Rationale: Critically ill patients who develop invasive pulmonary aspergillosis (IPA) have high mortality rates despite antifungal therapy. Diagnosis is difficult in these patients. Bronchoalveolar lavage (BAL) fluid galactomannan (GM) is a helpful marker of infection, although the optimal cutoff for IPA is unclear. We aimed to evaluate the BAL fluid GM and fungal culture results, demographics, and outcomes among a large cohort of mechanically ventilated patients with suspected pneumonia. Methods: A single-center cohort study of patients enrolled in the Successful Clinical Response in Pneumonia Therapy (SCRIPT) study from June 2018 to March 2023. Demographics, BAL results, and outcomes data were extracted from the electronic health record and compared between groups of patients who grew Aspergillus on a BAL fluid culture, those who had elevated BAL fluid GM levels (defined as >0.5 or >0.8) but did not grow Aspergillus on BAL fluid culture, and those with neither. Results: Of over 1700 BAL samples from 688 patients, only 18 BAL samples grew Aspergillus. Patients who had a BAL sample grow Aspergillus (n=15) were older (median 71 vs 62 years, p=0.023), had more days intubated (29 vs 11, p=0.002), and more ICU days (34 vs 15, p=0.002) than patients whose BAL fluid culture was negative for Aspergillus (n=672). The BAL fluid galactomannan level was higher from samples that grew Aspergillus on culture than those that did not (median ODI 7.08 vs 0.11, p<0.001), though the elevation of BAL fluid GM varied across BAL samples for patients who had serial sampling. Patients who grew Aspergillus had a similar proportion of underlying immunocompromise compared with the patients who did not, and while no statistically significant difference in overall unfavorable outcome, had longer duration of ventilation and longer ICU stays. Conclusions: In this large cohort of critically ill patients with a high number of BAL samples with GM levels, we found a relatively low rate of Aspergillus growth. Patients who eventually grew Aspergillus had inconsistently elevated BAL fluid GM, and many patients with elevated BAL fluid GM did not grow Aspergillus. These data suggest that the pre-test probability of invasive pulmonary aspergillosis should be considered low in a general ICU population undergoing BAL evaluation to define the etiology of pneumonia. Improved scoring systems are needed to enhance pre-test probability for diagnostic test stewardship purposes.

BDS holds US patent 10,905,706, "Compositions and methods to accelerate resolution of acute lung inflammation," and serves on the Scientific Advisory Board of Zoe Biosciences, for which he holds stock options. Other authors declare no conflicting interests.

SCRIPT is supported by NIH/NIAID U19AI135964. CAG is supported by NIH/NHLBI F32HL162377. BDS is supported by NIH awards R01HL149883, R01HL153122, P01HL154998, P01AG049665, and U19AI135964. RGW is supported by NIH grants U19AI135964, U01TR003528, P01HL154998, R01HL149883, R01LM013337. The funding sources did not have a role in the design, execution, or prior review of the study or in the data presented in this manuscript. Opinions expressed in this work do not necessarily reflect those of the funding sources.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This study was approved by the Northwestern University Institutional Review Board with study ID STU00204868.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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A significant portion of this data has been already made available through PhysioNet at https://physionet.org/content/script-carpediem-dataset/1.1.0/,39 a future update will include the new patients enrolled since the publication of the original dataset. Code is available at https://github.com/NUSCRIPT/gao_Aspergillus_2024.

https://physionet.org/content/script-carpediem-dataset/1.1.0/