Tuberculosis

Slide 1 · Tuberculosis

Pathogenesis • morphologic patterns • clinicopathologic diagnosis

Clinical pathology of Mycobacterium tuberculosis

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Explain survival of M. Tuberculosis in macrophages and the development of Th1 immunity.

Distinguish primary, postprimary, progressive, and disseminated tuberculosis.

Interpret granulomatous morphology alongside microbiologic and immune-based tests.

Recognize how impaired cellular immunity changes the clinical and tissue phenotype.

Slide 3 · Tuberculosis is both pulmonary and systemic

M. Tuberculosis causes a chronic infection that can persist silently or produce destructive disease.

The lung is the usual site of entry and a major site of clinical disease.

Lymphatic and hematogenous spread can seed distant organs.

The tissue response reflects the interaction between bacterial persistence and host immunity.

Slide 4 · The mycobacterial cell wall explains acid-fastness

Mycolic acids and waxy lipids

Unusual lipid-rich cell wall

Acid–alcohol resistance

Retains acid-fast stains

Diagnostic implication

Acid-fast bacilli can be visualized in suitable specimens

Acid-fastness is a property of the organism; It does not identify M. Tuberculosis by itself.

Slide 5 · Transmission is predominantly airborne

Active pulmonary source

Organisms released into sputum

Airborne exposure

Person-to-person transmission

Susceptible host

Inhaled organisms reach alveoli

Cavitary airway disease is particularly relevant to infectious sputum production.

Slide 6 · Mycobacterium bovis is a distinct exposure route

M. Bovis can produce oropharyngeal or intestinal tuberculosis after ingestion of contaminated milk.

Routine pasteurization makes this route uncommon where pasteurized milk is standard.

The exposure remains relevant where bovine tuberculosis and unpasteurized milk coexist.

Most pulmonary tuberculosis instead follows airborne human-to-human spread.

Slide 7 · The textbook burden figures refer to 2022

Approximately 10.6 million incident cases worldwide in 2022.

The same source reports approximately 1.3 million TB deaths in that year.

These are historical figures reproduced from the supplied 11th-edition text.

They must not be presented as current 2026 surveillance estimates.

Slide 8 · Exposure and progression have overlapping risk factors

Exposure-prone settings

Progression-prone conditions

Crowding and poverty

HIV infection or other immunosuppression

Prisons, shelters, long-term care

Diabetes and malnutrition

High-burden exposure environments

Silicosis, renal failure, Hodgkin lymphoma

Risk of inhaling infectious aerosols

Risk of failing to contain infection

Slide 9 · Infection is not synonymous with active disease

Latent infection

Active tuberculosis

Organisms may persist for years

Bacteria are associated with symptomatic disease

No clinical disease at present

Pulmonary or extrapulmonary manifestations

Immune sensitization may be detectable

Direct microbiologic tests assess disease

Reactivation possible if defenses fall

Airway disease may be transmissible

Slide 10 · Natural history depends on containment

Inhalation and primary infection

Effective Th1 containment

Granuloma → fibrosis ± calcification; Organisms may remain latent

Inadequate containment

Progressive primary disease or later reactivation → tissue destruction and spread

Slide 11 · Alveolar macrophages are the initial host cells

Inhaled bacilli

Reach distal airspaces

Alveolar macrophages

Phagocytose organisms

Interstitial migration

Infected phagocytes can spread organisms locally

Macrophages and dendritic cells become participants in early infection.

Slide 12 · Macrophage entry uses specific receptors

Phagocytosis involves mannose-binding lectin and complement receptor 3 (CR3).

Entry into macrophages does not ensure bacterial destruction.

The ability to survive after uptake is central to early intracellular replication.

Infected alveolar macrophages move into interstitial tissue.

Slide 13 · Tubercle bacilli prevent phagolysosome maturation

Phagocytosed bacillus

Contained in phagosomal vesicle

Impaired maturation

Phagosome–lysosome fusion blocked

Protected replication

Lysosomal microbicidal mechanisms avoided

Native schematic of a source-described intracellular sequence—not an electron micrograph.

