Pneumonia is a common acute respiratory infection, defined as an infection of the lung parenchym4 whereas community-acquired pneumonia (CAP) is defined as pneumonia acquired outside of hospital or healthcare facilities [1-3]. It is among the major health problems and is associated with high morbidity and short-term and long-term mortality in all age groups worldwide [2,4].

The stratification of the severity and prognosis of CAP is a vital feature, as it is one of the most common causes of mortality among other infectious diseases in developed countries [5].

CAP is also one of the leading causes of hospitalization that incurs significant healthcare costs. As disease presentation varies from a mild illness that can be managed as an outpatient to a severe illness requiring treatment in the intensive care unit (ICU), determining the appropriate level of care is important for improving outcomes in addition to early diagnosis and appropriate and timely treatment [6-9].

CAP requiring treatment in the ICU represents between 10% and 30% of patients hospitalized for CAP. In patients with severe CAP, the rates of complications, hospital stay, and mortality are high, the latter varying between 21% and 54%. It is particularly important to identify those patients who are at high risk of complications. and death [10]. CAP is. Most commonly caused by viruses and bacteria, but it can also be caused by other microbes [11].

The lipoproteins in the circulation are complex aggregates of lipids and proteins, classified according to their relative density into chylomicrons, very-low density lipoprotein (VLDL), intermediate- density lipoprotein (IDL), low-density lipoprotein (LDL), and high- density lipoprotein (HDL), which provide structure and function in lipid metabolism [12]. They also play a vital role in innate immunity, which is the most critical line of protection against pathogens [13].

Different researchers reported the association of decreased serum levels of lipoprotein cholesterol with an increased mortality rate among CAP patients [14,15]. A study by Chien YF et al. reported lower levels of HDL (41.8 vs 13.0 mg/dL) and LDL (62.3 vs 30.3 mg/dL) in survivors and non-survivor groups, respectively, suffering from severe CAP and admitted at ICU. The overall mortality rate was 37.5% [15].

Appropriate and effective tools for predicting CAP prognosis are very important for early identification of CAP severity and for its appropriate treatment. Lack of effective utilization of CAP diagnostic tools will not only increase the rate of morbidity and mortality but also increase the burden of patients on the ICU and workload on ICU physicians.

The use of serum lipoprotein cholesterol levels for predicting prognosis will be helpful in early diagnosis of the severity of CAP and decrease the time of CAP management. The present study aimed to determine the serum levels of lipoproteins in patients with severe community-acquired pneumonia (CAP) requiring intensive care unit (ICU) admission.

