Antiviral toxicities in pediatric solid organ transplant recipients

Abstract

Prophylaxis with valganciclovir (VGCV) is used routinely to prevent cytomegalovirus (CMV) infections in at‐risk pediatric solid organ transplant (SOT) recipients. However, the rate and factors associated with toxicities in this population are not well‐described. We conducted a retrospective cohort study of children undergoing SOT at our hospital from January 2012–June 2018. We evaluated the frequency of hematologic and renal toxicities from day 15 through 1‐year post‐SOT in relation to antiviral exposures, focused on VGCV prophylaxis. Marginal rate models were used to determine the risk of kidney injury and neutropenia in relation to VGCV prophylaxis. Among 281 SOTs, VGCV prophylaxis was administered on 20.1% of all follow‐up days. The incidence rates of kidney injury, leukopenia, and neutropenia were significantly higher during VGCV prophylaxis compared to when no antiviral agents were given. Using multivariable marginal rate models, receipt of VGCV prophylaxis was associated with development of kidney injury (rate ratio [RR] 1.79, 95% confidence interval [CI]: 1.22–2.65) and neutropenia (RR 4.82, 95% CI: 3.08–7.55). VGCV dosing did not impact the development of kidney injury or neutropenia. Toxicities are common with VGCV prophylaxis in pediatric SOT recipients.

New Insights on CMV Management in Solid Organ Transplant Patients: Prevention, Treatment, and Management of Resistant/Refractory Disease

“…Neutropenia is frequently observed after solid-organ transplantation. It occurs in up to 30–40% of patients within the first year after transplantation [ 9 – 11 ]. It is mainly related to use of myelotoxic drugs such as polyclonal antibodies, mycophenolic acid, mammalian target of rapamycin inhibitors, VGCV, and trimethoprim/sulfamethoxazole.…”

“…In a recent study that included 572 adults who received a kidney transplant and were CMV mismatched or had a panel reactive antibody rate ≥ 80%, 208 (36.3%) participants had neutropenia that was defined as absolute neutrophil count < 1000 cells/μl. In a pediatric cohort of SOT patients, VGCV prophylaxis was associated with neutropenia [ 11 ]. In patients presenting with neutropenia, physicians are prompted to either decrease or stop VGCV, decrease or stop mycophenolic acid, stop trimethoprim/sulfamethoxazole, or use of granulocyte colony stimulating factors (G-CSF).…”

“Weight‐ing” for an answer on optimal valganciclovir prophylaxis dosing in pediatric solid organ transplantation recipients

“…ValGCV, a pro‐drug of ganciclovir, is a deoxynucleoside analogue CMV DNA polymerase inhibitor indicated for the prevention of CMV disease in high‐risk pediatric kidney and heart transplant recipients when started within 10 days of SOT 1,3,4 . Primary dose‐limiting toxicities of valGCV include bone marrow suppression, including leukopenia and neutropenia and less frequently, nephrotoxicity, that is compounded by concomitant receipt of other nephrotoxic medications (e.g., calcineurin inhibitors) 4,5 …”

“…1,3,4 Primary dose-limiting toxicities of valGCV include bone marrow suppression, including leukopenia and neutropenia and less frequently, nephrotoxicity, that is compounded by concomitant receipt of other nephrotoxic medications (e.g., calcineurin inhibitors). 4,5 Despite the widespread use of valGCV as prophylaxis, there is a paucity of pediatric pharmacokinetic (PK) data to guide dosing recommendations in pSOT. The lack of a standardized strategy in all pediatric age ranges has resulted in considerable variability in valGCV dosing regimens and durations across pSOT centers, even within graft types at the same center, and suboptimal target exposures.…”

Prevention and management of CMV infection in pediatric solid organ transplant recipients

“…Several studies have demonstrated efficacy of ganciclovir and valganciclovir for the treatment of CMV in adult SOT recipients, and this is largely extrapolated to the pediatric SOT population ( 30 – 32 ). Hematologic toxicities such as leukopenia, neutropenia, thrombocytopenia, and anemia are well-known and reversible adverse effects of ganciclovir and valganciclovir ( 33 ). These agents are recommended to be used with caution in patients with pre-existing cytopenias, and use should be avoided when ANC < 500 cells/ml, platelet count is <25,000/ml, or hemoglobin <8 g/dl.…”