# DNB General Medicine — Paper 2: Model Answers

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## Q1. Generalized Lymphadenopathy / Hodgkin's Lymphoma

### a) Differential Diagnosis & Approach to Generalized Lymphadenopathy

**Definition:** Enlarged nodes (>1 cm) in ≥2 non-contiguous regions.

**Causes (Mnemonic: MIAMI):**
- **Malignant:** Hodgkin lymphoma, Non-Hodgkin lymphoma, CLL, ALL, metastatic carcinoma
- **Infections:** EBV, CMV, HIV, TB, toxoplasmosis, secondary syphilis, brucellosis
- **Autoimmune:** SLE, RA, sarcoidosis, serum sickness
- **Metabolic:** Hyperthyroidism, Gaucher's disease
- **Iatrogenic/Drugs:** Phenytoin, allopurinol, isoniazid

**Approach:**
- **History:** Duration, fever, night sweats, weight loss (B symptoms), travel, drug, sexual history
- **Examination:** Node size, consistency (rubbery = lymphoma; hard = metastasis; tender = infection), hepatosplenomegaly, rash
- **Investigations:**
  - CBC, peripheral smear, ESR, LDH, uric acid
  - HIV ELISA, Monospot, ANA, VDRL
  - Chest X-ray / CT scan
  - Lymph node excisional biopsy (histopathology + IHC + flow cytometry)
  - Bone marrow biopsy if hematologic malignancy suspected

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### b) Differences Between Hodgkin's (HL) and Non-Hodgkin's Lymphoma (NHL)

| Feature | Hodgkin's Lymphoma | Non-Hodgkin's Lymphoma |
|---|---|---|
| Cell of origin | Reed-Sternberg cells (B-cell) | B-cell (85%), T-cell (15%) |
| Age | Bimodal (15–35, >55 yrs) | Any age |
| Spread | Contiguous (predictable) | Non-contiguous |
| Mediastinal nodes | Common (>50%) | Less common |
| Extranodal involvement | Rare | Common (GI, CNS, bone marrow) |
| Bone marrow | Rarely involved | Frequently involved |
| Waldeyer's ring | Rare | Commonly involved |
| Histology | RS cells (CD15+, CD30+) | Diverse subtypes |
| Prognosis | Better (~80% cure) | Variable |
| Staging tool | Ann Arbor | Ann Arbor + IPI score |

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### c) WHO Classification of Hodgkin's Lymphoma

**1. Classical HL (95%)** — RS cells CD15+, CD30+:
- **Nodular Sclerosis (NS-HL):** Most common (60–70%); young women; collagen bands; mediastinal mass
- **Mixed Cellularity (MC-HL):** 20–25%; older males; EBV-associated
- **Lymphocyte-Rich (LR-HL):** ~5%; best prognosis
- **Lymphocyte-Depleted (LD-HL):** <1%; worst prognosis; elderly/HIV

**2. Nodular Lymphocyte-Predominant HL (NLPHL) (5%):**
- "Popcorn" (L&H) cells; CD20+, CD15−, CD30−; EBV negative; indolent

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## Q2. Azotemia & Polyuria

### a) Causes of Azotemia

**PRERENAL** (BUN:Cr >20:1; FENa <1%):
- Hypovolemia: vomiting, diarrhea, hemorrhage, burns
- Reduced cardiac output: CHF, cirrhosis, nephrotic syndrome
- Drugs: NSAIDs, ACE inhibitors, ARBs

**INTRINSIC RENAL** (BUN:Cr ≈10:1; FENa >2%):
- *Glomerular:* Acute GN, vasculitis, RPGN
- *Tubular (ATN):* Ischemic or nephrotoxic (aminoglycosides, contrast, rhabdomyolysis)
- *Interstitial:* Drug-induced AIN (NSAIDs, PPIs, penicillins), leptospirosis
- *Vascular:* HUS/TTP, malignant hypertension, cholesterol emboli

**POSTRENAL** (bilateral obstruction needed):
- Ureteral: stones, retroperitoneal fibrosis, pelvic malignancy
- Bladder neck: BPH, prostate/cervical cancer, neurogenic bladder

**Chronic causes:** Diabetic nephropathy, hypertensive nephrosclerosis, CKD (polycystic kidney, chronic GN)

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### b) Diagnostic Approach to Polyuria

