By Alexander S. Niven, MD
Associate Professor, Uniformed Services University of the Health Sciences, Clinical Associate Professor, University of Washington; Director, Medical Education and Research, Madigan Army Medical Center, Tacoma, WA
Dr. Niven reports no financial relationships relevant to this field of study.
The latest severe outbreak of Ebola virus disease (EVD) has resulted in approximately 28,424 confirmed or suspected cases and 11,296 deaths, with sporadic cases continuing in both Guinea and Sierra Leone.1 The massive scope of this severe outbreak included these countries and Liberia, with extension of EVD cases to local neighboring nations (including Mali, Nigeria, and Senegal) and to Europe and North America. The spread of EVD to developed countries has triggered massive government and medical efforts to better understand, prepare for, and manage potential EVD cases, and the relatively few confirmed cases in the United States last year triggered a frenzy of media coverage and widespread public concern.
The purpose of this special feature is to review what we have learned from the latest EVD outbreak about the presentation and management of patients with this deadly disease, our growing understanding of the manifestations and care of severe EVD in “resource-rich” environments, and healthcare system preparedness for the next outbreak one year after the first EVD case was reported in the United States.
EVD: EPIDEMIOLOGY, PATHOGENESIS, AND CLINICAL PRESENATION IN WEST AFRICA
The viral hemorrhagic fever now known as EVD was first discovered in 1976 near the Ebola River in what is now the Democratic Republic of Congo. There are five identified species of the family Filoviridae, genus Ebolavirus. Four are known to cause disease in humans: Ebola virus (Zaire ebolavirus, the cause in the 2014 outbreak); Sudan virus (Sudan ebolavirus); Taï Forest virus (Taï Forest ebolavirus, formerly Côte d’Ivoire ebolavirus); and Bundibugyo virus (Bundibugyo ebolavirus). The natural reservoir host of the Ebolavirus remains unknown, although experts suspect fruit bats are the most likely source. Both humans and other primates are susceptible end hosts.2
Transmission of Ebola virus is through direct contact of infected blood or body fluids (urine, saliva, sweat, feces, vomitus, breast milk, or semen) with mucous membranes or broken skin or through injury by contaminated objects, infected bats, or primates.2 After infection, the virus readily replicates in monocytes, macrophages, and dendritic cells and is then transferred through lymphatic channels to regional lymph nodes. This is followed by hematogenous spread to the liver, spleen, and other organs.3
Although the detailed pathogenesis of subsequent EVD infection is not well understood, infected monocytes disable the innate immune response by downregulating the expression of viral entry restriction factors such as interferon-inducible transmembrane proteins and upregulating the expression of factors such as cathepsin B and NPC1, which are critical for Ebola virus entry. Heavy glycosylation of the Ebola viral envelope glycoprotein shields the free virus from antibody neutralization, limiting the effectiveness of the humoral immune response. Ebola virus infection also prompts the synthesis of large amounts of pro-inflammatory cytokines that over time can also contribute to immune dysfunction and the loss of acquired cellular immunity mechanisms. The result is uncontrolled viral replication, dissemination, and pro-inflammatory cytokine production that leads to endothelial and epithelial disruption, loss of vascular integrity, and coagulation derangements.4
The incubation period for Ebola infection is 2 to 21 days, although most cases will manifest within 2 weeks of exposure (median time 8-9 days).5 The clinical presentation in the first 2-3 days is nonspecific and characterized by fever and malaise, followed by gastrointestinal symptoms of nausea, vomiting, and diarrhea, which usually improves by days 7-8. The hemorrhagic phase typically occurs during the peak of the illness (days 5-7), although the petechial rash with subsequent desquamation, coagulopathy, and subsequent bleeding complications were less commonly reported during this latest EVD outbreak.
