Treatment shortages, transmission fears rage on in Ebola outbreak

On March 23, WHO announced the presence of Ebola virus in the southern areas of Guinea. At that time, Guinea’s Ministry of Health reported 49 cases and 29 resulting deaths since December.

Since that first announcement, Ebola first spread to Guinea’s neighbors, Sierra Leone and Liberia, and later to Nigeria and Senegal, leading to 5,843 cases and 2,803 deaths as of Sept. 22, making this the largest and deadliest outbreak of Ebola since the disease was first discovered in 1976. It is also the first outbreak that occurred in the region of West Africa.

Ebola has caused a handful of outbreaks in Africa during the past 4 decades. But none of those compare to the magnitude of the current outbreak in West Africa, which WHO declared a public health emergency of international concern under the International Health Regulations.

A combination of factors led to this outbreak that is spiraling out of control, according to Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases. The outbreak is happening in a highly populated region with marginal health care delivery capabilities, combined with the fact that the area has a history of political upheaval and repression, he said.

“All of these things are the perfect storm for an outbreak of this proportion,” Fauci told Infectious Diseases in Children. “But the most important issue is related to where it is occurring geographically. Previous outbreaks have been in remote areas where response teams were able to come in and isolate patients, allowing the outbreak to die away. Here, the outbreak has spread into populous cities in countries where there are porous borders."

Infectious Diseases in Children spoke with several infectious disease specialists and others involved in outbreak response to discuss the Ebola outbreak and address issues about Ebola that US physicians should know.

Myths about transmission

Each of the experts said the most important point to convey is Ebola virus’s route of transmission. Since the outbreak began to take hold, there has been significant coverage in the mainstream media, sparking fears throughout the American public about the risk for Ebola within the United States.

Ebola is only spread through contact with bodily fluids from an infectious person or contaminated objects such as syringes, according to the CDC. It does not spread by airborne transmission.

“There are many myths about Ebola and this is one of them,” Nadia Qureshi, MD, assistant professor at Loyola University’s Stritch School of Medicine and a pediatric infectious disease specialist at Loyola University Health System, told Infectious Diseases in Children. “We have seen several, much smaller, outbreaks of Ebola in the past, and we would not have seen such small outbreaks had it been an airborne transmission. Misinformation has brought about a lot of panic and fear in the country.”

David Kuhar, MD, medical officer with CDC’s Division of Healthcare Quality and Promotion, is leading the team responsible for health care infection control in the United States and is providing guidance to health care workers on how to prevent the spread of Ebola in US hospitals.

According to Kuhar, the equipment needed to protect health care workers in US hospitals may be misunderstood, partly because of the images in the media related to Ebola care on the ground in West Africa. For example, there are people in field health settings wearing extensive full-body protective equipment. When people view these images, they believe this is the only way health care workers can come close to a patient with Ebola.

“What people don’t realize is that the circumstances in the field medical settings in Africa are very different than in a US hospital,” Kuhar said. “In the field, there may be people infected all around a provider while caring for one patient, and the potential risk for contact with infectious materials may be very unpredictable. In a US hospital, there is one patient in a single room. The circumstances are less chaotic.”

Isolation procedures

The fear only intensified when two American patients, who were infected with Ebola while performing missionary work in Liberia, returned to the United States for treatment. Kent Brantly, MD, and Nancy Writebol, who both worked for the Christian organization Samaritan’s Purse, were transported to a special isolation unit at Emory University to be treated for Ebola.

The special isolation unit was developed initially to isolate and treat CDC employees who may have been exposed to pathogens. The unit is housed in a separate space at Emory University Hospital and it has devoted laboratory equipment and personnel, according to Aneesh Mehta, MD, assistant professor of medicine in the division of infectious diseases at Emory.

Mehta is part of the treatment team that treated Brantly and Writebol, which included physicians, nurses, laboratory personnel and support staff all trained in special procedures to contain special pathogens. The unit is prepared to activate 24 hours a day, 365 days a year, and maintains readiness to care for up to three patients at a time.

