Immunocompromised Patients — Questions

Because VZV spreads largely from cell to cell, cell-mediated immunity rather than antibody is the decisive control. Children who cannot make antibody are not unusually susceptible to severe chickenpox, whereas any failure of T-cell immunity predisposes to severe primary disease and to reactivation.

The decline of this arm with age or immunosuppression is what permits zoster.

The recombinant glycoprotein E subunit vaccine with the AS01B adjuvant, given as two doses, has superseded the older live-attenuated zoster vaccine. It gives high, durable protection of around 90% that does not wane with age, and because it is non-live it is safe in the immunocompromised, the group at greatest need.

The childhood varicella vaccine prevents primary chickenpox, and immunoglobulin is for post-exposure prophylaxis, neither being active immunisation against zoster.

Antiviral treatment is indicated for complicated varicella and for any immunocompromised patient, in whom the disease can progress and disseminate. Aciclovir should be started as early as possible, given intravenously when the disease is severe.

Uncomplicated chickenpox in a healthy child is self-limiting and does not require antivirals.

Aciclovir must first be activated by the viral thymidine kinase, and resistance, which arises mainly during prolonged exposure in advanced HIV infection, is usually due to mutation of that kinase.

Foscarnet and cidofovir inhibit the viral DNA polymerase directly, without needing viral activation, so they retain activity against thymidine-kinase-deficient resistant strains.

A complete answer recognises the high-risk setting, works through diagnosis and staging, keeps the differential in mind, and sets out a graded management plan.

Recognise the setting

This is the highest-risk solid-organ scenario: an EBV-naive child (recipient negative) receiving a seropositive organ, now undergoing a primary EBV infection while immunosuppressed, in the first-year window when EBV-positive post-transplant lymphoproliferative disorder (PTLD) is most likely. The rising load and new lymphadenopathy should be treated as possible PTLD until proven otherwise.

Diagnosis and staging

Confirm and trend the EBV-DNA load, and take a focused history and examination. Definitive diagnosis needs tissue: an excisional lymph-node biopsy with histology, immunophenotype (including CD20), EBV-encoded RNA (EBER) staining and clonality, to place the lesion on the spectrum. Stage with cross-sectional imaging (with metabolic imaging where available), assess graft function, and add bone-marrow or central-nervous-system assessment if indicated. Supportive findings include a raised lactate dehydrogenase.

Keep the differential in mind

Fever and lymphadenopathy in a transplant child also raise infection and, where the graft is involved, rejection, and these can coexist with PTLD.

Management

Begin with reduction of immunosuppression, the foundation in a kidney recipient because the graft can, if necessary, be supported by dialysis. If the disease is CD20-positive and does not regress, add rituximab, and escalate to chemotherapy only if it fails or the histology is a true lymphoma. Manage jointly with oncology and the transplant team. Pre-emptive reduction of immunosuppression or rituximab on a rising load is also used in this high-risk group to prevent progression.

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 simian virus 40 (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 ~80% 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.

a. CMV hepatitis: the owl’s-eye intranuclear inclusion is the cytopathic hallmark of cytomegalovirus, and after liver transplant it must be separated from rejection and drug injury.

b. Immunohistochemistry on the biopsy for CMV antigen confirms tissue-invasive disease; a plasma CMV PCR is sent as a baseline for monitoring, though the blood load can be low in tissue-invasive disease.

c. First-line antiviral is intravenous ganciclovir 5 mg/kg 12-hourly (or oral valganciclovir 900 mg 12-hourly for non-severe disease with reliable absorption), continued for a minimum of two weeks and until the viral load clears below the local threshold. Reducing immunosuppression where feasible is a useful adjunct.

a. The viral load falls slowly, so a persistent level at two weeks does not by itself mean failure. Ganciclovir is continued because agents are not switched within the first two weeks if the patient is otherwise responding; adherence and correct dosing are confirmed; and reducing immunosuppression is attempted where the graft-versus-host disease allows.

b. True resistance is suspected only after adequate cumulative exposure (beyond two weeks, and generally four to six weeks of therapy) with a load that plateaus or rises. It is confirmed by genotypic sequencing: UL97 first, the commonest and conferring ganciclovir resistance; UL54 giving broader cross-resistance to foscarnet and cidofovir. It is more likely with prolonged exposure and heavy immunosuppression, as here.

c. Maribavir (an oral UL97-kinase inhibitor for refractory or resistant CMV) and letermovir (a terminase inhibitor, used for prophylaxis). Foscarnet is the established polymerase-active switch for confirmed UL97 resistance.

A complete answer recognises the likely diagnosis, confirms it, treats it, and anticipates the complication of immune recovery.

Recognise the diagnosis

At a CD4 count of 30, floaters and reduced acuity are CMV retinitis until proven otherwise: it is the commonest end-organ cytomegalovirus disease and appears at this depth of immunosuppression. Sight near the macula or optic disc is immediately at risk.

Confirm it

The diagnosis is clinical, made on dilated fundoscopy by an experienced examiner, who looks for well-demarcated full-thickness retinal necrosis with fluffy white opacification along the vessels and accompanying haemorrhage, with little vitritis. A blood cytomegalovirus polymerase chain reaction (PCR) supports the diagnosis and gives a baseline to follow, though it can be low in eye-limited disease. Where the appearance is atypical or a similar infection must be excluded (such as herpes simplex or varicella-zoster retinal necrosis, toxoplasma chorioretinitis or syphilis), PCR on an intraocular (aqueous or vitreous) sample can establish the cause.

Treat it

Start systemic valganciclovir or ganciclovir as induction then maintenance until immune recovery (a sustained CD4 count above 100), with intravitreal therapy for immediately sight-threatening lesions and foscarnet or cidofovir as alternatives. Antiretroviral therapy is essential, since durable control depends on restoring immunity.

Anticipate immune recovery

Warn of, and watch for, immune-recovery uveitis, a form of immune reconstitution inflammatory syndrome in which the recovering response inflames the eye and can itself threaten vision; it is managed with corticosteroids while both antiretroviral and anti-cytomegalovirus therapy continue.

Natalizumab blocks lymphocyte entry into the brain, removing the immune surveillance that contains JC virus, so PML is its defining hazard.

Risk stratification

Three factors set the risk. The serum JC virus antibody index: seronegative patients are at low risk, while a high index (conventionally above about 1.5) marks substantially higher risk. Prior use of immunosuppressant drugs raises risk further. So does duration of treatment, with risk climbing markedly beyond about two years. A patient who is seropositive with a high index, has had previous immunosuppression and has been treated for several years sits in the highest-risk group.

Monitoring

Seronegative patients are retested periodically, because seroconversion on therapy raises their risk. Higher-risk patients undergo more frequent magnetic resonance surveillance, every few months rather than annually, to detect early or presymptomatic lesions, since outcome is far better when PML is caught before it becomes symptomatic.

Management if PML develops

Stop natalizumab and accelerate its clearance with plasma exchange or immunoadsorption to restore normal lymphocyte trafficking. There is no specific antiviral. Restoring immune surveillance almost inevitably provokes an immune reconstitution inflammatory syndrome, which is then managed in its own right, with corticosteroids reserved for severe inflammation with raised intracranial pressure.

