- Filovirus, several subtypes: infects humans and non-human primates. Cause of Ebola virus disease (EVD) also called Ebola hemorrhagic fever.
- Ebola-Zaire, Ebola-Sudan, Ebola-Ivory Coast and Ebola-Bundibugyo infect humans.
- Ebola-Reston has only caused infection in non-human primates, Philippines.
- Enveloped, non-segmented negative-strand RNA virus. Characteristic thread-like viral particles when viewed under electron microscopy.
- Cause of hemorrhagic fever (HF), primarily in sub-Saharan Africa. Infection in primates and people by the Ebolavirus group:
- Human disease only known to be due to Ebola, Sudan, Tai Forest and Bundibugyo.
- Ebola virus (species Zaire ebolavirus)
- Sudan virus (species Sudan ebolavirus)
- Taï Forest virus (species Taï Forest ebolavirus, formerly Côte d’Ivoire ebolavirus)
- Bundibugyo virus (species Bundibugyo ebolavirus)
- Reston virus (species Reston ebolavirus)
- Bombali virus (species Bombali ebolavirus)
- Reservoir: believed to be zoonotic, but not proven.
- Wild animals believed to be source establishing a human infection that then leads to human-human spread.
- Traditionally outbreaks seen in Central African rain forests, more recently in major urban as well as rural environs.
- Pathogenesis: most data from primate models. Appears that virus affects both innate and adaptive immunity. High levels of pro-inflammatory cytokines, disruption of dendritic cells and activated macrophages impairs immune responses and triggers DIC. Extremely elevated viral loads in those with advanced infection, near death.
- Causes epidemic disease with a high mortality rate (25-90%, depending on the outbreak).
- Ebola outbreaks continue sporadically in Democratic Republic of the Congo (DRC), Ivory Coast, Gabon, Uganda, Sudan and Republic of the Congo.
- DRC: has had most Ebola outbreaks to date (8), epidemic ongoing since May 2017 and remains active in 2019, in part due to safety and logistic concerns in an effort to provide care, immunization and prevention education.
- 2687 reported confirmed cases of EVD (8/6/2019, WHO for updates), the overall fatality rate of 67%.
- The largest outbreak to date (2014-16) with notable firsts: occurring in West Africa (Guinea, Liberia, Sierra Leone with surrounding countries reporting cases: Nigeria, Senegal and Mali) and occurring in urban settings.
- Zaïre ebolavirus strain involved.
- Statistics (Apr 2016): 28,616 reported cases, 11,310 deaths (~40% mortality rate).
- Healthcare workers (HCWs): significantly affected.
- Mortality rate estimated to be as high as ~75% in some locales especially with limited resources but lower with intensive support.
- Survival in first-world countries (mostly HCWs) with access to advanced/ICU care much higher, with a mortality rate of 27.8% (5 of 18 pts, Nov 2014); and interestingly 2 HCWs who were secondarily infected (Dallas) both survived (so 100% of small number). This may be due to excellent supportive care/fluid and electrolyte management.
- Cases are seen due to the importation of virus into the U.S. and Europe.
- Local transmission to healthcare workers documented, unclear if potentially due to airborne transmission (secondary to high viral load in severely ill, advanced Ebola patients) vs. difficulties in achieving complete protection with personal protective gear.
- The transmission has been traditionally ascribed to close contact with infected individual involving blood or secretions or contaminated objects then entering through skin breaks or mucous membranes.
- Semen has been implicated as viral levels tend to be high and persist.
- Index cases of Ebola thought to be acquired through contact with an infected animal, e.g., fruit bat or a nonhuman primate.
- Incubation period 2-21 d, mean 8-10d.
- Symptoms: no pathognomonic features, so often not suspected until a cluster of unexpected deaths occurs.
- Infection may be categorized into three phases: nonspecific flu-like, GI and then death or survival
- Initial phase: Illness starts with nonspecific fever and headache, flu-like symptoms including myalgia, arthralgia and chills.
- The onset of fever later accompanied by sx including nausea, vomiting, abdominal pain, diarrhea, chest pain, cough, pharyngitis, photophobia, adenopathy, conjunctival injection (red eyes), jaundice, pancreatitis.
