To study about the significance of acute inflammatory serum bio markers and their correlation with mortality of acute Pneumonia in comparison with IL6, q-SOFA score and CT scan of chest findings.

This was a prospective cohort study conducted on 180 subjects of acute pneumonia, who were admitted in icu at KR hospital, Mysuru from February 2021 to October 2022. The study was started after getting Ethical Clearance from MMC & RI, Mysuru Ethical committee with the number EC REG:ECR/134/Inst/KA/2013/RR-19.

In the present study, sample size was calculated using the formula n= 4pq/d².[1,10]1

p = 32%, q = (100-p) = 68%, d = 11.25%.

Demographic data, pneumonia symptoms and past medical histories such as comorbidities and active medications, were obtained by patient interviews. All patients underwent standardized workup, including complete blood count, serum ferritin, hs-C-reactive protein (hs-CRP), serum LDH, RFT, LFT, IL 6, CT Chest and electrocardiogram. The systolic BP of less than 90mmhg was taken as hypotension, Respiratory rate of >22/min was taken as Tachypnoea and the heart rate of more than >100/min was considered as Tachycardia. 1, 2 The serum hs-CRP level of less than 1mg/L,7 the LDH level between 105 to 333IU/L8, the serum ferritin level between 11 to 336µg/L, normal serum IL6 was 0 to 43.5pg/ml, normal NLR was between 0.78 to 3.53 and normal WBCs count between 4000 to 11000/µl were considered as normal ranges in this study. 9 The common CT scan of chest findings in Acute pneumonia iirespective of the etiology were centrilobular nodules, ground glass opacities [GGO], and lobular areas of consolidation with bronchial wall thickening. 10 All the biochemical investigations were done on day 1 and day 5 of admission to the hospital. The CT chest was done on day 1 of the study in all patients and grading of severity was done by lobes involvement with scoring. There were 0 to 4 score with percentage of lobe involvement. The 0% with 0 score, <25% with 1 score, 25% to 50% with 2 score,50% to 75 % 3 score and >75 % with 4 score. Total 25 score were there, in that score between 0 to 8 was considered as mild pneumonia, 8 to 16 was moderate pneumonia and the score >16 was considered under severe pneumonia. The acute pneumonia staging was done based on clinical features and CURB 65 score [Confusion (Abbreviated Mental test score ≤ 8 or new disorientation in person, place, or time), raised blood Urea nitrogen (> 7 mmol/L), raised Respiratory rate (≥ 30/min), low Blood pressure (diastolic ≤ 60 mmHg or systolic < 90 mmHg), Age ≥ 65 years], in to 3 stages, such as stage 1 with score<1, stage 2 with score of 2 and stage 3 with score of 3 and above. 11 T The q-SOFA score was recorded for all the patients on day 1 and day 5 of admission. The patients were followed up for the whole in hospital stay duration. The results were tabulated and studied to find the association between early elevated serum acute inflammatory bio markers, IL6,q-SOFA score and CT scan of chest severity score with the mortality due to acute pneumonia.

In the present study, the acute inflammatory serum biomarkers and their correlation with the clinical features, the severity and outcome of acute pneumonia was tabulated as follows

Predominantly female patients with the age of more than 60 years have got affected with the acute pneumonia. The salient features were fever, cough, breathlessness and Tachypnoea in majority of patients. The impaired consciousness and Hypotension were found in 35(19.44%) and 68(37.77%) patients respectively. All the acute inflammatory markers including serum IL6 were significantly elevated in most of the patients of acute pneumonia. [Table 1]

Table 2

	The Number of Patients(%) With Mean Serum Biomarkers
	LDH level – (Mean ± SD)	FERRITIN level - (Mean ± SD)	hs-CRP level - (Mean ± SD)	NLR - (Mean ± SD)	WBCs count - (Mean ± SD)	IL6 level - (Mean ± SD)	q-SOFA score - Mean ± SD	CT score	P value
Clinical Features	550.76±112.45 units/ml in numbers (%)	680.56±124.68µg/l in numbers (%)	12.65±3.4mg/l in numbers (%)	4.68±1.21(%)	15630.15±1540.05/µl (%)	158.68±46.45pg/ml (%)	2.5±0.8	>16
Fever	172(95.55)	174(96.66)	174(96.66)	174(96.66)	174(96.66)	174(96.66)	176(97.77)	78(43.33)	0.01
Cough	175(97.22)	171(95)	178(98.88)	178(98.88)	179(99.44)	179(99.44)	179(99.44)	84(46.66)	0.001
Breathlessness	168(93.33)	172(95.55)	169(93.88)	172(95.55)	172(95.55)	172(95.55)	172(95.55)	84(46.66)	0.01
Tachycardia	176(98.88)	172(95.55)	169(93.88)	176(98.88)	176(98.88)	176(98.88)	178(98.88)	84(46.66)	0.05
Hypotension	56(31.11)	68(37.77)	64(35.55)	68(37.77)	68(37.77)	67(37.22)	68(37.77)	78(43.33)	0.04
Tachypnoea	176(97.77)	169(93.88)	178(98.88)	178(98.88)	178(98.88)	178(98.88)	179(99.44)	84(46.66)	0.01
SpO2<95%	130(72.22))	126(70)	132(73.33)	132(73.33)	128(71.11)	132(73.33)	132(73.33)	84(46.66)	0.05

