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DNB General Medicine Paper 2 — Model Answers

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QUESTION 1 [10 marks]

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

1. History: Age, duration, associated symptoms (fever, night sweats, weight loss — "B symptoms"), medications, travel history, sexual history, occupational exposure
2. Physical examination: Size (>1 cm significant; >2 cm warrants biopsy), consistency (hard = malignancy; soft/tender = infection), fixation, hepatosplenomegaly, skin lesions
3. Investigations:
   • CBC with differential (lymphocytosis → viral/leukemia)
   • ESR, LDH, uric acid
   • Peripheral smear (atypical lymphocytes in EBV; blasts in leukemia)
   • Monospot/Paul-Bunnell, HIV ELISA, Toxoplasma IgM
   • Mantoux/IGRA for TB
   • ANA, anti-dsDNA (if autoimmune suspected)
   • Chest X-ray (mediastinal widening → lymphoma/sarcoidosis)
   • CT neck/chest/abdomen/pelvis for staging
   • Lymph node biopsy: Indicated if node >2 cm, hard/fixed, "B symptoms," no response to treatment in 4–6 weeks. Excision biopsy preferred over FNAC for lymphoma

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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]

1. Nodular Sclerosis HL (NSHL) — Most common (65–70%); young women; mediastinal mass; collagen bands dividing nodes into nodules; lacunar cells; best prognosis
2. Mixed Cellularity HL (MCHL) — 20–25%; bimodal age; EBV-associated; classical RS cells abundant
3. Lymphocyte-Rich HL (LRHL) — Rare; excellent prognosis; few RS cells
4. Lymphocyte-Depleted HL (LDHL) — Rare; elderly; HIV-associated; RS cells predominate; worst prognosis

1. Nodular Lymphocyte-Predominant HL (NLPHL) — RS variant = "popcorn/LP cells"; CD20+, CD45+, CD15−, CD30−; indolent; excellent prognosis; late relapses possible

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QUESTION 2 [10 marks]

a) Causes of Azotemia [5]

• Hypovolemia: hemorrhage, vomiting, diarrhea, diuretics, burns
• Decreased cardiac output: CHF, cardiogenic shock, cardiac tamponade
• Systemic vasodilation: sepsis, anaphylaxis, liver failure (hepatorenal syndrome)
• Renal vasoconstriction: NSAIDs, ACE inhibitors in bilateral RAS, calcineurin inhibitors
• Severe hypoalbuminemia (nephrotic syndrome, cirrhosis)

• Tubular: ATN (ischemic, nephrotoxic — aminoglycosides, contrast, myoglobinuria)
• Glomerular: Acute glomerulonephritis (IgA nephropathy, RPGN, lupus nephritis)
• Interstitial: Acute interstitial nephritis (drugs — NSAIDs, β-lactams; infections — hantavirus, leptospirosis)
• Vascular: Renal artery/vein thrombosis, TTP/HUS, atheroembolic disease

• Ureteric: bilateral calculi, retroperitoneal fibrosis, malignancy
• Bladder outlet obstruction: BPH, prostate cancer, bladder neck obstruction
• Urethral: stricture, posterior urethral valves (pediatric)

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b) Diagnostic Approach to Patient with Polyuria [5]

• Serum glucose (exclude diabetes mellitus)
• Serum electrolytes: Na+, K+, Ca2+ (hypercalcemia, hypokalemia cause nephrogenic DI)
• Serum osmolality and urine osmolality simultaneously
• Serum creatinine/BUN

• Deprive water until weight loss of 3% or plasma osm >295 or urine osm plateaus
• Measure urine osmolality hourly
• Then administer DDAVP (desmopressin) 2 mcg SC/IV and measure urine osm 1 hour later

• Central DI: DDAVP (intranasal, oral, or parenteral)
• Nephrogenic DI: Low-salt/low-protein diet; thiazide diuretics (paradoxical); NSAIDs; amiloride (for lithium-induced)