**Definition:** Urine output >3 L/day.

**Step 1:** 24-hour urine to confirm true polyuria.

**Step 2 — Urine osmolality:**
- Uosm >700 → **Solute/osmotic diuresis** (DM, mannitol, high-protein feeds)
- Uosm <300 → **Water diuresis** → proceed to Step 3

**Step 3 — Water Deprivation Test (Miller-Moses):**
Withhold water until Uosm plateaus → give DDAVP 2 mcg IM

| Response | Diagnosis |
|---|---|
| Uosm rises >50% after DDAVP | Central DI |
| Minimal response to DDAVP (<10%) | Nephrogenic DI |
| Uosm rises >500 before DDAVP, minimal further rise | Primary polydipsia |

**Causes Summary:**
- **Central DI:** Trauma, neurosurgery, craniopharyngioma, sarcoidosis, autoimmune, idiopathic
- **Nephrogenic DI:** Lithium, hypercalcemia, hypokalemia, CKD, genetic (V2R mutation)
- **Primary polydipsia:** Psychogenic, hypothalamic lesion

**Additional:** MRI brain (absent posterior pituitary bright spot on T1 in central DI), serum ADH levels.

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## Q3. Syncope: Etiology & Evaluation

### Etiology

**1. Reflex (Neurally Mediated) ~40%:**
- Vasovagal: emotional stress, pain, prolonged standing; prodrome of pallor/nausea
- Situational: cough, micturition, swallowing
- Carotid sinus syndrome: elderly, triggered by neck rotation

**2. Orthostatic Hypotension ~10%:**
- Autonomic failure (Parkinson's, MSA), diabetes, amyloidosis
- Drugs: antihypertensives, diuretics, nitrates, TCAs
- Volume depletion: hemorrhage, Addison's

**3. Cardiac ~15% (highest mortality risk):**
- *Arrhythmic:* SSS, AV block, VT/VF, long QT (Romano-Ward, Jervell-Lange-Nielsen), Brugada, WPW
- *Structural:* Severe AS, HOCM, cardiac tamponade, PE, pulmonary hypertension, atrial myxoma

**4. Cerebrovascular (<5%):** Vertebrobasilar TIA

**5. Psychogenic:** Pseudosyncope (no true LOC)

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### Evaluation

- **History & Exam (most important):** Prodrome, posture, triggers, witnesses, medications, family history SCD; orthostatic BP measurement; carotid sinus massage (age >40)
- **12-lead ECG:** Mandatory in all — AV block, BBB, long QT, delta wave, Brugada pattern
- **Echocardiogram:** Structural heart disease (AS, HOCM)
- **Holter/Event recorder:** Suspected arrhythmia; implantable loop recorder (ILR) for infrequent episodes
- **Tilt-table test:** Suspected vasovagal/orthostatic
- **EP study:** High-risk cardiac (wide QRS, structural disease, suspected VT)
- **Blood tests:** CBC, glucose, electrolytes, troponin, BNP
- **CT/MRI brain:** Only if neurological signs present (not routine)

**Risk stratification:** ROSE rule, San Francisco Syncope Rule, EGSYS score.

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## Q4. Peripheral Neuropathy & NCS

### a) Clinical Features & Evaluation

**Motor:** Distal weakness, wasting, foot/wrist drop, hyporeflexia/areflexia

**Sensory:** Tingling, burning, allodynia (positive); numbness, sensory ataxia (negative)

**Autonomic:** Postural hypotension, gastroparesis, bladder dysfunction, anhidrosis

**Patterns:**
- Symmetric distal (stocking-glove): DM, alcohol, nutritional
- Mononeuropathy: Compression (CTS), trauma
- Mononeuritis multiplex: Vasculitis, DM, leprosy
- Polyradiculopathy: GBS, CIDP

**Common Causes:** DM, alcohol, B12/B1 deficiency, uremia, hypothyroidism, GBS, CIDP, leprosy, HIV, drugs (vincristine, isoniazid), hereditary (CMT), vasculitis, paraproteinemia

