Hypersensitivity* Reactions - define*; classify, discuss; Type I Hypersensitivity Reactions - discuss 2. Amyloid***** - define, classify*, molecular structure, special stains***; physiochemical properties 3. Sago Spleen; Amyloidosis of Spleen - gross, microscopic features 4. Autoimmune Disorders - mechanisms 5. Neoplasms found in patients with HIV infection 1. Autoimmunity - define, pathogenesis 2. AIDS - etiology, routes of transmission, natural history (phases), diagnosis answer in detail covering imp points as welll in exaam point of view 2mbbs pathology refer robbin harsh moham add diagrams as well cover required points for muhs exam Add histo pathology diagram and gross as well for exam easy to draw diagram

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Here is your comprehensive 2nd MBBS Pathology notes for MUHS exam, based on Robbins/Cotran Pathologic Basis of Disease, Harsh Mohan, and Jawetz Microbiology:

2nd MBBS PATHOLOGY - MUHS EXAM NOTES

TOPIC 1: HYPERSENSITIVITY REACTIONS

Definition

Hypersensitivity is a condition in which an exaggerated or augmented immune response occurs that is harmful to the host. It requires a presensitized state - reactions typically occur after the second encounter with a specific antigen (allergen).

Robbins: "Hypersensitivity refers to the tissue-damaging immune reactions that may be elicited by exogenous environmental antigens or by endogenous self-antigens."

Classification (Gell & Coombs, 1963)

Type	Name	Mechanism	Mediators	Time	Examples
I	Immediate / Anaphylactic	IgE-mediated	Mast cells, basophils, histamine	Seconds-minutes	Anaphylaxis, asthma, hay fever, urticaria
II	Cytotoxic / Antibody-dependent	IgG/IgM against cell surface	Complement, ADCC	Hours	Hemolytic anemia, Goodpasture syndrome, ABO incompatibility
III	Immune complex-mediated	Antigen-antibody complexes	Complement, PMNs	Hours	SLE, serum sickness, post-strep GN
IV	Delayed / Cell-mediated	T lymphocytes	Cytokines, macrophages	24-72 hrs	TB (tuberculin test), contact dermatitis, graft rejection

TYPE I HYPERSENSITIVITY (IMMEDIATE) - Detailed

Definition

Type I hypersensitivity manifests in tissue reactions occurring within seconds after antigen combines with specific IgE antibody. Also called immediate hypersensitivity or allergy/atopy.

Mechanism (Step-by-Step)

┌─────────────────────────────────────────────────────────────────┐
│              TYPE I HYPERSENSITIVITY - MECHANISM                │
│                                                                 │
│  SENSITIZATION PHASE (1st Exposure)                             │
│  Antigen (allergen) → B cell → Plasma cell                     │
│       → IgE production                                         │
│       → IgE binds to Fc-ε-RI on MAST CELLS & BASOPHILS        │
│                                                                 │
│  ELICITATION PHASE (2nd Exposure)                               │
│  Same antigen enters → Cross-links IgE on mast cells           │
│       → DEGRANULATION                                          │
│       → Release of PREFORMED & NEWLY FORMED mediators          │
│                                                                 │
│  ┌─────────────────┐    ┌──────────────────────────────────┐    │
│  │PREFORMED (stored)│    │ NEWLY FORMED (synthesized)       │    │
│  │- Histamine       │    │ - Prostaglandins (PGD2)          │    │
│  │- Heparin         │    │ - Leukotrienes (LTC4, LTD4, LTE4)│   │
│  │- Eosinophil      │    │ - Platelet activating factor     │    │
│  │  chemotactic     │    │ - Cytokines (IL-4, IL-5, TNF-α)  │    │
│  │  factor (ECF)    │    │                                  │    │
│  └─────────────────┘    └──────────────────────────────────┘    │
└─────────────────────────────────────────────────────────────────┘

Diagram (Easy to Draw in Exam)

     1st EXPOSURE              2nd EXPOSURE
         |                          |
    [ALLERGEN]                 [ALLERGEN]
         |                          |
    [B cell] → IgE           [IgE on mast cell]
         |                      cross-linked
    IgE binds to                    |
    mast cell Fc-ε-RI          DEGRANULATION
    (sensitization)                 |
                             ┌──────┴──────┐
                         EARLY            LATE
                         (mins)          (hrs)
                             |              |
                        Histamine      Leukotrienes
                        Edema          Prostaglandins
                        Bronchospasm   Cytokines
                        Vasodilation   Tissue damage

