Diagnostic limitations and challenges in current clinical guidelines and potential application of metagenomic sequencing to manage pulmonary invasive

Pulmonary invasive fungal infections (pIFI) significantly impact patients with hematological malignancies (HM), largely due to the immunocompromised state caused by the underlying disease and intensive chemotherapy. Conditions such as invasive pulmonary aspergillosis and mucormycosis are prevalent in this population, with azole antifungal prophylaxis sometimes exacerbating the issue by contributing to drug resistance. Pneumocystis jirovecii pneumonia (PCP) presents additional risks for HM patients compared to HIV patients. Diagnosing pIFI remains complex, as clinical symptoms are often nonspecific, and standard diagnostics, including fungal cultures and biomarkers like Aspergillus galactomannan and β-D-glucan, have limited sensitivity and specificity. Rapid and accurate diagnosis is essential for initiating antifungal therapy, but current methods can be invasive and ineffective, underscoring the urgent need for more reliable diagnostic techniques.

Current management guidelines for HM patients with suspected pIFI emphasize the use of non-invasive, non-culture-based diagnostics alongside standard-of-care (SOC) tests to improve diagnostic accuracy. Despite the development of multiple fungal diagnostic biomarkers in recent years, diagnosing pIFI remains a challenge due to the limitations in the current diagnostic landscape. Novel diagnostic tools are critically needed to enable timely and targeted antifungal treatments, which could improve patient outcomes. While emerging data suggest the potential of metagenomic sequencing as a pathogen-agnostic diagnostic approach, more robust multicenter studies are necessary to validate its effectiveness. Combining advanced microbial detection with SOC testing could enhance the diagnostic yield for pIFI and positively influence clinical outcomes for patients with HM.

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