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Risk factors for Mycobacterium ulcerans infection
International Journal of Infectious Diseases 14 (2010) e677–e681
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International Journal of Infectious Diseases journal homepage: www.elsevier.com/locate/ijid
Review
Risk factors for Mycobacterium ulcerans infection Kathryn H. Jacobsen *, Jeannie J. Padgett Department of Global and Community Health, College of Health and Human Services, George Mason University, 4400 University Drive 5B7, Fairfax, VA 22030, USA
A R T I C L E I N F O
A B S T R A C T
Article history: Received 16 June 2009 Received in revised form 25 September 2009 Accepted 5 November 2009
Mycobacterium ulcerans infection (Buruli ulcer) causes necrotizing lesions that may lead to scarring, contractures, osteomyelitis, and even amputation. Despite decades of research, the reservoirs and modes of transmission for M. ulcerans remain obscure. A thorough evaluation of the potential risk factors examined in comparative epidemiological studies may help to identify likely transmission routes. A systematic search of the literature found that poor wound care, failure to wear protective clothing, and living or working near water bodies were commonly identified risk factors. Socioeconomic status, BCG vaccination, and direct water contact were not associated with significantly increased or decreased risk of infection. Additional comparative studies are required to clarify the potential roles of water contact and insect bites in transmitting M. ulcerans to humans. ß 2010 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Corresponding Editor: Sheldon Brown, New York, USA Keywords: Mycobacterium ulcerans Buruli ulcer Risk factors Transmission
1. Introduction Mycobacterium ulcerans infection, alternately known as Buruli ulcer, Bairnsdale ulcer, Daintree ulcer, Mossman ulcer, and Searls’ ulcer, causes necrotizing lesions that can lead to scarring and contractures, and in some cases to osteomyelitis and amputation. The lesions often appear on a limb, but may occur on any part of the body.1–4 While the majority of cases are found in west and central Africa, the geographic range is not limited to the tropics. Cases have also been reported from Australia, South America, Mexico, China, Japan, and several island nations in the Pacific and Indian Oceans, such as Papua New Guinea, Malaysia, Indonesia, and Sri Lanka.2,5,6 M. ulcerans infection is a generally painless ulcerative disease with a characteristic progression.2,3,7–12 After an incubation period of up to three months or longer, initial infection presents as erythema and induration at the infection site. This stage is followed by the formation of a nodule, papule, or raised plaque on the skin that slowly progresses through the dermis and into the subcutaneous tissue and often the fascia. The absence of pain means that a person with the infection often delays seeking care until the ulcer is at an advanced stage. At diagnosis, the characteristic presentation is a necrotic skin ulcer with edges that are undermined and tunneled. In other words, the ulcer typically has overhanging margins and is usually larger in diameter under the skin than at the
* Corresponding author. Tel.: +1 703 993 9168; fax: +1 703 993 1908. E-mail address: [email protected] (K.H. Jacobsen).
surface. Advanced infection may affect nerves, blood vessels, and connective tissue. Subcutaneous fat is usually affected and osteomyelitis can occur, especially when multiple lesions are present, and may lead to contractures and to amputation.3,8,13–16 The subsequent disability may lead to limitations in work and schooling.8,17–19 Scarring from the infection is also associated with psychological distress20–22 and stigma.20,22–24 Anti-mycobacterial therapy may significantly reduce the amount of necrosis, especially when therapy is initiated soon after the lesion appears and continues for several months.2 Commonly used drugs for treating this Gram-positive bacterial infection include quinolones like ciprofloxacin, macrolides like clarithromycin, aminoglycosides like streptomycin, and other antimycobacterials such as rifampin.2,3,11,25 The use of a combination of rifampin and an aminoglycoside is recommended.26,27 For larger lesions, surgical excision is often required, and may necessitate the use of skin grafts.2,3,11,12 Negative pressure drains and heat therapy may encourage post-surgical healing,3 but successful treatment often requires lengthy hospital stays.4 Topical treatments with chemicals such as hypochlorite, chlorhexidine, iodine derivatives, nitrites, phenytoin powder, and clay may also promote healing but have not yet been thoroughly tested.25 Despite decades of research, the mode of transmission of M. ulcerans remains obscure. Several recently published review articles have discussed potential reservoirs, vectors, and transmission mechanisms, but no articles have systematically examined possible risk factors for infection. A thorough analysis of known risk factors for the infection may help to identify likely transmission routes and to eliminate unlikely pathways.
