Prevention of viral infections in hematopoietic cell transplant recipients

INTRODUCTION — Hematopoietic cell transplant (HCT) recipients, especially those who have received allogeneic transplants, are at increased risk for a variety of infections depending upon their degree of immunosuppression and exposures. The term "hematopoietic cell transplantation" will be used throughout this topic as a general term to cover transplantation of hematopoietic cells from any source (eg, bone marrow, peripheral blood, umbilical cord blood). (See "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells".)

Infection in HCT recipients is associated with high morbidity and mortality. Viruses of major importance in HCT recipients include herpes simplex virus, varicella-zoster virus, cytomegalovirus, Epstein-Barr virus, respiratory viruses (eg, influenza, parainfluenza, respiratory syncytial virus, adenovirus, severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]), human herpes virus 6, hepatitis B, and hepatitis C. Antiviral prophylaxis or pre-emptive therapy against some of these viruses is recommended for HCT recipients and will be discussed here.

An overview of infections following HCT, evaluation for infections before HCT, prophylaxis of other infections in HCT recipients, and immunizations in HCT candidates and recipients are presented separately. (See "Overview of infections following hematopoietic cell transplantation" and "Evaluation for infection before hematopoietic cell transplantation" and "Prevention of infections in hematopoietic cell transplant recipients" and "Prophylaxis of invasive fungal infections in adult hematopoietic cell transplant recipients" and "Prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults" and "Immunizations in hematopoietic cell transplant candidates and recipients".)

EVALUATION BEFORE HCT — The pretransplantation evaluation is designed to prevent post-transplant infections by excluding unsuitable donors and defining specific infection control policies and antimicrobial prophylaxis and therapy regimens, which will be necessary after transplantation. Laboratory testing for evidence of past infectious exposures is performed to detect asymptomatic infection in the HCT donor or candidate. Some tests are recommended for all HCT donors and candidates, whereas others are appropriate in selected individuals with epidemiologic risk factors (table 1) [1,2]. Serologic testing is used as an indicator of significant past exposures. During the coronavirus disease 2019 (COVID-19) pandemic, most clinicians test for severe acute respiratory syndrome coronavirus 2 (typically by polymerase chain reaction on a nasopharyngeal specimen) prior to initiating the conditioning regimen because of the potential for asymptomatic and potentially devastating illness in immunocompromised patients. (See "COVID-19: Diagnosis", section on 'Diagnostic approach'.)

The evaluation for infection before HCT is discussed in greater detail separately. (See "Evaluation for infection before hematopoietic cell transplantation".)

TIMELINE FOR INFECTIONS — The types of infections to which HCT recipients are most vulnerable can be roughly divided based upon the time elapsed since transplantation. The three periods are:

●Pre-engraftment – From transplantation to approximately day 30

●Immediate postengraftment – From engraftment to day 100

●Late postengraftment – After day 100

This division into time periods is artificial, but it is helpful in the management of the HCT recipient. The timing and length of interval of each of these phases may vary according to the source of stem cells, degree of human leukocyte antigen (HLA) and minor histocompatibility antigen match, the type and intensity of conditioning regimen used, and any manipulation the graft has had prior to transplant, immunosuppressive therapy (especially glucocorticoids and/or antithymocyte globulin), and the presence of graft-versus-host disease. In general, allogeneic HCT recipients are at risk for infection during all three periods (figure 1), whereas autologous transplant recipients are typically only vulnerable to infection during the pre- and immediate postengraftment periods (figure 2). During each of these time periods, patients can develop bacterial, fungal, viral, and/or parasitic infections, although during each period certain pathogens tend to cause disease more than others (table 2).

The timeline for infections is discussed in greater detail separately. (See "Overview of infections following hematopoietic cell transplantation", section on 'Timeline for infections'.)

DEFINITIONS OF PROPHYLAXIS AND PRE-EMPTIVE THERAPY — Approaches to the prevention of infection in HCT recipients include primary prophylaxis, secondary prophylaxis, and pre-emptive therapy.

●Primary prophylaxis – Primary prophylaxis involves the administration of an antimicrobial drug to prevent infection in patients at increased risk.

●Secondary prophylaxis – Secondary prophylaxis involves the administration of prophylactic doses of an antimicrobial drug to prevent recurrent infection.

●Pre-emptive therapy – Pre-emptive therapy involves starting antimicrobial therapy based upon screening with a sensitive assay (eg, polymerase chain reaction) in an attempt to detect early infection. The goal of pre-emptive therapy is to avoid progression to invasive disease. Pre-emptive therapy may be favored over prophylaxis when the antimicrobial therapy is particularly toxic (eg, for cytomegalovirus). (See 'Pre-emptive therapy' below.)

HERPESVIRUSES — Reactivation of herpesviruses is common after HCT [3]. Prophylactic and/or pre-emptive strategies are employed for herpes simplex virus (HSV)-1 and -2, varicella-zoster virus (VZV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV).

Herpes simplex virus — We test all HCT candidates for HSV-1 and HSV-2 immunoglobulin G (IgG) antibodies prior to transplantation [1]. HCT recipients who are seropositive for HSV-1 and/or HSV-2 should receive antiviral prophylaxis during the early transplant period. The usual approach involves starting an antiviral agent when the conditioning regimen is started and continuing it until engraftment or until mucositis resolves, whichever is longer; most patients require HSV prophylaxis for approximately 30 days following transplantation. We give a longer course to patients with a history of frequent recurrences of HSV. As acyclovir is continued for a much longer period in VZV-seropositive recipients, the duration of acyclovir is typically driven by VZV seropositivity, and some centers have stopped checking HSV serologies in VZV-positive patients. (See 'Varicella-zoster virus' below.)

Acceptable options for HSV prophylaxis include intravenous (IV) acyclovir (5 mg/kg IV every 12 hours or 250 mg/m² IV every 12 hours) or, if tolerated, oral acyclovir (400 or 800 mg twice daily) or oral valacyclovir (500 mg twice daily) [1,3-8]. The use of famciclovir has not been studied adequately in HCT recipients, so we do not use it [1].

The risk of HSV reactivation is highest during the first month following allogeneic HCT [3]. A meta-analysis of nine randomized trials of antiviral prophylaxis (mostly acyclovir) compared with placebo during the pre-engraftment period in HCT recipients demonstrated a reduction in HSV disease rates in those who received prophylaxis (relative risk 0.19, 95% CI 0.11-0.31), but no reduction in overall mortality [5]. Two trials showed no differences in outcomes between acyclovir and valacyclovir [9,10].

Varicella-zoster virus — VZV can cause severe disease in patients who have undergone HCT. Most VZV infections after HCT are due to reactivation of endogenous virus in seropositive patients. Accordingly, all patients should be tested for VZV IgG antibody prior to autologous or allogeneic HCT [1]. The period of risk extends through at least the first year following HCT [11] and for a longer period in those requiring ongoing immunosuppression.

Antiviral prophylaxis — We recommend that VZV-seropositive (VZV IgG-positive) allogeneic and autologous HCT recipients be given an oral prophylaxis regimen of valacyclovir (500 mg twice daily) or acyclovir (800 twice daily) for one year following transplantation, and we suggest that longer prophylaxis be given to patients requiring ongoing immunosuppression, such as those with graft-versus-host disease (GVHD) [1]. Of these agents, we prefer valacyclovir given its greater bioavailability and the need for high levels of active acyclovir to inhibit VZV in vitro. Patients who cannot take oral medications should be given IV acyclovir (5 mg/kg IV every 12 hours or 250 mg/m² IV every 12 hours).

In patients receiving T cell-suppressive therapies (eg, ≥1 mg/kg prednisone equivalents per day, bortezomib, alemtuzumab, and purine analogs such as fludarabine or cladribine), prophylaxis should continue until the immunosuppressive therapy is completed [1]. Some clinicians recommend continuation of prophylaxis for six months after discontinuation of immunosuppressive therapy, but this has not been adequately studied. If VZV reactivation occurs beyond the period at risk, a treatment course should be completed, and prophylaxis should then be resumed and continued for at least six months after all T cell suppressive therapies have been stopped.

VZV prophylaxis following allogeneic HCT has been shown to be effective in VZV-seropositive patients in multiple randomized trials [12-14]. In one larger trial, 77 allogeneic HCT recipients were randomly assigned to receive oral acyclovir (800 mg twice daily) or placebo given from one to two months until one year following transplantation [12]. Acyclovir significantly reduced VZV infections at one year (hazard ratio 0.16, 95% CI 0.04-0.74), but it did not reduce mortality. There was no difference between the groups in VZV-specific T helper cell responses, indicating that antiviral prophylaxis does not impede the development of protective immune responses. Poststudy VZV disease primarily occurred in patients with continued need for systemic immunosuppression, suggesting that continuation of prophylaxis beyond one year might be beneficial in such patients.

The potential benefit of a longer course of VZV prophylaxis was addressed in a retrospective population-based study of three sequential cohorts of 2635 VZV-seropositive patients who were undergoing allogeneic or autologous HCT [15]. The first cohort received acyclovir from the day of transplantation until engraftment, the second cohort received acyclovir or valacyclovir for one year, and the third cohort received acyclovir or valacyclovir for one year or for six months after immunosuppressive drugs were discontinued, whichever was longer.

The following findings were noted [15]:

●Consistent with the findings in the randomized trials, prophylaxis for one year or longer significantly reduced VZV disease compared with prophylaxis only through engraftment (8.8 versus 25 percent in allogeneic HCT recipients; 8.2 versus 22 percent in autologous HCT recipients).

●The magnitude of benefit after one year of prophylaxis persisted after drug discontinuation compared with patients who received prophylaxis only through engraftment. Thus, there was no evidence of rebound VZV disease.

●Continuation of prophylaxis beyond one year in allogeneic HCT recipients who remained on immunosuppressive therapy led to a further reduction in VZV disease compared with prophylaxis for one year (4.5 versus 8.8 percent).

●Administration of prophylaxis for one year led to a significant improvement in overall survival in both allogeneic and autologous HCT recipients (adjusted hazard ratio 0.8 in allogeneic HCT recipients compared with prophylaxis only through engraftment). Compared with one year of prophylaxis, use of prophylaxis for longer than one year did not significantly affect overall mortality or non-relapse mortality.

This study confirms the benefit of VZV prophylaxis in VZV-seropositive patients for at least one year following HCT in both allogeneic and autologous HCT recipients.

VZV postexposure prophylaxis — Exposure to VZV may result from contact with a contagious individual who has varicella-zoster (chickenpox) or herpes zoster (shingles), including an immunocompromised patient with disseminated infection or any individual with whom the susceptible HCT recipient had contact that is either intimate (eg, hugging, touching), close (face-to-face contact of ≥5 minutes) or repetitive (household members, patients in the same or adjacent rooms), or to a patient who develops a varicella-like rash following live VZV vaccination.

