Marburgviruses and Ebolaviruses

OVERVIEW: What every clinician needs to know

Pathogen name and classification

Filoviruses (family Filoviridae, order Mononegavirales) are viruses with a single-stranded, monopartite RNA genome of negative polarity that form filamentous enveloped virions. Their replication cycles are restricted to the cytosol of infected host cells.

In particular:

Marburg virus (MARV) and Ravn virus (RAVV): species Marburg marburgvirus, genus Marburgvirus
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Bundibugyo virus (BDBV): species Bundibugyo ebolavirus, genus Ebolavirus
Ebola virus (EBOV): species Zaire ebolavirus, genus Ebolavirus
Sudan virus (SUDV): species Sudan ebolavirus, genus Ebolavirus
Taï Forest virus (TAFV): species Taï Forest ebolavirus, genus Ebolavirus

MARV and RAVV are the etiological agents of Marburg virus disease (MVD).

BDBV, EBOV, SUDV, and TAFV are the etiological agents of Ebola virus disease (EVD).

What is the best treatment?

Although multiple products have been utilized in the treatment of patients with EVD, no FDA-approved specific antiviral therapies are available for MVD or EVD.
The most promising anti-filoviral agents currently in development are EBOV-specific antibodies and antibody cocktails, both of which are potentially available as emergency Investigation New Drugs (eINDs) in the US. These agents are undergoing clinical trials in Western Africa.
Other promising products include phosphorodiamidate morpholino oligomers (PMOs) and small interfering RNAs (siRNAs), both of which show efficacy in animal models. Small interfering RNAs are undergoing phase I human clinical trials. Also, highly promising is a synthetic adenosine analog (BCX4430), which has been successful in nonhuman primate models of MVD even if given at later stages of infection. The antiviral drug favipiravir is efficacious in mouse models and is already in use as an anti-influenza drug in Japan. Historically, however, most therapeutics that demonstrate efficacy in mouse models of EVD fail in more advanced animal models.
Hyperimmune equine immunoglobulin is approved in Russia for emergency treatment of laboratory infections. Its clinical efficacy is unclear as it did not have a measurable effect on the lethal clinical course of a Russian researcher infected with guinea pig-adapted EBOV.
Post-exposure vaccination with recombinant vesicular stomatitis Indiana virus (rVSV) expressing EBOV, SUDV, or MARV glycoproteins has shown promise in animal models.
A recent ring vaccination trial conducted in Guinea demonstrated that the rVSV-EBOV vaccine may be highly efficacious in preventing EVD in clusters of people with potential exposure to a known source patient.
In the case of an occupational exposure in the US, healthcare providers should seek immediate consultation with filovirus experts, (e.g., the Centers for Disease Control and Prevention [CDC], the United States Army Medical Research Institute of Infectious Diseases [USAMRIID], the National Institutes of Health [NIH], and the Food and Drug Administration [FDA]) to ascertain any recent breakthroughs in potential treatment.
Although specific antiviral therapies are not available, appropriate clinical management appeared to offer significant benefit in previous cases. Survival can likely be increased through aggressive goal-directed therapy with the objective of maintaining organ function for as long as possible, providing time for immune clearance and re-establishment of homeostasis. Whereas focal necrosis in major organs, particularly the liver, lymphocyte depletion, microvascular dysfunction, and activation/dysregulation of clotting pathways are pathological features of filovirus disease, studies have not yet identified a single definitive cause of severe disease. Septicemia and shock, rather than frank hemorrhage, are the generally accepted cause of death.
In the absence of any other definitive evidence, care should be directed at reversal of the commonly encountered hypotension/hypoperfusion, hemorrhage, diffuse intravascular coagulopathy (DIC), acute kidney injury, electrolyte abnormalities, and shock. Care should follow general guidelines for the management of severe sepsis.
Filovirus infection may predispose to bacterial and fungal secondary infections, or individuals may have contracted filoviral infection in an area endemic with other infections. Therefore, clinicians should monitor patients closely for any indication of secondary infection and should have a low threshold for administration of empiric broad-spectrum antimicrobials. Filovirus infection is not a contraindication for intubation, positive pressure ventilation, vasopressor drugs, renal replacement therapy, or other commonly used supportive care for critically ill patients. In addition, pain management and administration of antiemetics may be necessary for maintaining patient comfort. Very little data exist regarding the management of children with filovirus infection. Although children may generally be less affected, they can develop fulminant disease and should probably be managed with strategies similar to those with severe sepsis.
The currently ongoing EVD outbreak in Western Africa due to EBOV infection is the largest to date with 28,637 cases currently (as of December 27, 2015), many of which have been cared for in specially equipped and staffed isolation units. Prominent clinical features of disease in this outbreak have included a predominance of gastrointestinal symptoms, especially watery diarrhea with profound fluid loss that is described as “cholera-like.” Hypovolemia and electrolyte abnormalities appear to be early and significant contributors to more serious disease, and older age and higher initial viral loads have been associated with worse outcomes.
Treatment strategies in Western Africa currently focus on early oral rehydration with oral rehydration salts (ORS), intravenous hydration when patients cannot take sufficient oral fluids, correction of electrolyte abnormalities, provision of early empiric antibiotic therapy for the severely ill or for indications of co- or super-infection, and maintenance of appropriate hygiene and nutrition.
Clinicians should note the challenge of delivering even basic clinical care in the setting of restrictive isolation procedures, infection control precautions, or personal protective equipment (PPE). Effective pre-event planning will enable successful care and should focus on instituting the minimal safe and appropriate PPE; appropriate engineering barriers; proper supply and equipment; standard procedures for decontamination of environment, equipment and personnel; point of care laboratory testing; infectious waste management; and clinical management guidelines.

