DNB General Medicine Paper 2 — Model Answers

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QUESTION 1

a) Differential Diagnosis and Approach to Generalized Lymphadenopathy [4]

• Node characteristics: size, consistency, tenderness, mobility, matting
• Firm/rubbery: lymphoma; Hard/fixed: metastatic; Tender: infection; Matted: TB/lymphoma
• Assess for hepatosplenomegaly, skin rash, joints, oral cavity

• CBC with differential: lymphocytosis (CLL, viral), atypical lymphocytes (EBV), pancytopenia
• Peripheral smear: blast cells, lymphoma cells
• ESR, CRP, LDH, uric acid
• Blood culture, Monospot test (EBV), HIV ELISA, Toxoplasma IgM, ANA/anti-dsDNA, VDRL
• Chest X-ray/CT scan (mediastinal nodes → lymphoma, sarcoidosis)
• Bone marrow biopsy (if hematologic malignancy suspected)
• Lymph node biopsy (excisional preferred for histopathology, IHC, flow cytometry)
• If TB suspected: Mantoux, IGRA, AFB culture, GeneXpert

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b) Differences between Hodgkin's Lymphoma (HL) and Non-Hodgkin's Lymphoma (NHL) [3]

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c) WHO Classification of Hodgkin's Lymphoma [3]

• Nodular sclerosis (NS-HL) — Most common (60–70%); young women; collagen bands; lacunar cells; mediastinal mass
• Mixed cellularity (MC-HL) — 20–25%; older males; RS cells amid mixed inflammatory infiltrate; EBV associated
• Lymphocyte-rich (LR-HL) — ~5%; best prognosis; few RS cells amid lymphocytes
• Lymphocyte-depleted (LD-HL) — <1%; worst prognosis; rare RS cells; elderly, HIV-associated

• Characterized by "popcorn" (lymphocytic/histiocytic, L&H) cells
• CD20+, CD15−, CD30−; EBV negative
• Indolent behavior; late relapses possible

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QUESTION 2

a) Enumerate Causes of Azotemia [5]

• Hypovolemia: vomiting, diarrhea, hemorrhage, burns
• Decreased effective arterial volume: CHF, liver cirrhosis (hepatorenal), nephrotic syndrome
• Drugs: NSAIDs (reduce renal prostaglandins), ACE inhibitors/ARBs (reduce efferent tone), calcineurin inhibitors
• Bilateral renal artery stenosis

• Acute glomerulonephritis (post-streptococcal, IgA nephropathy, RPGN)
• Vasculitis (ANCA-associated, lupus)

• Ischemic ATN (prolonged prerenal)
• Nephrotoxic ATN: aminoglycosides, contrast media, myoglobin (rhabdomyolysis), hemoglobin

• Acute interstitial nephritis (drugs: penicillins, NSAIDs, PPIs; infections: leptospirosis, hantavirus)

• Renal vein thrombosis, HUS/TTP, malignant hypertension, cholesterol emboli

• Ureteral obstruction: stones, retroperitoneal fibrosis, pelvic malignancy
• Bladder neck obstruction: BPH, prostate/cervical cancer, neurogenic bladder
• Urethral obstruction: stricture, phimosis

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b) Diagnostic Approach to the Patient with Polyuria [5]

• Hypernatremia/high osmolality → Diabetes Insipidus (DI) or primary polydipsia (PP)
• Normal/low osmolality with glucosuria → Diabetes mellitus

• Uosm >700 → Solute diuresis (osmotic); diabetes mellitus, mannitol, high-protein diet
• Uosm <300 → Water diuresis (hypotonic): DI or primary polydipsia

• Withhold water until Uosm plateaus (2 consecutive readings <30 mOsm/kg change) or >3% body weight loss
• Then give DDAVP (desmopressin) 2 mcg IV/IM
• Interpretation:
  • Central DI: Uosm <300 before DDAVP → rises >50% after DDAVP
  • Nephrogenic DI: Uosm low before and after DDAVP (<10% rise)
  • Primary Polydipsia: Uosm rises to >500 before DDAVP; minimal further rise after

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QUESTION 3

Etiology of Syncope and Evaluation of Syncope in Adults [5+5]

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Etiology of Syncope

• Vasovagal syncope: Emotional stress, pain, prolonged standing; preceded by pallor, nausea, diaphoresis
• Situational syncope: Cough, micturition, defecation, swallowing, post-exercise, valsalva
• Carotid sinus syndrome: Elderly; triggered by neck turning, tight collar

• Primary autonomic failure: Parkinson's, MSA, Lewy body dementia
• Secondary autonomic failure: Diabetes (autonomic neuropathy), amyloidosis, renal failure
• Drug-induced: Antihypertensives, diuretics, α-blockers, nitrates, tricyclics, dopamine agonists
• Volume depletion: Hemorrhage, dehydration, Addison's disease

• Bradyarrhythmias: Sick sinus syndrome, AV block (2nd/3rd degree), pacemaker malfunction
• Tachyarrhythmias: VT, VF, SVT with rapid rate; Long QT syndrome (drug-induced or congenital: Romano-Ward, Jervell-Lange-Nielsen); Brugada syndrome; WPW syndrome

• Obstructive: Severe aortic stenosis, HOCM, cardiac tamponade, pulmonary embolism, pulmonary hypertension
• Acute MI, atrial myxoma

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Evaluation of Syncope

• Prodrome (vasovagal), position at onset, activity, triggers, witnesses, recovery time, medications, family history (SCD in young → channelopathy)
• Orthostatic BP (lying/standing after 1, 3 minutes) → >20 mmHg systolic or >10 mmHg diastolic drop
• Cardiovascular examination: murmurs (AS, HOCM), carotid sinus massage (in >40 years)

• AV block, BBB, pre-excitation (delta wave = WPW), long QT, Brugada pattern, Q waves, LVH

• ROSE rule, San Francisco Syncope Rule, EGSYS score — predict 30-day serious outcome

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QUESTION 4

a) Clinical Features and Evaluation of Peripheral Neuropathy [5]

• Positive symptoms: Paresthesias (tingling, burning), dysesthesias, allodynia, neuropathic pain (lancinating, burning — worse at night)
• Negative symptoms: Numbness, loss of sensation, sensory ataxia (Romberg positive)

