13.2 Mycobacterial Infections: Cutaneous Tuberculosis, Leprosy & Atypical Mycobacteria

13.2 Mycobacterial Infections: Cutaneous Tuberculosis, Leprosy & Atypical Mycobacteria

Cutaneous Tuberculosis (Mycobacterium tuberculosis)

Cutaneous tuberculosis represents less than 1.5% of all extrapulmonary manifestations of tuberculosis, yet it carries immense clinical significance. Cutaneous manifestations depend fundamentally upon two interrelated variables:

1. The Route of Infection: Exogenous inoculation, endogenous spread (contiguous extension or autoinoculation), or hematogenous dissemination.
2. The Host Cell-Mediated Immunity (CMI): Ranging from robust CMI with paucibacillary pathology to absent or anergic CMI with teeming, multibacillary proliferation.

Classification of Cutaneous Tuberculosis

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|                     CLASSIFICATION OF CUTANEOUS TUBERCULOSIS                         |
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| 1. EXOGENOUS INOCULATION:                                                            |
|    - Tuberculous Chancre: Non-sensitized host (no prior immunity), multibacillary    |
|      -> Indurated ulcer + prominent regional lymphadenopathy (Primary Complex)       |
|    - Tuberculosis Verrucosa Cutis (TVC): Sensitized host (moderate-high CMI)         |
|      -> Warty, hyperkeratotic plaque (Prosector's wart)                              |
|                                                                                      |
| 2. ENDOGENOUS SPREAD:                                                                |
|    - Scrofuloderma: Contiguous spread from underlying tuberculous node/bone/joint    |
|      -> Cold abscess, breakdown, draining fistulae, cord-like scars                  |
|    - Lupus Vulgaris: Post-primary, moderate-high CMI, hematogenous/lymphatic spread  |
|      -> Red-brown plaque with "apple-jelly" nodules on diascopy, risk of SCC        |
|    - Orificial Tuberculosis: Autoinoculation from advanced visceral TB; low CMI      |
|      -> Painful, punched-out mucosal/orificial ulcers, teeming bacilli               |
|    - Acute Miliary Tuberculosis: Widespread hematogenous seeding; anergic/infants     |
|                                                                                      |
| 3. TUBERCULIDS (Sterile hypersensitivity reactions, bacilli absent on culture/stain): |
|    - Erythema Induratum of Bazin (Lobular panniculitis + vasculitis on calves)       |
|    - Papulonecrotic Tuberculid (Symmetrical necrotic papules on extensor limbs)      |
|    - Lichen Scrofulosorum (Tiny follicular lichenoid papules on trunk)               |
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1. Exogenous Inoculation Forms

Tuberculous Chancre (Primary Inoculation Tuberculosis)

• Host Setting: Occurs in an individual with zero prior immunity to M. tuberculosis (tuberculin skin test / Mantoux negative at baseline; typically non-BCG-vaccinated infants or children).
• Pathogenesis: Direct percutaneous inoculation of M. tuberculosis through minor abrasions or lacerations (e.g., contaminated instruments, ritual circumcision, ear piercing).
• Clinical Presentation: Approximately 2 to 4 weeks post-inoculation, a small, painless, firm, reddish-brown papule or nodule develops at the inoculation site. It ulcerates to form a shallow, painless, indurated ulcer with undermined borders, a granular base, and thin purulent discharge. Within 3 to 8 weeks, marked, non-tender regional lymphadenopathy develops. The cutaneous ulcer combined with the regional lymphadenopathy forms the tuberculous primary complex of the skin (analogous to the Ghon complex in the lung).
• Evolution: Tuberculin skin test converts from negative to strongly positive after 3 to 6 weeks. Untreated, the ulcer may heal spontaneously over 3 to 12 months with scarring, but bacilli can disseminate hematogenously.

