Clinical
Viral Infection in Transplant Recipients
Last reviewed 18 June 2026
Transplantation depends on suppressing the immune system, and that suppression is what lets viruses cause disease. Two settings dominate: solid-organ transplantation (SOT), where lifelong drug immunosuppression prevents rejection of the graft, and haematopoietic stem-cell transplantation (HSCT), where the recipient passes through a period with almost no immune system while a donor-derived one engrafts. Across both, three factors determine viral risk: the net state of immunosuppression, the timeline of infection, and donor and recipient serostatus. Cytomegalovirus and Epstein-Barr virus are the two dominant pathogens.
Determinants of risk
The net state of immunosuppression
Whether a virus causes disease is set not by any single factor but by a composite estimate of the patient’s vulnerability, the net state of immunosuppression. It sums the immunosuppressive drugs (their dose, duration, sequence and type, with anti-T-cell antibodies such as antithymocyte globulin and the now-withdrawn OKT3 raising risk most, and mTOR inhibitors such as sirolimus lowering CMV risk), host factors (neutropenia, lymphopenia, low immunoglobulin, breached skin and mucosal barriers, indwelling lines, uraemia, diabetes, malnutrition), and the burden of immunomodulating viruses already present (CMV, EBV, the hepatitis viruses), which themselves further suppress immunity. Because risk is the sum of these, two patients on the same drug regimen can have very different vulnerability, and treating a rejection episode or graft-versus-host disease with extra immunosuppression renews the risk of infection.
Donor and recipient serostatus, and why it inverts
For the latent viruses carried in or controlled by the graft, the key question is which party contributes the virus and which contributes the immunity to contain it. The answer differs fundamentally between the two transplant types, and CMV is the clearest example.
In solid-organ transplant the graft is the source of virus: CMV lies latent in the donor organ. The seronegative recipient of a seropositive organ (D positive, R negative) is therefore at highest risk, undergoing a primary infection with no pre-existing CMV-specific immunity while immunosuppressed. This mismatch makes up roughly 15 to 25 per cent of solid-organ transplants and, without prophylaxis, almost always transmits, with severe disease.
| CMV serostatus (SOT) | Risk | Reason |
|---|---|---|
| D positive, R negative | Highest | Primary infection from the graft in a recipient with no CMV immunity |
| D positive, R positive | Intermediate | Reactivation or donor-strain superinfection against partial immunity |
| D negative, R positive | Intermediate | Reactivation of the recipient’s own latent virus, contained by existing immunity |
| D negative, R negative | Lowest | No CMV present; small residual risk from blood products |
In stem-cell transplant the logic reverses, because the graft is the new immune system, not the source of virus. The recipient’s own latent CMV is the main reservoir, so the seropositive recipient (R positive) is the at-risk axis, and the danger is greatest when the donor is seronegative (D negative, R positive): the donor-derived immune system has never encountered CMV and so transfers no CMV-specific T cells to control the recipient’s reactivation. A seropositive donor (D positive, R positive) can help reconstitute CMV immunity and is therefore somewhat less dangerous. Without modern prevention, around 80 per cent of seropositive recipients develop CMV infection and historically 20 to 35 per cent developed disease, whereas a seronegative recipient of a seropositive graft (D positive, R negative) has about a 30 per cent risk of primary infection.
| CMV serostatus (HSCT) | Risk | Reason |
|---|---|---|
| D negative, R positive | Highest | Recipient’s latent CMV reactivates and the new donor immune system carries no CMV-specific T cells to control it |
| D positive, R positive | High | Reactivation, but a seropositive graft can help reconstitute CMV immunity |
| D positive, R negative | Lower | Primary infection from the graft (around 30 per cent) in a recipient the donor immunity can still help |
| D negative, R negative | Lowest | No CMV present; residual risk only from blood products |
The same principle (which party contributes the virus, and which the immunity) shapes EBV, HHV-6 and HHV-8 risk: the seronegative, often paediatric, recipient is at risk of primary infection and its consequences.
Solid-organ versus stem-cell transplantation
Beyond serostatus, the two settings differ in the timing and pattern of infection. In solid-organ transplant the immunosuppression is sustained but the recipient’s immune system is otherwise intact, so prophylaxis is well tolerated and most disease is reactivation or donor-derived. In stem-cell transplant the recipient is profoundly immunodeficient until the graft engrafts and slowly rebuilds immunity over months, a process delayed and prolonged by graft-versus-host disease (GVHD) and the immunosuppression used to treat it. Because prophylactic drugs can be marrow-toxic and slow engraftment, HSCT centres often prefer pre-emptive monitoring, and T-cell depletion of the graft (to prevent GVHD) markedly raises the risk of CMV, EBV-driven lymphoproliferation, adenovirus and HHV-6, because it removes the very cells that control these viruses.
