Download Prognostic Significance and Risk Factors of Untreated

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CONCISE COMMUNICATIONS
Prognostic Significance and Risk Factors of Untreated Cytomegalovirus Viremia
in Liver Transplant Recipients
Andrew D. Badley, Robin Patel, Daniel F. Portela,
William S. Harmsen, Thomas F. Smith, Duane M. I1strup,
Jeffery L. Steers, Russell H. Wiesner, and Carlos V. Paya
Divisions of Infectious Diseases and Microbiology and Departments of
Biostatistics and Liver Transplantation Unit, Mayo Clinic,
Rochester, Minnesota
To study whether cytomegalovirus(CMV)viremia is a reliable marker of impending CMV disease
and thus a guide for preemptive antiviral therapy, 126 consecutive liver transplant recipients were
followed by routine CMV blood cultures in the absence of antiviral prophylaxis or treatment for
viremia. Seventy-three patients (58%) developed CMV infections, and 36 (29%)had more than one
infection episode: 29 patients (23%) had organ involvement and 45 (36%) had viremia. Within a
same episode, CMV viremia was 90% sensitive and 80% specific for predicting concurrent organ
involvement but preceded organ involvement in only 9 (31%) of 29 patients. In a separate analysis,
untreated isolated CMV viremia in the first CMV infection episode was followed by organ involvement in a subsequent episode in 9 (33%) of 28 patients, mainly in the donor-positive, recipientnegative (D+/R-) population. The results indicate that CMV viremia is not an ideal marker to
guide preemptive antiviral treatment in liver transplant recipients but is a good marker in D+/Rpatients.
Cytomegalovirus (CMV) is an important opportumstrc
pathogen in solid-organ transplant recipients. It directly causes
morbidity and mortality, indirectly influences immunosuppression, and possibly leads to chronic allograft dysfunction [1].
To decrease the incidence of CMV infection in liver transplant
recipients and thus its impact on morbidity and mortality, recent
clinical research has focused on the role of prophylaxis and
preemptive therapy. Prophylactic strategies involve the administration of antiviral agents from the time of transplant to decrease the incidence of CMV infection. Because prophylactic
therapy has been of moderate or little success in CMV-seronegative liver transplant recipients who receive CMV-seropositive
organs [2,3], preemptive strategies have been proposed. These
strategies are based on a clinical or laboratory characteristic
that identifies patients deemed to be at high risk for developing
CMV infection. Such measures are being used for liver transplant patients receiving OKT3 [4, 5], and their use has been
suggested for patients with preclinical CMV infection, as measured by CMV antigenemia [6] or polymerase chain reaction
(PCR) detection of viral DNA [7].
Preemptive therapy is used for patients with CMV viremia
on the basis of the postulate that viremia is a reliable predictor
of subsequent organ involvement. CMV viremia is a marker
of CMV disease in renal transplant recipients [8]; however, in
bone marrow transplant recipients, in whom the pathogenesis
of CMV infection differs from that of solid-organ transplant
recipients, the sensitivity ofCMV viremia is 45% for predicting
subsequent organ involvement [9]. Moreover, in human immunodeficiency virus (HIV)-infected patients, the ability of CMV
viremia to predict disease is significantly low [10].
To establish the predictive value of CMV viremia as a
marker of concomitant and impending CMV organ involvement, a population of solid-organ transplant recipients is required. The study population must have prospective viral culture surveillance, but antiviral prophylaxis and treatment for
isolated viremia must be precluded. Results from such studies,
which may differ among different types of solid-organ transplants, would establish whether the easily accessible and relatively simple diagnosis of viremia should be used as a marker
for preemptive therapy. For this purpose, we analyzed a defined
and homogeneous cohort of liver transplant recipients who
fulfilled the above characteristics.
Materials and Methods
Received 12 June 1995; revised 6 October 1995.
Reprints or correspondence: Dr. Carlos V. Paya, Division of Infectious
Diseases, Mayo Clinic, 200 First St. S.W., Guggenheim 501, Rochester, MN
55905.
The Journal of Infectious Diseases 1996; 173:446-9
© 1996by The Universityof Chicago. All rights reserved.
