THE CDC FIELD EPIDEMIOLOGY MANUAL

Multinational Outbreak Investigations

Frank Mahoney and James W. Le Duc

Introduction

Sharing information about infectious disease outbreaks among affected countries dates back to the earliest recorded history and spans the centuries up to the modern era (Table 15.1). More formal coordination of international outbreak response originated in the nineteenth century, when printed materials were widely distributed and publications about analyses of outbreak data and international prevention strategies became widespread. This chapter provides perspective regarding coordination of international outbreak responses, which have evolved substantially since the efforts of the nineteenth and twentieth centuries.

Table 15.1
Historical background of sharing information about infectious disease outbreaks among affected countries
Date Event
430 BCE Thucydides describes an outbreak with high mortality that ravages Athens, Greece, causing widescale panic and fear among the city’s 315,000 residents (1). Symptoms include abrupt onset of fever, headache, fatigue, and pain in the stomach and extremities, accompanied by severe vomiting, diarrhea, and bleeding from the mouth (1–3). Dehydration becomes so profound that men plunge themselves into wells. Illness frequently ends in death in 7–9 days. Healthcare workers are often affected, but those who survive are able to treat others without becoming reinfected. Modern physicians speculate that this rapidly fatal hemorrhagic fever was caused by Ebola virus disease (2,3).
460–370  BCE Hippocrates describes clinical and epidemiologic features of epidemic-prone diseases and outbreaks (4).
1st century BCE–1st century AD In a book on agriculture, Marcus Terentius Varro recommends building houses far away from swamps because of creatures too small to be seen with the eye but that enter the body and cause disease (5). Another agriculturist, Lucius Junius Moderatus Columella (4–c. 70 ad), also warns that swamps release pestilential vapors and produce swarms of insects that cause harm (5). During the same era, the Greeks and Romans develop systems for isolation and treatment of patients with epidemic diseases (6), a practice that continues throughout the Middle Ages and into modern times (5,6).
1829–1849 A cholera pandemic furthers development of the principles of modern epidemiologic investigations, including characterization of disease by person, place, and time (7). During the outbreak, in 1832, Amariah Brigham publishes a dot map and trade routes that detail cholera’s spread on a global scale (8,9). Commissions are established and information shared within days and sent on ships, trains, and coaches to other affected countries.
1851 The first International Sanitary Conference is convened in Paris to harmonize conflicting and costly maritime quarantine requirements of different European nations (10).
1892 The first international agreement addressing cholera is signed at the seventh International Sanitary Conference in Venice.
1893 and 1894 Conferences in Dresden and Paris result in two additional agreements relating to cholera.
1897 Countries adopt an agreement regarding ways to prevent the spread of plague.
1903 The four previous agreements are consolidated into one international sanitary agreement.
1907 Government representatives in Rome agree to establish an Office International d’Hygiène Publique (OIHP) in Paris, with a permanent secretariat and a permanent committee of senior public health officials to oversee international rules regarding quarantining of ships and ports to prevent spread of plague and cholera and to administer other public health agreements.
1924 After World War I, the League of Nations Health Organization is established with an initial focus on detection and response to epidemics in Europe; it later becomes an organization in Geneva, Switzerland, laying the foundation for the core functions of the World Health Organization (WHO).
1946 OIHP is dissolved and its epidemiologic service is incorporated into the Interim Commission of WHO.
1948 WHO is formally established and revises and consolidates the International Sanitary Regulations.
1969 The International Sanitary Regulations are renamed the International Health Regulations (IHR); this first version includes a passive reporting system for cholera, yellow fever, and plague. WHO publishes key features of the diseases in the Weekly Epidemiologic Record and describes maximally acceptable measures for preventing the diseases from spreading internationally by setting standards for seaports and airports to prevent disease transmission.
2005 With the growth in international travel and trade and the emergence of international disease threats, the World Health Assembly calls for a substantial revision to the IHR; the third edition is established by the 58th World Health Assembly (11).

