Life-threatening mycobacteria infection

Clinics in Dermatology (2005) 23, 254 – 257

Life-threatening mycobacteria infection William R. Faber, MD* Department of Dermatology A0-221, Academic Medical Center, University of Amsterdam, PO Box 22700, 1100 DE Amsterdam, Netherlands

Abstract Most mycobacteria cause localized and often harmless infections of the skin. Leprosy, which dates back to approximately 60 bc in India,1 was supposed to be eliminated as a public health problem by the year 2000.2 With a new case detection rate between 600,000 and 700,000 yearly however,3 leprosy, with its sometimes devastating consequences, will be with us for many years to come. Buruli ulcer, named after the area in Uganda where prevalence was high, has spread to new areas, especially in Africa.4 D 2005 Elsevier Inc. All rights reserved.

Introduction In immunocompromised patients, infections with nontuberculous mycobacteria may lead to extensive disease.5 Recently, it was found that patients with genetic deficiencies in cytokine type I receptors suffer from sometimes fatal infections by weakly pathogenic mycobacteria.6

Leprosy In 1982, an effective chemotherapy for leprosy, the socalled multiple drug therapy, was introduced.7 As humans are the only reservoir and source of infection with Mycobacterium leprae, it was expected that the number of new cases would diminish steadily through continued application of multiple drug therapy, preferably administered in an early stage of the disease. Although by the end of 2003 more than 3 million patients have been treated and the relapse rate after multiple drug therapy is very low, the * Fax: +31 20 696 0076. 0738-081X/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2004.06.006

number of new detected cases has remained fairly stable between 600,000 and 700,000 yearly.8 The consequences of leprosy are caused by peripheral nerve damage, which can be gradual during an uncomplicated course, rapid during reversal reaction, and intermittent due to repeated erythema nodosum leprosum–type reactions. The nerve damage leads to deformities and disabilities, which are graded according to the World Health Organization classification.9 Early treatment can diminish but not prevent disabilities, and approximately 8% of patients are disabled at the time of diagnosis.10 One of the consequences of nerve damage is the neuropathic foot, which is prone to ulceration. In a study of 260 newly examined patients in Nepal, ulcers were found in 8.5% of patients.11 Recently, in a survey of 57 patients with arrested leprosy with grade II disabilities, 23 foot ulcers were found in 14 patients (WRF, unpublished observations, 2004). It is estimated that with an annual frequency of 0.2%,12 0.27%13 carcinomas, mainly squamous cell carcinomas, develop in these ulcers. They occur most frequently in male patients in the borderline part of the leprosy spectrum at the age of 60 to 70 years. Predisposing

Life-threatening mycobacteria infection factors are the following: long duration of ulcers, persistent irritation and traumatization, chronic infection, poor hygiene, environmental factors, genetic factors, and repeated destructive therapeutic treatments.14 These ulcers generally clinically present as cauliflower-like tumors.15,16 These carcinomas can be fatal: death due to metastatic disease is found in percentages ranging from 5% to 24%.12,13,17 Erythema nodosum leprosum (type II reaction), which occurs in multibacillary patients, is characterized by the occurrence of crops of painful nodules, with a predilection on the extremities, which may ulcerate and are often accompanied by severe general malaise and systemic toxemia.18 Other organs are frequently affected with inflammations such as iritis and iridocyclitis, orchitis, lymphadenitis, arthritis, and neuritis. The course is often an episode with remissions and exacerbations over months to years.19 In the presulfone days, death from amyloid disease was not uncommon. In these days, where patients with severe erythema nodosum leprosum are treated with systemic steroids for prolonged periods, complications due to treatment with steroids can develop and erythema nodosum leprosum can still be a crippling condition.

Buruli ulcer Buruli ulcer, caused by Mycobacterium ulcerans, is the world’s third most common mycobacterial disease in immunocompetent people.20 It was described by Sir Albert Cook in patients from Uganda in the Mengo Hospital Notes,21 and it is named after Buruli county near the Nile river in Uganda where it was diagnosed in 1959.22 The association between M ulcerans infection and this type of skin ulceration was established in 1948 in Australia.23 Since then it has spread especially in Africa and has reached high prevalence in parts of West Africa4,24-26; it has been diagnosed in all continents except Europe and North America. Buruli ulcer commonly affects poor people in remote areas, and children below the age of 15 years are predominantly affected.4,24,25 The classic clinical picture is a painless, firm, movable subcutaneous nodule, which ulcerates with undermined edges up to 15 cm, and with adjacent, often extensive, indurated edema. Ulcers may remain small but often affect large areas, such as an entire leg or arm, and may severely damage important structures, such as the breast, genitalia, and eyes; bones may also be affected.27 In addition, nonulcerative edematous and plaquelike forms occur.4 Because of the extensive ulceration with scar formation, gross deformities and contractures are common.28 Treatment is surgical, with excision extending into healthy tissue, as treatment with antimycobacterial drugs is in general disappointing, although M ulcerans is sensitive to

255 several drugs in vitro20; amputation of limbs may be necessary.