0022-1899/96/7302~0023$0 1.00
Patients. One hundred twenty-six consecutive patients who
underwent a first liver transplant at the Mayo Clinic between March
1986 and June 1989 were included in this study. These patients
did not receive ganciclovir, immunoglobulin, or other anti-CMV
prophylaxis. Ganciclovir, which was available only on a compassionate basis, was limited to treatment of documented organ
involvement and was not available for patients with isolated vire-
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1996; 173 (February)
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Concise Communications
mia. Patients who had more than one transplant were included in
the analysis for the first transplant only. Twenty-five patients
(19.8%) received prednisone immunosuppression within the 3
months prior to the transplant. Thirty-six patients (28.8%) had a
Roux-en-Y procedure. The mean age at transplant was 41.5 years
(median, 43.8; range, 4.5-61.5). Seventy-four patients (58.7%)
were male. Pretransplant diagnoses included primary biliary cirrhosis (33 patients), primary sclerosing cholangitis (30 patients),
hepatitis C (7 patients), hepatitis B (l patient), a-I-antitrypsin
deficiency (3 patients), alcoholic liver disease (2 patients), cryptogenic cirrhosis (26 patients), autoimmune chronic active hepatitis
(4 patients), fulminant hepatitis (10 patients), tumors (3 patients),
and other (7 patients). Thirty-six transplant recipients were CMV
seropositive but received CMV-negative donor organs (D-/R+),
20 were D+/R-, 22 were D-/R-, and 46 were D+/R +; 2 patients
did not have complete CMV serologic data.
Patients were given oral selective bowel decontamination starting on the day of liver transplant and continuing for 21 days or until
hospital discharge, whichever was longer [II]. Perioperatively,
patients were given a low bacterial diet, cefotaxime (l g/6 h), and
tobramycin (80 mg/8 h) until 48 h after the transplant. CMVseronegative patients who received a CMV-seronegative organ
(D-/R-) were given CMV-negative blood for the first 24 U of
red blood cells required. The immunosuppressive regimen included
prednisone, cyclosporin, and azathioprine as previously described
[9]. Rejection was diagnosed histologically with liver biopsy specimens. Routine liver biopsies were done at weeks I, 3, 12, 26, and
52; other biopsies were obtained whenever hepatic dysfunction
occurred. Cellular rejection episodes were treated intravenously
with I g of methylprednisone every other day for 6 days or with
1 or 2 g of methylprednisone for 2 days, followed by a prednisone
taper. For steroid-resistant rejection, OKT3 (Ortho Pharmaceuticals, Raritan, NJ) was administered (5 mg/kg/day for 10 days).
Serology and viral culture. Anti-CMV IgG and IgM were
measured by an indirect immunofluorescence assay [II]. Blood
cultures were done by tube cell and rapid shell vial techniques,
and urine cultures were done by shell vial techniques [7]. Blood
and urine samples were cultured for CMV at weekly intervals for
a minimum of 8 weeks after transplantation and whenever CMV
infection was suspected. Thereafter, CMV cultures were done routinelyat 3, 6, and 12 months or whenever CMV infection was
clinically suspected.
Clinical definitions. CMV infection was defined as the isolation of CMV from any body fluid or tissue, the detection of CMV
in tissue (see below), or the detection of new serum IgM against
CMV. CMV infection was considered asymptomatic when it occurred without clinical symptoms and signs or laboratory abnormalities; CMV infection was considered symptomatic when it occurred in conjunction with clinical symptoms or signs compatible
with CMV disease or with documented evidence of organ invasion
(i.e., a tissue biopsy specimen demonstrating cytomegalic inclusion
bodies, positive cultures, DNA hybridization. and/or positive immunofluorescence for CMV). CMV viremia was defined when a
blood specimen was positive for CMY by shell vial assay or tube
cell culture. A patient was considered to have a relapsing episode
of CMV infection when one or more of the above definitions for
CMV infection were met> 30 days after the previous manifestation of CMV infection. Ganciclovir (5 mg/kg) was given intravenouslyevery 12 h for 14 days only when organ invasion by CMV
Table 1. Manifestations of CMV infection in 73 of 126 liver transplant recipients.
Viremia
No. of
patients
28
Viruria
Asymptomatic
Symptomatic
Organ
involvement
+
+
1
+
6
+
2
+
+
6
2
+
+
+
1
26
+
+
+
Total
NOTE.
37
+
+
+
I
10
35
29
53 transplant patients did not develop CMV infection.
was documented, as part of the criteria established by the manufacturer for its use on a compassionate basis.
Statistics. For risk factors that could be measured before or at
the time of transplantation, the log-rank test was used. Continuous
variables, such as age, were analyzed by the Cox proportional
hazards model and the log-rank test, with which values above the
75th percentile were compared to values below that percentile. For
risk factors that occurred at various times after transplantation,
such as allograft rejection or its treatment, time-dependent Cox
proportional hazards models were used. These methods for this
type of analysis in transplant recipients have been previously described by our group [II]. Risk factors initially defined from this
analysis were evaluated using a multivariate time-dependant Cox
model analysis and included pretransplantation diagnosis; sex; age;
CMY donor and recipient serostatus; HLA matching; active CMV
infection at the time of transplantation; immunosuppression within
3 months before transplantation; Roux-en-Y biliary anastomosis;
preoperative levels of creatinine, bilirubin, alanine aminotransferase, globulin, and pseudocholinesterase; prothrombin time; total
intraoperative surgical time; amounts of transfused total and autologous red blood cells, fresh frozen plasma, and cryoprecipitate;
amount of transfused and postoperative platelets; type of immunosuppression; number of rejection episodes; treatment of rejection
with OKT3; and, when appropriate, CMV infection and asymptomatic and symptomatic viremia.
