Ebola virus disease

Abstract

Ebola virus disease (EVD) is a severe and frequently lethal disease caused by Ebola virus (EBOV). EVD outbreaks typically start from a single case of probable zoonotic transmission, followed by human-to-human transmission via direct contact or contact with infected bodily fluids or contaminated fomites. EVD has a high case-fatality rate; it is characterized by fever, gastrointestinal signs and multiple organ dysfunction syndrome. Diagnosis requires a combination of case definition and laboratory tests, typically real-time reverse transcription PCR to detect viral RNA or rapid diagnostic tests based on immunoassays to detect EBOV antigens. Recent advances in medical countermeasure research resulted in the recent approval of an EBOV-targeted vaccine by European and US regulatory agencies. The results of a randomized clinical trial of investigational therapeutics for EVD demonstrated survival benefits from two monoclonal antibody products targeting the EBOV membrane glycoprotein. New observations emerging from the unprecedented 2013-2016 Western African EVD outbreak (the largest in history) and the ongoing EVD outbreak in the Democratic Republic of the Congo have substantially improved the understanding of EVD and viral persistence in survivors of EVD, resulting in new strategies toward prevention of infection and optimization of clinical management, acute illness outcomes and attendance to the clinical care needs of patients.

Fig. 1. Filovirus taxonomy and Ebola virus transmission.

a | Taxonomy of the genus Ebolavirus. Thus far, five ebolaviruses have been associated with human infections, and four of them have been identified as pathogens. b | The natural reservoir host(s) of Ebola virus (EBOV) has (have) yet to be identified. Multiple data indicate a direct or indirect role of bats in EBOV ecology, but to date, EBOV has not been isolated from, nor has a near-complete EBOV genome been detected in any wild animal. However, it is tempting to speculate that Ebola virus disease (EVD) is a zoonosis (that is, an infectious disease caused by an agent transmitted between animals and humans) because retrospective epidemiological investigations have often been able to track down the probable index cases of EVD outbreaks. These individuals had been in contact with wild animals or had handled the carcass of a possible accidental EBOV host^,. c | Scanning electron microscopic (SEM) image of EBOV particles (green) budding from grivet cells. d | Transmission electron microscopic (TEM) image of EBOV particles (green) budding from grivet cells^,. ^aThe kingdom name has been approved by the International Committee on Taxonomy of Viruses (ICTV) but has yet to be ratified. Parts c and d courtesy of J. Wada and J. Bernbaum, NIH/NIAID Integrated Research Facility at Fort Detrick, Frederick, MD, USA.

Fig. 2. Ebola virus disease outbreaks.

The map shows the location and years of all reported Ebola virus disease (EVD) outbreaks. Two cases of laboratory-acquired EVD occurred in Russia (not shown). Adapted with permission of McGraw-Hill Education, from Harrison’s principles of internal medicine, Jameson, J. L. et al, vol. 2, 20th edn, 2018 (ref.).

Fig. 3. Reconstructed EBOV transmission chains during the 2013–2016 Western African EVD outbreak.

Molecular evidence using hundreds of individual Ebola virus (EBOV) genomes sequenced from individual patients indicates that in the index case of the outbreak, EBOV was acquired by unknown means at the end of 2013 in or around Guéckédou in Guinea. From there, person-to-person transmission enabled EBOV to spread (coloured lines) throughout the country, to cross borders and ultimately to affect a total of 15 countries (see also Fig. 2). The direction of EBOV spread is represented by the lines and goes from the thick end to the thin end. White borders delineate the provinces (Guinea), districts (Sierra Leone) and counties (Liberia). Adapted from ref., Springer Nature Limited.

Fig. 4. EBOV genome and life cycle.

a | Ebola virus (EBOV) has a linear, non-segmented, negative-sense, single-stranded RNA genome (~19 kb) expressing seven structural proteins and several non-structural proteins from seven genes: NP encodes nucleoprotein NP, VP35 polymerase cofactor VP35, VP40 matrix protein VP40, GP glycoprotein GP_1,2 and secreted glycoproteins (not shown), VP30 transcriptional activator VP30, VP24 RNA complex-associated protein VP24, and L large protein L^,. b | The binding of EBOV particles to the attachment factors on the host cell surface is mediated by the homotrimeric structural glycoprotein GP_1,2, which is formed of three heterodimers consisting of subunits GP₁ and GP₂ that are connected by a disulfide bond (1). Binding to the host cell membrane triggers viral particle endocytosis (2). In the late endosome, GP_1,2 is sequentially cleaved by cathepsin B (CatB) and cathepsin L (CatL) (3) to expose the receptor-binding site of the GP₁ subunit. A low pH induces GP₁ interaction with the EBOV receptor NPC1, with subsequent GP₂-mediated fusion of the particle envelope with the endosomal membrane and thereby expulsion of the ribonucleoprotein complex (predominantly RNA + NP) into the cytosol (4). There, the filovirus genome is replicated (5) and the filovirus genes are transcribed into mRNAs (6). Viral proteins are translated in the cytosol or, in the case of GP_1,2, into the endoplasmic reticulum (ER) (7). Mature progeny ribonucleoprotein complexes and viral proteins are transported to the plasma membrane, where particle budding occurs (8). NPC1, NPC intracellular cholesterol transporter 1; ORF, open reading frame. Part a courtesy of J. Wada, NIH/NIAID Integrated Research Facility at Fort Detrick, Frederick, MD, USA. Part b adapted from ref., Springer Nature Limited.

