable approach to rabies control.

Dog ecology

Dog ecology has been studied and reported as part of understanding, designing and interpret- ing the sero-epidemiology of rabies in Bali by Putra and colleagues in several Balinese publi- cations (Putra and Gunata, 2009; Putra et al.,

Figure 2.1 Confirmed human rabies deaths in Bali, 2008–2015 (2015 data are up to June 2015)

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18 David C. Hall, Anak Agung Gde Putra, Iwan Willyanto and Edi Basuno

2009, 2011). It was also noted as an important part of a transdisciplinary, ecohealth-based approach to policy formulation to address rabies in Bali (Willyanto et al., 2012). These studies have identified several important findings with respect to free-roaming indigenous (kampung) dog ecology including:

• There are close to half a million free-roaming dogs in Bali and about 10,000 ‘high bred’ dogs (i.e., not free-roaming and kept as house pets).

• The free-roaming dog-to-human ratio is about 1:8.

• The largest age group of free-roaming dogs captured, vaccinated and released are less than one year of age.

• The majority of free-roaming dogs observed are three years of age or younger.

• Dog density is highest around urban areas at 256/km2, with density in peri-urban at 184/ km2 and rural village areas at 129/km2.

• Puppies are least likely to be born during the wet season (December to May).

• Free-roaming dogs tend to congregate near sites associated with people and food includ- ing temples, garbage drops, markets and beaches.

• Among kampung dog-keepers (e.g., fishermen, guard dog needs), there is a preference for an intact male dog.

In a rabies control and elimination campaign, knowledge of dog ecology can be highly valuable to increasing efficacy. From the work conducted in Bali, we know a well-planned strategy would target truly free-roaming dogs (such as catch, vaccinate, tag and release tactics) as well as con- tained dogs, although the former are far more difficult to handle and vaccinate. A strategy should also consider that free-roaming dogs tend to stay close to human habitation, very young dogs will require a second booster in a matter of months, and vaccination programmes would be

best to target two seasons: first, the pre-breed- ing season in the first two months of the year and, second, in October and November with the appearance of new-born puppies.

From the above data and estimates from Putra et al. (2011, 2013), it seems the coverage rate of free-roaming dogs in the first two waves of vac- cination was closer to 10 per cent, which was far from the minimum of 70 per cent required to stop maintenance of the disease in the dog population. As well as the challenges noted above, understanding of dog ecology in Bali as well as the role of communities and coopera- tive coordination with government was crucial to mounting a successful catch-and-release vaccination campaign.

2.4 Community/participatory approach

The response to the Bali rabies epidemic has demonstrated the need for a participatory approach to solving a complex problem, involv- ing numerous stakeholders including several levels of government, health professionals including veterinarians and physicians, epide- miologists and ecologists, communications and logistics experts and, of course, members of the local community. The village community plays a particularly important role in Bali in part because of the free-roaming nature of the dogs, making it difficult for outsiders to identify locally cared- for dogs that are fed and considered part of the community.

Communication is a vital element of a suc- cessful participatory approach to rabies control as much for human post-exposure treatment as prevention and control of rabies in dogs. Of 104 cases of human rabies investigated from 2008 to 2010 (Susilawathi et al., 2012), 92 per cent had history of a dog bite but fewer than 6 per cent had their wounds treated and received PEP vaccine (none received PEP immunoglobulins).

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One Health approaches to rabies control in Bali, Indonesia 19

The authors concluded this was primarily due to lack of awareness of rabies risk, understanding of rabies in dogs or the need for urgent post-bite care, and limited awareness or availability of PEP treatment. Because Bali had been free of rabies up to 2008, there was a general lack of awareness or concern for either rabies following a dog bite or for control of rabies in communities. Thus communication and educational programmes would be essential to raising public awareness and assisting in identifying rabies cases in dogs, helping human bite victims seek urgent medical care, and implementing a surveillance and rapid response mechanism.

Effective collaboration with community part- ners can take several years to foster and maintain, but in a transdisciplinary participatory approach, community members are as vital a stakeholder as governments and scientists. Components of effective collaborations with communities in Bali vary depending on the regency and community, but there are several commonalities:

• Communities are a part of the government- led PDSR/DSO and ICBM programmes.

• Multilevel age-appropriate training and edu- cation programmes in recognizing the threat of rabies and management of free-roaming dogs in the community.

• Heightened awareness of how to respond to dog bites.

• Improved participation in mass rabies vac- cination of dogs including post-vaccination marking with a long-lasting collar to prevent culling of vaccinated dogs.

• Training and signposted identification of community members who act as village rabies awareness wardens; children are taught to seek help from these respected commu- nity members in the event of dog threats or attacks.

• Community environmental management to reduce the risk of rabies including garbage management.

• Improved animal welfare of free-roaming dogs including veterinary care and awareness of sterilization as a healthy option to prolong the life and welfare of all dogs.

It is worth noting the importance of a com- munity-based One Health approach in rabies control has been appreciated in other countries in Asia, notably Bhutan. The dog-neutering pro- gramme in Bhutan ensures that feral dogs are also vaccinated against rabies during concurrent public awareness campaigns and vaccination of pet dogs. The neuter and vaccination pro- gramme is well described in Tenzin et al. (2012a, 2012b), and engages veterinary professionals, para-professionals and community members. The awareness programme engages profession- als from human and animal health and includes the development of new inter-sectoral govern- ment guidelines for the prevention of rabies in humans. The ongoing collaborations (at all lev- els of government service) and the joint disease investigations conducted by field staff from the Department of Public Health and Department of Livestock in Bhutan demonstrate a genuine commitment to the One Health approach.

2.5 Impact on tourism

More than 40 per cent of tourism income in Indonesia comes from Bali (Bali Daily, 25 January 2013), generating more than US$5.4 billion in 2012, up from US$4 billion in 2011. The eco- nomic impact on tourism in Bali attributable to fear of rabies has not been calculated. However, despite travel warnings for Bali because of rabies that have been issued by the governments of Australia, UK and the US, arrivals to Bali have increased significantly every year since the first case was reported (Figure 2.2) and show no sign of decreasing. The absence of evidence of a slowdown in tourism is made more surpris- ing given that Indonesia is the second highest

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20 David C. Hall, Anak Agung Gde Putra, Iwan Willyanto and Edi Basuno

reported country after Thailand for travellers who were bitten by animals and received rabies PEP (Gautret et al., 2015). Despite these data being made available to travellers online and via health personnel, there seems to be a general lack of awareness among travellers of the risks, as well as a lack of pre-travel advice issued by health professionals. Furthermore, most trav- ellers neither seek nor receive pre-exposure rabies vaccination (Gautret et al., 2015), and of those who are bitten, less than a third seem to seek any medical care at all (Piyaphanee et al., 2012). Our conclusion is that rabies has had no appreciable impact on tourism in Bali, but that travellers and health professionals may not be well aware of either the epidemic or pre-travel prevention options.

Policy development

Prior to the rabies epidemic in Bali, no policies existed for dog control, dog-bite surveillance or canine rabies vaccination. Today there are mul- tiple informal policies in place to address these

matters, including the guidelines for engage- ment and support of the PDSR, DSO and ICBM programmes described above. A formal rabies control and elimination policy recognized by provincial and federal governments and formu- lated with the cooperation of all stakeholders, whether it be a set of standard operating pro- cedures or a provincial decree, has not been developed in Bali. Current vaccination policy is guided by two main elements: first, techni- cal cooperation agreements that are developed between the governments of Bali and Indonesia and partners including FAO, international donors and NGOs; and, second, community-led initiatives that operate as part of wider pro- grammes.

Well-developed One Health policies are needed for broad zoonotic control and elimi- nation programmes to guide science-based decision-making and allocation of resources in a coordinated manner with understanding of lon- ger-term needs such as the role of surveillance, while being cognisant of shorter-term demands including controlling free-roaming biting dogs and having urgent access to PEP treatment. But

Figure 2.2 Arrivals of foreign tourists to Bali, Indonesia from 2008 to 2014. Calculations by Hall using data

from Bali provincial government.

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One Health approaches to rabies control in Bali, Indonesia 21

just as is the case for HPAI in Southeast Asia (Cork et al., 2015), policy to support rabies con- trol in Bali faces a challenge: how to formulate strict and enforceable standards while minimiz- ing disruption of property rights. The benefits of a One Health approach to this policy formu- lation problem include the opportunities for dialogue and agreement among stakeholders by taking a participatory approach, recognition of the complexity of a health problem allowing changing standards and methods, and adopting a transdisciplinary approach that reduces mar- ginalization of important stakeholders while bringing together critical expertise.

Among the policy challenges Bali faces in rabies control and elimination are two important barriers that have yet to be overcome: a reliance on foreign aid for programme inputs including vaccines, and clear distinction between commu- nity, provincial and central government policy intent and results. Of Indonesia’s total revenue from tourism, at least 40 per cent is generated by Bali (Bali provincial government, 2015), amounting to several billion US dollars per annum. This is clearly worth protecting, but so too does it seem extraordinary that a fraction of these funds are not used to completely cover the costs of maintaining vaccine and PEP supplies. The second barrier is harder to overcome, in part due to the devolution of Indonesian gover- nance structure and responsibility, but here One Health offers part of a means to solution through participatory approaches to problem-solving, and recognition of the importance of addressing social inequities in zoonotic disease control.

2.6 The Rabies vaccination/ culling debate

For many infectious diseases for which (1) con- sequences of human infection are devastating to health or economics or both, (2) there exists an identified non-human animal reservoir or

vector, and (3) an effective animal vaccine exists, passionate longstanding debates have arisen regarding elimination of the animal reservoir/ vector versus vaccination. Two examples are the debate over elimination versus vaccination for brucellosis of bison in Canada’s vast Wood Buffalo National Park (Nishi et al., 2006) and elimination of tuberculosis maintained by bad- gers in farming areas of the UK (Enticott et al., 2012). The polemic of rabies control through vaccination versus culling has generated consid- erable heated debate in Bali and shows little sign of resolving. This section serves to identify ele- ments of the debate but not to take sides in order to highlight the need for objective assessment of options as well as point out vulnerabilities of both approaches.

This chapter has pointed out that there has been progress, albeit slow, in controlling rabies in Bali, predominantly through transdisciplinary approaches involving investigation in ecology, community engagement, communications and control of virus movement through primarily vaccination and, to a lesser extent, culling. For a rabies vaccination programme to be successful in Bali (i.e., eliminate the virus) several ele- ments are required including: sufficient coverage of all dogs in Bali (greater than 70 per cent); no gaps in vaccination coverage either in time or geographic location; effective delivery of long- term single-dose vaccine, available whenever needed; and a well-coordinated delivery system that includes participation of communities and local government.

Townsend and colleagues (2013) have dem- onstrated the importance of several of these factors and the need for effective surveillance to detect rabies positive cases. Under poor surveil- lance conditions, which reflect the reality of low income and low technical capacity situations, the authors also show that vaccination is more effec- tive at controlling rabies than is culling. They also demonstrate that high rates of vaccination coverage are critical to achieving high control or

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22 David C. Hall, Anak Agung Gde Putra, Iwan Willyanto and Edi Basuno

elimination of rabies in Bali, and even the slight- est breaks in coverage jeopardize success.

An analysis of the economic efficiency of vac- cination versus culling including the option of PEP for humans is yet to be rigorously devel- oped for Bali. Despite limited support and under challenging logistic conditions, Zinsstag and colleagues have shown that rabies control using vaccination and PEP can be achieved cost- effectively in parts of Africa (Zinsstag et al., 2009, 2015). Their analysis noted the need for vigilant prolonged efforts and that the results are highly context-dependent.

From a practical viewpoint, the Bali provin- cial government has demonstrated little patience with epidemiologic simulations that argue in support of expensive and logistically demanding high vaccination coverage when canine cases and human deaths continue, and Governor Made Pangku Pastika has been very vocal about his support for culling (Jakarta Post, 2014). At the same time, to encourage home containment of dogs and vaccination, the Bali provincial gov- ernment is enforcing a rabies prevention bylaw enacted in 2009 that stipulates dog owners must keep their dogs at home and have them vacci- nated regularly or face a maximum of six months in prison or a fine of Rp 50 million (US$4,100).

Both strategic sides of the control and elimi- nation argument have weaknesses. It is clearly incorrect to jump to a conclusion that either method will never work to control rabies;3 under perfect conditions either method would contain and eliminate rabies. A more sensible analysis, recognizing that perfect conditions are next to impossible, would clearly state programme objectives (control versus elimination under an achievable time horizon), assess the limitations of each method, examine the resources avail- able and realistic constraints to utilization, and develop a corresponding strategy that engages all stakeholders in a transdisciplinary, participa- tory approach. At time of writing, this debate shows no sign of resolving, much like the situ-

ation with brucellosis in bison in Canada and tuberculosis in badgers in the UK.

2.7 Rabies as a One Health problem

Rabies is most burdensome for both humans and dogs in countries in Africa and Asia in which resources for tackling public health problems, mostly human and financial capital, are highly constrained. As a result, high-profile diseases including malaria and influenza get first prior- ity, leaving rabies on the WHO list of neglected tropical diseases (Holmes, 2015). It is the lowest income and less well-educated communities that one finds highest rates death from rabies, iden- tifying the social inequity of rabies prevention.

For these reasons, successful control and elimination of rabies requires a well-coordi- nated, sustainably funded, and carefully planned approach that includes participation of all stakeholders as well as integration of health dis- ciplines, appropriately targeted communication programmes, and supporting policies for sustain- able implementation. Add to this the necessity of understanding dog ecology and the complexity of the disease, and it is clear addressing rabies requires a One Health approach. The WHO has noted that key among the limiting factors in a successful programme are access and afford- ability of dog vaccination and PEP biologicals (Holmes, 2015) as well as rapid response to seek treatment following a dog bite. All three of these factors are most constrained in low-income communities.

It is also unfortunate that human health and animal health disciplines are not always work- ing together to tackle rabies. In Bali, this has not been the case, where primary healthcare providers have trained and developed rabies PEP planning in consult with communities and ani- mal health workers who are most likely to be the first persons aware of a person being bitten by a dog. However, shared communication systems

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One Health approaches to rabies control in Bali, Indonesia 23

and data obstacles remain, despite willingness to exchange knowledge of dog bites and persons or communities at risk. This reduces the efficiency of surveillance and of planned prevention and response efforts, particularly with respect to which communities should be targeted.

Similarly, a key outcome of shared knowl- edge and improved cooperation between animal and human health professionals is awareness of risk of exposure following a dog bite. If health professionals are sharing knowledge of risk and of vaccination status of dogs in communities, the overuse of PEP treatment can be avoided, avoiding mistakes of overuse and prolonged unnecessary concern for rabies such as occurred in Bhutan (Léchenne et al., 2015; Tenzin et al., 2011).

2.8 Conclusions

Dogs have shared our environment for millen- nia, as has the rabies virus. The response to rabies in Bali has gone through several stages of culling, vaccination and combinations thereof under various manifestations of institution-led response and stakeholder engagement. In 2015, there still is no clear unwavering policy estab- lished in terms of mechanism of prevention and response, although there has been consider- able progress in surveillance, understanding of dog ecology, cooperation between animal and human health authorities and participation of all key stakeholders in controlling rabies. Strong differences of opinion continue to influence rapid response to new rabies cases, but at least it is clear that in 2014, cases of dog bites, dog rabies, and human deaths in Bali were markedly reduced from what they were in 2009 and 2010.

A number of factors led to the One Health response that developed in fighting the rabies epidemic in Bali. The initial culling strategy resulted in a backlash of bad press, both domes- tic and international, which was unexpected in

part because the local government did not place substantial weight on the somewhat unconven- tional bond between the community and the free-roaming dogs. Once that had been realized and the role of NGOs accepted, the strategy included mass vaccination, but there still were missing pieces of the transdisciplinary approach. Key among these was better understanding of dog ecology and ways and means to engage with community partners. At the same time, it was clear that solving the rabies problem would require a partnership between human and ani- mal health personnel, as had worked for HPAI.

A recognition of the need to address social equity as well as communication became evident early in the campaign as programmes accommo- dated low-income village residents who needed access to vaccines and PEP treatment as well as improved understanding at the village level of how to prevent and respond to dog bites. Technology and transdisciplinary approaches were modified and adopted to complement these programmes and to support and encourage community participation.