The incubation period for VZV is 10 to 21 days. Hence, all HCT recipients should avoid exposure to potentially contagious individuals who have been exposed to VZV, particularly between days 10 to 21 after that individual's exposure or until all skin lesions have crusted. Because individuals infected with the VZV are contagious for 24 to 48 hours before the typical rash develops, it is difficult to prevent transmission of VZV to susceptible hosts.

VZV-seronegative HCT recipients who were transplanted within the previous 24 months, as well as those transplanted >24 months earlier requiring continued immunosuppression (eg, for chronic GVHD), should be given varicella-zoster immune globulin (VariZIG) within 10 days of contact with a person with either chickenpox or shingles [1,16]. In addition, VZV-seronegative patients undergoing conditioning for HCT who are exposed to an individual who has a varicella-like rash following varicella vaccination should receive VariZIG. Close contact for adults is defined as continuous household contact, hospital contact in the same two- to four-bed room, or prolonged face-to-face contact with an infectious individual.

HCT recipients who were seropositive prior to transplantation and who are highly immunosuppressed due to high-dose glucocorticoid therapy or a T cell-depleted allograft and who are exposed to an individual with chickenpox, shingles, or a postvaccine varicella-like rash should also receive VariZIG.

If VariZIG is not available, postexposure valacyclovir (1 g orally three times daily) should be given from exposure until day 22 following exposure [1].

Details regarding formulation and dosing of VariZIG are discussed separately. (See "Post-exposure prophylaxis against varicella-zoster virus infection".)

Herpes zoster vaccines — Studies evaluating inactivated herpes zoster vaccines in HCT recipients are discussed separately. (See "Immunizations in hematopoietic cell transplant candidates and recipients", section on 'Zoster vaccine'.)

Cytomegalovirus

Risk of CMV — The risk of CMV reactivation is significant in allogeneic HCT recipients. Although some autologous HCT recipients reactivate CMV, the incidence of CMV disease is low in these patients. The risk of post-transplant CMV infection and CMV disease is significantly influenced by both donor and recipient CMV serostatus, which is determined before transplant; serostatus is used to help determine the appropriate prophylaxis or pre-emptive strategy. The lowest risk of post-transplant CMV is in CMV-seronegative recipients given grafts from CMV-seronegative donors. Hence, selection of the donor with the most appropriate CMV serologic status is a key preventive measure in a human leukocyte antigen (HLA)-identical sibling setting. However, when performing transplantation from an unrelated donor, the HLA match (especially a match at the HLA-A, B, C, or DRB1 loci) supersedes CMV serostatus. Umbilical cord blood grafts contain few memory T cells and, hence, generally offer no protection against CMV [12]. A CMV match should generally be prioritized over other factors such as blood group or age.

Recipients who are CMV-seropositive are at greatest risk for the development of CMV disease after transplant [17]. This is especially true when given grafts from CMV-seronegative donors due to lack of donor-transferred CMV-specific immunity during host reactivation of endogenous latent CMV. Accordingly, CMV-seropositive patents should be monitored closely for CMV reactivation and either given CMV prophylaxis or pre-emptive therapy, as discussed below. Donor selection for HCT is discussed in greater detail separately. (See "Donor selection for hematopoietic cell transplantation".)

Other risk factors for CMV reactivation include use of a hematopoietic cell graft from an unrelated or mismatched donor, T cell depletion of the donor graft, use of anti-thymocyte globulin (ATG) or alemtuzumab, post-transplant cyclophosphamide (PTCy) [18], development of graft versus host disease, and use of high-dose steroids. A study of a peptide-based enzyme-linked immunospot CMV assay tested at two-week intervals after transplant suggested that this measure of CMV cell-mediated immunity could predict the likelihood for clinically significant CMV infection as an independent risk factor when adjusted for other known risk factors [19].

A registry-based study of >2700 allogeneic HCT recipients reported that among CMV-seropositive transplant recipients, PTCy was associated with a two-fold higher risk of CMV infection, compared with patients receiving calcineurin-based GVHD prophylaxis [18]. This effect was most notable in CMV-seropositive recipients of haploidentical grafts, who had a marginally lower incidence of GVHD, but those with CMV infection had lower overall survival and greater non-relapse mortality.

CMV prevention — Prevention of primary CMV infection is best achieved by the selection of a CMV-seronegative donor for CMV-seronegative recipients, when possible. To prevent transfusion-transmitted CMV disease in CMV-seronegative recipients whose donor is also CMV-seronegative, blood products that are CMV safe (either obtained from CMV-seronegative donors, leukocyte depleted, or pathogen reduced) should be used [1]. Intravenous immunoglobulin and CMV-specific immunoglobulin prophylaxis have limited, if any, effect on the prevention of primary CMV infection [20-22]; we recommend against their use.

It is important to prevent CMV disease in CMV-seropositive recipients who receive grafts from either CMV-seronegative or CMV-seropositive donors and in CMV-seronegative recipients who receive allografts from CMV-seropositive donors. This can be accomplished by using either a prophylactic or pre-emptive approach [1]. We prefer a pre-emptive approach for most patients. Both approaches have been associated with a survival benefit compared with no prophylaxis and no pre-emptive therapy [23,24]. The evidence regarding the efficacy of each approach is discussed in detail below. (See 'Efficacy' below and 'Primary prophylaxis' below.)

Pre-emptive therapy — Most centers favor a pre-emptive approach for CMV in HCT recipients rather than a prophylactic approach to minimize toxicity from antiviral agents. A pre-emptive approach involves serial testing for CMV (eg, by PCR of whole blood or plasma) following transplantation and treating only those who develop viremia [1]. We also prefer a pre-emptive approach over a prophylactic approach for most patients, except for the highest risk patients discussed below. (See 'Primary prophylaxis' below.)

This approach is supported by the observation that, in most HCT recipients, CMV can be detected in blood or respiratory samples while a patient is asymptomatic, one to two weeks before onset of symptomatic CMV disease (usually pneumonitis). The risk of CMV disease is significantly reduced by the pre-emptive administration of ganciclovir in patients with CMV infection detected by PCR or pp65 antigenemia testing of the blood [25-27]. One study demonstrated that the initial CMV viral load and the rate of increase of virus in the blood correlate with the risk of developing CMV disease in liver transplant, renal transplant, and HCT recipients [28]. Because CMV reactivation may occur in the setting of neutropenia and because of the lower sensitivity of the CMV pp65 antigenemia assay when neutropenia is present, quantitative plasma PCR assays are preferred for monitoring for CMV viremia. (See "Overview of diagnostic tests for cytomegalovirus infection" and "Approach to the diagnosis of cytomegalovirus infection", section on 'Approach to diagnosis'.)

Monitoring for CMV reactivation — The frequency and duration of monitoring depend on the type of HCT (allogeneic versus autologous), history of CMV infection or disease, and the allograft manipulation:

●Allogeneic HCT – Monitoring by plasma CMV PCR should be performed weekly in CMV-seropositive recipients of allografts from CMV-seronegative donors (CMV D-/R+), in CMV-seropositive recipients of allografts from CMV-seropositive donors (CMV D+/R+), and in CMV-seronegative recipients of allografts from CMV-seropositive donors (CMV D+/R-) and should start at engraftment (around day +20 to 25) and continue until at least day +100 [1]. We monitor particularly high-risk patients with CMV PCR twice weekly; such patients include recipients of T cell-depleted allografts, HLA-mismatched allografts, or umbilical cord blood allografts, as well as patients who are receiving alemtuzumab. As there is a small but measurable risk for acute transmission of CMV from blood products, we also monitor CMV D-/R- patients weekly or every other week for several months, especially in those receiving transfusions. Monitoring until day +365 or longer is recommended in patients at highest risk for developing late CMV disease. Such patients include those who develop CMV infection during the first 100 days, recipients of mismatched or unrelated donor transplantation, those treated with glucocorticoids for GVHD, and those who have low CD4 counts or undetectable CMV-specific T cells.

After day 100 post-transplant, the testing frequency may be decreased in selected patients. Although the optimal frequency has not been adequately studied, we generally test patients with tapering immunosuppression (eg, <1 mg/kg per day prednisone equivalents) and who have had three consecutive negative tests every other week. Testing may be stopped if two additional tests are negative in the setting of continuous tapering of immunosuppression.

●Autologous or syngeneic HCT – Monitoring for CMV viremia is not generally done in recipients of autologous or syngeneic transplants because, although CMV reactivation is frequent, the risk of CMV disease is low. Weekly monitoring, started around day +20 and continued until day +100, is recommended in patients who develop CMV infection during the first 60 days following transplantation or who are recipients of CD34-selected grafts. Less frequent monitoring is appropriate after day +100. Other autologous HCT recipients who may benefit from a pre-emptive strategy include patients who received total body irradiation, patients who received T cell-depleted grafts, and patients who received alemtuzumab, fludarabine, cladribine, or 2-chlorodeoxyadenosine within the previous six months [1].

Patients with profound T cell immunodeficiency are at higher risk of CMV infection than other patients even prior to commencing the conditioning regimen. These patients should therefore undergo testing with CMV PCR within two weeks of commencing the conditioning regimen and should receive anti-CMV therapy if found to be viremic.

When to start pre-emptive therapy — The decision to start pre-emptive therapy depends most importantly on the patient risk group (underlying immunosuppression and risk of progression to CMV disease). Additional factors include the time after HCT and the assay utilized (PCR or antigenemia). Most centers use PCR assays and this is preferred because of their greater sensitivity, particularly in leukopenic patients. The threshold of positivity has historically been 500 or 1000 copies/mL. However, it should be noted that there are no established cutoff values to definitively diagnose active CMV infection.

One study evaluated a combination of viral load monitoring and patient risk factors (eg, treatment with high-dose glucocorticoids or anti-T cell antibodies) for a risk-adapted approach to trigger pre-emptive therapy [29]. Patients received pre-emptive therapy for a plasma viral load ≥100 copies/mL if receiving ≥1 mg/kg of prednisone or anti-T cell therapies, for a plasma viral load of ≥500 copies/mL, or if a ≥5-fold viral load increase from baseline was detected. Similar rates of CMV disease, toxicity, and non-relapse mortality were observed in patients managed according to this protocol compared with a historical comparison group that was monitored using the CMV antigenemia assay and started for any positive level.

The adoption of an international standard for quantification (World Health Organization [WHO] international units [IU]/mL) has led to a reduction in variability due to different assays used at different centers, but many of the trials were done prior to the adoption of this standard. In one center (the center conducting the study just mentioned), the conversion factor to the WHO standard was 4 copies = 1 IU [30]. (See "Overview of diagnostic tests for cytomegalovirus infection" and "Approach to the diagnosis of cytomegalovirus infection".)

