IFN-γ signature in the plasma proteome distinguishes pediatric hemophagocytic lymphohistiocytosis from sepsis and SIRS

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by pathologic immune activation in which prompt recognition and initiation of immune suppression is essential for survival. Children with HLH have many overlapping clinical features with critically ill children with sepsis and systemic inflammatory response syndrome (SIRS) in whom alternative therapies are indicated. To determine if plasma biomarkers could differentiate HLH from other inflammatory conditions and to better define a 'core inflammatory signature' of HLH, concentrations of inflammatory plasma proteins were compared in 40 patients with HLH to 47 pediatric patients with severe sepsis or SIRS. Fifteen of 135 analytes were significantly different in HLH plasma compared to SIRS/sepsis, including increased interferon-γ (IFN-γ)-regulated chemokines CXCL9, CXCL10 and CXCL11. Further, a two-analyte plasma protein classifier including CXCL9 and IL-6 was able to differentiate HLH from SIRS/sepsis. Gene expression in CD8+ T cells and activated monocytes from blood were also enriched for IFN-γ pathway signatures in peripheral blood cells from patients with HLH compared to SIRS/sepsis. This study identifies differential expression of inflammatory proteins as a diagnostic strategy to identify critically ill children with HLH, and comprehensive unbiased analysis of inflammatory plasma proteins and global gene expression demonstrates that IFN-γ signaling is uniquely elevated in HLH. In addition to demonstrating the ability of diagnostic criteria for HLH and sepsis or SIRS to identify groups with distinct inflammatory patterns, results from this study support the potential for prospective evaluation of inflammatory biomarkers to aid in diagnosis of and optimizing therapeutic strategies for children with distinctive hyperinflammatory syndromes.

Case report: Optimized ruxolitinib-based therapy in an infant with familial hemophagocytic lymphohistiocytosis type 3

“…The IL-6 level in our case was consistently below this cutoff ( Figure 1D ). The CXCL9/IL-6 ratio is discriminately elevated in HLH compared with systemic inflammatory response syndrome/sepsis ( 7 ). Similarly, we observed that serum CXCL9 which is IFN-γ-inducible CXCR3 ligands and reflecting amplification of IFN-γ signaling wathway ( 41 ), was consistently higher than the normal range throughout the clinical course in our case ( Figures 1C, D ).…”

“…However, specific cytokines that allow discrimination between FHL and secondary HLH have not been defined ( 6 ). Also, proteome analysis did not identify differential expression between primary and secondary HLH ( 7 ). Monitoring of serum cytokine profiles is effective in evaluating inflammatory status in cell therapies, infections, cancers, and auto-immune diseases ( 8 ).…”

Refractory systemic onset juvenile idiopathic arthritis: current challenges and future perspectives

“…Intravenous immunoglobulin (IVIG) has been used with mixed success in several case reports and could be considered in refractory cases [ 85 , 86 ]. IFN-γ is a critical cytokine in HLH/MAS pathophysiology [ 36 , 87 ]. Emapalumab, a monoclonal antibody that binds IFN-γ, is effective and has gained approval for the treatment of refractory primary HLH [ 37 ].…”

Pediatric inborn errors of immunity causing hemophagocytic lymphohistiocytosis: Case report and review of the literature

“…as a new biomarker that correlates with severity and other laboratory findings. 58 While it is helpful differentiating HLH from sepsis, it does not distinguish primary from secondary HLH; yet, its major advantage is that treatment response correlates with a markedly decrease of blood CXCL9 levels. 59 Also, it has been described that the absence of high HLA-DR expression on T cells almost excluded primary forms of HLH with high sensitivity and specificity, as polyclonal activated CD8 + T cells are seen in FHL and virus-induced HLH, as seen in our patient.…”

“…In this regard, both SAP and XIAP proteins can be measured by FC 57 . Recently, IFN‐γ‐regulated chemokine‐9 (CXCL9) has been proposed as a new biomarker that correlates with severity and other laboratory findings 58 . While it is helpful differentiating HLH from sepsis, it does not distinguish primary from secondary HLH; yet, its major advantage is that treatment response correlates with a markedly decrease of blood CXCL9 levels 59 .…”