1201-9712/$36.00 – see front matter ß 2010 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijid.2009.11.013
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This paper presents a brief introduction to the clinical characteristics of the disease followed by an evaluation of the risk factors analyzed in comparative studies of the disease. The paper concludes with an examination of theories of transmission in light of the risk factor analysis, and highlights questions that need to be addressed in future studies. 2. Methods Articles were identified by searching several abstract databases for both ‘Mycobacterium ulcerans’ and ‘Buruli ulcer’, and by examining the reference lists of included papers for additional relevant articles. This extensive search of the literature from all years and languages yielded more than a dozen comparative studies that allow for the direct identification of risk factors, because they compare individuals with and without the disease. Most of the analysis in this paper is based on information extracted from these comparative studies, which are summarized in Table 1. While caution must be taken when comparing studies that were conducted in different parts of the world, used different control populations (as noted in the Table), and might have had slightly different case definitions, comparing the findings of a diversity of published reports is an essential step in clarifying what is known and what is not known about the etiology of the disease. In addition, the search identified well over 50 case series and clinical trial reports in which all participants had M. ulcerans infection, and more than 30 review articles and environmental studies. Despite their usefulness in clarifying the natural history of disease and evaluating the effectiveness of various treatment protocols, case series and clinical trial reports are of limited assistance in identifying risk factors, since they usually only report on the number or proportion of cases that exhibit a particular characteristic, and do not compare these counts or rates to the general or unaffected population. However, several of these studies that provide essential information about agent, host, and environmental characteristics linked to M. ulcerans infection and are also referenced in this paper. 3. Results 3.1. Demographics Most case–control studies matched participants by age and sex, so it is impossible for these matched studies to assess age and sex differences between cases and controls. Of the comparative studies that did not match on these characteristics, one found a higher rate of M. ulcerans disease among children aged 5–14 years,28 while others found no statistically significant differences by age
group.8,16 The sites of lesions may also vary with age. For example, studies in West Africa have found that children tend to develop lesions on the trunk, head, neck, and upper limbs, while adults tend to develop lesions on the lower limbs.10,14,29,30 Although cross-sectional surveys and case series seem to indicate that children and adolescents have higher rates of infection by M. ulcerans than adults,4,10,13,29,31–41 only a few of these studies based their observations on patient counts rather than rates, so it is not clear if the higher numbers of cases in young people is simply a reflection of a population structure that has a relatively large proportion of children or if there truly is an increased rate in children. For example, children aged 0–14 years were responsible for half of the total number of cases of Buruli ulcer in a case series from Benin, but the rate of infection was considerably higher in adults over age 60 than it was in children.14 (Some other studies, mostly from Australia, have found a higher number of infections in adults than children.42–45) Similar challenges make it difficult to identify potential differences in the proportion of males and females affected by age group, but the comparative studies that evaluated sex as a risk factor consistently found no association between sex and M. ulcerans infection.8,16,28,46–48 Although some age groups may have an increased risk of infection in some areas, there do not appear to be significant differences in risk by sex. 3.2. Socioeconomic status Only a few comparative studies evaluated socioeconomic risk factors for M. ulcerans infection, and the results were mixed. One study found increased risk among individuals from households with low ownership rates,49 but another study found no association between infection and household spending per day.16 One study found an increased risk of infection associated with participation in agricultural activities,28 but most found no association.16,50,51 One study focusing on education found an increased risk among those with only a primary education,16 but another study found no association between education and infection.22 No association was found between M. ulcerans infection and other proxies for socioeconomic status, such as household size,16 livestock ownership,47 or the construction materials used to form the walls and floors of the house.16 Most of the comparative studies were conducted in rural areas, which suggests that rural residents have an increased risk of M. ulcerans than urban residents. Proving that rural residence is a risk factor will require studies that directly compare rates in areas with different population densities, but recent landscape-based models suggest that this will be true.52 It seems reasonable to assume that individuals with lower socioeconomic status will have reduced
Table 1 Comparative studies of risk factors for Mycobacterium ulcerans Country
Year
Sample size
Comparison population
Matching variables
Reference
Australia Benin Benin Benin Benin Cameroon
2005 2002–2003 2002–2003 2000–2002 1997–2003 2006
658 (49 cases, 609 controls) 1039 (426 cases, 613 controls) 1497 (324 cases, 1173 controls) 892 (15 cases, 877 controls) 3843 (2399 cases, 1444 controls) 326 (163 cases, 163 controls)
1991 2000 2000 1999 1991 not listed 1969–1972
412 (312 cases, 100 controls) 270 (121 cases, 149 controls) 212 (106 cases, 106 controls) 102 (51 cases, 51 controls) 180 (90 cases, 90 controls) 66 (33 cases, 33 controls) Hundreds (47 cases)
Unmatched Age, sex Age, sex Unmatched Unmatched Age, village, classroom (for primary school children) Unmatched Age Age Age, sex, BCG Age, sex Age, sex Unmatched
46 53 49, 51 30 28 16
Coˆte d’Ivoire Ghana Ghana Ghana Ghana Ghana Uganda
8 47 48 50 1 22 54
Uganda
1970–1971
144 (72 cases, 72 controls)
Population-based controls Community controls Neighbor controls Community controls Hospital controls Community and family controls Community controls Neighbor controls Neighbor controls Hospital controls Neighbor controls Hospital controls Population-based prospective cohort study Neighbor controls
Age, sex
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access to early diagnosis and treatment, which may increase the severity of the ulcer and the risk of long-term disability as a result of the infection, but there is no evidence that incidence rate is strongly associated with socioeconomic status. 3.3. Health and hygiene Although cases and controls in one study did not have differential recall of penetrating injuries,47 wound care and hygiene appear to be associated with risk of M. ulcerans infection. Failure to immediately care for wounds by washing them with soap and bandaging them has been associated with an increased risk of infection.16,46,51 Using soap for washing is associated with a decreased risk of infection.47,51 Washing clothes has also been found to be protective.8,16 Other healthcare-related factors may also be related to M. ulcerans infection. Proximity to a hospital has been associated with a decreased risk of infection.28 No consistent association has been found between most infections and comorbidities like diabetes and cancer,46 but HIV/AIDS may increase the risk of infection.47,53 Household exposure does not appear to be particularly risky, since several studies found no association between having a family member with M. ulcerans infection and developing an ulcer.47,50,51 While these studies do not prove that poor wound care increases the incidence of M. ulcerans infection, better wound management and earlier medical intervention, if necessary, seem likely to reduce the severity of infection and would be appropriate to include as part of a comprehensive prevention and control strategy. 3.4. BCG vaccination Although an early study of BCG and Buruli ulcer suggested that BCG conferred protection against M. ulcerans infection,41 most evaluations of BCG have not found the vaccine to be effective in conferring protection against incident infection.1,16,28,46,47,49 BCG may confer some protection against osteomyelitis,37,38 although other studies have found only a weak or no association between BCG and osteomyelitis.49 BCG may also be associated with improved healing of ulcers following surgery40 and a reduction in recurrence of disease following surgery.35 However, the possible association of BCG with improved clinical outcomes does not indicate that BCG protects against incident cases. 