Abstract:
Current 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 clinical criteria. We also developed two 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 <16 years with verified familial and/or
genetic FHL (n=341) or Griscelli syndrome type 2 (GS2) (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 two 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 the number of diagnostic criteria fulfilled from 17 variables studied, reveled
almost similar diagnostic thresholds as the existing criteria, with accuracy 99.1% (sensitivity
97.1%; specificity 99.5%). Notably, assessment of the original HLH-2004 criteria revealed accuracy
97.4% (sensitivity 99.0%; specificity 97.1%). Since cellular cytotoxicity assays here constitute a
separate diagnostic strategy, HLH-2004 criteria without 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.
להורדת הפידיאף:
Blood 2024025077. https://doi.org/10.1182/blood.2024025077
