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Observational Study
. 2021 Feb;9(3):e14693.
doi: 10.14814/phy2.14693.

Biological subphenotypes of acute respiratory distress syndrome may not reflect differences in alveolar inflammation

Nanon F L Heijnen  1 , Laura A Hagens  2 , Marry R Smit  2 , Marcus J Schultz  2   3   4   5 , Tom van der Poll  6   7 , Ronny M Schnabel  1 , Iwan C C van der Horst  1 , Robert P Dickson  8   9   10 , Dennis C J J Bergmans  1 , Lieuwe D J Bos  2 ; BASIC consortium
Affiliations
Observational Study

Biological subphenotypes of acute respiratory distress syndrome may not reflect differences in alveolar inflammation

Nanon F L Heijnen et al. Physiol Rep. 2021 Feb.

Abstract

Biological subphenotypes have been identified in acute respiratory distress syndrome (ARDS) based on two parsimonious models: the "uninflamed" and "reactive" subphenotype (cluster-model) and "hypo-inflammatory" and "hyper-inflammatory" (latent class analysis (LCA) model). The distinction between the subphenotypes is mainly driven by inflammatory and coagulation markers in plasma. However, systemic inflammation is not specific for ARDS and it is unknown whether these subphenotypes also reflect differences in the alveolar compartment. Alveolar inflammation and dysbiosis of the lung microbiome have shown to be important mediators in the development of lung injury. This study aimed to determine whether the "reactive" or "hyper-inflammatory" biological subphenotype also had higher concentrations of inflammatory mediators and enrichment of gut-associated bacteria in the lung. Levels of alveolar inflammatory mediators myeloperoxidase (MPO), surfactant protein D (SPD), interleukin (IL)-1b, IL-6, IL-10, IL-8, interferon gamma (IFN-ƴ), and tumor necrosis factor-alpha (TNFα) were determined in the mini-BAL fluid. Key features of the lung microbiome were measured: bacterial burden (16S rRNA gene copies/ml), community diversity (Shannon Diversity Index), and community composition. No statistically significant differences between the "uninflamed" and "reactive" ARDS subphenotypes were found in a selected set of alveolar inflammatory mediators and key features of the lung microbiome. LCA-derived subphenotypes and stratification based on cause of ARDS (direct vs. indirect) showed similar profiles, suggesting that current subphenotypes may not reflect the alveolar host response. It is important for future research to elucidate the pulmonary biology within each subphenotype properly, which is arguably a target for intervention.

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Figures

FIGURE 1
FIGURE 1
Alveolar inflammation per ARDS (sub)phenotype. Subscription: Boxplots indicate mean values with inter‐quartile range and 95% range. Individual datapoints are also shown. Cluster subphenotypes are depicted in green for uninflamed and red for reactive. LCA subphenotypes are illustrated in blue for hypo‐inflammatory and orange for hyper‐inflammatory. Indirect ARDS is shown in light purple and direct ARDS in darker purple. For all comparisons, the p‐value was >0.1, without correction for multiple testing. Only uncorrected concentrations are depicted. Abbreviations: Myeloperoxidase (MPO) ng/ml, interleukin 1 beta (IL‐1b) pg/ml, interleukin 6 (IL‐6) pg/ml, interleukin 8 (IL‐8) pg/ml, interferon gamma (IFN‐ƴ) pg/ml, tumor necrosis factor‐alpha (TNFα) pg/ml, 16S rRNA genes copies/ml
FIGURE 2
FIGURE 2
Log2 difference between alveolar and plasma concentration per (sub)phenotype. Subscription: Bars indicate mean values with a standard error of the mean. Positive values indicate a higher alveolar concentration, while a negative value indicates a higher plasma level of the biomarker. Cluster subphenotypes are illustrated in green for uninflamed and red for reactive. LCA subphenotypes are depicted in blue for hypo‐inflammatory and orange for hyper‐inflammatory. Indirect ARDS is shown in light purple and direct ARDS in darker purple. For all comparisons, the p‐value was >0.1, without correction for multiple testing. Abbreviations: Interferon gamma (IFN‐ƴ) pg/ml, interleukin 1 beta (IL‐1b) pg/ml, interleukin 6 (IL‐6) pg/ml, interleukin 8 (IL‐8) pg/ml, and tumor necrosis factor‐alpha (TNFα) pg/ml
FIGURE 3
FIGURE 3
In‐depth analysis of the lung microbiome per ARDS (sub)phenotype. Subscription: Left‐to‐right: Principal coordinate (PCO) analysis of bacterial communities, rank abundance analysis, and random forest analysis. (a) cluster‐subphenotype: reactive (green) and uninflamed (red). (b) LCA‐subphenotypes: hypo‐inflammatory (blue) and hyper‐inflammatory (orange). (c) etiology phenotype: Indirect (light purple) and Direct (dark purple). Bacterial communities did not significantly differ for individual subphenotypes (PCO). Rank abundance analysis only showed enriched Prevotellaceae in patients with “direct” ARDS. However, random forest analysis did not confirm this family as a discriminating taxonomic group
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