- Rash manifesting as erythema → maculopapular may arise d5-7 and subsequently desquamate. Desquamation interestingly correlates with survival.
- Nonspecific symptoms progress to a severe systemic inflammatory response with coagulopathy and hemorrhagic evidence (petechiae, ecchymoses and mucosal bleeding), multi-organ system failure resembling septic shock.
- Lymphopenia common.
- High viral load: in fatal cases 3 logs higher than survivors
- Fatal cases often preceded by hypovolemic shock, multiple organ failure and hemorrhage (in ~50-60%).
- 2014-16 Ebola outbreak: hemorrhagic complications seen in 30-40%, rarely the cause of death.
- Diagnosis: suspect in a seriously ill traveler returning from an endemic area.
- Ddx: important in the febrile patient from West Africa to focus not only upon Ebola, as many other infections can produce similar pictures.
- A number of patients have had a delay in diagnosis due to Ebola considerations when they had an equally life-threatening disease with falciparum malaria.
- Other severe tropical ills to consider include malaria, typhoid fever, Shigella, meningococcemia, leptospirosis, plague, Borrelia spp. (relapsing fever), measles, anthrax, typhus or spotted fevers, yellow fever, Chikungunya fever, Lassa fever, Dengue and severe viral hepatitis (Hepatitis A, B or E).
- Lab: diagnosis in early infection may be difficult as symptoms such as rash and red eyes are nonspecific. Consider if symptoms suggestive + possible exposure (blood, body fluids or objects from EVD pt, infected fruit bat or primate, semen from recovered EVD pt) to EVD within 21d of symptom onset.
- Early infection may cause leukopenia and then evolve to neutrophilia with left shift and atypical lymphocytes.
- Transaminase elevations
- Coagulopathy c/w DIC
- Viral diagnostics:
- RT-PCR (preferred for early diagnosis, contact the local health department or perform via an in-house platform)
- Single negative test early in infection does not exclude. Repeat over 72h if suspicion remains.
- Peak viral load days 3-7. Fatal cases with very high viremia, 10-100x that of survivors.
- The seminal fluid remains positive for months to years after recovery from EVD.
- Serology: blood or other specimens analyzed by antigen-capture ELISA IgM and IgG
- Helpful for paucisymptomatic or asymptomatic EV infections as the viral load may be very low.
- Serology best determined 3 weeks or later after acquisition (if known).
- Viral culture
- Immunohistochemistry (tissue analysis mainly in autopsy settings)
- Contact your local health department as soon as possible if a patient suspected with hemorrhagic fever syndrome.
SITES OF INFECTION
- Bloodstream: viremia, generalized endothelial cell dysfunction leading to widespread organ damage and shock.
- CNS: somnolence, delirium, coma
- Skin/mucous membranes:
- Ecchymoses around needle puncture sites
- Day 5: maculopapular rash develops in most patients
- GI: vomiting, diarrhea
- Liver: jaundice, liver failure (secondary to shock or direct involvement by virus)
- Kidney: renal failure, hemorrhage
- Lung: respiratory failure due to viral infection leading to necrosis, ARDS accompanying shock
- Gonads: orchitis, can be prolonged during convalescence
- Limited studies suggest virus presence in semen is higher and longer than in plasma.
- Primary importance is to isolate suspected patients and institute strict infection control methods by nursing protocols including personal protective gear, respirators.
- DIC: heparin efficacy is unclear in human Ebola infection. Activated protein C (Xigris) has some benefit in the primate model of infection, but is no longer available in U.S. Anti-coagulation protein rNAPc2 has shown 33% efficacy in non-human primate Zaire-Ebola infection.
- Patients are empirically likely to get empiric antimalarials and broad-spectrum antibiotics.
- Fluid/electrolyte management as possible in setting, taking into account myocardial and pulmonary dysfunction. This, especially if instituted early in infection, is likely to be the most important feature that will contribute to survival.
- Fluid losses due to vomiting or diarrhea may be substantial. Two to four liters/day described as average, reports as high as 12L/d described.
- Some advocated for concurrent broad-spectrum antibiotics due to concern for bacterial gut transmigration.
- If diagnostics not available, consider empiric antimalarial therapy, as co-infections described and believe to contribute to a worse outcome.