**Evaluation:**
- Blood: FBC, glucose/HbA1c, renal/LFTs, TFTs, B12, SPEP, ANA, ANCA, HIV, VDRL
- NCS + EMG (key diagnostic test)
- CSF: Albumino-cytological dissociation (GBS/CIDP)
- Nerve biopsy (sural): Vasculitis, amyloid, leprosy
- Genetic testing: PMP22 (CMT1A)

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### b) Nerve Conduction Study (NCS)

**Parameters Measured:**

| Parameter | Reflects |
|---|---|
| Conduction velocity (CV) | Myelination |
| Amplitude (CMAP/SNAP) | Axon number |
| Distal latency | Terminal myelination |
| F-wave | Proximal conduction |
| H-reflex | S1 pathway (Achilles reflex equivalent) |

**Axonal vs. Demyelinating Pattern:**

| Feature | Axonal | Demyelinating |
|---|---|---|
| Amplitude | ↓↓ | Normal/mildly reduced |
| Conduction velocity | Normal/mildly reduced | Markedly reduced (<75% LLN) |
| Distal latency | Normal/mild prolongation | Prolonged (>130% ULN) |
| Conduction block | Absent | Present (>50% amplitude drop) |
| Temporal dispersion | Absent | Present |
| Examples | DM, alcohol, uremia | GBS, CIDP, CMT1 |

**Applications:** Characterize neuropathy, localize entrapment (CTS: prolonged median distal latency), monitor progression, differentiate from radiculopathy/plexopathy.

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## Q5. Antiphospholipid Syndrome (APS)

### a) Definition & Types of aPL Antibodies

**APS:** Autoimmune thrombophilic disorder with recurrent arterial/venous thrombosis and/or pregnancy morbidity in the presence of persistently positive antiphospholipid antibodies.

**Types:**
1. **Lupus anticoagulant (LA)** — clotting assay (dRVVT); strongest predictor of thrombosis
2. **Anticardiolipin antibodies (aCL)** — IgG, IgM, IgA; ELISA
3. **Anti-β2 glycoprotein I (anti-β2GPI)** — IgG, IgM, IgA; most specific
4. **Non-criteria:** Antiphosphatidylserine, antiprothrombin antibodies

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### b) Pathogenesis, Diagnostic Criteria & Management

**Pathogenesis:**
- aPL target β2GPI → bind endothelial cells → NF-κB → tissue factor → procoagulant state
- Platelet activation via GPIb → thromboxane A2 → thrombosis
- Complement activation (C3, C5a) → trophoblast injury → pregnancy loss
- Inhibit annexin A5, protein C/S → disrupted anticoagulation
- **Two-hit hypothesis:** aPL = first hit; trigger (pregnancy, surgery, infection) = second hit

**Revised Sapporo/Sydney Criteria (≥1 clinical + ≥1 lab, 12 weeks apart):**

*Clinical:*
1. Arterial/venous/small vessel thrombosis
2. Pregnancy morbidity: ≥1 fetal death ≥10 weeks; ≥1 premature birth <34 weeks (eclampsia/placental insufficiency); ≥3 consecutive abortions <10 weeks

*Laboratory (moderate-high titer):*
1. Lupus anticoagulant (ISTH criteria)
2. aCL IgG/IgM (>40 GPL/MPL or >99th percentile)
3. Anti-β2GPI IgG/IgM (>99th percentile)

**Management:**
- **Primary prevention (no thrombosis):** Low-dose aspirin ± hydroxychloroquine (SLE-APS)
- **Venous thrombosis:** Warfarin (INR 2–3) — indefinite; DOACs inferior (TRAPS trial)
- **Arterial thrombosis:** Warfarin INR 2–3 ± aspirin
- **Obstetric APS:** LMWH + low-dose aspirin throughout pregnancy
- **Catastrophic APS (CAPS):** Anticoagulation + high-dose steroids + plasma exchange or IVIG; eculizumab for refractory disease

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## Q6. Podocyte Injury & Nephrotic Syndrome

### a) Structural & Molecular Basis of Podocyte Injury

**Podocyte anatomy:** Cell body → primary processes → foot processes (pedicels) → **slit diaphragm (SD)** between foot processes.

