In the early 1990s, efforts to eradicate river blindness came up against an unexpected problem: a rare parasitic worm that seemed to cause serious neurological adverse events in patients treated with the anti-filarial drug ivermectin. David Holmes reports on how the battle against the worm might finally be turning.
There are neglected tropical diseases, and then there is loiasis: a rare filariasis that is caused by the nematode worm Loa loa. Loiasis has come increasingly to light as a result of the serious adverse neurological events that very rarely arise in patients infected with L loa when they undergo treatment for another neglected tropical disease, onchoceriasis, a filarial disease more commonly known as river blindness. Confused? You wouldn’t be alone, but a small group of researchers have been slowly unravelling the L loa enigma.
As early as 1991, reports were starting to emerge of severe adverse neurological events in a handful of patients treated with ivermectin in areas of Cameroon and the Democratic Republic of Congo (DRC) where loiasis and onchoceriasis are co-endemic. Although the incidence of serious adverse events (SAEs) is low (22 out of 17 877 people in Cameroon treated with ivermectin in a study published in The Lancet), about 9% of these events are neurological. According to Farrah Mateen, a neurologist by training who now specialises in international health at Johns Hopkins University in Baltimore, MD, USA, “the range of symptoms that have been reported is pretty impressive”. They include cases of coma, some of which result in encephalopathy, parkinsonism, or death. The first signs, which appear after about 12 h, usually include fatigue and generalised athralgia, but can also include mutism and incontinence. After a day or so, more severe disorders of consciousness start to manifest.
According to a 1955 review by the eminent Belgian neurologist Ludo van Bogaert, the first case report of a L loa worm, extracted from a woman’s eye, was published in 1770 by a French surgeon at San Domingo in the Caribbean. van Bogaert argued, rather presciently as it turns out, that the neurological manifestations of L loa were a subject “of some importance in view of the increasing availability of highly potent anti-filarial drugs”, but the filariasis was nevertheless considered largely benign until, in the late 1980s and early 1990s, the first cases of SAEs began to be described in regions that were co-endemic for L loa and Onchocerca volvulus, and where ivermectin treatment for O volvulus was ongoing.
In 1995, a coalition led by the World Bank and WHO set out to eradicate onchoceriasis by rolling out the African Programme for Onchoceriasis Control. The programme works by creating a community-based distribution network for the broad-spectrum antiparasitic drug ivermectin, which when delivered as a one-time dose (150 μg/kg) kills and protects against theO volvulus parasite that causes onchoceriasis. About 90 million people were treated last year through the programme in the 12 countries of subsaharan Africa where onchoceriasis persists; ivermectin will be donated indefinitely through the Mectizan Donation Program until the disease is eradicated. Now, as the programme moves from control towards an end game of elimination, and therefore into increasingly remote areas where populations have until now remained untreated, it has become increasingly important to look at the problems caused by L loa, explains Adrian Hopkins, Director of the MDP. “In the past there was the justification for ivermectin treatment because onchoceriasis definitely shortens life, so taking the risk was justified in areas with very high levels of onchoceriasis. But if we talk about eradication then we’re talking about treating in areas where there is a very low prevalence of onchoceriasis, so we have to make sure we’ve got as much information as we can”, he says.
Michel Boussinesq, Director of Research at the Institut de Recherche pour le Developpement in Montpellier, France, has worked for over 20 years on the epidemiology of onchocerciasis and ivermectin-based control strategies, and was one of the first to look into the relationship between L loa and ivermectin SAEs. “The first studies were done in the early 1990s, and our first task was to demonstrate that there was a relationship between the SAEs and L loa”, he says. Boussinesq was part of the team that published the Lancet study that established that the risk of developing marked or serious reactions to ivermectin was significantly higher when the filarial load exceeded 8000 microfilariae per mL of blood, and was very high for loads of more than 50 000 microfilariae per mL.
