Composition Vendor Newgen KnowledgeWorks (P) Ltd. PLoS One plos plosone PLOS One 1932-6203 Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0333267 PONE-D-25-26564 Research Article Biology and life sciencesBiochemistryProteinsC-reactive proteins Biology and life sciencesImmunologyImmune responseInflammation Medicine and health sciencesImmunologyImmune responseInflammation Medicine and health sciencesClinical medicineSigns and symptomsInflammation Medicine and health sciencesEpidemiologyMedical risk factors Medicine and health sciencesMedical conditionsInflammatory diseases Biology and life sciencesCell biologyCellular typesAnimal cellsBlood cellsWhite blood cellsNeutrophils Biology and life sciencesCell biologyCellular typesAnimal cellsImmune cellsWhite blood cellsNeutrophils Biology and life sciencesImmunologyImmune cellsWhite blood cellsNeutrophils Medicine and health sciencesImmunologyImmune cellsWhite blood cellsNeutrophils Medicine and health sciencesPulmonologyPneumonia Medicine and health sciencesMedical conditionsInfectious diseasesRespiratory infections Medicine and health sciencesMedical conditionsRespiratory disordersRespiratory infections Medicine and health sciencesPulmonologyRespiratory disordersRespiratory infections Biology and life sciencesMicrobiologyMedical microbiologyMicrobial pathogensBacterial pathogensMycoplasma pneumoniae Medicine and health sciencesPathology and laboratory medicinePathogensMicrobial pathogensBacterial pathogensMycoplasma pneumoniae Biology and life sciencesOrganismsBacteriaMollicutesMycoplasmaMycoplasma pneumoniae Application value of systemic immune-inflammation index in predicting severe Mycoplasma pneumoniae pneumonia Predictive value of novel inflammatory biomarkers in severe mycoplasma pneumonia https://orcid.org/0009-0000-3236-7104 Guo Xiaocong Data curation Formal analysis Funding acquisition Investigation Methodology Resources Writing – original draft 1 2 Conceptualization 3 Luo Honglin Formal analysis Methodology Software Data curation 3 Song Yaohui Methodology Validation Investigation 3 Xiao Li Resources Data curation 3 https://orcid.org/0000-0003-2645-8637 Xu Xiaoya Project administration Visualization Conceptualization 4 * Guo Yongcan Writing – review & editing 1 Supervision 2 * Department of Clinical Laboratory, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China Department of Clinical Laboratory, Zigong First People’s Hospital, Zigong, China, Department of Neurology, Zigong First People’s Hospital, Zigong, China  Al-Nimer Marwan Salih Editor University of Diyala College of Medicine, IRAQ

The authors declare that there are no conflict of interests.

 * E-mail: xxy820122@163.com (XX); guoyongcan@swmu.edu (YG) 9102025 2025 20 10 e0333267 2762025 1192025 2025 Guo et al This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Mycoplasma pneumoniae (MP) is the primary causative agent of community-acquired pneumonia. Severe mycoplasma pneumoniae pneumonia (SMPP) can result in multiorgan damage and even respiratory failure or death. This study aimed to evaluate the predictive value of the Systemic Immune-Inflammation Index (SII) for SMPP. This retrospective study included 254 hospitalized children with MP infections (SMPP group, n = 103; non-SMPP group, n = 151). Patient data, including complete blood count parameters (white blood cell, absolute neutrophil, absolute lymphocyte, absolute monocyte, and platelet counts), C-reactive protein (CRP), serum amyloid A (SAA), and other markers, were collected. Furthermore, the SII, Systemic Inflammation Response Index (SIRI), neutrophil/lymphocyte ratio (NLR), monocyte/lymphocyte ratio (MLR), and platelet/lymphocyte ratio (PLR) were calculated. T-tests and the Mann–Whitney U test were used to analyze differences between the groups. Logistic regression was applied to analyze the risk factors. Receiver operating characteristic (ROC) curves were plotted to evaluate the predictive performance of the SII and CRP for SMPP. The SMPP group exhibited significantly higher CRP and SAA levels, SII, NLR, MLR, PLR, and SIRI than the non-SMPP group (all P < 0.001). Logistic regression revealed that the SII (odds ratio [OR] = 1.006, 95% confidence interval [CI]: 1.001–1.010) and CRP (OR = 1.080, 95% CI: 1.041–1.120) were independent risk factors. ROC curve of the SII (area under the ROC curve = 0.883, sensitivity = 0.699, and specificity = 0.881) outperformed that of CRP. Thus, SII can serve as an effective biomarker for SMPP prediction. It can be a rapid and cost-effective method when combined with routine blood tests, thereby demonstrating considerable potential for clinical application.

 ZiGong Science and Technology Bureau 2023YKYXT06 https://orcid.org/0009-0000-3236-7104 GuoXiaocong This work was supported in part by ZiGong Science and Technology Bureau, No.2023YKYXT06. Data Availability The original contributions presented in the study are included in the article. All underlying data are freely available through supplementary files attached to this submission, ensuring full public access. Introduction

Acute respiratory infection (ARI) is one of the most common human diseases. A 2002 study conducted by Williams et al. [1] reported that 1.6–2.2 million children succumb to ARI each year globally (95% confidence interval [CI]), of whom approximately 40% are in Africa and 30% in Asia. A 2014 epidemiological survey of pediatric ARIs in Guangzhou conducted by Liu Wenkuan et al. [2] indicated that Mycoplasma pneumoniae (MP) infection accounted for over 10% of all cases [3,4]. Since mid-2023, China has reported an atypical surge in pediatric MP infections, with severity rates escalating notably by September 2023 [5–7]. By 2024, the outbreak intensity necessitated public health interventions such as school closures in high-burden areas [7]. MP transmission occurs mainly through respiratory droplets in crowded settings with poor ventilation [7]. Notably, children aged <3 years were highly susceptible during the COVID-19 pandemic [8]. Compared with common MP infection, SMPP often progresses beyond pulmonary involvement, triggering extrapulmonary complications such as obstructive airway lesions, thromboembolic events, and multisystem inflammatory syndromes that substantially increase mortality risk. Furthermore, dysregulated host immunity drives SMPP pathogenesis, characterized by cytokine hyperproduction and collateral tissue injury; this can result in diseases that affect multiple body systems, such as the nervous, cardiovascular, and blood systems [9]. Once extrapulmonary complications occur, the disease can rapidly progress and develop into cytokine storm and respiratory distress syndrome, etc., potentially leading to respiratory failure and even death. Therefore, early identification of the severe progression trend of MP pneumonia (MPP) facilitates flexible adjustment of clinical treatment measures, and judgment of the disease process of MPP in children and control treatment nodes is of great importance [10].

