Diagnostic guidelines for familial hemophagocytic lymphohistiocytosis revisited
•We present updated diagnostic criteria for FHL including revised clinical criteria and guidelines on genetic and cellular diagnostic assays.•HLH-2004 criteria (without NK-cell function) have significant validity (accuracy 99%) tested against infections and systemic inflammation. [Display omitted] C...
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| Veröffentlicht in: | Blood 2024-11, Vol.144 (22), p.2308-2318 |
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| creator | Henter, Jan-Inge Sieni, Elena Eriksson, Julia Bergsten, Elisabet Hed Myrberg, Ida Canna, Scott W. Coniglio, Maria Luisa Cron, Randy Q. Kernan, Kate F. Kumar, Ashish R. Lehmberg, Kai Minoia, Francesca Naqvi, Ahmed Ravelli, Angelo Tang, Yong-Min Bottai, Matteo Bryceson, Yenan T. Horne, AnnaCarin Jordan, Michael B. |
| description | •We present updated diagnostic criteria for FHL including revised clinical criteria and guidelines on genetic and cellular diagnostic assays.•HLH-2004 criteria (without NK-cell function) have significant validity (accuracy 99%) tested against infections and systemic inflammation.
[Display omitted]
Current hemophagocytic lymphohistiocytosis 2004 (HLH-2004)–based diagnostic criteria for familial hemophagocytic lymphohistiocytosis (FHL) are based on expert opinion. Here, we performed a case-control study to test and possibly improve these criteria. We also developed 2 complementary expert opinion–based diagnostic strategies for FHL in patients with signs/symptoms suggestive of HLH, based on genetic and cellular cytotoxicity assays. The cases (N = 366) were children aged |
| doi_str_mv | 10.1182/blood.2024025077 |
| format | Article |
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[Display omitted]
Current hemophagocytic lymphohistiocytosis 2004 (HLH-2004)–based diagnostic criteria for familial hemophagocytic lymphohistiocytosis (FHL) are based on expert opinion. Here, we performed a case-control study to test and possibly improve these criteria. We also developed 2 complementary expert opinion–based diagnostic strategies for FHL in patients with signs/symptoms suggestive of HLH, based on genetic and cellular cytotoxicity assays. The cases (N = 366) were children aged <16 years with verified familial and/or genetic FHL (n = 341) or Griscelli syndrome type 2 (n = 25); 276 from the HLH-94/HLH-2004 databases and 90 from the Italian HLH Registry. All fulfilled the HLH-94/HLH-2004 patient inclusion criteria. Controls were 374 children with systemic-onset juvenile idiopathic arthritis (sJIA) and 329 + 361 children in 2 cohorts with febrile infections that could be confused with HLH and sepsis, respectively. To provide complete data sets, multiple imputations were performed. The optimal model, based on 17 variables studied, revealed almost similar diagnostic thresholds as the existing criteria, with accuracy 99.1% (sensitivity 97.1%; specificity 99.5%); the original HLH-2004 criteria had accuracy 97.4% (sensitivity 99.0%; specificity 97.1%). Because cellular cytotoxicity assays here constitute a separate diagnostic strategy, HLH-2004 criteria without natural killer (NK)–cell function was also studied, which showed accuracy 99.0% (sensitivity, 96.2%; specificity, 99.5%). Thus, we conclude that the HLH-2004 criteria (without NK-cell function) have significant validity in their current form when tested against severe infections or sJIA. It is important to exclude underlying malignancies and atypical infections. In addition, complementary cellular and genetic diagnostic guidelines can facilitate necessary confirmation of clinical diagnosis.
