Predictive value of increased C-reactive protein levels in preterm infants on respiratory function at five to six years of age: a cohort study

Predictive value of increased C-reactive protein levels in preterm infants on respiratory function at five to six years of age: a cohort study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Predictive value of increased C-reactive protein levels in preterm infants on respiratory function at five to six years of age: a cohort study Alexander Humberg, Mats Fortmann, Rebecca Dappen, Claudia Roll, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7358959/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 Apr, 2026 Read the published version in Communications Medicine → Version 1 posted You are reading this latest preprint version Abstract Objective The multifactorial pathophysiology of chronic lung disease in very low birthweight infants (VLBWI) includes inflammatory driven trauma of the lungs. Study Design Multicentre observational study to evaluate the predictive value of C-reactive protein (CrP) levels in VLBWI within the first 28 days of life on forced expiratory volume (FEV 1 ) at 5-6 years of age. A CrP level exceeding 10 mg/l was considered as elevated, with recurrent elevations defined as at least two values >10 mg/l at intervals of 14 days or more. Univariate analyses, linear regression models, and predictive models with adjustments for gestational age, birth weight, born small-for-gestational age, antenatal steroid usage, cerebral haemorrhage, periventricular leukomalacia, cerebral palsy, surgical treatment of necrotizing enterocolitis, duration of mechanical ventilation, duration of oxygen therapy within the first 28 days, presence of BPD, intelligence quotient, and weight at five year follow-up were used. Result 353 VLBWI born between 2009 and 2015 with median gestational age of 27.6 (25.7-29.4) weeks were included. Infants with recurrent CrP elevations demonstrated significantly higher rates of bronchopulmonary dysplasia (BPD) (59.5% vs. 17.3%, p < 0.001) and z-scores of FEV 1 < 5 th percentile at five to six years (71.9% vs. 35.3%, p < 0.001). Absence of recurrent CrP elevations showed a negative predictive value of 94.2%, but the positive predictive value was only 19.8%. Conclusion The absence of recurrent CRP elevations in VLBWI seems to be associated with better long-term pulmonary outcome, highlighting the potential utility of inflammatory biomarkers in risk stratification for chronic lung disease. Health sciences/Medical research Health sciences/Health care Bronchopulmonary dysplasia chronic lung disease very low birthweight preterm lung function neonatal sepsis C-reactive protein VLBWI FEV1 Figures Figure 1 Introduction Premature birth affects a variety of organ systems with increased risk for medical morbidity and long-term sequelae 1 . One of the main complications is bronchopulmonary dysplasia (BPD), a serious respiratory complication affecting infants with disrupted alveolarization, microvascular development, thickening of the basement membrane and lymphocytic infiltration 2 , 3 . BPD is a multifactorial condition with diverse endotypes that include infection-inflammation-driven and placental dysfunction-related mechanisms. These endotypes contribute to distinct clinical phenotypes, necessitating a shift toward precision medicine in BPD management. Emerging evidence highlights the potential of targeted therapeutic approaches tailored to these endotypes, as for example IL-1 receptor antagonists in mitigating inflammation-driven lung injury or anti-fibrotic agents like nintedanib for fibrotic endotypes of chronic lung disease 4 , 5 . The C-reactive protein (CrP), an acute phase protein, is the clinically most used inflammation and infection marker in neonates that rises several hours after the onset of inflammation 6 . Few studies described an association of postnatal elevated CrP levels with BPD 7 , 8 . From these observations it seems that an early detected CrP increase within the first days of life is associated with the development of BPD and can be taken as a biomarker for the prediction of BPD independently from the presence of either early- or late-onset sepsis 9 , 10 . Although BPD is a commonly used marker of lung injury, there is a growing consensus that it is a relatively poor predictor of long-term lung health. Children born preterm present with impaired lung function, regardless of a BPD diagnosis 11 – 13 and it is currently perceived that BPD is a relatively poor indicative factor for neonatal lung injury 14 – 16 . Given the limitations of BPD as a diagnostic marker, there is an urgent need for new, reliable predictive parameters that can identify VLBWI at high risk for chronic respiratory issues early on. Personalized management of BPD has the potential to improve long-term pulmonary outcomes by aligning therapeutic strategies with the specific molecular and clinical profiles of affected infants. The objective of this study was to investigate whether elevated CrP levels within the first 28 days of life, particularly when recurrent, were associated with compromised respiratory function at five to six years in VLBWI. Subjects and methods Study population The German Neonatal Network (GNN) is a multicentre observational population-based cohort study enrolling VLBWI with < 1500 g birth weight from 2009–2016 and < 1000g birth weight since 2017 in Germany ( www.vlbw.de ) 17 . Yearly on-site-monitoring by a study nurse or paediatrician experienced in neonatology ensures proper assessment of clinical data. In the context of this study, VLBWI < 1500 g birth weight and extremely low birth weight infants (ELBWI, < 1000 g birth weight) born in 4 GNN sites (University of Lübeck, Vest Children's Hospital Datteln, Altona Children's Hospital Hamburg, University Hospital Münster) between 1st of January 2009 and 31st of December 2015 and with information about laboratory CrP levels were included. Exclusion criteria included lethal abnormalities and missing data on CrP levels. Ethics Approval by the local ethics committee for research in human subjects of the University of Lübeck (file number 08–022 and 14–220) and by the local ethics committees of all participating centres has been granted. The GNN was funded by the German Ministry for Education and Research (BMBF-grant-No: 01ER0805 and 01ER1501). Laboratory measurements of CrP values CrP levels were measured using serum or plasma samples, carried out as directed by physicians by medical indication (e.g. suspicion of infection or monitoring the progress of a confirmed infection), and recorded retrospectively. The analysis of the CrP level was conducted using the standard Tina Quant CrP test and the Cobas c 701 analyzer from Roche. The determination of the CrP concentration is accomplished through an immunological turbidimetry test. Definition of recurrent CrP elevations Recurrent CrP increases were defined based on the dynamics of the CrP laboratory values and the following characteristics: a) the first value had to exceed 10 mg/l, b) there had to be a minimum interval of > 14 days between 2 values of > 10 mg/l and a decrease in CrP to < 5 mg/dl had to be demonstrated in the meantime. Further definitions are given in the supplementary material. Follow-up At the age of five to six years, participating children born preterm and included in the GNN were recruited for a structured follow-up evaluation. During the recruitment process, the study team reached out to the hospital where the children were born to schedule follow-up assessments. Families were randomly contacted and invited for follow-up with a particular emphasis on infants born before 28 weeks of gestational age. The follow-up examination encompassed various components, including interviewing the child's parents or caregivers, measuring the child's body parameters, neuro-motor developmental assessment and lung function testing 18 . Measurement of lung function at five to six years Lung function parameters were assessed using spirometry involving the utilization of a flow sensor and the Easy-on PC software (manufactured by ndd Medizintechnik AG, Zurich, Switzerland). The execution of lung function measurements followed a standardized protocol, commencing with a ten-minute resting phase. Subsequently, the child assumed a comfortable sitting position on a chair. Nasal flow was prevented by a nose clip. Recording the parameters requires maximal expiration, which was achieved through visual representations on a notebook. Children were encouraged to blow out candles on the notebook, inflate a balloon as fully as possible with a single breath, or set a swing in motion through exhalation. Up to ten attempts could be made by each child with the best attempt being considered for analysis. Valid attempts involved maximal expiration to zero flow, followed by deep inhalation and a strong exhalation. Additionally, the quality of attempts was noted based on the