1. A 52-year-old CMV donor-positive/recipient-negative (D+/R-) kidney transplant recipient, now eight weeks post-transplant on tacrolimus, mycophenolate, and prednisone, completed valganciclovir prophylaxis two weeks ago. He presents with low-grade fever, malaise, and mild leukopenia. Plasma CMV PCR, undetectable during prophylaxis, is now rising on serial testing. He has no diarrhea, dyspnea, or visual symptoms. What is the most appropriate next step?
A) Reassure and repeat CMV PCR in one month, since prophylaxis was completed
B) Begin empiric foscarnet, since post-prophylaxis CMV is presumptively ganciclovir-resistant
C) Initiate treatment-dose valganciclovir (or IV ganciclovir) for this episode of post-prophylaxis CMV infection and continue serial CMV PCR to confirm response
D) Permanently discontinue mycophenolate and start letermovir as treatment
E) Obtain colonoscopy and bronchoscopy before any antiviral therapy
ANSWER: C
Rationale:
This is the classic late-onset CMV picture in a D+/R- recipient after prophylaxis is stopped. Option C is correct: a rising CMV viral load with compatible symptoms in a high-risk recipient who has just finished prophylaxis represents late-onset CMV infection, and the standard response is treatment-dose valganciclovir or IV ganciclovir with serial PCR to confirm a virologic response; immunosuppression is also reviewed.
Option A: Option A is incorrect: a rising load with symptoms requires treatment, not a one-month delay.
Option B: Option B is incorrect: resistance is not presumed at first episode — it is suspected only when the load fails to fall after about two weeks of adequate therapy, then confirmed by genotyping.
Option D: Option D is incorrect: letermovir is a prophylactic agent with a low resistance barrier and is not first-line treatment for active replication; abruptly stopping mycophenolate entirely is not the indicated step.
Option E: Option E is incorrect: there are no localizing tissue-invasive symptoms, so empiric pan-endoscopy is unnecessary and should not delay antiviral therapy. Late-onset CMV after prophylaxis is the recognized trade-off of the universal prophylaxis strategy.
2. A 40-year-old allogeneic HSCT recipient with CMV viremia has been on therapeutic-dose IV ganciclovir for 15 days. Her CMV viral load has not declined by even one log10 and her symptoms persist. Adherence and dosing have been verified, and renal function is normal. What is the most appropriate next step?
A) Continue the same ganciclovir for another two weeks before reassessing
B) Suspect ganciclovir resistance and send genotypic resistance testing of the UL97 and UL54 genes to guide the next agent
C) Add corticosteroids to suppress the inflammatory component of CMV disease
D) Switch immediately to letermovir monotherapy as definitive treatment
E) Stop all antiviral therapy and rely on immune reconstitution alone
ANSWER: B
Rationale:
Failure of the viral load to fall by at least one log10 after about two weeks of adequate therapy is the trigger to investigate resistance. Option B is correct: persistent or non-declining CMV viral load despite confirmed adequate ganciclovir dosing and adherence should prompt suspicion of resistance, and genotypic testing of UL97 (phosphotransferase) and UL54 (DNA polymerase) identifies the mutation and directs the next agent — for example, foscarnet for isolated UL97 resistance.
Option A: Option A is incorrect: simply continuing a failing regimen wastes time and allows disease progression.
Option C: Option C is incorrect: corticosteroids do not treat CMV replication and would deepen immunosuppression.
Option D: Option D is incorrect: letermovir is a prophylactic agent with a low resistance barrier and is not appropriate as treatment for active, high-level replication.
Option E: Option E is incorrect: abandoning antiviral therapy in active CMV disease is unsafe; immune reconstitution is an adjunct, not a substitute. Genotype-guided switching is the rational pathway when first-line therapy fails.
3. The HSCT recipient from the prior scenario has genotyping that returns an isolated UL97 mutation (codon 594) with a wild-type UL54 gene. She remains neutropenic (ANC 600/microliter). Which management plan is most appropriate?