Two prevention strategies.

• Universal prophylaxis: an antiviral (usually valganciclovir) given to all at-risk recipients for a fixed period after transplant.
• Pre-emptive therapy: serial viral-load surveillance, treating only when the load crosses a threshold.

Infection versus disease. CMV infection is detection of the virus (for example viraemia on PCR), which may be asymptomatic; CMV disease is that detection together with attributable findings, either a viral syndrome (fever, malaise, cytopenias) or tissue-invasive end-organ involvement.

Why D positive, R negative is high risk. The donor kidney carries latent CMV while the seronegative recipient has no pre-existing CMV immunity, so the graft transmits virus into a host who undergoes a primary infection with no CMV-specific T cells to control it. Without prevention this group has an 80 to 100% risk of infection and a 50 to 70% risk of disease.

• Encephalitis or meningoencephalitis: haemorrhagic, necrotising infection of the brain.
• Hepatitis: which can progress to fulminant hepatic failure, classically in pregnancy or immunosuppression.
• Pneumonitis: with, in severe dissemination, adrenal involvement, widespread mucocutaneous lesions and coagulopathy.

• More frequent, severe and prolonged disease: large, persistent, slowly healing or atypical ulcers, including heaped hypertrophic (pseudotumour) lesions in advanced HIV.
• Dissemination and visceral involvement: oesophagitis, hepatitis, pneumonitis and encephalitis, which can be life-threatening.
• Diagnostic challenge: atypical presentations mean reliance on PCR (polymerase chain reaction), with culture kept for resistance testing.
• Antiviral resistance: prolonged high-level replication selects thymidine-kinase-mutant aciclovir-resistant virus, requiring foscarnet or cidofovir despite their nephrotoxicity.
• Management: intravenous aciclovir for severe disease and long-term suppressive therapy during deep immunosuppression; a flare can occur as immune reconstitution inflammatory syndrome when antiretroviral therapy is started.

A complete answer explains what the international unit fixes, why it matters, and the residual variation it does not remove.

What it fixes. Before standardisation, every laboratory reported CMV DNA in its own copies per millilitre against 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, letting results be expressed in international units per millilitre (IU/mL).

Why it matters. Standardised reporting lets viral-load thresholds be shared between centres and written into guidelines (triggering pre-emptive therapy, defining response, suspecting resistance), and it allows multicentre trials and the transfer of a patient between laboratories without losing the thread of monitoring.

The residual limits. Standardisation reduces but does not abolish variation. Even WHO-calibrated assays are not fully interchangeable, differing in gene target, amplicon size and extraction, so a patient should still be followed on one assay and one specimen type throughout. Specimen type matters in its own right: a whole-blood load runs roughly one log10 higher than a plasma load from the same patient. Because of this residual variation there is no single universal disease-defining cutoff, and thresholds remain assay-specific.

A complete answer covers the pathogenesis, the stem-cell-specific risk, EBV-DNA monitoring, and the treatment principles.

Pathogenesis

EBV infects B cells for life and, in its latent state, can switch on a growth programme that drives the B cell to proliferate. This is normally controlled by EBV-specific cytotoxic T cells. Transplant immunosuppression targets T cells, removes that surveillance, and lets EBV-driven B cells grow unchecked.

The stem-cell-specific risk

After stem-cell transplant the graft is the new immune system, so the highest-risk patient is a seropositive recipient of a seronegative or T-cell-depleted donor: the recipient carries EBV, but the new donor immunity brings no EBV-specific T cells. Most such PTLD is donor-derived, EBV-positive, and appears within the first year.

Monitoring

High-risk patients undergo EBV-DNA surveillance of the blood, most intensively in the early months. A high or rising load flags risk and can trigger pre-emptive treatment before disease declares itself, though thresholds are not standardised and a load never substitutes for a tissue diagnosis once a lesion is present.

Treatment

The principles are to reduce immunosuppression where graft-versus-host disease allows, give rituximab for CD20-positive disease (including pre-emptively on a rising load), escalate to chemotherapy for disease that does not respond, and, because the disease is EBV-positive, restore immunity with EBV-specific T cells, which are particularly effective in the stem-cell setting. Antivirals have no role against the latent virus.

A complete answer defines PTLD, sets out the older histological categories, explains the 2022 reframing, and adds the practical functional view.

Definition

Post-transplant lymphoproliferative disorder (PTLD) is an overgrowth of lymphocytes, almost always B cells, that arises after transplantation when immunosuppression weakens the T cells that normally control Epstein-Barr virus (EBV). It is best defined as a spectrum rather than a single disease, running from a reactive, polyclonal hyperplasia, through clonal neoplasia, to frank malignant lymphoma.

The older histological categories

The previous World Health Organization scheme treated PTLD as a standalone entity with four categories: non-destructive (early) lesions, polymorphic PTLD, monomorphic PTLD (usually a diffuse large B-cell lymphoma), and classic Hodgkin lymphoma PTLD. An EBV-encoded RNA (EBER) stain is performed on every case to establish EBV status.

The 2022 change

The 2022 World Health Organization 5th edition and the International Consensus Classification both stopped treating PTLD as its own entity and placed it within a larger family: lymphoid proliferations and lymphomas arising in immune deficiency and dysregulation. The histological categories survive, but each lesion now carries a three-part name: the histological diagnosis, the driving virus (EBV or Kaposi sarcoma-associated herpesvirus), and the immune setting (here, post-transplant, solid organ or bone marrow).

The functional view

In practice the spectrum is read as quintessential, EBV-driven PTLD (reactive hyperplasia to EBV-positive large-cell neoplasia, much of it controllable with low-intensity treatment) versus post-transplant lymphoma (a true lymphoma needing lymphoma-directed treatment), with EBV-negativity the principal warning sign of the latter.

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 simian virus 40 (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.

PML is a directly cytopathic disease that emerges only when cellular immunity fails.

Reactivation under immunosuppression

Most adults carry JC virus as a lifelong, low-level persistent infection of the kidney and lymphoid tissue, controlled by T-cell immunity. PML is reactivation of this infection, not a new one: almost all patients are already seropositive, and disease appears only with profound immunosuppression, classically advanced HIV with a low CD4 count or treatment with agents such as natalizumab. Loss of JC-virus-specific CD8 cytotoxic T cells is the decisive failure.

Reaching and damaging the brain

Two molecular changes license neurovirulence: rearrangement of the non-coding control region from the urinary archetype to the disease-associated prototype, which raises replication in glial cells, and mutation of the VP1 receptor-binding site favouring the serotonin 5-HT2A receptor on glia. Infected B-lineage cells are thought to carry the virus across the blood-brain barrier. There it replicates lytically in oligodendrocytes, the myelin-producing cells. Because each oligodendrocyte myelinates many axons, their destruction produces expanding, coalescing demyelination of the subcortical white matter, with the histological triad of enlarged oligodendrocyte nuclei, bizarre reactive astrocytes and foamy macrophages, and little inflammation until immune reconstitution supervenes.

A complete answer describes both prevention strategies and gives an advantage and a disadvantage of each.

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 over-treatment of patients who would never have developed CMV.

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.

A complete answer covers how resistance arises, how common it is and in whom, and what to use instead.

