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Clinical manifestations and diagnosis of Ebola virus disease
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Clinical manifestations and diagnosis of Ebola virus disease
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jun 2016. | This topic last updated: Apr 28, 2016.

INTRODUCTION — The family Filoviridae consists of two genera, the Ebola and Marburg viruses, which are among the most virulent pathogens of humans [1]. The Zaire species of Ebola virus, discovered in an outbreak in Zaire (the present Democratic Republic of the Congo) in 1976, is the causative agent of the 2014-2015 epidemic in West Africa, where the case fatality rate is estimated to be as high as 70 percent [2]; rates in earlier outbreaks reached 80 to 90 percent [3].

Epidemics of Ebola virus disease are generally thought to begin when an individual becomes infected through contact with the body fluids of an infected animal. Once the individual becomes ill or dies, the virus spreads to others who come into direct contact with their blood or other body fluids. On rare occasions, Ebola virus disease has resulted from accidental laboratory infections [4], and there is concern that the virus might be used as an agent of bioterrorism.

The clinical manifestations and diagnosis of Ebola virus disease will be reviewed here. The epidemiology, pathogenesis, treatment, and prevention of this disease are discussed elsewhere. (See "Epidemiology and pathogenesis of Ebola virus disease" and "Treatment and prevention of Ebola virus disease".)

CLINICAL MANIFESTATIONS — During the nearly 40 years since the first recognized Ebola outbreaks in Zaire and Sudan in 1976, a number of publications have described the clinical and laboratory features of this disease [1,5,6]. That information is now being supplemented by a rapidly increasing number of case reports and large patient series from the epidemic in West Africa that describe the clinical manifestations and disease course of Ebola virus disease among those in West Africa, as well as those treated in American and European hospitals (table 1) [7-12].

Although most features of Ebola virus disease in West Africa match earlier descriptions, two aspects appear to differ:

Major hemorrhage is less common. Thus, the term "Ebola virus disease" is now being used, rather than the earlier name "Ebola hemorrhagic fever."

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

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) [7,13,14]. There is no evidence that asymptomatic persons still in the incubation period are infectious to others. All symptomatic individuals should be assumed to have virus in the blood and other body fluids, and appropriate safety precautions should be taken [15]. (See "Epidemiology and pathogenesis of Ebola virus disease", section on 'Transmission' and "Treatment and prevention of Ebola virus disease", section on 'Infection control precautions'.)

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 [12,16].

Common signs and symptoms reported from the 2014-2015 West African outbreak include fever, fatigue, headache, vomiting, diarrhea, and loss of appetite [7,13,17]. Reports have also described weakness, myalgias, as well as a high fever accompanied by relative bradycardia as seen in typhoid fever [6,16].

Rash — A diffuse erythematous, nonpruritic maculopapular rash may develop by day five to seven 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 [5,6,18-21]. During the 2014-2015 outbreak in West Africa, rash was reported as rare in Sierra Leone [7]; however, it was clearly described in case reports of infected healthcare workers [11,16].

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) [11], nausea, vomiting, and abdominal pain. During the 2014-2015 West African outbreak, vomiting and diarrhea have resulted in severe fluid loss, potentially leading to dehydration, hypotension, and shock [7-10].

Hemorrhage — Despite the traditional name of "Ebola hemorrhagic fever," major bleeding (eg, massive gastrointestinal bleeding) is not seen in the majority of patients. Case series from the 2014-2015 outbreak in West Africa 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 [13,22]. 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 'Pregnancy'.)

Neurologic — Patients may develop a syndrome suggestive of meningoencephalitis, with findings such as an altered level of consciousness, stiff neck, and/or seizures. These clinical manifestations present later in the course of disease, typically after day 10 [10].

Ocular — Individuals can present with signs and symptoms of uveitis (eg, blurred vision, photophobia, blindness) during the acute phase of illness [23]. In addition, uveitis has been documented during convalescence. (See 'Convalescence' below.)

Other findings — Patients with Ebola virus disease may also develop hiccups, chest pain, and/or shortness of breath. In addition, conjunctival injection and dark red discoloration of the soft palate are common physical findings [19]. Pregnant women may experience spontaneous miscarriages [22].

Reports of past outbreaks have largely focused on cases of severe and fatal illness, but the spectrum of Ebola virus infection may include milder cases that have escaped detection [24-27]. One report that reviewed past serosurveys from Central Africa suggested "asymptomatic" Ebola virus infections could occur [28]. However, the majority of the studies employed somewhat nonspecific assays, and all lacked control groups, preventing any firm conclusions. More reliable information on the occurrence of mild cases of Ebola virus infection is expected to emerge from the 2014-2015 epidemic.

