Ebola: Back in the DRC

August, 1976. A new infection was causing panic in Zaire. Hospitals became death zones, as both patients and medical staff succumbed to the disease. Reports of nightmarish symptoms trickled in to scientists in Europe and the US, who sent investigators to determine the cause and stem the epidemic. Concurrently, they would find out, the same thing was happening hundreds of miles to the north in Sudan. In all, 284 would be infected in that country, and another 358 in Zaire–over 600 cases (and almost 500 deaths) due to a mysterious new disease in just a few months’ time.

The new agent was Ebola, but remarkably, the outbreaks were unrelated, at least as far as any direct epidemiological links go. No one had brought the virus from Sudan to Zaire, or vice-versa. Molecular analysis showed that the viruses causing the outbreaks were two distinct subtypes, subsequently named for their countries of origin, Ebola Zaire and Ebola Sudan.

While Uganda is currently battling another outbreak of Ebola Sudan, rumors in the past week have suggested that this virus may have spread to former Zaire (now the Democratic Republic of Congo), where Ebola has reappeared 4 additional times since the first discovery there in 1976. It’s now been confirmed that Ebola is again present in the DRC, with an (unconfirmed) 6 deaths. However, it’s not related to the Uganda outbreak. Reminiscent of 1976, the strain that’s circulating currently in the DRC is the Bundibugyo subtype, which was first identified in Uganda in a 2007-8 outbreak in that country, rather than the Sudan type causing the current Ugandan epidemic. Interestingly, every previous outbreak of Ebola in the DRC has been caused by the Zaire type of Ebola, so the appearance of Bundibugyo is a first–though not altogether surprising given that the outbreak province borders Uganda.

Is this just coincidence that Ebola has twice now broken out in two different places at the same time, but with different viral subtypes? Hard to say. Though we can now say it’s fairly likely that bats are a reservoir host for Ebola and other filoviruses, we can’t say for sure that bats are the *only* reservoir. Indeed, we know that some outbreaks have occurred because the index case was in contact with an infected ape or their meat–were these animals originally infected by a bat, or by another source? How does the ecology of an area affect the chances of an outbreak occurring? Were there reasons that humans might be increasingly exposed to the virus in these different areas–Zaire and Sudan in 1976, DRC and Uganda in 2012–at the same time? Weather conditions? Trade/industry? Host migration or dispersal? We know with another bat-borne virus, Nipah, that changes in farming practices led to increased proximity of fruit bats and farmed pigs–allowing pigs to come into contact with virus-laden bat guano, become infected with Nipah, and subsequently transmit the virus to farmers. Things that may seem completely inconsequential–like the placement of fruit trees–can actually be risk factors for viral emergence. Is there a common factor here, or just bad luck? Only additional hard-won knowledge of filovirus ecology will be able to tell.

Ebola resurfaces in Uganda–history and analyses of Ugandan Ebola

Uganda just can’t catch a break. They’ve recently been hit with nodding disease, a mysterious syndrome where children repeatedly nod their heads and undergo serious seizures, typically leading to death. Now they’re in the grips of another Ebola outbreak. This will be the fourth time the country has suffered through Ebola since 2000, when the virus was first found in the country:

The first occurred in August of 2000; the first case died in Gulu on the 17th of September. Despite an investigation, doctors were unable to determine where or how she had contracted the disease. Her death was followed by the deaths of her husband, two children, and several other family members. This was reported to the Ministry of Health in October of that year, near the peak of the epidemic. An investigation and intervention to control the disease followed, and the epidemic was declared to be over in January of 2001. A total of 425 patients from 3 villages (Gulu, Masindi, and Mbarara) across Uganda were identified based on symptoms and/or laboratory data. 224 of them died, with a resulting mortality rate of 53%; an eerie echo of the 1976 Ebola outbreak in Sudan. Indeed, sequence analysis showed the infecting strain to be the Sudan subtype of Ebola; the first time this type had surfaced since the 1979 outbreak in Sudan. It is hypothesized that Sudanese rebels, who carried out regular attacks around Gulu, may have accidentally introduced the virus in some manner, though this has not been confirmed.

