Questions

Viral Infection in Transplant Recipients — Questions

Study questions for Viral Infection in Transplant Recipients.

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.

25 questions: 14 MCQ, 11 written.

High-priority (past-paper) questions only

Why D positive, R negative is the highest risk

The seronegative recipient has no CMV-specific memory immunity. When a seropositive donor organ delivers latent CMV, the recipient undergoes a primary infection in an immunologically naive host who is also pharmacologically immunosuppressed, so the virus is poorly contained. Without prophylaxis this group has the highest rates of infection (around 80 to 100 per cent) and of CMV disease (around 50 to 70 per cent), which is exactly why prophylaxis is targeted to them.

The other combinations

D negative, R positive (option B) carries intermediate risk: the recipient’s own latent virus can reactivate, but pre-existing immunity limits it.
D positive, R positive (option D) is also intermediate (reactivation or superinfection against partial immunity), not the highest.
D negative, R negative (option C) is the lowest risk, since neither party carries CMV; the small residual risk is community or transfusion acquisition, mitigated by using leucodepleted or CMV-negative blood.
Option E is wrong because serostatus is precisely what stratifies risk and determines the prevention strategy.

The two strategies

Universal prophylaxis gives an antiviral to every at-risk patient for a fixed period after transplant (for example valganciclovir for 3 to 6 months, or letermovir in seropositive stem-cell recipients), regardless of whether virus is detectable. It reliably prevents early disease but has three drawbacks: late-onset disease once the drug stops (the immune response has not been primed by exposure), drug cost and toxicity, and selection of resistance.
Pre-emptive therapy withholds the drug and instead monitors the viral load at regular intervals (typically weekly), starting treatment only when replication crosses a threshold. This spares drug exposure, cost and resistance, but depends on reliable, frequent, standardised monitoring and can miss rapidly rising viraemia between tests.

Why the distinction matters

The choice is driven by risk and by monitoring capacity. Stem-cell transplant centres often favour pre-emptive CMV management, while solid-organ programmes commonly use prophylaxis for the highest-risk strata such as the seronegative recipient of a seropositive organ. Options B and C reverse the two definitions, D conflates them, and E wrongly ties them to the transplant type rather than to the treatment trigger.

Why A

There is no antiviral of proven benefit, so the mainstay is stepwise reduction of immunosuppression, guided by the plasma viral load, to restore BK-virus-specific T-cell control; this clears the virus in about 80 per cent of patients. Aciclovir and ganciclovir have no useful activity against BK virus, a randomised trial of levofloxacin showed no effect, and increasing immunosuppression would worsen replication.

Why viral load, not serology

Immunosuppression blunts the antibody response, so serology is unreliable in transplant recipients: a patient may have active, even severe, viral disease without a diagnostic antibody rise. Quantitative PCR instead detects and measures the virus itself, which has three advantages:

It diagnoses active infection directly, independent of immune status.
The viral load provides a threshold to trigger pre-emptive therapy before disease develops (used for CMV, EBV, BK and adenovirus).
Serial loads monitor the response to treatment, with a falling load confirming efficacy and a rising or plateauing load suggesting resistance or non-adherence.

Reporting in WHO international units per millilitre (IU/mL) standardises results across assays and laboratories, so thresholds can be shared and a patient followed even if the testing platform changes.

Why the distractors are wrong

B is false: antibody responses are not reliable in the immunosuppressed. C describes microbiological culture, not the viral-load principle. D overstates the position, as immunoglobulin is reduced rather than wholly absent. E inverts reality, since the antibody rise is late and unreliable here.

A complete answer separates the specimen used for decisions from the one used for screening, states the surveillance schedule, and makes management hinge on immunosuppression.

Specimens

The plasma BK virus DNA load is the decision marker: virus in the blood reflects significant renal replication and is what triggers and monitors treatment. Urinary shedding is near-universal in reactivation, so it is sensitive but not specific, and a high urine load alone does not establish nephropathy. Proven nephropathy requires a renal biopsy with viral cytopathic change and positive SV40 large T antigen immunohistochemistry, taking at least two cores including medulla because the disease is focal.

Screening schedule

All kidney transplant recipients are screened for plasma BK virus DNA at intervals: conventionally monthly until about nine months after transplant, then every three months until two years. A sustained plasma load above 10,000 copies per millilitre is taken as presumptive nephropathy and prompts intervention before the graft is damaged.

Management

The mainstay is stepwise reduction of immunosuppression to restore BK-virus-specific T-cell control: reduce the antimetabolite to no more than half its dose and lower the calcineurin-inhibitor target, which clears the virus in around 80 per cent of patients. There is no antiviral of proven benefit, and adjuncts are reserved for failure of reduction. The important caveat is concurrent acute rejection: if rejection coexists, it is treated first and immunosuppression reduced only afterwards, because the two conditions demand opposite changes.

Features

BK-virus haemorrhagic cystitis is high-level replication of BK virus in the urothelium, causing denudation and bleeding of the bladder lining. It is of late onset, some two to twelve weeks after engraftment, and is defined by the combination of cystitis symptoms (dysuria, frequency, suprapubic pain), visible haematuria with clots, and a high urine BK virus load. Two transplant-specific factors amplify it: prior urotoxic conditioning, in which cyclophosphamide and its metabolite acrolein damage the bladder epithelium, and the inflammatory surge of immune reconstitution at engraftment.

Distinction from early cystitis

Early haemorrhagic cystitis, occurring in the first days after transplant, is due to conditioning toxicity alone and is brief; it is not caused by BK virus. The later onset, the high urine BK load and the timing around engraftment separate BK-virus cystitis from this earlier urotoxic form.

Management

Management is largely supportive: hydration, bladder irrigation, evacuation of clots, and transfusion of platelets or red cells as needed, while returning cellular immunity brings the infection under control. There is no antiviral of proven benefit. Reducing immunosuppression, the mainstay in renal nephropathy, is constrained here by the risk of graft-versus-host disease.

Why it matters

The two conditions look alike but demand opposite treatment. Both present as graft dysfunction with a rising creatinine and both show an interstitial inflammatory infiltrate with tubulitis on biopsy, yet nephropathy is treated by reducing immunosuppression while rejection is treated by augmenting it. Choosing wrongly harms the graft: cutting immunosuppression in rejection accelerates it, and increasing it in nephropathy fuels viral replication.

How they are distinguished

A high and rising plasma BK virus load points to nephropathy, which is then confirmed on biopsy by viral cytopathic change with positive SV40 large T antigen immunohistochemistry. Acute rejection is favoured by features such as endarteritis and, in antibody-mediated rejection, C4d deposition along peritubular capillaries, in the absence of viral staining. The two can coexist, and biopsy with the SV40 stain is what separates them. When both are present, rejection is treated first and immunosuppression reduced only afterwards.

A complete answer divides the post-transplant course into three risk periods, maps the dominant infections to each, and explains why prophylaxis shifts rather than abolishes the pattern.

The first month: nosocomial and donor-derived

Early infection is dominated by surgical and healthcare-associated problems (wound, line and catheter infection, anastomotic leaks, aspiration) rather than by opportunistic viral reactivation, because the cumulative effect of immunosuppression has not yet peaked. The main viral event is herpes simplex virus (HSV) reactivation. Rare but important donor-derived transmissions present in this window as unexplained encephalitis or hepatitis, including West Nile virus, lymphocytic choriomeningitis virus, rabies and (now very rarely, through screening) HIV.

One to six months: the opportunistic window

This is the period of greatest vulnerability, when the net state of immunosuppression is highest. Cytomegalovirus (CMV) is the central pathogen. Alongside it come Epstein-Barr virus (EBV) and the risk of post-transplant lymphoproliferative disorder, human herpesvirus 6 and 7, BK polyomavirus (especially in kidney recipients), reactivating hepatitis B and C, and the community respiratory viruses. Non-viral opportunists such as Pneumocystis also cluster here.

After six months: community-acquired, with a tail

Most patients are now on stable, lower-dose immunosuppression and behave much like the general community, so respiratory viruses predominate. Two groups diverge: those who complete a course of CMV prophylaxis can develop late-onset CMV once it stops (especially the seronegative recipient of a seropositive graft), and a minority with chronic graft dysfunction or repeated rejection needing intensified immunosuppression stay at sustained opportunistic risk. Late EBV-driven disease and HPV-related malignancy also emerge in this period.