Mediators of Type I Hypersensitivity

PRIMARY (Preformed - released immediately):

Histamine - vasodilation, increased capillary permeability, bronchospasm
Heparin - anticoagulant effect
Eosinophil chemotactic factor (ECF) - attracts eosinophils
Proteases - tissue damage

SECONDARY (Newly formed - synthesized after activation):

Prostaglandins (PGD2) - bronchoconstriction, vasodilation
Leukotrienes LTC4, LTD4, LTE4 (SRS-A = Slow Reacting Substance of Anaphylaxis) - potent bronchoconstriction, increased vascular permeability
Leukotriene B4 (LTB4) - chemotaxis of leukocytes
Platelet Activating Factor (PAF) - activates platelets, causes bronchoconstriction
Cytokines: IL-4, IL-5, IL-13, TNF-α

Clinical Manifestations of Type I

Form	Features
Systemic Anaphylaxis	Life-threatening; urticaria, bronchospasm, laryngeal edema, hypotension, shock; triggered by drugs (penicillin), bee stings, food (peanuts)
Atopy (Local)	Genetic predisposition; elevated IgE; hay fever, asthma, eczema, urticaria
Bronchial Asthma	Bronchospasm, wheezing, eosinophilia
Allergic Rhinitis	Hay fever, sneezing, watery discharge
Food Allergy	Nausea, vomiting, diarrhea

Types II, III, IV (Brief for Completeness)

TYPE II - Cytotoxic:

Antibodies (IgG/IgM) directed against cell surface antigens
Mechanisms: Complement lysis, ADCC (antibody-dependent cellular cytotoxicity), opsonization
Examples: Transfusion reactions (ABO), Rh hemolytic disease of newborn, Goodpasture syndrome (anti-GBM), Graves' disease, Myasthenia gravis

TYPE III - Immune Complex:

Antigen-antibody complexes deposited in tissues → activate complement → PMN recruitment → tissue damage
Examples: SLE, serum sickness, post-streptococcal GN, Arthus reaction
Key: Complement consumption → hypocomplementemia during acute phase

TYPE IV - Delayed (Cell-Mediated):

T lymphocytes sensitized by antigen; release cytokines on second contact
CD4+ Th1 cells → activate macrophages (granuloma formation)
CD8+ CTLs → direct cytotoxicity
Examples: Tuberculin (Mantoux) test, contact dermatitis (poison ivy), graft rejection, granulomatous diseases (TB, sarcoidosis)

TOPIC 2: AMYLOID - DEFINITION, CLASSIFICATION, STRUCTURE, STAINS

Definition

Amyloid is an extracellular deposit of abnormal, misfolded proteins that aggregate into insoluble fibrils, which accumulate in tissues and cause organ dysfunction by pressure atrophy and disruption of tissue architecture.

Robbins: "Amyloidosis results from abnormal folding of proteins, which become insoluble, aggregate, and deposit as fibrils in extracellular tissues."

Molecular Structure

┌────────────────────────────────────────────────────────┐
│              MOLECULAR STRUCTURE OF AMYLOID            │
│                                                        │
│  Misfolded protein → β-sheet configuration             │
│         ↓                                              │
│  Monomers self-assemble                                │
│         ↓                                              │
│  AMYLOID FIBRIL                                        │
│  - Non-branching fibrils, 7.5-10 nm diameter           │
│  - Antiparallel β-pleated sheet configuration          │
│  - Cross β-sheet structure (perpendicular to fibril    │
│    axis) = gives apple-green birefringence             │
│         ↓                                              │
│  + Serum Amyloid P component (SAP) - all amyloids      │
│  + Glycosaminoglycans (heparan sulfate)                │
│  + Apolipoprotein E                                    │
└────────────────────────────────────────────────────────┘

Key structural features:

Beta-pleated sheet (cross-β structure) - universal property
Non-branching fibrils (7.5-10 nm wide, 30-100 nm long)
All forms contain Serum Amyloid P (SAP) component and glycosaminoglycans
The β-pleated sheet conformation is responsible for the characteristic optical property (apple-green birefringence)