Tuberculosis Verrucosa Cutis (Prosector's Wart / Anatomist's Wart)

• Host Setting: Occurs in individuals with moderate to high prior immunity to M. tuberculosis (Mantoux/IGRA strongly positive).
• Pathogenesis: Exogenous percutaneous reinoculation in previously sensitized individuals (pathologists, mortuary attendants, butchers, veterinarians handling infected bovine tissue, or patients auto-inoculating from their own active sputum).
• Clinical Presentation: Commences as a solitary, asymptomatic, firm, violaceous papule on exposed acral areas (dorsal fingers, hands, knuckles, soles). It slowly expands into a heavily hyperkeratotic, warty, verrucous, indurated plaque with an inflammatory erythematous-to-violaceous border. Fissuring may yield pus or purulent crusts upon lateral compression. Regional lymphadenopathy is notably absent.
• Histopathology & Bacillary Load: Prominent pseudoepitheliomatous hyperplasia, dense hyperkeratosis, and well-formed tuberculoid granulomas with Langhans giant cells in the upper dermis. Bacilli are extremely scarce (paucibacillary); Ziehl-Neelsen stains are almost always negative; diagnosis relies on PCR or tissue culture.

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2. Endogenous Spread Forms

Scrofuloderma (Tuberculosis Colliquativa Cutis)

• Pathogenesis: Direct contiguous extension of M. tuberculosis from an infected underlying deep structure—most commonly cervical or submandibular lymph nodes, but also tuberculous osteomyelitis, joint synovium, or epididymis—into the overlying subcutaneous tissue and skin.
• Clinical Presentation: Commences as a firm, painless, subcutaneous cold nodule or swelling anchored to the underlying diseased lymph node. The nodule softens, becomes fluctuant (caseous liquefaction), suppurates, and breaks through the skin surface to form chronic ulcers and fistulising, discharging sinus tracts. Watery, purulent, or caseous discharge drains continuously. Secondary bacterial infection is common. Healing occurs over years, producing characteristic irregular, puckered, reticulated, cord-like hypertrophic scars.
• Bacillary Load: High bacterial load (multibacillary); acid-fast bacilli are readily demonstrated on Ziehl-Neelsen stains of sinus tract discharge or granulation tissue.

Lupus Vulgaris

• Clinical Significance: The most common post-primary form of cutaneous tuberculosis, accounting for >50–70% of cutaneous TB cases in Europe.
• Host Setting: Develops in individuals with moderate to high cell-mediated immunity and high delayed-type hypersensitivity. Arises from hematogenous or lymphatic seeding from an internal active or dormant focus, or contiguous extension.
• Predilection Site: Head and neck in >80% of European patients—predominantly the nose, cheeks, earlobes, and chin.
• Clinical Morphology:
  • Commences as a soft, reddish-brown or yellow-brown plaque that expands with extreme indolence over decades.
  • Apple-Jelly Nodules on Diascopy (Pathognomonic Sign): When a clear glass slide or plastic spatula is pressed firmly against the lesion (vitropression), the surrounding vascular erythema blanches completely, revealing underlying translucent, yellowish-brown, soft "apple-jelly" nodules, which represent discrete dermal tuberculoid granulomas.
  • Destructive Behavior: Lupus vulgaris slowly invades and destroys underlying cartilage (resulting in mutilation of the nasal tip and septum, "parrot-beak" deformity, or destruction of the auricular pinna), but characteristically spares underlying bone.
  • Malignant Transformation: A feared long-term complication in 1% to 3% of chronic lupus vulgaris lesions is the development of aggressive cutaneous squamous cell carcinoma (Marjolin-like degeneration) or, rarely, basal cell carcinoma within the scarred, chronic granulomatous tissue.
• Histopathology: Typical caseating or non-caseating tuberculoid granulomas (epithelioid histiocytes, Langhans giant cells, dense mantle of mature lymphocytes) in the mid-dermis. Bacilli are very sparse (paucibacillary); cultures are positive in only ~30–50% of cases.