Results
CMV infections. Seventy-three (58%) of the 126 patients
developed CMV infection. The initial virologic manifestation
of CMV disease was organ involvement alone in 2 patients,
viruria in 29, symptomatic viremia with organ involvement in
17, symptomatic viremia without organ involvement in 15, and
asymptomatic viremia either alone or with viruria in 10 patients
(table I). Only 2 episodes ofCMY disease occurred z-S weeks
after transplantation.
Thirty-eight (52.0%) of the 73 CMY-infected patients had
CMY disease, and more than one indication of disease occurred
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Table 2. Number of liver transplant recipients organ involvement
as a function of CMV viremia.
Organ involvement
Present
Absent
Total
Viremia
Present
Absent
26
3
19
78
45
28
Total
29
97
126
NOTE. Positive predictive value = 26/(26 + 19) = 58%; negative
predictive value = 78/(78 + 3) = 96% sensitivity = 26/29 = 90% (95%
confidence interval [eI] = 73%-98%); specificity = 78/97 = 80% (95% CI
= 65%-93%).
in 36 (49.3%) of them. The frequency of CMY disease was
highest in D+/R- patients. The cumulative probabilities of
being free of disease at 60 days were as follows for the different
transplant groups: D-/R-, 80.2% (95% confidence interval
[CI] = 64.6%-99.6%); D-/R+, 88.9% (95% CI = 79.2%99.8%); D+/R-, 21.1% (95% CI = 8.8%-50.3%); and D+/
R+, 56.5% (95% CI = 43.5%-73.3%).
Ability of viremia to predict concurrent organ involvement.
While 19 patients had CMY organ involvement as their initial
CMY manifestation, 29 had CMY organ involvement at some
point during the study. Eleven patients had CMY hepatitis, 8
had pneumonia, 2 had gastrointestinal CMY, and 1 had CMY
retinitis. Seven remaining patients had more than one organ
involved. Of these 29 patients, 26 (90%) also had viremia at
the time of CMY organ infection. The value of concurrent
viremia as a predictor of organ involvement was assessed by
a 2 X 2 table analysis (table 2). This analysis revealed a sensitivity of 90%, a specificity of 80%, and positive and negative
predictive values of 58% and 96%, respectively.
Frequency of viremia preceding organ involvement. The
low positive predictive value of concurrent viremia to predict
organ involvement prompted us to determine the frequency
with which viremia (either symptomatic or asymptomatic) preceded organ involvement. This was done in two ways. First,
we determined in how many patients organ involvement was
preceded by viremia within the same CMY infection episode,
and, second, we determined in how many patients with CMY
viremia organ involvement developed in a subsequent CMY
infection episode. The former analysis examines the frequency
that patients with organ involvement have preceding viremia
(and thus the utility of viremia as a preemptive marker). The
latter analysis examines the risk of untreated viremia.
The first analysis disclosed that among the 29 patients with
CMY organ involvement, 17 (58%) had viremia that developed
at the same time as the organ involvement, 9 (31%) had viremia
(8 symptomatic, 1 asymptomatic) a minimum of3 days (mean,
16.6; median, 9) preceding organ involvement, and 3 never
had documented viremia. In the second analysis, 28 patients
JID 1996; 173 (February)
had viremia (26 symptomatic, 2 asymptomatic) as the first
CMY episode, which was initially not associated with organ
involvement and was not treated. Of the second group of 28
patients, 9 subsequently developed organ involvement in another infection episode > 30 days after the first, generating an
incidence of CMY organ involvement of 32% in patients with
untreated CMY viremia. Among these 9 patients, 5 (56%) were
classified as D+/R-, 2 (22%) as D+/R+, and I each (11%)
as D-IR- and D-/R+.
Risk-factor analysis. Univariate risk-factor analysis for the
development of CMY viremia (symptomatic or asymptomatic)
revealed that fulminant hepatitis (P = .03) and preoperative
liver dysfunction (P = .05), as measured by total bilirubin
above the 75th percentile (> 16.2 mg/dl.), were significant risk
factors. CMY donor-positive serostatus was most highly correlated with the development of viremia (P < .01). When data
were analyzed for the development of symptomatic viremia
alone (with or without organ involvement), CMY recipientpositive serostatus (P = .02) and CMY donor-positive serostatus (P < .01) were associated with an increased risk of symptomatic viremia. Having received OKT3 immunosuppression
was not statistically associated with an enhanced risk of symptomatic viremia (P = .08). The only identified risk factor for
the development of asymptomatic viremia was a low preoperative level of pseudocholinesterase «2 U/mL; P = .02).
