Lessons from Ebola and readiness for new emerging infectious threats
Authors: Michelle A. Barron, Donald Y.M. Leung
Journal: Journal of Allergy and Clinical Immunology (2015)

Throughout history, human subjects have served as incidental hosts to many infectious diseases that have resulted in epidemics. Many of these infectious diseases are vector-borne or zoonotic in origin. In more recent times, the global spread of HIV-1, outbreaks related to avian influenza, and the emergence of severe acute respiratory syndrome and Middle Eastern respiratory syndrome, to name a few, profoundly illustrate how an infection can spread worldwide in a very rapid fashion (Table I).1WHO, Global Alert and Response (GAR), disease outbreaks by year. Available at: http://www.who.int/csr/don/archive/year/en/. Accessed January 12, 2015.Google Scholar In this issue of the Journal, Kampmann et al2Kampmann B. Roca A. Saidu Y. Ebola: a holistic approach is required to achieve effective management and control.J Allergy Clin Immunol. 2015; 135: 856-867Abstract Full Text Full Text PDF Scopus (37) Google Scholar and Lindblad et al3Lindblad R. El Fiky A. Zajdowicz T. Ebola in the United States: current perspectives.J Allergy Clin Immunol. 2015; 135: 868-871Abstract Full Text Full Text PDF Scopus (4) Google Scholar describe the ongoing Ebola virus disease (EVD) outbreak that is currently ravaging West Africa, and Petidemange et al4Petitdemange C. Wauquier N. Vieillard V. Control of immunopathology during chikungunya virus infection.J Allergy Clin Immunol. 2015; 135: 846-855Abstract Full Text Full Text PDF Scopus (48) Google Scholar describe how the immune system might be promoting the viral spread and immunopathology of chikungunya virus (CHIKV) infection.Table IEmerging and re-emerging infectious disease outbreaks, 2005-20141WHO, Global Alert and Response (GAR), disease outbreaks by year. Available at: http://www.who.int/csr/don/archive/year/en/. Accessed January 12, 2015.Google ScholarEmerging or re-emerging infectious diseaseYear(s) of epidemicsGeographic distributionNo. of reported casesNo. of reported deathsEbola hemorrhagic virus2014-present∗Data are current as of January 3, 2015.Nigeria, Sierra Leone, Mali, DRC, Liberia, Guinea, Senegal, Spain, United Kingdom, United States20,7478,2352005-2012Uganda, DRC, RC247101Chikungunya virus2014American Samoa1,1480Florida1102013-2014Caribbean Islands, including Puerto Rico and USVI10,800 (Puerto Rico, 3,801; USVI, 183)42006India1.25 million0Mayotte2,8330Mauritius6,0000Seychelles8,8180La Réunion Island (France)3,1150Avian influenza (H7N9)2014-presentChina115Middle Eastern respiratory syndrome (MERS-CoV)2012-presentSaudi Arabia, United Arab Emirates, Qatar, Oman, Jordan, Kuwait, Yemen, Iran, Lebanon941347Lassa fever2012Nigeria62470Pandemic H1N1 2009 influenza2009-2010Worldwide651,44918,449Enterovirus 712008, 2012Cambodia, China4,57476Dengue hemorrhagic virus2008-2012Portugal, Cape Verde, Brazil, Madagascar, Timor-Leste139,9604,894Rift Valley fever2006-2012Mauritania, South Africa, Madagascar, Sudan, Kenya, Somalia1,624379Marburg hemorrhagic virus2005-2014Angola, Uganda, Netherlands396340Avian influenza (H5N1)2005-2014Cambodia, Indonesia, Egypt, Hong Kong, Cambodia, Laos, Bangladesh, Turkey, Iraq, Azerbaijan, Pakistan, China, Thailand, Vietnam, Myanmar, Djibouti, Canada, Nigeria649385Plague2005-2014Madagascar, Peru, China, DRC1,423147Cholera2005-2013Mexico, Sierra Leone, DRC, RC, Haiti, Pakistan, Zimbabwe, Iraq, Guinea Bissau, Vietnam, Sudan, Angola, Benin, Burkina Faso, Guinea-Bissau, Mali, Mauritania, Niger, Senegal334,43011,123Yellow fever2005-2013Sudan, Cameroon, DRC, Mali, Ethiopia, Chad, RC, Cameroon, Ghana, Senegal, Sierra Leone, Côte d'Ivoire, Guinea, Uganda, Central African, Republic, Liberia, Burkina Faso, Paraguay, Brazil1,371358DRC, Democratic Republic of the Congo; RC, Republic of the Congo; USVI, US Virgin Islands.∗ Data are current as of January 3, 2015. Open table in a new tab DRC, Democratic Republic of the Congo; RC, Republic of the Congo; USVI, US Virgin Islands. In 2013, global mortality caused by infectious disease was attributed to lower respiratory tract infections (2.7 million), HIV/AIDS (1.3 million), tuberculosis (1.3 million), and diarrheal disease (2.0 million).5GBD 2013 Mortality and Causes of Death CollaboratorsGlobal, regional, and national age–sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.Lancet. 2015; 385: 117-171Abstract Full Text Full Text PDF PubMed Scopus (5920) Google Scholar The global burden caused by emerging and re-emerging infectious diseases is difficult to predict because the effect on human populations depends on the rate and degree to which they spread across geographic areas. Factors that can contribute to the emergence/re-emergence of infectious diseases include biological, genetic, economic, environmental, political, and social factors.6Morens D.M. Folkers G.K. Fauci A.S. The challenge of emerging and re-emerging infectious diseases.Nature. 