criteria described above, as well as cooperation during the procedure and any remarks regarding potential accompanying factors, issues, or anomalies. Statistical analysis The baseline characteristics of maternal and neonatal variables were represented in the form of medians, interquartile ranges (IQR), counts, frequencies, and 95% confidence intervals (CI) for column percentages. Unadjusted comparisons were assessed using the Chi-square test and the Mann-Whitney U-Test. FEV 1 and FVC were documented in litres. The FEV 1 and FVC z-scores were calculated according to the Global Lung Function Initiative 19 with z-scores < -1.644 according to values < 5th percentile. Linear regression models were computed for the z-scores of FEV 1 and FVC and adjusted for gestational age, birth weight, born small-for-gestational age, antenatal steroid usage, cerebral hemorrhage, periventricular leucomalacia, cerebral palsy (Gross Motor Function Classification System ≥ 1), surgical treatment of necrotizing enterocolitis, mechanical ventilation, duration of mechanical ventilation, duration of oxygen therapy within the first 28 days, presence of BPD, intelligence quotient, and weight at five year follow-up. The diagnostic performance of recurrent CrP elevations was assessed using sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for the outcome FEV 1 z-score < 5th percentile. Receiver operating characteristic (ROC) curves were utilized to evaluate the predictive performance of various neonatal variables for the defined outcomes. The area under the curve (AUC) and corresponding % confidence intervals were calculated for each variable to quantify its ability to distinguish between outcome groups. Variables with AUC values closer to 1 were considered strong predictors, while values near 0.5 indicated no predictive power. Statistical significance of the AUC was determined using asymptotic p-values. Missing values were ignored. All statistical analyses were carried out using SPSS software (IBM SPSS Statistics for Windows, Version 29.0, Munich, Germany). Figures were created using python language version 3.13.0 with matplotlib v3.9.3 20 . Raw data were generated at the University of Luebeck and the University of Muenster. Derived data supporting the findings of this study are available from the corresponding author on request. Results Study population Between January 1st 2009 and December 31st 2015, 13849 infants < 1500 g birth weight were enrolled in the GNN (shown in Fig. 1 ). Of these infants, 3848 were assessed for follow-up at the age of five to six years. After exclusion of infants not evaluated for CrP levels as these centres did not participate in CrP value collection, primary data sets of 353 preterm infants with five to six year follow-up and CrP measurement remained for analysis. Infants with single elevation of Crp were more frequently born SGA than those with no elevations of CrP (26.1% [95% CI 15.1–40.0] vs. 12.8% [9.2–17.3], p = 0.01). However, differences were more evident in children with multiple CrP elevations. These infants were born at lower gestational age (25.6 [24.4–27.6] weeks vs. 28.1 weeks [26.1–29.7], p < 0.001) and birth weight (685g [540–870] vs. 990 g [540–870], p < 0.001) with higher rates of born SGA (35.7% [22.6–50.8] vs. 12.8% [9.2–17.3], p 10mg/l n = 46 Recurrent elevation of CrP > 10 mg/l n = 42 Total cohort n = 353 Gestational age [weeks] # 28.1 (26.1–29.7) 26.1 (25.0–29.0) 25.6 (24.4–27.6) 27.6 (25.7–29.4) Birth weight [g] # 990 (780–1265) 815 (680–1110) 685 (540–870) 957 (725–1220) SGA (< 10th percentile) 34 (12.8 [9.2–17.3]) 12 (26.1 [15.1–40.0]) 15 (35.7 [22.6–50.8]) 61 (17.3 [13.6–21.5]) Female sex 125 (47.2[41.2–53.2]) 23(50.0 [35.9–64.1]) 16 (38.1 [24.6–53.2]) 164 (46.5 [41.3–51.7]) Multipara 106 (40.0 [34.2–46.0]) 20 (43.5 [29.9–57.8]) 14 (33.3 [20.6–48.3]) 140 (39.7 [34.7–44.8]) Antenatal administration of steroids 237 (89.4 [85.3–92.7]) 44 (95.7 [86.8–99.1]) 40 (95.2 [85.6–99.0]) 321 (90.9 [87.6–93.6]) Surfactant administration 199 (75.1 [69.6–80.0]) 40 (87.0 [75.1–94.4]) 40 (95.2 [85.6–99.0]) 279(79.0 [74.6–83.0]) ICH 37 (14.0 [10.2–18.5]) 6 (13.0 [5.6–24.9]) 9 (21.4 [11.2–35.5]) 52 (14.7 [11.3–18.7]) PVL 2 (0.8 [0.2–2.4]) 3 (6.5 [1.9–16.4]) 2 (4.8 [1.0-14.4]) 7 (2.0 [0.9–3.9]) NEC requiring surgery 1 (0.4 [0.0-1.8]) 1 (2.2 [0.2–9.7]) 6 (14.3 [6.2–27.1]) 8 (2.3 [1.1–4.2]) SIP requiring surgery 2 (0.8 [0.2–2.4]) 1 (2.2 [0.2–9.7]) 6 (14.3 [6.2–27.1]) 9 (2.6 [1.3–4.6]) invasive ventilation 121 (45.8 [39.9–51.9]) 32 (69.6 [55.4–81.4]) 41 (97.6 [89.4–99.7]) 194 (55.1 [49.9–60.3]) Clinical signs of chorioamnionitis 63 (23.8 [19.0-29.2]) 10 (21.7 [11.8–35.1]) 11 (26.2 [14.8–40.8]) 63 (23.8 [19.0-29.2]) Amount of CrP values > 10 mg/l 0 1 (1) 4 (3–10) 0 (0–1) Frequency of CrP determinations 4 (3–6) 7 (5–9) 12 (9–14) 5 (3–8) Table 1 : Cohort characteristics stratified by amount of CrP levels > 10 mg/l, categorical variables are given as n(%) with corresponding 95% confidence interval (CI), continuous variables as median (IQR) if appropriate (#). Abbreviation: CrP: C-reactive protein, SGA: small for gestational age, ICH: intracerebral hemorrhage, PVL: periventricular leucomalacia, NEC: necrotizing enterocolitis, SIP: spontaneous intestinal perforation Univariate analyses VLBWI with single CrP elevation had significantly higher rates of bronchopulmonary dysplasia (BPD) (34.8% [22.3–49.1] vs. 17.3% [13.1–22.3], p = 0.006), oxygen need at discharge (8.7% [3.0-19.4] vs. 1.5% [0.5–3.5], p = 0.004) and higher rates for z-scores < 5th percentile for FEV 1 (61.8% [45.0-76.6] vs. 35.3% [29.0–42.0], p < 0.001) and FVC (50.0% [33.8–66.2] vs. 37.3% [30.8–44.0], p < 0.001) (see supplementary table 1 ). In comparison to cases with no elevation of CrP, the group exhibiting recurrent elevation of CrP showed significantly higher incidences of BPD (59.5% [44.5–73.3] vs. 17.3% [13.1–22.3], p < 0.001), increased oxygen requirement at discharge (14.3% [6.2–27.1] vs. 1.5% [0.5–3.5], p < 0.001), and a lower median weight at five to six-year follow-up (16.6 kg [15.1–19.2] vs. 18.6 kg [16.7–20.7], p < 0.001). Regarding respiratory function and related parameters, recurrence of elevated CrP was associated with reduced lung function as evidenced by decreased FEV 1 (0.77 [0.67–0.91] vs. 0.97 litres [0.85–1.12], p < 0.001). Moreover, z-scores of FEV 1 and FVC were significantly reduced in infants with recurrent elevations and the percentage of individuals with FEV 1 and FVC z-score < 5th percentile is markedly higher in the recurrent elevation of CrP group 71.9% [54.9–85.1] vs. 35.3% [29.0–42.0] (p < 0.001) and 81.3% [65.4–91.8] vs. 37.3% [30.8–44.0] (p < 0.001,) respectively. VLBWI with recurrent CrP elevations differed significantly from children with a single CrP elevation with respect to BPD rate (59.5% [44.5–73.3] vs. 34.8% [22.3–49.1], p = 0.020), median weight at 5 years of age (16.6kg (15.1–19.2) vs. 18.6kg (16.6–19.3), p = 0.034), a higher rate for gross motor function scale (GMFCS) scores ≥ 1 (43.6% [28.9–59.1] vs. 20.5% [10.6–34.0], p = 0.023), as well as reduced median lung parameters for FEV (0.77 l (0.67–0.91) vs. 0.93 (0.80–1.06), p = 0.009) and FVC (0.8 l (0.66–0.94) vs. 1.01 l (0.83–1.15), p = 0.002) and a higher rate of z-score values < 5th percentile for FVC (81.3% [65.4–91.8] vs 50.0% [33.8–66.2], p = 0.008). Adjusted analyses To adjust for possible confounding variables, z-scores of lung function were tested in a linear regression model. Scatterplots with the fitted regression line are examined to ensure model assumptions were met. The residuals appeared to be independent (Durbin-Watson). In this analysis, several factors exhibited associations with reduced lung function. Recurrent elevations of CrP correlated with decreased FEV 1 and FVC z-scores (Table 3 and table 4), indicating that this factor was linked to decreased lung function. However, single increases of CrP were not correlated with reduced FEV 1 and FVC values (see supplementary table 2a and 2b). Notably, higher weight at five to six-year follow-up demonstrated a positive correlation with FVC z-scores, suggesting that increased weight is linked to improved values. This result highlighted the importance of weight gain, while also suggesting the negative impact of recurrent elevations in CrP levels on the respiratory function of these individuals in their early childhood years. Table 2 Linear regression model for respiratory long-term outcome Variables z-score of FEV 1 B (SD) Beta T p-value GMFCS ≥ 1 -0.041 (0.197) -0.015 -0.2 0.834 Weight at 5YFU [kg] 0.013 (0.019) 0.048 0.7 0.498 IQ 0.012 (0.006) 0.138 2.1 0.038 Duration of mechanical ventilation [days] 00.405 (0.238) -0.179 -1.7 0.090 Recurrent CrP > 10 mg/l -0.718 (0.234) -0.213 -3.1 0.002 Table 2 : Linear regression model for respiratory long-term outcome. Model further adjusted for gestational age, birth weight, antenatal administration of steroids, IVH, surgical treatment for necrotizing enterocolitis, birth