Pathology

Definitions

Causes of Cell Injury

• Hypoxia and ischaemia — the commonest cause. Ischaemia is worse than pure hypoxia, since it removes substrate as well as oxygen
• Physical agents — trauma, extremes of temperature, radiation, electric shock
• Chemical agents and drugs — poisons, alcohol, paracetamol, even hypertonic glucose or salt
• Infections — viruses, bacteria, fungi, parasites
• Immunological reactions — hypersensitivity and autoimmunity
• Genetic defects — enzyme deficiencies, abnormal proteins
• Nutritional imbalance — deficiency and excess alike
• Ageing — cellular senescence

Mechanisms of Cell Injury

Ischaemia — oxygen supply falls → Oxidative phosphorylation stops; ATP falls → Na+/K+ ATPase fails → sodium and water enter → cellular swelling → Anaerobic glycolysis → lactic acid → pH falls → chromatin clumps → Ribosomes detach from the rough endoplasmic reticulum → protein synthesis falls → Calcium enters the cytosol → activates phospholipases, proteases, endonucleases and ATPases → membrane damage — mitochondrial, lysosomal and plasma membranes → irreversible injury and necrosis

Reversible and Irreversible Injury Compared

Morphology of Reversible Injury

• Cellular (hydropic) swelling — the first manifestation of almost all injury; the organ is pale, heavy and turgid
• Fatty change (steatosis) — accumulation of triglyceride, chiefly in the liver, heart and kidney
• On light microscopy — vacuolation, eosinophilia, swelling

Free Radical Injury

• Generated by normal respiration, radiation, drug metabolism, transition metals (Fenton reaction) and nitric oxide
• Chief species — superoxide, hydrogen peroxide and the hydroxyl radical, the last being the most damaging
• Damage by lipid peroxidation of membranes, cross-linking of proteins, and DNA strand breaks
• Removed by superoxide dismutase, catalase, glutathione peroxidase, and by antioxidants such as vitamins A, C and E
• Clinically important in reperfusion injury, chemical toxicity (carbon tetrachloride, paracetamol), oxygen toxicity, inflammation and ageing

Applied Aspects

• Myocardial infarction — irreversible injury begins after about 20–30 minutes of total ischaemia; troponin rises within 3–4 hours and is the marker of choice
• Reperfusion injury — restoring blood flow paradoxically worsens damage through a burst of free radicals, calcium overload and neutrophil influx
• Paracetamol poisoning — the toxic metabolite NAPQI depletes glutathione; treated with N-acetylcysteine, which replenishes it
• Ischaemic preconditioning — brief episodes of ischaemia protect against a later prolonged one, a phenomenon exploited in cardiac surgery
• Different cells tolerate ischaemia differently — neurones die within 3–5 minutes, myocardium in 20–30 minutes, fibroblasts survive hours; this dictates the urgency of resuscitation
• Carbon tetrachloride is the classic experimental hepatotoxin, converted by cytochrome P450 to a free radical that destroys the endoplasmic reticulum within minutes
• Enzyme leakage is the basis of most diagnostic tests — troponin and CK-MB for myocardium, ALT and ast for liver, amylase and lipase for pancreas; the enzyme identifies the tissue and the level suggests the extent
• Hypothermia protects by lowering metabolic demand, which is why cardiac surgery is performed with the patient cooled and why drowning in cold water carries a better prognosis
• Cyanide and carbon monoxide cause histotoxic hypoxia — oxygen reaches the cell but cannot be used; the arterial oxygen saturation may look normal
• Chemical injury acts by two routes — directly, as with mercuric chloride binding sulphydryl groups, or after metabolic conversion to a toxic metabolite, as with paracetamol and carbon tetrachloride
• Heat shock proteins are induced by stress and refold damaged proteins, and are among the cell's first defences against injury

Definitions

Nuclear Changes in Necrosis

• Cytoplasm becomes intensely eosinophilic, from loss of ribosomal RNA and denatured protein
• Nuclear changes take 4 to 12 hours to appear, which is why very early infarcts look normal under the microscope

Types of Necrosis

• Dry gangrene — arterial occlusion, tissue is dry, shrunken and black, with a clear line of demarcation; little infection
• Wet gangrene — venous obstruction or superadded infection; moist, swollen, foul, no clear line; far more dangerous, with systemic toxaemia
• Gas gangrene — Clostridium perfringens; crepitus from gas in the tissues

Apoptosis

Physiological

• Embryogenesis — interdigital webs, involution of the paramesonephric ducts
• Hormone-dependent involution — endometrium, lactating breast after weaning
• Deletion of self-reactive lymphocytes
• Cell turnover in proliferating populations such as the gut crypts

Pathological

• DNA damage from radiation and cytotoxic drugs
• Accumulation of misfolded proteins
• Viral infection, both directly and by cytotoxic T cells
• Duct obstruction causing atrophy of pancreas or kidney

Mechanisms of Apoptosis

Intrinsic (mitochondrial) pathway — the commoner → Loss of survival signals or DNA damage → BAX and BAK exceed bcl-2 → Mitochondrial permeability rises → cytochrome C released → Forms the apoptosome with APAF-1 → activates caspase 9 → extrinsic (death receptor) pathway — FAS–FAS ligand or TNF binding → Activates caspase 8 → Both converge on the executioner caspases 3 and 6 → Endonuclease activation → DNA fragmentation; cytoskeletal breakdown → apoptotic bodies formed and phagocytosed — NO inflammation

Necrosis and Apoptosis Compared

Applied Aspects

• Caseous necrosis is virtually diagnostic of tuberculosis in the right clinical setting, and is the reason a Ghon focus and cold abscess behave as they do
• Fat necrosis of the breast follows trauma and forms a hard, fixed lump with skin tethering that mimics carcinoma clinically and on imaging
• Excessive apoptosis contributes to neurodegenerative disease and to ischaemic injury; too little allows cancer and autoimmunity
• P53 triggers apoptosis in cells with irreparable DNA damage; its loss is the commonest genetic abnormality in human cancer
• Most chemotherapy and radiotherapy work by inducing apoptosis, which is why tumours with defective apoptotic pathways are resistant
• Bcl-2 overexpression from the t(14;18) translocation blocks apoptosis and is the basis of follicular lymphoma — a cancer of failure to die rather than excess division
• Councilman bodies in viral hepatitis and apoptotic bodies in the gut in graft-versus-host disease are apoptosis seen down the microscope
• Gangrene of the foot in diabetes combines large-vessel disease, microangiopathy, neuropathy and infection, and is the commonest reason for non-traumatic amputation in India
• Apoptosis is recognised histologically as a shrunken, deeply eosinophilic cell with a condensed fragmented nucleus, without any surrounding inflammatory reaction
• Phosphatidylserine flips to the outer leaflet of the apoptotic cell membrane and acts as the "eat me" signal for phagocytes; it is the basis of the annexin V assay
• Necroptosis is a regulated form of necrosis, morphologically necrosis but genetically programmed, now recognised in several diseases

