Achieving Sustainable Global Capacity for Surveillance and Response to Emerging Diseases of Zoonotic Origin: Workshop Summary (2008)

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5 Laboratory and Epidemiological Capacity T he workshop focused on issues related to laboratory and epidemio- logical capacity because countries depend on diagnostic systems to detect human and animal diseases and to conduct disease surveil- lance. Presentations addressed the following topics: laboratory capacity in resource-constrained countries, the activities of OIE Reference Laboratories, personnel training, and the standardization of assays worldwide. Finally, two case studies focused on the experience and challenges in establishing a sustained operation of laboratories in Tanzania, and on clinical laboratory and epidemiological field training in Southeast Asia. Veterinary and Agricultural Laboratory Capacity in Resource-Constrained Countries James Pearson, former director of the National Veterinary Services Laboratory and senior staff member of the World Organization for Ani- mal Health (OIE), provided an update on veterinary and agricultural laboratories in resource-constrained countries. He began by describing the laboratory biosafety standards that have been established to protect humans, animals, and the environment. Both the World Health Orga- nization (WHO) and the U.S. government have published laboratory standards for humans and the environment, he noted, while OIE has developed standards for protecting animals and the environment (OIE, 2004; WHO, 2004; PHS/CDC/NIH, 2007). These standards overlap sig- 69 

70 GLOBAL SURVEILLANCE OF ZOONOTIC DISEASES nificantly. Pearson provided an overview of four containment levels  spelled out in these standards. Pearson explained that the key laboratory capacity issue is that many procedures for higher levels of biosafety are difficult for resource- c ­ onstrained countries to establish or maintain. Specifically, he explained, biosafety level 2 (BSL-2) laboratories are widely used and available, but, as far as he is aware, few if any laboratories meet all the requirements for BSL-3 in resource-constrained countries. If true, this means that many countries lack the capacity to isolate viruses such as avian influenza. The few BSL-3 laboratories that do exist in underresourced regions—Morocco, South Africa, and Thailand each have a BSL-3 laboratory—may provide support to other countries as well. In general, the high cost of some of the equipment, such as animal inoculation cages, is a principal impediment to setting up a laboratory that meets higher biosafety level requirements. Pearson also noted that few postmortem facilities in resource-­challenged countries are meeting even BSL-1 standards, so that personnel may be exposed to significant risks. The alternative to using facilities that lack sufficient protection is for personnel to conduct testing in the field, wear HAZMAT suits, and bury the animal. This approach, however, may not provide adequate protection. The skill and training of staff are critical, he added. Upgrading training (e.g., training that covers clinical signs, diag- nostic tests, optimal response, and disease reporting and control) may be a higher priority, in many cases, than establishing laboratories that meet higher levels. In Pearson’s view, resource-constrained countries in general have conscientious laboratory workers who have received excellent train- ing and have much of the equipment and supplies they need. On the other hand many resources are in short supply, such as facilities with capacity above BSL-1, specialized equipment (e.g., biosafety cabinets), and electric generators. Field forces are small, many personnel need more sophisticated training, and surveillance systems are not providing sufficient samples from the field. He summarized the situation by observing that BSL-2 laboratories are widely used and available in many countries. Although access may not   These recommended containment or biosafety levels (BSL) describe safe methods for managing infectious materials in the laboratory environment where they are being handled or maintained. There are four BSLs, with BSL-1 representing a basic level of containment relying on standard microbiological practices and BSL-4 representing the most advanced containment when working with dangerous and exotic agents that pose a high individual risk of life-­threatening disease (which may be transmitted via the aerosol route and for which no vaccine or therapy is available). The increasing numbers correspond to the increasing levels of protection for personnel and the environment. The purpose is to reduce or eliminate exposure of laboratory workers, other persons, and the outside environment to potentially hazard- ous agents. Each combination is specifically appropriate for the operations performed, the documented or suspected routes of transmission of the infectious agents, and the laboratory function or activity (PHS/CDC/NIH, 1999, 2007). 