weight < 10th percentile, duration of mechanical ventilation, duration of oxygen therapy within the first 28 days, BPD and PVL (data not shown). R 2 : 0.265; Durbin-Watson: 1.930; F = 4.426 with p < 0.001; Abbreviation: B: unstandardized coefficients, Beta: standardized coefficients, IQ: intelligence quotient Table 3 Linear regression model for respiratory long-term outcome Variables z-score of FVC B (SD) Beta T p-value GMFCS ≥ 1 -0.474 (0.223) -0.145 -2.3 0.035 Weight at 5YFU [kg] 0.043 (0.021) 0.139 2.0 0.045 IQ 0.013 (0.007) 0.132 2.0 0.044 Duration of mechanical ventilation [days] -0.043 (0.268) -0.016 -0.2 0.873 Recurrent CrP > 10 mg/l -1.114 (0.268) -0.287 -4.2 < 0.001 Table 3 : Linear regression model for respiratory long-term outcome. Model further adjusted for gestational age, birth weight, antenatal administration of steroids, IVH, surgical treatment for necrotizing enterocolitis, birth weight < 10th percentile, duration of oxygen therapy within the first 28 days, BPD and PVL (data not shown). R 2 : 0.296; Durbin-Watson: 1.959; F = 5.153 with p < 0.001; Abbreviation: B: unstandardized coefficients, Beta: standardized coefficients, IQ: intelligence quotient Accuracy of tests Testing of recurrent CrP elevations on the outcome FEV 1 z-score < 5th percentile demonstrated a sensitivity of 71.9%. Specificity was 60.9%. The positive predictive value (PPV) was 19.8% and negative predictive value (NPV) was 94.2%. Supplementary analyses Frequency of CrP determinations grouped by recurrent elevations > 10 mg/l against all other infants with single and no CrP elevation is given in supplementary Fig. 1. Highest frequencies of CrP determination are found within the first days of life. Infants with recurrent CrP elevations have continuously higher values of CrP during the first 28 days of life (supplementary Fig. 2) and higher values of inflammatory markers in the white blood count (supplementary table 3), indicating a higher systemic inflammatory impact. Furthermore, infants with worse respiratory long-term outcome show higher median CrP levels over the first 28 days of life (supplementary Figs. 3 and 4). However, median levels of CrP were not associated with worse respiratory outcome (supplementary table 4a and 4b). Independent from early diagnosis of BPD, frequencies for long-term respiratory sequalae are increased represented in the group of recurrent CrP elevations (supplementary table 5). The ROC analysis evaluated the predictive power of neonatal clinical parameters on long-term respiratory outcome prediction (supplementary table 6 and 7). Among the tested variables, CrP elevations > 10 mg/L within the first 28 days of life emerged as a significant predictor of z-scores of FEV1 and FVC < 5th percentile. In addition, ventilation duration and diagnosis of BPD showed a significant predictive relationship. Concerning the prediction of lower FVC values, other variables such as gestational age and birth weight also demonstrated significant, albeit weaker, associations. Discussion This study investigated the association between elevated CrP levels within the first 28 days of life in VLBWI and long-term respiratory function at the age of five to six years. Our findings revealed a significant correlation between recurrent elevation of CrP during the neonatal period and adverse respiratory outcomes in later life. We could further show that the absence of recurrent CrP elevations has potential at correctly excluding individuals without reduced lung function. However, the low sensitivity indicates a considerable proportion of true cases are missed and limits its utility as a standalone diagnostic tool for identifying all positive cases. Furthermore, regarding our ROC analysis, our findings highlight the multifactorial nature of long-term pulmonary outcomes in preterm infants. Systemic inflammation, as evidenced by CrP elevations, prolonged mechanical ventilation, and the diagnosis of BPD, represent key contributors to reduced respiratory parameters at 5 years of age. We here used the measurement of FEV 1 and FVC via spirometry as a standard pulmonary function test for neonatal outcome-measurement 21 . Our study aligns with previous research linking early inflammation or immune-dysregulation 22 to adverse respiratory outcomes. Stimulation of inflammatory cascades, involving cytokines and pattern recognition receptors, can lead to endothelial cell activation, oxidative stress, cell death, and microvascular complications, contributing to lung injury in neonates 23 – 26 . Studies have shown associations between elevated levels of serum eosinophil chemotactic factors, TNF-α, IL-1β, IL-6, IL-8, and other pro-inflammatory markers with the occurrence and prognosis of BPD 27 . Furthermore, reductions in neonatal sepsis prevalence appear to correlate with a decreased incidence of BPD, suggesting a potential link between postnatal sepsis and the risk of BPD in premature infants 28 . Rodent models of postnatal sepsis-induced lung injury using systemic LPS exposure in newborn mice highlight the vulnerability and an ontogenic window in early lung development to inflammation-induced disruptions, affecting lung morphogenic pathways critical for distal acinar development 25 , 26 , 29 . These data underscore the role of endothelial cells in both developmental angiogenesis and sepsis-induced dysmorphic angiogenesis, indicating that factors like vascular endothelial growth factor (VEGF), angiopoietins, and FOSL1 play complex roles in this process 30 – 32 . An altered elastic fibre assembly, mesenchymal and fibroblast growth factor downregulation, and protease-mediated lung extracellular matrix degradation also play an important role in sepsis-induced lung injury 33 , 34 . Induction of CrP expression is significantly influenced by IL-6 and IL-1, leading to activation of phagocytic cells, production of inflammatory cytokines, and regulation of the complement pathway, potentially resulting in adverse vascular events when elevated 35 . In clinical settings, monitoring of CrP levels is one of the most widely used detection methods for neonatal sepsis. The relationship between CrP and diseases, particularly in premature infants, has garnered significant attention as it may aid to early detect a risk for respiratory long-term complication and may guide future interventions for BPD to improve prognoses. Studies have consistently linked elevated CrP levels with bronchopulmonary dysplasia (BPD) in preterm infants 7 . Elevated CrP levels, particularly on day 28 of life, have been associated with BPD and increased mortality risk, indicating a systemic inflammatory response 7 . Notably, elevated CrP levels have been observed early before clinical symptoms of BPD manifestation, highlighting its potential as an early diagnostic marker 10 . One strength of this study is that results of respiratory outcome are adjusted for several risk factors impacting respiratory outcome, like gestational age, birth weight and mechanical ventilation. Besides these variables, increased recurrent CrP values are associated with poor expiratory airflow at age five to six years. Furthermore, evaluation of lung function parameters assessed by a consistent team of physicians and nurses suggests a high consistency of the data. Despite its strengths, our study might have limitations worth considering. For instance, the focus on expiratory airflow as an outcome might not encompass the entirety of respiratory function. Additionally, the absence of detailed mechanistic insights or direct causality between long-term lung impairment and increased CrP values might warrant further investigations. Furthermore, studies have indicated a systemic inflammatory response associated with Ureaplasma spp. in premature neonates, leading to elevated CrP levels. This chronic systemic inflammatory response may be linked to the development and persistence of lung injury. We here also cannot control for potential effects as the presence for ureaplasma spp . is not recorded in our data set. The retrospective nature of our study may introduce bias and limit the establishment of causal relationships. The absence of planned blood samples in the GNN dataset constrained the availability of CrP data, potentially affecting the representativeness of the sample. Additionally, the study's reliance on CrP as a sole inflammatory marker may overlook the contribution of other inflammatory factors. Our follow-up cohort has a risk of selection bias. For the follow-up, we chose a random invitation practice. However, it is possible that the invitation process and voluntary participation in the follow-up studies resulted in a bias towards presenting an incompletely balanced group. Furthermore, while efforts are made to adjust for confounding variables, residual confounders might influence the observed associations. Further studies should therefore take additional factors as environmental exposures like genetic predispositions, histologic