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QUESTION 3 [10 marks]

Etiology of Syncope [5]

• Vasovagal syncope (common faint): prolonged standing, emotional stress, pain, venipuncture — mediated by Bezold-Jarisch reflex
• Situational syncope: cough, micturition, defecation, deglutition, post-exercise
• Carotid sinus syncope: carotid hypersensitivity (elderly men, tight collars)

• Primary autonomic failure: Parkinson's disease, multiple system atrophy, pure autonomic failure
• Secondary autonomic failure: DM neuropathy, amyloidosis, spinal cord disorders
• Drug-induced: antihypertensives, diuretics, tricyclics, phenothiazines, alcohol
• Volume depletion: hemorrhage, adrenal insufficiency, dehydration

• Arrhythmias (commonest cardiac cause):
  • Brady: sinus node dysfunction (sick sinus syndrome), AV block (2nd/3rd degree), pacemaker malfunction
  • Tachy: VT, VF, SVT, pre-excitation (WPW), torsades de pointes (long QT)
• Structural heart disease:
  • Obstructive: AS, HOCM, pulmonary embolism, pulmonary hypertension, cardiac tamponade
  • Non-obstructive: ACS, aortic dissection

• Subclavian steal syndrome (vertebrobasilar territory)
• TIA in basilar territory

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Evaluation of Syncope in Adults [5]

1. Detailed history: Prodrome (nausea, diaphoresis → vasovagal), posture, activity, duration, recovery, witnesses, medications, family history (sudden death)
2. Physical exam: Vitals in both arms (dissection), lying/standing BP (postural drop = >20 mmHg systolic), cardiac auscultation, carotid sinus massage (with resuscitation facilities), neurological exam
3. 12-lead ECG: QT prolongation, delta wave (WPW), epsilon wave (ARVC), LBBB, complete AV block, ST changes

• Congestive heart failure, Hematocrit <30%, ECG abnormality, Shortness of breath, Systolic BP <90 mmHg
• Any positive → high risk → admit and investigate

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QUESTION 4 [10 marks]

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

• Positive symptoms: tingling (paresthesia), burning, allodynia, hyperalgesia
• Negative symptoms: numbness, sensory loss in glove-and-stocking distribution
• Loss of proprioception → sensory ataxia (positive Romberg's)
• Loss of vibration sense (large fiber) vs. pain/temperature (small fiber)

• Distal weakness (foot drop, wrist drop in radiculoneuropathy)
• Muscle wasting and fasciculations (with anterior horn cell involvement)
• Decreased/absent deep tendon reflexes (LMN pattern)

• Postural hypotension, gastroparesis, diarrhea/constipation, urinary retention, erectile dysfunction, anhidrosis, pupillary abnormalities

1. Classification by pattern:
   • Symmetric distal polyneuropathy (most common — metabolic/toxic)
   • Mononeuropathy (single nerve — entrapment, trauma)
   • Mononeuritis multiplex (multiple individual nerves — vasculitis, DM, leprosy)
   • Radiculopathy, polyradiculopathy, plexopathy
2. Blood investigations: FBG/HbA1c, CBC, ESR, B12/folate, thyroid function, renal/liver function, serum protein electrophoresis, immunofixation, anti-MAG antibodies, ANA, ANCA, cryoglobulins, HIV, hepatitis B/C serology
3. Nerve conduction studies (NCS) + EMG — cornerstone of electrophysiological evaluation
4. CSF analysis: Elevated protein without pleocytosis (albuminocytologic dissociation) in GBS and CIDP
5. Nerve biopsy: Sural nerve — for vasculitic neuropathy, amyloid, leprosy; indicates onion-bulb formation (CIDP/CMT), necrotizing vasculitis
6. Skin punch biopsy: Intraepidermal nerve fiber density (IENFD) — gold standard for small fiber neuropathy
7. Genetic testing: For CMT (PMP22 duplication in CMT1A), hereditary neuropathies