• Weakness (distal > proximal in length-dependent neuropathies)
• Wasting, foot drop, wrist drop
• Absent/reduced reflexes (areflexia)

• Symmetric distal (stocking-glove): Length-dependent; DM, alcohol, nutritional deficiencies
• Mononeuropathy: Single nerve; compression (CTS, ulnar), trauma, vasculitis
• Mononeuritis multiplex: Asymmetric, multiple nerves; vasculitis, DM, leprosy, sarcoidosis
• Polyradiculopathy: Guillain-Barré, CIDP
• Cranial neuropathies: DM, sarcoidosis, syphilis, vasculitis

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b) Nerve Conduction Study (NCS) [5]

1. Motor NCS: Stimulate nerve, record CMAP from muscle (e.g., median nerve → APB)
2. Sensory NCS: Stimulate digit, record SNAP (orthodromic) or vice versa (antidromic)
3. F-waves: Late response; assesses proximal nerve segments
4. H-reflex: Electrophysiological analog of Achilles tendon reflex

• Diagnose and characterize neuropathy type (axonal vs demyelinating, length-dependent vs non-length-dependent)
• Localize entrapment neuropathies (CTS: prolonged median distal motor latency)
• Monitor disease progression or response to treatment
• Differentiate polyneuropathy from radiculopathy or plexopathy
• Combined with EMG for complete peripheral nervous system evaluation

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QUESTION 5

a) Definition and Types of Antiphospholipid Antibodies [2]

1. Lupus anticoagulant (LA) — Detected by clotting assay (dRVVT, APTT mixing studies); paradoxically prolongs APTT but causes thrombosis in vivo; strongest predictor of thrombosis
2. Anticardiolipin antibodies (aCL) — IgG, IgM, IgA classes; IgG most significant; measured by ELISA
3. Anti-β2 glycoprotein I antibodies (anti-β2GPI) — IgG, IgM, IgA; β2GPI is the true autoantigen; IgG most specific
4. Others (non-criteria):
   • Antiphosphatidylserine antibodies
   • Antiprothrombin antibodies
   • Anti-phosphatidylethanolamine antibodies

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b) Pathogenesis, Diagnostic Criteria, and Management of APS [2+3+3]

1. Endothelial activation: aPL-β2GPI complexes bind endothelial cells → upregulate adhesion molecules (VCAM-1, ICAM-1) and tissue factor → procoagulant state
2. Platelet activation: aPL activate platelets via GPIb receptor → thromboxane A2 release → thrombosis
3. Complement activation: aPL activate complement (C3, C5a) → trophoblast injury → pregnancy loss
4. Inhibition of anticoagulant pathways: Inhibit annexin A5 (anticoagulant shield on trophoblasts), protein C/S activation, antithrombin activity
5. Two-hit hypothesis: aPL antibodies create a "prothrombotic state" (first hit); a second hit (infection, surgery, pregnancy, OCP) triggers clinical thrombosis

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1. Vascular thrombosis: ≥1 episode of arterial, venous, or small vessel thrombosis in any tissue/organ (confirmed by imaging or histopathology)
2. Pregnancy morbidity:
   • ≥1 unexplained fetal death at ≥10 weeks gestation
   • ≥1 premature birth at <34 weeks due to eclampsia/severe pre-eclampsia/placental insufficiency
   • ≥3 unexplained consecutive spontaneous abortions at <10 weeks (excluding anatomic/hormonal/chromosomal causes)

1. Lupus anticoagulant (LA) — by ISTH criteria
2. Anticardiolipin antibodies (IgG or IgM) — moderate to high titer (>40 GPL/MPL or >99th percentile)
3. Anti-β2GPI antibodies (IgG or IgM) — >99th percentile

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• Low-dose aspirin (75–100 mg/day) for SLE or high-risk aPL profile
• Hydroxychloroquine in SLE-APS (reduces aPL titers and thrombosis risk)

• Venous thrombosis: Long-term warfarin (INR target 2.0–3.0) — indefinite therapy
• Arterial thrombosis: INR 2–3 (some guidelines suggest 3–4) ± low-dose aspirin
• Direct oral anticoagulants (DOACs — rivaroxaban) showed inferiority to warfarin in high-risk aPL in TRAPS trial — warfarin remains standard

• Low-dose aspirin + Low Molecular Weight Heparin (LMWH) throughout pregnancy
• Women with prior thrombosis: therapeutic LMWH + aspirin
• Warfarin contraindicated in first trimester

• Triple therapy: Anticoagulation (heparin) + high-dose corticosteroids + plasma exchange or IVIG
• Eculizumab (complement inhibitor) for refractory cases
• Treat precipitating factors (infection)

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QUESTION 6

a) Structural and Molecular Basis of Podocyte Injury in Primary Nephrotic Syndrome [5]

• Cell body (rests on GBM periphery)
• Major processes (primary processes)
• Foot processes (pedicels) — interdigitate with adjacent podocytes
• Slit diaphragm (SD) — filtration barrier between foot processes (~40 nm wide); composed of nephrin, podocin, CD2AP, TRPC6, Neph1

1. Foot process effacement (FPE): The hallmark ultrastructural change on EM. SD proteins (esp. nephrin) are downregulated → loss of charge barrier and size selectivity → proteinuria. Actin cytoskeleton reorganization (Rho GTPase signaling) drives foot process retraction.
2. Immune-mediated injury:
   • Minimal Change Disease (MCD): T-cell dysfunction → circulating permeability factor (proposed: suPAR, soluble CD80/B7-1) → podocyte injury without histological changes on LM. CD80 expression on podocytes increases under stress.
   • FSGS: suPAR (soluble urokinase plasminogen activator receptor) → integrin activation → FPE. Anti-CD40 antibodies implicated in primary FSGS.
   • Membranous Nephropathy (MN): Anti-PLA2R antibodies (M-type phospholipase A2 receptor — found in 70–80% of primary MN) → immune complex deposition in subepithelial space → complement activation (C5b-9 → MAC) → podocyte injury. Anti-THSD7A antibodies in 5–10%.
3. Complement activation: Sub-epithelial immune complexes (MN) → classical pathway → MAC (C5b-9) → disrupts podocyte mitochondria → ROS production → actin cytoskeletal damage → proteinuria
4. Podocyte depletion: Podocytes have limited regenerative capacity. Once they detach from GBM → apoptosis/necrosis → bare GBM exposed → adhesion to Bowman's capsule → segmental sclerosis (FSGS progression)
5. mTOR and VEGF signaling: mTORC1 hyperactivation in podocytes → cellular hypertrophy, mitochondrial dysfunction. VEGF-A secreted by podocytes maintains endothelial fenestrations.

