Clinical features and prognostic factors of adult patients with hemophagocytic lymphohistiocytosis: a retrospective study of 130 adult patients

doi:10.21203/rs.3.rs-2374660/v1

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Clinical features and prognostic factors of adult patients with hemophagocytic lymphohistiocytosis: a retrospective study of 130 adult patients

https://doi.org/10.21203/rs.3.rs-2374660/v1

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Background Hemophagocytic lymphohistiocytosis (HLH) is a syndrome with high mortality rate that is becoming increasingly common in adults in recent years. The mechanism of HLH in adults is poorly understood. This single-center study focused on the clinical features and prognostic factors of adult HLH patients.

Methods We reviewed the medical records of adult HLH patients (age≥15 years) diagnosed and treated at our institution from 2013 to 2022. Patients were followed from index date of prescription until death, or until August 31, 2022. Cox regression analysis was used to estimate hazard ratios (HR) and 95% confidence intervals (CI).

Results 130 (78 men, median age, 46 years) satisfied the HLH-2004 diagnostic criteria and were included in the study. 57 (43.8%) patients were malignancy-associated HLH. The median OS of the cohort was 61 days (95% CI 14–108). According to a multivariate Cox retrospective analysis, malignancy-associated HLH (HR=2.421, 95% CI 1.107–2.631, P=0.016) predicted a poorer outcome. Lower platelet count was related with both 30-day mortality (HR=0.987, 95% CI 0.976–0.998, P=0.018) and overall mortality (HR=0.993, 95% CI 0.987–0.999, P=0.019). The adoption of etoposide-related regimens reduced 30-day mortality (HR=0.453, 95% CI 0.252–0.815, P=0.008) and was strongly correlated with a better outcome (HR=0.629, 95% CI 0.407–0.972, P=0.037).

Conclusion Our study demonstrated that early diagnosis of HLH and identification of the underlying causes are crucial, low platelet count predicts poor outcome, and that therapy with etoposide dramatically improved prognosis.

adult

etoposide

hemophagocytic lymphohistiocytosis

HLH-2004 criteria

prognosis

Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening clinical syndrome with rapid progression. It manifests as systemic hyperinflammation caused by pathological immune activation associated with polyclonal T lymphocytes and macrophages [1]. HLH is frequently classified into two categories: primary HLH caused by genetic defects and secondary HLH caused by underlying disorders such malignancies, infections, rheumatic immunological illnesses [2]. The common presentations of HLH including fever, splenomegaly, pancytopenia, hyperferritinemia, coagulopathy, elevations of inflammatory markers, and hemophagocytosis in bone marrow or other organs [3]. HLH was originally described as a disease that developed in childhood, but is now increasingly being found in adults as well [4]. While the majority of clinical guidelines, prospective studies, and treatment trials of HLH have focused on pediatric patients, the mechanism of HLH in adults is poorly understood [3]. We conducted a retrospective research of 130 HLH patients (age ≥ 15 years) following standardized selection criteria at our center over a 10-year period to describe the underlying diseases, clinical features, prognostic factors, and outcomes of adult HLH.

Study patients

A total 130 adult patients (aged 15 years and older) with HLH who were primarily diagnosed at Wuhan Union Hospital of Tongji Medical College, Huazhong University of Science and Technology from January 2013 to August 2022, were enrolled in this study. All patients were diagnosed with HLH based on the Histiocyte Society's HLH-2004 criteria [5] and were assessed based on HScore criteria [6] to support the diagnosis. For all patients enrolled in the study, relevant demographics, assessment of underlying diseases, clinical characteristics, laboratory parameters, treatments, and outcomes were all documented. Malignancy-associated hemophagocytic lymphohistiocytosis (MHLH) was diagnosed by biopsy of bone marrow, tumor, or lymph nodes, and all patients were categorized as MHLH or non-MHLH. This study was authorized by the Ethics Committee of Wuhan Union Hospital of Tongji Medical College, Huazhong University of Science and Technology (UHCTIECSOP0160301).

