Chapter 184. Tuberculosis and Infections with Atypical Mycobacteria

Tuberculosis is still an important worldwide disease. There were an estimated 9.27 million incident cases globally of TB in 2007.1 This is an increase from 9.24 million cases in 2006, to 8.3 million cases in 2000 and 6.6 million cases in 1990. Most of the estimated number of cases in 2007 were in Asia (55%) and Africa (31%), with small proportions in the Eastern Mediterranean region (6%), the European region (5%) and the Americas (3%). The five countries that ranked first to fifth in terms of total numbers of cases in 2007 were India, China, Indonesia, Nigeria, and South Africa. Of the 9.27 million incident cases in 2007, an estimated 1.37 million (14%) were HIV positive; 79% of these HIV-positive cases were in the African region.

In 2008, a total of 12,898 incident tuberculosis (TB) cases were reported in the United States; the TB rate declined 3.8% from 2007 to 4.2 cases per 100,000 population, the lowest rate recorded since national reporting began in 1953. In 2008, the TB rate in foreign-born persons in the United States was 10 times higher than in US-born persons. TB rates among Hispanics and blacks were nearly eight times higher than among non-Hispanic whites, and rates among Asians were nearly 23 times higher than among non-Hispanic whites. To ensure that TB rates decline further in the United States, especially among foreign-born persons and minority populations, TB prevention and control capacity should be increased. Additional capacity should be used to (1) improve case management and contact investigations; (2) intensify outreach, testing, and treatment of high-risk and hard-to-reach populations; (3) enhance treatment and diagnostic tools; (4) increase scientific research to better understand TB transmission; and (5) continue collaboration with other nations to reduce TB globally.2

HIV-positive people are about 20 times more likely than HIV-negative people to develop TB in countries with a generalized HIV epidemic, and between 26 and 37 times more likely to develop TB in countries where HIV prevalence is lower.

The so-called atypical Mycobacteria (Mycobacteria other than Mycobacteria tuberculosis, or MOTT) cause skin disease more frequently than does M. tuberculosis. They exist in various reservoirs in the environment. Among these organisms are obligate and facultative pathogens as well as nonpathogens. In contrast to the obligate pathogens, the latter do not cause disease by person-to-person spread.

See reference 3. (eTable 184-0.1)

The pandemic of acquired immunodeficiency syndrome (AIDS), with its profound and progressive suppression of cellular immune functions, has led to a resurgence of tuberculosis and the appearance or recognition of new mycobacterial pathogens. The Mycobacterium avium-intracellulare (MAI) complex is the most common cause of disseminated bacterial infections in patients with AIDS in the United States, but is much less frequently so in Europe. In AIDS patients, Mycobacterium kansasii is more common than M. tuberculosis. The incidence of tuberculosis in patients with AIDS is almost 500 times than that in the general population. Cutaneous disease in AIDS patients is frequently caused by MOTT.

Epidemiology

Tuberculosis of the skin has a worldwide distribution. Once more prevalent in regions with a cold and humid climate, it now occurs mostly in the tropics. Cutaneous TB incidence parallels that of pulmonary TB and developing countries still account for the majority of cases in the world. The emergence of resistant strains and the AIDS epidemic have led to an increase in all forms of TB (Table 184-1).

The two most frequent forms of skin tuberculosis are lupus vulgaris (LV) and scrofuloderma (Fig. 184-1). In the tropics, LV is rare, whereas scrofuloderma and verrucous lesions predominate. LV is more than twice as common in women than in men, whereas tuberculosis verrucosa cutis is more often found in men. Generalized miliary tuberculosis is seen in infants (and adults with severe immunosuppression or AIDS), as is primary inoculation tuberculosis. Scrofuloderma usually occurs in adolescents and the elderly, whereas LV may affect all age groups.

The Mycobacterium

Mycobacteria multiply intracellularly, and are initially found in large numbers in the tissue.

M. tuberculosis, M. bovis, and, under certain conditions, the attenuated BCG organism cause all forms of skin tuberculosis.

In LV, the bacteria often have virulence as low as that of the BCG. Large number of bacteria can be found in the lesions of a primary chancre or of acute miliary tuberculosis; in the other forms, their number in the lesions is so small that it may be difficult to find them.

M. tuberculosis may become dormant in the host tissue.

New diagnostic tools are emerging,4,5 as described below.

The Host

The human species is quite susceptible to infection by M. tuberculosis, with big differences among populations and individuals. Populations that have been in long-standing contact with tuberculosis are, in general, less susceptible than those who have come into contact with Mycobacteria more recently, presumably reflecting widespread immunity from subclinical infection. Age, state of health, environmental factors, and particularly the immune system are of importance. In Africans, tuberculosis frequently takes an unfavorable course, and tuberculin sensitivity may be more pronounced than in whites.