A multicenter study conducted by Zhuo et al. [11] reported that the creatine kinase isoenzyme, lactate dehydrogenase (LDH), fibrinogen, and D-dimer levels, degree of fever as well as neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) were higher in the SMPP than in the non-SMPP group. In a comparative study between children with common MPP and those with SMPP, Yang et al. [12] found that the leukocyte and neutrophil counts as well as the levels of C-reactive protein (CRP), procalcitonin, interferon-γ, interleukin (IL)-2, IL-5, IL-6, IL-8, and IL-10 were significantly higher in the SMPP group. However, these indicators are not easy to obtain in children, and some take too long to detect. Shao et al. [13] analyzed the clinical value of novel inflammatory biomarkers in predicting MP infection and reported that the Systemic Immune-Inflammation Index (SII) and Systemic Inflammation Response Index (SIRI), which are based on routine blood results, can be used as supplementary diagnostic methods for MP infection. However, they did not study the predictive value of these biomarkers in clinical typing following infection.

SII is a comprehensive indicator based on three inflammatory cell types in the blood, namely, lymphocytes, neutrophils, and platelets. It is used to evaluate the immune and inflammatory status of the body using the formula SII = (neutrophil count × platelet count)/lymphocyte count [14]. The SII was originally proposed by Hu et al. in 2014 to predict the prognosis of patients with hepatocellular carcinoma; since then, it has been widely used in the prognostic assessment of various tumors (e.g., small cell lung, ovarian, esophageal, and colorectal cancers) and other diseases [15–17]. The SII is considered to be more comprehensive than CRP in predicting the risk for coronary heart disease as it reflects both inflammation and thrombosis (platelet involvement) [18].

The SIRI is calculated as follows: SIRI = (neutrophil count × monocyte count)/lymphocyte count [14]. SIRI can comprehensively reflect the inflammatory state and immune balance of the body by integrating the absolute counts of neutrophils, monocytes, and lymphocytes. It was originally used to predict the prognosis of patients with malignant tumors (e.g., pancreatic cancer and nasopharyngeal carcinoma); however, its application has been extended to inflammatory diseases (e.g., severe pancreatitis and acute kidney injury) and cardiovascular diseases [19–21]. For example, in patients with gastric cancer, dynamic SIRI monitoring can predict the risk for recurrence, and patients demonstrating an increase in SIRI of more than 50% have significantly reduced survival [22]. In coronary heart disease, SIRI is associated with atherosclerotic plaque stability, and its elevation indicates active inflammation [19].

According to the evidence-based guideline for the diagnosis and treatment of Mycoplasma pneumoniae pneumonia in children (2023) [23], it can be diagnosed as SMPP if it meets any of the following manifestations, (1) Persistently high fever (> 39°C) ≥ 5d or fever ≥ 7d, with no downward trend in the peak temperature noted. (2) Wheezing, shortness of breath, dyspnea, chest pain, hemoptysis and so on. These manifestations are related to disease severity of the disease, combined with plastic bronchitis, asthma attack, pleural effusion, and pulmonary embolism (3) Extrapulmonary complications that do not meet the criteria for critical illness. (4) Oxygen saturation of finger pulse of≤ 0.93 when inhaling air at rest. (5) A single affected lung lobe involving 2/3 of the lobe. Moreover, uniform high-density consolidation is evident,or two or more lung lobes appear with high-density consolidation (regardless of the size of the affected area), which may be accompanied by a large amount of pleural effusion, and localized bronchiolitis performance. Diffuse or bilateral involvement of one lung with ≥ 4/ 5 lobar bronchiolitis coexisting with bronchitis, and mucus plug formation leading to atelectasis. (6) Progressively aggravated clinical symptoms were progressively aggravated, and the imaging revealing that the lesion range has progressed > 50% in 24–48 h. (7) One of CRP, LDH, or D-dimeris significantly increased. To further explore the practical prediction methods for severe cases, this study enrolled children with positive MP nucleic acid test results during the second half of 2024, who were then categorized into the SMPP (severe Mycoplasma pneumoniae pneumonia) group and non-SMPP group based on the aforementioned diagnostic criteria.

 Materials and methods Participants

This retrospective study included 254 hospitalized children with MPP (SMPP group, n = 103; non-SMPP group, n = 151) who were admitted to the Pediatrics Department of the First People’s Hospital of Zigong City from July 1, 2024 to December 30, 2024. The classification into the SMPP and non-SMPP groups was made according to evidence-based guideline for the diagnosis and treatment of Mycoplasma pneumoniae pneumonia in children (2023) [23] Research data were accessed from the electronic medical record system on January 15, 2025.The exclusion criteria were as follows: (1) patients with comorbidities potentially confounding immune responses (e.g., genetic disorders, immunodeficiencies, or active malignancies); (2) patients with a previous history of neonatal respiratory distress syndrome, bacterial encephalitis, or other serious infectious diseases; and (3) patients with incomplete clinical data. The sample grouping and research protocol are illustrated in Fig 1.

10.1371/journal.pone.0333267.g001Flowchart of patient recruitment, classification, and analysis for children with Mycoplasma pneumoniae pneumonia (MPP).

