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Adenovirus-Associated Central Nervous System Disease in Children

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Adenovirus-Associated Central Nervous System Disease in Children ARTICLE IN PRESS THE JOURNAL OF PEDIATRICS • www.jpeds.com ORIGINAL ARTICLES Adenovirus-Associated Central Nervous System Disease in Children Kevin L. Schwartz, MD, MSc1,2, Susan E. Richardson,MD3, Daune MacGregor,MD4,5, Sanjay Mahant, MD, MSc4,6, Kamini Raghuram,MD4,6, and Ari Bitnun, MD, MSc4,7 Objective To characterize the spectrum and salient clinical features of adenovirus-associated neurologic disease in immunocompetent children. Study design Previously healthy children (aged 1 month-18 years) with central nervous system (CNS) disease associated with adenovirus infection were identified via the Encephalitis Registry (1996-2016) and Microbiology Database (2000-2016) at The Hospital for Sick Children, Toronto, and by systematic review of the literature. The data were pooled and analyzed to identify the spectrum of illness, clinical outcome, and risk factors for death or neurologic impairment. Results Neurologic complications associated with adenovirus infection in our institution included febrile sei- zures, encephalitis, acute disseminated encephalomyelitis, and aseptic meningitis. A total of 48 immunocompe- tent children with adenovirus-associated CNS disease were included in the pooled analysis—38 from the literature and 10 from our institution. In 85% of cases, the virus was detected in the respiratory or gastrointestinal tract, but not the cerebrospinal fluid. Eighteen of the 48 (38%) patients either died or suffered permanent neurologic se- quelae. Predictors of adverse outcome included younger age, coagulopathy, the absence of meningismus, sero- type 2 virus, and the presence of seizures. After multivariable adjustment, only seizures remained a significant risk factor. Conclusion Adenovirus is a rare cause of CNS disease in immunocompetent children. Disease spectrum is vari- able, ranging from mild aspetic meningitis and fully reversible encephalopathy to severe, potentially fatal, acute necrotizing encephalopathy. (J Pediatr 2018;■■:■■-■■). denovirus is a common pediatric infection typically manifesting as a febrile respiratory illness, gastrointestinal infec- tion, or conjunctivitis. In contrast, central nervous system (CNS) disease due to adenovirus is rare. In 3 large prospec- A tive encephalitis cohorts involving 789 patients, who primarily were adults, no case was attributable to adenovirus.1-3 However, in 1 pediatric study conducted in Finland, adenovirus was implicated in 5% of childhood encephalitis cases, suggest- ing a more significant role in children.4 Meningitis and a transient adenovirus-associated encephalopathy also have been de- scribed in a small number of children.5,6 In a retrospective pediatric study conducted in Taiwan and published in 2013, 3.3% (109 of 3298) of children with culture-confirmed adenovirus infections had symptoms or signs of neurologic dysfunction.7 The purpose of this study was to better characterize the spectrum and salient clinical features of CNS disease associated with adenovirus in previously healthy immunocompetent children. To do so, we combined data from The Hospital for Sick Chil- dren (SickKids) Microbiology Database and Encephalitis Registry with a systematic review of the literature. Methods Previously healthy children, aged 1 month to 18 years, with neurologic symptoms associated with adenovirus infection were identified from 3 different sources, the SickKids Microbiology Database, the SickKids Encephalitis Registry, and by systematic review of the literature. The SickKids Microbiology Database was used to determine the incidence and spectrum of neurologic complications, including febrile seizures, associated with adenovirus detections (January 1, 2000-December 31, 2016). The En- cephalitis Registry Database was used to evaluate the role of adenovirus in acute childhood encephalitis and to describe the salient clinical features of adenovirus encephalitis (January 1, 1996-December 31, 2016). A systematic review of the literature, conducted in January 2017, was used to identify cases of adenovirus-associated neurologic disease, extract patient- specific clinical data where possible, and combine these data with those From the 1Public Health Ontario; 2Dalla Lana School of Public Health; 3Division of Microbiology, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children; 4Department of Paediatrics, University of Toronto; 5Division of Neurology; 6Division of Paediatric Medicine; and 7Division of Infectious Diseases, The Hospital for Sick Children, Toronto, Ontario, Canada CNS Central nervous system The authors declare no conflicts of interest. CSF Cerebrospinal fluid PCR Polymerase chain reaction 0022-3476/$ - see front matter. © 2018 Elsevier Inc. All rights SickKids