IQ&A. --- # 🦠 EDIC PART 2 VIVA/OSCE — VIRAL INFECTIONS IN THE ICU ## Q&A with Pattern Recognition | Immunocompromised Host Focus **Sources: Goldman-Cecil Medicine, Harrison's 22E (2025), Katzung's Pharmacology, NIH/HIVMA/IDSA OI Guidelines May 2026, IDSA Vaccine Guidelines 2026** --- > **HOW TO USE:** Each Q has a **PATTERN** box - the clinical clues the examiner puts in front of you. Recognise the pattern → name the diagnosis → explain it → manage it. That is the EDIC formula. --- ## 🔴 PART 1: CYTOMEGALOVIRUS (CMV) --- ### Q1 — The Classic Transplant Setup **EXAMINER:** "A 45-year-old man, 8 weeks post-renal transplant on tacrolimus and mycophenolate, presents with 10 days of fever, malaise, and a new dry cough. CMV serology before transplant: donor was CMV positive, recipient was CMV negative. What is your thinking?" **PATTERN TO RECOGNISE:** > Post-transplant 1-6 month window + **D+/R- serology** + fever + systemic symptoms = **CMV Disease** until proven otherwise (D+/R- = highest risk combination) **ANSWER:** **Why D+/R- is the highest risk:** - Donor organ contains latent CMV (CMV seropositive donor = D+) - Recipient has NO prior immunity (CMV seronegative = R-) - Transplanted organ brings live latent virus → primary CMV infection in an immunosuppressed host = most severe form **CMV Disease Spectrum:** 1. **CMV viraemia** (detectable blood PCR, no symptoms) - common 2. **CMV syndrome** - fever, malaise, myalgia, leukopenia, thrombocytopenia, mildly elevated LFTs 3. **Tissue-invasive CMV disease:** - **CMV pneumonitis** - fever, dry cough, bilateral infiltrates (WORST prognosis) - **CMV colitis** - diarrhoea, abdominal pain, haematochezia, weight loss - **CMV oesophagitis** - odynophagia, deep linear ulcers on endoscopy - **CMV retinitis** - floaters, visual loss, "pizza-pie" fundus (haemorrhages + fluffy white exudates) - **CMV hepatitis, adrenalitis, encephalitis** (rare) **Diagnostic workup:** - **Quantitative CMV PCR (plasma)** = standard monitoring test - gives viral load - CMV antigenemia (pp65 antigen) - older test, still used in some centres - BAL for CMV PCR/culture if pneumonitis suspected - Colonoscopy with biopsy if colitis suspected (histology: CMV intranuclear inclusions = **"owl's eye" cells**) **Treatment (NIH/IDSA OI Guidelines 2025, Katzung 2025):** | Severity | Drug | Dose | Duration | |---|---|---|---| | **Severe / Tissue-invasive / Pneumonitis** | **Ganciclovir IV** | 5 mg/kg q12h (induction) | 14-21 days, then step-down | | Step-down / non-sight-threatening retinitis / mild-moderate | **Valganciclovir PO** | 900 mg BD (induction) × 21 days | Then 900 mg OD maintenance | | Ganciclovir-resistant or intolerant | **Foscarnet IV** | 90 mg/kg q12h | Until viral load undetectable | | **Refractory/resistant post-transplant CMV** | **Maribavir PO** (NEW - 2026 guideline) | **400 mg BD** | Until PCR negative | **Maribavir - EDIC MUST KNOW:** - First-in-class terminase complex inhibitor - Active against CMV resistant to ganciclovir AND foscarnet AND cidofovir - Key advantage: **does NOT cause myelosuppression or nephrotoxicity** (unlike all other CMV drugs) - Approved for refractory/resistant post-transplant CMV (SOT and HSCT) - Added to NIH/IDSA OI Guidelines **July 2025 update** **Letermovir - EDIC MUST KNOW:** - Used for **prophylaxis** (NOT treatment) in CMV seropositive HSCT recipients - 480 mg once daily IV or oral - Does NOT cause myelosuppression - Not active against resistant CMV that is already failing ganciclovir --- ### Q2 — Two Monitoring Strategies **EXAMINER:** "You are managing a CMV-positive HSCT recipient. What are the two approaches to CMV prevention and when do you choose each?" **PATTERN:** > HSCT + CMV seropositive = pick your prevention strategy carefully **ANSWER:** | Strategy | Definition | When used | Pros | Cons | |---|---|---|---|---| | **Universal Prophylaxis** | Give antiviral to ALL patients of that type from day of transplant | HSCT (CMV seropositive), D+/R- SOT | Simple, prevents primary CMV | Drug toxicity (myelosuppression with ganciclovir), cost, selects resistant virus | | **Pre-emptive Therapy** | Monitor weekly CMV PCR → treat when viral load rises (before symptoms) | Many SOT centres, HSCT | Less drug exposure, fewer side effects | Requires close surveillance, may miss rapid risers | | **Prophylaxis agents:** Valganciclovir 900 mg OD or Letermovir 480 mg OD | | | | | | **Pre-emptive treatment threshold:** Varies; treat rising/high-level viraemia | | | | | --- ### Q3 — The