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b) Prognostic and Therapeutic Implications of Podocytopathies in Adults [5]

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• First-line: Prednisolone 1 mg/kg/day (max 80 mg) for 8–16 weeks; complete remission in >80% adults within 16 weeks
• Frequent relapsers/steroid-dependent: Cyclophosphamide (most frequently used) or cyclosporine/tacrolimus (CNI)
• Rituximab: Anti-CD20 agent; emerging as steroid-sparing in frequently relapsing MCD; depletes B cells → reduces circulating permeability factor

• Steroid-sensitive FSGS (tip lesion): Prednisolone as MCD
• Steroid-resistant FSGS: Cyclosporine A (target trough 125–175 ng/mL) + low-dose prednisolone; tacrolimus alternative
• Genetic FSGS (NPHS2, ACTN4): Steroids generally ineffective; avoid nephrotoxins; support RAAS blockade
• Sparsentan (dual RAAS + endothelin receptor antagonist): Approved for IgA nephropathy; in trials for FSGS
• Voclosporin (CNI): Superior to cyclosporine in some studies for FSGS

• Low-risk (proteinuria <4 g/day, stable GFR): Conservative therapy (RAAS blockade, BP control, statins)
• Medium/high-risk: Cyclophosphamide-based Ponticelli regimen (alternating steroids + CYC, 6 months) OR CNI (cyclosporine/tacrolimus)
• Rituximab: Now first-line for primary MN in many guidelines (STARMEN, MENTOR trials); anti-PLA2R titer monitoring guides therapy
• Anti-PLA2R titer decline predicts clinical remission

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QUESTION 7

a) Etiopathogenesis and Clinical Features of Leptospirosis [5]

• Caused by Leptospira interrogans (pathogenic spirochete)
• Gram-negative, motile, thin, coiled spirochete with characteristic hooked ends
• Maintained in nature by asymptomatic carrier animals (rodents — primary reservoir, also cattle, dogs, pigs)
• Zoonosis: Humans are incidental hosts

• Leptospires shed in animal urine → contaminate water/soil
• Human infection: skin abrasions, mucous membranes (conjunctival, oral, nasal) — direct contact with infected urine, contaminated water/soil
• Occupational risk: Farmers, sewage workers, veterinarians, soldiers, recreational water sports
• Outbreaks follow floods (tropical/subtropical regions)

1. Entry through skin/mucosa → leptospiremia (1st week)
2. Hematogenous spread to all organs (liver, kidney, lung, meninges, muscles)
3. Leptospires produce lipopolysaccharide (LPS) (induces TNF-α, IL-1, IL-6) and pore-forming toxins → endothelial damage
4. Vascular injury is central — vasculitis without true inflammatory infiltrate; endothelial dysfunction → hemorrhage and organ dysfunction
5. Liver: Hepatocellular damage; canalicular cholestasis; Kupffer cell hypertrophy
6. Kidney: Tubulointerstitial nephritis → AKI; urinary cast, proteinuria; hypokalemia due to tubular dysfunction
7. Lungs: Pulmonary hemorrhage syndrome — alveolar hemorrhage; diffuse alveolar damage (Weil-like pulmonary syndrome)
8. Muscle: Myositis → elevated CK, myalgias (particularly calf muscles)
9. Immunological phase (2nd week): Antibody production → immune complex deposition → uveitis (late complication)

• Abrupt onset high fever (39–40°C), rigors
• Severe headache, myalgia (especially calf and lumbar — characteristic)
• Conjunctival suffusion (non-purulent bilateral conjunctival injection without discharge) — pathognomonic
• Rash (maculopapular/petechial), lymphadenopathy
• Hepatomegaly, splenomegaly
• Nausea, vomiting, diarrhea

• Apparent brief improvement ("saddle-back fever") → recurrence
• Aseptic meningitis (fever, headache, neck stiffness, CSF: lymphocytic pleocytosis, ↑ protein, normal glucose)
• Uveitis (can occur weeks to months later — anterior, intermediate, panuveitis)
• Most patients recover at this stage

• Jaundice + AKI + Bleeding = classic triad
• Deep jaundice (markedly elevated bilirubin, predominantly conjugated; LFTs usually mildly elevated — distinguishing from viral hepatitis)
• AKI: Oliguria/anuria; non-oliguric AKI common; hypokalemia
• Pulmonary hemorrhage syndrome: Life-threatening; hemoptysis, respiratory failure, ARDS (most common cause of death in modern outbreaks)
• Thrombocytopenia, hemorrhage (petechiae, ecchymoses, pulmonary, GI)
• Myocarditis, arrhythmias, cardiac failure

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b) Scoring System Used in Diagnosis of Leptospirosis [2]

• Score ≥26 with Part C: Confirmed leptospirosis
• Score ≥26 without Part C (Parts A+B alone): Probable leptospirosis (treat)
• Score 20–25: Possible — further investigate

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c) Management of Leptospirosis [3]

• Hospitalization for moderate-severe disease
• IV fluids (aggressive fluid resuscitation for AKI)
• Monitor urine output, renal function, electrolytes (correct hypokalemia)

• AKI: Dialysis (hemodialysis or peritoneal) if oliguric despite fluid resuscitation
• Pulmonary hemorrhage: Mechanical ventilation, lung-protective strategy; methylprednisolone (500 mg IV daily × 3 days — limited evidence)
• Thrombocytopenia/Bleeding: Platelet transfusion if <20,000 or active bleeding
• Meningitis: Benzylpenicillin IV
• Uveitis (late): Topical/systemic corticosteroids + mydriatics

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QUESTION 8

a) Diseases Included Under Spondyloarthritis [2]

• Ankylosing spondylitis (AS) — radiographic axial SpA (definite sacroiliac joint changes on X-ray)
• Non-radiographic axial SpA (nr-axSpA) — sacroiliitis on MRI only or clinical features without radiographic changes

