Buruli ulcer disease

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Buruli Ulcer Disease: Cutting off the surgery

T.E. Hoornweg, s1619578; Supervisor: T.S. van der Werf

Buruli Ulcer Disease (BUD) is one of the fourteen neglected tropical diseases assigned by the World Health Organization (WHO)1. Although the first report of BUD dates back to 1897, the first definitive description is from The Democratic Republic of Congo in 19481. However, in recent years many countries of sub-Saharan Africa are endemic for BUD and an alarming increase in number of detected cases has been reported from distinct regions of Benin, Côte d'Ivoire and Ghana. There the disease imposes a large burden on affected populations, leading to social stigmatization and loss of livelihood1-3.

The disease is mainly found in riverine areas with a humid hot, climate. It has been observed scattered around the world, with foci in Africa, Asia and South America. However, BUD has also been found to occur in temperate climates in Australia. Up to now mode of transmission is still not completely elucidated, although penetrating skin trauma in and around water is thought to inoculate Mycobacterium ulcerans - the disease causing pathogen - into subcutaneous tissues 2,4-6.

Buruli Ulcer is mainly observed in children, affecting the subcutaneous fat tissue4. Clinical picture ranges from painless nodules to large undetermined lesions that heal spontaneously but slowly. The disease does not have many systemic effects, probably because of production of Mycolactone - a diffusible cytotoxin with immunomodulary properties7,8 - by M. ulcerans5,6. Still, extensive scarring of lesions can lead to contracture of the limbs, blindness, deformities and other adverse outcomes. 1,2,4-6

Since 1948, many different therapies have been explored, but until recently extensive debridement surgery was still the standard therapy for disease1. Although early excision of non-ulcerated papules and nodules is curative, surgical management of advanced disease is difficult5. Unfortunately, many patients present late since they live in rural areas and families cannot afford time to attend hospitals or because patients firstly attend a ritual healer as they believe witchcraft and curses are the cause of disease9. Furthermore, many patients fear surgery, as many patients suffer from functional impairments after surgery, or do not have access to surgical treatment1,4,6,9,10.

Sometimes, for instance in patients witch facial lesions surgery is not even an option. And yet, as surgical treatment does not only have a poor acceptability and high costs, it also can not completely remove all bacteria and recurrences of disease are common1. Therefore, there is a great need for other treatments than surgical debridement.

Other treatments, like antimycobacterial agents, are active against M. ulcerans in vitro, and are bacteriocidal in animal models1,4. However, these results were not met in clinical impressions. Only very few randomized controlled trials were done and those existing are too small or inconclusive11,12. Therefore, possible beneficial effects could be overlooked because good agent regimens were never properly tested or because effects are not directly visible because of irreversible tissue damage and necrosis6,13.

Based on pilot studies and some observational studies the WHO recommended a combination of rifampicin an streptomycin for 8 weeks for managing BUD, hoping to reduce surgery and decrease relapse. A small clinical trial showed a minimum of 4 weeks treatment with this combination inhibits growth of M. ulcerans in nodules and plaques13,14. However, the size of the trial was too small to be conclusive and efficiency in preventing relapse was not evaluated.

Therefore, Nienhuis et al. set up a large randomized control trial investigating whether antimycobacterial treatment was able to cure BUD and whether a switch to oral treatment, which is preferred over injection of antimicrobial therapeutics in endemic African, would yield comparable results1.

In their study Nienhuis et al. randomly assigned patients with early, limited, confirmed M. ulcerans infection into two research groups. In one group patients received 8 weeks of treatment with rifampicin and streptomycin, in the other group patients received 4 weeks treatment with rifampicin and streptomycin followed by an oral combination of clarithromycin and rifampicin for 4 weeks. Treatment was directly observed at the nearest health facility and patients were followed up to one year after the start of treatment. Primary endpoint of their study was recurrence-free healing at one year after start of treatment without extensive surgical debridement.

151 patients enrolled in the study were divided in a group of 76 patients receiving 8 weeks of intramuscular injections of rifampicin and streptomycin and 75 patients receiving 4 weeks rifampicin and streptomycin injections, followed by 4 weeks oral treatment of rifampicin and clarithromycin. Overall healing rate was 93% and no significant difference in primary endpoint was found between both groups. Also no recurrence of disease was observed and few but similar rates of side effects were recorded in both groups.

Nienhuis et al. concluded that limited BUD can be safely and effectively treated by antimycobacterials without debridement surgery. Furthermore switching to oral therapy after 4 weeks provides similar efficacy as 8 weeks of intramuscular rifampicin and streptomycin injections.

Thus in this study Nienhuis et al. prove efficacy of antimicrobial treatment and clear paths for less expensive and better distributable therapies against BUD, preferentially oral treatment. This is a major advance as the majority of patients live in remote resource-poor, rural areas. Also it establishes antimycobacterial treatment for people, in whom streptomycin treatment is not an option. Because antimicrobial treatment is preferred logistically, financially and ethically over debridement surgery, this finding should have a huge clinical impact on the management of BUD.

However, although the study has a large proportion of patients which could be followed up to 52 weeks after start of treatment and almost all patients were laboratory confirmed M. ulcerans cases, it should be said that the set-up of the study was not completely optimal. The trial team performing measurements were not blinded for treatment allocation and also patients were aware of which treatment they were given. Also there was no formal external monitoring. Partly, this could be prevented by designing the study double blind, double dummy, but such a set-up would inevitably raise ethical questions about unnecessary injection of placebo into children risking development of injection abscesses or other side effects and causing harm and stress on the children.