International Health Regulations

The International Health Regulations (IHR) agreement forms the basis for international collaboration and coordination on detection and response to outbreaks (Box 15.1). As an international agreement, IHR is binding for all 196 World Health Organization (WHO) Member States. IHR focuses on preventing, protecting against, controlling, and responding to the international spread of disease without unnecessary interruptions to traffic and economic trade. The 2005 edition contains key changes from the previous two versions, including

  • Not limiting the scope to specific diseases or manners of transmission, but covering “illnesses or medical conditions, irrespective of origin or source,”
  • Member States’ obligations for developing core public health capacities to detect and respond to outbreaks,
  • Member States’ responsibility for notifying WHO of events that might constitute a public health emergency of international concern.
  • WHO authorization for considering unofficial reports of public health events and obtaining verification from Member States’ Parties concerning such events,
  • Procedures for WHO’s Director-General to declare a “public health emergency of international concern” and issuance of corresponding temporary recommendations (11).

A public health emergency of international concern is defined as an extraordinary event that might constitute a public health risk to other countries through international spread of disease and require an internationally coordinated response (11). Although the current IHR includes considerable responsibilities for Member States and WHO, no provisions are included for ensuring Member States comply with the legally binding agreement.

Box 15.1
International Response to Severe Acute Respiratory Syndrome

While the International Health Regulations (IHR) were being developed, the global community was responding to an outbreak of unknown origin that was named severe acute respiratory syndrome (SARS) (12). The rapid spread of SARS highlighted the importance of coordination and collaboration on international outbreak response as the virus spread across the globe in 2003. During the outbreak, information was shared electronically, thus providing detailed knowledge about the outbreak’s causative agent, mode of transmission, and other epidemiologic features. The real-time sharing of information was essential for providing guidance about clinical management and protective measures to prevent further spread. The World Health Organization issued a series of recommendations to stop international spread, and airports screened passengers for a history of contacts who were ill with SARS or clinical illness compatible with SARS. Despite remarkable spread, the outbreak was successfully contained within 4 months and represents a good example of how the IHR mechanisms can be successfully applied during coordination of outbreak responses (12).

Mechanisms of Cooperation in International Outbreak Investigations

As outlined in IHR, the responsibility for detecting, investigating, and responding to outbreaks resides within the nation’s health authority where the outbreak is occurring. At times, a nation’s capacity for responding might be overwhelmed, necessitating outside technical assistance. National health authorities might be hesitant to request assistance because of economic and political concerns, including the impact outbreaks can have on different sectors. The roles and responsibilities of different partners for international support during outbreak responses are outlined in the following sections.

Ministries of Health

Management of outbreaks by national health authorities has evolved, and most countries use some type of structured management system to respond. During the recent Ebola virus disease outbreaks, Nigeria, Liberia, Sierra Leone, and Guinea established emergency operations centers (EOCs) and an incident management system (IMS) to coordinate outbreak response and international support. Within the IMS, EOC managers established technical working groups, co-chaired by technical partners, for managing different aspects of the response (e.g., clinical management, surveillance, laboratory support, communication, and contact tracing) (13). During complex outbreaks such as Ebola, most countries coordinate requests for assistance through WHO; however, authorities might directly request assistance from partners or Member States. In addition, Member States can offer unsolicited support through diverse channels, including WHO.

WHO

The Emergency Response Directorate at WHO provides technical assistance to Member States for early detection and response to infectious disease outbreaks of international concern. In the aftermath of the Ebola epidemic, WHO experienced criticism about weak initial response and underwent a reform process for responding to outbreaks of international concern (14). This reform culminated in a World Health Assembly resolution in 2016 to adopt the Health Emergencies Programme “to deliver rapid, predictable, and comprehensive support to countries and communities as they prepare for, face or recover from emergencies caused by any type of hazard . . .” The reorganization in Geneva convened infectious disease subject-matter and emergency response experts under a centralized management system that is organized into five areas of work:

  • Infectious hazard management.
  • Country health emergency preparedness.
  • Health emergency information and risk assessment.
  • Emergency operations.
  • Core services.

This organizational structure is generally mirrored within WHO’s regional offices. WHO also maintains a roster of technical experts through the Global Outbreak Alert and Response Network (GOARN) who can support all aspects of international outbreak responses (15).

