ZMapp Fairs No Better than the Nigerian Treatment of Ebola*
By Lisa Egan
As several countries in West Africa continue to struggle with the worst Ebola outbreak in history, the news worldwide has been flooded with stories about the mysterious and horrifying virus.
Photos of victims with the telltale hemorrhagic rash, bleeding from the eyes, ears, and nose, and stories of the stricken vomiting and coughing up blood add to the terror associated with this deadly virus.
But what exactly IS Ebola, and how does it kill?
Ebola is an infection with a virus of the family Filoviridae, genus Ebolavirus. So far, only two members of this family of viruses have been identified – Marburgvirus and Ebolavirus. Five subspecies of Ebolavirus have been identified, four of which can cause disease in humans:
- Ebola virus (Zaire ebolavirus)
- Sudan virus (Sudan ebolavirus)
- Taï Forest virus (Taï Forest ebolavirus, formerly Côte d’Ivoire ebolavirus)
- Bundibugyo virus (Bundibugyo ebolavirus)
The fifth subspecies, Reston virus (Reston ebolavirus), is the one that has not caused disease in humans (but it can be fatal in non-human primates). This is the strain that killed dozens of lab monkeys at a research facility in Reston, VA, in 1989. Four workers at that facility tested positive for Ebola. In 1996, nine lab workers were exposed to this strain after handling infected animals. None of those infected developed symptoms or became ill, but they did develop antibodies to the strain. It is possible that the Reston strain can be transmitted via small-particle aerosols (airborne), but that hasn’t been confirmed.
Filovirus infections are transmitted via close personal contact with an infected individual or their bodily fluids (including through contact with contaminated medical equipment).
According to the CDC, “although in the laboratory the viruses display some capability of infection through small-particle aerosols, airborne spread among humans has not been clearly demonstrated.”
A study released last week showed that the strain causing the current outbreak in West Africa has gone through a surprisingly high amount of genetic drift. Those mutations may make treatment and diagnosis harder.
But can those mutations make Ebola virus change enough to become truly airborne, like the flu?
In his article Can Ebola Go Airborne? Dr. Scott Gottlieb said it is possible, but unlikely:
The widespread belief is that the Ebola virus would be very unlikely to change in a way that would allow the individual virus particles to be concentrated, and remain suspended in respiratory secretions — and then infect contacts through inhalation. The Ebola virus is comprised of ribonucleic acid (RNA). Such a structure makes it prone to undergoing rapid genetic changes.
But to become airborne, a lot of unlikely events would need to occur. Ebola’s RNA genome would have to mutate to the point where the coating that surrounds the virus particles (the protein capsid) is no longer susceptible to harsh drying effects of being suspended in air. To be spread through the air, it also generally helps if the virus is concentrated in the lungs of affected patients.
For humans, this is not the case. Ebola generally isn’t an infection of the lungs. The main organ that the virus targets is the liver. That is why patients stricken with Ebola develop very high amounts of the virus in the blood and in the feces, and not in their respiratory secretions.
Regarding the chances of an outbreak occurring in the United States, Dr. Gottlieb had this to say:
We will certainly see cases diagnosed here, and perhaps even experience some isolated clusters of disease. Health-care workers in advanced Western nations maintain infection controls that can curtail the spread of non-airborne diseases like Ebola.
The current outbreak in West Africa is caused by the Zaire ebolavirus. If infection is properly diagnosed quickly, and treatment is given promptly, a full recovery is likely.
However, the very nature of the Ebola virus can make early detection tricky. Early symptoms are similar to those of many far less harmless diseases. Fever, headache, weakness, diarrhea, and vomiting often present in the early stages, and can lead to a misdiagnosis – and delayed treatment.
What is intriguing – and terrifying – about Ebola is that the virus itself doesn’t kill people – the immune system’s reaction to it does.
“The normal job of the immune system is to eliminate infections,” virologist Christopher Basler explained to NPR. “But when it’s activated at extreme levels or it’s out of control, it becomes damaging to the host.”
In his article titled Ebola: A Dangerous Virus, But How Does it Really Kill?, Professor Edward Oparaoji explains how Ebola invades the body and causes the immune system to go into overdrive:
It disguises itself and stealthily evades detection and “arrest” by the “security guard” – dendritic cells and macrophages. Once inside and secured, the virus disarms the “security guard” rendering them incapable of sending signals for help to the protective “commandoes” – the antibodies and cytokines, to eliminate the “suspect” Ebola. As a result, the virus starts to multiply and invade more cells with reckless abandon, unchallenged, causing cells to die and explode. It is at this stage that the (host) immune system suddenly becomes aware that it has been overrun.