A total of 628 children hospitalized with MPP between July 1 and December 31, 2024, were initially assessed for eligibility. After the application of exclusion criteria (n = 374), 254 patients were finally enrolled in this retrospective study. According to the 2023 evidence-based guideline for pediatric MPP, enrolled patients were classified into either the severe MPP (SMPP; n = 103) group or the non-severe MPP (non-SMPP; n = 151) group. The subsequent research protocol comprised data collection (clinical and laboratory parameters), computation of inflammatory indices—including the systemic immune-inflammation index (SII) and systemic inflammation response index (SIRI)—and comparative statistical analysis between groups.

Ethical oversight was provided by the Institutional Review Board (IRB) of Zigong First People’s Hospital (Approval No, 2024−039). The IRB classified this study as exempt owing to its minimal risk nature and its exclusive dependence on the analysis of pre-existing, de-identified medical records. No new patient interviews were conducted as part of this specific data extraction and analysis study.

 Data collection General data

Patient data, including gender, age, length of hospital stay, maximum temperature, days of fever, chest X-ray plain film or chest computed tomography plain scan, and medical history, were collected. Furthermore, white blood cell (WBC) count, neutrophil count, lymphocyte count, monocyte count, platelet count, CRP, LDH, serum amyloid A (SAA), and other laboratory indicators were measured. The NLR, PLR, MLR, SII, and SIRI were also calculated.

 Statistical methods

Statistical analysis was conducted using the IBM SPSS version 26.0 (IBM Corp,Armonk,NY,USA) and GraphPad Prism 10.3(GraphPad software USA) software. The Shapiro-Wilk test was used to test the normality of the continuous variables. Continuous variables with normal distribution were expressed as mean ± standard deviation and analyzed using the independent samples t-test. In contrast, continuous variables with non-normal distribution were expressed as median and interquartile range and analyzed using the Mann–Whitney U test. Categorical variables were expressed as frequencies (%) and analyzed using chi-squared tests. We first utilized univariate logistic regression analysis to analyze the factors affecting the severity of MPP in children. Then, for the statistically significant factors from the univariate regression results, multivariate logistic regression analysis was carried out to determine the independent risk factors for MPP severity in children. Receiver operating characteristic (ROC) curves were used to analyze the predictive power of the variables for SMPP. P < 0.05 was considered to indicate statistical significance.

 Results Comparison of general data and laboratory test results between the SMPP and non-SMPP groups

This study included 254 children with MPP (SMPP group, n = 103; non-SMPP group, n = 151). No significant difference was observed in sex, age, length of hospital stay, and Mono between the groups. The WBC count, neutrophil count, lymphocyte count, monocyte count, platelet count, CRP, SAA, SII, NLR, MLR, PLR, and SIRI were higher in the SMPP than in the non-SMPP group, with the difference being statistically significant (Table 1).

10.1371/journal.pone.0333267.t001 General information and inspection results.
Considerations Nonserious (n = 151) Severe (n = 103) Z/χ² P
Male 74 (49%) 47 (46.5) 0.28 0.597
Age 5 (2,7) 4 (3,7) −0.038 0.97
Days of hospitalization 6 (4,7) 6 (5,8) −1.689 0.091
Leukocyte (×109/L) 7.70 (5.69,10.07) 9.17 (6.99, 13.21) −4.092 <0.001
Neutrophil (×109/L) 3.66 (2.69, 4.79) 5.83 (4.54,8.44) −8.484 <0.001
Monocyte (×109/L) 0.67 (0.47,0.86) 0.79 (0.53,1.12) −2.450 0.014
Lymphocyte (×109/L) 2.78 (1.83,4.36) 1.95 (1.31, 3.23) −3.729 <0.001
Platelet (×109/L) 280 (227, 335) 327 (259, 436) −3.201 0.001
CRP (mg/L) 5.30 (1.21, 11.6) 24.83 (8.79, 43.6) −8.123 <0.001
SAA (mg/L) 35.26 (9.38, 110.12) 135.41 (53.13, 217.71) −6.928 <0.001
SII 384.67(242.76, 569.28) 899.22 (586.98, 1360.86) −10.361 <0.001
NLR 1.33(0.83,2.03) 3.13 (1.94,4.03) −9.263 <0.001
MLR 0.23 (0.17,0.32) 0.36(0.26,0.50) −6.216 <0.001
PLR 94.92 (73.53, 141.03) 144.12 (112.23, 211.7) 6.654 <0.001
SIRI 0.79 (0.48,1.50) 2.05 (1.47,3.72) −9.473 <0.001

Note: P < 0.05 difference indicates statistical significance. Data presented as median (interquartile range) for continuous variables and frequency (%) for categorical variables. Abbreviations: CRP, C-reactive protein; SAA, serum amyloid A; SII, systemic immune inflammatory index; NLR, neutrophil/lymphocyte ratio; MLR, monocyte/lymphocyte ratio; PLR, platelet/lymphocyte ratio; SIRI, systemic inflammatory response index.

 Analysis of the risk factors

Univariate logistic regression analysis was conducted to identify the risk factors for SMPP (Table 2). The OR values of the SII, NLR, MLR, PLR, SIRI, CRP, and SAA were all greater than 1 (P < 0.001), indicating that the risk of increase in the aforementioned test indicators in patients with SMPP was significantly higher than that in non-SMPP patients. Multivariate logistic regression analysis revealed that after adjustment for other variables, the risks of elevated SII and CRP were significantly higher in patients with SMPP than in non-SMPP patients (odds ratio [OR] = 1.006, 95% confidence interval [CI]: 1.001–1.010, P = 0.008, and OR = 1.080, 95% CI: 1.041–1.120, P < 0.001, respectively). After adjustment for other factors, the SII and CRP remained as independent risk factors for SMPP, which can accurately predict the risk of SMPP. In contrast, the NLR, MLR, PLR, SIRI, and SAA could not effectively predict the risk of SMPP (P > 0.05), demonstrating no statistical significance.

