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Global Laboratory Networks: Integrating from the Ground Up

WORKING TOWARD LONG-TERM GOALS OF DISEASE SURVEILLANCE

Ali Khan began by asking two rhetorical questions: What is surveillance? What is the laboratory’s goal? According to the U.S. National Strategy for Biosurveillance, “biosurveillance is the process of gathering, integrating, interpreting, and communicating essential information related to all-hazards threats or disease activity affecting human, animal or plant health to achieve early detection and warning, contribute to overall situational awareness of the health aspects of an incident, and to enable better decision making at all levels.”¹ The main issue is action: how do we take action in our communities to prevent disease? He highlighted several aspects of the definition, including its systematic nature: the process of gathering, integrating, interpreting, and communicating all essential information; the focus on early detection and warning; and the importance of overall situational awareness and better decision making.

Further, as identified in a training course through the University of Nebraska Medical Center,² performing and investing in biosurveillance enables public health systems to:

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¹ The White House. 2012. National Strategy for Biosurveillance, p. 2.

² Chapman, L. E. 2012. Biosurveillance. Epidemiology Infectious Disease course, University of Nebraska Medical Center.

• Detect new diseases and epidemics
• Document spread of disease
• Develop estimates of morbidity and mortality
• Identify potential risk factors for disease
• Facilitate research
• Inform design of studies that can test hypotheses
• Plan and assess impact of interventions
• Inform decision making and actions

Laboratory Response Within the United States

A national laboratory system enhances reciprocal data flow and data monitoring by connecting the government to the front lines of healthcare, including hospital, university/research, commercial, and private laboratories. Two-way communication between national labs and practitioners is key. Khan described the U.S. Laboratory Response Network (LRN), a national network of local, state, and national laboratories conducting public health, food, animal diagnostic, and environmental testing.³ The LRN provides the infrastructure and capacity to respond to biological threats, chemical terrorism, and other public health emergencies. On the biological side, the LRN consists of about 150 labs, mostly in public health, representing U.S. states, but also in Australia, Canada, Mexico, South Korea, and the United Kingdom. One LRN goal is to expand membership to broaden the scope of biological agent detection, particularly among veterinary diagnostic, food and water testing, and private and commercial laboratories.

The LRN structure for biological threats has three tiers. The first tier consists of sentinel labs. These are the thousands of hospital-based labs that have direct contact with patients and could be the first facility to spot a suspicious specimen.⁴ They are responsible for referring a suspicious specimen to the correct reference lab. Reference labs, which make up the second tier, can detect and confirm threat agents, ensuring timely local response in the event of a threat. Many reference labs can themselves produce conclusive results, allowing local authorities to respond quickly if needed rather than relying on confirmation from a centralized lab. At the top of the structure,

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³ For more information, see http://emergency.cdc.gov/lm/index.asp.

⁴ Seraphin, S. 2006. Review: Detection and Identification of Unknown Substances. Cambridge University Press. doi: 10.1017/S1431927606066694.

national labs have unique resources to handle highly infectious agents and have the ability to identify specific agent strains.

Global Health Security Agenda and the Lab Component

The new International Health Regulations (IHRs) now require countries to develop the capacity to detect, investigate, and report any public health emergencies of international concern, such as disease outbreaks, to the international community through the World Health Organization (WHO). Credible and accessible laboratory services capable of producing reliable results in a timely manner are the cornerstone of a country’s capacity to investigate such events. In recent years, there have been significant advances in laboratory capacity, but in many countries, reliable confirmation of suspected infectious diseases is hindered by a lack of standardized methods, insufficient funds, a lack of suitably trained staff, and a lack of proper laboratory supplies.⁵

In response to these new requirements and the assistance required to meet them, the Global Health Security Agenda (GHSA) was launched in February 2014.⁶ It is a growing partnership that now includes nearly 50 nations, international organizations, and nongovernmental stakeholders. The GHSA helps build countries’ capacities and elevates health security as national and global priorities. It takes a multilateral and multisectoral approach to strengthen overall global capacity by improving each nation’s capacity to prevent, detect, and respond to human and animal infectious disease threats that occur naturally, accidentally, or deliberately. The GHSA also facilitates collaborative capacity-building efforts toward specific, measurable targets around biological threats and enhances meeting core capacities required by the IHRs, World Organization of Animal Health’s Performance of Veterinary Services Pathway, and other relevant global health security frameworks.