LABORATORY AND EPIDEMIOLOGICAL CAPACITY 71 always be controlled in these labs, “the personnel with excellent training are doing a lot of good, accurate diagnostic work” despite inadequate equipment, lack of reagents, and supply- or cold-chain management chal- lenges. He also noted that few countries have BSL-3 or BSL-4 laboratories. A few of the BSL-2 laboratories incorporate some BSL-3 precautions, and many receive other support from OIE Reference Laboratories (discussed below), but limited resources and poor infrastructure have restricted disease surveillance and laboratory response in some countries. The Reference Laboratory Perspective— The Global H5N1 Crisis Ilaria Capua, of OIE, used the example of the highly pathogenic avian influenza (H5N1) crisis to illustrate the role that the OIE Reference L ­ aboratories—one or more laboratories designated as centers of expertise on one of the animal or human diseases OIE monitors—play in disease sur- veillance and response. Altogether, OIE has established a network of more than 160 Reference Laboratories in 32 countries, covering 95 diseases. Capua listed the principal responsibilities of those laboratories: • Assist countries in diagnosis of index cases; • Confirm laboratory results; • Provide training on avian influenza diagnostic techniques; • Produce and supply reference reagents; and • Provide advice and support for the management and control of the disease. Capua set the stage with a quick description of the H5N1 virus, not- ing that it is “the most aggressive virus in the animal kingdom—[inducing] a devastating disease, capable of killing birds within 48 hours of infection.” Once considered a rare disease, it is now capable of infecting approximately 50 bird species and 10 mammal species, she noted, and is endemic in poultry on at least three continents. For every human infected, at least 1 million ani- mals are infected. Thus, the disease is a threat to food security for developing countries, and also presents a unique threat compared to past disease because it is the first highly pathogenic one to become endemic in such a vast area. In short, it is “an enemy that we don’t really know very well.” The current epizootic of avian influenza reached Africa in January 2006. Africa was not prepared, Capua explained, though the OIE Refer- ence Laboratory community quickly realized that the virus would spread and “there would be no way to stop it.” Africa had not previously expe- rienced a highly pathogenic avian influenza epizootic, and most African countries lacked an early warning system in their poultry populations. 

72 GLOBAL SURVEILLANCE OF ZOONOTIC DISEASES Veterinary diagnostic services were completely unprepared to detect and diagnose highly pathogenic avian influenza (H5N1), and few understood the relationship between wild bird ecology, husbandry practices, and the spread of the disease. Moreover, birds succumb to many lethal infections on the ­ African continent, so the spread of highly pathogenic avian influ- enza (H5N1) was not immediately seen as a priority. As a result, significant delays in notification occurred—15 to 34 days elapsed between the initial event and notification to OIE in the countries first affected. Since the highly pathogenic avian influenza (H5N1) crisis began, how- ever, OIE has increased the number of veterinary laboratories diagnosing avian influenza, implemented training and networking in a number of coun- tries, and increased funding for disease surveillance of wild and domestic birds. That example illustrated both the gaps in the system and its capac- ity to respond. But Capua also considered the question of sustainabil- ity. She presented data from a 2007 Food and Agriculture Organization of the United Nations (FAO) survey of 20 western and central African countries that showed most of those countries have adequate laboratory infra­structures, though “the quality of the facilities and the diagnostic perfor- mance is ­heterogeneous—from zero to 10.” Laboratory staff are present and have received basic training. Equipment is available, though in some cases no personnel are available to maintain it. On the other hand, two of the countries surveyed have no facilities, and an additional three had facilities that were not functioning at the time of the survey. Many laboratories need renovation or upgrades, and many staff need customized training on specific issues. Labo- ratories surveyed also lacked reagents because of cost, lack of local suppliers, or rapid deterioration in extreme environmental conditions. Most important, Capua explained, is that in most laboratories diagnostic activity is limited by a lack of samples to be tested, perhaps because funds for surveillance and monitoring are limited. In response to these deficiencies, Capua explained, OIE has focused on involving veterinary services in international research projects and developing other strategies to build international connections. Capua closed her remarks with a discussion of the vital importance of sharing information. Information sharing is vital because it is very likely that “whatever viruses are predominant in animals will be the cause of human infection,” she explained, and because it is primarily veterinarians who possess the isolates that will be the key to preparing for a pandemic. She continued by mentioning that “interpreting information available from evolv- ing animal viruses on a permanent basis” is the way to prepare, yet there are often significant delays between the isolation of particular viruses and publi- cation of papers documenting such findings. OIE has made the sharing of this type of information a formal goal. Capua expressed hope that in the future, the global influenza programs that identify which mutations are dangerous 

