Concurrent triple viral co-infection in a patient with metastatic renal cell carcinoma: A case report

Abstract

There are limited reports of concomitant infection with hepatitis B virus, Epstein–Barr virus, and cytomegalovirus. This case represents the first documented instance of such a triple infection in an individual with metastatic renal cell carcinoma undergoing combined immunotherapy with ipilimumab and nivolumab. This is the case of a 40-year-old male patient with past medical history notable for type 1 diabetes mellitus and renal cell carcinoma who exhibited liver function abnormalities suggestive of viral liver injury, particularly due to hepatitis B virus reactivation. Interestingly, despite the triple infection, the patient experienced relatively mild disease progression, with liver function tests showing a downward trend, likely due to timely intervention with tenofovir. This case highlights the complexity of viral interactions in immunocompromised patients and emphasizes the need for further research into optimal management strategies.

Introduction

Globally, over a quarter of a billion individuals are afflicted with hepatitis B virus (HBV) infection. ¹ While there are multiple reports of HBV infection with hepatitis D or human immunodeficiency virus, there is limited literature on concomitant HBV infection alongside Epstein–Barr virus (EBV) and cytomegalovirus (CMV) infections. Individually, more than 95% of all individuals have been infected by EBV but are usually asymptomatic. ² Similarly, CMV affects nearly two-thirds of the population and remains asymptomatic in healthy people. ³ However, these infections pose significant risks, particularly to those with compromised immunity or those experiencing dual infections (Table 1). ⁴

Table 1.

Laboratory values table.

Postop day	AST (U/L)	ALT (U/L)	ALP (U/L)	Bilirubin (mg/dL)	HBV DNA (IU/mL)
5	576	1320	153	Normal	33,900,000
6	631	1448	171	Normal	33,900,000
20	196	460	–	Normal	–

ALT: alanine transaminase; AST: aspartate transaminase; ALP: alkaline phosphatase; HBV: hepatitis B virus.

In immunosuppressed settings, such as malignancy, immunotherapy, or corticosteroid use, latent viruses like HBV, CMV, and EBV can reactivate, leading to significant clinical complications. ⁵ HBV reactivation is a known risk with immune checkpoint inhibitors (ICIs) like ipilimumab and nivolumab, especially when combined with corticosteroids such as dexamethasone. ⁶

Current evidence on managing the simultaneous reactivation of HBV, CMV, and EBV in cancer patients receiving ICIs remains scarce. This case report highlights such a triple infection in a patient with renal cell carcinoma (RCC).

Case report

A 40-year-old male with a medical history notable for type 1 diabetes mellitus and metastatic RCC of clear cell type presented to the emergency department for altered mental status. The patient had undergone one session of immunotherapy with ipilimumab and nivolumab 8 days before his presentation to our center. Upon admission, the patient exhibited left-sided paralysis, facial droop, and convulsions. Magnetic resonance imaging revealed a hemorrhagic metastatic lesion in the right frontal lobe with associated vasogenic edema progression. There was also a 3 mm leftward midline shift, which necessitated craniotomy. The following day, dexamethasone was initiated.

During his hospitalization, laboratories showed a reduced platelet count of 97 × 10³/µL as well as an absolute lymphocyte count of 0.96 × 10³ µL. This prompted liver function tests. From postoperative days 5 to 6, the aspartate transaminase (AST) and alanine transaminase (ALT) increased from 576 to 631 U/L and 1320 to 1448 U/L, respectively. The serum alkaline phosphatase increased from 153 to 171 U/L. Further testing also confirmed HBV surface antigen positivity, surface antibody <3.50, HBV core antibody positivity, HBV DNA of 33,900,000 IU/mL, and HBV envelope antigen and antibody positivity. Serum tests were positive for CMV (CMV DNA, QN polymerase chain reaction (PCR): 1140; CMV DNA QN Log in IU/mL, PCR: 3.06). Plasma levels for CMV DNA, QN PCR, and CMV DNA QN Log in IU/mL, PCR were 993 and 3.00. EBV viral capsid immunoglobulin G levels were measured at >750.00 while immunoglobulin M levels were <36.00. EBV nuclear antigen levels were 256, and EBV DNA, QN PCR copies/mL, and EBV DNA, QN PCR Log copies/mL were 1050 and 3.02, respectively. Viral tests for herpes virus 1 and 2, varicella-zoster virus, and hepatitis D antibody were negative. Anti-smooth muscle, anti-nuclear, and anti-mitochondrial antibodies were negative. Ceruloplasmin, ferritin, transferrin saturation, and alpha-1 antitrypsin tests were unremarkable. Despite these concerning laboratory findings, the patient remained asymptomatic.