3.5. Insect bites The results from studies that evaluated the potential association between insect bites and M. ulcerans infection were inconclusive. In one study, cases were more likely than controls to recall having mosquito bites on the lower legs.46 In another study, cases were more likely than controls to recall being bitten by insects while wading in water or mud.16 These cases, however, were also more likely than controls to believe that bites cause Buruli ulcer,16 and that may have contributed to biased recall of past bites. A third study found no differential recall of insect bites near water.47 The use of mosquito repellants and barriers was also somewhat inconsistent. Two studies found a decreased risk of infection with mosquito net use16,51 and a third found that use of insect repellant was associated with decreased risk of infection.46 However, another study found no association between bed-net use and infection,47 and two studies found that the use of mosquito coils was not associated with a decreased risk of infection.16,47 These studies do not provide strong evidence for or against an insect vector being involved in the transmission process. Wearing protective clothing, however, does seem to be associated with a reduced risk of infection. Many studies identified not wearing long-legged trousers as a risk factor for M. ulcerans
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infection,8,16,46,47 and some studies also found an increased risk associated with not wearing long-sleeved shirts.16,47 The protective effect of covering clothing was noted to be especially strong among farmers.16,47 Gardening gloves46 and shoes,8,47 however, were not found to be protective, perhaps because hands and feet are rare sites for ulcers, so the benefits of protecting these areas provides minimal benefit compared to more likely sites of ulceration. Protective clothing may prevent not only insect bites, but also scratches and other cuts and lacerations that could provide a portal of entry to the agent. 3.6. Water contact Several studies have noted that cases were more likely to drink water from unprotected stagnant waters such as ponds and swamp waters than from protected water sources such as wells or freeflowing water sources such as rivers,28,51,54 but one found an increased risk with use of river water50 and other studies have found no differences in case status by drinking water source.1,16,47,55 Infection with M. ulcerans has not been found to be associated with the source of water used for cooking,50 bathing,50,55 or washing.47,50 Some studies have found an increased risk of infection associated with wading in water,16,47 but recreational and occupational activities such as gardening,46,55 hunting,47 fishing,8,16,47 and swimming8,50 have not usually been linked with infection. Several studies – though not all1 – have found an association between proximity of the home or farm site to a water source and increased risk of infection.8,16,46,47,51 Living near non-water features such as a forest or plantation16 or walking through areas like bush and forest47 have not been associated with infection. In other words, living near water appears to be risky, but direct contact with water does not. This may suggest that water, mud, or insects that live on or near water are related to transmission, but does not clarify their specific roles. 4. Discussion 4.1. Reservoir The primary risk factor for M. ulcerans infection seems to be living in proximity to a body of water, even if contact with water is not consistently shown to increase the risk of infection. Artificial water bodies, such as lakes created from the damming of streams, modification of wetlands in resort areas, flooding, and agricultural irrigation systems, have been reported as possible factors contributing to outbreaks,56,57 and M. ulcerans has been detected in water from outbreak zones.58,59 The agent has been detected in water from both endemic and non-endemic sites,60 so the presence of M. ulcerans in a particular region may not indicate whether humans in that area are at risk. Animals have also been theorized to serve as reservoirs for infection. For example, some fish, especially those that feed on insects, and some mollusks have tested positive for M. ulcerans,61,62 and may serve as reservoirs of infection, but are unlikely to be directly involved in transmission to humans. 4.2. Portal of entry There are two primary theories about the portal of entry for M. ulcerans into the human body.56 The more popular theory is that trauma to the skin provides a site for introduction of M. ulcerans into the body.63 Existing abrasions or lacerations could serve as the portal, or a wound could be created by the bites of potential insect or other vectors or by plants. Although failure to immediately wash wounds was found to be a risk factor in several of the studies examined in the previous section, most studies did not ask individuals with Buruli ulcer about recent skin conditions at or
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near the ulcer site. Although recall bias, in which cases are more likely than controls to remember wounds, may be a limitation, future studies would benefit from more closely exploring this aspect of medical history. The second main theory is that the agent may be able to enter the respiratory system if it is aerosolized from water and inhaled or ingested, or that aerosols from ponds and swamps may contaminate the skin surface. This has not been widely tested and is based primarily on one investigation of an outbreak in Australia.64 4.3. Mode of transmission Several hypotheses about the mode of transmission have been proposed.2,5,25,57 One possibility is that insects transmit the bacterium. Public health research from Australia shows that the incidence of M. ulcerans strongly correlates with the incidence of other vector-borne infections.65 The proposed mechanical vectors are biting aquatic bugs from the order Hemiptera, including insects from the families Naucoridae and Belostomatidae, that feed primarily on other water bugs, snails, and small fish, but occasionally bite humans.66 These insects are usually found near the roots of several types of aquatic plants, but they also fly between swamps and ponds, so they could be involved in infecting persons who have not had water contact.66 However, although the bacterium has been detected in these insects,60,62,66,67 laboratory studies have not specifically shown that the insects are capable of transmitting the agent to humans, and recent field research has not supported the hypothesis that these insects are primary vectors of M. ulcerans.68 A second possibility is that direct transmission occurs when a susceptible body part comes into contact with contaminated water, soil, aquatic plants, or the biofilm on aquatic plants. However, although laboratory-based studies have demonstrated that biofilm-attached bacteria can form on organic material from aquatic plants,69 studies of the roots, stems, and leaves of aquatic plants collected from endemic areas have not resulted in positive cultures.66 The evaluation of risk factors presented in this paper does not rule out any of these modes of transmission, nor does it point to one most likely mechanism. 5. Conclusions The goal of this paper was to identify common risk factors for M. ulcerans disease and to use this information to examine likely modes of transmission for M. ulcerans. There do not appear to be significant differences in risk of disease by sex, participation in agricultural activities, BCG vaccination status, or household exposure to M. ulcerans. Potential differences in risk by age vary significantly by world region. There are mixed results for socioeconomic status, drinking water source, and the use of insect repellents and barriers, although proximity to a body of water and failure to wear covering clothing are consistently associated with an increased risk of M. ulcerans disease. Thus, an examination of currently identified risk factors and unassociated factors does not provide strong evidence for or against vector-borne transmission or transmission via direct water contact. Further research on environmental reservoirs and possible hosts or vectors is required to clarify possible modes of transmission, and additional comparative studies are needed to refine the specific exposures that may facilitate infection and disease. Conflict of interest: The authors have no conflicts of interest to disclose. References 1. Amofah GK, Sagoe-Moses C, Adjei-Acquah C, Frimpong EH. Epidemiology of Buruli ulcer in Amansie West district, Ghana. Trans R Soc Trop Med Hyg 1993;87:644–5.