2004; 430: 242-249Crossref PubMed Scopus (1457) Google Scholar EVD is a re-emerging virus in which biologic, economic, political, and social factors are all contributing to the current epidemic in West Africa. Ebola viruses, members of the Filoviridae family, were discovered in 1976 and have been responsible for major outbreaks of hemorrhagic fever in Africa since that time. From 1976-2013, the vast majority of outbreaks have occurred in remote rural locations in central African countries.7Feldmann H. Geisbert T.W. Ebola haemorrhagic fever.Lancet. 2011; 377: 849-862Abstract Full Text Full Text PDF PubMed Scopus (1022) Google Scholar The current outbreak in West Africa was first recognized in March 2014 in Guinea.8Dixon M.G. Schafer I.J. Ebola viral disease outbreak—West Africa, 2014.Morb Mortal Wkly Rep. 2014; 63: 548-591PubMed Google Scholar The outbreak quickly spread to involve neighboring Liberia and then Sierra Leone. There are intensive ongoing efforts to contain this outbreak. As of January 5, 2015, there have been in excess of 20,000 confirmed, probable, and suspected cases of EVD in Guinea, Liberia, and Sierra Leone, with more than 8000 deaths (http://www.who.int/csr/disease/ebola/situation-reports/en/?m=20150107). The long incubation period of the disease (1-21 days) and the thousands of travelers from the affected areas that enter the United States, Europe, Asia, and other parts of Africa raised concerns for global spread of this disease. The US Centers for Disease Control and Prevention urged clinicians to be alert to the possibility of Ebola virus. Travel history to a country with ongoing EVD outbreaks should prompt isolation of subjects until symptoms and need for testing can be assessed. Use of personal protective equipment, including gowns, gloves, masks, and eye protection, along with standard infection control practices, were also recommended.9Frieden T.R. Damon I. Bell B.P. Kenyon T. Nichol S. Ebola 2014—new challenges, new global response and responsibility.N Engl J Med. 2014; 371: 1177-1180Crossref PubMed Scopus (190) Google Scholar These recommendations proved to be insufficient when a patient from Liberia presented to a Dallas, Texas, hospital emergency department on September 25, 2014, with fever, abdominal pain, and headache and was given the misdiagnosis of sinusitis. The patient was subsequently confirmed as the first imported case of EVD. Forty-eight close contacts without the use of complete personal protective equipment were identified, including 21 health care workers with potential exposures to body fluid. All 48 contacts were placed under direct monitoring for 21 days after the last exposure. The patient died on October 8, 2014. Three days after the patient's death, a nurse involved in the patient's care had a fever and was given a diagnosis of EVD. A second nurse with similar exposure to the patient who had died presented 6 days after the patient's death with rash and fever and was also subsequently given a diagnosis of EVD.10Chevalier M.S. Chung W. Smith J. Weil L.M. Hughes S.M. Joyner S.N. et al.Ebola virus disease cluster in the United States—Dallas County, Texas, 2014.Morb Mortal Wkly Rep. 2014; 63: 1087-1089PubMed Google Scholar Both nurses were hospitalized and recovered without incident. The use of humanized mAbs targeting Ebola virus and convalescent plasma from EVD survivors, as well as new antivirals, are being investigated for the treatment of those with EVD.3Lindblad R. El Fiky A. Zajdowicz T. Ebola in the United States: current perspectives.J Allergy Clin Immunol. 2015; 135: 868-871Abstract Full Text Full Text PDF Scopus (4) Google Scholar Three clinical trials are expected to begin in Ebola treatment centers in Guinea and Liberia in early 2015. This has raised many issues regarding optimal clinical trial design and the ethics of not making a potentially lifesaving treatment available immediately. Although these treatment strategies provide hope, the largest challenge that remains includes addressing the cultural paradigms that have contributed to the spread of the disease and restoration of a functional health infrastructure in countries that have been plagued by war and civil unrest.2Kampmann B. Roca A. Saidu Y. Ebola: a holistic approach is required to achieve effective management and control.J Allergy Clin Immunol. 2015; 135: 856-867Abstract Full Text Full Text PDF Scopus (37) Google Scholar Ebola virus has garnered significant media attention because of the high mortality rate and the lack of commercially available treatments. Similar media attention has not been generated for CHIKV, although the significance of this disease cannot be underestimated. CHIKV is a mosquito-transmitted RNA virus first isolated from a patient in Tanzania in 1953 during a large outbreak of severe fever associated with crippling joint aches. Since that time, periodic outbreaks have been reported in Asian and African countries.11Morrison T.E. Reemergence of Chikungunya virus.J Virol. 