Ebola virus disease (EVD) was first identified in humans in 1976 and was quickly recognized to be a highly contagious illness with a high fatality rate during multiple small and sporadic outbreaks, which arose in remote, isolated villages primarily in central Africa through 2012. The disease was known to cause marked gastrointestinal symptoms with profound watery diarrhea, electrolyte abnormalities, occasional bleeding, and organ failure leading to death in 60–90 percent of patients. EVD is caused by any one of several subtypes of ebolavirus (with the most common causative agent being Zaire Ebola virus, or EBOV) in the family filovidirae, along with Marburg virus—a viral pathogen with similar presenting symptoms and fatality rates.1
The 2013–2016 West African Ebola outbreak is by far the largest and most complex outbreak of EVD in history. It is the first to spread in large population centers (including national capitals) as well as abroad via air travel. It is believed that this outbreak began in December 2013 with a child in Guinea. From this index case, EVD spread rapidly in Guinea and to neighboring Sierra Leone and Liberia—fueled by poverty, poor national health care infrastructures, suboptimal sanitation and waste disposal, and local customs (especially surrounding death) that exposed many community members to EBOV during burial rituals, which can persist for many days on corpses of those who have died from EVD. Given the slow initial pace of the international governmental response to the accelerating outbreak, distant spread by air travel to other countries in Africa (e.g., Nigeria, Mali) as well as resource-rich settings like the United States seemed unavoidable. Furthermore, as the global response accelerated, there was a dramatic rise of health care workers (HCWs) from other continents traveling to provide medical assistance, including direct patient care throughout the affected region. Almost inevitably, numerous HCWs developed EVD and were evacuated by their governments to their home countries.
The first cases of EVD in resource-rich settings arrived via medical evacuation of two HCWs to Emory University Hospital (EUH) in Atlanta, Georgia, in early August 2014, which were followed shortly by other HCWs who were evacuated to Spain, the United Kingdom, France, Germany, and Italy. As of October 2, 2015, there have been nearly 30 known cases of EVD managed in North America and Europe to date and a total of 28,412 cases and 11,296 deaths globally as a result of the ongoing outbreak.2
This chapter will focus on the clinical management of EVD in resource-rich settings and the lessons learned and applied in managing EVD. Moving forward, understanding the lessons and implications of EVD management in resource-rich settings will hopefully provide a model for governments, public health agencies, hospital, and clinicians to develop robust global infrastructures to better respond to future outbreaks and pandemics of other transmissible high-risk infections.
There are few centers in the United States and Western Europe equipped to care for highly infectious illnesses under strict biocontainment isolation protocols. Under contract from the US Centers for Disease Control and Prevention, EUH has long maintained, operated, and staffed one such facility. The design of a biocontainment facility and the unique challenges to patient care and protocols have been developed and published in the past,3 but these biocontainment facilities and procedures have rarely been tested and challenged previously, except during the 2002–2003 SARS outbreak. Furthermore, the challenges of maintaining staffing and biocontainment skills training for such a facility, which had only been very rarely used throughout its existence, cannot be understated.
As EUH and other hospitals became aware that they would be receiving evacuated individuals with EVD, preparations to receive patients had to be accelerated. These preparations included refreshing skills for facility staff still employed at each center, as well as identifying and training new clinical staff—namely, subspecialty physicians (e.g., critical care, anesthesia, etc.) and additional nurses and ancillary staff to provide appropriate staffing levels to care for multiple concurrent patients. Published protocols and guidelines served as the basis for the local protocols at EUH.4
While the basics of EVD and its clinical course have been widely described from the current and prior outbreaks,5 few HCWs at these biocontainment facilities (and none at EUH) had direct firsthand experience of EVD management. As a result, collaboration between national and international experts was necessary to develop the capacity to treat patients with EVD. Furthermore, given the inadequate development of national health care resources in Guinea, Sierra Leone, and Liberia and the isolated nature of prior outbreaks, little was known about the spectrum of clinical phenotypes of EVD beyond the described high fevers, gastroenteritis with brisk vomiting and diarrhea, hepatitis, encephalopathy (i.e., confusion and lethargy), and occasional hemorrhage.