He goes on to explain how the immune system responds:
It then begins a belated over the top uncoordinated defense, launching its entire immunological arsenal at once, through massive release of cytokines – the (host) immune system equivalence of “shock and awe” response to the already widely spread virus. This most extreme immune response, which also signals the terminal phase of the infection, is referred to as the “cytokine storm”- It is this cytokine storm, the host response to the Ebola that kills. During this condition, the (host) immune system turns on itself, attacking every organ in the body, bursting blood vessels and making the infected person bleed both internally and externally, through the orifices (eyes, nose, etc.). This also involves vomits and diarrhoea, causing severe low blood pressure and/or hypotensive shock and subsequently, death.
Other viral infections like Bird Flu and SARS can cause the immune system to launch an intense attack as well, but not with as much ferocity as it does with Ebola.
Survival requires stopping the cytokine storm and resulting hypotensive shock from occurring. Professor Oparaoji explains how this is done:
This can be accomplished through appropriate timely Anti-Ebola drug (ZMapp) or vaccine treatment, when available, and/or aggressive effective supportive treatment – such as maintenance of oxygenation, fluid and electrolyte therapy, blood pressure control with vasopressors, prevention and treatment of secondary infections, pain control and nutritional support, among others.
He also points out that treatment with the ZMAPP drug and Nigeria’s supportive treatment protocol don’t yield results that are that much different: 33% of people treated with ZMAPP have died, compared to 40% who were treated per Nigeria’s standard supportive treatment.
Medical missionaries Dr. Kent Brantly and Nancy Writebol were the first people to use ZMAPP. Both received supportive care at Emory University Hospital in Atlanta, and both have fully recovered. Dr. Brantly also received a unit of donated blood from a 14-year-old boy who recovered from Ebola. Similar treatment (via plasma antibodies) was used in an outbreak in 1995, with stunning results: 7 of the 8 treated with blood from convalesced patients survived.
But was their recovery due to the use of ZMAPP or something else?
At this point, we don’t know:
“They are the very first individuals to have ever receive this agent,” Dr. Bruce Ribner, director of Emory’s Infectious Disease Unit, told a news conference. “There is no prior experience with it, and frankly, we do not know whether it helped them, whether it made no difference, or even, theoretically, if it delayed their recovery.”
Doctors who have experience treating Ebola say that early and aggressive supportive care (like the care Professor Oparaoji described) is crucial to recovery. The physical condition of a person infected with Ebola also matters:
“And clearly for any acutely ill patient, nutritional status is extremely important,” Ribner said.
“If you have somebody who’s well-nourished and somebody who is poorly nourished and they suffer the same illness, infectious or otherwise, the person with better nutrition has better survival outlook.”
ZMAPP is one of several Ebola treatments being developed. But, no matter which drug – if any – proves to be a useful treatment, time will be of the essence. It only takes viruses a few days to replicate and spread, and once the damage becomes widespread it can be impossible to reverse.
Regarding treatment with the blood of convalesced patients, well, it has been said that it would take a lot of plasma to make that a viable option. At this point, it doesn’t appear that anyone is seriously pursuing the use of that treatment modality, although there has been some discussion about it.
As with any disease, an ounce of prevention is worth a pound of cure.
While making hospital rounds a few days ago a colleague stopped me to talk about the Ebola epidemic. He asked: “aren’t there survivors of the disease?” I said: “yes” and he again asked: “why don’t they use the blood from those survivors to treat patients?” “That’s exactly what the Congolese doctors did in the ’95 outbreak!” I exclaimed. “Makes sense, better than palliative care” he concluded with.
In 1995 at the height of the Kikwit Ebola outbreak in the Democratic Republic of Congo as described in the PBS documentary “Ebola-The Plague Fighters”, the Congolese doctors were faced with an unthinkable scenario. Their head nurse had become infected and they could see her rapidly dwindling in front of their eyes. They then decided to do something unprecedented in Ebola treatment; they found Ebola survivors drew their blood, screened it for hepatitis and HIV and transfused it into the nurse and 7 other patients. In the nurse and six patients their symptoms reversed despite initially showing signs of advanced disease and they completely recovered. Out of the 8, one patient suffered a head injury and died. This gave the doctors an 87.5 percent success rate, a rate that has not been matched in any other outbreak and certainly not in the current outbreak. Their scientific findings were later published in the Oxford Journal of Infectious Disease.
Why did this work?
The human body fights against infection with foreign organism like viruses and bacteria by producing antibodies called IgM (acute) and IgG (delayed) that kill the foreign organism. In Ebola most patients cannot mount an adequate response before being killed by the virus. In that outbreak around 20% of the patients mounted a strong enough response to survive. Their blood thus contained large amounts of antibodies which when injected into another patient killed the virus and the patient survived. In West Africa 40% of people are surviving so the potential pool of candidates is quite large.