As the campaign to rid Bali of rabies approaches its fifth wave of dog vaccination in 2015, Bali has learned that an integrated, transdisciplinary, par- ticipatory approach to zoonotic disease control and elimination is preferable to and more likely to be successful than a centrally coordinated effort. This has been an evolving One Health strategy that has come about through necessity as well as reflection on successes and constraints. There are opportunities to learn from the One Health approach developed in Bali to address rabies and other zoonotic diseases elsewhere, including many of the WHO neglected tropical diseases found in many lower-income countries.

Endnotes

1 Meningitis is inflammation of the lining of the brain, one of the clinical consequences of rabies.

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24 David C. Hall, Anak Agung Gde Putra, Iwan Willyanto and Edi Basuno

2 Lyssa translates not only as rage but is also the name for the Greek goddess of anger. Lyssaviruses are closely related to the rabies virus and are classified in the same family, the Rhabdoviridae.

3 Rabies was eliminated from the UK in the early twentieth century through culling combined with licensing and muzzling of dogs. In contrast, a dec- laration in 2007 by the CDC of the elimination of rabies from dogs in the US noted that the primary reason for this success was vaccination of pets, both in the past and ongoing.

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chapter 3 Integrating a One Health approach to

avian influenza control in New Zealand

Wlodek L. Stanislawek, Thomas G. Rawdon and Susan C. Cork

3.1 Introduction

The emergence of a number of new strains of avian influenza (AI) in recent years (To et al., 2014) as well as other zoonotic viruses, such as H1N1 influenza virus from pigs and severe acute respiratory syndrome (SARS), Nipah and Hendra viruses from bats (Ksiazek et al., 2003, Field et al., 2007) triggered organizations work- ing in the human and animal health fields to seriously examine disease transmission risks between animals and humans. Due to the fre- quent movement of animals and humans within and between countries, viruses not currently endemic continue to pose a potential risk to countries such as New Zealand. Significant dis-

ease outbreaks caused by any infectious disease can be economically, socially, medically and envi- ronmentally costly. Given the complex ecology of potentially zoonotic diseases such as avian influenza, developing effective plans for disease prevention and control demands an effective interdisciplinary and interagency solution. The ‘One Health’ approach engages a wide range of experts to deal with the varied challenges required to prevent and control zoonotic dis- eases such as avian influenza. This collaborative approach has also been adopted by policymakers in New Zealand in response to a recognized need for more effective and sustainable measures to address emerging diseases (Barrett et al., 2011).

Abstract

With the unprecedented spread of avian influenza (subtype H5N1) across Asia in 2004, and the potential for a new influenza pandemic in humans, New Zealand enhanced its wild bird and poultry surveillance activities. The government also put together an interdisciplinary team to update its pandemic preparedness plan. Pandemic planning requires coordinated global actions as well as actions at the national level. Good governance, public education and stakeholder engagement is essential. In this chapter we outline the complex biology of avian influenza and illustrate the importance of interagency cooperation when developing disease preparedness and response plans.

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Integrating a One Health approach to avian influenza control in New Zealand 27

In 2004, the New Zealand government established the interagency National Centre for Biosecurity and Infectious Disease (NCBID). This reflected a recognition of the value of the implementing the One World, One Health concept.1 The aim was to facilitate enhanced collaboration between organizations such as the Investigation and Diagnostic Centre2 (Ministry for Primary Industries, MPI, previously known as the Ministry of Agriculture & Forestry), Environmental Science and Research (ESR), AgResearch and AsureQuality to more effi- ciently coordinate the management of zoonotic diseases in particular (Hope, 2009). ESR pro- vides core diagnostic and surveillance support for the Ministry of Health3 whereas AgResearch4 and AsureQuality5 are semi-commercial enter- prises that provide technical support to the Ministry of Primary Industries and Industry stakeholders.

A key motivator for developing enhanced collaborations between these government agen- cies is the fact that approximately 75 per cent of emerging infectious diseases in the human population have originated from domestic and wild animals (Jones et al., 2008; WHO, 2008).

3.2 The National Centre for Biosecurity and Infectious Diseases

In 2008, the World Health Organization (WHO) published a document on behalf of the World Organisation for Animal Health (OIE), the Food and Agriculture Organization of the United Nations (FAO) and WHO, suggesting the need for a reliable mechanism for sharing information and surveillance data to ensure a coordinated international response and risk reduction pro- cess in order to improve the management and prevention of zoonotic diseases (WHO et al., 2008). At a country and local level, New

Zealand has demonstrated a strong commitment to enhance collaborations between agencies responsible for human and animal health in order to prevent and manage emerging zoonotic diseases. An important step was the establish- ment of a group of co-located organizations responsible for diagnostic and epidemiologi- cal work in both the animal and human health fields. Establishing supporting infrastructure and expertise on a single site has fostered cross- collaboration, resulting in a coordinated team approach to problem-solving. A decade later, the establishment of NCBID has provided an excel- lent example of proximity, breaking the barriers created by years of separated disciplines and narrow thinking.

The international concerns about the risk of human infection with influenza type A (H1N1) in 2009 demonstrated the value to the human health sector of engaging the diagnostic and epidemiological expertise of the animal health sector in New Zealand. MPI’s epidemiologists and disease response personnel worked effec- tively alongside staff in the Ministry of Health and ESR to assess potential risks from pigs. At the same time, the Animal Health Laboratory scientists worked side-by-side with ESR labora- tory staff to examine samples collected as part of disease surveillance activities. Effective shar- ing of ideas and technical resources was possible because of the establishment of NCBID. This interagency collaboration has built resilience by cross-skilling, which is crucial to ensure sustainable scientific and technical capability and capacity given the small population pool and remoteness of New Zealand. Interagency partnerships between human and animal sci- entists and technical staff at NCBID and other institutions has also facilitated ongoing col- laborations for the development of assays and field testing of a mobile PCR system developed by Lincoln University, testing mobile sequence analysis technology (O’Keefe, 2009; Hope, 2009).

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28 Wlodek L. Stanislawek, Thomas G. Rawdon and Susan C. Cork

3.3 Influenza viruses and their genomic characteristics

Avian influenza viruses are commonly found in wild waterfowl and frequently cause no clinical signs in these birds. However, the ecology of avian influenza viruses is complex and changes in viral genetic structure can result in increased virulence and enhanced risk of transmission from their natural reservoirs to other species. Although humans exposed to avian influenza viruses can become infected, in most cases this does not result in clinical disease unless the viral strains have become adapted to humans or the viral load is high enough to overcome natural levels of specific and non-specific immunity.

Influenza viruses are members of the Orthomyxoviridae family. These are enveloped viruses that contain a segmented single-stranded RNA genome. There are three genera of influ- enza virus: influenza type A, influenza type B and influenza type C. Influenza types A and C infect multiple species, while influenza type B almost exclusively infects humans. Only viruses of the influenza A genus are known to infect birds. Influenza A viruses (Plate 1) are typi- cally classified into different subtypes based on the antigenic properties and genetic sequences of their surface haemagglutinin (HA) and neur- aminidase (NA) glycoproteins. HA subtypes H1-16 and NA subtypes N1-9 are found in a wide range of avian species, whereas subtypes H17-18 and N10-11 are found in bats (To et al., 2014).

The two external glycoproteins are particularly important as the HA glycoprotein is responsible for virus attachment to the target cell, and the NA glycoprotein is needed for virion maturation and release (Hampson, 2002).

Wild birds have been found to be infected with all known subtypes of Influenza A viruses (Kawaoka et al., 1988; Alexander, 2000; Olsen et al., 2006). Water birds, including anseriformes (e.g., ducks, geese and swans, etc.) and charadri- iformes (e.g., gulls, terns, knots, plovers etc.), are recognized as the primary natural reservoirs of influenza A viruses (Webster et al., 1992; Olsen et al., 2006; Hurt et al., 2006; Krauss and Webster, 2010). Passerine birds (e.g., spar- rows, crows etc.) may also serve as reservoirs for avian influenza viruses but the low prevalence of infection in these birds suggests that they are primarily spillover hosts from avian influ- enza (AI) virus-infected poultry or water birds (Vandergrift et al., 2010). The importance of AI viruses in wild birds was not fully appreciated until the connection between viruses in these birds, outbreaks in poultry and the potential for the development of human pandemic strains was realized. Influenza virus transmission in wild and domestic animals and humans is inti- mately connected. Evidence suggests that viral transmission – particularly in domestic poultry with subsequent spillover to other domestic animals – may cause human pandemics.

For influenza A viruses to become highly pathogenic, the haemagglutinin glycoprotein that is produced as a precursor (HA0) requires post-translational cleavage by host proteases. The HA0 precursor proteins of low pathogenic strains of avian influenza (LPAI) have a single basic amino acid (arginine) at the HA0 cleav- age site but highly pathogenic strains (HPAI) contain a series of basic amino acids at the cleav- age sites of the HA0, which allows the virus to replicate widely in many tissues throughout the infected host resulting in severe disease and death (Rott, 1992; Stieneke-Grober et al., 1992;

Veterinary Public Health (VPH) was defined by the WHO consultation on ‘Future Trends in Veterinary Public Health’ held in Teramo, Italy in 1999 as ‘the sum of all contributions to the physical, mental and social well-being of humans through an understanding and application of veterinary science’ (www. who.int/zoonoses/vph/en).

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Integrating a One Health approach to avian influenza control in New Zealand 29

Walker et al., 1992). Therefore, sequences of multiple basic amino acids at the cleavage site of HA0, along with other virulence characteris- tics, can determine pathogenic properties of the virus. In most cases, only AIV subtypes H5, H7 and (more recently) H10 have been shown to cause serious disease outbreaks in susceptible poultry. However, H9 and other subtypes have also caused disease in cases where there are con- current infections in poultry flocks i.e. bacteria, mycoplasma, viruses etc. (Capua and Alexander, 2009).

Low pathogenic avian influenza subtypes H5 and H7 viruses are generally regarded as potential precursors of HPAI strains and their detection in a commercial poultry flock results in the implementation of disease control measures. At least two key mechanisms may contribute to the development of highly pathogenic strains: antigenic drift and antigenic shift.

Antigenic drift is a process of gradual accu- mulation of mutations (or insertion) primarily of HA and NA surface antigens. Mutations in other genes (PB2, PB1, PA and NS) also play an impor- tant role in virus pathogenicity (Hampson, 2002; Krauss and Webster, 2010; Neverov et al., 2014). The segmented genome of influenza virus (Plate 1) can also exchange segments if different strains co-infect the same host, which can lead to a new gene constellation and new virus. This process is called reassortment or antigenic shift. Most known major influenza epidemics in humans were the result of virus mutations caused by such reassortment events. This was the case for the 1957 (H2N2) and the 1968 (H3N2) pandem- ics, as well as for the swine flu in 2009 (H1N1) (Lindstrom et al., 2004; Bastien et al., 2010).

An important factor in the development of virulence is tissue tropism, i.e., the ability of the virus to attach to the host cell (Baigent and McCauley, 2003). Influenza A viruses attach to host cells by binding of the haemagglutinin (HA) protein to sialosaccharides on the host cell surface. The HAs of influenza A viruses

from different host species typically have dif- ferent binding preferences. Sialic acid (SA) is linked to different carbohydrates either by α-2,3 (SAα-2,3Gal) or α-2,6 (SAα-2,6Gal) glycosidic bond. The HAs of human influenza A bind pref- erably to SAα-2,6Gal whereas avian influenza HAs favor SAα-2,3Gal. The latter are prominent in avian species (Rogers and Paulson, 1983; Suzuki, 2005; Connor et al., 1994).

Therefore, the type and distribution of SA is considered to be an important factor in the sus- ceptibility of different host species to influenza A viruses and is believed to be one of the major factors preventing strains of AI crossing the species barrier (Suzuki et al., 2000).

Since all genes in the virus are linked to each other, any mutations in one gene, or any changes in gene constellations in the virus, will lead to the creation of a new virus subtype or differ- ent genotypes within a virus; for example, at least nine different genotypes of avian influenza H5N1 have been identified (Li et al., 2004).

3.4 Avian influenza in New Zealand

The first published report on avian influenza viruses (AIV) in New Zealand birds was a result of work conducted between 1975 and 1978 by researchers from the Medical Council of New Zealand Virus Research Unit. This group recog- nized the importance of influenza surveillance in wild birds in order to obtain information on the ecology of influenza A viruses and the influenza status of New Zealand’s waterfowl. Samples were collected from 286 birds (terns, gulls, shearwa- ters and mallard ducks) in Dunedin (Otago area, South Island) New Zealand. A number of AI viruses were isolated in this study but only from mallard ducks (Anas platyrhynchos, introduced to New Zealand by European and North American settlers from as early as 1860s). Isolates char- acterized included subtypes H1N3, H4N6 and H11N3 (Austin and Hinshaw, 1984). Such studies

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30 Wlodek L. Stanislawek, Thomas G. Rawdon and Susan C. Cork

provide important baseline data, which can be used to identify AI viruses currently in the country and to help predict the arrival or development of new strains in the future.

Two further surveys of wild birds were conducted by the Ministry of Agriculture and Forestry (MAF; now Ministry for Primary Industries, MPI) in 1989 (Stanislawek, 1992; Stanislawek et al., 2002). These studies focused primarily on mallard ducks (Anas platyrhynchos) and the first H5N2 AI low pathogenic influenza (LPAI) virus was isolated in 1997 (Temuka, South Island of New Zealand) in addition to H4N6 and H6N4 subtypes. In all these stud- ies, cloacal swabs were collected from ducks in various locations in the North Island and South Island of New Zealand.

Since 2004, MAF/BNZ has also carried out surveillance for AI on selected species of migratory birds (i.e., shorebirds crossing the Asia-Pacific flyway) and also resident birds (pre- dominantly mallard ducks) in response to the spread of strains of highly pathogenic avian influ- enza (HPAI) H5N1 around the world and with the potential for introduction of new avian influ- enza viruses to New Zealand. (Stanislawek et al., 2013).To date, more than 10,000 birds have been sampled from both islands of New Zealand (Plate 2a and b). Samples were collected from red knot (Calidris canutus), bar-tailed godwits (Limosa lapponica) and turnstones (Arenaria inter- pres) as the representatives of migratory birds and from mallard ducks (Anas platyrhynchos), paradise shelducks (Tadorna variegate), grey teal (Anas gracilis), black-billed gulls (Chroicocephalus bulleri), black backed gulls (Larus dominicanus), lit- tle blue penguins (Eudyptula minor), yellow-eyed penguins (Megadyptes antipodes), sooty shearwa- ters (Puffinus griseus) and wrybils (Anarhynchus frontalis) as representatives of resident birds of New Zealand.

New Zealand is not on the common migra- tion pathway for key species of waterfowl, although vagrant waterfowl from Australia are

occasionally encountered (Williams et al., 2004). Non-migratory waterfowl, predominantly mal- lard ducks, are sampled in the summer months throughout New Zealand, with a particular focus on coastal areas where they may have had con- tact with migratory shorebirds, or where large numbers of juvenile ducks congregate (Plate 2a). The absence of waterfowl migration substan- tially limits the potential of introduction of avian influenza viruses into New Zealand. Thus far, all New Zealand AIV isolates have been obtained from wild mallard ducks including subtypes: H1, H2, H3, H4, H5, H6, H7, H9, H10, H11 and H12. All nine neuraminidase types associated with these viruses were detected (Stanislawek, unpublished data). All the H5 and H7 isolates were pathotyped and confirmed to be LPAI based on the HA cleavage site assessment (Stanislawek et al., 2007; Langstaff et al., 2009).

Initiatives that build on the One Health concept and MPI’s commitment to stakeholder consultation and engagement included New Zealand’s commercial poultry surveillance pro- gramme (2008–2009) (Rawdon et al., 2010). These are important activities with regard to the government mandate to protect the ‘pub- lic good’ because AIV are potentially zoonotic diseases and disease prevention and control is a joint responsibility that requires both govern- ment and stakeholder support. In addition, New Zealand is a member of the international com- munity and the OIE, the latter requires regular disease surveillance for diseases such as AI that are relevant to trade.

The AI surveillance programme carried out in commercial poultry flocks in New Zealand required extensive consultation with the poul- try industry. This was in order to determine appropriate trigger-points for disease reporting and intervention and was important because of the potential financial and market access reper- cussions of any detection of AIV in commercial poultry. It was also important to agree on a com- prehensive communications plan for the public

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Integrating a One Health approach to avian influenza control in New Zealand 31

in order to reduce fear and unjustified concerns over food safety. The latter was especially impor- tant due to growing international concerns over the pandemic potential of H5N1 avian influenza strains and the wide, and often reactive, cover- age by the national and international media.