Definition

• They lie between the normal cell and the injured cell; when the capacity to adapt is exceeded, cell injury follows

Types of Adaptation

Hypertrophy and Hyperplasia

• The two often occur together in tissues that can divide — the pregnant uterus shows both
• Permanent cells can only hypertrophy — cardiac and skeletal muscle and neurones cannot divide
• Pathological hyperplasia is a fertile soil for cancer, as in endometrial hyperplasia progressing to carcinoma — though hyperplasia itself is not malignant

Atrophy

• Causes — disuse (immobilised limb), denervation (poliomyelitis), loss of blood supply (senile brain atrophy), inadequate nutrition (cachexia, marasmus), loss of endocrine stimulation (endometrium after the menopause), pressure (tumour compressing adjacent tissue), and ageing
• Autophagy — the cell digests its own organelles in autophagic vacuoles; undigested residue persists as lipofuscin, the "wear and tear" pigment of brown atrophy
• The cells are smaller but not dead, and function is diminished rather than lost

Metaplasia

• Metaplasia is adaptive but has a price — squamous epithelium in the bronchus resists smoke but loses cilia and mucus secretion, so clearance fails
• It is a soil for malignancy — squamous carcinoma of the bronchus and adenocarcinoma in Barrett oesophagus arise in metaplastic epithelium
• The direction of change follows the stress: where a tougher lining is needed, squamous appears; where secretion is needed, columnar

Intracellular Accumulations

Applied Aspects

• Left ventricular hypertrophy on the ECG or echocardiogram is a marker of long-standing hypertension and an independent predictor of cardiac events
• Barrett oesophagus requires surveillance endoscopy, since it may progress through dysplasia to adenocarcinoma
• Metaplasia and hyperplasia are reversible if the stimulus is removed — bronchial metaplasia regresses after stopping smoking, which is the strongest argument to give a patient
• Dysplasia is graded as mild, moderate and severe; severe dysplasia merges with carcinoma in situ and is treated as pre-malignant
• Pathological calcification — dystrophic occurs in dead or dying tissue with a normal serum calcium (atheroma, damaged heart valves, caseous nodes); metastatic occurs in normal tissue with hypercalcaemia (hyperparathyroidism, bone metastases, vitamin D excess)
• Metastatic calcification favours acid-secreting tissues — gastric mucosa, kidney, lung and systemic arteries — because their internal alkalinity promotes precipitation
• Psammoma bodies are laminated calcific concretions seen in papillary carcinoma of the thyroid, serous ovarian tumours and meningioma
• Benign prostatic hyperplasia is hyperplasia, not hypertrophy, despite the older name "prostatic hypertrophy" — a distinction examiners enjoy
• Brown atrophy of the heart in cachexia and old age is due to lipofuscin accumulation, and is of no functional consequence
• Anthracosis is harmless; silicosis and asbestosis are not — the difference lies in whether the particle provokes fibrosis, not in whether it is deposited
• Hepatic steatosis is reversible if alcohol is stopped, but progresses through steatohepatitis to cirrhosis if it is not — the single most useful thing to tell a patient
• Fatty change in the liver of protein-energy malnutrition reflects impaired apolipoprotein synthesis, and is a feature of kwashiorkor
• Autophagy is now recognised as a survival mechanism in starvation, and its failure contributes to neurodegenerative disease and to ageing

Definition

• The name is a misnomer — Virchow believed it was starch-like
• All amyloids share the same physical structure despite entirely different chemical composition, which is why a single stain identifies them all
• Composed of 95% fibril protein and 5% P component and glycosaminoglycans

Staining and Identification

Classification

• In India AA amyloid from tuberculosis and chronic infection remains the commonest form, whereas AL predominates in the West — a genuinely important regional difference that changes the investigation
• Systemic forms are AL, AA and dialysis-associated; localised forms include those in the brain, thyroid and islets

Pathogenesis

An abnormal or excessive precursor protein is produced → It is incompletely degraded, or is inherently unstable → Intermediate fragments misfold into the beta-pleated sheet → The sheets aggregate into insoluble fibrils → Which resist proteolysis and are deposited extracellularly → Progressive pressure atrophy of the surrounding parenchyma

Organ Involvement

Amyloid Compared with Hyaline Change

• "Hyaline" says nothing about composition — it is a purely morphological word, and amyloid is one of the many things that look hyaline. This is a distinction examiners like, and students conflate

Diagnosis and Applied Aspects

• Biopsy is essential — abdominal fat pad aspiration and rectal biopsy are safest; renal biopsy has the highest yield but carries a bleeding risk
• Congo red with polarised light confirms it; immunohistochemistry then types it, and the type determines the treatment entirely
• Serum and urine electrophoresis with immunofixation to detect a paraprotein in suspected AL
• Treatment is of the underlying cause — chemotherapy for the plasma cell clone in AL, control of the chronic infection or inflammation in AA
• Deposits regress slowly if the source is removed, so treating tuberculosis or rheumatoid arthritis effectively can reverse the proteinuria
• Cardiac amyloid carries the worst prognosis, with a median survival of months if untreated
• Avoid blind liver biopsy in suspected amyloid — the organ is friable and fatal haemorrhage is a recognised hazard
• Digoxin and calcium channel blockers are avoided in cardiac amyloid, because the drug binds to the deposits and toxicity occurs at ordinary doses
• Amyloid in Alzheimer disease is localised to the brain and causes no systemic disease, which is why one word covers such disparate conditions
• Suspect amyloid in any patient with a chronic inflammatory disease who develops proteinuria — in Indian practice, most often long-standing tuberculosis, bronchiectasis or rheumatoid arthritis

Definition

• It is fundamentally protective, but is capable of causing considerable harm of its own
• Requires a vascular supply, so it cannot occur in avascular tissue such as the cornea or articular cartilage

The Cardinal Signs

Vascular Events

Transient vasoconstriction — a few seconds only → vasodilatation of arterioles → increased flow → heat and redness → Increased vascular permeability → protein-rich fluid escapes as an exudate → swelling → Loss of fluid raises the viscosity of the blood → stasis → Leucocytes move to the periphery of the stream — margination → And begin to adhere to the endothelium

Exudate Compared with Transudate

Cellular Events

Margination — leucocytes move to the vessel periphery as stasis develops → rolling — loose, transient adhesion mediated by selectins (E, P and L) → adhesion — firm; mediated by integrins binding ICAM-1 and VCAM-1 → transmigration (diapedesis) — between endothelial cells, mediated by PECAM-1 (CD31) → chemotaxis — directed movement along a chemical gradient → phagocytosis — recognition and attachment, engulfment, killing and degradation

• Neutrophils predominate in the first 6–24 hours; monocytes after 24–48
• Exceptions — lymphocytes predominate in viral infection, eosinophils in allergy and parasitic infestation, and neutrophils persist for days in Pseudomonas infection