Mechanism

Aciclovir is a guanosine analogue that must first be activated by the viral thymidine kinase (TK) and then by cellular kinases; aciclovir-triphosphate inhibits the viral DNA polymerase and terminates the growing DNA chain. Resistance therefore arises in two ways:

• Thymidine-kinase mutations (much the commonest): TK-deficient, TK-low-producing, or TK with altered substrate specificity, all of which prevent activation of the drug.
• DNA polymerase mutations (less common), which can also confer cross-resistance to other polymerase inhibitors.

Prevalence

Resistance is rare in immunocompetent people (around 1% or less) but much more common in the profoundly immunocompromised, such as those with advanced HIV or haematopoietic stem-cell transplants, where prolonged high-level replication under drug pressure selects resistant virus.

Alternative treatment

• Foscarnet (a pyrophosphate analogue) and cidofovir (a nucleotide analogue) inhibit the viral DNA polymerase directly and do not need thymidine kinase, so they remain active against TK-mutant virus; both are limited by nephrotoxicity.
• Reducing immunosuppression where possible, topical options such as cidofovir gel, and newer helicase-primase inhibitors are additional considerations.

A complete answer states the competing goals, how the spectrum sets intensity, the graded ladder, and the points commonly overlooked.

The two goals

Management balances two aims that often conflict: eradicate the PTLD and preserve the graft. Reducing immunosuppression serves the first but risks the second, and which wins depends on whether the organ can be supported by other means (a failing kidney can return to dialysis; a failing heart cannot).

Let the spectrum set the intensity

Quintessential, Epstein-Barr virus (EBV)-driven PTLD is treated with the lowest-intensity approach that works, escalating only as needed. A post-transplant lymphoma is treated from the start as the corresponding lymphoma would be in an immunocompetent patient.

The graded ladder

Reduce immunosuppression first, for every subtype. Add rituximab for CD20-positive disease. Escalate to chemotherapy (such as rituximab with CHOP, often in a response-guided sequence) for disease that does not respond or for true lymphomas. In EBV-positive disease, especially after stem-cell transplant, restore EBV-specific T cells. Localised complications may need surgery, and central-nervous-system disease is treated as a primary central nervous system lymphoma.

Points commonly overlooked

Antivirals have no role against the latent virus. CD20 status determines whether rituximab can work. A blood EBV-DNA load guides suspicion and tracks response but does not diagnose disease. Newer approaches (agents targeting CD30, antibodies against interleukin-6, and expanding cellular therapies) may broaden the options, but availability differs widely between settings.

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 (PCR). In a patient with compatible neurology and characteristic imaging, a positive result confirms the diagnosis (laboratory-confirmed progressive multifocal leukoencephalopathy) 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 the diagnosis. Routine cerebrospinal fluid is usually otherwise normal, which helps separate it 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 the disease 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 an established case; it is a risk-stratification tool in the natalizumab setting.

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, preventing early disease but also meaning the patient is never exposed to enough virus to build CMV-specific T-cell immunity. When the drug stops, 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 course ends, so 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.

The result is meaningful precisely because the site is privileged.

A positive result signifies central nervous system disease

JC virus is not normally present in cerebrospinal fluid, unlike urine and blood, where most healthy adults shed or harbour the virus without consequence. Detection of JC virus DNA in the cerebrospinal fluid therefore indicates replication within the central nervous system rather than incidental persistence. In a patient with a compatible clinical picture and characteristic magnetic resonance imaging, a positive PCR confirms the diagnosis as laboratory-confirmed PML and removes the need for brain biopsy. Viral load can be quantified to support monitoring.

Interpret with the clinical and radiological context

The result is read together with the syndrome and the imaging, not alone. A positive PCR without compatible clinical or radiological features should prompt review rather than an immediate diagnosis. The converse caveat also matters: because the assay misses about a quarter of proven cases, a negative result does not exclude PML, so the positive result is the more decisive of the two.

A complete answer explains what controls EBV, identifies the high-risk combination in each setting, and gives the single reason they differ.

What controls EBV. EBV-infected B cells are held in check by EBV-specific cytotoxic T cells. PTLD risk is highest whenever the virus is present but those specific T cells are absent.

Solid-organ transplant. The patient keeps their own immune system; the organ is what is foreign. The danger is a seronegative recipient receiving a seropositive organ (donor positive, recipient negative), who meets EBV for the first time while immunosuppressed and has no EBV-specific T cells to contain the primary infection.

Stem-cell transplant. Here the logic reverses because the graft becomes the new immune system. The danger is a seropositive recipient given a seronegative or T-cell-depleted graft (donor negative, recipient positive): the recipient already carries EBV, but the incoming donor immunity brings no EBV-specific T cells to control it. Most PTLD after stem-cell transplant is therefore donor-derived, EBV-associated, and appears within the first year.

The single reason. In both cases the high-risk patient is the one with EBV present but no matching T-cell immunity. Because the immune system comes from the recipient in solid-organ transplant but from the donor in stem-cell transplant, the serostatus that creates that mismatch flips.

A complete answer explains the spectrum, the Epstein-Barr virus (EBV)-driven imbalance that produces it, the functional grouping, and how each follows through to treatment intensity.

The spectrum

PTLD is not one disease but a continuum: a reactive, polyclonal hyperplasia at one end (resembling infectious mononucleosis, architecture preserved, no genetic hallmarks of malignancy), a clonal neoplasia in the middle, and a monoclonal malignant lymphoma at the other end. The same label therefore covers lesions of very different behaviour.

What drives progression

Progression reflects the balance between EBV-driven B-cell proliferation and T-cell control of EBV: EBV promotes proliferation, EBV-specific T cells normally restrain it, and immunosuppression removes that restraint. How far a patient progresses depends on how far EBV is driving the disease and how much T-cell control has been lost.

The functional grouping

The functional reading sorts the spectrum into quintessential, EBV-driven PTLD (hyperplasia through EBV-positive large-cell neoplasia) and post-transplant lymphoma (a true lymphoma behaving as in an immunocompetent patient). EBV status is the principal discriminator: EBV-positive disease is more often the controllable, quintessential form; EBV-negative disease raises concern for a true lymphoma.

How this guides management

Treatment intensity follows position on the spectrum. Quintessential disease is treated with the lowest-intensity approach that works, escalating only as needed: reduce immunosuppression, then add rituximab for CD20-positive disease, then chemotherapy if it does not respond. A post-transplant lymphoma is treated from the outset as the matching lymphoma would be in an immunocompetent patient. EBV-positive disease, especially after stem-cell transplant, can also be treated by restoring EBV-specific T cells. Position on the spectrum therefore determines the intensity of treatment.

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 helps 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. It plays no part in choosing the donor, the HLA match, the conditioning regimen or the transplant date.

This is chronic hepatitis E (HEV RNA persisting beyond three months), seen almost exclusively with the zoonotic genotypes 3 and 4 in immunosuppressed hosts. The evidence-based first step is to reduce immunosuppression where the graft allows, particularly calcineurin inhibitors such as tacrolimus, because this restores the host response and clears the virus in a meaningful minority of patients. If viraemia persists, ribavirin monotherapy is the usual next step and clears most remaining cases.