proved chorioamnionitis, hemodynamic relevant factors during prematurity, respiratory infections, parental smoking or vaccination status into account 36 . From our data it can be assumed, that infections detected by increased CrP levels increase the risk for developing respiratory complications. From our data we cannot distinguish between recurrent infections reflected by different CrP elevations or a possible underlying sustained inflammation leading to a continuous process of inflammatory process. In conclusion, our study conveys information about the impact of systemic inflammation on respiratory outcomes in preterm infants. Our findings highlight the importance of early inflammatory markers in predicting long-term respiratory health and warrant further research to explore interventions for mitigating the impact of inflammation on neonatal lung injury and subsequent respiratory complications. Our findings emphasize the need for individualized approaches to monitoring neonatal inflammation and its progression. This perspective aligns with the growing interest in tailoring treatment strategies based on endotype classification 37 . Interventions targeting the inflammatory pathways, such as IL-1 receptor antagonists like anakinra, hold promise in mitigating inflammation-driven lung injury 38 , 39 . While BPD has traditionally been used as a predictor, it is now recognized as a relatively poor measure of neonatal lung injury 40 . Therefore, there is a need for new and feasible diagnostic methods to better understand lung injury in these vulnerable infants and to predict their future respiratory health accurately. This knowledge is essential for assessing interventions aimed at early prevention and treatment of lung disease in preterm infants. The measurement of recurrent CrP elevations in a combined model with other risk factors such as mechanical ventilation could be a clinical tool for further risk assessment studies. Further research is warranted to elucidate the mechanisms linking early inflammation to CLD development and to evaluate the feasibility of integrating inflammatory monitoring into clinical practice. Abbreviations 5YFU five to six year follow-up examination AUC area under the curve BPD bronchopulmonary dysplasia CrP C-reactive protein EDTA ethylene diamine tetraacetic acid FEV 1 forced expiratory volume in one second FEV 1 % forced expiratory volume in one second as a percentage of predicted FVC forced vital capacity FVC% forced vital capacity as a percentage of predicted g gram GMFCS gross motor function scale GNN German Neonatal Network ICH intracerebral hemorrhage IQ intelligence quotient kg kilogram NEC necrotizing enterocolitis PVL periventricular leukomalacia ROC receiver operating characteristic s seconds SGA small for gestational age SIP spontaneous intestinal perforation VLBWI Very low birthweight infants WPPSI Wechsler Preschool and Primary Scale of Intelligence – Third Edition Declarations Conflict of Interest Competing Interests: All authors declare no financial competing interests. Ethics approval and consent to participate This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the University of Lübeck (file numbers 08-022 and 14-220) and the ethics committees of all participating centres. Informed consent was obtained from the parents or legal guardians of all participants. Availability of Data and Materials Raw data were generated at the University of Luebeck and the University of Muenster. Derived data supporting the findings of this study are available from the corresponding author on request. Funding The German Neonatal Network was funded by the German Ministry for Education and Research (BMBF-grant-No: 01ER0805 and 01ER1501). Author Contributions MF, RD and AH wrote the manuscript; RD, WG and AH performed the analytic calculations; AH, CH EH and WG planned the study; MF, RD, CR, MK, AW, CH, JS and AH performed the data acquisition, MF, RD, CR, AW, CH, EH, WG, AH contributed to the design and implementation of the research. All authors discussed the results and commented on the manuscript. References Patel R. Short- and Long-Term Outcomes for Extremely Preterm Infants. Am J Perinatol 2016; 33 : 318–328. Galderisi A, Calabrese F, Fortarezza F, Abman S, Baraldi E. Airway Histopathology of Adolescent Survivors of Bronchopulmonary Dysplasia. J Pediatr 2019; 211 : 215–218. Thébaud B, Goss KN, Laughon M, Whitsett JA, Abman SH, Steinhorn RH et al. Bronchopulmonary dysplasia. Nat Rev Dis Prim 2019; 5 : 78. Pierro M, Van Mechelen K, van Westering-Kroon E, Villamor-Martínez E, Villamor E. Endotypes of Prematurity and Phenotypes of Bronchopulmonary Dysplasia: Toward Personalized Neonatology. J Pers Med 2022; 12 : 687. Ding KL, Smith C, Seedorf G, Abman SH. Nintedanib preserves lung growth and prevents pulmonary hypertension in a hyperoxia-induced lung injury model. Pediatr Res 2025; 97 : 1676–1683. Hengst JM. The Role of C-reactive protein in the evaluation and management of infants with suspected sepsis. Adv Neonatal Care 2003; 3 : 3–13. Ambalavanan N, Ross AC, Carlo WA. Retinol-Binding Protein, Transthyretin, and C-Reactive Protein in Extremely Low Birth Weight (ELBW) Infants. J Perinatol 2005; 25 : 714–719. D’Angio CT, Ambalavanan N, Carlo WA, McDonald SA, Skogstrand K, Hougaard DM et al. Blood Cytokine Profiles Associated with Distinct Patterns of Bronchopulmonary Dysplasia among Extremely Low Birth Weight Infants. J Pediatr 2016; 174 : 45-51.e5. Leroy S, Caumette E, Waddington C, Hébert A, Brant R, Lavoie PM. A Time-Based Analysis of Inflammation in Infants at Risk of Bronchopulmonary Dysplasia. J Pediatr 2018; 192 : 60-65.e1. Yang Y, Li J, Mao J. Early diagnostic value of C-reactive protein as an inflammatory marker for moderate-to-severe bronchopulmonary dysplasia in premature infants with birth weight less than 1500 g. Int Immunopharmacol 2022; 103 : 108462. Sanchez-Solis M, Perez-Fernandez V, Bosch-Gimenez V, Quesada JJ, Garcia-Marcos L. Lung function gain in preterm infants with and without bronchopulmonary dysplasia. Pediatr Pulmonol 2016; 51 : 936–942. Lombardi E, Fainardi V, Calogero C, Puglia M, Voller F, Cuttini M et al. Lung function in a cohort of 5‐year‐old children born very preterm. Pediatr Pulmonol 2018; 53 : 1633–1639. Hagman C, Björklund LJ, Bjermer L, Hansen‐Pupp I, Tufvesson E. Perinatal inflammation relates to early respiratory morbidity and lung function at 12 years of age in children born very preterm. Acta Paediatr 2021; 110 : 2084–2092. Hjalmarson O, Brynjarsson H, Nilsson S, Sandberg KL. Persisting hypoxaemia is an insufficient measure of adverse lung function in very immature infants. Arch Dis Child - Fetal Neonatal Ed 2014; 99 : F257–F262. Priante E, Moschino L, Mardegan V, Manzoni P, Salvadori S, Baraldi E. Respiratory Outcome after Preterm Birth: A Long and Difficult Journey. Am. J. Perinatol. 2016; 33 : 1040–1042. Vollsæter M, Skromme K, Satrell E, Clemm H, Røksund O, Øymar K et al. Children Born Preterm at the Turn of the Millennium Had Better Lung Function Than Children Born Similarly Preterm in the Early 1990s. PLoS One 2015; 10 : e0144243. Humberg A, Härtel C, Rausch TK, Stichtenoth G, Jung P, Wieg C et al. Active perinatal care of preterm infants in the German Neonatal Network. Arch Dis Child Fetal Neonatal Ed 2020; 105 : 190–195. Nissen G, Hinsenbrock S, Rausch TK, Stichtenoth G, Ricklefs I, Weckmann M et al. Lung Function of Preterm Children Parsed by a Polygenic Risk Score for Adult COPD. NEJM Evid 2023; 2 . doi:10.1056/EVIDoa2200279. Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH et al. Multi-ethnic reference values for spirometry for the 3–95-yr age range: the global lung function 2012 equations. Eur Respir J 2012; 40 : 1324–1343. Hunter JD. Matplotlib: A 2D Graphics Environment. Comput Sci Eng 2007; 9 : 90–95. Merino‐Hernández A, Muñoz‐Cutillas A, Ramos‐Navarro C, Bellón‐Alonso S, Rodríguez‐Cimadevilla JL, González‐Pacheco N et al. Long‐term lung function follow‐up of preterm infants less than 32 weeks of gestational age. Pediatr Pulmonol 2024; 59 : 2922–2931. Pagel J, Twisselmann N, Rausch TK, Waschina S, Hartz A, Steinbeis M et al. Increased Regulatory T Cells Precede the Development of Bronchopulmonary Dysplasia in Preterm Infants. Front Immunol 2020; 11 . Kurata H, Ochiai M, Inoue H, Kusuda T, Fujiyoshi J, Ichiyama M et al. Inflammation in the neonatal period and intrauterine growth restriction aggravate bronchopulmonary dysplasia. Pediatr Neonatol 2019; 60 : 496–503. Mai J, Virtue A, Shen J, Wang H, Yang X-F. An evolving new paradigm: endothelial cells – conditional innate immune cells. J Hematol Oncol 2013; 6 : 61. Choi CW, Lee J, Oh JY, Lee SH, Lee HJ, Kim B Il. Protective effect of chorioamnionitis on the development of bronchopulmonary dysplasia triggered by postnatal systemic inflammation in neonatal rats. Pediatr Res 2016; 79 : 287–294. Shrestha AK, Bettini ML, Menon RT, Gopal VYN, Huang S, Edwards DP et al. Consequences of early