Systemic Immune Inflammation Index,Systemic Inflammation Response Index,Aggregate Index of Systemic Inflammation,and Follistatin-Like Protein-1 Levels in Children Diagnosed with Pneumonia

Abstract

Background:

This study aims to evaluate systemic immune inflammation index, systemic inflammatory response index (SIRI), aggregate index of systemic inflammation (AISI), and follistatin-like protein-1 (FSTL-1) levels in children with pneumonia and healthy controls.

Methods:

The study was carried out at the Seydisehir State Hospital between February 1, 2024 and June 1, 2024. The patient group included 44 children diagnosed with pneumonia and the control group included 45 healthy children without any disease. Index values obtained from hemogram data. Enzyme-linked immunosorbent assay was used to measure FSTL-1 levels.

Results:

A total of 89 participants, 44 in the patient group and 45 in the healthy control group, were included in the study. White blood cells, monocyte, eosinophil, neutrophil, c-reactive protein, SIRI, and AISI levels were significantly higher in the patient group than in the control group. FSTL-1 levels were higher in the patient group, but did not differ statistically significant. The patient and control groups were compared in the receiver operating characteristics analysis, we found the highest area under curve (AUC) in the SIRI (AUC: 0.754) and AISI (AUC: 0.713) parameters.

Conclusion:

In conclusion, compared to healthy controls, SIRI and AISI levels were significantly higher in the patient group, and the highest AUC values belonged to these indices. Therefore, we believe that SIRI and AISI indices, which are inexpensive and simple tests, are useful for early diagnosis and treatment of pneumonia.

Introduction

Pneumonia is a lung infection, usually caused by a virus or bacteria.^1–3 WHO guidelines define pneumonia as an acute episode of illness with cough or breathlessness associated with rapid breathing, with age-specific cutoffs for increased respiratory rate. Pneumonia and bronchiolitis are both diseases of the respiratory tract, but they occur in different anatomical areas and have different characteristics. Pneumonia affects the lung tissue (alveoli), while bronchiolitis affects the small airways (bronchioles). Pneumonia can affect people of all ages, but bronchiolitis is more common in babies and young children.⁴ Pneumonia is the number one cause of hospital admissions in children in developed countries and the number one cause of death in children in developing countries.⁵ Diagnosis is based on clinical findings, radiological imaging, and laboratory results. Clinical diagnosis is difficult because symptoms are nonspecific and vary with age. Rapid diagnosis and appropriate treatment are essential.^1,6,7 In pneumonia, the inflammatory response helps to control the infection and heal the lungs. However, in some cases, excessive inflammation can lead to lung damage and complications. Inflammatory markers are important in guiding treatment and differentiating bacterial from viral pneumonia.^1,8,9

Systemic immune inflammation index (SII), systemic inflammatory response index (SIRI), and aggregate index of systemic inflammation (AISI) are new markers related to inflammation.^10–12 These indices are obtained by calculation from the data of the hemogram. The SII was calculated as (number of neutrophils) × (number of platelets)/(number of lymphocytes), SIRI as (number of neutrophils) × (number of monocyte)/(number of lymphocyte) and AISI as (number of neutrophil) × (number of monocyte) × (number of platelet)/(number of lymphocyte). It has been observed that elevated SII, SIRI, and AISI values, which can be obtained from the ratio of simple hemogram parameters, are associated with inflammation and worse prognosis.^12–16 There are many studies in the literature investigating increased neutrophil–lymphocyte ratio (NLR) and platelet–lymphocyte ratio (PLR).^17,18 In a study conducted in 2022, it was emphasized that NLR was significantly higher in 60 children with community-acquired pneumonia compared to healthy controls.¹⁹ In another study conducted in the same year,²⁰ it was emphasized that PLR has clinical importance in the diagnosis of bacterial infectious pneumonia in children. The research on SII, SIRI, and AISI is limited and is attracting a lot of attention.

