Sepsis is a life-threatening organ dysfunction resulting from a dysregulated host response to infection. It remains a major global health problem, contributing significantly to morbidity, mortality, and healthcare burden worldwide. Recent estimates suggest that over 30 million people are affected by sepsis annually, with nearly 6 million deaths attributed to it each year—figures that are likely underestimated due to poor surveillance, especially in low- and middle-income countries (LMICs) like India [1]. In India, sepsis accounts for a substantial proportion of ICU admissions, and its associated mortality remains high.

The INDICAPS study reported that nearly 28% of ICU patients developed sepsis, and approximately 42% of those patients succumbed to the illness [2]. Efforts to better understand and manage sepsis have led to evolving definitions, culminating in the Sepsis-3 criteria which define sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection, operationalized by an increase in SOFA score of ≥2 points [3]. Despite these advances, early diagnosis and accurate prognostication remain difficult due to the heterogeneity of clinical presentations and the complexity of the inflammatory response [4]. Emerging evidence suggests that certain biomarkers may assist in risk stratification and prognosis in sepsis. Among them, high-density lipoprotein (HDL) has gained interest for its potential immunomodulatory and protective roles. HDL particles, primarily composed of apolipoprotein A1 (ApoA1), not only facilitate reverse cholesterol transport but also exert anti-inflammatory, antioxidant, anti-apoptotic, and endothelial-stabilizing effects [5–7]. Experimental studies and clinical observations indicate that HDL levels drop significantly in patients with sepsis and that lower HDL concentrations are associated with worse outcomes, including higher mortality [8–10]. Van Leeuwen et al. demonstrated that HDL levels in septic patients could drop by as much as 50% compared to recovery states [8], while Chien et al. reported that patients with low HDL at the onset of severe sepsis had significantly increased 30-day mortality [9]. Furthermore, studies using ApoA1-null mice have shown heightened susceptibility to sepsis, while administration of HDL mimetics improved survival in animal models [10].

Given the high mortality associated with sepsis and the pressing need for simple, cost-effective prognostic tools in resource-limited settings, this study was undertaken to evaluate the prognostic significance of serum HDL levels in sepsis. Conducted at M.K.C.G. Medical College, Odisha, the study aimed to (1) measure changes in HDL levels in sepsis patients and (2) assess their prognostic value in relation to clinical outcomes

Study Design and Setting

This hospital-based longitudinal observational study was conducted in the Department of General Medicine at Maharaja Krishna Chandra Gajapati (M.K.C.G.) Medical College and Hospital, Berhampur, Odisha. The study spanned a two-year period from November 2017 to November 2019.

Study Population

The study included adult patients (aged ≥18 years) admitted to the Medicine ward and Intensive Care Unit (ICU) with a clinical diagnosis of sepsis, as defined by the Sepsis-3 criteria. Sepsis was identified based on the presence of suspected or confirmed infection and an acute increase in Sequential Organ Failure Assessment (SOFA) score by ≥2 points [1]. The quick SOFA (qSOFA) scoring system—altered mental status (GCS <15), systolic blood pressure <100 mmHg, and respiratory rate >22 breaths/min—was used as an initial screening tool.

Inclusion Criteria

• Patients aged ≥18 years with clinical diagnosis of sepsis as per Sepsis-3 criteria.
• Admission to medicine ward or ICU of M.K.C.G Medical College.
• Provided informed written consent to participate.

Exclusion Criteria

• Patients on statins.
• Those diagnosed with chronic liver disease, chronic kidney disease, diabetes mellitus, thyroid dysfunction, or malignancy.
• Patients with chronic inflammatory diseases (e.g., HIV, SLE, rheumatoid arthritis).
• Individuals with malabsorption syndromes.
• Patients who expired or were discharged before day 4 of hospital stay.
• Those referred to higher centers or who left against medical advice.

Sample Size and Sampling Technique

A total of 105 eligible patients were included using a convenient sampling method based on inclusion and exclusion criteria.

Data Collection and Study Instruments

A pre-designed, pre-tested structured questionnaire was employed to collect demographic, clinical, and biochemical information. Clinical parameters, including SOFA and qSOFA scores, were recorded at admission. Blood samples were collected on day 1 and again on day 4 to measure serum HDL levels and other laboratory markers (total cholesterol, platelet count, bilirubin, creatinine, etc.).

Follow-Up

Patients were followed prospectively until discharge or death. Day 1 (D1) and Day 4 (D4) serum HDL levels were measured and correlated with patient outcomes (survival, mortality), ICU admission, and duration of hospital stay.

Biochemical Analysis

Serum HDL was measured using standard enzymatic methods in the hospital’s central biochemistry laboratory. All biochemical measurements were performed adhering to quality control protocols.

Ethical Considerations

The study protocol was approved by the Institutional Ethics Committee (IEC) of M.K.C.G. Medical College. Written informed consent was obtained from each participant or their legal representative prior to enrollment. The study adhered to the principles outlined in the Declaration of Helsinki.

Statistical Analysis

Data were entered and analyzed using IBM SPSS version 21.0. Descriptive statistics were used to summarize categorical variables as proportions and continuous variables as means ± standard deviations. The chi-square test was used for comparison of proportions. The independent t-test was used to compare means between survivors and non-survivors, and between discharge durations (<6 days vs ≥6 days). Pearson correlation was applied to assess relationships between HDL levels and clinical scores. A p-value <0.05 was considered statistically significant.

A total of 105 patients diagnosed with sepsis were included in the study. The baseline demographic and clinical characteristics are summarized in Table 1.

