CMV in the Transplant Patient

Cytomegalovirus (CMV) is the single most important viral pathogen of transplantation, both for the disease it causes directly and for the indirect harm it does to the graft and to the immune system. It threatens recipients of both solid-organ transplantation (SOT) and allogeneic haematopoietic stem-cell transplantation (HSCT).

Definitions

Precise definitions distinguish the relevant states:

• CMV infection is detection of the virus (by PCR, antigen or culture) at any site, which may be asymptomatic.
• CMV disease is infection together with attributable clinical findings, in one of two forms: a viral syndrome (fever, malaise, cytopenias) or tissue-invasive end-organ disease.
• Surveillance is the serial testing of an asymptomatic at-risk patient to detect infection and trigger pre-emptive therapy; monitoring is the serial testing of a patient on treatment to judge the response.
• Primary prophylaxis gives an antiviral to all at-risk patients for a fixed period; secondary prophylaxis continues a suppressive antiviral after a first treated episode; pre-emptive therapy withholds the drug and treats only when surveillance detects a viral load above threshold.

Epidemiology, pathogenesis and indirect effects

Epidemiology

CMV was first recognised in transplantation in the mid-1960s, when CMV-associated pneumonitis appeared in renal recipients given the early cytotoxic immunosuppressants. It has since become the major viral pathogen of transplantation, and the antiviral era has reshaped its behaviour. In the 1980s, CMV-related mortality was 10 to 30 per cent in allogeneic stem-cell recipients; with ganciclovir it has fallen to 2 to 6 per cent. Effective suppression has also shifted the onset of disease: in the pre-antiviral era it appeared at two to three months, whereas under antiviral prophylaxis reactivation and disease are delayed into the four to twelve month period (the late-onset problem). The best agents have not abolished late CMV in the stem-cell population, and CMV reactivation remains an independent risk factor for lower overall survival after allogeneic transplant.

Pathogenesis

CMV is a betaherpesvirus that establishes lifelong latency, chiefly in cells of the myeloid lineage. Under the immunosuppression of transplantation, control by CMV-specific T cells fails and the virus reactivates (or, in a naive recipient, establishes primary infection from the graft). Even in a seropositive recipient, the donated organ is usually the source: rather than simple reactivation of the recipient’s own virus, reinfection with a new donor strain is the more common event, which is why a seropositive donor adds risk and why cadaveric organs (carrying more latent virus) transmit more CMV than living-donor organs. Transmission is not universal even in the highest-risk pairing, more than one donor strain may be passed at once, and donor-derived virus can coexist with the recipient’s own reactivation; older donors (over 60) transmit more, reflecting a higher latent burden. The intensity of immunosuppression drives the viral load, but the agent matters too: mTOR inhibitors (sirolimus, everolimus) lower the incidence of CMV infection and disease, an effect used deliberately in some regimens. The disease CMV then causes is of two kinds.

The direct disease is the tissue injury of the syndromes below. The indirect effects flow from CMV’s powerful immunomodulating activity and are arguably as important: acute and chronic allograft rejection, bronchiolitis obliterans in the lung, transplant vasculopathy in the heart, chronic allograft nephropathy in the kidney, and an increased risk of other infections (Aspergillus, Pneumocystis) and of EBV-driven lymphoproliferation, along with new-onset diabetes after transplant. CMV and rejection are bidirectional risk factors for one another, and in stem-cell transplant CMV and graft-versus-host disease (GVHD) aggravate each other. Preventing CMV therefore protects the graft as well as the patient, which is part of the argument for universal prophylaxis.

Donor and recipient serostatus risk

Because CMV is latent and transmissible in the graft, the donor (D) and recipient (R) serostatus sets the risk, and crucially the high-risk combination inverts between the two transplant types.

Setting	Highest-risk serostatus	Why
Solid-organ	D positive, R negative	The graft carries CMV; a recipient with no CMV immunity undergoes a primary infection
Stem-cell	D negative, R positive	The recipient’s own latent CMV reactivates and the new donor immune system has no CMV-specific T cells to control it

In solid-organ transplant the graft is the source of virus, so the seronegative recipient of a seropositive organ (D positive, R negative, about 15 to 25 per cent of transplants) is at highest risk and is the group prophylaxis most targets. In stem-cell transplant the graft is the new immune system, so the seropositive recipient (R positive) drives risk through reactivation, worst when the donor is seronegative (D negative, R positive) and cannot transfer CMV-specific immunity. Without prevention, around 80 per cent of seropositive stem-cell recipients become infected and historically 20 to 35 per cent developed disease, while a seronegative recipient of a seropositive graft has about a 30 per cent risk of primary infection. Among solid-organ recipients the risk also tracks the organ, being highest for lung, small-bowel and pancreas transplants and lowest for kidney. Without preventive measures the D positive, R negative solid-organ recipient has an 80 to 100 per cent risk of CMV infection and a 50 to 70 per cent risk of disease, whereas the risk in D positive, R positive recipients is lower and in D negative, R negative recipients is essentially nil.

