The International Ebola Emergency
Sylvie Briand, M.D., Eric Bertherat, M.D., Paul Cox, B.A., Pierre Formenty, M.P.H., Marie-Paule Kieny, Ph.D., Joel K. Myhre, M.A., Cathy Roth, M.B., B.Chir., Nahoko Shindo, Ph.D., and Christopher Dye, D.Phil.
August 20, 2014
On August 8, 33 weeks into the longest, largest, and most widespread Ebola outbreak on record, the World Health Organization (WHO) declared the epidemic to be a Public Health Emergency of International Concern (PHEIC). This declaration was not made lightly. A PHEIC is an instrument of the International Health Regulations (IHR) — a legally binding agreement made by 196 countries on containment of major international health threats.
The August 8 statement made by WHO Director-General Margaret Chan followed advice from the independent IHR Emergency Committee. Reviewing all the available evidence, the committee concluded that further international spread of Ebola could have serious consequences. Their concern was based on the continuing transmission of Ebola in West African communities and health facilities, the high case fatality rate of Ebola virus disease (EVD), and the weak health services of Guinea, Liberia, Sierra Leone, Nigeria, and other neighboring countries at risk for infection.
A Public Health Emergency carries immediate consequences for all IHR signatories (see Box 1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). For the four currently affected countries, the Emergency Committee made several recommendations. Heads of state should declare a national emergency, activate national disaster-management mechanisms, and establish emergency operations centers. There should be no international travel of infected persons or their contacts. In areas of intense transmission — especially the border areas of Sierra Leone, Guinea, and Liberia — the provision of clinical care to affected populations could be used as a basis for reducing people's movement. Funerals and burials should be conducted in the presence of fully trained personnel so as to reduce the risk of spreading infection. And extraordinary supplementary measures, such as quarantine, may be implemented if necessary. These recommendations constitute a robust response to an extraordinary event but are not intended to be coercive. Rather, they should be introduced with the understanding and collaboration of affected communities.
The current outbreak has caused more cases and deaths than any previous EVD epidemic. It appears to have started in the Guéckédou district of Guinea. The first case was recorded in December 2013, but that case was probably not the first in this outbreak. Until the end of April 2014, most cases were reported from Guinea, with a small number in bordering parts of Liberia and Sierra Leone (see graph). In late April, a dip in reported cases in Guinea gave hope that the epidemic was beginning to subside and could be confined largely to one country. That hope was abandoned as the number of confirmed cases in Liberia and Sierra Leone rose sharply during May. By August 16, the cumulative number of confirmed, probable, and suspected cases of EVD in the three worst-affected countries plus Nigeria was 2240, with 1229 deaths. The ratio of deaths to cases implies a case fatality rate of 55%. However, this estimate is approximate, since some cases and deaths (perhaps many) have been missed; in particular, contact tracing in Guinea during the initial period was far from adequate, allowing further opportunities for transmission. Moreover, the fatality rate varies markedly among geographic sites, ranging from 30 to 90% in this epidemic.
Although the largest number of cases was reported in the week starting July 28, the data compiled from Guinea, Liberia, and Sierra Leone give little indication that incidence has begun systematically to decline (see graph). As yet, there is no persuasive evidence that the epidemic is under control. And the recent discovery of cases in Nigeria, which shares no border with Guinea, Liberia, or Sierra Leone, highlights the risk of wider spread across Africa and to other continents. Beyond the immediate health concerns, Ebola is also becoming a humanitarian and economic emergency: schools are being closed, agriculture and mining are under threat as workers leave the affected areas, and cross-border commerce has slowed.
