Development and validation of dynamic clinical subphenotypes in acute pancreatitis patients using vital sign trajectories in intensive care units: a multinational cohort study
Abstract Acute pancreatitis (AP) is a heterogeneous inflammatory condition. Although emerging therapeutic strategies targeting pathways such as calcium signaling, TNF-α, the NLRP3 inflammasome, and HMGB1 have shown promise, their efficacy may be limited by the underlying biological heterogeneity of...
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| Format: | Article |
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Nature Publishing Group
2025-06-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-025-02261-4 |
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| author | Zichen Wang Wen Wang Jiayue Xu Qiao He Che Sun Shuangyi Xie Kang Zou Qing Xia Xin Sun |
| author_facet | Zichen Wang Wen Wang Jiayue Xu Qiao He Che Sun Shuangyi Xie Kang Zou Qing Xia Xin Sun |
| author_sort | Zichen Wang |
| collection | DOAJ |
| description | Abstract Acute pancreatitis (AP) is a heterogeneous inflammatory condition. Although emerging therapeutic strategies targeting pathways such as calcium signaling, TNF-α, the NLRP3 inflammasome, and HMGB1 have shown promise, their efficacy may be limited by the underlying biological heterogeneity of the disease. In this multinational retrospective cohort study across three large ICU databases (ICU-HAI, MIMIC-IV, and eICU-CRD), we used group-based trajectory modeling of early vital signs to identify four distinct AP subphenotypes: hyperinflammatory, hypertensive, hypotensive, and hypoinflammatory. These subtypes differed markedly in 30-day mortality, inflammatory burden, and hemodynamic stability. Compared to the hypertensive phenotype, hyperinflammatory and hypotensive patients had significantly higher 30-day mortality risks (HR = 3.38 and HR = 1.87, respectively), while the hypoinflammatory phenotype carried no excess risk. Fluid resuscitation responses were phenotype-specific: hyperinflammatory patients benefited from higher fluid volumes, whereas hypoinflammatory patients were at risk of fluid overload. Notably, distinct subphenotypes displayed unique responses to fluid intake over the first two ICU days. For hyperinflammatory phenotype, the algorithm-estimated lowest-risk fluid range was 4100–4300 mL on day 1 and 3400–3600 mL on day 2; for phenotype hypoinflammatory phenotype, the optimal ranges were 2800–3800 mL and 1400–2600 mL, respectively. Early use of lactated Ringer’s solution, which inhibited NLRP3, was associated with reduced mortality in hypotensive phenotype. These findings underscore the clinical relevance of early physiological trajectories and support precision fluid resuscitation based on subtype. This study establishes the largest early-trajectory-based classification of AP to date, offering new insights into immune and vascular mechanisms that drive heterogeneity and therapeutic responsiveness. |
| format | Article |
| id | doaj-art-989b2f101a9b4f9eb8910d8390fc0c96 |
| institution | OA Journals |
| issn | 2059-3635 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Publishing Group |
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| series | Signal Transduction and Targeted Therapy |
| spelling | doaj-art-989b2f101a9b4f9eb8910d8390fc0c962025-08-20T02:30:59ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352025-06-0110111010.1038/s41392-025-02261-4Development and validation of dynamic clinical subphenotypes in acute pancreatitis patients using vital sign trajectories in intensive care units: a multinational cohort studyZichen Wang0Wen Wang1Jiayue Xu2Qiao He3Che Sun4Shuangyi Xie5Kang Zou6Qing Xia7Xin Sun8Institute of Integrated Traditional Chinese and Western Medicine, Chinese Evidence-based Medicine Center and Cochrane China, West China Hospital, Sichuan UniversityInstitute of Integrated Traditional Chinese and Western Medicine, Chinese Evidence-based Medicine Center and Cochrane China, West China Hospital, Sichuan UniversityInstitute of Integrated Traditional Chinese and Western Medicine, Chinese Evidence-based Medicine Center and Cochrane China, West China Hospital, Sichuan UniversityInstitute of Integrated Traditional Chinese and Western Medicine, Chinese Evidence-based Medicine Center and Cochrane China, West China Hospital, Sichuan UniversityInstitute of Integrated