Clinical manifestations and diagnosis of Ebola virus disease

INTRODUCTION — The family Filoviridae includes the genera Ebolavirus and Marburgvirus, which are among the most virulent pathogens of humans [1-3]. The genus Ebolavirus consists of six species: Zaire, Sudan, Bundibugyo, Tai Forest, Reston, and Bombali [4]. Of these, only the first four have caused recognized disease in humans; all but the Reston virus are indigenous to Africa. Several other genera of filoviruses have recently been identified in animals, but there is no evidence that they cause disease in humans.

The Zaire species of Ebola virus was the first to be discovered [5]. From 1976 through 2013, it caused multiple outbreaks in the Democratic Republic of the Congo (DRC) and neighboring countries in Central Africa, with case fatality rates often approaching 90 percent. Those outbreaks usually involved fewer than 100 cases and were contained within a period of weeks to a few months. In 2014, the Zaire virus appeared in West Africa, producing an epidemic in Liberia, Guinea, and Sierra Leone that took more than two years to bring under control [6]. There were nearly 29,000 total cases (suspected, probable, or confirmed), of which more than 15,000 were laboratory confirmed, and the overall case fatality rate was approximately 40 percent. Since then, the Zaire species has been responsible for additional epidemics, including several outbreaks in the DRC [7,8]. A subsequent outbreak in Guinea in early 2021 appears to have resulted from persistent human infection since the 2014 West African epidemic, though the manner of persistence could not be determined [9,10]. (See "Epidemiology and pathogenesis of Ebola virus disease".)

The Sudan species of Ebola virus was also discovered in 1976 [11]. In five outbreaks in Uganda and Sudan, including one that ended in January 2023, case fatality rates have averaged approximately 50 percent. The Bundibugyo species has been responsible for small outbreaks in Uganda and the adjacent DRC [12], while the Ivory Coast virus has caused one nonfatal case [13]. The Reston virus, which has been found in pigs in the Philippines, and the Bombali virus, identified as viral RNA in African bats, are not known to cause disease in humans.

Epidemics typically begin when a human comes into contact with an infected animal or its body fluids [1,3]. However, the persistence of virus in persons who have recovered from Ebola virus disease may potentially be a source of infection for new outbreaks [9,14-16]. Person-to-person transmission is based upon direct physical contact with the body fluids of a living or deceased patient. Patients typically present with a nonspecific febrile syndrome that may include headache, muscle aches, and fatigue [1,3,17]. Vomiting and diarrhea frequently develop during the first few days of illness and may lead to significant volume losses. A maculopapular rash is sometimes observed. Despite the traditional name of "Ebola hemorrhagic fever," major bleeding is not found in most patients, and severe hemorrhage tends to be observed only in the late stages of disease. Some patients develop progressive hypotension and shock with multiorgan failure, which typically results in death during the second week of illness. By comparison, patients who survive infection commonly begin to show signs of clinical improvement during the second week of illness.

The experience of the 2014-2016 West African epidemic demonstrated that the mortality associated with Ebola virus disease may be reduced through adequate supportive care [6]. It also accelerated the investigation of therapies and vaccines for treatment and prevention of the Zaire species of Ebola virus [15,16]. As an example, two different monoclonal antibody therapies were found to be beneficial in the “PALM” clinical trial conducted in the North Kivu epidemic in the DRC [17]. In addition, the rVSV-ZEBOV vaccine, first found to provide significant protection in West Africa, was given to more than 300,000 people during the course of the North Kivu epidemic and to more than 30,000 people during the 2020 outbreak in the Équateur Province [8].

This topic will discuss the clinical manifestations and diagnosis of Ebola virus disease. Detailed discussions of the epidemiology, pathogenesis, treatment, and prevention of Ebola virus disease are found elsewhere. (See "Epidemiology and pathogenesis of Ebola virus disease" and "Treatment and prevention of Ebola virus disease".)

CLINICAL MANIFESTATIONS — During the nearly 40 years between the first recognized Ebola outbreaks in Zaire and Sudan in 1976 and the beginning of the 2014-2016 epidemic in West Africa, several publications described the clinical and laboratory features of the disease [5,11,18]. That information was supplemented by many patient series from Ebola treatment units in West Africa and case reports of patients treated in the United States and in Europe (table 1) [19-24].

Although most features of Ebola virus disease in the West African epidemic matched earlier descriptions, patients differed in two respects:

●Major hemorrhage was less common than previously described. Thus, the name of the disease was changed from "Ebola hemorrhagic fever" to "Ebola virus disease."

●Volume losses from vomiting and diarrhea made a greater contribution to severe illness than previously recognized.