Pre-emptive regimens — For initial (induction) pre-emptive therapy, one of the following agents may be used:

●Ganciclovir 5 mg/kg IV every 12 hours

●Valganciclovir 900 mg orally twice daily is an acceptable alternative for patients who can tolerate oral therapy, especially in patients at low risk for CMV disease and who have low viral loads

●Foscarnet 60 mg/kg IV every 8 hours is an alternative for patients who cannot take ganciclovir or valganciclovir

●Letermovir is a potential alternative that has considerably less toxicity. It has not been studied for this indication in HCT recipients, but, in a phase IIa study in renal transplant recipients, letermovir pre-emptive therapy was found to be promising [31].

●Maribavir is a potential alternative to valganciclovir with similar efficacy but has more gastrointestinal toxicity and less myelosuppression. (See 'Efficacy' below.)

Pre-emptive therapy is continued for a minimum of two weeks with weekly PCR monitoring. If CMV viremia is no longer present within two weeks, treatment can be stopped but continued monitoring is needed, since reactivation frequently recurs and will necessitate another course of pre-emptive therapy. If CMV is still detected at two weeks but is declining, maintenance dosing should be given until CMV is no longer detectable.

Maintenance therapy options include ganciclovir 5 mg/kg IV once a day, valganciclovir 900 mg orally once a day, or foscarnet 60 mg/kg IV once a day. Increases in the CMV viral load during the first couple of weeks of pre-emptive therapy is usually due to host immunodeficiency, especially the use of high-dose glucocorticoids [32], rather than ganciclovir resistance, as noted below. Ganciclovir should be continued at full dose beyond two weeks in patients with an increasing viral load to prevent breakthrough CMV disease. In individuals requiring prolonged antiviral therapy or with prolonged immunodeficiency, testing for ganciclovir resistance and substitution of foscarnet should be considered.

The doses of ganciclovir, valganciclovir, and foscarnet should be adjusted in patients with renal dysfunction.

Ganciclovir and valganciclovir can result in neutropenia; when the absolute neutrophil count (ANC) decreases to <2000 cells/microL, we recommend starting granulocyte colony-stimulating factor (G-CSF) 300 mcg daily and continuing ganciclovir or valganciclovir provided that the ANC stays >1000 cells/microL. Holding other myelosuppressive drugs such as trimethoprim-sulfamethoxazole is also recommended. Ganciclovir or valganciclovir may be restarted when the ANC is >1000 cells/microL for two consecutive days. In patients with persistent neutropenia, we switch to foscarnet.

The pharmacology of ganciclovir, valganciclovir, and foscarnet is discussed separately. (See "Ganciclovir and valganciclovir: An overview" and "Foscarnet: An overview".)

Persistent or rising viremia during pre-emptive therapy — Persistent detection of CMV viral load in patients receiving therapy with ganciclovir or valganciclovir during the first 100 days after HCT is not uncommon (approximately 25 percent of patients have persistent viral load for >5 weeks) and does not necessarily represent resistance to ganciclovir. Similarly, up to 40 percent of patients receiving therapy with ganciclovir, valganciclovir, or foscarnet may have an intermittent rise of viral load for up to three weeks after the start of therapy [32].

The clinical importance of increases in CMV pp65 antigenemia during pre-emptive therapy was evaluated in a report of 119 HCT recipients [32]. A rise in antigenemia two- to fivefold was associated with glucocorticoid administration, most often for GVHD. Increases in antigenemia were not significantly associated with the development of active CMV disease. Although drug resistance in CMV has been reported in HCT patients with CMV disease [33], it does not appear to be as common a problem as in other populations exposed to long durations of ganciclovir therapy.

Management of rising CMV viral load during induction therapy is as follows:

●If viral load rises >2 times baseline after initiation of ganciclovir or valganciclovir, induction dosing should be continued until levels start declining.

●If viral load rises for >3 weeks on continuous induction treatment doses of ganciclovir, valganciclovir, or foscarnet (or if progression to symptomatic CMV disease occurs), resistance due to either host factors (most commonly) or antiviral drug resistance should be considered.

•Ganciclovir resistance should be considered in patients with rising viral load beyond day +100, in patients with a history of ganciclovir therapy prior to HCT, and in patients transplanted for underlying immunodeficiency or who received prolonged immunosuppressive therapy such as antithymocyte globulin, alemtuzumab, or prolonged courses of purine analogs.

•Antiviral therapy should be changed and testing for resistance should be performed. Patients receiving ganciclovir or valganciclovir should be switched to foscarnet. Although resistance to two or three agents does occur, it is rare.

CMV resistance is discussed in greater detail separately. (See "Approach to the diagnosis of cytomegalovirus infection", section on 'Resistance testing'.)

Rising viral load during valganciclovir maintenance therapy may be due to poor adherence and/or drug absorption (severe diarrhea or gastrointestinal GVHD) and should lead to restarting induction doses of IV ganciclovir and close monitoring for CMV disease.

Duration of pre-emptive therapy — For the first episode of viremia, a minimum of two weeks of therapy should be given and therapy can be stopped if CMV is no longer detectable, as noted above (see 'Pre-emptive regimens' above). If the CMV viral load is declining, then maintenance should be continued until virus is no longer detectable. Continued surveillance is needed due to the common occurrence of reactivation needing a repeat course of pre-emptive therapy.

Subsequent episodes of reactivation may require shorter courses depending on the severity of immunosuppression and the presence of dose-limiting drug toxicities.

Efficacy — The efficacy of pre-emptive therapy has been demonstrated in several trials [24-28,34]. As an example, in a trial in which allogeneic HCT recipients who were CMV-seropositive or who had received a CMV-seropositive allograft were screened for CMV excretion by cultures from multiple sites [24], 72 patients who were virus excreters were randomly assigned to receive ganciclovir (5 mg/kg IV twice daily for one week, then once daily for the first 100 days) or placebo. The incidence of CMV disease was markedly reduced (3 versus 43 percent) and overall survival was significantly increased by ganciclovir. The primary adverse effect was neutropenia, which occurred in 30 percent of patients.

Another randomized trial showed that foscarnet (90 mg/kg IV twice daily) was as effective as ganciclovir (5 mg/kg IV twice daily) for pre-emptive therapy of CMV infection in allogeneic HCT recipients [35]. Despite in vitro synergy between ganciclovir and foscarnet, the combination of the two drugs (both at one-half of the usual dose) was not more effective than full-dose ganciclovir [36]. The combination regimen was also associated with more toxicity. The efficacy of cidofovir (5 mg/kg IV once weekly for two weeks) has been less well studied [37], and cidofovir is associated with substantial toxicity, particularly nephrotoxicity.

Valganciclovir is a valyl-ester prodrug of oral ganciclovir that has a bioavailability of nearly 70 percent (compared with 7 percent for oral ganciclovir) and, at doses of 450 to 900 mg, produces serum ganciclovir levels that are similar to those achieved with intravenous ganciclovir administered at 2.5 to 5 mg/kg, respectively [38]. Small studies have suggested that valganciclovir has similar efficacy as IV ganciclovir [39-42], but there is variability in levels, likely associated with differences in enterocyte metabolism of the prodrug.

Because the development of GVHD after HCT can alter the absorption of orally administered drugs, the pharmacokinetic profile of valganciclovir was assessed in the HCT population. A randomized multicenter crossover trial compared the exposure (area under the curve [AUC]) to ganciclovir with administration of valganciclovir (900 mg orally twice daily) or intravenous ganciclovir (5 mg/kg twice daily) as pre-emptive therapy for CMV disease in 48 adults following HCT [43]. The following findings were noted:

●Patients with or without intestinal GVHD who received valganciclovir had a higher exposure to ganciclovir than those who received IV ganciclovir (mean AUC after 12 hours, 53.8 ± 18.0 mcg/mL per hour with valganciclovir versus 39.5 ± 13.9 mcg/mL per hour with IV ganciclovir for patients with no GVHD; 52.9 ± 21.8 mcg/mL per hour with valganciclovir versus 33.1 ± 13.0 mcg/mL per hour with IV ganciclovir for patients with grade I to II intestinal GVHD).

●Absolute bioavailability of ganciclovir after valganciclovir administration was about 75 percent in patients with or without intestinal GVHD.

●No differences in severe ganciclovir-related toxicity were observed between the two groups and efficacy and safety were comparable at 84-day follow-up.

Because of the above findings, many centers have adopted valganciclovir as a substitute for the more costly and inconvenient IV ganciclovir for preemptive therapy.

Maribavir is an orally bioavailable benzimidazole riboside with activity against CMV that blocks egress of viral capsids through inhibition of protein kinase UL97 and that is not myelosuppressive [44]. In a phase II open-label trial, 161 allogeneic HCT recipients or solid organ transplant recipients with CMV reactivation (CMV deoxyribonucleic acid [DNA] of 1000 to 100,000 copies/mL in blood or plasma) were randomly assigned to receive maribavir at 400, 800, or 1200 mg twice daily or the standard dose of valganciclovir for up to 12 weeks as pre-emptive therapy [44]. The percentage of patients who had undetectable CMV DNA in plasma within six weeks was similar (79 percent in the maribavir group and 67 percent in the valganciclovir group; risk ratio 1.2, 95% CI 0.95-1.51). Among HCT recipients, a higher percentage of patients in the maribavir group than in the valganciclovir group had a response to therapy at six weeks (75 versus 48 percent). Two patients receiving maribavir 800 mg twice daily who initially had a response developed recurrence of CMV infection within six weeks of starting therapy; both patients had viruses possessing T409M-resistance mutations in UL97 protein kinase. The incidence of serious adverse effects was higher in the maribavir group than in the valganciclovir group (44 versus 32 percent), with gastrointestinal side effects dominating. Although not US Food and Drug Administration approved for this use, maribavir (400 mg twice daily) has been approved for the treatment of adults and pediatric patients (at least 12 years of age) with post-transplant CMV infection or disease that is refractory to at least one treatment.

Primary prophylaxis

Early postengraftment — Most HCT centers have favored a pre-emptive approach as discussed in the previous section (see 'Pre-emptive therapy' above) rather than a prophylactic approach, but increasingly, centers are giving greater consideration to prophylaxis in patients at high risk for CMV reactivation as noted above.

CMV prophylaxis has been studied using a variety of agents, including ganciclovir, valganciclovir, letermovir, foscarnet, acyclovir, and valacyclovir [34,45-56], as well as the investigational agents, brincidofovir (CMX001) and maribavir [57-59]. Among the available agents, intravenous ganciclovir has been the most effective, but its use is limited by bone marrow toxicity [45,46]. High-dose acyclovir and valacyclovir are less myelosuppressive than ganciclovir and appear to have some efficacy for CMV prophylaxis, but these agents have inferior in vitro activity against CMV than ganciclovir [48-52]. (See 'Efficacy' above.)

