Leprosy and tuberculosis are chronic mycobacterial infections that elicit granulomatous inflammation. Both infections are curable, but granulomatous injury to cutaneous structures, including cutaneous nerves in leprosy, may cause permanent damage. Both diseases are major global concerns: tuberculosis for its high prevalence and mortality, and leprosy for its persistent global presence and high rate of neuropathic disability. Cutaneous manifestations of both leprosy and tuberculosis are frequently subtle and challenging in dermatologic practice and often require a careful travel and social history and a high index of suspicion.
Key points
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Cutaneous lesions are rare in tuberculosis but are common in leprosy.
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Mycobacterium tuberculosis is cultivable; Mycobacterium leprae is not.
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Both infections are curable, but optimal multidrug regimens for them are different.
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Standard Ziehl-Neelsen staining may fail to stain many M leprae, because they are weakly acid-fast compared with M tuberculosis.
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A delay or failure to diagnose cutaneous tuberculosis may be associated with mortality if there is concomitant systemic disease; delay or failure to diagnose leprosy is associated with a high risk of peripheral neuropathy and disability.
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Hypoesthesia and intraneural or perineural localization of granulomas are helpful in distinguishing leprosy from tuberculosis clinically and histologically.
Introduction
Tuberculosis (TB) and leprosy, the 2 major mycobacterial infections of humans, are classic granulomatous diseases that still affect millions of people. Both infections are now curable, but no highly effective vaccine is yet available for either of them. Both are ancient scourges with a wide range of cutaneous manifestations, and both are infamous for their ability to mimic other diseases and sometimes fool even the most skilled diagnostician.
Etiopathogenesis
TB and leprosy are both chronic infections, but they are very different diseases ( Table 1 ). Mycobacterium tuberculosis is cultivable; Mycobacterium leprae is not. M leprae infects peripheral nerves; M tuberculosis does not. Untreated tuberculosis has a high mortality; untreated leprosy has a high disability rate due to peripheral neuropathy. Cutaneous lesions are typical of leprosy, but rare in tuberculosis.
| TB | Leprosy | |
|---|---|---|
| Etiologic agent | M tuberculosis | M leprae |
| Acid-fastness | Strong (Ziehl-Neelsen stain) | Weak (Fite stain preferred) |
| Growth in tissue | Extracellular or in macrophages | Obligate intracellular pathogen, in macrophages and Schwann cells |
| Cultivable | Yes | No |
| Growth temperature | 37°C | 33°C |
| Number of protein genes | 3993 | 1614 |
| Number of pseudogenes | 6 | 1133 |
| Transmission | Airborne droplets | Probably airborne |
| Initial site of infection | Periphery of lung | Nose and nasopharynx |
| Cutaneous infection | Uncommon | Typical, very common |
| Infection of peripheral nerves | No | Yes |
| Infection is curable | Yes | Yes |
| CMI | Mainly 2 polar types; strong and weak CMI | Full spectrum from strong to none |
| Outcome if untreated | High mortality | Very low mortality; high disability rate from peripheral neuropathy |
| Vaccine | BCG (variable protection) | BCG (variable protection) |
The cell-mediated immune response (CMI) to these agents is the critical determinant in individual susceptibility to these infections and in the range of clinical and histologic appearances of their cutaneous lesions ( Fig. 1 ). The organisms express pathogen-associated molecular patterns on their surfaces, which are recognized by pattern recognition receptors of macrophages and dendritic cells, facilitating phagocytosis. Innate immunity to mycobacteria is mediated by macrophages and dendritic cells, including Langerhans cells in the skin, and may be sufficient to prevent further progression of the infection.
If innate immunity is insufficient, mycobacterial antigens are presented to CD4+ T cells, initiating the acquired CMI. Based largely on inherited immunologic capabilities, CMI in most individuals will be driven by activated CD4+ T lymphocytes elaborating tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2), stimulating macrophage release of interferon-γ (IFN-γ), the TH1 pattern of cytokines. TH1 responses are associated with the formation of well-organized granulomas. The epithelioid macrophage is a specialized cell producing large quantities of cytokines, with enhanced microbicidal activity. Such granulomas are associated with limited proliferation of mycobacteria. Caseous necrosis is thought to be a result of the death and regeneration of the epithelioid cells within the granuloma, a process mediated by TNF-α and proteases.