How prophylaxis reshapes the timeline

Antiviral prophylaxis does not abolish infection; it delays it. CMV prophylaxis moves disease out of the one-to-six-month window into a late-onset form appearing after the drug is stopped. The classic timeline is therefore a guide to the differential diagnosis at a given point, not a fixed schedule, and it must be read against what prophylaxis the patient has received.

Pathogenesis

BK virus persists for life in the renal tubular epithelium and urothelium and is held in check by cellular immunity. After kidney transplantation the immunosuppression needed to protect the graft permits uncontrolled lytic replication, and the replicating virus is frequently donor-derived, carried in with the kidney. Infected tubular cells enlarge with intranuclear inclusions, round up and slough into the urine as decoy cells, and lyse, releasing virus and provoking an interstitial inflammatory infiltrate. The process is graded through three histological stages, from early cytopathic change with little inflammation, through interstitial inflammation and tubulitis, to tubular atrophy and fibrosis, the last representing irreversible scarring and graft loss.

Specimens for screening versus diagnosis

Screening uses the plasma BK virus DNA load, which reflects renal replication and is the marker that triggers pre-emptive treatment; urine load and decoy cells are more sensitive but less specific, useful as a first filter rather than a decision point. Diagnosis of proven nephropathy is histological: a renal biopsy showing viral cytopathic change with an inflammatory infiltrate, confirmed by SV40 large T antigen immunohistochemistry. Because the infection is focal and favours the medulla, at least two cores including medulla are taken, and a negative stain does not exclude early disease.

A complete answer links each laboratory test to the clinical and radiological picture, since the diagnosis is made on the combination rather than on any single result.

Cerebrospinal fluid JC virus PCR

The central test is detection of JC virus DNA in cerebrospinal fluid by polymerase chain reaction. In a patient with compatible neurology and characteristic imaging, a positive result confirms the diagnosis (laboratory-confirmed PML) and removes the need for brain biopsy. Detection in the cerebrospinal fluid is meaningful because the virus is not normally present there, unlike urine and blood, where asymptomatic shedding is common. Quantification is useful for monitoring. The key limitation is sensitivity: the assay misses roughly a quarter of histologically proven cases, particularly at low viral load or after antiretroviral therapy has reduced it, so a negative result does not exclude PML. Routine cerebrospinal fluid is usually otherwise normal, which helps separate PML from the meningoencephalitides that produce a pleocytosis.

When the PCR is non-informative

Where the result is negative but suspicion persists, the options are to repeat the test, to measure an intrathecal anti-JC virus antibody response, or to proceed to stereotactic brain biopsy. Biopsy remains the definitive test, showing the histological triad of demyelination, enlarged oligodendrocyte nuclei and bizarre astrocytes, with confirmation by viral protein on immunohistochemistry or viral genome by in situ hybridisation.

Putting it together

The laboratory does not diagnose PML in isolation: it supplies the virological confirmation that, set against the clinical syndrome and the magnetic resonance imaging appearance, allows the case to be graded as possible, probable or laboratory-confirmed. The serum JC virus antibody index has no role in diagnosing an established case; it is a risk-stratification tool in the natalizumab setting.

A complete answer keys the three phases to engraftment, names the dominant viruses in each, and explains the effect of graft-versus-host disease (GVHD).

Pre-engraftment (to around day 30)

Profound neutropenia and mucosal injury from conditioning dominate. Herpes simplex virus is the characteristic herpesvirus reactivation of this phase, and community respiratory viruses acquired around admission can seed the lungs. Bacterial and fungal infection are the larger overall threat here.

Early post-engraftment (engraftment to about day 100)

Neutrophils have recovered but cellular immunity is still absent, which is the period of greatest opportunistic viral risk. CMV reactivation peaks. Also characteristic are human herpesvirus 6 (encephalitis, fever, marrow suppression and delayed engraftment), EBV and post-transplant lymphoproliferative disorder, adenovirus (especially in children), BK polyomavirus haemorrhagic cystitis, and continuing respiratory-virus risk.

Late (after day 100)

As immunity slowly reconstitutes, varicella-zoster virus reactivation becomes characteristic, alongside late CMV and ongoing respiratory-virus infection.

The effect of graft-versus-host disease

GVHD and the immunosuppression used to treat it are the main reason the late phase is prolonged. Chronic GVHD keeps cellular immunity suppressed for months or years, extending the window of risk for CMV, VZV and respiratory viruses well beyond day 100 and making these patients behave, immunologically, as though they were still early after transplant.

The HPV burden in long-term transplantation

HPV-related disease rises with the duration and intensity of immunosuppression. Cutaneous warts increase from around 15 per cent at transplant to over 80 per cent at 20 years, and, more importantly, cutaneous squamous cell carcinoma (SCC) becomes markedly more common, with ultraviolet light as a cofactor. The usual skin-cancer ratio is reversed so that SCC outnumbers basal cell carcinoma, and these cancers can behave aggressively and metastasise. Anogenital and cervical dysplasia are also increased, with cervical cancer rising several-fold.

Addressing the risk

Prevention and surveillance combine: sun protection and regular skin examination, cervical cytology, and HPV vaccination of candidates before transplant. Where lesions or cancers develop, reducing immunosuppression or switching to an mTOR inhibitor lowers the risk.

Why the distractors are wrong

HPV does not cause a blood-borne viraemia or pneumonia (B), it does not cause hepatocellular carcinoma (C, which describes hepatitis B or C), cervical cancer does not develop within a single year and is detected by cytology rather than prevented by routine hysterectomy (D), and the risk is increased, not absent, in the immunosuppressed (E).

Why B

Decoy cells are infected tubular and urothelial cells bearing ground-glass intranuclear inclusions, shed into the urine during BK-virus reactivation; they are a sensitive but non-specific marker of replication. They are not malignant cells, are distinct from the owl-eye cells of cytomegalovirus, and have nothing to do with eosinophils or red-cell casts.

Two cystitis patterns after stem-cell transplant

Early (first days, around conditioning): chemical cystitis caused directly by urotoxic conditioning agents (cyclophosphamide, ifosfamide, busulfan).
Late (after engraftment, typically weeks 3 to 6): BK polyomavirus haemorrhagic cystitis, with a high urinary BK load, as in this case.

The timing separates the two, which is why option B (placing chemical cystitis weeks after engraftment) is wrong.

Diagnosis and management

BK haemorrhagic cystitis is a bladder disease, not the renal-allograft nephropathy (option C), and the urinary load alone does not equate to disease: 50 to 80 per cent of stem-cell recipients have high viruria but fewer than 20 per cent develop cystitis, so viruria is necessary but not sufficient (option E is wrong). Management is largely supportive: hydration, bladder irrigation, analgesia and transfusion as needed; no antiviral is of proven benefit, though cidofovir is sometimes tried. Option D is wrong because this is BK, not CMV, disease.

The unifying principle

The lever depends on whether an effective drug exists. For BK polyomavirus nephropathy, post-transplant lymphoproliferative disorder (PTLD), adenovirus disease and chronic hepatitis E, there is no reliably effective specific antiviral, so the mainstay is to reduce immunosuppression and let the recovering virus-specific T-cell response control the infection (with rituximab added for PTLD, or cidofovir tried for adenovirus, as adjuncts).

By contrast, where a good drug exists the drug leads:

CMV (option B): ganciclovir, valganciclovir, letermovir and foscarnet are the primary treatment, with reduction of immunosuppression an adjunct, not a replacement.
HSV (option C): aciclovir is highly active regardless of immune state; immunosuppression need not be stopped for it to work.
Influenza (option D): neuraminidase inhibitors given early do improve outcome.

Option E overstates a useful principle: reducing immunosuppression always helps, but it is balanced against the risk of rejection and does not remove the need for specific antivirals where they are effective.

The syndrome

The picture is post-transplant acute limbic encephalitis caused by human herpesvirus 6 (HHV-6B) reactivation, which characteristically occurs early after stem-cell transplant (around weeks 2 to 4). The features are anterograde amnesia, seizures, the syndrome of inappropriate antidiuretic hormone secretion (hyponatraemia), and bilateral medial temporal lobe signal change on MRI.