Balancing toxicity with efficacy of ganciclovir or valganciclovir prophylaxis, the limited clinical experience with letermovir prophylaxis, and the alternative of ganciclovir or valganciclovir given pre-emptively, CMV prophylaxis is best reserved for allogeneic HCT patients at high risk for CMV reactivation and/or disease, such as CMV-seropositive recipients (CMV R+) or seronegative recipients who receive a graft from seropositive donor (CMV D+/R-) who received a T cell–depleted allograft, an HLA-mismatched allograft, an umbilical cord blood allograft [60], alemtuzumab [61], or post-transplant cyclophosphamide [18]. In such high-risk patients, strategies to prevent disease include increased frequency of polymerase chain reaction (PCR) monitoring (eg, twice weekly) as part of a pre-emptive approach and/or administration of prophylaxis targeted toward CMV.

There is no consensus on the most appropriate approach, and the decision of whether to give prophylactic or pre-emptive therapy should be made on a case-by-case basis, taking into account the risk profile of each patient, with the best case for benefit in high-risk patients.

For centers that use CMV prophylaxis in high-risk patients, we would favor letermovir over other agents. Letermovir (480 mg orally or IV once daily or, in patients taking cyclosporine, 240 mg once daily) should be initiated after HCT and continued through week 14. Letermovir is active against CMV but does not have activity against HSV or VZV; thus, clinicians will need to provide prophylaxis against these viruses when indicated.

An alternative regimen for high-risk patients is ganciclovir from day -8 to day -2, followed by high-dose valacyclovir (2 g orally three times daily) with twice-weekly PCR monitoring starting at the time of HCT and continuing until engraftment or longer in patients on glucocorticoids. We do not use acyclovir for CMV prophylaxis.

The data to support various regimens include the following:

●Letermovir – Letermovir is an anti-CMV agent with a novel mechanism of action; it inhibits the viral terminase subunit pUL56, a component of the terminase complex involved in DNA cleavage and packaging that has no equivalent target enzyme in the human body [53]. Letermovir was approved by the US Food and Drug Administration and Health Canada in November 2017 for CMV prophylaxis in adult CMV-seropositive (CMV R+) allogeneic HCT recipients [62,63]. The usual dose of letermovir is 480 mg IV or orally once daily through 100 days following HCT. Potential use after this period is discussed elsewhere. (See 'Late postengraftment' below.)

In a multicenter phase II trial that included 131 CMV-seropositive allogeneic HCT recipients, patients were randomly assigned to one of three oral doses of letermovir (60, 120, or 240 mg) or placebo once daily for 12 weeks following engraftment [53]. The reduction in incidence of all-cause prophylaxis failure was dose dependent. All-cause prophylaxis failure was defined as discontinuation of the study drug because of virologic failure or for any other reason (eg, an adverse event, nonadherence, or withdrawal of consent). The incidence of all-cause prophylaxis failure was 29 percent with 240 mg of letermovir, 32 percent with 120 mg of letermovir, 48 percent with 60 mg of letermovir, and 64 percent with placebo; the difference between letermovir and placebo was statistically significant for the 240 and 120 mg doses but not for the 60 mg dose. UL56 genotyping was performed on the blood of 12 patients enrolled in the trial who had virologic failure; a letermovir-resistance mutation, UL56 V236M, was identified in the blood of one patient who received 60 mg of letermovir [54]. This mutation likely arose by mutation of a replicating wild-type virus at a suboptimal letermovir dose.

In a multicenter phase III trial, 495 CMV-seropositive allogeneic HCT recipients with undetectable CMV viral loads received letermovir 480 mg daily (or 240 mg daily if receiving cyclosporine given drug-drug interaction) for CMV prophylaxis or placebo beginning within the first 28 days after HCT and continuing through week 14 [64]. By 24 weeks following HCT, fewer patients receiving letermovir developed clinically significant CMV (defined as CMV disease or CMV viremia leading to pre-emptive therapy) compared with those who received placebo (37.5 versus 60.6 percent). Among those who developed clinically significant CMV infection, most had CMV viremia rather than CMV disease. CMV viremia resulting in pre-emptive therapy occurred in 52 of 325 patients receiving letermovir (16.0 percent) and 68 of 170 patients receiving placebo (40.0 percent). CMV disease occurred in 5 of 325 patients receiving letermovir (1.5 percent) and 3 of 170 patients receiving placebo (1.8 percent) and involved the gastrointestinal tract in all patients. One patient had breakthrough CMV viremia during letermovir treatment; CMV genotyping revealed that the CMV isolate had the letermovir-resistance mutation, UL56 V236M. Among patients who had received letermovir, the incidence of clinically significant CMV infection after prophylaxis increased beginning around week 18, a finding that reflected ongoing or new periods of CMV risk mostly as a result of GVHD and glucocorticoid use. In a subsequent post hoc analysis of 50 patients who developed clinically significant CMV infection in the letermovir group and had genotyping data available, three were found to have UL56 gene mutations [65].

All-cause mortality at week 24 following HCT was lower in letermovir recipients compared with placebo recipients (10.2 versus 15.9 percent), a difference that was statistically significant [64]. All-cause mortality at week 48 following HCT was lower in letermovir recipients (20.9 versus 25.5 percent), but this difference was not statistically significant. There was no statistically significant mortality difference in either the high-risk or the low-risk subgroup at week 48. The prevention of clinically significant CMV infection by letermovir was consistent in high-risk and low-risk patients, but the lower mortality in letermovir recipients was more pronounced in high-risk patients than low-risk patients. High-risk patients were defined as those having a related donor with at least one mismatch at one of the specified three HLA gene loci (HLA A, B, or DR), having an unrelated donor at one of the specified four HLA gene loci (HLA A, B, C, or DRB1), having a haploidentical donor, receiving umbilical cord blood as the stem cell source, receiving a T cell-depleted allograft, or having GVHD of grade ≥2 that led to the use of prednisone (or its equivalent) at a dose of ≥1 mg/kg per day.

In a post-hoc analysis performed to further investigate the effects of letermovir on all-cause mortality, the incidence of all-cause mortality at week 48 in the letermovir group was similar in patients with or without clinically significant CMV infection (15.8 versus 19.4 percent) [66]. In contrast, in the placebo group, all-cause mortality at week 48 was higher in patients with versus those without clinically significant CMV infection (31 versus 18.2 percent) despite the use of pre-emptive therapy for CMV infection. The hazard ratio for all-cause mortality in patients with clinically significant CMV infection at week 48 for letermovir versus placebo was 0.45 (95% CI 0.21-1.00). These results suggest that there may be a benefit to avoiding clinically significant CMV infection and potentially toxic antivirals such as ganciclovir.

In the phase III trial, time to engraftment was similar in those who received letermovir or placebo [64]. Letermovir was associated with a modestly higher incidence of vomiting (18.5 versus 13.5 percent) and edema (14.5 versus 9.4 percent) than placebo. Acute kidney injury occurred in 9.7 percent of letermovir recipients and 13.0 percent of placebo recipients. Atrial fibrillation or flutter was reported in 4.6 percent of patients receiving letermovir compared with 1.0 percent of patients receiving placebo, but further analysis did not show a relationship with letermovir exposure.

A subsequent study has suggested that the detection of CMV DNA in blood in patients receiving letermovir prophylaxis may indicate abortive viral infection, rather than active viral replication [67].

In a single-center retrospective study of 333 allogeneic HCTs (with CMV seropositive donors or recipients) found fewer clinically significant CMV infections and CMV-related deaths were reported up to day 90 post-HCT with letermovir use than without letermovir use [68]. However, more CMV infections and CMV-related deaths between day 90 and 364, abrogated the one-year survival benefit. Patients with serum IgG levels <400 mg/dL at day 100 were particularly susceptible to later CMV infection. This finding suggests that letermovir early after transplant may be associated with a delay in reconstitution of immune protection. A similar concern was noted in an earlier study of CMV cellular immunity in patients receiving letermovir [69]. Whether or not this concern will be overcome by extending the duration of letermovir prophylaxis to 200 days is the subject of investigation.

There are several considerations that should be kept in mind. Letermovir appears to avoid the myelosuppressive effects and other toxicities of ganciclovir, a significant advantage. Letermovir has important interactions with commonly used immunosuppressive drugs due to effects on cytochrome P4503A and organic anion transporters. Letermovir increases cyclosporine, tacrolimus, and sirolimus exposure, and the levels of these drugs should be monitored and the dose reduced as needed [70]. Letermovir decreases exposure to voriconazole, likely via induction of CYP2C9/19, but it does not appear to alter exposure to posaconazole [71]. Additionally, there are interactions with drugs that are inhibitors of organic transporters, including some anti-cancer drugs, particularly tyrosine kinase inhibitors, which may be used after HCT in some patients. There are many other drug interactions described in the package insert and likely even more will be identified with more study (and use) of this drug over time. These pharmacologic attributes are important to consider for the safe use of this drug.

There are several other important caveats. Letermovir is active against CMV but does not have activity against other herpesviruses, including HSV and VZV. Thus, clinicians will need to provide prophylaxis against these viruses when indicated. The letermovir prophylaxis trial used a lower threshold of CMV DNAemia (>150 copies/mL for high-risk patients and >300 copies/mL for low-risk patients through week 14 after HCT; >300 copies/mL for all patients thereafter) than most centers use [64]. The results for CMV DNAemia were reported in copies/mL; 1 international unit/mL in the assay used corresponded to 1.1 copies/mL. There was no difference in CMV disease between the two groups. While mortality was higher at 24 weeks in the placebo group, the mortality at 48 weeks was not significantly different. The study's definition of high-risk versus low-risk patients has been debated. For example, it is not clear why ATG use was not deemed to confer high risk for CMV disease. However, letermovir appeared to have an antiviral benefit in both patients given ATG and in haploidentical transplant patients (although using different pre-emptive trigger thresholds). Given these considerations, a clear recommendation is difficult to make as to the merits of letermovir prophylaxis versus pre-emptive therapy in standard-risk patients, while the case for benefit in high-risk patients is stronger. As noted above, for centers that use CMV prophylaxis in high-risk patients, we would favor letermovir for safety reasons over ganciclovir or foscarnet.

