Browsing by Author "DeRisi, Joseph L."

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    Central Nervous System Virus Infection in African Children with Cerebral Malaria
    (American Society of Tropical Medicine and Hygiene, 2020-07) Postels, Douglas G.; Osei-Tutu, Lawrence; Seydel, Karl B.; Xu, Qian; Li, Chenxi; Taylor, Terrie E.; John, Chandy C.; Mallewa, Macpherson; Solomon, Tom; Agbenyega, Tsiri; Ansong, Daniel; Opoka, Robert O.; Khan, Lillian M.; Ramachandran, Prashanth S.; Leon, Kristoffer E.; DeRisi, Joseph L.; Langelier, Charles; Wilson, Michael R.; Pediatrics, School of Medicine
    We aimed to identify the contribution of central nervous system (CNS) viral coinfection to illness in African children with retinopathy-negative or retinopathy-positive cerebral malaria (CM). We collected cerebrospinal fluid (CSF) from 272 children with retinopathy-negative or retinopathy-positive CM and selected CSF from 111 of these children (38 retinopathy positive, 71 retinopathy negative, 2 retinopathy unknown) for analysis by metagenomic next-generation sequencing. We found CSF viral coinfections in 7/38 (18.4%) retinopathy-positive children and in 18/71 (25.4%) retinopathy-negative children. Excluding HIV-1, human herpesviruses (HHV) represented 61% of viruses identified. Excluding HIV-1, CNS viral coinfection was equally likely in children who were retinopathy positive and retinopathy negative (P = 0.1431). Neither mortality nor neurological morbidity was associated with the presence of virus (odds ratio [OR] = 0.276, 95% CI: 0.056-1.363). Retinopathy-negative children with a higher temperature, lower white blood cell count, or being dehydrated were more likely to have viral coinfection. Level of consciousness at admission was not associated with CNS viral coinfection in retinopathy-negative children. Viral CNS coinfection is unlikely to contribute to coma in children with CM. The herpesviruses other than herpes simplex virus may represent incidental bystanders in CM, reactivating during acute malaria infection.
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    Pulmonary Metagenomic Sequencing Suggests Missed Infections in Immunocompromised Children
    (Oxford University Press, 2019-05-17) Zinter, Matt S.; Dvorak, Christopher C.; Mayday, Madeline Y.; Iwanaga, Kensho; Ly, Ngoc P.; McGarry, Meghan E.; Church, Gwynne D.; Faricy, Lauren E.; Rowan, Courtney M.; Hume, Janet R.; Steiner, Marie E.; Crawford, Emily D.; Langelier, Charles; Kalantar, Katrina; Chow, Eric D.; Miller, Steve; Shimano, Kristen; Melton, Alexis; Yanik, Gregory A.; Sapru, Anil; DeRisi, Joseph L.; Pediatrics, School of Medicine
    BACKGROUND: Despite improved diagnostics, pulmonary pathogens in immunocompromised children frequently evade detection, leading to significant mortality. Therefore, we aimed to develop a highly sensitive metagenomic next-generation sequencing (mNGS) assay capable of evaluating the pulmonary microbiome and identifying diverse pathogens in the lungs of immunocompromised children. METHODS: We collected 41 lower respiratory specimens from 34 immunocompromised children undergoing evaluation for pulmonary disease at 3 children's hospitals from 2014-2016. Samples underwent mechanical homogenization, parallel RNA/DNA extraction, and metagenomic sequencing. Sequencing reads were aligned to the National Center for Biotechnology Information nucleotide reference database to determine taxonomic identities. Statistical outliers were determined based on abundance within each sample and relative to other samples in the cohort. RESULTS: We identified a rich cross-domain pulmonary microbiome that contained bacteria, fungi, RNA viruses, and DNA viruses in each patient. Potentially pathogenic bacteria were ubiquitous among samples but could be distinguished as possible causes of disease by parsing for outlier organisms. Samples with bacterial outliers had significantly depressed alpha-diversity (median, 0.61; interquartile range [IQR], 0.33-0.72 vs median, 0.96; IQR, 0.94-0.96; P < .001). Potential pathogens were detected in half of samples previously negative by clinical diagnostics, demonstrating increased sensitivity for missed pulmonary pathogens (P < .001). CONCLUSIONS: An optimized mNGS assay for pulmonary microbes demonstrates significant inoculation of the lower airways of immunocompromised children with diverse bacteria, fungi, and viruses. Potential pathogens can be identified based on absolute and relative abundance. Ongoing investigation is needed to determine the pathogenic significance of outlier microbes in the lungs of immunocompromised children with pulmonary disease.