We do not yet have an Ebola vaccine or specific antiviral treatments, but evidence from the current and previous epidemics indicates that transmission can be interrupted by infection-control measures. The mode of transmission is well known: the chance of infection is high if there is direct contact with blood, secretions, organs, or other body fluids of infected persons. Patients become infectious once they are symptomatic (2 to 21 days after infection) and may remain infectious even after symptoms subside (virus persists in body fluids). The primary animal reservoirs of Ebola are probably fruit bats, and human infection can be acquired from intermediate mammalian hosts, including domestic pigs and primates. But this epidemic is almost certainly being sustained by person-to-person transmission through physical contact. Although contact with infected body fluids carries great risk, Ebola virus does not usually spread rapidly through large populations. From previous epidemics it has been calculated that 1 primary human case generates only 1 to 3 secondary cases on average, as compared with 14 to 17 for measles in West Africa.
These observations point to immediate priorities for control: early diagnosis with patient isolation, contact tracing, strict adherence to biosafety guidelines in laboratories, barrier nursing procedures and use of personal protective equipment by all health care workers, disinfection of contaminated objects and areas, and safe burials. Patients with Ebola require symptomatic treatment and intensive care, and clinical reports suggest that better supportive care improves patients' chances of survival. The establishment of emergency operations centers is critical, as are communication and social mobilization programs, both to help affected populations understand and comply with control measures and to help health authorities understand how these measures can be introduced in a culturally sensitive way.
These recommended control methods are, of course, more easily recited than implemented. Extraordinary resources are required by any health service confronted by Ebola; those in Guinea, Liberia, and Sierra Leone are severely stretched. Health services are understaffed. Essential personal protective equipment is in short supply. Capacities for laboratory diagnosis, clinical management, and surveillance are limited, and delays in diagnosis impede contact tracing.
On top of these problems, health services are operating in a climate of fear and discrimination. Some contacts of patients with confirmed cases have evaded follow-up by medical teams (which ideally covers the full incubation period of 3 weeks). Some patients and their contacts have been ostracized in areas where Ebola is thought to be a product of witchcraft. Health care workers are aware of the risks they face: more than 150 health care workers have already been infected, and at least 80 have died. Fear has also turned to hostility against national and international response teams and has compromised care delivery and transport of essential equipment and samples to laboratories.
This epidemic's unprecedented scale has been a surprise, but the response is now firmly under way. The August 8 declaration kick-started a plan to stop the epidemic that will cost at least $100 million to enact in Guinea, Liberia, Sierra Leone, and Nigeria between now and the end of 2014. Key elements of the plan are to strengthen the field response through surveillance, case investigation, patient care, and contact tracing; activate and test preparedness plans in countries at risk; and coordinate the response internationally. Supporting national governments, the World Bank has pledged to help fill the funding gap.
At the national level, Liberia and Nigeria have declared national emergencies and are screening people arriving at and departing from airports and seaports. Guinea has closed its borders with Liberia and Sierra Leone. Members of Liberia's National Traditional Council have addressed their communities throughout the country. The engagement of local communities is vital. We have already seen how, in Télimélé, site of a cluster of cases in Guinea, transmission was rapidly curtailed with the support of community leaders.
Monitoring of funds raised and disbursed, and of control measures implemented, is now intense. Above all, we are looking for a sustained decrease in incidence, from week to week and district by district, with no sign of further geographic spread. In the coming days and weeks, that will be our primary measure of success in preventing infections and saving lives.
The full text and graphics for this article can be found at: http://www.nejm.org
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Ebola 2014 — New Challenges, New Global Response and Responsibility
Thomas R. Frieden, M.D., M.P.H., Inger Damon, M.D., Ph.D., Beth P. Bell, M.D., M.P.H., Thomas Kenyon, M.D., M.P.H., and Stuart Nichol, Ph.D.
August 20, 2014
Since Ebola virus was first identified in 1976, no previous Ebola outbreak has been as large or persistent as the current epidemic, and none has spread beyond East and Central Africa. To date, more than 1000 people, including numerous health care workers, have been killed by Ebola virus disease (EVD) in 2014, and the number of cases in the current outbreak now exceeds the number from all previous outbreaks combined. Indirect effects include disruption of standard medical care, including for common and deadly conditions such as malaria, and substantial economic losses, insecurity, and social disruption in countries that were already struggling to recover from decades of war.
