American Journal of Transplantation 2004; 4: 1219–1226
Blackwell Munksgaard
C Blackwell Munksgaard 2004
Copyright doi: 10.1111/j.1600-6143.2004.00505.x
Minireview
Cytomegalovirus and Lung Transplantation
Martin R. Zamora∗
Division of Pulmonary Sciences and Critical Care
Medicine, and the Lung Transplant Program, University of
Colorado Health Sciences Center, Denver, CO
∗
Corresponding author: Martin Zamora,
Marty.Zamora@uchsc.edu
Cytomegalovirus (CMV) infection remains a serious
problem in lung transplant recipients. Development
of potent oral antiviral agents, molecular techniques
for the detection of infection and its response to therapy and the emergence of isolates with antiviral resistance have had significant impacts on the approach to
CMV in these patients. This article discusses the following issues as part of a comprehensive CMV management strategy in lung transplant recipients: (1)
Prevention strategies in the era of potent oral antiviral agents, (2) the role of new diagnostic techniques
in the management of CMV, (3) treatment regimens
for established CMV infection or disease, (4) the potential impact of treatment of CMV on the indirect
effects on long-term allograft function, and (5) the incidence, risk factors for and impact of ganciclovir resistance following lung transplantation.
Key words: Antiviral resistance, ganciclovir, polymerase chain reaction, valganciclovir
Received 7 September 2003, revised and accepted for
publication 25 March 2004
seronegative recipients of seropositive organs are at the
highest risk of severe disease and require prophylaxis, despite more than a decade of experience with lung transplantation and ganciclovir availability, management of the
CMV seropositive recipient remains controversial.
Risk of CMV Infection and Disease in Lung
Transplant Recipients
The incidence of CMV infection and disease following lung
transplantation in the postganciclovir era ranges from 30
to 86% with an associated mortality rate of 2–12% (1). Innate host immunity, the type of organ transplanted with
its viral burden, viral coinfection and the net state of immunosuppression affect the risk of developing CMV infection. The Papworth group showed that seronegative
heart–lung recipients of CMV-positive organs are at the
highest risk of developing severe, sometimes fatal, disease (8). Lung transplantation involves the transfer of large
amounts of lymphatic tissue harboring greater amounts of
latent CMV than other organs, theoretically increasing the
risk and severity of CMV infection (9). Therefore, some authors recommend that all lung transplant recipients should
be considered high-risk. Coinfection with other betaherpesviruses (HHV-6 and HHV-7) with inherent immunomodulating properties enhances CMV replication (10). Use of
antilymphocytic antibodies for induction therapy or treatment of steroid-resistant rejection increases the rate of
CMV reactivation (11).
CMV and Acute Chronic Allograft Injury
Introduction
CMV remains the most important pathogen following lung
transplantation (1). Its effects on morbidity and mortality
can be divided into direct effects of tissue injury and clinical illness and indirect effects leading to long-term adverse
sequelae in the lung allograft. Accumulating evidence suggests the indirect effects of CMV may be at least as important as its direct effects. Via mechanisms of enhanced
allorecognition, CMV has been associated with, though not
causally linked to, the development of acute and chronic
rejection (2). Potential immunomodulatory effects of CMV
may predispose patients to infection with opportunistic organisms or the development of post-transplant lymphoproliferative disease (3,4). Cytomegalovirus increases the
costs associated with solid organ transplants by 40–50%
(5–7). These observations have prompted various strategies for the prevention, early diagnosis and treatment
of CMV infection. While there is general consensus that
The relationship between CMV and allograft injury is bidirectional (12). Cytokines, chemokines and growth factors
are induced in response to both CMV infection and rejection, resulting in activation of the vascular endothelium and
inflammatory cells. The proinflammatory cytokine, tumor
necrosis factor (TNF), is a key signal in reactivating CMV
from latency. TNF-induced activation of protein kinase C
and nuclear factor-jB (NFjB) leads to expression of CMV
immediate early proteins triggering the onset of viral replication. As TNF is released during allograft rejection, it is
not surprising that CMV reactivation occurs in response
to acute rejection. Intensified immunosuppression to treat
rejection can amplify viral replication: following antilymphocyte agents, the incidence of CMV disease increases from
10 to 15–65% (1).