Tuberculin Reaction (Koch Phenomenon)

An extract of M. tuberculosis (tuberculin) was shown to produce a different skin reaction in sensitized individuals than in naive individuals, and this difference became the basis of a widely used diagnostic test. This reaction is a delayed-type hypersensitivity reaction, induced by Mycobacteria during primary infection. This “old tuberculin” has now been replaced by purified protein derivative (PPD). More recently, purified species-specific antigens have been developed.6

Local intradermal injection (the method most widely used) leads to the local tuberculin reaction, which usually reaches its maximum intensity after 48 hours. It consists of a sharply circumscribed area of erythema and induration, and in highly hypersensitive recipients or after large doses, a pallid central necrosis may appear.

In an attempt to quantify the tuberculin reaction, an assay known as the QuantiFERON®-TB Gold test was developed to measure specific antigen-driven interferon-γ synthesis by whole blood cells and was approved by the FDA in 2005.

Tuberculin sensitivity usually develops 2–10 weeks after infection and persists throughout life. The state of sensitivity of an individual infected with M. tuberculosis is of considerable significance in the pathogenesis of tuberculosis skin lesions.

In patients with clinical tuberculosis, an increase in skin sensitivity usually indicates a favorable prognosis, and in tuberculous skin disease accompanied by high levels of skin sensitivity, the number of bacteria within the lesions is small. Tuberculin sensitivity (skin reactivity) is not necessary for immunity, however, and sensitivity and immunity do not always parallel each other.

Route of Infection

Cutaneous inoculation leads to a tuberculous chancre or to tuberculosis verrucosa cutis (Fig. 184-2), depending on the immunologic state of the host.

Spread of Mycobacteria may occur by continuous extension of a tuberculous process in the skin (scrofuloderma) by way of the lymphatics (LV), or by hematogenous dissemination (acute miliary tuberculosis of the skin or LV).

Histopathology

The hallmark of tuberculosis and infections with some of the slow-growing atypical Mycobacteria is the tubercle: an accumulation of epithelioid histocytes with Langhans-type giant cells among them and a varying amount of caseation necrosis in the center, surrounded by a rim of lymphocytes and monocytes. Although this tuberculoid granuloma is highly characteristic of several forms of tuberculosis, it may be mimicked by deep fungal infections, syphilis, and leprosy, as well as other diseases. As in leprosy, the histopathologic features of skin tuberculosis may be reflective of the host's immune status.

Polymerase Chain Reaction Procedure

The polymerase chain reaction (PCR) procedure has been used increasingly to ascertain the presence of mycobacterial DNA in skin specimens.7 Although the detection of specific DNA in tissues has yielded valuable information and will conceivably gain importance in the future, interpretation of the results of these tests in individual patients is still problematic.8 In one study, samples from 16 of 20 patients with sarcoidosis contained mycobacterial DNA, both tuberculous and nontuberculous.9 In another study of patients with confirmed or highly probable cutaneous tuberculosis or with erythema induratum, believed to indicate a host response to the infection, PCR testing showed 100% sensitivity and specificity in multibacillary disease. In paucibacillary disease, PCR testing showed 55% sensitivity and specificity, and only 80% of PCR-positive patients responded to antituberculosis therapy.7

QuantiFERON®-TB Gold (QFT-G) Test

In 2005, the FDA approved QFT-G as an in vitro diagnostic aid. In this test, blood samples are mixed with antigens and controls. For QFT-G, the antigens include mixtures of synthetic peptides representing two M. tuberculosis proteins: (1) ESAT-6 and (2) CFP-10. After incubation of the blood with antigens for 16–24 hours, the amount of interferon-γ (IFN-γ) is measured.

If the patient is infected with M. tuberculosis, their white blood cells will release IFN-γ in response to contact with the TB antigens. The QFT-G results are based on the amount of IFN-γ that is released in response to the antigens.

Although more sensitive than the tuberculin skin test, the QFT-G may be negative in patients with early active tuberculosis and indeterminate results are more common in immunocompromised individuals and young children. Another similar assay, the T-SPOT®.TB test, measures the number of IFN-γ-producing T cells and is currently available in Europe. QFT-G testing is indicated for diagnosing infection with M. tuberculosis, including both TB disease and latent TB infection. Whenever M. tuberculosis infection or disease is being diagnosed by any method, the optimal approach includes coordination with the local or regional public health TB control programs.

Infection with M. tuberculosis used to be thought to result in characteristic clinical features.10 However, with increasing number of cases in immunocompromised individuals and improved diagnostic tools, many uncharacteristic manifestations have been discovered.

Primary Inoculation Tuberculosis (Tuberculous Chancre, Tuberculous Primary Complex)

Epidemiology

Tuberculous chancre and affected regional lymph nodes constitute the tuberculous primary complex in the skin. The condition is believed rare, but its incidence may be underestimated. In some regions with a high prevalence of tuberculosis and poor living conditions, primary inoculation tuberculosis of the skin is not unusual. Children are most often affected.

Etiology and Pathogenesis

Tubercle bacilli are introduced into the tissue at the site of minor wounds. Oral lesions may be caused by bovine bacilli in nonpasteurized milk and occur after mucosal trauma or tooth extraction. Primary inoculation tuberculosis is initially multibacillary, but becomes paucibacillary as immunity develops.

