Neonatal Pneumonia With a Fatal Outcome Due to a Re-emergent Recombinant Adenovirus Serotype

To the Editors: We read the recent paper “Adenovirus pneumonitis and disseminated viremia in a neonate successfully treated with steroids, cidofovir and extracorporeal membrane oxygenation (ECMO)” with interest; this adenovirus was a species B that was not subtyped.1 We cared for 2 patients with fatal neonatal disseminated adenovirus infection despite treatment with cidofovir and ECMO and report them to highlight the seriousness of the infection despite aggressive support and therapy and to emphasize the importance of adenovirus typing when available. Case 1: A previously healthy 14-day-old presented in August 2019 with 1 day of fever, cough and congestion. He was born after 39 weeks’ gestation via an uncomplicated vaginal delivery and was discharged from the newborn nursery on day 3 of life. He did well at home until the presentation. There was a sick cousin at home with upper respiratory symptoms but no travel history. A complete evaluation to rule out sepsis was performed and was unrevealing. A viral respiratory panel was also sent, and he was started on empiric ampicillin and cefotaxime. Respiratory viral panel on admission was positive for adenovirus, later typed as recombinant strain human adenovirus (HAdV)-55; chest radiograph was notable for right-sided opacities. He initially required 1 L oxygen via nasal cannula; however, over the next 24 hours, the patient’s respiratory status rapidly declined, requiring mechanical ventilation, which was quickly escalated to high-frequency oscillatory ventilation. Serum adenovirus polymerase chain reaction from the following day revealed a viral load of 150 million copies/mL. He was started on cidofovir, 1 mg/kg 3 times weekly with probenecid. Due to worsening oxygenation, he was cannulated onto ECMO on day 4 of admission, on which he remained. He ultimately died of bleeding complications at 5 weeks of age. During the hospital course, serum adenoviral load gradually decreased to 6 million copies/mL 4 days before death. An immunology evaluation, which included human immunodeficiency virus testing, immunoglobulins, and T- and B-cell flow cytometry, was not suggestive of an immunodeficiency. Case 2: A second 14-day-old full-term male infant was transferred from the same referring hospital 2 weeks after Case 1. Everyone at home was well, but his 2-year-old sibling did attend day care. He also presented with fever, cough, congestion and hypoxia. He also had a respiratory viral panel that was positive for adenovirus on admission and a viral load 2 days later of 640 million copies/mL; this virus was later typed as recombinant strain HAdV-59. He was also started on cidofovir, required ECMO and was given a dose of intravenous immunoglobulin. Although serum viral load decreased to 1200 copies/mL after 4 weeks of cidofovir, this patient also died, at 8 weeks of life, due to bleeding complications. In both cases, adenovirus typing was performed at the Centers for Disease Control and Prevention following referral by the Chicago Department of Public Health using real-time polymerase chain reaction. There are at least 88 reported serotypes of human adenoviruses, with certain types associated with specific clinical syndromes. For example, HAdV-3, HAdV-4 and HAdV-7 are commonly associated with respiratory illness, while serotypes 40 and 41 are often associated with gastroenteritis. Some types, such as HAdV-7, have been associated with more severe respiratory illness in children.2–5 Adenoviruses have the potential for recombination. Recombination can lead to potential changes in the tissue tropism of the virus, making a strain more likely infect different organs, though this does not necessarily lead to more severe disease. Recombinant type HAdV-55 was first reported in China in 2006, contains an HAdV-14 fiber with HAdV-11 hexon protein, and has been implicated as the cause of severe pneumonia outbreaks in Asia and Europe, though it has not been reported in the United States nor has it previously been identified as a cause of severe disease in a neonate.6–10 The virus isolated in Case 2, HAdV-59, was also the result of recombination, but despite the epidemiological link to case 1, it was the result of recombination of an HAdV–H25 hexon protein and HAdV-9 fiber protein, and has not been widely reported as a cause of severe disease or outbreaks.11 Unfortunately, neonatal adenovirus therapy is often fatal despite intensive support and attempted therapy, independent of type. Nevertheless, typing and testing for recombination are at the very least useful for understanding their circulation and clinical manifestations, particularly in vulnerable populations such as neonates and the immune compromised.