The features of acute pneumonia, like fever, cough, breathlessness, tachypnoea were found in majority of patients[p value 0.05]. The total mean WBCs count, serum IL6 and NLR (Neutrophils to Lymphocytes ratio) was also highly elevated in most of the patients of acute pneumonia. There was significant correlation between the main clinical features of acute pneumonia with that of elevated WBCs count, NLR, IL6, acute inflammatory biomarkers and chest CT severity score. [Table 2 ]

Table 3

		Stages of acute pneumonia			P value
Main parameters level		Mild	moderate	severe
At Day 1	Mean hs-CRP ± SD (mg/l)	14.65±3.6	18.11±2.4	22.12±3.7	0.01
	Mean LDH ± SD (units/l)	460.25±45.64	568.35±98.54	612.41±112.28	0.05
	Mean Ferritin ± SD (µg/l)	789.61±21.6	886.65±113.56	996.48±156.6	0.05
	Mean NLR ± SD	3.90±1.2	4.20±1.18	5.45±2.01	0.04
	Mean WBCs count ± SD (cells/µl)	12452.53±1233.12	14563.12±1634.54	16346.56±1452.23	0.05
	Mean IL6 ± SD (pg/ml)	116.23±25.45	168.46±65.78	289.76±76.84	0.01
	Mean q-SOFA score	1.5	2	2	0.01
	CT severity score	<8	8 to 16	>16	0.05
At Day 5	Mean hsCRP ± SD (mg/l)	16.65±4.6	22.11±2.51	24.12±4.7	0.01
	Mean LDH ± SD (units/ml)	660.25±45.54	768.35±88.54	814.41±102.28	0.05
	Mean Ferritin ± SD(µg/l)	989.61±124.06	986.65±113.26	1096.48±146	0.05
	Mean NLR ± SD (Neutrophils/ Lymphocytes ratio)	4.1±1.03	4.14±2.18	5.68±2.48	0.01
	Mean WBCs count ± SD (cells/µl)	13542.12±957.56	16453.56±1278.34	16789.78±1286.92	0.06
	Mean IL6 ± SD (pg/ml)	165.46±38.56	257.68±58.87	356.69±98.64	0.01
	Mean q-SOFA score	2	2.5	3	0.01

There was ascending and significant correlation between acute inflammatory serum biomarkers,IL6,NLR, Total WBCs count and CT chest findings with stages of acute pneumonia.[P value -0.01] [Table 3]

Table 4

	In Hospital Outcome (Mean Duration Stay of 10 Days)		P value
Biomarkers	In 135 (75%) survived Patients	In 45 (25%) Died patients
Serum LDH (units/l) [mean ± SD]	451.31±41.34	618.34±45.51	0.06
Serum FERRITIN (µg/l) [mean ± SD]	414.12±34.62	780.64±67.81	0.05
Serum hs-CRP (mg/l)[mean ± SD]	09.12±3.44	15.34±3.69	0.01
Blood WBCs (count/µl) - mean ± SD	13452.53±1243.12	16564.45±1563.23	0.01
Blood NLR (Neutrophils / Lymphocytes ratio) -mean ± SD	3.89±1.24	5.48±2.43	0.01
Mean q-SOFA score	2	3	0.01
Serum IL6 (pg/ml) - mean ± SD	146.34±78.46	259.76±98.68	0.01
CT severity score - mean ± SD	12.51±04.23	22.12±8.56	0.05

There was statistically significant association between elevated levels of acute serum biomarkers, IL6, q-SOFA score and mortality of acute pneumonia. [P value-0.01] The 45(25%) patients with high level of serum biomarkers, IL 6, q-SOFA score and CT severity score had mortality. [Table 4]

