MICROBIOLOGY

• Filovirus has several subtypes, including infecting humans and non-human primates. The cause of Ebola virus disease (EVD, Fig) is 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 in the 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 is 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 are believed to be the source of human infection that leads to human-human spread.
  • Traditionally, outbreaks are seen in Central African rain forests and, more recently, in major urban and rural environs.
• Pathogenesis: most data from primate models. Appears that the virus affects both innate and adaptive immunity. High levels of pro-inflammatory cytokines, disruption of dendritic cells, and activated macrophages impair immune responses and trigger DIC. Significantly elevated viral loads in those with advanced infection, near death.

CLINICAL

• 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.
  • Uganda: September 2002 outbreak (click the link for updates) in the Mubende District.
    • Sudan species, the outbreak in five districts as of 10/15/22, outbreak ended in January 2023.
    • The concern is also that the Ebola vaccine does not cover this species.
  • DRC: has had the most Ebola outbreaks to date (8); an epidemic has been ongoing since May 2017 and remains active, partly due to safety and logistic concerns about providing care, immunization and prevention education.
    • In August 2022, public health authorities announced a case of Ebola virus disease in the Beni health zone in the province of North Kivu.
    • 2018-2020 outbreak, declared ended. Second largest-ever outbreak with an overall fatality rate of 67%.
  • The largest outbreak to date (2014-16), with notable firsts, occurred in West Africa (Guinea, Liberia, Sierra Leone, with surrounding countries reporting cases: Nigeria, Senegal and Mali) and occurred 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.
    • In some locales, the mortality rate is estimated to be as high as ~75%, especially with limited resources, but lower with intensive support.
      
      • Survival in first-world countries (mostly HCWs) with access to advanced/ICU care was 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 a small number). This may be due to excellent supportive care/fluid and electrolyte management.
  • Cases are seen due to the importation of viruses 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 individuals 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 are thought to be acquired through contact with an infected animal, e.g., a 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 death or survival.
  • Initial phase: Illness starts with nonspecific fever and headache, flu-like symptoms including myalgia, arthralgia and chills.
    • The onset of fever is later accompanied by sx, including nausea, vomiting, abdominal pain, diarrhea, chest pain, cough, pharyngitis, photophobia, adenopathy, conjunctival injection (red eyes), jaundice, and 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 is common.
    • High viral load: in fatal cases, 3 logs higher than survivors
  • Fatal cases are often preceded by hypovolemic shock, multiple organ failure and hemorrhage (in ~50-60%).
    • 2014-16 Ebola outbreak: hemorrhagic complications were seen in 30-40%, rarely the cause of death.
• Diagnosis: suspect in a seriously ill traveler returning from an endemic area.
  • Ddx: essential in the febrile patient from West Africa to focus not only on Ebola, as many other infections can produce similar pictures.
    • Several 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 include malaria, typhoid fever, Shigella, meningococcemia, leptospirosis, plague, and Borrelia spp. (relapsing fever), measles[13], 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 complex as symptoms such as rash and red eyes are nonspecific. Consider if symptoms are 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 into neutrophilia with left shift and atypical lymphocytes.
    • Transaminase elevations
    • Thrombocytopenia
    • Coagulopathy c/w DIC
  • Viral diagnostics:
    • RT-PCR (preferred for early diagnosis; contact the local health department or perform via an in-house platform)
      • A single negative test early in infection does not exclude.
        • Repeat over 72 hours 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.
    • Antigen detection:
      • FDA-approved OraQuick® Ebola Rapid Antigen Test (2019)
        • A rapid diagnostic test (RDT) for the Ebola virus in both symptomatic patients and recently deceased people
        • Use is only suggested when more sensitive molecular testing is not readily available.
          • A NEGATIVE TEST DOES NOT RULE OUT DISEASE
        • All test results (positive and negative) must be verified through real-time reverse transcriptase-polymerase chain reaction (rRT-PCR) testing at a Laboratory Response Network (LRN) or CDC.
    • 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 is best determined three weeks or later after acquisition (if known).
    • Viral culture (BSL-4 pathogen)
    • Immunohistochemistry (tissue analysis mainly in autopsy settings)
• Contact your local health department as soon as possible if a patient suspected with hemorrhagic fever syndrome.
  • Guidance on specimen testing and transport: http://www.cdc.gov/vhf/ebola/hcp/interim-guidance-specimen-collection-subm...

