{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T13:43:25Z","timestamp":1790603005676,"version":"4.1.0"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T00:00:00Z","timestamp":1681776000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"<jats:sec><jats:title>Objectives<\/jats:title><jats:p>We aimed to describe Familial Hemophagocytic Lymphohistiocytosis (F-HLH) patients' clinical features, intensive care courses, and outcomes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Multi-center retrospective cohort study of pediatric patients diagnosed with F-HLH from 2015 to 2020 in five tertiary centers in Saudi Arabia. Patients were classified as F-HLH based on their genetic confirmation of known mutation or on their clinical criteria, which include a constellation of abnormalities, early disease onset, recurrent HLH in the absence of other causes, or a family history of HLH.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Fifty-eight patients (28 male, 30 female), with a mean age of 21.0\u2009\u00b1\u200933.9 months, were included. The most common principal diagnosis was hematological or immune dysfunction (39.7%), followed by cardiovascular dysfunction in 13 (22.4%) patients. Fever was the most common clinical presentation in 27.6%, followed by convulsions (13.8%) and bleeding (13.8%). There were 20 patients (34.5%) who had splenomegaly, and more than 70% of patients had hyperferritinemia &amp;gt;500\u2005mg\/dl, hypertriglyceridemia &amp;gt;150\u2005mg\/dl and hemophagocytosis in bone marrow biopsy. Compared to deceased patients 18 (31%), survivors had significantly lower PT (<jats:italic>p<\/jats:italic>\u2009=\u2009041), bilirubin level of &amp;lt;34.2\u2005mmol\/L (<jats:italic>p<\/jats:italic>\u2009=\u20090.042), higher serum triglyceride level (<jats:italic>p<\/jats:italic>\u2009=\u20090.036), and lesser bleeding within the initial 6\u2005h of admission (<jats:italic>p<\/jats:italic>\u2009=\u20090.004). Risk factors for mortality included requirements of higher levels of hemodynamic (61.1% vs. 17.5%, <jats:italic>p<\/jats:italic>\u2009=\u20090.001) and respiratory (88.9% vs. 37.5%, <jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.001) support, and positive fungal cultures (<jats:italic>p<\/jats:italic>\u2009=\u20090.046).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Familial HLH still represents a challenge in the pediatric critical care setting. Earlier diagnosis and prompt initiation of appropriate treatment could improve F-HLH survival.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fped.2023.1152409","type":"journal-article","created":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T05:46:45Z","timestamp":1681796805000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Presentations and outcomes of familial hemophagocytic lymphohistiocytosis in the pediatric intensive care units (PICUs)"],"prefix":"10.3389","volume":"11","author":[{"given":"Fahad","family":"Alsohime","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamad-Hani","family":"Temsah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rawan M.","family":"Alotaibi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reham M.","family":"Alhalabi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"AlEnezy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aly Abdelrahman","family":"Yousef","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdullah Mohammed","family":"Alzaydi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hussam Sameer","family":"Inany","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayman","family":"Al-Eyadhy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Almazyad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Alharbi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdulaziz Abdullah","family":"Alsoqati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdurahman","family":"Andijani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Abu Ghazal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamal","family":"El Masri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maher","family":"Doussouki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raheel Farooq","family":"Butt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saleh","family":"Alshehri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Alsatrawi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaramia","family":"Macarambon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gamal M.","family":"Hasan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdulrahman","family":"Alsultan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,4,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"S82","DOI":"10.1016\/j.bbmt.2009.11.014","article-title":"Histiocytic disorders: recent insights into pathophysiology and practical guidelines","volume":"16","author":"Filipovich","year":"2010","journal-title":"Biol Blood Marrow Transplant"},{"key":"B2","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1182\/blood.V78.1.51.51","article-title":"Treatment of hemophagocytic lymphohistiocytosis with chemotherapy and bone marrow transplantation: a single-center study of 22 cases","volume":"78","author":"Blanche","year":"1991","journal-title":"Blood"},{"key":"B3","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1002\/pbc.21039","article-title":"HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis","author":"Henter","year":"2007","journal-title":"Pediatr Blood Cancer"},{"key":"B4","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1016\/S0889-8588(05)70521-9","article-title":"Infection- and