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Prognostic Factors of Death in 151 Adults With Hemophagocytic Syndrome: Etiopathogenically Driven Analysis

Objective To characterize the etiologies and clinical features at diagnosis of patients with hemophagocytic lymphohistiocytosis (HLH) and correlate these baseline features with survival using an etiopathogenically guided multivariable model. Patients and Methods The Spanish Group of Autoimmune Diseases HLH Study Group, formed in 2013, is aimed at collecting adult patients with HLH diagnosed in internal medicine departments between January 3, 2013, and October 28, 2017. Results The cohort consisted of 151 patients (91 men; mean age, 51.4 years). After a mean follow-up of 17 months (range, 1-142 months), 80 patients died. Time-to-event analyses for death identified a worse survival curve for patients with neoplasia (P<.001), mixed microbiological infections (P=.02), and more than 1 infection (P=.01) and glucocorticoid monotherapy (P=.02). According to univariate analyses, platelets of less than 100,000/mm3 (hazard ratio [HR], 3.39; 95% CI, 1.37-8.40), leukopenia (HR, 1.81; 95% CI, 1.01-3.23), severe hyponatremia (HR, 1.61; 95% CI, 1.02-2.54), disseminated intravascular coagulation (HR, 1.87; 95% CI, 1.05-3.34), bacterial infection (HR, 1.99; 95% CI, 1.09-3.63), mixed microbiological infections (HR, 3.42; 95% CI, 1.38-8.46), and 2 or more infectious triggers (HR, 2.95; 95% CI, 1.43-6.08) were significantly associated with death. In contrast, peripheral adenopathies (HR, 0.63; 95% CI, 0.40-0.98) and the immunosuppressive drug/intravenous immunoglobulin/biological therapies (HR, 0.44; 95% CI, 0.20-0.96) were protective against all-cause mortality. Multivariable Cox proportional hazards regression analysis identified 2 or more infectious triggers (HR, 3.14; 95% CI, 1.28-7.68) as the only variable independently associated with death. Conclusion The mortality rate of adult patients diagnosed with HLH exceeds 50%. Infection with more than 1 microbiological agent was the only independent variable associated with mortality irrespective of the underlying disease, epidemiological profile, clinical presentation, and therapeutic management.

H emophagocytic lymphohistiocytosis (HLH, also called hemophagocytic syndrome) is an immune-mediated life-threatening disease caused by impaired natural killer (NK) and cytotoxic T-cell function. 1 It was first described in 1939 by pediatricians, and therefore the disease has been characterized overwhelmingly in children, although the number of studies in adults is increasing. Etiopathogenically, genetic defects are linked to the development of HLH in children, whereas adults have a more complex scenario, with 2 main groups of etiological factors: underlying diseases and conditions that increase the risk of developing HLH, and external factors that initiate the pathogenic hyperinflammatory process (overwhelmingly infections). 2 The heterogeneous pathogenic scenario in adults, in which different predisposing diseases and conditions are often mixed with different triggers, together with the high mortality rate, makes HLH one of the most complex and lifethreatening clinical diseases.
Prognostic studies in large cohorts of adult patients with HLH are limited. Some studies have focused on patients with a specific underlying disease or trigger, including HLH-related lymphoma, 3 Still disease, 4 lupus, 5 human immunodeficiency virus infection, 6 and Epstein-Barr virus infection. 7 However, large studies include etiologically unselected patients, the largest of which are recently reported French studies including 162 patients, 8,9 and a Chinese study including 205 patients. 10 In these studies, mortality rates varied widely, and a large list of prognostic factors was identified. Several clinical factors contribute to this heterogeneity, including significant differences in the frequency of underlying diseases, the rate of patients recruited from intensive care units (ICUs), the definition of the main outcome studied (death), and the statistical approaches used. These factors make the identification of independent prognostic factors of survival that could be extrapolated and therefore generalized to other HLH adult populations difficult.
The aim of this study was to characterize the etiologies and clinical features at diagnosis in a large cohort of Spanish adult patients with HLH and correlate these baseline features with survival using an etiopathogenically guided multivariable statistical model.

Patients
The HLH Study Group of the Spanish Group of Autoimmune Diseases (Grupo de Enfermedades Autoinmunes Sistémicas) was formed in 2013 with the aim of collecting a large series of Spanish adult patients with HLH diagnosed in internal medicine departments with substantial experience in the management of patients with systemic diseases. Between January 3, 2013, and October 28, 2017, 151 consecutive patients who fulfilled at least 5 of the 8 criteria proposed by the Histiocytosis Society in 2004 11 were included. The study protocol was approved by the Clinical Research Ethics Committee of the Hospital Clinic of Barcelona (HCB/ 2016/0183) and complied with the ethical standards of the Declaration of Helsinki. The institutional review board waived the need for informed consent because of the retrospective design and the high rate of mortality.

