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Functional Limitations after Surgical or Antibiotic Treatment for Buruli Ulcer in Benin

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  • 1 Programme National Lutte contre la Lèpre et l’Ulcère de Buruli, Ministère de la Santé, Cotonou, République du Bénin; Departments of Internal Medicine and Pulmonary Diseases and Tuberculosis, Infectious Diseases and Tuberculosis Service, University Medical Centre Groningen, University of Groningen, RB Groningen, The Netherlands; Department of Rehabilitation, University Medical Centre Groningen, University of Groningen, RB Groningen, The Netherlands

Almost half of patients have functional limitations after treatment of Buruli ulcer disease. Antibiotic treatment (along with surgery) was introduced in the National Program for Buruli ulcer in Benin in 2005. The aim of this study was to compare functional limitations in patients who were treated by antibiotics, surgery, or both, using a validated questionnaire. One hundred seventy-nine former patients in Lalo, Benin were retrieved and interviewed in their village. Hospital records were used to gather data about size of lesion at presentation and treatment provided. No significant differences in resulting functional limitations were found between the different treatments. Larger lesions (> 15 cm cross-sectional diameter) at presentation; lesions on a joint, muscular atrophy, and amputation were all associated with a higher risk for functional limitations. Advantages of antibiotic treatment may involve other domains, like costs of treatment or a change in help-seeking behavior.

INTRODUCTION

Buruli ulcer is an infectious disease caused by Mycobacterium ulcerans affecting skin, subcutaneous tissue and sometimes, bone. The mystery of the natural reservoir of the bacillus, and the mode of transmission to man have not been elucidated as yet. Mycobacterium ulcerans has been identified by molecular tools from the environment—and recently, cultured1—and it is generally believed to be either a zoonosis or an infection by an environmental micro-organism. Many different animal species appear to test positive in endemic areas,25 but a typical vector has not been convincingly identified. 6,7 Case control studies among people living in endemic areas have identified risk factors to contract the disease; there is a striking association with stagnant and slowly flowing water bodies.810 The disease has emerged in recent decades in several West African countries, with the highest case load in Côte d’Ivoire, Ghana, and Benin; in endemic regions, prevalence rates of around 150/100,000 population have been reported. 11

Patients may either present with a nodule, a plaque, or an oedema. The most frequent lesion is an ulcer. In rural Africa, patients tend to report to the hospital late in the course of the disease and some long-standing and extensive lesions that have affected joints and bone may have advanced to a stage that amputation is the only reasonable option for these extensive lesions to heal. 11 Indeed, with increasing patient delay, lesions tend to become larger resulting in more severe functional limitations. In Benin, focus group discussions revealed that people believe that this disease may be natural, “sent directly by God,” or induced by another person through sorcery. 12 Most interviewees admitted that they would first see a traditional healer before considering treatment in a hospital. In Ghana, most healthy respondents (without Buruli ulcer) said they would attend the hospital with an ulcerative lesion but would try herbal treatment if the lesion were a nodule; patients who had Buruli ulcer admitted that they would only go to the hospital if lesions became larger than expected. 13 Fear of surgery might be one of the factors associated with patients’ decision to postpone having treatment in a hospital.

Surgical treatment consists of two stages. In the first stage the aim is to excise all dead tissue, including a healthy tissue margin around the lesion—typically 3–4 cm. 14 Generally, this procedure results in a large surgical lesion that needs to be skin grafted in a second stage. 15 The whole procedure requires long hospitalization. In Benin, the median duration of hospitalization decreased over time reaching a median duration of 1 month only in 2001, but most authors have reported a median duration of hospital admission of around 3 months. 16,17 The large skin defect that results from surgical resection leaves the patient with a lesion especially painful during changing of dressings, and during exercise with daily activities. Surgery is difficult to perform in settings with poor resources, as there are very limited possibilities for general anesthesia and blood transfusion. Moreover, it requires extensive technical surgical skills and expensive dressing materials. Finally, with such extensive surgery, patients eventually heal at the expense of more severe sequelae than would result from less extensive surgery, conceivably resulting in more functional limitations, especially if no form of physical therapy is given to prevent contractures.