**Key SD proteins & mutations:**

| Protein | Gene | Mutation → Disease |
|---|---|---|
| Nephrin | NPHS1 | Congenital NS of Finnish type |
| Podocin | NPHS2 | Familial FSGS (AR) |
| CD2AP | CD2AP | FSGS |
| TRPC6 | TRPC6 | Familial FSGS (AD) |
| α-actinin-4 | ACTN4 | Familial FSGS (AD) |
| WT1 | WT1 | Denys-Drash, Frasier syndrome |

**Mechanisms of Injury:**
1. **Foot process effacement (FPE):** SD protein loss (nephrin downregulation) → actin cytoskeletal reorganization → proteinuria (hallmark on EM)
2. **MCD:** T-cell dysfunction → circulating permeability factor (suPAR, CD80) → FPE
3. **FSGS:** suPAR → β3-integrin activation → FPE; APOL1 variants (G1/G2) in African patients → rapid progression
4. **MN:** Anti-PLA2R antibodies (70–80%) → subepithelial immune complexes → C5b-9 (MAC) → podocyte mitochondrial damage → proteinuria
5. **Podocyte depletion:** Limited regenerative capacity; detached podocytes → bare GBM → segmental sclerosis (FSGS)

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### b) Prognostic & Therapeutic Implications of Podocytopathies

**Prognosis:**
- **MCD:** Excellent; >80% steroid remission; risk of frequent relapse
- **FSGS:** Tip variant → good; Collapsing FSGS → worst; APOL1 G1/G2 → rapid progression
- **MN:** Anti-PLA2R titer predicts remission; 1/3 spontaneous remission, 1/3 stable, 1/3 progressive
- **Genetic FSGS (NPHS2):** Steroid-resistant; early renal failure; low transplant recurrence risk

**Treatment:**
- **MCD:** Prednisolone 1 mg/kg/day × 8–16 weeks; relapsers: cyclophosphamide or CNI; Rituximab for frequent relapsers
- **FSGS:** Steroid-resistant → cyclosporine ± prednisolone; Genetic FSGS: RAAS blockade, avoid steroids
- **MN:** Low-risk → conservative (RAAS blockade); Medium/high-risk → Rituximab (first-line, MENTOR trial) or Ponticelli regimen (CYC + steroids)
- **All:** ACEi/ARB, BP target <125/75, statins, anticoagulation if albumin <2.5 g/dL

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## Q7. Leptospirosis

### a) Etiopathogenesis & Clinical Features

**Organism:** Leptospira interrogans — Gram-negative spirochete with hooked ends; zoonosis (rodents = primary reservoir)

**Transmission:** Skin abrasions/mucous membranes via water/soil contaminated with animal urine; occupational (farmers, sewage workers); outbreaks after floods

**Pathogenesis:**
1. Entry → leptospiremia (1st week) → hematogenous spread
2. LPS + pore-forming toxins → endothelial injury → vasculitis
3. Liver: hepatocellular damage + cholestasis
4. Kidney: tubulointerstitial nephritis → AKI, hypokalemia
5. Lungs: alveolar hemorrhage/ARDS (commonest cause of death)
6. Muscle: myositis → elevated CK, calf pain
7. Immune phase (2nd week): antibody production → uveitis (late)

**Clinical Features — Biphasic illness:**

*Phase 1 (Days 1–7 — Leptospiremic):*
- Abrupt fever, rigors, severe headache
- **Conjunctival suffusion** (pathognomonic — non-purulent bilateral injection)
- Myalgia (calf muscles characteristic), nausea, vomiting

*Phase 2 (Days 7–21 — Immune):*
- Brief improvement → fever recurrence ("saddle-back")
- Aseptic meningitis, uveitis (can appear weeks later)

*Severe — Weil's Syndrome (10%):*
- **Jaundice + AKI + Bleeding** (classic triad)
- Pulmonary hemorrhage syndrome (life-threatening)
- Thrombocytopenia, myocarditis

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### b) Faine's Criteria (Modified — Scoring System)

| Feature | Score |
|---|---|
| Conjunctival suffusion | 4 |
| Meningism | 4 |
| Muscle pain/calf tenderness | 4 |
| Fever | 2 |
| Headache | 2 |
| Jaundice | 1 |
| Oliguria | 2 |
| Flood/water exposure | 5 |
| Occupational exposure | 5 |
| Animal contact | 1 |
| Positive MAT serology | 15–25 |

