Dermatologic Therapy, Vol.

21, 2008, 154161 Printed in the United States All rights reserved

Copyright Blackwell Publishing, Inc., 2008

DERMATOLOGIC THERAPY
ISSN 1396-0296

Blackwell Publishing Inc

Management of cutaneous tuberculosis

EVANGELINE B. HANDOG*,, TERESITA G. GABRIEL & ROSARIO TRINIDAD V. PINEDA

*Department of Dermatology, Asian Hospital Medical Center, Philippines, Research Institute for Tropical Medicine, Department of Health, Philippines, Philippine Dermatological Society, Philippines

ABSTRACT: Cutaneous tuberculosis (TB) is an extrapulmonary form of tuberculosis, which may be classied based on the immunologic state of the host. Chemotherapy still remains the treatment of choice. The management of cutaneous TB follows the same guidelines as that of TB of other organs, which can be treated with a short course four-agent chemotherapeutic regimen given for 2 months followed by a two-drug regimen for the next 4 months. This chapter highlights current treatment recommendations for cutaneous TB. The important factors to consider in the choice of optimal treatment includes the type of cutaneous involvement, stage of the disease, level of immunity, and general condition of the patient. The highest priority in any cutaneous TB control program is the

proper, accurate, and rapid detection of cases and the availability of chemotherapy to all tuberculosis patients until cure. Contact tracing is also an important component of efcient tuberculosis control.
KEYWORDS: cutaneous tuberculosis, management, TB, tuberculosis

Introduction
The genus Mycobacterium causes more suffering for humans than all other bacterial genera combined (1). Many authors have reported tuberculosis, caused by mycobacterium tuberculosis and which was classied as pulmonary and extrapulmonary to have been part of human history since prehistoric times and up to now, remains a major public concern in developing countries. According to the World Health Organization, there are more than 14 million people living with TB as of March 2007. In 2005, 3.9 million of the estimated 8.8 million new TB cases worldwide were diagnosed by laboratory testing and 629,000 were HIV positive. Global access to TB treatment is improving but remains low. Those with active TB who receive no treatment can infect an average of 1015 people annually (2).
Address correspondence and reprint requests to: Evangeline B. Handog, MD, FPDS, FAAD, Room 316 Asian Hospital and Medical Center, 2205 Civic Drive, Filinvest Corporate City, Alabang, Muntinlupa City, Metro Manila, Philippines, 1780, or email: handogmd@pacic.net.ph.

TB continues to be in the top 10 causes of morbidity and mortality in the Philippines. The declining incidence of cutaneous TB worldwide was the result of improved therapy, reduction in the size of the active reservoir of infection, and increased immunoresistance to infection. However, it was also noted that cutaneous TB re-emerged in those parts of the world where the incidence of HIV infection and multidrug-resistant tuberculosis is high. One vital factor in curbing the increase in cutaneous TB is the initiation of proper treatment that not only encompasses an effective regimen but also ensures compliance with and response to management. The important factors to determine the clinical presentation of cutaneous TB include the pathogenicity of the organism, its antibiotic resistance prole, the portal of infection, the immune status of the host, particularly the presence or absence of acquired immunodeciency syndrome (AIDS) secondary to infection with human immunodeciency virus (HIV), and various local factors in the skin such as relative vascularity, trauma, lymphatic drainage, and proximity to lymph nodes.

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FIG. 1. Classication of cutaneous tuberculosis.

Classication and diagnosis

Diagnosis of cutaneous TB is challenging and requires the correlation of clinical and histopathologic ndings and diagnostic testing. In addition to traditional acid-fast bacilli (AFB) smears and cultures, there has been increased utilization of polymerase chain reaction because of its rapidity, sensitivity, and specicity. Mycobacterial culture still remains to be the most reliable method in determining the presence of live mycobacteria and their sensitivity to antibiotics and to monitor treatment response. The bacillary load in cutaneous TB is usually less than in pulmonary TB (3).