Like most viral illnesses, it was assumed that patients would present with a range of symptoms and severity. However, no publications had described this range of symptoms prior to the arrival of the first evacuated HCWs with EVD. As facilities prepared to care for EVD evacuees in resource-rich settings, many clinical teams were uncertain of the full spectrum of clinical needs these patients would require. Would the patients require advanced life support interventions such as mechanical ventilation for respiratory failure, vasopressors for shock, or renal replacement therapies (i.e., hemodialysis) for acute kidney failure? Could such therapies be provided in an isolation environment? From personal communications with clinicians who initially responded to the outbreak in West Africa, all reported an absence of respiratory manifestations, but would this be the case in resource-rich settings? At a minimum, biocontainment centers around the world were inexperienced at providing advanced life support therapies (e.g., mechanical ventilation, hemodialysis, invasive procedures) in isolation. Ultimately, despite attempts to prepare, when challenged with critically ill patients, protocols for these advanced services had to be developed on the fly.
Following infection by contact with infected bodily fluid, there is an incubation period of 2–21 days prior to the onset of EVD symptoms, which most commonly begin with profound fatigue, headache, poor appetite (anorexia), fevers, muscle and joint pains, and rash.6 This initial prodromal phase of illness is followed by a gastroenteritis/hepatitis phase characterized by progressive high spiking fevers, nausea with occasional vomiting, and voluminous watery diarrhea (as much as 10–12 L/day). Complications of this brisk diarrhea can include severe electrolyte disturbances and dehydration. Furthermore, there is evidence of liver inflammation (hepatitis) and muscle injury.7 In the absence of advanced life support measures or inadequate access to basic oral or intravenous rehydration solutions in resource-poor settings, it is during this gastroenteritis/hepatitis phase of illness that most fatalities from EVD occur as a result of complications from diarrhea and dehydration, leading to organ failure and death.8
While taking care of a patient with EVD can never be taken lightly or for granted, as biocontainment isolation units in resource-rich settings prepared to possibly care for EVD evacuees, it was felt that mortality rates should be much lower than in West Africa. Specifically, in these settings, ready access to oral and intravenous rehydration options, laboratory support, and electrolyte replacement options would, in theory, minimize the risk of death during this diarrheal phase, allowing for a patient’s native immune system to develop a response and clear the infection. Early experience treating EVD in resource-rich settings followed such a pattern, with the first two cases cared for at Emory demonstrating moderate symptoms over these early phases followed by steady decline in viral load and recovery to hospital discharge.9 Shortly after Emory’s initial experience, a UK national contracted EVD in Sierra Leone and was evacuated to London; his course of disease demonstrated a similar pattern to the Emory experience.10
While these early experiences demonstrated that supportive care was an effective treatment plan for EVD, concern remained given that these early cases experienced only moderate viral loads11 as initial and peak viral loads are known to correlate with mortality.12 Thus, it was acknowledged that the spectrum of clinical effects (phenotype), especially in severe EVD, remained unclear. However, beginning with a third case treated at EUH in September 2014, it became evident that EVD may manifest in a more severe form, leading to multi-organ failure requiring advanced life support, including acute hemodialysis and mechanical ventilation.13
This patient at EUH had high viral loads at diagnosis, which progressively increased to markedly high levels over the first 10 days of illness. The course of disease in this case was characterized, as usual, by high fevers, voluminous diarrhea, acute hepatitis, and poor appetite over the first week. However, beginning approximately on day 8 of illness, the patient’s mental status deteriorated, with progressive confusion and encephalopathy. He also developed worsening oxygen levels (hypoxia), respiratory distress, and kidney failure. As a result, on day 9 of illness, with development of progressive respiratory failure, advanced life support was required to prevent his death.14 Thus, this patient became the first EVD patient in the world known to have been managed with invasive mechanical ventilation and renal replacement therapy (i.e., continuous hemodialysis).15 Over the next 12 months, approximately 30 total EVD patients have been managed to date in the resource-rich settings of North America and Europe, several of whom became critically ill with severe EVD requiring advanced life support.16
With the above experiences in resource-rich settings, it has become clear that patients with EVD presenting with high viral loads and high peak viral loads have experienced a common pattern of multi-organ failure. While patients with mild to moderate EVD begin to experience resolution of fever, gastrointestinal, and other symptoms around days 8–10 of illness, patients with severe EVD and high viral loads develop progression of symptoms during days 8–12 of illness, characterized by the development of respiratory distress, pulmonary edema, decreasing urine output, acute kidney failure, and worsening mental status (i.e., encephalopathy).17 Specifically, respiratory distress and hypoxia have led to respiratory failure, requiring both noninvasive ventilation support and invasive mechanical ventilation. Acute kidney failure has necessitated the use of renal replacement therapy in several reported18 and unreported cases (personal communication, T. Uyeki, US Centers for Disease Control and Prevention).
