Case of The Year: A Preterm Infant with Liver Failure of Unknown Origin

Abstract Text: Baby C was born at 31 weeks and 6 days at an outside hospital with a birth weight of 2030 grams, to a 27-year-old G2 now P2 mother. Prenatal history was notable for SARS CoV2 infection and frequent E.coli UTIs. Maternal serologies were negative, non-reactive, only GBBS status was unknown. The neonate was delivered via urgent C-section for decreased fetal movement and abdominal pain. Baby C had an unremarkable NICU course for a premature newborn, until a rising direct bilirubin (2.2 mg/dL), elevated transaminases (ALT 999 u/L, AST 2,304 u/L, GGT 696 u/L), coagulopathy (PT 24.7 seconds, aPTT 60.6 seconds, fibrinogen 114 mg/dL), and a low platelet count (29,000) were identified on day of life (DOL) 7. She was then transferred to our facility with concern for liver failure of unknown origin.

After arrival at our level IV NICU, the hepatologist’s exam was notable for a large, hard liver, low tone, jaundice, and bruising at puncture sites. A comprehensive diagnostic evaluation ensued, guided by hepatology, genetics, and infectious disease (ID) specialists. High on the list of differential diagnoses were liver failure due to metabolic causes, other inherited causes, or infection. The NICU team and specialists believed that genetic/metabolic disease seemed likely, and there was a high index of suspicion that this was liver failure with non-infectious etiology. Urine organic acids, serum organic acids, urine succinyl acetone, STAT cholestasis panel, critical whole exome sequencing, and PCR for adenovirus, HSV-6, and entero-parechovirus were collected. A liver ultrasound with doppler was obtained. Results of CMV and HSV studies drawn at the outlying hospital were followed. Then, on DOL 8-9, the infant’s blood PCR, film array viral panel, CSF culture, throat swab, and pooled specimens all resulted positive for enterovirus (EV); she was diagnosed with EV sepsis, hepatitis, meningitis, and eventually myocarditis.

Peripartum EV is highly underdiagnosed (Belov et al., 2021). However, EV infections are common in pregnant women and neonates. Symptoms in newborns range from asymptomatic infection to life-threatening disease (Chuang & Huang, 2019). Further, neonatal EV myocarditis has a high mortality rate, with the potential for severe cardiac damage (Bersani et al., 2020; Torres-Torres et al., 2015).

She subsequently required mechanical ventilation, and developed seizures, runs of supraventricular tachycardia (SVT), and an episode of atrial flutter necessitating cardioversion. After the ID team filed an emergency investigational new drug application, the FDA Center for Drug Evaluation and Research Division of Antivirals authorized pocapavir for emergency/compassionate use for this neonate. Pocapavir is an antiviral being developed mainly for treatment of chronic poliovirus infection in primary immunodeficiency; it has some activity against nonpolio EVs (Committee on Infectious Diseases, AAP, 2021). It has been used successfully in several severe EV cases in neonates, including EV myocarditis (Chuang & Huang, 2019). Pocapavir was received by our facility on DOL 13, and a 14-day course of treatment was started.

Baby C improved clinically by the end of treatment with pocapavir, there were no critical sequelae of EV infection, and there were no notable adverse effects of pocapavir. She had a prolonged hospital course, including time in the CTICU for escalated treatment with antiarrhythmics for SVT. She was discharged at approximately two and a half months of age, with cardiology, neurodevelopmental, hepatology, and ID follow-up. Notably, information from her first appointments with cardiology, hepatology, and ID reveal that the specialists are pleased with her progress.

It is not entirely clear whether pocapavir successfully treated this infant’s EV infection. Blood PCR and nasopharyngeal swab were positive at the end of treatment. However, she improved clinically by the end of treatment, and no critical sequelae of EV infection and no notable adverse effects of pocapavir were observed. Similar findings are noted in the first case report of pocapavir use in neonatal EV sepsis (Torres-Torres et al., 2015). Implications for clinical practice from this case review include understanding the prevalence of EV and potential for critical illness for neonates with EV infection. Additionally, thinking outside the box, such as ideas for treatment and/or supportive care that are supported by (some) evidence that could potentially help in extreme circumstances and most probably will not hurt. Lastly, the vital importance of the collaboration of the interdisciplinary team is evident throughout this case.

Needs Assessment and Presentation Description : This case discusses the presentation, comprehensive diagnostic evaluation, diagnosis, supportive care, treatment, and clinical course of a neonate with liver failure of unknown origin. It underscores the importance of understanding the numerous effects of the disease process revealed in the case and the vital nature of close collaboration of the interdisciplinary team.