Questions
CMV in the Transplant Patient — Questions
Study questions for CMV in the Transplant Patient.
Mock Exam mode
Sit this set one question at a time. Multiple-choice questions mark themselves; written questions reveal a tickable mark scheme so you can score your own answer. You get a combined score at the end.
23 questions: 17 MCQ, 6 written.
- High priorityMCQ
A seropositive stem-cell transplant recipient on pre-emptive CMV surveillance has a low-level plasma CMV PCR that was negative the week before. How should the result be interpreted and acted on?
- A. There is no single universal viral-load cutoff; a rising trend and the patient's risk guide action, so a low first-positive in a high-risk patient prompts early treatment while a borderline value in a low-risk patient may be repeated in a few days
- B. A single low-level positive result should always be ignored until the viral load has risen above one million international units per millilitre, the universally agreed threshold at which CMV disease becomes inevitable in every patient
- C. Any detectable CMV at all, however low, mandates immediate full induction antiviral therapy in every transplant recipient, because the viral-load value carries no useful information beyond being positive or negative
- D. The absolute value can be ignored entirely as long as the patient has no fever, since pre-emptive therapy is started on the basis of clinical symptoms of CMV disease rather than on any surveillance viral-load result
- E. The result should be converted from international units to copies per millilitre before any decision, because pre-emptive thresholds are defined only in copies and international units cannot be used to guide pre-emptive therapy during routine post-transplant surveillance
Show answer
Correct answer: A
How to read a surveillance viral load
Pre-emptive therapy is triggered by the viral load, but there is no single universal cutoff, because thresholds remain assay-specific even in international units. Two things guide the decision:
- The trend. Both a higher initial load and a faster rate of rise predict progression to disease, so serial values matter more than one reading. A first-positive after a negative warrants close attention.
- The patient’s risk. In a high-risk patient (such as one with graft-versus-host disease, on steroids, T-cell-depleted or mismatched), treatment is started promptly at any confirmed viraemia; in a lower-risk patient a borderline low value may be repeated in a few days and treated only if it rises.
The distractors invent a universal threshold (B), discard the quantitative information (C), make pre-emptive therapy symptom-driven rather than load-driven (D), or misunderstand that international units are exactly what modern thresholds use (E).
- High priorityMCQ
A transplant recipient has established CMV disease. Which best describes the first-line treatment and how its duration is decided?
- A. Intravenous ganciclovir or oral valganciclovir at induction dosing, continued for at least two weeks and until the viral load has cleared below the threshold, with intravenous therapy chosen for severe or sight-threatening or life-threatening disease
- B. Oral letermovir at a fixed prophylactic dose for exactly two weeks regardless of the viral load, since it is the most potent agent against established tissue-invasive CMV disease in the transplant recipient and clears it fastest
- C. A single high dose of intravenous foscarnet, repeated only if the patient remains febrile, with no need for viral-load monitoring because clinical response alone reliably indicates that the infection has been fully eradicated
- D. Oral valaciclovir at the dose used for varicella-zoster, continued lifelong, because aciclovir-class drugs are the established first-line treatment for tissue-invasive CMV disease in solid-organ and stem-cell recipients alike
- E. Reduction of immunosuppression alone with no antiviral, since restoring immunity is sufficient to clear established CMV disease and antiviral drugs add nothing once organ involvement has already developed in the patient, whatever the severity of disease at presentation
Show answer
Correct answer: A
First-line treatment
The first-line agents are intravenous ganciclovir or its oral prodrug valganciclovir at induction dosing. Valganciclovir is suitable for non-severe disease where gut absorption is reliable; intravenous ganciclovir is preferred for severe, sight-threatening or life-threatening disease, or where absorption is uncertain.
Deciding the duration
Treatment is given for a minimum of two weeks and continued until the viral load has cleared below the local threshold (commonly to undetectable on consecutive samples) and the patient has responded clinically. An important rule is not to switch agents within the first two weeks if the patient is improving, since the viral load may take that long to fall. Where reasonable, reducing immunosuppression is a useful adjunct, but it does not replace the antiviral (so option E is wrong). Letermovir (B) is prophylaxis only, foscarnet (C) is not first-line and needs monitoring, and aciclovir-class drugs (D) are not effective treatment for CMV disease.
