A104-25 Emergence of a Non-classical Monocyte Phenotype Is Associated With Poor 3-month Physical Recovery After Acute Respiratory Distress Syndrome (ARDS)

Rationale

ARDS survivors frequently experience long-term intensive care unit-acquired weakness (ICUAW). Monocyte-driven inflammation is implicated in severe and prolonged ARDS; however, the post-discharge monocyte landscape and its association with physical recovery remains poorly characterized.

Methods

We conducted a nested case-control study within an ongoing prospective multicenter cohort of ARDS survivors. Sixteen ARDS survivors with ICUAW at hospital discharge were sampled 1:1 based on 3-month physical recovery status assessed with validated surveys and performance measures, with matching on demographics, comorbidities, and ARDS severity. We performed single-cell transcriptomics with Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq) of peripheral blood mononuclear cells at hospital discharge and 3-months, and in 4 non-ARDS healthy controls. Cell types were identified using a random forest-based multimodal classifier. Differential gene expression analyses were performed in Scanpy. Gene Set Enrichment Analysis were performed using the Molecular Signatures Database Hallmark gene sets.

Results

Non-recovered ARDS survivors, recovered survivors, and healthy controls did not differ significantly in age (median [IQR] 63 [40-66] vs. 50 [32-66] years vs. 52 [45-61]; p = 0.80). ARDS survivor groups had similar Charlson comorbidity burden (0.5 [0-2] vs. 1 [0.5-2], p = 0.60), initial ARDS severity (PaO₂/FiO₂ 147 [74-199] vs. 139 [78-203], p = 0.87), and hospital length of stay (21 [10-29] vs. 20 [18-32] days, p = 0.60). At discharge, most patients had difficulty standing; non-recovered and recovered groups had low percent-predicted 6-minute walk distance (6MWD) (0 [0-13] vs. 59 [0-88], p = 0.12) and high prevalence of frailty criterion for weak grip (100% vs. 75%, p = 0.47). At 3 months, non-recovered survivors had lower percent-predicted 6MWD (8 [0-49] vs. 65 [60-75], p < 0.01) and higher prevalence of weak grip (75% vs. 12.5%, p = 0.04). Cell clustering on Uniform Manifold Approximation and Projection plots revealed a novel CD16⁺HLA-DRhi nonclassical monocyte population enriched in non-recovered survivors at 3-months with reduced expression of genes for monocyte patrolling (SELPLG), innate immune signaling (HCK), and metabolic resilience (PRDX3) (FDR q < 0.001). Compared to healthy controls, non-recovered and recovered survivors had differential expression of 20 gene pathways within monocytes (FDR q < 0.1). Non-recovered survivors demonstrated downregulation of transforming growth factor-β and tumor necrosis factor-α signaling, with upregulation of interferon-α and interferon-γ signaling at 3 months (Figure 1).

Conclusions

In ARDS survivors, poor physical recovery at 3 months is associated with the emergence of a non-classical monocyte population with transcriptomics suggestive of innate immune dysfunction, inflammatory signaling, and impaired coordination of tissue repair.

This abstract is funded by: NHLBI R01 HL 164777