2.3 Diagnostic Efficacy of Criteria for Severe Invasive Pulmonary Aspergillosis

Invasive pulmonary aspergillosis (IPA) is a life-threatening fungal infection in the ICU. With the increasing use of broad-spectrum antibacterial agents, immunosuppressants, and targeted monoclonal antibodies, the incidence of IPA in the ICU continues to rise, resulting in extremely high mortality rates.

Currently, multiple professional societies have established tissue pathology-based “gold standards” alongside several clinical diagnostic criteria tailored for non-neutropenic hosts. Concurrently, diagnostic tools centered on bronchoalveolar lavage fluid (BALF) galactomannan (GM) assays, Aspergillus polymerase chain reaction (PCR), and serum biomarkers have been widely adopted in clinical practice. However, given the profound heterogeneity of ICU populations, significant discrepancies frequently exist among these diagnostic criteria, leading to suboptimal diagnostic concordance and persistent challenges with misdiagnosis and missed diagnoses. Therefore, accurately evaluating and optimizing the performance of existing diagnostic algorithms in this high-risk, heterogeneous, and complex patient population, bridging the gaps between disparate criteria, and ultimately transitioning from a “one-size-fits-all” diagnostic framework to a more precise, individualized early identification strategy are critical to advancing the diagnosis and management of IPA.

I. Implementation and Challenges of Different IPA Diagnostic Criteria in the ICU
ICU patients often lack classic immunocompromised host factors, present with nonspecific clinical and radiological features, and rarely yield tissue pathology for definitive diagnosis. Consequently, IPA has emerged as a pressing diagnostic and therapeutic challenge in critical care infectious diseases. To address these difficulties, several diagnostic criteria have been sequentially developed, including the European Organization for Research and Treatment of Cancer/Mycoses Study Group Education and Research Consortium (EORTC/MSG ERC) consensus for immunocompromised populations, the ICU-specific Aspergillus ICU (AspICU) diagnostic criteria and its modified version (AspICU with biomarkers, AspICU-BM), and the latest consensus on invasive fungal diseases in adult ICU patients (FUNDICU). Each criterion emphasizes different aspects, collectively forming a multidimensional diagnostic toolkit for IPA in the ICU setting.

(I) EORTC/MSG ERC Consensus: Traditional “Gold Standard” and Limited ICU Applicability
The 2020 updated EORTC/MSG ERC consensus represents a classic research standard for diagnosing invasive fungal diseases. Its core methodology stratifies patients into proven, probable, and possible categories based on a combination of host factors, clinical features, and microbiological evidence. Strengths: The criteria are rigorously defined and highly specific, serving as the cornerstone for clinical trials and epidemiological research. Limitations: The major limitation lies in the strict definition of “host factors,” primarily targeting classic immunocompromised populations such as those with hematological malignancies, solid organ transplantation, or long-term high-dose immunosuppressant use. Most ICU patients (e.g., severe influenza, acute exacerbation of COPD, decompensated cirrhosis, severe trauma) are at high risk for IPA but do not meet these traditional host factor definitions. Consequently, a substantial number of patients are classified as “possible” or remain unclassifiable, leading to delayed diagnosis and treatment. Thus, when directly applied to the general ICU population, the EORTC/MSG ERC criteria exhibit suboptimal sensitivity.

(II) AspICU Diagnostic Criteria: Initial Exploration of an ICU-Specific Standard
To address the aforementioned limitations, the AspICU criteria were specifically designed for the ICU environment. This standard broadens the scope of host factors and anchors diagnosis on positive Aspergillusculture from respiratory samples, clinical features, and radiological abnormalities, aiming to distinguish colonization from infection. Strengths: Highly practical and closely aligned with ICU clinical practice. Limitations: (1) Microbiological standards rely heavily on culture, which is time-consuming and has limited sensitivity; (2) GM testing was explicitly excluded due to historical concerns about its reliability in non-neutropenic patients; (3) More sensitive molecular diagnostic techniques were not incorporated. These factors increase the risk of missed IPA diagnoses in the ICU.