Morphological Patterns and Outcomes

Applied Aspects

• Leucocyte adhesion deficiency — type 1 from a defect of the integrin beta-2 chain, type 2 from a selectin ligand defect; recurrent bacterial infection with NO pus formation and delayed separation of the umbilical cord
• Chronic granulomatous disease — deficient NADPH oxidase, so the respiratory burst fails; recurrent infection with catalase-positive organisms, diagnosed by the nitroblue tetrazolium or dihydrorhodamine test
• Chediak–Higashi syndrome — defective phagolysosome fusion, with giant granules in leucocytes and partial albinism
• Myeloperoxidase deficiency is relatively common but usually mild, since the oxygen-independent systems compensate
• Corticosteroids suppress inflammation at many points, which is why they are so effective and why they so readily mask infection
• Aspirin and NSAIDs inhibit cyclo-oxygenase, reducing prostaglandin synthesis and so pain, fever and vasodilatation

General Principles

• Cell-derived mediators are either preformed in granules (histamine, serotonin, lysosomal enzymes) or synthesised on demand (prostaglandins, leukotrienes, cytokines, nitric oxide)
• Plasma-derived mediators circulate as inactive precursors requiring proteolytic activation — complement, kinin and coagulation systems
• Most have a very short half-life, decaying or being inactivated quickly — a built-in safety mechanism
• One mediator can stimulate the release of another, giving amplification

Vasoactive Amines

• Histamine release is triggered by physical injury, IgE-mediated (type I) reactions, C3a and C5a (anaphylatoxins), and substance P

Arachidonic Acid Metabolites — the Eicosanoids

Membrane phospholipid → phospholipase A2 — inhibited by corticosteroids → arachidonic acid → Two pathways diverge: → cyclo-oxygenase — inhibited by aspirin and NSAIDs → prostaglandins and thromboxane → 5-lipoxygenase — inhibited by zileuton → leukotrienes

Cytokines and Chemokines

Plasma-derived Mediators

• All three plasma systems are triggered by activated hageman factor (factor XII), which is why they run together — a single point of initiation

Mediators Grouped BY Function — the Examination Answer

Other Cell-derived Mediators

• α1-antitrypsin deficiency lets neutrophil elastase act unopposed, destroying alveolar walls — the mechanism of panacinar emphysema in young non-smokers

Applied Aspects

• Corticosteroids inhibit phospholipase A2 and so block both arms; NSAIDs block only cyclo-oxygenase — which is why steroids are more powerful and why NSAIDs can worsen asthma by shunting arachidonate down the leukotriene pathway
• Selective COX-2 inhibitors spare gastric COX-1 and cause fewer ulcers, but by leaving platelet thromboxane untouched while reducing endothelial prostacyclin they raise cardiovascular risk
• Leukotriene antagonists (montelukast) are used in asthma; antihistamines in allergy
• Anti-TNF agents transformed the treatment of rheumatoid arthritis and Crohn disease, but reactivate latent tuberculosis — a major consideration in India, where screening before starting them is mandatory
• Hereditary angio-oedema — C1 inhibitor deficiency allows unchecked bradykinin production, causing recurrent non-itchy swelling; ACE inhibitors cause the same by blocking bradykinin breakdown

Definition

Causes

• Persistent infection by organisms of low toxicity that resist killing — Mycobacterium tuberculosis and leprae, Treponema, fungi
• Prolonged exposure to a toxic agent — exogenous such as silica, or endogenous such as lipid in atherosclerosis
• Immune-mediated (hypersensitivity) disease — autoimmune disease such as rheumatoid arthritis; allergic disease such as asthma
• Following acute inflammation that fails to resolve
• Foreign bodies — suture, talc, splinters

Cells of Chronic Inflammation

Macrophage activation

Granulomatous Inflammation

• Epithelioid cell — an activated macrophage with abundant pink cytoplasm and an elongated vesicular nucleus, resembling an epithelial cell; it is secretory rather than phagocytic
• Giant cells form by the fusion of 20 or more epithelioid cells

Causes of Granulomatous Inflammation

Acute Compared with Chronic Inflammation

Applied Aspects

• Tuberculosis remains the commonest cause of granulomatous inflammation in India; diagnosis needs acid-fast staining, culture and molecular testing (CBNAAT), not histology alone
• Sarcoidosis gives non-caseating "naked" granulomas with few lymphocytes; Schaumann and asteroid bodies may be seen but are not specific
• Anti-TNF therapy reactivates latent tuberculosis, because TNF is required to hold the granuloma together — a striking demonstration that the granuloma is an active, maintained structure
• Chronic inflammation predisposes to malignancy — chronic gastritis to gastric carcinoma, ulcerative colitis to colonic carcinoma, and chronic osteomyelitis sinuses to squamous carcinoma
• Chronic inflammation causes secondary (AA) amyloidosis, which must be suspected if proteinuria appears in a patient with long-standing tuberculosis or rheumatoid arthritis
• Anaemia of chronic disease — IL-6 induces hepatic hepcidin, which traps iron in macrophages; the anaemia is normocytic with a low serum iron but a high ferritin, distinguishing it from iron deficiency
• Sinuses and fistulae are characteristic of chronic inflammation, since the persisting agent prevents closure — seen in chronic osteomyelitis, tuberculosis and Crohn disease
• Systemic features of chronic inflammation are low-grade fever, weight loss, fatigue and a raised ESR, and they are often what brings the patient in
• Corticosteroids and immunosuppressants control chronic inflammation but at the cost of reactivating latent infection, which is the central dilemma in treating it

Definitions

Capacity of tissues to regenerate

• Regeneration also needs an intact connective tissue framework — the liver regenerates after partial resection but scars in cirrhosis, because the reticulin framework is destroyed

Granulation Tissue

• Soft, pink and granular to the naked eye, bleeding easily
• Named from its appearance, not from granulomas — a persistent source of confusion
• Progressively becomes less vascular and more collagenous, ending as a pale avascular scar

Healing BY First Intention (primary Union)

• Tensile strength is only about 10% at one week; it rises rapidly over 4 weeks and reaches 70–80% of normal by 3 months, which it never exceeds
• This is why sutures are removed at about a week but the patient is warned against strain for months

Healing BY Second Intention (secondary Union)

Factors Influencing Healing

Growth Factors in Healing

• TGF-beta is the key to fibrosis everywhere — excessive activity underlies keloid, hepatic cirrhosis and pulmonary fibrosis alike, and it is the target of most anti-fibrotic research
• Matrix metalloproteinases remodel collagen and require zinc; they are balanced by tissue inhibitors, and the balance decides whether a scar matures or thickens

Complications and Applied Aspects

• Deficient scar formation — wound dehiscence and incisional hernia; commonest after abdominal surgery with raised intra-abdominal pressure
• Excessive formation — hypertrophic scar stays within the wound boundary and often regresses; keloid grows beyond it, does not regress, recurs after excision, and is far commoner in dark skin — a frequent problem in Indian practice
• Exuberant granulation ("proud flesh") protrudes above the surface and prevents epithelialisation; treated by cautery or excision
• Contracture after burns, especially across a flexor surface, requires splinting, physiotherapy and often surgical release
• Vitamin C is required for the hydroxylation of proline and lysine; without it collagen is unstable, old scars break down, and this is the mechanism of scurvy
• Malignant change in a chronic scar or sinus — the Marjolin ulcer, a squamous carcinoma arising in a burn scar or chronic osteomyelitis sinus

