The natural clinical course of Ebola virus infection varies markedly between the different viral species and according to the level of supportive medical care available. The most lethal species is Zaire ebolavirus, which has a reported case fatality rate of up to 90%. The average case fatality rate is approximately 50%, although rates have varied from 25% to 90% in other past outbreaks.[2]​ Most epidemics have taken place in resource-poor settings that have little supportive care; therefore, the case fatality rate in other settings could be <40%.[113]

Younger children (<5 years of age) and adults over 40 years of age have a higher mortality rate compared with adolescents and younger adults. Women have a slightly better survival rate compared with men.[190] High viral load, acute kidney injury, and neurologic involvement are also predictors of poor outcome.[4][18][20][21][22][98][99][112][173][174][175]

An observational study from an outbreak in 1995 showed a marked decrease in the case fatality rate from 93% to 69% between the initial and final phases of the outbreak.[191] This suggests that later cases were recognized earlier, and possibly received higher quality of care.

Pregnant women have a high incidence of miscarriage, and infection is frequently fatal in these women.[21][168][170][171]

Data on the effects of HIV infection on prognosis are being awaited. One study suggests that infection with GB virus C, an immunomodulatory pegivirus that is present in up to 28% of West Africans, is associated with better survival from acute Ebola virus disease.[192]

Infection course

Patients who die tend to develop clinical signs early on in the infection, with death usually attributed to shock and multi-organ failure, typically occurring between days 6 and 16 of infection.[4][13][14][15] Patients who eventually recover exhibit isolated fever for several days with improvement typically around days 6 to 11.[112]

Prognostic indicators

Observational studies have shown that patients with fatal disease develop advanced features of infection (e.g., prostration, obtundation, hypotension, neurologic involvement) earlier in the course of infection compared with patients who survived with an observed median survival of 9 days from symptom onset.[4][13] Acute kidney injury and higher viral load both correlate with adverse outcome and increased mortality.[20][21][22][70][108][110] Biomarkers as prognostic indicators require further study.[13][93][112]

Recovery and convalescence

Patients who live through the second week of infection have a >75% chance of surviving.[16] Patients are usually discharged from the isolation facility when they are ambulant, self-caring, lack significant symptoms (e.g., diarrhea, vomiting, bleeding), and have 2 negative reverse transcriptase-polymerase chain reaction (RT-PCR) results for Ebola virus taken 48 hours apart.[108] Viral shedding in seminal fluid may continue for more than a year and a half after recovery.[43][48][49][51][52][54][55][193][194][195] The virus was detected in semen in 62% of men 4 to 6 months after recovery from acute infection.[193] Another study found that 63% of men tested positive for the virus in their semen 12 months or longer after recovery, with the longest interval between discharge from a treatment unit and sample collection being 565 days.[194] It has also been detected in semen for up to 548 days after disease onset in 5% of men.[195] Shedding of Ebola virus in semen may be intermittent; one study reported the reappearance of viral Ebola virus RNA in the semen of 30 male patients after two consecutive negative test results.[196]Sexual transmission of the virus from a man to his sexual partner has been confirmed by genomic studies in Liberia.[53] Ebola virus has also been detected in vaginal fluid.[56] The World Health Organization (WHO) recommends that men should be offered semen testing every month from 3 months after symptom onset and be abstinent or use condoms ideally until two negative semen tests taken one month apart (or at least 12 months after resolution of symptoms).[50] Virus has been detected in sweat (up to day 40), urine (up to day 30), conjunctival fluid (up to day 22), feces (up to day 19), and breast milk (up to day 17), even in the absence of viremia.[197]

Patients who survive commonly exhibit a protracted recovery characterized by arthralgias (76% to 77%), fatigue (69%), ocular symptoms (14% to 60%), headache (48% to 54%), abdominal pain (54%), anemia (50%), skin disorders (49%), and auditory symptoms (24%).[198][199][200]A longitudinal study that compared Ebola virus antibody-positive survivors with antibody-negative close contacts (controls) over a period of 12 months found that six symptoms were reported significantly more often among survivors compared to controls: urinary frequency (14.7% versus 3.4%); headache (47.6% versus 35.6%); fatigue (18.4% versus 6.3%); muscle pain (23.1% versus 10.1%); memory loss (29.2% versus 4.8%); and joint pain (47.5% versus 17.5%). More survivors also had abnormal chest, abdominal, neurologic, and musculoskeletal findings compared to controls.[196]

Late manifestations during convalescence may include orchitis, myelitis, parotitis, pancreatitis, hepatitis, and psychosis.[17] Survivors are also at risk of uveitis (anterior, posterior, or panuveitis), which may lead to secondary structural complications, vision impairment, or blindness.[201] One retrospective, uncontrolled, cross-sectional study found that approximately 28% of survivors developed Ebola-associated uveitis, and 3% developed Ebola-associated optic neuropathy. In patients with uveitis, 38.5% of patients were found to be blind (visual acuity >20/400).[202] One survivor had acute uveitis with detection of viable Ebola virus 14 weeks after the onset of infection and 9 weeks after the clearance of the virus from the blood.[203][204] Unilateral white cataracts and a novel retinal lesion following the anatomic distribution of the optic nerve axons have also been reported.[205] The etiology of these manifestations is unclear but could be related to immune complex phenomena or the persistence of Ebola virus in immune-privileged sites. Regular checkups of survivors are recommended for at least 18 months after recovery.[195]

It is likely that survivors of infection acquire lifetime immunity to the same strain of Ebola virus. Survivors have been shown to have long-lasting T-cell responses and a continuous high titer of neutralizing antibodies.[206] As a consequence of this, patients who have recovered from infection have been invaluable in caring for patients with active infections. However, our understanding of viral persistence in sanctuary sites remains incomplete. One expatriate healthcare worker presented with Ebola virus meningoencephalitis (RT-PCR of CSF and plasma were positive for Ebola virus) 9 months after recovering from severe primary Ebola virus disease in 2015.[207] A case of late-onset encephalitis and polyarthritis has also been reported,[208] as has a case of possible transmission from a persistently infected survivor over a year after recovery.[209] The possibility of prolonged persistence and late re-emergence of clinical disease will probably alter the epidemiologic and clinical approach to survivors who present with subsequent illnesses. This is also a theoretical concern for the management of women who become pregnant soon after recovery from acute Ebola infection.

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