Association of serum oncostatin M with disease severity and mortality in community-acquired pneumonia with diabetes mellitus

Abstract

BACKGROUND

Patients with community-acquired pneumonia (CAP) and comorbid diabetes mellitus (DM) have an increased risk of severe disease and adverse outcomes, but biomarkers that may facilitate early severity and prognostic assessment remain limited.

AIM

To investigate the associations of serum oncostatin M (OSM) levels with disease severity and mortality in patients with DM-CAP.

METHODS

A prospective, single-center study of 410 patients with CAP was conducted from November 18, 2020 to November 20, 2021. The patients were classified into the CAP and DM-CAP groups. Patients in the DM-CAP group were further divided into the severe CAP (SCAP) and non-SCAP (NSCAP) groups. Serum OSM levels on days 1 and 6 after admission were measured using enzyme-linked immunosorbent assay. The associations between OSM levels and inflammatory markers, disease severity scores, and 1-year mortality were examined in the DM-CAP group. Factors associated with 1-year mortality in the DM-CAP group were further evaluated using univariable and multivariable logistic regression analyses. The potential value of OSM and other parameters for assessing disease severity and 1-year mortality was evaluated using receiver operating characteristic curve analysis.

RESULTS

Serum OSM levels were significantly higher in the DM-CAP group than in the CAP group. Among patients with DM-CAP, serum OSM levels were significantly higher in the SCAP group than in the NSCAP group (P = 0.001) and were particularly elevated in patients who died during the 1-year follow-up. Serum OSM levels were positively correlated with the pneumonia severity index and confusion, uremia, respiratory rate, blood pressure, and age ≥ 65 years (CURB-65) scores, neutrophil and white blood cell counts, interleukin-6 and interleukin-8 levels, the neutrophil-to-lymphocyte ratio, disease severity, and 1-year mortality. In the exploratory multivariable logistic regression model, age, blood urea nitrogen and OSM were independently associated with 1-year mortality in the DM-CAP group. The combination of the CURB-65 score and serum OSM levels showed potential prognostic value for 1-year mortality in this cohort.

CONCLUSION

Serum OSM levels were associated with disease severity and 1-year mortality in patients with DM-CAP and showed potential prognostic value in this cohort. These exploratory findings require validation in larger, independent cohorts.

Key Words: Oncostatin M; Community-acquired pneumonia; Diabetes mellitus; Severity; Mortality

Core Tip: This prospective observational study investigated the clinical value of serum oncostatin M in patients with community-acquired pneumonia complicated by diabetes mellitus. Serum oncostatin M levels were significantly elevated in these patients and were associated with disease severity, inflammatory burden, and 1-year mortality. Oncostatin M was an independent predictor of mortality, and its combination with confusion, uremia, respiratory rate, blood pressure, and age ≥ 65 years score improved prognostic performance. These findings suggest that oncostatin M may serve as a useful adjunctive biomarker for risk stratification and prognosis prediction in this high-risk population.

INTRODUCTION

Community-acquired pneumonia (CAP) is a major infectious disease that imposes a substantial mortality burden worldwide, accounting for approximately 4 million deaths annually and 7% of all deaths, despite improvements in prevention and clinical management[1]. Diabetes mellitus (DM) is one of the most common chronic diseases worldwide, and China has the largest number of adults with diabetes. Currently, approximately 140 million adults in China have diabetes[2]. Diabetes can lead to impaired immune function and metabolic disorders. Because of impaired immune function, people with diabetes are more likely to develop pneumonia, which may progress to severe disease. A previous study showed that people with diabetes had a 1.4-fold higher risk of pneumonia than those without diabetes[3], and DM was independently associated with the development of severe CAP (SCAP). Additionally, mortality is higher among patients with SCAP[4]. Therefore, early identification of patients at high risk of SCAP and mortality is important.

Oncostatin M (OSM) is a multipotent cytokine of the interleukin-6 (IL-6) family that is expressed in various tissues and cells and is mainly secreted by activated T lymphocytes, monocytes, and macrophages[5]. It has various biological functions, including the stimulation of hematopoiesis, regulation of cholesterol metabolism, and promotion of macrophage differentiation[6]. OSM can promote or suppress inflammation and regulate immune responses in different microenvironments. Previous studies of the role of OSM in pulmonary diseases have mainly focused on idiopathic pulmonary fibrosis[7,8], severe asthma[9], chronic sinusitis[10,11] and chronic obstructive pulmonary disease[12]. However, OSM also appears to play an important role in pulmonary infections. A single-center study of 150 patients with severe pneumonia found that OSM levels were significantly elevated at admission among patients with an oxygenation index of ≤ 250 mmHg, and among those who died. OSM levels were also found to be associated with 30-day mortality (r = -0.228, P = 0.001)[13]. Studies of patients with coronavirus disease 2019 (COVID-19) have also reported increased plasma OSM concentrations, which were closely associated with disease severity[14,15]. Our previous work demonstrated that serum OSM levels were associated with disease severity and in-hospital mortality in patients with CAP[16]. Despite this progress, the role of serum OSM in patients with DM-CAP remains unclear. In this study, we investigated the associations of serum OSM levels with disease severity and 1-year mortality and explored the potential prognostic value of OSM in patients with DM-CAP.