The outbreak's spread to densely populated Lagos, Nigeria, is worrisome, and the situation there is evolving rapidly. Lagos has a population roughly equivalent to that of Guinea, Sierra Leone, and Liberia combined, and it took nearly 2 weeks to establish the first effective isolation and treatment facilities there. Nigeria has since greatly improved its response, but whether it acted in time to stop a large outbreak is not yet clear. Given the extensive mobility and air travel in West Africa, EVD could reach other countries in the region and beyond. Every day that disease transmission remains uncontrolled, the likelihood of spread to unaffected countries increases.
The Centers for Disease Control and Prevention (CDC) is working intensively with partners to help stop the outbreak at its source in Africa. We are also assisting the four affected countries to improve their exit-screening protocols to help protect the rest of the world, including the United States. Each month, several thousand travelers from affected areas enter the United States, and even more people travel to and from Europe, other parts of Africa, and Asia. As long as Ebola is spreading in these regions, clinicians need to be alert to the possibility of EVD, take a travel history, and promptly isolate and test ill travelers who have returned from these regions in the past 21 days and have symptoms consistent with EVD. The CDC has issued detailed guidelines regarding identifying, isolating, diagnosing, and treating patients. There is also specific guidance for airline flight crews, cleaning personnel, and cargo personnel to minimize their risk of exposure.
Stopping the outbreak at the source in Africa will take many months. Three core interventions have stopped every previous outbreak and can stop this one as well: exhaustive case and contact finding, effective response to patients and the community, and preventive interventions.
Identifying infected persons quickly requires accessible diagnostic and treatment facilities. In the current outbreak, the number of patients has far exceeded local capacity, which has resulted in a vicious cycle in which more cases lead to overloading of facilities which leads to more cases. Laboratory testing with real-time polymerase chain reaction is sensitive and specific and can return results within hours; it is now becoming more widely available in the affected areas.
Responding to cases involves isolation and treatment of patients, contact tracing, and monitoring each contact for 21 days after exposure. It is difficult to isolate and care for patients with EVD, not because the disease is particularly infectious or the virus particularly hardy, but because a single lapse can be devastating. Neither negative air flow nor special respirators are essential; meticulous attention to gown, glove, mask, and eye protection and great care while removing protective equipment are key. Improved hospital infection control throughout the region would prevent a substantial number of EVD and other illnesses. Soap and water or alcohol-based hand sanitizers readily disrupt the envelope of this single-stranded RNA virus, and decontamination with dilute bleach is effective and readily available even in remote settings.
Provision of supportive care, particularly fluid and electrolyte management and treatment of bacterial superinfections, can significantly improve survival. Contacts need to be identified and their temperature monitored daily for 21 days after exposure; if they develop fever, they will also need to be immediately isolated, tested, and if tests are positive, interviewed to identify contacts, each of whom must then be followed for 21 days. Social mobilization and culturally appropriate health education efforts are critical to successful case identification and tracking of contacts.
There are three key preventive interventions. The first is meticulous infection control in health care settings. The greatest risk of transmission is not from patients with diagnosed infection but from delayed detection and isolation. Since the early symptoms of EVD — fever, nausea, vomiting, diarrhea, and weakness — are nonspecific and common, patients may expose family caregivers, health care workers, and other patients before the infection is diagnosed.
Second, educating and supporting the community to modify long-standing local funeral practices to prevent contact with body fluids of people who have died from EVD, at least temporarily until the outbreak is controlled, will close the second major route of propagation of the virus. This is a culturally sensitive issue that requires culturally appropriate outreach and education.
And third, avoiding handling of bush meat (wild animals hunted for sustenance) and contact with bats (which may be the primary reservoir of Ebola virus) can reduce the risk of initial introduction of Ebola virus into humans. Bush meat consumption could be reduced through socioeconomic development that increases access to affordable protein sources. Where bush meat consumption continues, safer slaughter and handling can be encouraged. The potential effect of deforestation and other environmental changes on increasing human–bat contacts needs to be further studied and addressed.