- High priorityMCQ
A transplant recipient has refractory CMV with a confirmed UL97 mutation conferring ganciclovir resistance. Which option best describes appropriate salvage therapy?
- A. Switch to maribavir (an oral UL97 inhibitor licensed for refractory or resistant CMV) or to foscarnet; letermovir is not used as salvage because it is a prophylactic agent with a low barrier to resistance
- B. Switch to letermovir monotherapy, since its terminase target is unaffected by UL97 mutations and it has a high barrier to resistance, making it the established salvage agent for ganciclovir-resistant CMV disease
- C. Increase the ganciclovir dose and continue it unchanged, because UL97 mutations only slow viral clearance rather than cause true resistance, so higher exposure of the same drug will overcome the mutation reliably
- D. Stop all antiviral therapy and rely solely on reducing immunosuppression, since no antiviral retains activity once a UL97 mutation is present and immune reconstitution is the only remaining effective option available
- E. Switch to high-dose oral valaciclovir, because aciclovir-class drugs act through a different viral enzyme and therefore remain fully effective against UL97-mutant ganciclovir-resistant cytomegalovirus in this setting
Show answer
Correct answer: A
Salvage for resistant CMV
With a confirmed UL97 mutation (ganciclovir resistance), the active options are:
- Maribavir, an oral inhibitor of the UL97 kinase itself, licensed specifically for refractory or resistant post-transplant CMV and not myelosuppressive (though resistance to it, via UL97 and UL27, can emerge);
- Foscarnet, which acts on the polymerase and does not need UL97 activation, so it retains activity (limited by nephrotoxicity).
Reducing immunosuppression is a valuable adjunct to let immunity help, but not a substitute for an active drug.
Why the distractors are wrong
Letermovir (B) has a low barrier to resistance and is a prophylactic agent, not salvage. Simply increasing ganciclovir (C) does not overcome a true UL97 mutation. Stopping all antivirals (D) abandons effective salvage options. Aciclovir-class drugs (E) are not effective treatment for CMV disease at all.
- High priorityMCQ
In a transplant recipient being monitored for cytomegalovirus, what is the difference between CMV infection and CMV disease, and why does it matter?
- A. Infection is detection of the virus (for example viraemia on PCR) which may be asymptomatic, whereas disease is that detection together with attributable findings, either a viral syndrome or tissue-invasive end-organ involvement
- B. Infection means the virus is latent and silent in the tissues, whereas disease simply means the virus has been detected in the blood by PCR, regardless of whether the patient has any symptoms attributable to it
- C. Infection refers only to a primary first encounter with the virus in a seronegative recipient, whereas disease refers only to reactivation of latent virus in a seropositive recipient after the transplant
- D. Infection and disease are interchangeable terms once the viral load rises above the laboratory cutoff, and both require the same immediate full-dose antiviral treatment to prevent organ damage
- E. Infection is diagnosed by serology showing a rising antibody titre, whereas disease is diagnosed only by culturing the virus from blood, the two being defined by which laboratory test happens to be positive in the immunosuppressed recipient
Show answer
Correct answer: A
The distinction
- CMV infection is detection of the virus (by PCR, antigen or culture) at any site, which may be entirely asymptomatic, since CMV is latent for life and reactivates without necessarily causing harm.
- CMV disease is infection plus attributable clinical findings, in one of two forms: a viral syndrome (fever, malaise, cytopenias) or tissue-invasive end-organ disease (pneumonitis, colitis, hepatitis, retinitis).
Why it matters
The distinction drives management. A pre-emptive strategy deliberately treats asymptomatic infection (detected by surveillance viral load) precisely to prevent it progressing to disease, so “infection” is a trigger to act, not yet a diagnosis of illness. Conversely, because the virus can be detected without causing disease, a positive test must always be read in clinical context. The distractors variously equate detection with disease (B, D), confuse the infection/disease axis with the primary/reactivation axis (C), or misassign the diagnostic tests (E).
- High priorityMCQ
In allogeneic haematopoietic stem-cell transplantation, which donor (D) and recipient (R) CMV serostatus carries the highest risk?