Slide 14 · Coronin and calcineurin support intracellular survival

Bacillus-containing phagosome

Recruitment of host coronin

Coronin-dependent signaling

Activation of calcineurin

Fusion defect

Impaired phagosome–lysosome fusion

The source describes this mechanism as a contributor to phagolysosome blockade.

Slide 15 · Early infection can disseminate before immunity matures

Initial weeks

Intracellular replication in alveolar macrophages

Before ~3 weeks

Bacteria can enter blood and seed multiple sites

Clinical state

Often asymptomatic or mildly influenza-like

Early hematogenous seeding does not imply that clinically apparent lesions develop in every seeded site.

Slide 16 · Innate recognition begins adaptive immune signaling

Mycobacterial ligands

Lipoarabinomannan and CpG DNA

Innate receptors

TLR2 and TLR9

Host response

Amplification of innate and adaptive immunity

Neutrophils can also be infected; The organism resists their killing.

Slide 17 · Dendritic cells connect the lung to draining nodes

Lung infection

Dendritic cells acquire mycobacterial antigens

Draining lymph node

Antigen presentation to naive T cells

Differentiation

Development of antimycobacterial Th1 cells

A cellular immune response becomes evident after approximately three weeks.

Slide 18 · IL-12 and IL-18 favor Th1 differentiation

Antigen-presenting cell

Produces IL-12 and IL-18

Activated T cell

Differentiates toward Th1

Th1 effector response

IFN-γ activates macrophages

TLR2 stimulation contributes to dendritic-cell IL-12 production.

Slide 19 · IFN-γ is central to macrophage activation

Th1-derived IFN-γ enables macrophages to contain intracellular M. Tuberculosis.

It stimulates microbicidal machinery within activated phagocytes.

It promotes antimicrobial peptide activity and autophagy.

Insufficient Th1 function predisposes to dissemination and reactivation.

Slide 20 · Activated macrophages use several effectors

Reactive species

Nitric oxide and reactive oxygen species

Antimicrobial peptides

Defensins, including cathelicidin

Autophagy

Sequestration and destruction of intracellular bacteria

These effects are promoted by IFN-γ; No single mechanism alone explains containment.

Slide 21 · Granulomas are a product of cellular immunity

Th1 cytokines

IFN-γ activates macrophages

Cellular organization

Epithelioid histiocytes and giant cells

Tissue response

Granuloma formation ± central caseation

This response constrains infection but can also injure tissue.

Slide 22 · A tubercle has a recognizable cellular architecture

Central caseation

Granular, acellular-appearing necrotic center

Epithelioid histiocytes ± giant cells

Activated macrophage aggregates

Peripheral lymphocytes / fibroblastic rim

Schematic—not a histologic specimen

Slide 23 · TNF promotes granuloma-associated recruitment

Activated macrophages

Release TNF and chemokines

Monocyte recruitment

Additional macrophages accumulate

Granuloma maintenance

Sustained cellular response

TNF-antagonist therapy increases the risk of tuberculosis reactivation.

Slide 24 · Protective immunity creates immunopathology

Containment benefit

Tissue injury cost

Macrophage activation inhibits replication

Th1-driven caseation

Granuloma restricts bacterial spread

Granuloma coalescence and necrosis

Fibrosis can stabilize the primary focus

Cavitation can destroy lung architecture

Latency may persist for decades

Reactivation with waning host defenses

Slide 25 · Several host states weaken TB control

HIV-associated CD4+ T-cell loss disrupts Th1-dependent resistance.

Glucocorticoids, TNF antagonists, and transplant immunosuppression increase risk.

Renal failure, malnutrition, and advanced age can compromise containment.

Risk reflects both the host immune response and prior exposure.

Slide 26 · IL-12-pathway defects can cause severe mycobacterial disease

Inherited impairment of the IL-12/Th1 axis illustrates the necessity of cellular immunity.