Antimycobacterial agents inhibit the growth of M. ulcerans in human tissues. 18 Moreover, appropriate antibiotics probably inhibit the production of mycolactone, 19 which is the major pathogenetic factor of M. ulcerans.20 It is hypothesized that with antibiotics, less extensive excision is required to obtain cure. With antibiotics alone, small lesions (diameter < 5 cm) successfully heal in about 81% of the cases. 21 After 2005, patients with ulcerated lesions first received antibiotic treatment, and if necessary, followed by surgery that tended to be less aggressive—typically, 1–2 cm rim into apparently healthy tissue.

Surgery may have its side effects but antibiotic treatment may impose several other problems. Antibiotic treatment requires daily injections with Streptomycin (10 mg/kg body weight) and oral Rifampicin, 15 mg/kg body weight. Apart from potential renal, auditory and vestibular toxicity with aminoglycoside antibiotics, the injections with streptomycin also pose an important logistic problem, although the need for prolonged daily dressings in case of longer treatment duration should be balanced against the impact and costs of surgery. Finally, antibiotic treatment with streptomycin is not an option for pregnant women, who are treated by surgery.

Functional limitations after treatment of Buruli ulcer have been studied, 22 and a questionnaire to assess functional limitations was developed 23 and validated 24 during the time that antibiotic treatment was uncommon. We showed earlier that higher scores for Buruli ulcer—related functional limitation correlated with school drop-put and loss of jobs. 25 Following the provisional guidelines of the World Health Organization (WHO), antibiotic treatment (along with surgery) was introduced in the National Program for Buruli ulcer in Benin in 2005. The aim of this study was to compare functional limitation scores in patients in Lalo, one of the treatment centers in Benin, that were treated before 2005 with surgery and patients treated after 2005 with surgery, antibiotics, or a combination of both.

METHODS

Study population.

In 2006, the 271 patients treated in the years 2003–2006 for Buruli Ulcer in Lalo, Benin (Center de Dépistage et de Traitement de l’Ulcère de Buruli de Lalo) were contacted based on records kept by hospital administration. Individuals could participate in the study if their treatment of Buruli ulcer was completed at least 3 months earlier, when functional limitations are expected to have stabilized. Excluded were patients younger than 3 years of age and patients that were not in the hospital administration of Lalo’s health center but reported spontaneously to the study team. Patients were interviewed in their home village between July 2006 and May 2007 and were asked general questions about consequences of Buruli ulcer disease (BUD) on education and occupation. Data were retrieved on the size of lesion (in cm diameter) at start of the treatment, location of the lesion, age, duration of admission or follow-up from the hospital, and type of treatment (including whether physical therapy was given or not) were obtained from the patient’s hospital record and the BU1 WHO. At follow-up, the Buruli ulcer functional limitation score (BUFLS) questionnaire was applied, the lesion of the former Buruli ulcer was inspected, and muscular atrophy was registered if present.

All participants or their caretakers agreed to inclusion in the study. The study protocol was reviewed and approved by the local hospital and health authorities in Benin.

Treatment of Buruli ulcer patients.

Before 2005, all Buruli ulcer patients received surgery as treatment. In the first month of 2005 treatment was changed; patients without contraindication for antibiotic treatment (e.g., pregnancy) were treated with streptomycin and rifampicin daily. Antibiotic treatment was continued for 8 weeks. After 4 weeks of treatment, patients were evaluated; in case the lesion reduced to less than 50% of initial size, surgical treatment was added to antibiotic treatment. Another reason to add surgical treatment would be if no further reduction of size was achieved after week 4 of antibiotic treatment. Patients with a contraindication for antibiotic treatment, with very severe and extensive Buruli ulcers, or patients that for logistical reasons could not receive daily antibiotic treatment received surgical treatment only.

Questionnaire.

A questionnaire previously developed, tested, and described in detail was used to assess functional limitations 25 (Appendix 1). Questions correspond to patient’s ability to perform 19 day-to-day activities; food preparation, personal care, daily work activities, and mobility. Functional limitation scores were recorded on an ordinal scale; 0 points indicate an activity was not limited, 1 point indicates an activity was carried out with difficulties, and 2 points indicate an activity is not possible. The sum of the scores was then divided by the maximal score applicable for the patient and multiplied by 100. “No limitations” is indicated by a zero score and a high score indicates more functional limitation.

Data analyses.

Data analyses were performed using SPSS (version 14.0, SPSS, Chicago, IL); χ2 tests and t tests, or Mann-Whitney U (MWU) tests as appropriate were used for the univariate analyses. Role of antibiotic treatment on functional limitations was analyzed by a logistic regression analysis (manually entered). The variables as presented in the univariate analysis were studied on confounding and effect modification.

