Disease Overview
Mycobacterium ulcerans was first identified in Australia, and Mycobacterium ulcerans was identified as the causative agent of the disease. This bacterium is a non-colour-producing group of Mycobacterium, and colonies can be formed generally after 3-5 weeks on Roche medium at 30°C, similar to those of Mycobacterium tuberculosis. The ecology of this bacterium is not yet clear, may be tropical soil saprophytic bacteria, the infection is closely related to the environment, the patient often has a history of trauma.
Symptoms and signs
It starts as an isolated, painless, firm subcutaneous nodule that slowly increases in size. After a few months the nodules have an itchy surface and form blisters. Upon rupture, a necrotic ulcer forms and rapidly expands to the periphery. The margins are irregular and subterranean. The surrounding skin is elevated and hyperpigmented. The ulcerated surface is covered with yellowish gray loose necrotic tissue. The number of ulcers is mostly single, but satellite ulcers may occur around them. The ulcers are as small as 2 mm in diameter and can occupy the entire lower extremity. The local lymph nodes are not enlarged and the patient has no systemic symptoms. Although the lesions have a tendency to heal spontaneously, they can persist for months or even years if left untreated. After healing, severe deformities often result due to scar contracture.
Pathophysiology
1.Pre-ulcer
Subcutaneous fatty tissue necrosis, disappearance of cell nuclei, fibrin deposition, fine calcium deposits in the necrotic area, and increased reticular fibers. After antacid staining, a large number of antacid bacilli were seen in the necrotic area without obvious inflammatory reaction, which may be due to the strong tissue-destroying toxin produced by the bacilli.
2.Ulcer stage
Necrosis reaches the epidermis, causing the epidermis to degenerate and form ulcers. Dermis collagen fiber degeneration, small blood vessels around the inflammatory cell infiltration, colonies with necrosis to the surface extension, in the dermis can also see bacteria. There is often secondary infection on the surface of the ulcer, and Gram-positive cocci or bacilli can be seen at this time, resulting in fibrin and neutrophil exudative reactions.
3.Late stage of ulcer
About 3 weeks after ulcer formation, a marked inflammatory reaction occurs, and giant cells and foam cells can be seen in some lesions. At this stage, lymphocytic infiltration in a band-like distribution is seen under the epidermis, or scattered nodule-like granulation tissue of nodules appears above the necrotic cells, whereupon the necrotic tissue is dissolved or discharged by phagocytosis, and replaced by granulation tissue.
Diagnostic tests
A solitary nodule or ulcer with no local lymph node enlargement, no systemic symptoms, and a flaccid ulcer base is characteristic. A large number of acid-resistant bacilli can be seen in smears and tissue sections from the ulcer base. The diagnosis can be confirmed by bacterial culture and animal inoculation test. If there is a serious secondary infection, the diagnosis can be easily misdiagnosed. The disease needs to be differentiated from leprosy, yaws, lymphatic tuberculosis, gangrenous pyoderma, deep abscess rash, syphilitic dendrites, sclerosing erythema, sarcoma, and squamous carcinoma.
Treatment options
Small nodules should be excised, and larger nodules or ulcers are excised followed by skin grafting. Application of anti-tuberculosis and anti-leprosy drugs, especially anti-leprosy drug clofazimine, can be expected to cure earlier. In addition, secondary infections should be actively prevented.
Buruli ulcer is a disseminated disease caused by Mycobacterium ulcerans infection resulting in extensive destruction of skin and soft tissues, directly affecting the appearance, disfiguring the shape, and causing large ulcers on the legs and arms, resulting in loss of joint function and disability. since 1980, the disease has appeared in more than 30 countries in tropical and subtropical regions of Africa, the Americas, Asia, and the Western Pacific. In view of the expanding geographic spread of the disease, the threat to travelers, the serious consequences of the disease itself, and the limited knowledge of the disease, a brief description of Mycobacterium ulcerans – Buruli ulcer is presented.
History and current status of the epidemic
In 1897, a British physician, Cook, described a skin ulcer disease in Uganda consistent with Buruli ulcer, and in 1948, Professor Maccallum and colleagues in Australia described in detail the characteristics of six patients with the disease near Melbourne. They were also the first scientists to isolate the causative microorganism Mycobacterium ulcerans. After 1961 many cases occurred in Bururi County, Uganda, giving rise to the most widely used name for the disease, Bururi ulcer. Since then, tens of thousands of cases have been reported in countries such as Côte d’Ivoire, Benin, Ghana, Australia, Cameroon, Congo, Gabon, Sudan, Togo, and Uganda. A number of patients have been reported in the Lishui region of Zhejiang, China.