Clinical Findings

The chancre initially appears 2–4 weeks after inoculation and presents as a small papule, crust, or erosion with little tendency to heal. Sites of predilection are the face, including the conjunctivae and oral cavity, as well as the hands and lower extremities. A painless ulcer develops, which may be quite insignificant or may enlarge to a diameter of more than 5 cm (Fig. 184-3). It is shallow with a granular or hemorrhagic base studded with miliary abscesses or covered by necrotic tissue. The ragged edges are undermined and of a reddish-blue hue. As the lesions grow older, they become more indurated, with thick adherent crusts.

Wounds inoculated with tubercle bacilli may heal temporarily but break down later, giving rise to granulating ulcers. Mucosal infections result in painless ulcers or fungating granulomas. Inoculation tuberculosis of the finger may present as a painless paronychia. Inoculation of puncture wounds may result in subcutaneous abscesses.

Slowly progressive, regional lymphadenopathy develops 3–8 weeks after the infection (Fig. 184-3) and may rarely be the only clinical finding. After weeks or months, cold abscesses may develop that perforate to the surface of the skin and form sinuses. The lymph nodes draining the primary glands may also be involved. Body temperature may be slightly elevated. The disease may take a more acute course, and in half of the patients, fever, pain, and swelling simulate a pyogenic infection. Early, there is an acute nonspecific inflammatory reaction in both skin and lymph nodes, and Mycobacteria are easily detected by Fite stain. After 3–6 weeks, the infiltrate and the regional lymph nodes acquire a tuberculoid appearance and caseation may occur.

Diagnosis

Any ulcer with little or no tendency to heal and unilateral regional lymphadenopathy in a child should arouse suspicion. Acid-fast organisms are found in the primary ulcer and draining nodes in the initial stages of the disease. The diagnosis is confirmed by bacterial culture. The PPD reaction is negative initially and later converts to positive (Fig. 184-3).

Differential Diagnosis

The differential diagnosis encompasses all disease with a primary complex (Box 184-1).

Course

If untreated, the condition may last up to 12 months. Rarely, LV develops at the site of a healed tuberculous chancre. The regional lymph nodes usually calcify.

The primary tuberculous complex usually produces immunity, but reactivation of the disease may occur. Hematogenous spread may give rise to tuberculosis of other organs, particularly of the bones and joints. It may also lead to acute miliary disease with a fatal outcome. Erythema nodosum occurs in approximately 10% of cases.

Tuberculosis Verrucosa Cutis (Warty Tuberculosis, Prosector's Wart, Lupus Verrucosus)

Etiology and Pathogenesis

Tuberculosis verrucosa cutis is a paucibacillary disorder caused by exogenous reinfection (inoculation) in previously sensitized individuals with high immunity.

Inoculation occurs at sites of minor wounds or, rarely, from the patient's own sputum. Members of professional groups handling infectious material are at risk. Children may become infected playing on contaminated ground.

Clinical Findings

Lesions usually occur on the hands or, in children, on the lower extremities as a small asymptomatic papule or papulopustule with a purple inflammatory halo. They become hyperkeratotic and are often mistaken for a common wart. Slow growth and peripheral expansion lead to the development of a verrucous plaque with an irregular border (Fig. 184-4). Fissures discharging pus extend into the underlying brownish-red to purplish infiltrated base. The lesion usually is solitary, but multiple lesions may occur. Regional lymph nodes are rarely affected.

Lesions progress slowly and, if untreated, persist for many years. Spontaneous involution eventually occurs, leaving an atrophic scar.

Histopathology

The most prominent histopathologic features are pseudoepitheliomatous hyperplasia with marked hyperkeratosis, a dense inflammatory infiltrate, and abscesses in the superficial dermis or within the pseudoepitheliomatous rete pegs. Epithelioid cells and giant cells are found in the upper and middle dermis. Typical tubercles are uncommon, and the infiltrate may be nonspecific.

Differential Diagnosis

(Box 184-2)

Lupus Vulgaris (Tuberculosis Luposa)

Epidemiology

LV is an extremely chronic, progressive form of cutaneous tuberculosis occurring in individuals with moderate immunity and a high degree of tuberculin sensitivity. Once common, LV has declined steadily in incidence. It has always been less common in the United States than in Europe. Females appear to be affected two to three times as often as males; all age groups are affected equally.

Etiology and Pathogenesis

LV is a postprimary, paucibacillary form of tuberculosis caused by hematogenous, lymphatic, or contiguous spread from elsewhere in the body. Spontaneous involution may occur, and new lesions may arise within old scars. Complete healing rarely occurs without therapy.

Clinical Findings

Lesions are usually solitary, but two or more sites may be involved simultaneously. In patients with active pulmonary tuberculosis, multiple foci may develop. In approximately 90% of patients, the head and neck are involved. LV usually starts on the nose, cheek, earlobe, or scalp and slowly extends onto adjacent regions. Other areas are rarely involved.