Confirmation and a pitfall

Diagnosis is by HHV-6 DNA PCR on cerebrospinal fluid and plasma. The important pitfall is chromosomally integrated HHV-6: in people who carry the integrated viral genome in every nucleated cell, PCR shows a persistently very high load that does not indicate active disease. A load that falls with treatment supports a causative role.

Treatment and the distractors

Treat with ganciclovir or foscarnet; aciclovir is inactive against HHV-6. The distractors are wrong on pattern or timing: HSV encephalitis is possible but the MRI and post-transplant context favour HHV-6; CMV CNS disease is uncommon and not the typical limbic picture; JC virus causes white-matter PML, not medial temporal limbic disease; and EBV CNS lymphoma presents as a mass lesion, not this acute encephalitic syndrome.

The concept

The net state of immunosuppression is an integrative estimate of how vulnerable a given patient is, summing several contributions rather than any single variable:

the immunosuppressive drugs: their dose, duration, sequence and type, with anti-T-cell (antilymphocyte) antibodies raising risk most and some agents (mTOR inhibitors) lowering CMV risk;
host factors: neutropenia, lymphopenia, low immunoglobulin, breaches of mucosal and skin barriers, indwelling catheters and lines, uraemia, diabetes and malnutrition;
the burden of immunomodulating viruses already present (CMV, EBV, human herpesvirus 6, hepatitis B and C), which themselves further suppress immunity.

Why it matters

Because risk is the sum of these, two patients on the same drug regimen can have very different vulnerability. The concept guides individualised prevention: it explains why adding anti-rejection therapy for a rejection episode reopens the opportunistic window, and why controlling neutropenia and removing devices reduces risk. The distractors each reduce a multifactorial state to one variable (a drug level, serostatus, HLA match, or radiation dose).

Why D

The plasma BK virus DNA load is the decision marker, because virus in the blood reflects significant renal replication; a sustained plasma load above 10,000 copies per millilitre is taken as presumptive nephropathy and prompts pre-emptive reduction of immunosuppression. Urinary shedding and decoy cells are sensitive but not specific, serology does not guide treatment, and a creatinine rise alone is non-specific.

Herpes simplex

HSV reactivates earliest, within the first month. Aciclovir or valaciclovir prophylaxis during this period cuts HSV reactivation from around 70 per cent to under 5 per cent. (CMV prophylaxis with ganciclovir or valganciclovir also covers HSV, so separate aciclovir is not needed while that is running.)

Varicella-zoster

VZV reactivation (zoster) is late, often after day 100, and can disseminate. A seronegative recipient exposed to chickenpox or shingles is given varicella-zoster immunoglobulin within the recommended window, with aciclovir post-exposure prophylaxis as an adjunct. Live varicella and zoster vaccines are contraindicated after transplant and should be given to seronegative candidates before transplant; the non-live recombinant zoster vaccine is an option after transplant where available.

Why the distractors are wrong

B wrongly calls these infections harmless; C gives a live vaccine when it is contraindicated; D withholds prophylaxis until after disease and misstates the resistance picture (long-term prophylaxis actually keeps resistance low); and E misapplies immunoglobulin to everyone and assumes CMV prophylaxis always covers HSV.

A complete answer covers the spectrum of viruses and what drives progression, the diagnostic approach, and virus-specific and supportive management.

The viruses and the risk of progression

Respiratory syncytial virus (RSV), influenza, parainfluenza virus, human metapneumovirus, rhinovirus and SARS-CoV-2 are acquired from the community or nosocomially, not by reactivation. They usually begin as an upper-respiratory illness but can progress to the lower tract and pneumonia, which carries high mortality in stem-cell recipients. Progression is driven by lymphopenia and pre-engraftment timing, and for influenza by older age. In lung-transplant recipients these viruses are also linked to acute rejection and bronchiolitis obliterans.

Diagnosis

A multiplex respiratory PCR on a nasopharyngeal sample, and on bronchoalveolar lavage where lower-tract disease is suspected, identifies the virus rapidly and guides isolation and specific therapy.

Management

RSV: aerosolised ribavirin, sometimes with immunoglobulin, started at the upper-tract stage before respiratory failure gives the best chance of preventing progression in high-risk patients.
Influenza: a neuraminidase inhibitor (oseltamivir) started early reduces progression; prolonged shedding and resistance occur in the immunosuppressed.
Parainfluenza, metapneumovirus and rhinovirus have no proven antiviral, so care is supportive.
For all of them, infection control is essential, since these viruses cause nosocomial outbreaks: isolation, hand hygiene and staff and visitor screening, with elective transplant deferred if the candidate has a respiratory infection at the time of conditioning.

A complete answer identifies the high-risk groups, explains viral-load surveillance, and gives the management ladder.

Who is at risk

Adenovirus is most dangerous after allogeneic stem-cell transplantation, particularly in children and above all with T-cell depletion (in vivo antithymocyte globulin or ex vivo graft manipulation), which removes the cellular immunity needed to control it. Graft-versus-host disease and cord-blood or mismatched donors add risk. It usually appears within the first three months.

Clinical disease

Infection ranges from asymptomatic shedding to disseminated, frequently fatal disease: gastroenteritis and hepatitis, pneumonia, haemorrhagic cystitis and nephritis, and multi-organ failure. Detectable and rising adenovirus in the blood is the key predictor of dissemination.

Monitoring

High-risk patients are monitored with quantitative real-time PCR on blood and, because shedding there precedes viraemia, on stool and urine. Pre-emptive treatment is triggered by viraemia, not by stool positivity alone, since most stool-positive patients never develop disease.

Management

Reduce immunosuppression to let adenovirus-specific T cells recover. Cidofovir, or its oral lipid-ester brincidofovir (less nephrotoxic), is given pre-emptively on confirmed viraemia, with close attention to renal toxicity and hydration. Adoptive transfer of donor-derived adenovirus-specific T cells is an effective option for refractory disease where it is available.

A complete answer covers timing relative to immunosuppression, the live-vaccine rule, protection of close contacts, and re-vaccination after stem-cell transplant.

Vaccinate before transplant

Vaccine responses are far better before immunosuppression begins, so the candidate’s schedule should be completed during the transplant assessment: inactivated influenza (annually), pneumococcal vaccines, and hepatitis B (checking that a protective anti-HBs response is achieved), along with any catch-up doses needed.

The live-vaccine rule

Live attenuated vaccines (measles-mumps-rubella, varicella, and live zoster) can cause disease in an immunosuppressed host and are contraindicated after transplant. A seronegative candidate should therefore receive them before transplant, allowing an adequate interval (commonly at least four weeks) before immunosuppression starts. Inactivated vaccines carry no such risk and may be given or boosted at any time, although the response is weaker once immunosuppressed.

Protect the household

Because the recipient may respond poorly and cannot receive live vaccines, protect them indirectly by cocooning: vaccinate household and close contacts, especially with annual inactivated influenza, and avoid live oral poliovirus vaccine in contacts. Contacts given other live vaccines rarely transmit, though a varicella-vaccine rash warrants care.

Re-vaccinate after stem-cell transplant

Haematopoietic stem-cell transplantation erases established immune memory, so recipients are effectively unimmunised and need a full re-vaccination programme. Inactivated vaccines are usually restarted around 6 to 12 months after transplant, with live vaccines deferred until immune reconstitution is secure (commonly around two years, off immunosuppression and free of graft-versus-host disease).

Passive immunisation

Where active vaccination is not possible, specific immunoglobulin gives short-term passive cover after an exposure, for example varicella- zoster immunoglobulin for a seronegative recipient exposed to chickenpox or shingles.

A complete answer covers the virus and its tumours, the seroprevalence-driven epidemiology, and the management.

The virus and its tumours

HHV-8 (Kaposi sarcoma-associated herpesvirus) causes Kaposi sarcoma, and also primary effusion lymphoma and multicentric Castleman disease. In transplant recipients Kaposi sarcoma is typically the earliest post-transplant malignancy, arising either from reactivation of the recipient’s own latent virus or, less often, from a donor-derived infection transmitted in the graft.