Cytomegalovirus infection of the vascular endothelium and
smooth muscle cells likely plays an important role in the
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Zamora
pathogenesis of vascular injury seen in acute and chronic
rejection. Cytomegalovirus up-regulates endothelial adhesion molecules such as VCAM, ICAM, LFA-1 and VLA4, which increases the number of inflammatory cells in
the graft. Injury may also occur via molecular mimicry:
sequence homology and immunologic cross-reactivity between CMV immediate early antigens and the HLA-DR b
chain have been demonstrated and CMV induces a glycoprotein homologous to MHC class I antigens (13). Cytomegalovirus also induces antiendothelial cell antibodies, which may participate directly in the development of
chronic rejection. While CMV prophylaxis has been shown
to decrease the incidence of acute rejection, therapy of established disease with ganciclovir alone may not prevent
the long-term sequelae of CMV-induced graft injury (2).
Addition of immunoglobulin preparations which have immunomodulatory properties may be required to limit acute
inflammatory events and the progression to chronic allograft injury. Similar strategies have shown efficacy in bone
marrow transplant recipients to decrease graft vs. host
disease (14).
In lung transplant recipients, CMV has been associated
with chronic allograft injury or bronchiolitis obliterans syndrome (BOS); the major limiting factor to long-term survival
after lung transplantation. Cytomegalovirus pneumonitis
and positive CMV serology may be risk factors for BOS;
however, these associations are still being debated (2,15–
18). Given that BOS is typically progressive despite augmented immunosuppressive therapy, strategies to prevent
BOS are paramount in controlling this devastating complication of lung transplantation. Prevention and treatment of
CMV infections may therefore be important strategies to
limit the development of BOS.
Strategies to Prevent CMV Infection
Three potential mechanisms of CMV infection have been
recognized: transmission by the donor organ, blood products or reactivation of latent virus in the recipient. Presence
of antibody to CMV in the recipient, whether endogenous
or passively transferred, provides partial protection against
the development of serious and sometimes fatal disease.
Absent endogenous antibody protection, primary CMV infections, particularly CMV pneumonitis or gastrointestinal
disease, may be quite severe with mortality rates of 2–20%
(19).
Based on these potential mechanisms of infection, four
strategies to prevent CMV infection have been utilized:
matching the donor–recipient pair by CMV serologic status,
use of CMV-negative blood products, antiviral agents to
suppress viral replication and immunoglobulin preparations
to provide passive immunization. The use of CMV-negative
or leukocyte-reduced blood products clearly decreases the
incidence of CMV transmission and infection following lung
transplantation (17). In CMV-negative bone marrow trans1220
plant recipients, seronegative blood results in an incidence
of CMV infection transmission of 1.3% while leukocytereduced CMV-positive blood results in a transmission rate
of 2.4% with CMV disease rates of 0% and 2.4%, respectively (20). Therefore, it seems prudent to strictly adhere to
use of CMV-negative blood products in seronegative lung
transplant recipients. Seromatching recipients and donors
may be ideal but is impractical given the current shortage
of donor organs. Furthermore, seromatching, while perhaps desirable, is most likely no longer necessary to prevent the direct effects on morbidity and mortality given
the efficacy of antivirals and immunoglobulins in decreasing the incidence and severity of primary CMV infections.
However, caution may still be warranted when performing
CMV-mismatched transplants, as the long-term sequelae
of CMV infections on allograft function remains unknown.
Many retrospective or case-controlled series have demonstrated the benefit of antivirals or immunoglobulin preparations alone or in combination in decreasing or delaying
the onset of CMV infection following lung transplantation.
However, to date, primarily owing to the lack of randomized, controlled trials comparing regimens, the ‘ideal’ strategy for the prevention, monitoring and treatment of CMV
remains controversial.