The poultry industry in New Zealand is considered small in comparison to many other developed countries. Approximately 16 million meat chickens (broilers) are present at any one time on about 170 farms across the country. Around 3.3 million layer hens are also present on around 150 commercial farms (with more than 100 birds per farm). Every year, there are also approximately 1.5 million ducks and turkeys in commercial flocks. Although most poultry pro- duction is for the New Zealand market, there is also a growing export market of hatching eggs, live one-day-old chickens and meat product to neighbouring countries (Kerry Mulqueen, pers. comm., 2015).

Active surveillance of all the key sectors making up New Zealand’s commercial poultry industry (for egg and meat production), includ- ing broiler, caged/barn layer, free range layer, pullet rearer and turkey broilers, was carried out using an epidemiologically robust cross-sectional design. An extensive serological survey found no evidence of antibodies to H5 or H7 AIV (i.e., OIE reportable subtypes) in commercial chickens or turkeys, indicating that there was no active infection with these subtypes. This provided evidence of good compliance with biosecurity practices in the poultry industry. However, the survey did identify evidence of historic exposure to LPAI subtypes on a single free-range layer farm (Rawdon et al., 2010). The latter identifies a potential risk pathway posed by free-range opera- tions. This is not unexpected and is most likely a result of contact with wild birds and sources of environmental contamination.

In addition to formal surveillance activi- ties, NCBID staff also developed a collaborative research project to examine birds in backyard

poultry farms adjacent to wetlands with water- fowl. This surveillance initiative included sampling of humans on the selected farms. During the study, interdisciplinary partners had to examine key research questions from a range of new perspectives and to deal with a wide range of stakeholders from both the public health and livestock sectors. The study was com- plicated due to the range of approvals required and the ethical compliance processes that had to be navigated on both the human and animal side as well as the need for confidentiality. Due to the potential concerns over finding AIV-positive birds and also the need to educate the public about disease risk, the Ministry of Health and MPI developed common risk communication plans. The studied farms were monitored for a year and staff gathered information on biosecu- rity practices, assessed risk pathways and looked for seasonal risk patterns. Research findings confirmed exposure of backyard flocks to LPAI viruses and the differential exposure-risk levels between chicken and duck flocks on these farms (Zheng et al., 2010). As well as encouraging the development of strong working relationships across the human and animal health sectors, findings from the research also identified key disease risk pathways such as direct contact with wild birds or use of drinking water contaminated with AIVs for both humans and poultry. With this in mind, an enhanced passive surveillance programme has been put in place to monitor bird disease and mortality events, for all bird populations in New Zealand, reported via MPI’s exotic disease reporting hotline.

The MPI hotline is a freephone number that allows immediate contact 24/7 with MPI telephone operators dedicated to direct- ing calls to on-call specialists including veterinarians, horticulturalists and marine biologists covering New Zealand’s primary

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32 Wlodek L. Stanislawek, Thomas G. Rawdon and Susan C. Cork

3.5 Avian influenza in humans

Avian influenza viruses have been reported to cause disease in humans as early as 1959. However, infection with avian influenza in humans was not really taken seriously as a global public health concern until 1997 when new strains of the H5N1 virus surfaced, causing 33 per cent human mortality in Hong Kong. Historically, the avian influenza subtypes involved in human infection, in addition to H5N1, were H6N1, H7N2, H7N3, H7N7, H7N9, H9N2, H10N7 and H10N8 (To et al., 2014). However, as demon- strated by the emergence of the H7N9 zoonotic strain in China in 2013, pandemic emergence remains a concern in the region and globally, and a new strain with the potential to infect humans could arise at any time. Given the complex biol- ogy of AI, and the difficulties in implementing effective biosecurity and effective disease control policy across developing countries, it is likely that surveillance for new and emerging AIV in ani- mals (especially in pigs and poultry) and humans will need to continue. ESR’s National Influenza Centre in Wellington, New Zealand conducts sea- sonal human influenza A and B diagnosis and also the capability to detect (using specific RT/PCRs and virus isolation) H5N1 and H7N9 viruses. The recent emergence of H10N8 AIV in China prompted ESR to develop appropriate PCR based assays to detect this virus if needed.

No human infections with avian influenza viruses have been detected in New Zealand to date (Sue Huang, pers. comm., 2014).

3.6 Pathways of introduction for AI viruses to New Zealand

The location of New Zealand as an island in the Pacific Ocean provides a high degree of natural biosecurity. However, a number of possibilities have been identified for the entrance of new AIV in to New Zealand, these are (1) migratory birds and vagrants; (2) contaminated export products or equipment; (3) people travelling; and (4) smuggling illegal live birds or products. New Zealand lies at the south-eastern extremity of the East Asian-Australasian Flyway, which was (and still is) of particular relevance for the intro- duction of novel AIV in the region, especially given the spread of H5N1 across Asia from 2004. The isolation of AIV from migratory shorebirds in Australia (Hurt et al., 2006) highlights the potential risk of introducing novel strains into New Zealand, but this presents a low risk path- way for New Zealand (Langstaff et al., 2009).

During the global spread of H5N1, wild bird surveillance activities were enhanced. However, because of New Zealand’s geographical isolation, relatively few Arctic-breeding migratory shore- birds actually reach the country. In total, about 200,000 birds representing 47 species arrive, but the vast majority of these comprise only three species: bar-tailed godwits, red knots and ruddy turnstones (Williams et al., 2006). Godwits are believed to fly directly to New Zealand, knots have stopovers in East Asia and turnstones have a number of stops in the Pacific before they reach New Zealand (Williams et al, 2006) (Plate 3). For these birds to introduce AIV to New Zealand, they would have to be infected before or during migration. On arrival, they could then shed the virus while cohabiting with endemic shorebirds, gulls, waterfowl and other species, and thereby introduce infection. However, sur- veillance carried out between 2004 and 2010 indicates that migratory birds pose a very low risk for the introduction of AI into New Zealand, as no AIV has been isolated from migratory birds

sectors. Bird events are sent to an on-call veterinarian who triages cases following a standardized approach, and follows up with appropriate sampling and testing in order to rule in or rule out suspected cases of AI and other exotic diseases (McFadden et al., 2007; Rawdon et al., 2007b).

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Integrating a One Health approach to avian influenza control in New Zealand 33

over the seven years of surveillance. Since 2011, New Zealand has focused on resident waterfowl mallard ducks (Stanislawek et al., 2013). Sample collection from wild birds is a very specialized procedure that requires the expertise of orga- nizations involved in studies of bird ecology, i.e., Department of Conservation (DOC), Fish and Game Councils and ornithological societ- ies in New Zealand. These organizations work together with MPI to share expertise and learn what can be expected in the event of sampling in an outbreak situation. Wild birds, particularly waterfowl such as mallard ducks, grey ducks, paradise ducks, geese and swans are the natural reservoir for AIV, and these water birds also are more likely to mingle with backyard poultry.

The increasing importation of products/ equipment and the movement of people (poten- tially infected with influenza viruses or bringing infected products, such as contaminated feath- ers and poultry products) dramatically increases the possibility of the introduction of influenza A viruses into New Zealand (Pharo, 2003). The human entry pathway is of particular relevance to pig herds given their susceptibility to human influenza viruses. The intensive management systems employed on pig farms also makes disease spread more likely if a new virus was introduced. Pigs are regarded as a ‘mixing vessel’ for influenza viruses because any co-infection of humans with human and avian influenza viruses may lead to the creation of new viruses with human pandemic potential (i.e., due to antigenic drift). Despite very rigid biosecurity procedures at airports and ports around New Zealand, the above are the most likely routes of introduc- tion of novel influenza viruses into the country. It also remains difficult to implement rigorous screening of human passengers for disease, although this has been attempted in the face of disease outbreaks such as SARS.

3.7 A governance framework for Avian Influenza response planning and delivery

The need to increase interdisciplinary coopera- tion between the key scientific and professional groups, such as human and animal researchers, conservationists, commercial poultry operators and relevant government ministries, in the man- agement of AI is well-recognized internationally. Due to the complex ecology and zoonotic poten- tial of AIV, avian influenza requires a One Health approach. Policies developed for the preven- tion and control of AIV also have to consider the potential disease risks to wild birds, this is especially important in New Zealand, which is home to many unique flightless birds (e.g., the kiwi (Apteryx spp.), takahe (Porphyrio hochstetteri) and kakapo (Strigops habroptilus) and some of the world’s most endangered species, including the black stilt (Himantopus novaezelandiae), Campbell island teal (Anas nesiotis) and orange-fronted parakeet (Eupsittula canicularis).

The Ministry of Primary Industries (MPI) looks after policy related to the forest, agricul- tural and fisheries sectors. MPI has expertise in risk assessment and in animal and plant health. The mandate of MPI also includes responsibil- ity for fisheries, wildlife and food safety. For avian influenza response planning, MPI engaged a two-tiered One Health team, comprising a multisectoral and multidisciplinary Technical Advisory Group (TAG), complemented by a similarly diverse Stakeholder Advisory Group (SAG). The approach separates the technical/ scientific aspects of disease prevention and response planning, from the consideration of the socioeconomic aspects that relate to the govern- ment responsibility to consider ‘public good’. The approach cements interdisciplinary relation- ships and helps avoids duplication and conflict of interest. The approach also helps ensure coor- dination and effective communication, under the complex setting presented by AI. Government

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34 Wlodek L. Stanislawek, Thomas G. Rawdon and Susan C. Cork

leadership of a response to AIV would be MPI in the case of an outbreak in poultry, but this lead would be handed over to the Ministry of Health in the case of an outbreak of AIV in humans. In either case, both ministries and other agencies such as the police, social services and emergency management would need to work closely with municipalities and the relevant stakeholders to deliver a timely well-coordinated response. There is no magic formula for the success of a One Health approach. Success requires strong governance, agreed goals, clear communica- tion and a common, unambiguous language. Importantly, these integral components have to be delivered within a framework of cooperation and partnership.

3.8 Development of a response policy for avian influenza

The basis for all biosecurity investigation and response in New Zealand is the Biosecurity Act 1993. Under the Act, the chief technical offi- cer is responsible for the overall management, coordination and leadership during an initial investigation and a response to an incursion of an exotic animal disease. A generic policy gov- erning an MPI response to risk organisms such as AI sets out MPI’s framework for response to organisms that could harm people, the environment, and/or the economy (Ministry of Agriculture and Forestry, 2008). The MPI’s Technical Response Policies for AIV of Regulatory Concern builds on this generic framework and principles and provides an overview of approved policies following interdepartmental, TAG, SAG and industry consultation (Ministry of

Technical decision-making and operational elements

The TAG is comprised of experts with scientific competencies such as virologists, epidemiolo- gists, biologists, ornithologists and veterinarians who review the context of the situation and the associated risks. The TAG reviews and recommends appropriate technical response man- agement option(s) to the chief technical officer (CTO). Along similar lines, the SAG is tasked with reviewing response management option(s) developed in consultation with the TAG in light of primary production/commerce, environment, social (including human health) and cultural values. TAG and SAG members are paid by MPI and sign a conflict of interest document for confidentiality and scientific impartiality throughout the advisory and review process.

The SAG is comprised of individuals with relevant skills and experience particular to AIV and its potential impacts, including policy advisers from the MoH and DOC and industry advis- ers from the Poultry Industry Association of New Zealand (PIANZ), Egg Producers Federation of New Zealand (EPFNZ), Ostrich and Emu Standards Council (OESC), Australasian Regional Association of Zoological Parks and Aquaria (ARAZPA), Game Preserves and the MPI Maori Strategic Unit with knowledge of Tikanga Maori (Maori customs). Tikanga Maori includes as a core value ‘Kaitiakitanga’, a term meaning guardianship, protection and preservation of Taonga. Taonga refers to all natural resources such as forests, rivers and lakes, plants and animals. Inclusion of Maori cultural input is critical when agreeing and implementing disease manage- ment approaches in New Zealand, given the potential affects any interventions may have on land, vegetation and protected animals.

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Integrating a One Health approach to avian influenza control in New Zealand 35

Agriculture and Forestry, 2006). Both the TAG and SAG were instrumental in the embedding and adoption of the Technical Response Policies.

Due to the complex disease ecology of avian influenza and the range of susceptible spe- cies (including humans), the policy sets out a matrix of response actions. As indicated earlier, a ‘whole-of-government’ response would be adopted for AIV strains affecting animals that could affect humans, such as H5N1 (Ministry of Agriculture and Forestry, 2011). In the event of this scenario, each agency has defined roles and has identified key documents and legisla- tion that could be relevant while controlling a pandemic (Howell, 2006, Rooney, 2008). On the other hand, a response to non-zoonotic strains would be led by MPI and managed within the MPI’s Memorandum of Understanding (MOU) on biosecurity activities between MPI and DOC, Ministry of Fisheries (now amalgamated with MPI) and the MOH (October 2006), and opera- tional guidelines developed between DOC and MPI (December 2008).

3.9 A foundation for poultry sector response preparedness

Due to the zoonotic implications, especially to poultry farmers and workers on both com- mercial and backyard farms, and because of the possibility of widespread disruption and economic impacts in the commercial poultry sectors, a number of broad collaborative proj- ects have been developed. These projects aim to fill gaps in knowledge around poultry farm loca- tions, bird types and numbers, and importantly the various husbandry, biosecurity and human health protection practices in place. Factors that could influence the potential disease trans- mission or exposure risk for farmers and farm workers, the farm’s poultry and other poultry farms connected by industry networks, were also assessed.

Initiatives included:

• an ongoing census of all commercial poul- try farms, with locations and bird types and numbers recorded online in Agribase – this ensured that farm locations and population demographics were immediately available in the event of an incursion (Sanson and Scott, 2003; Lockhart et al, 2010a);

• surveys of biosecurity practices, animal hus- bandry and human protective measures on commercial and backyard farms – important in understanding appropriate intervention points and modifiable behaviours to mitigate risk to other farms and humans from poten- tial AIV transmission pathways (Geale et al., 2006, p. 778; Lockhart et al., 2010a, 2010b; Rawdon et al., 2007a, 2007b, 2008, 2012a, 2012b; Zheng et al., 2010);

• studies of movement patterns of poultry and other conveyors in and between the commercial and backyard sectors – findings were incorporated into network analyses to understand which farms would be impor- tant contributors to disease spread, and how risk varied by season and across the coun- try (Lockhart et al., 2010b; Rawdon and Stevenson, 2011);

• development of a disease spread simulation model covering both the commercial and backyard sectors, that incorporated many of the population demographic and movement pattern parameters elucidated through the various other studies – outputs were impor- tant to understand likely spread scenarios and the contingency arrangements and resource requirements for a response to AIV (Rawdon and O’Leary, 2010; Stevenson et al., 2013).

The approach was designed to prepare New Zealand should exotic or emerging strains of AIV be detected, although the outputs would play an important role and prepare a strong foundation for resilience to any disease threat. Many of these

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36 Wlodek L. Stanislawek, Thomas G. Rawdon and Susan C. Cork

preparedness initiatives had their foundation in a cross-sector partnership approach across the human and animal health sectors. Learnings from poultry sector preparedness work in turn have had preparedness benefits for diseases in other livestock sectors.

3.10 Conclusion

The government response to avian influenza provides a good example of effectively applying the One Health approach in New Zealand. The preparedness activities and collaborative studies undertaken by human and animal health orga- nizations have provided a solid foundation for working together on other zoonotic diseases. This chapter demonstrates the value of a col- laborative and coordinated approach with many valuable opportunities for joint surveillance and response preparedness. The 2009 response to influenza A (H1N1) demonstrated the value to the human health sector of diagnostic and epidemiological expertise in the animal sec- tor, with MPI’s epidemiologists and response personnel working with the Ministry of Health and ESR, and laboratory scientists and technical staff working with ESR staff. This was possible because of the proximity of staff at NCBID and the key relationships in place that fostered effec- tive communication. This collaborative approach also allowed the sharing of resources and has built resilience due to enhanced information- sharing and cross-skilling. The latter is crucial in order to ensure sustainability of scientific and technical capability and capacity given the small population pool and remoteness of New Zealand.

Endnotes

1 www.oie.int/for-the-media/editorials/detail/article/ one-world-one-health.

2 www.biosecurity.govt.nz/pests/animals/ahl. 3 www.esr.cri.nz/capabilities/Pages/NCBID.aspx. 4 www.agresearch.co.nz. 5 www.asurequality.com.