The initial lesion is a brownish-red, soft or friable macule or papule with a smooth or hyperkeratotic surface. On diascopy, the infiltrate exhibits a typical apple jelly color. Progression is characterized by elevation, a deeper brownish color (Fig. 184-5), and formation of a plaque (see Fig. 184-5). Involution in one area with expansion in another often results in a gyrate outline border. Ulceration may occur. Hypertrophic forms appear as a soft nodule (see eFig. 184-3.1) or plaque with a hyperkeratotic surface (eFig. 184-3.2). The mucosae may be primarily involved or become affected by the extension of skin lesions. Infection is manifest as small, soft, gray or pink papules, ulcers, or friable granulating masses.

After a transient impairment of immunity, particularly after measles (thus the term lupus postexanthematicus), multiple disseminated lesions may arise simultaneously in different regions of the body as a consequence of hematogenous spread from a latent tuberculous focus. During and after the eruption, a previously positive tuberculin reaction may become negative but will usually revert to positive as the general condition of the patient improves.

Histopathology

The most prominent histopathologic feature is the formation of typical tubercles. Secondary changes may be superimposed: epidermal thinning and atrophy or acanthosis with excessive hyperkeratosis or pseudoepitheliomatous hyperplasia. Acid-fast bacilli are usually not found. Nonspecific inflammatory reactions may partially conceal the tuberculous structures. Old lesions are composed chiefly of epithelioid cells and may be impossible to distinguish from sarcoidal infiltrates (see eFig. 184-4.1).

Diagnosis

Typical LV plaques may be recognized by the softness of the lesions, brownish-red color, and slow evolution. The apple jelly nodules revealed by diascopy are highly characteristic; finding them may be decisive, especially in ulcerated, crusted, or hyperkeratotic lesions. The result of the tuberculin test is strongly positive except during the early phases of postexanthematic lupus. Bacterial culture results may be negative, in which case the clinical diagnosis can usually be supported by positive PCR results for M. tuberculosis.

Differential Diagnosis

(Box 184-3)

Complications

Involvement of the nasal or auricular cartilage may result in extensive destruction and disfigurement (Fig. 184-6). Atrophic scarring, with or without prior ulceration, is characteristic, as is recurrence within a scar. Fibrosis may be pronounced and mutilating.

Dry rhinitis is often the only symptom of early nasal LV, but lesions may also destroy the cartilage of the nasal septum. Scarring of the soft palate and laryngeal stenosis also occur.

Course

LV is a very long-term disorder and without therapy progresses over many years to functional impairment and disfiguration (see Fig. 184-6). Long-standing LV may lead to the development of carcinoma (see Fig. 184-6). Squamous cell carcinomas outnumber basal cell carcinomas by far, and the risk of metastases is high. In 40% of patients, there is associated tuberculous lymphadenitis, and 10%–20% have active pulmonary tuberculosis or tuberculosis of the bones and joints.11 Pulmonary tuberculosis is 4–10 times more frequent in patients with LV than in the general population.

Scrofuloderma (Tuberculosis Colliquativa Cutis)

Epidemiology

Prevalence is higher among children, adolescents, and the aged.

Etiology and Pathogenesis

Scrofuloderma is subcutaneous tuberculosis leading to cold abscess formation and a secondary breakdown of the overlying skin. It may be either multibacillary or paucibacillary.

Scrofuloderma represents contiguous involvement of the skin overlying another site of infection (e.g., tuberculous lymphadenitis, tuberculosis of bones and joints, or tuberculous epididymitis).

Clinical Findings

Scrofuloderma most often occurs in the parotidal, submandibular, and supraclavicular regions and may be bilateral. It first presents as a firm, subcutaneous nodule, usually well defined, freely movable, and asymptomatic. As the lesion enlarges, it softens. After months, liquefaction with perforation occurs, causing ulcers and sinuses (Fig. 184-7). The ulcers are linear or serpiginous with undermined, inverted, bluish edges and soft, granulating floors. Sinusoidal tracts undermine the skin. Clefts alternate with soft nodules. Scar tracts develop and bridge ulcerative areas or even stretches of normal skin. Tuberculin sensitivity is usually pronounced.

Histopathology

Massive necrosis and abscess formation in the center of the lesion are nonspecific. However, the periphery of the abscesses or the margins of the sinuses contain tuberculoid granulomas.

Diagnosis

If there is an underlying tuberculous lymphadenitis or bone and joint disease, the diagnosis usually presents no difficulty. Positive results on culture confirm the diagnosis.

Differential Diagnosis

(Box 184-4)

Course

Spontaneous healing does occur, but the course is very protracted, and it may be years before lesions have been completely replaced by scar tissue. Presence of the typical cribriform scars permits a correct diagnosis, even after the process has become quiescent. LV may develop at or near the site of scrofuloderma.

Metastatic Tuberculous Abscess (Tuberculous Gumma)

Etiology and Pathogenesis

Clinical Findings

Histopathology

Differential Diagnosis

Orificial Tuberculosis (Tuberculosis Ulcerosa Cutis Et Mucosae, Acute Tuberculous Ulcer)

Etiology and Pathogenesis

Orificial tuberculosis is a rare form of tuberculosis of the mucous membranes and orifices that is caused by autoinoculation of Mycobacteria from progressive tuberculosis of internal organs.