- Hemodialysis for renal failure or ECMO for ARDS may be employed if available and needed. Hemodialysis has appeared effective in survival (anecdotal, Emory: Atlanta, Georgia), and cannot be considered futile therapy.
- In the second week, the patient either defervesces with marked improvement or dies in shock with multiorgan failure, often accompanied by anuria, DIC, liver failure.
- A range of approaches under study aims to limit viral expansion by limiting virally triggered severe inflammation.
- Antiviral treatment appears most promising with REGN-EB3 or mAb-114 with mortality rates of 6-11% compared to ZMapp or remdesivir (24-33%). The trial outlined in the chart below was halted early in August 2019, published findings expected in fall 2019.
- Most have been studied in animal models, but human data growing.
- WHO will determine outside of clinical trials which to potentially employ on a compassionate/emergency basis. (Table adapted from Malvy, Lancet 2019 with updates)
Viral polymerase inhibitor
Open-label w/ historical controls
99 participants, 20% mortality (mild viral load), 91% (high load)
No difference in mortality with low or high viral load compared to historical controls.
Hyperimmune serum, neutralizing antibodies
Open-label w/ historical controls
84 participants, 31% mortality (between d3-16) compared to 38% in controls. OR adjusted for viral load 0.88 (95% CI, 0.51-1.151
No statistical survival benefit but low numbers.
Three monoclonal antibodies
Open-label w/ historical controls
72 participants (enrollment targets not reached), mortality at d28 was 22% compared to 37% in control among high viral load patients.
Suggested benefit but not statistically proven given low numbers.
Open-label w/ historical controls
12 participants, mortality at d14 = 25%, trial halted after futility analysis.
No overall survival benefit. Concern for systemic side effects in healthy volunteers.
New trials (3) underway (2019)
Under the WHO trial umbrella
Monoclonal antibodies thought better than ZMapp
Preliminary findings/news release
Preliminary findings show mortality much better with mAb-114 or REGN-EB3 than ZMapp or remdesivir.
- Notify local hospital infection control, public health officials immediately of suspected cases. Isolate the patient and follow protocols.
- Identification of cases, epidemic.
- For most up-to-date recommendations: see http://www.cdc.gov…
- Diagnostic and transport protocols.
- Infection control, personal protective equipment (PPE)
- Education and strict process (donning/doffing) likely more important than actual types of gear assuming adequate protection of skin and mucous membranes.
- PAPR recommendations and environmental cleaning now incorporated.
- Guidance for Environmental Infection Control in hospitals
- Infection control manual from CDC for suggestions in an African setting: http://www.cdc.gov…
- Barrier nursing in negative pressure room if available, strict contact precautions, use of respiratory precautions preferred.
- Employ properly sterilized medical equipment.
- Protection from body fluid/skin/mucous membrane contact during the preparation of the dead for a funeral.
- Vaccines: under study, VSV-ZEBOV (Merck), ChA3-EBO-Z (GSK), Ad26 (JNJ), GamEvac-Combi (Gamalei, Russia).
- WHO: ready to deploy rVSV-vectored Ebola vaccine in event of an outbreak.
- Use in DRC outbreak 2018-2019 but hampered by logistics and civil unrest hampering ring vaccination strategy.
- Screening: healthcare encounters, returning travelers (at certain U.S. airports for those within 21d of being in Guinea, Liberia, or Sierra Leone) with fever or GI symptoms.
- Following recovery, the virus has been documented in "immune-privileged" sites: testes (+ semen), eye (+ ocular fluid).
- Likely has an occasional role in continued the transmission of the virus.
- Among survivors, many have sequelae that may last > 1 year:
- Ocular deficits, ocular pain
- Hearing loss, tinnitus
- Swallowing disorders
- Chronic fatigue
- Difficulty sleeping
- Intense arthralgia
- Memory loss, neurocognitive symptoms
- Substantial advances made in the ecology of Ebolavirus, transmission/prevention, vaccination effects, diagnosis and management.
- Outbreaks continue due to the inability for health agencies to enter areas with civil strife and community mistrust.
- Outbreaks continue to occur sporadically in sub-Saharan Africa, so watch for travelers (health care personnel) with serious febrile illness.
- For suspected patients, please see CDC site for comprehensive information on infection control recommendations, diagnostic methods and treatment.
