An improved index for diagnosis and mortality prediction in malignancy-associated hemophagocytic lymphohistiocytosis

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome that may complicate hematologic malignancies (HM). The appropriateness of current criteria for diagnosing HLH in the context of HMs is unknown because they were developed for children with familial HLH (HLH-2004) or derived from adult patient cohorts in which HMs were underrepresented (HScore). Moreover, many features of these criteria may directly reflect the underlying HM rather than an abnormal inflammatory state. To improve and potentially simplify HLH diagnosis in patients with HMs, we studied an international cohort of 225 adult patients with various HMs both with and without HLH and for whom HLH-2004 criteria were available. We used classification and regression tree and receiver operating curve analysis to identify the most useful diagnostic and prognostic parameters and optimize laboratory cutoff values. Combined elevation of soluble CD25 (>3,900 U/ml) and ferritin (>1,000 ng/ml) best identified HLH-2004 defining features (sensitivity 84%, specificity 81%). Moreover, this combination, which we term the 'optimized HLH inflammatory' (OHI) index, was highly predictive of mortality (hazard ratio 4.3; confidence interval 3.0-6.2) across diverse HMs. Furthermore, the OHI index identified a large group of patients with high mortality risk that were not defined as having HLH by HLH-2004/HScore. Finally, the OHI demonstrates diagnostic and prognostic value when used for routine surveillance of patients with newly diagnosed HMs as well as those with clinically suspected HLH. Thus, we conclude that the OHI index identifies HM patients with an inflammatory state associated with a high mortality risk and warrants further prospective validation.

Registry data analysis of hematopoietic stem cell transplantation on systemic chronic active Epstein–Barr virus infection patients in Japan

“…From our results, we conclude that sIL‐2R is a characteristic and ideal marker for not only disease activity but also the outcome of sCAEBV. Recently, Zoref‐Lorenz et al proposed an optimized HLH inflammatory index, the combination of ferritin and sIL‐2R, as a marker to diagnose malignancy‐associated HLH and to predict mortality 23 . In the future, we hope to investigate if ferritin, an inflammatory marker, is associated with sCAEBV.…”

“…Recently, Zoref-Lorenz et al proposed an optimized HLH inflammatory index, the combination of ferritin and sIL-2R, as a marker to diagnose malignancy-associated HLH and to predict mortality. 23 In the future, we hope to investigate if ferritin, an inflammatory marker, is associated with sCAEBV.…”

Matrin3 (MATR3) Expression Is Associated with Hemophagocytosis

“…Diagnosis of secondary HLH relies on clinical signs/symptoms, including fever, organomegaly, cytopenia, hypertriglyceridemia, hyperferritinemia, and elevation of serum soluble CD25 (sCD25) and soluble interleukin-2 receptor (sIL-2R) levels. However, owing to heterogeneous presentation and complex etiology, the diagnosis criteria of HLH are not well established [ 9 , 21 , 22 , 23 ]. Although BM hemophagocytosis is uncommon but is the hallmark of diagnosis [ 24 ].…”

Simple Evaluation of Clinical Situation and Subtypes of Pediatric Hemophagocytic Lymphohistiocytosis by Cytokine Patterns

“…Immediate evaluation of HLH and its severity is required so that an early treatment can be quickly initiated. Some prognostic models integrating clinical and laboratory parameters presented excellent performance both in adults and in children (25)(26)(27). However, the approach that could be used to quickly evaluate the HLH subtype and clinical situation is lacking.…”