The multinational outbreak of Ebola in 2014 to 2015 alarmed global health experts and created a new sense of urgency in the infectious disease community.67 The epidemic began in Guinea, spread to neighboring countries in West Africa and despite infection control measures, cases occurred in the United Kingdom, Italy, Spain, and the United States. This epidemic is the largest documented, greater than all previous outbreaks combined, and the case fatality rate was estimated to be 70%.68
Ebola virus disease, formerly known as Ebola hemorrhagic fever, is an acute, severe, and often fatal syndrome affecting multiple organ systems and is caused by the viruses of the Ebolavirus genus. Ebola viruses are non-enveloped, non-segmented, negative-sense, single-stranded RNA part of the Filoviridae family. The virus was first identified in 1976 in outbreaks in Zaire and Sudan, and is endemic in West Africa. Five species of Ebola virus have been identified: Zaire ebolavirus, Sudan ebolavirus, Tai Forest ebolavirus, Bundibungyo ebolavirus and Reston ebolavirus and the Z. ebolavirus was responsible for the latest outbreak.69,70 Ebola virus is a highly contagious zoonotic pathogen transmitted from bats and non-human primates to humans. It is believed that several species of carpophagous (fruit-eating) bats may represent a natural reservoir. Non-human primates (ie, monkeys and apes) and humans can be infected with and transmit the virus.69 Handling or consuming infected animals (bats and bushmeat) or contact with their feces and saliva (ie, eating fruit blemished by bats) can spread the disease from these natural vectors.71
Human-to-human transmission occurs primarily through direct contact with infected bodily fluids. While asymptomatic patients are not contagious, once symptoms occur the virus can be found in blood, urine, vomit, diarrhea, and semen. Ebola virus is not spread through water, or food (excluding bushmeat) and there is no evidence of airborne transmission.72 The people at highest risk for infection are those in close, direct contact (ie, family and healthcare workers) with sick persons due to their exposure to virus-containing bodily fluids. In the healthcare and laboratory settings, use of improperly sterilized needles, contaminated syringes, and needle stick injuries represent a high risk exposure. As the infection progresses, the viral load in bodily fluids increases, thus the remains of those who succumbed to the disease are highly contagious.69,72
Ebola virus enters the human body by direct contact with breaks in skin surfaces, mucosal surfaces, or by parenteral transmission. The route of transmission affects the incubation period and patient outcome; with a shortened time and increased severity after parenteral transmission compared to contact exposures.70 Upon inoculation, the virus replicates rapidly and infects numerous cell types and organ systems resulting in apoptosis, tissue damage and necrosis. Ebola virus also triggers release of cytokines and inflammatory mediators causing subsequent vascular leak and a systemic inflammatory response. The insult to various cell types and organs, coupled with the inflammatory response causes a wide array of effects such as gastrointestinal dysfunction, hepatic injury, coagulation defects, immunosuppression, hypotension resulting in multi-organ failure, and shock.73,74 The mortality rate is approximately 50%, with values ranging from a low of 25 up to 90%.29
After an incubation period of 4 to 10 days (range 2-21 days), illness begins with an abrupt onset of flu-like symptoms: fever, chills, headache, malaise, and myalgia as well as nonspecific symptoms such as vomiting, diarrhea, and abdominal pain. A maculopapular rash can appear by day 5 to 7 of the infection.70,74 The disease rapidly progresses and multiple organs are affected. Symptoms are severe and prolonged with reports describing more than 8 to 10 liters of stool and other bodily fluid losses over 24 hours, intractable nausea and vomiting that precludes oral hydration, significant weight loss, and high fever lasting more than 2 weeks.75 Secondary bacterial infections can also occur from gut translocation.76 Gastrointestinal manifestations lead to severe electrolyte imbalances, and with the progression of the infection patients ultimately may die of hypovolemic shock and multi-organ failure 6 to 16 days after onset of symptoms.74 Although Ebola virus is classified as a viral hemorrhagic fever, major bleeding is not a defining symptom. In early outbreaks, severe bleeding diathesis occurred in less than half of the cases, at the peak of the illness and presented as petechiae, ecchymoses, oozing from venipuncture sites, mucosal hemorrhaging, and blood in the stool.81 In the 2014 to 2015 outbreak, bleeding was documented in less than 20% of the cases.78 Thus, the term EVD is now used rather than Ebola hemorrhagic fever to refer to the clinical syndrome.