Statistical methods

Categorical variables were presented as frequency (percentage), and continuous values were presented as median (range). The Pearson’s Chi-square tests and Mann-Whitney U tests were used to define differences between the categorical and continuous variables, respectively. The primary outcome of this study was overall survival (OS), calculated as the number of days between the diagnosis date and the death date or the final follow-up date. Patients alive at the last recorded follow-up were censored. Univariate Cox regression analysis was used to estimate the relationship of potential predictors to long-term survival status. Multivariable Cox regression with the stepwise forward selection was performed to analyze the influence of relevant variables (variables with P < 0.05 in the univariate Cox regression were subsequently entered into the model) on overall survival. Survival curves were estimated by the Kaplan-Meier method and compared using the long-rank test. In all analyses, P < 0.05 was considered a statistically significant difference. Analyses were performed using the SPSS version 19.0 statistical software (ver. 20.0; IBM Corp., Armonk, NY, USA).

Of the 193 reviewed medical records containing the diagnosis, 130 met the strict inclusion criteria for the study. At diagnosis, the median age was 46 years (range 16–87 years), with a preponderance of male patients (78 patients, 60.0%). Hyperferritinemia (99.2%) is one of the most frequent clinical manifestations, with a median serum ferritin of 5,404.2 μg/L (range 114.6–40,000.0 μg/L), followed by fever (93.1%), splenomegaly (90.0%), and thrombocytopenia (86.9%). Table 1 demonstrates the clinical characteristics and laboratory findings of patients meeting the HLH-2004 criteria. At least two hematopoietic lineages of cytopenia (neutrophils<1.0×10⁹/L, hemoglobin<90 g/L, platelets<100×10⁹/L) were present in 57.7% of the patients. High levels of fasting triglycerides and soluble interleukin-2 receptor (sIL-2R) were observed in 40.8% and 45.8% of patients, respectively. Reduced fibrinogen concentrations and NK-cell activity were present in 38.5% and 56.3% of the patients, respectively. Hemophagocytosis in bone marrow samples was detected in 110 patients (84.6%). Table 2 shows the laboratory characteristics for all patients as well as a comparison of MHLH and non-MHLH patients. At presentation, the median temperature, triglyceride, and fibrinogen levels were 39.4 °C (36.0–43.0 °C), 2.67 mmol/L (range 0.68–13.75 mmol/L) and 1.74 g/L (range 0.55–7.41 g/L), respectively. In addition to the diagnostic criteria findings, 17 (13.1%) patients had hepatomegaly, 64 (49.2%) patients had hyperbilirubinemia (total bilirubin level>21 μmol/L). It was also documented that an elevated level of aspartate transaminase (AST, 76.9%) and alaninetransaminase (ALT, 64.6%) were present, with a median level of 72 U/L (range 7–1,673 U/L) and 71 U/L (range 6–1,450 U/L), respectively. HScore was calculated in all adult patients with a median of 230 and a range of 91 to 309. On comparing MHLH and non-MHLH patients, only serum ferritin (P=0.016) and sIL-2R (P=0.006) showed significant differences.

57 (43.8%) patients were diagnosed with MHLH, with the remaining 73 (56.2%) instances being non-MHLH patients. Table 3 indicates the prevalence of underlying conditions across all 130 HLH patients. Malignancies were the most common triggering conditions in our group, and hematological malignancies—particularly T/NK-cell lymphoid lymphoma (32/57, 56.1%)—were the main contributors to MHLH. Of these, 18 patients were diagnosed with extranodal NK or T-cell lymphoma, 7 with peripheral T-cell lymphoma, 5 with NK-cell lymphoma, 1 with angioimmunoblastic T-cell lymphoma, and 1 with anaplastic large cell lymphoma. 20 patients (15.4%) had diffuse large B-cell lymphoma (DLBCL), and the remaining 3 with Hodgkin lymphoma, chronic myelomonocytic leukemia, myelodysplastic syndrome, and nasopharyngeal carcinoma, respectively. 56 individuals (43.1%) had an underlying infection, predominantly viral infection, including 19 patients with Epstein-Barr virus (EBV), 6 with cytomegalovirus (CMV), 5 with enterovirus, 5 with Hepatitis B virus (HBV), and 1 with Herpes simplex virus (HSV). In our patient cohort, adult-onset still disease (7/130, 5.4%), dermatomyositis (4/130, 3.1%), and Sjögren's syndrome (3/130, 2.3%) were the most frequently occurring autoimmune disorders associated with HLH. Additionally in 12 cases (9.2%), the underlying conditions of HLH were unknown. 4 patients were identified had HLH-related gene mutations, whose gene mutation types and clinical characteristics are summarized in Supplementary Table S1.