• Psoriatic arthritis (PsA) — Arthritis with psoriasis; CASPAR criteria
• Reactive arthritis (ReA) — Post-infectious (Chlamydia, Salmonella, Shigella, Campylobacter, Yersinia); previously Reiter's syndrome
• Enteropathic arthritis (IBD-associated) — Ulcerative colitis and Crohn's disease
• Undifferentiated SpA — Features of SpA but not fitting any specific category
• Juvenile SpA (Enthesitis-related arthritis) — subtype of JIA

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b) Role of HLA-B27 in Pathogenesis [2]

1. Arthritogenic peptide hypothesis: HLA-B27 presents self-peptides from joint or bacterial proteins → CD8+ T-cell cytotoxic response → joint inflammation. Molecular mimicry between bacterial antigens (Klebsiella nitrogenase, Chlamydia heat-shock protein) and self-peptides presented by B27.
2. Misfolding hypothesis (Unfolded Protein Response — UPR): HLA-B27 heavy chains misfold → accumulate in ER → UPR → NF-κB activation → pro-inflammatory cytokines (TNF-α, IL-23, IL-17). This is increasingly favored.
3. HLA-B27 homodimers: Free heavy chains (β2-microglobulin-free) form dimers on cell surface → bind NK cell receptors (KIR3DL2) → activate NK and CD4+ T cells → IL-17 production
4. IL-23/IL-17 axis: Central to SpA pathogenesis; HLA-B27 drives IL-23 production → Th17 cells → IL-17A → entheseal and bone inflammation, new bone formation (syndesmophytes)
5. Microbiome: Gut dysbiosis in AS → leaky gut → increased bacterial LPS exposure → innate immune activation → SpA inflammation (gut-joint axis)

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c) Diagnosis and Management of Ankylosing Spondylitis with Current Biologic Agents [6]

• Radiological criterion: Sacroiliitis grade ≥2 bilateral OR grade 3–4 unilateral
• Clinical criteria (≥1 required):
  1. Low back pain ≥3 months, improved with exercise, not relieved by rest
  2. Limited lumbar spine motion in both sagittal and frontal planes
  3. Reduced chest expansion (<2.5 cm at 4th intercostal space)

• In patients with ≥3 months back pain and onset <45 years:
  • Imaging arm: Sacroiliitis on X-ray or MRI + ≥1 SpA feature
  • Clinical arm: HLA-B27 positive + ≥2 SpA features
• SpA features: Inflammatory back pain, arthritis, enthesitis (heel), uveitis, dactylitis, psoriasis, IBD, good response to NSAIDs, family history of SpA, HLA-B27, elevated CRP

• HLA-B27 (positive in ~90%)
• CRP/ESR (elevated in ~50%; normal doesn't exclude)
• X-ray pelvis: Sacroiliitis grading (0–4); bamboo spine (squaring, syndesmophytes, fusion)
• MRI sacroiliac joints: Active inflammation (bone marrow edema — STIR sequence); best for early/nr-axSpA
• BASMI, BASFI, BASDAI scores: Monitor disease activity

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• Physiotherapy and exercise (essential — maintains spinal mobility)
• Patient education, smoking cessation
• NSAIDs are first-line pharmacotherapy

• Diclofenac, indomethacin, naproxen, etoricoxib — continuous dosing superior to on-demand
• Reduce symptoms, may slow radiographic progression

• Risankizumab, Guselkumab: Approved for PsA; being studied in AS

• Tofacitinib (JAK1/3), Upadacitinib (JAK1-selective), Filgotinib: Oral; approved for axSpA; avoid in cardiovascular high-risk patients
• Upadacitinib 15 mg once daily — approved; may have superior anti-inflammatory efficacy

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QUESTION 9

a) Classification of Systemic Vasculitis Based on Vessel Size (Chapel Hill Consensus Nomenclature, 2012) [2]

• Giant cell arteritis (GCA) / Temporal arteritis
• Takayasu arteritis (TAK)

• Polyarteritis nodosa (PAN)
• Kawasaki disease

• Granulomatosis with polyangiitis (GPA) — formerly Wegener's [c-ANCA/PR3-ANCA]
• Microscopic polyangiitis (MPA) [p-ANCA/MPO-ANCA]
• Eosinophilic granulomatosis with polyangiitis (EGPA) — formerly Churg-Strauss [p-ANCA/MPO-ANCA, eosinophilia]

• Anti-GBM disease (Goodpasture syndrome)
• Cryoglobulinemic vasculitis
• IgA vasculitis (Henoch-Schönlein purpura)
• Hypocomplementemic urticarial vasculitis

• Behçet's disease
• Cogan's syndrome

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b) Pathogenesis of ANCA-Associated Vasculitis [3]

• PR3-ANCA (c-ANCA pattern) → GPA
• MPO-ANCA (p-ANCA pattern) → MPA and EGPA

1. Priming of Neutrophils: Infections (Staphylococcus aureus in GPA — nasal carriage), complement activation (C5a), TNF-α prime neutrophils → translocate PR3/MPO to cell surface and into microparticles
2. ANCA Binding: ANCA (IgG) bind surface-expressed PR3 or MPO → cross-link Fc receptors → neutrophil activation
3. Neutrophil Activation and Degranulation:
   • Activated neutrophils release ROS, proteases (elastase, PR3, MPO)
   • Adhere to endothelium via upregulated β2-integrins and PECAM-1
   • Neutrophil Extracellular Traps (NETs): Chromatin + granule enzymes released → further endothelial damage; NETs are major source of citrullinated antigens, possibly initiating autoimmunity
4. Endothelial Damage: Granule enzymes and ROS → endothelial injury → fibrinoid necrosis → pauci-immune vasculitis (minimal immune complex deposits)
5. Complement Activation (alternative pathway): C5a generated → C5aR on primed neutrophils → amplification loop (C5aR1 blockade by avacopan now therapeutic)
6. Granuloma Formation (GPA-specific): Activated macrophages (M1 polarization) form granulomas around areas of necrosis → multinucleated giant cells → tissue destruction (necrotizing granulomatous inflammation)
7. T-cell involvement: Th1 cells (IFN-γ) and Th17 cells drive granuloma formation; regulatory T-cell deficiency → failed suppression of autoreactive B cells producing ANCA

