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Editorial
. 2025 Sep;211(9):1549-1551.
doi: 10.1164/rccm.202506-1390ED.

Finding the Four-Leaf CLOVERS: Biologic Subphenotypes and Fluid Tolerance in Sepsis

Georgios D Kitsios  1   2 , Sivasubramanium V Bhavani  3 , Faraaz A Shah  1   2   4
Affiliations
Editorial

Finding the Four-Leaf CLOVERS: Biologic Subphenotypes and Fluid Tolerance in Sepsis

Georgios D Kitsios et al. Am J Respir Crit Care Med. 2025 Sep.
No abstract available

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Figures

Figure 1.
Figure 1.
Biologic subphenotypes and fluid tolerance in sepsis: a new paradigm. This schematic depicts the evolution of fluid management in sepsis over recent decades. Early approaches emphasized uniform liberal fluid administration to “fill the tank.” Subsequent strategies focused on dynamic physiologic assessments of fluid responsiveness—whether a patient’s cardiac output would improve with additional fluid, such as with the passive leg raise test, or arterial waveform indices, such as PPV or SVV. This phase was followed by growing attention to fluid tolerance, using bedside tools such as B-lines on lung ultrasound or venous congestion indices (e.g., VeXUS) to identify patients at risk of harm from excess fluid. The secondary analysis of the CLOVERS study adds a new dimension by integrating biologic subphenotyping, distinguishing patients based on endothelial injury (angiopoietin [Ang]-1, Ang-2) and inflammation (sTNFR1). Notably, subphenotype (SP2) patients with worse endothelial injury and inflammation experienced harm from liberal fluids, whereas SP1 patients tolerated fluids without excess risk. These findings support a precision-medicine approach to sepsis resuscitation, tailoring fluid strategy to individual biology rather than relying on one-size-fits-all protocols. Generated with BioRender. CVP = central venous pressure; PPV = pulse pressure variability; sTNFR1 = soluble tumor necrosis factor receptor 1; SVV = stroke volume variability.
See this image and copyright information in PMC

Comment on

  • Molecular Phenotyping of Sepsis and Differential Response to Fluid Resuscitation.
    Kiernan E, Zelnick LR, Khader A, Coston TD, Bailey ZA, Speckmaier S, Lo JJ, Siew ED, Sathe NA, Kestenbaum BR, Himmelfarb J, Johnson NJ, Shapiro NI, Douglas IS, Hough CL, Bhatraju PK. Kiernan E, et al. Am J Respir Crit Care Med. 2025 Sep;211(9):1681-1688. doi: 10.1164/rccm.202412-2377OC. Am J Respir Crit Care Med. 2025. PMID: 40668865 Clinical Trial.

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