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3. Tuberculids: Cutaneous Hypersensitivity Reactions

Tuberculids are symmetrical, sterile skin eruptions arising in individuals with high cell-mediated immunity directed against an occult, silent, or active internal tuberculous focus (usually pulmonary, mediastinal, or renal).

• Diagnostic Hallmarks of Tuberculids:
  1. Strongly positive Tuberculin Skin Test (Mantoux) and positive IGRA.
  2. Total absence of acid-fast bacilli on Ziehl-Neelsen stain and negative mycobacterial culture of the cutaneous lesion (although sensitive PCR may detect fragmented mycobacterial DNA in a proportion of cases).
  3. Rapid and complete clearance of cutaneous lesions upon initiation of standard anti-tuberculosis therapy.

Erythema Induratum of Bazin (Nodular Vasculitis)

• Patient Profile: Predominantly young to middle-aged women (90%), often with relative circulatory stasis (erythrocyanosis, cold exposure).
• Clinical Presentation: Recurrent crops of tender, deep, violaceous, subcutaneous nodules and plaques located on the posterior aspects of the lower legs (calves), in contrast to erythema nodosum, which favors the anterior pretibial shins. Nodules frequently break down and ulcerate centrally, discharging oily or purulent fluid, and heal slowly over months with hyperpigmented, atrophic, depressed scars.
• Histopathology: A predominantly lobular panniculitis associated with granulomatous vasculitis involving medium-sized muscular arteries and veins within the adipose lobules, accompanied by prominent fat necrosis and caseous-like liquefactive necrosis.

Papulonecrotic Tuberculid

• Symmetrical, asymptomatic to mildly tender crops of dusky-red, firm papules that undergo central necrosis, forming crusts. Favors extensor surfaces of the elbows, knees, buttocks, and dorsal hands. Heals over 6 to 8 weeks leaving pathognomonic varioliform (pitted, depressed) scars.

Lichen Scrofulosorum

• Grouped, minute (1–2 mm), follicular or perifollicular, asymptomatic, lichenoid, yellow-brown to pink papules with tiny scales. Favors the trunk of children and young adults with active nodal or osseous tuberculosis. Rapidly responsive to antituberculous therapy.

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Diagnostic Modalities & Treatment of Cutaneous Tuberculosis

• Microscopy: Ziehl-Neelsen (ZN) or Kinyoun acid-fast stains (red bacilli on blue background); Auramine-rhodamine fluorescent stain (higher sensitivity).
• Culture: Lowenstein-Jensen (LJ) egg-based solid medium (takes 4–8 weeks; optimal 37°C) or automated liquid culture (Mycobacteria Growth Indicator Tube - MGIT, 10–21 days).
• Molecular Diagnostics: Nucleic Acid Amplification Tests (NAAT) such as GeneXpert MTB/RIF, which rapidly detects M. tuberculosis complex DNA and simultaneously detects mutations in the rpoB gene conferring rifampicin resistance within 2 hours.
• Immunodiagnostics: Interferon-Gamma Release Assays (IGRA: QuantiFERON-TB Gold Plus, T-SPOT.TB) measure IFN-gamma release by T lymphocytes stimulated by specific M. tuberculosis antigens (ESAT-6, CFP-10) not present in BCG or most atypical mycobacteria, avoiding false positives from prior BCG vaccination.

Standard WHO Antituberculous Regimen

Standard cutaneous tuberculosis is treated with the standard pulmonary four-drug regimen:

1. Intensive Phase (2 months): Four drugs daily: Rifampicin (R) + Isoniazid (H) + Pyrazinamide (Z) + Ethambutol (E) [2RHZE].
2. Continuation Phase (4 months): Two drugs daily: Rifampicin (R) + Isoniazid (H) [4RH]. Total duration: 6 months.
3. Prophylaxis: Daily Pyridoxine (Vitamin B6) 25–50 mg is co-prescribed to prevent isoniazid-induced peripheral neuropathy (via pyridoxine competition in GABA synthesis).
4. Toxicity Monitoring: Baseline and monthly liver transaminases (Rifampicin, Isoniazid, and Pyrazinamide are all hepatotoxic); serum uric acid (Pyrazinamide inhibits renal uric acid excretion, causing hyperuricemia and arthralgia); ophthalmological baseline check for visual acuity and red-green color discrimination (Ethambutol causes dose-dependent retrobulbar optic neuritis).