Retinitis Pattern **EXAMINER:** "HIV patient, CD4 count of 25 cells/µL, presents with floaters, visual loss in the left eye over 2 weeks. You perform fundoscopy. What are you looking for and what do you see?" **PATTERN:** > HIV + CD4 <50 + visual symptoms + floaters/loss of vision = **CMV Retinitis** **ANSWER:** **Classic fundoscopy description:** - **"Pizza-pie retinopathy"** = areas of white fluffy retinal infiltrates (necrosis) + haemorrhages scattered across the retina like toppings on a pizza - Lesions start near blood vessels (perivascular) - Progress from periphery inwards (if untreated → blindness) - **NO pain** (differentiates from uveitis/iritis) **Diagnosis:** - **Clinical fundoscopy** by experienced ophthalmologist = usually diagnostic - Quantitative CMV PCR blood (usually very high at CD4 <50) - Aqueous or vitreous PCR if diagnosis uncertain **Treatment (NIH/IDSA OI Guidelines 2026):** - **Sight-threatening lesion** (within 1.5 optic disc diameters of fovea or optic disc): - **Intravitreal ganciclovir or foscarnet injection** (immediate, by ophthalmologist) + systemic therapy - **Non-sight-threatening lesion:** - **Valganciclovir 900 mg BD × 21 days (induction)**, then **900 mg OD (maintenance)** - Continue maintenance until **CD4 >100 cells/µL for ≥3-6 months on ART** - **Start/optimise ART** - rising CD4 is the definitive prevention of progression **Complication: CMV Immune Recovery Uveitis (IRU)** - Paradoxical inflammatory reaction after ART-induced CD4 recovery - Causes vitritis, cystoid macular oedema, loss of vision - Management: intravitreal/periocular steroids --- ### Q4 — The "CMV in Non-Immunocompromised ICU" Twist **EXAMINER:** "Do non-immunocompromised critically ill patients in ICU reactivate CMV? Does it matter?" **PATTERN:** > This is an EDIC examiner testing whether you know CMV is NOT just a transplant/HIV problem **ANSWER:** **YES** - CMV reactivation occurs in ~30-35% of CMV-seropositive non-immunocompromised ICU patients, especially: - Sepsis patients - Burns patients - Major trauma - Prolonged ICU stay (>5 days) - Patients receiving steroids **Mechanism:** Critical illness causes immunoparesis → TNF/catecholamines → reactivation of latent CMV from CD14+ monocytes and endothelial cells **Does it matter?** - Observational data suggests ICU CMV reactivation is associated with: - Prolonged mechanical ventilation - Longer ICU stay - Higher mortality - However, **RCTs of antiviral treatment in non-immunocompromised ICU patients have NOT shown clear mortality benefit** (GRAIL trial, ViRAL trial) - Current consensus: **Routine CMV monitoring and treatment is NOT recommended** in immunocompetent ICU patients outside of clinical trials - **Exception:** If CMV pneumonitis is diagnosed as cause of respiratory failure in a previously immunocompetent patient - treat with ganciclovir **EDIC answer:** "CMV reactivation does occur in critically ill non-immunocompromised patients, but routine treatment is not currently standard of care - the evidence does not support it outside of transplant/HIV settings." --- ## 🟠 PART 2: HERPES SIMPLEX VIRUS (HSV) IN ICU --- ### Q5 — The Encephalitis Emergency **EXAMINER:** "A 38-year-old man is brought to ICU with confusion, fever, and two seizures. MRI brain shows signal abnormality in the left temporal lobe and insular cortex. What do you do?" **PATTERN TO RECOGNISE:** > Fever + confusion + seizures + **temporal lobe involvement on MRI** = **HSV Encephalitis** until proven otherwise **ANSWER:** **Why temporal lobe?** - HSV-1 travels via the olfactory nerve or trigeminal nerve (latent in trigeminal ganglion) → reaches temporal lobes and frontal lobes - Produces **haemorrhagic necrotising encephalitis** - most severe viral encephalitis - Classic MRI: T2/FLAIR hyperintensity in **mesiotemporal cortex, inferofrontal cortex, insular cortex** - usually unilateral or asymmetrically bilateral (Goldman-Cecil Medicine) **Initial management (do NOT wait for results):** 1. **Start Aciclovir IV IMMEDIATELY** - 10 mg/kg every 8 hours - while investigations pending (Harrison's 22E, 2025; Goldman-Cecil) 2. LP (if no contraindication/raised ICP) - send CSF for: - **HSV PCR** (sensitivity ~98%, specificity ~99% - gold standard) - Cell count (lymphocytic pleocytosis, may see RBCs - from haemorrhage) - Glucose, protein (glucose mildly low, protein elevated) - Oligoclonal bands, autoimmune panel (anti-NMDA receptor Ab to exclude autoimmune encephalitis) 3. EEG - temporal lobe periodic lateralised