A overstates interferon: it can clear chronic HEV but carries a rejection risk in organ recipients, so ribavirin is preferred. B is a category error, since nucleos(t)ide analogues target the HBV reverse transcriptase and have no activity against HEV. C is false in the immunosuppressed, where genotype 3 readily becomes chronic and can progress to cirrhosis if ignored. E is the wrong direction: more immunosuppression worsens HEV replication and persistence.

Human papillomavirus (HPV) disease accrues with the duration and intensity of immunosuppression, and the important long-term complication is cutaneous squamous cell carcinoma, with ultraviolet light as a cofactor and the usual skin-cancer ratio reversed so that squamous outnumbers basal cell carcinoma. Cutaneous warts rise from ~15% at transplant to over 80% at 20 years. Risk is addressed by sun protection, regular skin and cervical surveillance, HPV vaccination of candidates before transplant, and reducing immunosuppression or switching to a mechanistic-target-of-rapamycin (mTOR) inhibitor where disease develops.

HPV causes no blood-borne viraemia or pneumonia, does not cause hepatocellular carcinoma (that is hepatitis B or C), does not produce cervical cancer within a year (cytology detects it, hysterectomy does not prevent it), and the risk is increased, not absent.

Failure to heal on adequate aciclovir suggests aciclovir resistance, which arises through viral thymidine-kinase mutations with prolonged exposure. Because resistant virus cannot activate aciclovir, valaciclovir or famciclovir (all of which depend on the same kinase), the answer is to switch to foscarnet, which acts directly on the viral polymerase and needs no activation.

Raising the aciclovir dose or changing to another thymidine-kinase-dependent drug will not work against a resistant strain, a corticosteroid does not treat the infection, and ganciclovir shares the activation problem. A chronic herpes simplex ulcer persisting beyond a month is itself an AIDS-defining condition.

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 (a higher load and a faster rate of rise predict progression, so serial values matter more than one reading, and a first-positive after a negative warrants close attention) and 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 starts promptly at any confirmed viraemia; in a lower-risk patient a borderline value may be repeated in a few days).

The distractors invent a universal threshold (B), discard the quantitative information (C), make therapy symptom-driven (D), or misunderstand that modern thresholds use international units (E).

The seronegative recipient of a seropositive organ (D positive, R negative) has no cytomegalovirus (CMV)-specific memory immunity, so latent CMV delivered in the graft causes a primary infection in a naive, pharmacologically immunosuppressed host. Without prophylaxis this group has the highest rates of infection (~80 to 100%) and of CMV disease (~50 to 70%), which is why prophylaxis is targeted to it.

D negative, R positive and D positive, R positive are intermediate (reactivation contained by some pre-existing immunity); D negative, R negative is lowest (no CMV present); and serostatus is precisely what stratifies risk and sets the prevention strategy.

The dose-limiting toxicity of ganciclovir and valganciclovir is myelosuppression, especially neutropenia (in roughly a third of patients), monitored by the full blood count and managed with a granulocyte colony-stimulating factor or dose reduction; after stem-cell transplant it can impair engraftment. The main alternatives differ: foscarnet is limited by nephrotoxicity and electrolyte wasting (calcium, magnesium, potassium, phosphate), and cidofovir by nephrotoxicity (proximal tubular injury). This complementary profile is useful: a neutropenic patient can move to foscarnet, and one developing renal impairment away from it.

The distractors misassign the toxicity (A, B), invent one (C), or deny toxicity altogether (E).

First-line treatment is intravenous ganciclovir or its oral prodrug valganciclovir at induction dosing. Valganciclovir suits non-severe disease with reliable gut absorption; intravenous ganciclovir is preferred for severe, sight-threatening or life-threatening disease, or where absorption is uncertain. Treatment runs a minimum of two weeks and until the viral load clears below the local threshold, and agents are not switched in the first two weeks if the patient is improving, since the load falls slowly. Reducing immunosuppression is a useful adjunct.

Letermovir is prophylaxis only, valaciclovir does not treat CMV disease, foscarnet is not first-line and needs monitoring, and reducing immunosuppression does not replace the antiviral.

With a confirmed UL97 mutation (ganciclovir resistance), the active options are maribavir, an oral UL97-kinase inhibitor licensed for refractory or resistant CMV and not myelosuppressive, or foscarnet, which acts on the polymerase and does not need UL97 activation. Reducing immunosuppression is a valuable adjunct, not a substitute for an active drug.

Letermovir has a low resistance barrier and is prophylactic, not salvage (B); increasing ganciclovir does not overcome a true UL97 mutation (A); stopping all antivirals abandons effective options (C); and aciclovir-class drugs do not treat CMV disease (E).

Why E

BK virus attaches to branched gangliosides (GT1b and GD1b) displayed on renal tubular epithelium and urothelium and enters by caveolin-dependent endocytosis, which directs it to the urinary tract. JC virus, by contrast, uses a sialylated glycan with the serotonin 5-HT2A receptor and a clathrin route into glial cells, which is why it targets the brain. The other options describe unrelated viruses.

Cytomegalovirus end-organ disease, retinitis above all, is the classic very-late opportunistic infection, appearing below a CD4 count of about 50 cells per microlitre. It marks the deepest immunosuppression on the CD4 ladder.

The higher counts correspond to earlier events: zoster and more severe herpes simplex below 350, the AIDS threshold and disseminated zoster below 200, and chronic herpes simplex, the Epstein-Barr virus (EBV)-driven systemic lymphomas and progressive multifocal leukoencephalopathy below 100. Cytomegalovirus, with primary central nervous system lymphoma, sits at the bottom, below 50.

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.

Adoptive therapy with EBV-specific cytotoxic T cells restores the exact immunity that immunosuppression removed: T cells that recognise and kill EBV-infected B cells. It can only work where the tumour is EBV-positive, and it is most effective after stem-cell transplant, where the disease is almost always EBV-driven and donor-derived.

It is therefore not used for EBV-negative disease (which carries no EBV target), is not limited to Hodgkin or CD20-negative subtypes, and is not applicable to all PTLD. Off-the-shelf, third-party EBV-specific T cells are now reaching practice for relapsed or refractory EBV-positive disease, with little risk of graft-versus-host disease.

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. Whole blood detects cell-associated virus and is somewhat more sensitive at low levels, but is harder to standardise and runs about one log10 higher than a plasma load from the same patient. Because the numbers differ, a patient is followed on one specimen type and one assay throughout, and plasma and whole-blood results are not compared directly.

The distractors overstate whole blood’s standing (A), claim the two are interchangeable (C), reduce the choice to cost (D), or dismiss a valid specimen (E).

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 works 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.

The timing after engraftment with high urinary BK virus is late BK polyomavirus haemorrhagic cystitis, a bladder disease managed largely with supportive care (hydration, bladder irrigation, transfusion) as immunity recovers.

Chemical cystitis from urotoxic conditioning agents such as cyclophosphamide occurs early, in the first days, not weeks after engraftment. This is a bladder disease, not the renal-allograft nephropathy, and it is BK rather than cytomegalovirus. The high urinary load does not by itself equate to disease: ~50 to 80% of recipients have high viruria but under 20% develop cystitis, and here the patient is symptomatic.

