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Perspective| Volume 27, P74-77, October 01, 2014

Nodding syndrome—a new hypothesis and new direction for research

Open AccessPublished:August 22, 2014DOI:https://doi.org/10.1016/j.ijid.2014.08.001
Nodding syndrome—a new hypothesis and new direction for research
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      Highlights

      • •
        Nodding syndrome (NS) caused an epilepsy epidemic in South Sudan and northern Uganda.
      • •
        NS is mainly affecting children between 5 and 15 years of age.
      • •
        In many onchocerciasis endemic areas there is a high prevalence of epilepsy.
      • •
        Blackflies infected with microfilariae may also transmit another pathogen causing NS.
      • •
        Treating rivers with larvicides may stop NS epidemics.

      Summary

      Nodding syndrome (NS) is an unexplained neurological illness that mainly affects children aged between 5 and 15 years. NS has so far been reported from South Sudan, northern Uganda, and Tanzania, but in spite of extensive investigations, the aetiology remains unknown. We hypothesize that blackflies (Diptera: Simuliidae) infected with Onchocerca volvulus microfilariae may also transmit another pathogen. This may be a novel neurotropic virus or an endosymbiont of the microfilariae, which causes not only NS, but also epilepsy without nodding. This hypothesis addresses many of the questions about NS that researchers have previously been unable to answer. An argument in favour of the hypothesis is the fact that in Uganda, the number of new NS cases decreased (with no new cases reported since 2013) after ivermectin coverage was increased and with the implementation of a programme of aerial spraying and larviciding of the large rivers where blackflies were breeding. If confirmed, our hypothesis will enable new strategies to control NS outbreaks.

      Keywords

      1. Introduction

      Nodding syndrome (NS) is an unexplained neurological illness that has so far been reported from South Sudan, northern Uganda, and Tanzania.
      • Dowell S.F.
      • Sejvar J.J.
      • Riek L.
      • Vandemaele K.A.
      • Lamunu M.
      • Kuesel A.C.
      • et al.
      Nodding syndrome.
      Emerg Infect Dis. 2013; 19: 1374-1384
      NS mainly occurs in children aged between 5 and 15 years. The first clinical symptom is often an involuntary nodding of the head in a previously healthy child. Other types of epileptic seizures may follow, which in some children are accompanied by cognitive deterioration and stunted growth, leading to dwarfism and the absence of development of secondary sexual characteristics.
      • Dowell S.F.
      • Sejvar J.J.
      • Riek L.
      • Vandemaele K.A.
      • Lamunu M.
      • Kuesel A.C.
      • et al.
      Nodding syndrome.
      Emerg Infect Dis. 2013; 19: 1374-1384
      Various infectious, toxic, nutritional, psychosocial, and genetic causes have been proposed, but none have been confirmed. However, there appears to be a link between NS and onchocerciasis. NS is only known to occur in onchocerciasis endemic areas, and case–control studies have demonstrated a higher prevalence of onchocerciasis in individuals with NS than in controls.
      • Dowell S.F.
      • Sejvar J.J.
      • Riek L.
      • Vandemaele K.A.
      • Lamunu M.
      • Kuesel A.C.
      • et al.
      Nodding syndrome.
      Emerg Infect Dis. 2013; 19: 1374-1384
      A high prevalence of epilepsy has also been described in many onchocerciasis endemic areas,
      • Kaiser C.
      • Pion S.D.
      • Boussinesq M.
      Case–control studies on the relationship between onchocerciasis and epilepsy: systematic review and meta-analysis.
      PLoS Negl Trop Dis. 2013; 7: e2147
      and higher microfilarial loads have been found in skin snips of onchocerciasis patients with epilepsy than in those without.
      • Boussinesq M.
      • Pion S.D.
      • Demanga N.
      • Kamgno J.
      Relationship between onchocerciasis and epilepsy: a matched case–control study in the Mbam Valley, Republic of Cameroon.
      Trans R Soc Trop Med Hyg. 2002; 96: 537-541
      PCR tests on the cerebrospinal fluid (CSF) of NS patients have failed to identify Onchocerca volvulus DNA,
      • Winkler A.S.
      • Friedrich K.
      • Velicheti S.
      • Dharsee J.
      • Konig R.
      • Nassri A.
      • et al.
      MRI findings in people with epilepsy and nodding syndrome in an area endemic for onchocerciasis: an observational study.
      Afr Health Sci. 2013; 13: 529-540
      , 
      • Konig R.
      • Nassri A.
      • Meindl M.
      • Matuja W.
      • Kidunda A.R.
      • Siegmund V.
      • et al.
      The role of Onchocerca volvulus in the development of epilepsy in a rural area of Tanzania.
      Parasitology. 2010; 137: 1559-1568
      but these results are difficult to interpret as they may have been complicated by previous treatment with ivermectin.
      • Kaiser C.
      • Pion S.
      • Boussinesq M.
      Head nodding syndrome and river blindness: a parasitologic perspective.
      Epilepsia. 2009; 50: 2325-2326
      However, because O. volvulus microfilariae are not known to invade the brain, it is difficult to understand how O. volvulus could directly cause the neurological damage seen in NS patients.
      We therefore propose the aetiological hypothesis below.