A) Increase the ganciclovir dose, since the UL54 polymerase remains susceptible
B) Add maribavir to ganciclovir to potentiate ganciclovir activation
C) Start cidofovir as the only option, accepting guaranteed nephrotoxicity
D) Continue ganciclovir and add filgrastim, since the resistance is only partial
E) Switch to foscarnet, which requires no UL97-mediated activation and is non-myelosuppressive, while monitoring renal function and repleting calcium, magnesium, and potassium
ANSWER: E
Rationale:
This vignette requires applying both the resistance genotype and the patient's marrow status to agent selection. Option E is correct: an isolated UL97 mutation impairs ganciclovir activation, but wild-type UL54 leaves the polymerase susceptible to foscarnet, which needs no activation; foscarnet is also non-myelosuppressive, an advantage in this neutropenic patient, with the caveat that its nephrotoxicity and electrolyte wasting (hypocalcemia, hypomagnesemia, hypokalemia) require monitoring and repletion.
Option A: Option A is incorrect: dose escalation cannot overcome a UL97 activation defect.
Option B: Option B is incorrect: maribavir inhibits UL97, which would impair ganciclovir activation further — the combination is antagonistic.
Option C: Option C is incorrect: cidofovir is generally reserved given its nephrotoxicity and is not the preferred next agent when foscarnet is available for UL97 resistance.
Option D: Option D is incorrect: the resistance defeats ganciclovir regardless of neutrophil support, so continuing it is futile. Foscarnet is the standard switch for isolated UL97-mediated ganciclovir resistance.
4. Two days after starting foscarnet, the same patient develops perioral and fingertip tingling, muscle cramps, and a positive Chvostek sign during an infusion. An ECG shows a prolonged QTc. What is the most likely cause and the appropriate response?
A) Foscarnet-induced electrolyte disturbance — chelation of divalent cations causing hypocalcemia and hypomagnesemia; check and replete calcium, magnesium, and potassium, ensure repletion before subsequent infusions, and reassess the QTc
B) Tacrolimus neurotoxicity unrelated to foscarnet; no electrolyte evaluation is needed
C) Ganciclovir rechallenge effect; resume ganciclovir to stabilize the membrane
D) Acute hypercalcemia from foscarnet; treat with aggressive saline diuresis and bisphosphonates
E) An expected benign infusion reaction requiring no monitoring or intervention
ANSWER: A
Rationale:
The symptom cluster of perioral/peripheral paresthesias, tetany signs, cramps, and QTc prolongation during foscarnet points squarely to its characteristic electrolyte toxicity. Option A is correct: foscarnet chelates ionized divalent cations, producing hypocalcemia and hypomagnesemia (and often hypokalemia), which cause neuromuscular irritability (paresthesias, positive Chvostek sign, cramps) and QTc prolongation; the response is to measure and replete calcium, magnesium, and potassium, repletion before each infusion, and reassess the QTc.
Option B: Option B is incorrect: while tacrolimus can be neurotoxic, the tetany and QTc changes during foscarnet are best explained by foscarnet electrolyte wasting, and electrolytes must be checked.
Option C: Option C is incorrect: the patient has UL97-resistant CMV, so resuming ganciclovir is both ineffective and irrelevant to electrolyte correction.
Option D: Option D is incorrect: foscarnet causes hypocalcemia, not hypercalcemia, so the proposed treatment is exactly wrong.
Option E: Option E is incorrect: these are signs of a clinically important, potentially dangerous electrolyte derangement, not a benign reaction. Mandatory pre-infusion electrolyte repletion is a defining feature of safe foscarnet use.
5. A 33-year-old allogeneic HSCT recipient, day 50 post-transplant, develops progressive dyspnea, nonproductive cough, and hypoxemia. CT shows bilateral interstitial infiltrates. Blood CMV PCR is negative. The team is concerned about CMV pneumonitis. What is the most appropriate diagnostic and therapeutic approach?
A) Exclude CMV on the basis of the negative blood PCR and treat empirically for bacterial pneumonia only
B) Begin high-dose corticosteroids for presumed idiopathic pneumonia syndrome without further testing
C) Start letermovir, since it is the agent of choice for established CMV pneumonitis
D) Perform bronchoscopy with bronchoalveolar lavage for CMV testing; if CMV pneumonitis is confirmed, treat with IV ganciclovir plus IVIG and reduce immunosuppression where feasible, recognizing that blood CMV PCR can be negative in pneumonitis
E) Treat with foscarnet monotherapy and avoid IVIG, which has no role in pulmonary CMV
ANSWER: D
Rationale:
This vignette tests recognition that blood PCR can be falsely negative in tissue-invasive CMV and that pneumonitis is managed with combination therapy. Option D is correct: CMV pneumonitis, the most lethal CMV manifestation in allogeneic HSCT, requires bronchoalveolar lavage for diagnosis because blood CMV PCR is frequently negative; confirmed disease is treated with IV ganciclovir plus IVIG (which supplies CMV-specific neutralizing antibody at the alveolar surface) and reduction of immunosuppression where feasible.
