Ebola virus: Questions, answers, and more questions
ABSTRACTEbola virus causes a hemorrhagic fever with a high case-fatality rate. Treatment remains supportive although a variety of specific treatments are still in the early stages of investigation. This report reviews the clinical virology of Ebola virus, the reported proposed treatments, and the current outbreak.
KEY POINTS
- Ebola virus is spread by contact with body fluids, with no evidence to date that it is airborne.
- Ebola virus is likely maintained in a reservoir of small animals, possibly bats.
- The incubation period is about 5 to 7 days, during which the patient is not infectious.
- Symptoms begin abruptly, with fever, chills, and general malaise, which in some patients leads to weakness, severe headache, myalgia, nausea, vomiting, diarrhea, and abdominal pain.
- Once the disease is symptomatic, patients have high levels of virus in the blood and other body fluids and are therefore infectious.
- Survivors show improvement in the second week of illness, during which viremia resolves and virus-specific antibodies appear.
THE CURRENT OUTBREAK
The current outbreak is with Zaire ebolavirus. It seems to have started in a 2-year-old child who died in Meliandou in Guéckédou Prefecture, Guinea, on December 6, 2013. On March 21, 2014, the Guinea Ministry of Health reported the outbreak of an illness characterized by fever, severe diarrhea, vomiting, and a high case-fatality rate (59%) in 49 persons. On May 25, 2014, Kenema Government Hospital confirmed the first case of Ebola virus disease in Sierra Leone, probably brought there by a traditional healer who had treated Ebola patients from Guinea. Tracing led to 13 additional cases—all women who attended the burial.13
The Center for Systems Biology at Harvard University and the Broad Institute of Massachusetts Institute of Technology generated 99 Ebola virus genome sequences from 78 patients with confirmed disease, representing more than 70% of the patients diagnosed with the disease in Sierra Leone from May to mid-June 2014. They found genetic similarity across the sequenced 2014 samples, suggesting a single transmission from the natural reservoir, followed by human-to-human transmission during the outbreak. Continued human-reservoir exposure is unlikely to have contributed to the growth of this epidemic.14
As of October 14, 2014, there were 8,914 suspected and confirmed cases of Ebola virus infection, and 4,477 deaths.15
But how did Zaire Ebola virus make the 2,000-mile trek from Central Africa to Guinea in West Africa? There are two possibilities: it has always been present in the region but we just never noticed, or it was recently introduced. Bayesian phylogenetic analyses and sequence divergence studies suggest the virus has been present in bat populations in Guinea without previously infecting humans.
Why Guinea and why Guéckédou? Guinea is one of the poorest countries in the world, ranking 178th of 187 countries on the Human Development Index of the United Nations Development Programme, just behind Liberia (174th) and Sierra Leone (177th). In Guinea, the life expectancy is 56 years and the gross national income per capita is $440. The region has been systematically plundered and the forest decimated by clear-cut logging, leaving the Guinea Forest Region largely deforested, resulting in increased contact between humans and the small animals that serve as the source of infection.1
LIMITED CAPACITY, EVEN IN THE UNITED STATES
A few hospitals in the United States have dedicated units to handle serious infectious diseases such as Ebola: Emory University Hospital; Nebraska Medicine in Omaha; Providence St. Patrick Hospital in Missoula, MT; and the National Institutes of Health in Bethesda, MD. However, in total they have only 19 beds.
QUESTIONS, ANSWERS—AND MORE QUESTIONS
(The following is from a question-and-answer discussion that followed Dr. Brizendine’s Grand Rounds presentation.)
Q: Are there any differences between survivors and those who die of the disease? A: We do not know. Patient survival depends on early recognition and supportive care. There are disparities in the care of patients. Schieffelin et al16 analyzed the characteristics of patients who died or who survived in Sierra Leone and found that the mortality rate was higher in older patients and those with a higher viral load on presentation.
Q: Does the virus block production or release of interferon early in infection? A: Yes, it has been shown17 that Ebola virus protein VP24 inhibits signaling downstream of both interferon alpha/beta and interferon gamma by indirectly impairing the transport of a transcription factor termed STAT1. VP24 is also able to bind STAT1 directly. The resulting suppression of host interferon very early on in the incubation phase is key to the virulence of the virus.
Q: Does infection with one of the viral species confer immunity from other species? A: No, there is no cross-immunity.
Q: How soon do patients test positive? A: About 5 days after exposure, when they develop a fever. At this time patients are highly viremic, which PCR can detect.
Q: Before the virus is detectable in the blood, where is it? A: The liver, endothelial cells, antigen-presenting cells, and adrenal glands.
Q: Do we really need to quarantine ill patients and health care workers returning from Africa, per CDC recommendations? A: We don’t know everything, and some people do make bad decisions, such as traveling while symptomatic. I support a period of observation, although confinement is not reasonable, as it may pose a disincentive to cooperation.
Q: What is the role of giving plasma from survivors? A: Dr. Kent Brantly (see American citizens infected with Ebola) received the blood of a 14-year-old who survived. We don’t know. It is not proved. It did not result in improvement in animal models.
Q: Is the bleeding caused by a mechanism similar to that in enterohemorrhagic Escherichia coli infection? A: No. That is a bacterial toxin, whereas this is more like disseminated intravascular coagulation, with an intrinsic pathway anticoagulation cascade.
Q: How long does the virus remain viable outside the body? A: In one study,18 Ebola virus could not be recovered from experimentally contaminated surfaces (plastic, metal or glass) at room temperature. In another in which it was dried onto a surface,19 Ebola virus survived in the dark for several hours between 20 and 25°C. When dried in tissue culture media onto glass and stored at 4°C, it has survived for over 50 days.
Q: How long does the virus remain in breast milk? A: We know it has been detected 15 days after disease onset and think possibly as late as 28 days from symptom onset.3
Q: How are people actually infected? A: I believe people get the virus on their hands and then touch their face, eyes, or mouth. If you are wearing personal protective equipment, it must occur while doffing the equipment.
Q: Could we increase the sensitivity of the test so that we could detect the virus before the onset of symptoms? A: In theory it may be possible. The virus is somewhere in the body during the incubation period. Perhaps we could sample the right compartment in an enriched mononuclear cell line.
Q: When can patients who recover resume their normal activities? A: After their viral load returns to 0, I would still advise abstaining from unprotected sex and from breastfeeding for a few months. but as for other activities, no special precautions are needed.
Q: Does the virus appear to be mutating at a high rate? A: Looking back to 2004, mutations are occurring, but there is no sign that any of these mutations has contributed to the size of the outbreak by changing the characteristics of the Ebola virus. Can it become aerosolized? It has been suggested that the virus that caused the outbreak separated from those that caused past Ebola outbreaks but does not seem to be affecting the spread or efficacy of experimental drugs and vaccines. So, even though it is an RNA virus and mutations are occurring, no serious changes have emerged.14
BACK TO OUR PATIENT
The differential diagnosis for the patient described at the beginning of this paper includes travelers’ diarrhea, malaria, typhoid fever, yellow fever, meningococcal disease … and Ebola virus disease, although this is much less likely in view of the epidemiology and incubation period of this disease. When his stool was tested by enzyme immunoassay and culture, it was found to be positive for Campylobacter. He recovered with oral rehydration.