      2. Hypothesis

      The association between NS and onchocerciasis may be explained by the existence of a common vector – blackflies (Simulium spp – transmitting O. volvulus) and a second pathogen involved in the aetiology of NS.
      Such a pathogen could, for example, be a neurotropic virus transmitted by blackflies co-infected with O. volvulus microfilariae. Many laboratory studies have shown that arboviral transmission is enhanced in mosquitoes and other Diptera that concurrently ingest microfilariae,
      • Turell M.J.
      • Mather T.N.
      • Spielman A.
      • Bailey C.L.
      Increased dissemination of dengue 2 virus in Aedes aegypti associated with concurrent ingestion of microfilariae of Brugia malayi.
      Am J Trop Med Hyg. 1987; 37: 197-201
      , 
      • Turell M.J.
      • Rossignol P.A.
      • Spielman A.
      • Rossi C.A.
      • Bailey C.L.
      Enhanced arboviral transmission by mosquitoes that concurrently ingested microfilariae.
      Science. 1984; 225: 1039-1041
      and the same could be true for blackflies. In mosquitoes, microfilariae penetrate the midgut and introduce the virus directly into the haemocoel, allowing them to become infectious more quickly than normal.
      • Turell M.J.
      • Rossignol P.A.
      • Spielman A.
      • Rossi C.A.
      • Bailey C.L.
      Enhanced arboviral transmission by mosquitoes that concurrently ingested microfilariae.
      Science. 1984; 225: 1039-1041
      This has been demonstrated in experiments with Aedes taeniorhynchus co-infected with Rift Valley fever virus, and Aedes aegypti co-infected with dengue virus type 2 and Brugia malayi microfilariae.
      • Turell M.J.
      • Mather T.N.
      • Spielman A.
      • Bailey C.L.
      Increased dissemination of dengue 2 virus in Aedes aegypti associated with concurrent ingestion of microfilariae of Brugia malayi.
      Am J Trop Med Hyg. 1987; 37: 197-201
      It was also found that the biting midge, Culicoides nubeculosus, became infectious after ingesting blue tongue virus and Onchocerca cervicalis microfilariae, but not after ingesting the virus alone.
      • Mellor P.S.
      • Boorman J.
      Multiplication of bluetongue virus in Culicoides nubeculosus (Meigen) simultaneously infected with the virus and the microfilariae of Onchocerca cervicalis (Railliet & Henry).
      Ann Trop Med Parasitol. 1980; 74: 463-469
      A pathogen could also be an endosymbiont of O. volvulus microfilariae, for example Wolbachia bacteria. Wolbachia are known to play a role in the pathogenicity of onchocerciasis.
      • Bouchery T.
      • Lefoulon E.
      • Karadjian G.
      • Nieguitsila A.
      • Martin C.
      The symbiotic role of Wolbachia in Onchocercidae and its impact on filariasis.
      Clin Microbiol Infect. 2013; 19: 131-140
      Toxins secreted by Wolbachia are able to cause pruritus, skin inflammation, and ocular lesions.
      • Bouchery T.
      • Lefoulon E.
      • Karadjian G.
      • Nieguitsila A.
      • Martin C.
      The symbiotic role of Wolbachia in Onchocercidae and its impact on filariasis.
      Clin Microbiol Infect. 2013; 19: 131-140
      , 
      • Taylor M.J.
      Wolbachia in the inflammatory pathogenesis of human filariasis.
      Ann N Y Acad Sci. 2003; 990: 444-449
      However, we do not currently know how these toxins could damage the central nervous system (CNS) in the absence of microfilariae penetrating the brain.
      The hypothesis of a new pathogen transmitted by blackflies addresses many of the questions about NS that researchers have previously been unable to answer, including those listed below.