Follistatin-like protein-1 (FSTL-1) is a glycoprotein that is involved in a variety of physiological processes such as cardiovascular system, respiratory system, skeletal–muscular development, and homeostasis. FSTL-1 has been implicated in conditions such as cardiovascular disease, inflammation, cancer, and tissue damage.^21,22 In addition, FSTL-1 is thought to play a role in inflammatory processes and the immune system.²³ One study found that patients with bacterial sepsis had a threefold increase in FSTL-1 levels.²⁴ In another study, FSTL-1 was shown to act as a pro-inflammatory protein that plays an important role in the inflammatory response to disease.²⁵ Pro-inflammatory factors are upregulated in macrophages when FSTL-1 levels are elevated,²⁶ supporting the role of FSTL-1 in inflammation. Highly expressed in the lungs, it is essential for lung development and maintenance.^27,28 Some studies show that lung inflammation such as pneumonia and FSTL-1 may play an important role.^29–31

There are several studies evaluating NLR, PLR, SII, and SIRI parameters in patients diagnosed with pneumonia. However, there is no study in the literature assessing these parameters simultaneously in children diagnosed with pneumonia, evaluating AISI in pneumonia and comparing it with FSTL-1. Therefore, we aimed to evaluate SII, SIRI, AISI, and FSTL-1 levels in children diagnosed with pneumonia and healthy controls.

Materials and Methods

Study population

The study was carried out at the Seydisehir State Hospital between February 1, 2024, and June 1, 2024. Sample collection procedures were carried out after informed consent, ethics committee approval, and institutional approval of the hospital were obtained. Age, gender, presence of comorbidities, medications, and other laboratory information for the patient and control groups were obtained from the hospital’s automated system and by interviewing the patients.

The study included patients diagnosed with pneumonia at the Children’s Health and Diseases Clinic and healthy volunteers without any health problems who attended the same clinic for routine checkups. The diagnosis of pneumonia was made by evaluating clinical findings, radiological findings, and laboratory tests together.³² The patient group included 44 children diagnosed with pneumonia and the control group included 45 healthy children without any illness. The mean age of all participants was 7.00 (5.00–14.00) years. Age and gender were similar (P > 0.05) between patients and controls.

Children between 5 and 18 years of age with only pneumonia diagnosis were included in the patient group. Those with comorbidities other than pneumonia (diabetes, obesity, asthma, bronchitis, and the presence of chronic comorbidities) were excluded from this study. The control group included healthy children who were free of illness at routine examinations, had no infections in laboratory tests, and were age- and gender-matched to the patient population studied. Children with any inflammatory disease, asthma, bronchitis, pneumonia, and chronic diseases (diabetes, obesity, history of cardiovascular disease, drug use, etc.) were excluded from the study.

Biochemical analyses

The study was conducted on samples collected during routine procedures in patients and healthy controls, and no additional interventional procedures were performed. Plasma samples were collected in eppendorf tubes and stored at −80°C until FSTL-1 was measured. FSTL-1 concentrations were measured using the ELISA kit (Cat. No. E2702Hu BT-lab). Kit sensitivity was 3.32 ng/mL and the test range was 7–1.500 ng/mL.

Statistical analysis of data

Statistical Packages for the Social Sciences (SPSS) 18.0 (SPSS Inc., Chicago, IL, USA) was used to statistically analyze the study findings. Descriptive statistical methods (frequency, percentage, mean, standard deviation, median, and first−third quartile) were used to evaluate the data. Visual (histogram and probability plot) and analytical methods (Kolmogorov−Smirnov and Shapiro−Wilk tests) were used to analyze the conformity of the variables to the normal distribution. Non-normally distributed numerical data were compared with categorical data using Man−Whitney U test. Non-normally distributed numerical variables were correlated using Spearman’s correlation coefficient. In the evaluation of Spearman correlation coefficients, below 0.19 was considered as no correlation, between 0.20 and 0.39 as low correlation, between 0.40 and 0.69 as medium correlation, between 0.70 and 0.89 as high correlation, and above 0.90 as very high correlation. Comparisons of categorical data were made using the chi-square test. The diagnostic decision-making properties of FSTL-1, NLR, PLR, SII, SIRI, and AISI levels in predicting the disease were analyzed by receiver operating characteristics (ROC) curve and area under curve (AUC). P < 0.05 is statistically significant. Index values obtained from hemogram data.

Ethical approval

Ethical approval was obtained from KTO Karatay University, Non-Pharmaceutical and Medical Device Researches (No. 2024/001-E.77821, January 26, 2024).

Results

A total of 89 participants were included in the study. The patient and control groups did not differ in age or gender (P > 0.05). Table 1 shows sociodemographic characteristics data of the patient and control groups.

Table 1.