SITES OF INFECTION

• Bloodstream: viremia, generalized endothelial cell dysfunction leading to widespread organ damage and shock.
• CNS: somnolence, delirium, coma
• Skin/mucous membranes:
  
  • Petechiae
  • Hemorrhages
  • 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.

TREATMENT

FOLLOW-UP

• Following recovery, the virus has been documented in "immune-privileged" sites: testes (+ semen), eye (+ ocular fluid).
  
  • Likely has an occasional role in the continued transmission of the virus.
• Among survivors, many have sequelae that may last > 1 year[19]:
  • Ocular deficits, ocular pain
  • Hearing loss, tinnitus
  • Swallowing disorders
  • Chronic fatigue
  • Difficulty sleeping
  • Intense arthralgia
  • Memory loss, neurocognitive symptoms

OTHER INFORMATION

• See the CDC Clinician Ebola page for updated guidance.
• Substantial advances have been made in the ecology of Ebolavirus, transmission/prevention, vaccination effects, diagnosis and management.
  • Outbreaks continue due to the inability of health agencies to enter areas with civil strife and community mistrust.
  • Outbreaks continue to occur sporadically in sub-Saharan Africa, so watch for travelers (healthcare personnel) with febrile severe illnesses.
• For suspected patients, please see the CDC site for comprehensive information on infection control recommendations, diagnostic methods and treatment[3].
• In advanced cases, the virus was seen in all tissues and 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 was estimated to be 25-40% in the 2007 outbreak.
• The first reported case of filovirus HF was in 1967 in Germany, and the first likely Ebola HF was noted in Sudan and northern Zaire in 1976.
• The Ebola virus is a Biosafety Level 4 pathogen. Patients suspected of infection should have barrier nursing in a negative pressure room. Notify public health officials.
• In an endemic setting, it causes epidemic disease, spread by direct contact with blood and body fluids.
• U.S. 2014-15: most states assigned certain hospitals capable of treating Ebola-infected patients rather than having every health facility prepared.
  • Four U.S. federal bio-containment units [Emory/Atlanta, Nebraska, NIH, Montana] currently handle most infected patients.
  • Screening is essential to assess risk potential during the initial engagement of health care in EDs, urgent care centers, etc.

Basis for recommendation

1. Choi MJ, Cossaboom CM, Whitesell AN, et al. Use of Ebola Vaccine: Recommendations of the Advisory Committee on Immunization Practices, United States, 2020. MMWR Recomm Rep. 2021;70(1):1-12.  [PMID:33417593]

   Comment: rVSVΔG-ZEBOV-GP Ebola vaccine (Ervebo) is the first vaccine FDA-approved for this virus. Recommendations here are for adults with potential for occupational exposure in labs or biocontainment treatment centers in the US.
   

2. 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.
   

3. Centers for Disease Control and Prevention. Ebola Hemorrhagic Fever. http://www.cdc.gov/vhf/ebola/ (accessed 3/5/2024)

   Comment: Resource for most up-to-date information regarding diagnostics and management, including handling ill returning air passengers regarding the 2014 West African Ebola outbreak. A review of this information is needed, given the fast-moving pace and updated guidance as outbreaks occur. Details and links are provided for treatment and vaccines that are only FDA-approved for the Zaire ebolavirus.
   

4. WHO 2023 Infection Prevention and Control, Ebola and Marburg Diseases. https://iris.who.int/bitstream/handle/10665/372261/WHO-WPE-CRS-HCR-2023.1-eng.pdf (accessed 3/5/2024)

   Comment: This document updates the 2014 and 2016 Guidelines and offers 11 new recommendations.
   
   
   

References

5. PREVAC Study Team, Kieh M, Richert L, et al. Randomized Trial of Vaccines for Zaire Ebola Virus Disease. N Engl J Med. 2022;387(26):2411-2424.  [PMID:36516078]

   Comment: The trial focused on immunogenicity among three vaccines against the Zaire Ebola virus. No safety issues were identified, and all generated immune responses within two weeks.
   

6. Gao Y, Zhao Y, Guyatt G, et al. Effects of therapies for Ebola virus disease: a systematic review and network meta-analysis. Lancet Microbe. 2022;3(9):e683-e692.  [PMID:35803293]

   Comment: Monoclonals were more effective than ZMapp or remdesivir in mortality reduction.
   

7. Tomori O, Kolawole MO. Ebola virus disease: current vaccine solutions. Curr Opin Immunol. 2021;71:27-33.  [PMID:33873076]

   Comment: Vaccine studies have focused on Zaire Ebolavirus outbreaks in the DRC. However, even with a relatively effective vaccine for prevention, other strategies are necessary as well as understanding approaches for non-Zaire outbreaks.
   

