By Dean L. Winslow, MD, FACP, FIDSA
Professor of Medicine, Division of General Medical Disciplines, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine
Dr. Winslow reports no financial relationships relevant to this field of study.
SYNOPSIS: Forty-eight immunocompetent children with adenovirus-associated central nervous system disease were described. Thirty-eight percent of patients died or experienced permanent neurologic sequelae.
SOURCE: Schwartz KL, Richardson SE, MacGregor D, et al. Adenovirus-associated central nervous system disease in children. J Pediatr 2019;205:130-137.
Forty-eight immunocompetent children (10 from Toronto’s Hospital for Sick Children [SickKids] and 38 from the literature) with adenovirus-associated central nervous system (CNS) disease were reviewed. Twenty-six children with adenovirus-associated uncomplicated febrile seizures identified from the SickKids database were not included in the final analysis. Cases were identified by culture, PCR, or electron microscopy in blood, cerebrospinal fluid (CSF), or respiratory or gastrointestinal samples; other cases were identified by serologic testing. In 15% of cases, adenovirus was detected in the CSF or brain tissue, but CSF or brain tissue was not tested in all cases. The median age of the 48 children included in the analysis was 2 years, and 19 (40%) of them were female. Fever was documented in 45 (94%) children.
The most common prodromal symptoms were upper respiratory illness (23; 48%), followed by vomiting (11; 22%) and diarrhea (9; 19%). Pneumonia was diagnosed in 24 (50%). During hospitalization, hepatitis developed in 19 (40%) children and coagulopathy developed in seven (15%) children. Ten of the 48 (21%) children died and eight (17%) experienced permanent neurologic impairment, including five of the eight cases of encephalitis treated at SickKids.
By univariate analysis, factors identified by researchers that were associated with death or neurologic sequelae included younger age (1.5 vs. 2.7 years), coagulopathy, and seizures. Meningismus (presumably associated with the aseptic meningitis cases) was associated with full recovery. After adjusting for multiple variables, the only variable associated with poor outcome that retained statistical significance was the presence of seizures.
A closer look at the eight children from SickKids with adenovirus encephalitis revealed that four of eight had normal CT scans, but all had abnormal MRIs. Three of the four children with normal CT scans experienced full recovery. Neurologic sequelae seen in the other patients included profound impairment, global developmental delay, mild cognitive impairment, dystonia, and seizures.
The small number of patients presented in this case series suggests that adenovirus is a relatively rare cause of CNS disease in immunocompetent children. The absolute incidence of serious neurologic disease in children with adenovirus infection is unclear because most children with adenovirus infection are not hospitalized and they seldom are tested for specific viral pathogens.
The SickKids experience and literature review show that adenovirus-associated CNS disease displays a spectrum from transient complex partial seizures or transient infection-associated encephalopathy to severe encephalitis including necrotizing encephalopathy. It is likely that direct cytopathic effect of virus occurs in many cases. However, the 15% success in detecting adenovirus in CSF or brain tissue suggests strongly that it is likely that T-lymphocyte-mediated inflammation (as demonstrated in murine models) may be important.1
- Guida JD, et al. Mouse adenovirus type 1 causes a fatal hemorrhagic encephalomyelitis in adult C57BLJ/6 but not BALB/c mice. J Virol 1995;69:7674-7681.