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368 Part V: Therapeutic Principles Chapter 23: Hematopoietic Cell Transplantation 369

transplant physicians and centers. Two universally important measures Viral Infections
for reducing infections in immunocompromised transplant recipients Infection with herpesviruses can cause significant morbidity and mor-
are effective handwashing policies and a strategy for preventing trans- tality in HCT recipients. Most infections are a result of viral reactiva-
mission of respiratory viruses, including metapneumovirus, respiratory tion and follow a relatively predictable temporal pattern in the absence
syncytial virus, parainfluenza, and influenza. of prophylaxis: Herpes simplex virus (HSV) causes clinically apparent
The duration of neutropenia and severity of oral and gastroin- disease at approximately 2 to 3 weeks after HCT, CMV disease usually
testinal mucosal damage from the conditioning regimen are risk fac- occurs during the second to third month, and varicella-zoster virus
tors for infection before neutrophil recovery has occurred. Following (VZV) recurrences present at a median of 5 months after HCT. 334
neutrophil recovery, deficiencies of B- and T-cell–mediated immunity CMV is an important viral pathogen in HCT recipients. Infection
persist and increase susceptibility to opportunistic infections. Immune occurs from reactivation of latent virus or is newly acquired from the
recovery following autologous HCT is relatively rapid compared to donor graft or blood transfusions. Reactivation is a common problem
after allogeneic transplantation. Most autologous transplant recipients in allogeneic HCT, but is relatively rare after autologous HCT except
recover T-cell immunity specific for herpes viruses, including CMV, by in the setting of CD34+ selection and T-cell depletion. Before effec-
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3 months after transplantation. The degree and duration of immuno- tive prevention strategies were introduced, CMV infection developed in
deficiency following allogeneic HCT are influenced, in part, by the type 70 percent of CMV-seropositive transplant recipients and 32 percent of
of immunosuppressive therapy and severity of GVHD. Chronic GVHD CMV-seronegative recipients and was a frequent cause of TRM. Cur-
335
is associated with chronic B- and T-cell immune deficiencies that may rently, all allogeneic HCT recipients at risk for CMV infection (those
persist for years, and Ig production and reticuloendothelial function who are CMV-seropositive or who have a CMV-seropositive donor)
may also be impaired. 326–328 require monitoring with preemptive therapy for CMV reactivation;
this approach has markedly reduced the risk of progression to frank
Bacterial Infections CMV disease such as enteritis or pneumonitis. Prophylactic antiviral
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Bacterial infections are common during the period of immediate neu- therapy against CMV is used by some centers, particularly in high-risk
tropenia that follows the preparative transplantation regimen, and can situations such as UCB recipients. More commonly, allogeneic HCT
be caused by both Gram-positive and Gram-negative organisms. The recipients are monitored with plasma CMV polymerase chain reaction
329
increased risk of bacterial infections is not only caused by neutropenia, (PCR) assays at least weekly through at least day +100 after HCT, and
but also from loss of epithelial integrity from regimen-related injury, are treated preemptively if these studies yield values which exceed insti-
bacterial translocation, and the presence of indwelling intravenous tutionally established thresholds. The preemptive approach avoids the
334
catheters. Some centers institute preventive measures in addition to toxicity of universal antiviral prophylaxis, reduces the risk of acquired
rigorous hand washing, such as gowning and masking, although there antiviral resistance, and limits overtreatment of CMV while prevent-
is little evidence that these actions reduce infection risk. Removal of ing development of tissue disease. However, CMV tissue disease such
venous catheters is sometimes required for patients who do not respond as enteritis or pneumonitis can, rarely, develop despite negative plasma
promptly to treatment. Chapter 24 reviews specific strategies and regi- CMV PCR, and CMV enteritis or pneumonitis cannot be definitively
mens for treating bacterial infections in neutropenic patients. ruled out by blood tests alone.
Patients who require ongoing immunosuppressive therapy for Prophylaxis with acyclovir or, more potently, valacyclovir can
the control of chronic GVHD are at risk for recurrent bacteremia with reduce the risk of CMV reactivation after allogeneic HCT, but does not
encapsulated bacteria and sinopulmonary infections. Preventive strate- obviate the need for CMV surveillance. 337,338 Intravenous ganciclovir is
gies differ from institution to institution, although some form of anti- typically the first-line treatment for CMV reactivation or tissue disease,
biotic prophylaxis is often used in these patients. Infrequent bacterial although oral valganciclovir may be equally effective as preemptive
pathogens which should also be considered, especially in the presence therapy. 339,340 The most common adverse effect of these antiviral drugs
of pulmonary infiltrates or nodules, are Legionella, Nocardia, Mycobac- is myelosuppression, which often requires growth-factor support. Intra-
terium tuberculosis, and atypical mycobacteria. venous foscarnet is as effective as ganciclovir in CMV prevention and
treatment, and does not cause myelosuppression. However, foscarnet
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Fungal Infections is nephrotoxic and requires cumbersome pre- and posthydration, and
Fungal infections are serious and potentially fatal complications follow- is thus most often used as second-line therapy in patients who cannot
ing HCT, and are seen most commonly in allogeneic HCT recipients as tolerate ganciclovir because of myelosuppression. Patients with CMV
a result of the requirement for postgrafting immunosuppressive med- reactivation are typically treated with an induction dose of anti-CMV
ication. The incidence of fungal infection varies considerably among therapy (ganciclovir, valganciclovir, or foscarnet) for at least 2 weeks,
transplantation centers because of a variety of factors, including geo- followed by maintenance antiviral therapy until CMV assays are per-
graphic location, nearby construction, and prophylactic regimens. sistently negative. It is not uncommon for patients to experience addi-
Candida and Aspergillus are the most common fungal pathogens; how- tional late reactivations after antiviral therapy is discontinued, and these
ever, other organisms can also cause life-threatening infections. Chapter patients require ongoing monitoring beyond day +100.
24 discusses the treatment and prophylaxis of fungal infections. Investigational approaches to CMV prevention and treatment
Fluconazole prophylaxis decreases the incidence of invasive and include CMX-001, an oral prodrug that is converted to cidofovir intra-
superficial Candida albicans infections and may decrease the 100-day cellularly and lacks renal toxicity. A placebo-controlled randomized
330
mortality in allogeneic HCT recipients. Fluconazole has limited activ- trial of CMX-001 as CMV prophylaxis in allogeneic HCT found that
ity against Candida krusei, Torulopsis glabrata, and Aspergillus species, this agent reduced the incidence of CMV activation from 37 percent
and some centers reported an increased incidence of resistant Can- to 10 percent. Diarrhea was the most common adverse effect; myelo-
342
dida infections in patients receiving prophylactic fluconazole. More suppression and nephrotoxicity were not observed. Letermovir, a novel
331
aggressive prophylaxis with mold-active agents such as voriconazole or terminase inhibitor, has also shown efficacy in preventing CMV reac-
itraconazole can prevent invasive mold infections, including aspergillo- tivation in allogeneic HCT in randomized, placebo-controlled clinical
sis, but these agents are associated with a higher risk of adverse events trials. Maribavir, another antiviral agent with a novel mechanism of
343
and no clear benefit to mortality. 332,333 action, was effective in preventing CMV in a randomized dose-finding

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