The Organism

• 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

Spread and Extrapulmonary Disease

• 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

• 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

Outcomes of Acute Inflammation

Morphological Patterns

Systemic Effects — the Acute Phase Response

IL-1, IL-6 and TNF released from activated macrophages → Act on the hypothalamus → PGE2 → raises the thermostat set point → fever → Act on the liver → acute phase proteins → Act on bone marrow → leucocytosis → Act on muscle and fat → catabolism, cachexia in prolonged illness

Changes in the White Cell Count

Systemic Inflammatory Response and Sepsis

• Uncontrolled release of TNF and IL-1 from severe infection gives septic shock: vasodilatation, increased permeability, myocardial depression, disseminated intravascular coagulation and multi-organ failure
• The mediators that are protective locally become lethal systemically — the essential paradox of inflammation
• Gram-negative endotoxin (lipopolysaccharide) is the classical trigger, acting through Toll-like receptor 4

Sequelae of Suppurative Inflammation

• Why an abscess must be drained — the pyogenic membrane is avascular so antibiotics penetrate poorly, the low pH inactivates many of them, and the high bacterial load overwhelms them. "Where there is pus, let it out" remains sound

Applied Aspects

• CRP guides antibiotic decisions and duration, and a persistently high value after treatment suggests a collection needing drainage
• ESR is raised in tuberculosis, malignancy, connective tissue disease and myeloma, and is a useful but wholly non-specific screening test
• Fever is a regulated rise in set point, not a failure of thermoregulation — which is why the patient feels cold and shivers as the temperature rises
• Antipyretics act by inhibiting hypothalamic prostaglandin synthesis, resetting the thermostat
• Relative bradycardia with fever suggests typhoid, and leucopenia with fever points away from a pyogenic cause — both useful bedside observations
• An abscess must be drained; antibiotics alone penetrate pus poorly and the low pH inactivates many of them
• Resolution requires an intact framework — lobar pneumonia resolves completely because the alveolar walls survive, whereas an abscess destroys them and heals by scar
• Procalcitonin rises specifically in bacterial infection and is used to guide whether antibiotics are needed and when they can be stopped
• Fibrinous exudate must be removed or organised — if it is not lysed it is invaded by granulation tissue, which is how constrictive pericarditis and pleural adhesions arise
• Neutropenia removes the ability to form pus, so a neutropenic patient with infection may have no localising signs and a normal chest radiograph — fever alone must be treated as an emergency
• Corticosteroids suppress every one of these systemic signs, so a patient on steroids may have a perforated viscus with neither fever nor a raised white count

Definition

Normal Fluid Exchange — the Starling Forces

At the arteriolar end, hydrostatic pressure exceeds oncotic pressure → Fluid moves out into the interstitium → At the venous end, oncotic pressure exceeds hydrostatic pressure → Most fluid is reabsorbed → The small residue is returned by the lymphatics → Oedema results when this balance is disturbed at any of these points

Pathogenesis — the Five Mechanisms

Transudate and Exudate

Morphology and Clinical Types

• Pitting versus non-pitting is the single most useful bedside distinction — low protein content pits, high protein content does not

Oedema in Specific Diseases

• The two non-pitting oedemas are lymphoedema and myxoedema — both because the interstitium contains protein or mucopolysaccharide rather than free water

Applied Aspects

• Pulmonary oedema is a medical emergency — the patient is breathless, orthopnoeic, with crepitations and pink frothy sputum; treated by sitting up, oxygen, diuretics and nitrates
• Filariasis remains an important cause of lymphoedema in India; Wuchereria bancrofti obstructs the lymphatics, giving elephantiasis of the leg and scrotum
• Nephrotic syndrome — proteinuria above 3.5 g a day, hypoalbuminaemia, oedema and hyperlipidaemia; the oedema is typically periorbital first
• Ascites in cirrhosis arises from portal hypertension, hypoalbuminaemia and secondary hyperaldosteronism together; the serum-ascites albumin gradient distinguishes portal from other causes
• Cerebral oedema kills by herniation, not by the swelling itself; the rigid skull permits no expansion
• Oedema is a sign, not a diagnosis — its distribution points to the cause: generalised suggests cardiac, renal or hepatic disease, localised suggests venous or lymphatic obstruction
• Diuretics remove fluid but do not correct the cause, and over-vigorous diuresis causes hypovolaemia, hypokalaemia and renal impairment
• Daily weight is the most reliable measure of fluid balance, more so than intake and output charts, and a kilogram corresponds to about a litre
• Pleural effusion is detected clinically only above about 500 mL, and on a chest radiograph above about 200 mL, so a small effusion is easily missed
• Albumin infusion is rarely justified for hypoalbuminaemic oedema, since it leaks into the interstitium and the effect is transient

Definition

• Haemostasis is the physiological version of the same process; thrombosis is haemostasis occurring in the wrong place or to excess

Virchow’s Triad — the Pathogenesis

Morphology

Thrombus compared with post-mortem clot

Fate of a Thrombus

• 1. Propagation — the thrombus enlarges and may occlude the vessel → 2.
• Embolisation — it detaches and travels to a distant site → 3.
• Dissolution (lysis) — fibrinolysis removes it
• effective only in a recent thrombus, which is why thrombolysis must be given early → 4.
• Organisation — ingrowth of granulation tissue converts it to a fibrous plug → 5.
• Recanalisation — new channels form through the organised thrombus, partly restoring flow

Clinical Effects

• Arterial thrombosis causes ischaemia and infarction — myocardial infarction, stroke, gangrene of a limb, mesenteric infarction
• Venous thrombosis causes congestion and oedema distal to it, and carries the risk of pulmonary embolism
• Deep vein thrombosis — calf pain, swelling, warmth; but over half are clinically silent, which is why the first sign may be a fatal pulmonary embolism
• Cardiac mural thrombus after infarction or in atrial fibrillation embolises to the brain, kidney, spleen and limbs

Sites and Special Forms of Thrombosis

• Cerebral venous sinus thrombosis is disproportionately common in Indian obstetric practice, from dehydration and the puerperal state, and must be considered in any young woman with headache and seizures after delivery

