Improved Etiological Diagnosis of Nonresolving or Slowly Resolving Pneumonia Through Combined Endobronchial Ultrasound‐Guided Biopsy and Metagenomic Sequencing

Background: Nonresolving or slowly resolving pneumonia (NRP) poses a diagnostic challenge because infectious and noninfectious etiologies often mimic community‐acquired pneumonia on imaging. Endobronchial ultrasound‐guided transbronchial lung biopsy (EBUS‐TBLB) improves tissue acquisition for peripheral lesions, whereas metagenomic next‐generation sequencing (mNGS) offers culture‐independent pathogen detection. Whether their combination enhances etiological clarification of NRP remains uncertain. Methods: A total of 109 consecutive adults with NRP unresponsive to standard antimicrobial therapy were randomized to EBUS‐TBLB alone ( n = 66) or EBUS‐TBLB + mNGS ( n = 43). Baseline characteristics, diagnostic yield, and procedure‐related complications were recorded. Diagnostic positivity, sensitivity for infectious agents, and safety profiles were compared using χ 2 or Fisher’s exact tests, with p < 0.05 considered significant. Results: Overall diagnostic yield increased from 50.0% with EBUS‐TBLB to 72.1% with the combined approach ( χ 2 = 4.37, p < 0.05). mNGS significantly improved detection of bacterial/fungal pneumonia (0% vs. 13.9%; p < 0.05) and pulmonary tuberculosis (0% vs. 20.9%; p < 0.05). Malignancy remained the predominant diagnosis (57.8% of all cases); yields for most tumor subtypes were comparable between groups. Complication rates did not differ between the two groups: minor bleeding (19.7% vs. 23.3%), hypoxia (50.0% vs. 48.8%), pneumothorax (4.5% vs. 0%), and delayed recovery (4.5% vs. 7.0%) ( p > 0.05). No severe adverse events occurred. Conclusions: EBUS‐TBLB + mNGS represents a paradigm shift in the diagnosis of complex respiratory cases, integrating imaging with advanced genomics to enhance precision medicine. In practice, early implementation of the EBUS‐TBLB + mNGS diagnostic protocol in patients with NRP can help exclude malignancy or confirm an infectious etiology.