Epidemiology

Risk tracks HHV-8 seroprevalence, which is geographically very uneven: under 5 per cent in Northern European blood donors but up to around 80 per cent in parts of sub-Saharan Africa. Post-transplant Kaposi sarcoma is therefore rare (under 1 per cent) in low-prevalence regions but reaches several per cent in high-prevalence populations, where it makes up the majority of all post-transplant cancers.

Clinical and management

Kaposi sarcoma presents as violaceous cutaneous nodules, but visceral involvement (gastrointestinal, pulmonary) occurs in up to 40 per cent and may bleed or obstruct. The mainstay of treatment is reduction of immunosuppression and a switch to an mTOR inhibitor (sirolimus), which is both immunosuppressive and antitumour and can drive regression. Visceral or refractory disease needs chemotherapy. Antivirals are of unproven benefit.

Why C

Proven nephropathy requires viral cytopathic change with positive immunohistochemistry for the SV40 large T antigen, using an antibody that cross-reacts with the BK-virus large T antigen to stain infected tubular nuclei. C4d marks antibody-mediated rejection, not BK disease; Congo red, silver and cytomegalovirus stains identify unrelated processes.

Why B

No antiviral has proven benefit against BK virus, and management rests on reducing immunosuppression. A randomised trial of levofloxacin showed no effect on viral load; cidofovir gives inconsistent results and carries nephrotoxicity and uveitis; and ganciclovir and aciclovir have no useful activity against BK virus.

High priorityMCQ
A solid-organ transplant is planned. Which donor (D) and recipient (R) cytomegalovirus serostatus combination carries the highest risk of CMV disease, and why?
- A. Seropositive donor into seronegative recipient (D positive, R negative), because the recipient meets CMV for the first time with no pre-existing CMV-specific immunity to contain a primary infection delivered in the graft
- B. Seronegative donor into seropositive recipient (D negative, R positive), because reactivation of the recipient's own latent CMV is inherently more dangerous than any primary infection acquired from the transplanted donor organ
- C. Seronegative donor into seronegative recipient (D negative, R negative), because neither party carries CMV and the recipient is therefore left wholly unprotected against acquiring the virus from the community afterwards
- D. Seropositive donor into seropositive recipient (D positive, R positive), because the simultaneous reactivation of two different CMV strains overwhelms whatever partial pre-existing immunity the recipient has to the virus
- E. The serostatus combination makes no difference to risk, because every transplant recipient receives identical CMV prophylaxis and monitoring regardless of donor and recipient antibody status before surgery
Show answer
Correct answer: A
Why D positive, R negative is the highest risk

The seronegative recipient has no CMV-specific memory immunity. When a seropositive donor organ delivers latent CMV, the recipient undergoes a primary infection in an immunologically naive host who is also pharmacologically immunosuppressed, so the virus is poorly contained. Without prophylaxis this group has the highest rates of infection (around 80 to 100 per cent) and of CMV disease (around 50 to 70 per cent), which is exactly why prophylaxis is targeted to them.

The other combinations

D negative, R positive (option B) carries intermediate risk: the recipient’s own latent virus can reactivate, but pre-existing immunity limits it.

D positive, R positive (option D) is also intermediate (reactivation or superinfection against partial immunity), not the highest.

D negative, R negative (option C) is the lowest risk, since neither party carries CMV; the small residual risk is community or transfusion acquisition, mitigated by using leucodepleted or CMV-negative blood.

Option E is wrong because serostatus is precisely what stratifies risk and determines the prevention strategy.
High priorityMCQ
In preventing cytomegalovirus disease after transplantation, which statement best distinguishes universal prophylaxis from a pre-emptive strategy?
- A. Prophylaxis gives antiviral drug to all at-risk patients for a fixed period regardless of viral load, whereas a pre-emptive strategy withholds the drug and treats only when serial viral-load monitoring detects replication
- B. Prophylaxis treats only patients who have developed symptomatic disease, whereas a pre-emptive strategy gives antiviral drug to every at-risk patient from the day of transplantation for a fixed defined period
- C. Prophylaxis relies on serial weekly viral-load monitoring to trigger treatment, whereas a pre-emptive strategy gives a fixed antiviral course to all seropositive donors and recipients alike from day one
- D. Prophylaxis and pre-emptive therapy are identical in practice, differing only in the particular antiviral chosen, and both begin treatment once the patient has detectable viraemia on a monitoring test
- E. Prophylaxis is used only in stem-cell transplantation while a pre-emptive strategy is used only in solid-organ transplantation, the two being defined by the type of transplant rather than by the trigger that starts antiviral treatment
Show answer
Correct answer: A
The two strategies

Universal prophylaxis gives an antiviral to every at-risk patient for a fixed period after transplant (for example valganciclovir for 3 to 6 months, or letermovir in seropositive stem-cell recipients), regardless of whether virus is detectable. It reliably prevents early disease but has three drawbacks: late-onset disease once the drug stops (the immune response has not been primed by exposure), drug cost and toxicity, and selection of resistance.

Pre-emptive therapy withholds the drug and instead monitors the viral load at regular intervals (typically weekly), starting treatment only when replication crosses a threshold. This spares drug exposure, cost and resistance, but depends on reliable, frequent, standardised monitoring and can miss rapidly rising viraemia between tests.

Why the distinction matters

The choice is driven by risk and by monitoring capacity. Stem-cell transplant centres often favour pre-emptive CMV management, while solid-organ programmes commonly use prophylaxis for the highest-risk strata such as the seronegative recipient of a seropositive organ. Options B and C reverse the two definitions, D conflates them, and E wrongly ties them to the transplant type rather than to the treatment trigger.
High priorityMCQ
The primary management of BK-virus-associated nephropathy in a kidney transplant recipient is to:
- A. Reduce immunosuppression under viral-load guidance
- B. Start high-dose intravenous aciclovir
- C. Add a fluoroquinolone such as oral levofloxacin for three months
- D. Increase immunosuppression to suppress the virus
- E. Begin intravenous ganciclovir
Show answer
Correct answer: A
Why A

There is no antiviral of proven benefit, so the mainstay is stepwise reduction of immunosuppression, guided by the plasma viral load, to restore BK-virus-specific T-cell control; this clears the virus in about 80 per cent of patients. Aciclovir and ganciclovir have no useful activity against BK virus, a randomised trial of levofloxacin showed no effect, and increasing immunosuppression would worsen replication.
High priorityMCQ
Why is quantitative nucleic-acid (viral-load) testing, rather than serology, the mainstay for diagnosing and monitoring viral infection in transplant recipients?
- A. Immunosuppression blunts antibody responses so serology is unreliable, whereas quantitative PCR detects and measures replication directly, enabling pre-emptive treatment and response monitoring for CMV, EBV, BK and adenovirus
- B. Serology is avoided only because it is slower to perform than PCR; antibody titres remain fully reliable in transplant recipients and would give exactly the same information if the results could be obtained quickly enough
- C. Quantitative PCR is preferred because it identifies the infecting bacterial or fungal organism directly, whereas serology can detect only viruses and so cannot guide the choice of antimicrobial therapy in these patients
- D. Viral-load testing is used because antibody cannot be measured at all in immunosuppressed patients, whose B cells are entirely absent so that they make no immunoglobulin of any class after the transplant procedure
- E. Serology is the true mainstay and PCR is reserved only for confirmation, because a rising antibody titre is the earliest and most specific marker of active viral disease after both solid-organ and stem-cell transplantation in the immunosuppressed host
Show answer
Correct answer: A
Why viral load, not serology

Immunosuppression blunts the antibody response, so serology is unreliable in transplant recipients: a patient may have active, even severe, viral disease without a diagnostic antibody rise. Quantitative PCR instead detects and measures the virus itself, which has three advantages:

It diagnoses active infection directly, independent of immune status.

The viral load provides a threshold to trigger pre-emptive therapy before disease develops (used for CMV, EBV, BK and adenovirus).

Serial loads monitor the response to treatment, with a falling load confirming efficacy and a rising or plateauing load suggesting resistance or non-adherence.

Reporting in WHO international units per millilitre (IU/mL) standardises results across assays and laboratories, so thresholds can be shared and a patient followed even if the testing platform changes.

