Secondary hemophagocytic lymphohistiocytosis (sHLH) is the more frequent presentation of hemophagocytic lymphohistiocytosis (HLH) in adults (1). It is a rare disease associated with rapid progression that arises from infectious, rheumatological, or neoplastic triggers. Accordingly, it is, respectively, classified as infection-associated HLH (IHLH), malignancy-associated HLH (MHLH), and autoimmune-associated HLH (AHLH) (1, 2). Persistent and atypical activation of cytotoxic CD8⁺ T cells and macrophages results in the release of inflammatory cytokines are central pathogenic mechanisms (2). Characteristic features of sHLH include unremitting fever, cytopenia, hepatosplenomegaly, coagulation dysfunction, and elevation of typical HLH biomarkers, such as high triglycerides, soluble IL-2R and ferritin level (2, 3). Inadequate clinical recognition of disease severity and prognosis often leads to therapeutic delays and high mortality rates. Therefore, it is essential to identify valuable prognostic markers of adult sHLH patients.

Generally, a lipid profile refers to direct or indirect estimates of total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-c), and low-density lipoprotein cholesterol (LDL-c) (4). Previous studies have suggested that serum lipid levels can indirectly measure pro-inflammatory cytokine bioactivity, even without obesity, diabetes, and metabolic syndrome (5). Additionally, components of cholesterol metabolism are essential in response to infection by moderating the immunological response during acute septic episodes (6). Moreover, the serum cholesterol levels may reflect a metabolic response of the organism to the inflammatory condition in septic patients, independent of diet or treatment (7). Consequently, systemic inflammation is associated with the lipid profile, which increases the likelihood of using it to assess the prognosis of diseases associated with inflammation.

Serum lipid anomalies are common among sHLH patients in clinical practice. Indeed, the HLH-2004 and ASH-2009 guidelines include hypertriglyceridemia as one of the main criteria for diagnosing of HLH (8, 9). Several observational studies have reported serum lipid anomalies in HLH cases (10); however, it has never been systematically studied, nor linked to disease severity or prognosis. Here, we present the first systematic prognosis research of the serum lipid in adult sHLH patients.

This study evaluated the prognostic efficiency of the lipid profile (TC, TG, HDL-c, and LDL-c) in sHLH patients before treatment for the first time. After adjusting the common prognostic factors, serum low HDL-c levels remain significantly independent risk factors for the prognosis of sHLH. Further analysis through restricted cubic spline (RCS) modeling indicated that elevated HDL-c levels had a significantly negative linear correlation with disease mortality.

Alteration in lipid profiles provides clinical information for patients’ risk evaluation and prognostic assessment. A notable observation in 247 patients with newly diagnosed sHLH was the contradictory coexistence of hypertriglyceridemia with hypocholesterolemia or low HDL-c or low HDL-c. Hypertriglyceridemia (≥ 3 mmol/L) in HLH is one of the well-known diagnostic criteria, and other studies have also shown that it may also predict a poor prognosis (17). Yu et al. (18) reported that elevated levels of triglyceride (68%) were associated with significantly lower 180-days OS rates in pediatric HLH. Consistent with these clinical observations, our results showed that an elevated triglyceride level at diagnosis correlates significantly positive with lower overall survival in adult HLH. In addition, a retrospective analysis of 227 pediatric HLH patients demonstrated that the decrease of HDL-c (99.1%) is widespread in pediatric HLH patients (10). Cascio et al. were the only authors that mentioned HDL reduction as an additional reason for the diagnosis of HLH, albeit in a footnote (19). However, data on cholesterol and cholesterol transporter levels in patients with adult sHLH are lacking, especially regarding their prognostic value. Serum lipid anomalies have also been identified in various other diseases, such as acute infections, acute fever infections with systemic inflammatory response syndrome, systemic lupus erythematosus, chronic rheumatoid arthritis, and incipient multiple organ dysfunction syndromes (5, 20–23).

