FormalPara Take-home messages

The clinical spectrum of Ebola virus disease ranges from mild to severe illness and is often associated with life-threatening complications that require advanced supportive and critical care.

Training, preparation and strict adherence to infection prevention and control practices by health workers have demonstrated the feasibility and safety of the provision of advanced critical care.

Recent Ebola-specific care advances including vaccine prevention, point-of-care diagnostics, effective anti-Ebola treatments, a wider consensus on provision of optimized care and an increased acceptance and capacity to conduct well-designed research are leading to improved clinical outcomes for patients.

Introduction

Ebola virus disease (EVD) has long been perceived as a rare Equatorial viral illness that leads to hemorrhagic fever and near certain death. Until recently there was a common view that little could be done for patients other than isolation and limited supportive care—a reasoning premised on the expected futility of care for patients with an illness of historically high mortality rate and a concern for risk of infection to healthcare workers [1,2,3]. However, over the past 5 years, alongside the West African outbreak, there has been improved characterization of the clinical course, recognition that Ebola frequently leads to a unique critical illness with multisystem organ failure [1,2,3,4,5,6,7,8], and that patients with Ebola virus that can be supported, treated and cured [5, 9,10,11].

Historical case-weighted mortality fell from approximately 70% in outbreaks prior to 2014, to 39% in the West African outbreak and 18.5% in patients with EVD who were treated in Europe and USA [12, 13]. Mortality has remained over 50% in the most recent outbreaks in the Democratic Republic of the Congo (DRC) [13]. Treatment has shifted from a focus upon isolation and oral rehydration (‘minimal-touch’) to one of optimized care involving rapid diagnostic testing, frequent or continuous monitoring of vital signs, individualized enteral and intravenous fluid treatment, intravenous vasoactive medications, supplemental oxygen, occasional mechanical ventilation, renal replacement therapy and now, specific and effective antiviral therapies [9,10,11,12, 14,15,16,17,18].

In this review, we highlight the need for clinicians to be able to recognize and manage Ebola-related organ dysfunction, and highlight that advanced supportive care is necessary of treatment for severely ill patients with EVD.

Epidemiology

Ebolaviruses fall under the order Mononegavirales and the filoviridae family, and whose viral genome comprises a single negative stranded RNA with negative polarity. Within the genus of Ebolavirus, 6 species have been identified, though only 4—Zaire Ebola virus, Bundibugyo virus, Sudan virus and Tai Forest virus—are known to cause disease in humans; no serious illness has been reported from Bombali or Reston ebolavirus [19, 20]. Non-human primates (NHP) and bats are considered the natural reservoirs of Ebola virus, with the virus capable of causing zoonotic outbreaks.

Since the first recognized EVD outbreak in 1976, approximately 30 others have occurred [13, 19], with the majority happening in equatorial sub-Saharan Africa. Previously, most outbreaks have occurred in rural and remote areas, and have been of relatively short duration. However, in 2014–2016, EVD spread throughout West Africa (predominantly Guinea, Liberia and Sierra Leone), fueled in part by a fragile pre-existing health system and lack of human resource capacity, and led to the world’s largest outbreak (28,610 cases with 11,308 deaths and a case fatality ratio of 39%) [13]. Since the West African outbreak, the Democratic Republic of the Congo (DRC) has faced three more EVD outbreaks. In the most recent, centered in Northeastern DRC, as of January 04, 2020, there have been 2233 deaths out of 3386 cases—the second largest Ebola outbreak in history [17, 21]. Now characterized as a public health emergency of international concern [17] there is a need for clinicians to be prepared to treat patients in both endemic or exported regions.

Clinical presentation

Demographics

Ebola virus (EV) can infect people of all ages—from infants to elderly—and infection can affect fetal development and viability. In previous outbreaks, 10-year age group-incidence for EVD increased linearly from infancy peaking at the 35–45 years age group and falling thereafter [22]. Attack rates have traditionally been higher among women and middle-aged people and lower in children and the elderly, probably due to differences in exposure risks. The current DRC outbreak has been epidemiologically notable for higher than previously recognized infections among children [17].

Transmission

Most human-to-human Ebola transmission is by direct exposure of the mucous membranes or non-intact skin to infectious body fluids such as blood, vomitus, stool, or with contaminated materials [19]. Inoculation of the virus into the body via needle stick or sharps injuries can occur in healthcare settings. Droplet or aerosol transmission is unlikely except under specific conditions such as when carrying out procedures in non-ventilated rooms on patients with high viral loads that increase the risk respiratory spread, such as bronchoscopy [23]. Survivors from previous outbreaks have shown persistent Ebola virus in some bodily fluids, such as semen in males, up to 500 days after recovery [24]; however, the viability and infectivity of the virus isolated from these sites is less certain.