Reactivation of varicella-zoster as shingles occurs at a relatively high CD4 count and is often the first clue to undiagnosed HIV in a young adult, so it should prompt HIV testing. As immunity falls further, zoster becomes multidermatomal or disseminated and can cause encephalitis, a retinal necrosis and a stroke-causing vasculopathy.

Reassurance alone misses an opportunity to diagnose HIV, lifelong suppression is not indicated for a single episode, a live vaccine is inappropriate when immunodeficiency is suspected, and a clotting screen is irrelevant.

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.

Universal letermovir or valganciclovir prophylaxis is not advised here, lifelong secondary prophylaxis is not indicated, and doing no monitoring ignores a real risk.

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 that detection plus attributable clinical findings, either a viral syndrome (fever, malaise, cytopenias) or tissue-invasive end-organ disease. The distinction drives management: a pre-emptive strategy deliberately treats asymptomatic infection to stop it progressing to disease, so a positive test is a trigger to act read in clinical context, not yet a diagnosis of illness.

The distractors equate detection with disease (B, D), confuse the infection/disease axis with primary versus reactivation (C), or misassign the diagnostic tests (E).

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, worst when the donor is seronegative (D negative), because the donor-derived immune system carries no CMV-specific T cells to control it.

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.

A pre-emptive strategy withholds antiviral and monitors the viral load at regular intervals (typically weekly), treating only when replication crosses a threshold. It spares drug exposure, cost and resistance, but depends on reliable, frequent, standardised monitoring and can be outrun by rapidly rising viraemia.

Option A is the definition of universal prophylaxis (antiviral to all at-risk for a fixed period, which risks late-onset disease when it stops); C wrongly waits for symptomatic disease; D describes prophylaxis; and E omits the treatment that pre-emptive monitoring is meant to trigger.

Both 2022 systems (the World Health Organization 5th edition and the International Consensus Classification) stopped treating PTLD as its own disease and folded it into one larger family: lymphoid proliferations and lymphomas arising in immune deficiency and dysregulation. The same lesions, with the same Epstein-Barr virus (EBV) biology, appear wherever immune control is lost (inherited immune defects, HIV, transplant, autoimmune disease, drugs, and the immune senescence of age), so they are classified once by shared biology.

The familiar histological categories survive, but each lesion now carries a three-part name (histology, virus, and immune setting); the standalone four-category option describes the older scheme. PTLD is not chronic active EBV infection, a reactive hyperplasia, or a Hodgkin subtype.

The functional framework splits the spectrum into quintessential, EBV-driven PTLD (reactive hyperplasia through to EBV-positive large-cell neoplasia, much of it controllable with low-intensity treatment) and post-transplant lymphoma (a true lymphoma that behaves as it would in an immunocompetent patient and needs lymphoma-directed treatment).

EBV-negativity is the principal warning sign for the second group: EBV-negative disease tends to arise late, be monomorphic, and behave aggressively. The other options point the opposite way, since EBV-positivity, polyclonality and early onset all favour quintessential disease, and tonsillar enlargement is a feature of reactive, non-destructive lesions.

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, so it does not impair engraftment, and it markedly reduces clinically significant CMV. Two caveats are practice-critical: it has no activity against herpes simplex or varicella-zoster virus, so aciclovir-class cover is still needed, and it has a low barrier to resistance, so it is a prophylactic agent, not a treatment. It also inhibits CYP3A, raising calcineurin-inhibitor levels.

The distractors give the wrong target (A, B), wrongly make it a treatment (C), or overstate its spectrum (D).

Oral hairy leukoplakia is an Epstein-Barr virus lesion: corrugated white plaques on the lateral border of the tongue that do not rub off. It is benign but a useful clinical marker of immunosuppression, needs no specific treatment, and regresses with immune recovery on antiretroviral therapy.

Herpes simplex, cytomegalovirus and human papillomavirus do not cause it. Candida causes oral candidiasis, which is also common in HIV, but its plaques wipe off and are fungal, unlike the adherent plaques of hairy leukoplakia.

Primary effusion lymphoma is a KSHV-positive lymphoma arising from monoclonal plasmablastic B cells, often co-infected with Epstein-Barr virus, that presents as malignant effusions in body cavities without a solid mass.

It is usually HIV-positive, is not human-papillomavirus-driven, forms no solid nodal mass, and is of B-cell rather than T-cell origin.

Proven nephropathy requires viral cytopathic change with positive immunohistochemistry for the simian virus 40 (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, and the Congo red, silver and cytomegalovirus stains identify unrelated processes.

Where no reliably effective antiviral exists, restoring virus-specific T-cell immunity is the mainstay, so reducing immunosuppression is primary for BK polyomavirus nephropathy, post-transplant lymphoproliferative disorder (PTLD), adenovirus disease and chronic hepatitis E (with rituximab or cidofovir as adjuncts).

Where a good drug exists, the drug leads: cytomegalovirus is treated with ganciclovir or valganciclovir; herpes simplex responds to aciclovir regardless of immune state; influenza benefits from early neuraminidase inhibitors. Reducing immunosuppression always helps but never removes the need for effective antivirals, and it is balanced against the risk of rejection.

No antiviral has proven benefit against BK virus, so management rests on reducing immunosuppression to restore virus-specific T-cell control.

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.

Why E

As with the other polyomaviruses, control depends on cellular immunity, so the central measure is to reduce immunosuppression where the underlying condition allows, supported by topical antivirals such as cidofovir. Chemotherapy, excision and radiotherapy are treatments for cancer, not for this benign follicular disease, and corticosteroids would deepen the immunosuppression that drives it.

Why D

There is no specific antiviral for JC virus; the single effective principle is to restore JC-virus-specific immunity, which in HIV means starting or optimising antiretroviral therapy. Aciclovir has no activity against polyomaviruses, cidofovir has not shown benefit, corticosteroids are reserved only for severe immune reconstitution inflammation, and mirtazapine is unproven and not a treatment in its own right.

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 ~80% 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 A

In a few immunosuppressed patients HPyV7 has been linked to a pruritic, brown, plaque-like hyperproliferative eruption. A neuroendocrine nodule is Merkel cell carcinoma, facial keratin spicules are trichodysplasia spinulosa, dermatomal vesicles are zoster, and a genital ulcer points to other causes.

This is post-transplant acute limbic encephalitis from human herpesvirus 6 (HHV-6B) reactivation, which occurs early after stem-cell transplant (around weeks two to four). Anterograde amnesia, seizures, the syndrome of inappropriate antidiuretic hormone secretion (hyponatraemia) and bilateral medial temporal lobe change on magnetic resonance imaging (MRI) are the signature. Diagnosis is by HHV-6 DNA polymerase chain reaction (PCR) on cerebrospinal fluid and plasma, treated with ganciclovir or foscarnet (aciclovir is inactive). The pitfall is chromosomally integrated HHV-6, which gives a persistently high load without active disease; a load that falls with treatment supports a causative role.

Herpes simplex encephalitis is possible but the imaging and post-transplant context favour HHV-6; cytomegalovirus central nervous system disease is uncommon and not this limbic picture; JC virus causes white-matter disease, not medial temporal change; and Epstein-Barr virus lymphoma presents as a mass lesion.