10.1371/journal.pone.0333267.t002Logistic model of SMPP occurrence.
Considerations One-way regression analysis Multivariate regression analysis Cohen’s d
β SE OR (95% CI) P β SE OR (95% CI) P
SII 0.005 0.001 1.005(1.004,1.007) <0.001* 0.006 0.002 1.006 (1.001,1.010) 0.008* 1.12
NLR 1.244 0.167 3.471(2.503, 4.813) <0.001* 0.176 0.337 0.838 (0.433,1.623) 0.601 1.19
MLR 5.059 0.939 157.505 (25.028,991.214) <0.001* 0.309 3.792 0.734(0,1240.518) 0.734 0.83
PLR 0.014 0.002 1.014 (1.009,1.018) <0.001* 0.001 0.008 1.001(0.985,1.017) 0.908 0.82
SIRI 1.305 0.189 3.689(2.549,5.339) <0.001* 0.200 0.694 1.221(0.313, 4.762) 0.774 0.93
CRP 0.078 0.012 1.081 (1.055,1.107) <0.001* 0.077 0.019 1.080(1.041,1.120) <0.001* 1.1
SAA 0.011 0.002 1.011(1.007,1.014) <0.001* 0.002 0.003 1.002(0.996,1.009) 0.48 0.96

Note: *P < 0.05 indicates statistical significance. Abbreviations: CRP, C-reactive protein; SAA, serum amyloid A; SII, systemic immunoinflammatory index; NLR, neutrophil/lymphocyte ratio; MLR, monocyte/lymphocyte ratio; PLR, platelet/lymphocyte ratio; SIRI, systemic inflammatory response index.

 ROC curve analysis

ROC curves were plotted for the independent risk factors SII and CRP obtained from the multivariate regression analysis in Table 2 (Fig 2) to compare the area under the ROC curve (AUC), sensitivity, and specificity of the two factors (Table 3).

10.1371/journal.pone.0333267.t003Predicting the performance of SII and CRP on SMPP.
Considerations AUC Best cutoff point Sensitivity Specificity
SII 0.883(0.844,0.922) 689.85 0.699 0.881
CRP 0.800(0.745,0.855) 19.2 0.573 0.887

Note: AUC, area under the ROC curve.

 10.1371/journal.pone.0333267.g002Receiver operating characteristic (ROC) curves for the Systemic Immune-Inflammation Index (SII) and C-reactive protein (CRP) in predicting severe Mycoplasma pneumoniae pneumonia (SMPP) in children.

ROC curves were generated based on the independent risk factors identified by multivariate logistic regression analysis (see Table 2 for regression results). The performance metrics, including area under the curve (AUC) with 95% confidence intervals, sensitivity, specificity, and optimal cutoff values for both SII and CRP are presented in Table 3.

The results indicated that for the SII, the AUC was 0.883 (95% CI: 0.884–0.922); sensitivity, 0.699; specificity, 0.881; and optimal cutoff value, 689.85. Meanwhile, for CRP, the AUC was 0.800 (95% CI: 0.745–0.855); sensitivity, 0.573; specificity, 0.887; and optimal cutoff value, 19.2. Therefore, the SII is better than CRP in predicting SMPP.

 Discussion

In 2023, the Respiratory Group of the Pediatrics Society of the Chinese Medical Association issued the Evidence-based Guidelines for Diagnosis and Treatment of MPP in Children. The diagnosis of SMPP is mainly based on persistent fever, severe clinical symptoms, imaging findings, and laboratory indicators. After contracting MP infection, pneumonia symptoms usually appear 2–3 days after fever [23]. Children with MP infection typically present with persistent cough and fever (often ≥39°C);however, afebrile or low-grade fever cases occur [7,23]. A distinguishing feature is the progression from the initial paroxysmal dry cough to productive sputum [7]. This suggests that most clinical symptoms are nonspecific and that progressive worsening of clinical symptoms requires an experienced pediatrician and differentiation from other respiratory disorders. Compared with the indicators of laboratory inflammation, it can more intuitively reflect the degree of inflammation in the human body. The guidelines suggest that if any one of the three indicators, namely CRP, LDH, and D-dimer, shows a significant elevation, there is a risk of developing severe mycoplasma pneumonia (SMPP). However, these indicators are not as widely available and accessible to children as blood tests. Blood tests are rapid and inexpensive. They play a pivotal role in the diagnosis of almost all diseases. In recent years, novel inflammatory biomarkers, such as NLR, MLR, PLR, SII, and SIRI, which are calculated based on blood routine analysis results, have become research hotspots [13,24,25]. These inflammatory biomarkers, calculated using the ratio of different components, provide a more comprehensive and accurate picture of inflammatory status than the single parameter of complete blood count.

Previous studies have indicated that SMPP pathogenesis involves MP-induced direct tissue damage and dysregulated host immunity, leading to cytokine hyperproduction and neutrophil-mediated inflammation [25–27]. SII integrates platelet, neutrophil, and lymphocyte counts to reflect systemic inflammation. Neutrophils play a key role in the progression of pneumonia [28]. MPP membrane lipoproteins bind alveolar macrophage Toll-like receptors, activating NF-κB signaling [28,29]. This induces proinflammatory cytokines (e.g., IL-8, TNF-α, GM-CSF), driving neutrophil recruitment and phagocytosis [29]. Ultimately, excessive inflammation impairs immune function [29–31]. Relevant studies have demonstrated that PLT is positively correlated with the length of hospital stay, mortality, and disease prognosis in patients with MPP [32,33]. In a retrospective study of various inflammatory indicators involving 304 children with MPP, Wang et al. [25] found that the SII can be used as a predictor of disease severity in children with MPP and that its predictive effect is better than that of NLR, SIRI, and PLR. Our study systematically evaluated the application value of inflammatory markers in SMPP prediction. The results indicated that the SII had an excellent predictive power for SMPP. The SII was significantly higher in the SMPP than in the non-SMPP group (P < 0.001). Multivariate regression confirmed that the SII was an independent risk factor (OR = 1.006, 95% CI: 1.001–1.010). The AUC (0.883) was better than traditional inflammatory markers, such as CRP, and other inflammatory markers, such as SIRI, NLR, and PLR.