Before the 2014 to 2016 epidemic, reports of Ebola outbreaks in Africa largely focused on severe and fatal illness, but the spectrum of Ebola virus infection may have also included milder infections that escaped detection [25-28]. One report that reviewed past serosurveys from Central Africa suggested "asymptomatic" Ebola virus infections could occur [29]. Subsequent studies, including a retrospective analysis of a large cohort of survivors and contacts from the West African epidemic, have reached similar conclusions [30-32].

Incubation period — Patients with Ebola virus disease typically have an abrupt onset of symptoms 6 to 12 days after exposure (range 2 to 21 days) [19-21]. There is no evidence that infected persons who have not yet developed signs of illness are infectious to others. However, all symptomatic individuals should be assumed to have virus in the blood and other body fluids, and appropriate safety precautions should be taken. (See "Epidemiology and pathogenesis of Ebola virus disease", section on 'Transmission' and "Treatment and prevention of Ebola virus disease", section on 'Infection control precautions during acute illness'.)

Signs and symptoms

●Initial syndrome – Most cases of Ebola virus disease begin with the abrupt onset of fever and chills, but low-grade fever and malaise may also precede the development of more severe symptoms [24,33].

Common signs and symptoms include fever, fatigue, headache, vomiting, diarrhea, and loss of appetite [19-21,34]. Reports have also described weakness, myalgias, as well as a high fever accompanied by relative bradycardia as seen in typhoid fever [18,33].

●Rash – A diffuse erythematous, nonpruritic maculopapular rash may develop by day 5 to 7 of illness. The rash usually involves the face, neck, trunk, and arms, and can desquamate; it is generally easier to see in light-skinned persons [18,35,36]. During the outbreak in Sierra Leone, rash was reported as rare [19]; however, it was clearly described in case reports of infected health care workers [23,33].

●Gastrointestinal – Gastrointestinal signs and symptoms are common and usually develop within the first few days of illness. These include watery diarrhea (up to 10 liters per day) [23], nausea, vomiting, and abdominal pain. Vomiting and diarrhea may result in severe fluid loss, potentially leading to dehydration, hypotension, and shock [19-22].

●Hemorrhage – Case series from the West African epidemic indicate that many patients develop some degree of bleeding during their illness, most commonly manifested as blood in the stool (about 6 percent), petechiae, ecchymoses, oozing from venipuncture sites, and/or mucosal bleeding [37]. Clinically significant hemorrhage may be seen in the terminal phase of illness and in pregnancy. (See "Treatment and prevention of Ebola virus disease", section on 'Considerations during pregnancy'.)

●Neurologic – Patients occasionally develop meningoencephalitis, with findings such as an altered level of consciousness, hyperreflexia, myopathy, stiff neck, gait instability, and/or seizures [22,38,39]. These clinical manifestations typically develop around days 8 to 10 of illness.

●Cardiac – Pulse-temperature dissociation with relative bradycardia may be observed during acute illness [20]. In addition, retrosternal chest pain attributed to pericarditis has been reported [18]. Myocarditis has also been described [40].

●Respiratory – Tachypnea and shortness of breath may represent hypoxia or hypoventilation due to respiratory muscle fatigue, contributing to pending respiratory failure. During the West African epidemic, this phenomenon was observed in nearly one-third of patients treated in Europe and the United States in the setting of intravenous fluid resuscitation [24].

●Ocular – Patients may develop conjunctival injection and/or signs and symptoms of uveitis (eg, blurred vision, photophobia, blindness) during the acute phase of illness [41]. In addition, uveitis has been documented during convalescence. (See 'Convalescence' below.)

Laboratory findings — Patients with Ebola virus disease typically develop leukopenia, thrombocytopenia, and serum transaminase elevations, as well as renal and coagulation abnormalities [3,19-21,42]. Other laboratory findings include a marked decrease in serum albumin, hypoglycemia, and elevated amylase levels (table 1).

●Leukopenia – Leukopenia usually presents as lymphopenia, followed by an elevated neutrophil count. Immature granulocytes and abnormal lymphocytes, including plasmacytoid cells and immunoblasts, may be seen in blood smears.

●Thrombocytopenia – Platelet counts decrease during the acute phase of illness, but generally do not fall below 50,000 to 100,000/microL. Platelet counts typically reach a nadir around day 6 to 8 of illness.

●Abnormal hematocrit – Patients with Ebola virus disease may present with an increased or decreased hematocrit. As an example, in one cohort study that evaluated 100 patients, 15 had an increased hematocrit upon presentation and 36 were anemic [42].

●Transaminase elevations – Because Ebola virus can cause multifocal hepatic necrosis, blood chemistry tests usually demonstrate elevated serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels [19]. In one study, AST levels correlated with viral load [43].