LABORATORY AND EPIDEMIOLOGICAL CAPACITY 73 and which regions are particularly at risk will work together with OIE, which has sequence and epidemiological information, to develop a common research and policy agenda to maximize the benefits of their work. The Application of NAHLN Principles to International Animal Health Efforts Within the United States, laboratories that provide veterinary diag­nostic laboratory capacity for foreign animal disease surveillance are coordinated through the National Animal Health Laboratory Network (NAHLN). This network, created in response to a Department of Homeland Security direc- tive, is designed to coordinate laboratory capacity at the state and federal levels for early disease detection, rapid response, and appropriate recovery to animal health emergencies. Barbara Martin, the network’s coordina- tor, explained that NAHLN is a partnership of the Cooperative State Research, Education, and Extension Service (CSREES) of the U.S. Depart- ment of Agriculture (USDA), and the American Association of Veterinary Laboratory Diagnosticians. According to the NAHLN website, the network includes 58 laboratories (including 2 national laboratories) in 45 states. Martin also noted their collaborative, international training activities with universities, the USDA’s Animal and Plant Health Inspection Service, Agri- cultural Research Service, and Foreign Agricultural Service; the Department of Defense; and the United States Agency for International Development (USAID). The three purposes of this network are early detection, rapid response, and appropriate recovery. The network focuses on: • Standardized, rapid diagnostic techniques; • Trained personnel and modern equipment; • Quality standards and proficiency testing; • Secure communication and rapid reporting systems; • Adequate biosafety and biosecurity measures; and • Scenario testing. Based on the coordinated approach NAHLN has established, ­Martin explained, the infrastructure and expertise of the nation’s veterinary diag- nostic laboratories are deployed in an efficient, strategic manner. An impor- tant part of their coordinated approach is to “get rid of the black-box syndrome,” that is, to help animal health officials to better understand what the laboratories do and what constraints they face. Through drills and simulations, they have worked to involve as many people as possible in preparation for a range of scenarios. “Partnerships are key to everything that we do,” Martin explained. Through strategic combinations of state 

74 GLOBAL SURVEILLANCE OF ZOONOTIC DISEASES and federal resources, they have supported standardized surveillance for high-priority diseases. NAHLN has also provided training for avian influenza viruses, foot- and-mouth disease (FMD), and brucellosis to laboratory scientists in 60 countries as part of a long-term goal of developing diagnostic exper- tise worldwide. The training, which has focused on resource-challenged countries, has addressed proficiency in conducting assays, maintaining biosafety and biosecurity standards, and developing country reference standards, as well as training for individuals who can then serve as ­trainers at home. The network has found success with this effort, particularly in building communication networks in other countries. However, because inter­national training is not part of the network’s core mission, finding funds to sustain this training is challenging. As discussed earlier, labora- tories in resource-challenged countries often lack adequate resources, so it is difficult for them to sustain the testing standards and procedures in which they were trained. Despite these challenges, Martin believes the NAHLN approach is a “practical stepwise approach to building capacity” internationally. The key question is “where would the commitment and resources come from?” Laboratories in Tanzania Tanzania is a resource-constrained country that faces challenges in establishing and sustaining laboratories, as described by Mmeta Yongolo of Tanzania’s Central Veterinary Laboratory. Yongolo suggested that Tanzania is a critical country from an integrated human and animal health perspec- tive. One third of the country is national park land, and there is “great diversity from the snow-capped mountain to organized animal preserves,” as well as extensive interaction among livestock, wildlife, and humans. Tanzania has a long tradition of collaborative laboratories, dating back to the country’s early colonial era. However, economic fluctuations and changing levels of funding from the World Bank have resulted in significant cutbacks to the laboratory system. Today, Tanzania’s new central labora- tory has the capacity to deal with many emerging viruses (the country also has existing laboratories with traditional veterinary capacity). The Central Veterinary Laboratory can diagnose diseases using serology, DNA-based techniques, and embryonated chicken eggs (ECE) and mice virus isolation techniques. The range of diseases include, but are not limited to Rift Val- ley fever (RVF), FMD, highly pathogenic avian influenza (H5N1), African swine fever, ­ Newcastle disease, rabies, rinderpest, and contagious bovine pleuropneumonia. Its staff is supplemented with medical and veterinary experts supplied by FAO, the University of Minnesota, USAID, OIE, and the United Nations Children’s Fund (UNICEF). 

