Ebola natural history

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief:  Michael Maddaleni, B.S.; Guillermo Rodriguez Nava, M.D. [2]; João André Alves Silva, M.D. [3]; Yazan Daaboul, M.D.

## Overview[edit | edit source]

The natural history of Ebola hemorrhagic fever is highly dependent on the Ebola virus species and the host immunity. The symptoms of Ebola hemorrhagic fever usually develop 2 to 21 days following exposure to Ebola virus. The clinical course of Ebola hemorrhagic fever has 2 phases, which may possibly be separated by a phase of "pseudoremission". The majority of patients develop severe symptoms that gradually worsen with time. Patients with non-fatal disease typically develop isolated high-grade fever that resolves within 7 to 10 days of disease onset. In contrast, fatal disease is associated with early clinical signs and symptoms, and these patients typically experience rapid clinical deterioration, including hemorrhagic, infectious, and neurological complications, and die 6 to 16 days following the onset of symptoms. Recovery from Ebola depends on good supportive care and the patient’s immune response. People who recover from Ebola infection develop antibodies that last for at least 10 years, possibly longer. It is not known if people who recover are immune for life or if they can become infected with a different species of Ebola. Patients who survive are susceptible to late complications that are not related to the acute illness. The most common long-term complication of Ebola virus among survivors is arthralgia of the large joints that is usually not accompanied by findings on physical examination.

## Natural History[edit | edit source]

The natural history of Ebola hemorrhagic fever is highly dependent on the Ebola virus species and the host immunity. The symptoms of Ebola hemorrhagic fever usually develop 2 to 21 days following exposure to Ebola virus. The clinical course of Ebola hemorrhagic fever has 2 phases, which may possibly be separated by a phase of "pseudoremission".[1] The clinical course of Ebola virus is a spectrum of manifestations. If left untreated, patients may remain asymptomatic or develop mild non-fatal disease, but the majority of patients develop severe symptoms that gradually worsen with time. Patients with non-fatal disease typically develop isolated high-grade fever that resolves within 7 to 10 days of disease onset. In contrast, fatal disease is associated with early clinical signs and symptoms, and these patients typically experience rapid clinical deterioration and die 6 to 16 days following the onset of symptoms.[2][3]

### Phase 1: Early, Non-specific Signs and Symptoms[edit | edit source]

* Early symptoms include high-grade fever, chills, myalgias, arthritis, and generalized fatigue that typically develop within 6 to 13 days of viral incubation (incubation period ranges from 2 to 21 days). Early symptoms typically persist for approximately one week.[4]
* Without treatment, patients subsequently develop non-specific multisystem symptoms, including constitutional (asthenia and anorexia), respiratory (cough and nasal discharge), and gastrointestinal (abdominal pain, nausea, and vomiting) manifestations.
* During this phase, work-up is usually remarkable for leucopenia with lymphopenia.
* At day 5-7 following onset of symptoms, patients may develop cutaneous flushing or a characteristic desquematous, maculopapular, non-pruritic, erythematous rash with a centripetal distribution.
* Patients with non-fatal disease usually develop non-life-threatening symptoms that self-resolve approximately 7 to 10 days following onset of symptoms. When no improvement is observed within one week of phase 1 symptoms, patients are more likely to deteriorate into the potentially fatal phase 2 symptoms.[5]

### Pseudoremission Phase[edit | edit source]

* A phase of pseudoremission, that typically occurs at day 7-8 of symptoms onset and lasts for 1 to 2 days, may be observed prior to the development of neurological and hemorrhagic manifestations.[1][4]
* Patients often report significant improvement in clinical symptoms with adequate food intake and mobility.[4]
* In the minority of cases, patients recover during this phase and survive. However, the majority of cases progress into developing life-threatening complications.

### Phase 2: Life-threatening Signs and Symptoms[edit | edit source]

* A second phase of manifestations, characterized by hemorrhagic and neurological manifestations, typically develops during the peak of the illness.
* Approximately 50% of patients develop mucosal and visceral hemorrhage.
* At advanced stages, patients' symptoms worsen; and patients develop multisystem failure (renal failure, hepatic failure, and pancreatitis), dyspnea, convulsions, encephalopathy, diffuse coagulopathy (disseminated intravascular coagulopathy), hypovolemic shock, and eventually death.[6][7][3]
* In contrast to early leucopenia, the late course of the disease is often characterized by prolonged prothrombin time (PT) and partial thromboplastin time (PTT), neutrophilia with left shift and atypical lymphocytes, thrombocytopenia, elevated liver enzymes, hyperproteinemia, and proteinuria.[2][3]
* Patients typically experience rapid clinical deterioration and perish within 6 to 16 days following the onset of symptoms.