●Coagulation abnormalities – Prothrombin (PT) and partial thromboplastin times (PTT) can be prolonged and fibrin degradation products elevated, consistent with disseminated intravascular coagulation. These changes are most prominent in severe and fatal cases.

●Renal abnormalities – Proteinuria is a common finding, and renal insufficiency with elevated blood urea nitrogen and creatinine can be seen in both the early and late stages of disease [19,42]. Acute kidney injury is exacerbated by excessive fluid loss from diarrhea and vomiting without adequate volume replacement but may also develop as a result of direct viral-mediated damage of renal tissues in the absence of severe volume loss [42].

●Electrolyte abnormalities – Patients may develop significant electrolyte disturbances (eg, hyponatremia, hypokalemia, hyperkalemia, hypomagnesemia, and hypocalcemia) secondary to the gastrointestinal manifestations of the disease. Such individuals may require frequent repletion of electrolytes to prevent cardiac arrhythmias. (See "Treatment and prevention of Ebola virus disease", section on 'Supportive care'.)

Disease course — Patients who survive Ebola virus disease typically begin to improve during the second week of illness. Fatal disease has been characterized by more severe clinical signs and symptoms early during infection, with progression to multiorgan failure with death typically occurring in the second week. (See "Treatment and prevention of Ebola virus disease", section on 'Prognostic factors'.)

Some patients develop secondary complications related to their disease and/or the treatments they receive [44,45]. These include bacterial sepsis, respiratory failure associated with aggressive fluid resuscitation, and/or lung and kidney injury. (See "Treatment and prevention of Ebola virus disease", section on 'Supportive care'.)

Convalescence — The convalescent period of Ebola virus disease is prolonged and can persist for more than two years [46].

●Convalescent patients can suffer from weakness, fatigue, muscle and joint pain, insomnia, headache, urinary frequency, memory loss, and failure to regain weight that was lost during illness, resulting in significant disability. During and after the West African epidemic, these findings were supported in several studies, including one that included nearly 1000 survivors [47-50].

●Other clinical manifestations include:

•Retro-orbital pain, uveitis, and hearing loss [46,47,51,52].

•Extensive sloughing of skin and hair loss, which may result from virus-induced necrosis of infected sweat glands and other dermal structures [28].

•Symptoms of depression and anxiety [49]. A study of survivors of the 1995 outbreak in the Democratic Republic of the Congo found that some patients suffered depression and anxiety for more than two decades [53]. Another subsequent study found that depression and post-traumatic stress disorder were common among the survivors of the Ebola virus disease epidemic that occurred in the eastern DRC from 2018 to 2020 [54].

Symptoms and signs can be severe, and in one report of Ebola survivors after the outbreak of Ebola Sudan virus disease in Uganda in 2000, many patients were unable to resume their previous work activities [55]. A study of more than 300 survivors of the epidemic in West Africa found that a majority suffered from symptoms that interfered with their life, and more than half still reported symptoms at five years of follow-up [50]. It has been postulated that a higher Ebola viral load at the time of clinical presentation is associated with the development of symptoms during convalescence [52,56].

Some patients develop new clinical manifestations after recovery from their initial infection. In one report, the median time from discharge to onset of clinical manifestations was one to two weeks [52]. In this study of 277 Ebola survivors from the West African epidemic who were evaluated after discharge from a treatment center, 76 percent had arthralgias, 60 percent had new ocular symptoms (eg, blurry vision, light sensitivity, itchy eye), 24 percent had auditory symptoms (eg, tinnitus, hearing loss), and 18 percent had uveitis. The persistence of virus in the central nervous system and testes after apparent recovery is the subject of continuing research in laboratory animal models of Ebola virus disease [57].

Others develop late complications of Ebola virus disease, with manifestations developing months after they have recovered from their initial illness. As an example, one patient who had recovered from Ebola virus disease developed meningitis 10 months after her initial diagnosis, and infectious virus was recovered in the cerebrospinal fluid [58]. In another report, uveitis developed 14 weeks after Ebola virus disease was initially diagnosed, and the aqueous fluid contained infectious virus [51]. The role of persistent virus in causing clinical manifestations during convalescence is unclear; in one case report, immune activation was felt to contribute to the development of uveitis [59].

The prevalence of uveitis, unlike other conditions, continues to increase for at least two years after initial symptom onset. In a prospective longitudinal study, 516 Ebola virus disease survivors and 586 controls were followed for 12 months and underwent ophthalmologic exam [47]. The prevalence of uveitis in survivors increased from 26 percent a median of one year after symptom onset to 33 percent after an additional year of follow-up. The incidence of new uveitis was significantly higher among survivors compared with controls (178 versus 101 cases per 1000 person-years).