The Hospital for Sick Children reserved. https://doi.org10.1016/j.jpeds.2018.09.036 1 FLA 5.5.0 DTD ■ YMPD10302_proof ■ November 6, 2018 THE JOURNAL OF PEDIATRICS • www.jpeds.com Volume ■■ • ■■ 2018 from our institution to further characterize disease spec- cial assay on the Luminex platform (xTag-RVP Fast v2; Luminex trum, clinical outcome, and risk factors for death or neuro- Molecular Diagnostics, Toronto, Canada). Other specimens (eg, logic impairment. The study was approved by the SickKids tissue biopsies, CSF and other sterile fluids except blood, urine, Research Ethics Board. Verbal guardian consent, documented and eye swabs) were tested by PCR (in-house or commercial in the patient record, was obtained for the case description of real time, as above) and virus isolation, until the latter was dis- a child hospitalized at SickKids. continued at the end of 2008. Stool was tested by electron mi- croscopy. Serology was performed by complement fixation Inclusion and Exclusion Criteria and Definition of (antigen from Microbix Biosystems Inc, Mississauga, Canada) Neurologic Diagnoses until October 2001, after which it was discontinued. For cases identified in the SickKids Microbiology Database eli- gibility criteria included admission to SickKids, presence of neu- Literature Review rologic symptoms, and detection of adenovirus in a sterile or A systematic MEDLINE and EMBASE search was completed nonsterile site by direct fluorescent antibody staining, culture, with the assistance of a senior hospital librarian. Search strat- or polymerase chain reaction (PCR). Eligibility criteria for cases egy included terms for ‘adenoviridae,’‘adenovirus’ or ‘adeno- identified in the SickKids Encephalitis Registry included ad- virus infections’ combined with ‘encephalitis,’‘central nervous mission to SickKids, fulfillment of the inclusion criteria for the system viral disease,’‘viral/aseptic meningitis,’‘lymphocytic cho- Encephalitis Registry as delineated below and detection of ad- riomeningitis,’‘central nervous system,’‘brain,’‘meninges,’‘arach- enovirus as described for the Microbiology Database. Cases noid,’‘seizures,’ or ‘status epilepticus.’We restricted our search identified from the literature search were eligible for inclu- to the English language literature. sion if they had a neurologic diagnosis other than febrile sei- zures and microbiologic or serologic evidence of acute Statistical Analyses adenovirus infection. Children identified in any of the 3 sources For the purpose of describing the spectrum of adenovirus- were excluded if they had a pre-existing noninfectious neu- associated CNS disease and the salient clinical features of these rologic condition, a primary or secondary immune- entities, the data for cases identified in our institution were com- compromising condition, or a plausible alternative infectious bined with those identified from the literature review. Chil- or noninfectious etiology. dren with febrile seizures were excluded from this analysis. The For cases identified in the SickKids Microbiology Data- clinical and microbiologic characteristics of those with and base or the Encephalitis Registry, encephalitis was defined by without adverse outcome, defined as death or neurologic se- the presence of encephalopathy (depressed or altered level of quelae, were compared. Data were analyzed using SAS Enter- consciousness persisting for >24 hours) plus 2 or more of the prise Guide v 7.1 (SAS Institute, Cary, North Carolina) for following: fever (>38.0°C), seizures, focal neurologic deficits, associations by c2 or Fischer exact test as appropriate for cat- cerebrospinal fluid (CSF) pleocytosis (>5 cells/uL), electro- egorical variables, and by Wilcoxon Mann-Whitney test for con- encephalographic abnormalities, or diagnostic imaging tinuous variables. Statistical significance was set at P < .05. abnormalities.8,9 The diagnosis of isolated encephalopathy was Variables identified as significant risk factors for death or neu- reserved for children with encephalopathy who had fewer than rologic sequelae were evaluated in a multivariable logistic re- 2 of the secondary criteria listed above. Other diagnoses were gression model. in accordance with those listed in discharge and follow-up medical records. For cases identified in the literature search, Results diagnosis was in accordance with that specified in the origi- nal publication. Case Description A previously healthy 10-month-old female patient was brought SickKids Microbiology Methods to medical attention because of seizures and reduced level of The presence of adenovirus was tested for in nasopharyngeal consciousness following a prodromal illness of fever and di- aspirates by direct fluorescent antibody staining, viral isola- arrhea of 2 days’ duration (case 1 in Table I and Table II). At tion, PCR, or combination of tests. Direct fluorescent anti-
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