Donor-derived infection
A distinct mode of acquisition, most important in the first month, is transmission from the donor, and it comes in three patterns. Expected transmission of a latent virus the donor carries (CMV, EBV, HHV-8) is anticipated and managed by serostatus matching and prophylaxis. Unexpected transmission of an actively replicating agent is rare but can be devastating: clusters of West Nile virus, lymphocytic choriomeningitis virus and rabies traced to a single donor have killed most of the recipients, presenting as unexplained encephalitis or hepatitis. Donors are therefore screened by both serology and nucleic-acid testing (NAAT) for HIV, hepatitis B and hepatitis C; NAAT shortens the window period during which a recently infected donor is seronegative but viraemic, though a small residual risk remains, in the order of one in 100,000 to one in 400,000 per donor. Two former exclusions have been deliberately reversed by effective antivirals: organs from HIV-positive donors are now used for HIV-positive recipients, and organs from hepatitis C-positive donors are transplanted into negative recipients under a short course of direct-acting antiviral cover (for example sofosbuvir-velpatasvir for four weeks), which prevents established infection.
The timeline of infection
Infection follows a recognisable schedule that guides the differential diagnosis at any given point. The schedule is a guide rather than a fixed rule, and antiviral prophylaxis shifts it, typically by delaying herpesvirus disease until after the drug is stopped.
After solid-organ transplant:
| Period | Dominant viral problems |
|---|---|
| First month | HSV reactivation; rare donor-derived infection (West Nile virus, lymphocytic choriomeningitis virus, rabies) |
| One to six months | CMV, EBV, HHV-6 and HHV-7, BK polyomavirus (kidney), reactivating hepatitis B and C, community respiratory viruses |
| After six months | Community respiratory viruses; late-onset CMV once prophylaxis stops; HPV-related disease and late post-transplant lymphoproliferative disorder in those on sustained heavy immunosuppression |
After stem-cell transplant:
| Phase | Dominant viral problems |
|---|---|
| Pre-engraftment (to about day 30) | HSV reactivation; respiratory viruses |
| Engraftment to day 100 | CMV reactivation peaks; HHV-6 (encephalitis, marrow suppression); EBV lymphoproliferation; adenovirus; BK haemorrhagic cystitis |
| After day 100 | VZV reactivation; late CMV; respiratory viruses; risk prolonged by chronic GVHD |
Diagnosis and monitoring
Serology is unreliable in the immunosuppressed, because the antibody response is blunted: a patient can have severe disease without a diagnostic antibody rise, and a pre-transplant antibody result tells you about risk, not about current infection. Quantitative nucleic-acid testing (viral load) is therefore the backbone of diagnosis and monitoring. It detects active infection directly, provides a threshold to trigger pre-emptive treatment before disease develops (used for CMV, EBV, BK and adenovirus), and follows the response to therapy, with a falling load confirming efficacy and a rising load on adequate treatment suggesting resistance or non-adherence. Reporting in WHO international units per millilitre (IU/mL) standardises results across assays and laboratories so that thresholds can be shared, a refinement that postdates much of the older literature, which used assay-specific copy numbers.
Infection (virus detectable) is distinguished from disease (signs and symptoms): pre-emptive strategies deliberately treat infection to prevent disease. Some diagnoses still require tissue: BK nephropathy needs an allograft biopsy with SV40 large-T antigen staining, post-transplant lymphoproliferative disorder needs histology, and CMV gastrointestinal disease often needs biopsy to separate it from GVHD.
Beyond detecting the virus, immune monitoring is entering practice to gauge the host’s ability to control it. Assays of CMV-specific T cells (for example interferon-gamma release assays) independently predict who will develop significant CMV and are being used to decide how long to continue prophylaxis, while the load of torque teno virus, a harmless anellovirus carried by almost everyone, rises as immunosuppression deepens and is being explored as a global marker of the net state of immunosuppression. Both are promising but not yet standard of care.
Approach to the febrile or symptomatic transplant recipient
Symptoms are muted and misleading in the immunosuppressed, so the bedside approach differs from that in the immunocompetent host. Fever is neither sensitive nor specific: many infections, fungal ones especially, cause little or no fever, while up to a fifth of post-transplant fevers are non-infectious. Inflammatory signs are blunted by the immunosuppression, and a transplanted organ is denervated with altered lymphatic drainage, so localising findings shift or disappear.