**Interpretation:**
- Parts A+B score ≥26: Probable leptospirosis → treat
- With serology (Part C): Confirmed

**Gold standard serology:** MAT (Microscopic Agglutination Test) — ≥4-fold rise or single titer ≥1:400 in endemic areas.

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### c) Management

| Severity | Drug | Dose/Duration |
|---|---|---|
| Mild | Doxycycline PO | 100 mg BD × 7 days |
| | Amoxicillin PO | 500 mg 6-hourly × 7 days |
| Moderate-Severe | Benzylpenicillin IV | 1.5 MU 6-hourly × 7 days |
| | Ceftriaxone IV | 1 g daily × 7 days |

**Complications:**
- AKI: IV fluids; hemodialysis/PD if oliguric
- Pulmonary hemorrhage: Mechanical ventilation; methylprednisolone 500 mg IV × 3 days
- Uveitis: Topical steroids + mydriatics

**Prophylaxis:** Doxycycline 200 mg once weekly (high-risk exposure).

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## Q8. Spondyloarthritis & Ankylosing Spondylitis

### a) Diseases Under Spondyloarthritis (SpA)

**Axial SpA:**
- Ankylosing spondylitis (AS) — radiographic axSpA
- Non-radiographic axial SpA (nr-axSpA)

**Peripheral SpA:**
- Psoriatic arthritis (PsA)
- Reactive arthritis (ReA) — post-Chlamydia, Salmonella, Shigella
- Enteropathic arthritis (IBD-associated — UC, Crohn's)
- Undifferentiated SpA
- Juvenile SpA (Enthesitis-related arthritis)

**Shared features:** Sacroiliitis, asymmetric oligoarthritis, enthesitis, dactylitis, uveitis, HLA-B27 association, seronegative (RF negative)

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### b) Role of HLA-B27 in Pathogenesis

1. **Misfolding/UPR hypothesis (most favored):** HLA-B27 heavy chains misfold → accumulate in ER → Unfolded Protein Response → NF-κB → TNF-α, IL-17 → inflammation
2. **Arthritogenic peptide:** B27 presents self/bacterial peptides (molecular mimicry) → CD8+ T-cell attack on joints
3. **B27 homodimers:** Free heavy chains on cell surface → bind KIR3DL2 (NK receptors) → IL-17 production
4. **IL-23/IL-17 axis:** Central to SpA; B27 drives IL-23 → Th17 → IL-17A → entheseal inflammation, syndesmophyte formation
5. **Gut-joint axis:** Dysbiosis → leaky gut → LPS → innate immune activation → SpA

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### c) Diagnosis & Management of Ankylosing Spondylitis

**Modified New York Criteria (radiographic AS):**
- Sacroiliitis grade ≥2 bilateral or grade 3–4 unilateral on X-ray
- PLUS ≥1: Low back pain >3 months (improves with exercise, not rest); limited lumbar motion; reduced chest expansion (<2.5 cm)

**ASAS Criteria (2009 — includes nr-axSpA):**
- Back pain ≥3 months + age <45 years
- Imaging arm: Sacroiliitis (X-ray or MRI) + ≥1 SpA feature
- Clinical arm: HLA-B27 + ≥2 SpA features

**Investigations:** HLA-B27, CRP/ESR, X-ray pelvis, MRI SI joints (STIR sequence — active inflammation), BASDAI/BASFI scores

---

**Management:**

**Non-pharmacological:** Physiotherapy + exercise (essential), smoking cessation

**Step 1 — NSAIDs (first-line):** Diclofenac, indomethacin, etoricoxib — continuous dosing; may slow radiographic progression

**Step 2 — Sulfasalazine:** Peripheral arthritis only (no axial benefit)

**Step 3 — Biologic/Targeted DMARDs** (BASDAI ≥4 + failure of ≥2 NSAIDs):

*TNF Inhibitors:*
| Drug | Dosing |
|---|---|
| Adalimumab | 40 mg SC every 2 weeks |
| Etanercept | 50 mg SC weekly |
| Infliximab | 5 mg/kg IV (0,2,6 wks → 8-weekly) |
| Golimumab | 50 mg SC monthly |
| Certolizumab pegol | 400 mg SC × 3 doses → 200 mg biweekly |

*IL-17A Inhibitors:*
| Drug | Notes |
|---|---|
| Secukinumab | 150–300 mg SC monthly; first IL-17i approved |
| Ixekizumab | 80 mg SC monthly |
| Bimekizumab | Anti-IL-17A+F; approved 2023 |

