Microbial cell-free DNA sequencing of bronchoalveolar lavage fluid improves diagnostic yield and may add clinical utility in immunocompromised patients with severe pneumonia

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Abstract Background Despite sophisticated standard of care (SOC) testing (including bronchoalveolar lavage (BAL) fluid culture and multiplex PCR), the etiology of pneumonia in immunocompromised patients is frequently unknown. Microbial cell-free DNA (mcfDNA) sequencing increases diagnostic yield in plasma but remains understudied in BAL fluid. Methods This was a single center, retrospective, observational cohort study. Residual BAL fluid collected from immunocompromised, mechanically ventilated patients with suspected pneumonia was sent to Karius® for mcfDNA sequencing. Given the retrospective design, mcfDNA sequencing results were unavailable to clinicians. SOC testing results were compared to Karius® BAL (KT-BAL) test reports that classified identified microorganisms as Category One (always pathogenic), Category Two (usually pathogenic), or Category Three (rarely pathogenic). Findings 228 BAL fluid samples from 155 patients were analyzed. In pneumonia patients, KT-BAL yielded 18 additional Category One organisms, 138 additional Category Two organisms, and 313 additional Category Three organisms compared to SOC. Organisms missed by SOC and identified by KT-BAL included bacterial pathogens (99 patients), clinically relevant DNA viruses (34 patients), non- Candida fungi (11 patients), and parasites (1 patient). Compared to patients with Category One or Two organisms identified by both SOC and KT-BAL (n = 68), patients with organisms identified by KT-BAL alone (n = 87) had significantly more cumulative intubation days (11 [5, 20] days vs. 15 [8, 32] days, p = 0.035). Interpretation KT-BAL increased diagnostic yield for immunocompromised patients with suspected pneumonia with suggestion of prolonged respiratory failure in patients with pathogens missed by SOC.

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