Tuberculosis and leprosy

The organisms

• Mycobacteria have a waxy wall rich in mycolic acids, so they resist Gram staining, drying and many disinfectants, and stain acid-fast with Ziehl–Neelsen (or fluorescent auramine–rhodamine).
• M. tuberculosis: obligate aerobe, slow growing (4–8 weeks on Löwenstein–Jensen; liquid culture faster). Cord factor is a key virulence factor. Spread by airborne droplet nuclei from coughing patients, so household contacts (such as the family of a tailor with cavitary TB) are infected by inhalation.
• M. leprae: cannot be cultured on artificial media; it prefers cooler tissue (about 30 °C), so it settles in skin, peripheral nerves, nose, ear lobes, fingers, testes and anterior eye.
• Atypical (non-tuberculous) mycobacteria: environmental, not spread person to person, often resistant to standard drugs. M. avium complex (disseminated in AIDS with very low CD4), M. kansasii (lung), M. marinum (fish tank granuloma), M. ulcerans (Buruli ulcer).

Pathogenesis: primary and post-primary TB

• Alveolar macrophages ingest bacilli but cannot kill them, because the bacilli block phagosome–lysosome fusion.
• Over 3–8 weeks, Th1 cells release IFN-γ, activating macrophages into epithelioid cells that form granulomas: epithelioid cells, Langhans giant cells (horseshoe nuclei), a lymphocyte cuff and central caseous necrosis. The caseating granuloma is the diagnostic microscopic feature; finding AFB in it confirms TB. This type IV hypersensitivity also makes the tuberculin test positive.
• Primary TB: a subpleural Ghon focus in the lower upper lobe or upper lower lobe plus hilar node involvement forms the Ghon complex; once calcified it is a Ranke complex. Usually heals, leaving dormant bacilli (latent TB).
• Progressive primary TB in infants and the immunocompromised: miliary TB and meningitis.
• Post-primary (secondary) TB: reactivation when immunity falls (HIV, diabetes, malnutrition, steroids, anti-TNF drugs, silicosis, old age). It favours the apical and posterior segments of the upper lobes, where oxygen tension is highest. Caseation erodes into a bronchus to form a cavity packed with bacilli, so these patients are the most infectious.

Exam trap The Ghon focus is not apical; post-primary TB is apical because M. tuberculosis needs high oxygen.

Pleural and abdominal TB

• Tuberculous pleural effusion: lymphocyte-rich exudate; smear and Xpert are often negative because bacilli are few. A high adenosine deaminase (ADA) (over about 40 U/L) strongly supports TB; pleural biopsy shows granulomas. Lymphoma and cancer must still be considered in older patients.
• Tuberculous peritonitis: doughy abdomen, ascites, weight loss. Fluid is an exudate (protein over 25–30 g/L), lymphocyte predominant, with SAAG under 11 g/L (not portal hypertension) and raised ADA.
• Intestinal TB: the ileocaecal region is the commonest site (lymphoid tissue, stasis). Forms: ulcerative, hypertrophic (mass in the right iliac fossa) or both.
• TB ulcers are transverse, girdling the bowel with undermined edges, because they follow the circumferential lymphatics; they heal by fibrosis into short annular strictures. Typhoid ulcers lie along the long axis over Peyer's patches on the antimesenteric border and perforate rather than stricture.
• Multiple short small-bowel strictures causing obstruction are best treated by strictureplasty, which preserves bowel length; a limited ileocaecal resection is used for an ileocaecal mass. Strictures can worsen early in treatment as they heal.
• Intestinal TB mimics Crohn disease; starting steroids or anti-TNF drugs for presumed Crohn can disseminate TB.

Lymph nodes, cold abscess and surgery

• Cervical lymphadenitis (scrofula) is the commonest extrapulmonary form: matted, firm, non-tender nodes.
• Caseating nodes liquefy into a cold abscess (no heat or redness). When pus breaks through the deep fascia into a superficial pocket connected by a narrow neck, it forms a collar-stud abscess; untreated it bursts to form a chronic sinus.
• Aspirate a cold abscess through healthy skin at a non-dependent site (an oblique track) so no sinus forms; never incise and drain it like a pyogenic abscess.
• When a node is excised, send part fresh in sterile saline for culture, Xpert and drug sensitivity and part in formalin for histology; putting the whole node in formalin loses the chance to detect MDR-TB.

Bone and joint TB

• Pott's disease (spinal TB): thoracolumbar; starts at the anterior vertebral margins near the disc, so the disc space narrows early; anterior wedging gives gibbus; paravertebral or psoas cold abscess; paraplegia. A cervical lesion can produce a retropharyngeal cold abscess.
• Spina ventosa (tuberculous dactylitis): in young children; painless spindle-shaped swelling of a finger; X-ray shows the phalanx expanded like a balloon with a thin cortex.
• Joint TB (hip, knee) causes a cold swollen joint with marked wasting.