      2.1 Why is NS only present in a limited number of onchocerciasis endemic areas?

      The distribution of NS could be limited by the distribution of an appropriate disease vector. It is possible that only certain (cyto)species of blackfly are able to transmit the pathogen. It is also possible that NS occasionally occurs in hypo- and mesoendemic areas for O. volvulus, but only becomes epidemic in areas that are hyperendemic for O. volvulus. An argument for the latter is supported by the high prevalence of epilepsy seen in many onchocerciasis hyperendemic areas, and that NS-like features have been reported in several other onchocerciasis hyperendemic areas in the past. In 1938, a Mexican physician described a syndrome in Chiapas and Oaxaca, Mexico, characterized by epileptic seizures, stunted growth, and mental retardation in patients with onchocerciasis.
      • Casis Sacre G.
      El sindrome epileptico y sus reaciones con onchocercosis.
      Boletin de Salubridad e Higiene. 1938; 1: 11-31
      In Mabira Forest, 60 km east of Kampala, Uganda, a ‘Nakalanga syndrome’ outbreak (a syndrome with symptoms similar to NS) was described in 1950.
      • Raper A.B.
      • Ladkin R.G.
      Endemic dwarfism in Uganda.
      East Afr Med J. 1950; 27: 339-359
      NS-like features have also been reported in other onchocerciasis endemic areas in Liberia,
      • Gerrits C.
      A West African epilepsy focus.
      Lancet. 1983; 1: 358
      western Uganda,
      • Kaiser C.
      • Benninger C.
      • Asaba G.
      • Mugisa C.
      • Kabagambe G.
      • Kipp W.
      • et al.
      Clinical and electro-clinical classification of epileptic seizure in west Uganda.
      Bull Soc Pathol Exot. 2000; 93: 255-259
      Burundi,
      • Newell E.D.
      • Vyungimana F.
      • Bradley J.E.
      Epilepsy, retarded growth and onchocerciasis, in two areas of different endemicity of onchocerciasis in Burundi.
      Trans R Soc Trop Med Hyg. 1997; 91: 525-527
      and possibly the Central African Republic, Ethiopia, Mali,
      • Duke B.O.
      Onchocerciasis, epilepsy and hyposexual dwarfism.
      Trans R Soc Trop Med Hyg. 1998; 92: 236
      and Cameroon.
      • Pion S.D.
      • Kaiser C.
      • Boutros-Toni F.
      • Cournil A.
      • Taylor M.M.
      • Meredith S.E.
      • et al.
      Epilepsy in onchocerciasis endemic areas: systematic review and meta-analysis of population-based surveys.
      PLoS Negl Trop Dis. 2009; 3: e461

      2.2 Why do NS epidemics appear and disappear?

      An NS epidemic may appear in onchocerciasis hyperendemic areas when a non-immune population migrates to an area containing blackflies infected with an ‘NS pathogen’. Population displacement resulting from civil conflict has preceded NS outbreaks in both northern Uganda and South Sudan. An NS epidemic may subsequently decrease with increasing herd immunity. It may also decrease with increasing ivermectin coverage. This will reduce the likelihood of blackflies becoming infected with microfilariae and therefore transmitting a pathogen. NS epidemics may be interrupted by insecticide or larvicide use against blackflies.

      2.3 How can the current epidemiological situation in the three affected countries be explained?

      2.3.1 Northern Uganda

      Northern Uganda was engaged in a war with the Lord's Resistance Army between 1987 and 2008. About 1.8 million people in Gulu, Kitgum, and Pader districts were displaced into ‘protective’ internally displaced people camps, some for more than 15 years. Before displacement, frequent contact with blackfly-infested rivers had caused immunity in adults. Relief food was distributed in the camps and water was collected from boreholes resulting in less frequent contact with the rivers. As a result, children born in camps lacked immunity against the ‘NS pathogen’. People were released from the camps from 2006 and non-immune children came into contact with infected blackflies at rivers near their home villages. There was no ivermectin distribution during the war, and community-directed treatment with ivermectin was only started in 2009, and in the villages most affected by NS, in 2012. A combined lack of immunity and the absence of an ivermectin distribution programme potentially resulted in the NS epidemic

      Wamala JF, Nanyunja M. Ministry of Health Uganda and World Health Organization Uganda. Unpublished results.