Clinical diagnostic criteria for primary (also known as familial) hemophagocytic lymphohistiocytosis (HLH) were codified in 2004 (HLH-2004), and this score has endured over 2 decades. Now, through case-control analysis of international pediatric trial databases, Henter and colleagues report on the updated criteria on behalf of the Histiocyte Society. Use of these criteria streamlines the clinical diagnosis, discriminates primary HLH from other inflammatory disorders, and provides guidance on genetic testing.</description><identifier>ISSN: 0006-4971</identifier><identifier>ISSN: 1528-0020</identifier><identifier>EISSN: 1528-0020</identifier><identifier>DOI: 10.1182/blood.2024025077</identifier><identifier>PMID: 39046779</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adolescent ; Case-Control Studies ; Child ; Child, Preschool ; Clinical Trials and Observations ; Female ; Humans ; Infant ; Lymphohistiocytosis, Hemophagocytic - diagnosis ; Lymphohistiocytosis, Hemophagocytic - genetics ; Male ; Piebaldism - diagnosis ; Piebaldism - genetics ; Practice Guidelines as Topic ; Primary Immunodeficiency Diseases</subject><ispartof>Blood, 2024-11, Vol.144 (22), p.2308-2318</ispartof><rights>2024 American Society of Hematology</rights><rights>2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.</rights><rights>2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. 2024 American Society of Hematology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c369t-f5017e4bd39ce843c589c9ffdfa093279388bc751b6290323c779d98aef87ae73</cites><orcidid>0000-0003-2661-3086 ; 0000-0002-8297-2238 ; 0000-0002-5093-8422 ; 0000-0003-1409-5517 ; 0000-0002-9645-5856 ; 0000-0002-6192-9812 ; 0000-0003-3837-5337 ; 0000-0001-9658-0385 ; 0000-0002-0629-2126 ; 0000-0002-8306-8419 ; 0000-0002-6337-841X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,550,776,881</link.rule.ids><linktorsrc>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:160417949$$EView_record_in_Swedish_Publication_Index_(SWEPUB)$$FView_record_in_$$GSwedish_Publication_Index_(SWEPUB)$$Hfree_for_read</linktorsrc><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39046779$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:160417949$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Henter, Jan-Inge</creatorcontrib><creatorcontrib>Sieni, Elena</creatorcontrib><creatorcontrib>Eriksson, Julia</creatorcontrib><creatorcontrib>Bergsten, Elisabet</creatorcontrib><creatorcontrib>Hed Myrberg, Ida</creatorcontrib><creatorcontrib>Canna, Scott W.</creatorcontrib><creatorcontrib>Coniglio, Maria Luisa</creatorcontrib><creatorcontrib>Cron, Randy Q.</creatorcontrib><creatorcontrib>Kernan, Kate F.</creatorcontrib><creatorcontrib>Kumar, Ashish R.</creatorcontrib><creatorcontrib>Lehmberg, Kai</creatorcontrib><creatorcontrib>Minoia, Francesca</creatorcontrib><creatorcontrib>Naqvi, Ahmed</creatorcontrib><creatorcontrib>Ravelli, Angelo</creatorcontrib><creatorcontrib>Tang, Yong-Min</creatorcontrib><creatorcontrib>Bottai, Matteo</creatorcontrib><creatorcontrib>Bryceson, Yenan T.</creatorcontrib><creatorcontrib>Horne, AnnaCarin</creatorcontrib><creatorcontrib>Jordan, Michael B.</creatorcontrib><creatorcontrib>Histiocyte Society</creatorcontrib><title>Diagnostic guidelines for familial hemophagocytic lymphohistiocytosis revisited</title><title>Blood</title><addtitle>Blood</addtitle><description>•We present updated diagnostic criteria for FHL including revised clinical criteria and guidelines on genetic and cellular diagnostic assays.•HLH-2004 criteria (without NK-cell function) have significant validity (accuracy 99%) tested against infections and systemic inflammation.
[Display omitted]
Current hemophagocytic lymphohistiocytosis 2004 (HLH-2004)–based diagnostic criteria for familial hemophagocytic lymphohistiocytosis (FHL) are based on expert opinion. Here, we performed a case-control study to test and possibly improve these criteria. We also developed 2 complementary expert opinion–based diagnostic strategies for FHL in patients with signs/symptoms suggestive of HLH, based on genetic and cellular cytotoxicity assays. The cases (N = 366) were children aged <16 years with verified familial and/or genetic FHL (n = 341) or Griscelli syndrome type 2 (n = 25); 276 from the HLH-94/HLH-2004 databases and 90 from the Italian HLH Registry. All fulfilled the HLH-94/HLH-2004 patient inclusion criteria. Controls were 374 children with systemic-onset juvenile idiopathic arthritis (sJIA) and 329 + 361 children in 2 cohorts with febrile infections that could be confused with HLH and sepsis, respectively. To provide complete data sets, multiple imputations were performed. The optimal model, based on 17 variables studied, revealed almost similar diagnostic thresholds as the existing criteria, with accuracy 99.1% (sensitivity 97.1%; specificity 99.5%); the original HLH-2004 criteria had accuracy 97.4% (sensitivity 99.0%; specificity 97.1%). Because cellular cytotoxicity assays here constitute a separate diagnostic strategy, HLH-2004 criteria without natural killer (NK)–cell function was also studied, which showed accuracy 99.0% (sensitivity, 96.2%; specificity, 99.5%). Thus, we conclude that the HLH-2004 criteria (without NK-cell function) have significant validity in their current form when tested against severe infections or sJIA. It is important to exclude underlying malignancies and atypical infections. In addition, complementary cellular and genetic diagnostic guidelines can facilitate necessary confirmation of clinical diagnosis.