postnatal lipopolysaccharide exposure on developing lungs in mice. Am J Physiol Cell Mol Physiol 2019; 316 : L229–L244. Ambalavanan N, Carlo WA, D’Angio CT, McDonald SA, Das A, Schendel D et al. Cytokines Associated With Bronchopulmonary Dysplasia or Death in Extremely Low Birth Weight Infants. Pediatrics 2009; 123 : 1132–1141. Lapcharoensap W, Kan P, Powers RJ, Shaw GM, Stevenson DK, Gould JB et al. The Relationship of Nosocomial Infection Reduction to Changes in Neonatal Intensive Care Unit Rates of Bronchopulmonary Dysplasia. J Pediatr 2017; 180 : 105-109.e1. Shrestha AK, Menon RT, El-Saie A, Barrios R, Reynolds C, Shivanna B. Interactive and independent effects of early lipopolysaccharide and hyperoxia exposure on developing murine lungs. Am J Physiol Cell Mol Physiol 2020; 319 : L981–L996. Nitkin CR, Xia S, Menden H, Yu W, Xiong M, Heruth DP et al. FOSL1 is a novel mediator of endotoxin/lipopolysaccharide-induced pulmonary angiogenic signaling. Sci Rep 2020; 10 : 13143. Menden H, Welak S, Cossette S, Ramchandran R, Sampath V. Lipopolysaccharide (LPS)-mediated Angiopoietin-2-dependent Autocrine Angiogenesis Is Regulated by NADPH Oxidase 2 (Nox2) in Human Pulmonary Microvascular Endothelial Cells. J Biol Chem 2015; 290 : 5449–5461. Syed MA, Choo-Wing R, Homer RJ, Bhandari V. Role of Nitric Oxide Isoforms in Vascular and Alveolar Development and Lung Injury in Vascular Endothelial Growth Factor Overexpressing Neonatal Mice Lungs. PLoS One 2016; 11 : e0147588. Davey A, McAuley DF, O’Kane CM. Matrix metalloproteinases in acute lung injury: mediators of injury and drivers of repair. Eur Respir J 2011; 38 : 959–970. Aldridge AJ. Role of the Neutrophil in Septic Shock and the Adult Respiratory Distress Syndrome. Eur J Surg 2002; 168 : 204–214. Volanakis J. Human C-reactive protein: expression, structure, and function. Mol Immunol 2001; 38 : 189–197. Dankhara N, Holla I, Ramarao S, Kalikkot Thekkeveedu R. Bronchopulmonary Dysplasia: Pathogenesis and Pathophysiology. J Clin Med 2023; 12 : 4207. Durlak W, Thébaud B. BPD: Latest Strategies of Prevention and Treatment. Neonatology 2024; 121 : 596–607. Nold MF, Mangan NE, Rudloff I, Cho SX, Shariatian N, Samarasinghe TD et al. Interleukin-1 receptor antagonist prevents murine bronchopulmonary dysplasia induced by perinatal inflammation and hyperoxia. Proc Natl Acad Sci U S A 2013; 110 : 14384–9. Green EA, Metz D, Galinsky R, Atkinson R, Skuza EM, Clark M et al. Anakinra Pilot - a clinical trial to demonstrate safety, feasibility and pharmacokinetics of interleukin 1 receptor antagonist in preterm infants. Front Immunol 2022; 13 : 1022104. Bentsen MH, Markestad T, Øymar K, Halvorsen T. Lung function at term in extremely preterm-born infants: a regional prospective cohort study. BMJ Open 2017; 7 : e016868. Additional Declarations There is NO Competing Interest. Supplementary Files Supplementarymaterial.docx Supplementary Material Cite Share Download PDF Status: Published Journal Publication published 01 Apr, 2026 Read the published version in Communications Medicine → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7358959","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":500676406,"identity":"6a4f63b0-2915-4020-9fe5-b3b3e7f87bd8","order_by":0,"name":"Alexander Humberg","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-1226-0016","institution":"University Hospital Münster","correspondingAuthor":true,"prefix":"","firstName":"Alexander","middleName":"","lastName":"Humberg","suffix":""},{"id":500676407,"identity":"31ffd861-d76e-40f5-a8b7-6a165dfdaa5f","order_by":1,"name":"Mats Fortmann","email":"","orcid":"https://orcid.org/0000-0003-1676-8340","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Mats","middleName":"","lastName":"Fortmann","suffix":""},{"id":500676408,"identity":"ac6ce3cd-1fc1-4367-b61d-7e2418a1f4c7","order_by":2,"name":"Rebecca Dappen","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Rebecca","middleName":"","lastName":"Dappen","suffix":""},{"id":500676409,"identity":"4954c9a7-0c23-4712-b1ef-085d4be79598","order_by":3,"name":"Claudia Roll","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Claudia","middleName":"","lastName":"Roll","suffix":""},{"id":500676410,"identity":"0db20e12-63c6-413e-bba8-7f9f5dc1e4eb","order_by":4,"name":"Margarita Kozhuharova","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Margarita","middleName":"","lastName":"Kozhuharova","suffix":""},{"id":500676411,"identity":"83c2a15c-8a35-4ec6-ac94-9f21c95fe23b","order_by":5,"name":"Axel von der Wense","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Axel","middleName":"von der","lastName":"Wense","suffix":""},{"id":500676412,"identity":"13ff7c1a-b5ec-496c-88c7-841221154fc3","order_by":6,"name":"Christoph Härtel","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Christoph","middleName":"","lastName":"Härtel","suffix":""},{"id":500676413,"identity":"ef55bc46-2f98-4ffc-bef5-0c206df8b4d4","order_by":7,"name":"Julia Sandkötter","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Julia","middleName":"","lastName":"Sandkötter","suffix":""},{"id":500676414,"identity":"3550b6c0-ffc0-42f2-887f-9e338a3b1f65","order_by":8,"name":"Egbert Herting","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Egbert","middleName":"","lastName":"Herting","suffix":""},{"id":500676415,"identity":"4e2bd756-68c6-41f9-a92f-ee7560ac0c1a","order_by":9,"name":"Wolfgang Göpel","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Wolfgang","middleName":"","lastName":"Göpel","suffix":""}],"badges":[],"createdAt":"2025-08-12 20:10:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7358959/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7358959/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s43856-026-01569-8","type":"published","date":"2026-04-01T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":90903602,"identity":"2a17effe-db76-415e-9079-84fea02bd8e2","added_by":"auto","created_at":"2025-09-09 12:50:02","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":45154,"visible":true,"origin":"","legend":"\u003cp\u003eIn- and exclusion of infants from the GNN for current analysis. VLBWI = very low birthweight infants, CrP =C-reactive protein\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7358959/v1/79e61f5f9e3c39260466f62d.png"},{"id":106074231,"identity":"23d8aad7-2251-4e9d-b9a0-d3936f58615f","added_by":"auto","created_at":"2026-04-03 07:12:21","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1003808,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7358959/v1/2e6cf337-4caa-456d-b02f-4358dd0e11d8.pdf"},{"id":90905055,"identity":"89bea496-28a6-48d7-96d2-63bb29b38785","added_by":"auto","created_at":"2025-09-09 12:58:02","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":222265,"visible":true,"origin":"","legend":"Supplementary Material","description":"","filename":"Supplementarymaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-7358959/v1/b1d3db695a166efc5959a4c7.docx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Predictive value of increased C-reactive protein levels in preterm infants on respiratory function at five to six years of age: a cohort study","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePremature birth affects a variety of organ systems with increased risk for medical morbidity and long-term sequelae \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. One of the main complications is bronchopulmonary dysplasia (BPD), a serious respiratory complication affecting infants with disrupted alveolarization, microvascular development, thickening of the basement membrane and lymphocytic infiltration \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. BPD is a multifactorial condition with diverse endotypes that include infection-inflammation-driven and placental dysfunction-related mechanisms. These endotypes contribute to distinct clinical phenotypes, necessitating a shift toward precision medicine in BPD management. Emerging evidence highlights the potential of targeted therapeutic approaches tailored to these endotypes, as for example IL-1 receptor antagonists in mitigating inflammation-driven lung injury or anti-fibrotic agents like nintedanib for fibrotic endotypes of chronic lung disease \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe C-reactive protein (CrP), an acute phase protein, is the clinically most used inflammation and infection marker in neonates that rises several hours after the onset of inflammation \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Few studies described an association of postnatal elevated CrP levels with BPD \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. From these observations it seems that an early detected CrP increase within the first days of life is associated with the development of BPD and can be taken as a biomarker for the prediction of BPD independently from the presence of either early- or late-onset sepsis \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Although BPD is a commonly used marker of lung injury, there is a growing consensus that it is a relatively poor predictor of long-term lung health. Children born preterm present with impaired lung function, regardless of a BPD diagnosis \u003csup\u003e\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e and it is currently perceived that BPD is a relatively poor indicative factor for neonatal lung injury \u003csup\u003e\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Given the limitations of BPD as a diagnostic marker, there is an urgent need for new, reliable predictive parameters that can identify VLBWI at high risk for chronic respiratory issues early on. Personalized management of BPD has the potential to improve long-term pulmonary outcomes by aligning therapeutic strategies with the specific molecular and clinical profiles of affected infants.