      (Figure 1).
      Figure thumbnail gr1
      Figure 1Number of new cases of nodding syndrome between 1997 and 2013 in the districts of Kitgum, Lamwo, and Pader, in northern Uganda.
      A programme of aerial spraying and larviciding of the large rivers where blackflies were breeding was implemented in 2012. This was followed by a decrease in the incidence of NS, with no new cases officially reported in 2013.

      Ministry of Health Uganda and World Health Organization. A report on the epidemiology and burden of nodding disease in the districts of Kitgum, Lamwo and Pader, northern Uganda August 2010. WHO; 2011.

      , 

      Ministry of Health, Uganda. Epidemiological week 32 of 2014, 4th August - 10th August 2014.

      The already decreasing trend of new NS cases before spraying took place could have been a consequence of the intensified ivermectin programme (biannual distribution).

      2.3.2 South Sudan

      Sudan used insecticides to control river blindness until autonomy in 1972, when spraying stopped due to a lack of funding. People fled into forests infested by blackflies during the Second Sudanese Civil War (1983–2005) and it is conceivable that because of insecticide spraying in the past, the population had limited immunity. The first cases of NS appeared around 1990
      • Spencer P.S.
      • Palmer V.S.
      • Jilek-Aall L.
      Nodding syndrome: origins and natural history of a longstanding epileptic disorder in sub-Saharan Africa.
      Afr Health Sci. 2013; 13: 176-182
      and the prevalence has been increasing since. The prevalence of NS in Mvolo county has been estimated at 8.4% by the South Sudan Relief and Rehabilitation Commission (4025 NS patients out of 48 100 people) (Anthony Amba; personal communication), which is a doubling of prevalence compared to the 2003 estimate of 4.6%.
      • Tumwine J.K.
      • Vandemaele K.
      • Chungong S.
      • Richer M.
      • Anker M.
      • Ayana Y.
      • et al.
      Clinical and epidemiologic characteristics of nodding syndrome in Mundri County, southern Sudan.
      Afr Health Sci. 2012; 12: 242-248
      There are still new NS cases occurring in South Sudan (Mr S.A. Komoyangi, Chair, Diko Community Development Committee, Western Equatoria State, South Sudan; personal communication). The reason for this might be the low ivermectin coverage (only distributed annually).

      2.3.3 Tanzania

      Around 1850, the Wapogoro tribe fled from the Ulanga plains to isolated regions in the Mahenge mountains to avoid conflict with the Ngoni.
      • Spencer P.S.
      • Palmer V.S.
      • Jilek-Aall L.
      Nodding syndrome: origins and natural history of a longstanding epileptic disorder in sub-Saharan Africa.
      Afr Health Sci. 2013; 13: 176-182
      The prevalence of epilepsy in Mahenge was estimated to be 2% in 1970
      • Jilek W.G.
      • Jilek-Aall L.M.
      The problem of epilepsy in a rural Tanzanian tribe.
      Afr J Med Sci. 1970; 1: 305-307
      and 1.8% in 1989.
      • Rwiza H.T.
      • Kilonzo G.P.
      • Haule J.
      • Matuja W.B.
      • Mteza I.
      • Mbena P.
      • et al.
      Prevalence and incidence of epilepsy in Ulanga, a rural Tanzanian district: a community-based study.
      Epilepsia. 1992; 33: 1051-1056
      Over the last 10 years, the incidence of NS has been low and stable.
      • Winkler A.S.
      • Wallner B.
      • Friedrich K.
      • Pfausler B.
      • Unterberger I.
      • Matuja W.
      • et al.
      A longitudinal study on nodding syndrome—a new African epilepsy disorder.
      Epilepsia. 2014; 55: 86-93
      Because insecticides and larvicides have never been used in Mahenge, we hypothesize that the population has been exposed to the ‘NS pathogen’ for a long time. The fact that NS is endemic in Mahenge may be explained by an increase in acquired immunity of the local population over a very long period and good ivermectin coverage.

      2.4 Why are only children affected?

      Many infectious disease epidemics show a predisposition for very young children. The onset of NS between the ages of 5 and 15 years is probably explained by the following: (1) protection of very young children by the antibodies of their mothers; (2) the fact that very young children are less likely to spend a lot of time near rivers; (3) the incubation time of the disease; (4) treatment with ivermectin is only started after the age of 5 years. If the pathogen is a microfilarial endosymbiont, then young children may be at particular risk of developing the disease. It is also possible that, similar to other viral childhood infections, the ‘NS pathogen’ could lead to immunity for life, explaining why adults rarely develop the disease.