Classification of Amyloidosis (Robbins Table 6.17)

Pathogenesis of Amyloidosis from Robbins - showing AL, ATTRwt, AA, and ATTRv types

Fig. from Robbins: Pathogenesis of amyloidosis showing formation of amyloid fibrils and their types

A. Based on Distribution

Type	Description
Systemic (Generalized)	Affects multiple organs
Localized	Limited to single organ/tissue

B. Based on Biochemical Nature (Current Classification)

Amyloid Type	Fibril Protein	Precursor	Clinical Setting
AL (Amyloid Light chain)	Ig light chains (λ > κ)	Plasma cell (monoclonal)	Multiple myeloma, plasma cell dyscrasias - MOST COMMON
AA (Amyloid Associated)	Serum Amyloid A (SAA)	SAA protein (acute phase reactant)	Secondary/reactive amyloidosis - chronic inflammations (TB, RA, osteomyelitis, FMF)
ATTRwt	Wild-type transthyretin	Normal transthyretin (liver)	Old age - "senile systemic amyloidosis"; cardiac involvement
ATTRv	Variant transthyretin	Mutant transthyretin	Familial amyloid polyneuropathy (autosomal dominant)
Aβ2M	β2-microglobulin	β2-microglobulin	Hemodialysis-associated amyloidosis
Aβ	Aβ peptide (derived from APP)	Amyloid precursor protein	Alzheimer's disease (brain plaques)

C. Old/Traditional Classification

Type	Description
Primary	No predisposing disease; associated with plasma cell disorders; AL type
Secondary (Reactive)	Associated with chronic inflammatory disease; AA type
Heredofamilial	ATTRv - familial Mediterranean fever, familial amyloid polyneuropathy
Localized	Single organ; lung, skin, tongue, bladder
Endocrine	Medullary thyroid carcinoma (calcitonin precursor), type 2 DM (IAPP), pheochromocytoma
Senile	ATTRwt; heart predominantly; old age
Hemodialysis-associated	β2-microglobulin; carpal tunnel syndrome

Special Stains for Amyloid ⭐⭐⭐ (HIGH YIELD)

┌──────────────────────────────────────────────────────────────────┐
│                   SPECIAL STAINS FOR AMYLOID                     │
│                                                                  │
│  1. CONGO RED (Most specific, routinely used)                    │
│     - Normal light: SALMON PINK / ORANGE-RED color               │
│     - Polarized light: APPLE-GREEN BIREFRINGENCE ★★★            │
│       (pathognomonic for amyloid)                                │
│                                                                  │
│  2. CRYSTAL VIOLET (Metachromatic stain)                         │
│     - Amyloid appears PURPLE/ROSE color                          │
│     - Normal color of crystal violet = purple                    │
│     - Metachromasia = color change                               │
│                                                                  │
│  3. THIOFLAVIN T (Fluorescent stain)                             │
│     - Yellow-green FLUORESCENCE under UV light                   │
│     - Very sensitive but less specific                           │
│                                                                  │
│  4. PAS STAIN                                                    │
│     - Weakly positive (pale pink)                                │
│     - Diastase resistant                                         │
│                                                                  │
│  5. SIRIUS RED - Can also detect amyloid                         │
└──────────────────────────────────────────────────────────────────┘

Mnemonic for Congo Red appearance: "Salmon in the Sun turns Apple Green in the Dark"

Normal light → salmon/orange-red
Polarized light → apple-green birefringence

Physicochemical Properties of Amyloid

Property	Details
Solubility	Insoluble in physiologic solvents
Structure	Non-branching fibrils, 7.5-10 nm diameter
Configuration	Antiparallel β-pleated sheets
Staining	Congo red positive with apple-green birefringence
X-ray diffraction	Cross-β diffraction pattern (4.7 Å and 10 Å reflections)
Electron microscopy	Non-branching fibrils
Components	Fibrils + SAP (serum amyloid P) + glycosaminoglycans + Apo-E
Resistance	Resistant to proteolysis

TOPIC 3: SAGO SPLEEN / AMYLOIDOSIS OF SPLEEN

Gross Features (Two Patterns)