Why A

The disease occurs almost only in immunosuppressed patients, in whom loss of T-cell control permits productive replication of the virus in hair follicle cells. It is not a disease of primary infection, does not involve integration and transformation (that is Merkel cell polyomavirus), and has nothing to do with ganglionic latency or ultraviolet mutagenesis.

The diagnosis of PTLD is histological. It needs a tissue biopsy (preferably a generous excisional biopsy) characterised by morphology, immunophenotype (including CD20 status, which decides whether rituximab can be used), Epstein-Barr virus-encoded RNA (EBER) in-situ hybridisation for EBV, and clonality studies.

Blood tests cannot make the diagnosis: a high or rising EBV DNA load is only suggestive, a normal load does not fully exclude disease, and serology merely shows past exposure. Imaging localises and stages disease but does not characterise it. The blood load raises suspicion; the biopsy settles it.

CMV retinitis produces well-demarcated areas of full-thickness retinal necrosis, seen as fluffy or granular white opacification that spreads along the retinal vessels and is accompanied by retinal haemorrhages. Characteristically there is little vitreous inflammation, because the CD4 count is so low that the eye mounts only a weak inflammatory response, which is why prominent vitreous inflammation argues against the diagnosis.

A swollen disc, isolated cotton-wool spots, and a macular cherry-red spot point to other diagnoses. The appearance is characteristic enough that retinitis is diagnosed clinically on dilated fundoscopy by an experienced examiner.

Kaposi sarcoma is driven by human herpesvirus 8 under failing immune control, and antiretroviral therapy is first-line for limited cutaneous disease: restoring immunity often causes the lesions to regress without specific cancer treatment.

Systemic chemotherapy such as liposomal doxorubicin or paclitaxel is reserved for advanced, visceral or rapidly progressive disease, given alongside antiretroviral therapy. Surgery and radiotherapy have only local roles, and antivirals such as ganciclovir are of unproven benefit.

Reducing immunosuppression is the foundation of treatment for every subtype, because it gives the patient back the Epstein-Barr virus (EBV)-specific T cells that immunosuppression had removed. Early, EBV-driven, low-burden disease often responds to this alone.

The other options are later rungs on the graded ladder: rituximab is added for CD20-positive disease, chemotherapy (such as rituximab with CHOP) is reserved for disease that does not respond or for true post-transplant lymphomas, and EBV-specific T cells are used in EBV-positive disease, especially after stem-cell transplant. Antivirals have no role in treating established PTLD, because the latent virus offers them nothing to act on.

There is no specific antiviral for the JC virus. The only effective intervention is antiretroviral therapy, which restores CD4 immunity and lets the patient regain control of the virus; immune reconstitution is the principal determinant of survival, and antiretroviral therapy should not be delayed.

Ganciclovir, aciclovir and cidofovir have no useful activity against JC virus. Corticosteroids are used only to dampen a severe immune-reconstitution reaction (PML-IRIS), not as primary treatment, and the outlook remains poor even with antiretroviral therapy.

Unlike the non-viral opportunistic infections, where co-trimoxazole prophylaxis is standard, the viral infections are not prevented by routine antiviral prophylaxis. For cytomegalovirus the approach is early antiretroviral therapy, patient education (prompt reporting of visual symptoms) and targeted ophthalmological review at the lowest counts, rather than giving an antiviral to everyone.

Routine valganciclovir or letermovir prophylaxis, immunoglobulin and prophylactic intravitreal therapy are not recommended: they carry toxicity, cost and resistance without a survival benefit, and restoring immunity with antiretroviral therapy is what removes the risk.

Cell-free plasma EBV DNA is more specific for established EBV-positive disease, while whole blood (which also captures virus inside circulating cells) is more sensitive and so better for surveillance. Many centres therefore use whole blood to screen and plasma to help confirm.

Either sample is acceptable and both are in routine use, so options C to E are wrong. The deeper point is that neither result diagnoses PTLD: the load raises or lowers suspicion, but tissue biopsy makes the diagnosis, and loads cannot be compared between laboratories because assays differ.

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), and maribavir inhibits the UL97 kinase.

HIV depletes CD4 T lymphocytes, and with them the cell-mediated immunity that controls intracellular and latent viruses. The herpesviruses, the JC polyomavirus and the oncogenic viruses are all held in check by CD4-dependent T-cell responses, so as the CD4 count falls they reactivate and cause disease.

The other options are not the principal defect: antibody, complement and neutrophil function are relatively preserved (B-cell responses are in fact hyperactivated), and it is the loss of T-cell help, not humoral or innate effectors, that opens the door to the viral opportunistic infections.

The net state of immunosuppression is an integrative estimate that sums several contributions, not any single variable: the immunosuppressive drugs (dose, duration, sequence and type, with anti-T-cell antibodies raising risk most and mechanistic-target-of-rapamycin (mTOR) inhibitors lowering cytomegalovirus (CMV) risk); host factors (neutropenia, lymphopenia, low immunoglobulin, breached barriers, indwelling lines, uraemia, diabetes); and the burden of immunomodulating viruses already present (CMV, Epstein-Barr virus, human herpesvirus 6, hepatitis B and C).

Because risk is the sum of these, two patients on the same regimen can differ greatly in vulnerability. Each distractor reduces a multifactorial state to one variable: a drug level, a serostatus, a human leucocyte antigen (HLA) match, or a radiation dose.

Letermovir inhibits CYP3A, so it raises tacrolimus and cyclosporine levels; calcineurin-inhibitor concentrations must be monitored and doses reduced to avoid nephrotoxicity and over-immunosuppression. A second interaction to anticipate is overlapping myelosuppression: ganciclovir and valganciclovir add to the marrow suppression of mycophenolate and of the stem-cell graft, so the full blood count is watched.

Ganciclovir does not lower tacrolimus, valganciclovir does interact (myelosuppression), foscarnet does not require a calcineurin inhibitor (and is itself nephrotoxic), and aciclovir does not cancel ganciclovir.

Primary central nervous system lymphoma is almost always Epstein-Barr virus (EBV)-positive, so EBV DNA in the cerebrospinal fluid points to lymphoma rather than toxoplasmosis. Metabolic imaging helps in the same way (the lymphoma is hypermetabolic on positron emission tomography or thallium scanning, whereas toxoplasmosis is not), and brain biopsy resolves remaining doubt.

The other features do not separate the two: both occur at low CD4 counts, both cause focal deficits and constitutional symptoms, and both can appear as enhancing or ring-enhancing mass lesions on imaging.

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.

The depth of T-cell suppression is the central driver of PTLD, so T-cell-depleting induction (antithymocyte globulin, the historical OKT3) is strongly linked to early disease. Cumulative maintenance immunosuppression, by contrast, drives the late peak.

The other options reduce risk or are neutral: lower drug levels and aggressive tapering lessen the net immunosuppressive burden, calcineurin-inhibitor withdrawal is used to treat PTLD rather than cause it, and mTOR (mechanistic target of rapamycin) inhibitor maintenance carries no comparable early-onset signal. One agent worth remembering separately is belatacept, which is specifically associated with central-nervous-system PTLD in Epstein-Barr virus (EBV)-seronegative recipients.

