Buruli ulcer disease

old post

Saturday, 6 February 2010

From WHO documents and other sources.


The disease affects men and women equally.
About 75% of affected persons are children below 15 years and 80% of the lesions are on the limbs, mostly lower limbs.
Transmission of the disease has not been proved but it could be linked to entry of bacilli from environment through injury or wound, perhaps sometimes with some involvement of insects.

Mycolactone

A cytopathic toxin (Mycolactone ) is an unusual macrolide produced by Mycobacterium ulcerans and it is the primary virulence factor in Buruli ulcer.

* 743 Da molecule.

* 12 ring macrolide with polyketide side chains.

* Coded on plasmid pMUM001.This 174-kb plasmid bearing a cluster of genes encoding giant polyketide synthases (PKSs), and polyketide-modifying enzymes, and demonstrate that these are necessary and sufficient for mycolactone synthesis.

* Produces G0/G1 cell cycle arrest within 48 hours with apoptotic cell death within 72 hours in mammalian fibroblasts.

* Causes immunosuppression by blocking from interleukin 2 productionactivated T-lymphocytes and stops TNF-induced nuclear factor κβ activation.

Subtypes

* Mycolactone A - African strains
* Mycolactone B - African strains
* Mycolactone C - Australian strains
* Mycolactone D - Asian strains

Incubation period

Mycobacterium ulcerans infection (MUI) seems to have an average incubation period of 2-3 months.
It can develop in a localised form (papule or nodule) or as more diffuse forms (oedematous lesion or plaques).
Sometimes papules and nodules progress to small self-healing ulcers. It is possible that these lesions are more common and more often undiagnosed.
Nodules, oedematous lesions and plaques, if untreated, lead to more extensive ulcers, that can go deeper to the bones and that can also disseminate to other parts of the body.
The ulcers if not cared for can be life-threatening and lead to extensive disabilities.

Non-ulcerative forms

Papule



-Papule is a painless, raised skin lesion, less than 1 cm in diameter.

-The surrounding skin is reddened. Papules are commonly seen in Australia.



Nodule





-Nodule is a lesion that extends from the skin into the subcutaneous tissue and is 1–2 cm in diameter.

-It is usually painless but may be itchy, and the surrounding skin may be discoloured compared with adjacent areas.

-Nodules are commonly seen in Africa.

-Nodules are firm, attached to the skin but not to deeper tissue so can be moved.

-The nodules gradually increase in size and sometimes are surrounded by a firm oedematous area.

-At the nodular stage, treatment is simple and prevents deformities.



Plaque





-A plaque is a large painless swelling of more than 3 centimetres in diameter with clearly marked borders.

-This is a firm, elevated, well-demarcated lesion with irregular edges.

-The skin over the lesion is often reddened or otherwise discoloured.

-The lesions are more than 2 cm and up to 15 cm in diameter.

-The skin feels hard like cardboard.

-Treatment of this form of the disease can be difficult.



Oedematous area






-Oedema often involves the arms and the legs.

-Some times whole limb or large areas may be oedematous.

-It is firm, extensive non-pitting kind of swelling, usually not accompanied by pain or tenderness.

-The affected area has ill-defined margins. There may be colour changes over affected region and the disease may be accompanied by fever.

-Treatment of this form of the disease is difficult.

Ulcerative forms

All the initial forms (nodule, oedematous form or plaque) sooner or later lead to ulcerative lesions.
However, MUI ulcers can also be very extensive, covering large areas or limbs and going deep in to the bones.
The ulcers may be localised or be disseminated.
Usually all the ulcers caused by MUI are painless.



Small ulcers





- Minor ulcer of MUI is usually a small ulcer 1-2 cm in diameter that develops from a small nodule.

-The centre is necrotic and slightly undermined edge rapidly epitheliazes. These lesions tend to self-heal rapidly with other complications such as bone involvement or disssemination.

-Typical ulcers are not very painful and often have whitish-yellowish slough in the centre.

-With good treatment, small ulcers can heal with no deformity.



Large ulcers




-A Major ulcer of MUI arises from a nodule and is the form perceived as "classic Buruli ulcer".

-When fully developed, the edges are well-demarcated, undermined and typically demonstrate relative geometric symmetry.

-The centre of the ulcer may contain whitish cotton-wool like necrotic slough with scattered eschars. The surrounding skin is indurated and often hyperpigmented.

-It usually presents as single large ulcer.

-Bones close to the ulcer can develop osteitis. Without skin grafting and appropriate measures, such ulcer can heal, but such healing can result in disabling cicatricial contractures.

-These ulcers often lead to serious deformities and treatment at this stage is very difficult and expensive.

Large ulcers are very common because most affected people wait until it is too late.

Deformities

Arms and legs with deformities are common because affected people often go to hospital too late.
Trunk and face deformities are common because affected people often go to hospital too late.
Sometimes the eyes are damaged, which may lead to blindness.

Laboratory findings

In addition to the clinical diagnosis, at least one of the following laboratory findings is required to confirm the diagnosis of BU:

-acid-fast bacilli (AFB) in a smear stained by the Ziehl-Neelsen technique.