┌──────────────────────────────────────────────────────────────────┐
│                  AMYLOIDOSIS OF SPLEEN - GROSS                   │
│                                                                  │
│  PATTERN 1: SAGO SPLEEN                                          │
│  ────────────────────────                                        │
│  - Amyloid deposits in WHITE PULP (splenic follicles)            │
│  - Gross: Small translucent, pale gray, waxy nodules             │
│           resembling "TAPIOCA/SAGO GRAINS"                       │
│  - The follicles look like boiled sago seeds                     │
│  - Spleen may be normal or slightly enlarged                     │
│                                                                  │
│  PATTERN 2: LARDACEOUS SPLEEN (Bacon/Ham Spleen)                 │
│  ──────────────────────────                                      │
│  - Amyloid deposits in RED PULP (sinuses + connective tissue)    │
│  - Gross: Uniform waxy, firm, homogeneous enlargement            │
│  - Cut surface: resembles LARD (solidified fat/bacon)            │
│  - Spleen markedly ENLARGED (splenomegaly)                       │
│  - Appears like "ham" or "bacon" → lardaceous                    │
│                                                                  │
│  ADVANCED: Combination of both patterns                          │
└──────────────────────────────────────────────────────────────────┘

Robbins: "In one, the deposits are largely limited to the splenic follicles, producing tapioca-like granules on gross inspection, designated sago spleen. In the other pattern, the amyloid involves the walls of the splenic sinuses and connective tissue framework in the red pulp..."

Easy Exam Diagram for Sago Spleen

     SAGO SPLEEN                     LARDACEOUS SPLEEN
  (White pulp affected)            (Red pulp affected)
  
  ┌─────────────────────┐          ┌─────────────────────┐
  │  Normal red pulp    │          │                     │
  │  with WHITE nodules │          │   Uniform waxy      │
  │  (like white pearls │          │   enlarged spleen   │
  │  or sago grains)    │          │   with lard-like    │
  │  ○ ○ ○ ○ ○          │          │   consistency       │
  │     ○ ○ ○            │          │   throughout        │
  │  ○ ○ ○ ○ ○          │          │                     │
  └─────────────────────┘          └─────────────────────┘
  Small gray-white nodules         Homogeneous, large,
  (tapioca-like) on cross           waxy spleen
  section

Microscopic Features

┌──────────────────────────────────────────────────────────────────┐
│             AMYLOIDOSIS OF SPLEEN - MICROSCOPY                   │
│                                                                  │
│  H&E stain:                                                      │
│  - Amyloid appears as HOMOGENEOUS, EOSINOPHILIC (pink),          │
│    AMORPHOUS extracellular material                              │
│  - Deposits replace normal splenic architecture                  │
│  - Follicles / sinuses replaced by acellular pink material       │
│  - Pressure atrophy of surrounding cells                         │
│                                                                  │
│  Congo Red stain:                                                │
│  - Deposits stain salmon-pink/orange-red                         │
│  - Under polarized light → APPLE-GREEN BIREFRINGENCE             │
│                                                                  │
│  EM:                                                             │
│  - Non-branching fibrils in extracellular space                  │
└──────────────────────────────────────────────────────────────────┘

Histopathology description for exam:

Under H&E: Homogeneous, structureless, eosinophilic (pink), amorphous material deposited in the extracellular spaces
In sago spleen: deposits in and around the Malpighian corpuscles (white pulp/follicles)
In lardaceous spleen: deposits in sinusoidal walls and red pulp stroma
Congo red stain: salmon-pink color; apple-green birefringence under polarized light

TOPIC 4: AUTOIMMUNE DISORDERS - MECHANISMS / AUTOIMMUNITY

Definition

Autoimmunity is the failure of immunological tolerance to self antigens, resulting in immune reactions directed against the body's own tissues, causing tissue damage and organ dysfunction.