- In advanced cases, virus was seen in all tissues, body fluids. Evidence of continued virus in semen > 3 mos after recovery (by PCR) of uncertain significance.
- Fatality rates 50-90% typical, but strain-dependent. Ebola-Bundibugyo estimated to be 25-40% in 2007 outbreak.
- First reported case of filovirus HF 1967 in Germany, and first likely Ebola HF noted in Sudan and northern Zaire in 1976.
- Ebola virus is a Biosafety Level 4 pathogen. Patients suspected to have the infection should have barrier nursing in a negative pressure room. Notify public health officials.
- In endemic setting, causes epidemic disease, spread by direct contact with blood and body fluids.
- U.S. 2014-15: most states assigned certain hospitals as capable of treating Ebola-infected patients, rather than have every health facility prepared.
- Four US federal bio-containment units [Emory/Atlanta, Nebraska, NIH, Montana] have handled the majority of infected patients to date.
- Screening important to assess risk potential during initial engagement of health care in EDs, urgent care centers, etc.
Basis for recommendation
- Malvy D, McElroy AK, de Clerck H, et al. Ebola virus disease. Lancet. 2019;393(10174):936-948. [PMID:30777297]
Comment: The 2013-16 outbreak offered a setting for making real advancements in the diagnosis and management of EVD along with updates on current immunization and experimental therapeutics.
- Centers for Disease Control and Prevention. Ebola Hemorrhagic Fever. http://www.cdc.gov… (accessed 3/29/2019)
Comment: Resource for most up to date information regarding diagnostics, management including handling ill returning air passengers regarding the 2014 West African Ebola outbreak. Review of this information needed given fast moving pace and updated guidance.
Section: Basis for recommendation
- Guidance on Personal Protective Equipment (PPE) To Be Used By Healthcare Workers during Management of Patients with Confirmed Ebola or Persons under Investigation (PUIs) for Ebola who are Clinically Unstable or Have Bleeding, Vomiting, or Diarrhea in U.S. Hospitals, Including Procedures for Donning and Doffing PPE http://www.cdc.gov… (page last updated 8/30/2018, accessed 3/29/2019)
Comment: Though spread only by body fluids, given the lethality there is heightened concern (appropriately) about the levels of infection control necessary for patients and healthcare providers. HCW must receive comprehensive training and demonstrate competancy in Ebola-related infection control practices. This update from earlier versions includes new guidance on:
Expand the rationale for respiratory protection;
Clarify that the trained observer should not serve as an assistant for doffing PPE;
Suggest that a designated doffing assistant or “buddy” might be helpful, especially in doffing with the powered air purifying respirator (PAPR) option;
Modify the PAPR doffing procedure to make the steps clearer;
Change the order of boot cover removal. Boot covers should now be removed after the gown or coverall;
Clarify the types of gowns and coveralls that are recommended and provide a link to considerations for gown and coverall selection; and
Emphasize the importance of frequent cleaning of the floor and work surfaces in the doffing area.
Section: Basis for recommendation
- Loignon C, Nouvet E, Couturier F, et al. Barriers to supportive care during the Ebola virus disease outbreak in West Africa: Results of a qualitative study. PLoS One. 2018;13(9):e0201091. [PMID:30183718]
Comment: Interview-based determinations found that ethical complexities in low resource settings centering on 1) lack of material and human resources, 2) insufficient organizational structures for supportive clinical care and 3) delayed or insufficient execution of policies both global and national.
- Perkins MD, Dye C, Balasegaram M, et al. Diagnostic preparedness for infectious disease outbreaks. Lancet. 2017. [PMID:28577861]
Comment: With Ebola as a prime example, rapid diagnostics would greatly improve care and also help in control of outbreaks.
- Barnes KG, Kindrachuk J, Lin AE, et al. Evidence of Ebola Virus Replication and High Concentration in Semen of a Patient During Recovery. Clin Infect Dis. 2017. [PMID:28582513]
Comment: Single patient study finding virus in semen higher/longer than in blood suggesting another potential transmission mode.
- Colavita F, Biava M, Castilletti C, et al. Measles Cases during Ebola Outbreak, West Africa, 2013-2106. Emerg Infect Dis. 2017;23(6):1035-1037. [PMID:28518027]
Comment: Potentially an example of what happens in crises, breakdown of routine medical care, 80 patients seen for consideration of Ebola tested negative but Measles virus IgM was detected in 13 (16%) of the patients.