To achieve these goals, participating countries prepare a GHSA National Laboratory System Action Package consisting of a five-year target of “real-time biosurveillance with a national laboratory system and effective modern point-of-care and laboratory-based diagnostics.”⁷ The desired national impact includes effective use of a nationwide laboratory system

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⁵ WHO. Strengthening health security by implementing the International Health Regulations (2005). https://www.who.int/ihr/lyon/hls/en/.

⁶ For more information, see https://ghsaagenda.org.

⁷ See https://www.cdc.gov/globalhealth/security/actionpackages/national_laboratory.htm.

that is capable of safely and accurately detecting and characterizing known and novel pathogens causing epidemic disease in all parts of a country. It should also result in expanded deployment, utilization, and sustainability of modern, safe, secure, affordable, and appropriate diagnostic tests and devices.

Success within the GHSA National Laboratory System Action Package can be achieved in several ways. First, success is defined as ensuring that all laboratory operations are reliable, and specifically that labs can reliably conduct tests and produce accurate results and report them in a timely manner such that they are useful in clinical and public health settings. Second, the system should be able to undertake at least five of ten core tests. The ten core tests include six selected according to the IHR “immediately notifiable” list and WHO top ten causes of death in low-income countries, including polymerase chain reaction testing for influenza virus, viral culture for polio-virus, serology for HIV, microscopy for Mycobacterium tuberculosis, rapid diagnostic testing for Plasmodium spp., and bacterial culture for Salmonella enteritidis serotype typhi.⁸ The remaining four tests are selected by individual countries on the basis of their major national public health concerns. Third, success is defined as the ability to appropriately identify and collect outbreak specimens, and transport them safely and securely to accredited laboratories. Accredited laboratories, in turn, will have completed appropriate activities according to the Stepwise Laboratory Quality Improvement Process Towards Accreditation checklist, Strengthening Laboratory Management Towards Accreditation process, International Organization for Standardization standards, and WHO disease-specific programs.

Laboratories’ Exchange of Information

Providing timely results in a structured format is a challenge in the United States as it is in other countries. Currently only 58 percent of labs in the United States report data electronically for a variety of reasons.⁹ Current U.S. problems with collection and analysis of lab data include converting information into knowledge, working with multiple types of

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⁸ Ijaz, K., Kasowski, E., Arthur, R. R., Angulo, F. J., and Dowell, S. F. 2012. International Health Regulations—what gets measured gets done. Emerging Infectious Diseases, 18(7), 1054-1057. https://doi.org/10.3201/eid1807.120487.

⁹ Swain, M., and Patel, V. 2014. ONC Data Brief: Health Information Exchange among Clinical Laboratories. National Coordinator for Health Information Technology. https://www.healthit.gov/sites/default/files/onc-data-brief-14-testresultexchange_databrief.pdf.

lab information systems, hardware and software maintenance, explaining complex terminology plus a lack of exposure by information technology (IT) professionals, and timeliness.

One potential solution to communication issues involves implementing mHealth or eHealth. Given that cell phones are widely used in Pakistan, opportunities to utilize this technology for public health exist, such as for information about supplies of medication, medication reminder or healthy lifestyle text alerts, reporting, and interfacing with medical devices. As defined by the WHO, “Mobile health or mHealth, an area of electronic health (eHealth) … is the provision of health services, and information via mobile technologies such as mobile phones and personal digital assistants.”¹⁰ The ubiquity of mobile devices is transforming health care in resource-limited regions by providing epidemiologic surveillance, real-time data on medication stocks, patient text reminders for healthy behaviors, training for health workers, consultations with healthcare workers, and as portable medical devices. Mobile devices have an advantage over traditional methods of information transfer including communication to and from remote locations, current availability of the technology with no significant new IT support needed, and simpler hardware upgrades. The devices can tap into newer technologies as they develop. As an example, cell phones in Belize have been adapted to transmit a microscopic image of a blood smear as well as to receive U.S. Centers for Disease Control and Prevention data within seconds.