Normal Tolerance - Overview

Immunological tolerance = unresponsiveness to self antigens. Two mechanisms:

┌────────────────────────────────────────────────────────────────┐
│              MECHANISMS OF IMMUNOLOGICAL TOLERANCE             │
│                                                                │
│  1. CENTRAL TOLERANCE                                          │
│     - Occurs in THYMUS (T cells) and BONE MARROW (B cells)     │
│     - Immature lymphocytes that strongly recognize SELF        │
│       antigens → CLONAL DELETION (apoptosis)                   │
│     - B cells may undergo RECEPTOR EDITING to avoid            │
│       self-reactivity                                          │
│                                                                │
│  2. PERIPHERAL TOLERANCE                                       │
│     - Mature lymphocytes in peripheral tissues                 │
│     - Mechanisms:                                              │
│       a) ANERGY: T cells recognize self antigen without        │
│          costimulation → become unresponsive                   │
│       b) REGULATORY T CELLS (Tregs): CD4+CD25+ T cells        │
│          suppress self-reactive lymphocytes via IL-10, TGF-β  │
│       c) ACTIVATION-INDUCED CELL DEATH (AICD):                │
│          Fas-FasL interaction → apoptosis of activated cells   │
│       d) INHIBITORY RECEPTORS: CTLA-4 and PD-1 on T cells      │
│          deliver inhibitory signals                            │
└────────────────────────────────────────────────────────────────┘

Pathogenesis of Autoimmunity

Factors Leading to Breakdown of Tolerance:

1. Genetic Factors

Strong association with HLA genes (particularly HLA-DR, HLA-DQ)
HLA-DR3, DR4 → Type 1 DM, RA
HLA-DR2 → SLE, MS, Goodpasture syndrome
Non-HLA genes: PTPN22, CTLA4, NOD2 mutations

2. Infections (Environmental Triggers)

Role of infections in autoimmunity - molecular mimicry and costimulatory molecule induction

Fig. from Robbins: Role of infections in autoimmunity - (A) Induction of costimulators on APCs; (B) Molecular mimicry

Two key mechanisms by which infections trigger autoimmunity:

a) Induction of Costimulators on APCs:

Microbes activate APCs → express B7 costimulatory molecules
Self-reactive T cells (normally anergic) now receive both Signal 1 (antigen) AND Signal 2 (costimulation)
Result: Self-reactive T cell activation → autoimmunity

b) Molecular Mimicry:

Microbial antigens structurally resemble self antigens
T/B cells activated against microbe cross-react with self antigens
Example: Rheumatic fever - Streptococcal M protein mimics cardiac myosin → cardiac damage

3. Other Mechanisms

Mechanism	Explanation
Release of sequestered antigens	Normally "hidden" antigens (lens, sperm, myelin) exposed after injury → autoimmune response
Polyclonal B-cell activation	Certain microbes (EBV, LPS) activate many B-cell clones nonspecifically including autoreactive ones
Epitope spreading	Immune response spreads from original antigen to other self epitopes in same tissue
Sex hormones	Autoimmune diseases more common in females; estrogen may promote antibody production
Regulatory T-cell defects	Defects in Tregs (FOXP3 mutations → IPEX syndrome) allow self-reactive lymphocytes to escape control

Mechanisms of Tissue Damage in Autoimmune Disease

┌─────────────────────────────────────────────────────────────────┐
│         EFFECTOR MECHANISMS OF AUTOIMMUNE TISSUE DAMAGE         │
│                                                                 │
│  1. AUTOANTIBODIES (Humoural)                                   │
│     a) Direct cell damage: Anti-RBC (hemolytic anemia)          │
│        Anti-platelet (ITP)                                      │
│     b) Complement activation: Anti-GBM (Goodpasture's)          │
│     c) Receptor stimulation: TSH-receptor Ab (Graves' disease)  │
│     d) Receptor blockade: AChR-Ab (Myasthenia gravis)           │
│     e) Immune complex deposition: Anti-dsDNA (SLE)              │
│                                                                 │
│  2. T CELL-MEDIATED DAMAGE                                      │
│     - CD4+ Th1: Cytokines → macrophage activation               │
│       → granulomatous inflammation                              │
│     - CD8+ CTL: Direct cytotoxicity of self cells               │
│       Examples: T1DM (islet β-cell destruction)                 │
│                 Multiple sclerosis (myelin damage)              │
└─────────────────────────────────────────────────────────────────┘

TOPIC 5: NEOPLASMS IN PATIENTS WITH HIV INFECTION

AIDS-Defining Neoplasms (from Robbins Table 6.16)

The three AIDS-defining neoplasms are:

1. Kaposi Sarcoma (KS) ⭐⭐⭐

Etiology: HHV-8 (Human Herpesvirus 8 / Kaposi sarcoma-associated herpesvirus)
Most common AIDS-defining malignancy
Types:
- Classic KS (elderly Eastern European men)
- Endemic KS (Africa)
- Epidemic/AIDS-related KS (most aggressive)
- Transplant-associated KS
Morphology:
- Gross: Multiple purplish-red skin lesions (macules, plaques, nodules); also in oral mucosa, GI tract, lymph nodes, lungs
- Histology: Proliferating spindle cells (endothelial/perivascular cell origin), slit-like vascular spaces, red blood cells extravasating into spaces, chronic inflammatory infiltrate
CD4 count: Can occur even at >200 cells/μL, but more aggressive at lower counts

2. Non-Hodgkin Lymphoma (NHL) - Primary CNS Lymphoma ⭐⭐

Etiology: EBV-associated
Primary CNS lymphoma is AIDS-defining
Also peripheral high-grade B-cell NHL (Burkitt's lymphoma)
Histology: Large B-cell lymphoma with EBV-positive cells; CNS involvement
CD4 count: Usually <50 cells/μL for CNS lymphoma

3. Invasive Cancer of the Uterine Cervix ⭐

Etiology: HPV (Human Papillomavirus) - high-risk types 16, 18
Loss of cell-mediated immunity → HPV persists → cervical dysplasia → invasive carcinoma
Regular Pap smears mandatory in HIV-positive women

Other Malignancies Seen in HIV (Not Strictly AIDS-defining but High Yield)

Malignancy	Association
Hodgkin Lymphoma	EBV-related; increased incidence in HIV
Anal carcinoma	HPV 16/18
Hepatocellular carcinoma	Hepatitis B/C co-infection
Lung cancer	Increased risk (smoking + immunosuppression)
Burkitt's lymphoma	EBV; c-MYC translocation

TOPIC 6: AIDS - ETIOLOGY, ROUTES OF TRANSMISSION, NATURAL HISTORY, DIAGNOSIS

Definition

AIDS (Acquired Immunodeficiency Syndrome) is the end-stage of HIV infection, defined by the CDC as:

CD4+ T cell count < 200 cells/μL OR
CD4+ T cell percentage < 14% of total lymphocytes OR
Presence of an AIDS-defining condition (opportunistic infection or malignancy)

Etiology

┌─────────────────────────────────────────────────────────────────┐
│                     HIV - ETIOLOGY                              │
│                                                                 │
│  Virus: Human Immunodeficiency Virus (HIV)                      │
│  Family: RETROVIRIDAE                                           │
│  Genus: LENTIVIRUS                                              │
│                                                                 │
│  Two Types:                                                     │
│  HIV-1: Major global pandemic type (more virulent)              │
│  HIV-2: Mainly West Africa; less virulent; slower progression   │
│                                                                 │
│  STRUCTURE (important for exam):                                │
│  ┌──────────────────────────────────────┐                       │
│  │  Envelope (gp120 + gp41)             │                       │
│  │  → gp120: binds CD4 receptor         │                       │
│  │  → gp41: fusion with host cell       │                       │
│  │  Matrix protein: p17                 │                       │
│  │  Core (capsid): p24 [marker!]        │                       │
│  │  Genome: 2 copies ssRNA (diploid)    │                       │
│  │  Enzymes: Reverse transcriptase (RT) │                       │
│  │           Integrase                  │                       │
│  │           Protease                   │                       │
│  └──────────────────────────────────────┘                       │
│                                                                 │
│  HIV infects: CD4+ T cells (PRIMARY TARGET), macrophages,       │
│              dendritic cells, microglia (CNS)                   │
│  Coreceptors: CCR5 (early - macrophage tropic R5 strain)        │
│               CXCR4 (late - T-tropic X4 strain)                 │
└─────────────────────────────────────────────────────────────────┘