-histopathological study of a biopsy specimen showing typical necrosis and acid-fast bacilli.

-positive polymerase chain reaction (PCR) test for M. ulcerans.

-and/or positive culture of M. ulcerans.

Diagnosing M. ulcerans infection

Non painful nodules or ulcers with undermined edges can be easily recognised by experienced health personnel in endemic areas.

-Taking a swab from the undermined edges of an ulcer and staining it with Ziehl Neelsen stain for red-coloured acid fast bacilli can help in diagnosis of doubtful cases.

-Cultivation of M. ulcerans from exudates of ulcers or from appropriate biopsy materials in Lowenstein-Jensen media at 30-32°C is possible only at specialised laboratories but it requires 4-6 weeks.

-Specialised laboratories can also use more sophisticated techniques such as PCR for confirming the diagnosis.

Treatment

Recent research and clinical experience have shown that a combination of rifampicin and an aminoglycoside (streptomycin or amikacin) used together and given for eight weeks is promising in the management of M. ulcerans disease and are effective in curing small lesions.

-Used preoperatively, help in reducing the extent of surgical excision by as much as 50%.

-Used in peri-operative period, they reduce the chances of relapse of M. ulcerans infection.

- Recommended Drug dosage :

Rifampicin, 10 mg/kg body weight by mouth daily for 8 weeks;
Streptomycin, 15 mg/kg body weight by intramuscular injection daily for 8 weeks.

Role of Surgery

Large ulcers, plaques and oedmatous form lesions of MUI also need surgical excision, after an initial treatment with antibiotics for 8 weeks.

-Antibiotics (Rifampicine and Streptomycin) given one hour before the intervention give good coverage for perioperative period and reduce the risk of recurrence.

- All the involved tissues including deeper structures such as fascia, muscles, etc. may need to be excised. Exploratory incisions and blunt exploratory dissection can help in determining the extent of lesion. Marginal recurrences are frequent if excision is inadequate. In early cases, it may be curative. In more advanced cases, such treatment probably reduces the area that will require subsequent surgical excision.

Differential Diagnosis of M. ulcerans lesions

(1) - Actinomycosis

Actinomycosis is a subacute to chronic bacterial infection caused by filamentous, gram-positive, anaerobic to microaerophilic bacteria (Actinomyces israelii) that are not acid fast. It is characterized by contiguous spread, suppurative and granulomatous inflammatory reaction, and formation of multiple abscesses and sinus tracts that discharge sulfur granules. A Gram-stained smear of the specimen may demonstrate the presence of beaded, branched, gram-positive filamentous rods, suggesting the diagnosis. It may look like disseminated or plaque form of the MUI.


(2) - Tropical Phagedenic

Ulcer Tropical phagedenic ulcer, coinfection with Fusobacterium and a spirochete, Borrelia vincentii. It is characterized by necrotic ulceration associated with prominent tissue destruction. Usually it is associated with a nasty odor is caused by production of butyric acid. Antibiotic treatment is effective for eliminating the bacterial infection. Lesions of phagedenic ulcers are typically painful. The ulcer margins are raised and firm but not undermined.


(3) - Chronic ulcer of Cutanous Leishmaniasis

Leishmaniasis is a parasitic disease spread by the bite of infected sand flies. Persons with cutaneous leishmaniasis have one or more sores on their skin. Initially, the lesion is a small red papule up to 2 cm in size. The papule ultimately ulcerates. The sores can change in size and appearance over time. They often end up looking somewhat like a volcano, with a raised edge and central crater. Some sores are covered by a scab. The sores can be painless or painful. Some people have swollen glands near the sores.


(4) - Pyoderma gangrenosum

It is an inflammatory, ulcerative dermatitis of unknown etiology. The ulcers have irregular borders, with purulent necrotic exudate and are painful. It is associated with systemic diseases in at least 50% of patients who are affected. The diagnosis of PG is made by excluding other causes of similar appearing cutaneous ulcerations, including infection, malignancy, vasculitis, collagen vascular diseases, diabetes, and trauma. Two primary variants of PG exist: the classic ulceration usually observed on the legs and a more superficial variant known as atypical PG that tends to occur on the hands.

(5) - Cold Abscess

Cold abscesses are abscesses without the usual redness, inflammation and heat that accompanies them. These are chronic abscesses without any healing and tendency to create fistulas. The cold abscess may be caused by tuberculosis bacillus.


(6) - Yaws

Yaws is a remarkably common chronic infectious disease that occurs mainly in the warm humid regions of the tropics. Yaws features characteristic bumps on the skin of the face, hands, feet, and genital area. Almost all cases of yaws are in children under 15 years of age. Yaws is caused by Treponema pertenue. Yaws begins when the spirochete penetrates the skin at a spot where it was scraped, cut, or otherwise compromised. At the entrance site, a painless bump arises within 2-8 weeks and grows. Patients with yaws develop recurring crops of bumps and more swollen glands. These bumps may be painless like the mother yaw or they may be filled with pus, burst, and ulcerate. The affected child often experiences malaise and anorexia. In its late stage, yaws can destroy areas of the skin, bones, and joints and deform them.