Multivariate risk factor modeling for the development of
any CMY viremia confirmed the importance of CMY donor
serostatus (relative risk [RR] = 5.6, CI = 2.5-12.7, P < .01)
and preoperative liver dysfunction, as measured by increased
bilirubin (>16.2 mg/dL; RR = 2.2, C1 = 1.2-4.3, P = .01).
Multivariate modeling also confirmed that CMV donor-positive serostatus was a risk factor for symptomatic viremia (RR =
6.7, CI = 2.6-17.6, P < .01). Similarly, multivariate analysis
identified CMY donor-positive serostatus (RR = 5.9, CI =
2.4-14.4, P <.01) as a risk factor for the development of
symptomatic viremia with organ involvement. No risk factors
were significantly associated with asymptomatic viremia by
multivariate analysis. Last, symptomatic viremia proved to be
a risk factor for death or retransplant (RR = 1.9, CI = 1.03.6, P = .04).
Discussion
This study was designed to analyze whether CMY viremia
can be used as a marker for preemptive therapy in liver transplant patients not receiving anti-CMY prophylaxis and to identify risk factors that lead to the development of viremia in this
cohort of patients. Our data indicate that CMY viremia is a
sensitive but not specific marker of concurrent organ involvement. In addition, only one-third of patients with organ involvement have preceding viremia and only one-third of patients
with isolated viremia will progress to organ involvement.
Therefore, viremia is a poor marker by which to guide preemptive therapy.
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Given the substantial morbidity, mortality, and cost associated with CMY organ disease in patients with solid-organ transplants, clinically useful markers of impending CMY organ invasion are needed to target preemptive therapy strategies. CMY
viruria and serologic assays are nonspecific markers for CMY
tissue infection [12], and isolation of CMY from bronchoalveolar lavage done prospectively is impractical in abdominal
solid-organ transplant recipients. However, isolation of CMY
in peripheral blood mononuclear cells is relatively simple and
economical and has been suggested as a marker of CMY disease. In our study population, 32% of patients with untreated
isolated viremia developed CMY organ infection. In addition,
only 31% of patients with CMY organ infection had CMY
viremia that preceded organ involvement by ?3 days, thereby
indicating that viremia was a poor predictor of impending organ
infection. These data are consistent with results from a recently
published trial, in which a smaller number of liver transplant
recipients receiving prophylaxis with either acyclovir or ganciclovir had CMY viremia that preceded organ involvement in
25% and 22% of cases, respectively [13].
CMY viremia is a poor predictor of CMY organ involvement
(positive predictive value of 58%). Despite this, with a negative
predictive value of 96%, the chance of a patient having organ
involvement without coexisting viremia is extremely low.
Therein lies the clinical utility of CMY viremia as a marker of
CMY tissue infection. In addition, there was a disproportionate
number ofD+/R- viremic patients (5/9, 55%) compared with
D+/R- patients (20/124, 16%) in our study who progressed
to develop CMY organ infection in subsequent episodes. This
finding suggests a higher risk for mismatch organ transplant
patients (D+/R-) with viremia to develop invasive disease in
subsequent (> 30 days later) CMY infection episodes. It is not
known whether treating isolated CMY viremia will result in
decreased incidence of subsequent organ involvement; however, on the basis of these data, it seems logical that D+/Rtransplant patients should receive antiviral therapy at the time
of viremia, but organ recipients who belong to the other CMY
serogroups should not.
Aside from demonstrating that the previously identified risk
factor of donor CMY seropositivity predisposes to symptomatic
and asymptomatic CMY viremia, we also demonstrated that
the degree of preoperative liver dysfunction is an important risk
factor for the development of any clinically defined viremia.
Although OKT3 was found not to be strictly a statistically
significant risk factor (P = .08), a recent study with a larger
number of patients found it significant, although the end point
was CMY infection, not viremia in general [14]. In addition,
untreated symptomatic viremia is a risk factor for death or
retransplantation. What was surprising from this analysis is
that we could not find a specific risk factor that could identify
and differentiate symptomatic from asymptomatic viremia, although the fact that D+/R - patients have a higher incidence
of subsequent organ involvement if viremia is left untreated
places this group in the high-risk category.
449
Since CMY viremia is a nonspecific predictor of CMY tissue
infection, more accurate markers of impending invasive CMY
disease are needed. The roles that CMY antigenemia and PCR
detection of viral DNA play in predicting subsequent CMY tissue
invasion remain to be defined. Once a clinically useful method
for predicting CMY disease in solid-organ transplant patients is
validated, meaningful preemptive strategies can be designed.
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