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b) Nerve Conduction Study (NCS) [5]

1. Motor NCS: Records Compound Muscle Action Potential (CMAP) from muscle after stimulating motor nerve at ≥2 sites
   • CV = distance/latency difference
   • Normal median motor CV: >50 m/s
2. Sensory NCS: Records Sensory Nerve Action Potential (SNAP)
   • Orthodromic (physiological direction) or antidromic technique
   • Smaller amplitude than CMAP
3. F-waves: Late responses measuring conduction in proximal nerve segments (useful in radiculopathy and GBS)
4. H-reflex: Monosynaptic reflex arc equivalent of ankle jerk (S1 root assessment)

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QUESTION 5 [10 marks]

a) Definition of APS and Types of Antiphospholipid Antibodies [2]

• Primary APS: No underlying autoimmune disease
• Secondary APS: Associated with SLE (most common), other autoimmune disorders
• Catastrophic APS (CAPS): Rapid multiorgan thrombosis within 1 week; rare; high mortality

1. Lupus Anticoagulant (LA): Detected by functional coagulation assays (dRVVT, APTT-based tests); strongest predictor of thrombosis; paradoxically prolonged aPTT in vitro but prothrombotic in vivo
2. Anti-cardiolipin antibodies (aCL): IgG/IgM; measured by ELISA; IgG subtype more clinically relevant
3. Anti-β2-glycoprotein I antibodies (anti-β2GPI): IgG/IgM/IgA; directed against β2-GPI (actual target of aPL); most specific for APS

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

• β2-glycoprotein I (β2GPI) is the primary antigen; expressed on activated endothelium, platelets, and trophoblasts
• aPL bind to β2GPI on cell surfaces → endothelial activation → upregulation of adhesion molecules (ICAM-1, VCAM-1), tissue factor expression
• Platelet activation → enhanced thromboxane synthesis, platelet aggregation
• Complement activation (C5a, C5b-9) → pro-inflammatory state
• Inhibition of natural anticoagulants (protein C pathway, annexin A5 anticoagulant shield)
• In pregnancy: disruption of trophoblast invasion, placental thrombosis, complement-mediated injury → fetal loss

1. Vascular thrombosis: ≥1 episode of arterial/venous/small-vessel thrombosis in any organ
2. Pregnancy morbidity:
   • ≥1 unexplained fetal death at ≥10 weeks gestation (morphologically normal fetus)
   • ≥1 premature birth ≤34 weeks due to eclampsia/severe pre-eclampsia/placental insufficiency
   • ≥3 consecutive unexplained spontaneous abortions <10 weeks

1. Lupus anticoagulant present (by ISTH guidelines)
2. Anti-cardiolipin IgG or IgM in medium-to-high titre (>40 GPL or MPL)
3. Anti-β2GPI IgG or IgM (>99th percentile)

• Anticoagulate with unfractionated heparin/LMWH acutely, transition to warfarin (target INR 2–3 for venous; 3–4 for arterial)
• DOACs: Rivaroxaban shown inferior to warfarin for APS in TRAPS trial → warfarin remains standard

• Venous thrombosis: Warfarin INR 2–3 indefinitely
• Arterial thrombosis: Warfarin INR 3–4 ± aspirin, or INR 2–3 + low-dose aspirin

• History of thrombosis: LMWH + low-dose aspirin throughout pregnancy; switch to LMWH peri-delivery; resume warfarin postpartum
• Obstetric APS (no prior thrombosis): Low-dose aspirin ± prophylactic LMWH

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QUESTION 6 [10 marks]

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

• Highly differentiated, terminally differentiated epithelial cells on the outer surface of the glomerular basement membrane (GBM)
• Components: cell body, primary processes, secondary foot processes
• Slit diaphragm (SD): bridges between adjacent foot processes; key filtration barrier; composed of:
  • Nephrin (NPHS1 gene): transmembrane protein; forms backbone of SD; mutations → Finnish congenital NS
  • Podocin (NPHS2 gene): intracellular adaptor protein; anchors nephrin; mutations → FSGS
  • CD2AP: scaffolding protein connecting nephrin/podocin to actin cytoskeleton
  • FAT1/FAT2 cadherins, TRPC6 (cation channel; gain-of-function mutations → FSGS)