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Integrating a One Health approach to avian influenza control in New Zealand 39

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chapter 4 Applying a One Health, multi-scale approach

to understanding and preventing zoonotic parasite transmission in urban ecosystems:

Echinococcus multilocularis and Alveolar echinococcosis in North America

Alessandro Massolo and Stefano Liccioli

4.1 Introduction

Echinococcus multilocularis is a parasitic cestode of the family Taenidae, and it is the caus- ative agent of alveolar echinococcosis (AE) in humans, a disease with a case mortality rate of up to 90 per cent when untreated (Craig et al., 1996).

Infection of humans occurs by accidental ingestion of parasite eggs through contaminated food or close interactions with infected domestic dogs (Salb et al., 2008; Vaniscotte et al., 2011; Massolo et al., 2014). According to a 2014 report of the World Health Organization (WHO) and the UN’s Food and Agriculture Organization (FAO), E. multilocularis represents the third

Abstract

Echinococcus multilocularis is an emerging zoonotic parasite of the family Taenidae, and it is the causative agent of alveolar echinococcosis (AE) in humans, a disease with a case mortality rate of up to 90 per cent when untreated. The natural cycle of the disease involves wild canids as definitive hosts and rodents that serve as intermediate hosts. Infection of humans occurs by accidental ingestion of parasite eggs through contaminated food or close interactions with infected domestic dogs. In this chapter we describe the complex transmission dynamics of E. multilocularis at the interface of wildlife, domestic animals, humans and the environment, focusing on the emerging situation in a North American urban setting. We describe key eco- logical and socioeconomic factors that affect parasite distribution and the subsequent risk for humans at different geographical (local, regional and global) and temporal (seasonal and pluri- annual) scales. We also present various parasite control and risk management options based on a hazard analysis and critical control point (HACCP) approach.

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Preventing zoonotic parasite transmission in urban ecosystems 41

most significant food-borne parasite worldwide (FAO and WHO, 2014). Alveolar echinococcosis is estimated to affect more than 18,000 people each year on a global scale, with more than 90 per cent of these cases recorded in China (Torgerson et al., 2010), but with increasing rates in Europe since the 1990s (Davidson et al., 2012; Deplazes et al., 2015). Effectiveness of medical treatment for AE has improved in recent decades, and the reduction of life expectancy due to AE in 2005 (2–4 years) is significantly improved from what was observed in the 1970s (reduction of 18–20 years) (Torgerson et al., 2008). However, AE is still a severe disease that requires long-term (often lifelong) and highly expensive medical treatment (McManus et al., 2003; Vuitton et al., 2011). This is aggravated by (1) the high inci- dence of the disease in areas of the world where public healthcare is limited (e.g., China) and many infected people might not have access to proper diagnosis (Torgerson et al., 2010; Hegglin and Deplazes, 2013); (2) the pathogen cannot be eradicated, and that control is costly and tempo- rary (Hegglin and Deplazes, 2008, 2013); and (3) the long latency (5–15 years) in human patients, which further complicates epidemiological studies (Craig et al., 1996).

In North America, besides the cases doc- umented in the historic AE hotspot of St Lawrence Island (Alaska) (Rausch and Schiller, 1954, 1956; Fay and Rausch, 1964; Rausch et al., 1990a, 1990b), only two other cases of AE were reported as being locally acquired, until the most recent finding in Edmonton, Alberta, Canada (Massolo et al., 2014). Even though E. multilocularis is quite widely distributed in North America and its prevalence can be fairly high in wild hosts, it is unclear why only few human cases have been discovered until now (Massolo et al., 2014; Jenkins et al., 2015).

Echinococcus multilocularis relies on a complex transmission cycle involving domestic or wild canids as definitive hosts and small rodents and few lagomorph species as intermediate hosts

(Figure 4.1). The cycle is primarily sylvatic (i.e., maintained by wild host species), but in some circumstances (e.g., China) domestic dogs can play a relevant role in spreading and transmitting the parasite (Moss et al., 2013).

The transmission ecology of E. multilocularis is determined by the predator–prey interactions between definitive and intermediate hosts that occur at various geographical and temporal scales. These complex interactions between host(s), the parasite and the environment affect the degree of environmental contamination and the sub- sequent disease risk for people (Giraudoux et al., 2003, 2007). From the very first cases of AE diagnosed in Germany in 1855 (Vuitton et al., 2011) to the most recent discovery of numerous human cases in a hyper-endemic area in rural China (Craig et al., 1992, 2000), it has become evident that the degree of human exposure also depends on a number of socioeconomic factors (e.g., hygiene, dog management, type of vegeta- ble cultivations; McManus et al., 2003; Torgerson et al., 2010). This can be particularly relevant in population dense urban settings (Liccioli et al., 2015a), where the proximity of the parasite to people and pets may further increase the risk of zoonotic transmission.

For these reasons, tackling E. multilocularis represents a challenge well-suited for a multidis- ciplinary, collaborative and coordinated approach. In the following study we illustrate the value of applying the One Health framework to protect the health of animals, humans and the environment.

This chapter aims to describe the complex system that characterizes the transmission dynamics of E. multilocularis at the interface of wildlife, domestic animals and humans, focusing on the emerging situation in North American urban settings. We will examine the key eco- logical and socioeconomic factors that affect parasite distribution and risk for public health at different geographical scales (local, regional and global) and various parasite control and risk management options will be explored.

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42 Alessandro Massolo and Stefano Liccioli

In addition we present a framework, based on a hazard analysis and critical control point (HACCP) approach at multiple temporal and spatial scales, to help develop risk mitigation options to prevent the potential emergence (or re-emergence) of this parasite in urban settings in North America.

4.2 Disease ecology

The lifecycle of Echinococcus multilocularis

Echinococcus multilocularis is a dixenous (i.e., requiring two hosts to complete its develop- ment) cestode that is typically maintained in a sylvatic lifecycle (Figure 4.1) involving wild and domestic canids (i.e., foxes Vulpes spp., coy- ote Canis latrans and wolf Canis lupus; domestic and sylvatic dogs) as definitive hosts, and small mammals (mainly rodents and pikas) as inter- mediate hosts (Eckert and Deplazes, 2004).

In the definitive host, adults of E. multilocu- laris develop in the small intestine. Eggs of the parasite are shed through the faeces into the envi- ronment, where they can be accidentally ingested by an intermediate host. After the eggs hatch in the intestine, the larval stage migrates to the tar- get organs and develop in to the cystic stage (i.e. metacestode). In intermediate hosts, the multi- plication of metacestodes causes a multivesicular and infiltrating structure that grows rapidly and brings the development of the infectious stages (protoscolices) in 2–4 months (Eckert and Deplazes, 2004). At advanced stages of infection, the larval mass may extend through a metastatic process from the liver (the main target organ) to other organs of the abdominal cavity (e.g., spleen, pancreas, gastrointestinal tract) and reproductive organs as the structure grows (McManus et al., 2003). The parasite completes its cycle when infectious intermediate hosts are ingested by the competent definitive host, i.e., canids. Humans typically act as dead-end (i.e., accidental) hosts,

Figure 4.1 Life cycle of Echinococcus multilocularis. Modified from Gesy et al. (2013).

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Preventing zoonotic parasite transmission in urban ecosystems 43

who acquire infection by ingesting parasite eggs through contaminated food (e.g., berries and vegetables), soil, or through direct contact with faecal material from infected dogs (McManus et al., 2003).

4.3 The ecology of Echinococcus multilocularis in North America

Given the broad latitudinal distribution of the parasite across North America (Gesy et al., 2013), wild hosts of E. multilocularis are very diverse depending primarily on the local preda- tor–prey communities. In the Northern Tundra Zone (NTZ) of Alaska and Northern Canada, the parasite is historically maintained in a cycle involving the arctic fox Vulpes lagopus and its prey species, such as the northern vole Microtus oeconomus, the brown lemming Lemmus sibiricus and the northern red-backed vole Myodes rutilus (Massolo et al., 2014). After the 1960s, parasi- tological surveys have progressively delineated a second area of distribution – the Northern Central Region (NCR) – which today includes up to 13 states in the USA (North Dakota, South Dakota, Iowa, Minnesota, Montana, Wyoming, Nebraska, Illinois, Wisconsin, Indiana, Ohio, Missouri and Michigan), the prairie provinces of Canada (Alberta, Saskatchewan and Manitoba) and most recently, British Columbia (see Massolo et al., 2014, for a review).

The parasite exists globally in 18 different strains or genotypes (Nakao et al., 2009; Massolo et al., 2014), two of which are considered charac- teristic of North America (N1, Tundra zone and Alaska; N2, Central region; Nakao et al., 2009). However, while two Asian mitochondrial haplo- types have been reported in St Lawrence Island, Alaska (Nakao et al., 2009), recent research has provided evidence of European haplotypes in wild hosts in Canada (British Columbia, Alberta and Saskatchewan; Jenkins et al., 2012; Gesy et al., 2014; Massolo et al., 2014). This finding

has potential consequences for public health (Jenkins et al., 2012; Massolo et al., 2014), given that genetic differences among strains are hypothesized to be associated with variability in development and pathogenicity of larval stages (Bartel et al., 1992).

In the ecosystems of the central region of North America, coyotes and red foxes are the main definitive hosts, while the deer mouse (Peromyscus maniculatus) and meadow vole (Microtus pennsyl- vanicus) are considered to be the most important intermediate hosts (Eckert and Deplazes, 2004), although other species may become locally rel- evant depending on habitat characteristics as is the case for the southern red-backed vole (Myodes gapperi) (Liccioli et al., 2013).

Scientific evidence is still needed to ascer- tain whether the range of the parasite in North America is actually expanding, or whether it has instead passed undetected in previous studies (Davidson et al., 2012). However, coyotes have dramatically expanded their range in North America (40 per cent expansion in the past 50 years; Laliberte and Ripple, 2004), and have become increasingly common in urban areas (Baker and Timm, 1998). Today, aside from human–wildlife conflict issues (e.g., coyotes are considered by some as nuisance animals due to predation on pets, and to safety and health issues; Gehrt et al., 2009, 2010). Their presence inside urban settings has become a potential concern with regard to their role in the circula- tion of E. multilocularis, especially in recreational areas highly utilized by people and their dogs (Catalano et al., 2012; Liccioli et al., 2014). Indeed, the growth of urban red fox populations in the 1990s have been linked to the increase of AE incidence observed in endemic areas of Europe such as Lithuania (Bružinskaitė et al., 2007) and Switzerland (Schweiger et al., 2007).

Several ecological factors influence the pres- ence and transmission dynamics of E. multilocularis in urban settings. Infection in definitive and inter- mediate hosts varies spatially within a region, with

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44 Alessandro Massolo and Stefano Liccioli

areas of low parasite occurrence interspersed with pockets characterized by high parasite prev- alence (Liccioli et al., 2014). Preliminary results suggest that local variations in the proportion of competent intermediate host species in the prey assemblage are significant in the development of foci of hyper-endemicity (Liccioli et al., 2014), thus further stressing the importance of consid- ering the entire range of available prey species (Giraudoux et al., 2003; Liccioli et al., 2015a; Baudrot et al., 2016), as opposed to approaches focused on the abundance of intermediate host population alone (Saitoh and Takahashi, 1998; Raoul et al., 2010). Habitat characteristics determining the local distribution and relative abundance of small mammal species influence the epidemiology of the parasite. Furthermore, infection rates of small mammal intermedi- ate hosts are reported to fluctuate temporally, in accordance with their population dynamics and seasonal variations of climatic conditions. Specifically, highest prevalence is documented during fall and winter (Liccioli et al., 2014), when the age structure of intermediate host pop- ulations is highly skewed towards adult classes (which had longer exposure to parasite eggs; Burlet et al., 2011) and the survival of parasite eggs in the environment is longer (Veit et al., 1995). Other factors possibly influence the epi- demiology of the parasite on a number of levels. At the individual level, host susceptibility may further increase the heterogeneity of parasite infection. At a landscape scale, the configuration and connectivity of natural patches within urban settings are likely to influence parasite transmis- sion (Liccioli et al., 2015a). Indeed, gradients in urban densities (e.g., high-density versus low- density residential areas) may affect habitat permeability to hosts (and parasite) movements within urban green areas (e.g., Adkins and Stott, 1998), and between city settings and surround- ing habitats (Beier and Noss, 1998). Similarly, urban landscape composition may affect the diversity of the host community, with important

consequences on the dynamics and resilience of parasite transmission (Giraudoux et al., 2007).

Although recent work has significantly advanced our knowledge of E. multilocularis in North America (Catalano et al., 2012; Liccioli et al., 2012, 2013, 2014, 2015b; Gesy et al., 2013, 2014; Klein and Massolo, 2015; Massolo et al., 2014), further research is needed to fully understand the ecology of this parasite in urban settings. In particular, future research efforts should focus on (1) the role of rural areas in the maintenance of the urban lifecycle of the parasite; (2) predator response to variations in small mammal assemblages; (3) differences in intermediate and definitive host susceptibility to parasite infection; and (4) the role of definitive host community composition and intra species competition.

4.4 Socioeconomic determinants of disease transmission

Although E. multilocularis is typically main- tained in a sylvatic lifecycle, the risk of zoonotic transmission can be highly dependent on social and economic factors (Rausch et al., 1990b; Craig et al., 1996; Vuitton et al., 2003). This likely explains why the highest incidence of AE is observed in the rural communities of the Tibetan plateau (China Autonomous Region), where financial resources are limited (per capita annual income < US$500; Budke et al., 2005b) and education and hygiene are poor (Craig et al., 1992). In these settings, domestic dogs can play an important role in the parasite lifecycle and are often the primary source of infection of humans (Craig et al., 2000; Budke et al., 2005a) due to their close contact with owners. Analogous socioeconomic conditions were found in the historically infected area of St Lawrence Island (Alaska), where the incidence of AE in humans during 1950–1990 was among the highest ever recorded in the world, ranging from seven to

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Preventing zoonotic parasite transmission in urban ecosystems 45

98 cases/100,000 inhabitants (Nakao et al., 2009; Rausch and Schiller, 1956; Rausch et al., 1990a, 1990b; Schantz et al. 1995). However, the situation is generally much different in the rest of North America, where only three locally acquired cases of AE have been described, with the latest occurrence documented in 2013 in an immunosuppressed patient in Alberta (Massolo et al., 2014). Although human cases seem to be generally very rare, lack of data and possi- ble misdiagnosis (Somily et al., 2005; Massolo et al., 2014) severely limit the current knowl- edge about the impact of AE in North America (Massolo et al., 2014).

At present, there is no reliable information available to assess the risk of human infection occurring through direct contact with domestic dogs exposed to the parasite within urban areas. Indeed, the only published study that evaluated the role of dogs in the circulation of E. multilocu- laris refers to a control programme conducted in St Lawrence Island (Rausch et al., 1990b). However, preliminary results available for the metropolitan area of Calgary, Canada, suggest that in urban parks – and hyper-endemic areas in particular – the infection risk in dogs is not negligible (Massolo et al., 2014).

4.5 Parasite control and management of risk

As the parasite’s natural reservoir is mainly represented by wildlife species, AE is consid- ered a not-eradicable disease (Ito et al., 2003), for which disease prevention is the most effec- tive solution (Hegglin and Deplazes, 2013). Frequent anthelmintic treatment of dogs – to be achieved through increased awareness of public and veterinary practitioners – certainly repre- sents one of the management strategies to be implemented at the individual and community level (Hegglin and Deplazes, 2013; Takahashi et al., 2013; Massolo et al., 2014). Locally, anthel-

mintic treatment of wild reservoir species (i.e., foxes) has achieved interesting results in Japan (Takahashi et al., 2013) and Europe (Hegglin and Deplazes, 2008, 2013), although only in the short term unless regular treatment is main- tained. Nonetheless, treatment of wild definitive hosts is still considered one of the few actions that could be undertaken to reduce the preva- lence and hence the subsequent risk of zoonotic transmission (König et al., 2008).

At a regional scale, landscape changes (e.g., deforestation) can have dramatic effects on wildlife population dynamics, host densities and parasite prevalence, and thus ultimately can influence parasite transmission dynamics. Although empirical data are available for high endemic areas of China and Europe (Giraudoux et al., 2003, 2007; Vuitton et al., 2003), such information has not been obtained yet for North America.

At a global scale, humans have a very impor- tant role in shaping the distribution of E. multilocularis. The presence in North America of genetic variants closely related to European strains (Gesy et al., 2013) could suggest that pet travel has had an influence on the globalization of the parasite (Davidson et al., 2012). If this is the case, further introduction of new strains of the parasite is possible unless preventive measures and regulation (i.e., mandatory anthel- mintic treatment of dogs imported from outside North America) will be established (Massolo et al., 2014).