Serostatus is only the first of a hierarchy of risk factors that together determine who develops CMV complications:

Category	Higher-risk features
CMV infection itself	Seropositive donor, seronegative recipient (graft as the source); recipient age over 20 years
Donor mismatch (solid organ)	Greater HLA mismatch; certain HLA types (DR7, DRw6, B7)
Organ or graft type	Lung, small bowel, pancreas, kidney-pancreas highest; liver and heart intermediate; kidney lowest. Cadaveric over living donor; allogeneic over autologous stem-cell transplant
Immune status	Intensity and type of immunosuppressive regimen; absent CMV-specific lymphocyte immunity; rejection or GVHD; coinfections; higher CMV load on PCR

The single most important factor is the development of CMV infection itself, which is why surveillance and pre-emptive intervention are so central.

Clinical syndromes

• CMV syndrome: fever, malaise, and cytopenias (leukopenia, thrombocytopenia) without organ-specific involvement. It is the commonest form of CMV disease in solid-organ recipients, around 60 per cent.
• Pneumonitis: fever, dry cough and hypoxia with interstitial infiltrates. It is the most feared and historically most lethal manifestation after stem-cell transplant (mortality 10 to 30 per cent before effective therapy), diagnosed on bronchoalveolar lavage and lung biopsy and treated with ganciclovir combined with CMV immunoglobulin because of its immunopathological component.
• Gastrointestinal disease: oesophagitis, gastritis, enteritis or colitis at any level, presenting with odynophagia, abdominal pain, diarrhoea or bleeding. It is frequently impossible to separate from GVHD clinically and the blood viral load is often low, so endoscopic biopsy with histology or immunohistochemistry is needed, and the two conditions can coexist.
• Hepatitis: raised transaminases and cholestasis, common after liver transplant, where it must be distinguished from rejection and from drug injury, again often on biopsy.
• Retinitis: uncommon after transplant (unlike in advanced HIV) but sight-threatening, presenting with floaters, scotomata or visual loss and diagnosed clinically on fundoscopy with vitreous sampling where needed, since the blood load is a poor guide.
• Encephalitis (with a cerebrospinal fluid viral load) and nephritis are less common but recognised, and CMV can also cause an immunomodulatory worsening of graft function without a discrete syndrome.

Stem-cell recipients tend toward pneumonitis and gastrointestinal disease, solid-organ recipients toward the CMV syndrome and disease in the transplanted organ.

Diagnosis and monitoring

Serology has no role in diagnosing active disease in the immunosuppressed, in whom the antibody response is blunted; it is used only before transplant to establish serostatus and stratify risk. Even there it has pitfalls: a false-positive IgG can follow recent intravenous immunoglobulin or blood products, or maternal antibody in an infant under a year, and a false-negative can follow plasmapheresis, profound hypogammaglobulinaemia or B-cell-depleting therapy. CMV IgM is not used (poor specificity), and an equivocal result is treated as the higher-risk category.

Quantitative PCR of the blood is the backbone of diagnosis, surveillance and monitoring. Several points govern its use:

• Plasma is generally preferred (better standardisation, stable, usable in leukopenia); whole blood is more sensitive for low-level cell-associated virus but runs about one log10 higher and is harder to standardise, so a patient is followed on one specimen type throughout.
• Reporting in WHO international units per millilitre (IU/mL) allows thresholds to be shared, but even calibrated assays are not fully interchangeable, so there is no single universal cutoff.
• Both a higher load and a faster rate of rise predict progression, so the trend guides pre-emptive treatment more than any single value.
• Most assays have a lower limit of quantification of around 100 to 500 IU/mL (some newer assays reach about 35 IU/mL, which prompts earlier and longer treatment); results are best read as log10 values so that small, clinically irrelevant “blips” are not over-treated.
• Consensus pre-emptive thresholds (plasma) are roughly 100 to 1500 IU/mL in seronegative (R negative) recipients and 500 to 4000 IU/mL in seropositive (R positive) recipients, with any detectable virus treated in the highest-risk patients (graft-versus-host disease, high-dose steroids); the exact number is assay-specific.

pp65 antigenaemia is a semi-quantitative older method, labour-intensive and unusable in leukopenia, largely superseded by PCR.