Although granuloma formation has been understood as a host-protective strategy to limit spread of the mycobacteria, recent studies suggest that M tuberculosis may use the granuloma to shield itself from the host’s immunologic killing mechanisms and antimicrobial agents. Therapies targeting granuloma formation are being studied as adjunctive therapies for the treatment of TB.
Such a shielding effect of granulomas may play a role in the human tuberculosis and leprosy, but it is also apparent that in these 2 infections the well-organized epithelioid granuloma is associated with a high degree of CMI and a limited bacterial load. When CMI is weak or absent, a TH-2 response to mycobacterial infection results, characterized by the production of IL-4 and IL-10. In such individuals, well-organized granulomas do not develop, and mycobacteria proliferate and may reach large numbers, such as in lepromatous leprosy or tuberculosis in immunosuppressed individuals.
Antibodies play no role in protective immunity to M tuberculosis or M leprae . Negligible antibody production is elicited by either agent in individuals who have strong CMI and granulomatous responses. In general, therefore, tests for antibodies are not useful in the diagnosis of these infections, whereas assays for CMI mediators such as IFN-γ are sensitive and specific for tuberculosis, and measurements of CXCL-10 show promise for use in leprosy.
Introduction
Tuberculosis (TB) and leprosy, the 2 major mycobacterial infections of humans, are classic granulomatous diseases that still affect millions of people. Both infections are now curable, but no highly effective vaccine is yet available for either of them. Both are ancient scourges with a wide range of cutaneous manifestations, and both are infamous for their ability to mimic other diseases and sometimes fool even the most skilled diagnostician.
Etiopathogenesis
TB and leprosy are both chronic infections, but they are very different diseases ( Table 1 ). Mycobacterium tuberculosis is cultivable; Mycobacterium leprae is not. M leprae infects peripheral nerves; M tuberculosis does not. Untreated tuberculosis has a high mortality; untreated leprosy has a high disability rate due to peripheral neuropathy. Cutaneous lesions are typical of leprosy, but rare in tuberculosis.
| TB | Leprosy | |
|---|---|---|
| Etiologic agent | M tuberculosis | M leprae |
| Acid-fastness | Strong (Ziehl-Neelsen stain) | Weak (Fite stain preferred) |
| Growth in tissue | Extracellular or in macrophages | Obligate intracellular pathogen, in macrophages and Schwann cells |
| Cultivable | Yes | No |
| Growth temperature | 37°C | 33°C |
| Number of protein genes | 3993 | 1614 |
| Number of pseudogenes | 6 | 1133 |
| Transmission | Airborne droplets | Probably airborne |
| Initial site of infection | Periphery of lung | Nose and nasopharynx |
| Cutaneous infection | Uncommon | Typical, very common |
| Infection of peripheral nerves | No | Yes |
| Infection is curable | Yes | Yes |
| CMI | Mainly 2 polar types; strong and weak CMI | Full spectrum from strong to none |
| Outcome if untreated | High mortality | Very low mortality; high disability rate from peripheral neuropathy |
| Vaccine | BCG (variable protection) | BCG (variable protection) |
The cell-mediated immune response (CMI) to these agents is the critical determinant in individual susceptibility to these infections and in the range of clinical and histologic appearances of their cutaneous lesions ( Fig. 1 ). The organisms express pathogen-associated molecular patterns on their surfaces, which are recognized by pattern recognition receptors of macrophages and dendritic cells, facilitating phagocytosis. Innate immunity to mycobacteria is mediated by macrophages and dendritic cells, including Langerhans cells in the skin, and may be sufficient to prevent further progression of the infection.
If innate immunity is insufficient, mycobacterial antigens are presented to CD4+ T cells, initiating the acquired CMI. Based largely on inherited immunologic capabilities, CMI in most individuals will be driven by activated CD4+ T lymphocytes elaborating tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2), stimulating macrophage release of interferon-γ (IFN-γ), the TH1 pattern of cytokines. TH1 responses are associated with the formation of well-organized granulomas. The epithelioid macrophage is a specialized cell producing large quantities of cytokines, with enhanced microbicidal activity. Such granulomas are associated with limited proliferation of mycobacteria. Caseous necrosis is thought to be a result of the death and regeneration of the epithelioid cells within the granuloma, a process mediated by TNF-α and proteases.
