To the Editor:
Coronavirus disease 2019 (COVID-19) has resulted in a widespread pandemic in which various therapeutics have been studied. Targeted therapies focus on either the viral or the inflammatory phase to ultimately reduce disease progression. Tocilizumab, an interleukin 6 inhibitor, may have a role in preventing COVID-19–related disease progression.1 According to the current Infectious Disease Society of America (IDSA) guidelines, tocilizumab may be considered in addition to the standard of care (ie, steroids) in hospitalized patients with severe disease, defined as an Spo2 ≤94% on room air requiring supplemental oxygen, or with critical illness, defined as patients on mechanical ventilation and extracorporeal membrane oxygenation (ECMO).1 In addition, studies have indicated that patients with markedly elevated systemic inflammatory markers (C-reactive protein ≥75 mg/L) and elevated proinflammatory cytokines (ie, interleukin 6) may benefit from tocilizumab.1,2 Most recently, the RECOVERY trial demonstrated a reduction in the likelihood of the composite outcome of progression to mechanical ventilation or death, but did not improve survival.3 Notably, tocilizumab carries an FDA Black Box Warning for increased risk of serious infection (active tuberculosis, invasive fungal infections, and opportunistic bacterial and viral infections).4
In the case of serious infection that results secondary to tocilizumab therapy, treatment strategies are dependent on the infection isolated, patient-specific factors, and disease severity. There is currently a lack of literature on the optimal treatment dosing regimen in patients with cytomegalovirus (CMV) viremia and severe COVID-19 disease with progression to venovenous (VV) ECMO.4,5 Murphy and colleagues6 reported a case of a neonate with congenital CMV viremia on ECMO and assessed the pharmacokinetics of ganciclovir treatment. Noteworthy findings suggested that the standard 5 mg/kg every 12 hours was insufficient to obtain therapeutic area under the curve parameters.6,7 The authors therefore recommended an increased dosing protocol of 6 mg/kg every 12 hours in patients receiving ECMO. We report a case of dose-adjusted ganciclovir (6 mg/kg every 12 hours) treatment in a patient with CMV viremia secondary to tocilizumab for COVID-19 while on VV ECMO.
The patient was a 49-year-old man (actual body weight: 91.6 kg, ideal body weight: 68.4 kg, adjusted body weight [AdjBW]: 77.7 kg, body mass index: 35.97 kg/m2) with no significant medical history who was diagnosed with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection. He was admitted to an outside hospital, and initial management strategies consisted of remdesivir and corticosteroids, followed by convalescent plasma and tocilizumab, ultimately requiring invasive mechanical ventilation. Due to a lack of improvement over 14 days, the patient was cannulated for VV ECMO. He was then transferred to the flagship facility for higher level of care on hospital day 69. Data regarding systemic inflammatory markers and tocilizumab dosing were unavailable, as patient was transferred from an outside hospital.
The patient's clinical course was complicated by several nosocomial/opportunistic infections. Fifty-seven days after tocilizumab, bronchoalveolar lavage cultures were positive for Stenotrophomonas maltophilia, Pseudomonas aeruginosa, and an unidentified mold. Initial treatment consisted of levofloxacin, cefepime, inhaled tobramycin, and voriconazole for 5 days. Due to QTc prolongation (>600 milliseconds), therapy was adjusted to eravacycline, cefepime, inhaled tobramycin, and liposomal amphotericin B for an additional 9-day course. After speciation of the mold (Aspergillus terreus), antifungal therapy was rotated to isavuconazole for an additional 14 days given the concern for intrinsic resistance to liposomal amphotericin B. Sixty-two days after tocilizumab, the patient had a positive serum CMV polymerase chain reaction with a viral load of 107,933 copies/mL, log = 5.03 IU/mL. Due to severity of illness and concern for altered pharmacokinetic and pharmacodynamic parameters while on VV ECMO, dose-adjusted ganciclovir (6 mg/kg [450 mg based on AdjBW] every 12 hours) was initiated. Notably, the patient was thrombocytopenic before ganciclovir initiation (Table 1), which did worsen around day 12 of therapy. Ganciclovir was subsequently dose-adjusted to 4.5 mg/kg (350 mg) every 12 hours.
TABLE 1 -
Plasma CMV PCR Trends and Ganciclovir Dosing Throughout Hospitalization
|Day From Tocilizumab
||CMV Viral Load (0 Copies/mL)
||CMV Log (0 Copies/mL)
||Platelets (140–440 K/μL)
*6 mg/kg every 12 hours based on AdjBW.
†4.5 mg/kg every 12 hours based on AdjBW.
PCR indicates polymerase chain reaction.
The patient showed marked laboratory improvement with the higher dosing regimen. From an efficacy standpoint, the dose adjustment successfully reduced the CMV viral load from the initial 107,933 copies/mL to 2502 copies/mL over the course of 12 days (Table 1). From a safety perspective, this patient initially tolerated the 6 mg/kg every 12 hours regimen, but eventually developed thrombocytopenia. Although this may have been multifactorial, the most likely cause was secondary to ganciclovir, warranting a dose reduction. Despite laboratory improvement, the patient was unable to be successfully liberated from VV ECMO and ultimately expired. This is the first case report of an adult with CMV viremia on VV ECMO treated with dose-adjusted ganciclovir. It also provides an example of severe CMV viremia secondary to tocilizumab or SARS-CoV-2, suggesting a clinically relevant risk of infection after administration that should be weighed before administration. Literature will further benefit from additional explorations of therapeutic drug monitoring of ganciclovir to establish the optimal dosing regimen in the setting of CMV viremia in patients undergoing VV ECMO.
Leah Amundson, PharmD
Brandon Boelts, PharmD
Vivek Kataria, PharmD, BCCCP
Cedric Spak, MD, MPH
Baylor University Medical Center–Dallas
1. Bhimraj A, Morgan RL, Shumaker AH, et al. Infectious Diseases Society of America guidelines on the treatment and management of patients with COVID-19. Clin Infect Dis
2. Gupta S, Wang W, Hayek SS, et al. Association between early treatment with tocilizumab and mortality among critically ill patients with COVID-19. JAMA Intern Med
3. Salama C, Han J, Yau L, et al. Tocilizumab in patients hospitalized with Covid-19 pneumonia. N Engl J Med
4. Actemra (tocilizumab)
[package insert]. U.S. Food and Drug Administration website. Available at: https://www.gene.com/download/pdf/actemra_prescribing.pdf
. Revised March 2021. Accessed April 1, 2021.
5. Caldes A, Colom H, Armendariz Y, et al. Population pharmacokinetics of ganciclovir after intravenous ganciclovir and oral valganciclovir administration in solid organ transplant patients infected with cytomegalovirus. Antimicrob Agents Chemother
6. Murphy M, Danziger-Isakov L, Chamberlain A. 1420. Case report: ganciclovir subtherapeutic dosing in a pediatric patient on extracorporeal membrane oxygenation. Open Forum Infect Dis
7. Horvatits T, Kitzberger R, Drolz A, et al. Pharmacokinetics of ganciclovir during continuous venovenous hemodiafiltration in critically ill patients. Antimicrob Agents Chemother