(III) AspICU-BM Diagnostic Criteria: Evolution through Biomarker Integration
Proposed in 2021, the AspICU-BM criteria represent a significant refinement of the original AspICU standard. Strengths: The core advancement lies in the systematic integration of fungal biomarkers (including GM and Aspergillus PCR) into the diagnostic process. The standard is more flexible, requiring positive respiratory culture or typical/suggestive radiological findings as a premise. The required level of microbiological evidence is stratified based on the presence of EORTC/MSG ERC host factors (one criterion required if host factors are present; two criteria required if absent). Retrospective comparative studies have demonstrated that, compared to the original AspICU criteria, the AspICU-BM criteria identify a higher proportion of “probable” cases among histopathologically confirmed IPA patients. This significantly enhances diagnostic sensitivity, particularly for identifying patients lacking classic host factors, with negative respiratory cultures but positive biomarkers. Limitations: Derived from retrospective analysis, it still requires prospective validation. Its cohort is relatively complex, and biomarker testing is not yet routinely available in some medical centers.

(IV) FUNDICU Consensus: Toward Broad Consensus and Standardization
The 2024 FUNDICU consensus represents a major effort by international multidisciplinary experts to standardize research definitions for non-neutropenic adult ICU patients with invasive fungal diseases. For IPA, FUNDICU proposes a clearly structured “probable” definition, emphasizing the prerequisite of specific clinical signs/symptoms and introducing “ICU host factors” (e.g., severe influenza, COVID-19, moderate-to-severe COPD, decompensated cirrhosis). Its microbiological standards explicitly include BALF GM (≥1.0 OD index), serum GM (>0.5 OD index), and positive BALF Aspergillus culture, but PCR is not yet included due to insufficient evidence in the target population. The FUNDICU definition prioritizes specificity and comparability in research, making it rigorously designed but potentially less sensitive in clinical application compared to the AspICU-BM standard.

II. Insights from Recent Clinical Research
A multicenter retrospective study published in Clinical Infectious Diseases in 2025 systematically validated and compared the four major diagnostic criteria head-to-head in a real-world setting by analyzing 202 clinically diagnosed IPA patients. This study not only serves as an important test of existing diagnostic tools but also profoundly reveals the achievements, limitations, and future optimization directions of the current IPA diagnostic framework.

(I) Study Design and Core Findings: A Diagnostic Criteria Test
The study employed a highly clinically relevant stratified classification process. First, the EORTC/MSG ERC criteria were used to screen for “classic” immunosuppressed hosts. Remaining patients were evaluated under the ICU setting using three ICU-specific diagnostic criteria. This design accurately maps clinical decision pathways, yielding results with high practical guidance value. Core findings can be summarized in three points:

  • Divergent Performance of ICU-Specific Criteria: Among 112 ICU patients without traditional host factors, the three criteria showed significant performance differences. The FUNDICU criteria, with host factors closer to ICU reality, achieved a 53% clinical diagnostic concordance rate. Although nearly half of the patients remained unclassifiable, it significantly outperformed the other two. The AspICU criteria, overly reliant on respiratory culture and excluding serum GM, had a sensitivity as low as 4%, limiting its practicality. The AspICU-BM criteria, despite integrating biomarkers, showed a sensitivity of 26% and specificity of 63%, indicating that its inclusion criteria and thresholds may require further optimization in real-world settings.

  • “Gold Standard” Status and Limitations of EORTC/MSG ERC: Among 78 patients meeting traditional host factors, the EORTC/MSG ERC criteria demonstrated a 100% concordance rate, reaffirming its reliability and specificity as a research and clinical trial standard in classic high-risk populations (e.g., hematological malignancies, solid organ transplantation). However, this inversely confirms its deficiency of low sensitivity when directly applied to ICU patients.

  • Emergence of an “Undefined” Patient Population: The study identified 12 patients (6%) with IPA who lacked EORTC host factors and were admitted to the ICU. Most suffered from chronic diseases like interstitial lung disease or solid tumors and used long-term low-dose corticosteroids. This population sharply highlights the “blind spots” in existing diagnostic criteria, indicating that the IPA risk spectrum is broader than currently recognized.

(II) Core Value and Breakthroughs: From Validation to Evolution
This study transcends simple diagnostic criteria comparison, offering deeper significance:

  • Provides Critical Empirical Evidence: Previously, algorithm superiority was largely based on theoretical derivations or single-center studies. This study provides large-scale real-world data, offering core references for clinicians and guideline developers when selecting diagnostic tools. For immunosuppressed patients, the EORTC/MSG ERC criteria should be maintained; for ICU patients, the FUNDICU criteria represent the optimal current research framework, while the clinical diagnostic value of AspICU/AspICU-BM requires cautious evaluation.

  • Reveals Current Diagnostic Bottlenecks: The study explicitly identifies that the primary cause of FUNDICU missed diagnoses is an “incomplete host factor list.” Nearly half of the unclassified patients shared two common characteristics: post-complex cardiac surgery complications and moderate-to-severe ARDS. These reflect the core pathophysiological background of IPA in ICU patients: severe alveolar epithelial injury and adaptive immune response impairment.