The majority of cases of cutaneous TB are a manifestation of systemic involvement. The usual portal of entry of M. tuberculosis includes the lungs and the intestines, but the mucous membrane and skin occasionally show primary involvement. Cutaneous involvement may include papules, nodules, plaques, ulcerative lesions, warty tumors, or scarring reactions. Classication of cutaneous TB may be based on the immunologic state of the host (FIG. 1). The four most common forms of cutaneous TB encountered at the Research Institute for Tropical Medicine, Department of Health, Philippines are listed below.

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FIG. 2. Lupus vulgaris. A 34-year-old male patient with a

soft, tender, verrucous plaque with seropurulent discharge, brownish crusts, and hypopigmented atrophic center on the right leg.

FIG. 3. Tuberculosis verrucosa cutis. A 57-year-old female patient with a soft, nontender, verrucous, erythematous plaque with erosions and brownish crust, irregular border, hypopigmented and atrophic scar on the left anterior shin.

Scrofuloderma Lupus vulgaris Lupus vulgaris is an extremely chronic and progressive form of tuberculosis of the skin that occurs in individuals with moderate immunity and a high degree of tuberculin sensitivity. Clinical presentations include a plaque or planar form, an ulcerative or mutilating form, a vegetating form, a tumorlike form, and a papulonodular form. It is extremely chronic and without treatment, its course usually extends over the years. The disease is progressive and leads to signicant impairment of function and disguration. The most serious complication of long-standing lupus vulgaris is the development of carcinoma with squamous cell carcinoma outnumbering basal cell carcinoma (FIG. 2). Tuberculosis verrucosa cutis Tuberculosis verrucosa cutis is also known as warty TB. It is an indolent, warty, plaque-like form of cutaneous TB occurring as a result of the inoculation of organisms into the site of a previously infected patient who usually has moderate or high degree of immunity. The lesions progress slowly, and if untreated may persist for many years. Spontaneous involution does occur and results in sunken atrophic scars (FIG. 3). Scrofuloderma, also known as tuberculosis colliquativa cutis, is a subcutaneous TB that leads to cold abscess formation and a secondary breakdown of overlying skin. More often it occurs in the parotidal, submandibular, and supraclavicular regions as well as on the lateral aspects of the neck. The skin lesion rst presents as rm, subcutaneous nodule or as well-dened, freely movable asymptomatic inltrate. As the inltrate enlarges, it softens. Ulcers and sinuses develop and discharge watery and purulent or caseous material. Sinusoidal tracts undermine the skin and clefts dissecting subcutaneous pockets alternate with soft nodules (FIG. 4). Papulonecrotic tuberculids Papulonecrotic tuberculids consist of recurring crops of symmetrical, hard, dusky-red papules. These form crusts or may ulcerate leaving pigmented, atrophic scars over the course of a few weeks. New crops may continue to appear over months or years. The legs, knees, elbows, hands, and feet are the sites of predilection (FIG. 5). The manifestations of the disease in the skin are inuenced by previous infection or immunity and by the route of infection. Because of the virulence and resistance to phagocytosis by M.

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FIG. 4. Scrofuloderma. A 20-month-old male patient with a rm, smooth, movable, nontender, nonuctuant, erythematous nodule on the right lateral aspect of the neck.

tuberculosis, neutrophils are completely ineffective in dealing with this bacterial infection, whereas macrophages and their derivatives are characteristically seen in the cellular response. These lead to giant cell granuloma formation with or without necrosis and this underlies the varied clinical presentations of this infection (4).

Treatment
The management of cutaneous TB follows the same guidelines as that of TB of other organs, as the lesions in the skin often represent hematogenously or lymphatically dispersed disease from internal foci of infection. Rarely will TB of the skin be conned as strictly a cutaneous disease like tuberculosis verrucosa cutis and lupus vulgaris, which may exist without evidence of associated internal TB.

