Page 1891 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 109 Complications After Hematopoietic Cell Transplantation 1673

plasma CMV DNA PCR, though not as sensitive as whole blood Approach to Prevention and Treatment of
PCR, can be a valuable tool to monitor CMV during periods of BOX 109.1 Cytomegalovirus Infection
neutropenia when CMV antigenemia testing is unreliable. In addi-
tion, quantitative real-time PCR assays allow estimation of viral Prevention
load which can assist in determining need for therapy and risk of 1. Seronegative recipient with seronegative donor (allogeneic and
disease progression and in monitoring response among patients autologous): Transfuse only cytomegalovirus (CMV) safe blood
receiving anti-CMV treatment. Viral cultures of urine, saliva, blood products. Leukocyte depletion by filtration and blood from
or bronchioalveolar lavage (BAL), using either rapid shell-vial or CMV-seronegative donors are clinically equivalent alternatives.
routine culture techniques, have limited clinical utility since they 2. Seronegative recipient with seropositive donor (allogeneic): Deliver
are less sensitive than antigen or DNA detection techniques and only CMV-safe blood products (seronegative or leukocyte
take much longer to report. Shell-vial cultures of CMV from BAL depleted), but administer chemoprophylaxis as well to prevent
fluid are less specific for CMV pneumonia and can be positive in reactivation of donor-derived and transmitted latent virus.
asymptomatic seropositive patients without pneumonia who are 3. Seropositive recipients: Prophylaxis with acyclovir appears to be
somewhat useful. Use of immunoglobulin may be beneficial.
shedding CMV in oral or respiratory secretions. Despite this lack of There is no proven role for seronegative blood products.
specificity, even in asymptomatic patients, finding CMV in BAL Ganciclovir is highly effective when given prophylactically, but is
fluid is a strong predictor for the development of subsequent CMV myelosuppressive. Patients who must interrupt the course of
pneumonia, and treatment should be initiated. ganciclovir because of leukopenia are at risk for development of
CMV reactivation and disease. Ganciclovir (or valganciclovir) is
the current best prophylaxis in high-risk patients, but is not
Prevention and Treatment indicated for autologous recipients. Intensive surveillance and
early preemptive therapy may be equivalently effective.
4. All patients need periodic (weekly) monitoring for CMV
For seronegative recipients, the use of seronegative donors and antigenemia or CMV DNA polymerase chain reaction for 8–12
CMV-safe blood products is the mainstay of prevention of CMV weeks posttransplantation. Longer duration (beyond 12 weeks)
disease (Box 109.1). For high-risk patients (seropositive recipients surveillance is appropriate for allograft recipients, especially those
or seropositive donors for seronegative recipients), two general with graft-versus-host disease.
strategies can be used, both of which have been effective in reduc-
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ing early CMV infection rates to less than 10%. The first is the Treatment
“preemptive” approach, which involves prompt treatment of early 1. Asymptomatic infections (allogeneic and autologous): Ganciclovir
CMV viremia with ganciclovir, valganciclovir, or foscarnet before it or valganciclovir treatment of asymptomatic infection detected in
blood or bronchioalveolar lavage (BAL), by either molecular
can lead to clinical disease. The second is the “general prophylaxis” detection or antigenic methods, is recommended to prevent the
approach, in which all at-risk patients are treated with antiviral development of CMV pneumonia. Intensive induction treatment
prophylaxis. The former approach requires availability and frequent (2 weeks) followed by a maintenance phase of 5+ days/week
scheduled application of reliable and rapid early diagnostic tests. therapy for an additional 4–8 weeks is necessary.
The latter approach can reduce the rate of early CMV infection, 2. CMV pneumonia: Ganciclovir in combination with immunoglobulin
but does not impact mortality or the risk for late CMV infection is recommended. This should be instituted promptly. Once the
and is associated with a higher incidence of ganciclovir-induced disease has progressed to cause respiratory failure and ventilator
myelosuppression. Both approaches require aggressive surveillance dependence, survival is limited.
to allow prompt detection of infection. High-dose acyclovir or No Treatment
valacyclovir, although not as effective as ganciclovir, also reduces 1. Empiric CMV therapy for interstitial pneumonitis is not indicated
the incidence of CMV viremia, but continued surveillance for in seronegative recipients with seronegative graft and blood
CMV is still required with prompt initiation of preemptive therapy donors. Diagnostic evidence of CMV infection should be obtained.
with ganciclovir or foscarnet when viremia develops. Unlike ganci- 2. Empiric CMV therapy for interstitial pneumonitis is also not
clovir, which has to be administered intravenously, its prodrug indicated in patients whose BAL is negative for CMV by direct
valganciclovir, has excellent oral bioavailability and is often used for staining and molecular testing. However, BAL CMV studies have
prophylaxis and preemptive therapy of CMV infection among a small (<5%) false-negative rate, and close follow up and
monitoring is still required.
HCT recipients. Since autologous HCT recipients have a lower risk 3. Asymptomatic CMV viruria does not require therapy, but does
of CMV disease, the preemptive approach to preventing CMV need close follow up and serial blood viral testing for surveillance
infection is usually sufficient. Surveillance for CMV is continued of systemic disease.
weekly until at least day 100 posttransplant for high-risk patients
and is continued longer in patients with chronic GVHD on high-
dose immunosuppression.
CMV disease, especially pneumonia, must be diagnosed and liposomal formulation of cidofovir with good oral bioavailability
treated promptly as it remains associated with very high rates of (CMX-001, brincidofovir) is being studied in prophylaxis and treat-
mortality. The combined use of ganciclovir and IVIg has been the ment of CMV infections in HCT.
most successful treatment for CMV pneumonia, with resolution in
50% to 75% of nonventilator dependent patients. Prolonged therapy
(>2 months) with the combination is indicated because shorter treat- Other Latent Viral Infections
ment regimens have been associated with recurrence of CMV
pneumonia. Foscarnet can be effective in clinical settings in which Primary and reactivation infections of other herpesviruses can occur
ganciclovir fails or is associated with excess toxicity, usually myelosup- after transplantation. Herpes simplex virus (HSV) infection is
pression. Although treatment is generally similar, with ganciclovir or uncommon with the use of acyclovir or valacyclovir prophylaxis in
foscarnet plus immunoglobulin, CMV enteritis, hepatitis, and reti- seropositive patients. Acyclovir-resistant HSV infection can occur
nitis are variably responsive. Valganciclovir may be considered for in patients given low-dose prophylaxis or intermittent treatment and
treatment of mild to moderate CMV organ disease, although more in recipients of T-cell depleted grafts. Foscarnet is the drug of choice
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prolonged administration may be required. Adoptive cellular thera- for resistant disease with cidofovir reserved as an alternative agent.
pies (using approaches to enhance NK or infuse CMV-specific T VZV reactivation can occur in 30% to 50% of HCT recipients with
cells) are also being explored. Although rare, CMV antiviral resistance previous exposure to VZV, and can be effectively delayed and possibly
can occur and ganciclovir or foscarnet can be used as alternative drugs prevented by acyclovir prophylaxis. Acyclovir prophylaxis has been
for second-line therapy. Cidofovir can be considered when disease suggested for the 6–12 months after transplantation for VZV sero-
progresses despite treatment with ganciclovir and foscarnet and a positive autologous and allogeneic HCT recipients; patients with