- A. D negative, R positive
- B. D positive, R negative
- C. D positive, R positive
- D. D negative, R negative
- E. Serostatus does not affect the risk
Show answer
Correct answer: A
Why A (and the inversion)
In stem-cell transplant the graft is the new immune system, not the source of virus. The seropositive recipient (R positive) drives risk by reactivating their own latent CMV, and it is worst when the donor is seronegative (D negative), because the new donor-derived immune system carries no CMV-specific T cells to control that reactivation.
This is the mirror image of solid-organ transplant, where the graft is the source of virus and D positive, R negative is highest risk. The inversion is a favourite examination point.
- High priorityMCQ
Letermovir is used for primary CMV prophylaxis in seropositive allogeneic stem-cell transplant recipients. Which statement about it is correct?
- A. It inhibits the viral terminase (UL56) complex, is not myelosuppressive, and crucially has no activity against herpes simplex or varicella-zoster virus, so separate aciclovir-class cover is still required for those
- B. It inhibits the viral DNA polymerase, is strongly myelosuppressive like ganciclovir, and conveniently also covers herpes simplex and varicella-zoster virus, so no additional aciclovir-class prophylaxis is needed alongside it
- C. It is a first-line treatment for established tissue-invasive CMV disease, has a high barrier to resistance, and is the preferred agent for salvage of ganciclovir-resistant CMV when foscarnet cannot be used safely
- D. It is given only as pre-emptive therapy once the CMV viral load crosses a defined threshold, and it covers the whole herpesvirus group, replacing both ganciclovir and aciclovir in the stem-cell transplant setting entirely
- E. It works by blocking the UL97 kinase, requires routine therapeutic drug-level monitoring, and has no clinically important interactions with the calcineurin inhibitors used to prevent graft-versus-host disease
Show answer
Correct answer: A
Why A is correct
Letermovir inhibits the CMV terminase (UL56) complex, the machinery that cleaves and packages the viral genome, a target unique to CMV. Two properties make it valuable for prophylaxis in seropositive allogeneic stem-cell recipients: it is not myelosuppressive (unlike ganciclovir), so it does not impair engraftment, and it significantly reduces clinically significant CMV when given from transplant through about week 14.
The practice-critical caveats
- It is specific to CMV and has no activity against herpes simplex or varicella-zoster virus, so a patient on letermovir still needs an aciclovir-class drug to cover those herpesviruses (option B is wrong).
- It has a low barrier to resistance (selecting UL56 mutations), so it is a prophylactic agent, not a treatment for established disease or a salvage drug (options C and D are wrong).
- It is metabolised through and inhibits CYP3A, raising calcineurin inhibitor (tacrolimus, cyclosporine) levels, so doses are adjusted (option E is wrong).
- High priorityMCQ
Which of the following anti-CMV drug pairs cannot be used together?
- A. Ganciclovir + Foscarnet
- B. Ganciclovir + Letermovir
- C. Ganciclovir + Maribavir
- D. Letermovir + Valaciclovir
- E. Maribavir + Valaciclovir
Show answer
Correct answer: C
Why C
Ganciclovir and maribavir must not be combined. Maribavir inhibits the UL97 kinase, the very enzyme that phosphorylates (activates) ganciclovir; blocking it makes ganciclovir ineffective, so the two are antagonistic and are never given together.
The other pairs
The remaining combinations are not contraindicated on this basis: ganciclovir with foscarnet (different targets, sometimes combined in resistant disease), ganciclovir with letermovir, and letermovir or maribavir with valaciclovir (which covers herpes simplex and varicella-zoster, a gap left by both letermovir and maribavir).
High priorityExam-styleDiscuss the concepts of pre-emptive versus prophylactic antiviral therapy for CMV, and the risks of late-onset CMV disease. [10]
Model answer
A complete answer defines both prevention strategies with their advantages and disadvantages, then links late-onset disease to the prophylactic approach.
Universal (prophylactic) therapy
Prophylaxis gives an antiviral (typically valganciclovir, or letermovir in seropositive allogeneic stem-cell recipients) to every at-risk patient for a fixed period after transplant, regardless of the viral load.