Tissue-invasive disease needs compartment-specific testing, because the blood load may be low or negative (especially in gastrointestinal, pulmonary and retinal disease). Bronchoalveolar lavage is used for pneumonitis, cerebrospinal fluid for encephalitis, and vitreous sampling for retinitis. Definitive diagnosis of organ disease rests on biopsy histology showing the “owl’s-eye” inclusions, or immunohistochemistry, because PCR or culture on tissue can reflect contamination or shedding; a blood PCR is still sent to give a baseline for monitoring. Quantitative thresholds can aid interpretation: a plasma load above about 4 log10 (roughly 4000 IU/mL) supports gastrointestinal CMV (with imperfect predictive value), and in pneumonitis the bronchoalveolar lavage load (median around 4.5 log10) far exceeds and outperforms the plasma load.

Immune monitoring measures the patient’s CMV-specific cell-mediated immunity directly (for example by an interferon-gamma release assay). A positive result at the end of prophylaxis predicts freedom from later CMV events, so the approach is being explored to risk-stratify patients and to judge when immunity has recovered enough to stop prophylaxis. Its limits are real: performance is poor in the highest-risk D positive, R negative group (who rarely make CMV-specific immunity) and best in seropositive recipients, and the assays are costly, slow, unstandardised, and measure only the cellular arm, so the concept is more established than any single assay.

For monitoring, the viral load is checked at baseline and then about weekly (CMV kinetics make more frequent testing unhelpful), and only changes of a few fold are meaningful. A practical advance is home self-testing: finger-stick dried-blood-spot platforms can quantify the CMV load remotely, which may remove the main logistical barrier (frequent clinic blood draws) that has kept pre-emptive therapy out of routine solid-organ practice.

Prevention

The two strategies, universal prophylaxis and pre-emptive therapy, both prevent CMV disease, but they are not simply equivalent. Pre-emptive therapy has an immunological advantage: by permitting brief, low-level viraemia it lets the patient build neutralising-antibody and CD8 T-cell responses, which is why it produces less delayed-onset disease, whereas prophylaxis suppresses the virus so completely that immunity is never primed. A randomised trial even in high-risk D positive, R negative liver recipients found pre-emptive therapy effective and cost-effective against a 100-day prophylaxis course. The choice turns on risk and on monitoring capacity: solid-organ programmes have historically used prophylaxis for the highest-risk strata (the logistics of frequent monitoring being the barrier to pre-emptive therapy), while stem-cell centres prefer pre-emptive therapy to avoid marrow toxicity.

	Universal prophylaxis	Pre-emptive therapy
Usual setting	Standard in solid-organ; uncommon in stem-cell	Standard in stem-cell; uncommon in solid-organ
Strengths	Large evidence base; easy to coordinate; prevents infection, disease and the indirect effects (graft loss, other infections)	Lets natural CMV immunity develop; prevents delayed-onset disease; less neutropenia; possibly more cost-effective; reduces mortality in seropositive stem-cell recipients
Weaknesses	Delayed-onset (post-prophylaxis) disease; neutropenia; cost; over-treats patients who would never have developed CMV	Logistically demanding (frequent monitoring); thresholds and test frequency less defined; can be outrun by rapid viral-load doubling

Primary prophylaxis in solid-organ transplant is usually valganciclovir (900 mg daily, renally adjusted), for a duration set by the organ and serostatus:

Recipient	Typical prophylaxis
D positive, R negative (high risk)	Longer course (around 6 months; longest for lung and intestine)
R positive (moderate risk)	Shorter course (around 3 months)
D negative, R negative (low risk)	No antiviral; use CMV-negative or leucodepleted blood products

Prophylaxis in solid-organ transplant is generally started early (around day 10) and is not routinely recommended for chimeric antigen receptor (CAR) T-cell and other cellular-therapy recipients; instead, because CMV reactivation occurs in up to a third of them and is associated with higher mortality, the recommendation is surveillance of the high-risk patients for the first few weeks after the infusion.