Ganciclovir and maribavir must not be combined. Maribavir inhibits the UL97 kinase, the very enzyme that phosphorylates (activates) ganciclovir, so blocking it makes ganciclovir ineffective: the two are antagonistic.

The other pairs 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).

CMV causes harm in two ways. Direct disease is tissue invasion: pneumonitis, colitis, retinitis and hepatitis. Indirect effects flow from CMV’s immunomodulating activity, and allograft rejection and graft loss are the prime example, alongside bronchiolitis obliterans, transplant 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.

EBV association falls in bands across the spectrum. The reactive and early ends are almost always EBV-positive (non-destructive and polymorphic lesions, over 95%), and classic Hodgkin lymphoma PTLD and the EBV-positive mucocutaneous ulcer are usually positive too.

The monomorphic, lymphoma-like end is more mixed: large B-cell and Burkitt types are often positive, but T/NK-cell, high-grade B-cell and plasma-cell types are frequently EBV-negative (under half). The T/NK-cell lymphomas are therefore the least EBV-associated of the options, and sit at the post-transplant-lymphoma end that needs lymphoma-directed treatment.

Progressive outer retinal necrosis is an aggressive VZV retinitis seen in advanced HIV infection and a major threat to sight. Acute retinal necrosis is the corresponding VZV retinal disease in immunocompetent people.

Cytomegalovirus retinitis is a separate entity caused by a different virus, included here as a distractor rather than the answer.

In solid-organ transplant the seronegative recipient of a seropositive organ (donor positive, recipient negative) is at highest risk. Such a recipient meets Epstein-Barr virus (EBV) for the first time, a primary infection, while immunosuppressed and with no EBV-specific T cells to contain it. This is why PTLD falls disproportionately on children, who are most often EBV-naive at transplant.

The other combinations carry lower risk because the recipient already has EBV-specific memory T cells, or because a seronegative organ transmits no virus. Serostatus is one of the strongest single predictors, so the claim that it is irrelevant is wrong. The high-risk combination reverses in stem-cell transplant, where the graft is the new immune system.

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.

Early aciclovir or valaciclovir prophylaxis cuts herpes simplex virus (HSV) reactivation from ~70% to under 5% in the first month, and the ganciclovir or valganciclovir given for cytomegalovirus also covers HSV.

For varicella-zoster virus (VZV), a seronegative recipient exposed to chickenpox or shingles is given varicella-zoster immunoglobulin (not every recipient regardless of exposure), so option A is wrong. These reactivations are not self-limiting in the immunosuppressed; live varicella and zoster vaccines are contraindicated after transplant; and withholding prophylaxis until disease is wrong, since long-term prophylaxis keeps aciclovir resistance low.

CMV pneumonitis is the most feared and historically most lethal manifestation of CMV after allogeneic stem-cell transplant, with a mortality of 10 to 30% before effective therapy, reduced but not abolished by ganciclovir. Diagnosis rests on sampling the lung by bronchoalveolar lavage, supported by lung biopsy, since the blood viral load can be low or negative in lung disease. Treatment is ganciclovir combined with CMV immunoglobulin, because the lung injury has a substantial immunopathological component that antiviral therapy alone does not address.

The distractors trivialise the disease (A, D), rely on blood PCR alone (B), or deny the immune component and propose an inactive drug (E).

As immunity recovers on antiretroviral therapy, cytomegalovirus can drive an immune-recovery uveitis or retinitis that threatens vision even while the systemic infection improves. The other important viral causes of immune reconstitution inflammatory syndrome are JC virus (progressive multifocal leukoencephalopathy, sometimes fulminant) and human herpesvirus 8 (a Kaposi-sarcoma flare), and zoster commonly appears in the early weeks of therapy.

The remaining options are acute, self-limiting infections (hepatitis A, rhinovirus, rotavirus, norovirus) that are not associated with immune reconstitution inflammatory syndrome.

Aciclovir and ganciclovir must be activated by a viral thymidine kinase, which is made only when Epstein-Barr virus (EBV) is replicating (the lytic cycle). The proliferating B cells of PTLD carry EBV in its latent state: the virus is not replicating and makes no thymidine kinase, so the drugs are never activated and have nothing to act on.

This is why antivirals do not treat established disease, although they show a weak signal for prevention (where some lytic replication may be targetable). The drugs are not expelled by the cells, not intrinsically resistant, and not specific to cytomegalovirus.

Immunosuppression blunts the antibody response, so serology is unreliable: a patient can have severe disease without a diagnostic antibody rise. Quantitative polymerase chain reaction (PCR) instead measures the virus directly, diagnosing active infection independent of immune status, providing a threshold to trigger pre-emptive therapy (for cytomegalovirus, Epstein-Barr virus, BK and adenovirus), and following the response, with a rising load on treatment suggesting resistance or non-adherence. Reporting in WHO international units per millilitre (IU/mL) standardises results across assays.

Antibody responses are not reliable here; PCR is not a bacterial or fungal culture; immunoglobulin is reduced, not wholly absent; and the antibody rise is late, not the earliest marker.

Clinical and radiological features

PML presents subacutely over weeks with focal deficits that reflect lesion location rather than a single syndrome: limb weakness, visual field loss, cognitive or behavioural change, speech disturbance and ataxia. Fever and headache are characteristically absent. Magnetic resonance imaging shows one or more areas of subcortical white matter that are hyperintense on T2-weighted and FLAIR sequences and hypointense on T1, without mass effect and, in the untreated HIV setting, usually without contrast enhancement.

Differential diagnosis

The differential is the rest of the advanced-HIV brain. HIV encephalitis causes a more diffuse, symmetrical leukoencephalopathy with cognitive decline. Cerebral toxoplasmosis and primary central nervous system lymphoma both produce mass lesions with oedema and ring or homogeneous enhancement, unlike PML. Cytomegalovirus encephalitis tends to be periventricular. The lack of mass effect and enhancement, the multifocal white-matter pattern, and a positive cerebrospinal fluid JC virus PCR distinguish PML, with biopsy reserved for unresolved cases.

A complete answer explains the overlap, why blood tests do not settle it, and how biopsy resolves it.

Overlapping presentation. Gastrointestinal CMV disease and gut graft-versus-host disease (GVHD) present almost identically after allogeneic stem-cell transplant, with diarrhoea, abdominal pain, nausea and bleeding, so the clinical picture alone cannot separate them. The distinction matters because the treatments pull in opposite directions: CMV needs antiviral therapy and, where possible, less immunosuppression, whereas GVHD needs more immunosuppression.

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.

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. Importantly, the two can coexist: CMV can complicate GVHD, and the immunosuppression used to treat GVHD promotes CMV, so finding one does not exclude the other.

KSHV underlies all three; they separate cleanly on cell of origin, clonality and clinical behaviour.

Kaposi sarcoma occurs in four epidemiological forms (classic, endemic African, iatrogenic, AIDS-associated). Primary effusion lymphoma is universally KSHV-positive and usually co-infected with Epstein-Barr virus. Multicentric Castleman disease is KSHV-associated in essentially all HIV-positive cases, with the blood KSHV viral load tracking activity.

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.

