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

• Authors: Howard Lin, Baylor College of Medicine; Brooks P Scull, Baylor College of Medicine; Baruch Goldberg, Emory University; Harshal A Abhyankar, Baylor College of Medicine; Olive E Eckstein, Baylor College of Medicine; Daniel J Zinn, Baylor College of Medicine; Joseph Lubega, Baylor College of Medicine; Jennifer Agrusa, Baylor College of Medicine; Nader El Mallawaney, Baylor College of Medicine; Nitya Gulati, Baylor College of Medicine; Lisa Forbes, Texas Childrens Hospital; Ivan Chinn, Texas Childrens Hospital; Rikhia Chakraborty, Baylor College of Medicine; Jessica Velasquez, Baylor College of Medicine; Jordana Goldman, Texas Childrens Hospital; Dalia Bashir, Texas Childrens Hospital; Fong Lam, Texas Childrens Hospital; Eyal Muscal, Texas Childrens Hospital; Michael M Henry, Phoenix Childrens Hospital; Jay N Greenberg, Children's National Medical Center; Stephan Ladisch, Children's National Medical Center; Michelle L Hermiston, University of California San Francisco; Lauren K Meyer, University of California San Francisco; Michael Jeng, Stanford University; Ahmed Naqvi, The Hospital for Sick Children; Kenneth McClain, Baylor College of Medicine; Trung Nguyen, Texas Childrens Hospital; Hector Wong, Cincinnati Childrens Hosp Med Ctr; Tsz-Kwong Man, Baylor College of Medicine; Michael B Jordan, Cincinnati Childrens Hosp Med Ctr; Carl E Allen, Baylor College of Medicine
• Journal Title: BLOOD ADVANCES
• Volume: Volume 5, Number 17
• Publisher: ELSEVIER | 2021-09-10, Pages 3457-3467
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1182/bloodadvances.2021004287
• Subjects: Health Sciences, Oncology; Health Sciences, Immunology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Hematology; MACROPHAGE ACTIVATION SYNDROME; CYTOKINE RELEASE SYNDROME; INTERFERON-GAMMA; T-CELLS; DIAGNOSIS; INTERLEUKIN-18; DEFINITIONS; ETOPOSIDE; FERRITIN; PREDICTS

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 whether 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 with SIRS/sepsis, including increased interferon-g (IFN-g)-regulated chemokines CXCL9, CXCL10, and CXCL11. Furthermore, a 2-analyte plasma protein classifier including CXCL9 and interleukin-6 was able to differentiate HLH from SIRS/sepsis. Gene expression in CD81 T cells and activated monocytes from blood were also enriched for IFN-g pathway signatures in peripheral blood cells from patients with HLH compared with 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-g 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.