In stem-cell transplant, letermovir (480 mg daily, 240 mg with cyclosporine) is the preferred prophylactic agent in seropositive allogeneic recipients, because it is not myelosuppressive; it was first used from transplant through about week 14, and current guidance supports extending it to around day 200 (but not beyond) in defined high-risk groups, namely a mismatched or haploidentical donor, a cord-blood transplant, T-cell depletion, or high-dose corticosteroids. Two caveats are critical: letermovir has no activity against herpes simplex or varicella-zoster virus (so aciclovir-class cover is still needed) and has a low barrier to resistance (so it is for prophylaxis, not treatment). Secondary prophylaxis follows a first treated episode in patients who remain heavily immunosuppressed.

The drawback of any fixed-course prophylaxis is late-onset CMV disease after the drug stops, because the patient was never exposed to enough virus to build immunity; the highest-risk D positive, R negative solid-organ recipients are watched (or kept on pre-emptive surveillance) after the course ends. Prophylaxis also carries a real toxicity cost: valganciclovir caused neutropenia in around 40 per cent of liver recipients (versus 16 per cent off prophylaxis), and that neutropenia independently predicted mortality, while reducing the dose to spare the marrow risks breakthrough (often ganciclovir-resistant) viraemia.

Vaccines and antibody-based prevention

No CMV vaccine is yet licensed, but it remains an active field. Candidates across several platforms (subunit, viral-vectored, DNA and mRNA vaccines) have reduced viraemia or the need for antiviral drugs in trials without yet delivering a licensed product, and the timing of vaccination relative to transplant appears to matter. Separately, monoclonal antibodies against CMV entry glycoproteins are in development as a more specific alternative to polyclonal CMV immunoglobulin, having reduced viraemia and pre-emptive drug use in early trials.

Treatment

The first-line treatment of CMV disease is intravenous ganciclovir (5 mg/kg twice daily at induction) or oral valganciclovir (900 mg twice daily). Intravenous ganciclovir is chosen for severe, sight-threatening or life-threatening disease and where gut absorption is uncertain; valganciclovir suits non-severe disease. Treatment runs for a minimum of two weeks and until the viral load has cleared below the local threshold, and a key rule is not to switch agents in the first two weeks if the patient is improving, because the load falls slowly. Reducing immunosuppression where feasible is a useful adjunct.

The drugs differ in their dose-limiting toxicity, which guides switching:

• Ganciclovir and valganciclovir: myelosuppression, especially neutropenia (around a third of patients), monitored by full blood count and managed with a granulocyte colony-stimulating factor or dose reduction.
• Foscarnet: nephrotoxicity and electrolyte wasting (calcium, magnesium, potassium, phosphate).
• Cidofovir: nephrotoxicity (proximal tubular injury), given with probenecid and hydration.

Anti-CMV agents, with their targets, toxicities and resistance genes:

Agent	CMV target	Route	Main toxicity	Resistance	Treatment dose
Ganciclovir	DNA polymerase (UL54)	IV	Cytopenias (neutropenia)	UL97, UL54	5 mg/kg 12-hourly
Valganciclovir	UL54 (oral ganciclovir prodrug)	Oral	Cytopenias	UL97, UL54	900 mg 12-hourly
Foscarnet	UL54	IV	Nephrotoxicity, electrolyte wasting	UL54	60 mg/kg 8-hourly or 90 mg/kg 12-hourly
Cidofovir	UL54	IV	Nephrotoxicity, uveitis, neutropenia	UL54	5 mg/kg weekly
Letermovir	Terminase (UL56)	Oral or IV	Nausea; CYP3A interactions	UL56	Prophylaxis only (480 mg daily)
Maribavir	UL97 kinase	Oral	Dysgeusia	UL97, UL27	400 mg 12-hourly (refractory or resistant disease only)

Two points apply across these agents. First, letermovir and maribavir have no activity against the other herpesviruses (herpes simplex, varicella-zoster, HHV-6), which the older polymerase-targeting agents retain, so a patient on either still needs aciclovir-class cover. Second, maribavir must not be combined with ganciclovir or valganciclovir (their mechanisms are antagonistic) and is not used for CMV retinitis or encephalitis, because it penetrates the eye and central nervous system poorly; it is reserved for refractory or resistant disease, not first-line or pre-emptive use.

CMV immunoglobulin is used as an adjunct in pneumonitis and in selected severe disease.

Resistance and refractory CMV

Refractory CMV is disease or viraemia that progresses, or a viral load that rises by at least 1 log10, despite at least two weeks of correctly dosed therapy in an adherent patient, without a detectable resistance mutation; resistant CMV is refractory disease with a confirmed mutation. Resistance is uncommon overall (around 0 to 3 per cent) but is more likely with prolonged or repeated drug exposure and in the most immunosuppressed.

