Ebola virus disease and critical illness
While it may be advisable to concentrate or regionalize care for patients with EVD in specific hospitals, any health centre should be prepared to safely take a focused and relevant history from a patient with an infectious syndrome, and to mobilize the appropriate local and regional response. Many hospitals, even if not EVD referral centers, may be asked to care for patients until initial (and possibly subsequent) blood Ebola RT-PCR results are known. Therefore, it is essential that hospital staff are well trained and familiar with recommended IPC practices (and for EVD, standard and contact IPC precautions in particular). It is ideal to have an on-call inter-professional team who have undergone training in Ebola-specific IPC training.
While practiced IPC protocols are important to keep health workers safe, a very common clinical pitfall is to equate IPC practices with care. While Ebola-specific standardized IPC protocols are absolutely necessary, there will be situations requiring patient-specific IPC risk-assessments—most commonly involving patients at the beginning of, or in the convalescent phase of, their illness with minimal symptoms and no vomiting or diarrhoea (i.e., with very low risk of transmission). It is also important to remember that most patients suspected with EVD will not have EVD, but will have illness in need of prompt treatment—commonly malaria—that may require empiric treatment while awaiting diagnostic testing [84, 85]. Barriers to providing the standard of care to patients suspected of EVD will repeatedly arise: “We don’t have the capacity to do that… that is not part of our protocol.” Do not accept this when it negatively influences patient care. Instead, ask collectively “How can we safely solve this challenge, now, for the benefit of this patient?”
For hospitals and intensive care units (ICUs) that will provide definitive care for patients with EVD, there are many Ebola-specific considerations well beyond the scope of this review; however, a number deserve mention. Hospitals and ICUs will generally need to mould EVD planning to the local environment, and seek out the experience, guidance, protocols, and training from those who have substantial clinical and operational experience (Figs. 3, 4) [64, 86].
Second, the physical environment of a proposed Ebola treatment unit is a critical component of care. Ideally, there should be a large available physical space, sufficient for multiple isolation rooms, with very generously sized antechamber areas for donning and doffing, and a shared area from where clinical observation can occur (Fig. 4). There should be sufficient adjoining space to house dedicated diagnostic (e.g., portable radiograph and ultrasound machines, potentially point-of-care laboratory devices) and therapeutic (intravenous pumps, mechanical ventilator and circuits, dialysis machine and supplies) equipment. There should be ample nearby space to house packaged soiled PPE and medical waste that allows pick-up and proper disposal.
Third is the necessity for sufficiently numerous and trained inter-professional team of clinical (nurses, physicians, respiratory therapists, others) and patient support staff (coordinators, monitors, cleaners, patient transportation services, diagnostic and laboratory staff, and so forth), who are well practiced in the institutional Ebola care plan and their specific roles. Whether this team is led by infectious disease or critical care specialists, or both, is likely less important than establishing an inter-disciplinary model of continuity care throughout the hospital stay, oftentimes in a single geographic location that is institutionally appropriate.
Fourth, while EVD is accompanied by an increasingly well-characterized clinical gastrointestinal syndrome leading to fluid, electrolyte, and acid-base imbalance with multisystem organ dysfunction, there are no Ebola-specific therapies yet to be proven effective. However, intensive care medicine comprises experiential and evidence-based organ-supportive care, which should guide the care of patients with EVD—attention to fluid, electrolyte and acid-base balance, initiation of empiric and specific anti-infective therapy, and support for renal injury and respiratory failure as occurs for other potentially self-limited and survivable illnesses. Among patients with EVD treated in the USA and Europe, 41 % were deemed to have critical illness with 70 % receiving supplemental oxygen, 22 % with acute respiratory distress syndrome, 26 % invasive mechanical ventilation, 30 % intravenous vasoactive medications, and 19 % requiring dialysis [40].
For the most severely ill patients, clinical judgment is always necessary to balance risks and benefits of certain resuscitation strategies, including the initiation of cardiopulmonary resuscitation (CPR) [28, 87]. While there is a lack of clinical experience with CPR in EVD patients, it may be a reasonable consideration while correcting reversible abnormalities (i.e., hypoxia, severe electrolyte disturbance, arrhythmias) in settings where the option for advanced life-support exists. The decision to provide CPR should be guided by its medical indication and utility in that context, the ability to provide effective CPR, and the safety of those providing care including safe donning and doffing of PPE, in addition to patient preferences [88, 89].
Fifth, as with all critical illness, medical technical care is only one dimension of our support for patients and their families. Patients with EVD and their families require mechanisms to stay in audio and visual contact throughout the illness—ideally visual contact through transparent barriers or at safe distance, or direct contact with supervised donning and doffing of PPE—in addition to substantial psychosocial support during and after EVD.