Monitoring Techniques
Rapid and accurate diagnostic tests are critical for the appropriate management of CMV following lung transplantation. Qualitative or quantitative polymerase chain reaction
(PCR) [TaqMan (Applied Biosystems, Foster City, CA, USA)
CMV quantitative PCR and the COBAS AMPLICOR (Roche
Diagnostics, Pleasanton, CA, USA) CMV Monitor] using
serum, plasma or circulating peripheral blood leukocytes or
the pp65 antigenemia test (CMV-vue kit), are efficacious in
solid organ transplant and bone marrow transplant recipients (21–26). The hybrid capture assay, a non-PCR, molecular, quantitative and highly sensitive assay, has been shown
to be effective in lung transplant recipients (27,28). Each
test has their own advantages and disadvantages. The
quantitative PCR and hybrid capture assays are fully quantitative, molecular techniques. Qualitative PCR is much less
useful. PCR requires radioactive probes and most centers
use ‘homemade primers’ thereby precluding standardization. The pp65 antigenemia assay is only semiquantitative
(read as number of positive cells) although their readings
can be used in the same ways by clinicians experienced in
its interpretation and may be more labor intensive in that
the cells need to be spun and placed on slides within 6 h
of arrival to the laboratory.
The value of a quantitative assay such as viral load is seen
by its increased utilization by clinicians for assessing or
predicting the severity of illness or impending illness (29).
Weinberg et al. (30) evaluated serial CMV blood cultures,
antigenemia, and qualitative and quantitative plasma PCR
tests for their value in predicting CMV disease and for
American Journal of Transplantation 2004; 4: 1219–1226
Cytomegalovirus and Lung Transplantation
guiding preemptive therapy after lung transplantation. They
found that PCR and antigenemia tests were the most effective predictors of symptomatic CMV infections and the response to therapy. Cytomegalovirus PCR-measured DNA
increased 5–10-fold immediately preceding symptoms and
PCR and antigenemia levels decreased with anti-CMV therapy. A number of these monitoring tests are commercially
available and regardless of which method is chosen the
technique should be validated in each individual transplant
center.
but had limited efficacy in preventing CMV infection or
disease (15,31). Studies employing extended prophylactic therapy with ganciclovir for 6–12 weeks suggested that
prolonged ganciclovir infusion decreased the incidence of
CMV infection and disease (32), however, the benefit was
lost when patients were followed more than a year posttransplant (33). These reports point out the importance of
long-term follow up when comparing published reports
and confirm that ganciclovir monotherapy delays rather
than prevents the onset of CMV infection following lung
transplantation.
Prophylaxis of CMV Infection
The largest prospective trial utilizing ganciclovir monotherapy was reported by Hertz et al. (34). Ganciclovir was given
intravenously for 3 months post-transplant either daily or
thrice-weekly. There were no significant differences between groups with respect to freedom from CMV infection
or disease or in the incidence of BOS. Cytomegalovirus
disease developed in 18/35 (51%) of the daily patients vs.
11/37 (30%) of the thrice-weekly patients and emerged
shortly after termination of prophylaxis. While prolonged
thrice-weekly ganciclovir prophylaxis was as effective as
daily administration at delaying the onset of CMV infections, it was still associated with patient inconvenience,
catheter-related infections and increased costs.
Before the development of effective antiviral agents, CMV
caused illness in the majority of lung transplant recipients,
and primary infection in D+/R– recipients was severe and
often life-threatening (8). Following the development of
ganciclovir it soon became clear that the acute morbidity
and mortality of CMV infections could be controlled with
therapeutic courses of intravenous ganciclovir. Investigators then sought to determine whether prophylactic use
of ganciclovir or other agents could prevent CMV infection and disease following lung transplantation. Most approaches involved universal prophylaxis in which all patients receive prophylaxis for a predetermined amount of
time. This strategy aims for complete viral elimination but
is associated with increased costs, toxicities and the possibility of the development of resistance.
While it is difficult to summarize and compare the published reports on CMV prophylaxis in lung transplant recipients, as they utilized different lengths of prophylaxis
in patients receiving different immunosuppressive strategies based on the year of transplant, the published studies
can be categorized as those employing ganciclovir or immunoglobulin monotherapy or combination strategies.