Pathophysiology

Ebola virus gains entry into the body mainly via the mucous membranes (eyes, nose, and mouth). Its viral glycoprotein enhances receptor binding and attachment to the endosomes of cells [23]. The virus attacks dendritic cells, monocytes and macrophages, which then migrate to the lymph nodes where early viral replication and dissemination occurs before the onset of symptoms. Ebola virus disseminates to infect a broad range of cells including endothelial cells, hepatocytes, fibroblasts, and the adreno-cortical cells, among others. Ebola virus uses its structural and membrane proteins through a number of mechanisms to evade the host immune response [23, 25, 26]. Tissue damage happens via numerous but closely related mechanisms such as direct viral cytopathy, endothelial dysfunction, coagulation disruption, and likely, the host’s own inflammatory response [23]. Infected patients undergo a cell-mediated immune activation, however, patients that succumb to EVD may have a more limited functional T-cell-mediated response [4, 27].

Clinical presentation

Clinical suspicion of EVD should arise when considering a patient’s clinical syndrome and recent likelihood of exposure in an area where the virus is known to circulate [28]. An epidemiological history should include any recent (within 21 days) travel to an area with ongoing Ebola transmission, or contact history with infected persons or dead or possibly infected animals.

After exposure to Ebola virus, an incubation period of 3–21 days (mean 12.7, SD 4.3 days) [29] ensues where symptoms (Fig. 1) might present [30]. It is not uncommon for viral RNA to be undetectable by reverse transcriptase-polymerase chain reaction (RT-PCR) in the first 1–3 days after symptom onset. This necessitates re-testing all patients in whom clinical suspicion persists even after initial plasma RT-PCR results are negative if symptoms have been present for fewer than a few days [14].

Fig. 1
figure 1

Adapted from Rojek AM et al. [30]

A meta-analysis of proportion of 6168 EVD patients presenting with symptoms compared to reference data. Blue indicates a meta-analysis approximate with low or moderate heterogeneity, red is for a high heterogeneity of pooled estimates, and grey is the WHO reference data.

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Several observational studies [12, 16, 31, 32], have grouped the progression of EVD illness into three stages (Table 1). In the initial phase, most patients’ symptoms include a non-specific febrile illness with headache, fever, myalgia and general malaise, with or without a maculopapular rash. These early symptoms often overlap with those of common diseases in the tropics (such as malaria, typhoid fever, and other bacterial and arboviral infections), complicating clinical diagnosis [7].

Table 1 Stages of Ebola virus disease presentation.
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Some patients will progress to the second phase with asthenia and gastro-intestinal illness, including nausea, anorexia, abdominal pain, odynophagia, emesis and then watery diarrhea. This stage can range from mild symptoms to a severe state of illness characterized by intravascular volume depletion and electrolyte derangement [6, 32], hypotension, metabolic acidosis, hepatitis, pancreatitis, hypoglycemia and renal injury. Patients are typically with a high viral load and are correspondingly infectious in this phase of illness [14].

In the third phase of illness [4], multi-organ failure may occur, with acute kidney failure, hepatic failure, cardiac dysfunction and shock, altered level of consciousness, seizures, coagulopathy (petechiae, ecchymoses, at venipuncture sites and bleeding from mucosal membranes and peri-partum) or death [30,31,32,33].

Diagnostic testing for Ebola

The WHO recommends confirmation of EVD by RT-quantitative PCR [34]. There are over a dozen RT-PCR processing platforms, but only a few have had their limits of detection (LOD) verified by independent assessors, including the WHO endorsed Cepheid Xpert® assay, which targets nucleoprotein and glycoprotein antigens on the Ebola virus [34,35,36]. For screening suspected EVD patients in remote settings without access to PCR testing, WHO recommends use of highly sensitive and specific rapid diagnostic tests (RDTs). Table 2 outlines various RDTs available, with only a few, such as ReEBOV, Ebola eZYSCREEN and OraQuick, having undergone clinical validation [35, 37,38,39,40]. Laboratory testing for alternative or co-infections such as malaria and bacterial infections should be considered [8, 12, 23, 31], since these are often assumed to co-exist with Ebola in severely ill patients and may lead to over-prescription of antimalarials or antibiotics unless rapid tests (for malaria) and cultures (for bacterial infections) can rule these out.