Ebola-specific pharmacological prevention and therapeutics
Current EVD treatment focuses on supportive care [70] as there are no specific treatment options yet to be proven effective [70, 90, 91]. A number of Ebola-specific treatment strategies have undergone preliminary clinical trial investigation, including convalescent plasma, Favipiravir, Brincidofovir and TMK-130803 [92–97]. Transfusion of convalescent whole blood or plasma donated by EVD survivors has been used in this and prior EVD outbreaks [98] in an uncontrolled or compassionate-use basis [25, 79, 81, 99], and in animal models [100, 101]. One of three clinical trials of convalescent plasma therapy [94] has been completed and reported [102]. In this nonrandomized comparison to historical controls, transfusion of up to 500 ml convalescent plasma with unknown levels of neutralizing antibodies in 84 patients with confirmed EVD was not associated with a significant improvement in survival. While there were no serious adverse reactions in this trial, transfusion-related acute lung injury was described during convalescent plasma therapy in Spain [25]. Favipiravir (Toyama, Japan) [103], a pre-existing influenza virus inhibitor, has been administered for compassionate use outside West Africa [37, 38, 42]. In a multicenter, nonrandomized clinical trial in Guinea [104], 111 patients receiving Favipiravir had similar survival to that based upon historical control patients. The trial authors suggested that Favipiravir should be further studied in patients with medium to high viremia, but not in those with very high viremia [105]. Brincidofovir (Chimerix, USA), a nucleotide analog that inhibits RNA-polymerase with in vitro activity against Ebola [106], was administered to a small number of EVD patients for uncontrolled compassionate use [42, 79, 81, 99] and was tested in a phase 2 clinical trial in Liberia [95] that was stopped after the manufacturer withdrew study support [107]. TKM-130803 is a formulation of lipid-nanoparticle-encapsulated small interfering ribonucleic acids (siRNA) targeting two proteins involved in Ebola virus transcription and replication (Tekmira, USA, Canada). It was used in nonhuman primate Ebola virus infection as a postexposure treatment strategy [108] and in patients medically evacuated from West Africa in uncontrolled compassionate use [79, 81]. However, a phase 2 clinical trial (RAPIDE-TKM) in Sierra Leone [96] was halted according to pre-established stopping rules [109].
ZMapp, a monoclonal antibody cocktail (Leafbio, USA) [110], has been used under the emergency investigational new drug approvals from the Food and Drug Administration in patients treated in the USA, West Africa, and Western Europe [40, 76, 111]. ZMapp treatment of rhesus macaques resulted in 100 % survival even when started 5 days after lethal EBOV infection [110]. In the only randomized controlled trial of an investigational therapeutic for EVD, ZMapp plus standard of care was compared to standard of care alone for EVD patients in four countries, including the three most impacted West African countries. Due to the decline in EVD cases, this unblinded ZMapp randomized controlled trial only enrolled 72 of the prespecified target goal of 200 EVD patients; data were analyzed for 71 EVD patients, and mortality in the ZMapp treatment group was 22 % versus 37 % in the untreated group, but this difference was not statistically significant [112, 113].
The open-label, uncontrolled, and selected administration of other agents such as amiodarone [114], HMG-CoA reductase inhibitors, and angiotensin II receptor antagonists [115], and therapies to counteract vascular leak (FX06) [38] preclude any conclusions. In an observational study examining temporal trends in mortality among patients with EVD in one ETU in Guinea, 125 of 194 (64.4 %) patients receiving artemether–lumefantrine for malaria prophylaxis died as compared with 36 of 71 patients receiving artesunate–amodiaquine (50.7 %). In adjusted analyses, the risk ratio was 0.69 (95 % confidence interval, 0.54 to 0.89), with a stronger effect observed among patients without malaria [116]. These findings have not been confirmed in a randomized clinical trial.
Two vaccine candidates demonstrated efficacy in nonhuman primates [92, 117, 118]. A recombinant, replication-competent vesicular stomatitis virus-based vaccine expressing a surface glycoprotein of Zaire ebolavirus rVSV?G-EBOV-GP (rVSV) [118, 119] was evaluated in an open-label, ring vaccination trial involving 7651 people in 90 clusters, randomized to immediate or delayed (21 days) administration. The vaccine was well tolerated and in the immediate vaccination group there were no new EVD cases while in the delayed vaccination group there were 16 EVD cases [120]. Another candidate vaccine, cAd3-EBOV (cAd3) [117] remains under investigation [92, 121]. Other vaccine candidates are also under development and evaluation [122, 123].
Post-exposure Prophylaxis
Several healthcare personnel received post-exposure prophylaxis with different interventions, including a candidate Ebola vaccine, following potential high-risk exposures to Ebola virus; although Ebola virus disease did not occur in these individuals, no conclusions can be made about the effectiveness of these uncontrolled interventions [124–126].