- Advantages: simple to deliver, needs no surveillance monitoring, reliably prevents early disease, and may additionally blunt the indirect immunomodulatory effects of CMV (rejection, other infections).
- Disadvantages: drug cost and toxicity (ganciclovir myelosuppression), selection of resistance, and, above all, late-onset disease once the drug stops.
Pre-emptive therapy
Pre-emptive therapy withholds the drug and instead monitors the viral load at regular (usually weekly) intervals, starting treatment only when replication crosses a threshold.
- Advantages: spares drug exposure, toxicity, cost and resistance, and treats only those who actually need it.
- Disadvantages: depends on reliable, frequent, standardised viral-load testing, can be outrun by rapidly rising viraemia between tests, and does not suppress the indirect effects in patients who never cross the threshold. It is often preferred in stem-cell transplant to avoid marrow toxicity.
Late-onset CMV disease
Late-onset disease is CMV disease appearing after a fixed prophylactic course ends, characteristically beyond three to six months. It occurs because prophylaxis suppresses replication throughout, so the patient is never exposed to enough virus to build CMV-specific T-cell immunity; when the drug stops, an unprimed and still-immunosuppressed patient becomes vulnerable. The highest-risk group is the seronegative recipient of a seropositive organ (D positive, R negative), in whom up to a third may be affected.
It is managed by surveillance after prophylaxis stops (switching to a pre-emptive approach for a period), risk-adapted prophylaxis duration, immune monitoring to judge when protective immunity has recovered, and secondary prophylaxis after a first episode. This trade-off, prophylaxis preventing early disease but causing late disease, is a central argument for individualising the strategy to the patient and the transplant centre.
High priorityExam-styleHow is tissue-invasive CMV disease diagnosed in a transplant recipient, and why can the blood viral load be misleading? [6]
Model answer
A complete answer gives the compartment-specific approach, the role of histology, and the caveats that make blood PCR unreliable here.
The blood viral load can mislead
For tissue-invasive disease, a blood viral load may be low or even negative, particularly in gastrointestinal disease, pneumonitis and retinitis, so a negative blood PCR does not exclude end-organ CMV. Conversely, a positive blood PCR confirms infection but does not by itself prove that a given organ’s problem is due to CMV. A blood PCR should still always be sent, however, to give a baseline against which to monitor the response to treatment.
Compartment-specific diagnosis
- Pneumonitis: bronchoalveolar lavage, supported by lung biopsy. CMV on lavage by PCR outperforms culture, but a positive respiratory culture alone is hard to interpret because the virus is shed asymptomatically.
- Gastrointestinal disease: endoscopic biopsy with histology showing the characteristic “owl’s-eye” inclusions, or immunohistochemistry, is decisive. Disease is patchy, so multiple biopsies are taken.
- Central nervous system and retina: a cerebrospinal fluid viral load is the standard for encephalitis, and vitreous sampling for retinitis, since blood markers are poor predictors of these.
The key caveat
PCR or culture on tissue can reflect blood contamination or asymptomatic shedding rather than true invasion, so molecular detection is paired with histopathology or immunohistochemistry to confirm that the virus is actually invading the tissue.
High priorityExam-styleWhat is late-onset CMV disease in the transplant recipient, why does it occur, and how is the risk managed? [6]
Model answer
A complete answer defines the entity, gives the mechanism and the at-risk group, and explains how monitoring addresses it.
What it is
Late-onset CMV disease is CMV disease that appears after a fixed course of universal prophylaxis has finished, typically beyond three to six months in solid-organ recipients, rather than during the classic one-to-six-month window. It is the characteristic drawback of the prophylactic strategy.
Why it occurs
Prophylaxis suppresses CMV replication throughout the period it is given, which prevents early disease but also means the patient is never exposed to enough virus to build CMV-specific T-cell immunity. When the drug is stopped, an immunologically unprimed and still-immunosuppressed patient can develop primary or reactivated disease. The group at greatest risk is the seronegative recipient of a seropositive organ (D positive, R negative), in whom up to a third may develop late-onset disease.