Discussions of follow-up care for survivors and the risk of Ebola virus transmission during convalescence are found elsewhere. (See "Treatment and prevention of Ebola virus disease", section on 'Follow-up care' and "Treatment and prevention of Ebola virus disease", section on 'Sexual transmission'.)

Pregnancy — During the outbreak in West Africa, reports suggested that an atypical presentation of Ebola virus disease may be observed during pregnancy and fetal death may occur even if the mother has recovered. As examples:

●In Liberia, a woman presented in late pregnancy with mild lower abdominal and back pain, sparse contractions, and premature rupture of membranes, without fever or other signs or symptoms of Ebola virus disease [60]. Blood testing for Ebola virus was performed as part of routine care and returned positive with a high viral load. A vaginal swab tested on day 2 was also positive for Ebola virus. The mother died undelivered from complications related to Ebola virus disease seven days after admission.

●In Guinea, two pregnant women presented with Ebola virus disease and had fetal movement detected upon admission; both fetuses died even though the mothers survived [61]. The placenta and fetal blood remained positive for Ebola virus using reverse-transcription polymerase chain reaction (RT-PCR) testing up to seven days after the mothers' serum tested negative for virus.

Thus, pregnant women should be evaluated if they have a possible exposure and present with nonspecific signs and symptoms of Ebola virus disease (eg, abdominal pain) and/or pregnancy complications, such as preterm labor, vaginal bleeding, or premature rupture of membranes. (See 'Determining the risk of exposure' below.)

DIAGNOSIS — Whether Ebola virus disease is considered in the differential diagnosis of a patient with fever and flu-like symptoms will vary markedly depending upon the circumstances, in particular, whether a recognized Ebola epidemic is currently taking place. In addition, clinicians should remember that the acute onset of a febrile illness in a person who lives in or has recently been to West or Central Africa can result from a variety of local infectious diseases, including malaria, Lassa fever, and Marburg virus disease. (See "Epidemiology and pathogenesis of Ebola virus disease" and 'Differential diagnosis' below.)

In response to the 2014-2016 outbreak, the United States Centers for Disease Control and Prevention (CDC), the World Health Organization (WHO), and other international organizations provided recommendations for the evaluation and management of persons who may have been exposed to Ebola virus. The discussion below outlines key principles that should be used when considering the diagnosis of Ebola virus disease.

General approach

●Symptomatic patients – Even though there are no approved specific therapies for Ebola virus disease, it is essential to make the diagnosis as early as possible so that infection control procedures can be implemented to reduce the transmission of virus, and so that supportive measures can be initiated before the development of irreversible shock. (See "Treatment and prevention of Ebola virus disease".)

Patients who present with signs and symptoms consistent with Ebola virus disease (fever and/or severe headache, weakness, muscle pain, vomiting, diarrhea, abdominal pain, or unexplained hemorrhage) should be assessed to determine the likelihood of recent exposure to Ebola virus (table 2). In particular, they should be asked if they have traveled to an area with a recognized Ebola epidemic or had contact with a patient with possible Ebola virus disease within the 21 days prior to the onset of symptoms. (See 'Determining the risk of exposure' below.)

•Infection control precautions should be used for all symptomatic patients who may have been exposed to Ebola virus (ie, those who have had a high, moderate, or low-risk exposure). Infection control precautions should also be used for patients whose risk of exposure is unclear at the time of their initial presentation until a medical evaluation can be performed. (See 'Symptomatic patients with identifiable risk' below and "Treatment and prevention of Ebola virus disease", section on 'Infection control precautions during acute illness'.)

•Persons under investigation for Ebola virus disease should undergo testing for Ebola virus by RT-PCR, facilitated by local and state health officials. Specific details regarding laboratory testing are found below. (See 'Indications' below and 'Diagnostic tests' below.)

•Persons under investigation for Ebola virus disease should also be evaluated for other possible febrile diseases, including those that are common in areas where the patient traveled or resided (eg, malaria, typhoid fever, influenza). (See 'Differential diagnosis' below.)

The specific triage system used during the initial assessment of a patient with possible Ebola virus disease may vary depending on the physical setting (eg, emergency department, ambulatory clinic) and the known history of transmission in the community [62-64]. As an example, medical facilities, especially those in areas with widespread Ebola transmission, should designate areas for screening patients. (See "Epidemiology and pathogenesis of Ebola virus disease", section on 'Epidemiology'.)

In addition, the types of personal protective equipment (PPE) that are recommended for health care personnel caring for a patient depend upon the patient's clinical symptoms. The PPE used when caring for patients whose condition is associated with a high risk of direct contact with body fluids (eg, presence of vomiting, diarrhea, bleeding) are different from those used when evaluating a patient who does not present a hazard due to body fluid exposure. In all settings, only essential personnel who are trained in proper donning and removal of PPE should interact with the patient. A more detailed discussion on infection control precautions is found elsewhere. (See "Treatment and prevention of Ebola virus disease", section on 'Infection control precautions during acute illness'.)