      2.5 Why are non-immune adults not developing NS?

      It may be that the rate of infection in blackflies is low. In the event that the pathogen is a microfilarial endosymbiont, it may be that you need to become infected many times, similar to onchocerciasis, before you develop a serious disease. This could explain the low risk of disease development seen in occasional non-immune travellers who spend only a short time at the riverside.

      2.6 How can the severe stunting (dwarfism) be explained?

      Dwarfism could be caused by an infection with the ‘NS pathogen’ at an early age, when the child's brain is still developing. Hypothalamic-pituitary dysfunction has been described post-encephalitis
      • Schaefer S.
      • Boegershausen N.
      • Meyer S.
      • Ivan D.
      • Schepelmann K.
      • Kann P.H.
      Hypothalamic-pituitary insufficiency following infectious diseases of the central nervous system.
      Eur J Endocrinol. 2008; 158: 3-9
      and a similar stunted growth and lack of secondary sexual characteristics has also been observed in perinatally HIV-infected children who survived up to 18 years without antiretroviral therapy,
      • Lowenthal E.D.
      • Bakeera-Kitaka S.
      • Marukutira T.
      • Chapman J.
      • Goldrath K.
      • Ferrand R.A.
      Perinatally acquired HIV infection in adolescents from sub-Saharan Africa: a review of emerging challenges.
      Lancet Infect Dis. 2014; 14: 627-639
      and in perinatally human T-cell lymphotropic virus type 1 (HTLV-1)-infected children (K. Verdonck; personal communication). It is unlikely that the pronounced dwarfism is only caused by malnourishment because not all these children are particularly malnourished.

      2.7 How should the CSF and brain magnetic resonance imaging (MRI) findings observed in patients with NS be interpreted?

      The CSF of patients with NS is generally clear, with glucose and protein levels within normal limits.
      • Dowell S.F.
      • Sejvar J.J.
      • Riek L.
      • Vandemaele K.A.
      • Lamunu M.
      • Kuesel A.C.
      • et al.
      Nodding syndrome.
      Emerg Infect Dis. 2013; 19: 1374-1384
      , 
      • Winkler A.S.
      • Friedrich K.
      • Velicheti S.
      • Dharsee J.
      • Konig R.
      • Nassri A.
      • et al.
      MRI findings in people with epilepsy and nodding syndrome in an area endemic for onchocerciasis: an observational study.
      Afr Health Sci. 2013; 13: 529-540
      , 
      • Sejvar J.J.
      • Kakooza A.M.
      • Foltz J.L.
      • Makumbi I.
      • Atai-Omoruto A.D.
      • Malimbo M.
      • et al.
      Clinical, neurological, and electrophysiological features of nodding syndrome in Kitgum, Uganda: an observational case series.
      Lancet Neurol. 2013; 12: 166-174
      In a viral CNS infection one would expect an increased cell count and an increased total protein level. However, in subacute sclerosing panencephalitis, CSF findings are usually acellular with a normal or mildly raised protein concentration.
      • Garg R.K.
      Subacute sclerosing panencephalitis.
      J Neurol. 2008; 255: 1861-1871
      Therefore normal CSF findings do not exclude a chronic or subacute viral infection. Brain MRI has only been performed in a limited number of patients with NS.
      • Winkler A.S.
      • Friedrich K.
      • Velicheti S.
      • Dharsee J.
      • Konig R.
      • Nassri A.
      • et al.
      MRI findings in people with epilepsy and nodding syndrome in an area endemic for onchocerciasis: an observational study.
      Afr Health Sci. 2013; 13: 529-540
      , 
      • Sejvar J.J.
      • Kakooza A.M.
      • Foltz J.L.
      • Makumbi I.
      • Atai-Omoruto A.D.
      • Malimbo M.
      • et al.
      Clinical, neurological, and electrophysiological features of nodding syndrome in Kitgum, Uganda: an observational case series.
      Lancet Neurol. 2013; 12: 166-174
      , 
      • Idro R.
      • Opoka R.O.
      • Aanyu H.T.
      • Kakooza-Mwesige A.
      • Piloya-Were T.
      • Namusoke H.
      • et al.
      Nodding syndrome in Ugandan children—clinical features, brain imaging and complications: a case series.
      BMJ Open. 2013; 3
      None of the patients showed evidence of meningeal or parenchymal inflammation, or a focal brain lesion caused by a parasitic infection. Five patients from Tanzania and two patients from Uganda had aspecific hippocampus abnormalities, and in five Ugandan patients, cerebral atrophy was noted.
      • Dowell S.F.
      • Sejvar J.J.
      • Riek L.
      • Vandemaele K.A.
      • Lamunu M.
      • Kuesel A.C.
      • et al.
      Nodding syndrome.
      Emerg Infect Dis. 2013; 19: 1374-1384
      Brain MRI do not provide evidence of a viral CNS infection, but also do not suggest a parasitic infection of the brain.