Option A: Option A is incorrect: a negative blood PCR does not exclude tissue-invasive CMV, and missing it can be fatal.
Option B: Option B is incorrect: empiric steroids without diagnosis risk worsening unrecognized CMV.
Option C: Option C is incorrect: letermovir is prophylactic and not a treatment for established CMV pneumonitis.
Option E: Option E is incorrect: IVIG is a standard adjunct in CMV pneumonitis, and monotherapy is inferior in this severe manifestation. The combination of BAL-based diagnosis and ganciclovir-plus-IVIG therapy reflects the high mortality of this condition.
6. A 9-year-old EBV donor-positive/recipient-negative (D+/R-) intestinal transplant recipient develops cervical lymphadenopathy, fever, and a rapidly rising EBV viral load five months post-transplant. Biopsy shows early polymorphic EBV-positive post-transplant lymphoproliferative disorder (PTLD). Which intervention should be applied first, when clinically feasible?
A) Begin R-CHOP chemotherapy immediately for all PTLD
B) Start IV ganciclovir, since EBV is a herpesvirus susceptible to it
C) Reduce immunosuppression to allow recovery of EBV-specific cytotoxic T-cell surveillance, the first-line intervention in early PTLD
D) Proceed directly to four weekly doses of rituximab before any change in immunosuppression
E) Perform splenectomy to debulk the proliferating B cells
ANSWER: C
Rationale:
Pediatric primary EBV infection in a D+/R- recipient is a classic high-risk PTLD setting, and the management hierarchy starts with immune restoration. Option C is correct: reduction of immunosuppression is the first intervention in early polymorphic PTLD wherever feasible, allowing reconstitution of EBV-specific cytotoxic T cells, with response rates of roughly 20-40% in early disease.
Option A: Option A is incorrect: R-CHOP is reserved for aggressive monomorphic PTLD or failure of earlier steps, not first-line for all PTLD.
Option B: Option B is incorrect: latently infected B cells do not express viral thymidine kinase, so ganciclovir cannot be activated and is ineffective for established PTLD.
Option D: Option D is incorrect: rituximab is added when reduction of immunosuppression is insufficient or disease progresses — it complements, rather than precedes, the foundational step.
Option E: Option E is incorrect: splenectomy is not part of the standard hierarchy. The high donor lymphoid burden of intestinal transplants makes this child especially PTLD-prone, but the first lever remains reducing immunosuppression.
7. A 6-year-old recipient of a T-cell-depleted allogeneic HSCT is found on surveillance to have rising adenovirus viremia, with early hemorrhagic cystitis and transaminitis signaling disseminating disease. Pharmacological treatment is indicated. Which plan is most appropriate?
A) Begin ganciclovir, since it is the agent of choice for adenovirus
B) Start cidofovir with the standard nephroprotective protocol — oral probenecid before and after each infusion plus IV normal saline hydration — and check renal function and proteinuria before each dose, holding the drug if creatinine clearance falls below the contraindication threshold
C) Begin letermovir, which covers adenovirus through terminase inhibition
D) Withhold antivirals and rely solely on immune reconstitution, regardless of dissemination
E) Start full-dose cidofovir without probenecid or saline to maximize antiviral exposure
ANSWER: B
Rationale:
This vignette tests recognition that cidofovir is the principal agent for disseminated adenovirus and that it demands a specific nephroprotective protocol. Option B is correct: disseminated adenovirus in a T-cell-depleted HSCT recipient carries high mortality, and cidofovir is the principal pharmacological option; because cidofovir is taken up into proximal tubular cells via OAT1 and is nephrotoxic, each dose is given with oral probenecid (before and after) and IV saline, with renal function and proteinuria checked before each dose and the drug contraindicated below the defined creatinine-clearance threshold.