malignancy-associated hemophagocytic syndromes: secondary hemophagocytic lymphohistiocytosis","volume":"12","author":"Janka","year":"1998","journal-title":"Hematol Oncol Clin North Am"},{"key":"B5","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1309\/AJCP4ZDKJ4ICOUAT","article-title":"Kim as: hemophagocytic lymphohistiocytosis: an update on diagnosis and pathogenesis","volume":"139","author":"Rosado","year":"2013","journal-title":"Am J Clin Pathol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"e216","DOI":"10.1542\/peds.2005-1861","article-title":"Hemophagocytic lymphohistiocytosis complicating influenza A infection","volume":"118","author":"Mou","year":"2006","journal-title":"Pediatrics"},{"key":"B7","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1007\/s10156-012-0420-9","article-title":"Human parechovirus-3 infection in nine neonates and infants presenting symptoms of hemophagocytic lymphohistiocytosis","volume":"19","author":"Yuzurihara","year":"2013","journal-title":"J Infect Chemother"},{"key":"B8","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1111\/bjh.12293","article-title":"Advances in understanding the pathogenesis of HLH","volume":"161","author":"Usmani","year":"2013","journal-title":"Br J Haematol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1111\/j.1365-2249.2010.04302.x","article-title":"Familial haemophagocytic lymphohistiocytosis: advances in the genetic basis, diagnosis and management","volume":"163","author":"Gholam","year":"2011","journal-title":"Clin Exp Immunol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1097\/01.PCC.0000149131.72248.E6","article-title":"International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics","volume":"6","author":"Goldstein","year":"2005","journal-title":"Pediatr Crit Care Med"},{"key":"B11","first-page":"1079","article-title":"Pancytopenia-A six year study","volume":"49","author":"Kumar","year":"2001","journal-title":"J Assoc Physicians India"},{"key":"B12","first-page":"29","article-title":"The FHL study group of the histiocyte society. Diagnostic guidelines for hemophagocytic lymphohistiocytosis","volume":"18","author":"Henter","year":"1991","journal-title":"Semin Oncol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000001692","article-title":"Coagulation disorders and bleedings in critically ill patients with hemophagocytic lymphohistiocytosis","volume":"94","author":"Valade","year":"2015","journal-title":"Medicine"},{"key":"B14","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1002\/pbc.21039","article-title":"HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis","volume":"48","author":"Henter","year":"2007","journal-title":"Pediatr Blood Cancer"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13023-019-1279-y","article-title":"Clinical profiles and risk factors of 7-day and 30-day mortality among 160 pediatric patients with hemophagocytic lymphohistiocytosis","volume":"15","author":"Li","year":"2020","journal-title":"Orphanet J Rare Dis"},{"key":"B16","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1136\/jmg.32.8.623","article-title":"Consanguinity among the Saudi Arabian population","volume":"32","author":"El-Hazmi","year":"1995","journal-title":"J Med Genet"},{"key":"B17","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1111\/j.1651-2227.1991.tb11878.x","article-title":"Incidence in Sweden and clinical features of familial hemophagocytic lymphohistiocytosis","volume":"80","author":"Henter","year":"1991","journal-title":"Acta Paediatr Scand"},{"key":"B18","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1182\/asheducation-2015.1.177","article-title":"Pathophysiology and epidemiology of hemophagocytic lymphohistiocytosis","volume":"2015","author":"Allen","year":"2015","journal-title":"Hematology"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12969-019-0309-6","article-title":"Calm in the midst of cytokine storm: a collaborative approach to the diagnosis and treatment of hemophagocytic lymphohistiocytosis and macrophage activation syndrome","volume":"17","author":"Halyabar","year":"2019","journal-title":"Pediatr Rheumatol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1016\/S0022-3476(97)70196-3","article-title":"Neuropathologic findings and neurologic symptoms in twenty-three children with hemophagocytic lymphohistiocytosis","volume":"130","author":"Henter","year":"1997","journal-title":"J Pediatr"},{"key":"B21","doi-asserted-by":"publisher","first-page":"852","DOI":"10.1016\/S0002-9270(00)02425-4","article-title":"Hepatic manifestations of hemophagocytic syndrome: a study of 30 case","volume":"96","author":"Kerguenec","year":"2001","journal-title":"Am J Gastroenterol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1007\/s12098-020-03190-6","article-title":"Hemophagocytic lymphohistiocytosis in children","volume":"87","author":"Nandhakumar","year":"2020","journal-title":"Indian J Pediatr"},{"key":"B23","doi-asserted-by":"publisher","first-page":"E44","DOI":"10.1097\/PCC.0000000000002539","article-title":"Hemophagocytic lymphohistiocytosis in a PICU of a developing economy: clinical profile, intensive care needs, outcome, and predictors of mortality","volume":"22","author":"Parajuli","year":"2021","journal-title":"Pediatr Crit Care Med"},{"key":"B24","volume-title":"Genereviews\u00ae","author":"Adam","year":"2022"},{"key":"B25","doi-asserted-by":"publisher","first-page":"316","DOI":"10.7150\/thno.49713","article-title":"Immunopathogenesis and treatment of cytokine storm in COVID-19","volume":"11","author":"Kim","year":"2021","journal-title":"Theranostics"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12879-020-05706-z","article-title":"A