The disease often occurs in water bodies of slow-flowing rivers, ponds, swamps, and lakes among agriculturalists, and has the highest incidence in children under 15 years of age who play and swim in streams, with no difference in infection rates between men and women. The disease can develop in all seasons, but there is no evidence of human-to-human transmission yet.
The mode of transmission of the disease is still under investigation. Buruli ulcer will likely be the only mycobacteriosis transmitted to humans by insects.
Prevalence
Buruli ulcer has been reported in 30 countries in Africa, the Americas, Asia and the Western Pacific mainly in tropical and subtropical regions. In Côte d’Ivoire, approximately 24,000 cases have been recorded from 1978 to 2006. In Benin, approximately 7000 cases have been recorded from 1989 to 2006; in Ghana, more than 11,000 cases have been recorded since 1993. In Australia, most cases of Buruli ulcer disease have been reported recently – 25 cases in 2004, 47 cases in 2005 and 72 cases in 2006. Most recent cases have come from Victoria and the town of Pointe-à-Lance. Increasing numbers of cases are being reported from Cameroon, Congo, Gabon, Sudan, Togo and Uganda. After 30 years of no official reports, an evaluation conducted in November 2006 in southeastern Nigeria confirmed some cases of Buruli ulcer disease. Some patients have been reported in China, but the extent of the disease is unknown. Recent reports suggest that Brazil may have its first endemic epidemic of Buruli ulcer disease in the region bordering French Guiana. These figures may be only an indication of the presence of the disease and not reveal the magnitude of the problem.
Considerable research is needed to determine the exact prevalence and burden of the disease for a number of reasons, including
Inadequate knowledge of the disease among health workers and the general public, resulting in significant underreporting
The fact that those most affected by Buruli ulcer live in remote rural areas and have minimal contact with the health system
the variable nature of the clinical presentation of the disease leading to the misidentification of Buruli ulcer as other tropical skin diseases and ulcers; and the fact that Buruli ulcer is not a legally reported disease in many countries.
For these and other reasons, it is difficult to determine the number of people infected with the disease and the size and location of all endemic areas. Surveillance systems in endemic countries, as well as in countries that do not report Buruli ulcer but share borders with endemic countries, need to be vigilant. Other tropical and subtropical countries have the potential for endemic epidemics; ever-vigilant surveillance is essential. Occasionally travelers returning to North America or Europe from endemic areas become infected with Buruli ulcer, which can pose a serious diagnostic challenge to clinicians unfamiliar with the disease.
Signs and symptoms
Buruli ulcers usually begin as a painless, mobile lump on the skin called a nodule. The disease may present as a large sclerotic or diffuse swelling of the legs and arms. The strains of Mycobacterium ulcerans isolated from different clinical types of the disease in a given region appear to be identical, suggesting that host factors can play an important role in determining the different clinical manifestations. The development of the disease without pain and fever due to the local immunosuppressive properties of bacterial lactones or possibly as a result of other unknown mechanisms may partly explain why infected individuals do not usually seek prompt treatment. However, if left untreated, it can result in large ulcers with typically disfiguring margins. Sometimes the bones are attacked, causing severe deformities. In about a quarter of patients, scarring can cause limitations in limb movement and other long-term disabilities while the injury heals. Other diseases that may resemble brucellosis include: tropical crumbling ulcers, often called tropical ulcers; leishmaniasis, especially in South America; onchocerciasis nodes and fungal skin infections.
Diagnosis
In endemic areas, Buruli ulcers are usually diagnosed and treated by experienced health workers based primarily on clinical findings. Due to logistical and operational difficulties, laboratory diagnosis is rarely used to make decisions about treatment. However, laboratory diagnostics can be performed on swabs and tissues collected during treatment to retrospectively confirm the clinical diagnosis, but this is rarely done.
Four laboratory confirmation methods are generally used.