- Henao-Restrepo AM, Camacho A, Longini IM, et al. Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease: final results from the Guinea ring vaccination, open-label, cluster-randomised trial (Ebola Ça Suffit!). Lancet. 2017;389(10068):505-518. [PMID:28017403]
Comment: Vaccine proved helpful in a ring-stategy to limit Ebola. This vaccine is currently endorsed by WHO in case of outbreak although hasn’t yet been approved by any country.
- Kennedy SB, Bolay F, Kieh M, et al. Phase 2 Placebo-Controlled Trial of Two Vaccines to Prevent Ebola in Liberia. N Engl J Med. 2017;377(15):1438-1447. [PMID:29020589]
Comment: One of several studies that found rather late in the Liberia outbreak that these vaccines did elicit good immune responses. The effort also is seen as allowing clinical trials in an epidemic setting.
- PREVAIL II Writing Group, Multi-National PREVAIL II Study Team. A Randomized, Controlled Trial of ZMapp for Ebola Virus Infection. N Engl J Med. 2016;375(15):1448-1456. [PMID:27732819]
Comment: Largest RCT for Ebola, examing the monoclonal ab treatment + usual care v. only supportive care. Overall mortality in this trial was 30%. Trend toward lower mortality with ZMapp (22%) v. only supportive care (37%), but study fell short of pre-specified thresholds for statiscally proven efficacy.
- Holmes EC, Dudas G, Rambaut A, et al. The evolution of Ebola virus: Insights from the 2013-2016 epidemic. Nature. 2016;538(7624):193-200. [PMID:27734858]
Comment: Authors argue that genomic sequencing of pathogens can be very helpful in helping understand outbreaks and what actions may be needed to contain. This concept is not unique to Ebola but likely helpful as costs for this technology decline to understand that even MDR organisms seen in hospitals are local "outbreaks."
- Nielsen CF, Kidd S, Sillah AR, et al. Improving Burial Practices and Cemetery Management During an Ebola Virus Disease Epidemic - Sierra Leone, 2014. MMWR Morb Mortal Wkly Rep. 2015;64(1):20-27. [PMID:25590682]
Comment: Work to make safer community and burial practices may help staunch tranmission of Ebola. A needs assessment and recommendations for processes at a national level.
- Clark DV, Kibuuka H, Millard M, et al. Long-term sequelae after Ebola virus disease in Bundibugyo, Uganda: a retrospective cohort study. Lancet Infect Dis. 2015;15(8):905-12. [PMID:25910637]
Comment: One of a number of reports documenting a significant number of survivors with post-infectious sequelae. risk of ocular deficits (retro-orbital pain [RR 4·3, 95% CI 1·9-9·6; p< 0·0001], blurred vision [1·9, 1·1-3·2; p=0·018]), hearing loss (2·3, 1·2-4·5; p=0·010), difficulty swallowing (2·1, 1·1-3·9; p=0·017), difficulty sleeping (1·9, 1·3-2·8; p=0·001), arthralgias (2·0, 1·1-3·6; p=0·020), and various constitutional symptoms controlling for age and sex. Chronic health problems (prevalence ratio [PR] 2·1, 95% CI 1·2-3·6; p=0·008) and limitations due to memory loss or confusion (PR 5·8, 1·5-22·4; p=0·010) were also reported more frequently by survivors of Bundibugyo Ebola virus.
- Lamontagne F, Clément C, Fletcher T, et al. Doing today's work superbly well--treating Ebola with current tools. N Engl J Med. 2014;371(17):1565-6. [PMID:25251518]
Comment: Helpful perspective piece that combats fear and pervading sense that providing care may be hopeless and pose gravest of risks to HCWs. More resources and diligence at providing the best supportive care may well lower fatality.
- Bah EI, Lamah MC, Fletcher T, et al. Clinical Presentation of Patients with Ebola Virus Disease in Conakry, Guinea. N Engl J Med. 2014. [PMID:25372658]
Comment: Given that little has been well describe about the clinical features of Ebola, this report from Guinea helps fill gaps and finds that diarrrhea and fluid losses are among the important features and that use of IVF and other supportive managment may be important for lowering mortality rates, 43% in this series, lower than described in outlying areas with less resources. Most patients who died did so with a mean of 8d from initial onset of symptoms [range 7-11]. Increased risk of death also witnessed in patients older than 40 years [RR 3.49].