Three explanations must therefore be weighed in parallel for any new problem: infection, graft rejection or dysfunction, and drug toxicity (notably from calcineurin inhibitors), and more than one can be present at once. The likely infection is shaped by the transplanted organ:
| Transplant | Characteristic problems to consider |
|---|---|
| Kidney | BK nephropathy; ureteric stricture; urinary infection |
| Liver | Biliary leak or stricture; vascular thrombosis; Cryptococcus |
| Heart | Toxoplasma; Chagas disease (endemic donors); sternal wound infection |
| Lung | Respiratory viruses; fungi; Nocardia; airway anastomotic infection |
Because the signs are unreliable and tissue diagnosis is often decisive, the threshold for imaging, bronchoscopy or biopsy and for early specialist infectious-diseases input should be low. One caution applies once immunosuppression is reduced to treat a virus: restoring immunity can unmask an immune reconstitution inflammatory response (classically to cryptococcal infection), so clinical worsening after reduction is not always treatment failure.
Prevention
Prophylaxis versus pre-emptive therapy
Two strategies prevent disease from the latent viruses, and for CMV they are about equally effective at preventing disease. Universal prophylaxis gives an antiviral to every at-risk patient for a fixed period; it is simple, needs no monitoring, and may also blunt the indirect immunomodulatory effects of CMV, but it over-treats, carries drug toxicity and cost, and causes late-onset disease once it stops, because the immune response was never primed by exposure. Pre-emptive therapy withholds the drug and instead monitors the viral load at regular intervals, treating only when replication crosses a threshold; it spares toxicity, cost and resistance but depends on reliable, frequent, standardised monitoring and can be outrun by rapidly rising viraemia. SOT programmes often use prophylaxis for the highest-risk strata such as the D positive, R negative pair; HSCT centres frequently prefer pre-emptive CMV management to avoid marrow toxicity. A third tool, secondary prophylaxis, continues a suppressive antiviral after a first episode (for example of CMV) to prevent recurrence while the patient remains heavily immunosuppressed.
The regimens for the herpesviruses and hepatitis B:
| Virus | Strategy | Agent and dose | Duration |
|---|---|---|---|
| HSV (seropositive) | Prophylaxis | Aciclovir or valaciclovir | Conditioning until mucositis resolves (around day 30) |
| VZV (seropositive) | Prophylaxis | Valaciclovir or aciclovir | About 1 year after HSCT, longer if still immunosuppressed |
| CMV (seropositive HSCT) | Prophylaxis | Letermovir 480 mg daily | From transplant to about week 14, extendable |
| CMV | Pre-emptive | Weekly viral load, then ganciclovir, valganciclovir or foscarnet | Until viraemia clears |
| Hepatitis B (HBsAg or anti-HBc positive) | Prophylaxis | Entecavir or tenofovir | Until 6 months after immunosuppression stops |
A practical caveat: letermovir has no activity against HSV or VZV, so a patient taking it for CMV still needs aciclovir-class cover for the other herpesviruses, and it has significant drug interactions through CYP3A.
Vaccination
Vaccinate before transplant, when responses are best. Live vaccines (measles-mumps-rubella, varicella, live zoster) must precede immunosuppression with an adequate interval and are contraindicated afterwards, while inactivated vaccines (influenza, pneumococcal, hepatitis B) are given and boosted, accepting weaker responses once immunosuppressed. The household is protected by cocooning, vaccinating close contacts. After HSCT, established immune memory is lost and a full re-vaccination programme is needed, beginning months after transplant with inactivated vaccines and deferring live vaccines until immune reconstitution is secure. The stem-cell re-vaccination schedule is concrete:
| Timing after HSCT | Vaccines |
|---|---|
| From about 6 months | Inactivated: influenza (then annually for life), pneumococcal conjugate series, diphtheria-tetanus-pertussis, Haemophilus influenzae type b, inactivated polio, hepatitis B, HPV, meningococcal |
| From about 12 months | Recombinant (non-live) zoster vaccine, if off immunosuppression and free of GVHD |
| From about 24 months | Live vaccines (measles-mumps-rubella, varicella), only if seronegative, off all immunosuppression and free of GVHD |
Reducing immunosuppression
For the viruses with no reliably effective drug, the principal therapeutic measure is to reduce immunosuppression, allowing virus-specific T-cell immunity to recover. This is the primary move for BK nephropathy, EBV-driven lymphoproliferative disorder, adenovirus disease and chronic hepatitis E, always balanced against the risk of precipitating rejection or GVHD.
The viruses
The agents are summarised below; each is detailed in the sections that follow.