RESULTS

Study population.

In all, 271 patients were treated in the years 2003–2006 for Buruli ulcer in Lalo, Benin. Of these individuals, 92 could not be found; for 62 (67%) of these 92 individuals the address in the hospital file was incorrect, 19 (21%) had moved, and 11 (12%) died.

Functional limitation scores could be obtained for 179 patients (66% of the total number of 271 that were treated in the years 2003–2006).

The median age of participants at treatment was 12 years (Table 1); almost 10% had multiple lesions. Around 90% of patients had an ulcer of at least 5 cm in diameter. Around 4% had an ulcer that covered an entire arm or leg. Almost 50% had functional limitations; the mean score was 6.3, the median score was 0 (interquartile range [IQR] 0–8). Lesions treated with antibiotics with or without surgery were smaller than lesions treated with surgery only. No statistically significant differences were found in the number of ulcers not healed at follow-up and in the duration of admission. Eleven of the 69 participants treated with antibiotics did not receive surgery at all. These 11 participants had a functional limitation score similar to the other participants, 4 of them (36%) and a functional limitation score above zero. Of this small proportion of participants treated with antibiotics only, five patients (46%) had a lesion < 5 cm in diameter.

Table 2 shows that in 2006, one year after the introduction of antibiotic treatment, the percentage of patients with lesions > 15 cm seemed to decrease, whereas the number of small (< 5 cm) lesions seemed to increase. The percentage of patients with functional limitations was high in 2003, when the number of lesions > 15 cm was highest.

In Table 3, the association between characteristics of the lesion and its treatment and a functional limitation (a score > 0) was given. A lesion > 15 cm had the highest percentage of patients with a functional limitation.

Table 4 shows the result of the logistic regression on treatment with antibiotics plus or minus surgery versus surgery only and the outcome on development of functional limitations in these two treatment groups. The model was not influenced by the variables of lesions on a joint, muscular atrophy, amputation, physical therapy, number of months since end of treatment, age, and sex (the variables from Tables 2 and 3). No effect modification was found among the variables. The only variable that showed to be a confounder was the size of the lesion at the start of treatment. The crude (unadjusted) odds ratio (OR) for antibiotic treatment on the risk of functional limitation was 0.91 (95% confidence interval [CI]: 0.50–1.69). The adjusted OR for antibiotic treatment on the risk of functional limitation was 1.03 (0.51–2.07). Therefore, both the crude OR and the adjusted OR do not show a difference in functional limitation scores between the two groups.

DISCUSSION

In this follow-up study of 179 former Buruli ulcer patients, there was no difference in functional limitations between the group of patients with antibiotic treatment alone or added to surgical therapy compared with surgical therapy only. The number of patients treated with antibiotic treatment was rather small. In this study, treatment with surgery alone was not associated with an increased risk for functional limitations. Comparing treatment outcome of patients between two different hospitals in Ghana, more extensive surgery was associated with longer hospital admission duration, but this was only found in univariate analysis, not in a multivariate logistic regression. Use of rifampicin appeared associated with faster ulcer healing but this finding was not confirmed in the multivariate analysis. 26

A new finding not reported earlier—but not surprising—is that larger (> 15 cm cross-sectional diameter) lesions are significantly associated with residual functional limitations (= BUFLS > 0).

Localization of the lesion of Buruli ulcer at the site of a joint appeared to impair the range of motion after healing 22 and in the scoring system for functional limitation that was developed 23 and subsequently validated in a new cohort, 24 this was the most important independent predictor of subsequent functional limitation.

The results of the current study confirm earlier reports that lesions at a joint are associated with increased risk for residual functional limitations; furthermore, amputation and visible muscular atrophy were associated with increased chance of residual functional limitations in our study. Non-healed lesions, increased age, female sex, and a lesion at a distal part of an extremity were independent risk factors for functional limitation in an earlier study. 25 Physical therapy has improved over the last years in Benin. There is no individual data available on the intensity of physical therapy received by each patient; therefore, this variable could, unfortunately, not be incorporated into the analysis.