The source identifies IL-12 receptor β1 loss as one example.

Such defects increase susceptibility to severe tuberculosis.

They can also predispose to illness caused by ordinarily less virulent mycobacteria or BCG.

Slide 27 · Primary and postprimary TB are pathophysiologically distinct

Primary tuberculosis

Secondary tuberculosis

First infection of an unsensitized host

Disease in a previously sensitized host

Exogenous acquisition

Reactivation or exogenous reinfection

Subpleural initial focus and hilar node reaction

Classically apical upper-lobe focus

Often contained; May progress

Rapid tissue response; Cavitation relatively common

Slide 28 · Primary infection is often clinically inapparent

In healthy hosts the first infection frequently causes no clinical symptoms.

A transient fever or pleural effusion may occur.

The source states that clinically significant primary disease develops in a minority of newly infected people.

A small residual fibrocalcific Ghon focus may be the only evidence.

Slide 29 · The primary pulmonary focus is usually subpleural

Implantation

Distal airspace near pleura

Typical region

Lower upper lobe or upper lower lobe

Morphologic focus

Gray-white consolidation, often with caseation

A typical Ghon focus measuring about 1–1.5 cm.

Slide 30 · Ghon complex combines lung and nodal lesions

Peripheral Ghon focus

Distal airspace close to pleura

Hilar node reaction

Draining lymph-node caseation

Together: The Ghon complex

Lung: Schematic representation

Slide 31 · Primary disease can spread via lymph and blood

Pulmonary focus

Primary lesion in lung

Regional lymphatics

Draining nodes may become caseous

Bloodstream seeding

Remote tissues may receive bacilli

Early dissemination may occur even when later cellular immunity prevents overt organ lesions.

Slide 32 · Cell-mediated immunity usually heals the primary complex

Th1 control

Bacterial expansion is limited

Fibroblastic repair

Focus and nodes become fibrotic

Calcification

Residual radiologically visible lesion may persist

The text notes that viable bacilli may remain dormant in some apparently healed foci.

Slide 33 · Progressive primary TB can mimic bacterial pneumonia

Progressive primary TB

Typical postprimary pattern

Lobar consolidation

Apical upper-lobe involvement

Hilar lymphadenopathy

Lymph nodes less prominent early

Pleural effusion may occur

Cavitation develops relatively readily

Can disseminate to meninges or multiple organs

Can progress locally or disseminate

Slide 34 · Primary dissemination explains early severe presentations

Uncontrolled primary pulmonary infection

Lymphohematogenous spread

Meningeal involvement or systemic miliary disease

Pulmonary progression

Consolidation, regional nodes, and pleural involvement

Slide 35 · Both caseating and noncaseating tubercles occur

Caseating granuloma

Noncaseating granuloma

Central granular necrotic material

No central caseous necrosis

Surrounding epithelioid histiocytes

Epithelioid histiocytes persist

Giant cells and lymphocytic rim may be seen

Giant cells and lymphocytes may be seen

Typical, but not universal, morphology

Does not exclude tuberculosis

Slide 36 · Immunocompromise can abolish typical granulomas

Effective cellular immunity

Severe cellular immunodeficiency

Organized granulomas often present

Granulomas may be poorly formed or absent

Caseation may reflect tissue injury

Numerous organisms within macrophages

Bacillary load can be low in fibrotic lesions

Histology may be dominated by infected phagocytes

Slide 37 · Postprimary TB reflects reactivation or reinfection

Previously sensitized individual

Endogenous reactivation

Dormant organisms resume growth as immune resistance declines

Exogenous reinfection

New inoculum triggers disease in a previously exposed host

Slide 38 · Secondary TB classically begins near the apex

Postprimary apical focus

Small, sharply bounded focus close to apical pleura

Central caseation ± peripheral fibrosis

Cavitation may develop with disease progression

Lung: Schematic representation

Slide 39 · A sensitized host mounts a brisk local reaction

Pre-existing delayed-type hypersensitivity promotes prompt tissue inflammation.