| Virus | Typical timing | Key transplant syndromes | Management |
|---|---|---|---|
| Cytomegalovirus | 1 to 6 months (SOT); day 30 to 100 (HSCT) | CMV syndrome, pneumonitis, colitis, hepatitis, retinitis; indirect graft injury | Prophylaxis or pre-emptive ganciclovir, valganciclovir, letermovir; foscarnet or maribavir for resistance |
| Epstein-Barr virus | First year (peak), second peak years 5 to 10 | Post-transplant lymphoproliferative disorder | Reduce immunosuppression, rituximab, EBV-specific T cells |
| Herpes simplex virus | First month | Mucositis, oesophagitis, rarely disseminated visceral disease | Aciclovir or valaciclovir; early prophylaxis prevents most |
| Varicella-zoster virus | Late (after day 100) | Dermatomal then disseminated or visceral zoster | Aciclovir or valaciclovir; VariZIG for exposed seronegatives |
| Human herpesvirus 6 | Early HSCT (weeks 2 to 4) | Limbic encephalitis, fever, marrow suppression | Ganciclovir or foscarnet (beware integrated HHV-6) |
| Human herpesvirus 8 | Months to years | Kaposi sarcoma, primary effusion lymphoma, Castleman disease | Reduce immunosuppression; switch to an mTOR inhibitor |
| Adenovirus | First 3 months (paediatric HSCT) | Disseminated disease: enteritis, hepatitis, pneumonia, cystitis | Reduce immunosuppression; cidofovir or brincidofovir; adoptive T cells |
| BK polyomavirus | Months (kidney); late HSCT | Allograft nephropathy; haemorrhagic cystitis | Reduce immunosuppression; supportive care |
| JC polyomavirus | Late, often years | Progressive multifocal leukoencephalopathy | Reduce immunosuppression (outcome often poor) |
| Human papillomavirus | Years | Cutaneous squamous cell carcinoma; anogenital and cervical dysplasia | Surveillance; reduce immunosuppression or mTOR switch; vaccinate candidates |
| Hepatitis B | Any time (reactivation) | Reactivation, fibrosing cholestatic hepatitis | Entecavir or tenofovir prophylaxis; screen before immunosuppression |
| Hepatitis C | After liver transplant | Universal recurrence with accelerated fibrosis | Direct-acting antivirals (curable; HCV-positive donors now usable) |
| Hepatitis E | Any time (SOT) | Chronic genotype-3 hepatitis | Reduce immunosuppression, then ribavirin |
| Respiratory viruses | Seasonal or nosocomial | Upper-tract illness progressing to pneumonia | RSV ribavirin; influenza oseltamivir; otherwise supportive |
Cytomegalovirus
Cytomegalovirus is the single most important viral pathogen of transplantation, important both for the disease it causes directly and for its indirect effects. Directly, it produces a febrile CMV syndrome (fever, malaise, leukopenia and thrombocytopenia without organ involvement, which is around 60 per cent of CMV disease in solid-organ recipients) and tissue-invasive disease: pneumonitis, which is the most feared and lethal manifestation after stem-cell transplant; gastrointestinal disease at any level of the gut, often hard to separate from GVHD without biopsy; hepatitis; and, less commonly than in advanced HIV, retinitis, encephalitis and nephritis. Stem-cell recipients tend toward pneumonitis and gut disease, solid-organ recipients toward the CMV syndrome and disease in the transplanted organ.
The indirect effects flow from CMV’s immunomodulating activity and are arguably as important: acute and chronic allograft rejection, bronchiolitis obliterans in the lung, transplant vasculopathy in the heart, and an increased risk of other opportunistic infections (Aspergillus, Pneumocystis) and of EBV-driven lymphoproliferation. CMV and rejection are bidirectional risk factors for one another, and in stem-cell transplant CMV and GVHD aggravate each other.
Risk also varies by organ, tracking the latent viral burden in the graft and the immunosuppression it requires: lung, small-bowel and pancreas transplants carry the highest CMV risk, liver and heart an intermediate risk, and kidney the lowest. Infection (virus detectable by PCR or antigenaemia) is distinguished from disease (infection with attributable signs and symptoms): pre-emptive therapy deliberately treats infection to prevent disease, exploiting the fact that CMV replicates rapidly, with a viral-load doubling time of about a day, so a rising load gives early warning. Notably, even subclinical CMV in the seronegative recipient of a seropositive graft is associated with higher death from bacterial and fungal infection, a measure of the virus’s indirect immunosuppressive cost.
Diagnosis rests on quantitative PCR of blood, the most sensitive test, whose viral load predicts disease and guides pre-emptive therapy; older pp65 antigenaemia is semi-quantitative and unreliable in leukopenia. Prevention uses prophylaxis or pre-emptive therapy as described above. The established drugs are ganciclovir and its oral prodrug valganciclovir (first-line, main toxicity neutropenia), foscarnet (second-line, active against the common resistance mutation but nephrotoxic) and cidofovir (third-line, limited by renal toxicity); two newer agents, letermovir for prophylaxis and maribavir for refractory or resistant disease, have since been added. Resistance, suspected when the viral load rises after two weeks of adequate therapy, is most often due to UL97 (kinase) mutations conferring ganciclovir resistance, with UL54 (polymerase) mutations conferring broader resistance; genotypic testing guides the switch. Pre-emptive management depends on weekly plasma CMV PCR from engraftment to about day 100 (more frequent in the highest-risk patients, such as those receiving T-cell-depleted, mismatched or cord-blood grafts or alemtuzumab), with treatment triggered at a defined viral-load threshold. Maribavir, although well tolerated and free of marrow toxicity, underperformed valganciclovir for routine pre-emptive clearance and is therefore reserved for refractory or resistant disease rather than used first-line.