Definition of Variables
The date of HLH diagnosis was defined as confirmation of fulfillment of HLH criteria by the attending physician. For patients with recurrent hemophagocytic syndrome, only the first episode was considered. The end of follow-up was defined according to the last recorded Spanish National Healthcare System visit, which was the principal source of information on the health status. The primary outcome was all-cause mortality.
Variables assessed as prognostic factors for survival were collected by retrospective review of individual medical charts and classified into 4 groups:  were performed to study the crude measure of association between all variables and death. Statistically significant HLH-dependent variables were entered into a multivariable Cox proportional hazards regression analysis adjusted for HLH-independent variables, which permitted identification of variables independently associated with all-cause mortality. The hazard ratios (HRs) and their 95% CIs obtained in the Cox regression analysis were calculated. All significance tests were 2-tailed, and values of P<.05 were considered significant. All analyses were conducted using the R version 3.0.3 for Windows statistical software package.
Specific therapies for HLH included glucocorticoids in 129 (85%) patients, etoposide in 28 (19%), cyclosporine A in 28 (19%), IVIGs in 22 (15%), and rituximab in 12 (8%);  Figure 1 shows that the best survival curve was in patients with underlying autoimmune/rheumatic diseases and the worst was in those with neoplasia (log-rank P<.001). Figure 2 shows that the worst survival curves were for patients with mixed microbiological infections and those with bacterial infections (logrank P¼.02), whereas Figure 3 shows that the worst survival curve was in patients with more than 1 infectious trigger (log-rank P¼.01). Supplemental Figure 2 (available online at http://mcpiqojournal.org/) shows that the best survival curves were in patients treated with IDs/IVIGs/biologics and etoposide-based therapies and the worst was in those treated with GC monotherapy (log-rank P¼.02).   These variables were entered into a multivariable Cox proportional hazards regression analysis that identified 2 or more infectious triggers (HR, 3.14; 95% CI, 1.28-7.68) as the only variable independently associated with death (Table 3).