Applied Aspects

• Prophylaxis is the whole point — early mobilisation, graduated compression stockings, and low molecular weight heparin for surgical and immobile patients. Every one addresses a limb of Virchow triad
• D-dimer is useful for its negative predictive value — a normal value largely excludes thrombosis, but a raised one is non-specific
• Doppler ultrasound is the investigation of choice for deep vein thrombosis
• Antiphospholipid syndrome causes both arterial and venous thrombosis and recurrent fetal loss, and paradoxically prolongs the aPTT in vitro while causing thrombosis in vivo
• Thrombophlebitis migrans (Trousseau sign) — migratory superficial thrombophlebitis suggesting an occult malignancy, classically of the pancreas
• Post-thrombotic syndrome follows valve destruction after a deep vein thrombosis, giving chronic swelling, pigmentation and venous ulceration
• Warfarin needs heparin cover for the first few days, because protein C has a shorter half-life than the clotting factors and falls first — producing a transient PROcoagulant state and, rarely, warfarin-induced skin necrosis
• Arterial and venous thrombosis are prevented by different drugs — antiplatelet agents for arterial (where platelets dominate) and anticoagulants for venous (where fibrin dominates). This follows directly from the composition of each thrombus
• Recanalisation restores some flow but the vessel is never normal again, and the valves are permanently destroyed
• A thrombus in an artery causes pain, pallor, pulselessness, paraesthesia, paralysis and perishing cold — the six Ps of acute limb ischaemia, an emergency measured in hours
• Homans sign is unreliable and potentially dangerous, and has been abandoned in favour of imaging
• Superficial thrombophlebitis of the long saphenous vein near the saphenofemoral junction may propagate into the deep system and warrants anticoagulation, unlike thrombophlebitis elsewhere
• Anticoagulation does not dissolve an existing thrombus — it prevents propagation and allows the body’s own fibrinolysis to work, which is why improvement is gradual
• Duration of anticoagulation depends on whether the thrombosis was provoked: three months for a provoked event, longer or indefinite for an unprovoked or recurrent one
• Thrombosis in an unusual site — cerebral sinus, mesenteric or hepatic vein — should prompt a search for a myeloproliferative disorder or paroxysmal nocturnal haemoglobinuria

Definition

• Over 99% of emboli arise from a dislodged thrombus — hence the term thromboembolism
• The consequence is almost always ischaemic necrosis (infarction) of the tissue supplied

Classification

Pulmonary Thromboembolism

• Source — deep veins of the leg above the knee in over 95%; also pelvic and prostatic veins
• Risk factors — immobility, surgery (especially hip and knee), malignancy, pregnancy and the puerperium, oral contraceptives, obesity, previous thromboembolism, thrombophilia

Fat Embolism

• Source — fracture of a long bone (femur, tibia), orthopaedic surgery, severe burns, soft tissue trauma, and rarely acute pancreatitis or liposuction
• Fat globules and marrow enter torn venous sinusoids in the medullary cavity
• Two mechanisms — mechanical obstruction of pulmonary and cerebral vessels, and biochemical injury, as lipase releases free fatty acids that damage endothelium
• Classical triad — respiratory distress, neurological disturbance, and a petechial rash on the chest, axilla and conjunctiva
• Appears 24–72 hours after the injury — a latent period that distinguishes it from other causes of post-traumatic collapse
• Fat globules in urine and sputum; treatment is supportive, with early fixation of the fracture as the best prevention

Air and Amniotic Fluid Embolism

Other Types of Embolism

• The destination is decided by the source — venous emboli go to the lung, arterial emboli to the systemic circulation, and portal emboli to the liver. Stating this rule first answers most questions about where an embolus will lodge

Applied Aspects

• Prevention of venous thromboembolism is one of the most effective interventions in hospital practice — risk assessment on admission, early mobilisation, and prophylactic heparin
• Massive pulmonary embolism is treated with thrombolysis or embolectomy; submassive and small emboli with anticoagulation
• An inferior vena cava filter is used when anticoagulation is contraindicated or has failed
• Paradoxical embolism should be suspected when a systemic embolus occurs in a patient with a deep vein thrombosis and no cardiac source — look for a patent foramen ovale, present in about a quarter of people
• Septic emboli from infective endocarditis cause abscesses and mycotic aneurysms wherever they lodge
• Amniotic fluid embolism cannot be predicted or prevented; management is entirely supportive, with aggressive treatment of the DIC
• Air embolism during central line insertion is prevented by placing the patient head-down, so venous pressure at the puncture site stays positive
• Divers must ascend slowly, and the treatment of decompression sickness is recompression in a hyperbaric chamber followed by slow decompression
• Caisson disease is the chronic form, with avascular necrosis of the femoral and humeral heads — an occupational disease of tunnel and bridge workers
• Bone marrow embolism is found incidentally at autopsy after cardiopulmonary resuscitation and fractures, and is usually of no clinical consequence
• Nitrogen is far more soluble in fat than in water, which is why obese divers are at greater risk and why the nervous system and marrow are affected
• Trophoblastic emboli reach the lung in normal pregnancy without causing harm, and only massive amniotic fluid entry produces the syndrome
• Every embolus should prompt a search for its source — treating the embolus without finding where it came from invites a second one
• Talc granulomas in the lung of an intravenous drug user are a characteristic form of foreign body embolism, birefringent under polarised light

Definition

• It is a failure of perfusion, not necessarily of blood pressure — a normal pressure does not exclude shock, particularly in the young, in whom compensation is efficient until it suddenly fails

Classification

Pathogenesis of Septic Shock

Endotoxin (lipopolysaccharide) from gram-negative bacteria → Binds TOLL-like receptor 4 on macrophages and endothelium → Massive release of TNF, IL-1, IL-6 and nitric oxide → Widespread vasodilatation → falling systemic vascular resistance → Increased permeability → loss of fluid into the interstitium → Endothelial activation with tissue factor expression → disseminated intravascular coagulation → Myocardial depression, mitochondrial dysfunction and metabolic derangement → multi-organ failure

Stages of Shock

Morphology

• Kidney — acute tubular necrosis, the commonest and most important lesion
• Lung — diffuse alveolar damage; "shock lung" or acute respiratory distress syndrome with hyaline membranes
• Heart — subendocardial haemorrhage and contraction band necrosis
• Gut — mucosal haemorrhagic necrosis; stress ulcers
• Liver — centrilobular necrosis
• Suprarenal — cortical lipid depletion; waterhouse–friderichsen syndrome, bilateral haemorrhagic necrosis in meningococcal sepsis
• Brain — ischaemic encephalopathy

Compensatory Mechanisms in Shock

• The falling haematocrit after haemorrhage is a compensation, not the haemorrhage itself — immediately after a bleed, haemoglobin is normal because whole blood has been lost. This is a common and dangerous source of false reassurance

