Human-to-human transmission of Ebola virus usually occurs through direct contact between infectious body fluids of a patient with symptomatic EVD and mucous membranes and/or broken skin of an uninfected individual . During acute illness, Ebola virus can be detected in many body fluids, including blood, excrement, vomitus, sweat, breast milk, vaginal secretions, and semen . However, at different stages of the disease, these body fluids have varying levels of infectivity. The incubation period, which is the period of time between infection with Ebola virus and first symptom onset, is usually 4 to 10 days, but may be as brief as 2 days or as long as 21 days; during this time, risk of transmission of the virus is essentially zero [8, 9]. During the first few days of symptomatic disease, transmission seems to remain low; however, as the disease progresses, infectivity and potential for transmission increases significantly. During this period, viral loads in various bodily fluids increase exponentially, with viral loads reaching as high as billions of copies per milliliter of blood late in the disease . Infected patients also produce large quantities of infectious bodily fluids, as explosive diarrhea and vomiting become more common as the infection progresses .
As Ebola virus can remain viable in liquid or dried material for many days, transmission can occur from dead patients with EVD or from improper handling of waste materials from patients with EVD . Given these factors, people at highest risk for contracting EVD tend to be the people who are actively taking care of patients with EVD such as healthcare workers or other caretakers, people who are in close contact with patients with EVD in later stages of infection, and people who come into direct contact with dead patients with EVD, through burial or funeral practices [2, 13]. Although seemingly rare, Ebola can also be transmitted through sexual contact, even in the convalescent phase, as Ebola virus can persist in semen for months after recovery from the illness . A case of Ebola occurred in a woman in March 2015 whose only known Ebola contact was via unprotected sex with an EVD survivor; after genetic analysis it was confirmed that survivor’s and the patient’s Ebola virus genomes were identical and that the transmission likely occurred from sexual contact . Butchering and handling of bushmeat, including nonhuman primates and bats, have also previously been associated with outbreaks of Ebola . Aerosolized transmission of Ebola has not been established as a cause of disease in humans, although this mode of transmission has been described in monkeys . In most cases, prevention of transmission is achieved by appropriate barrier precautions and disinfection when dealing with patients with EVD and their waste. See Table 1 for a summary of epidemiological risk factors for EVD.
Clinical Manifestations of Acute Infection: Symptoms and Signs
Early EVD symptoms are relatively nonspecific and typically include a high fever, malaise, fatigue, headache, and generalized body aches. Symptoms may begin abruptly and progress over a few days to include abdominal pain, nausea, and high-volume vomiting and diarrhea. Other associated signs and symptoms include conjunctival injection, chest pain, arthralgias, myalgias, asthenia, and hiccoughs [7, 18]. Early in the disease course, symptoms may be mistaken for other tropical diseases, such as malaria, dengue, or cholera . A recent account of an Ebola treatment unit (ETU) in Monrovia, Liberia, describes the typical output from a patient with EVD as an estimate of 5 liters or more of watery diarrhea per day, lasting for up to 7 days and sometimes longer . This profuse vomiting and diarrhea can quickly lead to intravascular volume depletion, electrolyte disorders, hypoperfusion, and shock . Although Ebola has been traditionally known as a hemorrhagic fever, hemorrhagic manifestations are a late complication, and may be seen in only a minority of patients . These symptoms include petechiae, ecchymosis, oozing from venipuncture sites, mucosal hemorrhage, hematemesis, or melena . Women who are pregnant may have spontaneous abortions associated with significant bleeding .
Acute Neurologic Manifestations
In the acute phase, patients with EVD may present with a number of neurologic signs and symptoms, although serious neurologic manifestations are relatively infrequent. Most commonly, patients will complain of a nonspecific headache, which often presents as an early symptom. Altered mental status, from mild confusion to delirium with hallucinations, may also occur, but may be secondary to a host of variables, including electrolyte abnormalities and shock. In severe cases, coma may occur . Meningitis and encephalitis related to EVD have also been reported in the recent outbreak, as well as in prior outbreaks, although the incidence is not well documented [22–24]. During acute EVD, seizures have also been reported, although these are not well characterized .