In the present study, we found that increased TC, HDL-c, and LDL-c levels correlate significantly positive with overall survival. Univariate and multivariate analyses demonstrated that HDL-c was an independent prognostic factor for survival. These results are consistent with prior findings that the level of cholesterol and lipoproteins is one of the hallmarks of survival and demise in critical illness and inflammatory disorders (6, 24–26). Tanaka et al. employed 219 septic patients and found that patients with lower concentrations of lipoproteins at admission had higher 28-day mortality (27). While in multiple organ dysfunction patients, cholesterol was reported as a predictor of mortality (28). Similarly, a study revealed that reduced serum LDL-c level was an independent risk factor for the survival of patients with HBV-related acute-on-chronic liver failure (19). More recent studies have shown that low concentrations of TC, HDL-c and LDL-c were deeply associated with short-term mortality in intensive care unit septic patients (29). The strengths of this study include relatively large sample size and the first application of RCS to acquire greater statistical power and model flexibility to characterize the prognostic value of lipid profiles. Therefore, we could illustrate that lipid profiles are available for predicting the prognosis of untreated sHLH patients.

More than a decade ago, Dunham et al. reported that decreasing cholesterol levels indicated the development of infection or organ/metabolic dysfunction (30). Other investigators have reported that hypolipidemia is associated with the severity of COVID-19 (31). Thiemermann et al. (32) proposed that the magnitude of the reduction in circulating levels of HDL-c in sepsis/septic shock was positively related to the severity of the disease. Moreover, cytopenia and high levels of sCD25 are key biomarkers of HLH and are generally accepted as the severity index in sHLH (33, 34). This study built a Spearman association matrix to evaluate the relationship between lipoprotein concentrations and clinical parameters. We found that TC, HDL-c, and LDL-c have a positive association with higher hemoglobin and increased platelet count, and an inverse association with elevated sCD25, indicating that the decrease of TC, HDL-c, and LDL-c levels was positively related to the severity of the disease. Our findings suggest that serum lipid levels can indirectly measure of the severity of sHLH.

The underlying pathophysiological mechanism that changes lipid profile during the sHLH state is still unclear. One hypothesis could be that the lipid profile changes may result from cytokine release, which is central to the pathogenesis of HLH (5, 35, 36). Reportedly, decreased lipoprotein lipase activity caused by elevated TNF-α levels is accountable for increased triglyceride levels in HLH (37, 38). Several studies have revealed a strong inverse relationship between HDL-c levels and inflammatory markers, such as TNF-α, IL-1, IL-6, and INF-γ (39–42). In addition, HLH is characterized by cytokine storm and overwhelming inflammation, and at face value, these data and theories appeared to offer a more logical explanation for our present findings. Furthermore, injuries in the liver were the common symptoms of sHLH. Since liver is Since liver is an important organ for controlling cholesterol homeostasis, another possibility is that liver dysfunction might result in the disruption of cholesterol biosynthesis for controlling cholesterol homeostasis, another possibility is that liver dysfunction might result in the disruption of cholesterol biosynthesis (43). Hypocholesterolemia, low HDL-c, and low LDL-c might partially correlate with reduced cytokine-induced secretion, and/or reduced synthesis of hepatic apolipoproteins.

Our study also has several limitations: First, this is a retrospective single-center study, and potential selection bias may exist. The lack of a validation cohort might further weaken our results. Further studies, particularly a large cohort, are needed to verify our results. Second, more pro-inflammatory cytokines or inflammation markers need to be analyzed to fully establish the lipid profile’s performance characteristics. Third, the study was lacking a validation cohort.

Lipid profiles, which are strongly related to the disease status, are significantly associated with the overall survival of sHLH patients. A notable observation in our study was that HDL-c was more helpful in predicting the overall survival of patients with sHLH than triglyceride, total cholesterol, and LDL-c. Further studies would be warranted.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The study was approved by the Ethics Committee of the First Affiliated Hospital of Nanjing Medical University (ChiCTR2000032421), and informed consent was obtained from the patients.

WC and HQ conceived and designed the experiments. WC and XG performed the experiments. WC, LW, XG, LD and YS collected and organized the clinical materials. WC carried out data analysis. WC and HQ drafted the manuscript. All authors revised the manuscript critically and approved the final manuscript. All authors contributed to the article and approved the submitted version.