Resistance is confirmed by genotypic sequencing, most informative when the load is reasonably high (Sanger sequencing is reliable above roughly 1000 IU/mL and misses minority mutant populations below about 20 per cent):

• UL97 (the viral kinase): the commonest, emerging first, conferring ganciclovir and valganciclovir resistance.
• UL54 (the DNA polymerase): broader resistance, including cross-resistance to foscarnet and cidofovir.
• UL56 is sequenced if letermovir is failing, and UL27 in selected maribavir-refractory cases.

For salvage, maribavir (an oral UL97-kinase inhibitor licensed for refractory or resistant CMV and not myelosuppressive) and foscarnet are the mainstays; the mutation pattern directs the choice, since UL54 polymerase mutations can confer cross-resistance across ganciclovir, foscarnet and cidofovir. Treatment is increasingly genotype-directed: high-level UL97 mutations point to foscarnet or maribavir, and broad UL54 resistance to maribavir with adjunctive agents; breakthrough after an initial response prompts repeat genotyping, since further mutations can emerge. Brincidofovir, an oral lipid conjugate of cidofovir without nephrotoxicity, was investigated but failed its stem-cell prophylaxis trials and was abandoned for CMV. Letermovir, with its low resistance barrier, is not a salvage agent: treatment-emergent UL56 mutations arise readily, and sub-therapeutic dosing has caused breakthrough, so its off-label use in salvage is undefined.

Where drug options are exhausted, adoptive transfer of CMV-specific T cells restores cellular control directly: a study of drug-resistant or refractory solid-organ recipients saw most respond, with durable CMV-specific immunity in some. The practical limits are donor availability (autologous versus partially HLA-matched) and the time to generate the product, which third-party “off-the-shelf” banks of virus-specific T cells (often multivirus, covering CMV, EBV, adenovirus, BK and HHV-6) are beginning to overcome. Reducing immunosuppression supports all of these.

South African context

South African practice follows the same international principles, adapted to resources. The National Health Laboratory Service provides quantitative CMV viral-load testing reported in international units per millilitre, which underpins both pre-emptive surveillance and treatment monitoring. Valganciclovir (and intravenous ganciclovir) is the mainstay of prophylaxis and treatment in the public sector; foscarnet is reserved for resistant disease and toxicity at tertiary level. The newer agents letermovir and maribavir are not yet routinely available in the public sector, so resistant and refractory CMV is managed with the older drugs and by reducing immunosuppression. The choice between prophylaxis and pre-emptive therapy is shaped by the cost and availability of frequent viral-load monitoring at a given centre. (This section is intended as a general orientation and would be strengthened by a current South African transplant-CMV protocol.)

References and recommended reading

• Haidar G, Boeckh M, Singh N. Cytomegalovirus Infection in Solid Organ and Hematopoietic Cell Transplantation: State of the Evidence. The Journal of Infectious Diseases 2020;221(Suppl 1):S23-S31. DOI 10.1093/infdis/jiz454. The current review underpinning the prevention, immune-monitoring, vaccine, resistance and cellular-therapy sections.
• Khawaja F, Zamora D, Yong MK, Hakki M, et al. American Society for Transplantation and Cellular Therapy Series #11: Updated Cytomegalovirus Guidelines in Hematopoietic Cell Transplant and Cellular Therapy Recipients. Transplantation and Cellular Therapy 2025;31:727-741. The current consensus guideline; source for the anti-CMV agents table, the updated refractory definitions, and the cellular-therapy guidance.
• Hakki M, Boeckh M, Ljungman P; and the solid-organ chapter authors. Cytomegalovirus Infection after Stem Cell Transplantation; and after Solid Organ Transplantation. In: Bowden RA, Ljungman P, Snydman DR (eds.), Transplant Infections, 3rd edition, Chapters 22 and 23. Philadelphia: Lippincott Williams and Wilkins; 2010.
• Caliendo AM. Approach to the diagnosis of cytomegalovirus infection. UpToDate (Wolters Kluwer); accessed June 2026. The diagnostic methods, specimen choice and thresholds (paraphrased).
• Wingard JR. Prevention of viral infections in hematopoietic cell transplant recipients. UpToDate (Wolters Kluwer); accessed June 2026. Current letermovir and maribavir practice and pre-emptive monitoring (paraphrased).
• Zaia JA. Viral Infections in Organ Transplant Recipients. In: Richman DD, Whitley RJ, Hayden FG (eds.), Clinical Virology, 4th edition, Chapter 6. Washington: ASM Press; 2016.