MICROBIOLOGY

  • 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.
  • Reservoir: believed to be zoonotic, but not proven.
  • 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.

CLINICAL

  • Causes epidemic disease with high mortality rate (50-90%).
  • Ebola outbreaks continue sporadically in Democratic Republic of the Congo, Ivory Coast, Gabon, Uganda, Sudan and Republic of the Congo.
    • Largest outbreak to date (2014-15) 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 (Oct 2015): 28,457 reported cases, 11,312 deaths (~40% mortality rate).
        • Healthcare workers (HCW): 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 27.8% (5 of 18 pts, Nov 2014), and interestingly 2 HCW who were secondarily infection (Dallas) both survived (so 100% of small number). This may be due to excellent supportive care/fluid and electrolyte management.
    • Cases seen due to importation of virus into US, 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.
  • Transmission has been traditionally ascribed to close contact with infected individual involving blood or secretions or contaminated objects.
  • Incubation period 2-21 d, mean 8-10d.
  • Symptoms: no pathognomonic features, so often not suspected until cluster of unexpected deaths occur.
    • Infection may be categorized in three phases: non-specific 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.
      • 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.
    • Non-specific 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 Ebola outbreak: hemorrhagic complications seen in 30-40%, rarely the cause of death.
  • Diagnosis: suspect in seriously ill traveler returning from 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 delay in diagnosis due to Ebola considerations when they had equally life-threatening disease with falciparum malaria.
    • Lab: diagnosis in early infection may be difficult as symptoms such as rash and red eyes are nonspecific.
      • Early infection may cause leukopenia and then evolve to neutrophilia with left shift and atypical lymphocytes.
      • Transaminase elevations
      • Thrombocytopenia
      • Coagulopathy c/w DIC
    • Viral diagnostics:
      • RT-PCR (preferred, contact local health department or perform via in-house platform, e.g., Biofire)
      • Serology: blood or other specimens analyzed by antigen capture ELISA IgM & IgG
      • Viral culture
  • Contact local health department as soon as possible if 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:
    • 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

TREATMENT

Supportive Care

  • Primary importance is to isolate suspected patients and institute strict infection control methods by nursing protocols including personal protective gear, respirators.
  • Antiviral treatment has not been proven to be effective or commercially available.
    • Experimental treatments have been used on some patients. Efficacy is not known since limited number. See http://www.cdc.gov… For additional information or acquisition of drugs for infected patients.
      • Current experimental approaches: include monoclonal antibodies, convalescent sera, RNA interfering drugs
      • DIC: heparin efficacy is unclear in human Ebola infection. Activated protein C (Xigris) has some benefit in primate model of infection, but is no longer available in US. Anti-coagulation protein rNAPc2 has shown 33% efficacy in non-human primate Zaire-Ebola infection.
      • Ribavirin: no effect known on filoviruses, and given drug side effects on heme system--not recommended for Ebola.
    • Patients empirically likely to get empiric anti-malarials 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.
  • Other:
    • 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 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 second week, patient either defervesces with marked improvement or dies in shock with multiorgan failure, often accompanied by anuria, DIC, liver failure.

Prevention

  • Notify local hospital infection control, public health officials immediately of suspected cases. Isolate 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)
        • No consensus on optimal PPE.
        • Education and strict process (donning/doffing) likely more important than actual types of gear assuming adequate protection of skin and mucous membranes.
      • Guidance for Environmental Infection Control in hospitals
    • Infection control manual from CDC for suggestions in 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 preparation of dead for funeral.
  • Vaccines: under study
  • Screening: healthcare encounters, returning travelers (at certain US airports for those within 21d of being in Guinea, Liberia, or Sierra Leone) with fever or GI symptoms.

Selected Drug Comments

Drug

Recommendation

No drugs have been shown to be useful in the treatment or prevention of Ebola infection, but experimental therapies may be available.

FOLLOW-UP

  • Following recovery, virus has been documented in "immune-privileged" sites: tests (+ semen), eye (+ ocular fluid).
    • Unclear if this has role in continued transmission of virus.
  • Among survivors, many have sequelae that may last > 1 year [10]:
    • Ocular deficits, ocular pain
    • Hearing loss, tinnitus
    • Swallowing disorders
    • Chronic fatigue
    • Difficulty sleeping
    • Intense arthalgia
    • Memory loss, neurocognitive symptoms

OTHER INFORMATION

  • For suspected patients, please see CDC site for comprehensive information on infection control recommendations, diagnostic methods and treatment [1].
  • In advanced cases, virus 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 infection should have barrier nursing in negative pressure room. Notify public health officials.
  • In endemic setting, causes epidemic disease, spread by direct contact with blood and body fluids.
  • Outbreaks continue to occur sporadically in sub-Saharan Africa, so watch for travelers (health care personnel) with serious febrile illness.
  • US 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 majority of infected patients to date.
    • Screening (CDC checklist) important to assess risk potential during initial engagement of health care in EDs, urgent care centers, etc.

Basis for recommendation

  1. Centers for Disease Control and Prevention. Ebola Hemorrhagic Fever. http://www.cdc.gov/vhf/ebola/ (accessed 1/15/15)

    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.

  2. Centers for Disease Control and Prevention. Interim Guidance for Environmental Infection Control in Hospitals for Ebola Virus http://www.cdc.gov… (accessed 1/15/2015)

    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.

