WHO: Stall in Ebola decline highlights need for stronger response

Further progress against Ebola in Guinea and Sierra Leone is proving stubborn, with a drop in cases holding steady over the past 3 weeks, and response indicators showing a mixed picture for both countries last week, the World Health Organization (WHO) said today in its weekly report on the outbreak's trajectory.

In scientific developments, an animal study on the experimental drug TKM-Ebola showed promising findings, and researchers who followed Ebola survivors from a Uganda outbreak several years ago outlined several lingering problems that patients had.

33 new cases last week

The outbreak region reported 33 new lab-confirmed Ebola infections last week, a few less than the 37 cases reported the week before, the WHO said. With Liberia again reporting no new cases, all of the new ones were from Guinea and Sierra Leone. Guinea had 21, down from 28 the week before, and Sierra Leone had 12, up from 9 in the previous week.

Guinea's hot spot is Forecariah district, which borders Sierra Leone. Half of Sierra Leone's cases last week were reported from Western Area Urban district, which includes the capital, Freetown. Other districts reporting cases were Koinadugu, Kambia, and Port Loko.

Response indicators show that Ebola deaths are still occurring in the community in both Guinea and Sierra Leone. Those deaths are a sign that some people who are sick with Ebola aren't getting isolated or treated, posing a transmission risk. Sierra Leone had three such deaths last week, and Guinea had six.

The percentage of cases identified from known contacts, which shows how well transmission chains are being identified and tracked, was also below what responders hoped for both countries. Both Sierra Leone and Guinea levels were below 50% in the week to Apr 12.

The WHO said that community engagement, which has often been a challenge, appears to be improving in Guinea and Sierra Leone, but more efforts are needed to flag all transmission chains. It added that a case-finding and awareness campaign in Guinea's Forecariah district in the middle of April yielded 12 new confirmed cases, and similar campaigns are slated for other districts where infections are still occurring.

Responders in Guinea are still grappling with security issues, and four districts (Boffa, Boke, Conakry, and Kindia) reported resistance incidents last week, with the capital reporting at least one such event each day for the past 6 weeks, according to today's report.

In Liberia, health teams are still testing people for Ebola, but no new cases have been detected. If the country gets to the end of the 42-day incubation period since the last case without any new Ebola infections, it will be considered free of the disease on May 9.

No new health worker infections were reported in the outbreak countries last week, keeping the totals at 864 cases, including 503 deaths.

Overall, the number of confirmed, probable, and suspected cases in the three countries is at 26,044, with the number of deaths at 10,808, the WHO said.

TKM-Ebola shows promise in macaques

In research developments, a trial of the experimental Ebola drug TKM-Ebola in macaques found that it protected the animals after they received a lethal dose of the virus. A team from the University of Texas Medical Branch (UTMB) at Galveston and the drug's maker, Tekmira Pharmaceuticals, published its findings today in a letter to Nature.

TKM-Ebola is a short-strand RNA (siRNA) drug cocktail that was modified to target the new Makona outbreak strain that is responsible for fueling West Africa's outbreak. The drug targets three of seven Ebola virus proteins. UTMB said in a press release that the treatment is the first to be shown effective against the current outbreak strain.

Tests on the drug in patients infected with Ebola are currently under way in Sierra Leone. However, a phase 1 trial was paused in July after some subjects reported flulike symptoms. The US Food and Drug Administration had placed a clinical hold on the drug to probe the multiple-ascending-dose part of the trial, but it recently modified the hold to allow repeat dosing at a lower dose, clearing the way for the trial to resume.

In the animal trial, researchers infected six macaques with a lethal dose of the virus, and started treating three of them 3 days later after they showed advanced clinical signs and had detectable virus in their blood. The monkeys in the treatment group received the drug on days 4 through 9 after they were exposed to the virus.

Those that received TKM-Ebola had milder symptoms and fully recovered, while the controls died on days 8 and 9 after infection, similar to what clinicians have observed in the field when treating Ebola patients.

