MJA
MJA

Consensus recommendations for the diagnosis, treatment and control of Mycobacterium ulcerans infection (Bairnsdale or Buruli ulcer) in Victoria, Australia

Paul D R Johnson, John A Hayman, Tricia Y Quek, Janet A M Fyfe, Grant A Jenkin, John A Buntine, Eugene Athan, Mike Birrell, Justin Graham and Caroline J Lavender, on behalf of the Mycobacterium ulcerans Study Team*
Med J Aust 2007; 186 (2): 64-68. || doi: 10.5694/j.1326-5377.2007.tb00802.x
Published online: 15 January 2007
Epidemiology

Mycobacterium ulcerans was discovered in 1948 by Australian scientists who were investigating a cluster of patients with unusual skin ulcers in the Bairnsdale region of eastern Victoria.2 M. ulcerans is related to the causative agents of tuberculosis and leprosy, but is transmitted from the environment rather than from person to person.3 The major virulence factor is a lipid toxin, mycolactone, which causes necrosis of fat and subcutaneous tissue.4

M. ulcerans infection is not fatal, but can result in significant morbidity and is expensive to treat.5,6 It has been reported in more than 30 countries, and is currently a significant public health problem in sub-Saharan Africa (Buruli ulcer).3 In Australia, there are active foci in coastal Victoria (Bairnsdale ulcer),7 Far North Queensland (Daintree ulcer),8 and near Rockhampton.9 Single cases also occur elsewhere in the Wet Tropics. The reason for this patchy distribution is unknown, but molecular typing has shown differences between strains isolated from patients in different regions.10

BU continues to occur in low numbers in the Bairnsdale/Gippsland Lakes area. In 1980, a new focus was noted near Tooradin and Warneet (Box 1) on Westernport,7 and this was followed by significant outbreaks at East Cowes on Phillip Island (1992–1995),7,11,12 Frankston and Langwarrin (1990–1998),7 St Leonards (1998–2001), Point Lonsdale (since 2002)13 and Barwon Heads and Ocean Grove (since 2005). There are also frequent single cases from other parts of the Mornington and Bellarine Peninsulas.

The incidence of BU in Victoria has increased sharply in recent years (Box 2). It is unlikely that this increase is due to improved diagnosis, as there has been considerable publicity since 1994, and all diagnostic polymerase chain reaction (PCR) assays have been available at a single institution since 1995.14 BU was made formally notifiable in Victoria from January 2004. Although the incidence in Victoria is currently only 1.4 per 100 000 overall, it is estimated that up to 6% of the permanent population of East Cowes (1992–1995)15 and 1% of the permanent population of Point Lonsdale have required treatment. Visitors to endemic areas are also at risk, and brief contact may be sufficient to become infected.

Diagnosis

Once an ulcer is present, diagnosis is usually straightforward, provided BU is considered. Delays are most likely when patients present outside endemic areas, or when the patient has a non-ulcerative presentation (eg, nodule, papule, plaque or acute oedema).

Acid fast bacilli (AFB) smear-positive swabs or specimens from skin ulcers are strongly suggestive of M. ulcerans infection in patients from Victoria who have not travelled overseas.

IS2404 PCR,8,14,17 which can be performed directly from ulcer swabs, approaches 100% sensitivity and specificity (P D R J, J A M F, independent personal observations). Culture is also diagnostic, but generally takes several weeks. A positive M. ulcerans PCR result is sufficient evidence to proceed to treatment.

A negative M. ulcerans PCR result, when AFB are detected on the smear, is likely to indicate an alternative diagnosis.

A negative AFB smear and negative M. ulcerans PCR result make the diagnosis of BU unlikely, but it should not be completely excluded.

If an ulcer is present, obtain samples deep to the undermined edge using two standard cotton-tipped swabs. These swabs may be dry or of the standard transport medium type (swabs stored in charcoal transport medium should be avoided). Ensure that some material is visible on each swab. The swabs (one labelled “for PCR only”) should be sent to your usual pathology service for microscopy for AFB, M. ulcerans PCR, and culture. “Possible Bairnsdale ulcer” should be written on the clinical notes. A smear result is usually available within the same working day. Separate swabs or specimens should be obtained for other pathogens or conditions, depending on the clinical situation.

Other specimen types suitable for PCR include fresh tissue biopsies (preferably not stored in large volumes of buffer or saline, nor wrapped in gauze) and paraffin-embedded fixed tissue sections (not suitable for culture).

If an ulcer is not present but there is a suspicious plaque, necrotic patch, nodule or acute oedematous presentation in an at-risk patient, an incisional or excisional biopsy should be performed. Some patients notice an apparent increase in the rate of progression of the disease following biopsy, and this should be carefully discussed.