Although granuloma formation has been understood as a host-protective strategy to limit spread of the mycobacteria, recent studies suggest that M tuberculosis may use the granuloma to shield itself from the host’s immunologic killing mechanisms and antimicrobial agents. Therapies targeting granuloma formation are being studied as adjunctive therapies for the treatment of TB.
Such a shielding effect of granulomas may play a role in the human tuberculosis and leprosy, but it is also apparent that in these 2 infections the well-organized epithelioid granuloma is associated with a high degree of CMI and a limited bacterial load. When CMI is weak or absent, a TH-2 response to mycobacterial infection results, characterized by the production of IL-4 and IL-10. In such individuals, well-organized granulomas do not develop, and mycobacteria proliferate and may reach large numbers, such as in lepromatous leprosy or tuberculosis in immunosuppressed individuals.
Antibodies play no role in protective immunity to M tuberculosis or M leprae . Negligible antibody production is elicited by either agent in individuals who have strong CMI and granulomatous responses. In general, therefore, tests for antibodies are not useful in the diagnosis of these infections, whereas assays for CMI mediators such as IFN-γ are sensitive and specific for tuberculosis, and measurements of CXCL-10 show promise for use in leprosy.
Cutaneous tuberculosis
Epidemiology
TB remains the second leading cause of death worldwide, despite concerted measures to improve detection and treatment. The World Health Organization (WHO) estimates that 8.6 million people were diagnosed with TB in 2012 (122 cases per 100,000 population) and 1.3 million died of the disease. Although the incidence of TB has decreased 2% over the last decade, global efforts to reach the 2015 Millennium Development Goal of decreasing TB-related mortality by 50% are unlikely to succeed, and the increase in multidrug-resistant TB (MDR-TB) raises concerns of an epidemic of untreatable cases.
Skin involvement is a relatively rare extrapulmonary manifestation of systemic TB, comprising less than 1% to 2% of all cases. However, cutaneous TB is still an important differential diagnosis to consider in the age of HIV/AIDS, MDR-TB, and immunosuppressive therapies.
Etiopathogenesis
Cutaneous TB in humans is primarily caused by M tuberculosi s, although rarely this is due to Mycobacterium bovis . The development of cutaneous TB depends on multiple factors, including the route of infection, duration of exposure and previous sensitization, and the individual’s CMI.
Cutaneous manifestations of TB are immunologically driven; individuals without effective CMI face a higher risk of active disease with exudative lesions and disseminated miliary TB. The tuberculin skin test (purified protein derivative [PPD]), reflecting delayed hypersensitivity to M tuberculosis antigens, becomes positive 3 to 8 weeks after infection.
Histopathology
Typically, 3 to 6 weeks after infection, the classic tuberculoid granuloma develops, with a central focus of epithelioid histiocytes and Langhans giant cells surrounded by a mantle of lymphocytes. Caseation necrosis occurs in the center of the granuloma, often with calcification and fibrosis. The number of bacilli is roughly proportional to the amount of necrosis present. The histopathological features of different forms of cutaneous TB depend on source of infection (exogenous vs endogenous) and the host’s CMI.
Both sarcoidosis and lupus vulgaris (LV) are characterized by granulomas, but sarcoidal granulomas typically have minimal lymphocytic inflammation and no caseation necrosis. Perineural involvement helps to distinguish tuberculoid leprosy from cutaneous TB (see later discussion). The causative organism must be identified in other infections with a prominent granulomatous infiltrate (ie, atypical mycobacteria, leishmaniasis, blastomycosis, and chromomycosis). Tertiary syphilis can also be granulomatous; however, increased plasma cells and endothelial swelling help differentiate it from TB. Rosacea and panniculitis can exhibit a nonspecific nodular granulomatous infiltrate, but typical tuberculoid granulomas are absent. Rare cases of lupus miliaris disseminatus faceii, a controversial entity generally understood as a rosacea variant, have shown evidence of TB.