Recently Newsweek referred to this treatment by the Congolese doctors in reference to Kent Brantly receiving similar treatment in Liberia prior to receiving Zmapp.
The article quotes Heinrich Feldmann head of the National Institute Health’s Laboratory of Virology: “We use this in other infectious diseases, and we can—and should—use that experience and apply it to Ebola,”
This makes me wonder why haven’t the current countries affected reach out to the Congolese doctors for advice? This therapy works and the “magic serum” that was used to treat the American Aid workers is a more expensive and sophisticated form of this simple treatment the Congolese doctors had the vision to use.
The article again asks:
“Why are we still scrambling for an Ebola treatment 20 years later? The answer is that it has been essentially impossible to test. Why? Because Ebola only pops up occasionally, infects a relative few, and kills most. There’s no way, says Feldmann, to get enough plasma during an outbreak to treat others involved in that same outbreak. “Of course if you are collecting plasma now for the next outbreak, then you will have the time to do it,” Feldmann adds, though he is unaware of anyone collecting plasma during the current West African outbreak.”
Well now there’s more than enough potential plasma for anyone who wants it, in Sierra Leone alone there are at least 161 survivors according to official statistics, that’s more than enough donors to conclusively demonstrate that this therapy works. The Kikwit outbreak had a 20% survival rate, we have a 45% survival rate so there’s obviously enough circulating antibodies to handle Ebola.
What’s your deal?
People will ask aren’t you the guy who petitioned the FDA, why are you advocating this? Yes, I’ve recently petitioned the FDA to fast track all Ebola drug and vaccine research. In fact last Thursday the FDA partially released the hold on one of the drugs currently in research development named TKM-Ebola by Tekmira pharmaceuticals. Although this was a positive development the reality of widespread availability of medication in this Ebola epidemic seems unlikely. This is based on the fact that TKM-Ebola was only in phase 1 trials and we’re yet to determine if it’s effective in diseased individuals. Even if clinical field trials were started today, I doubt there’d be a large enough quantity to use in this epidemic. Zmapp had never been used in humans prior to 2 weeks ago and has many practical short term hurdles for widespread use. Fast tracking is to ensure we have drugs for the next Ebola epidemic not necessarily this one.
Debunking the “magic serum” myth
This may be a little hard to follow but stay with me here. According to media reports Dr. Brantly was diagnosed with Ebola on July 25th, the same day Nancy Writebol was diagnosed according to media reports. Dr. Brantly was treated with convalescent blood from a 14 yr. old survivor before receiving a single dose of Zmapp at least 5 hours later than Writebol who received 2 doses. In the glare of cameras on arrival at Emory Hospital Dr. Brantly walked in to the hospital while 2 days later Writebol was wheeled in on a stretcher. The point I’m making is that Dr. Brantly received convalescent blood, one fewer dose of Zmapp and is doing much better according to media reports. The conclusion I draw is that he benefited from convalescent blood most likely more than from Zmapp. Some people may argue that Dr. Brantly is younger but we’ve seen that survival of Ebola is age independent.
OK, so why isn’t it being used?
The opposing arguments I’ve met are that the sample size of the Kikwit paper is too small. Heck, it’s four times larger than the Zmapp sample size. Some doctors on the ground I’ve spoken to are hesitant to use blood transfusions due to the risk of transfusion transmissible infections (TTI’s). To that I say the 60-90 % mortality risk greatly outweighs the 1-5% TTI risk (where’s fivethirtyeight.com when you need them?).
The world is facing a public health emergency, populations have started panicking and desperation is setting in. Currently a patient diagnosed with Ebola has two choices: a) Go to an isolation ward, receive non curative supportive care and most likely die alone or b) die anyway but in the comfort of your own home and with your loved ones, transmission of disease be damned. Unfortunately too many people are choosing the latter option that is leading to the continued spread of the disease. The family of the unfortunate nurse in Nigeria is currently on the run, emphasizing point b).
At this point, populations have to be offered some treatment that can improve their survival; we can’t wait on scarce experimental therapy that has obviously been prioritized for use in the western hemisphere. The confidence of infected people in medical institutions has to be increased so that they’ll seek medical care immediately and lessen exposure to the community. This will hopefully reduce the rate of spread and stabilize the outbreak which continues to grow exponentially as we speak.
In 1995 Doctors in the Congo were faced with a similar dilemma and took the bold step of passive immunotherapy. Personally I would demand this treatment if in a position to require it and will demand it for anyone I know personally afflicted with Ebola. I exhort medical professionals in Sierra Leone to implement this therapy, desperate times require desperate measures. In this case the Sierra Leone government should obtain blood screening, type and cross matching equipment in the Ebola afflicted regions and implement this therapy immediately. We can’t wait for the international bureaucrats to fiddle while the world burns from Ebola.