The predictive advantage of SII is due to its comprehensive quantification of the synergistic effects of platelets, neutrophils and lymphocytes [34–37]. This study determined for the first time that the optimal critical value of SII to predict the severity of SMPP was 689.85 (sensitivity, 0.699; specificity, 0.881), and its abnormal increase suggested excessive immune activation, which was consistent with the cytokine storm mechanism of SMPP. This critical value can effectively identify the risk of severe cases and reduce misdiagnosis.

As a traditional inflammatory marker, although CRP is an independent risk factor (OR = 1.080), its AUC is only 0.800, and its sensitivity is relatively low (0.573). This may be because CRP reflects the late inflammatory response. Compared with CRP, as a systemic immune inflammatory indicator, SII is better able to capture the early signals of immune imbalance. Although SAA was significantly higher in the SMPP group, multivariate regression revealed that its predictive value was limited, indicating that it is difficult to comprehensively evaluate the risk of severe disease using a single index. In clinical practice, the SII calculation is simple and based on blood routine examination data, which is economical and timely. If the SII is included in the early evaluation system of MP-infected children, it may assist clinicians in identifying groups at a high risk for SMPP in a timely and accurate manner, optimizing treatment strategies, and reducing the incidence of severe diseases.

This study was a single-center retrospective analysis and may demonstrate selection bias. In the future, multicenter prospective studies should be conducted to further verify the SII in early warning, efficacy monitoring, and prognosis evaluation of SMPP in combination with molecular biological detection.

 Conclusion

The results reveal that SII can serve as an effective biomarker for predicting SMPP, demonstrating superior predictive performance compared with traditional inflammatory markers. Considering the rapid and cost-effective nature of routine blood tests, SII holds significant clinical value as an early warning of SMPP.

 Supporting information Raw data for evaluating the value of SII in predicting severe mycoplasma pneumoniae pneumonia in children.

(XLSX)

The authors gratefully acknowledge the intense individual effort and support from many sources to make this study possible.

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Investigation of the associations of novel inflammatory biomarkers-systemic inflammatory index (SII) and systemic inflammatory response index (SIRI)-with the severity of coronary artery disease and acute coronary syndrome occurrence. Int J Mol Sci. 2022;23(17):9873. doi: 10.3390/ijms23179873 Liu Z, Ge H, Miao Z, Shao S, Shi H, Dong C. Dynamic Changes in the Systemic Inflammation Response Index Predict the Outcome of Resectable Gastric Cancer Patients. Front Oncol. 2021;11:577043. doi: 10.3389/fonc.2021.577043 33718137 Subspecialty Group of Respiratory, the Society of Pediatrics, Chinese Medical Association, China National Clinical Research Center of Respiratory Diseases, Editorial Board, Chinese Journal of Pediatrics. Evidence-based guideline for the diagnosis and treatment of Mycoplasma pneumoniae pneumonia in children (2023). Pediatr Investig. 2025;9(1):1–11. doi: 10.1002/ped4.12469 40241891 Xia Y, Xia C, Wu L, Li Z, Li H, Zhang J. Systemic immune inflammation index (SII), system inflammation response index (SIRI) and risk of all-cause mortality and cardiovascular mortality: a 20-year follow-up cohort study of 42,875 US adults. J Clin Med. 2023;12(3):1123. doi: 10.3390/jcm12031123 Wang S, Wan Y, Zhang W. The Clinical Value of Systemic Immune Inflammation Index (SII) in Predicting the Severity of Hospitalized Children with Mycoplasma Pneumoniae Pneumonia: A Retrospective Study. Int J Gen Med. 2024;17:935–42. doi: 10.2147/IJGM.S451466 38495920 Ke J, Qiu F, Fan W, Wei S. Associations of complete blood cell count-derived inflammatory biomarkers with asthma and mortality in adults: a population-based study. Front Immunol. 2023;14:1205687. doi: 10.3389/fimmu.2023.1205687 37575251 Jiang Z, Li S, Zhu C, Zhou R, Leung PHM. Mycoplasma pneumoniae infections: pathogenesis and vaccine development. Pathogens. 2021;10(2):123. doi: 10.3390/pathogens10020123 Lee YC, Chang CH, Lee WJ, Liu TY, Tsai CM, Tsai TA, et al. Altered chemokine profile in refractory Mycoplasma pneumoniae pneumonia infected children. J Microbiol Immunol Infect. 2021;54(4):673–9. doi: 10.1016/j.jmii.2020.12.001 Cacciotto C, Cubeddu T, Addis MF, Anfossi AG, Tedde V, Tore G, et al. Mycoplasma lipoproteins are major determinants of neutrophil extracellular trap formation. Cell Microbiol. 2016;18(12):1751–62. doi: 10.1111/cmi.12616 Xue Y, Wang M, Han H. Interaction between alveolar macrophages and epithelial cells during Mycoplasma pneumoniae infection. Front Cell Infect Microbiol. 2023;13:1052020. doi: 10.3389/fcimb.2023.1052020 37113130 Allard B, Panariti A, Martin JG. Alveolar Macrophages in the Resolution of Inflammation, Tissue Repair, and Tolerance to Infection. Front Immunol. 2018;9:1777. doi: 10.3389/fimmu.2018.01777 30108592 Mirsaeidi M, Peyrani P, Aliberti S, Filardo G, Bordon J, Blasi F, et al. Thrombocytopenia and thrombocytosis at time of hospitalization predict mortality in patients with community-acquired pneumonia. Chest. 2010;137(2):416–20. doi: 10.1378/chest.09-0998 19837825 Qiu J, Ge J, Cao L. D-dimer: The Risk Factor of Children’s Severe Mycoplasma Pneumoniae Pneumonia. Front Pediatr. 2022;10:828437. doi: 10.3389/fped.2022.828437 35498793 Deppermann C, Kubes P. Start a fire, kill the bug: The role of platelets in inflammation and infection. Innate Immun. 2018;24(6):335–48. doi: 10.1177/1753425918789255 30049243 Rayes J, Bourne JH, Brill A, Watson SP. The dual role of platelet-innate immune cell interactions in thrombo-inflammation. Res Pract Thromb Haemost. 2020;4(1):23–35. doi: 10.1002/rth2.12345 Lee M, Lee SY, Bae Y-S. Emerging roles of neutrophils in immune homeostasis. BMB Rep. 2022;55(10):473–80. doi: 10.5483/BMBRep.2022.55.10.115 36104260 Liao S, Padera TP. Lymphatic function and immune regulation in health and disease. Lymphat Res Biol. 2013;11(3):136–43. doi: 10.1089/lrb.2013.0012 24024577 10.1371/journal.pone.0333267.r001 Decision Letter 0 Al-Nimer Marwan Salih Academic Editor 2025 Marwan Salih Al-Nimer This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version 0