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K.H. Jacobsen, J.J. Padgett / International Journal of Infectious Diseases 14 (2010) e677–e681 34. Hospers IC, Wiersma IC, Dijkstra PU, Stienstra Y, Etuaful S, Ampadu EO, et al. Distribution of Buruli ulcer lesions over body surface area in a large case series in Ghana: uncovering clues for mode of transmission. Trans R Soc Trop Med Hyg 2005;99:196–201. 35. Kanga JM, Kacou ED, Kouame´ K, Kassi K, Kaloga M, Yao JK, et al. La lutte contre l’ulce`re de Buruli: expe´rience de la Coˆte-d’Ivoire. Bull Soc Pathol Exot 2006;99:34–8. 36. Phanzu DM, Bafende EA, Dunda BK, Imposo DB, Kibadi AK, Nsiangana SZ, et al. Mycobacterium ulcerans disease (Buruli ulcer) in a rural hospital in Bas-Congo, Democratic Republic of Congo, 2002-2004. Am J Trop Med Hyg 2006;75:311–4. 37. Portaels F, Aguiar J, Debacker M, Gue´de´non A, Steunou C, Zinsou C, et al. Mycobacterium bovis BCG vaccination as prophylaxis against Mycobacterium ulcerans osteomyelitis in Buruli ulcer disease. Infect Immun 2004;72:62–5. 38. Portaels F, Aguiar J, Debacker M, Steunou C, Zinsou C, Gue´de´non A, et al. Prophylactic effect of Mycobacterium bovis BCG vaccination against osteomyelitis in children with Mycobacterium ulcerans disease (Buruli ulcer). Clin Diagn Lab Immunol 2002;9:1389–91. 39. Sopoh GE, Johnson RC, Chauty A, Dossou AD, Aguiar J, Salmon O, et al. Buruli ulcer surveillance, Benin, 2003-2005. Emerg Infect Dis 2007;13:1374–6. 40. Teelken MA, Stienstra Y, Ellen DE, Quarshie E, Klutse E, van der Graaf WT, et al. Buruli ulcer: differences in treatment outcome between two centres in Ghana. Acta Trop 2003;88:51–6. 41. Uganda Buruli Group, Epidemiology of Mycobacterium ulcerans infection (Buruli ulcer) at Kinyara, Uganda. Trans R Soc Trop Med Hyg 1971; 65:763-75. 42. James K, Attipou KK, James YE, Blakime M, Tignokpa N, Abete B. L’ulce`re de Buruli au Togo: a` propos d’une enqueˆte hospitalie`re. Sante 2003; 13:43-7. 43. Johnson PD, Azuolas J, Lavender CJ, Wishart E, Stinear TP, Hayman JA, et al. Mycobacterium ulcerans in mosquitoes captured during outbreak of Buruli ulcer, southeastern Australia. Emerg Infect Dis 2007;13:1653–60. 44. Quek TY, Henry MJ, Pasco JA, O’Brien DP, Johnson PD, Hughes A, et al. Mycobacterium ulcerans infection: factors influencing diagnostic delay. Med J Aust 2007;187:561–3. 45. Veitch MG, Johnson PD, Flood PE, Leslie DE, Street AC, Hayman JA. A large localized outbreak of Mycobacterium ulcerans infection on a temperate southern Australian island. Epidemiol Infect 1997;119:313–8. 46. Quek TY, Athan E, Henry MJ, Pasco JA, Redden-Hoare J, Hughes A, et al. Risk factors for Mycobacterium ulcerans infection, southeastern Australia. Emerg Infect Dis 2007;13:1661–6. 47. Raghunathan PL, Whitney EA, Asamoa K, Stienstra Y, Taylor Jr TH, Amofah GK, et al. Risk factors for Buruli ulcer disease (Mycobacterium ulcerans infection): results from a case–control study in Ghana. Clin Infect Dis 2005;40:1445–53. 48. Stienstra Y, van der Werf TS, van der Graaf WT, Secor WE, Kihlstrom SL, Dobos KM, et al. Buruli ulcer and schistosomiasis: no association found. Am J Trop Med Hyg 2004;71:318–21. 49. Nackers F, Dramaix M, Johnson RC, Zinsou C, Robert A, Biurrun Bakedano DE, et al. BCG vaccine effectiveness against Buruli ulcer: a case–control study in Benin. Am J Trop Med Hyg 2006;75:768–74. 50. Aiga H, Amano T, Cairncross S, Adomako J, Nanas OK, Coleman S. Assessing water-related risk factors for Buruli ulcer: a case–control study in Ghana. Am J Trop Med Hyg 2004;71:387–92. 51. Nackers F, Johnson RC, Glynn JR, Zinsou C, Tonglet R, Portaels F. Environmental and health-related risk factors for Mycobacterium ulcerans disease (Buruli ulcer) in Benin. Am J Trop Med Hyg 2007;77:834–6.