2014; 88: 11644-11657Crossref PubMed Scopus (217) Google Scholar The global spread of CHIKV has been dramatic. Within the last 10 years, the virus has spread from Africa to more than 80 countries on 5 continents, with 6 million confirmed cases and the most recent epidemics occurring in the Caribbean (Fig 1). It is noteworthy that in epidemics, cyclical transmission with a human-mosquito-human pattern can occur, allowing for rapid geographic distribution of this virus through travelers who are viremic and subsequently transmit the virus to local mosquitoes and back to human subjects.11Morrison T.E. Reemergence of Chikungunya virus.J Virol. 2014; 88: 11644-11657Crossref PubMed Scopus (217) Google Scholar This mechanism has also been seen in dengue fever, yellow fever, and West Nile virus. In addition, the more recent epidemics have been associated with a higher degree of morbidity and mortality. There is no population immunity to CHIKV in the Americas; as a result, it is anticipated that the number of cases will increase and spread to new areas in the region.12Staples J.E. Fischer M. Chikungunya virus in the Americas—what a vectorborne pathogen can do.N Engl J Med. 2014; 371: 887-889Crossref PubMed Scopus (112) Google Scholar The role of the immune response to CHIKV suggests a correlation with degree of illness and persistence of symptoms after resolution of the initial viremia.4Petitdemange C. Wauquier N. Vieillard V. Control of immunopathology during chikungunya virus infection.J Allergy Clin Immunol. 2015; 135: 846-855Abstract Full Text Full Text PDF Scopus (48) Google Scholar Preventative vaccines and the use of hyperimmune globulin for treatment remain in the early stages of investigation. What lessons have we learned from current and past epidemics caused by emerging or re-emerging diseases? First, travel and exposure history are extremely important and should be part of the standard questions asked of patients at every visit. With the increasing use of electronic medical records, development of a simplified algorithm that can question travel history at the time of intake can be used to identify patients who might be at risk. Second, surveillance efforts are very important in identifying new or re-emerging infections. Clinicians should have a low threshold for reporting clusters of unexpected infections to their public health departments. Third, more information about host susceptibility is needed. CHIKV was first identified as a pathogen decades ago when the prevalence of allergic disease was low. The prevalence of allergic diseases has reached epidemic proportions in the past 4 decades (more than one third of the general population). Unlike original sporadic cases when first described, the recent outbreak of CHIKV has been explosive. It is known that patients with allergic diseases, such as atopic dermatitis, are prone to disseminated viral infection, such as eczema herpeticum or eczema vaccinatum.13Bin L. Edwards M.G. Heiser R. Streib J.E. Richers B. Hall C.F. et al.Identification of novel gene signatures in patients with atopic dermatitis complicated by eczema herpeticum.J Allergy Clin Immunol. 2014; 134: 848-855Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar Work is needed to determine whether atopic status and the route of entry, such as intradermal inoculation of CHIKV by mosquito bites, might place patients with atopic dermatitis at high risk of disseminated viral infection. Indeed, patients with atopic dermatitis vaccinated transcutaneously have reduced neutralization antibodies to yellow fever virus that correlate with their serum IgE levels.14Slifka M.K. Leung D.Y.M. Hammarlund E. Raue H.P. Simpson E.L. Tofte S. et al.Transcutaneous yellow fever vaccination of subjects with or without atopic dermatitis.J Allergy Clin Immunol. 2014; 133: 439-447Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar More recently, intradermal Fluzone (Sanofi Pasteur, Swiftwater, Pa) was found to induce lower influenza hemagglutination inhibition antibody titers in patients with atopic dermatitis colonized with Staphylococcus aureus.15Leung D.Y.M. Beck L.A. Hanifin J.M. Schneider L.C. Paller A. David G. et al.A randomized, multi-center, NIH/NIAID funded study to assess the immunogenicity Of Fluzone intradermal and intramuscular vaccines in atopic dermatitis.J Allergy Clin Immunol. 2014; 133 ([abstract]): AB72Abstract Full Text Full Text PDF Google Scholar Lastly, research and development of vaccines and novel therapies for these types of infections are important and might be the only long-term solution to prevent further spread. Ebola in the United StatesJournal of Allergy and Clinical ImmunologyVol. 135Issue 4PreviewThe ongoing epidemic of Ebola virus in West Africa and attendant cases described in other parts of the world has focused attention on this heretofore rare disease. In this brief opinion article, we provide a short primer on the epidemiology, pathogenesis, clinical manifestations, US-based hospital preparedness, vaccine and therapy development, and control of Ebola virus disease for noninfectious disease physicians. Full-Text PDF