Effectiveness of Prophylactic Human Cytomegalovirus Hyperimmunoglobulin in Preventing Cytomegalovirus Infection following Transplantation: A Systematic Review and Meta-Analysis

Abstract

Cytomegalovirus (CMV) is a common infection occurring in patients undergoing solid organ transplantation (SOT) or hematopoietic stem cell transplantation (HSCT). CMV-specific hyperimmunoglobulin (CMVIG) has been used for the past four decades and is typically administered either prophylactically or pre-emptively. The present meta-analysis evaluated CMV infection rates in SOT patients who received prophylactic CMVIG. PubMed and the Cochrane Library were searched for studies published up to October 2021. The primary endpoint was CMV infection rate. Thirty-two SOT studies were identified (n = 1521 CMVIG-treated and n = 1196 controls). Prophylactic CMVIG treatment was often associated with a lower risk of CMV infection in transplant recipients. The average CMV infection rate was 35.8% (95% confidence interval [CI]: 33.4–38.2%) in patients treated prophylactically with CMVIG and 41.4% (95% CI: 38.6–44.2%) in the control group not receiving CMVIG (p = 0.003). Similar results were observed in analyses limited to publications evaluating currently available CMVIG products (Cytotect CP and Cytogam; p < 0.001). In combination with the established safety profile for CMVIG, these results suggest that prophylactic CMVIG treatment in patients undergoing solid organ transplantation may be beneficial, particularly in those at high risk of CMV infection or disease.

Hyperimmune Globulins for the Management of Infectious Diseases

“…CMV-specific hyperimmunoglobulin (CMVIG) is prepared from donors with high anti-CMV titers, but regular IVIG also contains CMV antibodies at lower titers [ 8 ]. CMVIG and regular IVIG has been used extensively, either prophylactically or pre-emptively, in SOT and HSCT, and the results of clinical trials have been the object of systematic reviews and meta-analysis [ 22 , 23 , 24 ]. A Cochrane review [ 22 ] concluded that in patients undergoing HSCT, routine prophylaxis with IVIG is not supported, but its use may be considered in lymphoproliferative disorder patients with hypogammaglobulinemia and recurrent infections for a reduction in clinically documented infections.…”

Evaluation of Two Different CMV-Immunoglobulin Regimens for Combined CMV Prophylaxis in High-Risk Patients following Lung Transplant

“…However, a further meta-analysis including only randomized clinical trials found that prophylactic use of CMV-Ig was associated with increased survival, decreased risk of CMV-associated death and CMV disease but had no effect on CMV infections and clinically relevant rejections compared to placebo, no treatment, or antiviral prophylaxis alone [ 15 ]. Lastly, the most recent systematic review and meta-analysis reported that the rate of CMV infection was significantly lower among those receiving CMV-Ig prophylaxis (35.8% vs. 41.4%) with no difference in the time to infection compared with no CMV-Ig prophylaxis, a non-CMV-Ig prophylactic treatment, or placebo [ 16 ].…”

“…International surveys on the management of CMV in lung transplantation in D+/R– patients have reported that CMV-Ig is used as part of the universal prophylaxis strategy by 32% of centers and 38% of clinicians [ 17 , 18 ]. Moreover, a recent systematic review on the effectiveness of CMV-Ig adjunctive prophylaxis following SOT reported that the dosing regimen and schedule were highly variable between studies and centers [ 16 ]: Among those using CMV-Ig in lung transplants, the most common regimen was 150 mg/kg within 72 h of transplantation and every 2 weeks thereafter, but the dosing ranged between 100 and 150 mg/kg and 1–2 mL/kg in some studies. Additionally, the number of doses ranged between 1 and 12, the interval between doses between 1 day and 1 month, and the median duration of therapy post-transplantation between 1 month and 1 year [ 16 ].…”

“…Moreover, a recent systematic review on the effectiveness of CMV-Ig adjunctive prophylaxis following SOT reported that the dosing regimen and schedule were highly variable between studies and centers [ 16 ]: Among those using CMV-Ig in lung transplants, the most common regimen was 150 mg/kg within 72 h of transplantation and every 2 weeks thereafter, but the dosing ranged between 100 and 150 mg/kg and 1–2 mL/kg in some studies. Additionally, the number of doses ranged between 1 and 12, the interval between doses between 1 day and 1 month, and the median duration of therapy post-transplantation between 1 month and 1 year [ 16 ]. The authors concluded that there is a lack of real-world non-interventional studies assessing the diverse off-label use of CMV-Ig in routine clinical practice, which would provide important insights into the clinical benefits of CMV-Ig [ 16 ].…”

“…Additionally, the number of doses ranged between 1 and 12, the interval between doses between 1 day and 1 month, and the median duration of therapy post-transplantation between 1 month and 1 year [ 16 ]. The authors concluded that there is a lack of real-world non-interventional studies assessing the diverse off-label use of CMV-Ig in routine clinical practice, which would provide important insights into the clinical benefits of CMV-Ig [ 16 ].…”