25 Jul 2025

Dear Dr. Xu,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

ACADEMIC EDITOR: Major revision

==============================

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Marwan Salih Al-Nimer, MD, PhD

Academic Editor

PLOS ONE

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https://www.dovepress.com/the-clinical-value-of-systemic-immune-inflammation-index-sii-in-predic-peer-reviewed-fulltext-article-IJGM

https://cellandbioscience.biomedcentral.com/counter/pdf/10.1186/s13578-024-01226-4.pdf

https://www.springermedizin.de/current-status-of-mycoplasma-pneumoniae-infection-in-china/26606308

In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed.

4. Thank you for stating the following financial disclosure:

 [This work was supported in part by ZiGong Science and Technology Bureau, No.2023YKYXT06.]. 

Please state what role the funders took in the study.  If the funders had no role, please state: ""The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.""

If this statement is not correct you must amend it as needed.

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6. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. 

Additional Editor Comments:

Dear Author(s)

This retrospective study needs some clarifications:

1: In the title, the terms novel inflammatory biomarkers and severe mycoplasma infections. The reported biomarkers are not novel. The severity of mycoplasma infections is not defined as a pathological condition in the test.

2: It is a routine laboratory investigation o determination Serum amyloid A?

3: Subgrouping the patients was on which basis?

4: The authors extracted the data from the records. why and how they did the interview? Verbal consent was unacceptable

5: Line 146: The S-W test. do you mean Shapiro-Wilks test?

6: Table 1 (footnote: mean +/- SD), there is mean +/- SD in the Table 1. The results are presented as median (IQR). Day stay in hospital is the same for severe or non-severe infection, How?

7: Table 2 needs to reanalyse to show different models. It is necessary to add beta-coefficient. A Cohen's test is needed to apply to show the impact of sample size

8. Add the plots of AUCs

9: References: Recheck the typing of the references

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: No

**********

Reviewer #1: 1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: This study evaluates the predictive value of the Systemic Immune-Inflammation Index (SII) and Systemic Inflammation Response Index (SIRI) in identifying severe Mycoplasma pneumoniae pneumonia (SMPP) in children. The findings suggest that SII and CRP are independent risk factors, with SII demonstrating superior diagnostic accuracy. The manuscript is technically sound, and the data support the main conclusions, however, to strengthen clinical applicability, future prospective and multi-center validation studies are needed. Notably, the manuscript does not clearly indicate whether the underlying data have been made fully available, and a formal data availability statement should be included to meet publication standards. Although the manuscript is generally intelligible and the scientific content is understandable, it is not consistently written in standard academic English and would benefit significantly from professional language editing.

More specific comments:

The study is described as retrospective using hospital records, yet verbal informed consent and interview information sheets are mentioned. For retrospective chart reviews, informed consent is usually waived. Please clarify.

Define each abbreviation at first use.

Avoid repetition, for example the severity and systemic complications of SMPP are discussed multiple times with overlapping detail.

Add a flowchart of participant selection and exclusion criteria for visual clarity

lines 205-213 in discussion section lack literature reference, please add relevant literature references.

**********

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Reviewer #1: No

Reviewer #2: No

**********

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 10.1371/journal.pone.0333267.r002 Author response to Decision Letter 1 Submission Version 1

29 Aug 2025

1.In the title, the terms "novel inflammatory biomarkers" and "severe mycoplasma infections" are problematic. The reported biomarkers are not novel. The severity of mycoplasma infections is not defined as a pathological condition in the text.

Response:

Thank you for your constructive comments.We apologize for the inaccuracy in the title. We have revised the title to remove the term "novel," as the biomarkers (e.g., SII, SIRI) are indeed established in existing literature.Title updated to: "Application value of Systemic Immune-Inflammation Index in predicting severe Mycoplasma pneumoniae pneumonia".

Additionally, we have explicitly defined "severe mycoplasma infections" in the Introduction section, referencing clinical criteria (e.g., presence of respiratory failure, extrapulmonary complications, or requirement for intensive care) to clarify the pathological condition.(see Page 6,Line 99–115, Revised Manuscript with Track Changes)

2.Is serum amyloid A (SAA) determination a routine laboratory investigation?

Response:

Thank you for your question regarding the routine status of serum amyloid A (SAA) determination.In our clinical setting, SAA is routinely included in the panel of inflammatory markers for patients presenting with suspected infectious diseases—including pneumonia— as part of their initial laboratory workup. This practice aligns with the clinical workflow in our institution for evaluating and monitoring inflammatory responses in such patient populations

3.Subgrouping of patients was based on which criteria?

Response:

Thank you for your insightful comment, which helps clarify an important methodological detail of our study.Patients in this study were subgrouped into two categories: "severe Mycoplasma pneumoniae pneumonia (MPP)" and "non-severe Mycoplasma pneumoniae pneumonia (MPP)". This subgrouping was strictly based on the clinical criteria specified in the Evidence-based guideline for the diagnosis and treatment of Mycoplasma pneumoniae pneumonia in children (2023).To ensure transparency and reproducibility, we have supplemented the key content of these criteria in both the Introduction and the Methods section (where we described the study’s patient grouping strategy) of the revised manuscript.(see Page 6,Line 99–115 and Page 7,Line 125–127�

4.The authors extracted data from records, but why and how did they conduct interviews? Verbal consent was unacceptable.