A summary of the frequency of presenting symptoms and physical findings from recently published case series from Guinea and Sierra Leone is provided in Table 1.6-8 Of note, most patients had stable hemodynamics on presentation, while pulse-temperature dissociation and hiccups also have been reported.9,10
Massive gastrointestinal losses with resulting volume depletion, occasional intestinal hemorrhage, electrolyte derangements, and acute kidney injury were the most common complications during hospitalization in these West African case series, with the caveat that laboratory testing was limited in both settings. The primary interventions in these studies included oral rehydration solution or intravenous fluids, electrolyte replacement, antiemetics, and antidiarrheal medications. Antimalarials and empiric antibiotics also were administered based on clinical suspicion and available laboratory testing for complicating conditions. Advanced age, medical comorbidity, weakness, dizziness, diarrhea, and respiratory, neurological, or hemorrhagic complications were all associated with a greater risk of death, with a case fatality rate in Guinea and Sierra Leone of 43% and 74%, respectively.7,8
Survivors of EVD from previous outbreaks have been reported to have long-term effects that significantly impact their activities of daily living, including uveitis with orbital pain and blurred vision, hearing loss, difficulty swallowing, difficulty sleeping, and limits due to memory loss and confusion.11
EVALUATION AND MANAGEMENT OF SEVERE EVD IN “RESOURCE-RICH” COUNTRIES
On Sept. 20, 2014, the CDC announced the first confirmed case of EVD in the United States, and 27 cases have been managed in the United States and Europe from this outbreak.12 This outbreak is the first that has marked the spread of EVD cases to “resource-rich” countries through the repatriation of infected healthcare workers, index cases traveling to these nations, and local spread from these index cases to other healthcare workers.13 Management of these cases in western tertiary care facilities has provided a more detailed description of the natural history of severe EVD, in addition to the significant challenges in care delivery that these patients present.
Laboratory abnormalities on presentation include leukopenia (with an increased proportion of neutrophils) and subsequent leukocytosis with associated atypical lymphocytes. Thrombocytopenia is characteristic, with a nadir that usually coincides with peak viral load (typically days 10-11). Transaminase elevations (AST > ALT) and elevated CPK levels are also common, with other electrolyte abnormalities reflecting the volume and type of gastrointestinal losses from vomiting and diarrhea. Prolongation of the international normalized ratio (INR) and partial thromboplastin time (PTT) have been less striking in the 2014 outbreak and are thought to be due predominantly to hepatic dysfunction. Hypoalbuminemia and lipemia can also be seen, the latter of which can interfere with common laboratory results.10
The differential diagnosis for patients returning from West Africa with a febrile illness can include malaria, typhoid fever, leptospirosis, rickettsiosis, African trypanosomiasis, Lassa fever, and cholera. Marburg virus, dengue, and Chikungunya infections may also have overlapping symptoms, in addition to more common etiologies such as hepatitis, bacterial sepsis, and influenza.14,15
The diagnosis of EVD can be established by rapid blood test detection of specific RNA sequences by PT-PCR or viral antigens by ELISA, which are positive by 3 days after the onset of symptoms. Testing should be repeated in high-risk subjects when initial results are negative.10 Measurement of Ebola IgM or IgG antibodies may also be useful to monitor the immune response to the infection over time.16
Severe EVD can involve the liver, gastrointestinal tract, skin, lungs, kidneys, and adrenal glands. The etiology of organ dysfunction is believed to be multifactorial based largely on primate research, suggesting that direct viral invasion and replication, unregulated release of pro-inflammatory cytokines, and microvascular thrombi from disseminated intravascular coagulopathy are likely mechanisms.17 Peak viral load levels and thrombocytopenia typically coincide with the onset of delirium, respiratory and renal deterioration, and low-grade vasopressor requirements (day 8-14 of illness) based on the recently published U.S. experience.18
Three U.S. patients required intubation and mechanical ventilation with a lung protective strategy, central line placement to assist with monitoring and replacement of intravascular volume, and continuous renal replacement therapy for acute kidney injury. Each patient was also treated with broad spectrum antibiotics for clinical or laboratory evidence of secondary infection, along with stress dose hydrocortisone. One of these patients survived without evidence of long-term organ sequelae, with intestinal ischemia or perforation with secondary sepsis being the likely cause of death in the other two cases.
With advanced supportive care, the observed mortality rate in developed countries has been reported to be 21-26%.19 Infection control concerns present a major barrier to the delivery of typical critical care interventions in “resource-rich” countries, limiting both the spectrum and frequency of diagnostic evaluation to bedside laboratory point-of-care testing and ultrasound. Cross sectional imaging, endoscopic procedures, and surgery are generally not available or provided to these patients, and the use of cardiopulmonary resuscitation remains controversial.20
There are several investigational vaccines for Ebola virus that are in Phase 1 and 2 testing for primary and post-exposure prophylaxis.21 Several experimental therapies have been used in Ebola patients, although at the current time no targeted therapy has been approved by the FDA. However, in 2014, the FDA did authorize the emergency use of brincidofovir, which is an oral nucleotide analogue developed for cytomegalovirus and adenovirus infections but with in vitro activity against Ebola virus.22
There is currently an ongoing prospective randomized trial of ZMapp, a mixture of three monoclonal antibodies.23 A Phase 2 trial of TKM-Ebola, an interfering RNA molecule, was closed this summer, and popular press reports have suggested no efficacy on interim analysis.24 Convalescent whole blood or plasma infusion from Ebola survivors also has been used.25
PREPAREDNESS AND PLANNING: WHERE ARE WE NOW?
