Hemophagocytic Syndrome and Critical Illness

Abstract

Hemophagocytic lymphohistiocytosis (HLH) comprises a heterogeneous group of diseases which are characterized by a hyperinflammatory state due to uncontrolled T cell, macrophage and histiocyte activation, accompanied by excessive cytokine production. This rare condition is almost uniformly fatal unless promptly recognized and treated. Much progress has been made in the last two decades in our understanding of the mechanisms underlying familial, and to a lesser extent, acquired cases of HLH. Recurrent mutations in more than 10 different genes have now been identified, involving biological pathways converging on intracellular vesicle trafficking, and cytolytic granule exocytosis. Mechanisms underlying the majority of acquired HLH cases, however, remain elusive, hampering both diagnostic evaluation as well as therapeutic management of these patients. Given that the majority of intensive care unit (ICU) patients with sepsis or multiorgan failure share many features of HLH, it is especially critical for pediatric and adult intensivists to be able to recognize patients with bona fide HLH and initiate treatment without delay. In this article, we review our current understanding of the pathophysiology, clinical testing, diagnosis, and treatment of patients with HLH, especially as it pertains to the care of critically ill patients in pediatric and medical ICUs.

A Rare Case of Hemophagocytic Lymphohistiocytosis Associated with Parvovirus B19 Infection

“…One hypothesized mechanism is that the infectious viral protein of the trigger inappropriately activates cytotoxic and helper T cells, which leads to excessive and uncontrolled cytokine release resulting in tissue damage [4, 7]. An additional hypothesis is that defective T cells and NK cells fail to properly remove antigen resulting in ongoing uncontrolled macrophagic activity [4, 7]. Soluble interleukin-2 receptor (soluble CD25) reflects the activation of T cells and NK cell activity.…”

“…It was reported that ferritin levels > 10,000 ug/L had 90% sensitivity and 96% specificity for HLH in a 2008 pediatric study [9]. It has been also shown that higher ferritin level at the time of diagnosis is associated with poorer prognosis and higher mortality [1-4]. It is therefore used as a prognostic factor to monitor the treatment effects.…”

“…It can be seen in a few other diseases including viral infections, especially EBV, and hematologic malignancies such as non-Hodgkin’s-lymphoma [10]. Its presence is estimated to have a sensitivity of 80% to 83% and a specificity of only 60% to diagnose HLH [4]. Therefore, its absence cannot rule out HLH and its presence alone is not sufficient for diagnosis.…”

“…Secondary HLH occurs more commonly in adults. It is believed to be triggered by autoimmune disease, infection or malignancy [4]. The most common infectious trigger is Epstein-Barr virus (EBV) infection [5].…”

Hemophagocytic Lymphohistiocytosis and Other Culture Negative Sepsis-Like Syndromes in the ICU

“…In patients diagnosed with HLH, ferritin levels reflect disease course and activity, and in children a marked decrease in ferritin (>96%) portends decreased short term mortality during HLH treatment [25]. In critically ill adults, however, the increased prevalence of conditions which elevate ferritin, such as infection, malignancy, autoimmune disease, liver injury and chronic blood transfusion make hyperferritinemia a nonspecific finding for HLH [26,27]. Only 3% of hospitalized patients with elevated ferritin levels (>2000 ng/mL) will have a diagnosis of HLH; patients are more likely to have liver injury or infection with elevated ferritin alone [28].…”