Why the distractors are wrong

B is false: antibody responses are not reliable in the immunosuppressed. C describes microbiological culture, not the viral-load principle. D overstates the position, as immunoglobulin is reduced rather than wholly absent. E inverts reality, since the antibody rise is late and unreliable here.
High priorityClinical scenarioA kidney transplant recipient, nine months post-transplant and still on full immunosuppression after earlier rejection episodes, has a rising serum creatinine and a rising BK virus load. Outline the specimens used, the screening schedule, and the management.
Model answer
A complete answer separates the specimen used for decisions from the one used for screening, states the surveillance schedule, and makes management hinge on immunosuppression.

Specimens

The plasma BK virus DNA load is the decision marker: virus in the blood reflects significant renal replication and is what triggers and monitors treatment. Urinary shedding is near-universal in reactivation, so it is sensitive but not specific, and a high urine load alone does not establish nephropathy. Proven nephropathy requires a renal biopsy with viral cytopathic change and positive SV40 large T antigen immunohistochemistry, taking at least two cores including medulla because the disease is focal.

Screening schedule

All kidney transplant recipients are screened for plasma BK virus DNA at intervals: conventionally monthly until about nine months after transplant, then every three months until two years. A sustained plasma load above 10,000 copies per millilitre is taken as presumptive nephropathy and prompts intervention before the graft is damaged.

Management

The mainstay is stepwise reduction of immunosuppression to restore BK-virus-specific T-cell control: reduce the antimetabolite to no more than half its dose and lower the calcineurin-inhibitor target, which clears the virus in around 80 per cent of patients. There is no antiviral of proven benefit, and adjuncts are reserved for failure of reduction. The important caveat is concurrent acute rejection: if rejection coexists, it is treated first and immunosuppression reduced only afterwards, because the two conditions demand opposite changes.
High priorityClinical scenarioDescribe BK-virus haemorrhagic cystitis after allogeneic haematopoietic stem cell transplantation, including its distinction from early cystitis and its management.
Model answer
Features

BK-virus haemorrhagic cystitis is high-level replication of BK virus in the urothelium, causing denudation and bleeding of the bladder lining. It is of late onset, some two to twelve weeks after engraftment, and is defined by the combination of cystitis symptoms (dysuria, frequency, suprapubic pain), visible haematuria with clots, and a high urine BK virus load. Two transplant-specific factors amplify it: prior urotoxic conditioning, in which cyclophosphamide and its metabolite acrolein damage the bladder epithelium, and the inflammatory surge of immune reconstitution at engraftment.

Distinction from early cystitis

Early haemorrhagic cystitis, occurring in the first days after transplant, is due to conditioning toxicity alone and is brief; it is not caused by BK virus. The later onset, the high urine BK load and the timing around engraftment separate BK-virus cystitis from this earlier urotoxic form.

Management

Management is largely supportive: hydration, bladder irrigation, evacuation of clots, and transfusion of platelets or red cells as needed, while returning cellular immunity brings the infection under control. There is no antiviral of proven benefit. Reducing immunosuppression, the mainstay in renal nephropathy, is constrained here by the risk of graft-versus-host disease.
High priorityClinical scenarioHow is BK-virus-associated nephropathy distinguished from acute rejection in a kidney transplant recipient, and why does the distinction matter?
Model answer
Why it matters

The two conditions look alike but demand opposite treatment. Both present as graft dysfunction with a rising creatinine and both show an interstitial inflammatory infiltrate with tubulitis on biopsy, yet nephropathy is treated by reducing immunosuppression while rejection is treated by augmenting it. Choosing wrongly harms the graft: cutting immunosuppression in rejection accelerates it, and increasing it in nephropathy fuels viral replication.

How they are distinguished

A high and rising plasma BK virus load points to nephropathy, which is then confirmed on biopsy by viral cytopathic change with positive SV40 large T antigen immunohistochemistry. Acute rejection is favoured by features such as endarteritis and, in antibody-mediated rejection, C4d deposition along peritubular capillaries, in the absence of viral staining. The two can coexist, and biopsy with the SV40 stain is what separates them. When both are present, rejection is treated first and immunosuppression reduced only afterwards.
High priorityExam-styleDescribe the classic timeline of infection after solid-organ transplantation, naming the viral infections that dominate each period and explaining how antiviral prophylaxis reshapes it. [10]
Model answer
A complete answer divides the post-transplant course into three risk periods, maps the dominant infections to each, and explains why prophylaxis shifts rather than abolishes the pattern.

The first month: nosocomial and donor-derived

Early infection is dominated by surgical and healthcare-associated problems (wound, line and catheter infection, anastomotic leaks, aspiration) rather than by opportunistic viral reactivation, because the cumulative effect of immunosuppression has not yet peaked. The main viral event is herpes simplex virus (HSV) reactivation. Rare but important donor-derived transmissions present in this window as unexplained encephalitis or hepatitis, including West Nile virus, lymphocytic choriomeningitis virus, rabies and (now very rarely, through screening) HIV.

One to six months: the opportunistic window

This is the period of greatest vulnerability, when the net state of immunosuppression is highest. Cytomegalovirus (CMV) is the central pathogen. Alongside it come Epstein-Barr virus (EBV) and the risk of post-transplant lymphoproliferative disorder, human herpesvirus 6 and 7, BK polyomavirus (especially in kidney recipients), reactivating hepatitis B and C, and the community respiratory viruses. Non-viral opportunists such as Pneumocystis also cluster here.

After six months: community-acquired, with a tail

Most patients are now on stable, lower-dose immunosuppression and behave much like the general community, so respiratory viruses predominate. Two groups diverge: those who complete a course of CMV prophylaxis can develop late-onset CMV once it stops (especially the seronegative recipient of a seropositive graft), and a minority with chronic graft dysfunction or repeated rejection needing intensified immunosuppression stay at sustained opportunistic risk. Late EBV-driven disease and HPV-related malignancy also emerge in this period.

How prophylaxis reshapes the timeline

Antiviral prophylaxis does not abolish infection; it delays it. CMV prophylaxis moves disease out of the one-to-six-month window into a late-onset form appearing after the drug is stopped. The classic timeline is therefore a guide to the differential diagnosis at a given point, not a fixed schedule, and it must be read against what prophylaxis the patient has received.
High priorityExam-styleDescribe the pathogenesis of BK-virus-associated nephropathy, and the specimens preferred for screening versus diagnosis. [10]
Model answer
Pathogenesis

BK virus persists for life in the renal tubular epithelium and urothelium and is held in check by cellular immunity. After kidney transplantation the immunosuppression needed to protect the graft permits uncontrolled lytic replication, and the replicating virus is frequently donor-derived, carried in with the kidney. Infected tubular cells enlarge with intranuclear inclusions, round up and slough into the urine as decoy cells, and lyse, releasing virus and provoking an interstitial inflammatory infiltrate. The process is graded through three histological stages, from early cytopathic change with little inflammation, through interstitial inflammation and tubulitis, to tubular atrophy and fibrosis, the last representing irreversible scarring and graft loss.

Specimens for screening versus diagnosis

Screening uses the plasma BK virus DNA load, which reflects renal replication and is the marker that triggers pre-emptive treatment; urine load and decoy cells are more sensitive but less specific, useful as a first filter rather than a decision point. Diagnosis of proven nephropathy is histological: a renal biopsy showing viral cytopathic change with an inflammatory infiltrate, confirmed by SV40 large T antigen immunohistochemistry. Because the infection is focal and favours the medulla, at least two cores including medulla are taken, and a negative stain does not exclude early disease.
High priorityExam-styleDiscuss the role of the virology laboratory in the diagnosis of a case of probable progressive multifocal leukoencephalopathy. [10]
Model answer
A complete answer links each laboratory test to the clinical and radiological picture, since the diagnosis is made on the combination rather than on any single result.

Cerebrospinal fluid JC virus PCR

The central test is detection of JC virus DNA in cerebrospinal fluid by polymerase chain reaction. In a patient with compatible neurology and characteristic imaging, a positive result confirms the diagnosis (laboratory-confirmed PML) and removes the need for brain biopsy. Detection in the cerebrospinal fluid is meaningful because the virus is not normally present there, unlike urine and blood, where asymptomatic shedding is common. Quantification is useful for monitoring. The key limitation is sensitivity: the assay misses roughly a quarter of histologically proven cases, particularly at low viral load or after antiretroviral therapy has reduced it, so a negative result does not exclude PML. Routine cerebrospinal fluid is usually otherwise normal, which helps separate PML from the meningoencephalitides that produce a pleocytosis.