      2.8 Can blackflies transmit pathogens?

      Blackflies can transmit vesicular stomatitis New Jersey virus to cattle, horses, and swine.
      • Mead D.G.
      • Howerth E.W.
      • Murphy M.D.
      • Gray E.W.
      • Noblet R.
      • Stallknecht D.E.
      Black fly involvement in the epidemic transmission of vesicular stomatitis New Jersey virus (Rhabdoviridae: Vesiculovirus).
      Vector Borne Zoonotic Dis. 2004; 4: 351-359
      There are no reports of blackflies transmitting arboviruses to humans. However with over 1700 Simulium species described worldwide, it is plausible that blackflies may transmit unidentified viruses from human and zoonotic origin.

      3. Directions for future research

      More precise incidence data on NS, epilepsy, and onchocerciasis in relation to blackfly distribution are required. At the same time, research should focus on the search for a new pathogen. Previous studies using multiplex PCR have not been able to identify a pathogen in the serum or CSF of NS patients.
      • Foltz J.L.
      • Makumbi I.
      • Sejvar J.J.
      • Malimbo M.
      • Ndyomugyenyi R.
      • Atai-Omoruto A.D.
      • et al.
      An epidemiologic investigation of potential risk factors for nodding syndrome in Kitgum District, Uganda.
      PLoS One. 2013; 8: e66419
      However, such methods may not be able to detect a new pathogen and it is conceivable that once nodding appears, the ‘NS pathogen’ may no longer be detectable in serum or even CSF. The way forward is to plan a metagenomic study of blackflies, microfilariae, and human samples (preferably brain tissue).
      In conclusion, NS may be caused by a new pathogen transmitted by blackflies. Similar to other vector-borne diseases, infection depends on a combination of the amount of exposure, percentage of insects carrying the pathogen, immunity, and chance. The burden of disease may be considerable, as the ‘NS pathogen’ may also cause epilepsy without nodding. The use of larvicides may be able to stop epidemics; however, if vector control is not sustained there may be an increase in clinical disease because of decreased immunity. Improving ivermectin coverage and increasing the frequency of its administration may reduce the capacity of the blackflies to transmit the pathogen. The planning of a clinical trial to evaluate these control strategies, either alone or in combination, should be considered.

      Acknowledgements

      We thank Kris Debref (Association of European Parliamentarians with Africa), John Bono (Minister of Health, Western Equatorial State, South Sudan), Richard Lako and Lucia Kur (Ministry of Health, South Sudan), Stephen Komoyangi (Diko Community Development Committee, South Sudan), Abdinasir Abubakar (WHO South Sudan), Jacob Podi and Anthony Amba (South Sudan Relief and Rehabilitation Commission), Andrea Bollini (OVCI, South Sudan), Emilio Ovuga, Richard Echodu, and Joyce Kaducu (Gulu University, Uganda), James Tumwine (Makerere University, Uganda), Charles Okot (WHO Uganda), Issa Makumbi and Benard Opar (Ministry of Health Uganda), Jozefien Buyze, Nathalie Van der Moeren, Karen Couderé, and Kevin Arien (Institute of Tropical Medicine, Antwerp, Belgium), and Geert Haesaert (University of Gent) for their support, providing information and advice.
      Conflict of interest: Robert Colebunders has received funding from the Flemish Interuniversity council (VLIR-UOS) to travel to South Sudan and Uganda. None of the authors has a conflict of interest.

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      Article Info

      Publication History

      Published online: August 22, 2014
      Accepted: August 8, 2014
      Received in revised form: August 4, 2014
      Received: July 24, 2014
      Corresponding Editor: Eskild Petersen, Aarhus, Denmark

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      DOI: https://doi.org/10.1016/j.ijid.2014.08.001

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