The prognostic value of NLR for early death in secondary Hemophagocytic lymphohistiocytosis patients: an analysis of 92 patients

Background: Hemophagocytic lymphohistiocytosis (HLH) a hyperinammation disease and have high early mortality. The neutrophil-lymphocyte ratio (NLR) plays a prognostic role in various inammation conditions. However, the role of NLR in HLH remains unknown. Results: 92 patients were collected from Sep 2014 to Dec 2019, the median age was 50 years (16-88) and 54 patients (58.6%) were male. 39 patients (42.3%) died during a 30-day follow-up. In addition, NLR was higher in nonsurvivor than survivor (P=0.005), higher NLR was correlated with older age (P=0.020), worse survival status (P=0.006), lower HB level (P=0.008), longer PT level (P=0.010), higher creatinine level (0.027) and higher IL-6 level (P=0.008)and in multivariate analysis, NLR (HR=2.508, 95%CI: 1.275-4.934), was indicated as an independent prognostic factor for early death. Conclusions: NLR was correlated with early death in HLH, suggest NLR could be used as a reference indicator for the monitoring and management of HLH. PLT), coagulation function (prothrombin time (PT), activated partial thromboplastin time (APTT), brinogen (FIB), D-Dimer), biochemical index (total bilirubin (TB), Triglyceride (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (AKP), Serum Ferritin (SF), Glutamyltranspeptidase (Y-GT), Albumin (ALB), Creatinine (CR), lactate dehydrogenase (LDH) and C-reactive protein (CRP)).

The prognostic value of NLR for early death in secondary Hemophagocytic lymphohistiocytosis patients: an analysis of 92 patients  1.395-5.542) were associated with a poorer prognosis, albumin ≥26g/L (HR=0.384, 95%CI: 0.192-0.768) was associated with a better prognosis, and could be used as independent predictors for 30-day-mortality (Table 3). In addition, the Kaplan-Meier curve according to NLR, APTT, and albumin were shown in gure 2.

Discussion
In this study, we analyzed the potential prognostic value of NLR for 30-day mortality in a cohort of 92 patients with secondary HLH, and found that NLR was higher in nonsurvivor patients, in addition, a higher NLR was associated with increased 30-day mortality, and multivariate analysis indicates NLR was an independent predictor of 30-day mortality. To our best knowledge, this is the rst study that investigates the relationship between NLR and the early death of HLH.
Based on the evidence published to date, secondary HLH was mainly secondary to malignancies and infections, and male patients had a higher incidence compared with female patients. Due to the rapidly progressing and limited speci c treatment, secondary HLH had high early mortality, which ranged from 20.4% to 43.4% [4,[14][15][16], our result was consisted with it. Given this, it is necessary to carry out a usefulness indicator to stratifying patients.
In recent years, NLR as an in ammation indicator has been well studied in various in ammation associated pathological conditions [10][11][12][13]. Higher NLR was correlated with more advanced disease stage in autoimmune disease [17,18] and it was proved to be an independent prognosis factor in infections disease [11,19], diffuse large B-cell lymphoma [20,21], and so on. Whilst, a higher NLR predicts increased 30-day mortality in critically ill patients [13,22,23]. In this study, we observed that nonsurvivor had a higher NLR compared with survivor, and higher NLR was correlated with older age, longer PT, higher creatinine, and lower HB. In addition, the univariate analysis identi ed the prognostic value of NLR, and multivariate analysis proved NLR was an independent prognosis factor for 30-day mortality. Above all, NLR is a reliable indicator to predict the early death in HLH.
The mechanism underlying the association of higher NLR and increased mortality in HLH patients remains unknown, we hypothesis that, on the one hand, the correlation between NLR and proin ammatory cytokines endowed the prognostic value of NLR. In HLH, excessive secretion of cytokines leads to local and systematic in ammation, tissues damage and organs failure, and higher measured cytokine levels was correlated with poorer outcomes [1,24]. Published data indicated that NLR has a positive correlation with proin ammatory cytokines, such as interleukins (IL-1ra, IL-6, IL-7, IL-8, IL-9, IL-12), interferon γ and macrophage in ammatory protein 1β [10]. And in our study, a positive correlation between NLR and IL-6 was also observed. On the other hand, the prognostic value of NLR may result from the relationship between NLR and dysregulated immune response (decreased NK cell activity and increased CD8+ T cell However, the present study also has several limitations that need to be acknowledged. First, the study was uncontrolled and retrospective in nature. Second, as a single-center analysis, we did not use ROC to determine the cutoff value of NLR for the prediction of mortality. Finally, HLH is a systematic syndrome, a single indicator may have a bias to evaluate prognosis. Future multicenter and prospective studies are required to overcome these limitations, and a prognostic scoring system is needed, our study may shed some light on it.
In conclusion, our current study emphasizes the potential role of NLR as prognostic factors for early death in HLH, suggests NLR could be used as a reference indicator for the monitoring and management of HLH.
Patients And Methods

Statistical analysis
The continuous variates are presents as median (min-max), Categorical variates are presents as frequencies (percentages). Student's T test and Mann-Whitney U test were used for continuous variates comparison when appropriate, and the Chisquare test was used for categorical variates. Univariate and multivariate analyses were performed with Cox regression. All variables with a P value less than 0.1 in the univariate analyses were included in multivariate analysis with a stepwise method to determine independent prognosis factors. Kaplan-Meier method was used for the survival curve.
All P values were two sided, and P values < 0.05 was determined to be statistically signi cant.

Consent for publication
Written informed consent was obtained from the parents of all subjects included in the study.

Availability of data and materials
The datasets analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests
All authors declare that they have no con ict of interest.

Con icts of interest:
The authors declare that there is no con ict of interests regarding the publication of this paper   Figure 1 Main triggering condition distribution in all patients, and distribution according to gender and age.