epileptiform discharges (PLEDs) = classic but not specific 4. Manage seizures (IV levetiracetam or lorazepam acutely) 5. Manage raised ICP if present **Treatment:** - **IV Aciclovir 10 mg/kg q8h × minimum 14-21 days** - Immunocompromised patients: 21 days minimum, consider longer - Switch to oral valacyclovir for step-down in mild cases only - Reduce dose for renal impairment (Aciclovir is renally cleared - can cause crystalline nephropathy) **EDIC KEY POINT:** You do NOT wait for the LP or MRI result to start aciclovir. The clinical diagnosis of possible HSV encephalitis is enough to treat. Delay = irreversible brain damage. --- ### Q6 — Aciclovir Mechanism & Toxicity **EXAMINER:** "How does aciclovir work and what are its side effects?" **ANSWER:** **Mechanism (Katzung/Goldman-Cecil):** 1. Aciclovir enters virus-infected cells 2. Virus-encoded **thymidine kinase** phosphorylates it (200× greater affinity for viral TK than human TK - this is the selectivity) 3. Host cell enzymes further phosphorylate to **aciclovir triphosphate** 4. This preferentially inhibits **viral DNA polymerase** → chain termination 5. Because it requires viral TK for activation, it is **selectively toxic to virus-infected cells** **Coverage:** HSV-1, HSV-2, VZV (very effective) | EBV (moderate) | CMV (minimal - needs ganciclovir instead) **Toxicity:** | Side Effect | What happens | Prevention/Treatment | |---|---|---| | **Crystalline nephropathy** | Aciclovir precipitates in renal tubules if inadequately hydrated | IV hydration, slow infusion (over 1 hour), dose-reduce in renal failure | | CNS toxicity | Confusion, tremor, encephalopathy (especially in elderly/renal failure) | Dose reduction | | Nausea, vomiting, headache | Common | Supportive | | Phlebitis | If IV extravasates (alkaline pH) | Use large vein, dilute well | **Valacyclovir** = prodrug of acyclovir (L-valyl ester); 3-5× better oral bioavailability; used orally when IV aciclovir is stepped down --- ### Q7 — HSV in the Immunocompromised ICU Patient **EXAMINER:** "How does HSV infection present differently in an immunocompromised patient compared to immunocompetent?" **PATTERN:** > Immunocompromised + HSV = more severe, more prolonged, can DISSEMINATE **ANSWER:** | Feature | Immunocompetent | Immunocompromised | |---|---|---| | **Oral/labial HSV** | Self-limiting cold sores | Severe painful ulcers, may be non-healing, atypical appearance | | **Genital HSV** | Recurrent self-limited | Severe, prolonged, ulcerative, may spread perianally | | **Oesophagitis** | Rare, self-limited | Common - odynophagia, dysphagia; punched-out shallow ulcers on endoscopy | | **Pneumonitis** | Very rare | Occurs (extension from tracheo-bronchitis) - bilateral infiltrates | | **Encephalitis** | Can occur (HSV-1) | More severe, higher mortality, longer treatment needed | | **Disseminated HSV** | Very rare | Liver (hepatitis), lung, adrenals, brain - can cause multi-organ failure | | **Aciclovir resistance** | Extremely rare | **Occurs** (especially in HIV/HSCT - TK-deficient mutants) | **Treatment in immunocompromised:** - **IV Aciclovir** for all severe/visceral/CNS HSV in immunocompromised (NOT oral - need reliable blood levels) - If aciclovir-resistant HSV (no improvement after 5-7 days, or TK mutation confirmed): **Foscarnet IV** (does not need viral TK) - Duration: until clinical resolution (often 14-21 days) - Prophylaxis: **Aciclovir** or **Valacyclovir** in HSCT/SOT recipients to prevent reactivation --- ## 🟡 PART 3: VARICELLA-ZOSTER VIRUS (VZV) IN ICU --- ### Q8 — Disseminated Zoster Emergency **EXAMINER:** "An 82-year-old woman on long-term prednisolone for SLE presents to ICU with fever, respiratory failure, and a rash. The rash has lesions at different stages - vesicles, pustules, and crusts - involving more than 3 dermatomes, including truncal lesions." **PATTERN TO RECOGNISE:** > Immunocompromised (steroids) + **rash in multiple dermatomes** + vesicles at different stages + respiratory failure = **Disseminated VZV (Disseminated Herpes Zoster)** **ANSWER:** **Normal vs Immunocompromised VZV:** | Presentation | Immunocompetent | Immunocompromised | |---|---|---| | **Dermatomal zoster** | Painful vesicular rash in ONE dermatome, self-limiting | Severe, prolonged, may not heal | | **Disseminated zoster** | >20 vesicles outside primary dermatome - RARE | **COMMON** -IN EDIC MOST IMPORTANT HIV,IRIS,CMV --- CAN U ADD THESE AND REWRITE EDIC STYLE VIVA

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