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52. Wagner T, Benbow ME, Brenden TO, Qi J, Johnson RC. Buruli ulcer disease prevalence in Benin, West Africa: associations with land use/cover and the identification of disease clusters. Int J Health Geogr 2008;7:25. 53. Johnson RC, Nackers F, Glynn JR, de Biurrun Bakedano E, Zinsou C, Aguiar J, et al. Association of HIV infection and Mycobacterium ulcerans disease in Benin. AIDS 2008;22:901–3. 54. Barker DJ, Carswell JW. Mycobacterium ulcerans infection among tsetse control workers in Uganda. Int J Epidemiol 1973;2:161–5. 55. Barker DJ, Ninkibigaya V. Buruli disease and patients’ activities. East Afr Med J 1972;49:260–8. 56. Duker AA, Portaels F, Hale M. Pathways of Mycobacterium ulcerans infection: a review. Environ Int 2006;32:567–73. 57. Merritt RW, Benbow ME, Small PL. Unraveling an emerging disease associated with disturbed aquatic environments: the case of Buruli ulcer. Front Ecol Environ 2005;3:323–31. 58. Ross BC, Johnson PD, Oppedisano F. Detection of Mycobacterium ulcerans in environmental samples during an outbreak of ulcerative disease. Appl Environ Microbiol 1997;63:4135–8. 59. Stinear T, Davies JK, Jenkin GA, Hayman JA, Oppedisano F, Johnson PD. Identification of Mycobacterium ulcerans in the environment from regions in southeast Australia in which it is endemic with sequence capture-PCR. Appl Environ Microbiol 2000;66:3206–13. 60. Williamson HR, Benbow ME, Nguyen KD, Beachboard DC, Kimbirauskas RK, McIntosh MD, et al. Distribution of Mycobacterium ulcerans in Buruli ulcer endemic and non-endemic aquatic sites in Ghana. PLoS Negl Trop Dis 2008;2:e205. 61. Eddyani M, Ofori-Adjei D, Teugels G, De Weirdt D, Boakye D, Meyers WM, et al. Potential role for fish in transmission of Mycobacterium ulcerans disease (Buruli ulcer): an environmental study. Appl Environ Microbiol 2004;70: 5679–81. 62. Kotlowski R, Martin A, Ablordey A, Chemlal K, Fonteyne PA, Portaels F. One-tube cell lysis and DNA extraction procedure for PCR-based detection of Mycobacterium ulcerans in aquatic insects, molluscs and fish. J Med Microbiol 2004;53:927–33. 63. Meyers WM, Shelly WM, Connor DH, Meyers EK. Human Mycobacterium ulcerans infections developing at sites of trauma to skin. Am J Trop Med Hyg 1974;23:919–23. 64. Hayman J. Postulated epidemiology of Mycobacterium ulcerans infection. Int J Epidemiol 1991;20:1093–8. 65. Johnson PD, Lavender CJ. Correlation between Buruli ulcer and vector-borne notifiable diseases, Victoria. Australia Emerg Infect Dis 2009;15:614–5. 66. Portaels F, Elsen P, Guimaraes-Peres A, Fonteyne PA, Meyers WM. Insects in the transmission of Mycobacterium ulcerans infection. Lancet 1999;353:986. 67. Portaels F, Meyers WM, Ablordey A, Castro AG, Chemlal K, de Rijk P, et al. First cultivation and characterization of Mycobacterium ulcerans from the environment. PLoS Negl Trop Dis 2008;2:e178. 68. Benbow ME, Williamson H, Kimbirauskas R, McIntosh MD, Kolar R, Quaye C, et al. Aquatic invertebrates as unlikely vectors of Buruli ulcer disease. Emerg Infect Dis 2008;14:1247–54. 69. Marsollier L, Stinear T, Aubry J, Saint Andre´ JP, Robert R, Legras P, et al. Aquatic plants stimulate the growth of and biofilm formation by Mycobacterium ulcerans in axenic culture and harbor these bacteria in the environment. Appl Environ Microbiol 2004;70:1097–103.
Contents lists available at ScienceDirect
International Journal of Infectious Diseases journal homepage: www.elsevier.com/locate/ijid
Review
Risk factors for Mycobacterium ulcerans infection Kathryn H. Jacobsen *, Jeannie J. Padgett Department of Global and Community Health, College of Health and Human Services, George Mason University, 4400 University Drive 5B7, Fairfax, VA 22030, USA
A R T I C L E I N F O
A B S T R A C T
Article history: Received 16 June 2009 Received in revised form 25 September 2009 Accepted 5 November 2009
Mycobacterium ulcerans infection (Buruli ulcer) causes necrotizing lesions that may lead to scarring, contractures, osteomyelitis, and even amputation. Despite decades of research, the reservoirs and modes of transmission for M. ulcerans remain obscure. A thorough evaluation of the potential risk factors examined in comparative epidemiological studies may help to identify likely transmission routes. A systematic search of the literature found that poor wound care, failure to wear protective clothing, and living or working near water bodies were commonly identified risk factors. Socioeconomic status, BCG vaccination, and direct water contact were not associated with significantly increased or decreased risk of infection. Additional comparative studies are required to clarify the potential roles of water contact and insect bites in transmitting M. ulcerans to humans. ß 2010 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Corresponding Editor: Sheldon Brown, New York, USA Keywords: Mycobacterium ulcerans Buruli ulcer Risk factors Transmission
1. Introduction Mycobacterium ulcerans infection, alternately known as Buruli ulcer, Bairnsdale ulcer, Daintree ulcer, Mossman ulcer, and Searls’ ulcer, causes necrotizing lesions that can lead to scarring and contractures, and in some cases to osteomyelitis and amputation. The lesions often appear on a limb, but may occur on any part of the body.1–4 While the majority of cases are found in west and central Africa, the geographic range is not limited to the tropics. Cases have also been reported from Australia, South America, Mexico, China, Japan, and several island nations in the Pacific and Indian Oceans, such as Papua New Guinea, Malaysia, Indonesia, and Sri Lanka.2,5,6 M. ulcerans infection is a generally painless ulcerative disease with a characteristic progression.2,3,7–12 After an incubation period of up to three months or longer, initial infection presents as erythema and induration at the infection site. This stage is followed by the formation of a nodule, papule, or raised plaque on the skin that slowly progresses through the dermis and into the subcutaneous tissue and often the fascia. The absence of pain means that a person with the infection often delays seeking care until the ulcer is at an advanced stage. At diagnosis, the characteristic presentation is a necrotic skin ulcer with edges that are undermined and tunneled. In other words, the ulcer typically has overhanging margins and is usually larger in diameter under the skin than at the
* Corresponding author. Tel.: +1 703 993 9168; fax: +1 703 993 1908. E-mail address: [email protected] (K.H. Jacobsen).