\u003c/p\u003e\u003cp\u003eThe objective of this study was to investigate whether elevated CrP levels within the first 28 days of life, particularly when recurrent, were associated with compromised respiratory function at five to six years in VLBWI.\u003c/p\u003e"},{"header":"Subjects and methods","content":"\u003cp\u003eStudy population\u003c/p\u003e\n\u003cp\u003eThe German Neonatal Network (GNN) is a multicentre observational population-based cohort study enrolling VLBWI with \u0026lt;\u0026thinsp;1500 g birth weight from 2009\u0026ndash;2016 and \u0026lt;\u0026thinsp;1000g birth weight since 2017 in Germany (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ewww.vlbw.de\u003c/span\u003e\u003c/span\u003e)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Yearly on-site-monitoring by a study nurse or paediatrician experienced in neonatology ensures proper assessment of clinical data. In the context of this study, VLBWI\u0026thinsp;\u0026lt;\u0026thinsp;1500 g birth weight and extremely low birth weight infants (ELBWI, \u0026lt; 1000 g birth weight) born in 4 GNN sites (University of L\u0026uuml;beck, Vest Children\u0026apos;s Hospital Datteln, Altona Children\u0026apos;s Hospital Hamburg, University Hospital M\u0026uuml;nster) between 1st of January 2009 and 31st of December 2015 and with information about laboratory CrP levels were included.\u003c/p\u003e\n\u003cp\u003eExclusion criteria included lethal abnormalities and missing data on CrP levels.\u003c/p\u003e\n\u003cp\u003eEthics\u003c/p\u003e\n\u003cp\u003eApproval by the local ethics committee for research in human subjects of the University of L\u0026uuml;beck (file number 08\u0026ndash;022 and 14\u0026ndash;220) and by the local ethics committees of all participating centres has been granted. The GNN was funded by the German Ministry for Education and Research (BMBF-grant-No: 01ER0805 and 01ER1501).\u003c/p\u003e\n\u003cp\u003eLaboratory measurements of CrP values\u003c/p\u003e\n\u003cp\u003eCrP levels were measured using serum or plasma samples, carried out as directed by physicians by medical indication (e.g. suspicion of infection or monitoring the progress of a confirmed infection), and recorded retrospectively. The analysis of the CrP level was conducted using the standard Tina Quant CrP test and the Cobas c 701 analyzer from Roche. The determination of the CrP concentration is accomplished through an immunological turbidimetry test.\u003c/p\u003e\n\u003cp\u003eDefinition of recurrent CrP elevations\u003c/p\u003e\n\u003cp\u003eRecurrent CrP increases were defined based on the dynamics of the CrP laboratory values and the following characteristics: a) the first value had to exceed 10 mg/l, b) there had to be a minimum interval of \u0026gt;\u0026thinsp;14 days between 2 values of \u0026gt;\u0026thinsp;10 mg/l and a decrease in CrP to \u0026lt;\u0026thinsp;5 mg/dl had to be demonstrated in the meantime.\u003c/p\u003e\n\u003cp\u003eFurther definitions are given in the supplementary material.\u003c/p\u003e\n\u003cp\u003eFollow-up\u003c/p\u003e\n\u003cp\u003eAt the age of five to six years, participating children born preterm and included in the GNN were recruited for a structured follow-up evaluation. During the recruitment process, the study team reached out to the hospital where the children were born to schedule follow-up assessments. Families were randomly contacted and invited for follow-up with a particular emphasis on infants born before 28 weeks of gestational age. The follow-up examination encompassed various components, including interviewing the child\u0026apos;s parents or caregivers, measuring the child\u0026apos;s body parameters, neuro-motor developmental assessment and lung function testing \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eMeasurement of lung function at five to six years\u003c/p\u003e\n\u003cp\u003eLung function parameters were assessed using spirometry involving the utilization of a flow sensor and the Easy-on PC software (manufactured by ndd Medizintechnik AG, Zurich, Switzerland). The execution of lung function measurements followed a standardized protocol, commencing with a ten-minute resting phase. Subsequently, the child assumed a comfortable sitting position on a chair. Nasal flow was prevented by a nose clip. Recording the parameters requires maximal expiration, which was achieved through visual representations on a notebook. Children were encouraged to blow out candles on the notebook, inflate a balloon as fully as possible with a single breath, or set a swing in motion through exhalation. Up to ten attempts could be made by each child with the best attempt being considered for analysis. Valid attempts involved maximal expiration to zero flow, followed by deep inhalation and a strong exhalation. Additionally, the quality of attempts was noted based on the criteria described above, as well as cooperation during the procedure and any remarks regarding potential accompanying factors, issues, or anomalies.\u003c/p\u003e\n\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eStatistical analysis\u003c/h2\u003e\n \u003cp\u003eThe baseline characteristics of maternal and neonatal variables were represented in the form of medians, interquartile ranges (IQR), counts, frequencies, and 95% confidence intervals (CI) for column percentages. Unadjusted comparisons were assessed using the Chi-square test and the Mann-Whitney U-Test.\u003c/p\u003e\n \u003cp\u003eFEV\u003csub\u003e1\u003c/sub\u003e and FVC were documented in litres. The FEV\u003csub\u003e1\u003c/sub\u003e and FVC z-scores were calculated according to the Global Lung Function Initiative \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e with z-scores \u0026lt; -1.644 according to values\u0026thinsp;\u0026lt;\u0026thinsp;5th percentile. Linear regression models were computed for the z-scores of FEV\u003csub\u003e1\u003c/sub\u003e and FVC and adjusted for gestational age, birth weight, born small-for-gestational age, antenatal steroid usage, cerebral hemorrhage, periventricular leucomalacia, cerebral palsy (Gross Motor Function Classification System\u0026thinsp;\u0026ge;\u0026thinsp;1), surgical treatment of necrotizing enterocolitis, mechanical ventilation, duration of mechanical ventilation, duration of oxygen therapy within the first 28 days, presence of BPD, intelligence quotient, and weight at five year follow-up. The diagnostic performance of recurrent CrP elevations was assessed using sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for the outcome FEV\u003csub\u003e1\u003c/sub\u003e z-score\u0026thinsp;\u0026lt;\u0026thinsp;5th percentile. Receiver operating characteristic (ROC) curves were utilized to evaluate the predictive performance of various neonatal variables for the defined outcomes. The area under the curve (AUC) and corresponding % confidence intervals were calculated for each variable to quantify its ability to distinguish between outcome groups. Variables with AUC values closer to 1 were considered strong predictors, while values near 0.5 indicated no predictive power. Statistical significance of the AUC was determined using asymptotic p-values. Missing values were ignored.\u003c/p\u003e\n \u003cp\u003eAll statistical analyses were carried out using SPSS software (IBM SPSS Statistics for Windows, Version 29.0, Munich, Germany). Figures were created using python language version 3.13.0 with matplotlib v3.9.3 \u003csup\u003e20\u003c/sup\u003e. Raw data were generated at the University of Luebeck and the University of Muenster. Derived data supporting the findings of this study are available from the corresponding author on request.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eStudy population\u003c/p\u003e\u003cp\u003eBetween January 1st 2009 and December 31st 2015, 13849 infants\u0026thinsp;\u0026lt;\u0026thinsp;1500 g birth weight were enrolled in the GNN (shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Of these infants, 3848 were assessed for follow-up at the age of five to six years. After exclusion of infants not evaluated for CrP levels as these centres did not participate in CrP value collection, primary data sets of 353 preterm infants with five to six year follow-up and CrP measurement remained for analysis.