The underlying disease is far advanced pulmonary, intestinal, or, rarely, genitourinary tuberculosis. Mycobacteria shed from these foci in large numbers are inoculated into the mucous membranes.

Clinical Findings

A small yellowish or reddish nodule appears on the mucosa and breaks down to form a soft ulcer with a typical punched-out appearance, undermined edges, and circular or irregular border (Fig. 184-8). The ulcer floor often exhibits multiple yellowish tubercles and bleeds easily. The surrounding mucosa is edematous and inflamed. Lesions may be single or multiple and are extremely painful, resulting in dysphagia.

The tongue is most frequently affected, particularly the tip and the lateral margins, but the soft and hard palates are also common sites. In advanced cases, the lips are involved, and the oral condition often represents an extension of ulcerative tuberculosis of the pharynx and larynx. In patients with intestinal tuberculosis, lesions develop around the anus, and in females with active genitourinary disease, the vulva is involved.

Histopathology

There is a massive nonspecific inflammatory infiltrate and necrosis, but tubercles with caseation may be found deep in the dermis. Mycobacteria are easily demonstrated.

Differential Diagnosis

(Box 184-5)

Course

Orificial tuberculosis is a symptom of advanced internal disease and usually portends a fatal outcome.

Acute Miliary Tuberculosis of the Skin (Tuberculosis Cutis Miliaris Disseminata, Tuberculosis Cutis Acuta Generalisata)

Etiology and Pathogenesis

Clinical Findings

Histopathology

Course

Sequelae of Bacille Calmette–Guérin Inoculation

Vaccination with attenuated bovine BCG appears to protect infants and young children from the more serious forms of tuberculosis, but its ability to prevent disease in adults remains uncertain. In the United States, guidelines for BCG immunization have been developed.12,13

In the normal course of BCG vaccination, an infiltrated papule develops after approximately 2 weeks, attains a size of approximately 10 mm after 6–12 weeks, ulcerates, and then slowly heals, leaving a scar. Vaccination may provoke an accelerated reaction in a previously infected person. The regional lymph nodes may enlarge, but usually heal without breaking down. Tuberculin sensitivity appears 5–6 weeks after vaccination.

The true incidence of complications caused by the BCG organism is difficult to ascertain, but it is extremely low in comparison to the great number of vaccinations performed in Europe in the past 50 years.14 Problems include the following:

• LV at or near the vaccination site (latency of months to years)
• Koch phenomenon in individuals sensitive to tuberculin [see Section “Tuberculin Reaction (Koch Phenomenon)”]
• Regional adenitis, sometimes severe and with systemic symptoms, more often in children
• After deep injection, local abscesses, excessive ulceration
• Scrofuloderma with suppuration for 6–12 months
• Generalized tuberculid-like reactions (rare)
• Generalized adenitis, osteitis, organ tuberculosis (e.g., in the joints) occasionally

Lichen scrofulosorum, erythema induratum, papulonecrotic tuberculids, lupus miliaris disseminatus faciei, and other eruptions with rather exotic designations were originally included in the tuberculids (Table 184-2).

With the sharp decline in incidence and the effective treatment of tuberculosis in developed countries, the tuberculids also became rare. However, this does not apply to areas in which tuberculosis is still common, and with the recent resurgence of tuberculosis associated with AIDS in some Western countries, some tuberculids are also being observed again.

The pathogenic relationship of the tuberculids to tuberculosis is still poorly understood. Although there is no doubt that such a relationship exists for some tuberculids, in other cases it appears highly unlikely.

PCR testing revealed M. tuberculosis DNA in skin lesions of erythema induratum/nodular vasculitis and papulonecrotic tuberculid in one series of patients, but in another, results were uniformly negative.18,19 Thus, M. tuberculosis infection may be responsible directly or indirectly for some cases of these diseases but not all, and the usefulness of lesional PCR testing may vary among clinical settings. Consistent with this statement, antituberculosis drugs are beneficial in some cases but not all; spontaneous involution may occur, and some patients appear to respond well to other therapies. It should be noted that, although not considered a tuberculid, sarcoidosis has been postulated to result from an immunologic reaction to mycobacterial antigens.20

The following discussion includes only those conditions for which a preponderance of the evidence supports a tuberculous etiology (see Table 184-2).

Lichen Scrofulosorum

Epidemiology and Pathogenesis

Lichen scrofulosorum is an uncommon lichenoid eruption ascribed to hematogenous spread of Mycobacteria in an individual strongly sensitive to M. tuberculosis. Usually associated with chronic tuberculosis of the lymph nodes, bones, or pleura, it has also been observed after BCG vaccination and in association with M. avium-intracellulare infections.21

Clinical Findings

Lesions are usually confined to the trunk and occur most often in children and adolescents with active tuberculosis. The lesions are asymptomatic, firm, follicular or perifollicular flat-topped yellowish or pink papules, sometimes with fine scale. Lichenoid grouping is pronounced, and lesions may coalesce to form rough, discoid plaques. Lesions persist for months, but spontaneous involution eventually occurs. Antituberculosis therapy results in complete resolution within weeks.

