T-cell activation profiles distinguish hemophagocytic lymphohistiocytosis and early sepsis

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a fatal disorder of immune hyperactivation which has been described as a cytokine storm. Sepsis due to known or suspected infection has also been viewed as a cytokine storm. While clinical similarities between these syndromes suggests similar immunopathology and may create diagnostic uncertainty, distinguishing them is critical as treatments are widely divergent. We examined T cell profiles from children with either HLH or sepsis and found that HLH is characterized by acute T cell activation, in clear contrast to sepsis. Activated T cells in patients with HLH were characterized as CD38^high/HLADR⁺ effector cells, with activation of CD8+ T cells being most pronounced. Activated T cells were polarized towards Tc1/Th1 differentiation, were proliferative, and displayed evidence of recent and persistent activation. Circulating activated T cells appeared to be broadly characteristic of HLH, as they were seen in children with and without genetic lesions or identifiable infections and resolved with conventional treatment of HLH. Furthermore, we observed even greater activation and type 1 polarization in tissue infiltrating T cells, described here for the first time in a series of patients with HLH. Finally, we observed that a threshold of >7% CD38^high/HLADR⁺ cells among CD8+ T cells had strong positive and negative predictive value for distinguishing HLH from early sepsis or healthy controls. We conclude that the cytokine storm of HLH is marked by distinctive T cell activation while sepsis is not, and that these two syndromes can be readily distinguished by T cell phenotypes.