Baseline Characteristics

The mean age of the study participants was 36.4 ± 16.2 years. Males comprised 51.4% of the sample, and 67.6% of patients resided in rural areas. Over half (55.2%) of patients were referred from government hospitals, and 20% required ICU admission during their hospital stay (Table 1).

Table 1. Baseline Characteristics of the Study Participants (N = 105)

Clinical and Biochemical Comparison: Survivors vs Non-Survivors

Of the 105 patients, 84 survived (80%) and 21 (20%) expired during hospitalization. Significant differences were observed in several parameters between survivors and non-survivors. Non-survivors had higher mean serum bilirubin (3.74 vs 2.01 mg/dL), creatinine (4.17 vs 2.16 mg/dL), and total leukocyte count (21372 vs 11228 /cumm). Importantly, HDL levels were markedly lower in non-survivors on both day 1 and day 4, with mean values of 12.00 ± 1.55 mg/dL and 11.33 ± 2.60 mg/dL respectively, compared to 20.63 ± 8.48 mg/dL and 24.32 ± 8.35 mg/dL in survivors (p < 0.001) (Table 2).

Table 2. Comparison of Clinical and Biochemical Parameters between Survivors and Non-Survivors

Association between HDL, SOFA, qSOFA Scores and Outcome

As shown in Table 3, mean SOFA and qSOFA scores were significantly higher among non-survivors compared to survivors (p < 0.001). Survivors had lower scores and exhibited a statistically significant improvement in HDL levels from day 1 to day 4. Patients who were discharged within 6 days also had higher HDL levels on admission and on day 4 than those with longer stays, suggesting that HDL could be a useful indicator of recovery duration.

Table 3. SOFA and qSOFA Scores and HDL Levels Based on Outcome and Duration of Stay

Correlation Analysis

A negative correlation was observed between HDL Day 1 levels and SOFA score, indicating that lower HDL at admission was associated with higher severity of illness (r = –0.410, p < 0.001). Similarly, a strong negative correlation was also found between HDL Day 1 and duration of hospital stay among survivors (r = –0.633, p < 0.001), further supporting HDL's prognostic value.

This study examined the prognostic role of serum high-density lipoprotein (HDL) levels in patients with sepsis and demonstrated that lower HDL levels at admission and poor improvement over the initial four days of hospitalization were significantly associated with adverse outcomes, including mortality and prolonged hospital stay.

The mean HDL level on day 1 in non-survivors was significantly lower than in survivors (12.00 ± 1.55 mg/dL vs. 20.63 ± 8.48 mg/dL, p<0.001), and a similar trend persisted on day 4 (11.33 ± 2.60 mg/dL vs. 24.32 ± 8.35 mg/dL). These findings are consistent with prior studies which have identified decreased HDL levels as a marker of disease severity in sepsis. Van Leeuwen et al. previously reported that HDL concentrations in septic patients can decrease by up to 50% during the acute phase of illness [11]. Similarly, Chien et al. found a strong inverse relationship between HDL levels at admission and 30-day mortality in severe sepsis patients [12]. Mechanistically, HDL is known to exert anti-inflammatory and endotoxin-neutralizing effects, which are especially relevant in the hyper inflammatory milieu of sepsis [13]. HDL binds lipopolysaccharide (LPS), a component of gram-negative bacterial walls, and facilitates its clearance via the scavenger receptor BI (SR-BI) pathway [14]. This detoxification process is not only more efficient than neutralization with monoclonal antibodies but also suppresses Toll-like receptor 4 (TLR4)-mediated inflammatory signaling in macrophages, as demonstrated in both in vitro and in vivo models [15].

In addition to its anti-inflammatory functions, HDL also plays a crucial role in preserving endothelial integrity and inhibiting thrombotic processes—two key aspects of sepsis pathophysiology. HDL has been shown to activate endothelial nitric oxide synthase (eNOS), reduce endothelial adhesion molecule expression, and suppress tissue factor production, thereby minimizing vascular injury and coagulopathy [16,17]. These effects make HDL a potential multipronged therapeutic target in septic patients.

The current study also identified statistically significant differences in SOFA and qSOFA scores between survivors and non-survivors, as well as between those discharged earlier (<6 days) and those requiring prolonged hospitalization. This finding further validates the utility of these scoring systems in stratifying risk and aligns with established guidelines [18]. Notably, HDL levels correlated negatively with both SOFA scores (r = –0.410) and duration of hospital stay (r = –0.633), reinforcing the association between low HDL and poor prognosis.

These observations are further supported by animal studies that demonstrate improved survival with HDL supplementation or ApoA1 overexpression. ApoA1-null mice exhibit increased mortality and reduced LPS clearance in sepsis models, whereas HDL mimetic therapy has been shown to improve survival outcomes [19,20]. Although such therapeutic strategies are still experimental, the prognostic utility of HDL is evident and reproducible across multiple clinical studies.

It is important to highlight that the present study was conducted in a resource-constrained setting in India, where access to advanced biomarkers and molecular testing is limited. In such contexts, readily available parameters like HDL can serve as valuable tools for early risk stratification. Additionally, because lipid profiles are commonly assessed in routine clinical care, integrating HDL into sepsis prognostication would require minimal additional infrastructure.

However, this study has some limitations. It was conducted in a single tertiary care hospital using a convenience sampling method, which may limit generalizability. Moreover, confounders such as nutritional status and prior undiagnosed chronic diseases could not be entirely ruled out despite rigorous exclusion criteria. Longitudinal follow-up beyond discharge was not performed, precluding an assessment of long-term outcomes.

Despite these limitations, the findings of this study underscore the potential role of HDL as a simple, cost-effective, and clinically relevant biomarker in sepsis. It provides a foundation for future multicentric studies and interventional trials exploring HDL-targeted therapies

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