By enabling multiple critically ill patients with severe EVD to survive, recover, and ultimately be discharged from the hospital, advanced life support for critical illness has contributed to a decrease in mortality from severe EVD in resource-rich settings (i.e., the United States and Europe) to as low as approximately 20 percent to date. However, despite advanced care options in the United States and Europe, severe EVD remains a potentially fatal disease, with multiple patients experiencing complications, including secondary bacterial infections, abdominal insults, fatal cardiac arrhythmias, and/or death.19 Unfortunately, given the limitations of care that still persist in biocontainment isolation (i.e., incomplete access to advanced imaging), the terminal events leading to death in fatal cases in the United States and Europe remain unclear.20
Biocontainment isolation for life-threatening communicable infectious diseases like EVD is used primarily as a means to isolate the patients from the general population and, more specifically, the greater hospital population (patients and HCWs) in an effort to limit the risk of disease transmission. However, it must be noted that managing a complex disease such as EVD in biocontainment isolation has proven a unique challenge for health care providers used to the comforts of contemporary acute care in modern tertiary hospital settings. All aspects of care are impacted by biocontainment isolation and personal protective equipment (PPE). Physical exams with stethoscopes and other techniques are markedly hampered by PPE, and patients are physically isolated in rooms with immediate access only to a nurse rather than the whole team of HCWs, as is standard in modern advanced health care settings, especially in intensive care units. When caring for a patient in strict biocontainment isolation, safety is of paramount importance and involves attention to patient safety, HCW safety, and population safety.21
Strict biocontainment isolation introduces risk for the patient. Whereas in a typical hospital setting, HCWs are usually readily available to assist a critically ill patient during an acute life-threatening event, in strict biocontainment isolation, there are a limited number of HCWs trained to provide care, and PPE and other barriers slow ease of access to the patient during an emergency situation. For example, if the patient has sudden breathing difficulty, bleeding, or other acute issues, it will take at least 10–15 minutes for additional HCWs to properly and safely don PPE in order to enter the isolation environment.
At the EUH biocontainment facility, a nurse was present inside the isolation room at all times, in full PPE, to care for the patient. Given the diversity of patient clinical needs, the potential need for advanced life support, and the isolation of the nurse from immediate support as discussed above, EUH only utilized intensive care unit nurse specialists with broad nursing expertise and experience to function in this role.
As the complexity of patients’ needs increased to include advanced life support, protocols and systems were put in place to help the nurse in the case of an emergency. In modern intensive care units, should an emergency occur—such as failure of mechanical ventilator, unplanned extubation (removal of breathing tube), cardiac arrest, bleeding, or complications from hemodialysis, and so on—help and support for the nurse is immediately available. However, in our biocontainment facility, the nurse would be addressing these sudden events without physical assistance for at least 10–15 minutes while other staff members donned PPE. As such, the nurse needed necessary equipment, training, and support to address these issues as soon as possible in order to maximize patient safety.
EBOV is transmitted to unprotected HCWs and other caregivers via contact with bodily fluids that contain viable virus (i.e., blood, sweat, gastric contents, stool/diarrhea, urine, semen, etc.). As a result, aside from isolating patients, all HCWs must use extensive PPE to protect themselves from exposure and minimize risk of transfer of the viral particles outside of the isolation environment. While PPE decreases HCW exposure and risk, it does not eliminate risk and can in fact introduce risk of transmission if there are failures of PPE equipment or the donning/doffing procedure.22 Given that every intervention/interaction with the patient has risk of disease transmission to HCWs, careful planning must be undertaken prior to all routine and, especially, complex interactions.
Maximizing HCW safety must go beyond proper PPE. At EUH, like other institutions, a constant buddy system was used to support all HCWs in PPE in the isolation room by providing easy communication and support in the isolation room. All donning and doffing of PPE is directed step by step and supervised by the buddy. HCW fatigue promotes errors, and wearing PPE causes fatigue quickly; thus, nurses were rotated out of the isolation room every 3–4 hours. Attempts were made to minimize risks of exposure to infected body fluids or possible needle sticks: central venous line for needleless blood draws inserted on admission, batching blood and sample collections, bowel management system to contain diarrhea, and frequent cleaning of environmental surfaces in the isolation room by HCWs. Furthermore, frequent PPE donning/doffing refresher training was provided for less frequent users (e.g., physicians, technicians, etc.). All unnecessary staff entry to isolation room was avoided; one or two physicians would examine the patient daily, and consultants were not admitted to the isolation room unless a necessary procedure or subspecialty-specific intervention was required.