Traditional Chinese and Western Medicine, Chinese Evidence-based Medicine Center and Cochrane China, West China Hospital, Sichuan UniversityInstitute of Integrated Traditional Chinese and Western Medicine, Chinese Evidence-based Medicine Center and Cochrane China, West China Hospital, Sichuan UniversityInstitute of Integrated Traditional Chinese and Western Medicine, Chinese Evidence-based Medicine Center and Cochrane China, West China Hospital, Sichuan UniversityInstitute of Integrated Traditional Chinese and Western Medicine, Chinese Evidence-based Medicine Center and Cochrane China, West China Hospital, Sichuan UniversityInstitute of Integrated Traditional Chinese and Western Medicine, Chinese Evidence-based Medicine Center and Cochrane China, West China Hospital, Sichuan UniversityAbstract Acute pancreatitis (AP) is a heterogeneous inflammatory condition. Although emerging therapeutic strategies targeting pathways such as calcium signaling, TNF-α, the NLRP3 inflammasome, and HMGB1 have shown promise, their efficacy may be limited by the underlying biological heterogeneity of the disease. In this multinational retrospective cohort study across three large ICU databases (ICU-HAI, MIMIC-IV, and eICU-CRD), we used group-based trajectory modeling of early vital signs to identify four distinct AP subphenotypes: hyperinflammatory, hypertensive, hypotensive, and hypoinflammatory. These subtypes differed markedly in 30-day mortality, inflammatory burden, and hemodynamic stability. Compared to the hypertensive phenotype, hyperinflammatory and hypotensive patients had significantly higher 30-day mortality risks (HR = 3.38 and HR = 1.87, respectively), while the hypoinflammatory phenotype carried no excess risk. Fluid resuscitation responses were phenotype-specific: hyperinflammatory patients benefited from higher fluid volumes, whereas hypoinflammatory patients were at risk of fluid overload. Notably, distinct subphenotypes displayed unique responses to fluid intake over the first two ICU days. For hyperinflammatory phenotype, the algorithm-estimated lowest-risk fluid range was 4100–4300 mL on day 1 and 3400–3600 mL on day 2; for phenotype hypoinflammatory phenotype, the optimal ranges were 2800–3800 mL and 1400–2600 mL, respectively. Early use of lactated Ringer’s solution, which inhibited NLRP3, was associated with reduced mortality in hypotensive phenotype. These findings underscore the clinical relevance of early physiological trajectories and support precision fluid resuscitation based on subtype. This study establishes the largest early-trajectory-based classification of AP to date, offering new insights into immune and vascular mechanisms that drive heterogeneity and therapeutic responsiveness.https://doi.org/10.1038/s41392-025-02261-4 |
| spellingShingle | Zichen Wang Wen Wang Jiayue Xu Qiao He Che Sun Shuangyi Xie Kang Zou Qing Xia Xin Sun Development and validation of dynamic clinical subphenotypes in acute pancreatitis patients using vital sign trajectories in intensive care units: a multinational cohort study Signal Transduction and Targeted Therapy |
| title | Development and validation of dynamic clinical subphenotypes in acute pancreatitis patients using vital sign trajectories in intensive care units: a multinational cohort study |
| title_full | Development and validation of dynamic clinical subphenotypes in acute pancreatitis patients using vital sign trajectories in intensive care units: a multinational cohort study |
| title_fullStr | Development and validation of dynamic clinical subphenotypes in acute pancreatitis patients using vital sign trajectories in intensive care units: a multinational cohort study |
| title_full_unstemmed | Development and validation of dynamic clinical subphenotypes in acute pancreatitis patients using vital sign trajectories in intensive care units: a multinational cohort study |
| title_short | Development and validation of dynamic clinical subphenotypes in acute pancreatitis patients using vital sign trajectories in intensive care units: a multinational cohort study |
| title_sort | development and validation of dynamic clinical subphenotypes in acute pancreatitis patients using vital sign trajectories in intensive care units a multinational cohort study |
| url | https://doi.org/10.1038/s41392-025-02261-4 |
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