Optimal treatment can be achieved, considering the following factors: the type of cutaneous involvement, the stage of the disease, the level of immunity, and the general conditions of the patient. Chemotherapy still remains the treatment of choice. It aims to cure the disease as rapidly as possible to prevent relapses and the emergence of resistant strains. The recommended regimen comprises an initial bactericidal or intensive phase and a continuation or sterilizing phase. The initial phase of the regimen is directed toward the rapid destruction of a large population of mycobacterium and resolution of symptoms. After completion of this phase, the patients become noninfectious. The initial, intensive chemotherapy includes daily isoniazid, rifampicin, pyrazinamide, and either ethambutol or streptomycin for 8 weeks (Tables 1 and 2). The continuation phase aims to eliminate the remaining dormant organisms. If therapeutic response is observed in isoniazid and rifampicin, these drugs are given either daily, three times weekly or two times weekly for 16 weeks (1). Surgical intervention is useful for the treatment of isolated lupus vulgaris and tuberculosis verrucosa cutis and some cases of scrofuloderma. Cutaneous TB is an extra-pulmonary form of TB being treated with a short-course four-agent chemotherapy regimen given for 8 weeks followed by a two-drug regimen for the next 16 weeks. Firstline drugs that are highly effective and which are used mainly in the initial treatment of susceptible organisms are isoniazid, rifampicin, pyrazinamide, and ethambutol. These drugs are well absorbed after oral administration, with peak serum level at 24 hours and elimination within 24 hours. These agents are recommended on the basis of their bactericidal activity, which is dened as the ability to rapidly reduce the number of viable organisms and render patients noninfectious. This group of drugs also has low rates of induction of drug resistance and has sterilizing activity as measured in terms of the ability to prevent relapses. Rifapentine

Table 1. Recommended dosage for initial treatment of cutaneous tuberculosis

Drug Isoniazid Rifampicin Pyrazinamide Ethambutol
a

Daily dose 5 mg/kg, max 300 mg 10 mg/kg, max 600 mg 2025 mg/kg, max 2 g 1520 mg/kg

Thrice-Weekly dose 15 mg/kg, max 900 mg 10 mg/kg, max 600 mg 30 40 mg/kg, max 3 g 25 30 mg/kg

Childrena 1015 mg/kg daily; 2030 mg/kg intermittent 1020 mg/kg

Dosage for children is similar, except that some authorities recommend higher doses of isoniazid and rifampicin. Source: Based on American Thoracic Society, Infectious Disease Society of America and Centers for Disease Control and Prevention.

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FIG. 5. Papulonecrotic tuberculid. A 32-year-old female patient with erythematous papules evolving into pustules developing central necrotic crust and healing with depressed scars on the chest, back and arms.

and rifabutin are two drugs related to to Rifampicin which can be used as substitutes in the treatment of cutaneous TB. To prevent isoniazid-related neuropathy, pyridoxine (1025 mg/day) should be added to the regimen given to persons at high risk of vitamin B6 deciency such as alcoholics, malnourished persons, pregnant and lactating women, and patients with conditions such as chronic renal failure, diabetes, and HIV infection or AIDS, which are also associated with neuropathy (5).

Second-line drugs used mainly in the treatment of patients with drug-resistant mycobacteria include these injectable drugs: streptomycin (formerly a rst-line agent), kanamycin, amikacin, and capreomycin; and these oral drugs: pyrazinamide, ethionamide, and cycloserine. These drugs have lower degree of efcacy and a higher degree of intolerability and toxicity; hence they are only used for patients with cutaneous tuberculosis resistant to the rst-line agents. Recently, uoroquinolone antibiotics such as ooxacin, levooxacin,