Khan provided additional examples. In Swaziland, a pilot study centered on providing remote clinics with laboratory results. These clinics were not equipped with computers or Internet access but were located within range of cellular phone networks. A system called LabPush was used at these clinics to connect with the national laboratory. Because the lab and clinics had a limitation of 140 characters per text (SMS) message, they use 10 tests deemed most essential for physicians to make clinical decisions. Nonetheless, qualitative data indicated much shorter turnaround time, fewer missing reports, ease of technical support, and better communication, all resulting in improved patient care. Drawbacks included the lack of direct printed reports, increased work time, and potential human error transcribing results from photo to paper forms and into charts.

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¹⁰ This 2011 definition was retrieved from who.int/goe/mobile_health/en.

Finally, Khan provided an overview of computerized information management systems designed for labs. One example is the Laboratory Information Management System in the United States, which

• Manages all data processing.
• Interfaces with analytical instruments.
• Sorts data and organizes it into various desired reporting formats.
• Stores all data for future reference and use.

EFFECTIVE CLINICAL DIAGNOSTIC SYSTEMS FOR RESOURCE-CHALLENGED ENVIRONMENTS: AN AFRICAN PERSPECTIVE

Leslie Lobel provided his presentation via web conference.¹¹ He began by summarizing the basic problem: many countries in the world cannot afford most of the diagnostics that are produced in high-resource countries, nor can they afford the infrastructure and equipment required for “high-technology” diagnostic laboratories. Thus, relatively few diagnostic tests are performed in low-resource countries and much of the diagnosis is a function of clinical presentation and, as a result, there is very little control over emerging and reemerging infectious diseases. However, high tech can be adapted to relatively simple and low-cost diagnostics that can be used effectively in very low-resource environments. Lobel also stated at the outset of his remarks that the One Health concept still has not been fully implemented globally. Coordination between human and animal health is better in Africa, especially in Uganda. In much of the United States and Europe, there is little evidence of the coordination needed to address the significant infectious disease challenges of the 21st century, which increasingly will be zoonotic.

What is needed to effectively control viral diseases on a global scale is global and local integration of diagnostics with standardization and optimization for various geographic disease ecosystems. Different parts of the world have different viral ecosystems and need to be standardized separately because the baseline cut-off values, for example, are different for African, Asian, and American patients for any given test. Test values should

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¹¹ Lobel, L., and Yavelsky, V. 2014. Effective Clinical Diagnostic Systems for Resource Challenged Environments: A Perspective from Uganda. A Joint Pakistan-U.S. Workshop on Strengthening and Sustaining a Network of Public and Animal Health Clinical Laboratories in Pakistan. Islamabad, September 27-29.

be coordinated and standardized on a local level, and at the same time, we need to integrate on a global scale to have effective global control of infectious diseases. As is the case in Uganda, centralized labs are key to effectively controlling diseases. It is impossible to have too many highly-functional labs throughout the country. Field-operable diagnostics that tie into central labs lead to solutions, requiring real-time diagnostics from portable devices. Individual diagnostics and vaccines that address individual ecosystems are needed. It is very clear from Lobel’s experience that in Africa, the diagnostics and vaccines commonly used do not work well because they were developed for one part of the world and deployed in other parts of the world with people who have different genetic backgrounds and different exposure histories. Globally-developed vaccines and diagnostics should be optimized locally. In short, “bio-intelligence” networks are needed. These networks would be the sum of diagnostic data that will provide insights into the health of populations and into the potential for future outbreaks and emergence of new diseases to better predict outbreaks. A global and local “bio-intelligence” network with central laboratories that tie into facile field-operated diagnostics with real-time data uploading to the central labs and diagnostics and vaccines to address individual geographic ecosystems would be useful.