These are straightforward interventions, but Ebola virus is a formidable enemy. If a single case is missed, a single contact becomes ill and isn't isolated, or a single lapse in infection control or funeral-practice safety occurs, another chain of transmission can start.
In addition to implementing stringent control efforts, we need to accelerate development and deployment of vaccines and antiviral treatment. Supportive medical care can reduce case fatality rates substantially (and probably contributed to the much lower — 23% — case fatality rate in the Marburg virus outbreak in Germany), but there are promising antiviral treatments and vaccines currently in development. Ethical issues have been raised about using experimental treatments and vaccines that are in very limited supply, but a vaccine that is safe and effective would further protect health care workers and potentially others in outbreak situations. Phase 1 clinical trials are expected to begin in the coming weeks, and intensive discussions are under way regarding how to evaluate and provide these vaccine candidates, with informed consent, for pre- or post-exposure prophylaxis.
In addition to acting to stop this outbreak, we should put systems in place to prevent another one. Earlier this year, the United States joined partner governments, the World Health Organization, and other multilateral organizations and nongovernmental actors to launch the Global Health Security Agenda, which aims to better protect all people from health threats. As the world faces the major threats of emerging or reemerging organisms, increased drug resistance, and the intentional or unintentional spread of virulent pathogens, we have three critical advances that will enable further action: increased societal commitment on a global scale; new technologies that allow us to work better, faster, and cheaper; and successes, ranging from better control of EVD in Uganda to the rapid and effective response to H7N9 influenza in China. The current EVD outbreak is a tragic illustration of the importance of improving global health security. The components of this strategy — prevent wherever possible, detect rapidly, and respond effectively — match the framework for stopping the EVD outbreak.
EVD is a painful reminder that an outbreak anywhere can be a risk everywhere. The Global Health Security Agenda aims to strengthen public health systems in countries that need it most in order to stop outbreaks before they become emergencies. We believe that stopping outbreaks in a way that leaves behind stronger systems to identify, stop, and prevent future health threats is a moral imperative.
The full text and graphics for this article can be found at: http://www.nejm.org
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Studying “Secret Serums” — Toward Safe, Effective Ebola Treatments
Jesse L. Goodman, M.D., M.P.H.
August 20, 2014
Ebola virus (EV), the cause of an ongoing deadly epidemic in West Africa, has been one of the world's most feared pathogens, causing catastrophic clinical disease and high mortality. Although the highest priority must be given to public health and infection-control measures that have contained past outbreaks, the current outbreak — the largest ever recorded — also highlights the need for effective treatment.
The report that two seriously ill American volunteers, Kent Brantly and Nancy Writebol, received an experimental cocktail of three monoclonal antibodies, never before administered to humans, has raised questions around the globe. Dubbed “secret serum” by the media, the treatment has generated hope, suspicion, accusations of inequity, and requests for additional product, of which, since the manufacturers provided three remaining doses to Liberia, there is now none.
The product received by Brantly and Writebol is ZMapp, containing antibodies against three EV glycoprotein epitopes, manufactured by expression in tobacco plants. The product conferred a survival benefit in infected nonhuman primates when administered 24 to 48 hours after infection and also appears to be beneficial even if started 4 to 5 days after infection, using fever and positive polymerase chain reaction as the treatment trigger — but these findings may not predict response in humans. No human safety studies were performed before the drug was administered to these two patients, whose condition reportedly improved soon after they received it. Although this report engenders hope, one cannot reach a sound conclusion on the basis of two patients' survival. Moreover, a third patient has now died despite reportedly having received ZMapp.