A complete answer states the principle and then works down the CD4 strata with examples.

The principle

As the CD4 count falls, cell-mediated control of the latent viruses fails in a predictable sequence, so the count both anticipates which infection to expect and frames how aggressively to treat and monitor. AIDS is defined by a CD4 count below 200 cells per microlitre or an AIDS-defining condition.

The ladder

• Below 350: herpes zoster, and more frequent and severe mucocutaneous herpes simplex.
• Below 200: multidermatomal or disseminated zoster; oral hairy leukoplakia.
• Below 100: chronic or visceral herpes simplex; Epstein-Barr virus (EBV)-driven systemic non-Hodgkin lymphoma; progressive multifocal leukoencephalopathy (JC virus).
• Below 50: cytomegalovirus end-organ disease (retinitis, colitis); EBV-driven primary central nervous system lymphoma.

Outside the ladder

Kaposi sarcoma (human herpesvirus 8) and HPV-related cancers occur across a range of counts, and hepatitis B is governed by coinfection rather than a threshold. The thresholds are a guide, and disease can present outside its usual band.

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 human papillomavirus-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.

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 the three viral drivers, the tumours each causes, and the central role of antiretroviral therapy.

Kaposi sarcoma (HHV-8)

Human herpesvirus 8 causes Kaposi sarcoma, violaceous skin and mucosal lesions (characteristically the palate and gingiva) that can involve the gut and lungs, and also primary effusion lymphoma and multicentric Castleman disease. Antiretroviral therapy is first-line for limited disease, with chemotherapy for advanced or visceral disease.

The AIDS lymphomas (EBV)

Epstein-Barr virus drives the AIDS-defining lymphomas: systemic non-Hodgkin lymphoma (diffuse large B-cell, Burkitt and plasmablastic types) and primary central nervous system lymphoma, which is almost always EBV-positive and is distinguished from cerebral toxoplasmosis by EBV DNA in the cerebrospinal fluid and by metabolic imaging. Treatment combines chemotherapy, often with rituximab for systemic disease and high-dose methotrexate for central nervous system disease, with antiretroviral therapy.

Cervical and anal cancer (HPV)

Human papillomavirus causes accelerated cervical and anal intraepithelial neoplasia and a several-fold higher risk of invasive cervical cancer (an AIDS-defining condition) and anal cancer, which is why regular cervical and anal screening is essential.

The role of antiretroviral therapy

All three are controlled by cell-mediated immunity, so antiretroviral therapy underpins management of each, with tumour-specific treatment added according to the malignancy.

A complete answer explains the immune defect, why it matters for these particular viruses, and the CD4-strata pattern of disease.

The immune defect

HIV infects and depletes CD4 T lymphocytes through several mechanisms acting together: direct killing of infected cells, syncytium formation, and, most importantly, the chronic immune activation that follows early depletion of CD4 cells from gut-associated lymphoid tissue and the resulting microbial translocation. The CD8 cytotoxic T cells that initially control the virus become exhausted. The result is progressive failure of cell-mediated immunity.

Why these viruses

Cell-mediated immunity is exactly the arm that contains the latent herpesviruses, the JC polyomavirus and the oncogenic viruses. As it fails, these viruses reactivate and cause disease, whereas antibody-controlled infections are comparatively spared.

The CD4-strata pattern

Disease appears in a predictable order as the count falls: zoster and more severe herpes simplex below 350; disseminated zoster and oral hairy leukoplakia below 200 (the AIDS threshold); chronic or visceral herpes simplex, Epstein-Barr virus (EBV)-driven systemic lymphoma and progressive multifocal leukoencephalopathy below 100; and cytomegalovirus end-organ disease with primary central nervous system lymphoma below 50. Kaposi sarcoma and HPV-related cancers occur across a range of counts.

Management

Because the defect is loss of CD4 immunity, antiretroviral therapy is the single most effective measure: restoring the CD4 count reverses the susceptibility, and specific antivirals are added only for the infections that need them.

A complete answer explains the surveillance mechanism, names the virus-tumour pairs, and notes the effect of restoring immunity.

Loss of surveillance. The latent oncogenic viruses persist for life in most adults but are normally held in check by T-cell surveillance, which removes infected and transformed cells. When that surveillance fails, in advanced HIV infection, after transplant immunosuppression, or in primary immunodeficiency, the latently infected cells proliferate unchecked and the associated cancers emerge.

The virus-tumour pairs. The characteristic pairings are Kaposi sarcoma-associated herpesvirus with Kaposi sarcoma and primary effusion lymphoma; Epstein-Barr virus with the B-cell lymphomas, including post-transplant lymphoproliferative disorder and the central nervous system lymphoma of advanced HIV; and high-risk human papillomavirus with cervical and other anogenital cancers, which are more common and more aggressive in women living with HIV.

HIV’s role and the effect of treatment. HIV itself encodes no oncogene and transforms no cell; its entire oncogenic contribution is the depletion of CD4 T cells and the resulting loss of control over the other viruses. Restoring immune function with antiretroviral therapy reduces the incidence of these cancers, though it does not abolish it.

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 simian virus 40 (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 states how central nervous system PTLD is treated and the reason it cannot simply follow the usual ladder.

The approach. PTLD in the central nervous system (CNS) is treated on the lines of a primary CNS lymphoma, using regimens designed to reach the brain (high-CNS-penetrating, methotrexate-based therapy, with radiotherapy or rituximab as appropriate), alongside reduced immunosuppression.

Why it differs. Most of the chemotherapy used for systemic PTLD does not cross the blood-brain barrier in useful concentrations, so standard systemic regimens leave CNS disease undertreated. CNS involvement is also a recognised adverse prognostic feature, which reinforces the need for a dedicated, brain-directed strategy rather than the systemic ladder alone.

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.

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 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.

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 IU/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.

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 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% in Northern European blood donors but up to ~80% in parts of sub-Saharan Africa. Post-transplant Kaposi sarcoma is therefore rare (under 1%) in low-prevalence regions but reaches ~4 to 5% 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% and may bleed or obstruct. The mainstay of treatment is reduction of immunosuppression and a switch to a mechanistic-target-of-rapamycin (mTOR) inhibitor such as sirolimus, which is both immunosuppressive and antitumour and can drive regression. Visceral or refractory disease needs chemotherapy, and antivirals are of unproven benefit.

Why B

HPyV7 is a near-universal, generally harmless component of the skin flora, with no recognised disease in immunocompetent people. PML is JC virus, haemorrhagic cystitis is BK virus, and HPyV7 is not oncogenic and does not cause hepatitis.

Why E

Control of the polyomaviruses depends on cellular immunity, so the principal measure is to reduce immunosuppression where the underlying condition allows, with supportive skin care otherwise. There is no antiviral of proven benefit, no vaccine, and the disease is benign, so excision and chemotherapy have no place.

Why E

Restoring immunity can provoke an immune reconstitution inflammatory syndrome, in which the returning T-cell response attacks JC-virus-infected cells; the formerly non-enhancing PML lesions develop enhancement and oedema and the patient worsens even as infection is being controlled. The timing after antiretroviral therapy and the new enhancement point to PML-IRIS rather than drug toxicity, simple progression, abscess or haemorrhage.