surface. Advanced infection may affect nerves, blood vessels, and connective tissue. Subcutaneous fat is usually affected and osteomyelitis can occur, especially when multiple lesions are present, and may lead to contractures and to amputation.3,8,13–16 The subsequent disability may lead to limitations in work and schooling.8,17–19 Scarring from the infection is also associated with psychological distress20–22 and stigma.20,22–24 Anti-mycobacterial therapy may significantly reduce the amount of necrosis, especially when therapy is initiated soon after the lesion appears and continues for several months.2 Commonly used drugs for treating this Gram-positive bacterial infection include quinolones like ciprofloxacin, macrolides like clarithromycin, aminoglycosides like streptomycin, and other antimycobacterials such as rifampin.2,3,11,25 The use of a combination of rifampin and an aminoglycoside is recommended.26,27 For larger lesions, surgical excision is often required, and may necessitate the use of skin grafts.2,3,11,12 Negative pressure drains and heat therapy may encourage post-surgical healing,3 but successful treatment often requires lengthy hospital stays.4 Topical treatments with chemicals such as hypochlorite, chlorhexidine, iodine derivatives, nitrites, phenytoin powder, and clay may also promote healing but have not yet been thoroughly tested.25 Despite decades of research, the mode of transmission of M. ulcerans remains obscure. Several recently published review articles have discussed potential reservoirs, vectors, and transmission mechanisms, but no articles have systematically examined possible risk factors for infection. A thorough analysis of known risk factors for the infection may help to identify likely transmission routes and to eliminate unlikely pathways.
1201-9712/$36.00 – see front matter ß 2010 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijid.2009.11.013
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This paper presents a brief introduction to the clinical characteristics of the disease followed by an evaluation of the risk factors analyzed in comparative studies of the disease. The paper concludes with an examination of theories of transmission in light of the risk factor analysis, and highlights questions that need to be addressed in future studies. 2. Methods Articles were identified by searching several abstract databases for both ‘Mycobacterium ulcerans’ and ‘Buruli ulcer’, and by examining the reference lists of included papers for additional relevant articles. This extensive search of the literature from all years and languages yielded more than a dozen comparative studies that allow for the direct identification of risk factors, because they compare individuals with and without the disease. Most of the analysis in this paper is based on information extracted from these comparative studies, which are summarized in Table 1. While caution must be taken when comparing studies that were conducted in different parts of the world, used different control populations (as noted in the Table), and might have had slightly different case definitions, comparing the findings of a diversity of published reports is an essential step in clarifying what is known and what is not known about the etiology of the disease. In addition, the search identified well over 50 case series and clinical trial reports in which all participants had M. ulcerans infection, and more than 30 review articles and environmental studies. Despite their usefulness in clarifying the natural history of disease and evaluating the effectiveness of various treatment protocols, case series and clinical trial reports are of limited assistance in identifying risk factors, since they usually only report on the number or proportion of cases that exhibit a particular characteristic, and do not compare these counts or rates to the general or unaffected population. However, several of these studies that provide essential information about agent, host, and environmental characteristics linked to M. ulcerans infection and are also referenced in this paper. 3. Results 3.1. Demographics Most case–control studies matched participants by age and sex, so it is impossible for these matched studies to assess age and sex differences between cases and controls. Of the comparative studies that did not match on these characteristics, one found a higher rate of M. ulcerans disease among children aged 5–14 years,28 while others found no statistically significant differences by age
group.8,16 The sites of lesions may also vary with age. For example, studies in West Africa have found that children tend to develop lesions on the trunk, head, neck, and upper limbs, while adults tend to develop lesions on the lower limbs.10,14,29,30 Although cross-sectional surveys and case series seem to indicate that children and adolescents have higher rates of infection by M. ulcerans than adults,4,10,13,29,31–41 only a few of these studies based their observations on patient counts rather than rates, so it is not clear if the higher numbers of cases in young people is simply a reflection of a population structure that has a relatively large proportion of children or if there truly is an increased rate in children. For example, children aged 0–14 years were responsible for half of the total number of cases of Buruli ulcer in a case series from Benin, but the rate of infection was considerably higher in adults over age 60 than it was in children.14 (Some other studies, mostly from Australia, have found a higher number of infections in adults than children.42–45) Similar challenges make it difficult to identify potential differences in the proportion of males and females affected by age group, but the comparative studies that evaluated sex as a risk factor consistently found no association between sex and M. ulcerans infection.8,16,28,46–48 Although some age groups may have an increased risk of infection in some areas, there do not appear to be significant differences in risk by sex. 3.2. Socioeconomic status Only a few comparative studies evaluated socioeconomic risk factors for M. ulcerans infection, and the results were mixed. One study found increased risk among individuals from households with low ownership rates,49 but another study found no association between infection and household spending per day.16 One study found an increased risk of infection associated with participation in agricultural activities,28 but most found no association.16,50,51 One study focusing on education found an increased risk among those with only a primary education,16 but another study found no association between education and infection.22 No association was found between M. ulcerans infection and other proxies for socioeconomic status, such as household size,16 livestock ownership,47 or the construction materials used to form the walls and floors of the house.16 Most of the comparative studies were conducted in rural areas, which suggests that rural residents have an increased risk of M. ulcerans than urban residents. Proving that rural residence is a risk factor will require studies that directly compare rates in areas with different population densities, but recent landscape-based models suggest that this will be true.52 It seems reasonable to assume that individuals with lower socioeconomic status will have reduced
