Ebola may have faded from the spotlight it enjoyed in the mid-1990s, but it’s still around, and as deadly and mysterious as ever.

Structure of an Ebola viral particle revealed via transmission electron micrograph. Photo credit: CDC/ Frederick Murphy.

It began in Kikyo, a remote village in western Uganda’s Bundibugyo district, during the twilight days of August. People grew ill with headache, fever, bloody diarrhea, and vomiting. Then they died. In mid-November, a young Ugandan doctor named Jonah Kule rode his motorcycle to the village to investigate. Witnesses say he suspected cholera, possibly typhoid. He sent blood samples from patients to international laboratories for testing. On November 29th, the same day that the U.S. Centers for Disease Control (CDC) identified the virus as Ebola, Kule developed a headache and checked into Mulago Hospital. Five days later, he died. That outbreak lasted nearly three more months, officially ending February 20, 2008.

Ebola may have faded from the spotlight of public attention it enjoyed during the mid- 90s, but that doesn’t mean it went away. Quite the opposite: the number of recorded major outbreaks has more than doubled since 2000. Researchers continue to investigate the virus, but licensed therapies and vaccines still escape them. Meanwhile, patient care during outbreaks remains limited, hampered by a lack of detailed clinical information, inadequate resources, and fear.

A complex and lethal virus, Ebola kills up to 90 percent of its victims. Five known strains exist, each named for their place of origin: Zaire, Sudan, Reston, Cote d’Ivoire and—as of 2007—Bundibuygo. Contrary to popular belief, fewer than 50% of Ebola patients experience massive bleeding, says Dr. Thomas Geisbert, Director of the Boston University National Emerging Infectious Diseases Laboratories. The disease actually closely mimics a condition called septic shock: the virus causes excessive clotting, blocking normal blood circulation and exhausting coagulating factors. The blood, with nowhere else to go, damages the internal walls of the blood vessels as it pushes against them from the inside. Major organs, starved of critical oxygen and nutrients, begin to fail.

Two nurses stand by an Ebola victim under their care during the first 1976 outbreak in Kinshasa, Zaire. Photo credit: CDC/Dr. Lyle Conrad, courtesy of wikicommons.

When Ebola first emerged in the summer of 1976, it took the world by surprise. No one knew where it had come from, what it was, or how to treat it. The World Health Organization (WHO) and an international commission descended on outbreak sites in the Sudan and Zaire (now the Democratic Republic of the Congo). Medical personnel quarantined patients and stopped the use of unsterilized needles while investigative teams set out to discover the source of the virus. They never found their answer, but within three months, the outbreaks ended as suddenly as they began. Over the next 20 years, the world watched with horrified fascination as another five major outbreaks erupted in sub-Saharan Africa, infecting 1105 individuals, of whom 802 would die.

Ebola’s macabre effects and unknown origins lent the disease a dark glamour that captured the public’s imagination. In 1994, Richard Preston published his sensationalized account of Ebola’s history, The Hot Zone, which shot to the top of the bestsellers list; a year later, the movie Outbreak fueled the public’s growing fascination with virulent disease. When a major outbreak erupted in Kikwit, Democratic Republic of Congo (formerly Zaire) that same year, Ebola had become if not quite a household word, then certainly a familiar one. Heavy media coverage allowed the public to watch— captivated—as WHO, Doctors without Borders and other organizations again leapt into the fray. But as the virus burned out six months later, the urgency passed and public interest waned. Ebola faded once again into the inscrutable African jungle.

But Ebola has come back. The past nine years have seen more major outbreaks than the twenty years following the virus’ debut. In 2000, the largest outbreak to date occurred in Uganda, killing more than half of the 425 patients over four months. The following October, Ebola appeared simultaneously in Gabon and the Republic of the Congo, lingering in both nations for about seven months. Two more outbreaks occurred in quick succession in the Republic of Congo, and another flared briefly in the Sudan, dying out in the summer of 2004. Then the virus withdrew for three years, before resurfacing in 2007 in Uganda and the Democratic Republic of the Congo. The most recent outbreak, again in the Democratic Republic of the Congo, was declared Christmas day 2008, ending only a few months ago this year in February. Researchers aren’t certain why so many outbreaks have occurred recently. Part of it may be that more healthcare workers are aware of Ebola and more likely to test for it. “I would guess that if you’d looked for Ebola in the Congo in that part of Africa 40 or 50 years ago, you’d have found it,” Geisbert says.

Red Cross members disinfect the body of an Ebola patient during the 1995 Kikwit outbreak. Photo credit: CDC/Ethleen Lloyd.

