To anyone who follows infectious disease outbreaks, it is no great surprise that the most immediate, looming threat, Ebola, has received scant attention until recently. Even now, the world’s response has been incomprehensibly and seemingly irresponsibly slow. Why is this the case? Likely because of disparities in the power and wealth of people affected by the epidemic.
The Washington Post has a good backgrounder, “The long and ugly tradition of treating Africa as a dirty, diseased place,” by professors Laura Seay and Kim Yi Dionne. They note the racism of the European colonizers, and how that led to “othering” of Africans, attributing inherent flaws to the people and their societies rather than to cultural differences, without any true basis or understanding. And they cite the “persistent association of immigrants and disease in American society.”
The impact of such “othering” was first really brought home to me in a provocative lecture by Eileen Stillwaggon in 2006, at a Global Network for Neglected Tropical Diseases conference. She spoke of the perception that AIDS was more prevalent in Africa because of different sexual mores—hypersexuality and promiscuity. Then she ripped this apart with eye-opening evidence of the links between helminth (worm) infections, schistosomiasis, malaria, and AIDS, effectively demonstrating that the parasitic infections strongly increase the susceptibility to HIV, explaining the difference in HIV rates between Africa and industrialized countries.
SARS vs. Ebola
SARS, or severe acute respiratory syndrome, is a viral infection that caused a pandemic in 2003. Transmitted by droplets and respiratory secretions, SARS is more readily spread than Ebola, which requires close contact with blood or secretions, but it is less deadly. Yet there was an immediate, coordinated global response to SARS, with unparalleled cooperation between countries and organizations.
In contrast, the world’s response to Ebola has been incredibly slow. Médecins Sans Frontières (MSF, Doctors Without Borders), a well-respected medical humanitarian response agency, provides care where others haven’t dared to go. They also serve as the canary in the mine—an early warning system for disasters that haven’t yet reached the threshold to garner attention from much of the wealthier world. They have worked to control more localized outbreaks of Ebola for years, and were reporting from the field months ago (March, 2014) about the current outbreak being “unprecedented.” With the agency now long overstretched and ignored, MSF International President Dr. Joanne Liu recently denounced the United Nations and the world’s lack of response. Dr. Liu noted that many countries have teams already trained to respond to biological threats, suggesting that these teams be rapidly deployed.
Certainly severe cuts in funding the World Health Organization (WHO) play a significant role in the tardy response. But so do apparent rivalries. Per the NYTimes, “One consultant thought it strange that the W.H.O. would not send Twitter messages with links to the C.D.C.'s Ebola prevention information, part of a policy not to promote material from other agencies. Various offices within the W.H.O.'s balkanized hierarchy also jockeyed for position.” And WHO was certainly warned by MSF, which it ignored.
I can’t agree enough with Laurie Garrett, when she begins her latest, must-read article explaining this debacle with “Public health officials knew Ebola was coming. They know how to defeat it. But they’re blowing it anyway…World, you still just don't get it.” And she aptly notes that MSF’s surprising and desperate call for military help is complicated by wariness of US intervention by Islamists and by the legacy of mistrust since the CIA’s vaccination ruse, which I wrote about last month. (For more on the need for and role of “Vaccine Diplomacy,” see here.)
What might be causing the difference between the world’s responses to these outbreaks? First, SARS occurred in wealthier countries, especially hitting China, Singapore, Hong Kong, and Toronto, with a few cases in the US. Because of the transmissibility and infections in major cities, as well as the virus's ability to survive air travel, there was concern about damage to world economies. So SARs engendered a coherent response, as noted by the CDC:
"Perhaps the most important legacy of SARS is the recognition of the critical need for a multilateral response, led by WHO, in the event of a rapidly moving but ultimately containable global epidemic.”
Ebola, on the other hand, is largely killing the poor, who are people of color, to boot. They are almost voiceless. And their deaths don’t threaten the economies of wealthy countries like outbreaks in Hong Kong or Singapore did. Is this the reason the response to date has been shockingly pathetic?