DISCUSSION
One of the most critical clinical conditions in adults is HLH, with an all-cause mortality rate reported in large series ranging between 42% 9 and 75%. 13 Eight studies have analyzed prognostic factors in large cohorts of adults (>50 patients) in the last 10 years (see Supplemental Table 3, available online at http://mcpiqojournal.org/) and found that most factors identified preexist the HLH diagnosis (epidemiological features, underlying diseases). Epidemiological features were key prognostic markers, especially age, 13-16 but also male sex, 13,15 together with underlying diseases, with patients with underlying neoplasia 9,10,14,15,17,18 having a poor prognosis compared with other etiologies. With respect to HLH presentation, only splenomegaly 13 was identified as a prognostic factor among HLH-related clinical features, while the number of prognostic laboratory markers was higher, including thrombocytopenia, 10,13,14,17 creatinine, 15 prothrombin time, 10,16 ferritin, 15 and fibrinogen. 16 Other prognostic factors identified were closely related to ICU admission (sequential organ failure assessment [SOFA] score, shock, and requirement for lifesustaining therapies such as renal replacement). 14,16,17 In total, these studies identified 13 different prognostic factors.
The wide list of prognostic factors identified until now for adult HLH may be due to several factors. First, the different frequencies of underlying diseases (which have per se a considerable influence on survival) included in each study; although all but 1 study 15 identify neoplasia as the most frequent underlying disease, the frequency ranges widely from 30% 14 to 77% 17 ; in addition, it is unclear how the frequent overlap between different etiologies (especially between underlying diseases and infections) was defined and analyzed. Another source of heterogeneity is that some studies included only patients admitted to the ICU 14,16,17 and different definitions of the primary outcome, including hospital mortality, 16,17 all-cause mortality, 10,13,15,18 and 1-month mortality. 9,14 The statistical approach was also heterogeneous, mainly including multivariable analysis using logistic regression models with different selection methods for variables at model entry, even though logistic regression is not recommended for the analysis of time-dependent outcomes. 19 Few studies used more appropriate time-toevent analysis approaches, such as Kaplan-Meier 9,18 or Cox-regression 10 models that allowed quantification of the measure of effect by means of HRs depending on the time of follow-up, whereas no study considered adjustment to control the confounding effects of overlapping or preexisting HLH variables.
Our results confirm, in the crude univariate analysis, the prognostic factors most frequently reported in previous studies, including age, male sex, underlying disease, thrombocytopenia, disseminated intravascular coagulation, infections, and therapeutic interventions. However, we also identified other, unreported factors, such as adenopathies, leukopenia, and severe hyponatremia. In the statistical adjustment, we used age and sex (usually used as variables of adjustment) but added underlying diseases. This pretest statistical design was based not only on the expected influence on patient survival of patient having a specific underlying disease, but also because some clinical and laboratory parameters identified in the crude analysis are closely linked to the clinical expression of the main underlying diseases (autoimmune diseases and neoplasia). According to the multivariable Cox proportional hazards regression analysis adjusted for HLH-independent variables, infection with more than 1 agent remained the only independent variable associated with survival in adult patients with HLH, an association that should be considered significant irrespective of the underlying disease, epidemiological profile, clinical presentation, and therapeutic management.
Therefore, we identified infection as the key independent factor for survival in adults with HLH. A few studies have focused on the role of acute infectious triggers in HLH survival, mainly in pediatric patients, 20,21 but also in adults treated with biological agents. 22 However, some descriptive studies have reported higher mortality rates in patients presenting with bacterial infections 13,23,24 or co-infections. 21,25 Our study reports, for the first time, that both the variety and number of infectious triggers implicated in HLH have a considerable influence on survival using time-to-event statistical models; the best survival curve was found for patients with parasitic/fungal infections, followed by those with viral infections, whereas the worst survival curves were for those with bacterial infections and multiple microbiological infections (of whom 71% also had bacterial infections in association with other microorganisms). Leishmaniasis, an endemic infection in Spain, was the most frequent parasitic infection related to HLH (8 cases, all born in Spain, of which 7 were reported from Madrid). These findings should encourage efforts to detect (and therefore treat) the infectious triggers of HLH (especially bacterial infections) as early as possible.
The time-to event analyses confirmed a worse prognosis of HLH in adult patients with underlying neoplasia, 18 and the protective effect of having an autoimmune/rheumatic disease; descriptive studies have also suggested a better prognosis for HLH related to autoimmune diseases, 13 with mortality rates of 13% in HLH-related autoimmune diseases, 26 9.5% in HLH-related adult-onset Still disease, 4 and 3% in HLH-related lupus. 5 This compares with mortality rates of more than 80% in HLH-related lymphoma, 13 and the figure Continued on next page may be even higher in patients with HLHrelated NK/T-cell lymphoma. 27 We also analyzed the role of therapeutic interventions in survival, and found better trends in patients treated with GCs plus other agents (IDs, IVIGs, or biologics) and those treated with etoposide. In contrast, patients treated with GC monotherapy and those who did not receive specific HLH therapy had the worst survival curves. Studies in children 20,28,29 and adults 5,8,30 have found similar results. These studies, together with our results, highlight the differentiated prognosis of HLH according to the underlying disease and the need for more-intensive immunosuppressive therapy than monotherapy with GCs. The survival rates reported in prognostic HLH studies including multiple etiologies should always be evaluated taking into account the frequency of each underlying disease in the corresponding cohort, and a lower survival rate should be expected in cohorts in which neoplasia predominates (clearly related to the high rate of high-grade associated hematological neoplasia) and a better rate in cohorts with a predominance of underlying autoimmune/ rheumatic disease (as observed in our study).
Our results and those of other studies analyzing prognostic factors associated with survival in adult HLH should be evaluated with caution because of the retrospective design and the lack of an international consensus on the management and treatment of adult HLH. Because of the rarity of the disease and the often-life-threatening presentation, prospective studies or randomized controlled trials in patients with HLH are extremely difficult, and it may be anticipated that the level of evidence will remain limited to retrospective studies. An additional limitation of our study, as occurs in retrospective multicenter studies, is the lack of a central review of laboratory and histopathological data to ensure a homogeneous diagnostic approach. Therefore, we are now working on the development of a Spanish diagnostic and therapeutic protocol for adult patients with HLH, searching for a nationwide homogeneous approach to the disease. One additional future task could be the worldwide collection and analysis of larger real-life data sets involving the main specialties involved in the care of these patients (intensive care, internal medicine, rheumatology, pediatrics, and hematology) and specific etiologically driven substudies considering the variety and combinations of the underlying diseases and infectious triggers. The complexity of these patients, in whom different etiopathogenic scenarios coexist, together with a mortality  To avoid multicollinearity with the number of triggers, the trigger group was not included in the model. rate of nearly 50%, poses a considerable clinical and therapeutic challenge.

CONCLUSION
This is the first study that characterizes the etiologies and clinical features at diagnosis of patients with HLH and correlates these baseline features with survival using an etiopathogenically guided multivariable model. The results suggest that the mortality rate of adult patients diagnosed with HLH exceeds 50%. There was worse survival for patients with neoplasia and mixed microbiological infections, with 1 or more infections being the only independent variable associated with mortality, irrespective of the underlying disease, epidemiological profile, clinical presentation, and therapeutic management.

ACKNOWLEDGEMENT
We thank David Buss for technical assistance.

SUPPLEMENTAL ONLINE MATERIAL
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