1. Effacement of foot processes (universal response to injury): Triggered by circulating permeability factors (suPAR, anti-CD40, CLCF1), immune complexes, or genetic mutations. F-actin cytoskeleton disruption → foot process retraction → loss of slit diaphragm → proteinuria
2. Slit diaphragm disruption: Loss of nephrin signaling → dysregulated actin polymerization via Nck/N-WASP pathway
3. Podocyte detachment and loss: Podocytes are terminally differentiated and cannot be replaced. Detachment (podocyturia) leads to denuded GBM → parietal epithelial cell migration → adhesion → segmental sclerosis (FSGS)
4. Circulating permeability factors: Idiopathic FSGS/MCD — soluble urokinase plasminogen activator receptor (suPAR), anti-CD40 antibodies cause podocyte activation
5. Immune-mediated: In MN — M-type phospholipase A2 receptor (PLA2R) antibody + IgG4 → subepithelial immune deposits → complement activation → podocyte injury
6. Hypertrophic stress: In hyperfiltration (reduced nephron mass) — FSGS from mechanical stress on remaining podocytes

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

• Minimal Change Disease (MCD)
• Primary FSGS (various subtypes — NOS, tip, cellular, collapsing, perihilar)
• Membranous nephropathy (MN) — also has podocyte as primary target

• First-line: Oral prednisolone 1 mg/kg/day (max 80 mg) for 4–8 weeks → taper
• Frequently relapsing/steroid-dependent: cyclophosphamide, tacrolimus, mycophenolate, rituximab
• Adults: slower response than children; 8–16 weeks before declaring resistance

• Primary FSGS: Prednisolone 1 mg/kg/day for ≥4 months; steroid-resistant → calcineurin inhibitor (tacrolimus/cyclosporine) ± mycophenolate
• Genetic FSGS: Steroids ineffective; CNI may partially help; supportive therapy; genetic testing before transplantation
• Rituximab: Emerging role in steroid-dependent FSGS/MCD (anti-CD20, depletes B cells; also direct podocyte stabilization via SMPDL-3b)
• Sparsentan (dual endothelin/AT1 receptor antagonist): Approved for FSGS

• Spontaneous remission possible — observe for 6 months with RAS blockade in low-risk
• Medium/high-risk: Cyclical cyclophosphamide + corticosteroids (Ponticelli regimen) OR calcineurin inhibitors (tacrolimus) OR rituximab (anti-CD20; targets B cells producing anti-PLA2R — now preferred 1st line)

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QUESTION 7 [10 marks]

a) Etiopathogenesis and Clinical Features of Leptospirosis [5]

• Caused by pathogenic spirochetes of genus Leptospira interrogans (>200 serovars)
• Common serovars: L. icterohaemorrhagiae (Weil's disease), L. canicola, L. pomona
• Reservoir hosts: Rodents (primary), dogs, livestock, wild animals; humans are incidental hosts

1. Entry: Via skin abrasions, mucous membranes, or conjunctiva — contact with urine-contaminated water/soil (farmers, sewage workers, flood victims, military personnel)
2. Bacteremia (leptospiremic phase, days 1–7): Spirochetes invade bloodstream → disseminate to all organs; fever due to endotoxin-like lipopolysaccharide; immune evasion via LPS structure
3. Tissue invasion: Endothelial invasion → vasculitis → tissue damage in liver, kidney, lung, meninges, muscle
4. Immune phase (days 7–14): Antibody production → immune-complex mediated injury; leptospires appear in urine (leptospiruria)
5. Mechanism of organ damage:
   • Liver: Canalicular cholestasis + hepatocyte swelling (not necrosis); elevated bilirubin disproportionate to transaminases
   • Kidney: ATN + interstitial nephritis; hypokalemia from proximal tubular dysfunction
   • Lungs: Pulmonary hemorrhage syndrome (ARDS-like) — direct endothelial injury; now leading cause of death
   • Muscle: Rhabdomyolysis; myalgia (gastrocnemius tenderness)
   • Meninges: Aseptic meningitis (immune phase)

