Scholarly article on topic 'Risk factors for Mycobacterium ulcerans infection'

Risk factors for Mycobacterium ulcerans infection Academic research paper on "Veterinary science"

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Abstract of research paper on Veterinary science, author of scientific article — Kathryn H. Jacobsen, Jeannie J. Padgett

Abstract 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.

Academic research paper on topic "Risk factors for Mycobacterium ulcerans infection"

Contents lists available at ScienceDirect

International Journal of Infectious Diseases

ELSEVIER 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

article info

abstract

Article history:

Received 16 June 2009

Received in revised form 25 September 2009

Accepted 5 November 2009

Corresponding Editor: Sheldon Brown,

New York, USA

Keywords:

Mycobacterium ulcerans Buruli ulcer Risk factors Transmission

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.

© 2010 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

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: kjacobse@gmu.edu (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 anti-mycobacterials 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 © 2010 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijid.2009.11.013

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 2005 658 (49 cases, 609 controls) Population-based controls Unmatched 46

Benin 2002-2003 1039 (426 cases, 613 controls) Community controls Age, sex 53

Benin 2002-2003 1497 (324 cases, 1173 controls) Neighbor controls Age, sex 49, 51

Benin 2000-2002 892 (15 cases, 877 controls) Community controls Unmatched 30

Benin 1997-2003 3843 (2399 cases, 1444 controls) Hospital controls Unmatched 28

Cameroon 2006 326 (163 cases, 163 controls) Community and Age, village, classroom 16

family controls (for primary school children)

Cote d'Ivoire 1991 412 (312 cases, 100 controls) Community controls Unmatched 8

Ghana 2000 270 (121 cases, 149 controls) Neighbor controls Age 47

Ghana 2000 212 (106 cases, 106 controls) Neighbor controls Age 48

Ghana 1999 102 (51 cases, 51 controls) Hospital controls Age, sex, BCG 50

Ghana 1991 180 (90 cases, 90 controls) Neighbor controls Age, sex 1

Ghana not listed 66 (33 cases, 33 controls) Hospital controls Age, sex 22

Uganda 1969-1972 Hundreds (47 cases) Population-based Unmatched 54

prospective cohort study

Uganda 1970-1971 144 (72 cases, 72 controls) Neighbor controls Age, sex 55

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 co-morbidities 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

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 free-flowing 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

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.

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