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c) Diagnostic Evaluation and Treatment Principles of Granulomatosis with Polyangiitis (GPA) [5]

• Upper respiratory: Sinusitis (chronic, destructive), nasal septal perforation, saddle-nose deformity, subglottic stenosis, otitis media, orbital pseudotumor
• Lower respiratory: Pulmonary infiltrates, nodules (may cavitate), pulmonary hemorrhage, hemoptysis
• Renal: Rapidly progressive GN (crescentic GN — pauci-immune); hematuria, proteinuria, AKI
• Other: Ocular (scleritis, episcleritis, proptosis), skin (leukocytoclastic vasculitis), nervous system (mononeuritis multiplex), arthralgia

• c-ANCA/PR3-ANCA: Sensitivity ~90% in severe GPA; titer correlates with disease activity
• CBC: Anemia, leukocytosis, thrombocytosis
• ESR, CRP: Elevated
• Urine analysis: Hematuria, RBC casts (active GN), proteinuria
• Serum creatinine/eGFR: Renal involvement
• Complement (C3, C4): Normal (pauci-immune — distinguishes from SLE/IgA vasculitis)
• ANCA-negative GPA: Biopsy essential

• Chest CT: Nodules (single/multiple, may cavitate — "cheerio sign"), ground-glass opacities (hemorrhage), infiltrates; more sensitive than X-ray
• CT sinuses: Mucosal thickening, bony destruction, pansinusitis

• Preferred sites: Kidney (most accessible) or lung (open/video-assisted thoracoscopy)
• Kidney: Focal necrotizing pauci-immune crescentic GN (scant or no immune deposits on IF)
• Lung: Necrotizing granulomatous vasculitis with geographic necrosis, palisading histiocytes, multinucleated giant cells
• Nasal/sinus biopsy: Less diagnostic (30–40% yield); shows necrosis with neutrophilic infiltrate

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1. Rituximab (RTX) + high-dose corticosteroids: Now first-line (RAVE and RITUXVAS trials)
   • Rituximab 375 mg/m² IV weekly × 4 doses OR 1000 mg × 2 doses (RAVE protocol)
   • Superior to cyclophosphamide for relapsing GPA and PR3-ANCA GPA
   • High-dose prednisolone 1 mg/kg/day with rapid taper
2. Cyclophosphamide (CYC) + corticosteroids: Alternative to rituximab
   • IV pulse CYC (15 mg/kg q2–3 weeks) preferred over oral (similar efficacy, less bladder toxicity — reduce hemorrhagic cystitis risk)
   • Oral CYC: 2 mg/kg/day — more bladder toxicity (mesna for prophylaxis)
3. Plasma exchange (PLEX): No longer routinely recommended after PEXIVAS trial (did not reduce renal failure/death); may consider in pulmonary hemorrhage with concurrent anti-GBM disease
4. Methylprednisolone pulses (1 g IV × 3 days) for severe life-threatening manifestations (pulmonary hemorrhage, rapidly worsening renal function)

• Rituximab (500 mg IV every 6 months × 2 years): Superior to azathioprine (MAINRITSAN trial)
• Azathioprine (2 mg/kg/day) or Methotrexate (for non-renal GPA): Alternatives after CYC-induced remission
• Low-dose prednisolone (5–10 mg/day) with gradual taper

• Avacopan (C5aR1 inhibitor): Approved 2021; replaces prednisolone in induction (ADVOCATE trial); steroid-sparing; given with RTX or CYC
• Belimumab, Obinutuzumab: Under investigation

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QUESTION 10

a) Structure, Mode of Transmission, and Pathogenesis of Epstein-Barr Virus (EBV) Infection [5]

• EBV (Human Herpesvirus 4, HHV-4) is a member of the Gammaherpesvirinae subfamily
• Double-stranded DNA virus (~172 kb genome)
• Structure (outer to inner):
  • Envelope: Lipid bilayer derived from host nuclear membrane; contains viral glycoproteins (gp350/220 — binds CD21/CR2; gp42 — binds HLA class II for B-cell entry; gH/gL for fusion)
  • Tegument: Protein layer between envelope and capsid; contains BNRF1, BGLF2 virion proteins
  • Icosahedral capsid: Composed of viral capsid antigen (VCA) proteins; 162 capsomeres
  • Core: Linear dsDNA genome (circularizes as episome in latently infected cells)

• VCA (Viral Capsid Antigen): IgM VCA → acute infection; IgG VCA → past infection
• EA (Early Antigen): Present in active replication (restricted and diffuse components)
• EBNA (EBV Nuclear Antigen): Appears 3–6 weeks after infection; persists lifelong; absence of EBNA in presence of VCA = acute EBV

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• Saliva ("kissing disease") — primary route; EBV shed in oropharyngeal secretions
• Blood transfusion and organ transplantation (EBV-negative recipients at risk of post-transplant lymphoproliferative disease — PTLD)
• Perinatal transmission: Rare
• Sexual transmission: Possible (EBV in genital secretions)
• High prevalence worldwide: >90% of adults seropositive; primary infection in childhood (subclinical) or adolescence/young adults (infectious mononucleosis)

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• EBV infects oropharyngeal epithelial cells (via EGFR entry) and B lymphocytes (via gp350 binding CD21/CR2 → gp42-HLA class II triggers membrane fusion via gH/gL)
• Lytic replication in epithelial cells → virus shed in saliva

• EBV enters B cells → circularizes DNA → latent program activated
• EBV drives B-cell proliferation through LMP1 (mimics activated CD40 → NF-κB → anti-apoptotic, promotes B-cell growth) and LMP2A (mimics BCR signaling → B-cell survival)
• EBNA proteins (EBNA1, 2, 3A, 3C, LP) drive viral replication in latently infected cells; EBNA2 transactivates viral and host genes

• Massive CD8+ T-cell expansion (atypical lymphocytes = activated cytotoxic T cells directed against EBV-infected B cells) — these are the "mononuclear" cells
• NK cells also activated
• Immune activation → fever, lymphadenopathy, splenomegaly, pharyngitis, hepatitis
• Cytokine storm (TNF-α, IFN-γ, IL-6) → constitutional symptoms