Table 1 Comparative studies of risk factors for Mycobacterium ulcerans Country
Year
Sample size
Comparison population
Matching variables
Reference
Australia Benin Benin Benin Benin Cameroon
2005 2002–2003 2002–2003 2000–2002 1997–2003 2006
658 (49 cases, 609 controls) 1039 (426 cases, 613 controls) 1497 (324 cases, 1173 controls) 892 (15 cases, 877 controls) 3843 (2399 cases, 1444 controls) 326 (163 cases, 163 controls)
1991 2000 2000 1999 1991 not listed 1969–1972
412 (312 cases, 100 controls) 270 (121 cases, 149 controls) 212 (106 cases, 106 controls) 102 (51 cases, 51 controls) 180 (90 cases, 90 controls) 66 (33 cases, 33 controls) Hundreds (47 cases)
Unmatched Age, sex Age, sex Unmatched Unmatched Age, village, classroom (for primary school children) Unmatched Age Age Age, sex, BCG Age, sex Age, sex Unmatched
46 53 49, 51 30 28 16
Coˆte d’Ivoire Ghana Ghana Ghana Ghana Ghana Uganda
8 47 48 50 1 22 54
Uganda
1970–1971
144 (72 cases, 72 controls)
Population-based controls Community controls Neighbor controls Community controls Hospital controls Community and family controls Community controls Neighbor controls Neighbor controls Hospital controls Neighbor controls Hospital controls Population-based prospective cohort study Neighbor controls
Age, sex
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access to early diagnosis and treatment, which may increase the severity of the ulcer and the risk of long-term disability as a result of the infection, but there is no evidence that incidence rate is strongly associated with socioeconomic status. 3.3. Health and hygiene Although cases and controls in one study did not have differential recall of penetrating injuries,47 wound care and hygiene appear to be associated with risk of M. ulcerans infection. Failure to immediately care for wounds by washing them with soap and bandaging them has been associated with an increased risk of infection.16,46,51 Using soap for washing is associated with a decreased risk of infection.47,51 Washing clothes has also been found to be protective.8,16 Other healthcare-related factors may also be related to M. ulcerans infection. Proximity to a hospital has been associated with a decreased risk of infection.28 No consistent association has been found between most infections and comorbidities like diabetes and cancer,46 but HIV/AIDS may increase the risk of infection.47,53 Household exposure does not appear to be particularly risky, since several studies found no association between having a family member with M. ulcerans infection and developing an ulcer.47,50,51 While these studies do not prove that poor wound care increases the incidence of M. ulcerans infection, better wound management and earlier medical intervention, if necessary, seem likely to reduce the severity of infection and would be appropriate to include as part of a comprehensive prevention and control strategy. 3.4. BCG vaccination Although an early study of BCG and Buruli ulcer suggested that BCG conferred protection against M. ulcerans infection,41 most evaluations of BCG have not found the vaccine to be effective in conferring protection against incident infection.1,16,28,46,47,49 BCG may confer some protection against osteomyelitis,37,38 although other studies have found only a weak or no association between BCG and osteomyelitis.49 BCG may also be associated with improved healing of ulcers following surgery40 and a reduction in recurrence of disease following surgery.35 However, the possible association of BCG with improved clinical outcomes does not indicate that BCG protects against incident cases. 3.5. Insect bites The results from studies that evaluated the potential association between insect bites and M. ulcerans infection were inconclusive. In one study, cases were more likely than controls to recall having mosquito bites on the lower legs.46 In another study, cases were more likely than controls to recall being bitten by insects while wading in water or mud.16 These cases, however, were also more likely than controls to believe that bites cause Buruli ulcer,16 and that may have contributed to biased recall of past bites. A third study found no differential recall of insect bites near water.47 The use of mosquito repellants and barriers was also somewhat inconsistent. Two studies found a decreased risk of infection with mosquito net use16,51 and a third found that use of insect repellant was associated with decreased risk of infection.46 However, another study found no association between bed-net use and infection,47 and two studies found that the use of mosquito coils was not associated with a decreased risk of infection.16,47 These studies do not provide strong evidence for or against an insect vector being involved in the transmission process. Wearing protective clothing, however, does seem to be associated with a reduced risk of infection. Many studies identified not wearing long-legged trousers as a risk factor for M. ulcerans
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infection,8,16,46,47 and some studies also found an increased risk associated with not wearing long-sleeved shirts.16,47 The protective effect of covering clothing was noted to be especially strong among farmers.16,47 Gardening gloves46 and shoes,8,47 however, were not found to be protective, perhaps because hands and feet are rare sites for ulcers, so the benefits of protecting these areas provides minimal benefit compared to more likely sites of ulceration. Protective clothing may prevent not only insect bites, but also scratches and other cuts and lacerations that could provide a portal of entry to the agent. 3.6. Water contact Several studies have noted that cases were more likely to drink water from unprotected stagnant waters such as ponds and swamp waters than from protected water sources such as wells or freeflowing water sources such as rivers,28,51,54 but one found an increased risk with use of river water50 and other studies have found no differences in case status by drinking water source.1,16,47,55 Infection with M. ulcerans has not been found to be associated with the source of water used for cooking,50 bathing,50,55 or washing.47,50 Some studies have found an increased risk of infection associated with wading in water,16,47 but recreational and occupational activities such as gardening,46,55 hunting,47 fishing,8,16,47 and swimming8,50 have not usually been linked with infection. Several studies – though not all1 – have found an association between proximity of the home or farm site to a water source and increased risk of infection.8,16,46,47,51 Living near non-water features such as a forest or plantation16 or walking through areas like bush and forest47 have not been associated with infection. In other words, living near water appears to be risky, but direct contact with water does not. This may suggest that water, mud, or insects that live on or near water are related to transmission, but does not clarify their specific roles. 