Donor CMV Serostatus and Dose Adjustments in CMV Prophylaxis Increase CMV Infection Risk after Lung Transplantation

Background: Although the risk of CMV reactivation after lung transplantation can be reduced by prophylaxis, the optimal prophylactic strategy has not been established.

Methods: We performed a cohort analysis of our 198 lung transplant recipients at Brigham and Women's Hospital from 1/08  - 12/14 to identify risk factors for CMV infection, using Cox proportional hazards models.

Results: Median age was 60 years (IQR 51, 65) and 125 (63%) were female.  Most common indications for lung transplant were interstitial lung disease (105, 53%), cystic fibrosis (29, 15%) and COPD (28, 14%). Median duration of CMV prophylaxis was 260 days (IQR 176, 378). CMV viremia developed in 36 patients (18%), 9 of whom also had CMV disease. CMV+ donor status (Figure 1, logrank p <0.001) and dose reduction of CMV prophylaxis due to renal impairment (Figure 2, logrank p 0.0009) were associated increased risk of CMV, while CMV prophylaxis, modeled as a time-varying covariate, was associated with a reduced risk of CMV, in univariable and multivariable models (Table). Among patients with CMV+ donors, risk of CMV viremia was independent of recipient CMV status. Six patients developed CMV viremia while receiving prophylaxis; 4 of whom had preceding reductions in valganciclovir dosing due to renal impairment. Three patients developed ganciclovir-resistant CMV infections; 2 of whom had a valganciclovir dose reduction due to renal dysfunction prior to development of resistance. CMV voremia was not associated with subsequent development of chronic lung allograft dysfunction or increased risk of death.

Conclusion: Donor CMV serostatus and CMV prophylaxis dose adjustments due to renal dysfunction were associated with higher rates of CMV infection, even after adjusting for time-varying exposure to herpesvirus prophylaxis. These patients may benefit from closer surveillance for CMV reactivation and monitoring of serum ganciclovir levels to ensure adequate dosing.

	Univariable Hazard Ratio (HR) (95% CI), p-value	Multivariable HR (95% CI), p-value
CMV D+ status	6.6 (2.8, 15.9), <0.001	9.4 (3.8, 23.3), <0.001
CMV prophylaxis dose reduction due to renal impairment	2.9 (1.4, 6.0), 0.004	2.8 (1.3, 6.2), 0.009
CMV prophylaxis	0.098 (0.04, 0.27), <0.001	0.046 (0.017, 0.13), <0.001

Table

Figure 1

Figure 2