Q4 LONG ANSWER 10M ★ High-yield

Describe the pathogenesis and morphology of tuberculosis. Differentiate primary from secondary tuberculosis.

Pathology · 2nd Professional — Para-Clinical

The Organism

Tuberculosis is a chronic granulomatous infection caused by Mycobacterium tuberculosis, an aerobic, non-motile, acid-fast bacillus.

Acid-fastness is due to the high content of mycolic acid in the cell wall; demonstrated by the ZIEHL–neelsen stain, in which the bacilli appear red against a blue background
Slow growing — a generation time of 18–24 hours; culture on Lowenstein–Jensen medium takes 4–8 weeks
Spread by droplet inhalation; Mycobacterium bovis by unpasteurised milk, causing intestinal and tonsillar disease
India carries about a quarter of the world burden, which makes this the single most important infectious disease in Indian pathology

Pathogenesis

Bacilli are inhaled and reach the alveoli → Ingested by alveolar macrophages, in which they multiply by blocking phagosome–lysosome fusion → After 2–3 weeks, antigen is presented and TH1 cells respond → IFN-gamma from T cells causes classical macrophage activation → Macrophages become epithelioid cells and fuse into langhans giant cells → granuloma forms, walling off the infection → The centre undergoes caseous necrosis from the combined effect of hypoxia and the immune reaction

The tissue damage of tuberculosis is caused by the immune response, not by any toxin — the organism produces none. This explains why disease appears only after sensitisation, and why it is so severe in the immunocompetent and so atypical in the immunosuppressed

Morphology

The tubercle (granuloma) — central caseous necrosis surrounded by epithelioid cells and Langhans giant cells, with a peripheral collar of lymphocytes and fibroblasts
Langhans giant cell — nuclei arranged in a horseshoe or ring at the periphery of the cell
Caseous necrosis — soft, white, structureless, resembling cottage cheese; architecture completely obliterated

Primary and Secondary Tuberculosis

Feature	Primary	Secondary (post-primary)
Occurs in	Previously unexposed person, often a child	Previously sensitised person
Site in lung	Lower part of the upper lobe or upper part of the lower lobe, near the pleura — the GHON focus	Apex of the upper lobe, where oxygen tension is highest
Lymph nodes	Prominently involved — the Ghon focus with hilar nodes forms the primary (Ghon) complex	Rarely involved
Cavitation	Rare	Common — caseous material is discharged into a bronchus
Tuberculin test	Converts from negative to positive	Positive
Usual outcome	Heals with fibrosis and calcification in over 90%	Progressive unless treated
Dissemination	Miliary spread if immunity fails	By bronchi, and haematogenous

CLINICAL PEARL

The site tells you which it is. Primary tuberculosis sits near the pleura in the mid-zone; secondary sits at the apex, because oxygen tension is highest there and the organism is a strict aerobe. A cavitating apical lesion on a chest radiograph is post-primary disease until proved otherwise.

Spread and Extrapulmonary Disease

Route	Result
Local	Extension within the lung
Bronchial	Tuberculous bronchopneumonia; laryngeal and intestinal tuberculosis from swallowed sputum
Lymphatic	Cervical lymphadenitis — "scrofula", the commonest extrapulmonary form in India
Haematogenous	Miliary tuberculosis — countless 1–2 mm lesions like millet seeds, in lung, liver, spleen, bone marrow and meninges
By direct seeding	Pleura, pericardium, peritoneum

Common extrapulmonary sites — lymph nodes, pleura, spine (POTT disease, causing gibbus and paraplegia), meninges, genitourinary tract (causing infertility), intestine (ileocaecal), and the suprarenal (causing Addison disease)

Fate of the Primary Complex and the Course of Infection

Outcome	Frequency	Features
Healing by fibrosis and calcification	Over 90%	The calcified Ghon complex remains visible on a chest radiograph for life; bacilli may survive within it
Progressive primary tuberculosis	Children, the malnourished, HIV	Enlargement and cavitation of the primary focus
Lymphohaematogenous spread	If immunity is poor	Miliary disease and tuberculous meningitis
Dormancy with later reactivation	About 5–10% lifetime risk	Post-primary disease, often decades later, when immunity wanes

Reactivation is precipitated by HIV, diabetes, malnutrition, corticosteroids, anti-TNF agents, chronic renal failure, silicosis, malignancy and old age
The tuberculin (Mantoux) test becomes positive 4–6 weeks after infection, marking the development of cell-mediated immunity — a type IV hypersensitivity reaction read at 48–72 hours

Diagnosis and Applied Aspects

Sputum microscopy with Ziehl–Neelsen or fluorescent staining; requires about 10,000 bacilli per mL, so it is insensitive but cheap and rapid
CBNAAT (GeneXpert) detects the organism and rifampicin resistance within two hours, and is now the recommended initial test in India
Culture remains the gold standard but takes weeks; liquid culture is faster
Mantoux test indicates exposure, not active disease; it is falsely negative in miliary disease, HIV and malnutrition, and falsely positive after BCG
HIV co-infection alters everything — granulomas are poorly formed or absent, the tuberculin test is negative, and extrapulmonary and disseminated disease is common
Multidrug-resistant tuberculosis is defined as resistance to at least isoniazid and rifampicin; it is a major and growing problem in India, driven by incomplete treatment
Directly observed treatment under the national programme exists precisely because irregular therapy breeds resistance
Pleural effusion in tuberculosis is an exudate with lymphocyte predominance and raised adenosine deaminase; the yield on smear is low because it is a hypersensitivity reaction rather than direct infection
BCG protects reliably against disseminated and meningeal tuberculosis in children, but its protection against adult pulmonary disease is variable
Tuberculosis of the spine (Pott disease) destroys the vertebral bodies while sparing the discs until late, producing the characteristic gibbus and a cold abscess that may track along the psoas
A "cold abscess" has no heat, redness or tenderness, because the reaction is granulomatous rather than pyogenic — the name states the pathology
Intestinal tuberculosis affects the ileocaecal region and produces transverse "girdle" ulcers, which heal with stricture — in contrast to the longitudinal ulcers of typhoid
Treatment is prolonged because the organism divides so slowly and persists within macrophages, which is why six months is the minimum and why default is so damaging
Contact tracing and screening of household members is as important as treating the index case, and is the part most often neglected
Tuberculous meningitis affects the basal meninges, causing cranial nerve palsies and communicating hydrocephalus; the CSF shows lymphocytosis with a high protein and a low glucose
Steroids are added in tuberculous meningitis and pericarditis, where the inflammatory response itself does much of the damage

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