MATERIALS AND METHODS

Study design and participants

A single-center, prospective study of patients hospitalized with CAP was conducted between November 18, 2020, and November 20, 2021, in the Department of Respiratory and Critical Care Medicine, Emergency Department, and intensive care unit (ICU). The subjects diagnosed with CAP who met the inclusion/exclusion criteria were enrolled[16]. CAP was diagnosed according to the Guidelines for the Diagnosis and Treatment of Community-Acquired Pneumonia in Chinese Adults (2016 revision)[17]. Patients were diagnosed with SCAP if they met one major criterion or at least three minor criteria for severe pneumonia[18]. To ensure data integrity, validity, and accuracy, all data were independently entered by trained personnel and verified by two investigators using EpiData. This study was approved by the Ethics Committee of Qingdao Municipal Hospital (No. KTLL202306084). All patients provided written informed consent.

Data collection

Data were collected for each patient using case report forms and included age, sex, clinical symptoms, chest computed tomography findings, and etiology; medications used before and during hospitalization, including antivirals, corticosteroids, and antibiotics; laboratory results obtained within 24 hours after admission, including complete blood counts, liver and kidney function tests, C-reactive protein (CRP), and procalcitonin (PCT); and length of hospital stay and in-hospital mortality. The confusion, uremia, respiratory rate, blood pressure, and age ≥ 65 years (CURB-65) score and pneumonia severity index (PSI) were calculated for each patient. Day 6 blood samples were available for 55 of the 87 patients. The remaining 32 patients did not undergo repeat blood sampling because they either declined the procedure or were discharged before the scheduled blood collection. Therefore, the analysis of day 6 OSM levels was performed using available cases without imputation of missing data. One-year all-cause mortality after enrollment was assessed by structured telephone interviews and recorded as a binary outcome. Because some patients or family members could not be reached or could not provide the exact date of death, complete time-to-event data were unavailable.

Measurement of serum OSM, IL-6, and IL-8 levels

Peripheral venous blood was collected into sterile serum-separating tubes on day 1 after admission and centrifuged within 3 hours at 3000 rpm for at least 10 minutes. The serum was separated and stored at -80 °C until analysis. Serum OSM, IL-6, and IL-8 levels were measured using quantitative enzyme-linked immunosorbent assay kits (Boster Bio, Pleasanton, CA, United States) according to the manufacturer’s instructions. During the assay, interference-blocking reagents were added to the diluted samples to minimize interference from rheumatoid factor, human anti-mouse antibodies, and other interfering substances. Negative controls were prepared using the sample diluent and normal human serum. The negative-control values were subtracted from all measurements to minimize the effects of potential interfering factors.

Definitions

Definitions are as follows: (1) Chronic heart diseases include heart failure and coronary atherosclerotic heart disease; (2) Cerebrovascular diseases include transient ischemic attack, cerebral infarction, vascular dementia, cerebral hemorrhage, and subarachnoid hemorrhage[19]; (3) DM includes type 1 diabetes, type 2 diabetes, mixed diabetes, and other specific types, but does not include pre-diabetes patients with hyperglycemia, impaired glucose tolerance, and impaired fasting glucose first detected during pregnancy[20]; (4) Chronic kidney disease includes chronic renal insufficiency, diabetic nephropathy, hypertensive renal impairment, nephrotic syndrome, chronic glomerulonephritis, lupus nephritis, immunoglobulin A nephropathy, and hereditary nephropathy[21]; (5) Chronic airway diseases include chronic obstructive pulmonary disease, bronchiectasis, and bronchial asthma; and (6) 1-year mortality: It is all-cause mortality.

Statistical analysis

Categorical variables were expressed as n (%). Continuous variables with a normal distribution, as assessed using the Kolmogorov-Smirnov test, were expressed as the mean ± SD; non-normally distributed variables were expressed as the median and interquartile range. The patients were divided into the CAP and DM-CAP groups. The χ² test or Fisher’s exact test was used to compare categorical variables. Student’s t-test or the Mann-Whitney U test was used to compare continuous variables, as appropriate. Receiver operating characteristic (ROC) curve analysis was performed, with the optimal cutoff determined using the Youden index. The area under the curve (AUC) and its 95% confidence interval (CI) were calculated to assess discriminatory performance. Spearman’s correlation analysis was used to examine the associations between OSM levels and disease severity scores and inflammatory markers. Variables were dichotomized as appropriate. Multicollinearity was assessed using the variance inflation factor, with values greater than 10 considered indicative of substantial multicollinearity. Variables with a value of P < 0.10 in the univariable logistic regression analysis were considered for inclusion in the multivariable logistic regression model for 1-year mortality among patients with DM-CAP. Variables independently associated with 1-year mortality were identified using a forward stepwise regression procedure. Given the limited number of deaths, the multivariable model was considered exploratory. Because complete and reliable dates of death were unavailable for some participants, time-to-event analyses, such as Kaplan-Meier and Cox proportional hazards analyses, were not considered appropriate. Odds ratios (ORs) with 95%CIs and P values were reported. SPSS version 26.0 (IBM, Armonk, NY, United States) and Prism version 9.5 (GraphPad Software, San Diego, CA, United States) were used for all statistical analyses.