GOARN

In April 2000, WHO established a formal network of partners to respond to infectious disease outbreaks, natural disasters, and other humanitarian emergencies. GOARN is a collaboration of institutions and networks, constantly alert and ready to respond rapidly to outbreaks. Key partners include academic and scientific institutions, medical and surveillance initiatives, laboratory networks, United Nations (UN) organizations, the Red Cross (the International Committee of the Red Cross, the International Federation of Red Cross, the Red Crescent Societies, and other national assistance societies), and international humanitarian nongovernmental organizations (e.g., Médecins sans Frontières, the International Rescue Committee, Medical Emergency Relief International [also known as MERLIN], and Epicentre). The network combines human and technical resources for rapid identification, confirmation, and response to outbreaks to prevent international spread and to develop capacity regarding long-term epidemic preparedness in selected Member States. All activities are aligned with the six work streams, including

  • Strengthening GOARN policies, operational procedures, and secretariat functions.
  • Expanding participation in the network.
  • Engaging partners in alert and risk assessment activities.
  • Engaging stakeholders through communications and advocacy.
  • Developing operational research and tools.
  • Preparing training programs in outbreak response.

Each of the WHO regional offices participates in GOARN, with many having a dedicated GOARN coordinator. In WHO’s Western Pacific Region, GOARN is a component of the Asia Pacific Strategy for Emerging Diseases work plan. GOARN receives multiple requests annually to support capacity-building in emergency preparedness.

Since GOARN was created, its partners have provided support during many public health emergencies, including the West Africa Ebola epidemic (Box 15.2). In partnership with WHO, GOARN deployed more than 1,100 experts in response to Ebola, including experts in surveillance, epidemiology, case finding, contact tracing, and information management and analysis. The GOARN Emerging and Dangerous Pathogens Laboratory Network deployed more than 25 mobile laboratories with more than 200 experts for providing diagnostic assistance for rapid case confirmation (16).

Box 15.2
International Response to the Ebola Virus Disease Outbreak (2014–2016)

Whereas the response to severe acute respiratory syndrome (SARS) highlighted the effectiveness of the International Health Regulations (IHR) mechanisms, the outbreak of Ebola virus disease across West Africa highlighted remarkable shortcomings of global response capacity. Few countries had capacity to detect and respond to the outbreak as obligated in the legally binding regulations.

Key challenges included response coordination, early detection and isolation of patients, clinical management of patients, and development of a skilled workforce to support clinical care and surveillance. All countries had logistical challenges regarding building and equipping treatment centers. Early in the response, national health authorities and partners were challenged by trying to reach a consensus regarding specific strategies for the overall response.

In addition to the limited capacity of affected countries, shortcomings existed in the World Health Organization’s response, including inadequate funding, limited staffing for operational support, and limited scale of the initial response (14). Bilateral support from several countries and the Global Outbreak Alert and Response Network (GOARN) helped address operational gaps.

During the response, more than 60 Ebola treatment centers were established in Sierra Leone, Liberia, and Guinea, and more than 40 organizations and 58 foreign medical teams were deployed, including 2,500 personnel to operate these centers. In response to outbreaks in settings without treatment units, community care centers were established (16).

Despite support from GOARN and partners, the outbreak highlighted the need for stronger international surge capacity for times when countries are overwhelmed by an outbreak and the importance of improving infection control capacity in developing countries.

UN Cluster System

Outbreaks of international concern often occur in countries experiencing a humanitarian emergency. In 2005, the UN General Assembly adopted a cluster system to improve capacity for responding to humanitarian emergencies (17). The system includes groups of humanitarian organizations (UN and non-UN) working in the main sectors of humanitarian response. On occasion, the cluster system has been involved in managing outbreak response, particularly when outbreaks occur during a humanitarian emergency (e.g., the 2017 outbreak of cholera in Somalia). Historically, outbreaks often lead to such humanitarian crises as the Ebola outbreaks in West Africa. The cluster system was not activated during the Ebola outbreaks; however, the UN established its Mission for Ebola Emergency Response, which helped coordinate the response.

Global or Regional Disease Surveillance and Laboratory Networks for Diseases of International Concern

Multiple global laboratory networks support early detection and response to infectious disease outbreaks. WHO organizes and supports many of these networks, including laboratory networks for polio, measles, influenza, invasive bacterial disease, and yellow fever (18). The European Center for Disease Prevention and Control also maintains multinational surveillance networks for Legionnaires’ disease, tuberculosis, antimicrobial resistance, Creutzfeldt-Jakob disease, diphtheria, and invasive bacterial vaccine-preventable diseases (19). In 1999, the US Department of Defense established the Global Emerging Infections Surveillance and Response (GEIS) system in its overseas laboratories and medical institutions. GEIS has made key contributions during multiple outbreaks, including the first report of a new strain of pandemic influenza in 2009 (20).