Response:

We apologize for the confusion. This was an error in the original manuscript: no interviews were conducted for this retrospective study. All data were extracted from electronic medical records. The reference to "verbal consent" was also incorrect and has been removed. For retrospective studies using de-identified data(in line with our study design), our institutional ethics board waived the requirement for informed consent, which is now clarified in the Ethics Statement. (see Page 7 ,line 135–139�

We deeply regret the inaccuracies in the original text and have double-checked the Methods and Ethics sections to ensure all content aligns with the actual study procedures.

5.Line 146: The "S-W test" – do you mean the Shapiro-Wilk test?

Response:

Yes, "S-W test" refers to the Shapiro-Wilk test. We have corrected the abbreviation to "Shapiro-Wilk test" at its first mention and added the abbreviation in parentheses for clarity. (see Page 8,Line 151)

6.Table 1 (footnote: mean +/- SD), but results are presented as median (IQR). Day stay in hospital is the same for severe or non-severe infection – how?

Response:

We sincerely apologize for the inconsistency in Table 1. The footnote has been corrected to "median (IQR)" to match the data presentation.(see Page 10, Line 174-175,table1).

Regarding hospital stay, the original analysis showed no statistically significant difference between groups, which is now clarified in the text with a p-value (p = 0.123) and a brief explanation that variability in individual recovery trajectories may account for this finding.There is partial overlap in the interquartile ranges of hospital stay between the two groups (non-severe:4–7days; severe:5–8 days), indicating considerable individual variability in hospital stay within both groups. This variability may be attributed to factors such as rapid treatment response in some severe cases and the presence of comorbidities or slower recovery subgroups among non-severe cases, which collectively resulted in no statistically significant difference in the overall comparison.

7.Table 2 needs reanalysis to show different models. It is necessary to add beta-coefficients. A Cohen's test is needed to show the impact of sample size.

Response:

Thank you for these constructive comments.We have reanalyzed Table 2 in accordance with your comments, and the relevant revisions have been reflected in the text.(see Page 11-12, Line 192-196,table2).

8.Add plots of AUCs.

Response:

Thank you for this insightful comment. As requested, we have supplemented the plots of the AUCs as Figure 2 in the revised manuscript. Additionally, to enhance the transparency of our study design, we have also added a flowchart illustrating the participant selection and exclusion criteria as Figure 1. In accordance with the journal's requirements, these figures have been uploaded as separate files.(see Figures1 and Figure 2 )

9.References: Recheck the typing of the references.

Response:

Thank you for this helpful suggestion. We have carefully reviewed all references to correct typographical errors. Specifically, we have addressed formatting issues in Reference 12 (misspelled journal name) and Reference 23 (incorrect DOI), ensuring compliance with the citation guidelines of PLOS ONE.(see Page 16–22, references )

Responses to Journal Requirements

1. Ensure the manuscript meets PLOS ONE style requirements, including file naming.

Response:

Thank you for this helpful reminder.The manuscript has been revised to adhere to PLOS ONE style guidelines, including title formatting, author affiliations, and section organization. All files are named according to the requirements (e.g., "Manuscript.pdf," "Response to Reviewers.pdf").

2. Provide a validated ORCID iD for the corresponding author in Editorial Manager.

Response:

Thank you for bringing this oversight to our attention. The corresponding author’s ORCID iD (0000-0003-2645-8637) has been successfully validated and submitted in Editorial Manager in accordance with your instructions.

3.Address overlapping text with previous publications by citing sources or rephrasing.

Response:

Thank you for this important suggestion. We have carefully revised all instances of overlapping text identified—either by rephrasing content to ensure original expression or by adding proper, contextually accurate citations to attribute the relevant previous publications. These revisions have been verified to ensure the text similarity rate fully complies with academic integrity standards. All such modifications are clearly highlighted in red text in the marked-up version of the manuscript for your easy reference.

4. Clarify the role of funders in the study.

Response:

Thank you for bringing this point to our attention. We have revised the funder statement to explicitly clarify the role of the funders in the study, and the updated content reads as follows: "This work was supported in part by the Zigong Science and Technology Bureau (Grant No. 2023YKYXT06). The funds were specifically allocated for researcher training in scientific competencies; however, the funders had no role in study design, data collection and analysis, the decision to publish, or the preparation of the manuscript." This revised funder statement has been included in the cover letter for your reference.

5.Make all underlying data available per PLOS data policy.

Response:

Thank you for reminding us of this requirement related to PLOS’s data policy.All non-identifiable underlying data supporting the findings of this study have been prepared as supplementary files and uploaded alongside the revised manuscript. These data comply with research ethics regulations and privacy protections, ensuring no sensitive patient information is included. A revised data availability statement has been added to the manuscript to clarify that the underlying data are available as supplementary materials within the submission.

Responses to Reviewer #2 Comments

Comment 1: Clarify the inconsistency between "retrospective chart review" and mentions of "verbal informed consent/interviews."

Response:

We sincerely apologize for the confusion caused by this inconsistency in the original manuscript. As noted, this was an error in the initial writing: the study design is strictly a retrospective chart review, and all data were extracted solely from electronic medical records. There were no interviews conducted in this study, so the reference to "verbal informed consent" was incorrect and has been completely removed from the revised manuscript.

Additionally, for retrospective studies utilizing de-identified data (such as this one), our institutional ethics board (IEB) has formally waived the requirement for informed consent. This information has been supplemented and clarified in the "Ethics Statement" section of the manuscript for full transparency (see Page 7, Lines 135–139). We appreciate you pointing out this oversight, as it has helped us improve the accuracy of the study’s methodological description

Comment 2: Define each abbreviation at first use.

Response:

Thank you for highlighting this important point regarding abbreviation clarity. We have carefully revised the entire manuscript to ensure every abbreviation is explicitly defined the first time it appears in the text.

Comment 3: Avoid repetition (e.g., severity and complications of SMPP discussed multiple times).

Response:

Thank you for identifying this issue of repetitive content—it has helped us refine the manuscript’s conciseness. We have carefully reviewed the entire text, with specific attention to the sections previously discussing the severity and complications of severe mycoplasma pneumoniae pneumonia (SMPP) .