## Complications[edit | edit source]

### Acute Complications of Advanced Disease[edit | edit source]

Ebola hemorrhagic fever usually leads to death by multiorgan failure and systemic complications. Infectious (overwhelming sepsis) and hemorrhagic (visceral bleeding and disseminated intravascular coagulopathy) complications are the most significant life-threatening causes of death associated with Ebola virus disease.[8] Generally, the following complications have been reported in patients with advanced Ebola virus disease[9]:

#### ENT[edit | edit source]

* Tinnitus
* Hearing loss
* Sudden bilateral blindness

#### Cardiovascular system[edit | edit source]

* Hypovolemic shock
* Disseminated intravascular coagulopathy (DIC)
* Acute heart failure
* Myocarditis
* Serous pericardial effusion

#### Respiratory system[edit | edit source]

* Epistaxis
* Acute respiratory distress syndrome (ARDS)
* Pulmonary edema
* Respiratory tract infections

#### Gastrointestinal system[edit | edit source]

* Hemoptysis
* Hematemesis
* Hematochezia and melena
* Pancreatitis
* Hepatitis

#### Genitourinary system[edit | edit source]

* Fetal loss
* Orchitis
* Hematuria
* Oligouria and anuria
* Urinary tract infections

#### Neurological system[edit | edit source]

* Hiccups (may herald further neurological symptoms and death)
* Dysesthesia and burning skin sensation
* Convulsions
* Meningitis
* Encephalopathy
* Coma

### Late Complications Among Survivors[edit | edit source]

Survivors of Ebola hemoarrhagic fever may present with late complications of the disease that are not related to the acute illness. However, the majority of these symptoms seem to resolve by 1-2 years.[10] The most common long-term complication of Ebola virus among survivors is arthralgias of the large joints that are not accompanied by physical exam findings. Other unexplained reported complications that have occurred between 2 weeks to 2 months[9], at 6-months, and 21-month follow-up of the acute Ebola infection are listed below[10]:

#### Constitutional signs and symptoms[edit | edit source]

* Persistent weight loss
* Extreme fatigue
* Anorexia
* Fever
* Headache

#### ENT[edit | edit source]

* Hearing loss
* Tinnitus
* Suppurative parotitis
* Gingival bleeding

#### Ocular disease[edit | edit source]

* Conjunctivitis
* Conjunctival bleeding
* Vision loss
* Uveitis

#### Musculoskeletal system[edit | edit source]

* Migratory arthralgias. Notably, arthralgias are the most common non-acute complication of Ebola virus. Arthralgias usually involve the large joints (knees, back, hips). Joint pain may be symmetric and is typically worse in the morning and following exertion. Arthralgias are typically not accompanied by signs on physical exam.
* Myalgias

#### Cardiovascular system[edit | edit source]

* Pericarditis
* Petechiae

#### Gastrointestinal system[edit | edit source]

* Abdominal pain
* Dysphagia
* Hiccups
* Melena
* Hematemesis

#### Genitourinary system[edit | edit source]

* Unilateral orchitis
* Amenorrhea

#### Neuropsychiatric system[edit | edit source]

* Myelitis
* Psychosis

## Prognosis[edit | edit source]

* Ebola infection is associated with poor survival. Case-fatality rates is highly dependent on the species of virus:[3]

* Zaire Ebola virus species: case-fatality rate of 60 - 90%
* Sudan Ebola virus species: case-fatality rate 40 - 60%
* Bundibugyo Ebola virus species: case-fatality rate 25%
* Côte d’Ivoire Ebola virus: case-fatality rate 0% (only 1 case reported)
* Reston Ebola virus: case-fatality rate 0% (Reston virus seems to be relatively harmless to humans)