4.6 Conceptual model of a One Health, multi-scale approach

The framework presented below is based on the hazard analysis and critical control points (HACCP) approach. HACCP (www.fda.gov/ Food/GuidanceRegulation/HACCP/default. htm), is based on a series of steps: (1) hazard analysis; (2) critical control points (CCPs); (3)

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46 Alessandro Massolo and Stefano Liccioli

critical limits; (4) monitoring procedures; (5) corrective actions; (6) verification procedures; and (7) record-keeping and documentation pro- cedures. Although more typically used in food safety quality control (FAO 1997; www.fao.org/ docrep/005/y1579e/y1579e03.htm), we have applied a modified HACCP to parasitic trans- mission excluding some of the typical steps in HACCP (6 and 7).

Ecological mechanisms and processes are spatially and temporally distributed. In this chapter we propose a multi-scale and tempo-

rally explicit approach for identifying hazards and critical control points to mitigate the risk of E. multilocularis transmission using the Calgary urban setting as a model.

We identify three key spatial scales (Figure 4.2):

1. Local (i.e., city, or district-wide). At this scale, different city parks may be characterized by different parasite prevalence in sylvatic hosts, thus affecting the risk for dogs to get infected during their off-leash activities and,

Figure 4.2 Spatial and temporal scales of corrective actions and monitoring of the critical control points for the

management of Echinococcus multilocularis infection risk. Modified from Catalano et al. (2012) and Torgerson

et al. (2010). Illustrations by James Butler; http://jamb-art.blogspot.co.uk. At a local scale, interventions in city

parks to reduce the prevalence in definitive hosts (baiting of wild canids and deworming of domestic dogs using

an effective anthelmintic) are to be conducted on seasonal or annual basis. At regional scale, deworming of dogs

and monitoring of human cases are the actions to be implemented in one to three years, whereas at global scale,

policy of deworming dogs that travel from areas of endemism (grey and dark grey areas) of different strains

should be developed and implemented in a medium-long timescale (10–15 years) to avoid the spread of the

different strains across the globe.

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Preventing zoonotic parasite transmission in urban ecosystems 47

consequently, for people to be exposed through their dogs.

2. Regional (i.e., provincial or regional). At this scale the parasite is distributed within the population or metapopulations of definitive hosts, and the processes of diffusion or inva- sion of allochthonous (i.e., originating in a different place) parasite strains may occur.

3. Global (i.e., continental and intercontinental). At this scale are the socioeconomic processes (e.g., wild and domestic canid mobility for trade or personal purposes) that facilitates invasions of allochthonous strains (or species) across or among continent/s.

We also identified critical time windows.

1. At local scale, most of the transmission among sylvatic hosts likely occurs in the win- ter (transmission from rodents to coyotes and potentially to dogs) and late summer (trans- mission from coyotes to rodents) seasons.

2. At regional and global scales, there is no spe- cific time at which the processes seem to occur, but monitoring should be carried out over several years to monitor the potential emergence of new human cases.

HACCP analysis: Calgary as a case study

Local scale

HAZARD IDENTIFICATION

At this scale the main hazard is the presence of infectious intermediate hosts that is directly related to their relative abundance (relative to the overall small mammal assemblage that coy- otes and dogs can prey upon) and affects the risk for coyotes and dogs to get infected.

CRITICAL CONTROL POINTS (CCPs)

Parasite prevalence in definitive and intermedi- ate hosts are typically correlated. As prevalence

in definitive hosts is much (10–100 times) higher than in intermediate hosts, the former should be used as critical control point.

CRITICAL LIMITS

• Winter/spring prevalence in coyotes (defini- tive host) in parks should be <40±5 per cent (i.e., significantly below average regional prevalence).

• Winter/spring prevalence in dogs (definitive hosts) should be ≤0.5 per cent (0/300 exam- ined dogs).

MONITORING PROCEDURES

Routine faecal collection of coyotes and dogs should be conducted in parks that are mostly used by owners to walk their dogs off-leash and that are used by resident coyotes during the win- ter and spring seasons. Faeces should be then submitted to screening for presence of Taeniidae eggs and positive cases submitted to further molecular analysis for species confirmation.

CORRECTIVE ACTIONS

At this scale, the interventions should be focused primarily on the main reservoir species (coyote), and on dogs that may act as a vector for the parasite into houses.

1. Deworming campaign:

a. Implement deworming of wild host canids with anthelmintic baits in the parks where prevalence in coyotes or dogs is above the critical limits.

b. Promote contemporary deworming of dogs at risk (walked off-leash and chasing mice) through information campaigns to dog-owners and veterinarians.

2. Enforcing dog management rules:

a. Be in control of dogs even when off-leash and impede them from predating/eating

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48 Alessandro Massolo and Stefano Liccioli

mice, as rodents affected by E. multilocu- laris are very likely to be preyed upon or found dead.

b. ‘Pick up after your dog’ to reduce spread of E. multilocularis eggs from dogs.

TEMPORAL SCALE

Anthelmintic baiting should be implemented just before and during winter, when most of the transmission to definitive hosts is known to occur in this ecosystem.

Monitoring of the status of infections in wild hosts should be: (1) implemented and carried out on a yearly basis during a single season (late winter–early spring) to optimize the likelihood to detect the peaks of infections in definitive hosts; (2) carried out consecutively for three years after the control campaign, and (3) if successful, carried out on a 3–4 years basis (cor- responding to a likely turnover of the resident population of urban coyotes).

KEY AGENCIES AND STAKEHOLDERS INVOLVED

Monitoring and corrective actions should be implemented by a local government agency (e.g., municipality) in collaboration with animal and bylaws services and Fish and Wildlife. The engagement of animal health professionals (i.e., Veterinarian Association) is key to promoting and implementing deworming and education campaigns.

Regional scale

At regional scale the priority is to keep the num- ber of human cases of alveolar echinococcosis locally acquired (i.e., not caused by infections acquired abroad) to zero. Implementation of per- sonal hygiene for at risk categories, in particular immuno-depressed patients, is key.

HAZARD IDENTIFICATION

Hazards that should be monitored include the ingestion of contaminated food (i.e., berries or

vegetables) and the presence of the European strain, which is known to be highly pathogenic for humans.

CRITICAL LIMITS

• The incidence of human cases of alveolar echinococcosis locally acquired should be equal to zero.

MONITORING PROCEDURES

Human patients that show undiagnosed hepatic lesions or anomalies should be tested for AE through immunohisto-chemistry testing and liver biopsies (histological and molecular diag- nostic tools). Monitoring immune-depressed patients is priority as they can be considered as sentinels of AE outbreaks in new geographical regions (Chauchet et al., 2014). Collaboration with the healthcare services is critical in this phase.

CORRECTIVE ACTIONS

• General public education campaigns on food- borne transmission and deworming of dogs for at-risk owner categories.

• Inform dog owners of the risk of travelling with dogs in highly endemic areas (e.g., Central Europe, Asia) and promote deworm- ing of dogs exposed to such strains.

TEMPORAL SCALE

Initially, continuous actions and monitoring should be implemented for a minimum of ten years, and follow-ups should be planned on a five-year basis.

KEY AGENCIES AND STAKEHOLDERS INVOLVED

State or provincial government/s should be engaged to promote education and information campaigns. The healthcare system/s should be engaged to prospectively monitor new cases and retrospectively investigate possible misdiag- nosed cases. Importantly, information sessions with health professionals (e.g., surgeons,

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Preventing zoonotic parasite transmission in urban ecosystems 49

diagnostic professionals, infectious disease spe- cialists) should be promoted.

At this level, veterinary associations can play an important role in educating customers on proper deworming practices. As with the healthcare system, information sessions should be promoted to inform the animal health profes- sionals of the new information available on the parasite.

Global scale

Invasion of allochthonous and potentially more pathogenic strains of E. multilocularis from Europe and Asia through dog movements (e.g., rescued dogs and owned dogs) is likely happen- ing or to happen (see Figure 4.2), as no policy is in place to impose deworming of dogs before travel (see Canada Food Inspection agency, www.inspection.gc.ca).

Regulating the translocation of potential hosts (e.g., dogs and foxes) is key for preventing the risk of introducing these new strains or new host species within new ecosystems and animal communities.

HAZARD

Introduction of allochthonous strains (or alloch- thonous species) of E. multilocularis that may have a higher level of virulence for humans.

CRITICAL LIMITS

No imported/travelling canids should be posi- tive for E. multilocularis.

CORRECTIVE ACTIONS

Implement a policy for deworming of canids when from areas with different strains of E. multilocularis.

MONITORING PROCEDURES

Imported canids should be randomly tested for E. multilocularis at their arrival to make sure the prevalence is below the critical threshold.

TEMPORAL SCALE

Continuous actions and monitoring should be implemented for a minimum of ten years, and follow-ups should be planned on a five- year basis. Implementation of new policies on mandatory of anthelmintic treatment on canids translocated from Asian or European endemic areas may take longer and so a longer timeline might be expected.

KEY AGENCIES AND STAKEHOLDERS INVOLVED

National and international agencies should be engaged (e.g., Canadian Food Inspection Agency, European committee), along with government and non-government agencies that assess the health risk and develop import health standards for dogs coming from endemic countries such as China and Europe.

4.7 Conclusions and recommendations

Recent research on the epidemiology of AE and the ecology of E. multilocularis worldwide has emphasized the value of undertaking sur- veillance studies aimed at detecting areas of higher risk for zoonotic transmission. From a management standpoint, field studies based on the collection and analysis of faecal samples col- lected from wild and domestic carnivores are invaluable, as they provide information on local environmental contamination (Deplazes et al., 2004). Sites with hyper-endemicity in wild hosts represent areas where intervention strategies could be attempted or prioritized.

Although very difficult to prevent, the risk of exposure to E. multilocularis can be reduced with simple interventions and by involving dif- ferent government/regulatory agencies and stakeholders. Mostly, education on food hygiene and deworming of dogs are the two key interven- tions that should be implemented at local and regional scales. At a more local scale, the critical

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50 Alessandro Massolo and Stefano Liccioli

intervention is reducing the level of infection in wild canids and domestic dogs. To achieve this, intervention should focus on deworming campaigns of local wild and domestic host popu- lations, as well as preventing dogs from at risk behaviours (i.e., chasing and predating upon mice). Field data identified fall and winter as the seasons during which infection of definitive hosts is more likely to occur, so baiting pro- grammes should ideally take place just before and during winter.

At a larger scale, the effects of translocations of domestic and wild hosts should be regulated and mandatory anthelmintic treatments imple- mented between areas where different strains are endemic. Current policies on the import and export of domestic dogs should be reassessed to include treating (with proper follow-up) for E. multilocularis.

At present, we believe that it is a priority to understand what the current incidence of human AE in North America is, and we recommend that regional authorities collaborate with research groups to conduct retrospective studies to assess the cases that have been misdiagnosed or simply not diagnosed (Somily et al., 2005; Massolo et al., 2014). Similarly, it is a priority to provide adequate information to animal and human health professionals to help prevent infections in dogs, and support early detection of human infections of alveolar echinococcosis.

Through this case study we wanted to illus- trate the importance of taking a One Health, multi-scale approach to identify and mitigate disease risks to humans associated with an emerging zoonotic parasite (Echinococcus multi- locularis). Identifying critical control points at different spatial and temporal scales to prevent disease transmission is a key component of an effective disease prevention and control pro- gramme. To implement such an approach, we need to engage a multidisciplinary team made of animal and human public health profession- als, experts in ecology, parasitology, veterinary

medicine, human medicine, as well as managers in charge of policy development and implemen- tation at local, regional and global scales.

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chapter 5 Mycobacterium tuberculosis in elephants

in Asia: taking a One Health approach

Susan K. Mikota, Gretchen E. Kaufman, Naresh Subedi and Ishwari P. Dhakal

5.1 Introduction

Tuberculosis (TB) is universally recognized as one of the most important and challenging diseases affecting the world today. It impacts both humans and animals and is found on every continent. Because of its ubiquitous nature, attempts to control or eradicate TB must utilize One Health principles to be most effective. In this chapter we will describe the case of tuber- culosis shared by elephants and humans in the country of Nepal, a country in the heart of Asia.

Tuberculosis (TB) is caused by bacteria in the genus Mycobacterium, which includes more than 100 species. Seven species comprise the major disease-causing mycobacteria and these are grouped together in the Mycobacterium tuberculosis complex (MTBC). Of the seven species, M. tuberculosis (the human form) and M. bovis (the bovine form) are of most concern for humans and animals.

Abstract

Tuberculosis is the leading cause of human death from a single infectious agent and has been designated a global public health crisis by the World Health Organization (WHO). The disease is endemic in many parts of South and Southeast Asia. There are a number of Mycobacteria known to cause tuberculosis in humans and animals, several are zoonotic, but M. tuberculosis is considered to be an obligate human pathogen with no known animal reservoirs. Animals that have close interactions with humans are known to have become infected with human strains. Tuberculosis in elephants is most often a result of infection with M. tuberculosis and has most often been reported in captive Asian elephants (Elephas maximus). Due to the complex ecol- ogy of the disease and the challenges of dealing with a ‘reverse zoonosis’ in a country where the disease is endemic in humans, it has been important to take a One Health approach to disease prevention and control. In this chapter we present a case study from Nepal.

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Mycobacterium tuberculosis in elephants in Asia: taking a One Health approach 55

5.2 Tuberculosis (TB) in humans

TB has been designated a global crisis by the World Health Organization (WHO) and is the leading cause of death from a single infectious agent. In 2013 there were an estimated nine million new TB cases and 1.5 million deaths worldwide (WHO, 2014). Of the nine million people who developed TB, 56 per cent were in the Southeast Asia and Western Pacific regions. TB in humans is a chronic, insidious disease spread by respiratory droplets dispersed during common behaviours such as coughing and sneez- ing. Symptoms include fever, chills, weight loss, chest pain, night sweats and coughing blood. Of the two billion people estimated to be infected worldwide, approximately 10 per cent will develop active disease; in most cases the body’s immune system is able to sequester the infection and prevent it from spreading.

In humans, a positive finding on a tuber- culin skin test (TST) or acid-fast stain (AFS) is typically followed by a chest radiograph and a sputum culture to confirm a diagnosis. Mycobacteria are in a group of microorganisms (including nocardia, rhodococcus and some protozoa) that are highlighted when stained by acid-fast techniques such as Ziehl-Neelsen. This technique is not specific for mycobacteria and a positive stain could indicate the presence of any of these organisms. Isolation of the organ-

ism is the ‘gold standard’ to diagnose TB and facilitates drug sensitivity testing and correct antibiotic selection. However, in much of the developing world where the TB burden is high and laboratory capacity may be lacking, the AFS is the major test used. If the AFS test is positive, treatment is initiated according to standard pro- tocols. Some of the tests used to diagnose TB are listed in Table 5.1

5.3 Tuberculosis (TB) in animals

While M. tuberculosis is an obligate human patho- gen with no known animal reservoirs (Comas et al., 2013), various related strains of TB affect a wide range of mammalian species. M. bovis (bovine tuberculosis or bTB) is more common in non-human mammalian species than M. tuber- culosis; domestic cattle are the natural reservoir. Bovine TB also affects humans and significant efforts have been put in place in most developed countries to eliminate bTB from domestic cattle. Recent spillover of M. bovis from cattle into wildlife has become a serious problem and is threatening conventional bTB control methods and sanitary policies. Affected species include badgers (Meles meles) in the UK, white-tailed deer (Odocoileus vir- ginianus) in the US, brushtail possums (Trichosurus vulpecula) in New Zealand, Cape buffalo (Syncerus caffer) in South Africa, and wild boar (Sus scrofa) in Spain (Fitzgerald and Kaneene, 2013).

In contrast, TB in elephants is most often a result of infection with M. tuberculosis, the human strain, and has most often been reported in captive Asian elephants (Elephas maximus). One case has been reported in a wild African ele- phant that had previous human contact (Obanda et al., 2013) and one case has been reported in a wild Asian elephant (Perera et al., 2015). In elephants, signs of TB are often absent until the disease is quite advanced. Elephants have never been truly domesticated and, like other wild animals, tend to mask signs of disease as a

Table 5.1 Diagnostic tests for TB

Direct tests* Indirect tests**

Culture Tuberculin skin test

Acid-fast stain ELISA

Nucleic acid amplification tests (PCR)

Serology

Gamma-interferon assays

* Direct tests detect the TB organism ** Indirect tests detect antigens or antibodies or measure cellular reactivity against TB antigens

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56 Susan K. Mikota, Gretchen E. Kaufman, Naresh Subedi and Ishwari P. Dhakal

survival strategy against predators. Weight loss is the most common sign observed in elephants; dyspnoea (difficulty breathing) may also occur in advanced cases. In some cases, elephants died of other primary causes although TB was also detected during post-mortem examination.