An alternative strategy to prolonged infusion of ganciclovir
is the use of oral ganciclovir. Bhorade et al. (28) found that
12 weeks of oral ganciclovir (3 g per day) decreased the
incidence of CMV to levels similar to those seen with intravenous ganciclovir. Cytomegalovirus disease developed
in 10/34(29%) lung transplant recipients with an average
onset of 4 months. However, 24% of the patients developed asymptomatic, breakthrough viremia. While none of
these patients developed CMV disease, this breakthrough
viremia may predispose to or be a marker of the emergence
of ganciclovir resistance (35).
Ganciclovir monotherapy (Table 1)
Early studies found that short courses of prophylactic ganciclovir (2–3 weeks) delayed the onset of CMV infection
The availability of valganciclovir, which provides antiviral exposure similar to intravenous ganciclovir (comparable AUCs), obviates the need for prolonged intravenous
Table 1: Intravenous ganciclovir for cytomegalovirus prophylaxis following lung or heart–lung transplantation (North American centers)
Author/year (ref.)
n
CMV prophylaxis
CMV onset
Outcome
Duncan et al. 1992
Pittsburgh (32)
Duncan et al. 1994
Pittsburgh (15)
Kelly et al. 1995
Seattle (33)
Soghikian et al. 1996
Stanford (31)
Hertz et al. 1998
Minnesota (34)
Total
13
72
13
GCV ×3 weeks
ACY ×2 months
GCV ×90 days
5/13 Inf (38%)
2/13 Dz (15%)
8/13 Inf (58%)
21
GCV ×6 weeks
145
52
(L + HL)
35
37
171
GCV ×5 weeks
85
GCV qd × 90d
GCV ×3/week
NR
268
17/21 Inf (81%)
8/21 Dz (38%)
42/52 Inf (86%)
27/52 Dz (55%)
18/35 Dz (51%)
11/37 Dz (30%)
Inf. 101/171 (59.1%)
Dz. 66/158 (41.8%)
n = number of patients in series receiving intravenous ganciclovir, L + HL = lung and heart–lung transplants, GCV = ganciclovir, ACY =
acyclovir, IVIG = standard intravenous immunoglobulin, NR = not reported, Inf = Infection, Dz = disease.
American Journal of Transplantation 2004; 4: 1219–1226
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access and allows prolonged high-level antiviral exposure. Valganciclovir was at least as effective as
oral ganciclovir in preventing CMV infections and produced more complete viral suppression without the
development of antiviral resistance in solid organ
recipients (36).
When the published results of intravenous ganciclovir
monotherapy are pooled, the incidence of CMV infection and disease remains 59% and 42%, respectively
(Table 1). While differing lengths of prophylaxis and types
of immunosuppression were employed in these studies,
taken in sum, these data suggest that while ganciclovir decreases the incidence of CMV infections compared with
placebo or oral acyclovir, there is still a significant incidence
of CMV infection following lung transplantation with ganciclovir monotherapy strategies.
CMV immune globulin monotherapy
An alternative strategy to ganciclovir monotherapy is CMV
hyperimmune globulin (CMV-IVIG). Maurer reported an incidence of CMV pneumonitis of 28% in patients receiving CMV-IVIG alone (37). Similarly, Gould et al. (38) reported an incidence of CMV disease of 23%. However,
a more recent study found that CMV-IVIG alone did not
prevent CMV viremia or pneumonitis (39). While this suggests that a randomized, controlled trial comparing these
regimens is warranted, it also begs the question as to
whether combination prophylaxis with both agents may be
more efficacious in the prevention of CMV following lung
transplantation.