Histopathology

Superficial tuberculoid granulomas develop around hair follicles or independent of the adnexa. Mycobacteria are not seen in the sections and cannot be cultured from biopsy material.

Differential Diagnosis

(Box 184-6)

Papulonecrotic Tuberculid

Epidemiology

Papulonecrotic tuberculid is a symmetric eruption of necrotizing papules, appearing in crops and healing with scar formation that occurs preferentially in children or young adults. It is rarely reported but may not be uncommon in populations with a high prevalence of tuberculosis.

Etiology and Pathogenesis

As a rule, bacteria cannot be demonstrated in lesions. In most cases, the tuberculin test shows a positive reaction, and associated pulmonary or extrapulmonary tuberculosis is common. LV has been reported to evolve with papulonecrotic tuberculid. Lesions are reported to respond promptly to antituberculosis therapy whether or not a tuberculous focus is identified.

In studies of skin lesions in patients with papulonecrotic tuberculid, M. tuberculosis DNA was detected in approximately 50% of the skin biopsies (11 out of 22 samples).22,23,24 M. kansasii infection was documented in one patient.25

Some cases of papulonecrotic tuberculid have been associated with discoid lupus erythematosus, arthritis, or erythema nodosum. Although papulonecrotic tuberculid is classified as an id reaction and therefore, by definition, is not due to direct involvement of the skin by the organism, some of the lesions have been positive on culture. It seems most likely that papulonecrotic tuberculid is a reaction to particulate tuberculous antigen and, in some cases, to living organisms as well.26

Clinical Findings

Sites of predilection are the extensor aspects of the extremities, buttocks, and lower trunk (Fig. 184-9), but the eruption may become widespread. Distribution is symmetric, and consists of disseminated crops of livid or dusky red papules with a central depression and an adherent crust over a crater-like ulcer. There is spontaneous involution, which leaves pitted scars.

Histopathology

Characteristically, a wedge-shaped necrotic area in the upper dermis extends into the epidermis. The inflammatory infiltrate surrounding this necrotic area may be nonspecific, but is usually tuberculoid. Involvement of the blood vessels is a cardinal feature and consists of an obliterative and sometimes granulomatous vasculitis leading to thrombosis and complete occlusion of the vascular channels.

Differential Diagnosis

(Box 184-7)

Nodular Vasculitis/Erythema Induratum of Bazin

(See Chapter 70)

Erythema Nodosum

(See Chapter 70)

In general, the management of cutaneous tuberculosis is similar to that of tuberculosis of other organs.27–30 Chemotherapy is usually the treatment of choice (Table 184-3A and eTable 184-3B), but ancillary measures may be required. Vaccines against M. tuberculosis have been attempted,27 but are still not available.

Although they are not yet established as a therapeutic option, cytokines such as interleukin 2, interferon-γ, interleukin 12, and granulocyte-macrophage colony-stimulating factor may help to control intracellular pathogens and thereby shorten the duration of therapy and overcome drug resistance.31 The immunomodulatory drug thalidomide (see Chapter 235) may prove to be useful in controlling problems related to the inflammatory response that may follow treatment of multibacillary infection and could become a useful adjunctive drug, as it is in the treatment of leprosy.

Special Considerations in Treating Tuberculosis of the Skin

In contrast to systemic infection, for which triple-drug therapy is recommended, tuberculosis verrucosa cutis and localized forms of LV without evidence of associated internal tuberculosis may be treated with isoniazid alone for up to 12 months. Because viable Mycobacteria have been found in clinically healed lesions, treatment should be continued for at least 2 months after complete involution of the lesions. Surgical intervention is quite helpful in scrofuloderma, because it reduces morbidity and shortens the required length of chemotherapy. Small lesions of LV or tuberculosis verrucosa cutis are also best excised, but tuberculostatics should be given concomitantly. Plastic surgery is important as a corrective measure in cases of long-standing LV with mutilation.

Extensively drug resistant (XDR) TB is defined as resistance to at least rifampicin and isoniazid from among the first line anti-TB drugs (which is the definition of MDR TB) in addition to resistance to any fluoroquinolone, and to at least one of the three injectable second-line anti-TB drugs used in TB treatment [(1) capreomycin, (2) kanamycin, and (3) amikacin]. The CDC and WHO have outlined that XDR TB poses a grave global public health threat and has a higher risk of death as it renders patients virtually untreatable with currently available drugs.32

MOTT were identified as human pathogens in 1938 (Mycobacterium fortuitum), in 1948 (Mycobacterium ulcerans), and in 1954 (Mycobacterium marinum). However, overshadowed by the infectious disease burden due to M. leprae and M. tuberculosis, the pathogenic potential of slow-growing MOTT species has been recognized only in recent decades. Because MOTT infections usually closely mimic infections with M. tuberculosis, and the bacteria have strict and often unusual requirements for culture, they are still probably underdiagnosed.