●Asymptomatic individuals – Asymptomatic individuals who have had a possible exposure to Ebola generally do not require strict isolation precautions. Such patients should be monitored so that they can be isolated if fever or other signs or symptoms occur. However, additional restrictions may be required depending upon the type of exposure. (See 'Asymptomatic individuals with identifiable risk' below.)

Determining the risk of exposure — The risk of exposure to Ebola virus helps to guide the evaluation and management of both symptomatic and asymptomatic individuals. (See 'Symptomatic patients with identifiable risk' below and 'Asymptomatic individuals with identifiable risk' below and 'Patients with no identifiable risk' below.)

An initial risk assessment for Ebola virus exposure should include a history of travel to a known Ebola outbreak area, any high-risk exposures (as described below), and use of appropriate PPE. (See "Epidemiology and pathogenesis of Ebola virus disease", section on 'Epidemiology' and "Treatment and prevention of Ebola virus disease", section on 'Infection control precautions during acute illness'.)

For health care workers, the level of exposure risk increases with the number of patients with known Ebola virus disease they are caring for.

Individuals should be considered to be at risk of Ebola virus disease if they have had a high-risk exposure within 21 days or any exposure with compatible symptoms. (See 'Signs and symptoms' above.)

In the United States, the CDC has put forth guidelines to identify at-risk individuals [65,66].

●A high-risk exposure includes any of the following:

•Direct physical contact with a person who has known or suspected Ebola virus disease

•Percutaneous (eg, needle stick) or mucous membrane exposure to blood or body fluids (eg, feces, saliva, sweat, urine, vomit, sputum, breast milk, tears, and semen) of a person with known or suspected Ebola virus disease

•Providing health care to a person with known or suspected Ebola virus disease without appropriate PPE or experiencing a breach in infection control precautions that results in potential for percutaneous, mucous membrane, or skin contact with the blood or body fluids of a patient with Ebola virus disease

•Processing blood or other body fluids of a person with symptomatic Ebola virus disease without appropriate PPE or standard biosafety precautions

•Direct contact with a dead body without appropriate PPE in an area where a recognized Ebola epidemic is occurring or with the body of a person who died of Ebola virus disease or a compatible illness or who died of unknown cause after a potential exposure to Ebola virus

•Living in the same household as a person with symptomatic Ebola virus disease

●Other exposures that put someone at risk for Ebola virus disease include having contact with semen from a man who has recovered from Ebola virus disease, handling wild animals or carcasses that may be infected with Ebola virus, or handling bats or nonhuman primates from endemic areas of Africa. (See "Epidemiology and pathogenesis of Ebola virus disease", section on 'Transmission from animals'.)

Initial assessment for Ebola virus disease

Symptomatic patients with identifiable risk — Clinical findings that are consistent with Ebola virus disease include fever and/or severe headache, weakness, muscle pain, vomiting, diarrhea, abdominal pain, or unexplained hemorrhage (see 'Clinical manifestations' above). Infection control precautions should be used for all symptomatic patients who have an identifiable risk for Ebola virus disease (see 'Determining the risk of exposure' above). In addition, the hospital infection control program, hospital leadership, and other appropriate staff should be notified, as well as local and state health departments.

Such patients should be isolated in a single room with a private bathroom and with the door to the hallway closed. All health care workers should use standard, contact, and droplet precautions, as well as personal protective equipment recommended for the care of patients with Ebola virus disease. A detailed discussion of infection control precautions is found elsewhere. (See "Treatment and prevention of Ebola virus disease", section on 'Infection control precautions during acute illness'.)

In patients who are suspected of having Ebola virus disease, phlebotomy and laboratory testing should be limited to tests that are essential for diagnosing or ruling out Ebola virus, assessing for an alternative or concurrent infection (eg, malaria), and/or emergency care. In consultation with local and state health officials, evaluation for other potential causes of their illness may also be indicated, particularly for those individuals whose recent history indicates a low risk of exposure to Ebola virus. (See 'Indications' below and 'Differential diagnosis' below.)

In the United States, certain hospitals have been designated as "Ebola assessment hospitals" and are prepared to evaluate and care for patients with possible Ebola virus disease until a diagnosis can be confirmed or ruled out [67].

Asymptomatic individuals with identifiable risk — Monitoring for symptoms and signs of Ebola virus disease should be performed for asymptomatic persons who have had an exposure to Ebola virus at any risk level (ie, high, moderate, or low risk). (See 'Determining the risk of exposure' above.)