Option A: Option A is incorrect: ganciclovir is not the agent of choice for adenovirus.
Option C: Option C is incorrect: letermovir is CMV-specific and inactive against adenovirus.
Option D: Option D is incorrect: withholding therapy in disseminating adenovirus is unsafe, though reduction of immunosuppression and adoptive T-cell strategies are important adjuncts.
Option E: Option E is incorrect: omitting probenecid and saline maximizes nephrotoxicity and is contraindicated. Brincidofovir avoids OAT1 uptake but did not show a survival benefit in a phase 3 adenovirus trial.
8. A 58-year-old kidney transplant recipient at month 5 has a plasma BK polyomavirus load rising above 10,000 copies/mL with a creatinine increasing from 1.3 to 1.8 mg/dL. Allograft biopsy confirms BK polyomavirus nephropathy. What is the cornerstone of management?
A) Start IV ganciclovir, which is virus-specific for BK polyomavirus
B) Begin letermovir, repurposing its terminase activity against BK
C) Intensify immunosuppression to protect the graft from concurrent rejection
D) Proceed to immediate allograft nephrectomy
E) Reduce immunosuppression — lower the calcineurin inhibitor target and reduce or stop the antimetabolite — to restore BK-specific cytotoxic T-cell control, since no antiviral is reliably effective, while monitoring graft function for rejection
ANSWER: E
Rationale:
BK nephropathy is managed primarily by restoring immune control because effective antivirals are lacking. Option E is correct: the cornerstone of BK nephropathy management is reduction of immunosuppression (lowering the calcineurin inhibitor target and reducing or stopping the antimetabolite) to allow BK-specific cytotoxic T-cell reconstitution, guided by serial plasma BK PCR, while watching graft function because the same reduction raises rejection risk.
Option A: Option A is incorrect: ganciclovir is not active against BK polyomavirus.
Option B: Option B is incorrect: letermovir is CMV-specific (the CMV terminase) and has no BK activity.
Option C: Option C is incorrect: intensifying immunosuppression worsens BK replication.
Option D: Option D is incorrect: nephrectomy is not first-line; the aim is to salvage the graft by restoring immune control. Low-dose cidofovir or leflunomide are reserved for refractory cases on limited observational evidence.
9. A 45-year-old woman with multiple sclerosis, JC virus antibody-positive and on natalizumab for 30 months, develops subacute right-sided weakness and behavioral change. MRI shows multifocal T2-hyperintense white-matter lesions without mass effect, and CSF JC virus PCR is positive. Which management approach is correct?
A) Discontinue natalizumab immediately and consider plasma exchange to accelerate its clearance, recognizing that no antiviral is effective against JC virus and that rapidly restoring CNS immune surveillance may precipitate immune reconstitution inflammatory syndrome (IRIS), which must be anticipated and managed
B) Continue natalizumab to limit the CNS inflammation contributing to her deficits
C) Start high-dose cidofovir, which reliably clears JC virus
D) Begin IV ganciclovir, since JC virus is a polyomavirus like BK
E) Deepen immunosuppression to slow JC virus replication
ANSWER: A
Rationale:
This is the prototypical natalizumab-associated PML vignette, with high-risk features (antibody-positive, duration beyond 24 months). Option A is correct: management requires immediate discontinuation of natalizumab, with plasma exchange used to hasten clearance, because recovery depends on restoring JC virus-specific T-cell surveillance and no antiviral is effective; the team must anticipate IRIS, since the rapid return of lymphocyte trafficking into the CNS can inflame PML lesions and may require corticosteroids.
Option B: Option B is incorrect: continuing natalizumab perpetuates the blockade of lymphocyte CNS entry that allowed PML.
Option C: Option C is incorrect: cidofovir has failed to show benefit against JC virus.
Option D: Option D is incorrect: ganciclovir is not active against JC virus despite the polyomavirus classification.
Option E: Option E is incorrect: deepening immunosuppression worsens PML by further impairing the needed T-cell response. Her risk profile reflects the validated natalizumab PML stratification by antibody index, treatment duration, and prior immunosuppressant use.