Variable treatment options are available for HLH patients based on the underlying condition and physician management decisions. Of the 57 patients with MHLH, 46 patients were treated with combined chemotherapy regimens or other cytotoxic medications such as etoposide, cyclophosphamide, and methotrexate, with 7 cases also receiving rituximab and 3 cases receiving anti-programming chemotherapeutic cell death-1 (anti-PD-1) therapy. 8 patients received treatment with corticosteroids alone and/or intravenous immunoglobulin (IVIG). 3 patients did not receive chemotherapy due to rapid progression of their condition and received only supportive treatment. Among the patients with non-MHLH, in addition to the treatment for the underlying condition, 20 patients received intravenous corticosteroids and/or IVIG, 51 patients received an etoposide-based regimen, such as HLH-1994 (steroids, etoposide), HLH-2004 (steroids, etoposide, Cyclosporin A), DEP (doxorubicin, etoposide, and methylprednisolone), and L-DEP (DEP regimen with PEG-asparaginase), and 2 patients did not receive any HLH treatment.

The median OS for all patients was 61 days (95% CI 14–108) (Fig. 1), with 87 fatalities (66.9%). 30-day mortality was 34.6%. Patients in MHLH group had a shorter OS compared with those in non-MHLH group (37 vs. 88 days, P=0.027, Fig. 2). MHLH was diagnosed in 44 of the 87 dead patients, including 28 T/NK-cell lymphoma, 15 B-cell lymphoma, and 1 nasopharyngeal carcinoma. In addition, 27 patients died from HLH associated to infection. Regardless of the underlying condition, the median OS of the cohort with an etoposide-based regimen was considerably longer than that of the group with a non-etoposide-based regimen (107 vs. 26 days, P=0.042, Fig. 3). In addition, we conducted Cox regression analysis to identify possible prognostic factors for both 30-day and overall mortality. In the univariate analysis (Table 4), the following factors were associated with 30-day mortality: low platelet level (P=0.001), low fibrinogen level (P=0.009), high triglyceride level (P=0.022), high total bilirubin level (P<0.001), and non-etoposide-based regimen (P=0.005). Multivariate analysis (Table 5) confirmed that low platelet level (HR=0.987, 95% CI 0.976–0.998, P=0.018) and non-etoposide-based regimen (HR=0.453, 95% CI 0.252–0.815, P=0.008) were both independent risk factors for 30-day mortality. In the univariate analysis of the final outcome, low neutrophil level (P=0.009), low platelet level (P=0.001), high total bilirubin level (P=0.009), associated malignancy (P=0.027), and non-etoposide-based regimen (P=0.044) were associated with poor outcome. Additionally, multivariate analysis confirmed low platelet level (HR=0.993, 95% CI 0.987–0.999, P=0.019), associated malignancy (HR=2.421, 95% CI 1.107–2.631, P=0.016), and non-etoposide-based regimen (HR=0.629, 95% CI 0.407–0.972, P=0.037) as independent predictors of poor overall survival.

HLH is a severe syndrome characterized by hyperinflammation and aberrant immune activation. Underlying defects from primary genetic dysfunction or other etiologies that enable sustainable activation of cytotoxic T cells is the core immunological feature and pathogenesis of HLH [1]. HLH can occur in patients of all ages, and HLH in adults is increasingly reported [3, 4]. In comparison to pediatric HLH, adult-onset HLH is more challenging to manage due to current knowledge gaps in etiology, diagnosis, and treatment. This single-center study focused on the clinical features and prognostic factors of adult HLH patients.