• After immune control, EBV persists in resting memory B cells (Latency 0 — minimal gene expression; only EBER, BART miRNAs)
• Periodic reactivation (especially during immunosuppression) → viral shedding in saliva

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b) Hematologic, Neurologic, and Hepatic Complications of EBV Infection [5]

1. Hemolytic anemia (immune-mediated):
   • Cold agglutinin hemolytic anemia (IgM anti-i antibodies) — most common; usually mild and self-limiting
   • Warm antibody AIHA (rare)
2. Thrombocytopenia: Immune-mediated platelet destruction; typically mild; rarely severe (<20,000/µL) causing bleeding; associated with anti-platelet antibodies
3. Aplastic anemia (rare but life-threatening): EBV-induced immune suppression of hematopoiesis; may trigger aplasia via T-cell suppression of marrow
4. Hemophagocytic Lymphohistiocytosis (HLH): EBV triggers uncontrolled macrophage and T-cell activation → phagocytosis of blood cells; presents with fever, cytopenias, hyperferritinemia, hypertriglyceridemia, elevated sCD25; associated with X-linked lymphoproliferative disease (XLP — SAP gene mutations) — EBV can cause fatal HLH in these patients
5. Agranulocytosis/Neutropenia: EBV-mediated neutrophil destruction; increases susceptibility to bacterial infections
6. Post-transplant lymphoproliferative disease (PTLD): EBV-driven B-cell proliferation in immunosuppressed transplant recipients; spectrum from polyclonal hyperplasia to monomorphic lymphoma (Diffuse large B-cell lymphoma); managed with reduction of immunosuppression ± rituximab
7. Burkitt lymphoma: EBV-associated (especially endemic African form); sporadic BL less EBV-associated; t(8;14) translocation (c-MYC/IgH)
8. Splenic rupture: Rare but potentially fatal; splenomegaly + minor trauma; avoid contact sports for 4–6 weeks after IM

---

1. Aseptic meningitis: Lymphocytic pleocytosis, elevated protein, normal glucose; usually self-limiting
2. Encephalitis: Direct viral invasion; confusion, seizures, focal neurological signs; EBV DNA in CSF by PCR; brainstem encephalitis possible
3. Guillain-Barré Syndrome (GBS): Post-infectious demyelinating polyneuropathy; ascending flaccid paralysis, areflexia; albumino-cytological dissociation in CSF
4. Cranial nerve palsies: Bell's palsy (CN VII), other cranial nerve involvement (III, VI)
5. Alice in Wonderland Syndrome: Altered body image perception (micropsia, macropsia, metamorphopsia); associated with EBV in children; neuropsychiatric
6. Acute cerebellar ataxia: Post-infectious; children; gait ataxia, dysmetria; usually self-limiting
7. Transverse myelitis: Spinal cord inflammation → paraplegia, sensory level, bladder dysfunction
8. Optic neuritis
9. CNS lymphoma: Especially in AIDS patients (EBV Latency III)
10. Chronic active EBV (CAEBV): Persistent EBV with neurological manifestations including encephalitis in EBV-driven T/NK cell lymphoproliferation

---

1. Acute hepatitis (most common hepatic complication): Present in >80% of IM cases; elevated transaminases (usually AST/ALT 2–10× ULN); typically anicteric; rarely severe
2. Cholestatic hepatitis/Jaundice: Conjugated hyperbilirubinemia; occurs in ~5% of IM; usually self-limiting; granulomatous hepatitis on biopsy
3. Fulminant hepatic failure (FHF): Rare (<0.5%); seen in immunocompromised, XLP patients, or primary EBV; massive hepatic necrosis; may require liver transplantation
4. Granulomatous hepatitis: Non-caseating granulomas in liver biopsy; associated with EBV; can mimic sarcoidosis, TB
5. Hepatic involvement in EBV-HLH: Elevated ferritin, transaminases; hemophagocytosis on bone marrow/liver biopsy; hepatosplenomegaly
6. EBV-associated hepatocellular carcinoma: Rare; EBV DNA found in some HCC specimens
7. Chronic hepatitis: Rarely, EBV can lead to chronic hepatic inflammation, especially in the setting of CAEBV

---

1. a concise, exam-style version of all 10 answers, and
2. clean Markdown/Word-ready text that you can export to PDF in one click (Print → Save as PDF).

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# DNB General Medicine — Paper 2: Model Answers

---

## 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

---

### b) Differences Between HL and NHL

| Feature | Hodgkin's | Non-Hodgkin's |
|---|---|---|
| Cell of origin | Reed-Sternberg (B-cell) | B-cell (85%), T-cell (15%) |
| Age | Bimodal (15–35, >55 yrs) | Any age |
| Spread | Contiguous | Non-contiguous |
| Mediastinal nodes | Common (>50%) | Less common |
| Extranodal involvement | Rare | Common |
| Bone marrow | Rarely involved | Frequently involved |
| RS cells | CD15+, CD30+ | Absent |
| Prognosis | Better (~80% cure) | Variable |

---

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

**1. Classical HL (95%)** — RS cells CD15+, CD30+:
- Nodular Sclerosis (NS-HL): 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. NLPHL (5%):** "Popcorn" cells; CD20+, CD15−, CD30−; indolent

---

## Q2. Azotemia & Polyuria

### a) Causes of Azotemia

**PRERENAL** (BUN:Cr >20:1; FENa <1%):
- Hypovolemia, CHF, cirrhosis, nephrotic syndrome; NSAIDs, ACEi, ARBs

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

**POSTRENAL:**
- Ureteral stones, retroperitoneal fibrosis, BPH, neurogenic bladder

**Chronic:** Diabetic nephropathy, hypertensive nephrosclerosis, CKD

---

### 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 diuresis (DM, mannitol, high-protein feeds)
- Uosm <300 → Water diuresis → Step 3

**Step 3 — Water Deprivation Test:**

| Response | Diagnosis |
|---|---|
| Uosm rises >50% after DDAVP | Central DI |
| <10% rise after DDAVP | Nephrogenic DI |
| Uosm >500 before DDAVP | Primary polydipsia |

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

---

## Q3. Syncope: Etiology & Evaluation

### Etiology

**1. Reflex (~40%):**
- Vasovagal (pain, prolonged standing, emotional stress); Situational (cough, micturition); Carotid sinus syndrome