This study was under taken to know the association between early elevated acute serum inflammatory biomarkers and the mortality of acute pneumonia in comparison with the elevated IL6, q-SOFA score and CT scan chest severity score. Indeed this study finds that, there was a strong and significant positive association between early elevated acute inflammatory serum biomarkers and the mortality of acute pneumonia in comparison with the elevated IL6, q-SOFA score and CT scan chest severity score of acute pneumonia. In this study, patients found with the mean age of more than 60.51±4.5 years were 99(55%). The predominant gender involved in this study was female patients [92(51.11%)]. Which was compared with the study by Richardson S-where the median age was 63 years and in that 37.5% were female patients. 12 This shows that the acute pneumonia was very common in the elderly age group patients with the female preponderance. In this study the predominant features were fever, breathlessness, cough, tachypnoea and tachycardia in majority patients. Which in comparison to study by Mandell A. Lionel et al, where it found that, the fever, dyspnoea ,cough with sputum, tachypnoea and tachycardia were seen in majority of patients, irrespective of the etiology of acute pneumonia.13 The acute severe espiratory failure with spo₂ of <90 was found in 68(37.77%) patients in this study. This shows that, the acute pneumonia could still be a one of the cardinal causes of acute respiratory failure. So high intensity life care, preferably respiratory ICU with close monitoring of patients was required to prevent mortality. 12, 13 The serum biomarkers, such as serum hs-CRP, ferritin, LDH, IL 6, NLR, Total WBCs count and q-SOFA score were equally elevated along with the mean CT severity score of 17.31 in most of the patients. This shows that, the studied serum bio markers have got high sensitivity in assessing the acute inflammation along with assessing the severity, staging and mortality of acute pneumonia. The serum hs-CRP and IL6 were highly elevated in all stages of acute pneumonia and also it was showing significant correlation with the severity and mortality of acute pneumonia[p value 0.01]. This was compared with the study by Kim Woo Min et al, where the acute serum biomarkers like hs-CRP, Ferritin, LDH, total WBCs count, q-SOFA score and IL6 were elevated in most of the patients and were correlating with the mortality of acute pneumonia. 14 The serum LDH, serum ferritin, hs-CRP, IL6 and q-SOFA score levels were significantly elevated along with high mean CT severity score [17.31] in all stages of pneumonia and were persistently raised even after 5^th day of admission. This once again reiterates that, the serum biomarkers, IL6, q-SOFA score and CT severity score were correlating with the severity and stages of acute pneumonia, irrespective of etiology. 15 This was in comparison with the study by Tseng Cheng Chia et al, states that the estimated acute inflammatory biomarkers, such as CRP, procalcitonin, D-dimer, lactate, albumin, high-mobility group protein B1 (HMGB1), IL6, interleukin-8 (IL-8), interleukin-10 (IL-10 ) and CT severity scores on day 1 and day 3 of ICU admission were elevated n patients of acute severe pneumonia than the patients of mild pneumonia and its complications. 16 In this study the estimated acute serum biomarkers were correlating with mortality, irrespective of stages of acute pneumonia. This again reiterates that, the early elevated acute serum bio markers have got high predictive value in assessing the mortality of acute pneumonia. This was correlated with the study by Tseng Cheng Chia et al and Paula Ramírez et. al., states that the acute serum bio markers were serially elevated in patients of death due to acute pneumonia than the survived ones. Which once again reiterates that, the serum acute inflammatory biomarkers have got positive association with the severity and mortality of acute pneumonia. 16, 17 The study by Nouvenne A states that, the serum acute inflammatory bio markers can be used in patients having multiple morbidity conditions, where they were having linear correlation with the severity of acute pneumonia and they could be used in segregating acute pneumonia patients. 18, 19 As per studies by Agnello L.et.al. and Zhydkov A.et.al. the acute biomarkers like serum procalcitonin and CRP were correlating with severity and mortality of acute pneumonia. [20,21] 20, 21 The acute inflammatory serum biomarkers could be used in deciding the need of admission to ICU, deciding about the change in treatment protocol and the timing of discharge of pneumonia patients. 22, 23, 24 The study by Tsai Min Chih revealed that ,the salivary CRP could be used in predicting the severity of acute pneumonia in paediatric patients and it was correlating with the serum hs-CRP level. 25 As per the study of Liu Jinrong.et al., the serum biomarkers could be used to decide and chose appropriate antibiotics to treat the acute pneumonia. 26 According to the study by Fernandez JF., irrespective of etiology and stage, the serum markers were highly cost effective tool in managing the acute pneumonia.27 So the high degree of acute inflammatory response along with elevated levels of serum acute biomarkers like hs-CRP, LDH, Ferritin, NLR and WBCs count plays a significant role in detecting the degree of damage caused to all organ tissues with multi organ dysfunction and deciding the type of medications in comparison with IL6 and CT chest.28, 14 The serum hs-CRP level, IL 6 level, NLR and WBCs counts were more significantly elevated [p value- 0.01] as compared to the serum ferritin and LDH level in patients of death due to acute pneumonia. The mean q-SOFA score was 3 and the mean CT severity score was 22.12 in patients of death due to acute pneumonia and it was positively correlating with all the early elevated serum acute inflammatory biomarkers including high NLR, WBCs count and IL6 level.

This study proves that, there is a irrefutable positive association between early elevated serum acute inflammatory biomarkers, Total WBCs count, NLR, IL6 level, q- SOFA score and chest CT severity score with that of mortality in acute pneumonia. This serum acute inflammatory biomarkers are significantly raised, as in comparison with the Total WBCs count, NLR, IL6 level, q- SOFA score and positive CT chest findings in acute pneumonia. So the early elevated serum acute inflammatory biomarkers are cost effective, feasible for all strata of patients and are noninferior to, NLR, Total WBCs count, IL6, q-SOFA score and CT scan of chest in predicting mortality of acute pneumonia.