*JAK Inhibitors (oral):*
- Upadacitinib 15 mg OD, Tofacitinib — for biologic failures; avoid in high CV risk

**Pre-biologic screening:** TB (IGRA/Mantoux), Hepatitis B/C.

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## Q9. Systemic Vasculitis, ANCA-Vasculitis & GPA

### a) Classification of Systemic Vasculitis by Vessel Size (Chapel Hill 2012)

**Large Vessel:**
- Giant cell arteritis (GCA)
- Takayasu arteritis

**Medium Vessel:**
- Polyarteritis nodosa (PAN)
- Kawasaki disease

**Small Vessel — ANCA-associated (AAV):**
- Granulomatosis with polyangiitis (GPA) — c-ANCA/PR3-ANCA
- Microscopic polyangiitis (MPA) — p-ANCA/MPO-ANCA
- Eosinophilic GPA (EGPA/Churg-Strauss) — MPO-ANCA + eosinophilia

**Small Vessel — Immune complex:**
- Anti-GBM disease (Goodpasture's)
- Cryoglobulinemic vasculitis
- IgA vasculitis (Henoch-Schönlein)

**Variable Vessel:** Behçet's disease, Cogan's syndrome

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### b) Pathogenesis of ANCA-Associated Vasculitis

1. **Neutrophil priming:** Infection (S. aureus), C5a, TNF-α → PR3/MPO translocate to neutrophil surface
2. **ANCA binding:** IgG-ANCA binds surface PR3/MPO → Fc receptor cross-linking → neutrophil activation
3. **Degranulation:** ROS + proteases released → endothelial adhesion → fibrinoid necrosis (pauci-immune)
4. **NETs:** Neutrophil extracellular traps → endothelial damage; source of citrullinated antigens initiating autoimmunity
5. **Complement amplification:** C5a generated → C5aR on primed neutrophils → positive feedback loop (target of avacopan)
6. **Granuloma formation (GPA-specific):** M1 macrophages → multinucleated giant cells → necrotizing granulomatous inflammation
7. **T/B cell:** Th17 + Th1 drive granuloma; deficient T-regs → uncontrolled ANCA-producing B cells

---

### c) Diagnostic Evaluation & Treatment of GPA

**Clinical triad:** ENT + Lungs + Kidneys

- ENT: Sinusitis, nasal septal perforation, saddle-nose, subglottic stenosis, orbital pseudotumor
- Lungs: Nodules (cavitating), pulmonary hemorrhage, hemoptysis
- Kidneys: Rapidly progressive GN (pauci-immune crescentic GN), hematuria, AKI

**Investigations:**
- **c-ANCA/PR3-ANCA:** Sensitivity ~90% in severe GPA
- CBC, CRP/ESR, urine analysis (RBC casts), creatinine
- Complement normal (pauci-immune — distinguishes from SLE)
- **Chest CT:** Nodules ± cavitation ("cheerio sign"), ground-glass opacities
- **CT sinuses:** Bony destruction, pansinusitis
- **Kidney biopsy (gold standard):** Focal necrotizing pauci-immune crescentic GN
- **Lung biopsy:** Necrotizing granulomatous vasculitis (geographic necrosis + giant cells)

---

**Treatment:**

**Induction (organ-/life-threatening disease):**
- **Rituximab + high-dose corticosteroids** (first-line; RAVE trial)
  - RTX 375 mg/m² IV weekly × 4 doses; Prednisolone 1 mg/kg/day with taper
  - Superior to CYC for relapsing GPA and PR3-ANCA disease
- **Cyclophosphamide + corticosteroids** (alternative): IV pulse CYC preferred (less bladder toxicity)
- **Methylprednisolone pulses** (1 g IV × 3 days): Pulmonary hemorrhage, rapidly worsening renal function
- **Avacopan (C5aR1 inhibitor):** Approved 2021; replaces prednisolone → steroid-sparing (ADVOCATE trial)

**Maintenance (12–24 months after remission):**
- **Rituximab** 500 mg IV every 6 months (MAINRITSAN trial — superior to azathioprine)
- **Azathioprine** 2 mg/kg/day or **Methotrexate** (non-renal GPA): Alternatives after CYC-induced remission

**Monitoring:** PR3-ANCA titers (rise predicts relapse), eGFR, urine analysis, PCP prophylaxis (co-trimoxazole DS 3×/week).