RESULTS

Patient characteristics

Of the 454 patients with pneumonia assessed for eligibility, 19 with incomplete data, 6 with outlying values, and 19 who were lost to 1-year follow-up were excluded. Finally, 410 patients with CAP were included in the analysis, of whom 87 (21.22%) had comorbid DM (Figure 1). The baseline characteristics of patients with and without DM were presented in Table 1. Compared with the CAP group, patients in the DM-CAP group were older, had more comorbidities and more severe disease, and had higher 1-year mortality. Altered consciousness, higher respiratory rates, and higher heart rates were also more common in the DM-CAP group. White blood cell (WBC), neutrophil (NEU), and lymphocyte (LYM) counts and the levels of CRP, PCT, creatinine (Cr), blood urea nitrogen (BUN), glucose, OSM, IL-6, and IL-8 differed significantly between the groups (P < 0.05).

Figure 1 Study flow chart. CAP: Community-acquired pneumonia; DM: Diabetes mellitus; AECOPD: Acute exacerbation of chronic obstructive pulmonary disease.

Table 1 Demographic and clinical characteristics of patients with community-acquired pneumonia in this study, n (%)/median (interquartile range).

Characteristics	CAP (n = 323)	DM-CAP (n = 87)	P value
Sex, male	186 (57.59)	57 (65.52)	0.181
Age, years	62 (41-74)	67 (61-78)	< 0.001
Underlying disease(s)
Chronic heart diseases	64 (19.81)	43 (49.43)	< 0.001
Hypertension	101 (31.27)	61 (70.11)	< 0.001
Chronic renal diseases	4 (1.24)	5 (5.75)	0.020
Cerebrovascular diseases	40 (12.38)	22 (25.29)	0.003
Chronic pulmonary diseases	22 (6.81)	9 (10.34)	0.899
Physical examination
T max, °C	36.80 (36.50-37.60)	36.90 (36.50-37.50)	0.701
Respiratory frequency ≥ 30 breaths/minute	8 (2.48)	5 (5.75)	0.002
Heart rates ≥ 100 beats/minute	61 (18.89)	24 (27.59)	0.002
Confusion	38 (11.76)	23 (26.44)	0.001
SBP < 90 mmHg or DBP ≤ 60 mmHg	17 (5.26)	7 (8.05)	0.326
Laboratory results
WBC (× 109/L)	7.75 (6.14-10.28)	8.54 (6.51-12.62)	0.010
NEU (× 109/L)	5.12 (3.53-7.54)	6.40 (4.30-10.86)	0.001
LYM (× 109/L)	1.58 (1.01-2.17)	1.34 (0.78-1.84)	0.013
CRP (mg/L)	19.70 (3.51-67.18)	47.11 (12.39-117.00)	0.001
PCT (μg/L)	0.06 (0.03-0.20)	0.16 (0.07-0.80)	< 0.001
Glu (mmol/L)	5.02 (4.55-5.97)	8.20 (6.11-12.17)	< 0.001
ALB (g/L)	37.37 (33.68-39.70)	36.07 (31.32-40.07)	0.094
Cr (μmol/L)	70.60 (58.14-83.49)	75.47 (63.58-100.20)	0.004
BUN (mmol/L)	4.80 (3.84-6.46)	6.04 (4.90-9.30)	< 0.001
Oncostatin M (pg/mL)	21.25 (9.76-44.59)	32.94 (14.54-72.34)	0.004
Interleukin-6 (pg/mL)	4.00 (2.15-8.30)	6.32 (3.38-15.21)	< 0.001
Interleukin-8 (pg/mL)	15.25 (11.19-22.02)	17.51 (12.76-31.09)	0.023
Chest CT
Multipolar infiltrates	168 (52.01)	54 (62.07)	0.095
Pleural effusion	53 (16.41)	19 (21.84)	0.237
Treatment
Intravenous hormone therapy	42 (13.00)	11 (12.64)	0.929
Vasoactive drug therapy	15 (4.64)	14 (16.09)	< 0.001
CURB-65 score	0 (0-1)	1 (0-2)	< 0.001
PSI score	61 (40-90)	85 (65-119)	< 0.001
In-hospital mortality	16 (4.95)	4 (4.60)	1.000
1-year mortality	34 (10.53)	17 (19.54)	0.024

Variables are expressed as n (%); mean ± SD for continuous variables conforming to a normal distribution; and median (interquartile range) for continuous nonparametric data. CAP: Community-acquired pneumonia; DM: Diabetes mellitus; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; WBC: White blood cell; NEU: Neutrophil; LYM: Lymphocyte; CRP: C-reactive protein; PCT: Procalcitonin; Cr: Creatinine; BUN: Blood urea nitrogen; Glu: Glucose; ALB: Albumin; CT: Computed tomography; CURB-65: Confusion, uremia, respiratory rate, blood pressure, and age ≥ 65 years; PSI: Pneumonia severity index.