Ebola returned to Uganda in August of 2007, causing 149 illnesses and 37 deaths until the outbreak was declared over in February of 2008. This mortality (36%) was significantly lower than most Ebola outbreaks. Interestingly, when scientists tested this virus, it also reacted strangely with their assays. Therefore, they determined the entire molecular sequence of the virus, and found that it was a whole new strain of Ebola, which they named Ebola Bundibugyo.

The third outbreak occurred just last year, as a single case in a 12-year-old girl, who died of the infection. I’ve not been able to find any follow-up identifying the 2011 strain, but Uganda has been hit previously by both the Sudan and the novel Bundibugyo strains of Ebola, and the current outbreak has been identified once again as Ebola Sudan.

In the current outbreak, which began in the Kibaale district in western-central Uganda, at least 20 have been affected and 14 have died. As of today, an additional six cases are suspected but not yet confirmed, and it appears to be affecting more than one village in the district. One death has also occurred at Mulago hospital in the capital of Kampala. The individual who died was reported to be:

… a health worker who “had attended to the dead at Kagadi hospital” in Kibale, Health Minister Christine Ondoa told reporters.

She is believed to have travelled independently to Kampala — possibly on public transport — after her three-month old baby died, Ondoa added.

Reports also note that other health care workers are in quarantine as a precaution. In Africa, Ebola has really been able to spread in previous outbreaks for two reasons: breakdowns in barrier nursing within hospitals (not wearing gloves/gowns; reusing needles; lack of handwashing/sanitation, etc.) and ritual funeral practices within villages, which put many family members in contact with the virus as they assist with cleansing the victim. Indeed, it appears that 9 of the deaths in this outbreak have come from a single family, so it’s quite possible many were sickened using this type of practice. However, now that Ebola has been confirmed and people are aware of this, stricter controls over these practices can be implemented, and health care workers are being urged to report any cases that may be Ebola to authorities.

Kampala is a city of a bit over a million people on Lake Victoria, southeast of the Kibaale district. The 2011 case originated from Luwero district, due east of the Kibaale district and north of Kampala. The 2000 outbreak occurred in the Gulu district in the north of the country, and the 2007 outbreak in the Bundibugyo district, in the west and neighboring Kibaale. It would seem that Ebola reservoirs (likely fruit bats) could very well be spread across Uganda’s central region, occasionally spilling over into the human populations and igniting these outbreaks. One story notes that “The site where most of the cases occurred are close to Kibale forest where there are a lot of monkeys and birdlife,” and while bats are not explicitly mentioned, they presumably would also be present. Non-human primates have also been implicated in previous outbreaks of Ebola as an amplifying species.

The reporting of the current outbreak was delayed, as patients didn’t have any noticeable bleeding–rather, diarrhea and vomiting were the main reported symptoms. However, while many reports I’ve seen are characterizing hemorrhagic symptoms as “typical,” these aren’t seen in all patients, and indeed the diarrhea, vomiting, and even hiccups are common symptoms of Ebola infection. As such, Uganda has been playing a bit of catch-up, but has certainly learned since the first (and worst) outbreak in 2000. Hopefully this one will end fairly quickly.

The emergence of “nodding disease”

The emergence of “new” diseases is a complicated issue. “New” diseases often just means “new to biomedical science.” Viruses like Ebola and HIV were certainly circulating in Africa in animal reservoirs for decades, and probably millenia, before they came to the attention of physicians via human infections. Hantavirus in the American southwest has likely infected many people, causing pneumonia of unknown origin, before the Four Corners outbreak led to the eventual identification of the Sin Nombre virus. Encroachment of humans into new areas can bring them into contact with novel infectious agents acquired via their food or water, or by exposure to new disease vectors such as mosquitoes or ticks. Occasionally, emerging diseases may be truly “new”–such as recombinant influenza viruses that resulted from a mixture of viruses from different host species to form a unique variant, different from either parent virus.

Nodding disease is one of those that has only recently appeared on the radar of those of us in public health, although it is not truly a “new” disease. It was first described 40 years ago, but this syndrome has been sufficiently rare as to not merit significant medical attention until 2010. Outbreaks of nodding disease have now occurred in South Sudan, Tanzania, and Uganda, affecting thousands of children. The disease first presents as cognitive difficulties; then the nodding starts, especially when children are provided food. They experience further cognitive decline, and ultimately regress to an almost infantile stage, where parents cannot leave them unattended for fear they may wander off or injure themselves by accident. Death appears to often be a result of such accidents: (drowning, falling into a cookfire) or starvation, as the seizures in the late stages of the disease seem to make it virtually impossible for the child to eat. No one is known to have recovered from the disease.