Routes of Transmission

┌──────────────────────────────────────────────────────────────────┐
│                   ROUTES OF HIV TRANSMISSION                     │
│                                                                  │
│  1. SEXUAL TRANSMISSION (Most common worldwide - 75-85%)         │
│     - Heterosexual (most common in Africa/Asia)                  │
│     - Homosexual/MSM (most common in developed countries)        │
│     - Receptive partner at higher risk                           │
│     - STIs (ulcerative) increase transmission risk               │
│                                                                  │
│  2. PARENTERAL (Blood-borne)                                     │
│     - IV drug users sharing needles                              │
│     - Blood transfusion (now rare with screening)                │
│     - Needle-stick injuries in healthcare workers                │
│       (risk ~0.3% per exposure)                                  │
│     - Clotting factor concentrates (hemophiliacs - pre-screening)│
│                                                                  │
│  3. VERTICAL (Mother to Child)                                   │
│     - Transplacental (antepartum) - 30-40%                       │
│     - Intrapartum (most common): during delivery - 50-60%        │
│     - Breast feeding (postpartum) - 10-20%                       │
│     - PMTCT (prevention): ART during pregnancy                   │
│                                                                  │
│  NOT transmitted by: casual contact, saliva, tears,              │
│  air-borne, insect vectors, food/water                           │
└──────────────────────────────────────────────────────────────────┘

Natural History / Phases of HIV Infection

╔══════════════════════════════════════════════════════════════════╗
║              NATURAL HISTORY OF HIV INFECTION                   ║
╠═════════════╦════════════╦════════════════════════════════════════╣
║  PHASE      ║  CD4 COUNT ║  FEATURES                             ║
╠═════════════╬════════════╬════════════════════════════════════════╣
║             ║            ║  - Flu-like illness (2-4 wks after    ║
║  PHASE 1:   ║  Initially ║    exposure)                          ║
║  ACUTE HIV  ║  drops,    ║  - Fever, lymphadenopathy, pharyngitis║
║  SYNDROME   ║  then rises║  - Maculopapular rash                 ║
║  (Acute     ║            ║  - High viral load, low CD4           ║
║  Serocon-   ║  >500      ║  - CD8+ T cell response controls      ║
║  version)   ║            ║    viremia temporarily                ║
║  (2-4 wks)  ║            ║  - Window period: 2-18 weeks          ║
╠═════════════╬════════════╬════════════════════════════════════════╣
║  PHASE 2:   ║            ║  - Clinically asymptomatic            ║
║  CHRONIC    ║  200-500   ║  - Low-level viral replication        ║
║  ASYMPTO-   ║  (declining║  - HIV harbored in lymph nodes         ║
║  MATIC      ║  slowly)   ║  - Duration: 7-10 years average       ║
║  PHASE      ║            ║  - Minor: oral thrush, herpes zoster  ║
║             ║            ║  - PGL (persistent generalized        ║
║             ║            ║    lymphadenopathy)                   ║
╠═════════════╬════════════╬════════════════════════════════════════╣
║  PHASE 3:   ║            ║  - AIDS-defining conditions appear    ║
║  AIDS       ║  < 200     ║  - Opportunistic infections           ║
║  (Final     ║  (crashes)  ║  - AIDS-defining neoplasms           ║
║  Stage)     ║            ║  - Wasting syndrome                   ║
║             ║            ║  - HIV encephalopathy/dementia        ║
╚═════════════╩════════════╩════════════════════════════════════════╝

CD4 Count and Corresponding Complications:

CD4 Count	Complications
> 500	Acute HIV syndrome; PGL
200-500	TB, oral candidiasis, herpes zoster, skin infections
100-200	PCP (Pneumocystis pneumonia), toxoplasmosis, cryptosporidiosis
50-100	CMV retinitis, Cryptococcal meningitis, disseminated MAC
< 50	Primary CNS lymphoma, CMV end-organ disease, disseminated MAC