When the PCR is non-informative

Where the result is negative but suspicion persists, the options are to repeat the test, to measure an intrathecal anti-JC virus antibody response, or to proceed to stereotactic brain biopsy. Biopsy remains the definitive test, showing the histological triad of demyelination, enlarged oligodendrocyte nuclei and bizarre astrocytes, with confirmation by viral protein on immunohistochemistry or viral genome by in situ hybridisation.

Putting it together

The laboratory does not diagnose PML in isolation: it supplies the virological confirmation that, set against the clinical syndrome and the magnetic resonance imaging appearance, allows the case to be graded as possible, probable or laboratory-confirmed. The serum JC virus antibody index has no role in diagnosing an established case; it is a risk-stratification tool in the natalizumab setting.
High priorityExam-styleOutline the three phases of infection risk after haematopoietic stem-cell transplantation and the viral infections characteristic of each, and state how graft-versus-host disease alters the pattern. [8]
Model answer
A complete answer keys the three phases to engraftment, names the dominant viruses in each, and explains the effect of graft-versus-host disease (GVHD).

Pre-engraftment (to around day 30)

Profound neutropenia and mucosal injury from conditioning dominate. Herpes simplex virus is the characteristic herpesvirus reactivation of this phase, and community respiratory viruses acquired around admission can seed the lungs. Bacterial and fungal infection are the larger overall threat here.

Early post-engraftment (engraftment to about day 100)

Neutrophils have recovered but cellular immunity is still absent, which is the period of greatest opportunistic viral risk. CMV reactivation peaks. Also characteristic are human herpesvirus 6 (encephalitis, fever, marrow suppression and delayed engraftment), EBV and post-transplant lymphoproliferative disorder, adenovirus (especially in children), BK polyomavirus haemorrhagic cystitis, and continuing respiratory-virus risk.

Late (after day 100)

As immunity slowly reconstitutes, varicella-zoster virus reactivation becomes characteristic, alongside late CMV and ongoing respiratory-virus infection.

The effect of graft-versus-host disease

GVHD and the immunosuppression used to treat it are the main reason the late phase is prolonged. Chronic GVHD keeps cellular immunity suppressed for months or years, extending the window of risk for CMV, VZV and respiratory viruses well beyond day 100 and making these patients behave, immunologically, as though they were still early after transplant.
MCQ
A patient is ten years after a kidney transplant on long-term immunosuppression. Which HPV-related complication are they most at risk of, and how is that risk addressed?
- A. Cutaneous squamous cell carcinoma, greatly increased by prolonged immunosuppression and ultraviolet exposure, addressed by sun protection, skin surveillance, and reducing immunosuppression or switching to an mTOR inhibitor
- B. Acute HPV viraemia with disseminated warts and pneumonia, arising within weeks of any transplant, treated with a course of intravenous cidofovir guided by serial HPV viral-load measurements made in the blood
- C. Hepatocellular carcinoma driven by HPV integration into liver cells, the commonest HPV-related cancer after solid-organ transplant, screened for with six-monthly serum alpha-fetoprotein and liver ultrasound scanning
- D. Immediate cervical cancer within the first post-transplant year, developing too fast for cytology screening to detect it, and therefore prevented only by routine hysterectomy in all candidates before transplant
- E. No increased HPV-related risk after transplant, because HPV is cleared normally in immunosuppressed patients and the immunosuppressive drugs themselves exert a direct antiviral effect against the virus in the skin and mucosa
Show answer
Correct answer: A
The HPV burden in long-term transplantation

HPV-related disease rises with the duration and intensity of immunosuppression. Cutaneous warts increase from around 15 per cent at transplant to over 80 per cent at 20 years, and, more importantly, cutaneous squamous cell carcinoma (SCC) becomes markedly more common, with ultraviolet light as a cofactor. The usual skin-cancer ratio is reversed so that SCC outnumbers basal cell carcinoma, and these cancers can behave aggressively and metastasise. Anogenital and cervical dysplasia are also increased, with cervical cancer rising several-fold.

Addressing the risk

Prevention and surveillance combine: sun protection and regular skin examination, cervical cytology, and HPV vaccination of candidates before transplant. Where lesions or cancers develop, reducing immunosuppression or switching to an mTOR inhibitor lowers the risk.

Why the distractors are wrong

HPV does not cause a blood-borne viraemia or pneumonia (B), it does not cause hepatocellular carcinoma (C, which describes hepatitis B or C), cervical cancer does not develop within a single year and is detected by cytology rather than prevented by routine hysterectomy (D), and the risk is increased, not absent, in the immunosuppressed (E).
MCQ
Decoy cells on the urine cytology of a transplant recipient are:
- A. Malignant urothelial cells indicating a high-grade invasive bladder carcinoma
- B. Epithelial cells with intranuclear inclusions shed in BK reactivation
- C. Cytomegalovirus-infected owl-eye cells
- D. Eosinophils indicating allergic interstitial nephritis
- E. Red-cell casts indicating glomerulonephritis
Show answer
Correct answer: B
Why B

Decoy cells are infected tubular and urothelial cells bearing ground-glass intranuclear inclusions, shed into the urine during BK-virus reactivation; they are a sensitive but non-specific marker of replication. They are not malignant cells, are distinct from the owl-eye cells of cytomegalovirus, and have nothing to do with eosinophils or red-cell casts.
MCQ
Four weeks after an allogeneic stem-cell transplant, and after engraftment, a patient develops painful haematuria, and BK virus is detected at high level in the urine. Which statement best fits this presentation?
- A. This is late-onset BK polyomavirus haemorrhagic cystitis, distinct from the early cystitis caused directly by conditioning agents such as cyclophosphamide, and managed mainly with supportive care as immunity recovers
- B. This is early conditioning-related chemical cystitis from cyclophosphamide, which characteristically begins several weeks after engraftment and is confirmed by the high level of BK virus that is found in the urine
- C. This is BK polyomavirus-associated nephropathy identical to the renal-allograft disease, and the high urinary BK level alone is sufficient to diagnose it without any need to measure the plasma BK viral load
- D. This is cytomegalovirus haemorrhagic cystitis, the commonest cause of late haematuria after a stem-cell transplant, and it should be treated promptly with ganciclovir guided by the urinary BK result
- E. The high urinary BK level confirms invasive disease in every case, because BK viruria is rare after transplant and is always accompanied by symptomatic haemorrhagic cystitis whenever it is detected in the urine after conditioning
Show answer
Correct answer: A
Two cystitis patterns after stem-cell transplant

Early (first days, around conditioning): chemical cystitis caused directly by urotoxic conditioning agents (cyclophosphamide, ifosfamide, busulfan).

Late (after engraftment, typically weeks 3 to 6): BK polyomavirus haemorrhagic cystitis, with a high urinary BK load, as in this case.

The timing separates the two, which is why option B (placing chemical cystitis weeks after engraftment) is wrong.

Diagnosis and management

BK haemorrhagic cystitis is a bladder disease, not the renal-allograft nephropathy (option C), and the urinary load alone does not equate to disease: 50 to 80 per cent of stem-cell recipients have high viruria but fewer than 20 per cent develop cystitis, so viruria is necessary but not sufficient (option E is wrong). Management is largely supportive: hydration, bladder irrigation, analgesia and transfusion as needed; no antiviral is of proven benefit, though cidofovir is sometimes tried. Option D is wrong because this is BK, not CMV, disease.
MCQ
Reducing immunosuppression is described as the first therapeutic lever for several viral infections after transplantation. For which group is it the primary intervention rather than an adjunct to a specific antiviral?
- A. BK polyomavirus nephropathy, post-transplant lymphoproliferative disorder, adenovirus disease and chronic hepatitis E, where restoring virus-specific T-cell immunity is the mainstay because no reliably effective antiviral exists
- B. Cytomegalovirus disease, where reducing immunosuppression replaces antiviral drugs entirely, so that ganciclovir or valganciclovir has no role at all in the management of established CMV infection after transplant
- C. Herpes simplex mucositis, where all immunosuppression must be stopped before aciclovir can work, because the drug is otherwise completely inactive against the virus in an immunosuppressed transplant recipient
- D. Influenza pneumonia, where withdrawal of immunosuppression is the definitive treatment and neuraminidase inhibitors such as oseltamivir add essentially nothing to the outcome in a transplant recipient
- E. Every viral infection after transplantation equally, since reducing immunosuppression is always the single most effective measure and specific antiviral drugs are never genuinely required in these patients at any point in their care
Show answer
Correct answer: A
The unifying principle

The lever depends on whether an effective drug exists. For BK polyomavirus nephropathy, post-transplant lymphoproliferative disorder (PTLD), adenovirus disease and chronic hepatitis E, there is no reliably effective specific antiviral, so the mainstay is to reduce immunosuppression and let the recovering virus-specific T-cell response control the infection (with rituximab added for PTLD, or cidofovir tried for adenovirus, as adjuncts).