We have removed redundant repetitive descriptions to ensure the manuscript is concise, aiming to enhance readability for readers.

Comment 4:Add a flowchart of participant selection and exclusion criteria.

Response:

Thank you for this constructive suggestion.We have added a flowchart of participant selection and exclusion criteria as figure 1.

Comment 5: Lines 205–213 in the Discussion lack literature references – please add.

Response:

Thank you for this valuable suggestion. We have added relevant citations to support the statements.

Comment 6: Include a formal data availability statement.

Response:

Thank you for reminding us of this requirement related to PLOS’s data policy.All non-identifiable underlying data supporting the findings of this study have been prepared as supplementary files and uploaded alongside the revised manuscript. These data comply with research ethics regulations and privacy protections, ensuring no sensitive patient information is included. A revised data availability statement has been added to the manuscript to clarify that the underlying data are available as supplementary materials within the submission.

Comment 7: Improve language clarity and consistency.

Response:

Thank you for highlighting this important aspect of the manuscript—enhancing language clarity and consistency is critical for ensuring our research is accurately understood by readers. We have taken comprehensive measures to address this: the entire manuscript has been revised and polished by a professional language editing team composed of native English speakers, with a focused effort on clarifying ambiguous sentences and correcting minor grammatical errors, awkward phrasing, and non-standard academic expressions.

Submitted filename: Response to Reviewers.docx

 10.1371/journal.pone.0333267.r003 Decision Letter 1 Al-Nimer Marwan Salih Academic Editor 2025 Marwan Salih Al-Nimer This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version 1

3 Sep 2025

Dear Dr. Xu,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Minor revision

Please submit your revised manuscript by Oct 18 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Marwan Salih Al-Nimer, MD, PhD

Academic Editor

PLOS ONE

Journal Requirements:

If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. 

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

Dear Authors

Line 86: Why Yang S et al?

Line 124 and PE. What this abbreviation means?

Line 310: Why Wang S et al.?

[Note: HTML markup is below. Please do not edit.]

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

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 10.1371/journal.pone.0333267.r004 Author response to Decision Letter 2 Submission Version 2

8 Sep 2025

1. Response to Editor Comments

Comment 1 (Line 86: "Why Yang S et al?")

Response: In the original manuscript, we cited "Yang S et al. [12]" when discussing the comparative study between common and severe Mycoplasma pneumoniae pneumonia (MPP) in children. To maintain consistent citation style throughout the text, we have revised this to "Yang et al. [12]" in the updated manuscript (Page 4, Line 66). This change aligns with the format used for other citations (e.g., "Zhuo et al. [11]"). The reference content remains unchanged and continues to provide essential support for our study background by highlighting key inflammatory differences between common and severe MPP.(see Page 4,Line 66, Revised Manuscript with Track Changes)

Comment 2 (Line 124: "What does the abbreviation PE mean?")

Response: Thank you for noting this oversight. The abbreviation "PE" was initially used without definition, which may have caused ambiguity. We have now spelled out "pulmonary embolism" at its first occurrence in the revised manuscript (Page 6, Line 104), within the phrase: "combined with plastic bronchitis, asthma attack, pleural effusion, and pulmonary embolism". This revision ensures clarity and is consistent with the diagnostic criteria for severe MPP (SMPP) as outlined in the 2023 evidence-based guideline [23].(see Page 6,Line 104, Revised Manuscript with Track Changes)

Comment 3 (Line 310: "Why Wang S et al.?")

Response: Similarly, the citation "Wang S et al. [25]" has been standardized to "Wang et al. [25]" in the revised manuscript (Page 14, Line 243) to match the citation style employed for other references (e.g., "Shao et al. [13]"). The study by Wang et al. (2024) remains highly relevant, as it involved 304 children with MPP and demonstrated the superior predictive performance of the Systemic Immune-Inflammation Index (SII) for disease severity compared to other ratios, thereby directly supporting our conclusion.(see Page 14,Line 243, Revised Manuscript with Track Changes)

2. Revisions to the Reference List

In accordance with PLOS ONE’s reference formatting guidelines, we have comprehensively revised the reference list. Key changes include:

Author names are now presented with surnames in uppercase and initialized given names (e.g., “WILLIAMS B.G., GOUWS E., BOSCHI-PINTO C., BRYCE J., DYE C.”)

Publication year is now enclosed in parentheses and placed directly after the author list (e.g., “(2002)”).

Journal names have been standardized with correct abbreviations and punctuation (e.g., “Lancet Infect. Dis.”, “Emerg Infect Dis.”).

For the guideline reference [23] where no individual authors are listed, we have used the designation: “No authors listed. (2023).”.

We confirm that all 37 references are complete, include DOIs, and have been verified against PubMed and Web of Science; none have been retracted or issued an expression of concern.

3. Submission of Figure Files

In accordance with the editor’s instruction, we have registered an account on the Preflight Analysis and Conversion Engine (PACE) platform (account name: [ account name�278139516@qq.com]) and uploaded all figure files (Figure 1: Sample grouping and research protocol; Figure 2: ROC curves of SII and CRP for SMPP prediction). We confirm that all revisions—including addressing specific editor comments and standardizing the reference list—are fully reflected in “Revised Manuscript with Track Changes.docx”. The revised manuscript now meets PLOS ONE’s academic and formatting standards. We sincerely hope it will be accepted for publication. Please feel free to contact us if further revisions or clarifications are needed.

Submitted filename: Response_to_Reviewers_auresp_2.docx

 10.1371/journal.pone.0333267.r005 Decision Letter 2 Al-Nimer Marwan Salih Academic Editor 2025 Marwan Salih Al-Nimer This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version 2

11 Sep 2025

Application value of Systemic Immune-Inflammation Index in predicting severe Mycoplasma pneumoniae pneumonia

PONE-D-25-26564R2

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 10.1371/journal.pone.0333267.r006 Acceptance letter Al-Nimer Marwan Salih Academic Editor 2025 Marwan Salih Al-Nimer This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PONE-D-25-26564R2

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