The 2014 EVD outbreak highlighted in graphic terms both the global implications of infectious disease management and the challenges that healthcare systems and providers face to effectively prepare and care for these patients.
The outbreak has had a devastating impact on the healthcare infrastructure and workforce in affected countries in West Africa, and the worldwide aid response to this situation was decidedly delayed.26 Many outside healthcare providers were understandably concerned for their own safety. Those who did volunteer faced stigma and lengthy state-imposed isolation periods upon their return, which largely disregarded the risk-stratified approach outlined by current CDC guidelines.27
Although the impact of public concern on repatriation remains an issue, the recognition of significant need for additional volunteers to support current and future efforts has prompted the publication of guidelines in addition to CDC guidance to facilitate individual planning and preparation.28,29 Availability of providers will continue to remain an issue, as many experts feel that appropriate containment of future EVD outbreaks relies on timely and effective management of index cases in nations where this infection is endemic. Further guidelines that highlight areas of both best practice and need for the management of critically ill patients in resource-poor environments published last year also serve as an important reference for individuals caring for EVD patients in West Africa.30
Awareness and recognition of potential Ebola infection by front-line primary care providers one year after the outbreak appears reasonably strong. A recent national survey of general internists reported that 70% of respondents had a practice-level protocol in place, and nearly all providers reported that they felt very (45%) or somewhat (52%) prepared to communicate information about and diagnose Ebola. More importantly, these respondents consistently provided responses to sample case-based scenarios that were concordant with current CDC guidelines.31
Former CDC guidelines to prevent nosocomial transmission of Ebola virus proved to be insufficient, and supply lines of personal protective equipment (PPE) recommended in the CDC’s revised guidelines proved grossly inadequate to meet the overwhelming demands of a U.S. healthcare system underprepared to care for EVD patients.32 The necessary adaptations and resource intensive requirements to care for these patients outside of dedicated specialty centers cannot be overemphasized and has been summarized in a compelling manner by Dr. Gary Weinstein from Texas Health Presbyterian Hospital in a CHEST 2014 presentation still available through popular media.33
The psychosocial challenges for healthcare providers providing care to EVD patients in PPE are also significant, and a detailed and thoughtful perspective that provides important considerations for planning and preparation was recently published.34
Hospital preparedness includes a wide range of activities, including infection-control planning, early recognition of potential cases, isolation practices, monitoring of healthcare staff, environmental cleaning, handling of large-volume infectious waste, diagnostics, systematic screening for exposures, and ensuring the availability, training, and appropriate use of PPE.
A survey distributed to members of the Emerging Infections Network in late 2014 demonstrated substantial preparedness but also significant variation across a cross-section of U.S. facilities.35 Eighty-nine percent of respondents reported that their hospital had a written protocol for managing and testing suspected Ebola patients and 73% had a dedicated team identified to care for these individuals. Despite a similarly high level of specific PPE protocols, however, only 43% reported full-scale drilling with simulated patients, and there was significant confusion on healthcare worker monitoring and isolation requirements. Sixty-eight percent of respondents reported that they would prefer transferring Ebola patients to a regional facility, and larger facilities generally demonstrated a greater level of preparedness.
These numbers highlight the need for a systematic strategy for delivery of care that likely emphasizes regional referral when possible to specialty care centers that have adequate staffing and resources to maintain a consistent and high state of readiness to care for these patients. A systematic review of available literature was recently published to help aid in current and future planning in this area, but the considerations to provide care to this challenging group of patients remains unique.36 The barriers to care that exist with EVD patients also emphasize the important role that developed countries have to play in both the development of preventive strategies through vaccination programs and advances in point-of-care diagnostics and management to further reduce the still significant mortality from this dreaded viral infection.
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