Epstein-Barr virus and post-transplant lymphoproliferative disorder
Epstein-Barr virus drives post-transplant lymphoproliferative disorder (PTLD), the proliferation of EBV-infected B cells that escapes control when immunosuppression removes the EBV-specific cytotoxic T cells that normally hold it in check. The spectrum runs from an early, polyclonal, mononucleosis-like proliferation to a late, monoclonal, often EBV-negative lymphoma, and EBV is a recognised group-1 carcinogen.
The dominant risk factor is primary EBV infection in a seronegative recipient (D positive, R negative), which raises early PTLD incidence roughly 10- to 76-fold and falls disproportionately on children, who are more often EBV-naive. The other major drivers are T-cell-depleting induction (antithymocyte globulin, the former OKT3) and the overall intensity of immunosuppression. Risk rises with the lymphoid content and immunosuppression of the organ: lowest in kidney recipients (around 1 to 2 per cent), higher in liver, heart and lung, and highest in intestinal and multivisceral transplants (up to around 15 per cent), with a bimodal timing of a first-year peak and a second peak at five to ten years.
PTLD is frequently extranodal (gastrointestinal tract, liver, lung, the allograft itself), and isolated central nervous system disease, a monomorphic CD20-positive B-cell lymphoma with a poor prognosis, accounts for a notable minority. After stem-cell transplant it appears early, before T-cell reconstitution, is often disseminated, and carries very high mortality, exceeding 75 per cent in fulminant disease and approaching 90 per cent in disseminated stem-cell PTLD.
Histologically, PTLD spans a recognised spectrum: early lesions (plasmacytic hyperplasia and an infectious-mononucleosis-like disease), polymorphic PTLD, monomorphic PTLD (most often a diffuse large B-cell lymphoma, less often a Burkitt, plasma-cell or rare T-cell disease), and a classical Hodgkin-type PTLD. The early and polymorphic lesions are usually EBV-positive and more likely to regress on reduced immunosuppression, whereas late monomorphic disease is frequently EBV-negative and behaves like an aggressive lymphoma that needs chemotherapy.
Diagnosis combines EBV-DNA load monitoring in blood, used for pre-emptive surveillance and for following treatment (a rising load can precede clinical disease, though it is imperfectly specific), with mandatory histology for the definitive diagnosis and clonality. The management ladder is: first, reduce immunosuppression, the single most important early step (remission in roughly a quarter to a half, though at the cost of rejection and with little effect on truly malignant late disease); then rituximab, the anti-CD20 antibody that is now first-line and responds in around half to three-quarters; then EBV-specific cytotoxic T cells where reducing immunosuppression is impossible, particularly after T-cell-depleted stem-cell transplant; and finally chemotherapy for monomorphic or refractory lymphoma. Antivirals do not treat established PTLD, because the proliferating B cells are not lytically infected. Disseminated disease still kills the majority.
Herpes simplex and varicella-zoster viruses
Herpes simplex virus reactivates earliest, almost always from the recipient’s own latent infection, with most disease in the first month and little after day 60. Before prophylaxis it affected 70 to 80 per cent of seropositive stem-cell recipients and 40 to 50 per cent of solid-organ recipients. The usual picture is painful orolabial or anogenital mucocutaneous ulceration, slow to heal and sometimes chronic and atypical; oesophagitis (often with a nasogastric tube), tracheobronchitis or pneumonia (in intubated lung and heart-lung recipients), and rarely a disseminated visceral infection with hepatitis that, though uncommon (around 0.3 per cent of solid-organ recipients), carries a mortality of 60 to 80 per cent. Diagnosis is by PCR, with culture or direct immunofluorescence on mucocutaneous lesions. Mucocutaneous disease is treated with oral valaciclovir, famciclovir or aciclovir, and visceral or disseminated disease with intravenous aciclovir, for at least ten days to avoid relapse and resistance. Aciclovir prophylaxis during the early period cuts reactivation from about 70 per cent to under 5 per cent, and the ganciclovir or valganciclovir given for CMV also covers HSV. Aciclovir resistance, through thymidine-kinase mutations, occurs in 2 to 5 per cent of stem-cell recipients and is treated with foscarnet.