  3. Feldmann H, Geisbert TW: Ebola haemorrhagic fever. Lancet 377:849, 2011  [PMID:21084112]

    Comment: Review comments on the human cost with thorough overview of known epidemiology, detection methods and infection control/supportive care. Authors also point out that this virus also greatly impacts the great ape population in Africa.

  4. Weber DJ, Rutala WA: Risks and prevention of nosocomial transmission of rare zoonotic diseases. Clin Infect Dis 32:446, 2001  [PMID:11170953]

    Comment: General review of how to approach the prevention of transmission of Ebola virus and other high grade pathogens

References

  1. Towner JS et al: Newly discovered ebola virus associated with hemorrhagic fever outbreak in Uganda. PLoS Pathog 4:, 2008  [PMID:19023410]

    Comment: A newly discovered Ebola virus associated with a recent outbreak in Uganda, fairly distantly related to the known Ebola viruses.

  2. Martin JE et al: A DNA vaccine for Ebola virus is safe and immunogenic in a phase I clinical trial. Clin Vaccine Immunol 13:1267, 2006  [PMID:16988008]

    Comment: A phase I clinical trial with promise for development of a vaccine against Ebola virus.

  3. Feldmann H et al: Effective post-exposure treatment of Ebola infection. PLoS Pathog 3:, 2007  [PMID:17238284]

    Comment: Animal model demonstration of a potential post-exposure treatment of Ebola virus infection, using injection of a live-attenuated recombinant vesicular stomatitis virus vector expressing the Ebola virus glycoprotein. This worked both in rodent and non-human primate models of infection.
    Rating: Important

  4. Daddario-DiCaprio KM et al: Postexposure protection against Marburg haemorrhagic fever with recombinant vesicular stomatitis virus vectors in non-human primates: an efficacy assessment. Lancet 367:1399, 2006  [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.
    Rating: Important

  5. Bah EI et al: Clinical Presentation of Patients with Ebola Virus Disease in Conakry, Guinea. N Engl J Med Nov 5  [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].
    Rating: Important

  6. Clark DV et al: Long-term sequelae after Ebola virus disease in Bundibugyo, Uganda: a retrospective cohort study. Lancet Infect Dis 15:905, 2015  [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.

  7. Del Rio C et al: Ebola Hemorrhagic Fever in 2014: The Tale of an Evolving Epidemic. Ann Intern Med Aug 19  [PMID:25133433]

    Comment: Helpful perspectives, from West Africa to developed countries.

  8. Dixon MG, Schafer IJ, EIS officer, CDC: Ebola viral disease outbreak - west Africa, 2014. MMWR Morb Mortal Wkly Rep 63:548, 2014  [PMID:24964881]

    Comment: Largest outbreak of EVD to date and the first to occur in West Africa. Spread likely due to poor coordination of public health interventions and isolation techniques.

  9. Fischer WA, Hynes NA, Perl TM: Protecting Health Care Workers From Ebola: Personal Protective Equipment Is Critical but Is Not Enough. Ann Intern Med 161:753, 2014  [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.

  10. Geisbert TW et al: Treatment of Ebola virus infection with a recombinant inhibitor of factor VIIa/tissue factor: a study in rhesus monkeys. Lancet 362:1953, 2003  [PMID:14683653]

    Comment: In Ebola virus infection, macrophages express tissue factor on their surfaces, which by attracting other components of the clotting cascade, resulting in localized thrombosis leading to excessive bleeding elsewhere. Treatment with recombinant factor VIIa/tissue factor led to prolonged survival and 1/3 survival rate, much better than controls.

  11. Lamontagne F et al: Doing today's work superbly well--treating Ebola with current tools. N Engl J Med 371:1565, 2014  [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.

  12. MacNeil A et al: Proportion of deaths and clinical features in Bundibugyo Ebola virus infection, Uganda. Emerg Infect Dis 16:1969, 2010  [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.

  13. Nielsen CF et al: Improving Burial Practices and Cemetery Management During an Ebola Virus Disease Epidemic - Sierra Leone, 2014. MMWR Morb Mortal Wkly Rep 64:20, 2015  [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.

  14. Leroy EM et al: Fruit bats as reservoirs of Ebola virus. Nature 438:575, 2005  [PMID:16319873]

    Comment: Possible demonstration of a zoonotic reservoir of Ebola virus.

  15. Roddy P et al: Clinical manifestations and case management of Ebola haemorrhagic fever caused by a newly identified virus strain, Bundibugyo, Uganda, 2007-2008. PLoS One 7:, 2012  [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%).

  16. Sobarzo A et al: Persistent immune responses after Ebola virus infection. N Engl J Med 369:492, 2013  [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.

  17. Stephenson J: Largest-ever Ebola outbreak still simmering in West Africa. JAMA 312:, 2014  [PMID:25096676]

    Comment: As of August 2014, >1000 deaths attributed to Ebola occuring in West Africa. WHO has declared a public health emergency. Most cases have occurred in Guinea, Liberia and Sierra Leone.

  18. Sullivan NJ et al: Accelerated vaccination for Ebola virus haemorrhagic fever in non-human primates. Nature 424:681, 2003  [PMID:12904795]

    Comment: This is a landmark paper showing the feasibility of developing an Ebola virus vaccine. The strategy is of particular importance because it can be used to obtain accelerated immunity which may be useful in outbreak or bioterrorism situations.

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Last updated: October 8, 2015