In 2006, one year after the introduction of antibiotic treatment of all patients with Buruli ulcer in Benin, the number of small (category I) lesions (< 5 cm) at presentation increased while the number of large (> 15 cm; category III) lesions decreased. This might reflect earlier reporting, perhaps as a result of the introduction of antibiotic treatment or of patient education. In Zagnanado in Benin, patient delay appears to have dropped earlier to 30 days in 2001. 27 In the Ga West District, 504 randomly selected heads of households were interviewed about their preferences of treatment if they had Buruli ulcer, and 72% believed sufferers of Buruli ulcer would first seek traditional treatment. Even when things would turn out bad after some time 48% would prefer a local nurse or doctor, while only 8% would go to the hospital. 28 The study was conducted in 2005, just after the introduction of antibiotic treatment, and no patients with Buruli ulcer were included in the study. However, the pattern of responses was strikingly similar to results from two earlier studies. The study from Benin was a qualitative study using focus group discussions. 12 In the earlier study in three other highly endemic areas in Ghana, 13 the interviewees were all patients who had been admitted to the hospital with various conditions, including Buruli ulcer.

In the current study, we were unable to retrieve 92 of 271 eligible study participants representing 34% of the total group of individuals treated in Lalo in the study period. Of these 92 individuals, 62 could not be found because addresses were incorrectly recorded in the hospital records. In rural Benin, there is no official recording system for addresses of houses; the address is usually descriptive but rather imprecise. In 19 of the individuals that could not be found, it was made clear by villagers that they moved out when asked about their whereabouts. Here, a potential bias may be caused by the fact that rural people with disabilities might flee to urban areas to avoid stigma and to gain independence. 29,30 People with more severe functional limitations after treatment of Buruli ulcer might have therefore preferentially moved out. Because all individuals deceased were 75 years of age and over, we do not think that this group represents a bias in our results; they did not appear to have died of a complication of Buruli ulcer disease.

The duration of treatment was similar for the different treatment options, yet it has to be kept in mind that antibiotic treatment can be given in the outpatient setting once the role of antibiotic treatment has been established and daily observed treatment guaranteed.

With the introduction of antibiotic treatment, new patients with Buruli ulcer are offered hope for healing without extensive and destructive surgery; but they still need to be encouraged to report early to prevent functional limitations resulting from extensive tissue damage caused by long patient delay. In the current study, no advantage on functional limitations was found since the start of antibiotic treatment. Yet, the advantages of antibiotic treatment may involve other areas, like costs of treatment or a change in help-seeking behavior. Future studies need to address functional limitations as outcome in randomized, controlled trials assessing the role of antibiotic treatment in Buruli ulcer and ways to shorten patient delay need to be studied. Earlier reporting may be the most important factor to fully benefit from antibiotic treatment without the need for additional surgery.

Table 1

Characteristics of participants (N = 179)*

Table 1
Table 2

Size of lesions and functional limitation scores in different treatment years

Table 2
Table 3

Univariate analysis of variables associated with functional limitation

Table 3
Table 4

Logistic regression model assessing role of antibiotic treatment on functional limitation (score > 0)*

Table 4
Appendix 1*
Not applicableNot at allWith difficultiesEasily, on normal level
* If more than 6 of 19 items of the questionnaire are not applicable for a patient, no functional limitation score can be calculated.
Preparation of food/eatingFetching water from pump
Pound fufu/manioc
Pouring water from a bottle into a glass cutting vegetables with a knife
Clothing/personal care takingPutting on T-shirt
Wash yourself
Cleaning yourself after toilet going
WorkingUsing a cutlass
Heave loads on head
Carry harvest home
Opening bottle with screw top
Tie a knot
MobilityWalking level ground
Walking uphill
Walking downhill
Running
Squatting
Kneeling
Standing up from floor

*

Address correspondence to Ymkje Stienstra, Departments of Internal Medicine, Division of Infectious Diseases. Current position at Department of Internal Medicine, Division of Infectious Disease, Tropical Medicine and AIDS, Academic Medical Center, University of Amsterdam, Building F4-222, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail: y.stienstra@amc.uva.nl

