Introduction
(Article introduction authored by ICU Editorial Team)
Pulmonary invasive fungal infections (pIFI) disproportionately affect patients with hematological malignancies (HM), primarily due to their underlying disease and intensive chemotherapy-induced neutropenia.
Conditions like invasive pulmonary aspergillosis and mucormycosis are more common in this population, potentially exacerbated by azole
antifungal prophylaxis, which may contribute to drug resistance.
Pneumocystis jirovecii pneumonia (PCP) also poses significant risks and challenges in HM patients compared to HIV patients.
Diagnosis is complicated by nonspecific clinical signs and challenging radiographic findings, with standard diagnostics like fungal cultures and biomarkers (e.g., Aspergillus galactomannan, β-D-glucan) having limitations in sensitivity and specificity.
Timely and accurate diagnosis remains critical for initiating appropriate antifungal therapy, but current methods are often invasive or insensitive, highlighting the need for more effective diagnostic strategies.
Current recommendations for diagnosing pIFI
We identified relevant professional society or consortium guidelines via a literature search of publications, available in English in the last 5 years (1 January 2017–30 September 2022), using PubMed Central(PubMed, https://www.ncbi.nlm.nih.gov/pmc/) with the following search criteria: (invasive fungal infection OR invasive fungal disease) AND (guideline OR definition) AND cancer.
Guidelines universally recommend chest imaging and tissue cultivation with direct microscopy/histopathology to confirm pulmonary invasive fungal infections (pIFI).
In high-risk hematological malignancy (HM) patients, invasive procedures like biopsy or bronchoalveolar lavage (BAL) are suggested if feasible.
Non-invasive blood fungal biomarkers (e.g., GM, BDG) and nucleic acid amplification tests vary in recommendation based on pathogen suspicion and clinical context.
However, these biomarkers’ diagnostic utility varies due to performance differences by test type and patient factors.
Aspergillosis diagnostics are more developed, utilizing GM, BDG, and PCR, but face sensitivity issues with antifungal use. Mucormycosis and PCP diagnostics are less robust, with limited standardization and specificity in available tests.
Multiple testing modalities are endorsed to enhance diagnostic accuracy, reflecting ongoing challenges and evolving evidence gaps in pIFI diagnosis guidelines.
Metagenomic sequncing
There’s ongoing interest in evaluating novel, non-culture, and non-invasive diagnostics for high-risk patients, particularly when invasive procedures aren’t feasible.
Metagenomic sequencing technologies like metagenomic next-generation sequencing (mNGS), targeted metagenomic NGS (tNGS), and microbial cell-free DNA (mcfDNA) sequencing offer high sensitivity and species-level identification of fungi, critical for guiding antifungal therapy in hematological malignancy (HM) patients at risk for pulmonary invasive fungal infections (pIFI). Despite requiring specialized skills, bioinformatics expertise, and costly equipment, these methods are promising as costs decrease and accessibility improves, potentially enhancing clinical laboratory diagnostics. Metagenomic next-generation sequencing (mNGS) detects microbial fragments post-cell disruption, but its limitation is primarily human genome dominance (>99%).
Targeted metagenomic NGS (tNGS) amplifies and sequences specific microbial genomes, aligning with standard diagnostic turnaround times despite operational demands.
Plasma microbial cell-free DNA (mcfDNA) metagenomic sequencing quantifies microbial DNA in blood, offering rapid results and broad diagnostic coverage for fungi and challenging microbes in HM patients.
Few studies highlight its efficacy, detecting fungal infections with high sensitivity and specificity, often exceeding conventional tests.
Challenges include false positives and interpreting commensal microbes, suggesting clinical context guides appropriate use alongside standard diagnostics for optimal patient outcomes.
Conclusion
Current management guidelines for patients with HM and suspected pIFI recommend non-invasive, non–culture-based fungal diagnostics in addition to SOC diagnostic testing to facilitate a more accurate diagnosis.
Despite the emergence of multiple fungal diagnostic biomarkers in recent years, pIFI diagnosis in individuals with HM remains challenging and the current pIFI diagnostic landscape is limited.
Novel diagnostic options are critically needed to allow timely and targeted antifungal therapies that potentially improve patient clinical outcomes.
Robust, high-quality evidence, including standardization and validation, is urgently needed to determine whether novel diagnostics should be included in updated guideline recommendations.
Meanwhile, emerging real-world data and experience support the use of metagenomic sequencing tests but need broad multicentre studies and compelling evidence to support their widespread clinical use.
The combination of powerful pathogen-agnostic and breadth of microbial detection in conjunction with SOC testing can optimize the diagnostic yield for all potential pathogens, especially for pIFI, thereby impacting the clinical outcomes of patients with HM.