Varicella-zoster virus reactivates later, characteristically after day 100 (a median of around five months after stem-cell transplant), with a cumulative risk of zoster of 10 to 20 per cent after autologous and 25 to 35 per cent after allogeneic transplant, and around 20 per 1000 patient-years after solid-organ transplant. In the immunosuppressed, dermatomal zoster is more likely to disseminate: cutaneous spread occurs in 15 to 30 per cent and a third of those develop visceral disease (encephalitis, pneumonitis, hepatitis, retinitis), and visceral VZV can occur without a rash, presenting as severe abdominal pain that mimics a surgical abdomen or GVHD. Primary varicella in a seronegative recipient, especially a child, is dangerous, with visceral involvement in about half and significant mortality. Severe, visceral or high-risk disease is treated with intravenous aciclovir, milder disease with oral valaciclovir or famciclovir. A seronegative recipient exposed to chickenpox or shingles is given varicella-zoster immunoglobulin within 10 days of exposure (which reduces disseminated disease by about three-quarters), with aciclovir post-exposure prophylaxis as an adjunct. Live varicella and zoster vaccines are given to seronegative candidates before transplant and are contraindicated afterwards; the non-live recombinant zoster vaccine is an option after transplant where available.
Human herpesviruses 6, 7 and 8
HHV-6 (mostly the HHV-6B variant) reactivates early after stem-cell transplant, around weeks two to four (before HHV-7 and CMV), in 35 to 42 per cent of allogeneic recipients and more after cord-blood transplant. Its signature illness is a post-transplant limbic encephalitis (anterograde amnesia, seizures, the syndrome of inappropriate antidiuretic hormone secretion with hyponatraemia, and bilateral medial temporal lobe change on MRI), with a mortality of around half; it also causes fever with rash, bone-marrow suppression with delayed engraftment, and, indirectly, facilitates CMV disease and invasive fungal infection. A crucial pitfall is chromosomally integrated HHV-6, an inherited state in which the viral genome sits in every nucleated cell and gives a persistently very high PCR load without active disease; a load that falls with treatment supports genuine infection. Aciclovir is inactive; encephalitis is treated with ganciclovir or foscarnet, though no prophylaxis is established.
HHV-7 is ubiquitous and reactivates slightly after HHV-6. It rarely causes disease in its own right and acts mainly as an immunomodulatory cofactor that amplifies CMV disease, with occasional reports of encephalitis.
HHV-8 (Kaposi sarcoma-associated herpesvirus) causes Kaposi sarcoma, and also primary effusion lymphoma and multicentric Castleman disease. In transplantation Kaposi sarcoma is typically the earliest post-transplant malignancy (a median of around 22 months), arising from reactivation of the recipient’s latent virus or, in 2 to 12 per cent of seronegative recipients of a seropositive graft, from donor-derived infection. Its frequency tracks HHV-8 seroprevalence, which is geographically very uneven: under 5 per cent in Northern European blood donors but up to around 80 per cent in parts of sub-Saharan Africa, so post-transplant Kaposi sarcoma is rare (under 1 per cent) in low-seroprevalence regions but reaches 4 to 5 per cent in high-prevalence populations, where it is the commonest post-transplant cancer. It presents as violaceous cutaneous nodules, but visceral involvement (gut, lung) occurs in up to 40 per cent and can bleed or obstruct. The mainstay of treatment is reduction of immunosuppression and a switch to an mTOR inhibitor (sirolimus), which is both immunosuppressive and antitumour and can produce regression; visceral or refractory disease needs chemotherapy. Antivirals are of unproven benefit.
Respiratory viruses
The community respiratory viruses, respiratory syncytial virus (RSV), influenza, parainfluenza virus, human metapneumovirus, rhinovirus and, now, SARS-CoV-2, are acquired from the community or nosocomially rather than by reactivation, and they share a pattern: an upper-respiratory illness that may progress to the lower tract and pneumonia, with a mortality in stem-cell recipients that is far higher than in healthy people. Progression and death are driven by lymphopenia and by pre-engraftment timing, and in lung-transplant recipients these viruses are additionally associated with acute rejection and bronchiolitis obliterans.
Infection and progression rates in the first hundred days after stem-cell transplant:
| Virus | Infection rate | Progression to lower tract | Mortality with pneumonia |
|---|---|---|---|
| Respiratory syncytial virus | 2 to 6 per cent | 20 to 40 per cent | 25 to 45 per cent |
| Parainfluenza virus | 4 to 7 per cent | 18 to 44 per cent | around 35 per cent |
| Human metapneumovirus | 3 to 6 per cent | 25 to 41 per cent | around 33 per cent |
| Influenza | 1 to 3 per cent | 15 to 18 per cent | around 25 per cent |
| Rhinovirus | up to 21 per cent | 2 to 4 per cent | around 20 per cent |
RSV causes winter outbreaks, often nosocomial, and progresses to the lower tract in 20 to 40 per cent of infected stem-cell recipients with high mortality once pneumonia develops; treatment is aerosolised ribavirin, sometimes with immunoglobulin, started at the upper-tract stage before respiratory failure, when it has the best chance of preventing progression. Influenza follows the community season; progression is driven by lymphopenia and older age, and neuraminidase inhibitors (oseltamivir) started early reduce it, though prolonged shedding and resistance occur in the immunosuppressed. Parainfluenza virus is epidemic in spring and summer, has no proven antiviral, and in lung recipients is strongly tied to rejection. Human metapneumovirus behaves like RSV and can cause rapidly progressive pneumonia. Rhinovirus is very common and usually a trivial upper-tract illness, but pre-engraftment lower-tract rhinovirus has been highly lethal. For all of them, infection control is central, because they cause nosocomial outbreaks, so isolation, hand hygiene and staff and visitor screening matter, and elective transplant is deferred when the candidate has a respiratory infection at conditioning. Isolation precautions are pathogen-specific (contact precautions for respiratory syncytial virus and parainfluenza, droplet for influenza, and contact plus droplet for adenovirus and SARS-CoV-2). Annual inactivated influenza vaccination is given for life from six months after transplant, and a neuraminidase inhibitor (oseltamivir) can be used for post-exposure prophylaxis during an outbreak.