How do patients contract this infection, and how do I prevent spread to other patients?

Epidemiology

Ebolavirus activity appears associated with unusually heavy rainfalls succeeding extended periods of dry weather.

Ebolaviruses that cause EVD are found in equatorial African humid rain forests, whereas marburgviruses are endemic in equatorial African arid woodlands.

Marburgvirus infections have been epidemiologically linked with visiting bat-infested caves and mines. MARV and RAVV have been isolated from Egyptian rousettes (Rousettus aegyptiacus) caught in a cave associated with a small MVD outbreak in Uganda, supporting the premise that exposure to bats is a major risk factor for acquiring MVD. The natural hosts of ebolaviruses remain elusive, although detection of EBOV genome fragments and anti-EBOV glycoprotein antibodies were detected in various fruit bats.

Another major risk factor for acquiring filovirus infections is exposure to apes and other nonhuman primates, and possibly other forest animals, such as duikers or bush pigs. Hunting primates or consuming primates found dead has been associated with subsequent disease outbreaks; however, TAFV remains the only virus unequivocally detected in a naturally infected nonhuman primate. Healthcare workers, laboratory technicians, and people who work with infected non-human primates are at risk for occupational infection.

The incidence of diagnosed, symptomatic human filovirus infection is very low. A total of 31,574 infections and 13,333 deaths have been recorded since the discovery of filoviruses in 1967 (data as of December 27, 2015), including laboratory accidents. Mortality (the number of overall deaths per population per time) is therefore low, but lethality is extremely high (mean case fatality rate [CFR]=42.23%). Filoviruses that cause human disease are endemic exclusively in Equatorial Africa, but export of the disease has resulted in cases elsewhere. Known locations of human filovirus outbreaks and cases include:

MARV: Angola, Democratic Republic of the Congo, West Germany/Germany (imported), Kenya, Netherlands (imported), Rhodesia/Zimbabwe, Uganda, USSR/Russia (laboratory accidents), and Yugoslavia (imported) (474 cases, 383 deaths, CFR=80.8%)

RAVV: Democratic Republic of the Congo, Kenya, and Uganda (3 cases, 2 deaths, CFR=66.7%)

BDBV: Democratic Republic of the Congo, Uganda (211 cases, 71 deaths, CFR=33.7%)

EBOV: Gabon, Guinea (with case exportation to Liberia, Mali, Nigeria, Senegal, Sierra Leone, Spain, and USA), Republic of the Congo, Russia (laboratory accidents), and Zaire/Democratic Republic of the Congo (30,106 cases, 12,465 deaths, CFR=41.4%). Case numbers for a current (2013-present) EVD outbreak due to EBOV in Western Africa are not yet definite but constitute the largest known outbreak in history, with 28,637 cases and 11,315 deaths (CFR=39.5%) as of December 27, 2015.

SUDV: Sudan/South Sudan, Uganda, UK (laboratory accident) (779 cases, 412 deaths, CFR=52.9%)

TAFV: Côte d’Ivoire (1 case, 0 deaths, CFR=0%)

The incidence of MVD and EVD has increased since 1967. This increase may be due to increased contact with yet-to-be-identified natural reservoirs of filoviruses or increased vigilance regarding surveillance and reporting.
Infection control issues

Infected people are not thought to be infectious during the incubation period. After the onset of clinical symptoms, transmission to susceptible individuals is through direct contact or contact with infected tissues or body fluids. Droplet and aerosol transmission have not been definitively proven but are theoretically possible. Therefore, contact precautions are of utmost priority.