●Ganciclovir followed by high-dose valacyclovir – In one study, high-risk (CMV R+) umbilical cord blood transplant recipients were found to have lower rates of CMV reactivation and disease with a hybrid approach that included administration of IV ganciclovir before HCT (5 mg/kg IV daily from day -8 to day -2), high-dose acyclovir (2 g IV three times daily) or valacyclovir (1 g orally three times daily) once oral administration was feasible after HCT, and twice weekly monitoring with serum CMV PCR [60]. At day 100, patients then received valganciclovir 900 mg once daily for one year. The patients treated with this approach were compared with historical controls who received HSV and VZV prophylaxis with acyclovir 800 mg orally twice daily or valacyclovir 500 mg orally twice daily (and, during periods of mucositis, acyclovir 250 mg/m² IV every 12 hours, adjusted for renal insufficiency) and anti-CMV pre-emptive therapy was initiated if CMV reactivation was detected. For patients at lower risk, we prefer screening to detect CMV viremia and initiating pre-emptive therapy for patients in whom virus is detected in blood samples. (See 'Pre-emptive therapy' above.)

●Acyclovir or valacyclovir – High-dose acyclovir was shown to reduce CMV infection and disease and improve survival in allogeneic HCT recipients [49,50] compared with low-dose short-course acyclovir. Valacyclovir, which has greater bioavailability than acyclovir, was compared with acyclovir given until week 18 after transplant and found to be associated with a lower rate of viremia with similar rate of survival to acyclovir in CMV R+ or D+ allogeneic HCT recipients; low rates of CMV disease were achieved (with ganciclovir added as pre-emptive therapy in patients who became viremic) [52].

●Ganciclovir – Intravenous ganciclovir, which has substantially greater anti-CMV activity than acyclovir or valacyclovir, has been shown to be associated with a substantial reduction in both infection and disease (almost complete absence of disease), but IV ganciclovir did not improve survival in these trials because it was associated with neutropenia and secondary bacterial and fungal infections [25,45,46]. There was no difference in the risk of CMV disease at day 180 or survival between ganciclovir prophylaxis and ganciclovir given as pre-emptive therapy, although there was less CMV disease before day 100 [25]. It is important to note that although survival improvement in individual ganciclovir trials was not seen, the trials were underpowered to detect survival differences. However, in an observational study, patients who received prophylactic ganciclovir had a survival benefit compared with patients who did not receive either antiviral prophylaxis or pre-emptive therapy [23].

The following investigational agents have been evaluated for CMV prophylaxis:

●Brincidofovir (CMX001) – Brincidofovir is an investigational orally bioavailable lipid acyclic nucleoside phosphonate that is converted intracellularly to cidofovir; unlike cidofovir, brincidofovir is not concentrated in the renal proximal tubules and is therefore not nephrotoxic [57]. Brincidofovir is approximately 400 times more potent than cidofovir in vitro against CMV, including ganciclovir-resistant strains. In a randomized phase II trial, CMV-seropositive allogeneic HCT recipients were randomly assigned to receive brincidofovir at several dose schedules or until week 13 posttransplant [57]. Among patients who received brincidofovir at a dose of 100 mg twice weekly, the incidence of CMV events (defined as CMV disease or a CMV DNAemia) was significantly lower compared with patients who received placebo.

In a phase III trial in which allogeneic HCT recipients were randomly assigned to receive brincidofovir 100 mg orally twice weekly or placebo for 14 weeks following transplant, the proportion of patients with clinically significant CMV infection (the primary endpoint of the trial) or who were imputed as having a primary endpoint event through week 24 following transplant was similar in the brincidofovir and placebo groups (51 versus 52 percent) [72]. Fewer brincidofovir recipients developed CMV viremia through week 14 compared with placebo recipients, but the difference was not statistically significant when imputed events were considered. Serious adverse events were more common among brincidofovir than placebo recipients (57 versus 38 percent), a difference that was driven by acute GVHD (32 versus 6 percent) and diarrhea (7 versus 3 percent). Of note, there is a possibility that brincidofovir may have caused histopathologic changes indistinguishable from GVHD, which could account for these observations. There was a trend toward higher mortality in the brincidofovir group. The future clinical development of this agent for CMV is uncertain at this time.

●Maribavir – Although a phase II trial of the orally bioavailable DNA synthesis inhibitor showed promise for CMV prevention [58], a phase III trial did not confirm a benefit, perhaps due to a suboptimal dosing schedule [59]. Data regarding the use of maribavir for pre-emptive therapy are discussed above. (See 'Efficacy' above.)

Late postengraftment — With effective prophylaxis and pre-emptive approaches employed during the early postengraftment period, most cases of CMV disease now occur during the late postengraftment period (between days 100 and 270) [73]. Data suggest that routine prophylaxis during the late postengraftment period is not warranted; however, in high-risk patients, CMV PCR monitoring is prudent with initiation of pre-emptive therapy if it becomes positive. (See 'Pre-emptive therapy' above.)

In a multicenter double-blind randomized trial, allogeneic HCT recipients at high risk for late CMV disease were randomly assigned to receive six months of valganciclovir (900 mg orally once daily) or placebo [34]. Patients could be enrolled if they were seropositive for CMV before HCT or if they had a seropositive donor. Seropositive recipients had to have either CMV infection with appropriate treatment course before random assignment; a history of graft-versus-host disease after transplantation requiring treatment with systemic glucocorticoids at doses >0.5 mg/kg; chronic extensive GVHD requiring treatment with glucocorticoids; or receipt of ganciclovir, valganciclovir, foscarnet, or cidofovir prophylaxis between engraftment and randomization. Seronegative recipients with seropositive donors had to have a CMV infection with appropriate treatment course before randomization. Valganciclovir prophylaxis recipients were enrolled a median of 97 days after HCT and placebo-pre-emptive therapy recipients were enrolled a median of 98 days after HCT. Plasma CMV PCR was monitored weekly, and the study drug was withdrawn when CMV viral load was >1000 copies/mL or >5 times the baseline value, and pre-emptive therapy was started with intravenous ganciclovir (5 mg/kg IV twice daily) or valganciclovir (900 mg orally twice daily); in neutropenic patients, foscarnet (90 mg/kg twice daily) was used instead. The primary composite endpoint (death, CMV disease, or other invasive bacterial or fungal infections by 270 days after HCT) occurred in 20 percent of valganciclovir recipients versus 21 percent of placebo-pre-emptive therapy recipients. There was no difference in the primary endpoint or its components 640 days after HCT. The incidence of CMV DNAemia ≥1000 copies/mL or a fivefold increase over baseline was reduced in the valganciclovir group (11 versus 36 percent). Severe neutropenia (absolute neutrophil count <0.5 × 10⁹ cells/L) was not significantly different in the two groups; however, more patients received hematopoietic growth factors in the valganciclovir prophylaxis group than in the placebo-pre-emptive therapy group (25 versus 12 percent).

In the United States, the Food and Drug Administration (FDA) updated the approval of letermovir for primary CMV prophylaxis to allow continuation through 200 days after HCT for patients at high risk for late CMV infection and disease [74]. This update was based on an unpublished trial that included 218 patients who had received letermovir for 14 weeks post HCT; those who were randomly assigned to continue letermovir until week 28 had fewer clinically significant CMV infections (end organ disease or need to initiate pre-emptive therapy) between week 14 and week 28 compared with those who received placebo (1.4 versus 17.6 percent). However, after discontinuation of letermovir at week 28, those patients had a higher increase in the rate of clinically significant CMV infection by 38 weeks than the placebo group (increase to 15.6 versus 19.0 percent). Thus, the longer duration of letermovir prophylaxis resulted in delayed onset of infection and only a modest reduction in infection rate.

Secondary prophylaxis — Patients with a history of CMV disease (eg, pneumonitis, gastrointestinal disease, retinitis) during the six months preceding HCT are at very high risk for reactivation (and death) after HCT [75], and transplant should be delayed until control of the disease is achieved with antiviral therapy; such patients should be given secondary prophylaxis once treatment has been completed. For secondary prophylaxis, we suggest a course of ganciclovir just before HCT, followed by either valacyclovir (2 g orally three times daily) or IV foscarnet (60 mg/kg every 12 hours in those with normal renal function) throughout the pre-engraftment period. We avoid ganciclovir and valganciclovir in this setting because of their bone marrow toxicity. After engraftment, we monitor with weekly CMV PCR testing. Another alternative is letermovir prophylaxis in such situations, although the drug has not yet been well studied for secondary prophylaxis. One trial suggested that it may have utility as secondary prophylaxis but was studied in only a small number of patients [76].

Holding acyclovir prophylaxis — Acyclovir prophylaxis should be held during therapy for CMV with ganciclovir, foscarnet, or cidofovir because these agents are also active against HSV and VZV. Acyclovir prophylaxis should be resumed when therapy with one of these agents is stopped. (See 'Herpes simplex virus' above and 'Varicella-zoster virus' above.)

Although letermovir is active against CMV, it does not have activity against other herpesviruses, including HSV and VZV. (See 'Early postengraftment' above.)

CMV vaccine development — There are currently no approved cytomegalovirus (CMV) vaccines, but several are being developed in an attempt to bolster host immune responses and prevent CMV viremia. ASP0113 (Transvax) is a plasmid CMV DNA vaccine that was found to be associated with reduced viremia rates and decreased duration of viremia and fewer recurrences of viremia in a double-blind, placebo-controlled phase II trial [77]. However, a phase III trial demonstrated improved T cell response to the CMV pp65 antigen but did not demonstrate a reduction in CMV end-organ disease or improved survival at one year [78]. Another promising vaccine, the Triplex vaccine, is a recombinant modified vaccinia Ankara vaccine encoding three immunodominant CMV antigens undergoing trials [79,80]. It has been shown to enhance reconstitution of adaptive NK and CMV-specific T cells after autologous HCT in patients with lymphoma and myeloma. However, the clinical impact of these on infection after allogeneic HCT remains to be seen. In early clinical testing, another vaccine, CMVPepVax, is a composite of pp65 fused with the P2 epitope of tetanus toxin combined with a TLR9 agonist and shows promise in seropositive allogeneic HCT recipients [81]. A randomized phase 2 trial in 61 eligible allogeneic HCT patients showed the vaccine to be safe but there was no difference in CMV viremia through 100 days [82]. CSJ148 is a combination of two human anti-CMV IgG1 monoclonal antibodies being evaluated in trials [83]. In a randomized phase 2 trial in allogeneic HCT recipients, there were favorable trends in reduced viral load and duration of preemptive therapy, but the primary efficacy endpoint was not met in reducing the need for pre-emptive therapy [84].

Epstein-Barr virus — EBV reactivation usually results from endogenous reactivation or transmission from the allograft and may be asymptomatic, cause a mononucleosis syndrome, or progress to a life-threatening EBV-related post-transplantation lymphoproliferative disorder (PTLD). (See "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders" and "Treatment and prevention of post-transplant lymphoproliferative disorders" and "Overview of infections following hematopoietic cell transplantation".)