Finally, in resource-rich settings, HCWs and administrations must redefine “success” when treating EVD. Rather than the norm, in which HCWs provide care to acutely ill patients with little regard for their own safety, HCW safety (i.e., no secondary HCW infections) must be included as a barometer of “successful” treatment of EVD or high-risk, highly contagious illnesses like EVD. In other words, rather than a sole focus on patient outcome as is the usual practice in resource-rich settings, successful treatment of EVD should be defined as no secondary transmission while striving for the best possible patient outcome.
Finally, while ethicists correctly argue that HCWs have an ethical duty to treat patients with EVD and other communicable diseases,23 this does not obviate the necessity to protect HCWs from infection to the fullest extent possible. In West Africa, deaths of HCWs from EVD have devastated an already unacceptably small core of HCWs and will have long-term ramifications on a fragile health care system,24 with a total of 880 confirmed HCW infections and 512 HCW deaths during the current outbreak.25
The final aspect of safety that must be considered is the hospital and population safety at large. EVD-infected patients must be isolated to minimize the risk to the general hospital and the surrounding community. At EUH and other resource-rich settings, this is accomplished by biocontainment isolation, in which patients are quarantined until infection has resolved and the virus has cleared from blood. Biocontainment isolation also necessitates a plan to manage highly infectious human and biomedical waste products. At EUH, local government and health department regulations governed methods for disposal of medical waste and bodily fluids. All medical equipment used on any given patient remained sequestered in the isolation room until terminal decontamination after patient discharge.
Furthermore, to limit risk to the rest of the hospital at EUH, all labs were processed in the biocontainment facility by specially trained lab technicians using point-of-care technology.26 The isolated EVD patients did not leave the isolation environment for advanced imaging or tests (i.e., no CT scans, MRIs, etc.). Staff underwent rigorous twice-daily temperature monitoring for 21 days after last known EVD contact.
The only proven effective therapy for EVD remains advanced supportive care. However, almost all patients managed in resource-rich settings have received some combination of experimental therapies in an uncontrolled fashion administered outside rigorous clinical trials in a desperate search for possible new treatment strategies. Bishop recently published a summary of experimental therapies, which have included: 1) humanized monoclonal antibodies (ZMapp); 2) convalescent human plasma (i.e., plasma from EVD survivors to share EVD-specific antibodies); 3) small interfering RNA (TKM-100802); 4) antiviral agents (e.g., brincidofovir, favipiravir, and others).27 Furthermore, Büttner et al. describe direct virus elimination from blood with a blood-purification technique called lectin affinity plasmapharesis.28 The patients managed at EUH received ZMapp, TKM-100802, and/or convalescent plasma transfusions.29 This uncontrolled use of multiple experimental therapies outside of rigorous clinical trials in the early care of EVD in the United States and Europe will make it very difficult to ascertain if any specific therapy was effective. There are now several randomized clinical trials attempting to scientifically evaluate these experimental therapies, including favipiravir (clinicaltrials.gov identifier NCT02329054), ZMapp (clinicaltrials.gov identifier NCT02363322), and convalescent plasma (clinicaltrials.gov identifier NCT02333578). However, as the current outbreak is thankfully waning, the number of patients eligible to enroll in these trials in the United States and Europe will be very limited.
EVD remains a complex, life-threatening illness. The only proven therapy remains advanced supportive care and life support. While biocontainment isolation does introduce new challenges in the care of critically ill patients, experiences around the world with EVD since 2014 have demonstrated that advanced life support can and should be provided safely in biocontainment isolation. While the tragedy of the current 2013–2016 EVD outbreak cannot be overstated, with over 11,000 deaths around the world, the dangers posed by EVD have yielded an invaluable opportunity for global pandemic preparedness to be tested and more robust systems developed. Given the risks of epidemic/pandemic potential posed by serious emerging infections made easier by the speed of global travel in the modern era, it would be disappointing if the lessons learned in the management of EVD around the world in this outbreak do not provide a model for governments, public health, hospitals, and clinicians to develop more robust global infrastructures to better respond in the future.