Preemptive Therapy
Some centers advocate preemptive therapy based on detection of CMV antigenemia or DNAemia in routinely collected blood samples. The advantage of this strategy is that
only high-risk patients are exposed to therapy, which would
be expected to decrease cost and toxicity. Several small
studies have suggested that this approach is indeed effective in lung transplant recipients. Egan et al. (22) showed
that preemptive treatment of CMV infection as determined
by antigenemia prevented progression to CMV disease in
heart and lung transplant recipients. Kelly et al. (45) found
that preemptive therapy directed by the antigenemia assay
was as effective as universal prophylaxis with 6 weeks of
intravenous ganciclovir and concluded that it was also more
cost-effective. There are several potential disadvantages of
preemptive therapy: (1) in large geographic regions, it may
be difficult to routinely obtain blood samples from the patients, (2) the cost of surveillance may be high, and (3) some
patients escape detection and present with severe CMV
disease. The latter was a problem in the report by Kelly
et al.: 5/19 patients presented with CMV pneumonitis and
the antigenemia test revealed zero positive cells (45,46).
Such problems with sensitivity and specificity await clarification in larger cohorts of lung transplant recipients. We
and others have found that a high viral load was associated
with a high degree of progression to symptomatic disease
and that following universal prophylaxis, routine monitoring followed by preemptive therapy was effective in preventing the progression to symptomatic disease (28,29).
Therefore, our center advocates a combination of the approaches with routine viral load monitoring at scheduled
clinic visits.
Treatment
Combination prophylaxis
Bailey et al. (40) reported an 86% incidence of CMV pneumonitis in D+/R– recipients treated with 2–3 weeks of intravenous ganciclovir and standard IVIG. Maurer et al. (37)
reported significant decreases in CMV pneumonitis in patients receiving CMV-IVIG and either ganciclovir or oral acyclovir (41% vs. 67%). Further, survival in the combination
therapy group approached that seen when both donor and
recipient were seronegative. Similarly, we have reported
that CMV-IVIG in combination with ganciclovir decreased
the incidence of CMV infection to 21% and disease to 31%,
their severity and delayed its onset (41).
More recently, Valantine et al. (42,43) reported improved
outcomes with fewer infections, decreased acute rejection and BOS at 12 and 24 months in the combined therapy group compared with the ganciclovir-only group. Similarly, Weill et al. (44) found that despite induction therapy
with daclizumab, when compared with a historical, casecontrolled group receiving ganciclovir alone, combination
prophylaxis decreased the incidence of CMV disease from
33% to 8%.
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Standard therapy for CMV disease consists of 2–4 weeks
of intravenous ganciclovir at a dose of 5 mg/kg twice daily
adjusted for renal insufficiency. Somewhat concerning,
Duncan et al. (2) found that treatment with intravenous ganciclovir as monotherapy did not prevent the long-term sequelae of CMV. Although no randomized, controlled treatment trials are available for the use of CMV hyperimmune
globulin for therapy in organ transplant recipients, many
centers add it to ganciclovir for the treatment of tissue
invasive CMV pneumonia or colitis. Studies in bone marrow transplant patients with CMV pneumonitis and murine
models of disseminated CMV infection suggest that the
combination of ganciclovir and CMV hyperimmune globulin may provide significant benefits for immunosuppressed
recipients with invasive disease (1,47).
One potential role for immunoglobulin therapy may be as
replacement therapy in patients with occult hypogammaglobulinemia (48). In these patients, tissue-invasive CMV
as well as other infectious complications were more common in the lowest IgG group. Recently, immunoglobulin
American Journal of Transplantation 2004; 4: 1219–1226
Cytomegalovirus and Lung Transplantation
replacement has been shown to decrease acute rejection
and infection in heart transplant recipients with hypogammaglobulinemia (49).
The vast majority of isolates causing first episodes of
CMV infections in lung transplant recipients are ganciclovir
sensitive. Despite this, oral ganciclovir, owing to its low
biovailability, has no role in the treatment of symptomatic
infection, as it may select resistant clones of CMV when
high viral loads and active viral proliferation are occurring.
However, oral ganciclovir may have a role in the prevention
of relapsing symptomatic disease. The risk of recurrent disease ranges from 20% in seropositive recipients to 60% in
those with primary disease (50). The use of oral ganciclovir
for 3 months following a full course of intravenous therapy
may decrease the risk of recurrent disease by up to 50%
(51,52). Whether the use of combination therapy followed
by oral ganciclovir decreases the recurrence risk further is
presently unknown.