The lesion initially tends to become locally walled off.

Regional lymph nodes are less prominent early than in primary TB.

Untreated lesions can progress to caseation and cavitation.

Slide 40 · Cavitation follows evacuation of caseous tissue

Coalescent caseation

Destruction of lung parenchyma

Erosion into bronchus

Necrotic material drains into airway

Irregular cavity

Residual ragged space with limited fibrous wall

Schematic mechanism; Not a radiograph or gross specimen.

Slide 41 · Cavitary disease can amplify transmission

Cavity communicates with airway

Caseous material and bacilli gain airway access

Cough and sputum

Organisms are expelled

Airborne exposure

New hosts can inhale infectious particles

Source-to-host spread is linked to the anatomy of the lesion.

Slide 42 · Vascular erosion explains hemoptysis

Expanding destructive lesion

Necrosis progresses through lung

Vessel wall involvement

Erosion of adjacent blood vessels

Clinical consequence

Hemoptysis

Hemoptysis is a complication of destructive pulmonary lesions; Its absence does not exclude TB.

Slide 43 · Systemic symptoms reflect inflammatory mediators

Insidious malaise, anorexia, and weight loss may precede prominent pulmonary symptoms.

Fever is often low grade and remittent, with night sweats.

Activated macrophage cytokines, including TNF, contribute to systemic illness.

Localized secondary disease can also be asymptomatic.

Slide 44 · Progressive lung disease produces respiratory symptoms

Sputum production may increase as pulmonary involvement progresses.

Sputum can change from mucoid to purulent.

Cavitation and tissue destruction are associated with bronchial involvement.

Pleuritic pain can signal extension to pleural surfaces.

Slide 45 · Progression can leave lasting architectural damage

Expanding apical lesion

Spread to adjacent lung and bronchi

Treatable inflammatory disease

Activity may be arrested with adequate therapy

Healed lung

Fibrosis distorts architecture; Cavities may persist or scar

The pathologic outcome depends on microbial control and host tissue repair.

Slide 46 · Pleural extension has several morphologic outcomes

Pleural manifestation

Structural implication

Serous pleural effusion

Fluid accumulation in pleural space

Tuberculous empyema

Infected pleural collection

Obliterative fibrous pleuritis

Healing with substantial fibrosis

Slide 47 · Anatomic pathways determine the pattern of spread

Progressive pulmonary focus

Airways and lymphatics

Endobronchial, laryngeal, regional, or pulmonary extension

Vascular routes

Miliary pulmonary or systemic dissemination

Slide 48 · Miliary pulmonary TB reflects hematogenous reseeding

Multiple tiny pulmonary foci

Hematogenous reseeding creates many distributed lesions

Individual foci may coalesce

Schematic distribution, not a gross specimen

Lung: Schematic representation

Slide 49 · Systemic miliary TB involves many organs

Dissemination mechanism

Frequent organ targets

Entry into systemic arterial blood

Liver and spleen

Widespread microvascular seeding

Bone marrow and adrenals

Formation of multiple small tubercles

Meninges and kidneys

Potential involvement of nearly any tissue

Fallopian tubes and epididymis

Slide 50 · Tuberculosis may present outside the lungs

Hematogenous seeding may produce clinically dominant disease in a single distant organ.

Meninges: Tuberculous meningitis.

Kidneys and adrenals: Renal tuberculosis or adrenal destruction.

Bone: Tuberculous osteomyelitis; Vertebral disease is Pott disease.

Fallopian tubes: Tuberculous salpingitis.

Slide 51 · Cervical lymphadenitis is a common extrapulmonary form

Tuberculous lymphadenitis often affects cervical nodes (“scrofula”).

It as the most frequent extrapulmonary presentation.

HIV-negative patients more often have localized, unifocal nodal disease.

HIV-positive patients often have multifocal disease and systemic involvement.