8. Mulangu S, Dodd LE, Davey RT, et al. A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics. N Engl J Med. 2019;381(24):2293-2303.  [PMID:31774950]

   Comment: A trial performed during the existing outbreak found both MAb114 and REGN-EB3 were superior to ZMapp in reducing mortality from EVD. At the primary endpoint of 28d, death had occurred in 61 of 174 patients (35.1%) in the MAb114 group, as compared with 84 of 169 (49.7%) in the ZMapp group (P=0.007), and in 52 of 155 (33.5%) in the REGN-EB3 group, as compared with 79 of 154 (51.3%) in the ZMapp subgroup (P=0.002). A shorter duration of symptoms before admission and lower baseline values for viral load and serum creatinine and aminotransferase levels each correlated with improved survival.
   

9. 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.
   

10. Perkins MD, Dye C, Balasegaram M, et al. Diagnostic preparedness for infectious disease outbreaks. Lancet. 2017;390(10108):2211-2214.  [PMID:28577861]

    Comment: With Ebola as a prime example, rapid diagnostics would greatly improve care and also help in the control of outbreaks.
    

11. 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;65(8):1400-1403.  [PMID:28582513]

    Comment: A single patient study found the virus in semen was higher/more extended than in blood, suggesting another potential transmission mode.
    

12. 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 found relatively late in the Liberia outbreak was that these vaccines did elicit good immune responses. The effort also is seen as allowing clinical trials in an epidemic setting.
    

13. 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 a crisis breakdown of routine medical care, 80 patients seen for consideration of Ebola tested negative. Still, Measles virus IgM was detected in 13 (16%) patients.
    

14. 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: The vaccine proved helpful in a ring strategy to limit Ebola. This vaccine is endorsed by WHO in case of an outbreak, although any country hasn’t yet approved it.
    Rating: Important
    

15. 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 them. 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."
    

16. PREVAIL II Writing Group, Multi-National PREVAIL II Study Team, Davey RT, et al. 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%. A trend toward lower mortality with ZMapp (22%) v. only supportive care (37%), but the study fell short of pre-specified thresholds for statistically proven efficacy.
    Rating: Important
    

17. Bah EI, Lamah MC, Fletcher T, et al. Clinical presentation of patients with Ebola virus disease in Conakry, Guinea. N Engl J Med. 2015;372(1):40-7.  [PMID:25372658]

    Comment: Given that little has been well describing the clinical features of Ebola, this report from Guinea helps fill gaps and finds that diarrhea and fluid losses are among the important features. The use of IVF and other supportive management may be necessary for lowering mortality rates, 43% in this series, lower than described in outlying areas with fewer resources. Most patients who died did so with a mean of 8d from the initial onset of symptoms [range 7-11]. Increased risk of death is also witnessed in patients older than 40 years [RR 3.49].
    Rating: Important
    

18. 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):20-7.  [PMID:25590682]

    Comment: Work to make safer community and burial practices may help staunch transmission of Ebola. A needs assessment and recommendations for processes at a national level.
    

19. 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 several 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.
    

20. 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: A helpful perspective piece that combats fear and pervading sense that providing care may be hopeless and pose the gravest of risks to HCWs. More resources and diligence in providing the best supportive care may lower fatalities.
    

21. 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):753-4.  [PMID:25155746]

    Comment: Authors, including the lead who provided care in West Africa, argue that PPE, if sufficient coverage demands more on proper practice and rituals to prevent HCW contamination.
    

22. 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.
    

23. 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 a vaccine can be derived to do similar.
    

24. 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: An outbreak in Bundibugyo, Uganda, in November 2007-February 2008, caused by a putative new species (Bundibugyo ebolavirus) with this report includes 93 putative cases, 56 laboratory-confirmed cases, and 37 deaths (CFR = 25%). This virus generally behaved similarly to earlier Ebola descriptions, although CFR is slightly lower. The most frequently experienced symptoms were non-bloody diarrhea (81%), severe headache (81%), and asthenia (77%).
    

25. 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; the mortality rate was lower than others at 40%--unclear if this new strain of Ebola accounted for the difference from the usual 50-90% mortality rate. Risk factors for death included older age.
    

Media

Ebola virus

Electron microscopic image of the Ebola filovirus, named after threadlike nature.
Source: CDC