Clinical characteristics of DM-CAP patients

Patients with DM-CAP were divided into the non-SCAP (NSCAP) group (n = 61) and the SCAP group (n = 26). Fifteen patients with SCAP (57.69%) died during the 1-year follow-up. The demographic and clinical characteristics of the participants were presented in Table 2. Compared with the NSCAP group, patients in the SCAP group were older, had more comorbidities and more severe disease, and had higher in-hospital and 1-year mortality. WBC, NEU, and LYM counts and neutrophil-to-lymphocyte ratio (NLR), CRP, PCT, albumin, Cr, BUN, OSM, IL-6, and IL-8 levels differed significantly between the groups (P < 0.05).

Table 2 Comparisons of clinical characteristics and outcomes among diabetes mellitus-community-acquired pneumonia patients, mean ± SD/n (%)/median (interquartile range).

Characteristics	NSCAP (n = 61)	SCAP (n = 26)	P value
Sex, male	38 (62.30)	19 (73.10)	0.333
Age ≥ 65 years	33 (54.10)	22 (84.62)	0.007
Underlying disease(s)
Chronic heart diseases	26 (42.62)	17 (65.38)	0.052
Hypertension	43 (70.49)	19 (73.08)	0.807
Chronic renal diseases	4 (6.56)	1 (3.85)	1.000
Cerebrovascular diseases	9 (14.75)	13 (50.00)	0.001
Chronic pulmonary diseases	7 (11.48)	2 (7.69)	0.899
Laboratory results
WBC (× 109/L)	7.47 (6.11-10.70)	12.46 (9.51-14.88)	< 0.001
NEU (× 109/L)	4.86 (3.69-7.87)	10.69 (7.50-12.93)	< 0.001
LYM (× 109/L)	1.41 (0.96-2.01)	0.92 (0.52-1.64)	0.058
NLR	3.48 (1.95-8.36)	10.77 (5.26-40.28)	< 0.001
CRP (mg/L)	39.18 (10.60-117.67)	51.14 (16.40-105.65)	0.330
PCT (μg/L)	0.09 (0.05-0.25)	0.38 (0.17-1.59)	0.003
ALB (g/L)	37.39 (32.14-40.23)	32.81 ± 5.23	0.007
Cr (μmol/L)	72.66 (63.27-86.53)	100.80 (66.92-153.10)	0.009
BUN (mmol/L)	5.62 (4.70-7.07)	9.70 (8.13-19.19)	< 0.001
Oncostatin M (pg/mL)	26.89 (11.03-58.93)	56.29 (35.59-139.19)	0.001
Interleukin-6 (pg/mL)	4.74 (2.77-13.84)	11.00 (4.71-17.65)	0.020
Interleukin-8 (pg/mL)	14.91 (12.24-23.02)	26.85 (20.19-49.61)	0.001
CURB-65 score	1 (0-1)	3 (2-3)	< 0.001
PSI score	71.00 (59.50-87.50)	137.50 (121.25-156.75)	< 0.001
In-hospital mortality	0 (0)	4 (15.38)	0.007
1-year mortality	2 (3.28)	15 (57.69)	< 0.001

Variables are expressed as n (%); mean ± SD for continuous variables conforming to a normal distribution; and median (interquartile range) for continuous nonparametric data. SCAP: Severe community-acquired pneumonia; NSCAP: Non-severe community-acquired pneumonia; WBC: White blood cell; NEU: Neutrophil; LYM: Lymphocyte; CRP: C-reactive protein; NLR: Neutrophil-to-lymphocyte ratio; PCT: Procalcitonin; ALB: Albumin; Cr: Creatinine; BUN: Blood urea nitrogen; CURB-65: Confusion, uremia, respiratory rate, blood pressure, and age ≥ 65 years; PSI: Pneumonia severity index.

OSM levels in CAP patients with DM

In CAP patients with DM, OSM levels on admission in the SCAP group [56.29 (35.59-139.19) pg/mL] were significantly higher than that in the NSCAP group [26.89 (11.03-58.93) pg/mL] (P = 0.001, Figure 2A). Day 6 OSM measurements were available for 55 patients. Among these patients, serum OSM levels were significantly lower on day 6 [15.73 (11.15-29.26) pg/mL] than on admission [35.99 (17.42-80.86) pg/mL] (P = 0.0003; Figure 2B).