Clinical diagnostic criteria for primary (also known as familial) hemophagocytic lymphohistiocytosis (HLH) were codified in 2004 (HLH-2004), and this score has endured over 2 decades. Now, through case-control analysis of international pediatric trial databases, Henter and colleagues report on the updated criteria on behalf of the Histiocyte Society. Use of these criteria streamlines the clinical diagnosis, discriminates primary HLH from other inflammatory disorders, and provides guidance on genetic testing.</description><subject>Adolescent</subject><subject>Case-Control Studies</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Clinical Trials and Observations</subject><subject>Female</subject><subject>Humans</subject><subject>Infant</subject><subject>Lymphohistiocytosis, Hemophagocytic - diagnosis</subject><subject>Lymphohistiocytosis, Hemophagocytic - genetics</subject><subject>Male</subject><subject>Piebaldism - diagnosis</subject><subject>Piebaldism - genetics</subject><subject>Practice Guidelines as Topic</subject><subject>Primary Immunodeficiency Diseases</subject><issn>0006-4971</issn><issn>1528-0020</issn><issn>1528-0020</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>D8T</sourceid><recordid>eNp1kc1v1DAQxS0EokvhzgnlyCVlbCexzQWh8lWpUi_t2XKc8cbgxIudXbT_PV52Ke2B04xmfu955EfIawoXlEr2rg8xDhcMWAOsBSGekBVtmawBGDwlKwDo6kYJekZe5PwdgDactc_JGVfQdEKoFbn55M16jnnxtlpv_YDBz5grF1PlzOSDN6EacYqb0ayj3R-wsJ82Yxx90RwmMftcJdz57BccXpJnzoSMr071nNx9-Xx7-a2-vvl6dfnxura8U0vtWqACm37gyqJsuG2lssq5wRlQnAnFpeytaGnfMQWccVuuHZQ06KQwKPg5qY---Rdutr3eJD-ZtNfReH0a_Sgdaikkh67wH4582Uw4WJyXZMIj2ePN7Ee9jjtNaUeVUE1xeHtySPHnFvOiJ58thmBmjNusOciSgqKCFRSOqE0x54Tu_h0K-hCc_hOc_hdckbx5eN-94G9SBXh_BLD86s5j0tl6nC0OPqFd9BD9_91_A0WIq_0</recordid><startdate>20241128</startdate><enddate>20241128</enddate><creator>Henter, Jan-Inge</creator><creator>Sieni, Elena</creator><creator>Eriksson, Julia</creator><creator>Bergsten, Elisabet</creator><creator>Hed Myrberg, Ida</creator><creator>Canna, Scott W.</creator><creator>Coniglio, Maria Luisa</creator><creator>Cron, Randy Q.</creator><creator>Kernan, Kate F.</creator><creator>Kumar, Ashish R.</creator><creator>Lehmberg, Kai</creator><creator>Minoia, Francesca</creator><creator>Naqvi, Ahmed</creator><creator>Ravelli, Angelo</creator><creator>Tang, Yong-Min</creator><creator>Bottai, Matteo</creator><creator>Bryceson, Yenan T.</creator><creator>Horne, AnnaCarin</creator><creator>Jordan, Michael B.</creator><general>Elsevier Inc</general><general>The American Society of Hematology</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><scope>ADTPV</scope><scope>AOWAS</scope><scope>D8T</scope><scope>ZZAVC</scope><orcidid>https://orcid.org/0000-0003-2661-3086</orcidid><orcidid>https://orcid.org/0000-0002-8297-2238</orcidid><orcidid>https://orcid.org/0000-0002-5093-8422</orcidid><orcidid>https://orcid.org/0000-0003-1409-5517</orcidid><orcidid>https://orcid.org/0000-0002-9645-5856</orcidid><orcidid>https://orcid.org/0000-0002-6192-9812</orcidid><orcidid>https://orcid.org/0000-0003-3837-5337</orcidid><orcidid>https://orcid.org/0000-0001-9658-0385</orcidid><orcidid>https://orcid.org/0000-0002-0629-2126</orcidid><orcidid>https://orcid.org/0000-0002-8306-8419</orcidid><orcidid>https://orcid.org/0000-0002-6337-841X</orcidid></search><sort><creationdate>20241128</creationdate><title>Diagnostic guidelines for familial hemophagocytic lymphohistiocytosis revisited</title><author>Henter, Jan-Inge ; Sieni, Elena ; Eriksson, Julia ; Bergsten, Elisabet ; Hed Myrberg, Ida ; Canna, Scott W. ; Coniglio, Maria Luisa ; Cron, Randy Q. ; Kernan, Kate F. ; Kumar, Ashish R. ; Lehmberg, Kai ; Minoia, Francesca ; Naqvi, Ahmed ; Ravelli, Angelo ; Tang, Yong-Min ; Bottai, Matteo ; Bryceson, Yenan T. ; Horne, AnnaCarin ; Jordan, Michael B.