Adenovirus
Adenovirus is most dangerous after allogeneic stem-cell transplantation, above all in children and with T-cell depletion, which removes the cellular immunity that controls it; risk rises stepwise with the depth of depletion, and with graft-versus-host disease and cord-blood or mismatched donors. It usually appears within the first three months, with overall infection rates of 12 to 42 per cent in paediatric stem-cell transplant, more than half of them asymptomatic. Disease ranges from gastroenteritis and hepatitis to pneumonia, haemorrhagic cystitis and nephritis, and disseminated multi-organ failure, fatal in 18 to 37 per cent of those who develop it. Viraemia, and a rising blood viral load, is the key predictor of dissemination, so high-risk patients are monitored by quantitative PCR on blood (and on stool and urine, where shedding precedes viraemia), with pre-emptive treatment triggered by viraemia rather than stool positivity alone, since most stool-positive patients never develop disease. Management is to reduce immunosuppression, give cidofovir (or its oral lipid-ester brincidofovir, less nephrotoxic) on confirmed viraemia, and, for refractory disease, transfer donor-derived adenovirus-specific T cells where available. In solid-organ transplant adenovirus is less common and often organ-directed (haemorrhagic cystitis and nephritis in kidney recipients, hepatitis in liver recipients).
Polyomaviruses and papillomaviruses
BK polyomavirus causes two distinct transplant diseases. In kidney transplantation it causes polyomavirus-associated nephropathy (1 to 10 per cent of recipients): latent virus in the renourinary tract reactivates and progresses through high-level viruria (with infected decoy cells shed in urine), then plasma viraemia, then tubular infection and an interstitial nephritis with progressive graft dysfunction. The diagnosis is staged from urine (decoy cells, high urinary DNA, sensitive but not specific) to plasma (a sustained load defines presumptive nephropathy and is the screening marker) to allograft biopsy showing cytopathic change with SV40 large-T antigen staining, which is definitive but can be missed if disease is focal. The histological grade predicts outcome, graft loss rising from under 10 per cent in early disease to over 80 per cent once there is established fibrosis, which is why many programmes screen plasma BK DNA three-monthly for the first two years to intervene before nephropathy becomes irreversible. The central difficulty is that nephropathy mimics rejection (both give a rising creatinine and an interstitial infiltrate) yet needs the opposite treatment: rejection needs more immunosuppression, BK nephropathy needs less, so misreading it accelerates graft loss. There is no antiviral of proven benefit. In stem-cell transplantation BK instead causes a late, post-engraftment haemorrhagic cystitis, distinct from the early chemical cystitis of conditioning agents such as cyclophosphamide; the great majority of recipients have high viruria but fewer than a fifth develop cystitis, which is managed supportively with hydration, irrigation and transfusion.
JC polyomavirus rarely reactivates to cause progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease of oligodendrocytes, usually late and after prolonged immunosuppression, and linked to rituximab and natalizumab. It presents with progressive focal deficits and asymmetric non-enhancing white-matter lesions, and is diagnosed by JC virus PCR in cerebrospinal fluid (high positive predictive value but imperfect sensitivity, so a negative result does not exclude it), with brain biopsy where doubt remains. Management is to restore immunity by reducing immunosuppression, but the outcome is often poor.
Human papillomavirus causes a slowly accruing burden of disease with the duration and intensity of immunosuppression: cutaneous warts rise from around 15 per cent at transplant to over 80 per cent at twenty years, and, more importantly, cutaneous squamous cell carcinoma becomes far more common, with ultraviolet light as a cofactor and the usual ratio reversed so that squamous outnumbers basal cell carcinoma; these cancers can metastasise. Anogenital and cervical dysplasia and a several-fold increase in cervical cancer also occur. Prevention combines sun protection, skin and cervical surveillance, and HPV vaccination of candidates before transplant, with reduction of immunosuppression or an mTOR switch where disease develops.