Treatment also appeared to protect the animals against liver and kidney dysfunction and blood disorders that occur during Ebola infection, which the team said suggests that TKM-Ebola benefits go beyond improving survival and curbing virus levels in the body.

Mark Murray, PhD, president of Tekmira, said in the UTMB press release that the study shows that the company can rapidly and accurately adapt its technology to target genetic sequences that emerge from new Ebola virus outbreaks.

Study profiles lingering symptoms

In the largest, long-term study so far on Ebola survivors, researchers yesterday reported in The Lancet Infectious Diseases that negative health effects can persist more than 2 years after infection.

A research team from the US Military HIV Research Program (MHRP) and their partners from Uganda followed people who were sickened during the 2007-08 Bundibugyo Ebola outbreak in Uganda that killed 39 people.

The observational study included 49 adults who had probable and confirmed Ebola infections and 157 seronegative contacts. Researchers started enrolling volunteers 29 months after the outbreak ended and recorded participants' health status, functional limitations, and demographics. Blood samples were obtained for analysis.

When compared with controls who weren't infected with the virus, survivors were significantly more likely to have vision problems, hearing loss, and neurologic issues such as difficulty with swallowing and sleeping. Survivors also reported more chronic health problems and limitations that were related to memory loss and confusion.

More specifically, survivors were twice as likely to have chronic health problems that lasted more than a year, including pain in the abdomen, back, and large joints, as well as fatigue, impotence, and severe headaches. Memory problems and confusion were six time more common in Ebola survivors.

Researchers said long-term effects in children who survive Ebola infections are likely to differ from that of adults, and more research is needed to gauge the impact of the disease on that group.

Col Nelson Michael, MD, PhD, director of the MHRP, said in a statement from the group, "The ongoing Ebola virus disease outbreak in West Africa has resulted in thousands of fatalities, but also thousands of survivors. The limited evidence from this study and the work of others indicates that strategies to address the long-term health needs of survivors are needed."

Expert: Results likely apply to current outbreak

In a commentary on the report in the same issue of Lancet Infectious Diseases, Daniel Bausch, MD, MPH, an Ebola expert from the Tulane School of Public Health and Tropical Medicine in New Orleans who is working with the WHO, said even though the Uganda study involves a different population and Ebola species, the findings probably apply to survivors of the strain circulating in Guinea, Liberia, and Sierra Leone.

He noted that similar long-term effects have been seen in early anecdotal reports from West Africa and from smaller studies on outbreaks in other African countries.

Bausch said the effects shouldn't be cast off as minor aches and pains, because in one report, survivors couldn't perform their previous jobs up to 1 year after infections, "with obvious economic consequences."

Services for survivors should be established, he said, but doing so will be challenging because of the current focus on acute outbreak control and reestablishing health systems. Ebola survivors might need specialty services, such as eye care and mental health, that aren't easily available in the outbreak countries, he added.

The study findings underscore that more work needs to be done to understand the frequency and severity of after-effects in survivors, especially exploring problems such as acute uveitis as they happen, Bausch said. He added that children need to be included in the studies and that knowledge of lingering symptoms could be gained from a more focused approach to tease out the pathogenic processes that are involved.

Bausch noted that the researchers weren't able to obtain cell-culture specimens to explore the issue of viral persistence in immunologically protected sites, including the gonads and semen in men and eye chambers.

The serologic testing the group did sheds some light on antibody response after Ebola infection, given that 49% of survivors tested negative for antibodies to any filovirus, Bausch said. "Because the original diagnostic samples were not available for retesting, whether this finding represents misdiagnosis at the time of the outbreak or decreasing antibody titer with time is unknown," he added.

Symptoms that persist in survivors more than 2 years after infection is a sad reminder that even for the fortunate who survive Ebola, their ordeal often is still not over, Bausch wrote. "Our collective public health and research response needs to carry on until it is."

See also:

Apr 22 WHO situation update

Apr 22 Nature letter

Apr 22 UTMB press release

Apr 21 Lancet Infect Dis study

Apr 21 Lancet Infect Dis commentary

Apr 22 MHRP press release

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