4. Discussion 4.1. Reservoir The primary risk factor for M. ulcerans infection seems to be living in proximity to a body of water, even if contact with water is not consistently shown to increase the risk of infection. Artificial water bodies, such as lakes created from the damming of streams, modification of wetlands in resort areas, flooding, and agricultural irrigation systems, have been reported as possible factors contributing to outbreaks,56,57 and M. ulcerans has been detected in water from outbreak zones.58,59 The agent has been detected in water from both endemic and non-endemic sites,60 so the presence of M. ulcerans in a particular region may not indicate whether humans in that area are at risk. Animals have also been theorized to serve as reservoirs for infection. For example, some fish, especially those that feed on insects, and some mollusks have tested positive for M. ulcerans,61,62 and may serve as reservoirs of infection, but are unlikely to be directly involved in transmission to humans. 4.2. Portal of entry There are two primary theories about the portal of entry for M. ulcerans into the human body.56 The more popular theory is that trauma to the skin provides a site for introduction of M. ulcerans into the body.63 Existing abrasions or lacerations could serve as the portal, or a wound could be created by the bites of potential insect or other vectors or by plants. Although failure to immediately wash wounds was found to be a risk factor in several of the studies examined in the previous section, most studies did not ask individuals with Buruli ulcer about recent skin conditions at or
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near the ulcer site. Although recall bias, in which cases are more likely than controls to remember wounds, may be a limitation, future studies would benefit from more closely exploring this aspect of medical history. The second main theory is that the agent may be able to enter the respiratory system if it is aerosolized from water and inhaled or ingested, or that aerosols from ponds and swamps may contaminate the skin surface. This has not been widely tested and is based primarily on one investigation of an outbreak in Australia.64 4.3. Mode of transmission Several hypotheses about the mode of transmission have been proposed.2,5,25,57 One possibility is that insects transmit the bacterium. Public health research from Australia shows that the incidence of M. ulcerans strongly correlates with the incidence of other vector-borne infections.65 The proposed mechanical vectors are biting aquatic bugs from the order Hemiptera, including insects from the families Naucoridae and Belostomatidae, that feed primarily on other water bugs, snails, and small fish, but occasionally bite humans.66 These insects are usually found near the roots of several types of aquatic plants, but they also fly between swamps and ponds, so they could be involved in infecting persons who have not had water contact.66 However, although the bacterium has been detected in these insects,60,62,66,67 laboratory studies have not specifically shown that the insects are capable of transmitting the agent to humans, and recent field research has not supported the hypothesis that these insects are primary vectors of M. ulcerans.68 A second possibility is that direct transmission occurs when a susceptible body part comes into contact with contaminated water, soil, aquatic plants, or the biofilm on aquatic plants. However, although laboratory-based studies have demonstrated that biofilm-attached bacteria can form on organic material from aquatic plants,69 studies of the roots, stems, and leaves of aquatic plants collected from endemic areas have not resulted in positive cultures.66 The evaluation of risk factors presented in this paper does not rule out any of these modes of transmission, nor does it point to one most likely mechanism. 5. Conclusions The goal of this paper was to identify common risk factors for M. ulcerans disease and to use this information to examine likely modes of transmission for M. ulcerans. There do not appear to be significant differences in risk of disease by sex, participation in agricultural activities, BCG vaccination status, or household exposure to M. ulcerans. Potential differences in risk by age vary significantly by world region. There are mixed results for socioeconomic status, drinking water source, and the use of insect repellents and barriers, although proximity to a body of water and failure to wear covering clothing are consistently associated with an increased risk of M. ulcerans disease. Thus, an examination of currently identified risk factors and unassociated factors does not provide strong evidence for or against vector-borne transmission or transmission via direct water contact. Further research on environmental reservoirs and possible hosts or vectors is required to clarify possible modes of transmission, and additional comparative studies are needed to refine the specific exposures that may facilitate infection and disease. Conflict of interest: The authors have no conflicts of interest to disclose. References 1. Amofah GK, Sagoe-Moses C, Adjei-Acquah C, Frimpong EH. Epidemiology of Buruli ulcer in Amansie West district, Ghana. Trans R Soc Trop Med Hyg 1993;87:644–5.
2. Johnson PD, Stinear T, Small PL, Pluschke G, Merritt RW, Portaels F, et al. Buruli ulcer (M. ulcerans infection): new insights, new hope for disease control. PLoS Med 2005;2:e108. 3. Johnson PD, Hayman JA, Quek TY, Fyfe JA, Jenkin GA, Buntine JA, et al. Consensus recommendations for the diagnosis, treatment and control of Mycobacterium ulcerans infection (Bairnsdale or Buruli ulcer) in Victoria, Australia. Med J Aust 2007;186:64–8. 4. Noeske J, Kuaban C, Rondini S, Sorlin P, Ciaffi L, Mbuagbaw J, et al. Buruli ulcer disease in Cameroon rediscovered. Am J Trop Med Hyg 2004;70:520–6. 5. Dega H, Chosidow O, Barete S, Carbonnelle B, Grosset J, Jarlier V. Infection a` Mycobacterium ulcerans. Ann Med Interne 2000;151:339–44. 6. World Health Organization. Buruli ulcer: progress report, 2004-2008. Wkly Epidemiol Rec 2008; 83:145-54. 7. Johnson PD, Veitch MG, Leslie DE, Flood PE, Hayman JA. The emergence of Mycobacterium ulcerans infection near Melbourne. Med J Aust 1996;164:76–8. 8. 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