The HLH-2004 diagnostic criteria and most of the earlier studies were based on pediatric HLH. It is increasingly known that pediatric and adult HLH have some differences in certain presentations. In a research [7] comparing the manifestations of HLH in children and adults, similar frequencies of fever and splenomegaly were observed, however the frequency of hepatomegaly was significantly different (18–67% vs. 95%). In both groups, the frequency of cytopenia, ferritin, hypertriglyceridemia, sIL-2R, impaired liver function, and hemophagocytosis was similar, but hypofibrinogenemia and hypoalbuminemia were different in frequency. In our study, the frequencies of fever, splenomegaly, and hepatomegaly were 93.1%, 90.0%, and 13.1%, respectively. Laboratory abnormalities included: cytopenias in two or three lineages (57.7%), hyperferritinemia (99.2%), elevated level of AST (76.9%), elevated level of ALT (64.6%), elevated sIL-2R (45.8%), reduced NK-cell activity (56.3%), and hyperbilirubinemia (49.2%). Hemophagocytosis was discovered in bone marrow or other tissues in 84.6% of patients. The frequency of hypertriglyceridemia (40.8%) and hypofibrinogenemia (38.5%) was significantly lower compared to other diagnostic criteria. Hejblum et al.[8] conducted a Delphi survey to identify helpful criteria for HLH in adults and discovered that the following 9 factors were significant: unilineage cytopenia, bicytopenia, pancytopenia, hemophagocytosis, fever, organomegaly, underlying predisposing disease, elevated ferritin, and elevated level of lactate dehydrogenase. Of these, serum ferritin is the most relevant acute phase reactant to HLH. However, its diagnostic utility differs between children and adults [7]. A retrospective study of pediatric HLH conducted in Texas revealed that a cutoff of 10,000 µg/L of serum ferritin levels was 90% sensitive and 98% specific for pediatric HLH. In 2015, another research of adults with HLH indicated that significantly high ferritin levels exceeding 50,000 µg/L were more prevalent in renal failure, infection, liver injury, and hematological malignancies, but were not specific to adult HLH. The authors concluded that normal serum ferritin levels have a high negative predictive value for HLH in adult patients [9]. Hypertriglyceridemia and hypofibrinogenemia, the two diagnostic criteria with the lowest positive rates in this study, lack consensus in the Delphi study [8] about their diagnostic efficacy in adults with HLH. Recent reports indicate that sIL-2R is a good to excellent diagnostic test for adult HLH [10, 11]. In our study, the rate of elevated sIL-2R (≥ 2,400 U/mL) was 45.8% (33/72), and mean sIL-2R levels were higher in MHLH group compared with non-MHLH group (P = 0.006). It is reported that a relatively high ratio between sIL-2R and ferritin is useful for distinguishing MHLH from non-MHLH [11, 12]. Reduced NK-cell activity were present in 56.3% (40/71) of the patients. In pediatric HLH, reduced NK-cell activity appears to have a substantially greater diagnostic sensitivity and specificity than in adult HLH [7]. Many researchers have realized the limits of adopting the pediatric HLH-2004 diagnostic criteria to adults. While the 8 clinical and laboratory features of HLH-2004 are important for adults, some studies have also identified features of adult presentation that are not included in the HLH-2004 criteria, such as elevated levels of transaminases, bilirubin, lactate dehydrogenase, D-dimer, etc., which are also of concern [3, 13, 14].

The most frequent cause of HLH is infection, and in adults, malignancy, particularly lymphoma, is another significant cause [3, 4, 15]. In our cohort, MHLH was diagnosed in 57 of 130 patients (43.8%), of which 32 had T/NK lymphoma. MHLH has been recognized to frequently occur in high-grade lymphomas, primarily T/NK lymphomas, but can also occur in B-cell lymphomas, leukemia, Hodgkin's lymphomas, and solid tumors [15, 16]. In lymphoma-associated HLH, T-cell lymphoma patients have a worse prognosis than B-cell lymphoma patients [17, 18]. HLH can be a manifestation of undiagnosed malignancy, or develop during the treatment of underlying malignancy. Current studies indicate that the common terminal pathway of HLH due to different etiologies is aberrant activation of T-cell and macrophages. Nevertheless, the mechanism of MHLH is not well understood [4, 19–21].