Laboratory findings — Patients with Ebola virus disease typically develop leukopenia, thrombocytopenia, and serum transaminase elevations, as well as renal and coagulation abnormalities [5,29]. Other laboratory findings include a marked decrease in serum albumin and elevated amylase levels (table 1).

Leukopenia — Leukopenia usually presents as lymphopenia, followed by an elevated neutrophil count [13]. Immature granulocytes and abnormal lymphocytes, including plasmacytoid cells and immunoblasts, may be seen in blood smears.

Thrombocytopenia — Platelet counts are usually in the range of 50,000 to 100,000/microL [13]. Platelet counts typically reach a nadir around day six to eight of illness [18,19].

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 [29].

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 [7]. In one study, AST levels correlated with viral load [30].

Coagulation abnormalities — Prothrombin (PT) and partial thromboplastin times (PTT) can be prolonged, and fibrin degradation products elevated, consistent with disseminated intravascular coagulation (DIC). 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 [7,29]. Acute kidney injury is exacerbated by excessive fluid loss from diarrhea and vomiting without adequate volume replacement, but may also develop in the absence of gastrointestinal symptoms [29].

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 [13]. 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 [31,32]. 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 [33]. Patients may present with weakness, fatigue, insomnia, headache, and failure to regain weight that was lost during illness. Other clinical manifestations include:

Acute arthralgias, which may result from the formation of antigen-antibody complexes during recovery [34].

Retro-orbital pain, uveitis, and hearing loss [33,35,36].

Extensive sloughing of skin and hair loss, which may result from virus-induced necrosis of infected sweat glands and other dermal structures [27].

Symptoms can be severe, and in one report of Ebola survivors after the outbreak in Uganda, many patients were unable to resume their previous work activities [37]. 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, but this awaits confirmation [36,38].

Some patients develop clinical manifestations soon after recovery from their initial infection. In a study of 277 Ebola survivors who were evaluated after discharge from an Ebola 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 [36]. The median time from discharge to onset of clinical manifestations was one to two weeks.

However, others appear to develop late complications of Ebola virus disease, with manifestations developing months after they have recovered from their initial illness. As examples:

In one patient, uveitis developed 14 weeks after Ebola virus disease was initially diagnosed, and the aqueous fluid contained infectious virus [35].

Another patient who had recovered from Ebola virus disease developed meningitis approximately 10 months after her initial diagnosis, and infectious virus was recovered in the cerebrospinal fluid [39,40].

Although viral RNA and infectious virus may persist in certain bodily fluids after infection, the importance of persistent virus as it relates to the clinical manifestations during convalescence is unclear [40]. In one case report, immune activation was felt to contribute to the development of uveitis [41].

Discussions of viral persistence and the risk of Ebola virus transmission are found elsewhere. (See "Epidemiology and pathogenesis of Ebola virus disease", section on 'Risk of transmission through different body fluids' and "Treatment and prevention of Ebola virus disease", section on 'Sexual transmission'.)

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

In Liberia, a pregnant 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 [42]. 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; however, both fetuses died even though the mothers survived [43]. The placenta and fetal blood remained positive for Ebola virus using polymerase chain reaction testing up to seven days after the mothers’ serum tested negative for virus.

Thus, pregnant women should be evaluated for Ebola if they have a possible exposure to Ebola virus and present with non-specific 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 — Although there are no approved specific therapies for Ebola virus disease, it is essential to make the diagnosis as early as possible, in order to initiate supportive measures before the development of irreversible shock and to institute infection control procedures. Thus, providers should ask patients who present with fever and/or other symptoms consistent with Ebola virus disease if they have travelled to the epidemic area or had contact with a patient with possible Ebola virus disease within 21 days prior to the onset of symptoms [13,44-48]. (See "Epidemiology and pathogenesis of Ebola virus disease", section on '2014-2015 outbreak in West Africa'.)

Whether Ebola virus disease is initially considered in the differential diagnosis of a patient with fever and flu-like symptoms will vary markedly with the circumstances. In the setting of the current 2014-2015 epidemic, there is a heightened level of suspicion, both in local residents and in healthcare workers returning from West Africa to their home countries.

However, clinicians should remember that the acute onset of a febrile illness in a person who lives in, or has recently been in West or Central Africa can result from a variety of local infectious diseases, including malaria and other causes of fever, such as Lassa and Marburg virus. (See 'Differential diagnosis' below and "Evaluation of fever in the returning traveler" and "Diseases potentially acquired by travel to West Africa".)

