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A Three-Step Screening Procedure for Early Identification of Children at High Risk of Hemophagocytic Lymphohistiocytosis

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Abstract

Purpose

The first step in diagnosing hemophagocytic lymphohistiocytosis (HLH) is to suspect its presence and then order the appropriate diagnostic tests. The development of screening procedures for HLH could facilitate early diagnosis. In this study, we evaluated the utility of fever, splenomegaly, and cytopenias as screening criteria for identifying pediatric HLH at an early stage, built a screening model using commonly measured laboratory parameters, and developed a step-wise screening procedure for pediatric HLH.

Methods

The medical records of 83,965 pediatric inpatients, including 160 patients with HLH, were collected retrospectively. The utility of fever, splenomegaly, hemoglobin level, and platelet and neutrophil counts at hospital admission as screening criteria for HLH was evaluated. For HLH patients who might be missed by screening based on the presence of fever, splenomegaly, and cytopenias, a screening model using common laboratory parameters was developed. Following that, a three-step screening procedure was then developed.

Results

The criteria of cytopenias affecting two or more lineages plus fever or splenomegaly had a sensitivity of 51.9% and a specificity of 98.4% for identifying HLH in pediatric inpatients. Our screening score model comprises six parameters: splenomegaly, platelet count, neutrophil count, albumin level, total bile acid level, and lactate dehydrogenase level. The use of the validation set had a sensitivity of 87.0% and a specificity of 90.6%. A three-step screening procedure has been developed: Step 1: Is fever or splenomegaly present? (Yes: risk for HLH should be considered, go to Step 2; No: less likely HLH); Step 2: Are cytopenias affecting at least two lineages? (Yes: consider HLH; No: go to Step 3); Step 3: Calculate the screening score. Is the sum of the score greater than 37? (Yes: consider HLH; No: less likely HLH). The overall sensitivity and specificity of the three-step screening procedure were 91.9% and 94.4%, respectively.

Conclusion

A significant proportion of pediatric HLH patients present at the hospital without having all three symptoms: fever, splenomegaly, and cytopenias. Our three-step screening procedure, utilizing commonly available clinical and laboratory parameters, can effectively identify pediatric patients who may be at high risk for HLH.

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Data Availability

The dataset used and analyzed in the current study is available from the corresponding author upon reasonable request.

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Acknowledgements

The authors would like to thank Dr. Youcai Deng for his valuable comments and suggestions. The authors would like to thank Dan Yang and Yu Tian for their assistance in data management.

Funding

This study was supported by the National Natural Science Foundation of China (Young Scientists Fund, No. 82102285, grant to XLi), the Hunan Provincial Natural Science Foundation of China (No. 2021JJ40270, grant to XLi), the Hunan Provincial Science and Technology Department Project (2020SK1014-3 and 2020SK2114, grant to XLu), the Hunan Provincial Key Laboratory of Emergency Medicine for Children (No. 2018TP1028, grant to ZX), and the Scientific Research Project of Hunan Provincial Health Commission (No. 202112050360, grant to XLi). The study sponsors have no role in the study design, data collection, data analysis, data interpretation, or writing of the report.

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Author notes

  1. Xun Li, Haipeng Yan, and Zhenghui Xiao contributed equally to this work and should be considered co-first authors.

Authors and Affiliations

  1. Pediatrics Research Institute of Hunan, Hunan Children’s Hospital, Changsha, China

    Xun Li, Ting Luo, Longlong Xie & Yufan Yang

  2. Department of Pediatric Intensive Care Unit (PICU) and Hunan Provincial Key Laboratory of Emergency Medicine for Children, Hunan Children’s Hospital, Changsha, China

    Xun Li, Haipeng Yan, Zhenghui Xiao, Ting Luo, Longlong Xie, Yufan Yang, Ling Gong, Zhexuan Tang, Minghui Tang, Jiaotian Huang, Xinping Zhang, Zhenya Yao, Ping Zang, Desheng Zhu & Xiulan Lu

  3. Department of Pediatric Hematology, Hunan Children’s Hospital, Changsha, China

    Mincui Zheng

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  1. Xun Li
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Contributions

HY and XLi contributed to the study’s conception, analyzed and interpreted the data, and wrote the manuscript. ZX, TL, LX, ZT, MT, LG, JH, XZ, and MZ contributed to the study design, interpreted the data, and revised the manuscript. ZY, PZ, and DZ performed chart reviews, interpreted the data, and revised the manuscript. XLu and ZX designed the study, interpreted the data, and revised the manuscript. All authors read and approved the final manuscript. The corresponding author (XLu) had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Xiulan Lu.

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Ethics Statement

The study protocol was reviewed and approved by the Medical Ethics Committee of the Hunan Children’s Hospital (HCHLL-2019-40 and HCHLL-2022-50).

Consent to Participate

Informed consent was waived by the Medical Ethics Committee of the Hunan Children’s Hospital because of the retrospective design. The authors had no access to information that could identify individual participants during and after data collection.

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Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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Supplementary information

Additional file 1

Supplementary Table S1. Distribution of investigated laboratory parameters among pediatric patients in the training set according to HLH status. Supplementary Table S2. Parameters of the multivariate logistic regression model. Supplementary Table S3. Performance of the three-step HLH screening procedure using standard and alternative scoring parameters (n=78050). (DOCX 22 kb)

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Li, X., Yan, H., Xiao, Z. et al. A Three-Step Screening Procedure for Early Identification of Children at High Risk of Hemophagocytic Lymphohistiocytosis. J Clin Immunol 43, 989–998 (2023). https://doi.org/10.1007/s10875-023-01458-y

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