To counteract blinding and monitoring problems, researchers let two independent wound experts from the University Medical Centre Groningen, blinded for treatment group, also assess primary study end point using digital photographs. Since their results did not alter the study results significantly, robustness of the study is strengthened.

Though, study design has another flaw. The WHO advocated 8 weeks of treatment with streptomycin and rifampicin. Yet there is no evidence that 8 weeks is the optimal length of treatment duration. In an earlier pilot study no viable Mycobacteria could be cultured after 4 weeks of treatment with Streptomycin and Rifampicin14. In this study only after four weeks this intramuscular treatment is switched to oral treatment witch Rifampicin and Clarithromycin. There could be a chance that at the time this switch was made no or very few viable Mycobacteria were left and oral treatment does not have any additional beneficial effect in M. ulcerans treatment. Therefore, I feel it cannot be said that oral treatment works as well as the injection treatment. Another interesting fact, supporting my thoughts, is that all 5 patients in which viable M. ulcerans was found after treatment, belonged to the group switched to oral treatment after 4 weeks. Interestingly, only 2 of the 5 patients belonged to the group that failed treatment, so the implication of these findings are not completely clear.

There are still a lot of questions on this topic that needs to be elucidated. For instance, it would be interesting to investigate why viable M. ulcerans could still be cultured from 3 patients in which disease did not recur within 52 weeks. Also the question whether oral treatment alone is sufficient for management of BUD remains to be answered. Moreover, the efficacy of antimycobacterials in more advanced BUD is not known. Another interesting question, which is not addressed in this study, is whether antimycobacterial treatment has effect on the prevention of disabilities. Because many patients of BUD get deformations, this is a very relevant question that should be addressed in the future. In addition, treatment of BUD with antimycobacterials is a time consuming process, so further investigation is needed to elucidate the possibility to speed up the beneficial effects of antimycobacterials. Hence a lot of research can and should still be done in the future.

Concluding, Nienhuis et al. showed the efficiency of antimycobacterial treatment for BUD in a large control randomized study. Furthermore, there was a low rate of recurrence, implicating the beneficial effects of antimycobacterial treatment over surgery. Switching to oral therapy after 4 weeks of streptomycin and rifampicin is shown to have similar clinical outcome as 8 weeks of intramuscular injections of streptomycin and rifampicin. However, in my opinion the study does not prove the effect of oral treatment and further studies have to be performed. Still, this study is a step forward proving efficiency and beneficial effects of other therapies than surgery in BUD, which will hopefully improve the treatment and management of Buruli Ulcer Disease.

References

  1. Nienhuis W.A. et al. Antimicrobial treatment for early and limited Mycobacterium ulcerans infection - a randomized controlled trial. RCT for BUD revision Oct 31, 2009 - 09-3057R1.
  2. Van der Werf T.S. et al. Mycobacterium ulcerans disease. Bull World Health Organ. 2005 Oct;83(10):785-91.
  3. Stienstra Y. et al. Factors associated with functional limitations and subsequent employment or schooling in Buruli ulcer patients. Trop Med Int Health. 2005 Dec;10(12):1251-7
  4. Stienstra Y. et al. Susceptibility to development of Mycobacterium ulcerans disease: review of possible risk factors. Trop Med Int Health. 2001 Jul;6(7):554-62.
  5. Van der Werf T.S. et al. Mycobacterium ulcerans infection. Lancet. 1999 Sep 18;354(9183):1013-8.
  6. Van der Werf T.S. et al. Mycolactones and Mycobacterium ulcerans disease. Lancet. 2003 Sep 27; 362 (9389): 1062-4.
  7. Philips R. et al. Immunosuppressive Signature of Cutaneous Mycobacterium ulcerans Infection in the Peripheral Blood of Patients with Buruli Ulcer Disease. J Infect Dis. 2009 Dec 1;200(11):1675-84.
  8. Coutanceau E. et al. Selective suppression of dendritic cell functions by Mycobacterium ulcerans toxin mycolactone. Journal of Experimental Medicine. 2007 Jun 11; 204(6): 1395-403
  9. Mulder A.A. et al. Healthcare seeking behaviour for Buruli ulcer in Benin: a model to capture therapy choice of patients and healthy community members. Transactions of the Royal Society of Tropical Medicine and Hygiene (2008) 102, 912-920
  10. Barogui Y. et al. Functional Limitations after Surgical or Antibiotic Treatment for Buruli Ulcer in Benin. Am. J. Trop. Med. Hyg., 81(1), 2009, pp. 82-87
  11. Espey D.K. et al. Pilot study of treatment of Buruli ulcer with rifampin and dapsone. Int J Infect Dis. 2002 Mar;6(1):60-5
  12. Revell W.D. et al. A controlled trial of the treatment of Mycobacterium ulcerans infection with clofazimine. Lancet 1973 Oct 20;2(7834):873-7.
  13. Sizaire V. et al. Mycobacterium ulcerans infection: control, diagnosis, and treatment. Lancet Infect Dis 2006; 6:288-96.
  14. Etuaful S. et al. Efficacy of the combination rifampin-streptomycin in preventing growth of Mycobacterium ulcerans in early lesions of Buruli ulcer in humans. Antimicrob Agents Chemother 2005;49(8):3182- 6.

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