While the cause(s) still remain mysterious, studies have been done trying to determine risk factors for disease development. A recent CDC-assisted study, for example, was carried out in the new country of South Sudan. This examined 38 matched cases and controls and examined dietary as well as infectious disease factors, looking at issues such as vitamin deficiencies, a history of hunger, and current infection with the parasite Onchocerca volvulus.

This particular agent is interesting, as the nematode already causes a well-known disease, river blindness. Like many parasites, the life cycle of O. volvulus is fascinating and complicated. Humans are the main host, who are initially infected via the bite of the black fly, which was herself infected with O. volvulus from a previous human meal. After inoculation, the nematode larvae migrate to the subcutaneous tissue of their human host, where they multiply and mature over the course of 6-12 months, eventually mating and producing microfilariae–little baby worms, up to 3000 per day per female nematode. It’s this life stage that are then ingested by black flies during a daytime meal, when the microfilariae migrate to the host’s skin. Within the fly, they will mature through three larval stages, ready to infect another human host.

How then do these worms cause blindness, if they live mainly in the subcutaneous tissues and, sporadically, the skin? The microfilariae also migrate to the surface of the cornea, and when these organisms die, they cause an intense immune response. Interestingly, this response seems to be due not to the worms themselves, but to their Wolbachia symbionts–bacteria species notorious for infecting parasites (and insects) and causing all sorts of weird things to happen. Repeated episodes of this inflammation can lead to keratitis, and the cornea eventually becomes opaque. O. volvulus can also cause intense skin itching, leaving dead and discolored patches of skin in addition to the characteristic blindness. In all, it’s a nasty disease but one that is relatively simple to treat if caught early, either with antiparasitic drugs or even with antibiotics such as tetracycline to kill the Wolbachia. The disease can also be prevented by fly mitigation and preventative doses of anti-parasitic medicines.

Testing for O. volvulus is relatively simple. The MMWR study used a “skin snip”–just as it sounds, taking a small piece of skin from the patient and examining it for microfilariae. However, this has the limitation that it may miss early infections (where microfilariae have not yet developed and spread) or mild infections (where there are fewer organisms per square millimeter of skin sample). They note that they also took blood samples to examine antibody responses, but those data were not yet available.

What they found was interesting. In one village, Maridi, they found a matched odds ratio of 9.3 (with the cases being more likely to be currently infected with O. volvulus than the controls), which agrees with an earlier study done in Tanzania which found high levels of infections in cases. However, no healthy controls were tested for comparison in that publication. Furthermore, in the South Sudan study, no statistically significant difference in parasite infection was found between cases and controls in the second village, Witto. Why the dramatic difference between the two locations in the same country? Don’t know. It could simply be related to small sizes (only 25 pairs were examined in Maridi, a “semi-urban” area, and 13 in Witto, described as rural). We also don’t know anything about temporality–were the patients affected before they developed nodding disease, or subsequent to the start of symptoms? Even though many questions remain, the Ugandan government is taking steps that look as if they believe a cause of nodding disease has been found, and that O. volvulus is that cause. While additional measures to stop the spread of the parasite are probably a good idea in any case (reducing river blindness is also good), I certainly wouldn’t call this case closed, and neither did the individuals speaking on this issue recently at ICEID, where this outbreak was discussed in at least two sessions I attended.

There is biologic plausibility for O. volvulus to cause a seizure disorder. Several other types of parasites can cause epileptic conditions, including the tapeworm Taenia solium, which can originate in beef or pork products. Could it be that O. volvulus is getting into the brain and causing pathology, leading to seizures? The 2008 Tanzanian study suggests no, as the cerebral spinal fluid was tested in 42 patients and found to be negative for O. volvulus DNA in all patients.