case of coinfection of a pediatric patient with acute SARS-COV-2 with MIS-C and severe DENV-2 in Mexico: a case report","volume":"21","author":"Jose","year":"2021","journal-title":"BMC Infect Dis"},{"key":"B27","doi-asserted-by":"publisher","first-page":"e0071","DOI":"10.1097\/CCE.0000000000000071","article-title":"Multimodal therapeutic approach of cytokine release syndrome developing in a child given chimeric antigen receptor-modified T cell infusion","volume":"2","author":"Bottari","year":"2020","journal-title":"Crit Care Explor"},{"key":"B28","doi-asserted-by":"publisher","first-page":"e303","DOI":"10.1097\/MPH.0000000000000916","article-title":"Critically ill children\u00a0with hemophagocytic lymphohistiocytosis: a case series of 14 patients","volume":"39","author":"Leow","year":"2017","journal-title":"J Pediatr Hematol Oncol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"271","DOI":"10.3109\/08880018.2013.858198","article-title":"Risk factors for early fatal outcomes among children with hemophagocytic lymphohistiocytosis (HLH): a single-institution case-series in Vietnam","volume":"31","author":"Dao","year":"2014","journal-title":"Pediatr Hematol Oncol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1111\/j.1651-2227.2011.02501.x","article-title":"Risk factors for early death in children with haemophagocytic lymphohistiocytosis","volume":"101","author":"Trottestam","year":"2012","journal-title":"Acta Paediatr"},{"key":"B31","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1097\/PCC.0b013e318198868b","article-title":"An unusual cause of multiple organ dysfunction syndrome in the pediatric intensive care unit: hemophagocytic lymphohistiocytosis","volume":"10","author":"Karapinar","year":"2009","journal-title":"Pediatr Crit Care Med"},{"key":"B32","doi-asserted-by":"publisher","first-page":"E185","DOI":"10.1097\/PCC.0000000000001827","article-title":"Outcomes analysis of children diagnosed with hemophagocytic lymphohistiocytosis in the PICU","volume":"20","author":"Gregory","year":"2019","journal-title":"Pediatr Crit Care Med"},{"key":"B33","doi-asserted-by":"publisher","first-page":"e311","DOI":"10.1097\/PCC.0000000000001980","article-title":"Etiologies and clinical outcomes of patients with secondary hemophagocytic lymphohistiocytosis at a tertiary PICU","volume":"20","author":"Dao","year":"2019","journal-title":"Pediatr Crit Care Med"},{"key":"B34","doi-asserted-by":"publisher","first-page":"2367","DOI":"10.1182\/blood-2002-01-0172","article-title":"Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation","volume":"100","author":"Henter","year":"2002","journal-title":"Blood"},{"key":"B35","doi-asserted-by":"publisher","first-page":"2728","DOI":"10.1182\/blood-2017-06-788349","article-title":"Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study","volume":"130","author":"Bergsten","year":"2017","journal-title":"Blood"},{"key":"B36","doi-asserted-by":"publisher","first-page":"86","DOI":"10.5045\/br.2021.2020308","article-title":"Genetic\u00a0and clinical characteristics of pediatric patients with familial hemophagocytic lymphohistiocytosis","volume":"56","author":"Al Ahmari","year":"2021","journal-title":"Blood Res"},{"key":"B37","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1097\/PCC.0b013e3182917a68","article-title":"Unscheduled readmissions to the PICU: epidemiology, risk factors, and variation among centers","volume":"14","author":"Czaja","year":"2013","journal-title":"Pediatr Crit Care Med"},{"key":"B38","doi-asserted-by":"publisher","first-page":"E959","DOI":"10.1097\/PCC.0000000000002406","article-title":"Unplanned PICU readmission in a middle-income country: who is at risk and what is the outcome?","volume":"21","author":"Mat Bah","year":"2020","journal-title":"Pediatr Crit Care Med"},{"key":"B39","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1097\/PCC.0000000000000735","article-title":"Description of PICU unplanned readmission","volume":"17","author":"Kotsakis","year":"2016","journal-title":"Pediatr Crit Care Med"},{"key":"B40","doi-asserted-by":"publisher","first-page":"e0193294","DOI":"10.1371\/journal.pone.0193294","article-title":"Survival after PICU admission: the impact of multiple admissions and complex chronic conditions","volume":"13","author":"Kalz\u00e9n","year":"2018","journal-title":"PLoS One"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2021.692849","article-title":"Diagnostic time lag of pediatric haemophagocytic lymphohistiocytosis and patient characteristics: a retrospective cohort study","volume":"9","author":"Li","year":"2021","journal-title":"Front Pediatr"},{"key":"B42","doi-asserted-by":"publisher","first-page":"1411","DOI":"10.1007\/s00277-016-2727-6","article-title":"Prognostic factors of early outcome in pediatric hemophagocytic lymphohistiocytosis: an analysis of 116 cases","volume":"95","author":"Bin","year":"2016","journal-title":"Ann Hematol"}],"container-title":["Frontiers in Pediatrics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2023.1152409\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T05:46:48Z","timestamp":1681796808000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2023.1152409\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,18]]},"references-count":42,"alternative-id":["10.3389\/fped.2023.1152409"],"URL":"https:\/\/doi.org\/10.3389\/fped.2023.1152409","relation":{},"ISSN":["2296-2360"],"issn-type":[{"value":"2296-2360","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,18]]},"article-number":"1152409"}}