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eInfants with single elevation of Crp were more frequently born SGA than those with no elevations of CrP (26.1% [95% CI 15.1\u0026ndash;40.0] vs. 12.8% [9.2\u0026ndash;17.3], p\u0026thinsp;=\u0026thinsp;0.01). However, differences were more evident in children with multiple CrP elevations. These infants were born at lower gestational age (25.6 [24.4\u0026ndash;27.6] weeks vs. 28.1 weeks [26.1\u0026ndash;29.7], p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and birth weight (685g [540\u0026ndash;870] vs. 990 g [540\u0026ndash;870], p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) with higher rates of born SGA (35.7% [22.6\u0026ndash;50.8] vs. 12.8% [9.2\u0026ndash;17.3], p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and increased rates of neurologic and abdominal complications (Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCohort characteristics\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNo Elevation of CrP\u003c/p\u003e\u003cp\u003en\u0026thinsp;=\u0026thinsp;265\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSingle elevation of CrP\u0026thinsp;\u0026gt;\u0026thinsp;10mg/l\u003c/p\u003e\u003cp\u003en\u0026thinsp;=\u0026thinsp;46\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRecurrent elevation of CrP\u0026thinsp;\u0026gt;\u0026thinsp;10 mg/l\u003c/p\u003e\u003cp\u003en\u0026thinsp;=\u0026thinsp;42\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTotal cohort\u003c/p\u003e\u003cp\u003en\u0026thinsp;=\u0026thinsp;353\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eGestational age [weeks]\u003c/b\u003e\u003csup\u003e\u003cb\u003e#\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e28.1 (26.1\u0026ndash;29.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e26.1 (25.0\u0026ndash;29.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e25.6 (24.4\u0026ndash;27.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e27.6 (25.7\u0026ndash;29.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBirth weight [g]\u003c/b\u003e\u003csup\u003e\u003cb\u003e#\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e990 (780\u0026ndash;1265)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e815 (680\u0026ndash;1110)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e685 (540\u0026ndash;870)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e957 (725\u0026ndash;1220)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSGA (\u0026lt;\u0026thinsp;10th percentile)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e34 (12.8 [9.2\u0026ndash;17.3])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12 (26.1 [15.1\u0026ndash;40.0])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e15 (35.7 [22.6\u0026ndash;50.8])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e61 (17.3 [13.6\u0026ndash;21.5])\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eFemale sex\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e125 (47.2[41.2\u0026ndash;53.2])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e23(50.0 [35.9\u0026ndash;64.1])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e16 (38.1 [24.6\u0026ndash;53.2])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e164 (46.5 [41.3\u0026ndash;51.7])\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMultipara\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e106 (40.0 [34.2\u0026ndash;46.0])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e20 (43.5 [29.9\u0026ndash;57.8])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e14 (33.3 [20.6\u0026ndash;48.3])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e140 (39.7 [34.7\u0026ndash;44.8])\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAntenatal administration of steroids\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e237 (89.4 [85.3\u0026ndash;92.7])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e44 (95.7 [86.8\u0026ndash;99.1])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e40 (95.2 [85.6\u0026ndash;99.0])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e321 (90.9 [87.6\u0026ndash;93.6])\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSurfactant administration\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e199 (75.1 [69.6\u0026ndash;80.0])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e40 (87.0 [75.1\u0026ndash;94.4])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e40 (95.2 [85.6\u0026ndash;99.0])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e279(79.0 [74.6\u0026ndash;83.0])\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eICH\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e37 (14.0 [10.2\u0026ndash;18.5])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6 (13.0 [5.6\u0026ndash;24.9])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9 (21.4 [11.2\u0026ndash;35.5])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e52 (14.7 [11.3\u0026ndash;18.7])\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePVL\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (0.8 [0.2\u0026ndash;2.4])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (6.5 [1.9\u0026ndash;16.4])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (4.8 [1.0-14.4])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e7 (2.0 [0.9\u0026ndash;3.9])\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNEC requiring surgery\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (0.4 [0.0-1.8])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (2.2 [0.2\u0026ndash;9.7])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6 (14.3 [6.2\u0026ndash;27.1])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e8 (2.3 [1.1\u0026ndash;4.2])\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSIP requiring surgery\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (0.8 [0.2\u0026ndash;2.4])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (2.2 [0.2\u0026ndash;9.7])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6 (14.3 [6.2\u0026ndash;27.1])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e9 (2.6 [1.3\u0026ndash;4.6])\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003einvasive ventilation\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e121 (45.8 [39.9\u0026ndash;51.9])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e32 (69.6 [55.4\u0026ndash;81.4])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e41 (97.6 [89.4\u0026ndash;99.7])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e194 (55.1 [49.9\u0026ndash;60.3])\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eClinical signs of chorioamnionitis\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e63 (23.8 [19.0-29.2])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10 (21.7 [11.8\u0026ndash;35.1])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e11 (26.2 [14.8\u0026ndash;40.8])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e63 (23.8 [19.0-29.2])\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAmount of CrP values\u0026thinsp;\u0026gt;\u0026thinsp;10 mg/l\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4 (3\u0026ndash;10)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0\u0026ndash;1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eFrequency of CrP determinations\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (3\u0026ndash;6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7 (5\u0026ndash;9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12 (9\u0026ndash;14)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e5 (3\u0026ndash;8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e: \u003cem\u003eCohort characteristics stratified by amount of CrP levels\u0026thinsp;\u0026gt;\u0026thinsp;10 mg/l, categorical variables are given as n(%) with corresponding 95% confidence interval (CI), continuous variables as median (IQR) if appropriate (#). Abbreviation: CrP: C-reactive protein, SGA: small for gestational age, ICH: intracerebral hemorrhage, PVL: periventricular leucomalacia, NEC: necrotizing enterocolitis, SIP: spontaneous intestinal perforation\u003c/em\u003e\u003c/p\u003e\u003cp\u003eUnivariate analyses\u003c/p\u003e\u003cp\u003eVLBWI with single CrP elevation had significantly higher rates of bronchopulmonary dysplasia (BPD) (34.8% [22.3\u0026ndash;49.1] vs. 17.3% [13.1\u0026ndash;22.3], p\u0026thinsp;=\u0026thinsp;0.006), oxygen need at discharge (8.7% [3.0-19.4] vs. 1.5% [0.5\u0026ndash;3.5], p\u0026thinsp;=\u0026thinsp;0.004) and higher rates for z-scores\u0026thinsp;\u0026lt;\u0026thinsp;5th percentile for FEV\u003csub\u003e1\u003c/sub\u003e (61.8% [45.0-76.6] vs. 35.3% [29.0\u0026ndash;42.0], p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and FVC (50.0% [33.8\u0026ndash;66.2] vs. 37.3% [30.8\u0026ndash;44.0], p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (see supplementary