1. Direct smear examination. An examination of an ulcer swab or smear from a tissue section that can be performed quickly in a local health facility that also performs TB microscopy. However, this method is less sensitive (about 40%) because Mycobacterium ulcerans is not uniformly located in the tissue and its numbers tend to decrease over time.
2. Culture of Mycobacterium ulcerans. A procedure used on ulcer swabs or tissue sections that takes 6-8 weeks or more; sensitivity is about 20-60%.
3.Synthetic chain reaction. A test performed on ulcer swabs or tissue sections, the results of which can be obtained within two days; sensitivity is about 98%.
4.Histopathology. A method that requires tissue sections; sensitivity is about 90%, and is also useful for differential diagnosis when the results of methods 1-3 are negative.
However, methods 2-4 are limited to reference and research laboratories that are usually far from endemic areas. An innovative dry reagent-based polymerase chain reaction that can be used in district hospital laboratories has recently been developed.
Since early disease – nodules – can be treated locally and inexpensively, there is an urgent need for an on-site simple and rapid diagnostic test for Buruli ulcer. However, early disease poses the greatest clinical diagnostic challenge. Mycobacterium ulcerans toxins are more widely distributed within the lesion than mycobacteria, suggesting that the development of an antibody to the bacterial lactone could lead to a rapid field diagnostic test. Similarly, genome sequencing of Mycobacterium ulcerans has revealed proteins that appear to be specific to Mycobacterium ulcerans. Detection of these proteins as potential antigens for the development of simple diagnostic blood tests and the development of antibodies against bacterial lactones are priority research priorities.
Treatment
Current treatment recommendations are as follows.
1. Rifampin and streptomycin/amikacin combination for 8 weeks as first-line treatment for all types of active disease. Nodal or uncomplicated cases can be treated without hospitalization.
2. Surgical excision of necrotic tissue, repair of skin defects and correction of deformities.
3. Interventions to minimize or prevent disability.
The cumulative experience of treating about 300 patients in Benin, Cameroon and Ghana has shown that 8 weeks of treatment with rifampicin and streptomycin according to WHO guidelines resulted in complete healing of about 50% of brucellosis. Interestingly, it is also possible to treat certain patients on an outpatient basis. The recurrence rate after antibiotic treatment was less than 2% compared to 16-30% with surgical treatment alone. These encouraging developments are changing the strategy for the control and treatment of Buruli ulcer disease, which focused on surgical treatment until 2004.
Social and cultural aspects
In developing countries, sociocultural beliefs and practices strongly influence the health care-seeking behavior of patients with Buruli ulcer. The first recourse is usually traditional treatment. In addition to the high cost of surgical treatment, fear of surgery and the resulting scarring and possible amputation can be prevalent. Stigma is an issue due to the disfigurement and also prevents people from seeking treatment. As a result, most patients seek treatment too late and the direct and indirect costs are quite high. The disease has a significant impact on the few health facilities that are available in the affected areas. Long hospital stays, usually more than three months per patient, mean a significant loss of productivity for adult patients and family caregivers, and a loss of educational opportunities for children. Long-term care for people with disabilities, most of whom are children under the age of 15, places an additional costly burden on affected families.
Prevention
Vaccination with BCG vaccine appears to provide some short-term protection against the disease. Although this protection is limited, it may be beneficial to ensure complete coverage of BCG vaccination in affected rural areas. A modified BCG-based vaccine, a live Mycobacterium ulcerans isolate based on surface proteins or the toxin itself, or a reasonably attenuated subunit vaccine are potential avenues for vaccine research. From a long-term perspective, a safe and effective vaccine that can target emerging endemic areas may be the most effective approach to fighting Buruli ulcer.
Control strategies
In the absence of effective tools to control Buruli ulcer, current control strategies aim to reduce the prolonged suffering, disability, and socioeconomic burden associated with the disease. At the annual meeting of the WHO Global Buruli Ulcer Initiative held in Geneva, Switzerland, March 14-17, 2005, the following control strategies were agreed upon.
Early detection of cases at the community level, as well as information, education and communication.
Training of health workers, school teachers and village health workers.
Case management (combination of antimicrobial, surgical and disability prevention/rehabilitation).
Laboratory confirmation of cases.
Standardized record keeping and reporting system using BU 01 and BU 02 forms and health mapping software HealthMapper.
Health facility strengthening.
Monitoring and evaluation of control activities.
