Diagnostic dilemmas in HLH: Can T‐cell phenotyping help?

Abstract

The diagnosis of hemophagocytic lymphohistiocytosis (HLH) can be a difficult one, and the distinction between primary versus secondary HLH can be particularly challenging during the early stages of diagnosis. This distinction is important to make as primary HLH requires allogeneic hematopoietic cell transplantation for a definitive cure. Flow cytometric screening tests for many of the genetic forms of HLH are available. However, not all patients with primary HLH are captured by these screening tests, due to the fact that no screening test is 100% sensitive, and additionally, some patients with "primary" forms of HLH may have mutations in genes which are yet to be discovered.

Lymphocyte-independent pathways underlie the pathogenesis of murine cytomegalovirus-associated secondary haemophagocytic lymphohistiocytosis

“…T cell populations were activated markedly and effector-differentiated in primary HLH, while this signature was mainly absent in patients with secondary HLH. T cell activation in virus-associated secondary HLH was situated between the spectrum from non-virus-associated secondary HLH to primary HLH [21,22]. Thus, in contrast with primary HLH, T cells do not appear to play a similar, dominant pathogenic role in secondary HLH, demonstrating that disease is not driven necessarily by over-activation of the adaptive immune system.…”

“…In addition, combined targeting of CD4 1 and CD8 1 T cells indicated that T cells were not required for disease pathogenesis, while functional T and B cells were dispensable to induce HLH-like disease in MCMV-infected SCID mice. T cell activation in virus-associated secondary HLH was situated between the spectrum from non-virus-associated secondary HLH to primary HLH [21,22]. In a CpG-induced model of macrophage activation syndrome (MAS), mice lacking T, B and NK T cells could still develop HLH [12].…”

“…In a model of virus-associated secondary HLH that we have described recently (illustrated in Supporting information, Fig. Viral infections were shown to shift the pattern of CD8 1 T cell activation in secondary HLH to overlap partially with the T cell phenotype observed in primary HLH [21,22]. Thus, the model represents a tool to unravel IFN-g-independent pathways of HLH pathogenesis, as reported recently in IFN-g receptor 1/2 (R1/2) or signal transducer and activator of transcription 1 (STAT-1)-deficient patients [16][17][18][19].…”

“…Patients with primary HLH possessed more highly activated effector CD8 1 cells and a unique cytotoxic CD4 1 T cell signature compared to patients with secondary HLH. Viral infections were shown to shift the pattern of CD8 1 T cell activation in secondary HLH to overlap partially with the T cell phenotype observed in primary HLH [21,22]. Thus, both animal and human data indicate that the lymphoid compartment is activated differentially and may play divergent roles in the pathogenesis of primary and secondary HLH.…”