Table 2 RDTs for the detection of Ebola virus.
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Laboratory abnormalities

Early in the course of EVD illness, leukocyte and lymphocyte counts often fall due to impaired immune response, while hemoglobin and hematocrit levels increase along with intravascular volume depletion [23]. Elevation in aspartate amino transferase (AST), alanine aminotransferase (ALT), and total serum bilirubin is common, generally believed to be due to direct viral cytopathic effect on hepatocytes [4, 12, 23]. Contributory pathology from rhabdomyolysis or myositis leads to high serum creatine kinase and AST levels [12, 23]. Elevated prothrombin time and activated partial thromboplastin time and increased d-dimers occur among patients with progressive illness [4, 8, 12, 23].

During the most severe phase of illness (Table 3), patients might have hyper- or hyponatremia, hyper- or hypokalemia, hypocalcemia and hypomagnesemia as a result severe vomiting and diarrhea; hypoglycemia secondary to reduced oral intake or depleted glycogen stores, and hypoalbuminemia, acute kidney injury, and both anion gap (lactate- or urea-associated) or non-anion gap (diarrhea-related bicarbonate losses) metabolic acidosis. [4, 8, 12, 23].

Table 3 Laboratory abnormalities observed in EVD patients by stage.
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Prevention

An overriding principle in providing EVD care is to ensure healthcare worker (HW) safety through strict infection prevention and control (IPC) practices. HWs involved in EVD care should adhere to both standard and transmission-based (contact and droplet) precautions for their safety [14]. Recommended personal protective equipment (PPE) when providing direct patient care includes: face shield/googles; fluid-resistant medical/surgical gown, surgical masks or N-95 respirators that maintain their shape and consistency in hot and humid environments; two pairs of gloves; waterproof apron; fluid-impermeable protective feet covering and a head cover [14, 41]. A buddy (two person) system while providing care, and PPE adherence supervisors are both advisable. Vaccination of frontline HWs should be a standard of clinical practice [16, 42].

Pre-exposure prophylaxis

Preliminary data on vaccination of populations at increased risk of infection, such as HWs, contacts of patients and contacts of contacts, with the rVSV ZEBOV-Gp, while utilizing the ring vaccination strategy in West Africa has shown a vaccine efficacy of 97.5% in people vaccinated at least 10 days before potential exposure, and an 88.1% efficacy in all the other analyses of EVD onset irrespective of timing [43]. Subsequently, a 26 vectored glycoprotein/MVA-BN (Ad26.ZEBOV/MVA-BN) vaccine developed by Johnson & Johnson has been deployed for evaluation in the current outbreak in DRC.

Treatment

The care for critically ill EVD patients is best offered in individual patient treatment rooms inside a facility that has the following features: a sectioned unit with separate areas for low risk patients in whom EVD has not been confirmed and who are not demonstrating ‘wet’ symptoms (vomiting and diarrhea); patients who have wet symptoms but as yet unconfirmed infection; and a section for confirmed EVD patients. Each section should have waste disposal areas; unidirectional flow of materials and personnel from the lowest risk zones to higher risk zones; and capacity to accommodate medical technologies such as oxygen delivery systems, mechanical ventilators and renal replacement systems [41]. Diagnostic laboratory testing should be either at the point of care and with a well-coordinated and timely system of safe transportation of samples to a dedicated laboratory equipped to process such specimens. There should be physical barriers to limit access to Ebola assessment and treatment areas to essential and trained personnel. However, there should be visual accessibility to patients by family and friends who provide important psychological support to patients.

Heath workers’ use of impermeable PPE while caring for EVD patients with infectious “wet’ symptoms puts them at increased risk for heat strain especially in hot and humid areas. This limitation can have the unintended consequence of reducing the time HWs can spend with patients and can limit the quality of care [2, 10, 16]. Thus, temperature and humidity control for HWs is an important element of caring for patients. This has been accomplished in the field through caring for patients in climate controlled hospitals, or through novel engineering solutions with individual patient rooms such as found in the (Alliance for International Medical Action—ALIMA) biosecure cubes (Fig. 2) that consist of transparent and air conditioned patient rooms, and come fitted with specialized ports to enable patient access and monitoring while in minimal PPE [10, 44].

Fig. 2
figure 2

Photo credit: Etinosa Yvonne/ALIMA [44]

A medical advisor for the Alliance for International Medical Action demonstrating a Biosecure Emergency Care Unit for outbreaks of infectious diseases.