Figure 2 Serum oncostatin M levels among patients with diabetes mellitus-community-acquired pneumonia. A: Comparison between the severe community-acquired pneumonia and non-severe community-acquired pneumonia groups on admission; B: Paired comparison of serum oncostatin M levels on admission and on day 6. OSM: Oncostatin M; SCAP: Severe community-acquired pneumonia; NSCAP: Non-severe community-acquired pneumonia.

Correlation between OSM levels and disease severity in CAP patients with DM

Among patients with DM-CAP, serum OSM levels were significantly higher in patients with high CURB-65 scores than in those with low CURB-65 scores (P = 0.009; Figure 3A). Similarly, serum OSM levels were significantly higher in the high-risk PSI group than in the low-risk PSI group (P = 0.003; Figure 3B). Correlation analysis showed that serum OSM levels on admission were positively correlated with CURB-65 scores (r = 0.327, P = 0.002), PSI scores (r = 0.353, P = 0.0008), IL-8 levels (r = 0.622, P < 0.0001), PCT levels (r = 0.621, P < 0.0001), NEU counts (r = 0.606, P < 0.0001), NLR (r = 0.588, P < 0.0001), IL-6 levels (r = 0.567, P < 0.0001), and WBC counts (r = 0.537, P < 0.0001) (Figure 4 and Table 3).

Figure 3 Oncostatin M levels between different confusion, uremia, respiratory rate, blood pressure, and age ≥ 65 years and pneumonia severity index groups. A: Oncostatin M (OSM) levels in patients with low confusion, uremia, respiratory rate, blood pressure, and age ≥ 65 years (CURB-65) scores (green circles) and high CURB-65 scores (red square); B: OSM levels in high-risk pneumonia severity index (PSI) group (cyan circles) and low-risk PSI group (purple diamond). OSM: Oncostatin M; CURB-65: Confusion, uremia, respiratory rate, blood pressure, and age ≥ 65 years; PSI: Pneumonia severity index.

Figure 4 Correlation between oncostatin M levels and multiple clinical indicators in 87 patients with diabetes mellitus-community-acquired pneumonia. A: Confusion, uremia, respiratory rate, blood pressure, and age ≥ 65 years score; B: Pneumonia severity index score; C: White blood cell; D: Neutrophil; E: Neutrophil-to-lymphocyte ratio; F: Procalcitonin; G: Interleukin-6; H: Interleukin-8. OSM: Oncostatin M; CURB-65: Confusion, uremia, respiratory rate, blood pressure, and age ≥ 65 years; PSI: Pneumonia severity index; WBC: White blood cell; NEU: Neutrophil; NLR: Neutrophil-to-lymphocyte ratio; PCT: Procalcitonin; IL-6: Interleukin-6; IL-8: Interleukin-8.

Table 3 Correlation analysis between serum oncostatin M and various inflammatory indicators.

Variable	Analysis	CURB‐65	PSI score	WBC	NEU	NLR	PCT	IL-6	IL-8
OSM	r/P value	0.327/0.002	0.353/0.0008	0.537/< 0.0001	0.606/< 0.0001	0.588/< 0.0001	0.621/< 0.0001	0.567/< 0.0001	0.622/< 0.0001

OSM: Oncostatin M; CURB-65: Confusion, uremia, respiratory rate, blood pressure, and age ≥ 65 years; PSI: Pneumonia severity index; WBC: White blood cell; NLR: Neutrophil-to-lymphocyte ratio; PCT: Procalcitonin; IL-6: Interleukin-6; IL-8: Interleukin-8; NEU: Neutrophil.

Correlation between the 1-year mortality and OSM in CAP patients with DM

In CAP patients with DM, OSM levels on admission in the deceased group [66.02 (38.19-161.56) pg/mL)] were significantly higher than that in the survival group [28.16 (11.56-58.95) pg/mL] (P = 0.002, Figure 5). The OSM level was significantly correlated with the 1-year mortality before treatment (r = 0.327, P = 0.002).

Figure 5 Statistically significant differences in oncostatin M levels were observed among survivors and non-survivors. OSM: Oncostatin M.

Application of the OSM levels in predicting 1-year mortality in CAP patients with DM

The potential prognostic value of OSM for disease severity and 1-year mortality among patients with DM-CAP was evaluated using ROC curve analysis. For 1-year mortality, the AUC for serum OSM was 0.738 (95%CI: 0.622-0.854). The optimal cutoff value was 35.62 pg/mL, with a sensitivity of 82.4% and a specificity of 62.9%. The AUCs for CURB-65 and PSI were 0.879 and 0.882, respectively, and were numerically higher than that for OSM alone. The combination of OSM and CURB-65 yielded an AUC of 0.903, which was numerically higher than that of CURB-65 alone. In contrast, combining OSM with PSI did not result in a numerically higher AUC than that of PSI alone (Table 4).

Table 4 Area under the curve and thresholds for predicting 1-year mortality in community-acquired pneumonia patients with diabetes mellitus.