The patient was subsequently started on tenofovir (a nucleoside reverse transcriptase inhibitor), which resulted in a downtrend in the liver function tests (Figure 1). A decrease in AST and ALT was measured until postoperative day 20 to 196 and 460 U/L, respectively. After a consultation with infectious diseases, it was concluded that the acute liver injury was due to HBV reactivation. Since the patient was immunocompromised, EBV serologies were deemed unreliable, and an EBV PCR viral load was used to assess viremia. This was elevated as well. In the setting of receiving immunotherapy for metastatic RCC, EBV and CMV likely contributed to the reactivation of HBV, since the viral loads for EBV and CMV were low, no treatment was necessary for either, and the patient was only treated for HBV. Immunotherapy continued throughout.

Figure 1.

Liver function tests and HBV DNA levels with tenofovir initiation on day 6.

Unfortunately, our patient decompensated and passed away from a cardiac arrest, secondary to metastatic RCC, about 3 months after initial presentation.

Discussion

RCC is characterized by its immunogenic nature, marked by a significant presence of dysfunctional immune cell infiltrates. The hostile metabolic environment in RCC impedes T-cell functionality, constraining T-cell immunity. ⁷ This intricacy is further complicated by the immune-modulatory effects of immunotherapy, which can predispose patients to hepatitis.

A notable case by Akar et al. ⁸ underscored the dearth of clinical exploration regarding HBV reactivation post-immunotherapy in RCC. They reported that after changing the immunotherapy from sunitinib to nivolumab in a patient with HBV, viral hepatitis reactivation was not detected. By contrast, our patient remained positive for hepatitis despite using nivolumab. This discrepancy may stem from the combined effects of ipilimumab–nivolumab immunotherapy and corticosteroid administration, both of which can modulate immune responses. While checkpoint inhibitors typically enhance immune activity, they may paradoxically trigger HBV reactivation in certain cases where antiviral prophylaxis is not administered sufficiently. ⁹ Corticosteroids further increase this risk by suppressing cytotoxic T-cell function and promoting viral replication. ¹⁰ Together, these therapies may have created an immunologic environment conducive to reactivation, underscoring the importance of HBV screening and antiviral prophylaxis when using immunotherapy, especially with concurrent steroid use.

Although the patient received combined ipilimumab and nivolumab 8 days prior to presentation, and dexamethasone was initiated the day after, we believe the timing of liver injury is consistent with HBV reactivation rather than de novo hepatitis. This conclusion is supported by the patient’s serologic profile, which included positive HBV surface antigen, core antibody, and envelope antigen, as well as the absence of protective surface antibodies. The extremely elevated HBV DNA level (33,900,000 IU/mL) also points toward a reactivation of chronic HBV infection rather than recent seroconversion. Notably, reactivation of latent HBV has been documented to occur rapidly in immunocompromised settings, particularly when ICIs and corticosteroids are used in combination. ¹¹ These agents may have synergistically disrupted immune control of latent HBV, resulting in abrupt reactivation. Distinguishing reactivation from de novo infection is clinically relevant, as it influences screening and prophylaxis strategies in patients undergoing immunotherapy or corticosteroid treatment.

A cohort study by Li et al. ¹² on nasopharyngeal carcinoma revealed a synergistic link between HBV surface antigen and EBV DNA load, amplifying distant metastatic risks. Though unexplored in RCC, the interplay of inflammatory infiltrates and immune system dysregulation induced by HBV and EBV underscores caution due to potential metastatic microenvironment alterations.

In contrast to Rao et al.’s ⁴ case featuring severe jaundice and coagulopathy in a dually infected patient, our case notably maintained normal bilirubin levels despite a triple infection. As discussed in their study, since a dual infection may lead to necrotic inflammatory changes, there may be progression to hepatocellular carcinoma. In a patient with RCC with such an infection, it is imperative to distinguish a metastasis from RCC from a second primary neoplasm.

The virus–virus interaction between CMV and HBV may have been one of the reasons for the milder disease trajectory of our patient. According to Bayram et al., ¹³ HBV replication is inhibited by the local induction of cytokines produced during CMV-induced hepatitis, and this inflammation can contribute to viral clearance of HBV. Such antagonistic effects may have mitigated the typical hepatocellular damage seen with HBV monoinfection or co-infection. By contrast, EBV’s role in liver injury is less well defined, rarely impacting liver pathology in immunocompetent individuals. ¹⁴ Thus, EBV likely had a minimal or neutral effect in this case. In addition, timely tenofovir treatment may have further attenuated liver injury. Together, CMV-induced cytokine suppression, EBV quiescence, and early antiviral therapy may have collectively mitigated hepatic damage. Since liver injury was attributed primarily to HBV reactivation rather than an immune-related adverse event, antiviral therapy was continued alongside.

Conclusion

In this case report, we report a rare presentation of concomitant HBV, EBV, and CMV in a patient with metastatic RCC. Our patient’s milder disease presentation makes this case particularly interesting. Even with a co-infection of HBV and EBV, it may be speculated that with a CMV infection, our patient reported better outcomes.