Monitoring frequency should be based on the risk of PTLD. The rate of EBV-related PTLD is highly variable and depends upon several factors, including the GVHD prophylaxis approach used (low with post-transplant cyclophosphamide; high with regimens that involve T cell depletion) and the type of graft (higher with cord blood than other types of allografts) [85]. Patients at high risk for EBV reactivation, especially children who received anti-T cell antibodies or an umbilical cord blood or T cell-depleted graft, should undergo weekly monitoring of EBV DNA by quantitative PCR in whole blood starting on the day of transplantation; monitoring should generally be continued for three months but should continue for a longer period in those who had early EBV reactivation and those receiving treatment for GVHD [86,87].

Serial monitoring is predicated on the observation that EBV viral loads often rise as early as three weeks prior to onset of EBV disease. Threshold values of EBV DNA depend upon the method used and the experience of the individual center, although many centers consider a level ≥100 genome equivalents/mL in whole blood or plasma to be significant, but the risk for PTLD is generally in patients with viral loads of >1000 genome equivalents. [86,88]. In addition to viral load monitoring, patients should be closely monitored for symptoms and/or signs attributable to EBV and PTLD.

Although acyclovir and ganciclovir inhibit EBV replication in vitro, these drugs are ineffective for preventing and treating PTLD and are therefore not recommended [1,86]. Strategies that are used to prevent the development of PTLD in HCT recipients with EBV reactivation include reduction of immunosuppression, administration of the anti-CD20 monoclonal antibody (rituximab), and administration of EBV-specific cytotoxic T cells. This is discussed in detail separately. (See "Treatment and prevention of post-transplant lymphoproliferative disorders", section on 'Prevention'.)

Human herpesvirus 6 — HHV-6 reactivation is most frequent within the first month following HCT, although it is typically not associated with disease manifestations (<1 percent). The most significant manifestation of HHV-6 is encephalitis, which results from reactivation in the central nervous system. Reactivation of HHV-6 has also been associated with bone marrow suppression and delayed platelet engraftment, rashes, pneumonia, and hepatitis. Prophylaxis against HHV-6 is not recommended because of the low risk of HHV-6 disease, the toxicity of the available antiviral drugs (ganciclovir, foscarnet, and cidofovir), and their variable in vitro activity against HHV-6. (See "Human herpesvirus 6 infection in hematopoietic cell transplant recipients".)

RESPIRATORY VIRUSES

Influenza

Immunization — Influenza vaccination remains the primary method for preventing influenza. The inactivated vaccine should be used in HCT recipients, and it should be given annually lifelong. The optimal inactivated vaccine type, dose, and dose schedule has not been established. Generally, immunization should be done during influenza season beginning six months following transplantation or beginning four months following transplantation if there is a community influenza outbreak (table 3) [89]. Early immunization may not result in protective responses in all patients or may provide only partial protection, but it is not harmful. Several strategies to optimize vaccine effectiveness have been explored ins small trials. A randomized trial of the Fluzone MT2010-08R influenza vaccine given as one dose versus two doses did not show improved serologic response rates with a second dose [90]. A small trial comparing standard-dose versus high-dose trivalent Fluzone vaccines found a higher percentage of patients achieved targeted antibody titers with the high-dose vaccine [91]. Preallogeneic transplant seasonal influenza vaccination of donors and recipients followed by revaccination within six months post-transplant may provide primed memory B cells to the recipient and a reduced risk for influenza infection [92]. In addition, vaccination of the close contacts of HCT recipients and of healthcare workers involved in their care is strongly recommended [93]. (See "Seasonal influenza vaccination in adults" and "Immunizations in hematopoietic cell transplant candidates and recipients".)

Chemoprophylaxis — Although vaccination remains the cornerstone of protection against influenza virus, pre-exposure or postexposure antiviral prophylaxis of HCT recipients is sometimes used, especially during local influenza outbreaks and with circulation of strains not included in the vaccine. The decision of whom to offer chemoprophylaxis should be made on a case-by-case basis and should be based on the nature of the exposure, the exposed patient's risk of developing complications from influenza, the ability to promptly administer antiviral therapy if symptoms develop, advice from public health authorities, and clinical judgment [94].

It is reasonable to offer pre-exposure prophylaxis to HCT recipients for whom the influenza vaccine is contraindicated, unavailable, or unlikely to be protective because of poor immune function (eg, in the first six months following HCT or in patients with graft-versus-host disease [GVHD]). Our definition of which patients are unlikely to be protected by the vaccine is slightly different from the related definition in the Infectious Diseases Society of America (IDSA) influenza guidelines; the guidelines state that pre-exposure prophylaxis can be considered in HCT recipients within the first 6 to 12 months following HCT, but we consider patients in the first six months following HCT and those with GVHD to be at highest risk [94]. Pre-exposure prophylaxis should be started as soon as influenza activity is detected in the community and continued for the duration of community influenza activity.

We consider prophylaxis for patients admitted to an inpatient unit in which multiple cases of influenza are occurring concurrently and for vulnerable patients presenting to a clinic where multiple patients with influenza infection are being seen. Chemoprophylaxis in this setting should be administered for a minimum of two weeks and continue for at least seven days after the last known case was identified [94].

We consider postexposure prophylaxis for HCT recipients for whom influenza vaccination is contraindicated, unavailable, or unlikely to be protective (in the first six months following HCT or in patients with GVHD) after household exposure to influenza [94]. We also consider postexposure prophylaxis (in conjunction with influenza vaccination) to unvaccinated household contacts of HCT recipients after household exposure to influenza. Postexposure prophylaxis should be started as soon as possible following exposure and no later than 48 hours after exposure. It should be continued for seven days after the most recent exposure to a close contact with influenza.

An alternative to postexposure prophylaxis is to educate patients and arrange for early empiric initiation of antiviral therapy [94].

Three classes of antiviral drugs are available for the prevention and/or treatment of influenza virus infections. The neuraminidase inhibitors, zanamivir and oseltamivir, are active against both influenza A and B, whereas the adamantanes, amantadine and rimantadine, are only active against influenza A. Because of high rates of resistance, particularly among influenza A (H3N2) subtype, and toxicity concerns, the adamantanes are generally not used for the prophylaxis of influenza infections [95-97].

Oseltamivir is safe and, although no prospective trials have been conducted in HCT recipients, it is likely to be effective at preventing influenza infections [98,99]. For chemoprophylaxis, oseltamivir is given at a dose of 75 mg orally once daily.

Baloxavir marboxil is a novel oral antiviral agent that blocks influenza A and B proliferation by inhibiting the initiation of messenger ribonucleic acid (mRNA) synthesis. It has been approved for the treatment of uncomplicated influenza but not for prophylaxis. Insufficient data are available to make recommendations for its use for prophylaxis in HCT recipients. However, of note, baloxavir has been shown to provide effective postexposure prophylactic efficacy in household contacts of patients with influenza [100]; thus, it could be useful for close contacts of patients. (See "Seasonal influenza in adults: Role of antiviral prophylaxis for prevention".)

Because of resistance of certain influenza subtypes to the adamantanes and to oseltamivir, knowledge of the local epidemiology of influenza viruses by type and subtype is critical when selecting influenza antiviral chemoprophylaxis, and important updates can be found on the United States Centers for Disease Control and Prevention website.

Pre-exposure and postexposure antiviral prophylaxis for influenza virus are discussed in greater detail separately. (See "Seasonal influenza in adults: Role of antiviral prophylaxis for prevention".)

Respiratory syncytial virus — Some clinicians recommend pre-emptive aerosolized ribavirin (aerosolized, oral, or intravenous) or respiratory syncytial virus (RSV) polyclonal or monoclonal antibody or combinations for patients with upper tract respiratory syncytial virus infection, especially those with lymphopenia (first three months after HCT) who are at high risk for progression to lower tract infection [101-104]. However, this requires additional study. (See "Respiratory syncytial virus infection: Treatment in infants and children" and "Respiratory syncytial virus infection: Prevention in infants and children", section on 'Immunoprophylaxis'.)

In a phase 2B randomized trial evaluating HCT recipients with RSV lower respiratory tract infection, presatovir (an investigational RSV fusion inhibitor) did not improve outcomes, including supplemental oxygen-free days, respiratory failure rates, or mortality, when compared with placebo [105]. No change in nasal RSV load was detected; resistance-associated substitutions in RSV fusion protein emerged in 21 percent of presatovir-treated patients but none in placebo recipients. Whether presatovir could be used as pre-emptive therapy is an open question. Similarly, a phase 2 trial of presatovir for the treatment of RSV upper respiratory tract infection in HCT recipients did not decrease viral load or progression to lower tract infection by day 9 but did reduce progression to lower tract disease by day 28 in a post-hoc analysis [106].

Ziresovir is a RSV fusion protein inhibitor in development [107].

Vaccines against RSV are in development and appear to have promise but none are clinically available [108].

Parainfluenza — Although candidate antiviral agents are in development, there are insufficient data about their safety and efficacy. (See "Parainfluenza viruses in adults", section on 'Treatment'.)

Adenovirus — There are insufficient data regarding the safety and efficacy of antiviral agents with activity against adenovirus. (See "Diagnosis, treatment, and prevention of adenovirus infection".)

Infection control — The following infection control precautions should be implemented to prevent transmission of respiratory viruses:

●Strict hand hygiene. (See "Prevention of infections in hematopoietic cell transplant recipients", section on 'Infection control measures'.)

●When an infection with a respiratory virus is suspected, patients should be placed on contact plus droplet precautions until a pathogen has been identified [1]. Pathogen-specific precautions include:

•Respiratory syncytial virus and parainfluenza virus – Contact precautions

•Influenza – Droplet precautions

•Adenovirus – Contact plus droplet precautions

•SARS-CoV-2 – Contact, droplet, and airborne precautions

●We favor the use of gloves and fitted surgical masks for health care workers and visitors of HCT recipients during respiratory virus outbreaks and during respiratory virus season in an attempt to reduce the risk of transmission of respiratory viruses to HCT recipients; some centers use gloves and masks year-round [109].

●Patients should wear masks when they are transported out of their room.

●Restricting access of HCT recipients to healthcare personnel and family members who have signs and symptoms of respiratory tract infection and avoidance of direct patient contact with small children during the respiratory viral season.

●Physical distancing from persons suspected of having a community-acquired respiratory virus infection should be observed whenever possible.

●Delay of HCT in patients with symptoms of upper or lower respiratory tract infection until signs and symptoms have resolved if possible.

Of note, viral shedding with most respiratory viruses may persist for a long period of time in HCT recipients, and prolonged outbreaks of respiratory syncytial virus and parainfluenza viruses have been reported from centers that practice surveillance and isolation policies [110-118].