• Phase 1 (leptospiremic, 4–7 days): Abrupt high fever, severe headache, myalgia (especially calves), conjunctival suffusion (pathognomonic — non-purulent conjunctival injection), pharyngitis, rash, hepatosplenomegaly, lymphadenopathy
• Brief afebrile period (2–3 days)
• Phase 2 (immune, 4–30 days): Recurrence of fever + aseptic meningitis, uveitis (late complication)

• Jaundice (deep; obstructive pattern; elevated direct bilirubin), AKI (non-oliguric initially), hemorrhagic manifestations (thrombocytopenia, DIC), myocarditis, pulmonary hemorrhage
• Pulmonary hemorrhage with renal failure syndrome (PHRS) — most severe form
• Uveitis can occur weeks to months after apparent recovery

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

• Headache: 2
• Fever: 2
• Conjunctival suffusion: 4
• Meningism: 4
• Muscle pain/tenderness: 4
• Jaundice/hepatomegaly: 1
• Renal manifestations: 2

• Contact with animals: 1
• Exposure to water/mud/flood: 4
• Occupation/area: 1

• Thrombocytopenia (<100,000): 2
• Elevated bilirubin/creatinine: 2
• Positive serology (MAT/ELISA): 10–15

• Score ≥26: Diagnosis confirmed/probable leptospirosis → treat
• Score 20–25: Probable — investigate further
• <20: Unlikely

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c) Management of Leptospirosis [3]

• Oral doxycycline 100 mg BD × 7 days (drug of choice for mild disease; also used as chemoprophylaxis 200 mg single dose weekly in endemic areas)
• Alternatives: Amoxicillin 500 mg TDS × 7 days; azithromycin 500 mg OD × 3 days

• IV penicillin G 1.5 MU every 6 hours × 7 days — historical gold standard
• IV ceftriaxone 1 g OD × 7 days (equivalent efficacy; easier administration — preferred)
• IV ampicillin/amoxicillin also effective

• AKI: IV fluids; avoid NSAIDs; dialysis (hemodialysis/CRRT) if oliguria/AKI severe; non-oliguric AKI with K+ wasting — correct hypokalemia
• Pulmonary hemorrhage: Mechanical ventilation (lung-protective), ECMO in refractory cases; methylprednisolone 1 g/day for 3 days (evidence limited)
• Thrombocytopenia/bleeding: Platelet transfusion if <20,000 or active bleeding
• Uveitis (late): Topical steroids + mydriatics

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QUESTION 8 [10 marks]

a) Diseases Included Under Spondyloarthritis [2]

1. Ankylosing Spondylitis (AS) / Radiographic axSpA
2. Non-radiographic axSpA (nr-axSpA)

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

1. Arthritogenic peptide hypothesis: HLA-B27 presents specific endogenous self-peptides to CD8+ T cells → cross-reactivity with microbial antigens (molecular mimicry) → cytotoxic T-cell attack on joint tissues (e.g., Klebsiella nitrogenase shares homology with HLA-B27)
2. HLA-B27 misfolding hypothesis: HLA-B27 is prone to misfolding in the ER → unfolded protein response (UPR) → NF-κB activation → IL-23, IL-17, TNF-α overproduction → inflammation
3. Heavy chain homodimer (B27 HC dimer) hypothesis: HLA-B27 homodimers expressed on cell surface engage NK cells and CD4+ T cells via KIR3DL2 → ILC3/Th17 activation → IL-17/IL-22 → entheseal and axial inflammation
4. Microbiome hypothesis: Gut dysbiosis in HLA-B27+ individuals → breach of intestinal mucosal barrier → bacterial translocation → mucosal immune activation → IL-23/IL-17 axis upregulation