Many infections have been identified in association with HLH. And EBV is reportedly the most prevalent cause of secondary HLH [3, 22, 23]. In our data, 4 infection-associated HLH patients had genetic mutations like perforin 1 (PRF1), UNC13D, STXBP2, LYST, which were associated with dysregulation of the immune response. It is currently recognized that HLH-related gene mutations are not only found in children, but also in adults [24, 25]. Additionally, in Chinese with HLH, UNC13D is the most common mutation, in Japan approximately 60–70% of familiar HLH cases have shown mutations in PRF1 or UNC13D, and in North America, PRF1 mutations are the most prevalent, followed by UNC13D and STXBP2 mutations [25–28]. Autoimmune disease was also one of the potential causes of HLH in our study, mainly adult-onset still disease (AOSD). According to previous research, systemic lupus erythematosus (SLE) was the most common autoimmune diseases associated with HLH in adults, and AOSD was found to be an independent risk factor for the development of HLH [29, 30].

According to the expert opinions in 2019, the treatment of adult HLH should consider a modified regimen for pediatric HLH (HLH-1994 and HLH-2004) [3]. The HLH-94 trial among pediatric patients showed the 5-year survival was 54% [31]. However, randomized controlled trials of this protocol in adults are absent. It is now abundantly obvious that timely diagnosis of HLH and prompt administration of both primary disease-specific treatment and HLH-specific treatment are crucial [3, 7, 32]. Etoposide is a highly specific chemotherapeutic drug for blocking T-cell proliferation and cytokine release in mice, and it treats HLH by selectively ablating activated T-cells [33]. Several studies have demonstrated that etoposide-based regimens, including HLH-1994, HLH-2004, DEP (doxorubicin, etoposide, and methylprednisolone), and L-DEP (DEP regimen plus PEG-asparaginase), are efficient treatment for HLH in adults [3, 34, 35]. In prior research [36, 37], both children and adults responded favorably to etoposide. Furthermore, since the adverse effects of etoposide include anemia, bleeding, and infection, the latest research suggest that moderately dosed etoposide may be beneficial in severe and/or refractory HLH [36, 38].

An analysis of reported cases and series of adult HLH studies indicated that the mortality rate of adult HLH ranging from 26.5–74.8% [32]. The mortality rate in this study was 66.9%, and the MHLH group had a significantly worse prognosis than the non-MHLH group. Similar results have been obtained in previous studies, and a single-center prospective cohort study noted that the 1-year survival rate for MHLH was less than 40% [18, 39, 40].

The poor prognosis of HLH has been linked to laboratory abnormalities such as low platelet counts, low albumin levels, high bilirubin levels, and high ferritin levels, among others, according to previous research [13, 41]. In our cohort, thrombocytopenia was revealed to be an independent predictor for both 30-day mortality and overall mortality. And Chellapandian et al.[42] found that thrombocytopenia was a consistent prognostic factor in adult HLH, which could be caused by bone marrow failure, hypersplenism, or disseminated intravascular coagulopathy (DIC).

The limitations of our investigation are explained in the following section. Firstly, it is a case-selection-based retrospective cohort research. Secondly, only nearly half of the patients had NK-cell activity and sIL-2R assessed. Thirdly, the selection of regimen is based on the physician's personal management decisions rather than randomly selected.

In this retrospective analysis of 130 individuals, malignancy was the leading cause of HLH in adults. MHLH has a poorer survival rate compared to non-MHLH. Platelet counts at diagnosis were related with both 30-day and overall mortality in patients with HLH. Etoposide-based regimens may improve prognosis, which needs to be validated in further multicenter and prospective research.

Acknowledgement None.

Author Contribution TTX and LVT performed material preparation and clinical data collection. TTX performed the data analysis and prepared the first draught of the article. JLX was in charge of organizing the study's design. All three writers offered substantial contributions to the study and endorsed the final version for publication.

Data Availability The data of our patients is available in the Department of Medical Records at Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology. These data can be released with consent from the patients and are available from the corresponding author upon reasonable request.

Funding This work was supported by the Young Top-notch Talent Cultivation Program of Hubei Province (No.2021017).

Ethics Approval All research procedures involving human participants complied with the ethical standards of the research committee (institutional and national) and with the 1964 Helsinki Declaration and its subsequent amendments. The study was authorized by the Ethics Committee of Wuhan Union Hospital of Tongji Medical College, Huazhong University of Science and Technology.

Informed consent Not applicable.

Conflict of Interest The authors declare no conflicts of interest.

