Sunday, August 4, 2013

Buruli Ulcer - Part III (Diagnosis and Treatment)

How is Buruli ulcer diagnosed
There are currently four standard laboratory methods that can be used to confirm Buruli ulcer.  For true confirmation of disease, it is recommended that at least two of these studies be performed:
  1. Identification of Acid-fast bacilli (AFB) on microscopic smear stained by Ziehl-Neelsen (ZN) technique.  This test is easy to perform and provides rapid results but has low sensitivity (60%) which could result in misdiagnosis.
  2. Positive IS2404 polymerase chain reaction (PCR) for DNA from M. ulcerans.  This is the primary method for confirmation because it has the highest sensitivity (95%) and results can be available within 48 hours, however, it requires a sophisticated laboratory to run the test.  The World Health Organization (WHO) recommends that at least 50% of cases reported be confirmed by PCR. 
  3. Histopathological (microscopic examination) study of the skin by biopsy.  These results are available rather quickly and have a high sensitivity (about 90%), however, it too requires a sophisticated laboratory to process results and the test is expensive to perform.
  4. Culture of the ulcer to identify M. ulcerans.  This test also requires a sophisticated laboratory to process the results and the findings can take up to eight weeks for positive identification.  This test also has the lowest sensitivity (20-60%), which again can lead to misdiagnosis.

With the exception of the AFB smear, there are currently no diagnostic tests available that can be used to rapidly and accurately confirm the diagnosis of Buruli ulcer in rural remote areas where the disease is most prevalent. 

Given the difficulty in obtaining laboratory testing, diagnosis of Buruli ulcer is most often based on the clinical findings.  In a known endemic area, a trained and experienced person can make the diagnosis of Buruli ulcer based on the following information: 
  • affected persons live in or have travelled to a known endemic area
  • most persons affected are children under 15 years of age
  • approximately 85% of the lesions occur on the arms or legs
  • lesions on the legs are twice as common as those on the arms

For more information regarding diagnosis see: 


How is it treated
Early diagnosis and treatment is essential as 80% of cases detected early can be cured with a combination of antibiotics.   However, before treatment is started other diseases that can cause similar symptoms should be excluded.  These include:
  • tropical phagedenic ulcers (painful, rapidly enlarging sores)
  • chronic lower leg ulcers due to arterial and venous insufficiency (often found in older and elderly populations)
  • diabetic ulcer
  • cutaneous leishmaniasis
  • extensive yaws
  • cellulitis which may look like oedema caused by M. ulcerans infection, however, in the case of cellulitis, the lesions are painful and the person is ill and febrile.

Early nodular lesions seen at the onset of M. ulcerans infections are occasionally confused with boils, lipomas, ganglions, lymph node tuberculosis, onchocerciasis nodules or other subcutaneous infections such as fungal infections and should be ruled out.   In Australia, papular lesions may initially be confused with an insect bite. 

The WHO recommends combination therapy with daily intramuscular streptomycin and oral rifampicin for 8 weeks for all stages of disease.   Other combinations include the use of rifampin with clarithroymycin (which is safer to use in pregnancy) or rifampin and moxifloxacin (a new combination still being studied).

Recent clinical trials have shown that early stages of disease, prior to ulceration, respond well to treatment with combination anti-mycobacterial therapy, leading to high cure-rates without surgery.

Surgical debridement (the removal of the dead tissue) and skin grafting is recommended to promote healing and correct deformities when the disease is more advanced.

Daily exercises to prevent disability are also recommended for anyone affected by this disease.

Recurrence of Buruli ulcer following antibiotic treatment is less than 2% compared to 16–30% for those treated with surgical debridement alone.

For more information see: 


What can be done to prevent it
There are still major challenges that remain in the prevention and control of Buruli ulcer.  These include:
  • lack of knowledge surrounding the reservoir and route of transmission of M. ulcerans
  • lack of rapid, accurate and cost effective diagnostic tests that can easily be performed in rural and
  • remote areas
  • lack of a preventative vaccine 
  • limited treatment options

Although there is no current vaccine available to prevent Buruli ulcer, some studies have shown that the
Bacille Calmette–Guérin (BCG) vaccine (a vaccine administered in some countries for protection against tuberculosis) appears to offer some short-term protection from the disease.