By contrast, where a good drug exists the drug leads:

CMV (option B): ganciclovir, valganciclovir, letermovir and foscarnet are the primary treatment, with reduction of immunosuppression an adjunct, not a replacement.

HSV (option C): aciclovir is highly active regardless of immune state; immunosuppression need not be stopped for it to work.

Influenza (option D): neuraminidase inhibitors given early do improve outcome.

Option E overstates a useful principle: reducing immunosuppression always helps, but it is balanced against the risk of rejection and does not remove the need for specific antivirals where they are effective.
MCQ
Three weeks after an allogeneic stem-cell transplant, a patient develops confusion, short-term memory loss, seizures and hyponatraemia, with bilateral medial temporal lobe change on MRI. Which infection is most likely, and how is it confirmed?
- A. Human herpesvirus 6 encephalitis, confirmed by HHV-6 DNA PCR on cerebrospinal fluid and plasma, while remembering that chromosomally integrated HHV-6 can give persistently high loads without active disease
- B. Herpes simplex encephalitis, confirmed by HSV DNA PCR on cerebrospinal fluid, which is the expected cause of limbic encephalitis at this point and responds rapidly to a standard intravenous course of aciclovir
- C. Cytomegalovirus encephalitis, confirmed by CMV DNA PCR on cerebrospinal fluid, this being the commonest cause of medial temporal lobe encephalitis in the first month after a stem-cell transplant
- D. JC virus progressive multifocal leukoencephalopathy, confirmed by JC virus DNA PCR on cerebrospinal fluid, with the bilateral medial temporal MRI change being typical of this demyelinating white-matter disease
- E. Epstein-Barr virus central nervous system lymphoma, confirmed by EBV DNA PCR on cerebrospinal fluid, which characteristically presents three weeks after transplant with amnesia, seizures and hyponatraemia
Show answer
Correct answer: A
The syndrome

The picture is post-transplant acute limbic encephalitis caused by human herpesvirus 6 (HHV-6B) reactivation, which characteristically occurs early after stem-cell transplant (around weeks 2 to 4). The features are anterograde amnesia, seizures, the syndrome of inappropriate antidiuretic hormone secretion (hyponatraemia), and bilateral medial temporal lobe signal change on MRI.

Confirmation and a pitfall

Diagnosis is by HHV-6 DNA PCR on cerebrospinal fluid and plasma. The important pitfall is chromosomally integrated HHV-6: in people who carry the integrated viral genome in every nucleated cell, PCR shows a persistently very high load that does not indicate active disease. A load that falls with treatment supports a causative role.

Treatment and the distractors

Treat with ganciclovir or foscarnet; aciclovir is inactive against HHV-6. The distractors are wrong on pattern or timing: HSV encephalitis is possible but the MRI and post-transplant context favour HHV-6; CMV CNS disease is uncommon and not the typical limbic picture; JC virus causes white-matter PML, not medial temporal limbic disease; and EBV CNS lymphoma presents as a mass lesion, not this acute encephalitic syndrome.
MCQ
Which best describes the "net state of immunosuppression" that determines a transplant recipient's risk of viral infection?
- A. A composite of the dose, duration and type of immunosuppressive drugs together with host factors such as neutropenia, mucosal injury, indwelling devices, metabolic derangement and the burden of latent immunomodulating viruses
- B. The single most important immunosuppressive drug in the regimen, judged by its trough blood concentration, which on its own predicts the recipient's susceptibility to every opportunistic viral infection after transplant
- C. The recipient's pre-transplant antibody titres to CMV and EBV, which together fix the lifetime risk of viral disease independently of whatever immunosuppression is actually given after the surgery
- D. The degree of HLA mismatch between the donor and the recipient, which determines the risk of viral infection directly and quite separately from the intensity of the drugs used to prevent rejection
- E. The total radiation dose received during conditioning, which is the sole determinant of infection risk and removes any need to consider drugs, host factors or the burden of latent viruses carried before transplant, such as cytomegalovirus and Epstein-Barr virus
Show answer
Correct answer: A
The concept

The net state of immunosuppression is an integrative estimate of how vulnerable a given patient is, summing several contributions rather than any single variable:

the immunosuppressive drugs: their dose, duration, sequence and type, with anti-T-cell (antilymphocyte) antibodies raising risk most and some agents (mTOR inhibitors) lowering CMV risk;

host factors: neutropenia, lymphopenia, low immunoglobulin, breaches of mucosal and skin barriers, indwelling catheters and lines, uraemia, diabetes and malnutrition;

the burden of immunomodulating viruses already present (CMV, EBV, human herpesvirus 6, hepatitis B and C), which themselves further suppress immunity.

Why it matters

Because risk is the sum of these, two patients on the same drug regimen can have very different vulnerability. The concept guides individualised prevention: it explains why adding anti-rejection therapy for a rejection episode reopens the opportunistic window, and why controlling neutropenia and removing devices reduces risk. The distractors each reduce a multifactorial state to one variable (a drug level, serostatus, HLA match, or radiation dose).
MCQ
Which specimen and result triggers pre-emptive treatment of BK virus in a kidney transplant recipient?
- A. A single urine sample showing decoy cells
- B. Urine BK virus DNA above 10,000 copies per millilitre on cytology
- C. BK virus IgG seroconversion in the recipient
- D. Plasma BK virus DNA above 10,000 copies per millilitre
- E. An isolated doubling of the serum creatinine
Show answer
Correct answer: D
Why D

The plasma BK virus DNA load is the decision marker, because virus in the blood reflects significant renal replication; a sustained plasma load above 10,000 copies per millilitre is taken as presumptive nephropathy and prompts pre-emptive reduction of immunosuppression. Urinary shedding and decoy cells are sensitive but not specific, serology does not guide treatment, and a creatinine rise alone is non-specific.
MCQ
Which statement best describes the prevention of herpes simplex and varicella-zoster virus disease in stem-cell transplant recipients?
- A. Aciclovir or valaciclovir prophylaxis in the early period prevents most HSV reactivation, a seronegative recipient exposed to chickenpox or shingles is given varicella-zoster immunoglobulin, and live varicella and zoster vaccines are avoided after transplant
- B. No prophylaxis is given for either virus after transplant, because HSV and VZV reactivation are both harmless in stem-cell recipients and resolve on their own once the transplanted graft has fully engrafted in the patient
- C. Live attenuated varicella vaccine is given routinely in the first month after transplant to prevent zoster, with aciclovir reserved only for the rare patient who develops disseminated herpes simplex despite that immunisation
- D. Valaciclovir prophylaxis is started only after the first episode of zoster has occurred, because giving it before that point rapidly selects for aciclovir resistance and provides no protection at all against herpes simplex reactivation
- E. Varicella-zoster immunoglobulin is given to all recipients regardless of serostatus or exposure, while herpes simplex is covered entirely by the cytomegalovirus prophylaxis and needs no specific aciclovir at any stage of the transplant course, before or after engraftment
Show answer
Correct answer: A
Herpes simplex

HSV reactivates earliest, within the first month. Aciclovir or valaciclovir prophylaxis during this period cuts HSV reactivation from around 70 per cent to under 5 per cent. (CMV prophylaxis with ganciclovir or valganciclovir also covers HSV, so separate aciclovir is not needed while that is running.)