Fig. 5. Conceptualized EVD pathogenesis.

Ebola virus particles enter the body through dermal injuries (microscopic or macroscopic wounds) or via direct contact via mucosal membranes. Primary targets of infection are macrophages and dendritic cells. Infected macrophages and dendritic cells migrate to regional lymph nodes while producing progeny virions. Through suppression of intrinsic, innate and adaptive immune responses, systemic distribution of progeny virions and infection of secondary target cells occur in almost all organs. Key organ-specific interactions occur in the gastrointestinal tract, liver and spleen, with corresponding markers of organ injury or dysfunction that correlate with human disease outcome. The question marks indicate speculated manifestations. RIG-I, antiviral innate immune response receptor RIG-I.

Fig. 6. Conceptualized clinical course of acute EVD over time.

The time course of the clinical manifestations (top), laboratory findings (middle) and viraemia and immune responses (bottom) in patients with Ebola virus disease (EVD). The coloured lines in the top and middle panels do not have defined start and end points as these may vary. Renal dysfunction is common and not well-characterized in patients with EVD; it is probably a multifactorial combination of hypovolaemia (related to gastrointestinal fluid losses, decreased fluid input, fever, hypoalbuminaemia and sepsis pathophysiology), intrinsic renal injury (acute tubular necrosis related to myoglobin pigment injury secondary to rhabdomyolysis or direct viral infection of tubular epithelial cells) or cytokine-mediated nephrotoxicity. Whereas respiratory symptoms and signs may reflect respiratory compensation for a primary metabolic acidosis, primary causes of hypoxaemic respiratory failure include acute lung injury (related to systemic inflammatory response syndrome and/or sepsis or Ebola virus (EBOV)-related cytokinaemia), pulmonary oedema (in the setting of capillary leak or direct infection) and viral pneumonia. Respiratory muscle fatigue may also contribute to ventilatory respiratory failure. Haemorrhagic manifestations include oozing from venepuncture sites, haemoptysis (coughing up blood), haematemesis (vomiting blood), melaena (dark stools as a result of bleeding) and vaginal bleeding. Neurological manifestations include meningoencephalitis and cerebrovascular accidents (such as strokes). ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CPK, creatine phosphokinase; Hb, haemoglobin; HCT, haematocrit; PLT, platelet; PMN, polymorphonuclear leukocyte; PT, prothrombin time; PTT, partial thromboplastin time; WBC, white blood cell count. ^aIncubation periods of 2–21 days have been reported. Bottom panel adapted with permission from ref., The American Association of Immunologists, Inc.

Fig. 7. Clinical sequelae in survivors of EVD.

Clinical sequelae in survivors of Ebola virus disease (EVD) that are supported by evidence that includes physical examination of the individuals. Studies reporting patient-reported symptoms are not included in this summary figure. EBOV, Ebola virus; PTSD, post-traumatic stress disorder. ^aIn the PREVAIL III clinical trial, a prospective, controlled study assessing symptoms in survivors that had a >10% increase in prevalence compared with control close contacts, this symptom had an increased odds ratio (P < 0.0001) compared with close contact controls. ^bIn the PREVAIL III clinical trial, in which symptoms in survivors were compared with symptoms in control close contacts (regardless of any increase in their prevalence in survivors), this symptom had an increased odds ratio (P < 0.01) compared with control close contacts. ^cData from uncontrolled cohorts, case series or case reports. ^dMost common abnormalities in neurological examinations are abnormal oculomotor examination, abnormal reflexes, tremor and abnormal sensory examination. ^eMost common abnormalities include irregular heart rate, cardiac murmur, decreased breath sounds, rales (crackling lung sounds) and wheezes. ^fMost common abnormalities include abdominal tenderness, mass or distension. ^gMost common abnormalities include muscle tenderness and decreased range of motion. Based on refs^,,,,,,–.