Sociodemographic Characteristics

Variables	Patient group (n: 44)	Healthy controls (n: 45)	P
Age	5.90 ± 3.00	7.50 ± 4.00	0.08
Gender
(F) (%)	24 (55)	21 (47)	0.45
(M) (%)	20 (45)	24 (53)	0.38

Age presented as mean ± SD, statistics for two groups: Mann−Whitney U test, statistics for gender: chi-square test.

P < 0.05.

SD, standard deviation.

Comparison of laboratory data between the patient group and the control group shows that white blood cell (WBC), monocyte, eosinophil, neutrophil, c-reactive protein, SIRI, and AISI levels were significantly higher in the patient group than in the control group. The levels of FSTL-1 were higher in the group of patients, but did not differ statistically significant. Some laboratory data of the patient and control groups are shown in Table 2.

Table 2.

Results of the Laboratory Tests in the Group of Patients and Control Group

Laboratory findings	Patient group (n: 44)	Healthy controls (n: 45)	P
WBC (10³/mm³)	10.12 (6.57–12.43)	7.52 (6.07–9.02)	0.03*
PLT (10³/mm³)	299.00 (219.00–370.00)	316.00 (279.50–374.00)	0.10
MPV (fL)	9.15 (8.90–9.75)	9.20 (8.80–10.85)	0.83
Lymphocyte (10³/mm³)	3.17 (2.33–5.77)	3.19 (2.51–4.42)	0.87
Monocyte (10³/mm³)	0.92 (0.67–1.35)	0.54 (0.44–0.69)	<0.01**
Eosinophil (10³/mm³)	0.80 (0.10–0.16)	0.12 (0.07–0.23)	0.00*
Basophil (10³/mm³)	0.30 (0.02–0.06)	0.03 (0.03–0.04)	0.87
Neutrophil (10³/mm³)	4.86 (2.26–6.70)	2.61 (2.11–3.67)	0.01*
NLR	1.27 (0.57–2.40)	0.79 (0.54–1.40)	0.05
PLR	85.68 (55.53–117.82)	92.35 (70.68–126.06)	0.37
SII	402.05 (163.04–739.56)	237.95 (171.15–396.15)	0.12
SIRI	1.22 (0.46–2.36)	0.37 (0.27–0.83)	<0.01**
AISI	326.64 (135.19–720.92)	110.47 (82.12–221.75)	<0.01**
CRP (mg/L)	22 (14.2–29.5)	3.00 (2.1–3.9)	<0.01**
FSTL-1 (ng/mL)	310.60 (204.06–445.61)	252.96 (217.86–399.98)	0.77

Data presented as median ± IQR, statistics for two groups: Mann−Whitney U test.

AISI, aggregate index of systemic inflammation; CRP, c-reactive protein; FSLT-1, follistatin-like protein-1; NLR, neutrophil–lymphocyte ratio; PLR, platelet–lymphocyte ratio; ROC, receiver operating characteristics; SII, systemic immune inflammation index; SIRI, systemic inflammatory response index; WBC, white blood cell.

*P < 0.05; **P < 0.01.

When the correlations of all participants were examined, there was a moderate positive correlation (P < 0.01) between WBC-AISI (r: 0.581), age-PLR (r: 0.578), WBC-SIRI (r: 0.515), age-SII (r: 0.415), and a weak negative correlation between age-FSTL-1 (r: −0.340, P < 0.01). Important correlation parameters obtained by evaluating the patient and control groups separately are shown in Table 3.

Table 3.

Spearman’s Correlation Coefficients of Patient and Control Groups

	Correlations	Correlation coefficient (r)	Level	P
Patient (n: 44)	Age-SII	0.568	Moderate
	Urea-NLR	0.560	Moderate	<0.01
	SIRI-Urea	0.542	Moderate
	SII-Urea	0.509	Moderate
	AISI-Urea	0.457	Moderate
	FSTL-1-Urea	−0.383	Low
	FSTL-1-Albumin	−0.300	Low	<0.05
Control (n: 45)	Age-PLR	0.629	Moderate	<0.01
	Age-SII	0.534	Moderate
	Age-FSTL-1	−0.334	Low

Statistics: Spearman’s correlation test.

P < 0.05 statistical significance.

AISI, aggregate index of systemic inflammation; FSTL-1, follistatin-like protein-1; NLR, neutrophil–lymphocyte ratio; PLR, platelet–lymphocyte ratio; SII, systemic immune inflammation index; SIRI, systemic inflammatory response index.

