{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T02:38:40Z","timestamp":1792463920617,"version":"4.5.0"},"reference-count":92,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T00:00:00Z","timestamp":1792368000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T00:00:00Z","timestamp":1792368000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Veterinary Clinical Pathol"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Hemophagocytic syndrome (HPS)\/hemophagocytic lymphohistiocytosis (HLH) is a life\u2010threatening hyperinflammatory syndrome characterized by immune dysregulation, cytokine overproduction, hemophagocytosis, cytopenias, and multiorgan dysfunction. Although diagnostic criteria are established in human medicine, standardized criteria and validated biomarkers are lacking in dogs and cats.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To review the pathogenesis, clinical and clinicopathologic features, diagnosis, and differential diagnoses of HPS\/HLH, with emphasis on dogs and cats, and to propose a framework for establishing standardized diagnostic criteria for canine HPS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Human and veterinary literature on HLH, HPS, and macrophage activation syndrome was reviewed, including diagnostic criteria, biomarkers, bone marrow morphology, immunohistochemistry, flow cytometry, and molecular diagnostics. Representative canine cases of secondary HPS and hemophagocytic histiocytic sarcoma were evaluated to illustrate diagnostic challenges.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>HPS results from dysregulated activation of cytotoxic lymphocytes and macrophages, with interferon\u2010\u03b3 playing a central role in sustaining hyperinflammation. In dogs and cats, HPS is most commonly associated with infections, neoplasia, and immune\u2010mediated disease. Clinical and laboratory findings are nonspecific, and although hemophagocytosis supports the diagnosis, it is neither required nor sufficient to establish HPS. Distinguishing reactive HPS from histiocytic neoplasia and other non\u2010neoplastic causes of hemophagocytic activity\u2014including drug\u2010associated changes, post\u2010transfusion hemophagocytosis, and PIMA\u2010associated histiocytic activity\u2014requires integration of cytomorphology, tissue distribution, immunophenotyping, and molecular diagnostics. Human HLH\u20102004 criteria and the H\u2010score provide useful diagnostic frameworks, but neither has been validated for veterinary species.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>HPS is a challenging and potentially fatal syndrome in dogs and cats, which requires comprehensive clinicopathologic evaluation. Prospective studies are needed to establish species\u2010specific diagnostic criteria and validate quantitative morphologic, immunophenotypic, molecular, and biomarker\u2010based approaches to distinguish HPS from infectious, immune\u2010mediated, and neoplastic disorders in which phagocytic activity is prominent.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/vcp.70155","type":"journal-article","created":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T01:40:39Z","timestamp":1792460439000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>In the Midst of<\/scp>\n                    a\n                    <scp>Cytokine Storm<\/scp>\n                    \u2014\n                    <scp>The Hemophagocytic Syndrome<\/scp>\n                    (Hemophagocytic Lymphohistiocytosis\/Macrophage Activation Syndrome)"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-6417-2444","authenticated-orcid":false,"given":"Joanne B.","family":"Messick","sequence":"first","affiliation":[{"name":"College of Veterinary Medicine Purdue University  West Lafayette Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,19]]},"reference":[{"key":"e_1_2_9_2_1","first-page":"9","article-title":"Diagnostic Guidelines for Hemophagocytic Lymphohistiocytosis. 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