“When this outbreak occurred in West Africa and we were informed that these patients would be transferred to our facility, we made the decision to activate the unit and take care of the patients there,” Mehta told Infectious Diseases in Children. “However, taking care of patients with Ebola does not necessarily require this level of isolation, and it does not require any type of special isolation beyond what most hospitals have.”

Mehta said that it is imperative, however, that health care workers are appropriately trained in the use of different levels of personal protective equipment (PPE), in case a higher level of PPE is needed for specific patient situations.

Risk to United States

At a media briefing in July, Stephan Monroe, PhD, deputy director of CDC’s National Center for Emerging and Zoonotic Infectious Diseases, said Ebola poses little risk to the US population, and this message has not changed since.

Despite this low risk, hospitals nationwide are preparing in case a patient tests positive for the infection in their facilities. Monroe said the CDC must be prepared for the “remote possibility that one of those travelers could get Ebola and return to the United States while sick.”

The CDC issued several health advisory notices since July to guide health care workers on the proper procedures to care for suspected or confirmed Ebola cases, as well as infection prevention and control measures.

“As a hospital epidemiologist, I’m following this outbreak closely to make sure that we are completely up to date with the most recent guidance from the CDC,” Judith O’Donnell, MD, chief of infectious diseases at Penn Presbyterian Medical Center in Philadelphia and clinical professor of medicine at the University of Pennsylvania, told Infectious Diseases in Children. “The general public is at incredibly low risk of acquiring this disease. But every institution in the United States needs to prepare for the possibility of seeing Ebola in their hospitals and have protocols in place to deal with potentially infected patients.”

Various interim guidance for handling patients with Ebola, ranging from environmental disinfection, isolation procedures, proper use of personal protective equipment and monitoring patients, among others, can be found on the CDC’s website.

Symptoms, treatment and recovery

The symptoms of viral hemorrhagic fever, caused by Ebola or other viruses, include fever, headache, nausea, vomiting, diarrhea and abdominal pain to start, and eventually progress to bleeding and hemorrhage. Some patients recover but many do not. In previous outbreaks of Ebola, the mortality rate has been as high as 90%. In this particular outbreak, the mortality rate is estimated to be 60% to 70%.

“These viruses set off a chain reaction within the human host that causes hemorrhage, causes the blood to not clot normally and causes the blood pressure to drop to dangerous levels,” O’Donnell said. “With the low blood pressure and bleeding, there can be organ failure. Along this cascade of events, there is a point of no return, and the body just shuts down and the patient dies.”

There is no treatment for Ebola. The core of therapy for these patients is supportive care, including keeping the blood pressure up, administering IV nutrition and fluids, and preventing the patient from going into shock. Nadia Qureshi

According to Mehta, there is no typical disease course for Ebola. In general, patients develop symptoms 2 to 21 days after exposure.

“The course of disease is highly variable from patient to patient, depending on their level of exposure, their underlying medical problems and their availability to access health care,” Mehta said. “My experience with Ebola is limited to these two patients at our facility, but what we understand from our colleagues in Africa is that patients can be sick for several weeks before recovery. Some patients improve, but it’s often a ‘pseudo’ remission, after which they develop symptoms again.”

Mehta said, in Africa, patients are considered recovered from Ebola if they have been asymptomatic for more than 72 hours. If available, PCR blood testing is recommended until the virus is no longer present.

Origin of outbreak

Ebola is a Filovirus in the same family as Marburg virus, which also causes viral hemorrhagic fever. Lassa fever, another concerning viral hemorrhagic fever, is an Arenavirus. All three have the same manifestation.

“Physiologically, all three of these viruses act very much in the same way and cause the same symptoms,” Fauci said. “All three are deadly, but when you look at severity, it’s very clear that the case fatality rate is much more significant for Ebola than the other two.”

The three viruses differ in origin. The animal reservoir of Ebola is believed to be a fruit bat, but this is not 100% certain, Fauci said. It also can infect non-human primates. Humans become infected either directly from a bat or by touching/eating infected bushmeat.