The diagnosis of TB in elephants is compli- cated by their large body size, which precludes performing chest radiographs. In addition, the TST commonly used in people and in cattle is not an accurate test for many non-cattle species, including elephants (Mikota et al., 2001; Gavier- Widen et al., 2002; Lewerin et al., 2005; Moller et al., 2005). A trunk-wash procedure (comparable to obtaining a sputum sample from humans) has evolved as the preferred method to collect respi- ratory samples from elephants for culture (Isaza and Ketz, 1999; Abraham and Davis, 2008), however, the sensitivity is low and negative trunk-wash culture results are not uncommon in infected elephants (false negative). In an out- break among elephants in a Swedish zoo, only seven of 189 trunk-wash samples collected over time were culture positive from five elephants with confirmed TB at necropsy (Moller et al., 2005); similar findings were reported in a study conducted in Thailand (Angkawanish et al., 2010). Intermittent shedding, contamination, overgrowth by other bacteria and difficulties with obtaining a sample from the lower respira- tory tract through the long trunk may account for some of the discrepancies.

Commercial serological tests that detect antibodies against the TB organism have been developed for a variety of domestic and wild species. These assays vary in accuracy but have demonstrated surprising sensitivity and speci- ficity in elephants (Greenwald et al., 2009; Lyashchenko et al., 2012).

5.4 Tuberculosis (TB) is a zoonotic One Health disease

Various strains of mycobacteria have a pre- ferred reservoir host, but are shared across the mammalian species. Recent molecular studies have shown that TB has been co-evolving with humans for tens of thousands of years and that animal-adapted TB strains diverged from human strains before the Neolithic Demographic Transition, the period when humans transi- tioned from a hunter-gatherer dominated to an agricultural lifestyle (Comas et al., 2013; Anon., 2008; Wirth et al., 2008).

The zoonotic transmission of TB (usually M. bovis) is well-documented and occurs through ingestion of infected material or direct contact with an infected animal. Transmission of M. tuberculosis and M. bovis from humans to dogs (Erwin, 2004), cattle (Ocepek et al., 2005) and wild animals (Michel et al., 2003; Fritsche et al., 2004) has also been documented.

Evidence suggests that M. tuberculosis may also move back into humans from an infected animal (e.g., human to elephant and back to human). Staff TST conversions are common following the diagnosis of TB in an elephant in a zoo or private facility, although most are not reported in the scientific literature. In one case, the same strain of TB was found in an elephant handler and three elephants at a private facility but the direction of transmission (elephant-to-human or human-to-elephant) could not be determined (Michalak et al., 1998). More definitive support for elephant-to-human transmission was demon- strated by an epidemiologic investigation of a TB outbreak at the Elephant Sanctuary in Tennessee in which nine staff members had skin-test con- versions (Murphree et al., 2011). Although the exact mode of transmission is unknown, in this case it was thought to be due to aerosolization from high-pressure cleaning. Human skin-test conversions have also been reported in other out- breaks involving elephants and chimpanzees (Pan

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Mycobacterium tuberculosis in elephants in Asia: taking a One Health approach 57

troglodytes) (Stephens et al., 2013), a rhinoceros (Diceros bicornis) and three Rocky Mountain goats (Oreamnos americanus) (Oh et al., 2002).

5.5 Why tuberculosis (TB) matters for the conservation of elephants in Asia

Asian elephants (Elephas maximus) are an endan- gered species. They have been listed on Appendix I of the Convention on Trade in Endangered Species of Wild Fauna and Flora (CITES) since 1975. Accurate data on the number of wild Asian elephants is lacking; the most recent figures esti- mate that ~43,000 elephants remain in the 13 range countries (Fernando and Pastorini, 2011). The vast majority of wild elephants are found in India and Sri Lanka; five countries have less than 200 elephants (see Table 5.2). Figures on the numbers of Asian elephants in captivity are also lacking.

Asia has one of the highest rates of human TB in the world (WHO, 2014). Currently, the bur- den of TB in wild and captive elephants in Asia is unknown. The case study in Nepal described below illustrates the challenges of managing TB in captive elephants and mitigating the potential impact on the conservation of this endangered species.

5.6 Nepal Case Study

Nepal has a population of approximately 30 mil- lion people; 45 per cent are infected with TB and 5,000–7,000 people die from the disease every year (National Tuberculosis Center, 2014). The National Tuberculosis Center and the Nepal Anti-tuberculosis Association (NATA) are the two main TB agencies.

Of the 400 laboratories in Nepal capable of diagnosing TB using AFS, only three perform cultures and only two have the capability to perform drug susceptibility testing. The latter is critical in managing drug-resistant infections. In 1996, Nepal instituted a Directly Observed Therapy Short Course (DOTS) programme in which healthcare workers observe patients tak- ing their medications to ensure compliance with treatment (see Plate 4). Multidrug resistance is a significant problem with estimates of 2.9 per cent in new cases and 11.7 per cent in recurrent cases (Poudel et al., 2013).

Nepalese people live in close proximity to domestic animals. Most of the meat consumed in Nepal is from buffalo and goat; cows are sacred among the largely Hindu population and are neither consumed nor euthanized if found to be bTB reactors. However, milk consumption is common and pasteurization of milk, which would prevent transmission of TB, is not uni- versally practised. In one study, 24 per cent of TB-positive Nepalese commonly consumed raw milk (Pandey et al., 2012).

Thus far, in the cases where culture has been performed, the causative agent of TB in elephants in Nepal has been M. tuberculosis, how- ever, elephants are at risk for infection with M. bovis due to intermingling with domestic cattle and buffalo.

Table 5.2 Asian elephant range countries

Bangladesh* Malaysia

Bhutan* Myanmar

Cambodia Nepal*

China* Sri Lanka

India Thailand

Indonesia Vietnam*

Laos

* countries with less than 200 wild elephants

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58 Susan K. Mikota, Gretchen E. Kaufman, Naresh Subedi and Ishwari P. Dhakal

History of the Nepal elephant healthcare and TB surveillance programme

Tuberculosis was first diagnosed in captive ele- phants in Nepal in 2002 (Gairhe, 2002). Between 2002 and 2009, a total of seven captive elephants died due to TB; several were valuable govern- ment patrol elephants in their prime (Pradhan, et al., 2011). Captive elephants in Nepal are used to patrol the national parks and other pro- tected areas and for conservation, research and tourist activities, which brings them into close proximity to wild elephants, rhinoceros and other TB-susceptible species. Wildlife officials in Nepal were concerned that TB could spread from captive elephants and threaten these wild populations.

In 2006, a comprehensive elephant TB screen- ing programme was conducted in the Chitwan district by a team of US and Nepalese veteri- narians, technicians, veterinary students and wildlife officials. A battery of tests – including culture and several commercial and experi- mental serological assays – were used to screen 120 elephants. Based on the results, elephants were assigned to one of four risk groups (high, moderate, low and undetermined) and manage- ment recommendations for each group were made to government authorities (Mikota et al., 2015).

The following year, Elephant Care International (ECI), and the Institute of Agriculture and Animal Science established a fellowship for a graduate veterinarian to continue monitoring the elephant population for TB. A workshop was held with key stakeholders during which the 2006 results were reviewed and a TB Action Plan was drafted. World Wildlife Fund (WWF) Nepal and ECI were awarded funding from the United States Fish and Wildlife Service (USFWS) Asian Elephant Conservation Fund in 2008 to con- tinue the TB work. Efforts were directed toward constructing a segregation stable, conducting

TB testing of all mahouts (elephant caretakers), continuing surveillance of elephants and initiat- ing treatment. A field office and small laboratory was established at the National Trust for Nature Conservation (NTNC), a local NGO, to provide a home for the elephant TB programme.

Building on the TB Action Plan drafted at the 2007 workshop, partners continued to develop a comprehensive written plan to man- age TB in Nepal elephants with input from the Department of National Parks and Wildlife Conservation (DNPWC), WWF-Nepal, NTNC, international wildlife veterinary consultants and representatives from the human medical community in Nepal. In 2011, as part of Nepal’s Elephant Action Plan, the Nepal Elephant Tuberculosis Control and Management Action Plan (2011–2015) (NETCMAP) was approved by the government of Nepal, Ministry of Forests and Soil Conservation, Department of National Parks and Wildlife Conservation (DNPWC, 2011). The Plan outlines methods to diagnose, treat and manage TB in elephants in Nepal.

The overarching goals of the Plan are to elimi- nate TB in captive elephants and any staff that work closely with them, to prevent transmission to the wild and to safeguard tourism, an impor- tant source of revenue for Nepal. The strategy to achieve these goals includes instituting and enforcing a sustainable testing, segregation and treatment programme for captive elephants and their handlers, and preventing TB-suspect or infected elephants from entering Nepal. The day-to-day activities of the Plan are managed by a veterinarian who is employed by NTNC with financial and technical support from international agencies.

NETCMAP and the programme that sup- ports it is managed by DNPWC in collaboration with NTNC, WWF-Nepal, the Buffer Zone Management Committee (BZMC) and Hotel Association Nepal (HAN), Chitwan Chapter. The complete Plan is available online (see supplementary materials).

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Mycobacterium tuberculosis in elephants in Asia: taking a One Health approach 59

Testing methods and sampling strategy

The cultures that were performed on trunk- wash samples collected in 2006 from elephants in Nepal were non-diagnostic due to contamina- tion, storage and transportation issues and did not yield any MTBC isolations from either the National TB Center in Nepal or the National Veterinary Services Laboratories in Ames, Iowa, USA (Mikota et al., 2015). Because of the known limitations of culture as a primary diagnostic technique, a decision was made by the One Health team to prioritize serological results in developing the management group algorithm. Improving culture and PCR methods remained a goal and the NETCMAP includes instructions for the collection of respiratory samples for culture and research.

The ElephantTB Stat-Pak test was licensed in the US as a screening test for elephants, in 2006; the DPP VetTB® test was not licensed until 2012. However, at the time that the NETCMAP was written, the DPP had been used as a research tool in Nepal for several years and positive results had correlated with confirmation of infection by culture in several elephants that had died. The DPP was therefore incorporated into the testing algorithm (see Plate 5).

Overview of management groups

Four management groups were established.

• Group 1 TB-free includes elephants that were non-reactive on the ElephantTB Stat-Pak test. These elephants were screened every other year with no segregation or work restrictions.

• Group 2 TB-suspect includes elephants reactive on the ElephantTB Stat-Pak assay and non- reactive on the DPP VetTB® test. There are two options for elephants in this group: (1) initiate prophylactic treatment; or (2) repeat

the DPP test in six months. If the DPP is reactive at this time, the elephant changes to Group 3. If the DPP remained non-reactive, the elephant is tested annually with the DPP.

• Group 3 TB-infected includes elephants that are reactive on both the ElephantTB Stat-Pak and DPP VetTB® tests and/or from whom MTBC organisms have been identified using culture or molecular techniques. The NETCMAP describes protocols for segregation, treat- ment and post-treatment monitoring (see Plate 6).

• Group 4 Untested includes calves not yet trained for blood collection and elephants that have recently entered Nepal.

The complete testing algorithm can be viewed in the NETCMAP in the supplementary materials.

Management recommendations

The NETCMAP document describes specific activities including programme management, testing, preventing the entry of infected ele- phants into Nepal, criteria for participation in elephant events, segregation, treatment, grazing practices, dung disposal, post-mortem examina- tion, human screening and education. Some of these topics are discussed in more detail below.

Testing

The NETCMAP outlined the following guide- lines for testing:

• All captive elephants in Nepal will be TB tested every one to two years.

• Any elephants purchased or hired from out- side of Nepal will be tested within 30 days prior to arrival.

• Procuring elephants from outside of Nepal is discouraged.

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60 Susan K. Mikota, Gretchen E. Kaufman, Naresh Subedi and Ishwari P. Dhakal

• The TB Plan veterinarian will have the author- ity to test (or retest) new elephants upon arrival in Nepal.

• All elephants participating in events such as elephant races or polo must have a current non-reactive test or have completed treatment.

All the captive elephants in Nepal have a TB programme number and are entered into a data- base that tracks changes in ownership. Most elephants are microchipped, so follow-up has not been a problem in Nepal. This may not be the case in other countries where elephants fre- quently change owners and are given new names.

Segregation

Segregation was designated to be an important management tool and segregation of infected elephants from wild elephants and other spe- cies (especially rhinoceros) was a stated priority. Segregation rather than treatment was considered to be an acceptable alternative for aged elephants.

Treatment

The detailed treatment regimens described in the NETCMAP are based on the protocols established in the Guidelines for the Control of Tuberculosis in Elephants developed in the US (Anon, 2010; also see supplementary material). TB drug dosages, methods for direct oral or rec- tal administration, monitoring during treatment and management of potential side-effects are described in detail (see Plate 7).

Minimizing tuberculosis transmission between humans and elephants

A strategy for minimizing the risk of disease transmission between humans and elephants

was implemented as an ‘integrated TB manage- ment programme’. This includes conducting further research and surveillance to better under- stand the ecology of TB across the environment and instituting measures to reduce the risk of transmission. All elephant handlers and any other staff working in close proximity to ele- phants are to be tested annually; new employees are to be tested before starting work. Workers testing positive must complete four weeks of treatment before working again with elephants. Family members of positive individuals will also be tested and treated as determined by public health agencies. TB testing and TB medications are available at no charge in Nepal through government programmes.

In addition, the Plan specifies the develop- ment of a TB education programme to minimize risk for elephant handlers and others that come into contact with elephants, including tourists. This programme includes basic information on the disease, how it is spread, and appropri- ate biosafety practices that should be practised to minimize the possibility of transmission. Handlers of known infected elephants are given additional training and appropriate personal protective gear by the programme.

The programme staff was charged with dis- tributing information for tourists and tour agencies about the Nepal Elephant Tuberculosis Control and Management Action Plan and to assist commercial enterprises to cooperate with the Plan without major disruption to their busi- ness. A certification programme was planned in which local elephant tourism agencies and owners could display a certificate of participa- tion in the programme. Subsequent follow-up efforts have introduced reduced working hours and diet diversification for working elephants to support overall health, minimize stress and improve immunity.

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Mycobacterium tuberculosis in elephants in Asia: taking a One Health approach 61

5.7 Discussion

Tuberculosis is a complicated disease. Even after decades of efforts by international governmen- tal and non-governmental agencies, it remains one of the most serious global disease issues for humans.

Worldwide, captive elephants are used by people – as draft animals, for processions, in temples, for entertainment in circuses and for education and conservation in zoos. The inher- ent stigma and fear associated with TB has implications for the owners of captive animals. Upon learning that his elephant has TB, a private owner may sell his elephant to an unsuspecting buyer. Commercial operations such as circuses may experience a loss of revenue from public fear. Stakeholders may lobby against regulations that impact animal movement and business. Perhaps the worst-case scenario would be for infected elephants in range countries to be released into the wild, suffering an untimely death and putting wild animals at risk.

In Nepal, as in many other Asian countries, there is intermingling between humans, domes- tic livestock and elephants and other wildlife. We know elephants are at risk for human TB but sharing grazing land with cows and buf- falo may also put them at risk for bovine TB. If wild elephant bulls breed with infected captive cows, TB could be transmitted to wild elephants. Infected elephants can also pose a risk to other wildlife such as rhinos (see Plate 8).

Nepal was the first Asian elephant range coun- try to acknowledge a TB problem in elephants and to take a proactive approach to address that problem. The collaboration between DNPWC, WWF-Nepal, NTNC, IAAS, ECI, the human health agencies and others was instrumental in developing both the programme and the policy that resulted. Continued collaboration will be important as this programme is updated.

Challenges and next steps

The programme is slowly transitioning to a self- sustaining model and as surveillance continues, it is anticipated that there will be fewer cases. The management of TB in elephants in Nepal and enforcement of the NETCMAP has not been without challenges. Many of these are outlined in the Plan itself and include insufficient tech- nical and managerial capacity, and insufficient financial resources.

There is not always financial and political support to address TB in elephants in a country where TB in humans is still an overwhelming issue. It is expensive to treat an elephant for TB. In Nepal, the private elephant owners have, for the most part, been responsible for the cost of treatment medications for their infected animal; funds to treat government-owned elephants have been provided from international sources. Although sceptical at first, the private own- ers have come to realize the importance of the programme and its benefits.

