SPECIAL REPORT
Ebola! Outbreak in West Africa raises Difficult Questions about Deadly Virus
Without effective vaccine, treatment Ebola mortality rate can hit 90%
By Philip R Fischer, MD
Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN.
Dr. Fischer reports no financial relationships in this field of study.
SOURCE: Centers for Disease Control and Prevention. Outbreak of Ebola in Guinea and Liberia. http://www.cdc.gov/vhf/ebola/outbreaks/guinea, accessed April 11, 2014.
In March 2014, Ebola virus infection emerged in Guinea, West Africa, and spread through communities in Guinea and Liberia. Additional reports of suspect cases in Sierra Leone and Mali are under investigation. As of April 14, 2014, the World Health Organization (WHO) and the Ministry of Health (MoH) of Guinea reported 168 probable and suspect cases, including 108 deaths. Of these suspect cases, 71 have been laboratory confirmed positive cases of Ebola hemorrhagic fever (EHF). One additional health care worker with clinical symptoms has been reported since April 7, increasing the total to 15 health care workers. All cases reported in Conakry, Guinea (20) have been laboratory confirmed. Other districts with confirmed and suspected cases include Guekedou, Macenta, Kissidougou, Dabola, and Djingaraye.
Initial reports came from forested areas in southeastern Guinea near the Liberia border. Subsequently, there were the aforementioned 20 cases reported in Conakry, the capital of Guinea on the western coast. The initial Liberia-based patients had recently traveled from Guinea. The CDC regularly updates a map showing the location of cases (http://www.cdc.gov/vhf/ebola/resources/distribution-map-guinea-outbreak.html).
Testing facilitated by the Pasteur Institute (laboratories in France and Senegal, collaborating in Guinea) confirmed that the causative agent in this outbreak is indeed Ebola virus, the Zaire ebolavirus strain that was last reported in 2009 in the Democratic Republic of Congo. Ministries of Health in the involved countries have been assisted by the WHO as well as by multi-national non-governmental groups including Doctors without Borders, International Red Cross, and Samaritan’s Purse.
COMMENTARY
Connected with concerned people around the world, many of us involved with Infectious Disease Alert were asked questions about Ebola as news media covered the current outbreak. Here, we review established knowledge and recent studies to provide a basis for responding to common questions.
Q: Should meeting organizers allow a physician and nurse from Guinea to attend a medical conference in Europe?
A: Responding to this question required an understanding of the transmission of Ebola virus, the pre-symptomatic incubation time, and measures to decrease the risk of becoming infected in healthcare settings.
It is not certain just how Ebola virus is transmitted, but it seems contagious to people who come into physical contact with a sick person or an infected animal, particularly fruit bats. The initial case in outbreaks sometimes seems to have picked up the virus through contact with an infected animal (such as a bat). Then, it seems that contact with infected blood and bodily secretions (or contaminated needles) can lead to transmission of the virus from one person to another, but the details of transmission are not fully known.1 The incubation period is usually eight to ten days, but it can range from two to 21 days.
Prevention of Ebola virus infection apart from outbreaks can be facilitated by avoiding contact with living or dead animals such as bats. During an outbreak, the infection can spread quickly in healthcare facilities. It is important to implement strategies whereby patients and staff avoid direct physical contact with sick individuals. Use of masks, gowns, and gloves is advised (even for visitors). Secretions and contaminated needles should be disposed without requiring direct human contact. (Full sterilization of needles can be effective if there is not an adequate supply of needles available.)
During an outbreak, any individual with Ebola-compatible symptoms should be isolated so as to decrease direct physical contact with uninfected people. People who have had contact with an infected person or his/her secretions should avoid contact with others during the period of two to 21 days following their last contact with the sick person.
The physician and nurse that served as the basis of this question were advised to avoid contact with bats and to follow careful mask-gown-glove procedures while having patient care contacts with potentially infected individuals. They were told to come along to the European meeting if they remained asymptomatic at least 21 days after any known contact with a potentially infected patient. So far, they have not had contact with seemingly infected patients, and they have not touched bats. If things continue to go well, they expect to attend the meeting.
Interestingly, an international traveler did import Lassa fever to Minnesota.2 While Lassa fever is sometimes asymptomatic and has a lower case-fatality rate than does Ebola, all health care providers must be careful to obtain travel histories, to isolate patients with suspected viral hemorrhagic fevers, and to avail themselves of etiologic testing for accurate diagnoses in patients. We must remain vigilant with the risks of imported diseases.
Q: A middle aged man arrived at a small mission hospital in Guinea with signs suggestive of Ebola virus disease. The hospital has no isolation rooms. Should they care for the patient or refer him elsewhere?
A: Faced with a patient who is sick with a possible viral hemorrhagic fever, a care team has several goals: 1) compassionately care for the patient while seeking a favorable medical outcome (cure), 2) protect health care workers and other patients at the facility from becoming infected, and, 3) collaborate with governmental and non-governmental groups to identify, track, and abort outbreaks.
Currently, there is no curative treatment for human Ebola virus disease. Care is supportive with institution of comfort measures, fluid management, provision of blood products as needed, and management of whatever super-infections and complications arise.
Isolation measures center on keeping the patient and his or her secretions and blood away from direct contact with other people. All persons involved in the care of the patient suspected of harboring Ebola virus should use protective masks, gowns, and gloves. Linens, and medical equipment contaminated with blood and secretions should be sterilized or discarded. Similarly, bodies of patients who succumb to Ebola should be handled without direct contact.