According to a report in The New England Journal of Medicine, this outbreak has been traced, phylogenetically and epidemiologically, to a 2-year-old child in Meliandou, Guinea, who died of Ebola on Dec. 13. The strain of the virus is the Zaire ebolavirus, which is historically one of the deadliest strains of the virus. The phylogenetic analysis identified a separate clade for this particular outbreak, which suggests this strain evolved from a common ancestor or the Zaire strains responsible for earlier outbreaks in the Democratic Republic of Congo and Gabon.

The two other Ebola strains that have caused outbreaks in sub-Saharan Africa include Sudan ebolavirus and the Bundibugyo ebolavirus, which along with the Z. ebolavirus have caused epidemics in the Democratic Republic of Congo, Sudan, Gabon and Uganda. The two additional strains of Ebola include Reston ebolavirus, which has been found only in the Philippines and has not infected humans, and Tai Forest ebolavirus, of which there is one documented human case in the Ivory Coast.

Travel advisories

The CDC issued a Level 3 travel warning in response to the outbreak, advising against all nonessential travel to Guinea, Liberia and Sierra Leone. Nigeria also issued a Level 2 travel warning that advised travelers to practice enhanced precautions.

The Peace Corps has temporarily removed volunteers from Liberia, Sierra Leone and Guinea because of the increasing spread of Ebola virus. In addition, Samaritan’s Purse also has temporarily halted operations in Liberia and evacuated nonessential personnel.

“The agency has been and will continue to closely monitor the outbreak of the virus in collaboration with leading experts from the CDC and the US Department of State,” Peace Corps officials said in a press release. “The Peace Corps has enjoyed long partnerships with the government and people of Liberia, Sierra Leone and Guinea and is committed to continuing volunteers’ work there. A determination on when volunteers can return will be made at a later date.”

Although the risk for acquiring Ebola during air travel is extremely low, WHO requested the affected countries perform exit screening at international airports, seaports and land crossings on all passengers with unexplained febrile illness and symptoms that are consistent with Ebola. In a recent media briefing, CDC Director Thomas Frieden, MD, MPH, said the CDC is assisting with these screening efforts in West Africa.

Frieden also said there are protocols in place to protect against the spread of the disease in the United States, which include notifying the CDC of ill passengers on a plane before arrival, investigating ill travelers and quarantining ill passengers when necessary at the CDC quarantine stations located at US ports of entry. It has also issued interim guidance for airline crew, cleaning personnel and cargo personnel regarding Ebola.

Experimental treatments

There is no vaccine or treatment approved for use in humans with Ebola. However, considerable attention has been devoted to experimental treatments and their role in the current outbreak.

The two American patients, Brantly and Writebol, received doses of an investigational treatment called ZMapp, a combination of three monoclonal antibodies developed by Mapp Biopharmaceutical. It has not been tested in humans for safety or effectiveness. However, according to the CDC, the treatment was arranged privately through officials at Samaritan’s Purse, who were referred to a company contact to pursue obtaining the experimental treatment.

“It’s too early to know whether it’s an effective treatment, as the only studies so far have been in primates,” Qureshi said. “We don’t even know the safety of the drug, as it hasn’t even gone to phase 1 clinical trials. Yes, these patients recovered, but we don’t know if it was due to the supportive measures or if it was because of ZMapp.”

The scramble for access of investigational agents prompted WHO to convene an advisory panel to deliberate the ethical considerations regarding the drugs’ use. According to its report, the panel “concluded unanimously that it would be acceptable on both ethical and evidential grounds to use as potential treatments, or for prevention, unregistered interventions that have shown promising results in the laboratory and in animal models but have not yet been evaluated for safety and efficacy in humans.”

On Aug. 12, Mapp Biopharmaceutical announced on its website that the available supply of ZMapp had been exhausted. Aside from the two American patients, it is reported that three Liberian doctors also received the investigational serum; one has since died. According to the CDC, two other companies, Tekmira Pharmaceuticals and BioCryst Pharmaceuticals, also have Ebola treatments that are in the early stages of development.

Fauci said the NIAID is accelerating efforts toward developing a vaccine, pushing up a trial to start in the beginning of September. He also said there are several therapeutic candidates in preclinical development.

