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

<b>Background:</b> 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. <b>Methods:</b> A total of 109 consecutive adults with NRP unresponsive to standard antimicrobial therapy were randomized to EBUS-TBLB alone (<i>n</i> = 66) or EBUS-TBLB + mNGS (<i>n</i> = 43). Baseline characteristics, diagnostic yield, and procedure-related complications were recorded. Diagnostic positivity, sensitivity for infectious agents, and safety profiles were compared using <i>χ</i> ² or Fisher's exact tests, with <i>p</i> < 0.05 considered significant. <b>Results:</b> Overall diagnostic yield increased from 50.0% with EBUS-TBLB to 72.1% with the combined approach (<i>χ</i> ² = 4.37, <i>p</i> < 0.05). mNGS significantly improved detection of bacterial/fungal pneumonia (0% vs. 13.9%; <i>p</i> < 0.05) and pulmonary <i>tuberculosis</i> (0% vs. 20.9%; <i>p</i> < 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%) (<i>p</i> > 0.05). No severe adverse events occurred. <b>Conclusions:</b> 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.