Both humans and viruses change over time, Lobel said. Human adaptive immune response must keep up in order to reach a balance with evolutions of infectious diseases. Unfortunately, today the world of infectious diseases is further ahead because we have been neglecting it for many years. Infectious disease is not going away, as seen in Africa (especially with regard to animal disease). Rinderpest once greatly affected the food supply in Africa, and now foot-and-mouth disease is having a similar effect. Likewise, while certain human diseases have been eradicated (e.g., small pox), other diseases emerge, such as Ebola in West Africa and Zika in Latin America.

Lessons can be learned from these situations. In West Africa, the “perfect storm” of viral disease occurred, precipitating the 2014 Ebola outbreak. A highly contagious virus and a population living at subsistence-level, poor infrastructure with no capacity for diagnostics, and a fairly weak medical system, allowed for a perfect precursor for a continual outbreak. The international community was not awake to the threat of infectious disease for many years. One contributing factor was the transition in focus from infectious disease to cancer, diabetes, and other chronic diseases of the well-resourced countries, starting in the 1970s. The global community is not united to combat infectious disease. Leaders in healthcare in the

east African community have come together (Kenya, Rwanda, Tanzania, Uganda) to address threats of infectious disease, and this has had a significant positive effect, especially on addressing HIV. In the Americas, the spread of Zika has shown how little is known about the effect of infectious disease history and concurrent infections on immunity and vaccine efficiency. For example, dengue fever has a significant effect on the Zika virus. There is also little known about the effect of cross reactivity on immunity and diagnostics accuracy, as is seen in Africa where the measles vaccine is less effective due to exposure to other diseases. This is hampering efforts to develop vaccines; we need bio-intelligence in advance of an outbreak to make rapid vaccine development possible. Lack of knowledge about cross-reactivity can also negatively affect diagnostics. This is vital because if this is not known, it does not matter how many kits or labs one has; the raw data will not be reliable. Vector control also has not been adequately addressed on a global scale for infectious disease control. This experience, too, shows the lack of unity in the global community. We should be working together and toward a seamless flow of information so that the world as a whole can control emerging infectious disease, Lobel stated.

Intellectual property considerations and other similar issues should not hamper global disease control. Another challenge that we need to overcome is the inaccurate belief that we are in a “post-infectious disease” world. People in the United States and Europe live in a sterile environment and have been vaccinated against many childhood infectious diseases, meaning that viral diseases are not widely seen in those environments. Whereas in Africa, infectious diseases are common. People living in a disconnected, polarized world should come together to address infectious disease, Lobel stated.

Finally, another key challenge is the lack of knowledge of infectious disease ecosystems; diagnostics are foundational for bio-intelligence and for enhancing our ability to communicate data at local and global levels. Bio-intelligence networks will allow us to rebalance the universe of infectious disease, including between humans and animals, leading to an ability to better control outbreaks.

Lobel concluded his presentation with key elements of such bio-intelligence networks:

• Global and local integration of diagnostics with standardization and optimization of assays for various geographic disease ecosystems, along with geographic and meteorological indexing of sampling and data.

• Central laboratories that tie into facile field-operated diagnostics with real-time data uploading to central laboratories (e.g., lateral flow tests linked with mobile phone–based technologies); these approaches and technologies currently utilized in Africa are leap-frogging systems in other parts of the world and are becoming the new normal in terms of diagnostic technologies for populations in a more cost-effective manner without the need for considerable infrastructure.
• Development of diagnostics and vaccines that reflect individual and geographic ecosystems.
• Locally standardized rapid response teams with standard operating procedures for sample collection and diagnostics during outbreaks.
• Development of global relationships so that data availability is seamless and instantaneous before, during, and after outbreaks.
• A global team of experts to coordinate global standardization and integration of diagnostics and data for seamless and real-time assessment of the infectious disease environment, similar to the United Nations, for infectious disease control; well-resourced countries cannot continue to be largely free of infectious disease without controlling infectious disease in other parts of the world.

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