Healthcare workers should follow strict barrier nursing techniques and avoid direct skin-to-skin contact with sick patients, patient body fluids or tissues, or contaminated material.

Fomites are a viable route of transmission, and reuse of medical equipment, including gloves, should be avoided at all costs. Sterilization/disinfection is relatively easy as filoviruses are enveloped RNA viruses and are, therefore, very susceptible to detergents, including bleach. A 1:100 solution of household bleach is commonly used for surface disinfection, while a 1:10 solution is used for excreta or corpses. Ideally, disposables should be autoclaved or burned.

Healthcare personnel and other staff in proximity to ill patients should wear PPE to protect against contact and splashes, including disposable gowns, gloves, and face-shield and/or goggles. Disposable shoe covers are advisable. Although airborne transmission has not been definitively demonstrated, it is theoretically possible, and airborne PPE, such as N-95 respirators, should be employed. Care should be taken to avoid aerosol-generating procedures. Airborne precautions should be used without question in the setting of patients with pulmonary disease or in the event of interventions with the potential of generating aerosols (e.g., suctioning, intubation).

The use of positive air pressure respirators (PAPRs) and other more elaborate positive pressure suits or gas masks is generally unwarranted and may induce fear in local populations, potentially leading to avoidance of hospitals. In very select circumstances, such as tertiary care settings, or high-risk procedures, such as intubation or suctioning in patients with pulmonary disease, the use of PAPRs would be reasonable.

In the US, the Centers for Disease Control and Prevention have provided guidance for hospitals on the infection control precautions for persons suspected of having EVD (http://www.cdc.gov/vhf/ebola/hcp/infection-prevention-and-control-recommendations.html) and monitoring of known contacts (http://www.cdc.gov/vhf/ebola/hcp/monitoring-and-movement-of-persons-with-exposure.html).

There is no FDA-approved vaccine to prevent MVD or EVD. Anti-filoviral vaccines currently in development are DNA vaccines, replication incompetent filovirus-like particles, and vectored vaccines using replication-incompetent recombinant adenoviruses, recombinant Venezuelan equine encephalitis replicons, rVSV, and recombinant replicating or inactivated rabies viruses.

There is no known effective or FDA-approved anti-viral medication at this time.

What host factors protect against this infection?

The gross pathology and histopathology of filovirus infections is predominantly determined by the onset of disseminated intravascular coagulation (DIC; micro and macro thrombi occluding smaller and larger blood vessels of most organs, especially liver, kidney, and spleen, thereby leading to development of focal necrosis downstream of the occlusion due to oxygen depletion); hemorrhagic diathesis when clotting factors are consumed; increased vascular permeability due to unknown causes resulting in edema; massive lymphocyte depletion in all lymphoid organs; and replication of filoviruses in cells including macrophages, monocyte-derived dendritic cells, hepatocytes, Kupffer cells, fibroblasts, and endothelial cells.

What are the clinical manifestations of infection with this organism?