- Fischer WA, Hynes NA, Perl TM. Protecting Health Care Workers From Ebola: Personal Protective Equipment Is Critical but Is Not Enough. Ann Intern Med. 2014;161(10):753-754. [PMID:25155746]
Comment: Authors including lead who provided care in West Africa, argue that PPE if sufficient coverage demands more on proper practice and rituals to prevent HCW contamination.
- Del Rio C, Mehta AK, Lyon Iii GM, et al. Ebola Hemorrhagic Fever in 2014: The Tale of an Evolving Epidemic. Ann Intern Med. 2014. [PMID:25133433]
Comment: Helpful perspectives, from West Africa to developed countries.
- Sobarzo A, Ochayon DE, Lutwama JJ, et al. Persistent immune responses after Ebola virus infection. N Engl J Med. 2013;369(5):492-3. [PMID:23902512]
Comment: Report of six survivors who all displayed neutralizing antibodies, 12 years after infection with the Gulu strain of Sudan Ebola virus. This suggests that there is likely durable immunity if one survives the infection raising hopes that perhaps a vaccine can be derived to do similar.
- Roddy P, Howard N, Van Kerkhove MD, et al. Clinical manifestations and case management of Ebola haemorrhagic fever caused by a newly identified virus strain, Bundibugyo, Uganda, 2007-2008. PLoS One. 2012;7(12):e52986. [PMID:23285243]
Comment: Outbreak in Bundibugyo, Uganda, November 2007-February 2008, caused by a putative new species (Bundibugyo ebolavirus) with this report including 93 putative cases, 56 laboratory-confirmed cases, and 37 deaths (CFR = 25%). In general, this virus behaved in similar fashion to earlier Ebola descriptions, although CFR is a bit lower. The most frequently experienced symptoms were non-bloody diarrhoea (81%), severe headache (81%), and asthenia (77%).
- MacNeil A, Farnon EC, Wamala J, et al. Proportion of deaths and clinical features in Bundibugyo Ebola virus infection, Uganda. Emerg Infect Dis. 2010;16(12):1969-72. [PMID:21122234]
Comment: Ugandan outbreak in 2007 with 56 cases documented by laboratory method; mortality rate was lower than others at 40%--unclear if this new strain of Ebola accounted for the difference from the normal 50-90% mortality rate. Risk factors for death included older age.
- Towner JS, Sealy TK, Khristova ML, et al. Newly discovered ebola virus associated with hemorrhagic fever outbreak in Uganda. PLoS Pathog. 2008;4(11):e1000212. [PMID:19023410]
Comment: A newly discovered Ebola virus associated with a recent outbreak in Uganda, fairly distantly related to the known Ebola viruses.
- Daddario-DiCaprio KM, Geisbert TW, Ströher U, et al. Postexposure protection against Marburg haemorrhagic fever with recombinant vesicular stomatitis virus vectors in non-human primates: an efficacy assessment. Lancet. 2006;367(9520):1399-404. [PMID:16650649]
Comment: Another post-exposure treatment trial on non-human primates infected with Ebola virus infection, using a live-attenuated recombinant vesicular stomatitis virus vector expressing the Ebola virus glycoprotein.
- Leroy EM, Kumulungui B, Pourrut X, et al. Fruit bats as reservoirs of Ebola virus. Nature. 2005;438(7068):575-6. [PMID:16319873]
Comment: Possible demonstration of a zoonotic reservoir of Ebola virus.
Independent monitoring board recommends early termination of Ebola therapeutics trial in DRC because of favorable results with two of four candidates (NIH media release, accessed 8/13/2019)
An independent data safety monitory board halted the PALM trial with preliminary findings that of the four arms, among 499 study participants, those receiving REGN-EB3 (6% mortality) or mAb114 (11%)had a greater chance of survival compared to participants in the other two arms (receiving Zmapp [24% mortality] or remdesivir [33%]). This information also derived from other sources, including the New York Times.
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