Identification of Mycobacteria Other Than M. Tuberculosis

As with other infectious diseases, the diagnosis of mycobacterial infection depends on the identification of the microorganism isolated from the host. Specimens for culture should be sent to a special laboratory familiar with the special growth requirements of these organisms.

Antigens for intradermal skin testing (PPDs) for many of the clinically relevant mycobacterial species have been prepared in analogy to PPD from M. tuberculosis, but their accessibility is very limited and they are therefore little used.

Histopathologic analysis is supportive but cannot distinguish among mycobacterial species, because all share similar histopathologic features.33

Treatment is summarized in Table 184-4. Importantly, some MOTT organisms are resistant to standard tuberculosis therapy. PCR testing for mycobacterial DNA is not yet reliable enough to play a role in the diagnosis of disease but can sometimes be useful in distinguishing among species.

Etiology and Pathogenesis

MOTT are widely distributed in nature and are usually commensals or saprophytes, rather than pathogens. Atypical Mycobacteria are usually acquired from environmental sources such as water or soil, and their role in disease reflects their natural distribution and, possibly, local lifestyles. These organisms are thought to cause mycobacterial skin disease more often than does M. tuberculosis. Cases tend to be sporadic, but certain types of exposures may lead to small community outbreaks.3,34 Any organ or organ system may be affected (Table 184-5), but MOTT seem much less likely to disseminate than M. tuberculosis, and infections usually run a more benign and limited course. As a rule, MOTT are much less responsive to antituberculosis drugs but may be sensitive to other chemotherapeutic agents.

Only two organisms, M. ulcerans and M. marinum, produce a characteristic clinical picture. An immunosuppressed state of the host or damage to a particular organ (e.g., in M. kansasii infection of the lung) facilitates these infections.

New mycobacterial pathogens are described from time to time, which suggests that their full pathogenic potential is not yet appreciated. Recently, an outbreak of skin disease caused by a nontuberculous Mycobacteria in Pacific Islanders from Satowan was reported in the literature.35 These patients presented with long-standing verrucous and keloidal plaques (locally known as “spam” disease) (Fig. 184-10). Histopathological and PCR data demonstrated a nontuberculous mycobacterial infection as the cause.

Skin Infections with Mycobacteria Other Than M. Tuberculosis

Mycobacterium Ulcerans (Buruli Ulcer Disease)

The natural habitat of M. ulcerans is still not known, and it has never been found outside the human body, but M. ulcerans infection occurs in wet, marshy, or swampy areas and seems to have to do with contaminated water. M. ulcerans is the third most frequent mycobacterial pathogen, after M. tuberculosis and M. leprae.

Clinical Findings

The disease is found most often in children and young adults, and affects females more often than males. A subcutaneous nodule gradually enlarges and eventually ulcerates. A blister may develop before ulceration. The ulcer is deeply undermined, and necrotic fat is exposed (Fig. 184-11). The preceding nodule as well as the ulcer is painless, and the patient continues to feel well. The painless nature of the ulcer has been attributed to nerve damage and tissue destruction caused by the toxin mycolactone. The lesions may occur anywhere on the body but tend to be limited to the extremities in adults. They may be large, involving a whole limb. The ulceration may persist for months and years, and healing and progression of the ulceration may occur in the same patient. This process may lead to appreciable and sometimes disabling scarring and lymphedema. Neither lymphadenopathy nor any constitutional signs appear at any time unless the disease process is complicated by bacterial superinfection.

Differential Diagnosis

(Box 184-8)

Mycobacterium Marinum (Mycobacterium Balnei, Fishtank/Swimming Pool Granuloma)

M. marinum occurs in freshwater and saltwater, including swimming pools and fish tanks.

Clinical Findings

Risk factors for M. marinum infection are a history of trauma and water- or fish/seafood-related hobbies and occupations. The disease begins as a violaceous papule at the site of a trauma 2–3 weeks after inoculation. Patients may have a nodule or a psoriasiform or verrucous plaque at the site of inoculation, usually the hands, feet, elbows, or knees (Fig. 184-12). The lesions may ulcerate. Usually, the lesions are solitary, but occasionally lymphocutaneous spread occurs. They may heal spontaneously within 1–2 years, with residual scarring. Occasionally, the lesions are suppurative, rather than granulomatous, and may be multiple in both normal or immunosuppressed hosts.

Differential Diagnosis

(Box 184-9)

Mycobacterium Kansasii

M. kansasii is the atypical Mycobacterium most closely related to M. tuberculosis. It is usually acquired from the environment. Endemic areas include Texas, Louisiana, the Chicago area, California, and Japan. Skin disease caused by M. kansasii usually occurs in adults, and is more common in individuals with underlying immunosuppression caused by Hodgkin disease, treatment for organ transplantation, or AIDS. Inoculation is usually attributable to minor trauma such as a puncture wound.

