Hemophagocytic lymphohistiocytosis (HLH) is an elusive disease with a grim prognosis. Many HLH patients develop respiratory failure and shock requiring critical care support, and early recognition and management by an intensivist are important for improving outcomes.
HLH is an inflammatory syndrome rather than a distinct disease, and is a result of immune dysregulation. HLH patients often present with fever, shock, and multiple organ failure necessitating ICU admission (1). In primary or familial HLH, impaired function of cytotoxic (CD8+) T cells and natural killer (NK) cells leads to persistent macrophage activation via interferon-gamma signaling (2). In secondary or acquired HLH, it has been postulated that constant stimulation of the immune system in the setting of infection, malignancy, or autoimmune disease may lead to secretion of excessive cytokines (3). A vast majority of HLH seen in adults is secondary or acquired HLH, although recent data suggest that some adults may have familial HLH genetic mutation variants that predispose to HLH (1).
In the largest global epidemiologic study of 2,197 patients with secondary HLH, the underlying trigger was identified as infection and/or malignancy in a vast majority of the patients; most of the patients were from East Asia, with a high number of patients with NK-T cell tumors resulting in a skewed demographic (4). Data from a single center at Johns Hopkins is more representative of the western population of HLH, with over 1/3 associated with malignancy, less than 1/3 associated with infection, approximately 15% associated with Epstein-Barr virus (EBV), 10% from autoimmune diseases, and 10% with idiopathic triggers (5).
The Histiocyte Society established diagnostic criteria for acquired HLH, and patients must demonstrate at least five of the following eight features: 1) fever, 2) splenomegaly, 3) cytopenias in at least two cell lines, 4) hypertriglyceridemia or hypofibrinogenemia, 5) elevated soluble interleukin (IL)–2 receptor, 6) decreased or absent NK cell activity, 7) ferritin elevation, and 8) hemophagocytosis in tissue (6). Despite the name of the disease, the presence of hemophagocytosis in the marrow, or any other tissue, is the least reliable and most variable finding (5). Some of these tests, namely soluble IL-2 receptor and the NK cell activity assay, are send-out tests at most institutions with a long turnaround time. There is no single pathognomonic finding of HLH, and this can often make it challenging to distinguish HLH from other causes of critical illness in the ICU, such as sepsis.
One of the diagnostic criterion of HLH is a ferritin greater than or equal to 500 µg/L, however, it can be challenging to interpret ferritin values in the ICU since a high ferritin can be seen in many critically ill patients as an acute phase reactant. Studies have previously demonstrated that a high ferritin value correlates with mortality (7). In a recent study published in Shock, 2,623 out of 6,340 ICU patients (41.4%) at a single institution had a ferritin elevation over 500 µg/L, but only 40 of those patients had HLH (8).
In this issue of Critical Care Medicine, the authors of the above Shock study used the identical database to retrospectively assess the ferritin levels in ICU patients to determine if the ferritin value correlated with HLH diagnosis, or other etiologies of illness by Lachman et al (9). Over a 12-year period at a single center, 2,623 patients were identified with a ferritin greater than or equal to 500 µg/L, and among those patients 40 (1.52%) were characterized as having HLH, while the other patients were classified as having sepsis with or without shock, or an alternative diagnosis. A 10-fold higher ferritin was noted in patients with HLH when compared with those without. The authors determined a ferritin cutoff of 9,083 µg/L correlated with a high specificity (91.9%) and sensitivity (92.5%) for HLH in the ICU (9). Their finding is similar to a pediatric study of 330 patients (10 with HLH) wherein a ferritin cutoff of greater than 10,000 µg/L was 90% sensitive and 96% specific for HLH (10).
The authors suggest that a higher ferritin value in ICU patients may help differentiate between HLH and sepsis; however, high ferritin values are seen in a number of diseases. A retrospective study from the Partners Healthcare System noted that very high ferritin values were more commonly seen in patients with renal failure and hepatocellular injury, rather than in HLH (11). In that study, the median ferritin at diagnosis in adult patients with HLH was 5,823 µg/L in 50 patients, although the study does not note how many of these patients required ICU care (11). Another Spanish prospective cohort study followed 151 patients with HLH and noted a ferritin greater than or equal to 10,000 µg/L in only 34.3% of the patients, although only 59 of the 151 patients were treated in an ICU, and so perhaps the sicker patients may have had higher ferritin values (12).
Among patients with HLH, higher ferritin values also suggest worse outcomes. In addition to using the ferritin value for diagnosis, in the above-mentioned study in Shock, the authors compared the ferritin values within those 40 HLH patients as a prognostic marker, and noted a difference in the ferritin value at diagnosis between survivors (16/40) and nonsurvivors (p = 0.021), and in the minimum ferritin value (2,195 µg/L in survivors vs 9,759 µg/L in nonsurvivors; p = 0.001). Ferritin, along with the soluble IL-2 receptor, is often used as a marker for HLH response, and patients with higher ferritin values are less likely to survive (1). A serum ferritin in HLH can be useful in diagnosis, prognosis, following treatment responses, and perhaps, as the study by Lachman et al (9) suggests, in differentiating between HLH and other critical illness, such as sepsis. Both HLH and sepsis can present with shock and multiple organ dysfunction, and of course, ongoing sepsis may trigger HLH, or an HLH patient on treatment may develop sepsis further complicating distinction.
It is clear that better identification of HLH patients is necessary, and this may be achieved by incorporating more sensitive markers into routine clinical use. Recently Cui et al (13) measured soluble CD163 (a monocyte/macrophage activation marker) as a possible additional marker for the recognition of HLH. Another group reported significantly higher monocyte human leukocyte antigen (HLA)-DR expression in a single patient with HLH when compared with patients with sepsis (14). In the most updated guidelines from the Histiocyte Society, other markers that may be more suggestive of HLH include elevated bilirubin, transaminases, hepatomegaly, elevated lactate dehydrogenase, and d-dimer levels, and some of these markers are included in the H-score, a validated tool for predicting the probability of HLH (15). In addition, a cytokine pattern of elevated interferon-γ and IL-10 with only mild elevation in IL-6 may correlate with patients having secondary HLH (1).
Once a diagnosis of secondary HLH is established, the goal is to treat the underlying trigger, that is, malignancy, infection, or autoimmune disease (5). High dose steroids and chemotherapy are used in critically ill patients requiring urgent treatment of HLH (1). Other treatment options include immunoglobulins, alemtuzumab (an anti CD52 antibody), anti-thymocyte globulin, anakinra (IL-1 receptor antagonist), tocilizumab (anti-IL–6 receptor antibody), rituximab (anti-CD20 antibody; used in Epstein-Barr virus disease), ruxolitinib (Janus kinase inhibitor), and most recently emapalumab (anti-interferon–γ antibody) (1).
Despite the inherent limitations of a single-center retrospective study, the article by Lachman et al (9) is the largest review of ICU patients with HLH. HLH remains a morbid disease with a mortality rate greater than 60% (12). Even with the challenges in identifying patients with HLH, over the past decade more patients have been diagnosed with HLH as more physicians are becoming aware of the disease. The study by Lachman et al (9) presents an important finding of markedly elevated ferritin in ICU patients with HLH when compared with other ICU patients with sepsis. The first step in improving outcomes and mortality must start with diagnosis, and the study by Lachman et al (9) is a step in that direction.
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