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Basic supportive care

Following the 2014–2016 EVD outbreak, a number of observational studies postulated that delivery of improved supportive care would reduce mortality from EVD [1,2,3,4,5,6,7,8,9, 12, 31, 32]. Basic supportive care recommendations [11] include: systematic monitoring and documentation of clinical signs and symptoms; a clinician to patient ratio of 1:4 but with emphasis placed on maximizing patient contact time; patient–family audio-visual communication; psychosocial care; provision of oral rehydration therapy to correct or prevent hypovolemia; parenteral fluids for patients unable to achieve sufficient enteral hydration; measurement of serum biochemistry with correction of identified electrolyte abnormalities; oxygen administration to achieve normal oxygen saturation; intravenous vasoactive medications for patients with fluid-resistant hypotension and organ hypoperfusion; pain management, antiemetics, and anxiolytics; nutritional support customized to patient assessment including treatment of hypoglycemia with intravenous glucose when necessary; and microbiological analysis to guide antimicrobial use, and in absence of such capacity, a low threshold for empirical use of broad-spectrum antibiotics and antimalarials, depending on the geographical context and symptoms [9,10,11,12, 14, 44, 45]. Provision of supportive care to patients will inevitably require a multi-disciplinary team of HWs: nurses, physicians, IPC personnel, laboratory personnel, and ideally, nutritionists, social and community workers, and psychologists. These recommendations derived from observational studies that generally found improved outcomes later in the outbreak compared to the beginning, attributed to improvements in multiple domains of care, including clinical monitoring and fluid administration [46].

Advanced supportive care

Data collected from patient cohorts admitted in Ebola Treatment Centres in Africa [4, 30] and in Europe and the USA [12] posited that approximately 50% of patients in either setting were critically ill and required advanced supportive care interventions. Described below is the management of common complications observed in patients with EVD.

Metabolic disturbance and renal injury has been observed as a complication of EVD in over 50% of patients in cohorts of patients during the West African outbreak [6,7,8, 12, 16, 23] and is likely multifactorial in etiology, including hypovolemia, hypotension and hypoperfusion, direct viral damage to the endothelium and renal tubular cells [6, 12,13,14, 23, 31], and occasional toxicity due to rhabdomyolysis or medications. Interventions include careful monitoring of urine output, maintaining adequate renal perfusion with fluids and vasoactive agents, avoiding nephrotoxic drugs and diuretics in hypovolemic patients, and treatment of other underlying cause(s) [10,11,12, 16]. Electrolyte disturbances such as hyperkalemia have commonly been reported in the context of Ebola-related renal injury. Temporizing measures for complications of acute kidney injury should be available, such as bicarbonate for metabolic acidosis, intravenous short-acting insulin and dextrose for hyperkalemia, and a diuretic trial in oliguric volume-replete patients. Where facilities and expertise are available, renal replacement therapy should be offered [11, 12, 16], as feasibility of delivering dialysis has been demonstrated in both resource-rich and resource-limited settings [12, 16, 47].

Cardiovascular complications have included arrhythmias and may often respond to normalization of serum electrolytes. Hypotension due to hypovolemia, vasodilation or impaired myocardial performance unresponsive to fluid resuscitation require intravenous vasopressor or inotropic support.

Coagulation abnormalities have included thrombocytopenia, vitamin K deficiency or liver-injury-related effects to the intrinsic and extrinsic pathways of coagulation, and rarely, disseminated intravascular coagulation. Clinical monitoring and measurement of blood counts and coagulation profiles can help to guide treatment with vitamin K and tranexamic acid, transfusion with red blood cells, platelets or plasma [11, 23, 44]. Early placement of a durable intravenous catheter of sufficient diameter to allow blood sampling (e.g., a peripherally inserted central catheter) facilitates safe blood sampling and administration of intravenous fluids or medications [12, 16].

Clinicians should anticipate that a proportion of patients will develop hypoxic or hypercapneic respiratory failure. Etiologies may be diverse, relating to pulmonary vascular leak and inflammatory insults, volume overload, impaired myocardial performance, pulmonary infections, decreased level of consciousness and aspiration, severe metabolic acidosis or hypoventilation syndromes. Over 70% of patients with EVD treated in Europe or USA required some form of respiratory support—invasive or non-invasive mechanical ventilation [12] or supplemental oxygen [1, 9,10,11,12, 16, 23].

Neurological complications such as altered mental status (confusion or coma), seizures, agitation and encephalopathy were reported in over 30% of patients treated in Europe, USA and West Africa [12, 30]. Interventions include treating underlying causes such as hypoglycemia, electrolyte imbalance, hepatic dysfunction, uraemia and viral or bacterial encephalitis or meningitis; and use of anticonvulsants, sedatives and antipsychotics as appropriate [11, 12, 14, 15].

