A woman in her fifties (height = 152 cm, weight = 37.5 kg, and body mass index = 16.2 kg/m2) underwent living-donor lobar lung transplantation to address thoracic sarcoidosis, pulmonary hypertension, and pulmonary aspergilloma. Both the recipient and donor tested positive for CMV IgG antibodies. Figure 1 shows the clinical course of valganciclovir doses, ganciclovir trough concentrations, and various other laboratory parameters. The patient was markedly cachexic at the time of transplantation. Consequently, postoperative recovery was slow, and the patient required a prolonged hospital stay.

Clinical course post lung transplantation. Valganciclovir doses, laboratory data, and ganciclovir trough concentrations are shown. The white box indicates the actual dosage administered, whereas the shaded box represents the dosage based on renal function, as recommended by the instructions provided in the package insert. The lower detection limit for ganciclovir was 100 ng/mL. The upper limit of the ganciclovir trough concentration was 872 ng/mL, which is borderline for severe leukopenia

The lung transplantation procedure was successful despite encountering excessive bleeding exceeding 11 L owing to severe pleural adhesion. Immunosuppressive regimens (basiliximab, mycophenolate mofetil, and corticosteroids) were initiated on postoperative day (POD) 1. Mycophenolate mofetil was orally administered at 1,000 mg/day, and the dosage was reduced in the presence of leukopenia. Corticosteroid therapy was initiated with intravenous methylprednisolone at 125 mg/day for 3 days after transplantation and reduced to a stable dose of oral prednisolone (0.4 mg/kg) using a weekly weaning regimen. Basiliximab was administered on PODs 1 and 5, followed by tacrolimus on POD 8, with trough concentrations maintained at 8–10 ng/mL. Antiviral prophylaxis with intravenous ganciclovir (2.5 mg/kg/day, as label-indicated) was initiated on POD 7 but temporarily discontinued on POD 11 due to the decrease in creatinine clearance (19 mL/min). Continuous hemodiafiltration was performed on PODs 12–21. The decrease in creatinine clearance was caused by acute right-sided heart failure associated with pulmonary artery stenosis. Subsequently, with pulmonary artery stenting, the hemodynamics improved, and creatinine clearance increased to 51 mL/min. During hospitalization, the patient was monitored weekly for CMV infection through microbiological blood tests for CMV (CMV antigen test, HRP-C7; LSI Medience, Tokyo, Japan). CMV reactivation was defined as the presence of more than 5/50,000 positive cells. The number of positive cells increased slightly to 3/53,200 on POD 43. Valganciclovir (450 mg/day; label-indicated dose) was initiated on POD 43. Moreover, antibody-mediated rejection developed on POD 74, necessitating therapeutic intervention involving plasma exchange from POD 74 to 78, a steroid pulse on POD 109 to 111, and anti-thymocyte globulin from POD 119 to 125.

The patient experienced continuous post-hemodiafiltration withdrawal and exhibited relatively impaired renal function, leading us to hypothesize that this condition might delay ganciclovir excretion and heighten the risk of severe leukopenia. To avoid cessation of valganciclovir prophylaxis, we performed TDM to maintain trough concentrations of ganciclovir below 872 ng/mL, which is less toxic than that previously reported by our group [9]. Serum ganciclovir concentrations were measured using liquid chromatography-tandem mass spectrometry as described previously [9]. The lower limit of quantification of ganciclovir using this method was 100 ng/mL. For this case, the target trough concentration range for ganciclovir was established at 300–800 ng/mL following consultations with infectious disease specialists and pharmacists to mitigate the risk of toxicity. Although the prophylactic target concentration range of GCV has not been established, it was anticipated, based on our previous study [9], that maintaining the trough blood concentration of GCV above 300 ng/mL would prevent CMV reactivation. The trough concentration of ganciclovir was 1,235 ng/mL on POD 64 and 963 ng/mL on POD 68. The white blood cell count decreased from 4,190/μL (POD 62) to 2,220/μL (POD 68) and was considered an adverse reaction to valganciclovir. Therefore, the valganciclovir dose was reduced from 450 mg/day to 450 mg/2 days on POD 69. The mycophenolate mofetil dose was reduced from 1,000 to 500 mg/day. Owing to the presence of melena and anemia, an upper gastrointestinal endoscopy was performed on POD 89, which revealed multiple gastric ulcers. A real-time polymerase chain reaction performed on a sample taken from the patient’s stomach was negative for CMV, ruling out a gastrointestinal CMV infection. The patient was prescribed vonoprazan for the management of multiple gastric ulcers. On POD 85, the white blood cell count improved to 5,520/μL, and the ganciclovir trough concentration decreased to 540 ng/mL. On POD 230, the white blood cell count had decreased to 2,950/μL. The trough concentration of ganciclovir showed an upward trend, reaching 571 ng/mL. Meanwhile, the serum creatinine increased from 0.4 mg/dL (POD 222) to 0.71 mg/dL (POD 230), and the creatinine clearance decreased from 59.8 mL/min (POD 222) to 39.4 mL/min (POD 230). Therefore, the valganciclovir dose was reduced from 450 mg/ 2 days to 125 mg/day (dry syrup formulation) on POD 231. On POD 236, the white blood cell count improved to 3,790/μL, but renal function worsened with a creatinine level of 0.99 mg/dL and a creatinine clearance of 30.1 mL/min. Additionally, because the ganciclovir trough concentration was 771 ng/mL, nearing the upper limit of the toxic range, the dosage of valganciclovir was reduced from 125 mg/day to 50 mg/day (dry syrup formulation). On POD 237, a gradual decrease in renal function was observed, and the patient was diagnosed with calcineurin inhibitor nephropathy and vitamin D-related toxicities. As a result, eldecalcitol 0.75 µg was discontinued because it was challenging to reduce the dose of tacrolimus from the standpoint of rejection prevention. After the discontinuation of eldecalcitol, renal function improved. On POD 243, the white blood cell count improved to 4,550/μL, and the ganciclovir trough concentration decreased to 283 ng/mL. On POD 256, the prophylactic administration of valganciclovir for CMV was completed because the risk of CMV infection was low. The patient was transferred to another hospital for rehabilitation on POD 257. During the observation period, we adjusted the ganciclovir trough concentration to within the optimal range of 300–800 ng/mL and noted no incidence of severe leukopenia related to valganciclovir administration. Furthermore, neutropenia and thrombocytopenia were not severe (Fig. 1), and no other adverse events or CMV reactivation were observed.