Impact of Cell Free Next-generation Sequencing in Children with Complicated Pneumonia

Background: Community acquired pneumonia (CAP) is a common disease in pediatrics. Complications of bacterial CAP include pleural effusions, empyema, lung abscess, and necrotizing pneumonia (cCAP). Current standard antimicrobial coverage for cCAP broadly includes Streptococcus pneumoniae and Staphylococcus aureus (including methicillin-resistant strains), but targeted therapy for a specific pathogen is ideal. Cell-free plasma next-generation sequencing (cfNGS), a culture independent and noninvasive diagnostic tool, has the potential to guide targeted therapy in pediatric cCAP.

Methods: We conducted a retrospective review of children aged 3 months to 18 years admitted with cCAP to a single tertiary children’s hospital. We compared the positivity rate of conventional microbiologic diagnostic testing with that of cfNGS and the impact of cfNGS on clinical management. Criteria for the diagnosis of cCAP was defined by current PIDS/IDSA guidelines including: pneumonia associated with significant parapneumonic effusion, empyema, lung abscess(es), or demonstration of necrotizing pneumonia on imaging. Children were excluded if they had nosocomial pneumonia, were immune-compromised, had underlying abnormal lung pathology, or active tuberculosis or coccidiomycosis. Manual chart review was done to determine if and how cfNGS results changed management, as assessed by the documented impression and plan of the clinical team at the time the cfNGS result returned.

Results: We identified 46 children with cCAP in whom cfNGS was sent during their hospitalization. Of the 34 children with blood cultures, only one (3%) was positive and of the 37 children with pleural fluid cultures, 10 (27%) were positive. cfNGS was positive with a causative organism in 41 of the 46 patients (89%). In 32 out of the 46 children (70%), cfNGS was the only means of pathogen identification (Table 1). The results of cfNGS changed management in 36 of 46 cases (78%) (Figure 1a) with antibiotics being narrowed in 29 of these cases (81%). In 6 of the 29 cases (17%), antibiotics were changed, and in one of these, the duration of antibiotic treatment was shortened. In one child, the cfNGS result led to broadening of antibiotic therapy (Figure 1b).

Conclusion: cfNGS provided a higher rate of bacterial diagnosis in this series of 46 children with cCAP than traditional microbiologic cultures and impacted management in 78% of cases. Well-designed prospective studies are needed to better characterize the clinical and antimicrobial stewardship benefit and cost-effectiveness of cfNGS in children with cCAP.