LABORATORY AND EPIDEMIOLOGICAL CAPACITY 75 Nevertheless, Tanzania faces significant challenges. The central labora- tory does not have the capacity to deal with all of the human and animal disease threats in the region, which include Ebola, Marburg, yellow fever, dengue fever, RVF, and West Nile fever. Their prevalence is not known and they are not well mapped, the host populations have not been well studied, and other factors associated with them have not been studied. Several other potential zoonotic diseases are suspected to be present in the region—Bun- yamwera, Pongola, Babanki, Semliki, and Sinbis viruses—yet their distribu- tion and prevalence are not well documented, and further research is needed on their biology and ecology. Tanzania’s laboratories also lack sufficient equipment, reagents, and trained personnel, and have not been able to fully comply with biosecurity and biosafety guidelines. All of these problems could be addressed with greater resources, but Yongolo explained that the national government has had only a limited appreciation for the urgency of the problem. Tanzania’s government must address hunger, widespread poverty, educational deficits, and other challenges in a constrained economic climate. And even given the importance of animals and animal health to not only the macro economy (e.g., eco-tourism in national parks which cover 1/3 of the country) but also to individual livelihoods, the laboratories are very dependent on foreign donors. Collaboration with a number of international partners has also been a very important asset for Tanzania’s public health system. Current partners include the Muguga Laboratory in Kenya; the Botswana Vaccine Institute; Veterinary Laboratory Agencies in the United Kingdom; the National Veterinary Services Laboratory in Ames, Iowa; and the University of Minnesota. Through these collaborations, the central laboratory has been able to handle or process many more samples than it could on its own, to reduce handling risks, and to confirm results. Yongolo suggested that a much greater degree of international collaboration would be the best way to improve disease detection, identification, and monitoring. He believes “the way forward is to establish a disease and virus survey” to better map diseases. “All of this can be done if we have long-term programs, not short-term programs.” building epidemiological capacity to address emerging infections in africa The Centers for Disease Control and Prevention (CDC) have focused significant attention on building laboratory and epidemiological capacity in strategic global locations that can serve regions with high threats and low resources. As part of a global strategy to monitor and respond to emerging infectious threats at the local, regional, and global levels, Robert Breiman 

76 GLOBAL SURVEILLANCE OF ZOONOTIC DISEASES of CDC-KEMRI in Nairobi, Kenya, explained, that CDC has established the International Emerging Infections Program (IEIP). IEIP has five labora- tories located in China, Egypt, Guatemala, Kenya, and Thailand. Breiman focused on his laboratory in Nairobi, the Kenya Medical Research Institute (KEMRI). Although Kenya’s IEIP laboratory was designed to establish diag­nostic and epidemiological capacity, it also conducts public health research and contributes to intervention strategies for high-impact diseases. The corner­ stones of the program are disease surveillance, rapid response to out- breaks, training and building local capacity, and applied research. When the laboratory opened in 2004, it was immediately faced with an outbreak of ­aflatoxicosis, but has also been deeply involved with cholera, typhoid, brucellosis, Chikungunya, and RVF. The RVF outbreak, Breiman explained, highlighted the weaknesses of the veterinary surveillance and response system in the region—as well as the importance of establishing a center that would address human and ani- mal health issues together. It also highlighted the importance of laboratory capacity, and the KEMRI has created two small BSL-3 labs that process specimens from throughout the region. KEMRI also has a partnership with the International Livestock Research Institute, and they are hoping to build capacity for veterinary surveillance through that partnership. KEMRI is involved in several types of disease surveillance. Their pri- mary surveillance objectives are to identify and characterize new or emerg- ing pathogens for human and select animal diseases, establish public health priorities in rural and urban settings, and provide a platform for evaluating the impact of interventions that have targeted high-priority diseases. KEMRI’s strategies include population-based surveillance in one rural and one urban site, which entails surveying the target populations (total- ing 55,000 people) every 2 weeks for respiratory and febrile illnesses and diarrheal disease. KEMRI sees 600 to 900 cases per 100,000 children each year. Free clinic care is available and specimens are collected, and the sur- veillance uncovers a range of problems. Perhaps most severe is bacteremic typhoid fever. KEMRI has a national reporting system that uses integrated disease surveillance and response and conducts sentinel surveillance in hospitals and refugee camps. To work around the lack of computer capacity in remote regions, KEMRI has also been promoting the use of cell phones   CDC’s Kenya International Emerging Infections Program through the Kenya Medical R ­ esearch Institute began in 2004 to establish diagnostic and epidemiological capacity in Kenya to address diseases of epidemic potential. The program is contributing to the development and widespread use of interventions to address high-impact diseases while conducting public health research of local, national, regional, and global importance (Breiman, 2008). 