The predictive power of NLR, PLR, SII, SIRI, AISI, and FSTL-1 was assessed using ROC curves and AUC analyses. ROC analysis between the patient and control group, we found the highest AUC in the SIRI and AISI parameters. Significant AUC values are shown in Table 4. Figure 1 shows the graph of the ROC analysis.

FIG. 1.

The ROC analysis for the SIRI, AISI, WBC, NLR, CRP, FSLT-1, PLR, and SII. AISI, aggregate index of systemic inflammation; CRP, c-reactive protein; FSLT-1, follistatin-like protein-1; NLR, neutrophil–lymphocyte ratio; PLR, platelet–lymphocyte ratio; ROC, receiver operating characteristics; SII, systemic immune inflammation index; SIRI, systemic inflammatory response index; WBC, white blood cell.

Table 4.

ROC Analysis Results of Some Parameters for the Differential Diagnosis of Pneumonia

Variables	AUC	Asymptotic Sig	95% Confidence interval
Variables	AUC	Asymptotic Sig	Lover bound	Upper bound
SIRI	0.754	0.000	0.650	0.857
AISI	0.713	0.001	0.601	0.825
WBC	0.684	0.003	0.567	0.801
NLR	0.621	0.049	0.501	0.740
CRP	0.618	0.064	0.537	0.775
FSTL-1	0.518	0.774	0.395	0.640
PLR	0.445	0.371	0.323	0.566

P < 0.05 statistical significance.

AISI, aggregate index of systemic inflammation; AUC, area under curve; CRP, c-reactive protein; FSLT-1, follistatin-like protein-1; NLR, neutrophil–lymphocyte ratio; PLR, platelet–lymphocyte ratio; ROC, receiver operating characteristics; SIRI, systemic inflammatory response index; WBC, white blood cell.

Discussion

In this study, a group of children diagnosed with pneumonia and a healthy control group were compared in terms of inflammatory indices obtained from hemogram data and FSTL-1 levels. SIRI and AISI indices were significantly higher in patients than in healthy controls. The patient group had higher levels of FSTL-1 levels were higher in the patient group, but this difference was not statistically significant.

The NLR and the PLR are measures of the degree of inflammation and immune status.³³ In a study of 60 children with community-acquired pneumonia and 30 healthy controls (aged: 1–6 years), WBC, neutrophils, lymphocytes, and NLR were significantly higher in the patient group than in the healthy controls.¹⁹ Results from a study of 58 children (aged 2 months to 18 years) showed that NLR and procalcitonin are important in determining severe community-acquired pneumonia in children.¹⁸ In another study, 50 cases of mycoplasma pneumonia, 50 cases of bacterial pneumonia, and 50 healthy children were included and it was reported that the NLR was significantly higher than in children with bacterial pneumonia than in children with mycoplasma pneumonia (P < 0.05) and healthy children (P < 0.05). In the same study, it was reported that the highest AUC value (0.803) belonged to the PLR value in the differential diagnosis of mycoplasma pneumonia and bacterial pneumonia.²⁰ In our study, we were not able to differentiate between types of pneumonia. Neutrophil and WBC levels were significantly higher in the patient group than in the healthy control group, but there was no significant difference in NLR and PLR levels between the groups. We also found an AUC value of 0.621 for NLR and 0.445 for PLR.

