Investigation of the relationship between red blood cell distribution width and mortality in patients with hemophagocytic lymphohistiocytosis: a retrospective study

ABSTRACT BACKGROUND: Red blood cell distribution width (RDW) is related to sepsis-related mortality. Hemophagocytic lymphohistiocytosis (HLH) is a syndrome caused by severe infection, tumors, or autoimmunity without a specific diagnosis. OBJECTIVE: To explore the correlation between RDW and mortality in patients with HLH. DESIGN AND SETTING: A retrospective study conducted in a hospital in China. METHODS: A total of 101 inpatients with HLH from January 1, 2017 to December 31, 2021 were divided into non-survivor (n = 52) and survivor (n = 49) groups. A non-parametric test was used to analyze demographic, clinical, and laboratory data between groups. Independent variables with P < 0.05 were analyzed using binary logistic regression to screen out mortality-related variables. Selected variables were subjected to multivariate logistic regression analysis, and those with strong correlations were screened. Receiver operating characteristic (ROC) curves of strongly correlated variables and area under curve (AUC) values were obtained. RESULTS: The APACHE II score, RDW, and platelet (PLT) and fibrinogen (FIB) levels (P < 0.05) different significantly. RDW, PLT, FIB were correlated with mortality. The AUC values of RDW, PLT, and FIB were 0.857, 0.797, and 0.726, respectively. RDW was associated with mortality in patients with HLH (P < 0.01, cut-off value: 16.9). The sensitivity and specificity of predicting mortality were 97.96% and 96.1%, respectively. CONCLUSION: Logistic regression analysis showed a correlation between RDW and patients’ mortality. Therefore, RDW can be used to predict mortality in patients with HLH.

RDW is also considered a novel inflammatory predictor in various conditions including functional bowel conditions, 17 autoimmune diseases, 18 rheumatoid arthritis, 19 degenerative vertebral conditions, 20 malignancy, 21 autoimmune hepatitis, 22 and even coronavirus disease 2019 infection. 23 Moreover, increased RDW has been linked with multiple hospital admissions in patients with chronic conditions. 24 Since RDW and cardiovascular conditions are associated with inflammation, RDW could also be associated with HLH prognosis.

OBJECTIVE
This study aimed to explore the correlation between RDW and mortality in patients with HLH.

Patients
This retrospective study was conducted among 105 inpatients with HLH from January 1, 2017 to December 31, 2021. According to the inclusion criteria, of these patients, three who were younger than 18 years and one with recurrence after treatment were excluded. Finally, a total of 101 patients were included in this study (Figure 1). These patients were divided into nonsurvivor (n = 52) and survivor (n = 49) groups.

Inclusion criteria
The patients involved in this study had to comply with the following requirements. First, the patient must be aged over 18 years.
Second, the patient must meet the following criteria (HLH-2004 diagnostic criteria): 25 1) fever ≥ 38.5 ℃; 2) splenomegaly; 3) cytopenia that affects at least two peripheral blood samples of three   1. Three patients were younger than 18 years old and did not meet the inclusion criteria. 2. One case was followed up in our hospital after being cured. A total of 101 cases met the inclusion criteria.
The variables with differences between the two groups were binary Logistic regression and multivariate Logistic regression.
None-parametric rank sum test was performed for death group (n = 52) and survival group (n = 49).
Relationship between platelet, fibrinogen RBC distribution width and mortality.

Parameter measurement
The non-rank sum test was used to analyze the following parameters of the two groups: patient age, sex, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, APACHE II death risk coefficient, sequential organ failure assessment (SOFA) score, blood routine, coagulation, liver and renal function, interleukin (IL)-2, IL-6, ferritin, bone marrow puncture, immunoglobulin, and hormone use. Moreover, this study also measured whether the liver and kidney were enlarged.

Statistical analysis
In this study, data were analyzed using the STATA statistical soft-

Comparison of clinical data and laboratory records
In this study, the demographics, clinical data, and laboratory results of patients with HLH in the non-survivor and survivor groups were analyzed and compared (

RDW, FIB, and platelets were positively correlated with mortality in patients with HLH
This study analyzed the correlation between RDW and other laboratory parameters (

AUC analyses of RDW, FIB, and platelets for the predictive ability on mortality in patients with HLH
To clarify the predictive ability of RDW, FIB, and platelets on mortality, ROC curves were drawn and analyzed in this study.
The AUC curve of RDW was 0.857 (Figure 2A), which was higher than that of FIB ( Figure 2B, AUC: 0.726) and platelet ( Figure 2C, AUC: 0.797) levels; however, there were no significant differences.

RDW demonstrated higher sensitivity and specificity for predicting mortality in patients with HLH
In this study, we assigned the cut-off level as 16.9%. Based on the cut-off value, the sensitivity of RDW for predicting patients' mortality was 97.96%, whereas the specificity was 96.1% ( Figure 3). However, the sensitivity and specificity of FIB were 90.9% and 59.6%, respectively. Therefore, RDW demonstrated higher sensitivity and specificity for predicting mortality in patients with HLH.

DISCUSSION
Adult HLH has received a lot of attention recently, but the current diagnostic criteria have some limitations for clinical patients. 26 Usually, patients with HLH can only be diagnosed in the middle and late stages of the disease; however, the initial stage is the      This is also a pathophysiological foundation for us to clarify the relationship between HLH and RDW. In this study, most adult HLH cases were induced by infection through blood phagocytosis. Therefore, this study explored whether there was a correlation between RDW and mortality in patients with adult HLH.
We found that RDW was positively correlated with mortality in patients with HLH and had a high prediction level. Furthermore, the sensitivity of RDW for predicting mortality was 97.96%, and the specificity was 96.1%, providing more auxiliary diagnostic evidence for patients with HLH.
Hormone pulse therapy is a double-edged sword for clinicians.
The application of sufficient hormone pulse at the right time is a rescue treatment for patients, but in the case of severe infection, high-dose hormone pulse may lead to the death of patients. More clinical studies are needed to provide a clinical basis for hormone pulse therapy. In this study, we found significant differences in hormone pulse therapy between non-survivor and survivor groups.
We also found that the RDW, and platelets and FIB levels had predictive values for mortality in patients with adult HLH. Fardet et al. 6 proposed HScore to predict the possibility of a single patient with HLH so that clinicians can make appropriate treatment decisions as soon as possible. However, HScore is a complex index that needs to be improved and comprehensively evaluated after several laboratory tests. Therefore, faster and more easily available laboratory indexes are needed to assist in the diagnosis of adult HLH. 6 This study showed that RDW was associated with mortality in patients with HLH. The cut-off value of RDW was 16.9. The sensitivity and specificity of predicting mortality were 97.96% and 96.1%, respectively. Logistic regression analysis showed a correlation between RDW and mortality. In summary, the RDW can be used as an important index to predict mortality in patients with HLH. The findings of this study suggest that RDW may be suitable as an auxiliary diagnostic method for HLH and an auxiliary means for predicting mortality in adult patients with HLH clinically.