A descriptive cross-sectional study was conducted in the Department of Pulmonology, Jinnah Postgraduate Medical Centre (JPMC), Karachi, over six months, from 2nd February, 2024, to 1st August 1, 2024. The sample size was calculated using OpenEpi software based on the 37.5% mortality rate among patients with severe community-acquired pneumonia (CAP) admitted to the intensive care unit (ICU), as reported by Chien et al. [15]. By considering a 95% confidence level and a 10% margin of error, the calculated sample size was 91 patients. A non-probability consecutive sampling technique was employed to recruit eligible participants. The study included male and female patients aged 18-80 years who were diagnosed with severe CAP requiring ICU admission for more than seven days. Patients with hyperlipidemia, those receiving lipid-lowering medications, pregnant women, and patients unwilling to participate were excluded. The study was conducted after obtaining permission from the Research Evaluation Unit (REU) of the College of Physicians and Surgeons Pakistan (CPSP) and Jinnah Postgraduate Medical Centre, Karachi. Written informed consent was obtained from eligible participants before enrollment. Demographic information, including age and gender, was recorded for each participant. Weight and height were measured using a digital weighing machine and stadiometer, respectively, and body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared (kg/m²). Vital signs, including body temperature, pulse rate, respiratory rate, and blood pressure, were recorded. Detailed medical histories were obtained to identify comorbidities and relevant risk factors, including diabetes mellitus (DM), hypertension (HTN), chronic obstructive pulmonary disease (COPD), and smoking status. The diagnosis of CAP was confirmed through chest radiography or computed tomography (CT), as appropriate. Blood samples were collected on days 1 and 7 of ICU admission and sent to the laboratory for measurement of serum high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol levels. Clinical outcomes, including total hospital stay, length of ICU stay, and mortality, were recorded during hospitalization and at discharge, as applicable. All findings were documented on a structured study proforma. Community-acquired pneumonia (CAP) was operationally defined as the presence of at least two symptoms, including fever (>38°C), cough with or without sputum, sore throat, rhinorrhea, dyspnea, or pleuritic chest pain, accompanied by new or progressive pulmonary infiltrates on chest X-ray or computed tomography (CT). Severe CAP was assessed using the CURB-65 score, which included confusion, blood urea nitrogen (BUN) >20 mg/dL, respiratory rate >30 breaths/min, systolic blood pressure <90 mmHg or diastolic blood pressure <60 mmHg, and age >65 years. Each criterion was assigned one point, and a score >2 was considered indicative of severe CAP. Serum lipoprotein cholesterol levels were assessed by measuring high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol on days 1 and 7 of ICU admission. The mean differences between these measurements were evaluated in relation to mortality. Low HDL cholesterol was defined as <40 mg/dL in men and <50 mg/dL in women, whereas levels above these thresholds were considered normal. LDL cholesterol levels <130 mg/dL were classified as normal or low, while levels >130 mg/dL were considered high. Diabetes mellitus (DM), hypertension (HTN), and chronic obstructive pulmonary disease (COPD) were operationally identified based on a history of receiving disease-specific treatment for more than six months. Current smoking was defined as having smoked more than 100 cigarettes during one's lifetime and continuing to smoke at the time of enrollment. Clinical outcomes included hospital stay, defined as the duration from hospital admission to discharge; length of ICU stay, defined as the duration from ICU admission to discharge; and mortality, defined as death occurring in the ICU among patients with severe CAP. Data were entered and analyzed using the Statistical Package for the Social Sciences (SPSS), version 25. Quantitative variables, including age, height, weight, BMI, pulse rate, blood pressure, respiratory rate, body temperature, CURB-65 score, serum HDL and LDL cholesterol levels on days 1 and 7, total hospital stay, and length of ICU stay, were summarized as means and standard deviations for normally distributed data. The Shapiro-Wilk test was used to assess normality, with a p-value greater than 0.05 indicating no statistically significant departure from normality. Non-normally distributed quantitative variables were expressed as medians and interquartile ranges (IQRs). Categorical variables, including gender, age groups, BMI categories, comorbidities, smoking status, categorized hospital stay, categorized ICU stay, and mortality, were presented as frequencies and percentages. Potential effect modifiers, including gender, age group, BMI classification, medical history of DM, HTN and COPD, smoking status, categorized hospital stay, and categorized ICU stay, were addressed through stratified analyses. Associations between categorical variables were evaluated using the chi-square test. Fisher's exact test was applied when expected cell frequencies were less than five, where appropriate. Differences in serum HDL and LDL cholesterol levels between independent groups were assessed using the independent-samples t-test for normally distributed data. A p-value of less than 0.05 was considered statistically significant.

The study involved 91 patients with severe community-acquired pneumonia (CAP), of whom 49.5% were male and 50.5% were female. Most patients were aged 18-40 years (56.0%), while 53.8% had a BMI above 24 kg/m².

The most prevalent comorbidity was hypertension (26.4%), followed by diabetes mellitus (12.1%) and chronic obstructive pulmonary disease (4.4%). Smoking was reported in 35.2% of patients (Table 1).

The mean age of the patients was 40.70 ± 17.44 years, with a mean BMI of 24.85 ± 5.50 kg/m² and a mean CURB-65 score of 2.09 ± 0.74. Mean HDL cholesterol increased from 25.78 ± 16.10 mg/dL on day 1 to 39.64 ± 16.82 mg/dL on day 7, while mean LDL cholesterol increased from 75.79 ± 37.74 mg/dL to 90.45 ± 41.89 mg/dL over the same period.