  • Illustrates the Dynamic Evolution Path of Diagnostic Criteria: By incorporating post-complex cardiac surgery complications and ARDS as new host factors, researchers created a modified “FUNDICU-Clinical” criteria. Studies showed its sensitivity increased from 44% to 97%, and the AUC rose from 0.59 to 0.80. This attempt demonstrates that ICU IPA diagnostic criteria are not rigid dogmas but should be iteratively updated based on accumulating clinical epidemiological data.

(III) Diagnostic Significance and Future Prospects
This study promotes diagnostic criteria from “stratification” to “integration” and “precision.” An ideal future diagnostic system may require a dynamic model: for patients clearly meeting EORTC host factors, classic criteria should be applied; for ICU patients, a standardized “FUNDICU-Clinical” criteria with an expanded host factor list continuously updated based on real-world evidence may be necessary. Furthermore, standardizing and incorporating molecular diagnostic technologies like Aspergillus PCR into diagnostic criteria can compensate for the sensitivity limitations of culture and GM. The study reiterates that strict “research definitions” aim to ensure case homogeneity and research comparability but may sacrifice clinical sensitivity. Therefore, in clinical practice, for highly suspected patients not meeting existing research criteria, initiating antifungal therapy based on comprehensive clinical assessment, imaging, and microbiological evidence remains rational and necessary. Clinical decision-making should not be constrained by research definitions. The “non-ICU, non-classic host factor” IPA population identified in this study is a new field urgently requiring exploration. Prospective studies are needed to clarify its exact epidemiology, risk spectrum, and optimal management strategies. Additionally, the modified “FUNDICU-Clinical” criteria require further validation in prospective, multicenter cohorts.

III. Clinical Guidance
This study published in Clinical Infectious Diseases marks the transition of IPA diagnosis from “criteria proposal” to “empirical optimization.” It fully affirms the diagnostic value of the EORTC/MSG ERC and FUNDICU criteria in their respective target populations while revealing coverage deficiencies in existing standards. Its most important contribution lies in using rigorous data analysis to not only indicate “which criteria are better” but also reveal “why they are insufficient” and “how to improve them.” Incorporating core ICU conditions like post-complex cardiac surgery complications and moderate-to-severe ARDS into diagnostic considerations reflects a deeper understanding of IPA pathogenesis. Future IPA diagnosis should evolve toward dynamic and precision models, integrating clinical phenotypes with advanced microbiological technologies, and continuously refining diagnostic criteria to cover broader patient populations, achieving early identification and individualized treatment.
(Wang Lihui, Yu Yueting; Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine)

References

  1. Trelles M, Murillo J, Fuenmayor Gonzalez L, et al. Prevalence of invasive fungal infection in critically ill patients: a systematic review and meta-analysis. BMC Infect Dis. 2025;25(1):896.

  2. Feys S, Carvalho A, Clancy CJ, et al. Influenza-associated and COVID-19-associated pulmonary aspergillosis in critically ill patients. Lancet Respir Med. 2024;12(9):728-742.

  3. Bocci MG, Cascarano L, Capecchi G, et al. Pulmonary aspergillosis in immunocompromised critically ill patients: prevalence, risk factors, clinical features and diagnosis-a narrative review. J Fungi (Basel). 2025;11(9):617.

  4. Donnelly JP, Chen SC, Kauffman CA, et al. Revision and update of the consensus definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. Clin Infect Dis. 2020;71(6):1367-1376.

  5. Blot SI, Taccone FS, Van den Abbeele AM, et al. A clinical algorithm to diagnose invasive pulmonary aspergillosis in critically ill patients. Am J Respir Crit Care Med. 2012;186(1):56-64.

  6. Hamam J, Navellou JC, Bellanger AP, et al. New clinical algorithm including fungal biomarkers to better diagnose probable invasive pulmonary aspergillosis in ICU. Ann Intensive Care. 2021;11(1):41.

  7. Bassetti M, Giacobbe DR, Agvaldohman C, et al. Invasive fungal diseases in adult patients in intensive care unit (FUNDICU): 2024 consensus definitions from ESGCIP, EFISG, ESICM, ECMM, MSGERC, ISAC, and ISHAM. Intensive Care Med. 2024;50(4):502-515.

  8. Hatzl S, Geiger C, Kriegl L, et al. Performance of diagnostic algorithms in patients with invasive pulmonary aspergillosis. Clin Infect Dis. 2025;80(5):1080-1087.