Such individuals should be monitored for 21 days after the last known exposure and should immediately report the development of fever or other clinical manifestations suggestive of Ebola virus disease. The type of monitoring (eg, self-monitoring and reporting versus direct observation by a designated health official), as well as the need for travel restrictions, restricted movement within the community, and/or quarantine, depend in part upon the type of exposure. Specific guidelines for management of asymptomatic individuals with an exposure to Ebola virus are typically dictated by public health authorities.

Patients with no identifiable risk — If after initial evaluation patients are determined to have no identifiable risk for Ebola virus infection, monitoring or diagnostic testing for Ebola virus disease is not warranted. However, if patients have fever and other signs or symptoms of infection, they should be evaluated for other causes of febrile disease (eg, malaria, Lassa fever, influenza). Appropriate infection control precautions will depend upon the patient's clinical findings, as well as the specific pathogens that are being considered. (See 'Determining the risk of exposure' above and 'Differential diagnosis' below and "Infection prevention: Precautions for preventing transmission of infection".)

Laboratory testing

Indications — Evaluation of all patients with suspected Ebola virus disease should be done in conjunction with local and state health departments. In the United States, certain hospitals may be designated as "Ebola assessment hospitals," which are prepared to evaluate and care for patients with possible Ebola virus disease until a diagnosis can be confirmed or ruled out.

●Testing for Ebola virus infection is performed in symptomatic patients with any possible risk of exposure to Ebola virus (high, moderate, or low risk). (See 'Symptomatic patients with identifiable risk' above.)

●Testing is not warranted for patients who have an identifiable risk but no signs or symptoms of Ebola virus disease. These patients should be monitored and tested if they become ill. (See 'Asymptomatic individuals with identifiable risk' above.)

●Testing is not warranted for patients without any identifiable risk of exposure to Ebola virus. (See 'Patients with no identifiable risk' above.)

Ebola virus is generally detectable in blood samples by RT-PCR within three days after the onset of symptoms; repeat testing may be needed for patients with symptoms for fewer than three days. According to CDC guidelines for discharging a person who is under investigation for Ebola virus disease, a negative RT-PCR test that is collected ≥72 hours after the onset of symptoms excludes Ebola virus disease. (See 'Diagnostic tests' below.)

Patients who have confirmed Ebola virus disease should be transferred to specialized Ebola treatment centers.

Diagnostic tests — Diagnostic tests for Ebola virus infection are principally based upon the detection of specific RNA sequences by RT-PCR in blood or other body fluids. Viral antigens can also be detected using immunoassays. In the United States, any presumptive positive Ebola test should be confirmed at the CDC.

●Nucleic acid testing – RT-PCR tests that detect specific RNA sequences have become the standard method of diagnosing Ebola virus disease. In spite of genetic diversity and the accumulation of sequence changes [68], RT-PCR testing remained mostly effective through the conclusion of the West African epidemic. However, one retrospective study found that the analytical methods used during the 2013 to 2016 West African epidemic sometimes underestimated viral load or failed to detect virus [69]. Clinicians should also be aware of possible viral RNA sequence differences when attempting to employ these assays to other Ebola outbreaks.

Viral RNA is generally detectable in serum by RT-PCR within three days after the onset of symptoms [20]. Results are available in approximately two to six hours, depending upon the assay that is used [70].

•Repeat testing may be needed for patients with symptoms for fewer than three days.

•A negative RT-PCR test that is collected >72 hours after the onset of symptoms rules out Ebola virus disease [20].

Blood is the preferred specimen for testing. Testing of simultaneously collected blood and saliva specimens has shown that viral RNA levels are much lower in saliva. As an example, in a group of 32 patients who were positive by blood testing, fewer than 10 percent were also detected by oral swab, indicating that saliva should not be used for diagnostic testing [71]. However, an oral swab from a cadaver may be useful for postmortem diagnosis because fatally infected patients have high viral titers in body fluids at the time of death.

●Rapid immunoassays – Several rapid immunoassays that detect Ebola virus antigen have been developed. Rapid lateral flow immunoassays for Ebola virus were developed initially during the West African epidemic [72,73]. Newer generation assays with different performance characteristics have subsequently been made available. Although some of these assays are faster, use different platforms, and/or don't require venipuncture, their sensitivity is not superior to that of lateral flow assays.

The results of a rapid immunoassay (both positive and negative) must be verified through RT-PCR testing. Use of one of these assays alone could result in inappropriate admission of uninfected persons to Ebola treatment units or failure to detect patients who are early in the disease course.

Rapid immunoassays are most useful to support a provisional diagnosis of Ebola virus disease based on clinical exam and exposure history in places where RT-PCR is not readily available. These tests are not intended to be used for general Ebola infection screening, testing of asymptomatic people, or testing of those without risk factors for Ebola infection. In addition, they should not be used to make triage decisions or to de-escalate infection precautions. Thus, when rapid RT-PCR assays are available, the role of these immunoassays is unclear.