Current prevention methods are based on early identification of cases with the main objective being to minimize the prevalence of Buruli ulcer as well as the life-long disability associated with the disease. 
To accomplish this, the following steps need to be taken:
  • information, education and communication at the community level to enhance early reporting
  • training of health workers and village volunteers to identify disease
  • laboratory confirmation of cases
  • standardized recording and reporting system as well as disease mapping
  • strengthening of health care facilities
  • monitoring and evaluation of control activities

In response to the above the WHO has developed technical and information materials to support the implementation of these activities.  More information may be found via the following link: http://www.who.int/buruli/control/en/


Current Efforts to Understand and Control the Disease:
The Global Buruli Ulcer Initiative (GBUI) is a partnership of Member States, academic and research institutions, donor agencies, nongovernmental organizations and the WHO that was established in 1998.  It is dedicated to raising awareness about Buruli ulcer, improving access to early diagnosis and treatment and promoting research to develop better tools for the treatment and prevention of disease.  

The WHO also holds regular meetings with all parties involved in Buruli ulcer control efforts.  These meetings provide an opportunity to share information, coordinate disease control and research efforts, and monitor progress.  These efforts have helped to raise the visibility of Buruli ulcer, and mobilized resources to fight it.

Under the WHO’s leadership and with support of non-governmental organizations, research institutions and governments of affected countries, steady progress has been made, changing the face of Buruli ulcer from a devastating, debilitating and difficult disease to one that can be treated and cured.

More information regarding the WHO's program can be found by going to WHO: Buruli ulcer elimination (BU) .


Research Initiatives to Improve the Understanding and Prevention of Buruli ulcer:
The WHO provides technical guidance, develops policies and coordinates control and research efforts.

Based on the need to improve control measures in the field, there are three main priorities for Buruli ulcer research:
  • improvements in antibiotic treatment
  • development of simple diagnostic tests
  • identifying the mode of transmission.

During the 5th WHO Advisory Group Meeting on Buruli Ulcer, held on 11–14 March 2002 in Geneva, Switzerland, a research subgroup identified six priority areas of research that could most likely to provide immediate direct benefit to Buruli ulcer patients in the medium term.   These were as follows:
  1. To better understand the mode of transmission
  2. Development of methods for early diagnosis
  3. Improvement of drug treatment and identification of new treatment modalities
  4. Development of effective vaccines
  5. To better understand cultural and socio-economic factors that may increase exposure to the disease as well as study the impact the disease has upon the community
  6. Improve upon reporting of incidence, prevalence and mapping of Buruli ulcer

There are also various networks and organizations now in place to further study Buruli ulcer and it’s impact.   These groups, identified by WHO, are as follows:

The World Health Organization Research Consortia

Research network
The following institutions are involved in Buruli ulcer research activities:

Partners of the Global Buruli Ulcer Initiative (per WHO)
The following donors and non governmental organizations (NGOs) are involved in Buruli ulcer control and research activities:


References:


Images:


Figure 1.Clinical symptoms of Buruli ulcer disease.(a) nodule on abdomen of a young child, (b) non-ulcerative edematous swelling of child's hand, (c), ulcer covering most of a young child's arm, (d) a plaque.
* Source: https://www.msu.edu/~merrittr/buruli_ulcer/bu_symptomsandtreatment.html


Buruli ulcer affecting large portion of the leg
* Source: http://ghitfund.org/en/about/globalhealth/disease/




A) Nonulcerative edematous lesion on the right middle finger as first seen; B) ulcerated lesions on the right middle finger ≈4 weeks later; C) extensive debridement, 5.5 weeks after first seen; D) cured lesion 5 months after first seen, 1 month after autologous skin graft. Photo and text from the CDC



Buruli ulcer affeting child's face
*Source: http://www.plasticsurgeryafrica.org/conditions_buruli1.htm



Healed Buruli lesions with scarring, right forearm and left knee.* Source: http://wwwnc.cdc.gov/eid/article/8/2/01-0119_article.htm



Typical deformity caused by buruli ulcer
*Source: http://www.fairmed.ch/en/topics/poverty_related_diseases/buruli_ulcer/buruli_history/




Leg deformity caused by Buruli ulcer infection
*Source: http://www.who.int/buruli/photos/complication_contracture_leg_large.jpg


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