A variety of responses have been proposed, most focused on getting the UN and WHO to take more active, leadership roles, and getting wealthier countries to fund relief efforts. Too much emphasis seems to be placed on securing an effective vaccine to prevent the epidemic from spreading further, rather than discussion of options that might actually reduce the present mortality rate of nearly 60%.
The one solution WHO is recommending for treatment is focusing on transfusions from Ebola survivors. As I said more than a month ago, “—transfusion of “convalescent serum” from patients who have recovered from the same illness—seems obvious. This was used successfully to treat influenza in the 1918 pandemic, polio in 1934, and measles, among others. Transfusions were tried in the Kikwit Ebola outbreak in 1995, with apparently good results. The problem is these patients also received better supportive care, muddying the conclusions…Given the long-standing successful history, the option of convalescent serum transfusion still seems worth pursuing as a potential, relatively low-tech treatment…” Of course, blood would need to be screened for hepatitis, HIV, and malaria first.
There are, however, some concerns of “antibody-dependent enhancement” in Ebola infected cells, which would paradoxically fuel the infection.
WHO is also focusing on vaccine development, with trials set to begin, but this will likely take months—if not years—to come to fruition, and is an enormously expensive undertaking with testing and manufacturing hurdles. The same is true of novel agents like the antibody ZMapp, aka the “secret serum.” Developing a supply of ZMapp has garnered significant attention, despite the total lack of knowledge about it’s efficacy in humans nor the inability to produce it in significant amounts, even if it were effective.
In the meanwhile, we’ll watch the deaths rise exponentially.
Rather than embark on these new, as yet totally untested drugs and vaccines when we are in the midst of a public health crisis in Africa, I fail to understand the WHO’s reluctance to focus on the possibility of using already existing drugs, many of which are available in large quantities, for Ebola. This is known as drug repurposing.
For example, experts David Fedson and Steven Opal have suggested using statins—inexpensive and readily available—because of their immunity enhancing effects and benefit in a clinical trial for sepsis. Yes, statins’ effect in Ebola is unknown. Surely this could be studied, at least in primates (if not immediately in humans), especially since they are relatively safe and already marketed drugs. Why is there no real push to do so? I fail to understand the rationale for opposing such studies, which could be done (almost) immediately and at relatively low cost. Safety and efficacy studies could be done in monkeys within weeks. WHO's threshold for trying a drug for Ebola in people - evidence of efficacy in monkeys - might make more sense to me if it weren’t for the exponential growth of the epidemic and the high fatality rate. It doesn’t now, given the urgency on the ground.
As yet unmentioned is that the voices of leading researchers in this debate may be influenced by the millions of dollars in research funding that has been pumped into Ebola. For instance, one of the premier Ebola researchers has argued against studying the use of repurposed drugs to treat Ebola. I do not doubt the legitimacy of his concerns, but he has a seeming conflict of interest that should be considered by decision makers, as he is the recipient of a multi-million dollar grant from the U.S. government to develop a vaccine. Concerns about safety of statins or other repurposed drugs could readily be studied if appropriate data is collected and monitored in real time by a Data Safety Monitoring Board (DSMB), just as is done in many trials of novel agents.
Other potential candidates, less widely used than statins, but already approved by regulatory agencies, include:
Selective estrogen receptor modulators (SERMs), including clomiphene and toremifene, which show anti-Ebola activity in mouse models
Favipiravir (Avigan), approved in Japan for treating influenza and effective in mice. The company, Toyama, a Fujifilm subsidiary, says it has enough drug on hand to treat 20,000 people now, and can continue production. The Department of Defense has partnered with Toyama’s American partner, MediVector, to develop the drug for new influenza viruses.