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c369t-f5017e4bd39ce843c589c9ffdfa093279388bc751b6290323c779d98aef87ae73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Adolescent</topic><topic>Case-Control Studies</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>Clinical Trials and Observations</topic><topic>Female</topic><topic>Humans</topic><topic>Infant</topic><topic>Lymphohistiocytosis, Hemophagocytic - diagnosis</topic><topic>Lymphohistiocytosis, Hemophagocytic - genetics</topic><topic>Male</topic><topic>Piebaldism - diagnosis</topic><topic>Piebaldism - genetics</topic><topic>Practice Guidelines as Topic</topic><topic>Primary Immunodeficiency Diseases</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Henter, Jan-Inge</creatorcontrib><creatorcontrib>Sieni, Elena</creatorcontrib><creatorcontrib>Eriksson, Julia</creatorcontrib><creatorcontrib>Bergsten, Elisabet</creatorcontrib><creatorcontrib>Hed Myrberg, Ida</creatorcontrib><creatorcontrib>Canna, Scott W.</creatorcontrib><creatorcontrib>Coniglio, Maria Luisa</creatorcontrib><creatorcontrib>Cron, Randy Q.</creatorcontrib><creatorcontrib>Kernan, Kate F.</creatorcontrib><creatorcontrib>Kumar, Ashish R.</creatorcontrib><creatorcontrib>Lehmberg, Kai</creatorcontrib><creatorcontrib>Minoia, Francesca</creatorcontrib><creatorcontrib>Naqvi, Ahmed</creatorcontrib><creatorcontrib>Ravelli, Angelo</creatorcontrib><creatorcontrib>Tang, Yong-Min</creatorcontrib><creatorcontrib>Bottai, Matteo</creatorcontrib><creatorcontrib>Bryceson, Yenan T.</creatorcontrib><creatorcontrib>Horne, AnnaCarin</creatorcontrib><creatorcontrib>Jordan, Michael B.</creatorcontrib><creatorcontrib>Histiocyte Society</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SwePub Articles full text</collection><jtitle>Blood</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext_linktorsrc</fulltext></delivery><addata><au>Henter, Jan-Inge</au><au>Sieni, Elena</au><au>Eriksson, Julia</au><au>Bergsten, Elisabet</au><au>Hed Myrberg, Ida</au><au>Canna, Scott W.</au><au>Coniglio, Maria Luisa</au><au>Cron, Randy Q.</au><au>Kernan, Kate F.</au><au>Kumar, Ashish R.</au><au>Lehmberg, Kai</au><au>Minoia, Francesca</au><au>Naqvi, Ahmed</au><au>Ravelli, Angelo</au><au>Tang, Yong-Min</au><au>Bottai, Matteo</au><au>Bryceson, Yenan T.</au><au>Horne, AnnaCarin</au><au>Jordan, Michael B.</au><aucorp>Histiocyte Society</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Diagnostic guidelines for familial hemophagocytic lymphohistiocytosis revisited</atitle><jtitle>Blood</jtitle><addtitle>Blood</addtitle><date>2024-11-28</date><risdate>2024</risdate><volume>144</volume><issue>22</issue><spage>2308</spage><epage>2318</epage><pages>2308-2318</pages><issn>0006-4971</issn><issn>1528-0020</issn><eissn>1528-0020</eissn><abstract>•We present updated diagnostic criteria for FHL including revised clinical criteria and guidelines on genetic and cellular diagnostic assays.•HLH-2004 criteria (without NK-cell function) have significant validity (accuracy 99%) tested against infections and systemic inflammation.