How the risk is managed
- Surveillance after prophylaxis stops: switching to viral-load monitoring (a pre-emptive approach) for a period after the prophylactic course ends, so that rising virus is caught and treated before disease.
- Risk-adapted prophylaxis duration: extending prophylaxis in the highest-risk patients, and using immune monitoring (CMV-specific T-cell assays) to judge when protective immunity has recovered and the drug can safely stop.
- Secondary prophylaxis after a first treated episode in those who remain heavily immunosuppressed.
This trade-off is one of the main arguments for a pre-emptive rather than a purely prophylactic strategy in some programmes.
High priorityExam-styleWhen should antiviral-resistant CMV be suspected in a transplant recipient, and how does genotypic resistance testing guide management? [6]
Model answer
A complete answer gives the clinical trigger, the genes tested and what each implies, and the resulting choice of agent.
When to suspect resistance
Resistance is suspected when the viral load fails to fall, plateaus, or rises despite adequately dosed therapy, in a patient who is adherent and has had cumulative antiviral exposure (generally beyond two weeks of correct treatment and around four to six weeks of total exposure). Important caveats: a failure of the load to fall in the first two weeks alone is not reliable evidence, because the response can be slow, and resistance is more likely with prolonged or repeated drug exposure and in the most immunosuppressed patients. Genotyping is most informative when the viral load is reasonably high (above about 1000 copies/mL).
Genotypic testing and what it implies
Resistance is confirmed by sequencing the viral genes that the drugs target:
- UL97 (the viral kinase that activates ganciclovir): mutations here are the commonest and emerge first, conferring ganciclovir and valganciclovir resistance.
- UL54 (the DNA polymerase): mutations confer broader resistance, including cross-resistance to foscarnet and cidofovir and additional ganciclovir resistance.
- UL56 is sequenced if letermovir is failing, and UL27 in selected maribavir-refractory cases.
How it guides management
The mutation directs the switch. Isolated UL97 ganciclovir resistance is treated by changing to foscarnet or maribavir; broader UL54 resistance narrows the options and may need combinations or investigational agents, alongside reducing immunosuppression where possible to let immunity help clear the virus.
High priorityExam-styleWhy are cytomegalovirus (CMV) viral loads reported in international units per millilitre rather than copies per millilitre, and what are the practical limits of this standardisation? [5]
Model answer
A complete answer explains what the international unit fixes, why it matters, and the residual variation it does not remove.
What the international unit fixes
Before standardisation, every laboratory reported CMV DNA in its own copies per millilitre, calibrated to its own standards, so a value from one assay could not be compared with another. The World Health Organization International Standard provides a single reference preparation against which commercial assays are calibrated, allowing results to be expressed in international units per millilitre (IU/mL).
Why it matters
Standardised reporting allows viral-load thresholds to be shared between centres and written into guidelines (for triggering pre-emptive therapy, defining treatment response, and suspecting resistance), and it allows multicentre trials and the transfer of a patient between laboratories without losing the thread of their monitoring.
The residual limits
Standardisation reduces but does not abolish variation. Even WHO-calibrated assays are not fully interchangeable, because they differ in gene target, amplicon size and extraction, so a single patient should still be followed on one assay and one specimen type throughout. Specimen type matters in its own right: a whole-blood viral load runs roughly one log10 higher than a plasma load from the same patient, so the two cannot be compared directly. Because of this residual variation, there is no single universal disease-defining cutoff, and thresholds remain assay-specific.
- MCQ
A CMV-specific cell-mediated immunity assay is most useful for deciding which of the following?
- A. When to stop CMV prophylaxis
- B. The choice of conditioning regimen
- C. Which donor organ to use
- D. The HLA match
- E. The transplant date
Show answer
Correct answer: A
Why A
Assays of CMV-specific cell-mediated immunity measure whether the patient has rebuilt the T-cell response that controls CMV. A positive result predicts freedom from later CMV events, so it can help decide when it is safe to stop prophylaxis and how to risk-stratify monitoring.
Its limits are real: performance is poor in the highest-risk D positive, R negative group, and the assays are costly, slow and unstandardised, so the concept is more established than routine use. It plays no part in choosing the donor, the HLA match, the conditioning or the transplant date.