Research on the development of accurate rapid diagnostic tests for Ebola virus disease is continuing [74-76], although their role in outbreak response and patient management remains unclear. More detailed information on these and other tests that have been approved under a US Food and Drug Administration (FDA) emergency use authorization can be found on the FDA website.

If testing is indicated, the local or state health department should be contacted immediately. In the United States, details on collection and handling of specimens from patients with suspected Ebola virus disease can be found in the CDC documents that provide guidance for laboratories and submission information. For clinicians outside the United States, the WHO has also issued guidance for the safe collection and shipment of samples from patients with suspected Ebola virus disease.

DIFFERENTIAL DIAGNOSIS — When evaluating a patient for possible Ebola virus disease, it is important to consider alternative and/or concurrent diagnoses, including infectious and noninfectious disorders. In one study that evaluated 770 ill nonimmigrant travelers returning from Guinea, Liberia, and Sierra Leone during a five-year period (September 2009 through August 2014), malaria was the most common diagnosis (40 percent), followed by acute diarrhea, without an identified causative agent (12 percent) [77].

The differential diagnosis depends, in part, upon the individual's symptoms, where they have traveled or resided, if they have had close contact with someone who is ill, their vaccination history, and their age and comorbid conditions. Since most patients suspected of possible Ebola virus disease will have travelled to and/or reside in Sub-Saharan Africa, the following disorders should be considered:

●Malaria – Travelers who develop a febrile illness after returning from Sub-Saharan Africa should be evaluated for malaria, which can present with similar findings to Ebola virus disease and may occur concurrently. Microscopic examination of blood smears and/or rapid antigen testing are typically used to diagnose malaria. (See "Laboratory tools for diagnosis of malaria" and "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children".)

●Lassa fever – Lassa fever is restricted to West Africa, though infected travelers have become ill in countries of Europe as well as in the United States. Although symptoms may be mild, approximately 20 percent of patients develop a severe clinical syndrome that can progress to fatal shock. Transmission to humans occurs primarily through exposure to the aerosolized excretions of local multimammate rats, or in rare cases, through contact with body fluids of infected individuals. Diagnosis is made by reverse-transcription polymerase chain reaction (RT-PCR) testing and/or serology. (See "Lassa fever".)

●Typhoid – Typhoid fever is a systemic illness characterized by fever and abdominal pain. The organism responsible for the enteric fever syndrome is Salmonella enterica serotype Typhi (formerly S. typhi). Worldwide, typhoid fever is most prevalent in impoverished areas that are overcrowded, with poor access to sanitation. The diagnosis is typically made through identification of the organism in blood cultures. (See "Enteric (typhoid and paratyphoid) fever: Epidemiology, clinical manifestations, and diagnosis".)

●Meningococcal disease – Patients infected with Neisseria meningitidis can present with meningitis and/or bacteremia, and certain signs and symptoms (headache, fever) may overlap with those seen in Ebola virus disease. Cultures of blood or cerebrospinal fluid are used to make the diagnosis. (See "Epidemiology of Neisseria meningitidis infection" and "Clinical manifestations of meningococcal infection".)

●Influenza – Influenza often presents with the abrupt onset of fever, headache, myalgia, and malaise, similar to the presenting signs and symptoms of Ebola virus disease. However, with influenza, these manifestations are usually accompanied by respiratory signs and symptoms, such as nonproductive cough, sore throat, and nasal discharge, which are not typically part of the Ebola syndrome. Direct fluorescent antibody or other rapid assays are used to diagnose influenza. (See "Seasonal influenza in adults: Clinical manifestations and diagnosis".)

●Measles – The prodromal phases of measles and Ebola virus disease are similar and are characterized by fever, malaise, and anorexia. However, in measles, this is followed by conjunctivitis, coryza, and cough, as well as a characteristic maculopapular, blanching rash that begins on the face. The diagnosis of measles is typically established via antibody or polymerase chain reaction (PCR) testing. (See "Measles: Clinical manifestations, diagnosis, treatment, and prevention".)

●Marburg virus disease – Marburg virus causes clinical manifestations similar to Ebola virus disease (see "Marburg virus"). Cases have been identified across Sub-Saharan Africa. The diagnosis is typically made by RT-PCR testing.

●Traveler's diarrhea – This condition develops during or within 10 days after returning from travel, most commonly from resource-limited regions. Patients typically present with malaise, anorexia, and abdominal cramps, followed by the sudden onset of diarrhea. Nausea, vomiting, and low-grade fever may also occur. When attempting to distinguish between travelers' diarrhea and diarrhea that occurs in Ebola virus disease, clinicians should note whether the condition appears to be part of a systemic illness or is mostly confined to the gastrointestinal tract. A patient who develops diarrhea in the setting of Ebola virus disease is likely to have a several-day history of fever, myalgia, fatigue, and other signs of a rapidly progressive systemic disease. (See "Travelers' diarrhea: Treatment and prevention".)