Clinical Findings

M. kansasii infection may present in several forms. Most frequently, there are papules in a sporotrichoid distribution. Sometimes, subcutaneous nodules extend to deeper structures and may result in a carpal tunnel syndrome or joint disease. An ulcerated plaque may also develop as a metastatic lesion. Disseminated disease caused by M. kansasii infection occurs in immunosuppressed patients, and such patients have cellulitis and abscesses rather than granulomatous lesions. The most commonly affected organ is the lung, usually in patients with other pulmonary conditions (silicosis, emphysema). Infection may also cause cervical lymphadenopathy. As with M. tuberculosis, M. kansasii present in nasopharyngeal secretions can lead to periorificial cutaneous infection. These infections usually progress slowly, although a chronic stable lesion or even spontaneous regression may occur. Drug therapy should be initiated as soon as the diagnosis is made.

Differential Diagnosis

(Box 184-10)

Mycobacterium Scrofulaceum

Mycobacterium scrofulaceum is widely distributed in the environment.

Clinical Findings

The usual manifestation of M. scrofulaceum infection is cervical lymphadenitis, frequently unilateral, in children, mainly between the ages of 1 and 3 years. Submandibular and submaxillary nodes are typically involved, rather than the tonsillar and anterior cervical nodes, as is characteristic for M. tuberculosis infection. There are no constitutional symptoms. Involved lymph nodes enlarge slowly over several weeks, and eventually ulcerate and develop fistulae. There is rarely an evidence of lung or other organ involvement. In most cases, the disease is benign and self-limited.

Differential Diagnosis

The differential diagnosis includes other forms of bacterial lymphadenitis; viral infections, including mumps and mononucleosis; and malignancy, including solid tumors, lymphoma, and leukemia.

Mycobacterium Avium-Intracellulare

M. avium-intracellulare encompasses organisms with a wide variety of microbiologic and pathogenic properties. Well over 20 subtypes can be separated by immunologic techniques, although this is not necessary for clinical purposes.

These organisms are usually grouped together with M. scrofulaceum in the so-called M. avium-intracellulare-scrofulaceum complex, but are separated here for clinical reasons. Whereas M. scrofulaceum produces only a benign, self-limited lymphadenopathy with no organ involvement, M. avium-intracellulare infection usually causes lung disease or, less frequently, osteomyelitis. It may also produce a cervical lymphadenitis with sinus formation that is clinically indistinguishable from tuberculous scrofuloderma.

Clinical Findings

Primary skin disease caused by M. avium-intracellulare has been reported in rare instances, presenting as single or multiple painless, scaly yellowish plaques, sometimes resembling LV, or as subcutaneous nodules with a tendency to ulceration and a slowly progressive, chronic course. Sometimes, skin involvement occurs secondary to disseminated infection with M. avium-intracellulare. Skin lesions have included generalized cutaneous ulcerations, granulomas, infiltrated erythematous lesions on the extremities, pustules, and soft-tissue swelling. M. avium-intracellulare infections are an important cause of morbidity in patients with AIDS (see Chapter 198).

Mycobacterium Szulgai, Mycobacterium Haemophilum, Mycobacterium Genavense

Mycobacterium szulgai, Mycobacterium haemophilum, and M. genavense are rarely found to cause human disease in cases of otherwise unexplained cervical lymphadenitis, cellulitis, draining nodules and plaques, bursitis, pneumonia, and subcutaneous granulomatous eruptions.

Mycobacterium Fortuitum, Mycobacterium Chelonae, Mycobacterium Abscessus

M. fortuitum, Mycobacterium chelonae, and Mycobacterium abscessus—three species of fast-growing, facultative pathogenic Mycobacteria—were previously grouped in the M. fortuitum complex but are now recognized as distinct species. These organisms seem to be widely distributed and can commonly be found in soil and water. Contamination of various materials, including surgical supplies, occurs but does not always result in clinical disease.

Clinical Findings

M. fortuitum, M. chelonae, and M. abscessus cause similar clinical diseases. Infection usually follows a puncture wound or a surgical procedure. The disease manifests itself as a painful red infiltrate at the site of inoculation; there are no signs of dissemination and no constitutional symptoms. Cold postinjection abscesses, especially in the tropics, may also be caused by fast-growing Mycobacteria. Recent cases in the United States have followed after pedicures and water immersion in salons.

The lesion is a dark red nodule, often with abscess formation and clear fluid drainage. Healthy children and adults may become infected, but disseminated disease usually occurs in hemodialysis patients or other immunologically compromised individuals. The disease course consists of multiple recurrent episodes of abscesses on the extremities or a generalized macular and papular eruption. Internal organs may be involved.

Histopathology

There is simultaneous occurrence of polymorphonuclear leukocyte microabscesses and granuloma formation with foreign body-type giant cells, the so-called dimorphic inflammatory response. There is usually necrosis but no caseation. Acid-fast bacilli may occasionally be found within microabscesses.

Diagnosis

Organisms of the M. fortuitum complex may be identified by special laboratories to permit a rational treatment.

The author thanks Bernard Naafs, MD, for his work on this chapter in the previous editions of this book.