---

## Q10. Epstein-Barr Virus (EBV) Infection

### a) Structure, Transmission & Pathogenesis

**Structure:**
- HHV-4, Gammaherpesvirinae; **double-stranded DNA virus** (~172 kb)
- Lipid envelope (gp350 binds CD21; gp42 binds HLA class II) → Icosahedral capsid (VCA proteins) → dsDNA core

**Viral Antigens:**
- VCA IgM → acute infection; VCA IgG → past infection; EBNA appears 3–6 weeks post-infection (persists lifelong)

**Transmission:**
- Saliva (primary — "kissing disease")
- Blood transfusion, organ transplantation (→ PTLD)
- Perinatal (rare); sexual transmission possible

**Pathogenesis:**
1. Oropharyngeal epithelial cell infection → lytic replication → viral shedding in saliva
2. B-cell infection via gp350/CD21 → EBV circularizes → latency
3. LMP1 (mimics CD40 → NF-κB → B-cell proliferation); LMP2A (mimics BCR → B-cell survival)
4. Massive CD8+ T-cell response → **atypical lymphocytes** (the "mononuclear" cells of IM)
5. Cytokine storm (TNF-α, IFN-γ) → fever, lymphadenopathy, splenomegaly, hepatitis
6. Long-term: EBV persists in resting memory B cells (Latency 0)

**Latency Programs:**

| Latency | Antigens | Disease |
|---|---|---|
| 0 | EBERs, miRNAs | Healthy carriers |
| I | EBNA1 | Burkitt lymphoma |
| II | EBNA1, LMP1, LMP2 | Hodgkin lymphoma, NPC |
| III | All EBNAs + LMPs | PTLD, immunocompromised |

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### b) Hematologic, Neurologic & Hepatic Complications

**Hematologic:**
1. **Hemolytic anemia** — Cold agglutinin (anti-i IgM); usually mild, self-limiting
2. **Thrombocytopenia** — Immune-mediated; rarely severe
3. **Aplastic anemia** — T-cell suppression of marrow; rare but life-threatening
4. **HLH (Hemophagocytic Lymphohistiocytosis)** — Fever, pancytopenia, hyperferritinemia, hypertriglyceridemia; fatal in XLP (SAP gene mutation) patients
5. **Agranulocytosis/Neutropenia** — EBV-mediated
6. **PTLD** — EBV-driven B-cell proliferation in transplant recipients; spectrum from polyclonal to monomorphic lymphoma (DLBCL); reduce immunosuppression ± rituximab
7. **Burkitt lymphoma** — t(8;14) c-MYC/IgH translocation; endemic form strongly EBV-associated
8. **Splenic rupture** — Rare; avoid contact sports for 4–6 weeks post-IM

**Neurologic:**
1. **Aseptic meningitis** — Lymphocytic pleocytosis; self-limiting
2. **Encephalitis** — Confusion, seizures; EBV PCR in CSF
3. **Guillain-Barré Syndrome (GBS)** — Post-infectious demyelinating polyneuropathy
4. **Cranial nerve palsies** — Bell's palsy (CN VII) most common
5. **Alice in Wonderland Syndrome** — Altered body perception (micropsia/macropsia)
6. **Acute cerebellar ataxia** — Children; post-infectious; usually self-limiting
7. **Transverse myelitis** — Paraplegia, sensory level, bladder dysfunction
8. **CNS lymphoma** — AIDS-related; EBV Latency III

**Hepatic:**
1. **Acute hepatitis** — Present in >80% of IM; elevated AST/ALT (2–10× ULN); usually anicteric
2. **Cholestatic hepatitis** — Conjugated hyperbilirubinemia; ~5% of IM; self-limiting
3. **Fulminant hepatic failure** — Rare (<0.5%); immunocompromised/XLP; may need transplant
4. **Granulomatous hepatitis** — Non-caseating granulomas; mimics sarcoidosis/TB
5. **HLH-associated hepatitis** — Hyperferritinemia, hepatosplenomegaly, hemophagocytosis on biopsy

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*— End of Answers —*