- MCQ
A stem-cell transplant recipient is on ganciclovir for CMV. What is its principal dose-limiting toxicity, and how do the main alternative agents differ?
- A. Myelosuppression, chiefly neutropenia, monitored by the full blood count and managed with growth factors or dose change, while foscarnet and cidofovir are instead limited by nephrotoxicity (and foscarnet by electrolyte wasting)
- B. Nephrotoxicity with proximal tubular injury, monitored by the creatinine, while foscarnet and cidofovir are by contrast limited mainly by bone-marrow suppression and the resulting profound neutropenia in the transplant recipient
- C. Severe hepatotoxicity requiring weekly liver-function monitoring, while foscarnet causes a dose-limiting cardiomyopathy and cidofovir causes an irreversible peripheral neuropathy that limits the duration of therapy in these patients
- D. A hypersensitivity rash that resolves on stopping the drug, with no need for laboratory monitoring, while foscarnet and cidofovir share the identical rash and are managed in exactly the same way during treatment
- E. There is no clinically important toxicity for any of these agents in the transplant setting, so none requires laboratory monitoring during treatment, and the choice between them rests purely on the route of administration
Show answer
Correct answer: A
Ganciclovir and its alternatives
- Ganciclovir and valganciclovir: the dose-limiting toxicity is myelosuppression, especially neutropenia (in roughly a third of patients), which is monitored by the full blood count and managed by dose adjustment or a granulocyte colony-stimulating factor. This matters particularly after stem-cell transplant, where it can impair engraftment.
- Foscarnet: limited by nephrotoxicity and electrolyte wasting (calcium, magnesium, potassium, phosphate), needing renal and electrolyte monitoring and hydration.
- Cidofovir: limited by nephrotoxicity (proximal tubular injury), given with probenecid and hydration, which restricts its use.
This complementary toxicity profile is useful: a patient who is neutropenic may be switched from ganciclovir to foscarnet, and one who is developing renal impairment away from foscarnet. The distractors misassign the toxicities (B), invent ones that do not apply (C, D), or wrongly claim these agents are free of toxicity (E).
- MCQ
For quantitative CMV PCR monitoring in a transplant recipient, how do plasma and whole-blood specimens compare, and which is generally preferred?
- A. Plasma is generally preferred for its better standardisation and usability in leukopenic patients, while whole blood is more sensitive for low-level cell-associated virus and runs about one log10 higher, so the two are not interchangeable
- B. Whole blood is always preferred because it is the only specimen that can be calibrated to the international standard, and plasma cannot be used at all in patients who are leukopenic after their conditioning chemotherapy
- C. Plasma and whole blood give identical viral-load values in international units, so a patient can be switched freely between the two specimen types during monitoring without any loss of comparability over time
- D. Plasma is preferred only because it is cheaper to process, since the two specimens are equally sensitive and equally easy to standardise across the different commercial assay platforms in routine use
- E. Whole blood should be avoided entirely because the cell-associated virus it contains represents latent, non-replicating genomes that never indicate active infection and only cause false-positive monitoring results during routine post-transplant surveillance
Show answer
Correct answer: A
Plasma versus whole blood
- Plasma is the more widely preferred specimen for routine monitoring: it is more readily standardised, is stable, needs a smaller volume, and can be used in leukopenic patients (who have few leukocytes).
- Whole blood detects cell-associated virus and is therefore somewhat more sensitive at low levels, but it is harder to standardise and a whole-blood load runs about one log10 higher than a plasma load from the same patient.
The practical rule
Because the two specimen types give different numbers, a patient should be followed on one specimen type and one assay throughout, and results from plasma and whole blood must not be compared directly (so option C is wrong). The other distractors overstate the case (B and E dismiss a valid specimen) or wrongly claim the two are equally standardised (D).
- MCQ
For which CMV manifestation is maribavir a poor choice?