LABORATORY AND EPIDEMIOLOGICAL CAPACITY 77 and text messaging to find out about disease rumors that need investiga- tion. Through its surveillance program, Breiman explained, KEMRI hopes to understand the incidence and prevalence of zoonotic and epizootic dis- eases in coexisting human and animal populations, the risk factors for humans and animals, and the potential of animal sentinels to provide early warning. Breiman noted what he calls one of KEMRI’s “most valuable contribu- tions” to the epidemiological capacity-building efforts: the Field Epidemiol- ogy and Laboratory Training Program (FELTP), an M.S. degree-granting public health program in applied epidemiology or laboratory manage- ment for Ministry of Health staff. The program is training its fifth cohort of students, which includes 20 residents from several countries. Thirteen graduates of the program, which is being expanded to include veterinar- ians as well as medical personnel, are now employed in the Kenya Ministry of Health, which previously lacked staff with significant epidemiological training. Some are holding leadership positions for integrated surveillance efforts, some are working in the reference laboratory system in Kenya, and some are serving as provincial medical officers and medical epidemiologists. KEMRI’s new effort to include veterinarians in the cohorts is significant, as is their outreach to the Ministry of Agriculture to bring a concerted focus to disease surveillance issues that affect the intrinsic connection of human and animal health. Laboratory and Field Training in Southeast Asia Another region with high population density, low resources, and high incidence of infectious disease is Asia. Jeremy Farrar of the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam, described conditions in that region. With half of the world’s human population and more than three-quarters of the world’s poultry living in South Asia, policies that work across political borders are of paramount importance in containing diseases. The sheer population density in India and China, he explained, places a tremendous burden on their public health systems, and public health for that region is important to the whole world. Echoing some of the earlier discussions, Farrar pointed out that Asia is a disease hotspot because it is particularly fertile ground for zoonotic pathogens to emerge from wildlife and domesticated animals, and for drug resistance to develop. He views drug resistance as “the world’s most important emerging health problem.” Farrar reported that infectious dis- ease accounted for 25 percent of all deaths in the patient population of the H ­ ospital for Tropical Diseases in Ho Chi Minh City, Vietnam—a facility with 600 beds dedicated to infectious disease patients, with more than 1,000 patients annually, and serving a population of nearly 40 million Vietnamese. 