The critical importance of supportive care is being overlooked in the rush to embrace high tech, new-fangled drugs. I learned this in the years I conducted clinical research on new therapies for sepsis. Each of these trials had a predicted mortality of ~50% as a requirement for enrollment. Our mortality dropped from ~50% to 10-15% over the course of the trials, though none of the drugs proved efficacious. The lower mortality was entirely attributable to our learning to be better at detecting and responding to early signs of organ failure and providing better supportive care, especially fluids and electrolytes. This same basic care undoubtedly had a major impact in the survival of Kent Brantley and Nancy Writebol, making it hard to know what, if any, contribution ZMapp had in their recovery.
That basic supplies like IV fluids and adequate Personal Protective Equipement (PPE) are running out, is unconscionable. As experts such as Tom Friedan, Director of CDC, have noted, we know how to stop the epidemic, and we know how to significantly reduce the rate of mortality, even in the absence of effective drugs and vaccines against Ebola. Supportive care alone might well dramatically reduce the mortality rate in this epidemic. We absolutely must organize the supply and logistics to adequately disseminate appropriate materials to provide supportive care to all Ebola patients throughout West Africa. This will require coordination and significant investment, but it may be one of our best options in the near term.
One thing that seems odd is that I have heard little call for the sick and their families to have a voice in the choice of treatment. It seems to me that WHO, in addition to providing for effective supportive care, might provide basic information about the various treatment options and then allow the patients and their families to choose from among those available: supportive care only, convalescent serum treatment, a repurposed drug, or something entirely new. Obviously, the difficulties of obtaining a true “informed” consent in these circumstances would be huge, but it would provide an attempt at autonomy.
The downside would be that without random assignment to treatments, the true effect of any given treatment would not be rigorously known. Given the scope and exponential growth of the crisis, this might still be a useful and effective approach, showing differences between groups, as there would be so many patients. (In Liberia alone, by December 1, “the cumulative number of cases would exceed 100,000,” according to Christian Althaus, of the University of Bern.) It is critical, that the data from these experiences is collected in a central location and analyzed in real time to adjust the treatment approaches as information becomes available--an adaptive clinical trial of sorts. While this will not replace the role of randomized controlled trials, it will supplement the very little information that is available and provide important autonomy for patients who are otherwise faced with few options.
If WHO is so concerned about a small potential risk with statins (or other) vs. as yet totally untested novel therapies, a timely DSMB overseeing trials could obviate those concerns. In addition, giving patients an option in experimental treatments has the added ethical advantage of having allowed the patients and their families to have a say in their treatment.
Of course, all of these options are but a pipe dream unless the WHO, UN, and countries band together to provide basic food, medical care, and PPE, which are the essential, as yet missing, elements, illustrated by this horrifying video of an infected patient escaping isolation to search for food.
Liberia had just one doctor for nearly 100,000 inhabitants before the outbreak. Since then, there have been 79 deaths among some 152 infected health care workers, according to WHO. The US response, announced yesterday? To send a 25-bed field hospital at a cost of $22 million. If the situation weren’t so dire, I might laugh at the absurdity. Laurie Garrett said it best in these tweets:
Katrina showed the failure of the Bush administration to recognize and respond to a disaster disproportionately affecting poor African-Americans in New Orleans. Now we have Ebola decimating poor African countries, and a broader lack of leadership, both with Obama and globally, is replaying this theme. As one commentator astutely noted, “Our failure as a global village is not the lack of leadership during Ebola campaign. Our failure was when we found it acceptable for 4 million people to be served by 50 doctors. When we found it acceptable for countries to have such high rates of poverty, unemployment etc.” Disparities. Poverty. Growing injustice…
What can we, as individuals do? Lobby, educate, and support Doctors Without Borders, the most effective group, with an active presence in Africa already.
Ian Mackay, for use of his graphs
MSF for photo: MSF staff members respond to the the Ebola epidemic in Guinea in March 2014 - Kjell Gunnar Beraas/MSF
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