“The threshold of risk is assumed to be about 30 000 microfilariae per mL of blood, and the proportion of people with such high loads in the most endemic villages is probably 5% max”, says Boussinesq. “So the proportion of people with high loads who are at risk is fairly high, but only a small proportion of these people develop an SAE: it’s not that everyone with a level of above 30 000 will develop a SAE, so there must be some other cofactors”.
Two of the biggest challenges facing investigators have been the rarity of cases, and the fact that almost all cases occur in extremely remote areas of the bush, so gathering information is difficult. But there are enough data to establish the general pattern of how most symptoms manifest, explains Hopkins. “It goes through a process: patients become disorientated and confused, and this can take place over a number of hours or half a day, progressing to a coma”, he explains.
Unpicking the pathogenesis, however, has been a tortuous process. “There have been two approaches”, says Charles Mackenzie, a Professor of Pathology at Michigan State University, MI, USA. “One is to try to see what went wrong by doing autopsies on patients. And then because the parasite is also found in mandrils and in baboons, which was understood many years ago by Brian Duke in Cameroon, the MDP assisted in setting up a programme to look at what happened in those infected animals after treatment in parasitologically similar situations of very high parasitic loads”, he explains.
The leading hypothesis that has emerged from these studies is that the sudden die off of L loa in patients treated with ivermectin can, in patients with a high parasitic load, trigger an immunological response. But the paucity of data means the jury is still out on the pathology. Indeed, Joseph Kamgno, Director of the Center for Research on Filariasis and Other Tropical Diseases (CRFilMT) at Yaounde in Cameroon, described a case in DRC in which a patient infected with L loadeveloped encephalopathy without any ivermectin treatment. “The mechanism is quite unclear”, says Kamgno.
Together with maintaining a very active surveillance programme to try to detect and report as many cases as possible, Kamgno’s group have also devised local guidelines for the supportive care that should be given to patients who become comatose. “One of the problems we have is that, sometimes, with patients that go comatose, a lot of people look for traditional remedies first, and particularly in the DRC the hospital has always been the last place to go if you have a coma, which means you get patients 3 or 4 days later, often with bed sores already well established. And patients often die from septicaemia through bed sores”, says Hopkins. “So part of the strategy is ensuring that the population understands what has to be done, and that if a patient gets confused or starts going comatose that they’re transferred to a centre set up specially for the management of these patients”.
The management itself is not complicated, consisting of supportive care, and provided patients have been well cared for, they should wake up over a period of 3 or 4 days. But what happens to the patients after they wake up is slightly more mysterious. “Initially we thought that when patients woke up, we didn’t think there were any real sequelae to that episode, but we need to do more research on that because it does seem to be that there might be a problem”, says Hopkins. “There are one or two teachers who say they can’t concentrate to go back to teaching, but we don’t have an awful lot of information on that”. Bringing some neurological evaluation to bear on the situation is something that Mateen is hoping to get started on soon, to try to see whether she can follow up some of those people who have reported SAEs. “Some of the basic questions are still unanswered”, she notes. “Did they survive? What’s their neurological situation? Are they cognitively intact? And there are a lot of other research issues: normative cognitive data are still being established in many of these regions”.
Meanwhile, researchers are trying to tackle L loa from other directions. The Gates Foundation has funded a project to test the feasibility of using automatic counting techniques to test people in the field, to identify patients who have high levels of the L loa parasite and exclude them from ivermectin treatment. Others are looking for alternatives to ivermectin that could be used to treat onchoceriasis in areas where L loa is endemic. A group led by Mark Taylor at the Liverpool School of Tropical Medicine, UK, are looking at targeting Wolbachia spp, bacterial symbionts of some filarial parasites that are present in onchoceriasis and lymphatic filariasis but not in loiasis. Killing the symbionts eventually kills off the O volvulusfilaria while leaving the L loa unharmed, although the treatment must be taken daily for 6 weeks, so isn’t yet amenable to large-scale treatment. But with the “host of research going on at the moment looking at the disease from every different angle”, Hopkins says, Loa loa looks like it might not be quite so neglected after all.