Development of capacity for molecular characterization of bacterial pathogens has led to formation of surveillance networks for foodborne disease (21,22). PulseNet International is a network of seven national and regional laboratory networks dedicated to tracking reported foodborne illness cases worldwide. Participating laboratories are supported by the Centers for Disease Control and Prevention ([CDC] US Department of Health and Human Services) and use standardized genotyping methods. Subtyping and epidemiologic information are shared in real-time among participating laboratories. PulseNet provides early warning of international foodborne and waterborne disease outbreaks through detection of case clusters associated with specific subtypes. This network of networks is an efficient means of defining the international scope of such outbreaks and is a crucial component of international outbreak investigations.

Field Work During International Investigations

Field work during international outbreak investigations can be challenging and thus requires unique skills for effectively contributing to the response. Deployed personnel should learn as much as possible before deployment, not only about the disease they will be investigating but also about the country and culture in which they will be working. Challenges experienced in the field often are related to the cultural context of the outbreak and involve working in settings with limited laboratory, data management, informatics, and human resource capacity. Field staff need to be flexible and learn how to be effective despite these constraints. Key challenges related to preparedness and field work include the following:

Figure 15.1

Fig15-1

Emergency Ebola treatment center using an old hospital ward with improvised water, sanitation, and hygiene (WaSH) stations until a more suitable center could be set-up: Nigeria, 2014.

Emergency Ebola treatment center using an old hospital ward with improvised water, sanitation, and hygiene (WaSH) stations until a more suitable center could be set-up: Nigeria, 2014.

  • Clarifying roles and responsibilities. Outbreaks frequently stress national response capacity, and, at times, who is responsible for performing which tasks is unclear. International teams might receive instructions with conflicting strategies coming from different parts of the government and experience a lack of cohesion regarding the overall response. Nigeria experienced such a crisis in 2014, with the arrival of a Liberian diplomat who had Ebola virus disease. The country lacked a disease importation plan and did not have capacity for safely isolating patients. Roles and responsibilities between federal and state officials lacked clarity. The initial response included different plans for establishing treatment centers, none of which was realistic in addressing the urgent need to isolate febrile contacts of the Liberian traveler. At one point, eight febrile contacts of the Liberian traveler were living in the community without a suitable place to receive care. After considerable debate about treatment options, the health ministry established an incident command team structure by using staff from the polio EOC to manage the outbreak (23). The team quickly identified an approach for isolating patients and containing the outbreak by converting an abandoned hospital ward into a treatment center as a stop-gap measure until a more suitable location was identified (Figure 15.1). During such crisis situations, consultants should establish and maintain strong relationships with different counterparts within the response, even when contentious problems arise and disagreements occur among partners.
  • Ensuring adequate technical capacity. Field epidemiologists deployed to outbreak settings might realize they are ill-equipped to address unique challenges they face in the field. When asked to accept an international assignment, candidates should receive clear tasks or terms of reference (TORs) and only accept assignments with TORs they are able to address. This was a problem during the Ebola response where specific technical skills were needed to support safe burials, water and sanitation procedures, clinical management of patients, and infection control. To address this concern, response partners developed training programs for personnel before their deployment. Despite this training, staff sometimes needed mentoring and guidance from experienced staff during their deployment.
  • Cross-cultural sensitivity. When conducting a field investigation, field staff must be sensitive to the cultural norms of the community where they are deployed and suitably adapt their approaches to field investigations and response. For example, unique burial practices had to be considered when designing safe burial interventions during the Ebola outbreak. When designing interventions, recognizing that local counterparts might have different and equally valid approaches to problem-solving is vital.
  • Working in fragile settings. Outbreaks frequently occur in fragile states or settings within a country where government systems and service delivery might be limited. Field staff need to navigate complicated security and political concerns carefully because of mistrust and tension between the government and the communities it serves. In such settings, engaging civil society organizations or community leaders as interlocutors to support field work and the response is often helpful. Neutral access negotiators (e.g., the Red Cross) can communicate with community leaders in affected areas and help recruit local teams from the affected communities to assist with the response.
  • Data and sample sharing. Nothing will get a field investigator a premature airplane ride home quicker than inappropriate sharing of data or clinical samples. Data or clinical sample sharing is often a contentious concern, and recognizing the sovereignty of national data and seeking permission of health authorities are crucial. Data sharing between institutions can also be contentious. Best practices include submitting all requests in writing and have a data sharing agreement with national health authorities; these actions will help ensure that everyone has a firm understanding of what data and clinical samples can be shared.