“An equal amount of importance should be placed on vaccines and treatment,” Fauci said. “We really need both.”

Unprecedented difficulties

WHO officials have said the magnitude of this outbreak, especially in Liberia and Sierra Leone, has been underestimated, in part because many families hide their infected loved ones in their homes because they believe they will be more comfortable. Some fear the stigma and social rejection that has often accompanied an Ebola diagnosis.

Treatment centers and clinics have closed, new treatment facilities are immediately filled with patients, and there are reports of mobbing incidents and riots at an Ebola holding facility in Liberia, according to a WHO statement. In addition, contact tracing is proving difficult because reports have suggested that patients are lying about their interactions with people, most likely due to fear.

The effect Ebola has had on health care workers has also proved to be an impediment to controlling the outbreak. More than 225 health care workers have become infected with Ebola virus and more than 120 have died, according to WHO. As a result, WHO has experienced difficulty recruiting medical staff to deploy to the region.

WHO has deployed nearly 400 people to respond to the outbreak, and on Aug. 24, it reported the first case of Ebola among one of these international health workers.

“The heavy toll on health care workers in this outbreak has a number of consequences that further impede control efforts,” a WHO statement read. “It depletes one of the most vital assets during the control of any outbreak. WHO estimates that, in the three hardest-hit countries, only one to two doctors are available to treat 100,000 people, and these doctors are heavily concentrated in urban areas.”

Curtailing the outbreak

This outbreak has garnered significant response around the world. Health officials in Guinea, Liberia, Nigeria and Sierra Leone are working with national and international partners, including the CDC, to respond to and control the outbreak. The CDC has deployed at least 60 members of its staff to the region to assist in the response, including surveillance, contact tracing, database management and health education.

It will not be easy to control the outbreak, especially because of the lack of effective treatment and a vaccine for Ebola, but it can be done, according to Frieden.

“We are fulfilling our promise to the people of West Africa, Americans, and the world, that CDC would quickly ramp up its efforts to help bring the worst Ebola outbreak in history under control,” Frieden said in a press release. “We know how to stop Ebola. It won’t be easy or fast, but working together with our US and international partners and country leadership, together we are doing it.”

Fauci said these public health measures, including isolation of patients and contact tracing, are the key to ending this outbreak.

“That’s what’s going to shut off the epidemic,” Fauci said. “We can’t wait for vaccines and drugs because they won’t come in time. This outbreak will end with proper public health practices.” — by Emily Shafer

References:

Baize S. N Engl J Med. 2014;doi:10.1056/NEJMoa1404505.
CDC. 2014 Ebola Outbreak in West Africa. www.cdc.gov/vhf/ebola/outbreaks/guinea/index.html. Updated Aug. 24, 2014; Accessed Aug. 26, 2014.

For more information:

Anthony S. Fauci, MD, can be reached through the NIAID media office, niaidnews@niaid.nih.gov.
David Kuhar, MD, can be reached through media representative Melissa Brower, ggk5@cdc.gov.
Aneesh Mehta, MD, can be reached at: aneesh.mehta@emory.edu.
Judith O’Donnell, MD, can be reached at: odonneju@uphs.upenn.edu.
Nadia Qureshi, MD, can be reached at: nqureshi@lumc.edu.

Disclosure: Fauci, Kuhar, Mehta, O’Donnell and Qureshi report no relevant financial disclosures.

Who should receive the very limited number of experimental Ebola treatments?

This is a complicated issue and an impossible ethics question to answer.

This is an issue that we don’t often confront and that’s part of why this is challenging. It’s similar to early experiences with HIV. The very first trials of AZT were controversial in a similar way: Only a small subset of people who were sick could get into the trial, and then only a subset of those people would have access to the drug. The argument from the HIV/AIDS community was that it was unfair to deny access to even this highly experimental drug in the way the clinical trial was set up. It was the converse of how we generally think of the ethics of research on new therapies. We are seeing a similar situation with experimental treatment for Ebola.
The assumption is that it provides more benefit than harm. In the case of AZT, there was some efficacy, and it certainly seemed better than watching people die from a horrible infection. But what if it had made people sicker and caused them to die more quickly? That’s exactly what we don’t know about these new therapies for Ebola. It happened to be the case that some the people who received this experimental therapy seem to have benefitted from it. Of course, we don’t know whether they would have otherwise gotten better. The numbers are too small and the conditions are uncontrolled, so nothing can really be surmised from this limited experience. It appears that there was some benefit to the people who received it, but without further research we don’t really know.