**2. Orthostatic Hypotension (~10%):**
- Autonomic failure (Parkinson's, MSA), DM, drugs (antihypertensives, diuretics, nitrates), volume depletion

**3. Cardiac (~15% — highest mortality):**
- Arrhythmic: SSS, AV block, VT/VF, Long QT (Romano-Ward), Brugada, WPW
- Structural: Severe AS, HOCM, cardiac tamponade, PE, pulmonary hypertension

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

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

---

### Evaluation

| Test | Indication |
|---|---|
| 12-lead ECG | All patients (mandatory) |
| Echocardiogram | Structural heart disease suspected |
| Holter/Event recorder | Suspected arrhythmia |
| ILR (implantable) | Infrequent syncope (up to 3 years) |
| Tilt-table test | Vasovagal/orthostatic suspected |
| EP study | High-risk cardiac (wide QRS, structural disease) |
| CT/MRI brain | Only if neurological signs present |

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

---

## Q4. Peripheral Neuropathy & NCS

### a) Clinical Features & Evaluation

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

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

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

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

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

---

### b) Nerve Conduction Study (NCS)

**Parameters:** Conduction velocity (myelination), Amplitude (axon number), Distal latency, F-wave (proximal), H-reflex (S1 pathway)

**Axonal vs. Demyelinating:**

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

---

## Q5. Antiphospholipid Syndrome (APS)

### a) Definition & aPL Antibody Types

**APS:** Autoimmune disorder with recurrent thrombosis/pregnancy morbidity + persistent positive antiphospholipid antibodies.

**Types:**
1. Lupus anticoagulant (LA) — strongest predictor of thrombosis
2. Anticardiolipin (aCL) — IgG/IgM/IgA
3. Anti-β2GPI — IgG/IgM/IgA; most specific
4. Non-criteria: Antiphosphatidylserine, antiprothrombin

---

### b) Pathogenesis, Criteria & Management

**Pathogenesis:**
- aPL bind β2GPI → endothelial activation (NF-κB → tissue factor); platelet activation (TXA2); complement activation (C5a → trophoblast injury); inhibit protein C/S and annexin A5
- Two-hit hypothesis: aPL (1st hit) + trigger (pregnancy/infection/surgery) = thrombosis

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

*Clinical:* Arterial/venous/small vessel thrombosis OR pregnancy morbidity (fetal death ≥10 wks; premature birth <34 wks; ≥3 consecutive abortions <10 wks)

*Lab (moderate-high titer):* LA (ISTH criteria); aCL IgG/IgM >40 GPL; Anti-β2GPI IgG/IgM >99th percentile

**Management:**
- Primary prevention: Low-dose aspirin ± hydroxychloroquine (SLE)
- Venous thrombosis: Warfarin INR 2–3 (indefinite); DOACs inferior
- Obstetric APS: LMWH + aspirin throughout pregnancy
- Catastrophic APS: Anticoagulation + high-dose steroids + plasma exchange/IVIG; eculizumab (refractory)

---

## Q6. Podocyte Injury & Nephrotic Syndrome

### a) Structural & Molecular Basis

**Slit diaphragm proteins & mutations:**

| Protein | Gene | Disease |
|---|---|---|
| Nephrin | NPHS1 | Congenital NS (Finnish type) |
| Podocin | NPHS2 | Familial FSGS (AR) |
| CD2AP | CD2AP | FSGS |
| TRPC6 | TRPC6 | Familial FSGS (AD) |
| WT1 | WT1 | Denys-Drash, Frasier |

**Mechanisms:**
- MCD: T-cell dysfunction → suPAR/CD80 → foot process effacement (FPE)
- FSGS: suPAR → β3-integrin → FPE; APOL1 G1/G2 → rapid progression in Africans
- MN: Anti-PLA2R → subepithelial complexes → C5b-9 (MAC) → podocyte injury
- Podocyte depletion → bare GBM → segmental sclerosis

---

### b) Prognostic & Therapeutic Implications

| Disease | Prognosis | Treatment |
|---|---|---|
| MCD | Excellent; >80% steroid CR | Prednisolone 1 mg/kg; relapsers: CYC/CNI/Rituximab |
| FSGS (steroid-resistant) | Variable; collapsing = worst | Cyclosporine ± prednisolone; genetic FSGS: RAAS blockade only |
| MN (primary) | 1/3 spontaneous remission | Low-risk: conservative; Medium/high-risk: Rituximab (MENTOR trial) or Ponticelli (CYC+steroids) |
| Genetic FSGS | Early renal failure; steroids ineffective | RAAS blockade, avoid nephrotoxins |

**All:** ACEi/ARB, BP <125/75, statins, anticoagulation if albumin <2.5 g/dL

---

## Q7. Leptospirosis

### a) Etiopathogenesis & Clinical Features

**Organism:** Leptospira interrogans — zoonosis; rodents = primary reservoir
**Transmission:** Skin/mucosa contact with contaminated water/soil; occupational risk; outbreaks post-floods

**Pathogenesis:**
- Entry → leptospiremia → LPS + toxins → endothelial injury (vasculitis)
- Liver (hepatocellular damage), Kidney (tubulointerstitial nephritis, hypokalemia), Lung (alveolar hemorrhage — commonest cause of death), Muscle (myositis, calf pain), Immune phase (uveitis)

**Clinical — Biphasic:**

*Phase 1 (Days 1–7):* Fever, rigors, severe headache, calf myalgia, **conjunctival suffusion** (pathognomonic), nausea

*Phase 2 (Days 7–21):* Aseptic meningitis; uveitis (late)

*Weil's Syndrome (10%):* **Jaundice + AKI + Bleeding**; pulmonary hemorrhage syndrome

---

### b) Faine's Criteria (Scoring)

Key scores: Conjunctival suffusion (4), Calf pain (4), Meningism (4), Flood/water exposure (5), Occupational exposure (5), Positive MAT serology (15–25)

**Score ≥26 (Parts A+B alone):** Probable → treat. With serology: Confirmed.

**Gold standard:** MAT (Microscopic Agglutination Test), titer ≥1:400.

---

### c) Management

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

Complications: Dialysis (AKI); Ventilation + methylprednisolone (pulmonary hemorrhage); Topical steroids (uveitis)
Prophylaxis: Doxycycline 200 mg weekly (high-risk)