 

Conclusion

Although considerable progress has been made on coordinating international outbreak response, the publication and revision of the IHR did not prevent the spread of Ebola in West Africa and highlights the need for continued refinement of global response to international outbreaks. Since 2009, there have been four declarations of public health emergencies of international concern. With each declaration, WHO and the global community have gained experience and learned lessons on coordinating response. Key efforts to support WHO include the work of GOARN, the global laboratory networks, and support from key organizations and Member States.

References
  1. Thucydides. History of the Peloponnesian War. Book 2. Oxford: Clarendon Press; 1900:137–40.
  2. Kazanjian P. Ebola in antiquity? Clin Infect Dis. 2015;61:963–8.
  3. Olson PE, Hames CS, Benenson AS, Genovese EN. Thucydides syndrome: Ebola déjà vu? (or Ebola reemergent?). Emerg Infect Dis. 1996;2:155–6.
  4. Pappas G, Kiriaze IJ, Falagas ME. Insights into infectious disease in the era of Hippocrates. Int J Infect Dis. 2008;12:347–50.
  5. Dehnhardt WL. ¿Hubo infectólogos en la Antigua Roma? [in Spanish]. Rev Chil Infect. 2010;27:165–9.
  6. Sabbatani S. Excursus sull’organizzazione dell’assistenza in tempi di pestilenza [Italian]. Le Infezioni in Medicina. 2003;3:161–7.
  7. McLeod KS. Our sense of Snow: the myth of John Snow in medical geography. Soc Sci Med. 2000;50:923–35.
  8. Koch T. 1831: The map that launched the idea of global health. Int J Epidemiol. 2014;43:1014–20.
  9. Brigham A. A treatise on epidemic cholera. including an historical account of its origin and progress, to the present period: compiled from the most authentic sources. Hartford, CT: H and F J Huntington; 1832.
  10. WHO. Origin and development of health cooperation. http://www.who.int/global_health_histories/background/en/external icon
  11. WHO. International Health Regulations (2005). 3rd ed. Geneva, Switzerland: WHO; 2016. p. 84. http://www.who.int/ihr/publications/9789241580496/en/external icon
  12. Heymann DL. The international response to the outbreak of SARS in 2003. Philos Trans R Soc Lond B Biol Sci. 2004;359:1127–9.
  13. Centers for Disease Control and Prevention. CDC’s response to the 2014–2016 Ebola epidemic—West Africa and United States. MMWR Suppl. 2016;65(Suppl 3):1–112.
  14. Woodall J. WHO reform: bring back GOARN and Task Force “Scorpio.” Infect Ecol Epidemiol. 2016;6:30237.
  15. WHO. Global Outbreak Alert and Response Network (GOARN). http://www.who.int/ihr/alert_and_response/outbreak-network/en/external icon
  16. WHO. 2015 WHO Strategic Response Plan, West Africa Ebola outbreak. http://www.who.int/csr/resources/publications/ebola/ebola-strategic-plan/en/external icon
  17. United Nations. Strengthening the coordination of humanitarian emergency assistance of the United Nations. Resolution 46/182. http://www.un.org/Docs/journal/asp/ws.asp?m=A/RES/46/182external icon
  18. WHO. Laboratory networks. http://www.who.int/immunization/monitoring_surveillance/burden/laboratory/en/external icon
  19. European Centre for Disease Prevention and Control. EUVAC.Net. http://ecdc.europa.eu/en/healthtopics/vaccine-preventable-diseases/euvac/Pages/index.aspxexternal icon
  20. Fry AM, Hancock K, Patel M, et al. The first cases of 2009 pandemic influenza A (H1N1) virus infection in the United States: a serologic investigation demonstrating early transmission. Influenza Other Respi Viruses. 2012;6:e48–53.
  21. Swaminathan B, Barrett TJ, Hunter SB, Tauxe R V. PulseNet: the molecular subtyping network for foodborne bacterial disease surveillance, United States. Emerg Infect Dis. 2001;7:382–9.
  22. Kirk MD, Little CL, Lem M, et al. An outbreak due to peanuts in their shell caused by Salmonella enterica serotypes Stanley and Newport—sharing molecular information to solve international outbreaks. Epidemiol Infect. 2004;132:571–7.
  23. Shuaib F, Gunnala R, Musa EO, et al. Ebola virus disease outbreak—Nigeria, July–September 2014. MMWR. 2014;63:849–54.