Infection control measures for HCT recipients and a discussion of general principles of infection control are presented in greater detail separately. (See "Prevention of infections in hematopoietic cell transplant recipients", section on 'Infection control measures' and "Infection prevention: Precautions for preventing transmission of infection".)

SARS-CoV-2 — Prevention of transmission of SARS-CoV-2, the virus that causes coronavirus disease 2019, is discussed separately. (See "COVID-19: Epidemiology, virology, and prevention" and "COVID-19: Vaccines" and "COVID-19: Considerations in patients with cancer".)

HEPATITIS VIRUSES

Hepatitis B virus — Hepatitis B virus (HBV) reactivation and transmission can result in severe hepatitis following HCT; all HCT candidates and donors should undergo testing for HBV, including HBV surface antigen (HBsAg), antibodies to HBV surface antigen (HBsAb), and antibodies to HBV core antigen (HBcAb) [1]. All HBcAb-positive and HBsAg-positive HCT donors and recipients should also undergo HBV DNA (viral load) testing. (See "Hepatitis B virus: Screening and diagnosis in adults" and "Evaluation for infection before hematopoietic cell transplantation", section on 'Pathogen-specific testing'.)

General concepts regarding the approach to HBV in HCT recipients include the following [1]:

●In HCT recipients, risk factors for HBV reactivation and exacerbation of HBV replication include high-dose glucocorticoids, fludarabine/rituximab, alemtuzumab, and bortezomib.

●HBV infection can be transmitted from HBsAg-positive donors to HBsAg-negative recipients, with severe clinical consequences when the recipient is HBV-naïve (ie, HBsAg-negative, HBsAb-negative, and HBcAb-negative) [119]. Use of HBsAg-positive and/or HBV viral load positive donors for HBV-naïve recipients should be avoided if a suitable donor without hepatitis B is available. HBV vaccination is especially important in HCT candidates who will be receiving an allograft from an HBsAg-positive donor.

●HBV-infected recipients – The approach to monitoring and treating HBV-infected HCT recipients depends in part on the patient's serologic status and on whether HBV viremia is present [1]:

•HBsAg-positive or DNA positive – When planning to transplant an HBV-infected patient (HBsAg-positive and/or detectable HBV viral load), the recipient should undergo noninvasive serologic and radiographic testing for fibrosis (eg, FibroSure test and ultrasound-based elastography) because the presence of chronic liver disease can increase transplant-related morbidity and mortality. (See "Noninvasive assessment of hepatic fibrosis: Overview of serologic tests and imaging examinations" and "Noninvasive assessment of hepatic fibrosis: Ultrasound-based elastography".)

For HBsAg-positive HCT candidates, because HBsAg clearance can be induced by adoptive transfer of a donor's natural immunity, equally suitable donors with natural immunity (HBsAb-positive and HBcAb-positive) are preferred over donors without natural immunity [120-122].

HCT recipients at substantial risk of an HBV flare (HBsAg-positive or DNA positive) should receive an antiviral agent [1,123-125], which should be continued for at least six months after autologous HCT and until six months after cessation of immunosuppression in allogeneic HCT recipients [1,126]. Because HBV is less likely to develop resistance against the newer antiviral agents (eg, entecavir, tenofovir) than against lamivudine and because those receiving a newer agent are less likely to develop HBV-related hepatitis or HBV reactivation [127,128], we favor the newer agents rather than lamivudine; using a newer agent is particularly important in patients with detectable HBV DNA or when prolonged therapy is needed, such as among patients receiving immunosuppressive therapy for graft-versus-host disease (GVHD) [129]. The usual dosing of entecavir is 0.5 mg orally once daily (1 mg once daily for those with lamivudine-refractory disease or lamivudine-resistant isolates) and the dosing of tenofovir is 300 mg orally once daily. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy" and "Entecavir in the treatment of chronic hepatitis B virus infection" and "Tenofovir and adefovir for the treatment of chronic HBV infection" and "Hepatitis B virus: Overview of management".)

•HBcAb-positive, HBsAg-negative, and HBsAb-negative – HCT candidates who are HBcAb-positive but HBsAg-negative and HBsAb-negative should be tested for HBV DNA, and entecavir or tenofovir should be given to those who have viremia. Those who do not have viremia should be vaccinated against hepatitis B. Some providers also give antiviral prophylaxis with lamivudine (100 mg orally daily), entecavir, or tenofovir to these patients; we favor this approach.

•HBcAb-positive and HBsAb-positive – If the HCT recipient is HBcAb-positive and HBsAb-positive (and DNA negative), the risk of reactivation is low during chemotherapy/conditioning but higher following prolonged treatment with glucocorticoids for GVHD. The recipient should be monitored after HCT with monthly serum alanine transaminase (ALT) measurements and, if an increase is seen, testing of DNA levels should be performed. HBsAb levels should be checked every three months; reduction in titers should prompt HBV DNA testing. Pre-emptive therapy with one of the newer anti-HBV agents (eg, entecavir, tenofovir) should be instituted if HBV DNA becomes detectable. A reasonable alternative is to give HBV prophylaxis with lamivudine 100 mg daily to patients who are HBcAb-positive and HBsAb-positive, especially those receiving treatment for GVHD.

●HBV-infected donors

•To minimize the risk of HBV transmission from a HBsAg-positive donor, HBV viral load testing should be performed, and, if the donor has a detectable viral load, the donor should be started as early as possible on anti-HBV therapy in an attempt to rapidly reduce the donor's serum HBV DNA as low as possible, preferably to undetectable levels, prior to HCT harvest [1,130,131]. The recipient should also be immunized with the hepatitis B vaccine.

Hepatitis B vaccination in HCT recipients is discussed separately. (See "Immunizations in hematopoietic cell transplant candidates and recipients", section on 'Hepatitis B'.)

•HCT recipients of allografts from donors who are DNA positive (or cells that are DNA positive) should be given hepatitis B immune globulin (HBIG) immediately following the graft infusion and again one month later. Such individuals should also receive an antiviral agent [1,123-125], which should be continued for at least six months after autologous HCT and until six months after cessation of immunosuppression in allogeneic HCT recipients [1,126]. Because HBV is less likely to develop resistance against the newer antiviral agents (eg, entecavir, tenofovir) than against lamivudine, we favor the newer agents, especially when prolonged therapy is needed, such as among patients receiving immunosuppressive therapy for GVHD [129]. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy" and "Entecavir in the treatment of chronic hepatitis B virus infection" and "Tenofovir and adefovir for the treatment of chronic HBV infection" and "Hepatitis B virus: Overview of management".)

Detailed recommendations for managing hepatitis B in HCT recipients are discussed in the 2009 HCT guidelines [1]. Recommendations for immunocompromised patients (including HCT recipients) at risk for hepatitis B reactivation are also discussed in detail separately. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy", section on 'Summary and recommendations'.)

Hepatitis C virus — HCT candidates should undergo testing for hepatitis C virus (HCV) antibodies and serum alanine aminotransferase prior to transplantation [1]. HCT donors should also be tested for HCV antibodies. HCV antibody-positive individuals should be further assessed for the chronic hepatitis C with a polymerase chain reaction (PCR) assay for HCV RNA. As with hepatitis B, hepatitis C-infected HCT candidates should undergo evaluation for chronic liver disease because it can increase transplant-related morbidity and mortality. If HCV RNA testing is negative, then the candidate has cleared HCV infection and is not at risk for HCV-related complications. If the HCV RNA is detectable, the candidate has chronic HCV infection. The HCV genotype should be determined in such patients. Assessment of the degree of liver fibrosis with noninvasive serologic and radiographic tests (eg, FibroSure test and ultrasound-based elastography) should be performed in all HCV-infected patients since this will impact decisions related to the HCT conditioning regimen and HCV treatment regimen. Patients with cirrhosis or fibrosis should not receive a myeloablative conditioning regimen containing either cyclophosphamide or total body irradiation ≥12 Gy because these regimens are associated with an increased risk of fatal hepatic sinusoidal obstruction syndrome (SOS; formerly veno-occlusive disease) following HCT [1,132]. (See "Noninvasive assessment of hepatic fibrosis: Overview of serologic tests and imaging examinations" and "Noninvasive assessment of hepatic fibrosis: Ultrasound-based elastography" and "Hepatic sinusoidal obstruction syndrome (veno-occlusive disease) in adults", section on 'Modifiable risk factors' and "Hepatic sinusoidal obstruction syndrome (veno-occlusive disease) in adults", section on 'Risk factors'.)

Although it is preferable to use an HCT donor who is not infected with HCV, when there is no alternative donor, transplantation may proceed. Some studies suggest no increase in short-term mortality in recipients of hepatitis C-positive allografts; however, there is a risk of developing cirrhosis [133]. Treatment of donors with chronic HCV infection (HCV antibody positive and HCV RNA positive) prior to stem cell collection may prevent transmission to the recipient, although the evidence to support this comes only from isolated case reports [134-136]. Despite the limited evidence, we favor treating HCT donors with chronic HCV infection prior to stem cell harvest.

Untreated HCV-infected individuals appear to have worse outcomes after HCT [137]. HCV-infected HCT candidates should therefore be treated, if feasible. Newer highly effective and well-tolerated directly acting antiviral drugs are now available and allow for treatment regimens that do not include interferon or ribavirin. Interferon and ribavirin are poorly tolerated in HCT candidates because they frequently cause cytopenias; the newer agents are not associated with hematologic toxicities. Although directly acting antivirals have not been specifically studied in the HCT population, it seems sensible that these should be used to clear viremia in donors and recipients prior to transplant if time permits. Guidelines on HCV infection among HCT donors and recipients from the American Society of Blood and Marrow Transplant Task Force for donor and patient management provide more detailed recommendations [138]. An HCV expert should be consulted for assistance with determining the most appropriate timing for initiating therapy and selection of an HCV regimen.

Management of hepatitis C infection is discussed in greater detail separately. (See "Overview of the management of chronic hepatitis C virus infection" and "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection" and "Management of chronic hepatitis C virus infection: Initial antiviral therapy in adults" and "Management of chronic hepatitis C virus infection: Antiviral retreatment following relapse in adults".)

OTHER VIRUSES — No antiviral prophylaxis is recommended for human herpes virus 7, parvovirus B19, enteroviruses, BK virus, JC virus, or human metapneumovirus. (See "Human herpesvirus 7 infection" and "Treatment and prevention of parvovirus B19 infection" and "Enterovirus and parechovirus infections: Epidemiology and pathogenesis" and "Overview and virology of JC polyomavirus, BK polyomavirus, and other polyomavirus infections" and "Human metapneumovirus infections".)