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Table 1 Clinical and laboratory findings according to the HLH-2004 criteria

Characteristics	No. (%) of patients
Fever (T≥38.5 °C)	121/130 (93.1)
Splenomegaly	117/130 (90.0)
Cytopenias (bicytopenia or pancytopenia)	75/130 (57.7)
Neutrophils<1.0×10⁹/L	48/130 (36.9)
Hemoglobin<90 g/L	76/130 (58.5)
Platelets<100×10⁹/L	113/130 (86.9)
Hypertriglyceridemia (≥3.0 mmol/L)	53/130 (40.8)
Hypofibrinogenemia (≤1.5 g/L)	50/130 (38.5)
Hyperferritinemia (≥500 μg/L)	129/130 (99.2)
Hemophagocytosis	110/130 (84.6)
Low/absent NK-cell activity	40/71 (56.3)
Elevated sIL-2R (≥2,400 U/mL)	33/72 (45.8)

Table 2 Clinical characteristics of all enrolled patients

	Total (N=130)	MHLH (N=57)	Non-MHLH (N=73)	P-value
Age (y), median (range)	46 (16–87)	46 (16–87)	45 (16–73)	0.245
Male (%), median (range)	78 (60.0)	39 (68.4)	39 (53.4)	0.083
T (°C), median (range)	39.4 (36.0–43.0)	39.4 (37.5–42.0)	39.4 (36.0–43.0)	0.561
ANC (×10⁹/L), median (range)	1.40 (0.01–23.09)	1.67 (0.01–13.96)	1.38 (0.01–23.09)	0.828
HB (g/L), median (range)	87 (52–147)	86 (54–147)	87 (52–137)	0.690
PLT (×10⁹/L), median (range)	42 (2–481)	37 (4–339)	44 (2–481)	0.322
FIB (g/L), median (range)	1.74 (0.55–7.41)	1.83 (0.55–7.14)	1.62 (0.55–7.41)	0.071
TG (mmol/L), median (range)	2.67 (0.68–13.75)	3.00 (0.74–8.37)	2.58 (0.68–13.75)	0.786
FER (μg/L), median (range)	5,404.2 (114.6–40,000.0)	3,966.0 (656.8–40,000.0)	6,460.10 (114.6–40,000.0)	0.016
TBIL (μmol/L), median (range)	21.0 (1.1–339.3)	22.8 (6.1–339.3)	17.4 (1.1–210.2)	0.597
AST (U/L), median (range)	72 (7–1673)	71 (10–1673)	75 (7–825)	0.843
ALT (U/L), median (range)	71 (6–1450)	69 (8–1450)	71 (6–715)	0.590
Splenomegaly (%)	117 (90.0)	50 (87.7)	67 (91.8)	0.444
Hepatomegaly (%)	17 (13.1)	6 (10.5)	11 (15.1)	0.446
Hemophagocytosis (%)	110 (84.6)	48 (84.2)	62 (84.9)	0.910
Low NK-cell activity (%)	40 (56.3)	16 (57.1)	24 (55.8)	0.912
Elevated sIL-2R≥2,400 U/mL (%)	33 (45.8)	19 (65.5)	14 (32.6)	0.006
HSCORE, median (range)	230 (91–309)	225 (91–294)	234 (122–309)	0.096

T, temperature; ANC, absolute neutrophil count; HB, hemoglobin; PLT, platelet; FIB, fibrinogen; TG, triglycerides; FER, ferritin; TBIL, total bilirubin; AST, aspartate aminotransferase; ALT, alanine aminotransferase.