With some emerging diseases, there is the risk that the incidence of a disease is increasing due only to awareness of an illness–the more doctors that recognize it, the more cases they will diagnose. However, there is anecdotal evidence that this isn’t the case with nodding disease:

Dr. Abubakar said in an interview that while the syndrome is known to have existed for some time in South Sudan, the recent spike in reported cases could only partially be explained by wider awareness and better surveillance. “It’s not only local authorities but local NGOs saying more children have been affected,” he said. Particularly striking, he said, is that in South Sudan “there are a number of displaced people from another location who did not have nodding. But after the displacement, when they moved to affected areas, after 2 years the children started developing the syndrome.”

Additional studies and more thorough surveillance are needed to confirm that this is true, which would suggest a localized focus of disease in multiple different areas (which does seem to be the case at this point in time).

The migration aspect is intriguing, suggesting some sort of environmental exposure–if it was simple genetics, where the children were living shouldn’t matter. However, this puts us back almost as square one, examining what is present in the local environment–both infectious and non-infectious agents including heavy metals and various toxins.

The work investigating nodding disease is still in its infancy, but already “nodding disease” has affected more individuals than all of the recorded cases of Ebola. Now that there is recognition of the disease, and some international support for research into its causes, hopefully better treatment and prevention efforts will follow.

Works cited

WInkler et al, 2008. The head nodding syndrome–clinical classification and possible causes. Epilepsia. 49(12):2008-15. Link.

CDC. 2012. Nodding Syndrome — South Sudan, 2011. MMWR. 61(03);52-54. Link.

Ebola in Uganda: current and past outbreaks

Via H5N1 and other sources, there’s at least one new Ebola case in Uganda:

The rare and deadly Ebola virus has killed a 12-year-old Ugandan girl and health officials said on Saturday they expected more cases.

The girl from Luwero district, 75 km (45 miles) north of the capital Kampala, died on May 6, said Anthony Mbonye, the government’s commissioner for community health, in the first outbreak of the virus in Uganda in four years.

“Laboratory investigations have confirmed Ebola to be the primary cause of the illness and death. So there is one case reported but we expect other cases,” he said.

Though we’ve known about Ebola in Africa since 1976, Ebola wasn’t recognized in Uganda until a bit over 10 years ago. Now, this is the third outbreak in this amount of time. The first occurred in August of 2000; the first case died in Gulu on the 17th of September. Despite an investigation, doctors were unable to determine where or how she had contracted the disease. Her death was followed by the deaths of her husband, two children, and several other family members. This was reported to the Ministry of Health in October of that year, near the peak of the epidemic. An investigation and intervention to control the disease followed, and the epidemic was declared to be over in January of 2001. A total of 425 patients from 3 villages (Gulu, Masindi, and Mbarara) across Uganda were identified based on symptoms and/or laboratory data. 224 of them died, with a resulting mortality rate of 53%; an eerie echo of the 1976 Ebola outbreak in Sudan. Indeed, sequence analysis showed the infecting strain to be the Sudan subtype of Ebola; the first time this type had surfaced since the 1979 outbreak in Sudan. It is hypothesized that Sudanese rebels, who carried out regular attacks around Gulu, may have accidentally introduced the virus in some manner, though this has not been confirmed.

Ebola returned to Uganda in August of 2007, causing 149 illnesses and 37 deaths until the outbreak was declared over in February of 2008. This mortality (36%) was significantly lower than most Ebola outbreaks. Interestingly, when scientists tested this virus, it also reacted strangely with their assays. Therefore, they determined the entire molecular sequence of the virus, and found that it was a whole new strain of Ebola, which they named Ebola Bundibugyo.

I couldn’t find any other details about the current outbreak–how she was infected, if she’s actually the index case or if there were previous deaths that have not yet been confirmed. (The girl died at the hospital–previous deaths may have gone unrecognized if they had died at home). I’m sure more details will be coming in the next days and weeks. What we’re left with now is the knowledge that in 11 years’ time, Uganda is now on its third Ebola outbreak. These have occurred in 3 different areas of the country (Gulu is toward the north, Kampala region in the south near Lake Victoria, and Bundibugyo in the southwest, almost due west of Kampala) and with 2 different strains (thus far). This again feeds my morbid fascination with the virus–what does this mean about Ebola reservoirs in Uganda? Are these cases bat-acquired? Other wildlife? Spillover from other countries, as suggested with the 2000-1 outbreak? As always, Ebola outbreaks tend to raise more questions than they answer.

[UPDATE: via Crawford Killian, CDC says current outbreak is due to Sudan strain.]