Diagnosis of HIV

┌──────────────────────────────────────────────────────────────────┐
│                     DIAGNOSIS OF HIV                             │
│                                                                  │
│  1. SCREENING TEST (Initial)                                     │
│     ELISA (Enzyme-Linked Immunosorbent Assay)                    │
│     - Detects HIV antibodies (anti-HIV IgG/IgM)                  │
│     - Highly SENSITIVE (>99.5%) but less specific                │
│     - Window period: 3-12 weeks (Ab seroconversion)              │
│     - 4th generation ELISA: detects p24 antigen + antibodies     │
│       (reduces window period)                                    │
│                                                                  │
│  2. CONFIRMATORY TEST                                            │
│     WESTERN BLOT                                                 │
│     - Detects antibodies to specific HIV proteins                │
│     - Positive: bands for gp41, gp120, gp160, p24, p31          │
│     - Highly SPECIFIC                                            │
│     - Required criteria: ≥2 of gp41, gp120/gp160, p24           │
│                                                                  │
│  3. VIROLOGICAL TESTS (Diagnosis + Monitoring)                   │
│     HIV RNA PCR (Viral Load)                                     │
│     - Detects HIV RNA (viral load)                               │
│     - Most sensitive for early/acute infection                   │
│     - Used for monitoring treatment response                     │
│     - Guides ART initiation                                      │
│                                                                  │
│  4. CD4+ T CELL COUNT                                            │
│     - Defines stage of disease                                   │
│     - Guides prophylaxis decisions                               │
│     - Monitors immune reconstitution on ART                      │
│                                                                  │
│  5. p24 ANTIGEN TEST                                             │
│     - Detects p24 core antigen                                   │
│     - Useful in window period before antibodies appear           │
│                                                                  │
│  6. RAPID HIV TESTS                                              │
│     - Point-of-care tests, results in 20-30 minutes              │
│     - Blood/oral fluid                                           │
│     - Still require confirmatory testing if positive             │
│                                                                  │
│  FOR INFANTS (<18 months) of HIV+ mothers:                       │
│  - Use HIV DNA PCR (not antibody tests - maternal IgG             │
│    crosses placenta and gives false positives)                   │
└──────────────────────────────────────────────────────────────────┘

Algorithm for HIV Diagnosis (NACO/WHO):

  Suspected HIV
       ↓
  ELISA (Screening) → NEGATIVE = Not infected (if no window period)
       ↓ POSITIVE
  Repeat ELISA (Different kit)
       ↓ POSITIVE
  Western Blot (Confirmatory)
       ↓ POSITIVE
  CONFIRMED HIV INFECTION
       ↓
  CD4 count + Viral load → Staging and treatment decisions

CDC Classification of HIV (1993)

Clinical Category	CD4 ≥500 (Cat 1)	CD4 200-499 (Cat 2)	CD4 <200 (Cat 3)
A: Asymptomatic/PGL	A1	A2	A3
B: Symptomatic (not A or C)	B1	B2	B3
C: AIDS-indicator conditions	C1	C2	C3

AIDS = Any Category 3 (CD4 <200) OR Any Category C condition

KEY MNEMONICS FOR EXAM

Hypersensitivity Types - "ACID":

Anaphylactic (Type I - IgE)
Cytotoxic (Type II - IgG/IgM)
Immune complex (Type III)
Delayed/DTH (Type IV - T cell)

Amyloid stains - "Congo Crystal Thioflavin":

Congo red → Apple green birefringence (under polarized light)
Crystal violet → Metachromasia (purple → pink/rose)
Thioflavin T → Yellow-green fluorescence

AIDS-defining neoplasms:

Kaposi sarcoma (HHV-8)
Lymphoma - Primary CNS (EBV)
Cervical carcinoma - Invasive (HPV)

HIV structure: "RT with p24 core and gp120/41 envelope"

QUICK SUMMARY TABLE FOR VIVA/EXAM

Topic	Key Points
Type I HS	IgE-mediated; mast cells; histamine; anaphylaxis/atopy
Amyloid stain	Congo red → apple-green birefringence under polarized light
Sago spleen	Amyloid in white pulp; tapioca-like nodules
Lardaceous spleen	Amyloid in red pulp; homogeneous waxy enlargement
Autoimmunity	Failure of tolerance; genetic + environmental; HLA associations
AIDS neoplasms	KS (HHV-8), CNS lymphoma (EBV), cervical cancer (HPV)
HIV CD4 <200	AIDS definition; PCP, CMV, lymphoma
HIV diagnosis	ELISA screening → Western blot confirmation → HIV RNA PCR

Sources: Robbins, Cotran & Kumar Pathologic Basis of Disease (10th ed., 9780443264528); Jawetz, Melnick & Adelberg's Medical Microbiology 28E; Cellular and Molecular Immunology (Abbas, Lichtman & Pillai); supplemented with Harsh Mohan Pathology concepts. All content MUHS 2nd MBBS exam-oriented.

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