78 GLOBAL SURVEILLANCE OF ZOONOTIC DISEASES He also noted that as many as 90 percent of infectious diseases worldwide are generally not diagnosed. Other lethal pathogens include severe respira- tory infection, diarrhea, malaria, severe dengue fever, and typhoid. “For all of these, Asia is the champion of the World Series,” he suggested, because of the burden of existing endemic disease, drug resistance, and the frequent emergence of new pathogens. Looking forward, Farrar believes the most promising approach to sustainable global disease surveillance and response is international col- laboration, but he was careful to say that large, international organizations are only part of the answer, and that “sustainable collaborative work must be based close to where the problems are.” Clinical and scientific capacity that is locally rooted is critical, which means that “we have to bridge that biotechnological divide, and bring that knowledge base to where things are that matter.” He illustrated the point with the example of the international response to the highly pathogenic avian influenza (H5N1) outbreak in Hong Kong in 1997. Experts flew to Hong Kong from around the world, and he observed that: “you almost could not get a flight.” Farrar explained that the efforts of CDC, WHO, the academic research community, and others were clearly valuable in that crisis, but expressed his personal view that the local response was most critical. Thus, he suggested, the challenge is to develop a new model. First, training should move from the academic centers in the West to where the problems are. A BSL-3 laboratory is only as strong as the individuals who staff it, and it would be far easier to train adequate numbers of expert personnel in high-need countries if more educational opportunities were made available where the need is greatest. Second, structures need to be developed to build collaboration and trust across institutions. This means sharing of data and samples and linking together various research centers. It also means linking the fields of public health, clinical science, and animal health, which have been “existing in parallel” for too long. Discussion The committee was eager to focus on opportunities and challenges for strengthening surveillance capacity to prevent, detect, and respond to emerging infectious diseases around the world. Thus, they structured the discussion around themes that emerged from this section’s presentations, but focused on a few big questions. First, many speakers advocated inte- grating resources that are currently dedicated to human health, agricultural safety, and animal health, and urged that resource integration be done at every level, from local field-based activities, through laboratory and report- ing systems, and up to the highest policy levels. Yet questions remained 

LABORATORY AND EPIDEMIOLOGICAL CAPACITY 79 about the feasibility of making this degree of integration a reality, and the group was asked to reflect on the challenges. No one questioned the value of greater integration, and numerous examples of specific collaborations were offered, but the challenge is clearly great. A participant observed that even within the United States, govern- ment agencies “don’t always talk to each other,” and that looking interna- tionally, “getting them to work and think collectively before a crisis is key.” Participants also identified more practical challenges: for example, combin- ing resources seems particularly logical in resource-challenged countries, but setting up and running a laboratory that meets international biosafety standards and protocols for both human and veterinary laboratory testing procedures could be a significant challenge. Others noted the cultural divide between the human and veterinary health communities. Because they have different cultures and generally train and work separately, the two groups often lack mutual respect and trust. Specific structures for developing communication and opportunities for col- laboration are therefore clearly needed. The prevailing sentiment seemed to be that greater integration is a widely shared goal and that it will come with time, but only when they focus their attention on maximizing the currently available funding streams. The rest of the discussion focused on the challenge of achieving long- term sustainable capacity around the world. Participants identified models of success that potentially could be replicated. The International Center for Diarrheal Disease and Research in Bangladesh, for example, has attracted international funding and provided competitive salaries, while providing opportunities for Bangladesh citizens to move up within the system and operate on an international level. At the same time, however, others sug- gested it is misguided to “see this through the prism of insisting that in a defined period of time these things will be [able to] stand alone without international funding and without international input.” It is important to understand that disease surveillance and response in high-risk regions of the world are critical for protecting everyone’s health. Moreover, it was sug- gested, the United States should be the first to recognize the benefits it has received from the international focus of its scientific work—“it [the U.S.] attracts some of the best people from around the world to come and work here, and America benefits from that.” Nevertheless, international grant funding tends to come in 3- to 5-year tranches and “the ministries know that at the end of 3 years it is gone.” Thus, policy planning is organized around these short time frames. But, it was suggested, “We need to encourage cooperation in the long term—not just when Washington or London is worried about H5N1.” Developing human capacity will require longer timelines: “You are not just talking 

80 GLOBAL SURVEILLANCE OF ZOONOTIC DISEASES about 3 years to train somebody or a week in a training program,” and the reality is that “you can’t build infrastructure and you can’t develop people without having the financial resources.” Participants pointed to creative strategies, such as developing funding packages that could only be used for projects that involve collaboration across sectors. Industry and the private sector were also cited as a relatively untapped resource. Technology offers potential solutions to many of the challenges of coordination, remote field work, and rapid response, and a large tech­ nology company such as Google has the potential to offer valuable support with data management, software, and related resources. The question was raised, in that context, whether technology—hand-held devices, mobile d ­ iagnostics—could actually make it possible to bypass some of the current challenges facing central laboratories. Without a doubt, new technologies have already proven to be valuable in many contexts, but participants agreed that reference laboratories are still necessary, and that a true tech- nological replacement remains “a long way off.”