Simple Evaluation of Clinical Situation and Subtypes of Pediatric Hemophagocytic Lymphohistiocytosis by Cytokine Patterns

Abstract

Background: Hemophagocytic lymphohistiocytosis (HLH) is a rapidly fatal disease caused by immune dysregulation. Early initiation of treatment is imperative for saving lives. However, a laboratory approach that could be used to quickly evaluate the HLH subtype and clinical situation is lacking. Our previous studies indicated that cytokines such as interferon (IFN)-γ and interleukin (IL)-10 were helpful for the early diagnosis of HLH and were associated with disease severity. The purpose of this study is to clarify the different cytokine patterns of various subtypes of pediatric HLH and to investigate the role of cytokines in a simple evaluation of disease feature.

Patients and methods: We enrolled 256 pediatric patients with newly diagnosed HLH. The clinical features and laboratory findings were collected and compared among different subtypes of HLH. A model integrating cytokines was established to stratify HLH patients into different clinical groups.

Results: Twenty-seven patients were diagnosed with primary HLH (pHLH), 179 with EBV-HLH, and 50 with other causes. The IL-6, IL-10, and IFN-γ levels and the ratios of IL-10 to IFN-γ were different among EBV-HLH, other infection-associated HLH, malignancy-associated HLH, familial HLH, and X-linked lymphoproliferative disease. Patients with the ratio of IL-10 to IFN-γ >1.33 and the concentration of IFN-γ ≤225 pg/ml were considered to have pHLH, with a sensitivity of 73% and a specificity of 84%. A four-quadrant model based on the two cutoff values was established to stratify the patients into different clinical situations. The HLH subtypes, cytokine levels, treatment regimens, treatment response, and outcomes were different among the four quadrants, with the 8-week mortality from 2.9 ± 2.9% to 21.4 ± 5.5% and the 5-year overall survival from 93.9 ± 4.2% to 52.6 ± 7.1%.

Conclusions: Different subtypes of HLH present distinct cytokine patterns. IFN-γ and the ratio of IL-10 to IFN-γ are helpful tools to differentiate HLH subtypes. A four-quadrant model based on these two parameters is a useful tool for a simple evaluation of the HLH situation.

Keywords: cytokines; hemophagocytic lymphohistiocytosis; interferon-gamma; interleukin-10; prognosis.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Xu, Luo, Song, Xu, Henter, Zhao, Wu and Tang.

Figures

Figure 1

Cytokine levels and cytokine patterns. (A) Box-and-whisker plots of IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ levels in HLH. Median levels (lines), 25th to 75th percentiles (box), and minimum to maximum values (whiskers) are shown for each cytokine. The numbers are the median and range of each cytokine. (B) Distinct cytokine patterns of different forms of HLH based on IL-6, IL-10, and IFN-γ. Median levels (lines), 25th to 75th percentiles (box), and 5th to 95th percentiles (whiskers) are shown for each cytokine. (C) Kaplan–Meier survival curves for 5-year overall survival (OS) of the patients with different subtypes of HLH. I-HLH, infection-associated HLH triggered by pathogens other than EBV; M-HLH, malignancy-associated HLH; FHL, familial HLH; XLP, X-linked lymphoproliferative disease.

Figure 2

Differentiation of primary HLH (pHLH) and secondary HLH (sHLH). (A) The receiver operating characteristic (ROC) curve for predicting pHLH by the ratio of IL-10 to IFN-γ. (B) The ROC curve for predicting sHLH by the IFN-γ level.

Figure 3

A four-quadrant model to differentiate HLH patients with different features. (A) Distribution of patients with EBV-HLH, I-HLH, M-HLH, FHL, and XLP in a four-quadrant diagram based on the ratio of IL-10 to IFN-γ (> 1.33 or ≤ 1.33) and the IFN-γ level (> 225 pg/ml or ≤ 225 pg/ml). (B) Kaplan–Meier survival curves for 5-year overall survival (OS) of the patients located in four quadrants. I-HLH, infection-associated HLH triggered by pathogens other than EBV; M-HLH, malignancy-associated HLH; FHL, familial HLH; XLP, X-linked lymphoproliferative disease; LLR, left lower quadrant; LUR, left upper quadrant; RUQ, right upper quadrant; RLQ, right lower quadrant.

Figure 4

Cytokine levels and ratios in four quadrants. Box-and-whisker plots of IL-6 (A), IL-10 (B), IFN-γ (C), and ratio of IL-10 to IFN-γ (D) were shown. Median levels (lines), 25th to 75th percentiles (box), and minimum to maximum values (whiskers) are shown. The numbers in the plots are the median concentration of each cytokine or ratio. LLR, left lower quadrant; LUR, left upper quadrant; RUQ, right upper quadrant; RLQ, right lower quadrant.