Medical treatments

Supportive care remains the cornerstone of patient treatment. A number of direct acting anti-Ebola agents were proposed and evaluated during the West African Ebola outbreak. Most were tested using methodologically weak study designs that precluded determination of efficacy, and await further evaluation [44, 45]. A systematic review [48] evaluated the potential effect of different anti-Ebola therapies on clinical outcomes of EVD patients. All but one of the studies were limited by their non-randomized designs. ZMapp (a cocktail of three monoclonal antibodies), was the only anti-Ebola therapy whose efficacy was tested in a randomized control trial against standard care. In the 72 enrolled patients, mortality in the intervention group was 22% vs 37% in the control group (confidence interval for risk difference, − 36 to 7%). Although ZMapp achieved a 91.2% posterior probability of superiority over standard care, it failed to reach the pre-set threshold of 97.5% probability to establish efficacy.

Health authorities and the WHO R&D blueprint under the ethical framework of monitored emergency use of unregistered and investigational interventions (MEURI) recommended expanded access to investigational therapies, including three monoclonal antibodies (MAb114, ZMapp, and REGN-EB3) and one antiviral agent (remdesivir) in the 2018–2019 DRC Ebola outbreak (Table 4) [44, 49].

Table 4 Current anti-Ebola therapies being implemented under compassionate use in the DRC
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REGN-EB3 is a cocktail of three monoclonal antibodies (REGN-3470, -3471, and -3479, all humanized from mice) targeting non-overlapping epitopes of Ebola virus. REGN-EB3 previously showed promise in reducing mortality in infected NHPs even when single doses of up to 150 mg/kg were administered 5 days post EVD infection. REGN-EB3 was also found to be well tolerated when it was tested in randomized placebo-controlled phase 1 trial involving 18 human participants [50].

VRC-EBOMAB092-00-AB (MAb114) is a single human monoclonal antibody (isolated from a human survivor) that targets a highly conserved epitope on the receptor-binding domain of the Ebola virus glycoprotein, thus preventing its interaction with the host cell receptor protein and blocking viral entry. In pre-clinical studies involving NHPs challenged with lethal doses of Ebola virus, single 50 mg/kg or 30 mg/kg doses of MAb114 given 5 days after viral exposure offered complete protection. In a subsequent human phase 1, open-label, dose escalation trial, MAb114 was given to 18 participants. MAb114 was well tolerated in all participants, with no reported site infusion reactions or serious adverse effects [51].

In a subsequent randomized controlled trial (n = 681) conducted under challenging field conditions, the safety and effectiveness of three drugs (MAb114, remdesivir, and REGN-EB3) was compared to the control drug ZMapp in Ebola patients receiving optimized standard of care (consisting of intravenous fluid resuscitation, daily clinical laboratory testing, correction of hypoglycemia and other electrolyte abnormalities, and use of broad-spectrum antibiotics and antimalarials, whenever indicated) [49, 52]. The trial was stopped early after MAb114 and REGN-EB3 were found to be superior to ZMapp in reducing 28-day mortality, with event rates of 35.1% for MAb114 [risk difference (RD) vs. ZMapp, − 14.6%, 95% CI − 25.2 to − 1.7%) and 33.5% for REGN-EB3 (RD vs. ZMapp, 17.8%, 95% CI − 28.9 to − 2.9%). Mortality among patients receiving ZMapp was 49.7% and among those receiving remdesivir was 53.1%. However, mortality rates in patients with high viral loads or those with organ dysfunction (high creatinine or transaminases) remained high (> 60% for all interventions), even in a trial setting of optimized standard of care. This observation validates the need for advanced supportive interventions tailored to patient-specific critical care needs whenever feasible, and continued research into refining more effective anti-Ebola therapeutics, either newer drug compounds or combinations of the current ones [52].

Conclusion

Management of patients with Ebola has evolved substantially over the past decade, from a clinical perspective of isolation and provision of oral rehydration therapy to one of treating the syndromic illness, specific patterns of organ dysfunction with oral and intravenous volume repletion, management of life-threatening electrolyte disturbances, support of renal dysfunction with dialysis, cardiovascular dysfunction with intravenous vasoactive medications, and oxygen and mechanical ventilation for respiratory failure. With attention to the provision of care for patients, mortality has dropped from 70 to 40% in resource-challenged Ebola Treatment Centre context and is under 20% in resource-rich environments. With the promise of effective vaccine and specific anti-Ebola virus medications, we now understand that most patients can be safely supported, treated and cured.