Slide 52 · Vertebral TB may create cold paraspinal abscesses

Vertebral involvement

Pott disease

Paraspinal extension

Cold abscess follows tissue planes

Presentation

Abdominal or pelvic mass may result

“Cold abscess” is a clinicopathologic term; This slide is a mechanism schematic.

Slide 53 · Intestinal TB may ulcerate and stricture the ileum

Ingested or swallowed organisms

Bovine exposure or infected sputum

Gut lymphoid tissue

Granulomatous inflammation

Mucosal injury and repair

Superficial transverse ulcers → strictures

The ileum is a characteristic site in the source description.

Slide 54 · Upper airway TB follows local spread

Origin

Airborne/lung disease with infectious respiratory material

Propagation

Lymphatic spread or contact with expectorated bacilli

Sites

Endobronchial, tracheal, and laryngeal mucosa

Minute granulomatous lesions may only be evident microscopically.

Slide 55 · TB testing answers two different questions

Is active disease present?

Has an immune response occurred?

AFB smear or culture

Interferon-γ release assay (IGRA)

PCR for mycobacterial DNA

Tuberculin/PPD skin test

Direct organism detection; Susceptibility testing

Evidence of immunologic sensitization

Specimen-based clinical diagnosis

Cannot alone identify active disease

Slide 56 · Sputum smears are rapid but not fully specific

An acid-fast smear looks for organisms that retain stain after acid–alcohol decolorization.

A positive acid-fast smear does not by itself identify the mycobacterial species.

Smear-negative disease can still be present, particularly in immunocompromised patients.

Use organism-specific molecular testing and culture in suspected active tuberculosis.

Slide 57 · Culture identifies viable organisms and enables DST

Solid media

Growth in about 3–6 weeks

Liquid media

The source reports results as early as ~2 weeks

Drug susceptibility testing

Comprehensive phenotypic testing requires culture

These time frames are textbook descriptions, not guarantees for individual specimens.

Slide 58 · Molecular assays speed organism and resistance detection

Clinical specimen

PCR amplification of mycobacterial DNA

Species detection

M. Tuberculosis identification

Resistance signal

Some assays also detect rifampin resistance

Molecular results complement, rather than universally replace, culture and susceptibility testing.

Slide 59 · Latent TB tests measure T-cell memory

Neither IGRA nor tuberculin testing reliably distinguishes latent infection from active tuberculosis.

Both reflect T-cell recognition of mycobacterial antigens.

Results must be interpreted with exposure, symptoms, imaging, and microbiology.

Immunosuppression may weaken test responses despite true infection.

Slide 60 · IGRA measures IFN-γ release after antigen challenge

Patient lymphocytes

Stimulated by M. Tuberculosis antigens

Antigen-specific T cells

Produce interferon-γ

Assay readout

Quantifies the host immune response

IGRA positivity is evidence of sensitization, not proof of active disease.

Slide 61 · Tuberculin testing is a delayed immune response

Intradermal PPD

Antigen introduced into skin

Delayed response

Palpable induration develops

Reading window

Reaction peaks at approximately 48–72 hours

Interpretation concerns measured induration and risk context; The source does not specify cutoffs here.

Slide 62 · Negative immune-based tests cannot exclude TB

False-negative immune tests occur with immunosuppression and malnutrition.

Active tuberculosis itself may be associated with impaired test responses.

Other cited settings include sarcoidosis, Hodgkin lymphoma, and certain viral infections.

Investigate suspected active disease with appropriate direct tests despite negative screening assays.

Slide 63 · BCG and atypical mycobacteria can affect TST

Tuberculin skin test

IGRA

May be positive after BCG vaccination

False-positive results from BCG are uncommon

May cross-react with atypical mycobacteria

More antigen-specific immunologic signal

Can be negative despite active TB

Can also be falsely negative with impaired T-cell immunity

Slide 64 · HIV weakens the main defense against tuberculosis

HIV-associated immune deficiency

Loss of CD4+ Th1 function

Reduced macrophage activation

Defective intracellular bacterial control

Clinical impact

Greater risk of active and disseminated tuberculosis

Antiretroviral treatment reduces, but does not eliminate, tuberculosis risk.