Variable	AUC	95%CI		Sensitivity (%)	Specificity (%)	Threshold	P value
		Lower limit	Upper limit
IL-6 (pg/mL)	0.596	0.458	0.733	64.7	67.1	> 9.10	0.222
IL-8 (pg/mL)	0.721	0.574	0.868	76.5	75.7	> 23.60	0.005
OSM (pg/mL)	0.738	0.622	0.854	82.4	62.9	> 35.62	0.002
PCT (μg/L)	0.751	0.606	0.897	82.4	75.7	> 0.28	0.001
CRP (mg/L)	0.575	0.420	0.730	17.6	98.6	> 233.92	0.341
WBC (× 109/L)	0.724	0.592	0.856	82.4	62.9	> 8.92	0.004
NEU (× 109/L)	0.748	0.628	0.868	82.4	62.9	> 7.12	0.002
NLR	0.718	0.583	0.845	82.4	55.7	> 5.05	0.005
CURB-65	0.879	0.803	0.955	94.1	74.3	> 1.5	< 0.0001
PSI score	0.882	0.788	0.975	88.2	81.4	> 109.50	< 0.0001
CURB-65 + OSM	0.903	0.837	0.970	94.1	82.9	> 0.21	< 0.0001
PSI score + OSM	0.879	0.784	0.974	88.2	77.1	> 0.17	< 0.0001

AUC: Area under the curve; CI: Confidence interval; IL-6: Interleukin-6; IL-8: Interleukin-8; OSM: Oncostatin M; PCT: Procalcitonin; CRP: C-reactive protein; WBC: White blood cell; NLR: Neutrophil-to-lymphocyte ratio; NEU: Neutrophil; CURB-65: Confusion, uremia, respiratory rate, blood pressure, and age ≥ 65 years; PSI: Pneumonia severity index.

The variance inflation factor values for the variables included in the multivariable model ranged from 1.196 to 4.314, indicating no substantial multicollinearity. As shown in Table 5, age (OR = 1.070, 95%CI: 1.004-1.141; P = 0.038), BUN (OR = 1.183, 95%CI: 1.049-1.333; P = 0.006), and OSM (OR = 1.008, 95%CI: 1.001-1.014; P = 0.030) were independently associated with 1-year mortality among patients with DM-CAP in the multivariable logistic regression model.

Table 5 Analysis of risk factors affecting the 1-year mortality in diabetes mellitus-community-acquired pneumonia patients.

Variable	Univariate analysis		Multivariate analysis
	OR (95%CI)	P value	OR (95%CI)	P value
Age, years	1.094 (1.035-1.156)	0.001	1.070 (1.004-1.141)	0.038
Sex, male	0.699 (0.236-2.073)	0.519
Chronic heart diseases	2.177 (0.724-6.542)	0.166
hypertension	0.960 (0.299-3.078)	0.945
Chronic renal diseases	1.031 (0.108-9.866)	0.979
Cerebrovascular diseases	3.556 (1.162-10.876)	0.026
Chronic pulmonary diseases	1.200 (0.226-6.370)	0.830
ALB (g/L)	0.863 (0.774-0.963)	0.009
Cr (μmol/L)	1.011 (1.003-1.020)	0.010
BUN (mmol/L)	1.218 (1.092-1.359)	< 0.0001	1.183 (1.049-1.333)	0.006
LYM (× 109/L)	0.618 (0.301-1.270)	0.190
NLR	1.043 (1.001-1.077)	0.008
PCT (μg/L)	1.198 (0.951-1.509)	0.125
CRP (mg/L)	1.005 (0.998-1.012)	0.177
IL-6 (pg/mL)	1.001 (0.977-1.026)	0.947
IL-8 (pg/mL)	1.034 (1.007-1.061)	0.013
OSM (pg/mL)	1.006 (1.000-1.012)	0.042	1.008 (1.001-1.014)	0.030

OR: Odds ratio; CI: Confidence interval; ALB: Albumin; Cr: Creatinine; BUN: Blood urea nitrogen; LYM: Lymphocyte; NLR: Neutrophil-to-lymphocyte ratio; PCT: Procalcitonin; IL-6: Interleukin-6; IL-8: Interleukin-8; OSM: Oncostatin M; CRP: C-reactive protein.

DISCUSSION

To the best of our knowledge, no previous study has investigated the associations of serum OSM levels with disease severity and mortality in patients with DM-CAP. Given that the coexistence of DM and CAP may substantially increase the risk of adverse outcomes, we conducted this study to investigate the potential value of OSM as a biomarker of disease severity and prognosis (Figure 6). Our main findings were as follows: (1) Serum OSM levels were higher in the DM-CAP group than in the CAP group; (2) Among patients with DM-CAP, serum OSM levels at admission were significantly higher in the SCAP group than in the NSCAP group; (3) Serum OSM levels were positively correlated with the PSI and CURB-65 scores and with NEU, WBC, IL-6, NLR, and IL-8 levels; and (4) serum OSM levels were independently associated with 1-year mortality among patients with DM-CAP. In this cohort, the combination of the CURB-65 score and serum OSM levels yielded a numerically higher AUC for 1-year mortality than CURB-65 alone, suggesting potential prognostic value.