It’s a challenge from an ethics perspective in knowing how to discuss what’s at stake. How do we understand risk and benefit and their appropriate balance? How do we think about informed consent, which of course is a mainstay of participation and research and also in clinical care? How do you inform somebody about what the risks and benefits are of something that has never been tried in a human before? And if you think that there’s some likelihood of benefit given that there’s so little else to offer, what’s the most appropriate way to allocate that scarce resource? We know more people need it than there is available supply. That’s when we start talking about first responders, or those who willingly put themselves in harm’s way to help others. Part of our social contract with those people is to come to their aid if something bad does happen to them. But what to do when we don’t know whether this is an efficacious drug? It’s as if we’re doing both a phase 1 clinical trial and thinking about how to allocate a scarce lifesaving resource at the same time, and that’s very confusing.

So at the moment, it’s an impossible ethics question to answer. But even if we knew it was an effective therapy, there’s a scarce number of doses available. There are no good ethical approaches for determining who should get the very few doses, when there are literally thousands of people who could benefit from it.

Jeffrey Kahn, PhD, MPH, is a Robert Henry Levi and Ryda Hecht Levi Professor of Bioethics and Public Policy, Johns Hopkins Berman Institute of Bioethics. Disclosure: Kahn reports no relevant disclosures.

Randomization would allow us to learn the most we can in this situation.

I certainly think it is not unethical to give these experimental treatments to people assuming that everyone has consented and have been fully informed about the fact that they are unproven. We don’t know if they work and we don’t really know the risks. I can certainly understand a doctor or nurse wanting to give the treatment and I can understand the patients wanting to receive it. I might very well want to receive it myself were I in that situation. So from the patient’s point of view, the family’s point of view or the doctor’s point of view, it would be very hard to say it’s unethical. It may benefit people who have this terrible disease.

The important thing is that it would be a mistake to give these in a way that we don’t, at the same time, learn as much as we can from that. That means giving them not in a “compassionate use” kind of way where you just sort of deploy them into the field and then scramble to find out as much as you can. But rather give them in the context of a thoughtful scientific protocol that has real scientific questions and real measurements to learn about how the drug works, what its effects are, what its adverse effects are, what its benefits are, etc. So my strong vote is to do this in the context of careful science, not just in a rush to do it in a “compassionate use” kind of way. I think the right way to do that scientifically is to use randomization: a group that gets the drug plus standard supportive care and a control group that only gets supportive care. I certainly advocate for doing the most rigorous science you can do under the circumstances and in that involves randomization.

It’s more difficult to determine who should receive the drug. The first consideration is who is most likely to benefit. I’m not an infectious disease expert or a virologist so I don’t know the answer to that question. But some careful thinking is needed the populations that are most likely to benefit. For example, in the animal studies for ZMAb — the predecessor to Zmapp — they were treated very early in the course of their infection, before they started to show symptoms. Those animal studies, tiny as they were, suggest that giving the drug in early infection is effective. That’s the data that we have to go on, and in accordance with those data, I would argue for given the treatment early in the course of the infection rather than as a last ditch effort to people who are critically ill.

In addition, there are people who are putting themselves on the front line fighting the epidemic: doctors, nurses, health care workers, funeral workers, etc. This obviously involves mostly local personnel, but there are international personnel as well. So if we really have to narrow things further, I would say that people who put themselves at risk in order to help combat the epidemic should have priority access, because of what they are doing and the risks they are taking on.

Steven Joffe, MD, MPH, is an Emmanuel and Robert Hart Associate Professor of Medical Ethics and Health Policy at University of Pennsylvania Perelman School of Medicine. Disclosure: Joffe reports no relevant disclosures.