Cytomegalovirus (CMV) antigenemia assay enables a rapid, quantitative, and noninvasive monitoring of CMV infection, which is widely used as a sign for starting preemptive therapy with ganciclovir after allogeneic hematopoietic stem cell transplantation. Nichols et al1 recently reported that host factors such as the receipt of corticosteroids were important for predicting antigenemia response to treatment with ganciclovir. Referring to their study, we performed an additional analysis with our patients to demonstrate that the inclusion of antithymocyte globulin (ATG) in the conditioning regimen could be another risk factor.

Eighty-seven adult patients underwent allogeneic hematopoietic stem cell transplantation in our center between April 1998 and May 2000. Among them, 84 patients (51 bone marrow transplantation and 33 peripheral blood stem cell transplantation) who showed engraftment were analyzed. An antigenemia assay was performed at least once a week after engraftment using the monoclonal antibody HRP-C7 (Teijin, Tokyo, Japan) raised against CMV immediate early antigen, as described in our risk-adapted and response-oriented preemptive therapy.2 High-level antigenemia was defined as a positive result with 10 or more positive cells per 50 000 cells. High-risk patients were defined as those who received transplants from alternative donors, those receiving ATG as part of the preparative regimen, those with grade II-IV acute graft-versus-host disease, and those receiving more than 0.5 mg/kg (methyl-) prednisolone. Ganciclovir was started when high-level CMV antigenemia developed in low-risk patients or when antigenemia at a level of 5 or lower was seen in high-risk patients, with an initial dose of 5 mg/kg twice daily. This was continued for at least one week until the antigenemia began to decrease, and was followed by a 5 mg/kg daily administration while antigenemia remained positive. We used the same definition as Nichols et al for rising antigenemia, which was an increase of 5 times the baseline antigenemia level, in the following analyses.

Rising antigenemia was observed in 7 (16%) of the 43 patients who received ganciclovir therapy at 1 (n = 4), 2 (n = 2), or 3 weeks (n = 1). In a univariate analysis, the recipients' age (40 or older) and the use of ATG were identified as risk factors for rising antigenemia (Table 1). The impact of steroid therapy could not be reliably evaluated since only a few patients required persistent/intensive treatment with a dose exceeding 2 mg/kg. A backward stepwise logistic regression analysis revealed that only the use of ATG independently affected the incidence of rising antigenemia. Therefore, our findings further support the possibility raised by Nichols et al that host factors mainly contribute to increasing viral load during preemptive therapy.

Table 1.

Risk factors for rising antigenemia

Odds ratioP
Patient age   
 Younger than 40 years 1.0  
 At least 40 years 6.5 (1.1-39) .04 
Donor type   
 Matched sibling 1.0  
 Alternative donor 1.3 (0.2-7.4) >.99 
HLA   
 Match 1.0  
 Mismatch 2.3 (0.4-12) .38 
Conditioning   
 Non-TBI 1.0  
 TBI 0.2 (0.04-1.2) .08 
Conditioning   
 Non-ATG 1.0  
 ATG 10.7 (1.7-66) .02 
Stem cell   
 Peripheral blood 1.0  
 Bone marrow 3.0 (0.3-28) .41  
Acute GVHD   
 Grades 0-1 1.0  
 Grades 2-4 1.8 (0.3-10) .68 
Odds ratioP
Patient age   
 Younger than 40 years 1.0  
 At least 40 years 6.5 (1.1-39) .04 
Donor type   
 Matched sibling 1.0  
 Alternative donor 1.3 (0.2-7.4) >.99 
HLA   
 Match 1.0  
 Mismatch 2.3 (0.4-12) .38 
Conditioning   
 Non-TBI 1.0  
 TBI 0.2 (0.04-1.2) .08 
Conditioning   
 Non-ATG 1.0  
 ATG 10.7 (1.7-66) .02 
Stem cell   
 Peripheral blood 1.0  
 Bone marrow 3.0 (0.3-28) .41  
Acute GVHD   
 Grades 0-1 1.0  
 Grades 2-4 1.8 (0.3-10) .68 

Numbers in parentheses show the 95% confidence interval of the odds ratio. HLA indicates human leukocyte antigen; TBI, total body irradiation; ATG, GVHD, graft-versus-host disease.

A total of 8 patients received ATG as part of a nonmyeloablative regimen (n = 5) or to prevent graft rejection in a mismatched transplant (n = 3). The use of ATG for conditioning has been shown to delay immune reconstitution after transplantation.3,4 Nonetheless, we could completely prevent the breakthrough CMV disease in such patients with profound immunosuppression by continuing the induction dosing until the antigenemia level began to decrease. The antigenemia level should be closely monitored even after starting ganciclovir, and the dose should be modified according to the response of the antigenemia level to ganciclovir treatment.

References

References
1
Nichols
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Corey
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Gooley
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et al
Rising pp65 antigenemia during preemptive anticytomegalovirus therapy after allogeneic hematopoietic stem cell transplantation: risk factors, correlation with DNA load, and outcomes.
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2
Kanda
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Preemptive therapy against cytomegalovirus (CMV) diseases guided by CMV antigenemia assay after allogeneic hematopoietic stem cell transplantation: a single-center experience in Japan.
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3
Saito
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et al
Successful nonmyeloablative transplant (NST) using a novel combination of cladribine (2-CdA)/busulfan (BU)/ATG: early full donor chimerism but delayed immune reconstitution [abstract].
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4
Duval
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et al
Higher dosage of pregraft antithymocyte globulin (ATG) may negatively influence immune reconstitution and survival after stem cell transplantation (SCT) [abstract].
Blood.
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788a