During the current outbreak, government health ministries and non-governmental groups are collaborating effectively to ensure that sampling and testing are available and that isolation supplies are distributed to health centers and hospitals in endangered areas. Hospitals should ensure that space and equipment are available should the need arise.
The non-hypothetical situation that prompted this question took place early in the outbreak when the hospital in question was not yet confident that they had the staff, space, and supplies to manage the patient. The patient was referred to a government hospital a few miles farther down the road but then reportedly left against medical advice during the first night at that facility — before testing could confirm the diagnosis.
Q: Ten percent of Ebola patients survive. Is there a way to predict clinical outcomes?
A: Ebola presents with fever and headache. Patients often have other aches and pains as well as fatigue and gastrointestinal symptoms before they develop hemorrhagic complications. In sub-Saharan Africa, these same symptoms can be due to malaria and typhoid fever, and several other less grave conditions. So, it is important during outbreaks to remember that not every sick person has Ebola. While isolating patients for the possibility of Ebola, they should receive appropriate evaluation and care for whatever else might be ailing them.
Anita McElroy and colleagues retrospectively studied biomarkers in stored serum taken from patients in the 2000-2001 Ugandan Ebola outbreak.3 Fifty-five different biomarkers were assessed.
Death was associated with higher levels of several pro-inflammatory cytokines; this suggests that an aggressive inflammatory response to the infection is part of the pathophysiology of severe disease. Elevated levels of ferritin, an acute phase reactant, were also associated with death. Interestingly, higher levels of sCD40L (a platelet-derived product that might reflect ongoing endothelial repair by activated platelets) were found in patients who survived.
These data give clues as to the pathophysiology of severe Ebola disease, but they do not yet help us clinically identify which patients are more likely to survive. Still, Ebola is a devastating infection, and aggressive supportive care is required for all potentially infected patients.
Q: We treat other serious viral infections. Why can’t we treat Ebola?
A: There is currently no medication available to favorably impact the outcome of Ebola virus infection. But, there are some potential treatments on the horizon.
BCX4430 is a novel synthetic adenosine analogue that inhibits RNA polymerase function and acts as a non-obligate RNA chain terminator.4 In rodent models of Ebola, post-exposure injection of this product prevents clinical disease. And, perhaps more relevant to humans, monkeys are protected from Marburg virus disease when they get this product up to 48 hours after exposure. If this broad-spectrum product turns out to be effective in primates with Ebola virus, too, then there might be potential that it would help humans.
Favipiravir is a pyrazinecarboxamide derivative known as T-705. In cell cultures, it suppresses replication of the Zaire strain of Ebola virus. Further, this product has promoted viral clearance, reduced biochemical evidence of severe disease, and completely prevented death in mice infected with Ebola virus up to six days prior to treatment.5,6 This product might soon reach the market as an influenza treatment, and human studies of its efficacy against Ebola virus infection are warranted.
Another approach to pharmacologic treatment of Ebola virus is to give passive immunization with specific monoclonal antibodies. In non-human primates, monoclonal antibody treatment was shown to fully cure experimentally infected animals even when administered days after the onset of clinical symptoms.7
So, there is currently no effective treatment for Ebola-infected humans. But, further studies with the adenosine analog and/or favipiravir and/or specific monoclonal antibodies might prove successful in identifying effective human therapies.
Q: Is there hope for a vaccine?
A. Similarly, there is currently no effective vaccine for Ebola virus infection. A variety of approaches toward development of Ebola vaccine have been tried — DNA vaccines, subunit vaccines, and both replicating and non-replicating viral vectors.8 In mice and guinea pigs, vaccines have been 60-100% effective in blocking the establishment of infection following exposure. Some of the strategies involving recombinant viral vector vaccines have also been evaluated in non-human primates with up to 100% efficacy in early studies.8 Experiments so far have been limited to phase I trials.
Tragically, Ebola virus is killing scores of people in West Africa. Isolation strategies can help stop the spread of this infection, and supportive care is sometimes helpful. Work continues on medical treatments and vaccinations, but no effective product has yet become available for clinical human use.
References
1. Centers for Disease Control and Prevention. Ebola hemorrhagic fever. http://www.cdc.gov/vhf/ebola Accessed April 11, 2014.
2. Olson J. Rare case of Lassa fever found in Minnesota traveler, Star Tribune, April 4, 2013: www.startribune.com/lifestyle/health/253926981.html
3. McElroy AK, et al. Ebola hemorrhagic fever: Novel biomarker correlates of clinical outcome. J Infect Dis 2014 Mar 26. PMID:24526742 [Epub ahead of print]
4. Warren TK, et al. Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430. Nature 2014 Mar 2. doi: 10.1038/nature13027. [Epub ahead of print]
5. Oestereich L, et al. Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal model. Antiviral Res 2014 Feb 26;105C:17-21.
6. Smither SJ, et al. Post-exposure efficacy of oral T-705 (Favipiravir) against inhalational Ebola virus infection in a mouse model. Antiviral Res 2014 Apr;104:153-5.
7. Qiu X, et al. Antibody therapy for Ebola: is the tide turning around? Hum Vaccin Immunother 2014 Feb 6;10(4).
8. Marzi A, et al. Ebola virus vaccines: an overview of current approaches. Expert Rev Vaccines 2014 Apr;13(4):521-31.
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