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Leprosy (Hansen Disease: Mycobacterium leprae & M. lepromatosis)

Leprosy is a chronic granulomatous infection caused by the obligate intracellular acid-fast bacillus Mycobacterium leprae (and the more recently identified Mycobacterium lepromatosis, causative of diffuse lepromatous leprosy and Lucio phenomenon). The pathogen possesses a unique lipid-rich cell wall (containing phenolic glycolipid-1 [PGL-1]) and displays a pathognomonic tropism for Schwann cells of peripheral nerves and macrophages.

The Ridley-Jopling Immunological Spectrum

The clinical, immunological, and histopathological manifestations of leprosy are not uniform; they form a continuous spectrum determined entirely by the host's specific cell-mediated immunity (CMI) against M. leprae:

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|                         RIDLEY-JOPLING LEPROSY SPECTRUM                              |
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| [TT] Tuberculoid  -->  [BT] Borderline  -->  [BB] Mid-      -->  [BL] Borderline -->  [LL] Lepromatous |
|      Leprosy           Tuberculoid           Borderline          Lepromatous           Leprosy          |
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| CMI: High/Intact       Moderate              Unstable/Diminished Weak                  Absent / Anic    |
| Th1 Response (IFN-g)   ---------------------------------------->                       Th2 (IL-4, IL-10)|
| Lesions: 1-3 solitary  3-10 asymmetrical     Multiple punched-out Innumerable           Diffuse, macules,|
| Hypopigmented/anesthetic plaques + satellites plaques ("swiss cheese") papules/plaques papules, nodules |
| Nerves: Single nerve,  1-2 nerves, marked    Asymmetrical,      Symmetrical, late       Symmetrical glove-|
| early enlargement      enlargement           multiple nerves    nerve involvement      stocking neuropathy|
| Bacilli: Absent (PB)   Scarce (PB)           Moderate (MB)      Numerous (MB)          Teeming / Globi   |
| Lepromin Test: +++     ++                    Negative           Negative               Negative (0)     |
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Clinical Hallmarks of Polar Forms

Tuberculoid Leprosy (TT - Polar Form)

• Immunity: Robust, vigorous Th1 cell-mediated immunity (IL-2, IFN-gamma) containing the infection.
• Cutaneous Lesions: Very few (1 to 3), solitary, large, well-demarcated hypopigmented or erythematous plaques with raised, dry, scaly borders and central clearing. Characterized by complete loss of cutaneous sensation (temperature first, then light touch, then pain), loss of sweating (anhidrosis), and loss of hair follicles within the plaque.
• Nerve Involvement: Early, severe, asymmetrical enlargement of a single peripheral nerve trunk adjacent to the plaque (e.g., greater auricular, ulnar, radial cutaneous, common peroneal). Nerve destruction may cause early isolated foot drop, claw hand, or facial palsy.
• Histopathology & Bacillary Load: Well-developed, non-caseating epithelioid cell granulomas with Langhans giant cells extending up to and abutting the basal epidermal layer (no Grenz zone) and invading cutaneous nerve branches. Acid-fast bacilli are absent or exceedingly sparse (Paucibacillary). Lepromin (Mitsuda) skin test is strongly positive.