MVD and EVD are clinically indistinguishable. Although there are slight fluctuations in the frequency or the duration and onset of observed clinical signs, statistically significant differences have not been uncovered. The most detailed clinical data obtained so far stem from EVD outbreaks in Kikwit, Zaire, 1995, and the 2013-present outbreak in Western Africa (EBOV); Durba and Watsa, Democratic Republic of the Congo, 1998-2000 (MARV+RAVV); and Bundibugyo, Uganda, 2007-2008 (BDBV).
Disease begins after an incubation period of 3-25 days (average 8-10 days) with a sudden onset of fever and influenza-like symptoms that may include malaise, severe frontal and temporal headaches, myalgia in the cervical and lumbar regions, sore throat, dry cough, retrosternal chest pain, frontal and occipital headache, and large joint arthralgia.
Disease is sometimes described as bi-phasic, with a 1-2-day relative remission separating the initial influenza-like phase from the later manifestations.
Clinical signs may progress to include photophobia, vertigo, non-purulent conjunctivitis, hiccups, facial edema, severe watery diarrhea, crampy abdominal pain, nausea, vomiting, fissures and vesicular lesions in the mouth, red tongue, dysphagia, a morbilliform (maculopapular) rash, and both internal and external bleeding (particularly at venipuncture sites).
Hemorrhagic symptoms may become evident at days 5-7 and include subconjunctival hemorrhage, petechiae, purpura, ecchymoses, epistaxis, hemoptysis, hematemesis, hematuria, melena, and bleeding from mucosal surfaces (nose, gastrointestinal tract, and vagina). Hepatomegaly may be present; jaundice is usually absent.
In the US, the CDC established a case definition for EVD that includes risk of exposure along with clinical signs. As of November 16, 2015, a person under investigation should have the clinical criteria of elevated body temperature or subjective fever or symptoms, including severe headache, fatigue, muscle pain, vomiting, diarrhea, abdominal pain, or unexplained hemorrhage; and an epidemiologic risk (http://www.cdc.gov/vhf/ebola/exposure/risk-factors-when-evaluating-person-for-exposure.html) factor within the 21 days before the onset of symptoms.
Laboratory abnormalities include thrombocytopenia, leukopenia with a left shift followed by leukocytosis, hypokalemia, and increased concentrations of creatinine, urea, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT) and serum amylase.
By inference from severe sepsis, serum lactate probably provides a useful marker for progression to severe disease and shock.
Death most often occurs between days 4 and 14 following infection due to shock/multiorgan failure. Shock is not due to hypovolemia as a result of external blood loss; however, hypovolemia due to fluid redistribution may cause of shock.
During the convalescent period of disease, arthalgia, myalgia, skin desquamation, alopecia, orchitis, and ocular manifestations (iritis, iridocyclitis, uveitis, choroiditis) may persist for extended periods of time. MARV, EBOV, and SUDV also persist in the liver and in semen for extended periods of time after reconvalescence, possibly leading to secondary infections via sexual transmission. Most recently, EBOV was found to persist in aqueous humor and cerebrospinal fluid following resolution of viremia.

What common complications are associated with infection with this pathogen?

EVD and MVD are frequently fatal. Additional complications arise during pregnancy, as infected pregnant women almost uniformly die during labor due to the consumed clotting factors and subsequent severe bleeding.
EVD and MVD are often complicated by secondary bacterial and fungal infections. Clinicians should consider broad antibacterial coverage and/or fungal coverage that is based upon local resistance patterns.

How should I identify the organism?

In the US, presumptive serum testing for filoviruses is available through designated Laboratory Response Network laboratories.
The US CDC has provided guidance to healthcare personnel in the US on specimen collection, transport, and testing. These procedures can be found at: http://www.cdc.gov/vhf/ebola/healthcare-us/laboratories/specimens.html.
RT-polymerase chain reaction (PCR) assays are the current standard for the diagnosis of filovirus infections. The sensitivity of these assays is higher than that of filovirus isolation in culture and a positive test result can easily be confirmed by antigen-capture ELISA. Detection limits with modern assays are in the range of 1,000-2,000 filovirus genome copies per milliliter of serum. There are currently no FDA-licensed PCR assays for filoviruses, but the CDC’s Laboratory Response Network and certain US Department of Defense microbiology laboratories are equipped with filovirus RT-PCR assays.
Filoviruses are the only human viruses that uniformly produce extended, pleomorphic filamentous virions (width: 80 nm, length 800-1,000 nm, but as long as 14,000 nm in tissue culture) that can be unequivocally identified by electron microscopy. However, electron microscopy cannot differentiate the individual filoviruses, although mean differences in particle length may provide hints towards their identities.
Filoviruses should not be grown outside a BSL-4-equivalent maximum-containment laboratory.

Filoviruses can be isolated in African green monkey kidney cells, such as Vero E6 or MA-104 cells, and in many other mammalian cell lines.

Antigen-capture enzyme-linked immunosorbent assay (ELISA) is the most important non-nucleic acid-based diagnostic test.

Culturing filoviruses is considered straight-forward. Filoviruses spread rapidly through susceptible cell types (one replication cycle lasts 12-21h), causing cell death that becomes visible as early as 24-48 hours after inoculation, depending on virus titer. Virus isolation fails occasionally.
In the past, filoviruses have been identified with indirect fluorescence assays (IFAs), but these have been abandoned because of high cross-reactivity and false-positive results.

How does this organism cause disease?

The main factor for spread is the filovirus surface spike glycoprotein GP, which binds to unknown cellular surface molecules and thereby determines cell tropism and mediates virus cell entry. Several structural proteins of filoviruses suppress the antiviral interferon response of infected cells.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

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