Figure 6 Graphical summary of serum oncostatin M as a potential biomarker for disease severity and prognosis in patients with diabetes mellitus-associated community-acquired pneumonia. In a prospective community-acquired pneumonia cohort of 410 patients, serum oncostatin M (OSM) levels were higher in diabetes mellitus-associated community-acquired pneumonia (DM-CAP) patients and correlated with disease severity, systemic inflammation, and 1-year mortality risk. The addition of OSM to confusion, uremia, respiratory rate, blood pressure, and age ≥ 65 years score improved prognostic performance, suggesting that OSM may complement conventional severity assessment and facilitate risk stratification in DM-CAP. CAP: Community-acquired pneumonia; DM: Diabetes mellitus; OSM: Oncostatin M; CURB-65: Confusion, uremia, respiratory rate, blood pressure, and age ≥ 65 years; PSI: Pneumonia severity index; WBC: White blood cell; NLR: Neutrophil-to-lymphocyte ratio; PCT: Procalcitonin; IL-6: Interleukin-6; IL-8: Interleukin-8; AUC: Area under the curve.

OSM is a pleiotropic cytokine belonging to the IL-6 family. It exerts diverse biological effects by binding to heterodimeric receptor complexes on the target cell membrane, including the OSM receptor β subunit and glycoprotein 130[22]. OSM is involved in tumor development and hematopoiesis[23,24]. Subsequent studies have also linked OSM to DM and its complications, including diabetic retinopathy, diabetic nephropathy, and diabetic macrovascular disease[25-27]. OSM expression has been reported to be elevated in DM. Albiero et al[28] identified a pathway whereby hyperglycemia increased OSM expression, which, in turn, sustained myelopoiesis and impaired hematopoietic stem cell mobilization in DM. Sanchez-Infantes et al[29] found that OSM messenger RNA (mRNA) levels were positively correlated with insulin levels and body weight but negatively correlated with glucose clearance in eight women with morbid obesity. These findings suggest a possible association between hyperglycemia and increased OSM expression.

Our previous work investigated the role of OSM in pulmonary infections. We found that serum OSM levels were independently associated with in-hospital mortality among patients with CAP and showed greater discriminatory performance than the PSI score[16]. In the present study, serum OSM levels were higher among patients with DM-CAP than among those with CAP alone. This finding suggests that DM may influence serum OSM levels in patients with CAP. However, because this observational study cannot establish causality, this hypothesis requires further investigation. Future studies should explore the molecular mechanisms underlying OSM signaling in DM-CAP and determine whether these pathways may represent potential therapeutic targets.

A study by Arunachalam et al[14], which included 76 COVID-19 patients found that patients with severe COVID-19 had higher OSM levels than those with mild and moderate COVID-19. Our previous study found that serum OSM in patients with CAP was closely related to disease severity[16]. In this study, we found that among CAP patients with DM, those with SCAP also had higher OSM levels at admission than in patients with NSCAP, consistent with the above findings. Collectively, these observations suggest that OSM may be associated with inflammatory responses and pneumonia severity.

Arunachalam et al[14] also found significantly higher levels of bacterial DNA in the plasma of patients with severe COVID-19 and ICU patients, and a significant correlation was found between bacterial DNA and blood levels of the inflammatory mediator OSM (r = 0.622, P < 0.001). These findings suggest an association between circulating OSM levels and plasma bacterial products in patients with COVID-19. Previous observational studies have reported a higher incidence of bacterial pneumonia among hospitalized patients with DM[3]. In our study, serum OSM levels were lower on day 6 than on admission among the 55 patients with available paired measurements. Although this temporal decrease may reflect changes during treatment and clinical recovery, the present data cannot establish whether OSM levels are directly related to circulating bacterial products or pneumonia etiology. Further studies are needed to clarify these potential associations and the underlying mechanisms.

The CURB-65 score and PSI are commonly used clinical assessment tools for evaluating CAP severity and prognosis. In particular, CURB-65 consists of only five components and is readily applicable in clinical practice[17]. Although its prognostic performance has been reported to be lower in patients with DM-CAP than in those with CAP without DM, it may still provide useful prognostic information[30]. We stratified patients according to their PSI and CURB-65 scores and found that serum OSM levels on admission were higher in patients with higher severity scores than in those with lower scores. Serum OSM levels on admission were positively correlated with both CURB-65 scores (r = 0.327, P = 0.002) and PSI scores (r = 0.353, P = 0.0008). These findings suggest that serum OSM levels may be associated with disease severity on admission.