In addition, the likelihood that the first two recipients would have died without therapy may have been significantly less than the approximately 50% so far noted in the current epidemic. Surviving beyond the first several days of EV illness may be predictive of overall survival, as it was in the 1995 Congo outbreak. Brantly reportedly became ill 9 days before receiving the product, and Writebol may have been sick at least as long. Brantly received a transfusion from a recovered patient, for which there is conflicting evidence of effectiveness, and high-quality supportive medical care may well improve survival, an issue that merits further emphasis. Finally, mortality often decreases over the course of Ebola outbreaks, perhaps because of enhanced diagnosis and care. More detailed clinical information from these and any other patients treated may help clarify the likelihood that any improvement is attributable to the treatment.
Similar or greater uncertainty pertains to other experimental therapies in clinical development for EV. These include the following: TkM-Ebola, small interfering RNAs targeting EV RNA polymerase L, which reduced mortality in a nonhuman primate model (the Food and Drug Administration placed a hold on a human safety study of TkM-Ebola owing to “cytokine release” but partially relaxed it to allow use in EV-infected patients); AVI-7537, which targets EV protein VP24 through an RNA interference technology, confers a survival benefit in nonhuman primates, and was tested as part of an earlier product in an unpublished safety trial (listed in ClinicalTrials.gov); and BCX-4430, an adenosine analogue that is active against EV in rodents and protected nonhuman primates from Marburg virus — but for which there are no recorded human safety trials. Several other therapeutics are in earlier phases of development, and some drugs approved for other indications, which have known safety profiles at clinically used doses, including chloroquine and imatinib, have shown activity against EV in vitro and, in some cases, in rodent models.
The current situation, though crystalizing relatively common issues of balancing access to investigational agents with the need for answers about what works, is nonetheless highly unusual: an acute outbreak of a frightening, often lethal disease, a high risk to health workers and their families, no known effective treatments, and a tantalizing suggestion of benefit from a drug not previously given to humans but in extremely limited supply. Furthermore, at this time, meaningful clinical evaluation of such new treatments is likely to be possible only in the countries where the outbreak is occurring, where the challenge is complicated not only by pressing demands of the crisis on health care and lack of clinical trial infrastructure but also by history and mistrust. In the heat of this moment, we need to think both carefully and humanistically.
A group of ethicists urgently convened by the World Health Organization to consider issues of access to experimental treatments stated both that it is “ethical to offer unproven interventions with an as yet unknown efficacy and adverse effects” and that “there is a moral duty to evaluate these interventions in the best possible clinical trials” (www.who.int/mediacentre/news/statements/2014/ebola-ethical-review-summary/en). The group has not yet discussed criteria and approaches for determining when and how to study such products or how to determine which ones are suitable for use. These questions are important because the consequences of unforeseen harm, both to patients and public trust, from premature or ill-advised widespread use of an experimental therapy that proves unsafe could be substantial and jeopardize both the outbreak response and efforts to develop treatments.
Clinical drug development is usually only begun once preclinical laboratory and animal testing have minimized concerns about toxicity and provided evidence supporting potential benefit. Some such core preclinical data should, even in an emergency, be required before new EV drugs are tested in humans, since without reasonable assurance regarding toxicity and potential benefit, there will almost always be too little information to presume equipoise. Next, before a drug is tested in sick people, unless it is expected to be potentially toxic as part of its action (e.g., some cancer drugs), it is almost always tested in small safety and pharmacokinetic studies in healthy volunteers, permitting determination of appropriate dosing and detection of common serious adverse effects. If an experimental product is used first in acutely ill, unstable patients, it may be impossible to recognize even severe adverse effects such as organ failure and death if such events are commonly part of the disease itself.
One approach to studying safety while making particularly promising drugs available early for patients with this devastating illness would be to allow limited emergency use in parallel with safety studies in healthy volunteers, provided that available data suggest potential benefit and low risk, that full informed consent can be obtained, and that patients can be carefully monitored and supported. Similarly, the experience in the first two people treated with ZMapp at least ruled out a universally severe adverse response. Thus, the regulatory flexibility shown in the United States, Spain, and Liberia in allowing its emergency use is not unreasonable.