- A. CMV encephalitis
- B. CMV gastrointestinal disease
- C. CMV viraemia
- D. CMV syndrome
- E. CMV hepatitis
Show answer
Correct answer: A
Why A
Maribavir penetrates the central nervous system and the eye poorly, so it should not be used for CMV encephalitis (or retinitis). It is an oral UL97-kinase inhibitor reserved for refractory or resistant CMV, and is effective for the other manifestations listed, but central-nervous-system or ocular disease calls for an agent that reaches those compartments, such as ganciclovir or foscarnet.
- MCQ
How is CMV best managed in high-risk CAR T-cell therapy recipients?
- A. Surveillance and pre-emptive therapy
- B. Universal letermovir prophylaxis
- C. Universal valganciclovir prophylaxis
- D. Lifelong secondary prophylaxis
- E. No monitoring is required
Show answer
Correct answer: A
Why A
CMV reactivation occurs in up to a third of chimeric antigen receptor (CAR) T-cell recipients and is linked to higher mortality, but routine prophylaxis is not currently recommended in this group. The guidance is surveillance of high-risk recipients (with quantitative viral-load monitoring) for the first few weeks after the infusion, treating pre-emptively if the load rises, rather than treating everyone or ignoring the risk.
- MCQ
Which anti-CMV drug inhibits the viral terminase complex?
- A. Ganciclovir
- B. Foscarnet
- C. Letermovir
- D. Maribavir
- E. Cidofovir
Show answer
Correct answer: C
The targets
- Letermovir inhibits the terminase (UL56) complex, which cleaves and packages the viral genome, a target unique to CMV. It is used for prophylaxis only and has no activity against other herpesviruses.
- Ganciclovir, foscarnet and cidofovir all act on the DNA polymerase (UL54).
- Maribavir inhibits the UL97 kinase.
- MCQ
Which drug interaction or overlapping toxicity is most important to anticipate when managing CMV in a transplant recipient?
- A. Letermovir raises calcineurin-inhibitor levels (tacrolimus and cyclosporine) through CYP3A, so those levels must be monitored and doses adjusted, and ganciclovir's myelosuppression adds to that of mycophenolate
- B. Letermovir reliably lowers calcineurin-inhibitor levels so far that the immunosuppression must be doubled, while ganciclovir protects the marrow and can therefore safely offset the myelosuppression caused by mycophenolate
- C. Valganciclovir has no interactions of any clinical importance with the standard transplant immunosuppressants, so neither drug levels nor blood counts need to be monitored while a patient is taking it for CMV
- D. Foscarnet must always be combined with a calcineurin inhibitor to work, and this combination has no additive renal toxicity, so renal function does not need monitoring during foscarnet therapy in these patients
- E. The only interaction that matters is between ganciclovir and aciclovir, which cancel each other out, so the two should never be co-administered, while calcineurin inhibitors have no relevant interactions with CMV drugs
Show answer
Correct answer: A
The interactions that matter
Managing CMV adds drugs to an already complex regimen, and two interactions stand out:
- Letermovir and the calcineurin inhibitors. Letermovir inhibits CYP3A, so it raises tacrolimus and cyclosporine levels; calcineurin-inhibitor levels must be monitored and doses reduced to avoid nephrotoxicity and over-immunosuppression.
- Overlapping myelosuppression. Ganciclovir and valganciclovir suppress the marrow, an effect that adds to that of mycophenolate (and to the cytopenias of stem-cell transplant), so the full blood count is watched and the antimetabolite dose may be reduced.
The distractors reverse the direction of the letermovir interaction (B), wrongly claim no interactions (C, E), or invent a non-existent foscarnet-calcineurin requirement while dismissing its real renal toxicity (D).
- MCQ
Which immunosuppressant class is associated with a lower risk of CMV infection and disease?
- A. mTOR inhibitors
- B. Calcineurin inhibitors
- C. Antithymocyte globulin
- D. High-dose corticosteroids
- E. Antimetabolites
Show answer
Correct answer: A
Why A
mTOR inhibitors (sirolimus, everolimus) are associated with a lower incidence of CMV infection and disease, an effect used deliberately in some regimens (and exploited in HHV-8 Kaposi sarcoma).
By contrast, antithymocyte globulin and other T-cell-depleting agents markedly raise CMV risk by removing the T cells that control it, and high-dose corticosteroids also increase risk; calcineurin inhibitors and antimetabolites are part of the standard background immunosuppression.