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gatioxacin, and moxioxacin are commonly used as second-line drugs. (Table 3) Cytokines, interleukin 2 (IL-2), interferon gamma, and granulocyte/macrophage colony-stimulating factor (GM-CSF), although not yet established as a therapeutic options, act by helping control intracellular pathogens, thereby shortening the duration of therapy and preventing drug resistance. Although effective anti-TB drugs are available in the developing countries, there are still many TB patients who are not cured. This is because many patients either stop or irregularly take their drugs. The long duration of treatment, 6 months on the average, makes it most likely for patients to be noncompliant to therapy. TB patients who do not adhere to the prescribed regimen are likely to become drug resistant. Treatment compliance is therefore a must. Factors leading to multidrug resistance include monotherapy, erratic drug ingestion, omission of one or more of the prescribed chemotherapeutic agents, suboptimal dosage, poor drug absorption, and insufcient number of active chemotherapeutic agents in a regimen. Both patient- and provider-related factors may affect compliance in the intake of anti-TB drugs. The patient-related factors include a lack of belief that the illness is signicant and warrants treatment, the presence of concomitant medical condition like substance abuse, lack of social support, and poverty. The provider-related factors that may promote compliance include proper education and encouragement of patients, the offering of convenient clinic hours, and the provision of incentives and enablers such as meals and bus tokens (5). Poor treatment compliance may lead to the following outcomes: chronic infectious illness, drug resistance, or death. The best way to prevent the occurrence of drug resistance is through regular intake of drugs for the prescribed duration. There are two established strategic approaches to address the problem of drug resistance and to ensure treatment compliance: directly observed treatment (DOT) and xed-drug combination (FDC) products. DOT works by assigning a responsible person to observe or watch the patient take the correct medications daily during the whole course of treatment. FDC products such as isoniazid/rifampicin, isoniazid/rifampin/pyrazinamide, and isoniazid/ rifampin/pyrazinamide/ethambutol are available as well. FDCs are strongly recommended as a means of minimizing the possibility of prescription error and of the development of drug resistance as a result of monotherapy (5).

1 injectable agentb + 3 of the following: ethionamide, cycloserine, quinolone antibiotic, para-aminosalicylicacid Throughout (24 months)

Resistance to all rst-line drugs

24 months Total duration of therapy

A uoroquinolone may strengthen the regimen for patients with extensive disease. Amikacin, kanamycin, or capreomycin. All agents should be discontinued after 26 months, depending upon tolerance and response.
b a

Pyrazinamide + ethambutol + quinolone antibiotic Streptomycin (or another injectable agentb) Throughout (1824 months)

Resistance to isoniazid and rifampicin

Rifampicin + pyrazinamide + ethambutola

Throughout (6 months)

Resistance to isoniazid

Table 2. Treatment regimen for cutaneous tuberculosis

Initial or bactericidal phase

Continuation or sterilizing phase

Chemotherapy

Rifampicin + isoniazid + pyrazinamide + streptomycin or ethambutol 2 months, daily Rifampicin + Isoniazid 4 months, daily 2/week or 3/week 6 months at least

First-line drugs

6 months

1824 months

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Table 3. Second-line drugs

Drug Capreomycin Kanamycin Ethionamide Para-aminosalicylic acid (PAS) Cycloserine Ciprooxacin Ooxacin Amikacin Clofazimine Daily dose (maximum dose) 1530 mg/kg (1 g) 1530 mg/kg (1 g) 1520 mg/kg (1 g) 150 mg/kg (12 g) 1520 mg/kg (1 g) 5001000 mg/kg 400800 mg/day 15 mg/kg 100300 mg/day

Testing for HIV is recommended for all patients diagnosed with TB because they may require longer courses of therapy. In addition, every effort should be made to culture the organism for sensitivity testing, since multidrug-resistant TB is common in some communities.

Completion of therapy is dened more accurately by the total number of doses taken than by the length of treatment. Bacteriologic monitoring of patients with cutaneous tuberculosis is not feasible and more difcult compared to that for pulmonary tuberculosis. In these cases, the response to treatment must be assessed clinically. Because viable mycobacteria can still be cultured from clinically healed lesions, treatment should be continued for at least 2 months after complete involution of the lesions. During therapy, drug toxicity should be observed. Closely monitor the occurrence of minor and major reactions to drugs, especially during the intensive phase (Table 4). The most common adverse reaction is hepatitis. Patients should be carefully educated about the signs and symptoms of drug-induced hepatitis such tea-colored urine and loss of appetite and should be instructed to discontinue promptly and to consult with their