Applied Aspects

• The single most useful marker of tissue perfusion is the serum lactate, and its fall with treatment predicts survival better than the blood pressure
• Urine output is the cheapest continuous monitor of perfusion — below 0.5 mL/kg/hour indicates inadequate renal perfusion
• Early goal-directed therapy in sepsis — fluids, cultures before antibiotics, antibiotics within the first hour, and vasopressors if fluid alone fails
• Anaphylaxis is treated with intramuscular adrenaline first, not antihistamines or steroids; delay is the commonest cause of death
• Cardiogenic shock is worsened by fluid, unlike every other type — which is why the diagnosis must be made before treatment begins
• Compensation is more efficient in children and the young, so blood pressure is maintained until a very late stage and then falls precipitously
• Capillary refill and skin temperature are useful bedside signs, and cost nothing — a cold, mottled periphery with a delayed refill indicates poor perfusion whatever the blood pressure
• Prognosis — hypovolaemic shock has the best outcome if the bleeding is stopped; cardiogenic and septic shock carry mortality of 50% or more
• Multi-organ dysfunction syndrome is the usual mode of death, and mortality rises steeply with each additional organ that fails
• The kidney is the most reliable early indicator, which is why hourly urine output is measured in every shocked patient
• Blood transfusion is given for haemorrhagic shock, but crystalloid first — and massive transfusion itself causes coagulopathy, hypothermia and hypocalcaemia
• Neurogenic shock is distinguished by bradycardia with hypotension, because the sympathetic outflow is lost — the one shock without a tachycardia
• Adrenal insufficiency must be considered in shock unresponsive to vasopressors, particularly in a patient recently on corticosteroids
• Anaphylaxis can recur hours later (biphasic), so a patient must be observed even after apparently complete recovery
• Obstructive shock is corrected mechanically, not pharmacologically — needle decompression for tension pneumothorax, pericardiocentesis for tamponade
• The "golden hour" in trauma reflects the fact that shock is fully reversible early and progressively less so with time

Definition

• Also called a consumption coagulopathy or defibrination syndrome
• Always secondary to another disease — it is never a primary diagnosis, and treating it means treating the cause

Causes

Pathogenesis

Two triggers, alone or together:

• → 1.
• Release of tissue factor — from damaged tissue, placenta, tumour or monocytes stimulated by endotoxin → 2.
• Widespread endothelial injury — exposing subendothelial collagen → Systemic activation of the coagulation cascade → Fibrin microthrombi throughout the microcirculation → Two consequences follow simultaneously: → ischaemia of tissues, and microangiopathic haemolysis as red cells are sheared → consumption of platelets and clotting factors, with secondary fibrinolysis → bleeding

Clinical Features

Laboratory Findings

• No single test is diagnostic — the diagnosis rests on the combination, in a patient with an appropriate underlying illness
• A falling platelet count and a rising D-dimer in a sick patient is the earliest and most useful pattern

DIC Compared with Other Causes of Bleeding

• Factor VIII separates DIC from liver disease — it is the one clotting factor not synthesised by hepatocytes, so it is normal in liver failure and low in DIC. A genuinely useful test when both are possible

Applied Aspects

• Treat the underlying cause — nothing else works: deliver the uterus in obstetric DIC, give antibiotics and source control in sepsis, and treat the leukaemia
• Support with fresh frozen plasma, cryoprecipitate and platelets where there is active bleeding; fibrinogen below 1 g/L needs cryoprecipitate
• Heparin is reserved for cases in which thrombosis dominates — digital gangrene, purpura fulminans — and is dangerous where bleeding predominates
• Acute promyelocytic leukaemia characteristically presents with DIC, which worsens when chemotherapy lyses the cells; ATRA (all-trans retinoic acid) differentiates the cells rather than lysing them and has transformed the outcome
• Snake bite is an important cause in rural India; viper venom activates coagulation directly, and the 20-minute whole blood clotting test is a simple bedside indication for antivenom
• Chronic, low-grade DIC in malignancy may present only as migratory thrombophlebitis or non-bacterial thrombotic endocarditis
• Purpura fulminans — extensive skin necrosis from dermal vessel thrombosis, seen in meningococcaemia and in severe protein C deficiency
• Renal cortical necrosis from obstetric DIC is an important cause of irreversible renal failure in India, and is largely preventable by good obstetric care
• Never treat the laboratory result alone — a low platelet count and prolonged times in a patient who is not bleeding and has no thrombosis need the cause addressed, not blood products
• Serial measurements matter more than any single value, because the trend distinguishes evolving DIC from a stable abnormality
• Tranexamic acid is generally avoided, since inhibiting fibrinolysis in the presence of widespread microthrombi may worsen organ ischaemia
• Prognosis depends almost entirely on the underlying cause — obstetric DIC often resolves completely once the uterus is emptied, whereas DIC in established sepsis carries a very high mortality
• The mortality of DIC is that of the disease that caused it, which is why it is described as a marker of severity as much as a diagnosis
• A normal D-dimer makes significant DIC very unlikely, which gives the test real value in excluding the diagnosis in a bleeding patient

Definition

• The immune mechanism is normal; it is the response that is excessive or misdirected
• Requires prior sensitisation — the first exposure causes no reaction
• Classified by Gell and Coombs into four types

The Four Types at a Glance

• Mnemonic — acid: Anaphylactic, Cytotoxic, Immune complex, Delayed
• Types I to III are antibody-mediated; type IV is cell-mediated — the single most useful division

Type I — Immediate Hypersensitivity

First exposure — antigen presented, TH2 response, IL-4 and IL-13 drive B cells to make IgE → IgE binds FcεRI receptors on mast cells and basophils — the person is now sensitised → Re-exposure — antigen cross-links two adjacent IgE molecules → Mast cell degranulation → immediate phase (5–30 minutes) — preformed histamine: vasodilatation, increased permeability, bronchospasm, mucus → late phase (2–24 hours) — newly synthesised leukotrienes, prostaglandins, cytokines; eosinophil infiltration and tissue damage

• The late phase causes the tissue damage, and is why asthma is treated with steroids rather than antihistamines alone
• Atopy — a genetic predisposition to exaggerated IgE responses; familial, with raised serum IgE and eosinophils

Type II — Antibody-mediated

Type III — Immune Complex Disease

Antigen–antibody complexes form in the circulation → Complexes of intermediate size in slight antigen excess are the pathogenic ones — too small to be cleared, too large to pass → Deposit where there is filtration or turbulence: glomeruli, joints, skin, small vessels, pericardium → Complement is activated → C3a and C5a → neutrophils are recruited and release lysosomal enzymes and radicals → fibrinoid necrosis and vasculitis

Type IV — Delayed (cell-mediated)

• No antibody is involved, so type IV cannot be transferred by serum — only by lymphocytes. This is the classical experimental proof
• Persistent antigen converts a delayed reaction into a granuloma after two to three weeks