Varicella-zoster

VZV reactivation (zoster) is late, often after day 100, and can disseminate. A seronegative recipient exposed to chickenpox or shingles is given varicella-zoster immunoglobulin within the recommended window, with aciclovir post-exposure prophylaxis as an adjunct. Live varicella and zoster vaccines are contraindicated after transplant and should be given to seronegative candidates before transplant; the non-live recombinant zoster vaccine is an option after transplant where available.

Why the distractors are wrong

B wrongly calls these infections harmless; C gives a live vaccine when it is contraindicated; D withholds prophylaxis until after disease and misstates the resistance picture (long-term prophylaxis actually keeps resistance low); and E misapplies immunoglobulin to everyone and assumes CMV prophylaxis always covers HSV.
Exam-styleDiscuss community respiratory virus infection in stem-cell and lung transplant recipients: the risk of progression, diagnosis, and management. [8]
Model answer
A complete answer covers the spectrum of viruses and what drives progression, the diagnostic approach, and virus-specific and supportive management.

The viruses and the risk of progression

Respiratory syncytial virus (RSV), influenza, parainfluenza virus, human metapneumovirus, rhinovirus and SARS-CoV-2 are acquired from the community or nosocomially, not by reactivation. They usually begin as an upper-respiratory illness but can progress to the lower tract and pneumonia, which carries high mortality in stem-cell recipients. Progression is driven by lymphopenia and pre-engraftment timing, and for influenza by older age. In lung-transplant recipients these viruses are also linked to acute rejection and bronchiolitis obliterans.

Diagnosis

A multiplex respiratory PCR on a nasopharyngeal sample, and on bronchoalveolar lavage where lower-tract disease is suspected, identifies the virus rapidly and guides isolation and specific therapy.

Management
- RSV: aerosolised ribavirin, sometimes with immunoglobulin, started at the upper-tract stage before respiratory failure gives the best chance of preventing progression in high-risk patients.
- Influenza: a neuraminidase inhibitor (oseltamivir) started early reduces progression; prolonged shedding and resistance occur in the immunosuppressed.
- Parainfluenza, metapneumovirus and rhinovirus have no proven antiviral, so care is supportive.
- For all of them, infection control is essential, since these viruses cause nosocomial outbreaks: isolation, hand hygiene and staff and visitor screening, with elective transplant deferred if the candidate has a respiratory infection at the time of conditioning.
Exam-styleDiscuss disseminated adenovirus infection after haematopoietic stem-cell transplantation: who is at risk, how it is monitored, and how it is managed. [8]
Model answer
A complete answer identifies the high-risk groups, explains viral-load surveillance, and gives the management ladder.

Who is at risk

Adenovirus is most dangerous after allogeneic stem-cell transplantation, particularly in children and above all with T-cell depletion (in vivo antithymocyte globulin or ex vivo graft manipulation), which removes the cellular immunity needed to control it. Graft-versus-host disease and cord-blood or mismatched donors add risk. It usually appears within the first three months.

Clinical disease

Infection ranges from asymptomatic shedding to disseminated, frequently fatal disease: gastroenteritis and hepatitis, pneumonia, haemorrhagic cystitis and nephritis, and multi-organ failure. Detectable and rising adenovirus in the blood is the key predictor of dissemination.

Monitoring

High-risk patients are monitored with quantitative real-time PCR on blood and, because shedding there precedes viraemia, on stool and urine. Pre-emptive treatment is triggered by viraemia, not by stool positivity alone, since most stool-positive patients never develop disease.

Management

Reduce immunosuppression to let adenovirus-specific T cells recover. Cidofovir, or its oral lipid-ester brincidofovir (less nephrotoxic), is given pre-emptively on confirmed viraemia, with close attention to renal toxicity and hydration. Adoptive transfer of donor-derived adenovirus-specific T cells is an effective option for refractory disease where it is available.
Exam-styleHow should vaccination be used to reduce viral infection risk around solid-organ or stem-cell transplantation? [8]
Model answer
A complete answer covers timing relative to immunosuppression, the live-vaccine rule, protection of close contacts, and re-vaccination after stem-cell transplant.

Vaccinate before transplant

Vaccine responses are far better before immunosuppression begins, so the candidate’s schedule should be completed during the transplant assessment: inactivated influenza (annually), pneumococcal vaccines, and hepatitis B (checking that a protective anti-HBs response is achieved), along with any catch-up doses needed.

The live-vaccine rule

Live attenuated vaccines (measles-mumps-rubella, varicella, and live zoster) can cause disease in an immunosuppressed host and are contraindicated after transplant. A seronegative candidate should therefore receive them before transplant, allowing an adequate interval (commonly at least four weeks) before immunosuppression starts. Inactivated vaccines carry no such risk and may be given or boosted at any time, although the response is weaker once immunosuppressed.

Protect the household

Because the recipient may respond poorly and cannot receive live vaccines, protect them indirectly by cocooning: vaccinate household and close contacts, especially with annual inactivated influenza, and avoid live oral poliovirus vaccine in contacts. Contacts given other live vaccines rarely transmit, though a varicella-vaccine rash warrants care.

Re-vaccinate after stem-cell transplant

Haematopoietic stem-cell transplantation erases established immune memory, so recipients are effectively unimmunised and need a full re-vaccination programme. Inactivated vaccines are usually restarted around 6 to 12 months after transplant, with live vaccines deferred until immune reconstitution is secure (commonly around two years, off immunosuppression and free of graft-versus-host disease).

Passive immunisation

Where active vaccination is not possible, specific immunoglobulin gives short-term passive cover after an exposure, for example varicella- zoster immunoglobulin for a seronegative recipient exposed to chickenpox or shingles.
Exam-styleWrite short notes on human herpesvirus 8 (HHV-8) and Kaposi sarcoma in the transplant recipient. [6]
Model answer
A complete answer covers the virus and its tumours, the seroprevalence-driven epidemiology, and the management.

The virus and its tumours

HHV-8 (Kaposi sarcoma-associated herpesvirus) causes Kaposi sarcoma, and also primary effusion lymphoma and multicentric Castleman disease. In transplant recipients Kaposi sarcoma is typically the earliest post-transplant malignancy, arising either from reactivation of the recipient’s own latent virus or, less often, from a donor-derived infection transmitted in the graft.

Epidemiology

Risk tracks HHV-8 seroprevalence, which is geographically very uneven: under 5 per cent in Northern European blood donors but up to around 80 per cent in parts of sub-Saharan Africa. Post-transplant Kaposi sarcoma is therefore rare (under 1 per cent) in low-prevalence regions but reaches several per cent in high-prevalence populations, where it makes up the majority of all post-transplant cancers.

Clinical and management

Kaposi sarcoma presents as violaceous cutaneous nodules, but visceral involvement (gastrointestinal, pulmonary) occurs in up to 40 per cent and may bleed or obstruct. The mainstay of treatment is reduction of immunosuppression and a switch to an mTOR inhibitor (sirolimus), which is both immunosuppressive and antitumour and can drive regression. Visceral or refractory disease needs chemotherapy. Antivirals are of unproven benefit.
MCQ
Proven BK-virus-associated nephropathy on renal biopsy is confirmed by:
- A. Congo red staining for amyloid
- B. C4d staining of peritubular capillaries
- C. Immunohistochemistry for SV40 large T antigen
- D. Silver staining for fungal hyphae
- E. Immunostaining for cytomegalovirus early antigen
Show answer
Correct answer: C
Why C

Proven nephropathy requires viral cytopathic change with positive immunohistochemistry for the SV40 large T antigen, using an antibody that cross-reacts with the BK-virus large T antigen to stain infected tubular nuclei. C4d marks antibody-mediated rejection, not BK disease; Congo red, silver and cytomegalovirus stains identify unrelated processes.
MCQ
Regarding drug therapy for BK-virus-associated nephropathy, which statement is correct?
- A. Levofloxacin reliably clears the virus from blood
- B. No specific antiviral is of proven benefit
- C. Cidofovir is curative and free of toxicity
- D. Ganciclovir is the treatment of choice
- E. Aciclovir prophylaxis prevents nephropathy
Show answer
Correct answer: B
Why B

No antiviral has proven benefit against BK virus, and management rests on reducing immunosuppression. A randomised trial of levofloxacin showed no effect on viral load; cidofovir gives inconsistent results and carries nephrotoxicity and uveitis; and ganciclovir and aciclovir have no useful activity against BK virus.