Viruses, Newborns, and Liver Failure

By Philip R. Fischer, MD, DTM&H

Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN

SYNOPSIS: Neonatal liver failure due to herpesvirus infection is rare but can be severe. Herpes simplex virus 1 (HSV-1) is a more likely cause than HSV-2. Only about two-thirds of affected patients survive, despite recommended treatment with parenteral acyclovir.

SOURCE:Kelgeri C, Kanthimathinathan HK, Couper M, et al. Aetiology, characteristics and outcomes of neonatal liver failure: Lessons learned over the last 3 decades. J Pediatr 2024; Aug 14:114245. doi: 10.1016/j.jpeds.2024.114245. [Online ahead of print].

Although rare, neonatal liver failure can progress rapidly and can be fatal. Neonatal liver failure typically is defined as liver-derived coagulopathy (international normalized ratio [INR] ≥ 2). The diagnosis and management can be challenging since the condition has multiple etiologies and varied presentations. From a single tertiary liver center in Birmingham, England, investigators reviewed neonatal liver failure over three decades and reported on etiologies and outcomes.

Inclusion in the study was based on age 28 days or less, biochemical evidence of liver injury, and a prothrombin time of at least 20 seconds that was not corrected with administration of vitamin K. Detailed medical records were reviewed retrospectively. Realizing that diagnostic testing and management strategies have evolved, findings were considered in 10-year groups from 1991 through 2020.

Of 126 newborns with liver failure during the study period, 98 (78%) were Caucasian, and half were female. Overall, 21% were born prematurely. Liver failure was caused by an infection in 37 (30%) of the children and by a metabolic disorder in 31 (25%). There were 21 admissions for neonatal liver failure in the first decade of the study and 65 during the third decade; the increase in referrals and admissions likely was due to improvements in diagnosis and increasing availability of effective treatments over the years of the study.

Herpes simplex virus (HSV) accounted for liver failure in 24 of the newborns (HSV-1 in 20, HSV-2 in four). Eight babies had enterovirus, and one had cytomegalovirus. Four newborns had bacterial infection accounting for liver failure.

Overall mortality was 43% (54% during the first decade of the study, 35% during the last; the temporal change between decades was not statistically significant). Of the 24 newborns with HSV-related liver failure, nine survived (one after liver transplantation, eight with native livers). One of four HSV-infected and one of one enterovirus-infected babies who were transplanted survived.

Alpha-fetoprotein levels were low in patients with HSV-induced liver failure, likely due to severe hepatic necrosis. The authors pointed out that antiviral therapy alone may be inadequate for HSV-related liver infection associated with secondary hemophagocytic lymphocytic histiocytosis and that concomitant steroids and/or other immunomodulators might be needed to overcome the hyperinflammation and cytokine storm that sometimes accompanies virus-induced hepatic failure. The low rates of survival following liver transplantation for HSV hepatitis likely are due to the prolonged viremia associated with HSV infection; supportive care, with patience, and acyclovir now are suggested for most newborns with HSV-induced liver failure.

Commentary

In neonates, HSV infection can present with localized lesions of the skin, eyes, and/or mouth, but it also can present with central nervous system, pulmonary, and/or hepatic involvement.¹ Disseminated disease, with liver involvement, is seen in about 25% of newborns infected with HSV.¹ Especially when skin lesions are not evident, the presentations of herpes are clinically similar to those of febrile newborns with serious bacterial infection.¹

Worldwide, approximately 500 million people are infected by HSV-2, and two-thirds of humans have HSV-1.² Globally, there are about 14,000 newborns with HSV infection each year.^2,3 In the United States, neonatal herpes infections occur in approximately one in 2,000 newborns.¹

Neonatal HSV infection usually (85% of cases) arises during the neonate’s passage through the birth canal (whether the mother is symptomatic at the time or not) but can occur following ascending pre-birth spread of HSV or via post-natal contact.² Both HSV-1 and HSV-2 cause neonatal hepatitis, and the predominance of HSV-1 as the causative strain in neonatal failure noted by Kelgeri and colleagues has been documented previously.^1,4

Prompt diagnosis of disseminated herpes infection is challenging in newborns, and it is important to maintain a high index of suspicion even though disseminated herpes is uncommon.

Prompt diagnosis of disseminated herpes infection is challenging in newborns, and it is important to maintain a high index of suspicion even though disseminated herpes is uncommon. Many febrile newborns do not benefit from medication for either bacterial or viral infections, but delayed diagnoses of either herpetic infection or serious bacterial infection can lead to worsened outcomes. Thus, presumptive treatment, pending diagnostic test results, often is instituted.

Around the world, serious bacterial infections (sepsis, pneumonia, meningitis) cause more than 500,000 newborn deaths each year.⁵ In view of the risk of fatal serious bacterial infections, various guidelines have been published to help guide the management of febrile newborns in various settings.⁵

A recent report details the diagnostic odyssey of a newborn with prolonged fever despite multiple courses of antibiotic treatment and despite multiple negative tests for viral pathogens.⁶ The child had Plasmodium malariae malaria despite the mother having seemed well and not having been in a malaria-endemic area for more than two years.⁶ The child did well following anti-malarial treatment.⁶

Parenteral acyclovir (20 mg/kg/dose given three times daily) is used for neonatal herpes with liver involvement.¹ The treatment should be continued for 21 days and should be followed by six months of oral acyclovir suppression.¹ Liver transplant is considered when the response to medical therapy is inadequate, but, as noted by Kelgeri and colleagues, prolonged HSV viremia and concomitant failure of other organs yield a poor prognosis after liver transplantation for HSV-induced hepatic failure.

References

1. American Academy of Pediatrics. Herpes Simplex. In: Kimberlin DW, Banerjee R, Barnett ED, et al, eds. Red Book: 2024 Report of the Committee on Infectious Diseases. American Academy of Pediatrics;2024:467-477.
2. De Rose DU, Bompard S, Maddaloni C, et al. Neonatal herpes simplex virus infection: From the maternal infection to the child outcome. J Med Virol 2023;95:e29024.
3. Pinninti SG, Kimberlin DW. Neonatal herpes simplex virus infections. Semin Perinatol 2018;42:168-175.
4. Verma A, Dhawan A, Zuckerman M, et al. Neonatal herpes simplex virus infection presenting as acute liver failure: Prevalent role of herpes simplex virus type I. J Pediatr Gastroenterol Nutr 2006;42:282-286.
5. Edmond KM. Introduction to evidence for global management of serious bacterial infections in young infants aged 0-59 days. Pediatrics 2024;154(Suppl 1):e2024066588B.
6. O’Mahony E, Ryan F, Hemandas H, et al. Cryptic congenital malaria infection causing fever of unknown origin in an infant. J Pediatr 2024; Aug 14:114237. doi: 10.1016/j.jpeds.2024.114237. [Online ahead of print].