[Display omitted]
Current hemophagocytic lymphohistiocytosis 2004 (HLH-2004)–based diagnostic criteria for familial hemophagocytic lymphohistiocytosis (FHL) are based on expert opinion. Here, we performed a case-control study to test and possibly improve these criteria. We also developed 2 complementary expert opinion–based diagnostic strategies for FHL in patients with signs/symptoms suggestive of HLH, based on genetic and cellular cytotoxicity assays. The cases (N = 366) were children aged <16 years with verified familial and/or genetic FHL (n = 341) or Griscelli syndrome type 2 (n = 25); 276 from the HLH-94/HLH-2004 databases and 90 from the Italian HLH Registry. All fulfilled the HLH-94/HLH-2004 patient inclusion criteria. Controls were 374 children with systemic-onset juvenile idiopathic arthritis (sJIA) and 329 + 361 children in 2 cohorts with febrile infections that could be confused with HLH and sepsis, respectively. To provide complete data sets, multiple imputations were performed. The optimal model, based on 17 variables studied, revealed almost similar diagnostic thresholds as the existing criteria, with accuracy 99.1% (sensitivity 97.1%; specificity 99.5%); the original HLH-2004 criteria had accuracy 97.4% (sensitivity 99.0%; specificity 97.1%). Because cellular cytotoxicity assays here constitute a separate diagnostic strategy, HLH-2004 criteria without natural killer (NK)–cell function was also studied, which showed accuracy 99.0% (sensitivity, 96.2%; specificity, 99.5%). Thus, we conclude that the HLH-2004 criteria (without NK-cell function) have significant validity in their current form when tested against severe infections or sJIA. It is important to exclude underlying malignancies and atypical infections. In addition, complementary cellular and genetic diagnostic guidelines can facilitate necessary confirmation of clinical diagnosis.
Clinical diagnostic criteria for primary (also known as familial) hemophagocytic lymphohistiocytosis (HLH) were codified in 2004 (HLH-2004), and this score has endured over 2 decades. Now, through case-control analysis of international pediatric trial databases, Henter and colleagues report on the updated criteria on behalf of the Histiocyte Society. Use of these criteria streamlines the clinical diagnosis, discriminates primary HLH from other inflammatory disorders, and provides guidance on genetic testing.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>39046779</pmid><doi>10.1182/blood.2024025077</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0003-2661-3086</orcidid><orcidid>https://orcid.org/0000-0002-8297-2238</orcidid><orcidid>https://orcid.org/0000-0002-5093-8422</orcidid><orcidid>https://orcid.org/0000-0003-1409-5517</orcidid><orcidid>https://orcid.org/0000-0002-9645-5856</orcidid><orcidid>https://orcid.org/0000-0002-6192-9812</orcidid><orcidid>https://orcid.org/0000-0003-3837-5337</orcidid><orcidid>https://orcid.org/0000-0001-9658-0385</orcidid><orcidid>https://orcid.org/0000-0002-0629-2126</orcidid><orcidid>https://orcid.org/0000-0002-8306-8419</orcidid><orcidid>https://orcid.org/0000-0002-6337-841X</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Adolescent Case-Control Studies Child Child, Preschool Clinical Trials and Observations Female Humans Infant Lymphohistiocytosis, Hemophagocytic - diagnosis Lymphohistiocytosis, Hemophagocytic - genetics Male Piebaldism - diagnosis Piebaldism - genetics Practice Guidelines as Topic Primary Immunodeficiency Diseases |
| title | Diagnostic guidelines for familial hemophagocytic lymphohistiocytosis revisited |
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