CMV Viremia and Colitis in Simultaneous Pancreas-Kidney Transplantation

Introduction

Cytomegalovirus (CMV), a non-segmented DNA virus belonging to the Herpesviridae family, causes most of the infections occurring in post-transplant patients, with an incidence rate of 40–80% in renal transplant patients, as suggested by a meta-analysis [1]. CMV infection can present with CMV viremia and a variety of clinical manifestations, ranging from mild constitutional symptoms to invasive disease, with many patients displaying no symptoms at all. The incidence of CMV infections depends on several factors, such as the seropositivity of donors or recipients, recipients with prolonged immunosuppression, or multiple comorbidities. Management of CMV infections often proves difficult in the setting of poor sensitivity to many drugs, as only 3 oral drugs are used in current clinical practice: valganciclovir, maribavir, and letermovir (used only for prophylaxis); hence, a careful approach to avoid drug resistance is essential.

Case Report

CMV VIREMIA DEVELOPMENT AND TREATMENT CHALLENGES:

On day 3 after kidney and pancreas transplantation, the patient was started on prophylactic PO valganciclovir 900 mg OD. Since this was a deceased donor kidney transplant (DDKT), prophylaxis was initiated after transplant. Despite this, she developed a very high viral load of 67 000 IU/mL on day 120 after transplantation. The dose of PO valganciclovir was increased to 900 mg BID. However, on day 150 after transplantation, no improvement was seen, with worsening viremia of 93 000 IU/mL, prompting resistant strain testing and ganciclovir resistance because the UL97 kinase mutation was detected. The treatment was switched to PO maribavir 400 mg OD. She initially responded well to maribavir, and her viral load reached 10 000 IU/mL on day 180.

On day 200 after transplantation, she presented to the Emergency Department with persistent (>2 weeks) watery diarrhea occurring 7–8 times daily, accompanied by chills, tremors, severe fatigue, and an elevated viral load of 472 000 IU/mL. She underwent a colonoscopy, revealing widespread erythematous and ulcerated mucosa throughout the colon, which was diagnostic of CMV colitis. Because the patient had received a kidney transplant, foscarnet was kept as a therapy of last resort. Moreover, high-dose IV ganciclovir has been found beneficial in resistant cases [2]. Hence, she was placed on IV ganciclovir at standard dosing starting at 5 mg/kg q12 hours, after which she experienced interval improvement/resolution of her symptoms. Given this, the transplant ID team increased the dose of ganciclovir to 10 mg/kg q12 hours based on the assumption that there was a mixed viral population, some of which were susceptible to ganciclovir, which was responsible for her improvement, with viral load falling from 481 000 IU/mL on day 203 to 123 000 IU/mL on day 210.

On day 220, her viral load rose from 123 000 IU/mL to 134 000 IU/mL in 10 days. It was confirmed that the patient harbored a mixed population of CMV strains on the PCR with varying levels of resistance detected at T409M, C480F, and L595W sites on nucleotide sequencing (Figure 1). Therefore, initial drug administration would lower the viral load by targeting the wild-type strain, and a little while later, it would start to rise as the resistant population would start to grow.

On day 221, IV Foscarnet 60 mg/kg q24 hours was started as the patient had no documented resistance against it. On day 235, the viral load dropped below 1000 IU/mL, IV foscarnet was discontinued, and she was transitioned to PO letermovir 480 mg OD as secondary prophylaxis. The patient underwent 2 subsequent CMV PCR tests on day 260 and day 267, which indicated that the viral load was essentially undetectable (detected but below the lower limit of quantification). At this point, letermovir was temporarily paused, and the patient was advised to undergo weekly CMV PCR monitoring. The need to resume letermovir would be determined if the viral load increased significantly (>500 IU/mL) (Figure 2).

Discussion

Controlling CMV viral replication after transplantation is crucial, as clinically significant CMV infection can lead to a direct increase in mortality [3] and a heightened risk of acute graft rejection [4]. With current preventive strategies, the incidence of CMV infection in kidney transplant recipients has been reduced to 17–92%, down from the previous range of 40–100%. Similarly, the occurrence of CMV disease decreased to 0–37% from as high as 67% [5]. This significant reduction highlights the effectiveness of preventive measures in mitigating CMV risk. However, a notable risk remains, as evidenced by our case, in which CMV colitis developed despite adequate ganciclovir prophylaxis, underscoring the need for ongoing monitoring and personalized treatment plans to manage and further reduce CMV-related complications.

Our patient was at high risk for developing CMV disease due to multiple factors: seronegative recipient status, seropositive donor status [6,7], female recipient sex [8], and simultaneous kidney-pancreas transplantation [5]. Additionally, extended exposure to anti-CMV drugs for over 3 months due to unknown resistance led to complications like persistent increases in CMV viral load despite more than 2 weeks of adequate dosing, failure of the viral load to decrease with appropriate treatment, and a resurgence in viral load after an initial decline. The presence of intermittent low-level viremia also played a role in the emergence of resistance [9].

Consequently, the treatment plan was meticulously crafted and continually updated with close monitoring of the patient’s laboratory results in alignment with the most recent guidelines and literature [5,6,10,11]. The approach began with initiating post-transplant CMV prophylaxis with ganciclovir for up to 6 months, based on its proven success in preventing the disease [6]. The treatment regimen was adjusted based on laboratory findings, taking into account the specific drug, dosage, and potential toxicity [5,10]. In case medication changes were necessary, decisions were made carefully to balance efficacy and safety. For instance, Foscarnet was held back as a last resort, as the nephrotoxicity of the drug could worsen kidney outcomes in our patient, and letermovir was introduced only after the CMV viral load fell below 1000 IU/mL. This threshold was selected because letermovir is known to achieve better virological outcomes when administered at lower viral loads, as opposed to when used with higher viral loads [11,12]. This tailored approach aimed to optimize treatment efficacy while minimizing risks.

This case report adds to the limited literature on resistant CMV colitis, emphasizing the need for continuous viral load monitoring and flexibility in changing therapy to best suit the patient, which are essential when dealing with mixed CMV strain populations. An initial positive response does not mean that we can stop monitoring; continuous observation remains critical. In mixed populations, an initial improvement might precede a sudden increase in the viral load. There is a need for further research and more comprehensive guidelines to advance the approach to CMV management in transplant patients.

Limitation of the study: Our case report is based on data from a single patient. Therefore, to generalize the findings, further research and additional data on CMV resistance in transplant recipients are warranted.

Conclusions

This case highlights the complexities of managing resistant CMV infections in transplant patients, emphasizing the importance of continuous viral load monitoring, personalized treatment regimens, and strategic therapeutic adjustments to prevent catastrophic outcomes. The case illustrates that even with prophylaxis, resistant strains can emerge, requiring a shift in antiviral therapy. The risk of nephrotoxicity associated with foscarnet use added to the challenges in managing CMV viremia. The ultimate transition to agents like foscarnet and letermovir, combined with careful monitoring, ultimately led to successful viral suppression. This case contributes to the growing understanding of CMV management in transplant patients and underscores the need for further research and more refined clinical guidelines for handling resistant CMV infections.