Additional topic reviews that discuss the evaluation of an ill returning traveler are found elsewhere. (See "Evaluation of fever in the returning traveler" and "Approach to illness associated with travel to West Africa".)

BIOTERRORISM — Ebola virus is classified as a Category A bioterror agent by the United States Centers for Disease Control and Prevention (CDC) and the National Institute of Allergy and Infectious Diseases (NIAID) [78,79]. In the case of a bioterror attack, patients with no history of travel to Central or West Africa or other possible exposure to an infected animal or an Ebola patient would develop Ebola virus disease and would be seen in doctors' offices or hospital emergency departments. The appearance of multiple patients with a similar, rapidly progressive illness would be especially suggestive of bioterrorism. Any clinician suspecting that such an event is unfolding should report it promptly to local and state health authorities. General concepts regarding bioterrorism are discussed elsewhere. (See "Identifying and managing casualties of biological terrorism".)

ADDITIONAL RESOURCES AND CONTACT INFORMATION — The following documents provide additional guidance on the clinical manifestations and diagnosis of filoviral infections.

WHO: Frequently asked questions on Ebola virus disease

WHO: Ebola virus disease fact sheet

CDC: Resources for parents, schools, and pediatric health care professionals

CDC: Is it Flu or Ebola?

CDC: Questions and Answers on Ebola

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ebola virus".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Ebola (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Causative agent – The Zaire species of Ebola virus, the causative agent of most outbreaks, including the 2014-2016 West African epidemic, is one of the most virulent human pathogens. Most cases are due to outbreaks in endemic areas. However, because of its virulence and high infectivity, Ebola virus is classified as a Category A bioterror agent. (See 'Introduction' above and 'Bioterrorism' above.)

●Incubation period – The incubation period is typically 6 to 12 days but can range from 2 to 21 days. (See 'Incubation period' above.)

●Signs and symptoms – Patients with Ebola virus disease usually have an abrupt onset of nonspecific symptoms and signs such as fever, malaise, headache, and myalgias. As the illness progresses, vomiting and diarrhea may develop, often leading to significant fluid loss. Patients with worsening disease display hypotension and electrolyte imbalances leading to shock and multiorgan failure, sometimes accompanied by hemorrhage (table 1). (See 'Signs and symptoms' above.)

●Evaluation – Whether Ebola virus disease is considered in the differential diagnosis of a patient with fever and flu-like symptoms will vary markedly depending upon the circumstances, in particular whether a recognized Ebola epidemic is currently taking place.

•For patients with clinical findings consistent with the disease (ie, fever and/or severe headache, weakness, muscle pain, vomiting, diarrhea, abdominal pain, or unexplained hemorrhage), clinicians should obtain a careful history to determine if they have had a possible exposure to Ebola virus within 21 days prior to the onset of symptoms. (See 'Diagnosis' above and 'Determining the risk of exposure' above.)

•All patients who have or are suspected of having Ebola virus disease should be promptly isolated. Infection control precautions should include hand hygiene; standard, contact, and droplet precautions; as well as the correct use of appropriate personal protective equipment. Hospital infection control staff, as well as the local or state health department, should be contacted immediately. (See 'Symptomatic patients with identifiable risk' above.)

•Medical evaluation of symptomatic patients with a history of exposure generally includes testing for Ebola virus and other likely pathogens. Whether laboratory testing for Ebola virus should be performed depends, in part, upon the relative likelihood that a patient was exposed to the virus and the presence of compatible clinical symptoms and/or laboratory findings (table 2). (See 'Indications' above.)

•Monitoring for symptoms and signs of Ebola virus disease should be performed for asymptomatic persons who have had an exposure to Ebola virus. (See 'Asymptomatic individuals with identifiable risk' above.)

●Diagnostic tests – Diagnostic tests for Ebola virus infection are principally based upon the detection of specific RNA sequences by reverse-transcription polymerase chain reaction (RT-PCR) testing in blood or other body fluids. Ebola virus is generally detectable in blood samples within three days after the onset of symptoms; repeat testing may be needed for patients with symptoms for fewer than three days duration. (See 'Diagnostic tests' above.)

●Differential diagnosis – The differential diagnosis will vary markedly with the clinical and epidemiologic circumstances. As an example, travelers returning from Sub-Saharan Africa should be evaluated for illnesses commonly seen in those areas, such as malaria. (See 'Differential diagnosis' above.)