General approach — The approach to evaluating patients with possible Ebola virus disease depends upon whether or not the individual displays appropriate signs and symptoms, how likely it is that the exposure will result in disease (ie, the level of risk), and when the exposure occurred.

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 immediately assessed to determine their risk of exposure to Ebola virus. (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, some, 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 'Patients with no identifiable risk' below and "Treatment and prevention of Ebola virus disease", section on 'Infection control precautions'.)

Testing for Ebola virus by reverse-transcription polymerase chain reaction (RT-PCR) should generally be performed for patients who have symptoms consistent with Ebola virus disease and have had an exposure that puts them at risk. In addition, they should be evaluated for other possible febrile diseases including those that are common in areas where the patient traveled or resided (eg, malaria, typhoid, influenza). (See 'Indications for initial testing for Ebola virus infection' below.)

By comparison, asymptomatic individuals who have had a possible exposure to Ebola should be monitored so that they can be isolated if signs or symptoms occur; additional restrictions may also be required, depending upon the type of exposure. (See 'Asymptomatic individuals with identifiable risk' below.)

The specific triage system and type of personal protective equipment (PPE) used during the initial assessment of a patient with possible Ebola virus disease may vary depending upon the setting (eg, emergency department, ambulatory clinic), risk of transmission in the community (eg, low versus high risk), and the patient's clinical symptoms [45,49-53]. As examples, medical facilities, especially those in areas with widespread Ebola transmission, should designate areas for screening patients [51,54]. In addition, the types of PPE that are recommended for healthcare personnel caring for a patient 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 [55-57]. 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'.)

In response to the 2014-2015 outbreak in West Africa, the United States Centers for Disease Control and Prevention (CDC), the World Health Organization (WHO), and other international organizations have provided recommendations for the evaluation and management of persons who may have been exposed to Ebola virus [13,46,47,58-64]. Their approaches depend upon when the exposure occurred, if the exposure was high risk or low risk, and whether or not the individual is displaying signs and symptoms consistent with Ebola virus disease.

The discussion that follows is consistent with the recommendations from the CDC in the United States [13,44,46,48,55]. Clinicians in other countries should consult with their ministries of health and/or the WHO for specific recommendations [60,62,63]. In general, the WHO and CDC provide similar recommendations for evaluating individuals with a possible exposure to Ebola virus disease [59-61]. In addition, the WHO includes a history of sexual intercourse with a sick person or a person recovering from Ebola virus disease when determining the risk of infection.

Initial assessment for Ebola virus disease

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.)

Patients are at risk for Ebola virus disease if they had an exposure that occurred within 21 days before the onset of symptoms. However, the level of exposure risk ranges from high to low to no known identifiable risk. For healthcare workers, the level of exposure risk can vary depending upon the intensity of the epidemic at their work site (ie, the risk of exposure is greater in areas of widespread Ebola virus transmission).

The level of risk defined below is consistent with CDC recommendations, which take into account uncertainty about the extent of Ebola virus spread in some urban areas in West Africa [46,65]:

High risk – A high-risk exposure includes any of the following:

Percutaneous (eg, needle stick) or mucous membrane exposure to blood or body fluids (eg, feces, saliva, sweat, urine, vomit, and semen) of a person with symptomatic Ebola virus disease

Exposure to the blood or body fluids of a person with symptomatic Ebola virus disease without appropriate personal protective equipment (PPE)

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 a country with widespread transmission or cases in urban areas with uncertain control measures

Having lived in the immediate household and provided direct care to a person with symptomatic Ebola virus disease

Some risk – Some risk of exposure includes any of the following:

In countries with widespread transmission or cases in urban areas with uncertain control measures:

-Direct contact while using appropriate PPE with a person with symptomatic Ebola virus disease (or their body fluids)

-Any direct patient care in other healthcare settings

Close contact in households, healthcare facilities, or community settings with a person with symptomatic Ebola virus disease. Close contact is defined as being within approximately three feet (one meter) of the infected person for a prolonged period of time while not wearing appropriate PPE

Low (but not zero) risk – A low-risk exposure includes any of the following:

Having been in a country with widespread transmission or cases in urban areas with uncertain control measures within the past 21 days and having no known exposures to Ebola virus

Having brief direct contact (eg, shaking hands), while not wearing appropriate PPE, with a person with Ebola while the person was in the early stage of disease

Brief proximity, such as being in the same room (but not an Ebola patient care area) for a brief period of time, with a person with symptomatic Ebola virus disease

Direct contact while using appropriate PPE with a person with symptomatic Ebola virus disease (or their body fluids) in countries without widespread transmission or cases in urban settings with uncertain control measures

