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Phagocyte Biology and its Disorders
Bone marrow histomorphological criteria can accurately diagnose hemophagocytic lymphohistiocytosis
Ferrata Storti Foundation
Eric Gars,1 Natasha Purington,1 Gregory Scott,1 Karen Chisholm,2 Dita Gratzinger,1 Beth A. Martin1* and Robert S. Ohgami1*
1Stanford University, CA and 2Seattle Children's Hospital and University of Washington, WA, USA
Haematologica 2018 Volume 103(10):1635-1641
BAM and RSO contributed equally to this work.
Hemophagocytic lymphohistiocytosis (HLH) is a rare multi-system inflammatory disorder with diagnostic criteria based on the HLH- 2004 trial. Hemophagocytosis is the only histomorphological cri- terion, but in isolation is neither specific nor sensitive for the diagnosis of HLH. While objective thresholds for clinical and laboratory criteria have been established, specific criteria for histomorphological evidence of hemophagocytosis in HLH have not been rigorously evaluated or established. We sought to determine if numerical and objective criteria for morphological hemophagocytosis could be identified, and if such cri- teria would aid in the diagnosis of HLH. We analyzed the morphological features of hemophagocytosis in 78 patients presenting with clinical fea- tures suspicious for HLH: 40 patients with and 38 patients without HLH. We demonstrate that non-nucleated erythrophagocytosis alone is a non-specific finding, while hemophagocytosis of granulocytes [1 per 1000 cells, area under the curve (AUC): 0.92, 95% Confidence Interval (CI): 0.86, 0.99], nucleated erythrocytes (4 per 1000 cells, AUC: 0.92, 95%CI: 0.87, 0.98), and at least one hemophagocyte containing multiple nucleated cells (AUC: 0.91, 95%CI: 0.85, 0.95) are strongly associated with HLH. Joint modeling of hemophagocytes containing engulfed granulocytes, nucleated erythrocytes, and lymphocytes effectively dis- tinguished between HLH and non-HLH (cross-validated AUC: 0.90, 95%CI: 0.83, 0.97).
Introduction
Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening syndrome that occurs secondary to severe systemic immune activation.1 Cytotoxic T-cell pro- liferation leads to increased cytokine production and activation of tissue resident macrophages. Ultimately, multi-system end organ damage caused by massive inflammation may lead to a fatal outcome without timely diagnosis and initiation of appropriate therapy.2
Hemophagocytic lymphohistiocytosis affects patients of all ages and occurs as an inherited disease, or secondarily in the setting of predisposing conditions that alter the normal immune response. The inherited form of the disease presents in early childhood and is associated with homozygous mutations in genes involved in CD8+ T-cell- and NK-cell-mediated immunity.3 These genetic forms of HLH are uniformly fatal without hematopoietic cell transplant or gene therapy. Secondary HLH may occur sporadically in healthy individuals, but is more often encountered in patients with hematologic malignancy, autoimmune disease, and iatrogenic immunosuppression. Virtually all cases are thought to require an infectious or non- infectious trigger to initiate the aberrant immune response, regardless of the under- lying immune dysfunction.4-7
Hemophagocytic lymphohistiocytosis presents abruptly over a period of several days to weeks with a consistent pattern of fever, pancytopenia, and splenomegaly. Common laboratory abnormalities include hyperferritinemia, hypofibrinogene- mia, hypertriglyceridemia, elevated soluble IL-2 receptor, and abnormal liver func-
Correspondence:
ericgars@stanford.edu or rohgami@stanford.edu
Received: December 17, 2017. Accepted: June 13, 2018. Pre-published: June 14, 2018.
doi:10.3324/haematol.2017.186627
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/10/1635
©2018 Ferrata Storti Foundation
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