Antiviral Resistance
Antiviral-resistant CMV is increasing in all solid organ
transplants and is particularly problematic following lung
transplantation with an incidence of 3–16% (53). These
estimates are imprecise, as much of the data has been
collected retrospectively and there is significant variability
among centers (54), some of which is owing to the fact
that genotypic testing of isolates provides greater sensitivity in detecting resistance than the culture-based methods
in use at most centers. It is concerning that antiviral resistance has been associated not only with treatment failure,
but poor long-term allograft function and decreased patient
survival. Kruger et al. (55) found an incidence of ganciclovir
resistance in their lung transplant cohort of 5.2%, which resulted in increased positive viral blood cultures, CMV pneumonia, decreased overall survival and the earlier onset of
BOS.
The most important risk factors for antiviral resistance are
D+/R– status and the intensity of immunosuppression.
Suboptimal antiviral prophylaxis, which may occur with oral
ganciclovir owing to its poor bioavailability, is another risk
factor for resistance. Finally, the intensity of the immunosuppressive regimen, particularly the use of antithymocyte
globulin or OKT3 for induction therapy or treatment of rejection episodes, is associated with the development of
antiviral resistance (56–58).
Resistance should be suspected in patients who fail to respond to intravenous ganciclovir therapy of tissue-invasive
CMV infections, who have persistent viremia or recurrent
viremia during or after ganciclovir prophylaxis. While neither has been validated, the lack of complete resolution of
clinical symptoms or the failure of the viral load (by antigenemia or PCR) to decline after 2–3 weeks of therapy
have been postulated to indicate the presence of a resisAmerican Journal of Transplantation 2004; 4: 1219–1226
tant isolate (54). Empiric switch therapy to foscarnet or
combination therapy with ganciclovir and foscarnet should
be performed while awaiting laboratory confirmation of resistance (59). Genotypic analysis is more sensitive than
phenotypic or plaque reduction assays and may provide a
more rapid diagnosis of resistance.
Ganciclovir resistance occurs by two mechanisms: mutations in the UL97 gene, which codes for a phosphotransferase important in the phosphorylation of ganciclovir to
its active form, and mutation in the UL54 gene, which encodes the viral DNA polymerase. Foscarnet and cidofovir
do not require phosphorylation for activation; thus the UL97
mutation does not confer cross-resistance to these agents.
However, mutations of the DNA polymerase confer crossresistance to ganciclovir and cidofovir but to foscarnet is
less predictable (60).
The management of antiviral-resistant CMV disease has
been to switch therapy to foscarnet, which is typically effective for the treatment of ganciclovir-resistant isolates.
With the emergence of cross-resistant strains the use of
cidofovir or combination antiviral therapy with or without
immunoglobulin preparations may be required. One such
approach has been to use intravenous ganciclovir at 50%
its typical dose with once-daily foscarnet, which is gradually
increased to a maximum of 125 mg/kg. This approach was
effective in solid organ transplant recipients in clearing the
infection and no recurrence was seen in the 6–30 months
of follow up (59). The immunosuppressive agent leflunomide has been shown in vitro to have activity against resistant isolates (61).
Two approaches have been advocated for the prevention
of ganciclovir resistance. As suboptimal prophylaxis is associated with resistance, more potent agents may be effective. Valganciclovir, which has greater bioavailability than
oral ganciclovir, may allow continual exposure to ganciclovir
and may prove to be useful in the future. However, careful
analysis of breakthrough viremia for resistance genotypes
will be necessary. The other approach is preemptive therapy, which limits exposure to antivirals only to those at
high risk as documented by active viral replication. Problems associated with this approach are the frequent monitoring which is required and patients who present with
invasive CMV disease. While prolonged exposure to intravenous ganciclovir was associated with the development
of resistance and it has been asserted that less antiviral
for shorter time periods is beneficial, it is still being debated whether prolonged exposure to potent antivirals or
intermittent exposure with preemptive therapy will induce
similar levels of resistance. Contrary to what is claimed
by advocates of the preemptive approach, such a strategy does not always prevent the emergence of ganciclovir resistance (35). Finally, given the association of CMV
pneumonia with BOS, this risk must be weighed against
that of developing ganciclovir resistance with prolonged
therapy.