Table 3 The distribution of underlying conditions in 130 patients with HLH

Underlying conditions	N (%)
Malignant tumor (n=57, 43.8%)
T/NK-cell lymphoma	32 (24.6)
Peripheral T-cell lymphoma	7 (5.4)
NK/T-cell lymphoma	18 (13.8)
NK-cell lymphoma	5 (3.8)
Angioimmunoblastic T-cell lymphoma	1 (0.8)
Anaplastic large cell lymphoma	1 (0.8)
B-cell lymphoma	20 (15.4)
Diffuse large B-cell lymphoma	20 (15.4)
Hodgkin lymphoma	1 (0.8)
Chronic myelomonocytic leukemia	1 (0.8)
Myelodysplastic syndrome	1 (0.8)
Solid tumor	1 (0.8)
Nasopharyngeal carcinoma	1 (0.8)
Infection (n=56, 43.1%)
Virus	36 (27.7)
Epstein-Barr virus	19 (14.6)
Cytomegalovirus	6 (4.6)
Enterovirus	5 (3.8)
Hepatitis B virus	5 (3.8)
Herpes simplex virus	1 (0.8)
Bacterial	3 (2.3)
Mycobacterial	4 (3.1)
Fungal	3 (2.3)
Not identified	10 (7.7)
Autoimmune (n=15, 11.5%)
Adult-onset still disease	7 (5.4)
Dermatomyositis	4 (3.1)
Sjögren's syndrome	3 (2.3)
Behcet's disease	1 (0.8)
Mendelian inherited conditions (n=6, 4.6%)	5 (3.8)
Idiopathic disease (n=12, 9.2%)	12 (9.2)

34 patients with both malignancy and infection (26.2%), 7 patient with infection and an autoimmune disorder (5.4%). Percentages may not add to 100 because of rounding.

Table 4 Univariate analysis of prognostic factors for 30-day mortality and overall mortality in newly diagnosed adult HLH patients

Characteristics	Death with 30 days			Overall
Characteristics	HR	95%CI	P value	HR	95%CI	P value
Age	1.005	0.987 to 1.023	0.599	1.010	0.997 to 1.023	0.147
Gender	1.690	0.902 to 3.168	0.102	1.163	0.755 to 1.792	0.493
Neutrophils	0.894	0.787 to 1.017	0.088	0.880	0.799 to 0.968	0.009
Hemoglobin	0.995	0.979 to 1.011	0.521	0.991	0.980 to 1.003	0.145
Platelets	0.981	0.970 to 0.992	0.001	0.991	0.985 to 0.996	0.001
Fibrinogen	0.695	0.529 to 0.913	0.009	0.907	0.783 to 1.051	0.192
Triglyceride	1.144	0.874 to 1.020	0.022	1.025	0.913 to 1.151	0.674
Ferritin	1	1	0.563	1	1	0.311
Total bilirubin	1.008	1.004 to 1.021	<0.001	1.005	1.001 to 1.009	0.009
Aspartate transaminase	1.001	1.000 to 1.002	0.217	0.999	0.998 to 1.001	0.595
Alaninetransaminase	1.001	0.999 to 1.002	0.524	0.999	0.997 to 1.000	0.099
Hepatomegaly	1.254	0.560 to 2.805	0.582	0.837	0.420 to 1.671	0.615
Splenomegaly	0.843	0.333 to 2.134	0.719	0.778	0.389 to 1.554	0.476
Hemophagocytosis	1.740	0.687 to 4.408	0.243	1.792	0.897 to 3.580	0.098
Low NK cell function	0.603	0.238 to 1.532	0.288	0.881	0.452 to 1.720	0.711
Elevated sCD25≥2400U/mL	0.996	0.412 to 2.306	0.993	0.893	0.459 to 1.740	0.740
Associated malignancy	1.691	0.946 to 3.024	0.076	1.612	1.055 to 2.464	0.027
Etoposide-based treatment	0.433	0.243 to 0.773	0.005	0.637	0.413 to 0.983	0.044

Table 5 Multivariate analysis of prognostic factors for 30-day mortality and overall mortality in newly diagnosed adult HLH patients

Prognostic factors	HR	95% CI	P
30-day motality
Platelets	0.987	0.976 to 0.998	0.018
Fibrinogen	0.871	0.676 to 1.124	0.289
Triglycerides	1.201	0.991 to 1.455	0.062
Total bilirubin	1.003	0.999 to 1.008	0.178
Etoposide-based treatment	0.453	0.252 to 0.815	0.008
Overall survival
Neutrophils	0.908	0.821 to 1.005	0.062
Platelets	0.993	0.987 to 0.999	0.019
Total bilirubin	1.443	0.999 to 1.007	0.149
Associated malignancy	2.421	1.107 to 2.631	0.016
Etoposide-based treatment	0.629	0.407 to 0.972	0.037

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Clinical features and prognostic factors of adult patients with hemophagocytic lymphohistiocytosis: a retrospective study of 130 adult patients

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