In humans, filovirus infection results in a spectrum of illness, but most recognized infections present as severe acute febrile illness with a high proportion of fatalities. The typical clinical presentation consists of acute onset of a non-specific febrile illness, including chills, headache, myalgia, nausea/vomiting, and diarrhea. A faint rash develops in 25-52% of patients in the first week [1]. Minor hemorrhagic manifestations are noted in some patients after a few days of illness (e.g., conjunctival hemorrhage, petechiae, ecchymoses, bleeding from puncture sites). In many instances, a biphasic pattern can occur, with a brief remission followed by a recurrence of fever and more severe late stage disease. In later stages of the severe forms of illness, patients demonstrate hypotension, shock, mucosal hemorrhages (typically from the gastrointestinal tract) and multi-organ system (particularly renal) failure [2,3]. Although autopsies demonstrate multifocal necrosis, they have generally not identified specific pathological lesions responsible for death [4]. Nevertheless, severe cases are frequently fatal, with ultimate demise attributed to the systemic effects of a septic shock-like syndrome. No licensed or approved specific medical countermeasures exist, making supportive care the cornerstone of patient management.

Provision of supportive care, as well as detailed documentation of the care given, is challenging in austere settings in which most large filovirus outbreaks occur. Laboratory equipment, supplies (particularly personal protective equipment), and adequate infrastructure are often lacking. Healthcare worker attrition and abandonment of suspected cases can result from actual infection or fear of infection, perceived inability to affect the clinical course, and community stigmatism. In some outbreaks, communities hide sick patients and dead bodies [5], thus, forcing efforts to focus on community surveillance.

In this review, we summarize the management approaches documented in published outbreak reports, conference proceedings, journal articles, and a recently published compendium of the filovirus literature [6]. We highlight gaps in knowledge of clinical management of filovirus patients and areas where our current outbreak response strategies could be enhanced to improve patient care.

There have been 34 recognized filovirus outbreaks, including sporadic cases and laboratory accidents, since 1967. Perhaps not surprisingly, the most detailed information on the clinical management of filovirus-infected patients came from outbreaks or cases occurring in developed countries. In general, the clinical care provided to filovirus patients has varied widely, primarily due to resource constraints of many outbreak settings.

We searched PubMed for articles relating to each filovirus disease outbreak individually, as well as for articles on treatment for filovirus infections (“Ebola AND treatment”, “Marburg AND treatment”, and “filovirus AND treatment”, species filter: Humans). We obtained additional references from a recent compendium of filovirus literature [6], as well as a recent review of the clinical and laboratory features of filovirus infection [1]. In total, we reviewed over 200 journal articles, outbreak reports, and conference proceedings [100,101,102,103,104]. Articles in German or French were screened using an online translation tool (Google Translate); a native speaker screened two articles in Russian [14,47].

Although there have been many advances in our understanding of the pathophysiology of filovirus infections and progress towards development of vaccines and therapeutics, insufficient attention has been paid to evaluating and improving the supportive care of filovirus patients. The contrast in the case-fatality observed in patients with access to modern hospital facilities versus those in resource-constrained settings has been previously noted, causing many to speculate that substantial improvements in survival could be made through enhanced supportive care [105,106]. Several management strategies have been attempted in outbreak settings, as summarized in this review, but none of the strategies have been implemented or documented to permit evaluation of the treatment efficacy. As noted by Colebunders et al., improvements in clinical documentation are required for basic evaluation of supportive treatment [50]. In the absence of a clinical trial, accurate collection and timely publication of observational data on patient demographics, clinical signs and symptoms, treatment, and clinical outcome are crucial.

Barring the development of an effective drug or vaccine, clearly the most critical need in the improvement of filovirus infection management are scientifically collected data to validate clinical interventions and provide a foundation for evidence-based guidance. As the pathologic process of filovirus infection resembles that of severe sepsis and septic shock, a reasonable management strategy is aggressive supportive care using standard protocols for severe sepsis [105,106,107]. The efficacy of early goal-directed therapy (EGDT) and the related Surviving Sepsis Campaign management protocols has been well established in highly-resourced medical facilities across a broad range of common pathogens [108,109,110,111]. Nevertheless, the applicability of these approaches has yet to be tested or validated with more exotic diseases (including filovirus infections) commonly presenting as severe sepsis in tropical or under-developed regions. In addition, although theoretically possible, such approaches have not been proven to be feasible in medical facilities in resource-limited settings [112,113].

EGDT requires early fluid resuscitation within the first 6 hours of presentation; most algorithms include an initial bolus of 20-40 ml/kg of crystalloid solution followed by frequent volume boluses sufficient to meet specific goal targets with respect to indices such as central venous pressure (CVP), mean arterial pressure, and mixed venous oxygen saturation (SvO₂). The rationale for this approach in severely septic patients was summarized in a meta-analysis [114]. Significant mortality benefit was seen in studies where hemodynamic optimization in critically ill patients was initiated before the development of organ failure when compared to those studies that achieved optimization after the occurrence of organ failure. Notably, fluid resuscitation alone can help to reduce the global tissue hypoxia that is central to the development of multi-organ dysfunction by increasing the cardiac output and improving oxygen delivery to the tissues [115]. While fluid resuscitation alone, as dictated by EGDT, may have benefit, the Surviving Sepsis Campaign created management protocols that are a group of interventions related to a disease that, when implemented together, result in better outcomes than when implemented individually [116]. The synergistic effect of appropriate therapies given together at the appropriate time may alter the pathophysiologic course of disease enough to improve the outcome. Finally, it should be noted that some experts argue that aggressive fluid resuscitation generally attributed to EGDT are actually contraindicated in the management of filoviruses, given the associated endothelial dysfunction and theoretical risk of pulmonary edema.

Evaluation of enhanced supportive care and development of tailored protocols for management of filovirus infections should be priorities in the response to future outbreaks. The challenges inherent in this task are considerable, but not insurmountable. Strategies for conducting clinical research in filovirus disease outbreak settings have been proposed, including establishment of a collaborative platform for development and approval of research protocols in advance of an outbreak [106,107]. Furthermore, the research capacity required to conduct clinical trials to evaluate sepsis management strategies in austere settings, namely the availability of institutional review boards, community outreach programs, trained personnel, clinical supplies, and laboratory diagnostics, could be adapted to filovirus disease outbreak settings. Provision of enhanced supportive care, accurate clinical documentation, and rigorous evaluation of innovative treatment strategies may improve patient outcomes in future filovirus disease outbreaks.