Authors’ addresses: Yves Barogui, Department of Internal Medicine, Division of Infectious Disease, Tropical Medicine and AIDS, Academic Medical Center, University of Amsterdam, Building F4-222, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. R. Christian Johnson, Ghislain Sopoh, and Ange Dossou, Programme National Lutte contre la Lèpre et l’Ulcère de Buruli, Ministère de la Santé, Cotonou, République du Bénin. Tjip S. van der Werf, Departments of Internal Medicine and Pulmonary Diseases and Tuberculosis, Infectious Diseases and Tuberculosis Service, University Medical Centre Groningen, University of Groningen, PO Box 30001 9700 RB Groningen, The Netherlands. Pieter U. Dijkstra, Department of Rehabilitation, University Medical Centre Groningen, University of Groningen, PO Box 30001 9700 RB Groningen, The Netherlands. Ymkje Stienstra, Departments of Internal Medicine and Pulmonary Diseases and Tuberculosis, Infectious Diseases and Tuberculosis Service, University Medical Centre Groningen, University of Groningen, PO Box 30001 9700 RB Groningen, The Netherlands.

Acknowledgments: We thank Bienvenu Gbemadon and Elie Hounsah for their assistance with data collection.

Financial support: This study was funded by the EU-FP6 (contract INCO-CT-2005-015476–project BURULICO), the Anna Foundation, and the AXA Insurance Company. Y. Stienstra received a grant from the NWO (Dutch Organization for Scientific Research).

REFERENCES

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    Portaels F, Meyers WM, Ablordey A, Castro AG, Chemlal K, de Rijk P, Elsen P, Fissette K, Fraga AG, Lee R, Mahrous E, Small PL, Stragier P, Torrado E, Van Aerde A, Silva MT, Pedrosa J, 2008. First cultivation and characterization of Mycobacterium ulcerans from the environment. PLoS Negl Trop Dis 2 :e178.

    • Search Google Scholar
    • Export Citation
  • 2

    Durnez L, Eddyani M, Mgode GF, Katakweba A, Katholi CR, Machang’u RR, Kazwala RR, Portaels F, Leirs H, 2008. First detection of mycobacteria in African rodents and insectivores, using stratified pool screening. Appl Environ Microbiol 74 :768–773.

    • Search Google Scholar
    • Export Citation
  • 3

    Johnson PD, Azuolas J, Lavender CJ, Wishart E, Stinear TP, Hayman JA, Brown L, Jenkin GA, Fyfe JA, 2007. Mycobacterium ulcerans in mosquitoes captured during outbreak of Buruli ulcer, southeastern Australia. Emerg Infect Dis 13 :1653–1660.

    • Search Google Scholar
    • Export Citation
  • 4

    Marsollier L, Robert R, Aubry J, Saint Andre JP, Kouakou H, Legras P, Manceau AL, Mahaza C, Carbonnelle B, 2002. Aquatic insects as a vector for Mycobacterium ulcerans.Appl Environ Microbiol 68 :4623–4628.

    • Search Google Scholar
    • Export Citation
  • 5

    Portaels F, Chemlal K, Elsen P, Johnson PD, Hayman JA, Hibble J, Kirkwood R, Meyers WM, 2001. Mycobacterium ulcerans in wild animals. Rev Sci Tech 20 :252–264.

    • Search Google Scholar
    • Export Citation
  • 6

    Williamson HR, Benbow ME, Nguyen KD, Beachboard DC, Kimbirauskas RK, McIntosh MD, Quaye C, Ampadu EO, Boakye D, Merritt RW, Small PL, 2008. Distribution of Mycobacterium ulcerans in Buruli ulcer endemic and non-endemic aquatic sites in Ghana. PLoS Negl Trop Dis 2 :e205.

    • Search Google Scholar
    • Export Citation
  • 7

    Benbow ME, Williamson H, Kimbirauskas R, McIntosh MD, Kolar R, Quaye C, Akpabey F, Boakye D, Small P, Merritt RW, 2008. Aquatic invertebrates as unlikely vectors of Buruli ulcer disease. Emerg Infect Dis 14 :1247–1254.

    • Search Google Scholar
    • Export Citation
  • 8

    Debacker M, Portaels F, Aguiar J, Steunou C, Zinsou C, Meyers W, Dramaix M, 2006. Risk factors for Buruli ulcer, Benin. Emerg Infect Dis 12 :1325–1331.

    • Search Google Scholar
    • Export Citation
  • 9

    Pouillot R, Matias G, Wondje CM, Portaels F, Valin N, Ngos F, Njikap A, Marsollier L, Fontanet A, Eyangoh S, 2007. Risk factors for Buruli ulcer: a case control study in Cameroon. PLoS Negl Trop Dis 1 :e101.

    • Search Google Scholar
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