IMMUNIZATION

Active immunization — Following transplantation, HCT recipients typically lose immunity to pathogens against which they were previously immunized. Thus, HCT recipients should be immunized against a number of pathogens following the return of immune competence (table 3). Other strategies for preventing infections in HCT recipients include pretransplant vaccination of HCT candidates with the usual vaccines that are indicated based upon age, vaccination history, and exposure history, and vaccination of household contacts. These issues are discussed in detail separately. (See "Immunizations in hematopoietic cell transplant candidates and recipients".)

Passive immunization — Use of intravenous immunoglobulin or virus-specific immunoglobulins (eg, varicella-zoster virus-specific immunoglobulin; VariZIG) for passive immunization against individual viruses is discussed above or separately. (See 'VZV postexposure prophylaxis' above and 'CMV prevention' above and 'Respiratory syncytial virus' above and 'Hepatitis B virus' above and "Hepatitis A virus infection: Treatment and prevention", section on 'Protection following exposure' and "Measles, mumps, and rubella immunization in adults", section on 'Post-exposure prophylaxis'.)

SUMMARY AND RECOMMENDATIONS

●Important viruses – Infection in hematopoietic cell transplant (HCT) recipients is associated with high morbidity and mortality. Viruses of major importance in HCT recipients include herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), respiratory viruses (eg, influenza, parainfluenza, respiratory syncytial virus, adenovirus), human herpes virus 6, hepatitis B, and hepatitis C. (See 'Introduction' above.)

●Herpes simplex virus – For HCT recipients who are HSV-seropositive (HSV immunoglobulin G [IgG]-positive), we recommend antiviral prophylaxis (Grade 1A). Acceptable options for HSV prophylaxis include intravenous (IV) acyclovir (5 mg/kg IV every 12 hours or 250 mg/m² IV every 12 hours) or, if tolerated, oral acyclovir (400 or 800 mg twice daily) or oral valacyclovir (500 mg twice daily). HSV prophylaxis should be given from conditioning until engraftment or until mucositis resolves, whichever is longer. (See 'Herpes simplex virus' above.)

●Varicella zoster virus – For VZV-seropositive (VZV IgG-positive) HCT recipients, we recommend antiviral prophylaxis for at least one year (Grade 1A). For patients requiring ongoing immunosuppression (eg, patients with graft-versus-host disease [GVHD]), we continue prophylaxis for six months after discontinuation of immunosuppressive therapy. Oral valacyclovir (500 mg twice daily) or acyclovir (800 mg twice daily) should be used for prophylaxis. Of these, we prefer valacyclovir. (See 'Varicella-zoster virus' above.)

For VZV-seronegative HCT recipients who were transplanted within the previous 24 months, as well as those transplanted >24 months earlier who require continued immunosuppression (eg, for chronic GVHD), and who were exposed to an individual with VZV infection (chickenpox, shingles, or a post-vaccine varicella-like rash) within the past 10 days, we recommend immunoprophylaxis with VariZIG (Grade 1B). When indicated, VariZIG should be administered as soon as possible. If VariZIG is not available, we give valacyclovir (1 g three times daily) from days 3 to 22 following exposure. (See 'VZV postexposure prophylaxis' above and "Post-exposure prophylaxis against varicella-zoster virus infection".)

●Cytomegalovirus – For most CMV-seropositive recipients of allografts from CMV-seronegative donors (CMV D-/R+), CMV-seropositive recipients of allografts from CMV-seropositive donors (CMV D+/R+), and CMV-seronegative recipients of allografts from CMV-seropositive donors (CMV D+/R-), we recommend weekly quantitative CMV testing and pre-emptive therapy for patients with CMV viremia rather than giving antiviral prophylaxis (Grade 1B). For pre-emptive therapy, IV ganciclovir or oral valganciclovir can be given. Foscarnet is an alternative. In patients who experience toxicity or are at risk for toxicity, maribavir or letermovir are alternatives. In most patients, weekly monitoring should be performed from engraftment until day +100. (See 'Pre-emptive therapy' above.)

An alternative approach for high-risk patients involves CMV prophylaxis and/or twice-weekly polymerase chain reaction (PCR) monitoring with initiation of pre-emptive therapy when CMV viremia is detected. High-risk patients include CMV-seropositive recipients (CMV R+) or seronegative recipients who receive a graft from seropositive donor (CMV D+/R-) who received a T cell–depleted allograft, a human leukocyte antigen (HLA)-mismatched allograft, an umbilical cord blood allograft, alemtuzumab, or use of post-transplant cyclophosphamide. The decision of whether to give prophylactic or pre-emptive therapy should be made on a case-by-case basis, taking into account the risk profile of each patient, although increasingly, more centers are adopting prophylaxis in the high-risk subgroups. When we give prophylactic therapy, we favor letermovir (480 mg orally or IV once daily or, in patients taking cyclosporine, 240 mg once daily) to begin after HCT and continued through week 14. Letermovir is active against CMV but does not have activity against HSV or VZV; thus, clinicians will need to provide prophylaxis against these viruses when indicated. An alternative regimen is ganciclovir from day -8 to day -2, followed by high-dose valacyclovir (2 g orally three times daily) with twice-weekly PCR monitoring starting at the time of HCT and continuing until engraftment or longer in patients receiving glucocorticoids. (See 'Primary prophylaxis' above.)

CMV-seropositive autologous HCT patients usually do not require routine CMV monitoring because of a low risk for CMV disease. Monitoring, started around day 20 post-transplant and continued until day 100 post-transplant, is recommended in patients who develop CMV infection during the first 60 days following transplantation or who are recipients of CD34-selected grafts. Other autologous HCT recipients who may benefit from a pre-emptive strategy include patients who received total body irradiation, patients who received T cell-depleted grafts, and patients who received alemtuzumab, fludarabine, or 2-chlorodeoxyadenosine within the previous six months. (See 'Monitoring for CMV reactivation' above.)

●Epstein-Barr virus – Patients at high risk for EBV reactivation, such as those who received anti-T cell antibodies or an umbilical cord blood or T cell-depleted graft, should undergo weekly monitoring of EBV DNA by quantitative PCR for at least three months after transplant. Pre-emptive strategies for EBV viremia with high viral loads to prevent the development of post-transplantation lymphoproliferative disorder (PTLD) should be considered. Such strategies include the reduction of immunosuppression, administration of the anti-CD20 monoclonal antibody (rituximab), and administration of EBV-specific cytotoxic T cells. (See 'Epstein-Barr virus' above and "Treatment and prevention of post-transplant lymphoproliferative disorders", section on 'Prevention'.)

●Respiratory viruses – Influenza vaccination remains the primary method for preventing influenza. The inactivated vaccine should be used in HCT recipients, and it should be given annually lifelong. Generally, immunization should be done during influenza season beginning six months following transplantation or beginning four months following transplantation if there is a community influenza outbreak (table 3). (See 'Influenza' above.)

Although vaccination remains the cornerstone of protection against influenza virus, pre-exposure or postexposure antiviral prophylaxis of HCT recipients is sometimes used during local influenza outbreaks. The decision of whom to offer chemoprophylaxis should be made on a case-by-case basis and should be based on the nature of the exposure, the exposed person's risk of developing complications from influenza, the ability to promptly administer antiviral therapy if symptoms develop, advice from public health authorities, and clinical judgment. (See 'Chemoprophylaxis' above.)

During the coronavirus disease 2019 (COVID-19) pandemic, most clinicians test for SARS-CoV-2 prior to initiating the conditioning regimen because of the potential for asymptomatic and potentially devastating illness in immunocompromised patients. (See "COVID-19: Diagnosis", section on 'Diagnostic approach'.)

Strict hand hygiene and isolation precautions should be implemented to minimize spread of respiratory viruses among HCT patients. (See 'Infection control' above.)

●Hepatitis B virus – Hepatitis B virus (HBV) reactivation and transmission can result in severe hepatitis following HCT; all HCT candidates and donors should undergo testing for HBV, including HBV surface antigen (HBsAg), antibodies to HBV surface antigen (HBsAb), and antibodies to HBV core antigen (HBcAb). All HBcAb-positive and HBsAg-positive HCT donors and recipients should also undergo HBV DNA (viral load) testing. When planning to transplant an HBV-infected patient (HBsAg-positive and/or detectable HBV viral load), the recipient should undergo noninvasive serologic and radiographic testing for fibrosis (eg, FibroSure test and ultrasound-based elastography) because the presence of chronic liver disease can increase transplant-related morbidity and mortality. (See 'Hepatitis B virus' above.)

Use of HBsAg-positive and/or HBV viral load positive donors for HBV-naïve recipients should be avoided if a suitable donor without hepatitis B is available. HBV vaccination is especially important in HCT candidates who will be receiving an allograft from a HBsAg-positive donor. (See 'Hepatitis B virus' above.)

For HCT recipients at substantial risk of a HBV flare (patients who are HBsAg-positive or HBV DNA positive) or acquisition from the donor (recipients of allografts from a donor who is DNA positive [or cells that are DNA positive]), we suggest administration of an antiviral agent such as entecavir, tenofovir, or lamivudine (Grade 2C). This regimen should be continued for at least six months after autologous HCT and until six months after cessation of immunosuppression in allogeneic HCT recipients. Specific recommendations regarding the choice of agent are provided above. (See 'Hepatitis B virus' above.)

The approach to HCT recipients who have been exposed to HBV in the past (HBcAb-positive, HBsAg-negative, and HBsAb-negative; HBcAb-positive and HBsAb-positive) is discussed above. (See 'Hepatitis B virus' above.)

●Hepatitis C virus – Both HCT candidates and donors should be screened for hepatitis C virus (HCV) antibodies prior to transplantation. Antibody positive individuals should be tested for HCV RNA. Hepatitis C-infected HCT candidates should undergo noninvasive serologic and radiographic testing for fibrosis. (See 'Hepatitis C virus' above.)

Although it is preferable to use an HCT donor who is not infected with HCV, when there is no alternative donor, transplantation may proceed. We suggest treating HCV-seropositive donors prior to stem cell collection in an effort to prevent transmission to the recipient (Grade 2C). (See 'Hepatitis C virus' above.)

HCV-infected HCT candidates and donors should be treated prior to transplant, if feasible. New antiviral therapies have become available but have not yet been evaluated for this indication. An HCV expert should be consulted for assistance with determining the most appropriate timing for initiating therapy and selection of an HCV regimen. (See 'Hepatitis C virus' above.)

●Immunizations – Immunizations should be given to HCT recipients following the return of immune competence to boost pathogen-specific immunity (table 3). Other strategies for preventing infections in HCT recipients include pretransplant vaccination of HCT candidates with the usual vaccines that are indicated based upon age, vaccination history, and exposure history; and vaccination of household contacts. (See "Immunizations in hematopoietic cell transplant candidates and recipients".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Elias Anaissie, MD, who contributed to earlier versions of this topic review.