Treatment

Small lesions sometimes resolve spontaneously, but this is thought to be uncommon. The rate of progression varies among patients. Even though host immunity progressively develops during infection, ulcers may become very extensive. Relapse after treatment is not uncommon,18 so regular follow-up is recommended.

Cure with medical therapy alone is possible, and there is increasing interest in this approach in western Africa.1,19 However, in Victoria, where there is ready access to surgery, we believe that surgery or combined surgical and medical therapy is the most efficient way of effecting cure. The trend in management is towards conservative surgery with macroscopic removal of necrotic tissue and the use of adjuvant antibiotics. Patients may be best managed by a team, with surgeons working with infectious diseases specialists, GPs and allied health practitioners.

For difficult or recurrent disease or when antibiotics and surgery are failing, other modes of therapy, including continuous heat therapy or hyperbaric oxygen, may be considered.

Surgery

In most situations, we recommend surgery that aims to remove all necrotic tissue, but preserves any involved deep structures (eg, tendons, nerves, joint capsules, major blood vessels). If bone is involved, it should be conservatively debrided.

Where possible, remove a small buffer of normal tissue, if doing this will not unduly increase the morbidity of the procedure. The skin defect should then be closed primarily, or by grafting if necessary.

An orientated resection specimen that includes the skin and subcutaneous tissue should be submitted for histopathology. There is evidence from a recent case series that AFB or granulomatous inflammation or necrosis at the margins predicts relapse and the need for antibiotic treatment.20 If margins are clear, drug therapy is usually not necessary. However, clinicians are advised to discuss the risk of relapse versus antibiotic cost and risk of side effects to assist patients in making an informed choice. PCR testing of resection margins is not recommended.

Hyperbaric oxygen

Some clinicians favour the use of hyperbaric oxygen to assist healing, and there are supportive data from a mouse model.21 An Italian group is investigating the use of adjuvant hyperbaric oxygen for BU in Benin, but results are not yet available.

Antibiotic therapy

In the laboratory, M. ulcerans is susceptible to a range of antibiotics. The WHO recommends the combination of oral rifampicin and parenteral streptomycin for initial treatment.1 The use of streptomycin (replaced by amikacin in Australia) combined with oral rifampicin is supported by animal data,22 a published case series from western Africa,19 and observational data presented at the annual meetings of the WHO Global Buruli Ulcer Initiative.23 In Victoria, where many patients are elderly, clinicians have encountered problems with toxicity from amikacin (renal, balance or hearing difficulties), and may prefer less toxic oral combinations. However, there is less human evidence to support this practice, and in animal models, oral-only combinations are less effective at killing M. ulcerans,24 with the possible exception of rifampicin plus moxifloxacin.25

Antibiotic treatment is relatively expensive, may require monitoring for toxicity, and is generally given for at least 3 months in total, with the intravenous component typically for 4 weeks. However, appropriate use of antibiotics allows more conservative surgery and reduces the risk of relapse. Box 3 presents recommendations for use of oral antibiotics, and Box 4 contains recommendations for use of intravenous amikacin.

Prevention of Bairnsdale ulcer

It is not understood why M. ulcerans outbreaks occur in new areas or why the disease has spread westwards from the original endemic area near the Gippsland Lakes. There are no public health interventions that can remove M. ulcerans from the environment, although there may be a natural cycle of human infection that lasts several years, after which the incidence of new cases in a given area abates. There is circumstantial evidence that nutrient enrichment of very low-lying coastal environments may be a factor in the appearance of outbreaks.7,12,28

M. ulcerans has been detected by PCR in plant material and mud obtained from swamps in endemic areas,29 a golf course irrigation system that used recycled water,28,29 and from aquatic water insects in Africa.30 At Point Lonsdale, M. ulcerans has been detected by PCR in soil and leaf litter from a stormwater drainage system, mud from a lake, and about 0.5% of more than 10 000 mosquitoes trapped during 2004–2006 (unpublished data). It is yet to be determined whether mosquitoes play a role in human disease.

Studies from African endemic areas have reported that farming activities close to rivers31 and swimming32 may be risk factors, and that wearing trousers31 and a shirt33 when working outdoors appears protective. A recent case–control study performed on the Bellarine Peninsula has shown that direct exposure to the environment and to mosquitoes are risk factors, and wearing protective clothing and insect repellent appears protective (unpublished data).

Morbidity and cost can be reduced by early diagnosis. Therefore, local doctors are central to early detection. When an outbreak occurs in a new area it may take some time for this disease to be recognised, so public health authorities need to provide timely information to both clinicians and the general public about disease activity and the location of new endemic areas.

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