Classification and Clinical Presentations
The classification of cutaneous TB has evolved from a model based on clinical morphology to one incorporating the route of transmission and immune status ( Table 2 ). In an individual with high CMI, few bacilli are noted histologically, and they are difficult to culture. Patients with low CMI have many mycobacteria, easily seen in Ziehl-Neelsen–stained sections and cultured. The presence of numerous acid-fast bacilli (AFB) indicates impaired CMI and suggests consideration of other entities such as leprosy (see Fig. 1 ).
| TB Type | Host Immunity to M tuberculosis | Clinical Presentation | Histologic Features | PPD |
|---|---|---|---|---|
| TVC | High | Hyperkeratotic papule or plaque, resolves spontaneously with scarring, often with lymphadenopathy | Pseudoepitheliomatous hyperplasia of epidermis with intense dermal infiltrate of neutrophils, lymphocytes, and some giant cells; ± bacilli | + |
| LV | Moderate to high | Plaque: gelatinous Hypertrophic: soft nodules Ulcerative: necrotic Vegetative: papule with ulceration or necrosis Commonly involving face/neck; “apple-jelly” appearance on diascopy | Tuberculoid granulomas embedded in sheets of lymphocytes, sparse or absent caseation, extensive fibrosis with healing; increased risk of developing nonmelanoma skin cancer in lesions; ± bacilli | ± |
| Tuberculids | Moderate to high | Papulonecrotic tuberculid, dusky small papules with central necrosis Lichen scrofulosorum, multiple grouped lichenoid papules Erythema induratum (Bazin), painful ulcerated nodules on posterior legs Nodular tuberculid, bluish-red nontender, nonulcerating nodules on legs Nodular granulomatous phlebitis, nonulcerating, subcutaneous nodules along leg veins of anterior and medial leg | Superficial granulomatous infiltrate, wedge-shaped necrosis, granulomatous vasculitis Variable dermal granulomas Granulomatous vasculitis at junction of deep dermis/subcutis Septal and lobular panniculitis with granulomatous vasculitis Epithelioid granulomas with Langhan giant cells in walls of cutaneous veins No bacilli | + |
| Scrofuloderma | Low | Nodule over affected cervical lymph node, suppurates and ulcerates with fistulae progressing to scarring | Ulcerated dermal abscess with scattered histiocytes, few lymphocytes, marked caseation necrosis containing numerous bacteria in the deeper structures; ++ bacilli | + |
| Tuberculosis cutis orificialis | Low | Painful papule that ulcerates with “punched-out” borders; usually oral cavity or genitourinary | Ulceration with underlying caseating granulomas; ++ bacilli | ± |
| Miliary tuberculosis | Low | Numerous discrete minute red to violaceous papulopustules, umbilication, hemorrhagic necrosis, crusting; heal with atrophic scarring | Focal necrosis with microabscesses surrounded by chronic inflammation; in HIV patients more pustular with numerous neutrophils; ++ bacilli | ± |
| Tuberculous gumma (metastatic tuberculous abscess) | Low | Indurated deep nodule(s) on trunk, face, extremities, becoming fluctuant with draining sinuses, ± ulceration | Tuberculous granulation tissue, massive necrosis, and abscess formation; ++ bacilli | ± |
| Tuberculous chancre | Naïve host | Usually follows penetration injury; inflammatory papule progresses to nontender, shallow, undermined ulcer with painless lymphadenopathy | Acute neutrophilic inflammation with necrosis in skin and affected lymph nodes. Granulomatous inflammatory infiltrate in later lesions; ++ bacilli (early), ± late | ± |
High immune forms
Tuberculosis verrucosa cutis (TVC) is a warty plaquelike form occurring most commonly on the extremities as a result of direct cutaneous inoculation in a previously sensitized individual ( Fig. 2 ). TVC can occur by accidental inoculation (ie, “prosector’s wart”), by autoinoculation from sputum in a patient with active TB, and in children with some immunity exposed to infected sputum. Clinically, TVC starts as an asymptomatic indurated papule, gradually evolving into a brownish-red verrucous plaque with a soft center, sometimes with keratinous discharge; this may spontaneously involute, forming a hypopigmented and atrophic scar, or it can become a large, exophytic, keloidal plaque, with rare sporotrichoid spread or lymphadenitis. Histologically, TVC shows epidermal hyperplasia with a mixed dermal infiltrate of neutrophils, lymphocytes, and some giant cells. Bacilli may or may not be identified. The differential diagnosis is broad, including fungal infections (sporotrichosis, blastomycosis, and chromomycosis) as well as leishmaniasis, tertiary syphilis, hypertrophic lichen planus, psoriasis, and squamous cell carcinoma.
