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This study aimed to characterize the clinical features and severity markers of ISCLS in critically and non-critically ill patients. We analyzed prospectively and retrospectively collected data on ISCLS cases from the Italian IRIS-CLS Registry (January 1995\u2013December 2023). A total of 124 acute episodes were identified in 32 patients; 61 episodes in 26 patients having complete records were included in the analysis. Monoclonal gammopathy was found in 20\/23 adults but was absent in all three pediatric patients, who exhibited IgA deficiency instead. At admission, patients presented with hypotension (systolic arterial pressure 87\u00a0mmHg [80\u2013105]), tachycardia (110\u00a0bpm [96\u2013130]), and hemoconcentration (hematocrit 57% [48\u201362.7]). ICU admission was required in 70.5%, and cardiac involvement occurred in 49.2% of episodes. Fluid volume infused correlated positively with rhabdomyolysis severity, and the need for renal replacement therapy was more frequent in patients receiving\u2009\u2265\u20093 L. No pharmacologic treatment was effective during the crises. Mortality was 9.8% per episode, and the day-1 Sequential Organ Failure Assessment score was a predictor of death (<jats:italic>p<\/jats:italic>\u2009=\u20090.0181). Immunoglobulin prophylaxis reduced attack frequency from 0.67 (0.4\u20131.07) to 0.4 (0.1\u20130.52) per year (<jats:italic>p<\/jats:italic>\u2009=\u20090.033). Two adults (8.7%) developed multiple myeloma during follow-up. This study provides a comprehensive overview of ISCLS in both critically and non-critically ill patients. We highlight clinical-biochemical-instrumental red-flags and emphasize the need for increased awareness and early recognition since effective treatments for acute shock remain elusive.<\/jats:p>","DOI":"10.1007\/s11739-025-03890-x","type":"journal-article","created":{"date-parts":[[2025,3,8]],"date-time":"2025-03-08T19:07:57Z","timestamp":1741460877000},"page":"991-1001","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Clarkson disease in critically and non-critically ill patients: insights from the Italian IRIS-CLS registry"],"prefix":"10.1007","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9616-803X","authenticated-orcid":false,"given":"Riccardo","family":"Colombo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4028-9588","authenticated-orcid":false,"given":"Jonathan","family":"Montomoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Lanzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Tosoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9664-2408","authenticated-orcid":false,"given":"Claudia","family":"Agabiti Rosei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Visani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2833-2288","authenticated-orcid":false,"given":"Franco","family":"Verlicchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2980-6158","authenticated-orcid":false,"given":"Chiara","family":"Cogliati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2773-734X","authenticated-orcid":false,"given":"Manuela","family":"Nebuloni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1078-1632","authenticated-orcid":false,"given":"Maddalena Alessandra","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,8]]},"reference":[{"key":"3890_CR1","doi-asserted-by":"publisher","first-page":"89","DOI":"10.3389\/fmed.2019.00089","volume":"6","author":"MA Wu","year":"2019","unstructured":"Wu MA, Tsvirkun D, Bureau L, Boccon-Gibod I, Inglebert M, Duperray A, Bouillet L, Misbah C et al (2019) Paroxysmal permeability disorders: development of a microfluidic device to assess endothelial barrier function. 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The remaining authors have no conflicts of interest to declare.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"The study was conducted in accordance with the 1964 Declaration of Helsinki and its most recent revision in 2024. Informed consent was obtained from patients whenever possible. When patients were unable to provide consent, it was obtained from their relatives when available. In cases where neither the patient nor their relatives were able to provide consent, the decision was made in accordance with applicable regulations and ethical guidelines.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Human and animal rights statement and Informed consent"}}]}}