10. A 38-year-old allogeneic HSCT recipient, three weeks post-transplant during profound T-cell lymphopenia, develops acute confusion, dense anterograde amnesia, and a seizure. MRI shows bilateral medial temporal lobe T2/FLAIR signal abnormality without hemorrhage. CSF HHV-6 PCR is positive and plasma HHV-6 is also detectable. Which statement best directs management?
A) The plasma HHV-6 positivity alone establishes encephalitis, so no CSF testing was needed and observation suffices
B) This is almost certainly inherited chromosomally integrated HHV-6, so antiviral therapy is contraindicated
C) Empiric acyclovir at HSV doses is adequate, since HHV-6 responds to acyclovir like HSV
D) Treat HHV-6 encephalitis with IV ganciclovir or foscarnet for at least three weeks or until clinical and virologic response, recognizing that CSF PCR — not plasma PCR — is required for diagnosis given frequent asymptomatic plasma reactivation after HSCT
E) Begin letermovir, since its terminase activity covers HHV-6 encephalitis
ANSWER: D
Rationale:
The timing (week 3, T-cell lymphopenia), the medial temporal MRI pattern, and CSF HHV-6 PCR positivity define post-transplant HHV-6B encephalitis. Option D is correct: HHV-6B encephalitis is treated with IV ganciclovir (5 mg/kg every 12 hours) or foscarnet (90 mg/kg every 12 hours) for at least three weeks or until response, and diagnosis rests on CSF HHV-6 PCR because plasma reactivation is common after HSCT (30-70%) without neurological disease.
Option A: Option A is incorrect: plasma positivity is nonspecific in this setting, which is exactly why CSF testing is needed, and observation is inappropriate for encephalitis.
Option B: Option B is incorrect: the clinical syndrome with CSF positivity indicates active encephalitis requiring treatment, not an integrated carrier state; iciHHV-6 would be confirmed by hair follicle testing in an asymptomatic patient.
Option C: Option C is incorrect: HHV-6 is treated with ganciclovir or foscarnet, not standard-dose acyclovir.
Option E: Option E is incorrect: letermovir is CMV-specific and not used for HHV-6 encephalitis. The medial temporal pattern can resemble HSV encephalitis but lacks the hemorrhagic component.
11. A 36-year-old man with HIV and a CD4 count of 30/microliter is diagnosed with CMV retinitis and started on anti-CMV therapy and antiretroviral therapy (ART). Six weeks later his HIV viral load is falling and his CD4 count has risen to 140/microliter, but his retinitis paradoxically worsens with new intraocular inflammation (uveitis). CMV viral parameters are improving. What is the most likely explanation and the appropriate response?
A) CMV antiviral resistance; switch to foscarnet immediately
B) Immune reconstitution inflammatory syndrome (IRIS): recovering CD4+ T cells are mounting inflammation against residual CMV antigen despite good viral control; continue ART and anti-CMV therapy and consider short-course corticosteroids to control intraocular inflammation, with ophthalmology involvement
C) ART-induced direct retinal toxicity; discontinue antiretroviral therapy
D) Primary failure of anti-CMV therapy; the falling CMV load confirms this
E) A new herpes simplex retinitis unrelated to the immune recovery
ANSWER: B
Rationale:
Worsening of a treated infection alongside improving virologic markers and a rising CD4 count is the signature of IRIS. Option B is correct: as immunity reconstitutes on ART, recovering CD4+ T cells react against residual CMV antigen, producing paradoxical inflammatory worsening (CMV IRIS, classically retinitis/uveitis) despite good virologic control; management is to continue ART and anti-CMV therapy and consider short-course corticosteroids to suppress the excessive inflammation without abrogating immune recovery, with ophthalmology co-management.
Option A: Option A is incorrect: improving CMV parameters argue against resistance.
Option C: Option C is incorrect: the picture is immune-mediated inflammation tied to immune recovery, not direct ART retinal toxicity, and stopping ART would be counterproductive.
Option D: Option D is incorrect: a falling CMV load indicates response, not failure.
Option E: Option E is incorrect: the worsening is of the same, already-diagnosed CMV retinitis in the context of immune recovery, not a new HSV infection. The same immune-reconstitution principle explains unmasking of EBV, adenovirus, or HHV-6 when transplant immunosuppression is reduced.
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