- MCQ
Which of the following is an indirect (immunomodulatory) effect of CMV in the transplant recipient?
- A. Allograft rejection
- B. Interstitial pneumonitis
- C. Haemorrhagic colitis
- D. CMV retinitis
- E. Acute hepatitis
Show answer
Correct answer: A
Direct versus indirect
CMV causes harm in two ways:
- Direct disease is tissue invasion: pneumonitis, colitis, retinitis, hepatitis (options B to E).
- Indirect effects flow from CMV’s immunomodulating activity: allograft rejection and graft loss, bronchiolitis obliterans, vasculopathy, and an increased risk of other infections and of EBV-driven lymphoproliferation.
The indirect effects are a major reason CMV worsens overall transplant outcomes and part of the rationale for universal prophylaxis.
- MCQ
Which statement best describes CMV pneumonitis after allogeneic stem-cell transplantation?
- A. It is historically the most lethal manifestation of CMV in this setting, is diagnosed with bronchoalveolar lavage (and lung biopsy), and is treated with ganciclovir combined with CMV immunoglobulin because of its immunopathological component
- B. It is a mild, self-limiting upper-respiratory illness that resolves without treatment, and bronchoalveolar lavage is contraindicated because sampling the lung reliably disseminates the virus to the bloodstream in these patients
- C. It is diagnosed solely on a positive blood CMV PCR with no need to sample the lung, and it responds best to letermovir monotherapy, which is the established first-line treatment for established CMV pneumonitis
- D. It occurs almost exclusively in solid-organ rather than stem-cell recipients, is never severe, and requires only a reduction of immunosuppression without any antiviral drug to achieve a complete and durable recovery
- E. It is caused by direct cytolytic destruction of alveoli alone with no immune component, so immunoglobulin has no role, and aciclovir is the treatment of choice given at the doses used for herpes simplex pneumonia in the stem-cell transplant recipient
Show answer
Correct answer: A
CMV pneumonitis
CMV pneumonitis is the most feared and historically most lethal manifestation of CMV after allogeneic stem-cell transplantation, with a mortality of 10 to 30 per cent before effective therapy, reduced (though not abolished) by ganciclovir. It presents with fever, dry cough and hypoxia with diffuse interstitial infiltrates.
Diagnosis rests on sampling the lung by bronchoalveolar lavage, supported by lung biopsy, since a blood viral load can be low or negative in tissue-invasive lung disease. Treatment is ganciclovir combined with CMV immunoglobulin: the combination is used because the lung injury has a substantial immunopathological component (an immune response to the infected lung), which antiviral therapy alone does not address.
The distractors trivialise the disease (B, D), rely on blood PCR and letermovir where neither is appropriate (C), or deny the immune component and propose an inactive drug (E).
Exam-styleHow is CMV gastrointestinal disease distinguished from graft-versus-host disease after allogeneic stem-cell transplantation, and why is this difficult? [5]
Model answer
A complete answer explains the overlap, why blood tests do not settle it, and how biopsy resolves it, and notes that the two interact.
Why it is difficult
Gastrointestinal CMV disease and gut graft-versus-host disease (GVHD) present in almost the same way after allogeneic stem-cell transplant, with diarrhoea, abdominal pain, nausea and bleeding, so the clinical picture alone cannot separate them. The distinction matters because their treatments pull in opposite directions: CMV needs antiviral therapy and, if possible, less immunosuppression, whereas GVHD needs more immunosuppression.
Why blood tests do not settle it
A blood CMV viral load is often low or negative in gastrointestinal CMV disease, so a negative blood PCR does not exclude it, and a positive one does not prove that the gut symptoms are due to CMV rather than GVHD.
How biopsy resolves it
The answer is endoscopic biopsy with histology, looking for the characteristic “owl’s-eye” inclusions, supported by immunohistochemistry for CMV. Because the disease is patchy, multiple biopsies are taken, and sensitivity is lower in seropositive recipients. Importantly, the two conditions can coexist: CMV can complicate GVHD, and the immunosuppression used to treat GVHD promotes CMV, so finding one does not exclude the other, and the biopsy is read for both.