Slide 65 · Advanced HIV alters pulmonary and tissue findings

Preserved cellular immunity

Marked CD4+ deficiency

Granulomas and cavitary destruction common

Characteristic granulomas may be absent

Cavitation can discharge bacilli into sputum

Less airway destruction may lower sputum bacilli

Apical disease can be prominent

Multifocal or atypical pulmonary patterns may occur

Disease may remain localized

Extrapulmonary involvement becomes more frequent

Slide 66 · The sputum smear paradox is immunopathologic

Stronger T-cell response

Cavitation and bronchial destruction

Cavity drains to bronchus

More bacilli reach sputum

Severe immune deficiency

High tissue burden yet smear can be negative

The source offers this as the likely explanation; It is not a universal rule.

Slide 67 · Diagnosis requires triangulation of evidence

Evidence domain

Interpretive limitation

Morphology: Granuloma ± necrosis

Not uniquely specific for M. Tuberculosis

Acid-fast stain

Shows bacilli, not species identity

PCR for M. Tuberculosis

Rapid direct detection; Specimen sensitivity varies

Culture and DST

Viable organism and phenotypic susceptibility

TST or IGRA

Sensitization; Does not classify active disease

Slide 68 · Anatomic patterns link morphology to clinical behavior

Dominant pattern

Pathologic / clinical connection

Primary subpleural focus + hilar nodes

Ghon complex; Can heal by fibrosis and calcification

Apical caseating postprimary focus

Fibrosis or cavitation with infectious sputum

Miliary small nodules

Blood-borne dissemination to lung or many organs

Disorganized lesions in immune deficiency

Higher bacillary loads without classic granulomas

Slide 69 · Clinical application: A healed primary complex

Clinical question

A previously asymptomatic individual has a small calcified pulmonary focus associated with calcified hilar lymph nodes. What process best explains this paired pattern?

Interpretation: A healed Ghon complex following primary infection.

Pathologic rationale

The subpleural parenchymal lesion and regional caseating nodes may undergo fibrosis and calcification when Th1 immunity controls the infection.

Slide 70 · Clinical application: A destructive apical cavity

Clinical question

An adult develops night sweats and weight loss. Imaging shows an apical lesion communicating with a bronchus; Sputum may be infectious. What pathologic sequence produced the cavity?

Interpretation: Postprimary caseation with bronchial erosion and evacuation of necrotic material.

Pathologic rationale

The sensitized host mounts a tissue-damaging reaction; Drainage of necrotic material produces a cavitary space.

Slide 71 · Clinical application: Extensive TB with few granulomas

Clinical question

A patient with advanced HIV has numerous acid-fast bacilli in tissue macrophages but little organized granulomatous inflammation. Does the absent classic granuloma exclude tuberculosis?

Interpretation: No. Defective T-cell immunity can prevent typical granuloma formation.

Pathologic rationale

In severely immunocompromised hosts, bacterial burden may be high despite minimal granulomatous architecture and a negative sputum smear.

Slide 72 · Five pathologic principles to retain

1

Intracellular survival precedes the protective Th1 response.

2

IFN-γ-mediated macrophage activation controls bacilli but can generate caseous necrosis.

3

Primary Ghon complexes and apical postprimary lesions have distinct anatomic patterns.

4

Cavitation links parenchymal destruction with airway infectiousness.

5

Granulomas, acid-fast staining, molecular tests, culture, and immune tests answer different diagnostic questions.

Slide 73 · Reference and figure conventions

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. Chapter 8, “Infectious Diseases,” pp. 334–338.

This lecture follows the textbook’s pathogenesis, morphology, clinical presentation, and diagnostic framework.

All displayed pathology diagrams are original schematics; they are not histologic, radiologic, or gross clinical specimens.

Epidemiologic numbers shown refer explicitly to 2022; test descriptions reflect the textbook, not a current practice guideline.