Although the documented elephant TB cases have thus far been due to M. tuberculosis, the risk of infection with M. bovis is unknown. The lack of a TB control programme for domestic species and lack of data regarding prevalence complicates assessing the risk for elephants.

Since 2007, four Nepalese veterinarians have been employed as the TB programme veterinar- ian. During their tenure, two completed Master’s degrees on TB-related topics and two of them are now pursuing PhDs overseas. Another has recently completed a Master’s programme on herpes virus infection in elephants and a fourth veterinarian is in a One Health Epidemiology Fellowship programme. The Nepal Elephant Healthcare and TB Surveillance Program has provided knowledge and skills that have enabled these talented individuals to qualify for higher educational opportunities. It is anticipated that these individuals will return to Nepal as the next generation of conservation leaders. The

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62 Susan K. Mikota, Gretchen E. Kaufman, Naresh Subedi and Ishwari P. Dhakal

turnover has, however, been challenging for the continuity of the programme.

Measures that enable early detection and prevention of elephant-to-human and human- to-elephant transmission of TB have not been fully realized. While the importance of personal protection has been presented to elephant care staff, it remains a difficult issue. Face masks certified to be protective against TB are not read- ily available in the country, and cooperation to wear personal protective equipment is often lacking except during post-mortem examina- tions. From a logistical standpoint, wearing a mask for long periods of time in a high-tem- perature, high-humidity climate may not be practical, and masks are not always worn even in human medical facilities that care for human TB patients. Policies requiring routine testing of people that maintain close sustained rela- tionships with working elephants have been implemented within government operations, but have not been completely addressed in the private sector.

The government, specifically DNPWC, can be credited with instituting and enforcing policies such as restricting test-positive elephants from participating in large events where elephants intermingle (such as elephant polo, races and festivals), despite limited staffing and resources. However, planned measures to significantly limit new cases, such as certification and systematic testing of elephants entering the country, espe- cially in the private sector where elephants are often hired seasonally and move back and forth between Nepal and India, have not yet been implemented.

Other challenges that have confronted the programme include accessibility of elephants for testing. Government elephants are moved between (often remote) posts and veterinary access has at times been limited. The pro- gramme is slated for regular review and renewal. Many of the challenges will have to be addressed in future iterations of the action plan and

continued efforts to successfully engage the private sector will need to be strengthened.

Importance of a One Health approach

TB is a classic One Health disease affecting humans, domestic livestock, and wildlife in an ever-narrowing interface. Because of the zoo- notic implications, a One Health approach is essential to investigate and manage TB when ele- phants are involved. A diagnosis of TB can evoke fear and concern among humans, especially in developed countries where it is less common, but also in heavy burden countries where it may have personal implications for elephant owners (income loss) or mahouts (job loss) in addition to personal health concerns. When TB occurs, engaging partners early on and maintaining open communication with stakeholders (which may include the public) are critical to a successful outcome.

Outbreaks that have occurred in zoos and other facilities have demonstrated how collab- orative efforts between zoo staff and local or sometimes national health service agencies can effectively address epidemiological, screening, treatment, public relations, and other issues (Oh et al., 2001; Stephens et al., 2013; Murphree et al., 2011).

One Health initiatives have evolved in Nepal in recent years. One such initiative involved the collaboration of organizations in Nepal, the UK and the US and was spearheaded by NTNC and the Zoological Society of London. It targeted the conservation areas and the buffer zones of the Terai and Himalayas with the aim of integrat- ing the human, livestock, wildlife and ecosystem health systems at the interface between envi- ronment, species and multi-host diseases. The Nepal Elephant Healthcare and TB Surveillance Program is an obvious fit for this initiative and is now managed under this One Health umbrella.

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Mycobacterium tuberculosis in elephants in Asia: taking a One Health approach 63

5.8 Conclusion

• TB is a complicated disease in elephants with political as well as medical challenges.

• Nepal is the first Asian elephant range coun- try to address this problem.

• The Nepal programme has succeeded and is ongoing because stakeholders and partners were brought together early and open com- munication was maintained.

• When working in another country it is impor- tant to engage with local wildlife officials and other stakeholders to fully understand the situation from their perspective and to be aware of limiting factors that may impact the development of viable solutions.

• Veterinary and human health authorities working together with shared goals and a common plan are a formula for success.

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Supplementary materials

Guidelines for the Control of Tuberculosis in Elephants 2008, www.aphis.usda.gov/animal_welfare/down- loads/elephant/elephant_tb.pdf

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chapter 6 Leptospirosis: an emerging health

issue in the Asia-Pacific region

Julie M. Collins-Emerson, Jackie Benschop and Stanley G. Fenwick

6.1 Introduction

Leptospirosis is a globally distributed zoonotic disease that is particularly common in the warm, wet conditions found in tropical and subtropi- cal climates (Hartskeerl et al., 2011). It is caused by the spirochaete Leptospira. There are cur- rently 21 recognized species of Leptospira divided

into approximately 300 serovars (KIT, 2014). A number of species are either classified as non- pathogenic or indeterminate in nature (Levett and Haake, 2009). Dual systems of classification are used; one serological, the other based on DNA sequence information. Both schemes have their uses; however, there is little correlation between them, with serologically closely related

Abstract

Leptospirosis (also known as Weil’s disease, field fever and rat catcher’s fever) is a neglected zoonotic disease caused by spirochaete bacteria in the genus Leptospira. It is considered both an emerging and a re-emerging disease. Up to 13 different species of Leptospira can cause disease in humans and these can be transmitted by both wild and domestic mammals. Most mammalian species can be infected with Leptospira; however, some serovars are bet- ter adapted to certain host species, including wild rodents and farm livestock. Leptospira are typically shed in the urine of the infected host(s), contaminating the environment and sub- sequently acting as a source of infection for other animals, including humans. In parts of the developing world, the disease most commonly occurs in farmers and in the urban poor, who live in cities with poor sanitary conditions, and outbreaks frequently follow flooding events. In most of the developed world it more commonly occurs in people whose work or recreational pursuits involve spending time in wet areas or on rural land where cases of the disease still occur in livestock. Due to the complex and dynamic ecology of this zoonotic disease, it has been valuable to take a One Health approach when dealing with outbreaks of leptospirosis. In this chapter we present contrasting case studies from New Zealand and Asia to highlight the need for a transdisciplinary approach to investigation, prevention and control.

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66 Julie M. Collins-Emerson, Jackie Benschop and Stanley G. Fenwick

serovars often falling into more than one lepto- spiral species by DNA classification.

Most mammalian species can be infected with Leptospira (Faine et al., 1999), however, some serovars are better adapted to certain host species than others. In such cases Leptospira can cycle within this host population, which acts as a reservoir for the organism. The Leptospira colonize the kidneys and are shed in the urine, contaminating the environment and subse- quently infecting other animals. Where a serovar is adapted to the host, the disease may be mild or sub-clinical in nature and colonization of the kidneys followed by urinary shedding may be for extended periods of time (Levett and Haake, 2009). In farmed animals this may result in reduced fertility, including abortions, and in suboptimal growth. In less benign serovar/host combinations, the disease is more severe and can be fatal. As the host–serovar combination mark- edly affects the presentation of the infection, it is sometimes helpful to consider leptospirosis as a collection of diseases.

Due to the difficulties in diagnosing the dis- ease both clinically and in the laboratory, and the fact that this zoonosis is prevalent in devel- oping countries where resources are stretched and surveillance is either poor or absent, the true burden of leptospirosis globally is difficult to ascertain. The most recent global incidence estimate is 1.03 million cases with 58,900 deaths annually, with tropical regions of South and Southeast Asia, Central and South America, Western Pacific and Africa having the highest burdens (Hagan et al., 2013). Leptospirosis is a widespread, neglected disease and one that is both emerging and re-emerging (Hartskeerl et al., 2011).

Leptospirosis can be difficult to diagnose clin- ically as symptoms can mimic other diseases and it is therefore easily misdiagnosed. In domestic animals leptospirosis is commonly sub-clinical. In humans, disease can be mild (anicteric) or severe (icteric), with the classic Weil’s disease

being severe and often resulting in jaundice and death. Laboratory diagnostic tests present chal- lenges as different tests are more suitable at various stages of the disease. Although culturing is a gold standard for a definitive diagnosis, there are limited windows of opportunity for cultur- ing the organism from various tissue samples. The use of the host’s serological response for diagnostic purposes can also present difficulties when the host is infected with a well-adapted serovar and a strong serological response may not be mounted. The limitations of different tests and the choice of test made at different stages of the disease mean that the disease often can go undiagnosed.

Changes in agricultural land use, human pop- ulation growth and associated increased urban densities, plus the pressure this places on the zones where human and wildlife populations interface and where climatic changes are trending to the more extreme, all contribute to the dynamic nature of leptospirosis. The increasing frequency of severe weather events associated with changes in climate, such as cyclones and associated flood- ing, has resulted in outbreaks of leptospirosis in countries such as Nicaragua, Honduras, Fiji and the Philippines. Also, while vaccination pro- grammes can decrease the prevalence of some serovars, this may create an opportunity for other serovars to gain a foothold or for there to be a change in the predominant host reservoir. Given the complex interactions between such factors, the prevalence and distribution of vari- ous leptospiral serovars and leptospirosis status worldwide is not static. This dynamism is evi- denced by a number of examples such as the rise in severe pulmonary haemorrhagic syndrome seen in South America (Gouveia et al., 2008), newly emergent serovars in American Samoa (Lau et al., 2012) and even in some genomic changes in the bacterium. The reduced size of the L. borgpetersenii sv. Hardjo (bovis) genome when compared to other serovars is speculated to repre- sent increasing host adaption coincident with the

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Leptospirosis: an emerging health issue in the Asia-Pacific region 67

shedding of genes used mainly for survival in the environment (Bulach et al., 2006).

Integral to the control or management of leptospirosis is the recognition of the interre- latedness of human, animal and environmental health, a concept encompassed by the terms ‘One Health’ and ‘ecohealth’. To highlight how the interaction of human, animal and environ- mental conditions influences the epidemiology of the disease, two case studies contrasting the different situations in regions of Asia-Pacific will be examined: New Zealand, with a temperate cli- mate; and SE Asia, where the climate is tropical.

6.2 Case study 1: Leptospirosis in New Zealand – a global disease but a local phenomenon.

New Zealand comprises two main islands that are geographically isolated and situated in the southern Pacific Ocean. Its remoteness con- tributed to it being the last significant land mass to be colonized with the first Polynesian peoples (NZ Māori) estimated to have arrived in significant numbers from around 1300 ce. In addition, it has resulted in a unique native fauna. New Zealand has only two native land mammals; both of which are bats. The ecologi- cal niches that are usually occupied by mammals in other parts of the world were instead filled in New Zealand by birds, a number of which are flightless. The first exotic mammals to arrive were rats (R. exulans) and the Polynesian dog brought by Māori. Europeans began to arrive in numbers from the very early 1800s and with their settlement came the introduction of production animals such as sheep, cattle, pigs, goats, additional domestic dogs and cats and other introduced mammals such as deer, the Australian possum, the European hedge- hog, weasels, stoats and mice. This history has resulted in an unusual situation where there is a very restricted number of pathogenic Leptospira

serovars known to be endemic in New Zealand, (L. interrogans serovars Pomona, Copenhageni and L. borgpetersenii svs. Balcanica [possum vari- ety], Ballum, Hardjo[bovis] and Tarassovi) all of which have arrived with mammals imported relatively recently and many that are domestic. Human leptospirosis in New Zealand is primar- ily associated with direct or indirect contact with livestock, which act as the largest reservoir for the bacteria. This is a very different situation to that in many other parts of the world where there are large numbers of leptospiral strains circulating in wildlife populations and spilling over into domestic stock and into the human population. This contrast will be explored more fully in the following section that discusses leptospirosis in SE Asia.

New Zealand is a sparsely inhabited coun- try of approximately 4.5 million people with large areas (~40 per cent) developed for pasto- ral farming of mainly beef and dairy cattle, and sheep, with commercial deer farming introduced in the late 1970s. The first documented case of leptospirosis in New Zealand was identified on a dairy farm in the South Island in 1951 where calves and six dairy farm workers contracted the disease (Bruere, 2003). The outbreak was attrib- uted to serovar Pomona. Leptospirosis continued to be mainly dairy or pig industry-associated until a national vaccination programme (bi- valent Pomona/Hardjo vaccine) was introduced at the beginning of the 1980s. This saw a cor- responding dramatic decline in reported cases of leptospirosis. Mild cases in people can mimic influenza and hence it frequently goes undi- agnosed or misdiagnosed. It is still the most commonly notified, non-foodborne zoonosis in New Zealand and the country has the high- est incidence of the disease in humans in the Organisation for Economic Co-operation and Development (OECD).

As much primary produce is exported, the NZ farming sector has become very respon- sive to market forces in the past few decades.

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68 Julie M. Collins-Emerson, Jackie Benschop and Stanley G. Fenwick

Initially, commercial deer production was very lucrative and these farms tended to carry deer solely but over time, as the profit margins declined, many farmers changed to mixed-spe- cies farming with combinations of sheep, cattle, and deer. Government subsidies that bolstered the rural sector ceased in 1984, resulting in marked changes in farming practices. A formerly strong focus on wool production shifted to that of producing more lamb meat. A boom in dairy profitability since the 1990s has seen a consider- able shift from dry stock farming to dairying and has also been responsible for the large numbers of dairy herds being transported from the North Island across the Cook Strait to the South Island to establish new dairying regions. To enable this conversion, large areas of more arid land in the South Island required irrigation and this has had a considerable impact on the environment. A reasonable conjecture is that the introduction of cattle to these areas and the augmented mois- ture levels in the top layers of soil may well have increased the environmental loading and also improved the survival times of Leptospira in this region. The transport of herds between the two main islands presented additional opportunities for Leptospira to cross to the South Island either in the cattle host or possibly via rats stowed away on stock trucks. Finally, these factors – plus climatic changes that have occurred in this time, including overall warmer weather and extreme weather events becoming more frequent – are thought to have contributed to a change in the epidemiology of leptospirosis in New Zealand. A change in the prevalence of leptospirosis in various stock classes has been observed in the past few decades. Research carried out in the late 1970s to early 1980s demonstrated a titre preva- lence (titre cut point > 48) in mixed-aged sheep averaging 20.5 per cent for Hardjo and 4 per cent for Pomona. The very low rate of successful isolation of leptospiral cultures from sheep kid- neys was interpreted by the authors as indicating sheep were likely to be sporadically infected by

Leptospira with cattle being the primary hosts (Blackmore et al., 1982). More recent serosur- veys, however, indicate that sheep either are or have now become reservoir hosts for Hardjo and Pomona (Dorjee et al., 2008). Deer are also very commonly infected with approximately 75 per cent of herds showing evidence of Hardjo and about 15 per cent with evidence of Pomona infections. Leptospirosis is also highly prevalent in beef cattle (>50 per cent) and approximately 30 per cent of dairy herds were found to be shed- ding in a recent survey (Heuer et al., 2012).

Given sheep, beef cattle and deer are nowadays more frequently run on mixed-species farms, it has raised the question as to whether this prac- tice has influenced the changing epidemiology of the disease in New Zealand. One area of cur- rent research is aimed at determining whether there are host-adapted strains of these Hardjo and Pomona or whether it is the same strain of each serovar freely circulating between the various stock classes. The answer is of impor- tance as it will significantly influence the disease management strategies in New Zealand.

The microscopic agglutination test (MAT) has been widely utilized as a diagnostic tool in New Zealand with DNA-based technology more recently included. Given the restricted number of serovars circulating in New Zealand and their particular serogroup affiliations, cross-reactivity between closely related serovars is not the sig- nificant issue found in many other countries and serological results are comparatively reliable regarding the identity of the infecting serovar.

In New Zealand, the majority of pork pro- ducers house their pigs. The introduction of serological testing of grower herds and vacci- nation programmes for breeding herds saw a dramatic decline in leptospirosis in commercial pig farms (Heuer et al., 2012). In addition, a certificate of Leptospira-free status is required by abattoirs before stock is accepted for slaugh- ter. These practices have resulted in few human cases now linked to commercial pig farming.