Genome sequencing
The complete genome sequence of Mycobacterium ulcerans was published in February 2007, and it will provide a solid foundation to help advance research on the development of simple and rapid diagnostic tests, new drug treatments, and vaccines. Sequencing of the Mycobacterium ulcerans genome has led to the identification of genes that produce bacterial lactones, revealing how bacterial lactones are synthesized. This information will help scientists develop methods to block bacterial lactone production, potentially providing a new option for treating Buruli ulcer.
Research Highlights
There are six main priorities for research on Buruli ulcer: modes of transmission; development of simple diagnostic tests; drug treatments and new therapies; development of a vaccine; social and economic research; and studies to determine incidence and prevalence.
WHO’s role
Since the involvement of WHO in 1998 in the control and research of Buruli ulcer, considerable attention has been drawn to the disease. Today, many endemic countries, researchers, NGOs and donors are engaged in activities to understand Buruli ulcer. Steady progress is being made in control and research under the coordination of WHO. The annual WHO Global Buruli Ulcer Action meeting is attracting significant participation. This meeting provides a forum for making important policy decisions to guide Buruli ulcer control and research activities.
The current wave of interest in neglected tropical diseases will undoubtedly promote clearer visibility of Buruli ulcer disease and help attract the resources needed to accelerate research efforts to develop new tools for diagnosis, treatment and prevention.
Etiology and symptom profile
Mycobacterium ulcerans is an environmental mycobacterium that belongs to the same family as the pathogens that cause tuberculosis and leprosy. This microorganism may be active only in specific aquatic environments, from where it is transmitted to humans through a mechanism that is not yet known. Mycobacterium ulcerans can grow slowly using human lesions and can also be cultured through mycobacterial media (provided that the culture temperature is maintained between 29°C and 33°C, which is lower than the temperature at which Mycobacterium tuberculosis is cultured). The bacterium produces a destructive toxin, bacteriolactone. This bacteriolactone suppresses the human immune response and destroys tissue. The toxic effect of the bacterial lactone may be the cause of the disease.
When Mycobacterium ulcerans infects the body, it can attack any part of the body and usually appears as a painless, mobile lump on the skin. Approximately 90% of injuries are in the extremities and 60% occur in the lower extremities. The disease may initially present with large sores or diffuse swelling on the legs and arms. The absence of pain and fever during the development of the disease, probably due to the suppressive properties of bacterial lactones on local immunity, prevents infected individuals from seeking prompt medical attention. However, if left untreated the lesion can result in a large ulcer with typical disfiguring margins. In some patients, secondary skeletal invasion may occur, causing severe deformities. In approximately one quarter of severe cases, scarring can result in limited limb movement and joint disability when the injury is healed by treatment.
Diagnosis and Differentiation
The disease is diagnosed primarily on the basis of the endemic area, the symptomatic features described above, and the characteristics of the ulcer site. Rarely can a diagnosis be made using laboratory tests. When ulcers are not yet evident, they are usually differentiated from tropical crumbling ulcers, leishmaniasis, onchocerciasis nodules, and fungal skin infections.
Direct microscopic observation with ulcer swabs is a quicker method, but the sensitivity is only 40%; culture of tissue sections and ulcer swabs takes 6-8 weeks or more, and the sensitivity is 20%-60%; polymerase chain reaction on ulcer swabs and tissue sections reveals the results within 2 days, and the sensitivity is up to 98%. When the above methods show negative results, histopathology can be used to help in the differential diagnosis.
Genome sequencing analysis of Mycobacterium ulcerans has revealed that it has specific proteins. Detection of these proteins as potential antigens and the study of antibacterial lactone antibodies are current priorities for exploration.
Treatment
1, Rifampin and streptomycin/amikacin combination for 8 weeks is the first-line treatment for active disease caused by all types of Mycobacterium ulcerans.
2. Surgical excision of necrotic tissue, repair of skin defects and correction of deformities.
Treatment with rifampicin plus streptomycin for 8 weeks resulted in healing in at least 50% of patients with Buruli ulcer according to WHO guidelines. The recurrence rate after a full course of antibiotics is less than 2%. The rate of surgical treatment alone is 16-30%. The disease was more surgically oriented until 2004. In the future, the emphasis should be on early detection and diagnosis, and the use of inexpensive oral rifampicin plus streptomycin injection at the time of “nodule” appearance can be effective.