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

• Low back pain ≥3 months, improves with exercise but not rest
• Limited lumbar spine motion in sagittal and frontal planes
• Limited chest expansion relative to normal for age/sex

• Bilateral sacroiliitis grade ≥2, OR unilateral sacroiliitis grade ≥3

• HLA-B27 (supportive but not diagnostic alone)
• ESR, CRP, ASDAS (Ankylosing Spondylitis Disease Activity Score), BASDAI
• X-ray: Sacroiliac joints (graded 0–4); spine — "bamboo spine" (syndesmophyte bridging), "shiny corners" (Romanus lesions), "squaring" of vertebrae
• MRI pelvis: Bone marrow edema (STIR sequences) = active sacroiliitis (key for nr-axSpA)

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QUESTION 9 [10 marks]

a) Classification of Systemic Vasculitis Based on Vessel Size [2]

• Giant Cell Arteritis (GCA) / Temporal arteritis
• Takayasu Arteritis

• Polyarteritis Nodosa (PAN)
• Kawasaki Disease

• Granulomatosis with Polyangiitis (GPA) — Wegener's
• Microscopic Polyangiitis (MPA)
• Eosinophilic Granulomatosis with Polyangiitis (EGPA) — Churg-Strauss

• IgA vasculitis (Henoch-Schönlein Purpura)
• Cryoglobulinemic vasculitis
• Anti-GBM disease (Goodpasture's)
• Hypocomplementemic urticarial vasculitis

• Behçet's disease
• Cogan syndrome

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b) Pathogenesis of ANCA-Associated Vasculitis [3]

• c-ANCA (cytoplasmic) = anti-PR3 (proteinase-3) → GPA (>90%)
• p-ANCA (perinuclear) = anti-MPO (myeloperoxidase) → MPA (>60%), EGPA

1. Priming of neutrophils: Infection, cytokines (TNF, IL-18), complement fragments (C5a) → neutrophils primed → PR3/MPO translocated from azurophil granules to cell surface
2. ANCA binding: ANCA bind surface-expressed PR3/MPO → Fc receptor and Fab2 engagement → neutrophil activation (respiratory burst, degranulation)
3. Neutrophil-mediated endothelial injury: Activated neutrophils adhere to vessel wall, release reactive oxygen species (ROS), proteases (PR3), neutrophil extracellular traps (NETs) → direct endothelial destruction → necrotizing vasculitis
4. Complement activation (alternative pathway): C5a generation amplifies neutrophil priming (feedback loop); C5a inhibition (avacopan) shows therapeutic benefit
5. Granuloma formation (GPA-specific): CD4+ Th1 cells, macrophages, PR3-specific T cells → granulomatous inflammation in upper/lower respiratory tract → tissue-destructive granulomas; B cells produce anti-PR3 ANCA
6. Endothelial activation: Upregulation of adhesion molecules → leukocyte trafficking; anti-endothelial cell antibodies also described

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c) Diagnostic Evaluation and Treatment of Granulomatosis with Polyangiitis (GPA/Wegener's) [5]

• Upper airway (90%): Chronic rhinosinusitis, bloody nasal discharge, nasal septal perforation, saddle-nose deformity, subglottic stenosis
• Lower airway (85%): Pulmonary nodules/cavities, alveolar hemorrhage, cough, hemoptysis
• Renal (75%): Rapidly progressive glomerulonephritis (pauci-immune); hematuria, casts, AKI
• Other: Orbital pseudotumor, scleritis/uveitis, mononeuritis multiplex, cutaneous vasculitis, arthritis, cardiac involvement