Genitourinary and genital TB

• Renal TB follows blood spread years after primary infection: frequency, loin ache, sterile pyuria (pus cells, no growth on routine culture). Send three early-morning urines for AFB and mycobacterial culture.
• Progression: calcification, caseous putty kidney, then a small, densely calcified non-functioning kidney: tuberculous autonephrectomy. Ureteric fibrosis gives a golf-hole ureteric orifice; a contracted thimble bladder causes severe frequency.
• Epididymal TB: painless, hard, craggy swelling beginning in the tail of the epididymis, beaded vas deferens (the most supportive sign), and a posterior scrotal sinus.
• Female genital TB: a major cause of infertility in Pakistan. Fallopian tubes are affected in almost all cases (bilateral), then endometrium. HSG shows rigid, beaded tubes (pipe-stem, tobacco-pouch fimbrial ends) and cornual block; endometrial damage causes amenorrhoea and adhesions.

Skin TB and other sites

• Lupus vulgaris: slowly spreading reddish-brown plaque, usually on the face, with central scarring; pressing with a glass slide (diascopy) shows apple-jelly nodules. Sarcoid can look similar, so culture or PCR may be needed. Squamous cell carcinoma can arise in long-standing scars.
• TB meningitis (basal; cranial nerve palsies; CSF high protein, low glucose, lymphocytes), pericarditis (constrictive), adrenal (Addison disease), miliary TB (millet-seed shadows, choroid tubercles).

Diagnosis

• Sputum: smear for AFB, culture (gold standard; gives drug sensitivity) and Xpert MTB/RIF, a rapid PCR that detects the rpoB gene mutation conferring rifampicin resistance (a marker for MDR-TB).
• Tuberculin skin test and interferon-γ release assay (IGRA) show infection, latent or active, not active disease. IGRA uses antigens (ESAT-6, CFP-10) absent from BCG, so it is not affected by BCG vaccination and is preferred for latent TB screening before biologics such as infliximab. Both may be falsely negative in immunosuppression and miliary TB.

Treatment and drug points

• Standard regimen: 2 months of isoniazid, rifampicin, pyrazinamide and ethambutol, then 4 months of isoniazid and rifampicin; longer for meningitis and spinal TB. Drugs are combined to prevent resistance; directly observed therapy improves adherence. BCG at birth protects mainly against miliary TB and meningitis in children.

• Drug-induced hepatitis (jaundice, or ALT over 3 times normal with symptoms or 5 times without): stop the hepatotoxic drugs, then reintroduce them one at a time once liver tests settle.
• When rifampicin is stopped, warfarin needs reducing again or the INR rises dangerously.

Leprosy

• Spread by nasal droplets after prolonged close contact; incubation of years. The cell-mediated immune response decides the form.

• Diagnosis rests on cardinal signs: a skin patch with loss of sensation, a thickened peripheral nerve (ulnar at the elbow, common peroneal, greater auricular, posterior tibial), and AFB on slit-skin smear; skin biopsy confirms early cases.
• WHO multidrug therapy: rifampicin, dapsone (inhibits dihydropteroate synthase, blocking folate synthesis; check G6PD first) and clofazimine (skin pigmentation); 6 months for paucibacillary, 12 months for multibacillary.
• Type 1 (reversal) reaction: borderline disease; cell-mediated immunity suddenly increases, often in the first months of treatment; existing patches become red and swollen and nerves become painful with new weakness. Give oral prednisolone and continue MDT.
• Type 2 reaction (erythema nodosum leprosum): multibacillary disease; immune complexes; tender nodules, fever, iritis, orchitis; steroids or thalidomide; continue MDT.

Remember Tuberculoid: strong immunity, few bacilli. Lepromatous: weak immunity, many bacilli in cool tissues.

How FCPS asks about this

• Why post-primary TB is apical: highest oxygen tension; Ghon focus lies in mid-zone with hilar nodes.
• Lymphocytic pleural or peritoneal exudate with low SAAG: raised ADA supports TB.
• Commonest site of intestinal TB and its ulcers: ileocaecal; transverse girdling ulcers that stricture (typhoid ulcers are longitudinal and perforate).
• Aspirating a cold abscess: through healthy skin at a non-dependent site; never incise.
• Calcified non-functioning kidney after old TB: autonephrectomy; beaded vas supports TB epididymitis.
• Why IGRA is preferred to Mantoux before infliximab: not affected by BCG.
• Leprosy patches flaring with painful ulnar nerve on MDT: type 1 reaction; prednisolone and continue MDT; dapsone inhibits dihydropteroate synthase.