Lepromatous Leprosy (LL - Polar Form)

• Immunity: Complete failure of specific Th1 cell-mediated immunity against M. leprae (characterized by a non-protective Th2 response with IL-4, IL-10, and high PGL-1 antibody titers).
• Cutaneous Lesions: Innumerable, bilaterally symmetrical, poorly demarcated, erythematous or yellowish-brown macules, papules, plaques, and succulent smooth nodules (lepromas). Generalized infiltration of the dermis.
• Facial Changes: Thickening and furrowing of facial skin over the forehead, nose, and cheeks produces the pathognomonic leonine facies (facies leontina). Infiltration causes widening of the nasal root, earlobe nodular thickening ("pendulous earlobes"), and destruction of hair follicles resulting in loss of the lateral third or total eyebrows and eyelashes (madarosis). Perforation of the nasal septum leads to saddle-nose deformity.
• Nerve Involvement: Diffuse, bilaterally symmetrical peripheral nerve trunk infiltration. Leads to a late, generalized, symmetrical glove-and-stocking sensory neuropathy, trophic plantar ulcers, neuropathic osteoarthropathy (Charcot joints), and resorption of phalanges.
• Systemic Infiltration: Bacillary invasion of the nasal mucosa (epistaxis, crusting), anterior chamber of the eye (iritis, keratitis, blindness), reticuloendothelial system (hepatosplenomegaly), and testes (testicular atrophy, azoospermia, gynecomastia).
• Histopathology: Massive, diffuse dermal sheets of foamy, lipid-laden macrophages (Virchow cells / lepra cells) packed with enormous clumps of acid-fast bacilli termed globi. The infiltrate is separated from the thinned epidermis by a conspicuous, narrow subepidermal uninvolved band of collagen termed the Grenz zone. Fite-Faraco stain teems with acid-fast bacilli (Multibacillary, bacterial index 5+ to 6+). Lepromin test is completely negative.

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Leprosy Reactions: Immunological Emergencies

Leprosy reactions are acute inflammatory exacerbations occurring in the chronic course of the disease, often triggered by the initiation of MDT, pregnancy, intercurrent infections, or emotional stress.

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WHO Multidrug Therapy (MDT) Regimens

To prevent the emergence of dapsone and rifampicin drug resistance, the World Health Organization (WHO) establishes standard MDT protocols:

Since the 2018 WHO guidelines, both PB and MB leprosy are treated with the same three drugs; only the duration differs.

1. Paucibacillary (PB) Leprosy (1 to 5 skin lesions, no nerve involvement, and no bacilli on slit-skin smear):
   • Rifampicin: 600 mg once monthly, supervised.
   • Clofazimine: 300 mg once monthly (supervised) PLUS 50 mg daily (unsupervised).
   • Dapsone: 100 mg daily, unsupervised.
   • Duration: 6 months.
2. Multibacillary (MB) Leprosy (> 5 skin lesions, OR any nerve involvement, OR bacilli on slit-skin smear regardless of lesion count):
   • Rifampicin: 600 mg once monthly, supervised.
   • Clofazimine: 300 mg once monthly (supervised) PLUS 50 mg daily (unsupervised).
   • Dapsone: 100 mg daily, unsupervised.
   • Duration: 12 months (completed within a maximum of 18 months).
3. Key Drug Toxicities:
   • Dapsone: Dose-dependent hemolysis (exacerbated in G6PD deficiency, which must be screened prior to initiation), methemoglobinemia, and severe Dapsone Hypersensitivity Syndrome (fever, exfoliative dermatitis, hepatitis, lymphadenopathy, leukocytosis; fatal if dapsone is not stopped immediately).
   • Clofazimine: Striking, reversible reddish-brown to bluish-black skin pigmentation and bodily fluid discoloration (occurring in >80%), severe ichthyosiform skin dryness (xerosis), and gastrointestinal enteropathy (crystal deposition in small intestine).
   • Rifampicin: Hepatotoxicity, orange-red discoloration of urine/tears, and potent induction of hepatic cytochrome P450 enzymes.