Mycobacterial infections and immune suppression Mycobacteria responsible for most cutaneous diseases are Mycobacterium marinum, M ulcerans, M fortuitum, M chelonae, and M avium-intracellulare, with the exclusion of M leprae. Cutaneous disease may be due to inoculation, by trauma, or iatrogenic; may be contiguous with underlying osteomyelitis or lymphadenitis; or may be part of disseminated disease.29 More rarely, infections are caused by Mycobacterium szulgai, M kansasii, and M haemophilum.30,31 In immunocompetent patients the disease is generally localized, although lymphatic spread, so-called nodular lymphangitis, is well known in, for instance, M marinum infections.32 In immunocompromised patients, however, disseminated disease is more common, and the clinical picture may be very variable. Several studies examined the relationship between HIV infection and leprosy. Initially, it was thought that because of the immune suppressive effect, a shift might develop toward the lepromatous pole of the leprosy spectrum in future cases of leprosy. It appears, however, that HIV infection has no significant influence on the risk of developing leprosy, of developing multibacillary rather than paucibacillary leprosy, and in the frequency of reactions.33-35 It is possible, however, that patients developing leprosy die of, for instance, tuberculosis before clinical signs of leprosy appear.36 It has been reported that reactions and neuritis are more severe.37,38 In this respect, it may have a deleterious effect that will lead to more extensive and irreversible nerve damage, resulting in deformities and disabilities. A gloomier picture develops if one supports the hypothesis that if M leprae infection is overlooked in HIV infection, HIV-positive patients may serve as a growing source of infection leading to an increase of patients with leprosy to be detected in the years to come.39 In addition, the course of M ulcerans infection does not seem to be influenced by the immune suppression caused by HIV infection, because an ulcer, which was diagnosed as M ulcerans disease, did heal with multiple antimycobacterial therapy40 and 3 cases of Buruli ulcer, diagnosed on clinical criteria and an examination positive for acid fast bacteria, were found to be HIV-positive without clinical signs. It was suggested that Buruli ulcer might be an early opportunistic infection,41 but the HIV epidemic in Africa has no definite links with the emergence of Buruli ulcer.20 The course of infection by other mycobacteria can be very variable not only with respect to clinical presentation, but also with respect to the course of the disease.5 The

256 diagnosis can be difficult because the clinical presentation can range from papules, nodules with or without abscesses, to plaques and ulcers. In addition, histopathologic examination and adequate culture facilities are required to determine the mycobacterial infection. Nowadays, polymerase chain reaction techniques can be helpful to determine the mycobacterial species.42 Skin lesions in Mycobacterium tuberculosis infections are seen during disseminated disease and acid-fast bacilli have been found in the skin lesions.43 The skin lesions have been described as (follicular) papules and nodules. There have been several reports of skin lesions in severely ill patients, which have been designated as (acute) miliary tuberculosis.44-46

Highly active antiretroviral treatment and mycobacterial infections Another way that mycobacterial infections can present themselves is during highly active antiretroviral treatment as part of the so-called immune restoration syndrome. An exacerbation of M marinum infection in 1 patient47 and disseminated cutaneous lesions due to Mycobacterium avium complex in another patient48 occurred. In addition, the development of borderline tuberculoid leprosy has been described.49 In addition, several other cases of leprosy after initiation of highly active antiretroviral treatment were presented at the 16th International Leprosy Congress in 2002 in Salvador, Brazil.

Host genetic factors Host genetic factors are important for the outcome of infections with intracellular pathogens. Recently, it has been found that deficiencies in type I cytokine receptors predispose to susceptibility to infection with intracellular bacteria, including mycobacteria. Protective immunity in these infections is dependent on an effective cell-mediated immune response. The activation of infected macrophages by interferon (IFN)-c is an important effector mechanism. Interferon-c is produced by antigen-specific T helper–type cells and natural killer cells and binds to IFN-c receptor complexes on the macrophage surface. Another type 1 cytokine interleukin (IL)-12, produced by antigen-presenting cells such as dendritic cells, macrophages, and monocytes, regulates the production of IFN-c. In patients with severe infections with otherwise poorly pathogenic mycobacteria and salmonella were unable to produce or to respond to IFN-c in vitro. Genetic analysis revealed mutations in different genes of the type I cytokine network, notably IL-12R-b1, IL-12c40, IFN-c R1, IFN-c R2, and STAT 1.6 In addition, mycobacterial infections that manifest themselves with skin lesions have been described with several mutations.6

W.R. Faber One female patient presented initially with skin lesions that at that time were diagnosed as lupus vulgaris. Although antimycobacterial treatment appeared successful, she suffered for many years from several relapses, every time increasing in extent. It was found that she had a partial IFN receptor deficiency, and the lesions were caused by the weakly pathogenic Mycobacterium asiaticum (Faber et al, manuscript in preparation). It has become clear that patients with inherited defects of the IL-12/IFN-c pathways display a variety of outcomes with respect to the susceptibility to mycobacterial infections. There is a spectrum of severity of infection, with severe/fatal outcome in complete IFN-c receptor deficiency and milder — although still severe—clinical course in partial IFN-c receptor deficiency and IL-12 genetic defects.50

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