Our previous study found that serum OSM levels on admission were positively correlated with WBC counts, NEU counts, PCT levels, IL-6 levels, and IL-8 levels among patients with CAP (P < 0.05)[16]. Cao et al[17] reported that OSM levels on the day of admission were significantly correlated with WBC (r = 0.53, P < 0.001) and PCT (r = 0.42, P < 0.01) in patients with sepsis. It is well known that during the progression of inflammation, inflammatory cells (WBC, NEU, etc.) activate and release a large number of inflammatory factors (PCT, CRP, IL-6, IL-8, etc.), which ultimately leads to a systemic inflammatory response syndrome. Several studies have demonstrated that PCT, IL-6 and IL-8 are potential prognostic risk factors in CAP patients[31-33]. In the present study, serum OSM levels were positively correlated with WBC counts, NEU counts, PCT levels, IL-6 levels, and IL-8 levels among patients with DM-CAP. These findings suggest that serum OSM levels may be associated with systemic inflammatory activity in patients with DM-CAP. The NLR is a readily available biomarker that has been associated with disease severity and prognosis in patients with pneumonia[34,35]. Consistent with these reports, serum OSM levels were also positively correlated with NLR among patients with DM-CAP.

In the present study, serum OSM levels were positively correlated with NEU counts and NLR among patients with DM-CAP. OSM has been reported to be expressed in multiple tissues and cell types, including NEUs and LYMs. We therefore hypothesize that NEUs may contribute to OSM production during pneumonia; however, the contribution of other host cell types to OSM expression cannot be excluded. This hypothesis is supported by findings from Traber et al[36]. Using fluorescence-activated cell sorting, the authors isolated different lung cell populations and quantified OSM mRNA expression in each cell type. In a murine model of Escherichia coli pneumonia, OSM mRNA levels in NEUs isolated from bronchoalveolar lavage fluid at 6 hours after infection were higher than those in other cell populations (60931 ± 18863; P < 0.05). These findings suggest that NEUs may be an important source of OSM during pneumonia. Traber et al[36] also proposed that the OSM-STAT1/STAT3-CXCL5 axis may contribute to NEU recruitment during early pneumonia. Collectively, these experimental findings suggest that OSM may be involved in inflammatory and immune signaling during pneumonia.

In the study including 130 patients with severe pneumonia by Lei et al[13], the OSM levels was significantly increased in the oxygenation index ≤ 250 mmHg group and in the death group upon admission and was also correlated with the 30-day mortality (r = -0.228, P = 0.001), which is an independent risk factor for high mortality in patients with severe pneumonia before treatment. Our previous study found that serum OSM is an independent risk factor for in-hospital mortality in patients with CAP[16]. In our exploratory multivariable analysis, serum OSM levels were independently associated with 1-year mortality among patients with DM-CAP. This indicates a close relationship between OSM levels and the prognosis of diabetic patients with CAP. Logistic regression was used instead of survival analysis because telephone follow-up did not provide reliable dates of death or censoring data for all patients. Therefore, 1-year mortality was treated as a binary endpoint, although this approach did not account for the timing of death. OSM showed potential prognostic value for 1-year mortality in our cohort and yielded a numerically higher AUC than the other individual laboratory indicators evaluated, including CRP, WBC, NLR, IL-6, and IL-8. The combination of OSM levels and the CURB-65 score yielded a numerically higher AUC than the CURB-65 score alone in our cohort (0.903 vs 0.879), whereas the combination of OSM and PSI did not yield a higher AUC than PSI alone. These findings may be related to the small sample size and limited number of deaths and require confirmation in larger studies.

The detection of OSM usually adopts enzyme-linked immunosorbent assay, which has been widely used in clinical laboratories and is technically feasible. Compared with conventional biomarkers (such as CRP and troponin), the detection cost of OSM is relatively high, which may limit its promotion in resource-limited areas. However, if OSM can significantly improve risk stratification or treatment decisions, its additional costs may be offset by clinical benefits. As a new type of biomarker, the value of OSM needs to be known by more and more people.

This study has several limitations. First, it was a single-center study with a relatively small DM-CAP cohort and only a limited number of deaths. The subgroup and multivariable analyses were exploratory and may be susceptible to limited statistical power, model instability, and overfitting. No prospective sample-size or power calculations were performed specifically for the subgroup, mortality endpoint, ROC analysis, or correlation analyses. Second, neither internal nor external validation was performed, and the prognostic model and ROC-derived cutoff were developed and evaluated in the same cohort; therefore, their performance may have been overestimated. Third, day 6 OSM measurements were unavailable for some patients because of refusal of repeat blood sampling or discharge before the scheduled collection, which may have introduced selection bias. Finally, incomplete information on glycated hemoglobin, diabetes duration, diabetes type, and antidiabetic treatment, as well as other unmeasured clinical and treatment-related factors, may have resulted in residual confounding. Larger, prospectively designed, multicenter studies with complete serial measurements and independent validation are needed to confirm these findings.

CONCLUSION

Serum OSM levels were higher in patients with DM-CAP than in those with CAP without diabetes and were associated with greater disease severity, inflammatory burden, and 1-year mortality. OSM may have potential as an additional prognostic biomarker in DM-CAP; however, the current findings are exploratory and require validation in larger, multicenter cohorts before clinical implementation.

ACKNOWLEDGEMENTS

The authors thank all the patients who participated in the study.