• c-ANCA/anti-PR3 (positive in 90% of active severe GPA; confirmatory)
• ANCA by indirect immunofluorescence + antigen-specific ELISA (both required per guidelines)
• CBC (anemia, leukocytosis, thrombocytosis), ESR, CRP
• Urine: RBC casts, proteinuria (active sediment = "nephritis")
• Serum creatinine
• Serology to exclude mimics: ANA, anti-GBM, ANCA-MPO

• CXR: Bilateral nodules, cavities, infiltrates
• HRCT chest: Better characterization of pulmonary lesions
• CT sinuses: Mucosal thickening, bony erosion
• CECT orbit if orbital involvement

• Open lung biopsy: Necrotizing granulomatous inflammation + vasculitis + microabscesses
• Renal biopsy: Pauci-immune focal segmental necrotizing/crescentic GN (no or minimal immune deposits on IF)
• Nasal/sinus biopsy: Often shows granulomatous inflammation (less specific)

• Rituximab 375 mg/m² weekly × 4 doses (or 1000 mg × 2 doses, 2 weeks apart) + high-dose IV methylprednisolone 1000 mg × 3 days → oral prednisolone taper
• OR Cyclophosphamide (IV pulse 15 mg/kg every 2–3 weeks OR oral 2 mg/kg/day) + steroids (traditional regimen)
• Rituximab preferred over CYC (RAVE trial: equivalent efficacy; fewer side effects; superior for relapsing disease)

• Rituximab 500 mg every 6 months × 18–24 months (preferred; MAINRITSAN trial)
• OR Azathioprine 2 mg/kg/day × 18–24 months
• Low-dose prednisolone taper → discontinue at 4–6 months

• Avacopan 30 mg BD (complement C5a receptor blocker — FDA approved; steroid-sparing; ADVOCATE trial)
• PCP prophylaxis (co-trimoxazole) during immunosuppression
• Bone protection (calcium, Vit D, bisphosphonates)
• Monitoring: ANCA titres, creatinine, BVAS score

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QUESTION 10 [10 marks]

a) Structure, Mode of Transmission, and Pathogenesis of EBV Infection [5]

• Epstein-Barr virus = Human Herpesvirus 4 (HHV-4)
• Member of Gammaherpesvirinae subfamily, genus Lymphocryptovirus
• Double-stranded linear DNA (~172 kbp), encoding ~80 proteins
• Structural components:
  • Core: dsDNA + viral proteins (EBNA-1–6, LMP-1, LMP-2A/B, EBERs, miRNAs)
  • Icosahedral capsid: 162 capsomers; viral capsid antigen (VCA)
  • Tegument: Protein layer between capsid and envelope
  • Lipid bilayer envelope: Contains viral glycoproteins — gp350/220 (major envelope protein; binds CR2/CD21), gp42 (binds HLA class II), gH/gL (fusion)
• Two strains: EBV-1 (more common, transforms B cells efficiently) and EBV-2

• Primary: Saliva ("kissing disease") — close oropharyngeal contact; infects oropharyngeal epithelial cells first
• Blood transfusion and organ transplantation (less common)
• Sexual transmission (documented)
• Vertical (mother to infant) — rare
• Ubiquitous: >95% of adults worldwide seropositive by age 40; primary infection in childhood usually subclinical; in adolescents/young adults → infectious mononucleosis