Table 4. Guide in managing short course chemotherapeutic drug side effects

Side effects Drugs responsible What to do? Minor side effects patient should be encouraged to continue taking medicines Gastro-intestinal intolerance Rifampicin Give medication at bedtime Mild skin reactions Any kind of drugs Give anti-histamines Orange-/red-colored urine Rifampicin Reassure the patient Pain at the injection site Streptomycin Apply warm compress Rotate sites of injection Burning sensation in the feet as a result Isoniazid Give pyridoxine (vitamin B6): 100200 mg of peripheral neuropathy daily for treatment 10 mg daily for prevention Arthralgia as a result of hyperuricemia Pyrazinamide Give aspirin or NSAID Flu-like symptoms (fever, muscle pains, Rifampicin Give antipyretics inammation of the respiratory tract) Major side effects: discontinue taking medicines and refer to physician immediately Severe skin rash as a result of Any kind of drugs Discontinue anti-TB drugs and refer hypersensitivity (especially to Physician Streptomycin) Discontinue anti-TB drugs and refer to Jaundice as a result of hepatitis Any kind of drugs Physician (especially Isoniazid, If symptoms subside, resume treatment Rifampicin and and monitor clinically Pyrazinamide) Impatient of visual acuity and color vision Ethambutol Discontinue Ethambutol and refer to an as a result of optic neuritis ophthalmologist Hearing impairment, ringing of the ear and Streptomycin Discontinue Streptomycin and refer to dizziness as a result of the damage of the Physician eighth cranial nerve Oliguria or albuminuria as a result of renal Streptomycin Discontinue anti-TB drugs and refer to disorder Rifampicin Physician Psychosis and convulsion Isoniazid Discontinue Isoniazid and refer to Physician Thrombocytopenia, anemia, shock Rifampicin Discontinue anti-TB drugs and refer to Physician
Source: Manual of Procedures for the National Tuberculosis Control Program, 2001. Department of Health, Republic of the Philippines.

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physicians. Baseline laboratory examinations such as complete blood count, liver and renal functions tests should be carried out before instituting therapeutic regimen. Hypersensitivity reactions usually require the discontinuation of all drugs and rechallenge to determine which agent is the culprit (5). Hyperuricemia and athralgia may be caused by pyrazinamide and are usually treated with by the acetyl salicylic acid; on the other hand, gouty arthritis would warrant the discontinuance of pyrazinamide. There are reports of individuals developing autoimmune thrombocytopenia secondary to rifampicin and optic neuritis secondary to ethambutol. This is an indication for patients to permanently discontinue the use of the said drugs upon appearance of these serious side effects.

countries and HIV-seropositive persons. Identication of active cases of tuberculosis should be followed by treatment. PPD-positive high-risk persons should also be treated for latent infection. Contact tracing is an important component of efcient tuberculosis control. The best way to prevent cutaneous TB is to diagnose infectious cases rapidly and administer appropriate treatment until cure. Additional strategies to prevent the spread of disease include BCG vaccination and treatment of persons with latent tuberculosis infection who are at high risk of developing active disease.

References
1. Tappeiner G, Klaus W. Tuberculosis and other mycobacterial infections. In: Freedberg I, et al., eds. Fitzpatricks dermatology in general medicine. USA: Mc Graw Hill, 2003: 19331945. 2. WHO Media centre. World Health Organization. Fact sheet No 4: Tuberculosis. March 2007. (Document: WHO/Programmes and projects/Media center/Fact sheet). 3. Barbagallo J, Tager P, Ingleton R, Hirsch R, Weinberg J. Cutaneous tuberculosis: diagnosis and treatment. Am J Clin Dermatol 2002: 38: 319328. 4. McKee P, Calonje E, Granter S, eds. Pathology of the skin. China: Mosby, 2005: 897898. 5. Raviglione M, OBrien R. Tuberculosis. In: Kasper D, et al., eds. Harrisons principles on internal medicine. USA: Mc Graw Hill, 2005: 962 963.

Conclusion
The highest priority in any cutaneous TB control program is the proper and accurate detection of cases and the availability of short-course chemotherapy for all TB patients under proper case management conditions. In addition, it is highly recommended in low-prevalence countries with adequate resources to screen high-risk groups such as immigrants from high-prevalence

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