Traveled on an aircraft with a person with Ebola virus disease while the person was symptomatic

No identifiable risk – Some exposures or situations have no identifiable risk of infection. These include:

Contact with an asymptomatic person who had contact with a person with Ebola virus disease

Contact with a person with Ebola virus disease before the person developed symptoms

Having been more than 21 days previously in a country with widespread transmission or cases in urban areas with uncertain control measures

Having been in a country with Ebola virus cases, but without widespread transmission or cases in urban settings with uncertain control measures, and not having any other exposure as defined above (eg, direct contact with a patient with Ebola virus disease)

Having remained on or in the immediate vicinity of an aircraft or ship during the entire time that the conveyance was present in a country with widespread transmission or cases in urban areas with uncertain control measures, and having had no direct contact with anyone from the community

These guidelines have been used to identify at-risk individuals during the 2014-2015 outbreak in West Africa. Individuals may also be at risk for Ebola disease if they have handled bats, rodents, or non-human primates from other endemic areas of Africa. (See "Epidemiology and pathogenesis of Ebola virus disease", section on 'Transmission from animals'.)

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 [13,58] (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 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 healthcare 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'.)

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 and/or emergency care [13,44,46-48,65,66]. 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 [67]. (See 'Indications for initial testing for Ebola virus infection' 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 [68,69].

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, some, 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 [46].

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 exposure risk level, and are described in detail in the CDC guidance for the monitoring and movement of persons with Ebola virus exposure [46]. Local authorities may also have specific regulations for management of asymptomatic individuals with Ebola virus exposure.

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 "General principles of infection control".)

Indications for initial testing for Ebola virus infection — Evaluation of all patients with suspected Ebola virus disease should be done in conjunction with local and state health departments [13,46,70]. 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 [68].

Testing for Ebola virus infection is performed in symptomatic patients with any possible risk of exposure to Ebola virus (high, some, 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 RT-PCR within three days after the onset of symptoms; repeat testing may be needed for patients with symptoms for fewer than three days duration [71]. 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 [72]. (See 'Laboratory diagnosis' below.)

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

Laboratory diagnosis — The laboratory diagnosis of Ebola virus infection is made by the detection of viral antigens or RNA in blood or other body fluids. This can be done using immunoassays or nucleic acid testing.

Guidance during the 2014-15 outbreak — In response to the 2014-15 outbreak in West Africa, the CDC has released guidelines for the evaluation of patients in the United States suspected of having Ebola virus disease [13,47]. If testing is indicated, the local or state health department should be contacted immediately. Any presumptive positive Ebola test should be confirmed at the CDC [73]. Clinicians, nurses, and laboratory workers need to be aware that CDC select agent regulations apply to the handling of patient specimens confirmed to contain infectious Ebola virus [74]. Additional 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 [71,73,75,76].

For clinicians outside the United States, the World Health Organization (WHO) has also issued guidance for the diagnosis, safe collection, and shipment of samples from patients with suspected Ebola virus disease [77-79].

Diagnostic tests — RT-PCR tests that detect specific RNA sequences have become the standard method of diagnosing Ebola virus disease. Viral RNA is generally detectable in serum by RT-PCR within three days after the onset of symptoms [8,71]. Results are available in approximately two to six hours, depending upon the assay that is used [80].

Repeat testing may be needed for patients with symptoms for fewer than three days duration [71].

A negative RT-PCR test that is collected >72 hours after the onset of symptoms rules out Ebola virus disease [8,72].

The demonstration of genetic diversity and rapid accumulation of sequence changes of Ebola virus in the West African epidemic indicates that careful monitoring will be needed to ensure the continued sensitivity of RT-PCR diagnostics [81].

A rapid chromatographic immunoassay (ReEBOV) that detects Ebola virus antigen is available and can provide results within 15 minutes [82]. However, the test is relatively insensitive (the limit of detection is 2.11 x 108 copies/mL), and it is also nonspecific [80,83]. As an example, one study found that 8 percent of suspected cases that were positive by the ReEBOV assay were negative by RT-PCR [83]. Thus, use of the immunoassay alone could lead to inappropriate admissions to Ebola treatment units. Other tests have been approved under a Food and Drug Administration (FDA) emergency use authorization and can be found on the FDA website (http://www.fda.gov/MedicalDevices/Safety/EmergencySituations/ucm161496.htm#ebola).

DIFFERENTIAL DIAGNOSIS — When evaluating a patient for possible Ebola virus disease, it is important to consider alternative and/or concurrent diagnoses, including infectious and non-infectious disorders. In one study that evaluated 770 ill non-immigrant 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 (12 percent) [84].