But some of the rise is likely genuine. Increased logging brings workers deeper into the rainforests and closer to the bats believed to harbor the virus. And should people return to their villages infected, few if any hospitals are equipped to readily counter the virulent fever. War and economic turmoil have decimated what healthcare infrastructure existed in the areas most frequently afflicted with the disease. “It’s hard to understand how they could deal with Ebola in a setting like that,” says Bill Johnston, president of the Jane Goodall Institute, which conducts health and education programs in the Sub-Sahara.

Meanwhile, the hunt for an Ebola vaccine continues. New approaches target specific proteins on the outer surface of the Ebola virus, called glycoproteins, which help the virus attach to and invade cells. The trick is getting the glycoprotein safely into someone’s body and stimulating their immune response enough to build resistance to Ebola. The National Institutes of Health (NIH), CDC, and other research teams shuttle the protein into the body by piggybacking it onto less deadly viruses, like the common cold. The cold virus enters the body and starts replicating, so the person’s immune system mounts an assault not only on the cold, but also on the accompanying Ebola protein. This model looked promising and even passed human safety trials—but 40-60 percent of the world’s population has already had a cold, so their immune systems would remember and destroy that virus before ever addressing the Ebola glycoproteins tagging along. Less common viruses are more effective because they don’t have that problem—but they carry potentially greater risks to immunocompromised patients. (In otherwise healthy people though, these vaccines appear to be safe: earlier this year, after a contaminated needle-stick injury, a Hamburg researcher safely tolerated a glycoprotein vaccine based on the vesicular stomatitis virus, part of the rabies family of viruses). Other avenues target critical genes in the Ebola replication system like VP-30, but that work is still in its infancy. Licensed, FDA-approved Ebola vaccines remain at least several years away, but “this isn’t a function of how brilliant the scientists are that work on it,” warns Dr. Gigi Kwik Gronvall, a Senior Associate at the Center for Biosecurity at the University of Pittsburgh Medical Center. “It’s a function of how difficult the virus is.”

New drug therapies for infected patients are also under development. Unfortunately, like vaccines, these are highly experimental. These newer therapies focus on stopping the excessive coagulation that Ebola causes. If the clots don’t form, then the body’s organs can get the nutrients they need to function, and stopped-up blood won’t leak out of increasingly damaged blood vessels. But even the most successful approaches save only about 30 percent of test monkeys. “There’s never going to be a magic bullet,” Geisbert says.

A doctor cares for an Ebola patient in a Yambuku, Zaire hospital theatre-cum-ICU in the first 1976 outbreak. Photo credit: CDC/Dr. Lyle Conrad.

In contrast to the progress made in laboratories, overall patient survival has remained relatively unchanged. The typical outbreak setting—rural Sub-Sahara—is rudimentary at best. Running water and electricity and even basic medical equipment are rare luxuries. Healthcare workers risk themselves with every patient they treat; a lethal dose of Ebola is as low as one virus particle—a needlestick injury contains many times that amount, says Dr. James Strong, hemorrhagic fever researcher with the Public Health Agency of Canada. Cultural differences add another dimension: indigenous populations fear foreign aid workers, who arrive in protective suits to whisk the ill away to isolation wards. Panicked, many flee—spreading the disease.

Yet inadequate clinical information poses the greatest obstacle to improved care. “It’s like with SARS. Even though any one hospital only saw a few patients, when you put it all together, you can say: here’s what the potassium levels are in SARS, here’s the kidney function.” says Dr. Daniel Bausch, a professor of tropical diseases at Tulane University. But, he adds, you don’t get that if it’s not systematically collected—as is the case with Ebola.

That may change. In the fall of 2006, an international group of experts in hemorrhagic fevers and healthcare met at the Public Health Agency of Canada in Winnipeg to discuss the need for improved care and research during outbreaks. In November of 2008, WHO convened an informal gathering of many of the same experts, including Bausch, to explore the possibility of establishing a clinical outbreak network. The consensus reached emphasized education and information—creating, for example, a standardized data collection strategy that could be implemented across a broad region. When an outbreak ends, researchers can take stock: what was done and what worked. Then experts could devise improved treatment strategies and decrease case-fatality ratios, earning the trust of their patients.

Although WHO’s meeting was purely a preliminary gathering of ideas and opinions, it’s a start. Ebola shows no signs of disappearing anytime soon, and although vaccines and therapeutics will ease the burden, they won’t be available for several years; the practicalities of patient care and research remain a priority. “If you think about it, you’re challenged not only to take care of the patient, but also to learn as much as you can about the disease in the same setting,” Bausch says. “The clinical and the clinical research part of it go hand in hand.”