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Leptospirosis: an emerging health issue in the Asia-Pacific region 69

The changes in New Zealand farming prac- tices from the early 1970s to 2014 (as discussed previously), possum and rodent control pro- grammes, increased urbanization, population growth and extreme climatic events could be expected to have influenced the dynamics of leptospirosis in the wildlife population. A sub- stantial body of research involving serological surveys and the collection of field isolates from wildlife was conducted in the 1970s and early 1980s. However, current information is lack- ing. There is some evidence that carriage of serovar Copenhageni is no longer restricted to the brown rat (R. norvegicus) populations in the north of the North Island but has drifted south, possibly abetted by mass dairy cattle stock truck movements. Conversion of farming areas from cropping to dairy has also in some cases resulted in additional boundary areas where native bush, which supports wildlife, now interfaces with dairy cattle farms, thus creating opportunity for new infection pressures. Another round of com- prehensive research investigating the current status of leptospirosis in New Zealand wildlife is now warranted to inform the understanding of the present day epidemiological landscape.

The demographics of human infection have also changed since the 1970s in that the inci- dence, serovar prevalence and the occupations most associated with the disease have altered. Traditionally, human infections in New Zealand were caused predominantly by serovars Hardjo (contact with cattle) and Pomona (contact with pigs) and infections, particularly with serovar Hardjo, were mostly anicteric. As mentioned previously, the introduction of vaccination programmes in the dairy and pork industries cor- related with a sharp decline in reported human leptospirosis cases in New Zealand. A gradual shift has been observed where human cases are increasingly associated with both farm and abat- toir workers. In 2013, of the 59 notified human cases, 22 worked in the meat processing indus- try and 18 were in farm-associated occupations

accounting for approximately 71 per cent of the cases (ESR, NZ, 2013). Another noted change is the rise in the comparative incidence of the predominantly rodent host serovar, Ballum. In 2011 there were as many human cases of Ballum infection as there were for serovars Hardjo and Pomona (ESR, NZ, 2011). This statistic may have been a result of fewer Hardjo and Pomona infections or indicate a change in the predomi- nant host or the dynamics between the serovars circulating. For example, vaccination pro- grammes against one serovar may create a niche that can be then filled by another serovar. In New Zealand, acute human leptospirosis often pres- ents similarly to influenza (headache, myalgia, chills, fever, nausea) and thus is grossly under- or misdiagnosed. However, more severe cases result in hospitalization and may lead to kid- ney and liver damage and meningitis. Humans rarely transmit the disease between themselves so, given this, humans can be viewed as ‘senti- nels’ signalling changes in the epidemiology of the disease dynamics in New Zealand.

Given New Zealand’s small exposed human population, it would not be financially viable for a company to make a leptospiral vaccine for human use. Furthermore, social acceptance of such a vaccine would be low as management of leptospirosis is viewed primarily as the respon- sibility of the livestock industry, as this is the main source for human leptospirosis. Prevention or management of human infection is therefore inextricably linked to the infection status of the country’s farm animals. The complex interde- pendence between the environment, domestic animals, humans and wildlife requires a col- laborative One Health approach to address the problem. Presently, effective stock vaccination programmes are a key component in prevent- ing or mitigating human leptospirosis in New Zealand.

A One Health approach is evidenced in a functional synergy between medical and vet- erinary experts working in clinical practice,

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70 Julie M. Collins-Emerson, Jackie Benschop and Stanley G. Fenwick

district health boards, universities and labora- tories in New Zealand. This is likely a result of the country having a centralized government, only one veterinary school, two medical schools and a general awareness of the importance of biosecurity and zoonotic diseases. New Zealand embraced a One Health approach to understand- ing zoonotic disease risks in the early 1980s with the establishment of the Veterinary Human Health Advisory Group under the auspices of the Ministry of Health – Centre for Disease Control, with members from multiple agen- cies and disciplines from government, academia and the private sector. Current synergistic work on leptospirosis includes joint investigations, publications, research proposals, projects and submissions on policy documents. An example of this multidisciplinary approach is a research proposal on persistent leptospirosis symptoms led by a veterinary epidemiologist and molecular biologist, with the research team comprising a public health epidemiologist and physician, an occupational physician, a clinical psychologist and an economist. Translation of science into policy is further evidenced by the recent (2012) adoption of Polymerase Chain Reaction as a laboratory confirmatory test by the Ministry of Health, the use of local scientific publications to inform Accident Compensation Commission policy (2014) and consultation with scientists in the production of Best Practice Guideline for the Prevention and Control of Leptospirosis for Worksafe NZ (2014).

Beyond scientific collaboration there is also deeply embedded community engagement around this disease that, both in its acute and chronic forms, has had a significant effect on rural communities. An exemplar of this engage- ment is the relationship between a community group representing farming interests and a uni- versity research group. The community group has supported research by fundraising to provide stipend support for university postgraduates and to source funding for leptospirosis research in

sheep and cattle, resulting in the production of a video for farmers on leptospirosis and in the development and maintenance of a leptospirosis website.

6.3 Case study 2: Leptospirosis in South East Asia – a re-emerging disease in an endemic area

In contrast to the situation in New Zealand, where there are limited serovars and a strong link between human disease and farm animals, leptospirosis in SE Asia involves a differ- ent epidemiology. Although the disease has been recognized for many years in the region, research has been limited and publications have been largely related to the description of clinical cases. Much of the early literature on leptospirosis came from Malaysia, with the first report of human cases being recorded in 1925 (El Jalii and Bahaman, 2004). Case reports were increasingly documented in the 1950s and 1960s in China, Malaysia and the Philippines, and by military doctors in Vietnam in the 1970s, with a large variety of serovars identified, most linked to rodent reservoirs. In the 1990s, other coun- tries in SE Asia began to progressively report and describe cases of leptospirosis. The disease is thus considered endemic in the region, with multiple wild animal reservoir hosts, but little understanding of the dynamic relationships between domestic and wild animals, humans and the environment exists.

Nevertheless, despite the longstanding endemnicity of leptospirosis in the region, the dis- ease is considered to be re-emerging, with severe outbreaks being recorded in Thailand, Malaysia and the Philippines in the past decade (Amilasan et al., 2012; Lim, 2011; Thaipadungpanit et al., 2007). In these countries exposure to contami- nated water, whether by occupation (e.g., rice farming); outdoor recreational activities, such as the Eco-Challenge Race in Malaysia (Sejvar et al.,

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Leptospirosis: an emerging health issue in the Asia-Pacific region 71

2003), which included activities such as kayak- ing, swimming, and caving; or through extreme climatic events causing flooding, such as typhoon Ketsana and tropical storm Parma that hit Manila in the Philippines in 2009), have been strongly linked to disease outbreaks. Additionally, in Thailand an outbreak was linked to the emer- gence of a particular dominant leptospiral clone (Thaipadungpanit et al., 2007). Two of these above scenarios will be explored in greater depth later in this chapter.

The annual incidence in SE Asia is high, at >10 cases per 100,000 population, during outbreaks and in high exposure risk groups this figure can reach >100 cases per 100,000 (Victoriano et al., 2009). Nevertheless, the true incidence of leptospirosis is likely to be under- reported due to poor healthcare systems in many countries in the region and the plethora of other infectious diseases with similar symptoms (den- gue, malaria, scrub typhus) (Hartskeerl et al., 2011).

One similarity between the epidemiology in New Zealand and SE Asia is that a large majority of infections are considered to be occupational in origin. However, the occupational risk profiles differ in the two areas. In New Zealand, infec- tions are largely linked to agricultural practices, with abattoir workers and farm workers most at risk, whereas in SE Asia the predominant risk group is people engaged in rice farming, where working barefoot in paddy fields is common and thus exposure to contaminated water is unavoidable. The serovar distribution and clini- cal disease picture are also markedly different from the situation in New Zealand, with a far wider spectrum of serovars, commonly associ- ated with rodent hosts, causing clinically more severe infections and mortalities in the SE Asia region. Little evidence for links between animal production and leptospirosis exist in SE Asia, with only a limited number of studies carried out in southern Vietnam and Thailand into the role of pigs and other farm animals as poten-

tial reservoirs of infection (Boqvist et al., 2005; Suwancharoen et al., 2013). Not surprisingly in these studies the serovars identified were also similar to those found in rodents in other sur- veys. So until further investigations are carried out, the domestic animal involvement in the epidemiology will remain unconfirmed.

In the humid tropics, leptospires survive for long periods outside the host in water contami- nated by animal urine, increasing the chances of infection of those in contact. Thus, as with rice farmers, other occupational and non- occupational groups who come in contact with contaminated water in SE Asian countries also regularly contract leptospirosis. Additionally, the disease in Asia is often associated with extreme climatic events (likely exacerbated by global warming), in particular flooding, with outbreaks following seasonal flooding events commonly reported from many countries in the region (Mendoza et al., 2013; Niwetpathomwat et al., 2005). In Malaysia and Thailand, ecotourism activities such as endurance running and river rafting have also resulted in cases of leptospiro- sis (Chusri et al., 2012; Sejvar et al., 2003) and in Malaysia survival training of army recruits at a number of rural training centres has resulted in infections and deaths (Lim et al., 2011).

In the following section, two scenarios men- tioned earlier in this chapter will be expanded to demonstrate a range of factors involved in the re-emergence of leptospirosis in SE Asia.

6.4 A prolonged outbreak of leptospirosis in Thailand linked to a dominant clone of Leptospira

Until 1995 the number of recorded human cases of leptospirosis in Thailand remained relatively low and stable, varying between 50 and 275 per year, and an annual incidence rate of 0.3/100,000 population (Tangkanakul et al.,

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72 Julie M. Collins-Emerson, Jackie Benschop and Stanley G. Fenwick

2005). Between 1996 and 2003, however, a huge increase in infections was noted, with a peak in 2000 of 14,285 cases, which, given the dif- ficulty in diagnosing the disease, is probably an underestimate. In 2000 the incidence rate was 23.7/100,000 population and the case fatality rate peaked in 1999 at 4.4 per cent. Notable epi- demiological and demographic features of the disease showed that it had a distinctive seasonal, occupational and gender association over this period (1996–2003). The leptospirosis season was consistently from June to December, with a peak in September–October, which is the rainy period in Thailand. Eighty per cent of cases were seen in male farmers, 15–45 years old, who are regularly exposed to rat urine and urine-contam- inated water. Prior to the epidemic in 1996, the male-to-female ratio was as high as 30:1 in some areas. However, this decreased annually from the start of the epidemic to a low point of 3:1 in the 2000–2003 period. Nevertheless, the majority of cases were still seen in agricultural workers.

The epidemic started in Nakhon Ratchasima province in the north-east of Thailand, preceded by a period of flooding, and by 1999 had spread to 64 provinces in the north-east, north and cen- tral regions of the country out of a total of 76 in the country. At the peak of the outbreak in 2000, the highest incidence was seen in the north-east provinces with a rate of 50 cases per 100,000 population recorded.

Evidence from isolates recovered between 2000 and 2005 showed that a single dominant clone, Multilocus Sequence Type ST34 of serovar Autumnalis, was responsible for the majority of human infections in the northeast province of Udon Thani and other parts of Thailand (Thaipadungpanit et al., 2007). This was supported by another study of Leptospira isolates recovered during the periods 2001–2002 and 2011–2012, with Autumnalis the major serovar identified in both periods (Thipmontree et al., 2014).

Rodent surveys for Leptospira have been car- ried out since the 1960s and have commonly

shown a high prevalence of infection, up to 66 per cent, with serovars the same as those causing human illness. During the outbreak, surveys of rodents were carried out in affected areas and a high prevalence of Leptospira infection was dem- onstrated in a number of species. To determine whether a link could be identified between ST34 and a maintenance host, eight isolates available from rodents captured in northeast Thailand were characterized. Seven strains (from B. indica (6) and B. savilei (1)), were L. interrogans serovar Autumnalis ST34. This confirmed the predomi- nance of the outbreak strain in a maintenance host, which in this case appears to be the bandi- coot rat (Bandicota indica), commonly found in rice fields throughout Thailand (Tangkanakul et al., 2005; Thaipadungpanit et al., 2007). It was also noted that an increased incidence of infected rats was seen during the rainy season, corresponding to an increase in human cases. Surveys of domestic animals performed in the same period showed a high seroprevalence for Leptospira, but with less obvious serovar compatibility with human infections.

Risk factors for leptospirosis were studied by Tangkanakul et al. (2000) and a strong asso- ciation was seen with walking through water, applying fertilizer, ploughing or removing rice shoots for more than six hours per day. The fac- tors contributing to the outbreak, however, are still largely speculative. These include chang- ing farming practices, climatic and ecological changes, increase in rodent numbers and a raised awareness of the disease in farmers and physicians following publicity and educational campaigns resulting in more notifications. While these could all have played a part, it is thought unlikely that they would have resulted in the dra- matic increase in human infections from 1996 to 2000. Thaipadungpanit et al. (2007) have sug- gested that the introduction of a more bioactive strain, serovar Autumnalis ST34, with a selec- tive advantage in the maintenance host (leading to a higher bacterial load and increased urinary

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Leptospirosis: an emerging health issue in the Asia-Pacific region 73

shedding) and a survival advantage in the exter- nal environment, such as increased resistance to desiccation, could have triggered the outbreak. The gradual decline in reported incidence since the peak in 2000 could be due to a number of factors including the promotion of safe prac- tices, such as the use of protective footwear and clothing, increased use of laboratory testing and early treatment of mild fevers with doxycycline (Tangkanakul et al., 2005; Thipmontree et al., 2014).

6.5 Occupational and recreational risk factors for leptospirosis in Malaysia

To date, 38 Leptospira serovars have been iso- lated in Malaysia from humans and animals. Infections have been observed in military per- sonnel at rural training centres and the disease is recognized as an occupational hazard for people engaged in agricultural and mining activities. Studies have reported a high enzootic incidence in the domestic animal population (Bahaman et al., 1987; El Jalii and Bahaman, 2004). Outdoor recreational activities have also been associated with leptospirosis in Malaysia, with one of the largest outbreaks reported among participants of an Eco-Challenge race in Sabah in 2000 (Sejvar et al., 2003). Three hundred and four athletes took part in the ten-day endurance race, which involved jungle trekking, kayaking, swimming, caving, climbing and mountain-biking. Many of the athletes became ill on returning home, prompting a public health investigation. Eighty athletes met the case definition for leptospiro- sis, with 26 of those hospitalized. Risk factors for the disease included kayaking, swimming in the Segama River, swallowing river water and caving. A number of athletes had taken doxy- cycline during the event and this was identified as a protective factor. Only one positive culture was acquired, and L. weilii was identified, a spe-

cies only recovered previously in SE Asia. One possible reason for the high attack rate was the weather, with high rainfall for several months before the event and heavy rain during the event. In addition, athletes all reported cuts and abra- sions that may have made them more prone to infection. Since this outbreak, a number of other reports have documented leptospirosis in endurance racers, kayakers and other athletes and recreational groups, and thus leptospirosis needs to be recognized as a cause of fever and illness by public health professionals treating returning travellers who have engaged in these activities.

Other individuals engaged in outdoor rec- reational activities in Malaysia have also been affected by leptospirosis. In 2010, six people died after exposure to contaminated water in a recre- ational park near Maran in Peninsular Malaysia. Subsequent investigations found leptospires in water in a recreational lake in Sibu, Sarawak and in a nearby National Service Training Centre (NSTC), resulting in some camps suspending water activities and to the temporary closure of several centres (Lim et al., 2011). In 2011, eight people who had been involved in searching for a drowned boy at a recreational area in eastern Malaysia died of leptospirosis and melioidosis co-infection as a result of exposure to contami- nated water (Sapian et al., 2012). Further cases associated with swimming in recreational water parks were documented in the northern state of Kedah, prompting the closure of several pic- nic areas while investigations were carried out. As Malaysians increasingly use water parks for recreation, the risks of contracting leptospirosis should be noted and appropriate communication methods developed to inform the public.

A serological study of 168 rodents collected from two NSTCs in 2008–2009 found that 17–18 per cent were positive for a range of serovars similar to those affecting humans in Malaysia. The recommendation of the authors was that to prevent leptospirosis in military trainees,

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74 Julie M. Collins-Emerson, Jackie Benschop and Stanley G. Fenwick

control of the rat population in NSTCs is critical (Mohamed-Hassan et al., 2010).

6.6 Conclusion

Leptospirosis is a dynamic, emerging and re- emerging disease of global significance. Two contrasting pictures of the disease have been described; the situation in New Zealand and that in SE Asia. Leptospirosis continues to be a significant public health problem worldwide and management strategies will need to be tai- lored to individual situations. Given the complex interrelationship between human, animal and environmental health, a One Health or ecohealth approach is required to respond to the challenges. As multiple human, animal and environmental factors are involved in communities where the risk of leptospirosis is high, only a multi-centric, transdisciplinary approach to control will effec- tively reduce the burden of this disease.

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