Hepatitis viruses
Hepatitis B reactivates when immunosuppression lifts immune control, and corticosteroids directly upregulate viral replication. An HBsAg-positive recipient will, untreated, reactivate near-universally, so high-barrier nucleos(t)ide analogue prophylaxis (entecavir or tenofovir) is started before transplant and continued, with transplant ideally undertaken only once the virus is suppressed. An occult or anti-HBc-positive recipient can also reactivate under intense immunosuppression, particularly rituximab, which is why hepatitis B serology is checked before any immunosuppression and prophylaxis given to those at risk. The serostatus of donor and recipient governs de novo hepatitis B from an anti-HBc-positive donor: the risk depends on the inoculum (highest for a liver graft, intermediate for a kidney, where 14 to 25 per cent of recipients seroconvert but under 2 per cent develop chronic hepatitis B) and on the recipient’s anti-HBs (around a 60 per cent risk in a non-immune recipient, falling to negligible once anti-HBs reaches 10 IU/mL through vaccination or past infection). Monthly hepatitis B immunoglobulin or a daily oral antiviral prevents de novo infection in almost all cases. In liver transplantation, hepatitis B immunoglobulin combined with a nucleos(t)ide analogue protects the graft, with increasingly immunoglobulin-sparing regimens.
Hepatitis C recurs universally and immediately after liver transplantation for HCV cirrhosis, with an accelerated natural history (a fifth cirrhotic at five years) and, in a minority, a severe fibrosing cholestatic hepatitis with rapid graft failure. After stem-cell transplant, hepatitis C can flare as immunosuppression is tapered, with reactivation reported in nearly all allogeneic but only a minority of autologous recipients, and long-term cirrhosis in a substantial fraction over fifteen to twenty years, accelerated by genotype 3. The 2010 standard of pegylated interferon and ribavirin has been entirely superseded by direct-acting antivirals, which cure over 95 per cent, are used before or after transplant, and have made it possible to transplant organs from HCV-positive donors into negative recipients with a short course of treatment.
Hepatitis E, not a feature of the older transplant literature, is now recognised to cause chronic genotype-3 infection in solid-organ recipients, in whom the impaired T-cell response fails to clear it; it is diagnosed by HEV RNA (serology being unreliable in the immunosuppressed) and managed by reducing immunosuppression and then giving ribavirin.
Antivirals and adjunctive therapies
The pharmacological toolkit is small and grouped by target:
- Herpes simplex and varicella-zoster: aciclovir, valaciclovir and famciclovir, with foscarnet for aciclovir-resistant disease. Where oral therapy is appropriate, most guidelines prefer valaciclovir (or famciclovir) over aciclovir, because its far better oral bioavailability achieves higher blood levels with simpler, less frequent dosing; intravenous aciclovir remains the choice for severe, visceral or disseminated disease.
- Cytomegalovirus: ganciclovir and valganciclovir (first-line), letermovir (prophylaxis), maribavir (refractory or resistant disease), foscarnet, and cidofovir.
- Adenovirus: cidofovir or brincidofovir, with no agent of high proven efficacy.
- Hepatitis B: entecavir and tenofovir. Hepatitis C: pan-genotypic direct-acting antivirals.
- Respiratory viruses: ribavirin for respiratory syncytial virus, and neuraminidase inhibitors (oseltamivir) for influenza.
Three adjuncts cut across these. Reducing immunosuppression restores virus-specific immunity and is the mainstay wherever no good drug exists (BK, PTLD, adenovirus, chronic hepatitis E). Adoptive transfer of virus-specific T cells, directed against CMV, EBV, adenovirus, BK or HHV-6, restores cellular control directly and is an effective option for refractory disease where available. Specific immunoglobulins give passive protection: varicella-zoster immunoglobulin after VZV exposure in a seronegative recipient, hepatitis B immunoglobulin in liver transplantation, and CMV immunoglobulin as an adjunct in selected CMV disease.
References and recommended reading
- 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. The framework, timeline and management principles.
- Bowden RA, Ljungman P, Snydman DR (eds.). Transplant Infections, 3rd edition. Philadelphia: Lippincott Williams and Wilkins; 2010. The per-virus chapters on CMV, EBV, HSV/VZV, HHV-6/7/8, respiratory viruses, adenovirus, polyoma and papilloma viruses, and the hepatitis viruses in transplantation.
- UpToDate (Wolters Kluwer): Infection in the solid organ transplant recipient and Prevention of viral infections in hematopoietic cell transplant recipients. Accessed June 2026. Used to update the cross-cutting framework and current antiviral practice (letermovir, maribavir, current respiratory-virus and adenovirus management).
- Burrell CJ, Howard CR, Murphy FA. Fenner and White’s Medical Virology, 5th edition. Academic Press / Elsevier; 2017.