Case Presentation: A 68-year-old man with a history of cryptogenic cirrhosis and hepatocellular carcinoma status post liver transplant with donor positive for cytomegalovirus (CMV), and recent treated CMV reactivation, was transferred from a nearby hospital with acute hypoxic respiratory failure requiring intubation secondary to Pneumocystis jirovecii pneumonia (PJP) identified on bronchoalveolar lavage. He was treated with high dose steroids and trimethoprim-sulfamethoxazole, later changed to clindamycin and primaquine due to worsening renal function. He had subsequent improvement of his hemodynamics and respiratory status allowing for extubation, but his course was subsequently complicated by recurrent hypoxic respiratory failure and ARDS requiring re-intubation and paralysis. Despite a prolonged course of treatment for PJP he remained ventilator dependent. On day 18 of intubation, serum CMV PCR was obtained showing active viremia (>260,000 IU/ml) and his persistent respiratory failure was attributed to CMV reactivation and pneumonitis in the setting of high dose steroids. Given the prolonged period of intubation his family chose to transition to comfort care and he passed away.

Discussion: This case was identified as part of a multi-center study evaluating diagnostic error in in-hospital death or ICU transfer. In this case reviewers felt a diagnostic error was HIGHLY LIKELY. The error was related to a number of diagnostic process faults, including: Anchoring bias and delay in considering a secondary infection, such as CMV, in an immunocompromised patient on high-dose steroids. His known CMV-positive donor liver, prior CMV reactivation, and failure to respond to treatment for PJP, should have prompted earlier consideration for CMV pneumonitis. While rare, CMV pneumonitis is a known co-infection of PJP particularly in solid organ transplant recipients. This risk is increased when steroids and immunosuppressants are used together. There was also a delay in transfer from a community hospital to receive more specialized care given his history of transplant which may have limited the scope of his initial work up. Other factors may have also contributed, such as: Inappropriate assumption by the primary and consulting teams that a previous negative serum CMV PCR after a course of valganciclovir prior to hospitalization decreased the likelihood of CMV reactivation. In addition, the atypical pulmonary appearance of these infections can overlap each other making differentiating them challenging. Harm resulting from the error: The lack of diagnosis and treatment of CMV reactivation likely contributed to his lack of improvement and prolonged ventilator dependence. This may have contributed to the family’s decision to pursue comfort care. Contextual factors: He presented to an outside hospital with limited subspecialty support despite a history of liver transplant and immunosuppression. In addition, he suffered from two rare and synergistic pulmonary infections, the second likely induced by the treatment of the first with high dose steroids.

Conclusions: Potential approaches to error prevention: Given his lack of improvement, an earlier diagnostic pause with re-evaluation and expansion of the differential diagnosis may have led to earlier diagnosis, treatment and prevention of this complication. Specifically, consideration of this patient’s immunosuppression and known risk of viral reactivation should have prompted consideration of more atypical causes of respiratory failure.