Epidemiologic data from the outbreak of 2014 to 2015 revealed gender-specific differences in the clinical characteristics of EVD. Despite similar risk factors, a larger proportion of females were infected. Compared to males, females presented with symptoms earlier but had a significantly higher survival rate.77 Predictors of mortality include early onset of severe symptoms, age greater than 45 years, unexplained bleeding, and an initial high viral load (greater than 10 million viral copies/mL [10 × 109/L]).74,78 Patients who recover tend to begin to improve around day 6 as they develop an antibody response.
Recovery is a prolonged process and characterized by weakness, fatigue, asthenia, arthralgias, and failure to thrive. Viral persistence in various bodily fluids for months has been reported, with one study documenting the presence of Ebola virus RNA in semen up to 9 months after infection.79 Long-term complications include hepatitis, myelitis, psychosis, uveitis, hearing loss, and tinnitus.70,80
Laboratory findings are usually nonspecific. In general, patients develop lymphopenia, neutrophilia, thrombocytopenia and increased liver enzymes with aspartate aminotransferase exceeding alanine aminotransferase. Significant electrolyte imbalances including hypokalemia, hyponatremia, hypocalcemia, and hypomagnesemia develop secondary to gastrointestinal losses. With disease progression, hyperamylasemia, and elevations in creatinine and blood urea nitrogen occur. Increased prothrombin time, activated partial thromboplastin time, and fibrin degradation products can also develop suggesting diffuse intravascular coagulation.74
Diagnosis of EVD is confirmed by detection of viral antigens or viral RNA from blood and other bodily secretions using molecular techniques.70 Reverse-transcriptase-polymerase-chain reaction (RT-PCR) assays are the most common detection method. They can be used remotely and provide results within 4 hours. RT-PCR is effective only after the onset of symptoms and it may take up to 3 days after the onset for viral loads to reach detectable levels.82 For samples collected prior to this timeframe, testing should be repeated in 48 hours after a negative result.80 Enzyme-linked immunosorbent assay (ELISA) can also be used to detect viral antigens and antibodies. Samples should be processed by national and international reference centers with high level of biosafety precautions.80,81
CLINICAL PRESENTATION Ebola Virus Disease General Signs and Symptoms
Initially an abrupt onset of fever, headache, fatigue, myalgia, weakness, anorexia, abdominal pain, diarrhea, and vomiting.
Profound dehydration from significant gastrointestinal losses and intractable nausea vomiting.
Maculopapular rash and unexplained hemorrhaging can occur as infection progresses.
Nonspecific, but in general include lymphopenia, neutrophilia, thrombocytopenia with increased liver enzymes with aspartate aminotransferase greater than alanine aminotransferase.
Significant electrolyte losses: hypokalemia, hyponatremia, hypocalcemia, and hypomagnesemia.
As infection progresses, hyperamylasemia, increased serum creatinine and blood urea nitrogen, and evidence of disseminated intravascular coagulation may be found (ie, prolonged bleeding time, elevated fibrin degradation products, and decreased fibrinogen).
Reverse-transcriptase-polymerase-chain reaction, or Enzyme-linked immunosorbent assay tests to identify the virus can be performed at specialized laboratories with high level of biosafety precautions.
During the outbreak in West Africa of 2014 to 2015, it was recommended to screen all patients prior to entering healthcare facilities.83,84 Patients manifesting with symptoms are further assessed for their risk of exposure to the virus: contact with an infected person with confirmed EVD within 21 days of the onset of infection, or travel to an endemic area (ie, West Africa). Asymptomatic individuals exposed to the virus should be monitored daily for 21 days from the last exposure for a fever greater than 38oC (greater than 100.4oF) and signs and symptoms of EVD. If there is a high degree of suspicion or signs and symptoms consistent with EVD, public health authorities should be immediately notified and medical evaluation and treatment begun while adopting the appropriate infection control precautions.85 If a fever develops within the 21-day monitoring period, isolation and medical evaluation is begun, and evaluation for other fever-inducing pathogens should begin. During the influenza season, CDC recommends administration of influenza vaccine at the first contact of the monitoring period if the individual has not been previously vaccinated, while chemoprophylaxis (ie, oseltamivir) is recommended for those individuals who have been exposed to the influenza virus.86
While assessing a patient for EVD, it is important to consider alternative and concurrent conditions that may present in the same way. The differential diagnosis depends upon their symptoms, travel history, personal contacts, immunization status and comorbid conditions. In travelers from or residents of Africa, malaria is the most common febrile illness and should be ruled out before beginning a course of therapy.87 Lassa fever (a viral hemorrhagic fever), dengue, and typhoid fever are also endemic in Africa. Other infectious causes to be considered include meningococcemia, pneumonia, and influenza.74,82,86