About the Discussion

@NEJM Ask the Authors: EBOLA--Clinical Care of Ebola Virus Disease in the United States and Germany

EDITORIAL

Out of Africa — Caring for Patients with Ebola

Although the Ebola virus was recognized in 1976, until now Ebola virus disease (EVD) had been confined to remote areas in Africa, occurring in discrete outbreaks. Even with the thousands of cases in the current outbreak, most cases occur in areas where tragically few resources are available to care for affected patients — in Guinea, Liberia, and Sierra Leone. However, a small number of patients have been transferred to hospitals with modern technology. In addition, in-country transmission has led to new cases of Ebola in Nigeria, Spain, and the United States. This is a troubling development, but it affords us the opportunity to observe the course of illness in a modern health care setting. The Journal has now published detailed clinical information about three patients transferred from West Africa to the United States or Germany in the midst of their illness.

Two patients, a physician and a missionary, were transferred from Liberia to the United States. Both presented with intravascular volume depletion, which in one patient was a consequence of continuing diarrhea. Although both patients required careful fluid resuscitation, neither needed many of the features of intensive care. In contrast, the third patient, who was transferred from Sierra Leone to Germany, was profoundly ill. He also had profuse diarrhea, requiring approximately 30 liters of intravenous fluid in the initial 72 hours. In addition, 3 days after the patient arrived in Germany, recurrent fever and hypotension developed, and he was found to have bacterial sepsis, probably owing to a loss of mucosal integrity. The course in this patient was complicated further by respiratory failure, encephalopathy, and altered mental status. Gratifyingly, all these complications resolved, and he was able to leave the hospital a month later. How much can we learn from these few reports? In large part, we are relearning from past experience. Like many survivors, these patients had marked improvement by 2 weeks after presentation. In the case of the patient treated in Germany, subsequent problems were probably the consequences of the tissue damage done by the virus rather than being due primarily to ongoing lytic viral infection. Ebola virus can infect a large variety of cells in vitro with a variety of specific adverse effects.

First, early diagnosis remains challenging. All these patients were treated initially for malaria — two empirically and one after a positive blood smear. One patient did not have detectable Ebola virus RNA until day 4 of his illness; the other two were not tested until day 5 or 6. There have been frequent reports of negative tests early in the disease, probably reflecting the low viral load at that point. This information suggests that patients are unlikely to transmit infection at symptom onset, but it also means that the diagnosis of EVD should continue to be entertained in those at risk who initially have negative results.

Clearly, the course of the disease is remarkably varied, which has important implications for the testing and assessment of new interventions. The uneven disease course will make it extraordinarily difficult to interpret the results of case reports, case series, and uncontrolled studies of new therapies. The two American patients who survived received an experimental cocktail of anti-Ebola antibodies during the course of their illnesses. Nevertheless, in the patient treated in Germany, who received no specific antiviral therapy, the viremia actually cleared earlier than it did in both the patients in the United States, which is consistent with prior data on viral clearance by an emerging immune response. Unless a new treatment is profoundly efficacious, it will be very difficult to assess its contribution without careful comparative studies.

Keeping health care workers and the broader community safe remains a daunting challenge, even in facilities, like those in Hamburg and Atlanta, dedicated to the care of patients with highly communicable diseases. The patient treated in Germany had an overwhelming bacterial infection, but because of biosafety restrictions, no facilities were available to identify the pathogen. Although not central to the treatment of this patient, it is easy to imagine that many tests that are a critical piece of the care of severely ill patients, including routine laboratory and microbiology testing and computed tomography, would not be available. In fact, to care safely for these patients, health care providers generally are allowed to spend only very limited amounts of time in patient care areas. Thus, patients cannot necessarily get the full benefits of care. But it is important to note that these experiences show that patients with EVD can be cared for safely in properly prepared centers.

The limited and varied data available to clinicians can also complicate public health decision making. In treatment centers in West Africa, patients who recover from EVD are generally sent home after blood testing for viral RNA is negative. Although Ebola virus RNA was not detected by sensitive RNA testing in the plasma at the time of recovery in the patient treated in Germany, urine and sweat testing remained positive for weeks. Similar observations have been made in semen from patients who have recovered from EVD, in which viral RNA can be detected for up to 3 months after clinical recovery. What the detection of RNA in some sites means in the context of clinical recovery is unclear. In previous outbreaks of Ebola, illness has not developed in the household contacts of discharged patients, despite the persistence of viral RNA. On the basis of this information, the treating clinicians in Germany elected to discharge the patient from the hospital 40 days after the start of his illness. This decision was quite reasonable; however, it will be important to continue to conduct epidemiologic studies to define and document the risk of transmission.

The most important take-home message from these case reports is the importance of intensive fluid management and care. The case fatality rate in the current outbreak is approximately 70%. It is unlikely that the patient treated in Germany would have survived without modern, state-of-the-art care. But approximately 30% of patients are surviving with only the modest support that is available in treatment centers in West Africa. Another filovirus infection, Marburg hemorrhagic fever, was associated with a mortality rate of approximately 25% in Germany but approximately 80% in sub-Saharan Africa, further suggesting that optimal supportive care plays a crucial role in the overall outcome of these infections. Although this news is encouraging for patients with access to an intensive care unit, it is only more discouraging for those in areas where such infections are endemic and even basic care is often unavailable. It will be a tremendous challenge to bring to all patients the benefits of routine care, such as intravenous fluid and electrolyte support, as part of the response to this epidemic, but it must be done.