The mean hospital and ICU stays were 5.91 ± 3.28 and 3.67 ± 2.09 days, respectively (Table 2).

Most patients (62.6%) remained hospitalized for 1-6 days, while 73.6% had an ICU stay of 1-4 days. Overall, 39 patients (42.9%) died, whereas 52 (57.1%) survived (Table 3).

Day 7 HDL cholesterol levels were higher among patients aged above 40 years, females, and those with diabetes mellitus. However, no statistically significant differences were observed across age, gender, BMI, comorbidities, smoking status, hospital stay, or ICU stay (all p > 0.05) (Table 4).

Day 7 LDL cholesterol levels were significantly higher among patients with BMI >24 kg/m² compared with those with BMI 14-24 kg/m² (p = 0.040). Although higher LDL cholesterol levels were observed among older patients and those with diabetes mellitus, these differences were not statistically significant.

No significant associations were identified with gender, hypertension, COPD, smoking status, hospital stay, or ICU stay (Table 5).

Table 1. Baseline demographic and clinical characteristics of patients

with severe community-acquired pneumonia (n = 91)

Table 2. Descriptive statistics of demographic, clinical, and laboratory parameters (n = 91)

Table 3. Duration of hospitalization, ICU stay, and mortality (n = 91)

Table 4. Comparison of HDL cholesterol levels on day 7 across demographic and

clinical characteristics (n = 91)

Table 5. Comparison of LDL cholesterol levels on day 7 across demographic and

clinical characteristics (n = 91)