Detailed neurological evaluations and investigations have been hard to perform on acutely ill patients in endemic regions. However, 1 patient admitted to the National Institutes of Health (NIH) was studied extensively. He developed profound muscle weakness in the first week of the illness, requiring intubation and ventilatory support. This was followed by meningoencephalitis as manifested by classical meningeal signs, delirium, eye movement abnormalities, and frontal release signs. He also had conjunctivitis (Fig. 1). When the meningeal signs gradually resolved and the patient was extubated, he was noted to have decreased short-term memory, hypomania, hyperphagia and insomnia, mild cerebellar signs, and mild weakness of the lower limbs. Over the next few days and weeks most of the symptoms gradually resolved. Three weeks after the onset of symptoms he had uveitis, which resolved with topical corticosteroids. Magnetic resonance imaging of the brain showed multiple punctate microvascular lesions in the white matter (Fig. 2). When seen 7 months later, he had chronic fatigue and decreased executive function . Assessment of severity of neurological symptoms necessitates the use of a numerical scale; however, existing scales do not take into account symptoms such as meningitis, hypomania, and hyperphagia. Hence, we have developed an Ebola scale that used the NIH’s stroke scale and added another 16 points for the additional signs (Table 2).
Neurologic assessment of patients in an acute setting poses multiple challenges. The patient needs to be admitted to an isolation unit with intensive care facilities. The physician needs to be trained in biosafety procedures and how to dress and wear multiple layers of protective clothing (Fig. 3). The process of changing clothes can take nearly 30 min. Only limited neurologic assessment is possible. For example, sensory examination and fundoscopy cannot be performed owing to the face shield. Ultimately, we were able to conduct an indirect ophthalmoscopy using an innovative technique . Physicians who examined the patients were required to monitor and report their own temperature for 21 days and travel restrictions were imposed upon them.
Confirmation of Ebola diagnosis is done by detection of Ebola RNA via reverse transcriptase polymerase chain reaction (RT-PCR) or through detection of viral antigens by enzyme-linked immunosorbent assay. RT-PCR is usually able to detect Ebola RNA within 3 days of symptom onset, but this may need to be repeated in PCR-negative patients who are suspected to have the disease, particularly early after symptom onset [1, 27]. In the patient seen at the NIH, the viral load in the blood paralleled the severity of the neurological symptoms (Fig. 4) .
Laboratory abnormalities seem to be somewhat variable but may include leukopenia or leukocytosis (with leukopenia typically early in the disease and leukocytosis later on), and thrombocytopenia. Transaminase testing often reveals abnormalities, usually with a greater elevation in aspartate transaminase than alanine transaminase . With the marked volume loss common in the recent outbreak, electrolyte derangements such as hypo- and hypernatremia, hypocalcemia, hypokalemia, and hypomagnesemia have often been reported . Renal insufficiency and lactic acidosis may also be commonly seen. Coagulation abnormalities such as prolongation of international normalized ratio and partial thromboplastin time may also occur, although these laboratory abnormalities were not as prominent in this outbreak compared with others . In cases of multiorgan failure, all of the above may be seen, often at markedly deranged values . There are very few reports of cerebrospinal fluid (CSF) analysis during acute EVD. However, in 2 different cases of encephalitis related to EVD, CSF analysis revealed Ebola virus present in the CSF. In the first case, a lumbar puncture was performed early in the course of disease, revealing a viral load of 1 × 106 viral copies/ml and a normal cell count and glucose in the CSF . In the second case, a lumbar puncture was performed at day 41 after EVD onset; Ebola virus was detected at a cycle threshold (CT) value of 37.6, but further CSF analysis was not available . Although not typical laboratory analyses, cytokine analyses on patients with Ebola have in the past revealed a “cytokine storm”, with increased proinflammatory cytokine and chemokine production in patients with Ebola, particularly in those with more severe disease .