* Patients who survived Ebola infection for two weeks are usually able to recover slowly, despite potential complications.[3]
* Survival for 11 days is generally associated with recovery.
* Desquamation of the maculopapular rash by the 5th or 7th day is often associated with survival.[3]
* Tachypnea is the strongest correlate of fatal outcome. It often appears a few hours before death. Other correlates of fatal outcome are hypotension, tachycardia and anuria.
* Severe hemorrhagic complications such as hematemesis, melena, epistaxis, ear bleeding and hematuria are associated with a poorer prognosis and are often associated with death within a week.[11]
* In pregnant women, there is an increased risk of miscarriage.[3]

## References[edit | edit source]

1. ↑ 1.0 1.1 Ndambi R, Akamituna P, Bonnet MJ, Tukadila AM, Muyembe-Tamfum JJ, Colebunders R (1999). "Epidemiologic and clinical aspects of the Ebola virus epidemic in Mosango, Democratic Republic of the Congo, 1995". J Infect Dis. 179 Suppl 1: S8–10. doi:10.1086/514297. PMID 9988156.CS1 maint: Multiple names: authors list (link)
2. ↑ 2.0 2.1 Ksiazek TG, West CP, Rollin PE, Jahrling PB, Peters CJ (1999). "ELISA for the detection of antibodies to Ebola viruses". J Infect Dis. 179 Suppl 1: S192–8. doi:10.1086/514313. PMID 9988184.CS1 maint: Multiple names: authors list (link)
3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 Feldmann H, Geisbert TW (2011). "Ebola haemorrhagic fever". Lancet. 377 (9768): 849–62. doi:10.1016/S0140-6736(10)60667-8. PMC 3406178. PMID 21084112.CS1 maint: PMC format (link)
4. ↑ 4.0 4.1 4.2 Muyembe-Tamfum JJ, Mulangu S, Masumu J, Kayembe JM, Kemp A, Paweska JT (2012). "Ebola virus outbreaks in Africa: past and present". Onderstepoort J Vet Res. 79 (2): 451. doi:10.4102/ojvr.v79i2.451. PMID 23327370.CS1 maint: Multiple names: authors list (link)
5. ↑ Casillas AM, Nyamathi AM, Sosa A, Wilder CL, Sands H (2003). "A current review of Ebola virus: pathogenesis, clinical presentation, and diagnostic assessment". Biol Res Nurs. 4 (4): 268–75. PMID 12698919.CS1 maint: Multiple names: authors list (link)
6. ↑ Peters CJ, LeDuc JW (1999). "An introduction to Ebola: the virus and the disease". J Infect Dis. 179 Suppl 1: ix–xvi. doi:10.1086/514322. PMID 9988154.
7. ↑ Feldmann H, Geisbert T, Kawaoka Y (2007). "Filoviruses: recent advances and future challenges". J Infect Dis. 196 Suppl 2: S129–30. doi:10.1086/520550. PMID 17940939.CS1 maint: Multiple names: authors list (link)
8. ↑ Parkes-Ratanshi R, Ssekabira U, Crozier I (2014). "Ebola in West Africa: be aware and prepare". Intensive Care Med. 40 (11): 1742–5. doi:10.1007/s00134-014-3497-z. PMID 25253023.CS1 maint: Multiple names: authors list (link)
9. ↑ 9.0 9.1 Bwaka MA, Bonnet MJ, Calain P, Colebunders R, De Roo A, Guimard Y; et al. (1999). "Ebola hemorrhagic fever in Kikwit, Democratic Republic of the Congo: clinical observations in 103 patients". J Infect Dis. 179 Suppl 1: S1–7. doi:10.1086/514308. PMID 9988155.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
10. ↑ 10.0 10.1 Rowe AK, Bertolli J, Khan AS, Mukunu R, Muyembe-Tamfum JJ, Bressler D; et al. (1999). "Clinical, virologic, and immunologic follow-up of convalescent Ebola hemorrhagic fever patients and their household contacts, Kikwit, Democratic Republic of the Congo. Commission de Lutte contre les Epidémies à Kikwit". J Infect Dis. 179 Suppl 1: S28–35. doi:10.1086/514318. PMID 9988162.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
11. ↑ Sureau PH (1989). "Firsthand clinical observations of hemorrhagic manifestations in Ebola hemorrhagic fever in Zaire". Rev Infect Dis. 11 Suppl 4: S790–3. PMID 2749110.

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