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et al. 2006; Lautenschlager et al. 2006; Potena et al. 2006). Infection by virus present
in the transplanted organ also develops in patients with a past HCMV infection
(superinfection or reinfection), further demonstrating the importance of the trans-
planted organ as a source of virus (Chou 1986; Gnann et al. 1998; Grundy et al.
1988). The incidence of clinically significant CMV infections in D
+
/R
+
allografts has
been reported to be increased as compared to D
-
/R
+
, suggesting that acquisition of a
new strain of virus from the transplanted organ results in disease more frequently than
reactivation of the recipient endogenous virus (Chou 1987; Grundy et al. 1988).
Several explanations have been offered for this interesting observation, yet none
has been definitively investigated. One potential explanation is that the graft-acquired
virus could be antigenically different than the endogenous virus, thus requiring a
somewhat more primary-like immune response for virus control and clearance, simi-
lar to a response following primary infection in a D
+
/R
-
transplant situation.
Alternatively, the newly acquired virus could encode additional virulence character-
istics not present in the endogenous virus of the recipient. Virus has been demonstrated
in mononuclear cells present in transplanted organs, and studies have demonstrated that
replicating virus can be recovered from mononuclear cells obtained from patients with
past infection when these cells are exposed to a mixture of cytokines derived from
allogenically stimulated lymphocytes (Soderberg-Naucler et al. 1997). Studies in
transgenic mice with a reporter gene under control of the major immediate promoter of
HCMV have demonstrated that this promoter-enhancer can be activated by inflamma-
tory cytokines such as TNF that are produced in animals with transplanted allografts
(Koffron et al. 1999; Hummel et al. 2001). In addition, more recent studies in an animal
model system have shown that renal allograft ischemia and reperfusion injury activates
the major immediate promoter of HCMV independently of TNF pathways, suggesting
that ischemia and reperfusion alone are sufficient to reactivate HCMV from a trans-
planted allograft (Kim et al. 2005).
Infectious virus has been proposed to disseminate to distant sites in polymorpho-
nuclear leukocytes and in infected endothelial cells detached from small vessels, as
discussed in the previous section. End-organ disease following HCMV infection in
both hematopoietic and solid organ allograft recipients has been most closely
correlated with the presence of replicating virus in the host and by increased virus
load as measured by PCR.
The quantity of virus measured in the blood or other body fluids has been
reported to be a predictor of acute disease regardless of pretransplantation risk factors
for HCMV infections in solid organ allograft recipients, such as an organ from a
infected donor transplanted into a noninfected recipient (D
+
/R
-
) (Cope et al. 1997;
Gor et al. 1998; Emery et al. 2000; Limaye et al. 2001; Martin-Davila et al. 2005;
Gentile et al. 2006). Thus, monitoring patients with quantitative PCR techniques
have provided a noninvasive method for identification of patients at risk for
disseminated infection, and patients identified prior to the development of overt
disease are more likely to benefit from antiviral therapy.
As was noted previously, many of these earlier studies were carried out in an
era when widespread antiviral prophylaxis was limited and preemptive approaches
for prevention of severe CMV infections represented standard of care. Antiviral