Applied Aspects

• Anaphylaxis is treated with intramuscular adrenaline, which reverses every effect of the mediators; antihistamines and steroids are adjuncts only
• Skin prick testing demonstrates type I; the Mantoux test demonstrates type IV, read at 48–72 hours
• Direct and indirect Coombs tests detect type II antibody on or against red cells
• Rh haemolytic disease is a type II reaction prevented entirely by anti-D immunoglobulin — one of the great successes of applied immunopathology
• Serum sickness is now seen with antivenom and antithymocyte globulin, appearing 7–10 days after the first exposure
• Contact dermatitis to nickel, chromate and rubber is a type IV reaction diagnosed by patch testing
• Desensitisation (allergen immunotherapy) shifts the response from IgE toward blocking IgG and regulatory T cells, and is the only treatment that alters the natural history of allergy
• Asthma is a type I reaction with a dominant late phase, which is why inhaled corticosteroids are the mainstay and bronchodilators alone are inadequate
• Transfusion reactions — acute haemolytic reactions are type II and ABO-related; febrile non-haemolytic reactions are caused by donor leucocytes and are prevented by leucodepletion
• Hyperacute graft rejection is a type II reaction, and acute cellular rejection a type IV one — the same classification applies throughout transplantation
• Tuberculin conversion indicates infection, not disease, and its interpretation must allow for BCG vaccination, which is universal in India
• Corticosteroids suppress all four types, which is why they are so widely used and so readily abused
• Penicillin can cause all four types — anaphylaxis (I), haemolytic anaemia (II), serum sickness (III) and contact dermatitis (IV); a single drug illustrating the entire classification
• Eosinophilia points to type I or to parasitic infestation, and both are common in India
• Total and specific IgE support a diagnosis of atopy, but skin prick testing remains more sensitive and far cheaper
• Latex allergy is an occupational hazard for health workers, and may be type I or type IV; the two require different tests
• Hypersensitivity is the mechanism behind much of clinical medicine — asthma, drug reactions, autoimmune disease, transplant rejection and the tuberculin test all belong to this single classification
• Omalizumab, an anti-IgE antibody, is used in severe allergic asthma and acts precisely at the first step of the type I pathway
• Type II and type III are distinguished by where the antigen is — fixed on a cell surface in type II, and free in the circulation forming complexes in type III. That single question separates them reliably

Definition

• Female to male ratio about 9:1; typically presents in young women of childbearing age
• Commoner and often more severe in Asian and African populations

Aetiology and Pathogenesis

Apoptotic cell debris is cleared inefficiently → Nuclear antigens — DNA, histones, ribonucleoproteins — persist → Loss of self-tolerance; autoreactive B and T cells are activated → autoantibodies against nuclear antigens → immune complexes form and deposit in tissues (type III) → Complement activation and neutrophil recruitment → Some antibodies also cause direct cytotoxicity (type II) — against red cells, platelets and leucocytes

Autoantibodies

Morphology

• LE cell — a neutrophil that has phagocytosed the denatured nucleus of another cell; historically important but no longer used diagnostically
• Haematoxylin bodies are the tissue equivalent of the LE cell

Clinical Features

• Mnemonic for the classification criteria — "soap brain MD": Serositis, Oral ulcers, Arthritis, Photosensitivity, Blood disorders, Renal, ANA, Immunological, Neurological, Malar rash, Discoid rash
• Constitutional — fever, fatigue and weight loss are almost universal
• Renal involvement determines the prognosis and is present in about half

Lupus Nephritis — the Who/isn Classes

• Immunofluorescence shows a "full house" — IgG, IgM, IgA, C3 and C1q all positive; this pattern is highly suggestive of lupus and is seen in few other conditions
• Class determines treatment — classes III and IV need aggressive immunosuppression, class V is managed as a membranous nephropathy

Applied Aspects

• Complement C3 and C4 fall during a flare, as they are consumed; together with a rising anti-dsDNA titre they are the best markers of activity
• Renal biopsy determines the class and therefore the treatment, and is indicated whenever there is proteinuria or an active urinary sediment
• Drug-induced lupus spares the kidney and central nervous system, is anti-histone positive and anti-dsDNA negative, and resolves on stopping the drug
• Antiphospholipid syndrome requires lifelong anticoagulation after a thrombotic event, and is a treatable cause of recurrent miscarriage
• Infection is now a leading cause of death, from the disease and from the immunosuppression used to treat it
• Hydroxychloroquine is given to nearly all patients, reduces flares and improves survival, and requires annual retinal screening
• Pregnancy should be planned during remission, since active disease and antiphospholipid antibodies both threaten the fetus
• SLE is a great mimic — it can present to almost any specialty, and the diagnosis is often delayed for years
• Photoprotection is genuinely effective and among the simplest interventions available to the patient

The Virus

• Single-stranded RNA with the enzymes reverse transcriptase, integrase and protease
• Envelope glycoproteins gp120 and gp41; core protein p24
• HIV-1 causes the world pandemic; HIV-2 is West African, less transmissible and slower

Transmission

Pathogenesis

Gp120 binds the CD4 molecule — the primary receptor → A CO-receptor is also required: CCR5 (macrophage-tropic, early) or CXCR4 (T-cell-tropic, late) → gp41 mediates fusion; the virus enters → reverse transcriptase makes DNA from the viral RNA — error-prone, hence rapid mutation and drug resistance → integrase inserts the provirus into the host genome — the basis of latency and of the reservoir that cannot be eradicated → Activation of the cell triggers replication and CD4 cell death → Progressive CD4 depletion → failure of cell-mediated immunity

• CD4 cells are lost by several mechanisms — direct cytopathic effect, apoptosis of infected and uninfected cells, killing by cytotoxic T cells, and syncytium formation
• Macrophages and dendritic cells are relatively resistant and act as a reservoir, carrying the virus to lymphoid tissue and the brain
• Homozygous CCR5-delta32 deletion confers near-complete resistance to sexually acquired infection — the observation that made CCR5 a drug target

Natural History

Opportunistic Infections and Tumours

• AIDS-defining tumours — KAPOSI sarcoma (caused by HHV-8), non-Hodgkin lymphoma (often EBV-driven), and invasive carcinoma of the cervix (HPV)
• Kaposi sarcoma is uncommon in India compared with Africa, because HHV-8 seroprevalence is low — a genuine regional difference

Morphology in AIDS

• The lymph node changes summarise the whole disease — an initial vigorous response, then progressive exhaustion of the lymphoid system

Diagnosis and Applied Aspects

• Fourth-generation ELISA detects both antibody and p24 antigen, shortening the window period to about two to three weeks; confirmed by a second test on a different platform
• The window period is the interval before antibody is detectable, during which the patient is highly infectious and the test may be negative
• CD4 count guides prophylaxis and staging; viral load monitors treatment — the two answer different questions
• Antiretroviral therapy is now started at diagnosis regardless of CD4 count, and an undetectable viral load makes sexual transmission effectively impossible
• Immune reconstitution inflammatory syndrome — paradoxical worsening as immunity recovers and mounts a response to a latent infection, most often tuberculosis; it is not treatment failure
• Post-exposure prophylaxis within 72 hours after a needlestick injury, and pre-exposure prophylaxis for those at high risk
• Prevention of parent-to-child transmission is one of the most effective public health interventions available in India, reducing transmission from 30% to under 2%
• Co-trimoxazole prophylaxis is started when the CD4 count falls below 200, and prevents Pneumocystis and toxoplasmosis
• Every patient with tuberculosis should be offered an HIV test, and every patient with HIV screened for tuberculosis — the two are inseparable in Indian practice
• Antiretroviral drugs act at each step of the life cycle — entry inhibitors, reverse transcriptase inhibitors, integrase inhibitors and protease inhibitors; combination therapy is essential because the virus mutates so rapidly
• The virus cannot be eradicated because the integrated provirus persists in resting memory CD4 cells, which is why treatment is lifelong
• Universal precautions apply to every patient, not only to those known to be infected, since most transmission risk comes from undiagnosed infection
• Stigma and disclosure remain major barriers to care in India, and confidentiality is both an ethical and a legal obligation
• Tuberculosis in HIV is often atypical — sputum-negative, extrapulmonary, with normal or lower-zone chest radiographs and absent cavitation, because granulomas cannot form without CD4 cells
• Antiretroviral therapy has converted HIV into a chronic manageable disease, with near-normal life expectancy if treatment is started early and taken consistently
• Cardiovascular, renal and metabolic complications of long-term therapy and of chronic inflammation are now the dominant clinical problems
• India's national programme provides free antiretroviral therapy, and adherence support is as important as the drugs themselves