1. Primary infection of oropharyngeal epithelium: Replicates lytically in oropharyngeal/salivary epithelial cells → viremia
2. B lymphocyte infection: Circulating EBV binds CR2 (CD21) on naive B cells via gp350; gp42 engages HLA-II for membrane fusion; enters B cells
3. Latency programs: EBV establishes 4 latency programs in B cells:
   • Latency III (growth program): Expresses all 9 latency proteins (EBNA 1–6, LMP-1, LMP-2A/B, EBERs) → B cell immortalization, polyclonal proliferation → targets: immunocompromised EBV lymphoma, PTLD
   • Latency II (default program): EBNA-1, LMP-1, LMP-2 → Hodgkin lymphoma, nasopharyngeal carcinoma
   • Latency I: EBNA-1 only → Burkitt lymphoma
   • Latency 0: No protein expression → true latent reservoir (resting memory B cells)
4. LMP-1 (Latent Membrane Protein-1): Functional homologue of CD40; activates NF-κB, JAK/STAT, PI3K pathways → B cell survival, proliferation, immune evasion
5. Host immune response: CD8+ cytotoxic T lymphocytes (CTLs) expand massively (up to 40% of circulating T cells) to control B cell proliferation → the "atypical lymphocytes" (Downey cells) seen in EBV mononucleosis are activated CD8+ T cells
   • If immune response inadequate (immunosuppression, X-linked lymphoproliferative disease/SAP mutation) → uncontrolled B cell proliferation → lymphoma
6. Lytic reactivation: Triggered by stress, immunosuppression → shedding in saliva; BZLF1/ZEBRA transcription factor triggers lytic cycle

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

1. Autoimmune hemolytic anemia (AIHA): Cold agglutinin type (anti-i antibody IgM) — occurs in first 2 weeks; usually self-limited
2. Immune thrombocytopenia (ITP): Antiplatelet antibodies; petechiae/purpura; usually resolves
3. Aplastic anemia: Pure red cell aplasia or pancytopenia — rare but severe
4. Neutropenia: Common (~50% of IM); usually mild and self-limiting
5. Hemophagocytic lymphohistiocytosis (HLH/HPS): Life-threatening; macrophage activation, cytopenias, hyperferritinemia, coagulopathy; associated with X-linked lymphoproliferative disease (SAP/SH2D1A mutations) or immunosuppression
6. Lymphoma:
   • Burkitt lymphoma (Africa — EBV >95%; sporadic ~20%)
   • Hodgkin lymphoma (mixed cellularity — EBV+)
   • Primary CNS lymphoma (EBV+ in HIV patients)
   • PTLD (post-transplant lymphoproliferative disorder) — Latency III; treated with reduction of immunosuppression ± rituximab
7. EBV+ diffuse large B cell lymphoma
8. Chronic active EBV disease (CAEBV): Persistent EBV in T/NK cells; fever, lymphadenopathy, multiorgan involvement
9. Splenic rupture: Most feared acute complication (~0.1–0.5%); splenomegaly + trauma or spontaneous; avoid contact sports for 3–4 weeks

1. Encephalitis/Meningoencephalitis: Most common CNS complication; fever, headache, altered consciousness, seizures; CSF pleocytosis
2. Aseptic meningitis: Mild, self-limiting
3. Guillain-Barré Syndrome (GBS): Post-infectious demyelinating polyradiculoneuropathy; ascending weakness
4. Alice in Wonderland Syndrome: Metamorphopsia (distorted perception of size/shape); linked to EBV in children
5. Transverse myelitis: Rare; acute cord dysfunction
6. Cerebellitis/acute cerebellar ataxia: Ataxia, nystagmus, tremor
7. Bell's palsy (facial nerve palsy): EBV implicated in some cases
8. Multiple sclerosis: EBV virtually 100% seroprevalent in MS patients; molecular mimicry between EBNA-1 and GlialCAM proposed as mechanism
9. Cranial nerve palsies, optic neuritis

1. EBV hepatitis: Nearly universal in IM (~80%); mild transaminase elevation (2–10× ULN); typically resolves in 1–3 months; jaundice uncommon
2. Cholestatic hepatitis: Elevated ALP and direct bilirubin; obstructive picture
3. Acute liver failure (ALF): Rare but potentially fatal; more common in immunocompromised or primary infection in older adults; massive hepatocyte necrosis; may require transplantation
4. Granulomatous hepatitis: Non-caseating granulomas in liver biopsy; associated with EBV
5. Sinusoidal infiltration: Atypical lymphocytes infiltrate hepatic sinusoids — typical histologic finding
6. Association with hepatocellular carcinoma: EBV-associated lymphoepithelioma-like cholangiocarcinoma; EBV implicated in rare subset of HCC

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