Can and should controlled clinical trials be performed for EV therapeutics? It is worth remembering that the majority of new drugs entering into clinical trials fail, most often because they lack efficacy or, less often, because of safety problems. Furthermore, using unproven therapies during emergencies, without adequately evaluating their effectiveness, may result in misleading, even harmful, conclusions. Before the 2001 anthrax attacks, for example, inhalational anthrax was considered to be 80 to 90% fatal even with antibiotic treatment. Yet with early diagnosis and state-of-the-art supportive care, mortality in 2001 was only 45%. If we had administered a harmless but ineffective investigational product to patients and compared the results with historical ones, we could have concluded that it saved many lives. And even if it had been highly toxic, killing 20% of recipients, we would have observed 65% survival and might have erroneously concluded that it had reduced mortality by 20%.
Thus, the current state of clinical evidence for EV investigational products makes meaningful clinical trials both ethical and essential. Furthermore, given the insufficiency of supply, a randomized trial could provide an equitable way of allotting drugs while finding out whether they work. Any studies should be designed to include interim analyses and stopping rules for clear benefit or toxicity. Practical questions must also be considered: study designs and data requirements should be streamlined to focus on the most critical information and outcomes, and performed in the most capable facilities. When sufficient doses of an unproven but promising therapy become available, it may be reasonable to consider administering it both within clinical trials and for “compassionate use,” particularly in places where trials cannot be conducted, provided that all patients can be adequately monitored. Full transparency, including culturally appropriate communication of what is known and not known about a drug's risks and benefits, and voluntary consent, under the appropriate country's leadership and authority, are critical for any investigational use.
As we move forward, quickly but cautiously, in using and testing new therapies, we have already learned some lessons from this outbreak — regarding the need to build trust, the need to enhance public understanding of experimental treatments and their safe evaluation, and the critical nature of the capacity both for public health intervention and to ethically field clinical studies under challenging conditions. When it comes to infectious diseases, we are increasingly one world and dependent on each other for knowledge, safety, and security.
The full text and graphics for this article can be found at: http://www.nejm.org
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Questions (CME available Allina Virtual Journal Club Participants)
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Questions (CME available Allina Virtual Journal Club Participants)
1. A Public Health Emergency of International Concern (PHEIC)
is a:
a. a. Sterile “Hand-Shake” agreement made by 2 or 3
countries on containment of major international health threats.
b. b. Legally binding agreement made by drug companies
to supply medications free of charge.
c. c. Legally binding agreement made by 196 countries
on containment of major international health threats.
d. d. Verbal agreement made by Emergency Physicians to
“Foam In and Foam Out” with every patient visit.
2. True or False: The mode of transmission is well known: the
chance of infection is high if there is direct contact with blood, secretions,
organs, or other body fluids. (The
infection is NOT transmitted through airborne exposure.)
3. The following are interventions that can prevent the spread
of ebola infection:
a. a. Negative air flow rooms
b. b. Special respirators for healthcare workers
exposed to the virus
c. c. Meticulous attention to gown, glove, mask, and
eye protection
d. d. Great care while removing protective equiptment
e. e. Use of sop and water or alcohol based hand
sanitizers
f. f. Use of dilute bleach for decontamination of
equiptment
g. g. All of the above
h. h. c, d, e, f
4. Earlier in 2014 the United States joined partner
governments, the World Health Organization, and other multilateral organizations
and nongovernmental actors to launch the Global Health Security Agenda which is
composed of 3 core ideals:
a. a. Pretention, Detonation, and Reprimand
b. b. Prevention, Detection, and Response
c. c. Protection, Detention, and Referral
d. d. Provocation, Dependence, and Resistance
5. True or False: A group of ethicists urgently convened by the
World Health Organization to consider issues of access to experimental
treatment stated both that it is “ethical to offer unproven interventions with
an as yet unknown efficacy and adverse effects” and that “there is a moral duty
to evaluate these interventions in the best possible clinical trials.”
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