Rapid diagnosis and early recognition of infection and initiation of treatment are extremely important in pediatric disease. SII, SIRI, and AISI have been frequently used as prognostic indicators of inflammation in recent years. The number of studies on SII and SIRI in children with pneumonia is increasing in the literature. AISI is a new inflammatory index that attracts attention and there are very few studies in the literature investigating this index in patients with pneumonia. In a study investigating the role of SII in the development of pneumonia in 395 patients diagnosed with acute stroke, it was highlighted that SII was an independent risk factor in predicting the development of pneumonia.³⁴ In a study conducted on a total of 6,802 patients (mean age: 62.3 years) diagnosed with viral and bacterial pneumonia in the emergency department, it was emphasized that SII was valuable in determining the clinical severity in patients with pneumonia. In the same study, it was reported that NLR, PLR, and SII values were significantly higher in the mortality group than in the survival groups and the AUC value for SII in predicting mortality was 0.626.³⁵ In the study conducted with 78 patients with severe mycoplasma pneumonia and 226 patients with nonsevere mycoplasma pneumonia, NLR, PLR, SII, and SIRI values were found to be significantly higher in children with severe mycoplasma pneumonia (P < 0.001). In the same study, the AUC values were found to be 0.940 for SII, 0.883 for SIRI, 0.885 for NLR, and 0.818 for PLR, and it was emphasized that the SII value was important in predicting the severity of the disease.³⁶ In our study, SIRI and AISI levels were significantly higher in the patient group than in the healthy control group, and the highest AUC value was obtained in SIRI and AISI. Studies investigating the association between AISI and pneumonia have generally focused on pneumonia in COVID-19 disease. A study of 267 patients with COVID-19 pneumonia, it was reported that the need for mechanical ventilation and increased mortality were high levels of NLR, SII, SIRI, and AISI levels on admission.³⁷ Another study of 169 chronic obstructive pulmonary disease patients hospitalized for COVID-19 disease reported that the AISI value was a reliable predictor of mortality.³⁸ There are no studies in literature evaluating AISI levels in pediatric patients diagnosed with pneumonia. Therefore, we could not compare our AISI results.

FSTL-1 is involved in processes such as cell growth and differentiation, tissue repair, inflammation, and immune response. It is critical for lung homeostasis and is highly expressed in the lung. However, the role of FSTL-1 in immunity to bacterial pneumonia is unknown. A 2019 study using in vitro and in vitro modeling showed that FSTL-1 plays an important role in the inflammatory response during Streptococcus pneumoniae infection and is a potential therapeutic target to reduce morbidity and mortality in patients with pneumonia.³⁰ Another study conducted in 2014 reported that overexpression of FSTL-1 promotes the production of inflammatory factors, whereas reduction of FSTL-1 suppresses this production.²⁴ In 2017, a study of 32 asthmatics and 25 healthy controls found that FSTL-1 levels were significantly higher in asthmatics. However, the details of the study suggest that FSTL-1 is elevated in asthmatics to contribute to airway remodeling.³⁹ In our study, FSTL-1 levels were higher in the patient group than in the healthy control group, but there was no statistical difference between the groups. In addition, the AUC value for FSTL-1 was 0.518. Among the results of our study, the negative correlation of FSTL-1 with urea and albumin suggests that this parameter may be influenced by renal function or diet. There are no studies investigating FSTL-1 levels in patients diagnosed with pneumonia. More detailed studies are needed to understand whether the increase in FSTL-1 levels correlates with the severity of the disease or whether it increases to contribute to the healing process.

Limitations of the Study

There are important limitations to this study. First, this study was conducted in a small hospital with few patients. Therefore, we did not have the opportunity to differentiate the types of pneumonia in the patient group, and we did not have tests to facilitate the diagnosis. Second, even though we asked the relatives about the presence of comorbidities, we are not sure about the accuracy of this information in pediatric patients. In addition, as the patients’ blood samples were only taken at the time of diagnosis, we could not follow-up these data with repeated measurements, and we have no information on the patients’ prognosis. Finally, we took the remaining plasma of seven patients under 5 years of age after the laboratory procedures were completed, but these plasma levels were insufficient (although bronchopneumonia is the main cause of death for children under 5 years of age), so we had to change the age limit of our study group to 5–18 years.

Conclusion

We designed this study assuming that inflammatory indices and FSTL-1 levels would be high in children diagnosed with pneumonia. However, although FSTL-1 levels were higher in the patient group than in the control group, the difference between the groups was not significant, suggesting that FSTL-1 measurement was not useful for the diagnosis and follow-up of pneumonia in this study. More extensive studies are needed to confirm what we have found to evaluate FSTL-1 for prognosis and to say that FSTL-1 is useless. In conclusion, the levels of SIRI and AISI as inflammatory indices were significantly higher in the patient group compared to healthy controls, and the highest AUC values belonged to these indices. Therefore, we believe that SIRI and AISI indices, which are inexpensive and simple tests, are useful for early diagnosis and treatment of pneumonia.

Footnotes

Authors’ Contributions

K.Y. and S.I.D. designed and wrote the article. S.I.D. obtained clinical data. K.Y. carried out statistical analysis. K.Y. and S.I.D. submitted the article to the journal. All the authors have read and agreed to submit the article as it stands.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

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