LV is a chronic and progressive form of cutaneous TB that occurs in patients with moderate to high CMI. Historically, LV has been the most common presentation of cutaneous TB in Asia and South Africa. It presents with multiple red-brown papules coalescing into plaques ( Fig. 3 ), developing a gelatinous quality centrally; its appearance on diascopy resembles “apple jelly.” Lesions run a variable course and may cause significant tissue destruction, heal with atrophic scarring, or have a prolonged course with minimal cutaneous damage. The most commonly affected areas were the head and neck in Europe, and the extremities, trunk, and buttocks in Asia. LV may originate from an underlying focus of TB in a lymph node, bone, or joint, by direct contiguous extension, or via lymphatic spread. It may result from reactivation of latent cutaneous TB or after exogenous inoculation, including Bacille Calmette-Guérin (BCG) vaccination. Involvement of the face may result from hematogenous spread, and acral lesions may result from reinoculation. Clinical variants include classic plaque-type, ulcerative, vegetating, tumorlike, papular, and nodular forms. Histologic findings often include typical tuberculoid granulomas surrounded by numerous lymphocytes, sparse caseation necrosis, and fibrosis ( Figs. 4 and 5 ). Bacilli may or may not be identified by acid-fast staining.
LV is morphologically diverse and can mimic a plethora of cutaneous conditions, such as Spitz nevus and lupus erythematosus, in early stages as well as rosacea and port-wine stains in chronic disease. Verrucous and vegetating lesions ( Fig. 6 ) can resemble deep fungal infections or other mycobacterial infections. Differentiating the “apple-jelly” lesions of LV from those of sarcoidosis and leprosy can be challenging, and subtle nuances such as the firm texture of leprosy nodules versus the more grainlike quality of sarcoid lesions may be the only clinical clues.
Tuberculids, first described by Darier in 1896, are hypersensitivity reactions to M tuberculosis or other mycobacterial antigen in a person with strong CMI against TB. Tuberculids classically include lichen scrofulosorum ( Fig. 7 ), papulonecrotic tuberculid ( Fig. 8 ), nodular tuberculid, erythema induratum (Bazin disease), and the more recently described nodular granulomatous phlebitis. Tuberculids tend to run a relapsing and remitting course, appearing in crops and healing with scarring. Although the histology of tuberculids can vary, they generally show granulomatous inflammation ( Fig. 9 ) and some degree of necrosis and vasculitis ( Figs. 10 and 11 ), suggesting that they are the result of released mycobacterial antigens from concurrent or distant TB. Tuberculids fail to show evidence of mycobacteria with special stains or cultures, but polymerase chain reaction (PCR) has detected mycobacterial DNA in some specimens.
Low immune forms
A tuberculous chancre results from cutaneous or mucosal inoculation in a person with a low level of CMI. It most commonly presents in children as an inflammatory papule at the site of inoculation on the face or extremities; after 2 to 4 weeks, this develops into a firm, shallow solitary ulcer with regional lymphadenopathy. Histologically, abundant neutrophils and numerous AFB are seen, with necrosis involving skin and lymph nodes. Later, lesions demonstrate more granulomatous inflammation with fewer bacilli. The differential diagnosis includes tularemia, other mycobacterial infections (especially Mycobacterium marinum ), sporotrichosis, and actinomycosis.
Scrofuloderma results from breakdown of skin overlying a contiguous tuberculous focus, most commonly a lymph node, bone, or joint, or a lacrimal gland or duct ( Fig. 12 ). It has been reported as the most common form in children, but is also seen in adults. Clinically, an abscess or fistula draining purulent material forms from an underlying focus of infection with subsequent induration and ulceration of the site. Histologically, an ulcerated dermal abscess with marked caseation necrosis is present, with scattered histiocytes, lymphocytes, and numerous AFB. The differential diagnosis includes sporotrichosis, hidradenitis suppurativa, actinomycosis, and syphilitic gumma.
Tuberculosis cutis orificialis ( Fig. 13 ) is a form of autoinoculation TB occurring in mucosal or orificial sites after local trauma. Patients are typically immunocompromised and are often severely ill with advanced visceral TB. Lesions present on the nose, mouth, tongue, lips, and infrequently, on the vulva, as small erythematous papules that rapidly break down, forming undermined and painful ulcers with violaceous edges. Histology demonstrates ulceration with underlying caseating granulomas. The clinical differential diagnosis is broad and includes herpes simplex, Crohn disease, malignancy, aphthous ulcers, paracoccidioidomycosis, and the Melkersson-Rosenthal syndrome.