---

## Q8. Spondyloarthritis & Ankylosing Spondylitis

### a) Diseases Under Spondyloarthritis

- Axial: Ankylosing spondylitis (AS), Non-radiographic axSpA
- Peripheral: Psoriatic arthritis, Reactive arthritis, Enteropathic arthritis (IBD), Undifferentiated SpA, Juvenile SpA

---

### b) Role of HLA-B27

1. **UPR/Misfolding (most favored):** B27 misfolds in ER → UPR → NF-κB → TNF-α, IL-17
2. **Arthritogenic peptide:** Molecular mimicry (bacterial/self) → CD8+ T-cell joint attack
3. **B27 homodimers:** Bind NK receptors (KIR3DL2) → IL-17 production
4. **IL-23/IL-17 axis:** B27 drives IL-23 → Th17 → entheseal inflammation + syndesmophytes
5. **Gut-joint axis:** Dysbiosis → leaky gut → innate immune activation

---

### c) Diagnosis & Management

**Modified New York Criteria:** Sacroiliitis grade ≥2 bilateral (X-ray) + ≥1 clinical feature (back pain >3 months; limited lumbar motion; reduced chest expansion <2.5 cm)

**Management — Step-up:**
1. **NSAIDs** (first-line): Diclofenac, indomethacin, etoricoxib — continuous dosing
2. **Sulfasalazine:** Peripheral arthritis only
3. **Biologics** (BASDAI ≥4, failure of ≥2 NSAIDs):

**TNF Inhibitors:** Adalimumab (40 mg SC q2wks), Etanercept (50 mg SC weekly), Infliximab (5 mg/kg IV), Golimumab (50 mg SC monthly), Certolizumab pegol

**IL-17A Inhibitors:** Secukinumab (first IL-17i; 150–300 mg SC monthly), Ixekizumab, Bimekizumab (anti-IL-17A+F; 2023)

**JAK Inhibitors:** Upadacitinib 15 mg OD, Tofacitinib — oral; for biologic failures

---

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

### a) Classification by Vessel Size (Chapel Hill 2012)

- **Large:** Giant cell arteritis, Takayasu arteritis
- **Medium:** Polyarteritis nodosa, Kawasaki disease
- **Small (ANCA):** GPA (c-ANCA/PR3), MPA (p-ANCA/MPO), EGPA (MPO-ANCA)
- **Small (Immune complex):** Anti-GBM disease, Cryoglobulinemic vasculitis, IgA vasculitis
- **Variable:** Behçet's, Cogan's

---

### b) ANCA-Associated Vasculitis Pathogenesis

1. Priming: Infection/TNF-α → PR3/MPO on neutrophil surface
2. ANCA binding → Fc receptor cross-link → neutrophil activation
3. Degranulation → ROS + proteases → fibrinoid necrosis (pauci-immune)
4. NETs → endothelial damage; source of autoantigens
5. C5a amplification loop → target of avacopan
6. Granuloma (GPA): M1 macrophages → giant cells → necrotizing granulomatous inflammation
7. Deficient T-regs → uncontrolled ANCA-producing B cells

---

### c) Diagnostic Evaluation & Treatment of GPA

**Clinical triad:** ENT (sinusitis, saddle-nose, subglottic stenosis) + Lungs (nodules, hemorrhage) + Kidneys (rapidly progressive GN)

**Investigations:**
- c-ANCA/PR3-ANCA (sensitivity ~90%)
- Urine analysis: RBC casts; Creatinine
- Chest CT: Cavitating nodules, ground-glass opacities
- Kidney biopsy: Focal necrotizing **pauci-immune** crescentic GN (gold standard)

**Induction:**
- Rituximab + high-dose corticosteroids (first-line, RAVE trial)
- CYC + corticosteroids (alternative); IV pulse preferred
- Avacopan (approved 2021 — steroid-sparing, ADVOCATE trial)
- Methylprednisolone pulses for pulmonary hemorrhage/severe AKI

**Maintenance:**
- Rituximab 500 mg IV q6months (MAINRITSAN — superior to azathioprine)
- Azathioprine/Methotrexate: Alternatives after CYC remission

**Monitor:** PR3-ANCA titers, eGFR, urine; PCP prophylaxis (co-trimoxazole DS 3×/week)

---

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

### a) Structure, Transmission & Pathogenesis

**Structure:** HHV-4, Gammaherpesvirinae; dsDNA (~172 kb)
- Envelope: gp350 (binds CD21/CR2 on B cells); gp42 (binds HLA class II)
- Icosahedral capsid (VCA proteins); dsDNA core (circularizes as episome in latency)
- Antigens: VCA IgM = acute; VCA IgG = past; EBNA = appears 3–6 wks, persists lifelong

**Transmission:** Saliva (primary); blood/organ transplant (→ PTLD); perinatal (rare)

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

**Latency Programs:**

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

---

### b) Complications

**Hematologic:**
1. Hemolytic anemia — Cold agglutinin (anti-i IgM); self-limiting
2. Thrombocytopenia — Immune-mediated; usually mild
3. Aplastic anemia — Rare; T-cell suppression of marrow
4. HLH — Pancytopenia, hyperferritinemia, hypertriglyceridemia; fatal in XLP (SAP mutation)
5. PTLD — EBV-driven lymphoproliferation post-transplant; reduce immunosuppression ± rituximab
6. Burkitt lymphoma — t(8;14) c-MYC/IgH; endemic form EBV-associated
7. Splenic rupture — Avoid contact sports 4–6 weeks post-IM

**Neurologic:**
1. Aseptic meningitis — Lymphocytic; self-limiting
2. Encephalitis — Confusion, seizures; EBV PCR in CSF
3. Guillain-Barré Syndrome — Post-infectious demyelinating polyneuropathy
4. Bell's palsy (CN VII)
5. Alice in Wonderland Syndrome — Micropsia/macropsia; children
6. Acute cerebellar ataxia — Post-infectious; children
7. Transverse myelitis
8. CNS lymphoma (AIDS-related)

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

---

*End of Answers — DNB General Medicine Paper 2*

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