Community-acquired pneumonia (CAP) represents a major global health challenge, contributing significantly to hospital admissions and healthcare costs. Severe cases of CAP often require intensive care unit (ICU) admission due to complications and progressive respiratory deterioration [16]. The pathophysiology of severe CAP involves complex interactions among pathogens, host immune responses, and systemic inflammation. Emerging evidence suggests that serum lipoproteins, including low-density lipoprotein (LDL) and high-density lipoprotein (HDL), may play important roles in these processes. Lipoproteins are essential for lipid transport and metabolism and also have significant roles in immune function and inflammatory responses. LDL is associated with inflammation and immune dysregulation, whereas HDL is generally considered to have anti-inflammatory and protective properties [17]. Alterations in the balance of these lipoproteins may influence the severity and progression of CAP. For instance, reduced HDL levels have been associated with increased inflammation and unfavorable outcomes in various inflammatory conditions. Investigating the relationship between lipoprotein levels and severe CAP may improve our understanding of the underlying disease mechanisms and help guide therapeutic strategies. Identifying specific lipoprotein profiles associated with severe CAP could facilitate the development of novel biomarkers for prognosis and treatment, potentially improving patient outcomes and optimizing resource allocation in critical care settings. The relationship between lipoprotein levels and severe community-acquired pneumonia requiring ICU admission is an emerging area of research that highlights the interaction among lipid metabolism, inflammation, and critical illness [18]. This discussion examines the role of lipoproteins in severe CAP, particularly their potential applications as prognostic biomarkers and therapeutic targets. Lipoproteins, including LDL and HDL, are essential for lipid transport and have well-established roles in cardiovascular health [19]. LDL primarily transports cholesterol from the liver to peripheral tissues, whereas HDL facilitates reverse cholesterol transport by carrying cholesterol from peripheral tissues back to the liver for elimination. Beyond their metabolic functions, lipoproteins influence immune responses and inflammatory processes, which are particularly relevant in severe CAP [20]. In severe infections such as CAP, systemic inflammation plays a pivotal role in disease progression. LDL has been implicated in promoting inflammation and immune dysregulation [21]. Elevated LDL levels may contribute to endothelial dysfunction and a pro-inflammatory state, potentially aggravating the severity of infection. Additionally, LDL can interact with pathogens and host immune cells, thereby influencing the overall inflammatory response. In contrast, HDL is generally considered to possess anti-inflammatory and protective properties. HDL particles exert several beneficial effects, including modulation of immune responses and inhibition of inflammatory pathways. HDL may enhance pathogen clearance and regulate the functions of macrophages and other immune cells [22]. Reduced HDL levels in patients with severe CAP may reflect impaired anti-inflammatory responses, potentially contributing to unfavorable clinical outcomes. Several studies have investigated the relationship between lipoprotein levels and CAP severity. Previous research has demonstrated that patients with severe CAP frequently exhibit altered lipoprotein profiles, including decreased HDL and increased LDL levels [22-24]. Lower HDL cholesterol levels have been associated with higher mortality rates and greater disease severity in various inflammatory conditions, including pneumonia [24]. This association may be explained by the role of HDL in reducing inflammation and supporting immune function. Although current evidence suggests an important role for lipoproteins in severe CAP, further research is required to clarify their precise contributions and underlying mechanisms. Large-scale clinical trials are needed to validate the prognostic value of lipoproteins and evaluate the effectiveness of targeted therapeutic interventions. Future investigations should also examine the interactions between lipoproteins and other inflammatory mediators to provide a more comprehensive understanding of their involvement in CAP progression. In the present study, the mean HDL cholesterol level increased from 25.78 ± 16.10 mg/dL on day 1 to 39.64±16.82 mg/dL on day 7. Similarly, the mean LDL cholesterol level increased from 75.79 ±37.74 mg/dL on day 1 to 90.45 ± 41.89 mg/dL on day 7. These findings demonstrated an increase in both HDL and LDL cholesterol levels during the first week of ICU admission, suggesting changes in serum lipoprotein concentrations during the course of severe CAP. Chien YF et al. reported lower HDL cholesterol levels in non-survivors than in survivors (13.0 vs. 41.8 mg/dL) [15]. Similarly, LDL cholesterol levels were lower in non-survivors than in survivors (30.3 vs. 62.3 mg/dL) among patients with severe CAP requiring ICU admission. The overall mortality rate in their study was 37.5% [15]. These findings highlighted the potential association between reduced serum lipoprotein cholesterol levels and unfavorable clinical outcomes in patients with severe CAP. Lipoproteins are increasingly recognized as important factors in the pathophysiology of severe community-acquired pneumonia. Their involvement in inflammatory regulation and immune function suggests that they may serve as potential prognostic biomarkers and therapeutic targets. Further investigation into serum lipoprotein alterations and their relationship with clinical outcomes may provide valuable insights for improving risk stratification, patient management, and prognosis in severe CAP. The findings of this study highlighted the potential clinical relevance of serum lipoprotein cholesterol levels in patients with severe community-acquired pneumonia (CAP) requiring intensive care unit (ICU) admission. The rise in HDL and LDL cholesterol between days 1 and 7 was observed, suggesting changes in lipid metabolism in critical illness. These parameters could be monitored serially with other severity assessment tools like CURB-65 and may give more clues to disease progression. Still, additional research is necessary to define their predictive value and clinical utility as independent risk factors for mortality. This study had several limitations, including its single-center design, relatively small sample size of 91 patients, and non-probability consecutive sampling technique, which may have limited the generalizability of the findings. The observational design did not allow causal interpretation, and lipoprotein levels were measured only on days 1 and 7, which may not reflect changes that occur during hospitalization. Furthermore, the absence of direct comparisons between survivors and non-survivors and adjustment for potential confounding factors limited the assessment of the independent association between lipoprotein cholesterol levels and mortality.

This study demonstrated notable changes in serum lipoprotein cholesterol levels among patients with severe CAP requiring ICU admission. A significant increase in both HDL and LDL cholesterol from day 1 to day 7 indicated dynamic changes in lipid metabolism in critical illness. The severe burden and severity of CAP in critically ill patients were underlined by the observed mortality rate of 42.9%. Furthermore, the significant association between BMI and LDL cholesterol levels indicated a possible influence of metabolic factors on lipid profiles. The results highlight the clinical relevance of measuring serum lipoprotein cholesterol as part of a comprehensive evaluation of severe CAP.