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 [13,22,85-87]. Since most patients suspected of possible Ebola virus disease will have travelled to and/or reside in West or Central Africa, the following disorders should be considered:

Malaria: Travelers returning from West or Central Africa should be evaluated for malaria [13]. Malaria 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 "Diagnosis of malaria" and "Clinical manifestations of malaria in nonpregnant adults and children".)

Lassa Fever: Lassa fever is a viral infection that is restricted to West Africa, though imported cases have been seen 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 rodents (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 [88]. (See "Diseases potentially acquired by travel to West Africa".)

Typhoid: Typhoid fever is characterized by a systemic illness with fever and abdominal pain. The organism responsible for the enteric fever syndrome is S. 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 "Epidemiology, microbiology, clinical manifestations, and diagnosis of typhoid fever".)

Meningococcal disease: Patients with meningococcal disease 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 cerebral spinal 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 often 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 "Clinical manifestations of seasonal influenza in adults" and "Diagnosis of seasonal influenza in adults".)

Measles: The prodrome phase of measles and the initial stage of Ebola virus disease are similar, and are characterized by fever, malaise, and anorexia. However, in measles, this prodrome is followed by conjunctivitis, coryza, and cough, as well as the 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 "Clinical manifestations and diagnosis of measles".)

Marburg virus disease: Marburg virus causes clinical manifestations similar to Ebola virus disease. Cases have been identified in Central Africa, but not in West Africa. The diagnosis is typically made by RT-PCR testing.

Travelers’ diarrhea: Travelers' diarrhea develops during or within ten days of returning from travel, most commonly to resource-limited countries or 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: Clinical manifestations, diagnosis, and treatment".)

Additional topic reviews that discuss the evaluation of an ill returning traveler are found elsewhere. (See "Evaluation of fever in the returning traveler" and "Diseases potentially acquired by 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) [89,90]. During the current Ebola epidemic, clinicians are focused on identifying a history of exposure to Ebola virus in patients presenting with fever and other signs and symptoms. In the case of a bioterror attack employing Ebola virus, patients with no possible exposure to an Ebola patient would develop the same 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 consolidated Ebola virus disease preparedness checklist, 2014

http://www.who.int/csr/resources/publications/ebola/ebola-preparedness-checklist/en/

WHO frequently asked questions on Ebola virus disease, 2014

http://www.who.int/csr/disease/ebola/faq-ebola/en/

WHO Ebola virus disease fact sheet N°103 (Updated August 2015)

http://www.who.int/mediacentre/factsheets/fs103/en/

CDC for general healthcare settings in West Africa: Guidance for drawing blood safely when caring for patients with confirmed or suspected Ebola

http://www.cdc.gov/vhf/ebola/hcp/international/drawing-blood-safely.html

CDC resources for parents, schools, and pediatric healthcare professionals

http://www.cdc.gov/vhf/ebola/children/index.html

CDC is it Flu or Ebola, 2014

http://www.cdc.gov/vhf/ebola/pdf/is-it-flu-or-ebola.pdf

CDC healthcare workers - could it be Ebola? 2014

http://www.cdc.gov/vhf/ebola/pdf/could-it-be-ebola.pdf

CDC what you need to know about Ebola, 2014

http://www.cdc.gov/vhf/ebola/pdf/what-need-to-know-ebola.pdf

CDC healthcare provider preparedness checklist for Ebola virus disease, 2014

http://www.cdc.gov/vhf/ebola/pdf/healthcare-provider-checklist-for-ebola.pdf

CDC healthcare facility preparedness checklist for Ebola virus disease, 2014

http://www.cdc.gov/vhf/ebola/pdf/healthcare-facility-checklist-for-ebola.pdf

CDC questions and answers on Ebola

http://www.cdc.gov/vhf/ebola/outbreaks/guinea/qa.html

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Basics topic (see "Patient information: Ebola (The Basics)")

SUMMARY AND RECOMMENDATIONS

The Zaire species of Ebola virus, the causative agent of the 2014-2015 West African epidemic, is one of the most virulent human pathogens. (See 'Introduction' above.)

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

Patients with Ebola virus disease usually have an abrupt onset of non-specific 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.)

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.)

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, some, or low risk). (See 'Asymptomatic individuals 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 or not 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. (See 'Indications for initial testing for Ebola virus infection' above.)

Diagnostic tests for Ebola virus infection are principally based upon the detection of specific RNA sequences by reverse-transcription polymerase chain reaction (RT-PCR) 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 'Laboratory diagnosis' above.)

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

Because of its virulence and high infectivity, Ebola virus is classified as a Category A bioterror agent. (See 'Bioterrorism' above.)

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