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Zamora
Future Directions in CMV Management
Most of the lung transplant literature to date has dealt
with the prevention and treatment of the direct effects
of CMV. Remaining to be answered, is whether the
prevention of CMV proliferation, or its treatment in the
asymptomatic phase, will limit its indirect effects. It has
been suggested that even asymptomatic viral proliferation
may be associated with the development of BOS in lung
transplant recipients. Therefore, it would seem that prevention of any CMV proliferation, or treatment of asymptomatic infections, would be a desirable goal. Preliminary
results from our institution suggest that preemptive treatment of asymptomatic CMV DNAemia is associated with
a decrease in the acute and chronic effects of CMV infection following lung transplantation when compared with
patients with symptomatic viremia or disease (62). The relationship between preemptive therapy and allograft response to CMV infections and augmented immunosuppression (as measured by opportunistic infections) was
also investigated in this study. Preemptive therapy of CMV
DNAemia decreased CMV-associated acute rejection, but
not infection. This suggests that preemptive therapy of
asymptomatic CMV infections attenuates the immune response in the allograft but not the augmented immunosuppressive state induced by CMV. Clearly further studies
are necessary to investigate the role of treatment strategies on the indirect effects of CMV infection following lung
transplantation.
Early clinical investigations with valganciclovir make maintenance therapy more convenient, however, there appear
to be potential dose-limiting properties (e.g. bone marrow suppression) (37,62). Frequent monitoring of complete
blood counts and serum creatinine will be required to properly dose-adjust valganciclovir. Profound neutropenia may
also increase the risk of fungal infection, which may counteract the benefit of preventing CMV. Future studies will be
necessary to determine the role of oral valganciclovir in universal or preemptive prophylaxis, as a single prophylactic
agent or in combination with immunoglobulin preparations
and possibly for treatment of established disease.
The development of ganciclovir-resistant isolates necessitates the development of newer drugs that have high oral
bioavailability, low toxicity and mechanisms of action that
will allow them to be used against ganciclovir-resistant isolates. The recognition that HHV-6 and HHV-7 are conducive
to the development of CMV infection and may be additive
to the indirect effects of CMV on allograft function suggests that antivirals with an expanded spectrum against
these viruses would be desirable.
Conclusion
Lung transplant programs still need to refine the types of
CMV prophylactic strategies that best match individual re1224
cipients of seropositive and seronegative allografts and the
type of immunosuppression utilized. It seems clear that
universal prophylaxis is warranted for high-risk D+/R– recipients. However, it remains unclear as to whether R+
recipients are also at higher risk than other solid-organ
recipients and whether they should receive universal prophylaxis or preemptive therapy. The use of antilymphocyte globulin would also appear to warrant the use of
targeted, preemptive therapy with intravenous ganciclovir
followed by 2–3 months of an oral agent. The development
of high oral bioavailable drugs such as valganciclovir may
provide a more convenient method of prophylaxis or treatment of CMV infections. There is a role for prophylactic
hyperimmune anti-CMV immunoglobulin, which may offer advantages for specific lung transplant recipients and
improve both short-term and long-term morbidity and mortality. However, better definitions for which patients likely
benefit from it are needed owing to the lack of pharmacoeconomic analyses of the various strategies. Combination therapy may also provide the opportunity to prevent
and treat chronic and progressive allograft injury, particularly in the thoracic organs. Finally, molecular techniques
should be employed for the detection of CMV infection,
for determining the response to and duration of therapy
and for the determination of the emergence of ganciclovirresistant isolates. Ongoing studies should help to answer
these issues as well as generating new hypotheses in the
role of CMV infection in chronic allograft failure following
lung transplantation.
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