Cerebrospinal fluid metagenome from which Leptospira santarosai was diagnosed

A 14-year-old boy from Wisconsin with severe combined immunodeficiency presented 3 times to a medical facility over 4 months with fever and headache that progressed to hydrocephalus and status epilepticus necessitating a medically-induced coma. An exhaustive diagnostic workup including brain biopsy was unrevealing. Within 48 hours after receipt of the sample, unbiased next-generation sequencing of the patient's cerebrospinal fluid and computational analysis using an ultra-rapid pipeline for comprehensive pathogen detection identified 475 of 8,187,737 sequences corresponding to the bacterial Leptospira genus, confirmed by phylogenetic analysis to be Leptospira santarosai. All subsequent conventional diagnostic assays for leptospirosis, including a previously validated real-time polymerase chain reaction, were negative. The patient responded dramatically when treated with appropriate antimicrobials, and he was discharged home 24 days later near his premorbid baseline.