Definition and Terminology

Mechanisms of Recognition

• Direct pathway — recipient T cells recognise intact donor MHC on donor dendritic cells carried in the graft; responsible for acute rejection
• Indirect pathway — recipient antigen-presenting cells process donor MHC and present it as peptide; responsible for chronic rejection
• CD8 cells kill graft cells directly; CD4 cells cause a delayed-type reaction and help B cells make antibody

Types of Rejection

Graft-versus-host Disease

• The reverse situation — immunocompetent donor T cells attack the recipient
• Three requirements — the graft must contain immunocompetent cells, the recipient must be immunosuppressed, and there must be an HLA difference
• Occurs chiefly after allogeneic bone marrow transplantation, and after transfusion of non-irradiated blood into an immunosuppressed patient
• Target organs — skin (rash), liver (jaundice) and gut (diarrhoea)
• Chronic form resembles systemic sclerosis, with skin fibrosis and sicca symptoms
• Prevented by HLA matching, immunosuppression, and irradiation of blood products for at-risk recipients

Immunosuppression

Corneal and Other Privileged Grafts

• Immune privilege is not absolute — it depends on the tissue remaining avascular and on the absence of prior sensitisation

Applied Aspects

• ABO compatibility and a negative lymphocyte cross-match are mandatory before transplantation; HLA matching improves long-term survival
• The kidney is the commonest transplanted organ, and living related donation predominates in India
• Graft biopsy is the only way to distinguish rejection from drug nephrotoxicity, since both present as a rising creatinine
• Long-term immunosuppression causes infection and malignancy — particularly skin cancer and Epstein–Barr-driven post-transplant lymphoproliferative disorder
• The cornea is the most successful graft because it is avascular and immunologically privileged; matching is usually unnecessary
• Non-adherence to immunosuppression is a leading cause of late graft loss, and in India cost is a major contributor to it
• Panel reactive antibody testing measures how sensitised a recipient is, and a highly sensitised patient may wait years for a compatible organ
• Brain-stem death certification underpins deceased donor transplantation, and its legal framework in India is the Transplantation of Human Organs Act
• Xenotransplantation is limited by hyperacute rejection against galactose-alpha-1,3-galactose, and by the risk of transmitting animal retroviruses
• The graft-versus-leukaemia effect means that some GVHD after marrow transplantation actually reduces relapse, so complete suppression is not the goal
• Calcineurin inhibitor nephrotoxicity mimics rejection in a renal graft, and only biopsy with drug levels can separate them — the commonest diagnostic problem in transplant medicine
• Chronic rejection has no effective treatment, so the whole strategy is prevention: adequate immunosuppression, control of blood pressure and lipids, and prompt treatment of acute episodes
• Living donation predominates in India, and deceased donation remains limited by low consent rates and by the logistics of organ retrieval
• Cytomegalovirus is the commonest opportunistic infection after transplantation, and prophylaxis or pre-emptive monitoring is routine
• Commercial organ trading is prohibited, and the law requires authorisation committee approval for unrelated donation
• The waiting list far exceeds supply, which is why deceased donor programmes and public awareness matter as much as surgical technique

Classification

Primary Immunodeficiencies

• The pattern of infection tells you which arm has failed.
• Antibody or complement defects give recurrent pyogenic bacterial infection.
• T cell defects give viral, fungal and intracellular infection.
• Phagocyte defects give staphylococcal and fungal abscesses with poor pus formation. The history narrows the diagnosis before any test is done.

Secondary Immunodeficiency — Far Commoner

Approach to Investigation

Full blood count with differential — lymphocyte and neutrophil numbers → Serum immunoglobulins (IgG, IgA, IgM) and specific antibody responses → Lymphocyte subsets by flow cytometry — CD4, CD8, B and NK cells → Complement — C3, C4 and CH50 → Neutrophil function — nitroblue tetrazolium or dihydrorhodamine test → HIV serology in every case → Genetic testing where a specific primary disorder is suspected

Pattern of Infection BY Defect

Applied Aspects

• Suspect immunodeficiency with recurrent, severe, persistent or unusual infections, infection with organisms of low virulence, failure to thrive, or a family history
• Post-splenectomy sepsis from encapsulated organisms carries a high mortality; prevented by vaccination against pneumococcus, meningococcus and Haemophilus influenzae b, plus prophylactic penicillin
• Live vaccines are contraindicated in T cell deficiency and in significant immunosuppression — BCG in an infant with SCID is fatal
• Blood products must be irradiated for severely immunodeficient patients, to prevent transfusion-associated graft-versus-host disease
• Immunoglobulin replacement transforms the outlook in antibody deficiencies; bone marrow transplantation is curative in SCID
• In India, malnutrition and tuberculosis remain the dominant causes of acquired immunodeficiency, and are far more common than any inherited disorder
• Maternal IgG protects the infant for the first 3 to 6 months, which is why most antibody deficiencies present only after that
• Newborn screening for SCID by measuring T cell receptor excision circles allows transplantation before infection occurs, and transforms survival
• Recurrent infection at a single site usually indicates a local anatomical problem rather than immunodeficiency — an obstruction, a foreign body or a fistula
• Consanguinity raises the risk of autosomal recessive primary immunodeficiency, which is relevant in parts of India
• The ten warning signs of primary immunodeficiency — including two or more pneumonias in a year, failure to thrive, recurrent deep abscesses and persistent thrush — are a practical screening tool for general practice
• Antibody deficiency is treatable and often missed for years; the average delay to diagnosis of common variable immunodeficiency is measured in years, during which bronchiectasis develops irreversibly
• Autoimmunity and malignancy accompany many primary immunodeficiencies, because immune regulation fails alongside immune defence
• Genetic counselling is an essential part of management, since most primary immunodeficiencies are single-gene disorders with a defined recurrence risk
• An HIV test is mandatory in every case of suspected immunodeficiency, whatever the age, before any inherited disorder is considered
• Correcting malnutrition restores immune function, which makes it the single most effective immunological intervention available at population level
• Vaccination of household contacts protects a patient who cannot be safely vaccinated themselves — a practical measure often forgotten
• Antibiotic prophylaxis reduces infection in several primary immunodeficiencies, and is used lifelong after splenectomy in children

Definition