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Non-Tuberculous (Atypical) Mycobacteria (NTM)

Runyon Classification of Non-Tuberculous Mycobacteria

Divided according to growth velocity (slow growers > 7 days vs rapid growers < 7 days) and pigment production:

1. Group I: Photochromogens (Slow growers): Produce yellow/orange carotenoid pigment only when exposed to light (Mycobacterium marinum, M. kansasii).
2. Group II: Scotochromogens (Slow growers): Produce pigment in both the dark and light (M. scrofulaceum, M. gordonae).
3. Group III: Non-chromogens (Slow growers): Non-pigmented or buff-colored (M. ulcerans, M. avium-intracellulare complex [MAC]).
4. Group IV: Rapid Growers (< 7 days): M. fortuitum, M. chelonae, M. abscessus.

1. Mycobacterium marinum (Fish-Tank Granuloma / Swimming-Pool Granuloma)

• Transmission: Ubiquitous in freshwater and saltwater environments. Inoculation occurs when an individual with a minor cut or abrasion cleans a domestic tropical fish tank, handles saltwater fish/crustaceans, or uses non-chlorinated swimming pools.
• Pathobiology: Optimal growth occurs at 30°C to 32°C, explaining its strict clinical restriction to cooler acral body areas (hands, fingers, wrists) and failure to produce systemic visceral infection.
• Clinical Presentation: Following an incubation period of 2 to 4 weeks, a solitary, violaceous, indurated papule, verrucous nodule, or crusted plaque develops at the inoculation site (typically the dominant hand). In approximately one-third of patients, the infection displays sporotrichoid lymphocutaneous spread—characterized by a linear chain of secondary subcutaneous erythematous nodules that develop sequentially along the ascending lymphatic drainage of the arm.
• Treatment: Monotherapy or dual therapy with Clarithromycin 500 mg q12h, Doxycycline 100 mg q12h, or Minocycline 100 mg q12h, continued for at least 1 to 2 months after complete clinical resolution (total duration typically 3 to 6 months).

2. Mycobacterium ulcerans (Buruli Ulcer)

• Geographic Distribution: Endemic in tropical wetland areas of West and Central Africa (e.g., Côte d'Ivoire, Ghana, Benin) and coastal southeastern Australia (known as the "Bairnsdale ulcer").
• Toxin Pathogenesis: M. ulcerans secretes mycolactone, a cytotoxic, immunosuppressive, polyketide exotoxin encoded on a giant virulence plasmid (pMUM001). Mycolactone induces apoptosis of mammalian cells (adipocytes, fibroblasts, endothelial cells) while simultaneously silencing local nerve signaling and suppressing cellular inflammatory cytokine production.
• Clinical Presentation: Commences as a painless, firm, non-tender subcutaneous nodule, plaque, or localized non-pitting edema. Driven by mycolactone-induced necrosis of adipose tissue, the skin ulcerates centrally, evolving into a painless, expansive ulcer with characteristic deeply undermined, scalloped edges, a necrotic yellowish-white sloughing floor, and severe edema of surrounding skin. Despite massive destruction, systemic signs and pain are conspicuously absent early. Healing leads to severe, disabling fibrotic contractures and limb deformities.
• Treatment: Oral Rifampicin (10 mg/kg daily) combined with oral Clarithromycin (7.5 mg/kg twice daily) for a standardized duration of 8 weeks. Surgical debridement and skin grafting are reserved for large, non-healing ulcers.

3. Rapid-Growing Mycobacteria (M. fortuitum, M. chelonae, M. abscessus)

• Context: Environmental saprophytes causing post-procedural cutaneous infections following cosmetic procedures (mesotherapy, liposuction, dermal fillers), contaminated pedicure footbaths, body piercing, and acupuncture or tattoos.
• Presentation: Multiple, chronic, tender, erythematous subcutaneous nodules, fluctuating abscesses, and non-healing draining sinuses developing weeks to months after the procedure.
• Treatment: Resistant to standard antituberculous agents. Therapy must be guided by susceptibility testing; regimens utilize Clarithromycin, Amikacin, Cefoxitin, Ciprofloxacin, or Tigecycline.