table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eIn comparison to cases with no elevation of CrP, the group exhibiting recurrent elevation of CrP showed significantly higher incidences of BPD (59.5% [44.5\u0026ndash;73.3] vs. 17.3% [13.1\u0026ndash;22.3], p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), increased oxygen requirement at discharge (14.3% [6.2\u0026ndash;27.1] vs. 1.5% [0.5\u0026ndash;3.5], p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and a lower median weight at five to six-year follow-up (16.6 kg [15.1\u0026ndash;19.2] vs. 18.6 kg [16.7\u0026ndash;20.7], p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Regarding respiratory function and related parameters, recurrence of elevated CrP was associated with reduced lung function as evidenced by decreased FEV\u003csub\u003e1\u003c/sub\u003e (0.77 [0.67\u0026ndash;0.91] vs. 0.97 litres [0.85\u0026ndash;1.12], p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Moreover, z-scores of FEV\u003csub\u003e1\u003c/sub\u003e and FVC were significantly reduced in infants with recurrent elevations and the percentage of individuals with FEV\u003csub\u003e1\u003c/sub\u003e and FVC z-score\u0026thinsp;\u0026lt;\u0026thinsp;5th percentile is markedly higher in the recurrent elevation of CrP group 71.9% [54.9\u0026ndash;85.1] vs. 35.3% [29.0\u0026ndash;42.0] (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and 81.3% [65.4\u0026ndash;91.8] vs. 37.3% [30.8\u0026ndash;44.0] (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001,) respectively.\u003c/p\u003e\u003cp\u003eVLBWI with recurrent CrP elevations differed significantly from children with a single CrP elevation with respect to BPD rate (59.5% [44.5\u0026ndash;73.3] vs. 34.8% [22.3\u0026ndash;49.1], p\u0026thinsp;=\u0026thinsp;0.020), median weight at 5 years of age (16.6kg (15.1\u0026ndash;19.2) vs. 18.6kg (16.6\u0026ndash;19.3), p\u0026thinsp;=\u0026thinsp;0.034), a higher rate for gross motor function scale (GMFCS) scores\u0026thinsp;\u0026ge;\u0026thinsp;1 (43.6% [28.9\u0026ndash;59.1] vs. 20.5% [10.6\u0026ndash;34.0], p\u0026thinsp;=\u0026thinsp;0.023), as well as reduced median lung parameters for FEV (0.77 l (0.67\u0026ndash;0.91) vs. 0.93 (0.80\u0026ndash;1.06), p\u0026thinsp;=\u0026thinsp;0.009) and FVC (0.8 l (0.66\u0026ndash;0.94) vs. 1.01 l (0.83\u0026ndash;1.15), p\u0026thinsp;=\u0026thinsp;0.002) and a higher rate of z-score values\u0026thinsp;\u0026lt;\u0026thinsp;5th percentile for FVC (81.3% [65.4\u0026ndash;91.8] vs 50.0% [33.8\u0026ndash;66.2], p\u0026thinsp;=\u0026thinsp;0.008).\u003c/p\u003e\u003cp\u003eAdjusted analyses\u003c/p\u003e\u003cp\u003eTo adjust for possible confounding variables, z-scores of lung function were tested in a linear regression model. Scatterplots with the fitted regression line are examined to ensure model assumptions were met. The residuals appeared to be independent (Durbin-Watson).\u003c/p\u003e\u003cp\u003eIn this analysis, several factors exhibited associations with reduced lung function. Recurrent elevations of CrP correlated with decreased FEV\u003csub\u003e1\u003c/sub\u003e and FVC z-scores (Table \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and table 4), indicating that this factor was linked to decreased lung function. However, single increases of CrP were not correlated with reduced FEV\u003csub\u003e1\u003c/sub\u003e and FVC values (see supplementary table 2a and 2b).\u003c/p\u003e\u003cp\u003eNotably, higher weight at five to six-year follow-up demonstrated a positive correlation with FVC z-scores, suggesting that increased weight is linked to improved values. This result highlighted the importance of weight gain, while also suggesting the negative impact of recurrent elevations in CrP levels on the respiratory function of these individuals in their early childhood years.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eLinear regression model for respiratory long-term outcome\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eVariables\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e\u003cp\u003ez-score of FEV\u003csub\u003e1\u003c/sub\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB (SD)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBeta\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eT\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eGMFCS\u0026thinsp;\u0026ge;\u0026thinsp;1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-0.041 (0.197)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-0.015\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-0.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.834\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eWeight at 5YFU [kg]\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.013 (0.019)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.048\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.498\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eIQ\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.012 (0.006)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.138\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.038\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDuration of mechanical ventilation [days]\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e00.405 (0.238)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-0.179\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-1.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.090\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRecurrent CrP\u0026thinsp;\u0026gt;\u0026thinsp;10 mg/l\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-0.718 (0.234)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-0.213\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-3.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.002\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e: \u003cem\u003eLinear regression model for respiratory long-term outcome. Model further adjusted for gestational age, birth weight, antenatal administration of steroids, IVH, surgical treatment for necrotizing enterocolitis, birth weight\u0026thinsp;\u0026lt;\u0026thinsp;10th percentile, duration of mechanical ventilation, duration of oxygen therapy within the first 28 days, BPD and PVL (data not shown). R\u003c/em\u003e\u003csup\u003e\u003cem\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/em\u003e\u003c/sup\u003e: \u003cem\u003e0.265; Durbin-Watson: 1.930; F\u0026thinsp;=\u0026thinsp;4.426 with p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Abbreviation: B: unstandardized coefficients, Beta: standardized coefficients, IQ: intelligence quotient\u003c/em\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eLinear regression model for respiratory long-term outcome\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eVariables\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e\u003cp\u003ez-score of FVC\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB (SD)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBeta\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eT\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eGMFCS\u0026thinsp;\u0026ge;\u0026thinsp;1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-0.474 (0.223)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-0.145\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-2.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.035\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eWeight at 5YFU [kg]\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.043 (0.021)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.139\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.045\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eIQ\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.013 (0.007)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.132\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.044\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDuration of mechanical ventilation [days]\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-0.043 (0.268)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-0.016\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-0.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.873\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRecurrent CrP\u0026thinsp;\u0026gt;\u0026thinsp;10 mg/l\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-1.114 (0.268)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-0.287\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-4.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e: \u003cem\u003eLinear regression model for respiratory long-term outcome. Model further adjusted for gestational age, birth weight, antenatal administration of steroids, IVH, surgical treatment for necrotizing enterocolitis, birth weight\u0026thinsp;\u0026lt;\u0026thinsp;10th percentile, duration of oxygen therapy within the first 28 days, BPD and PVL (data not shown). R\u003c/em\u003e\u003csup\u003e\u003cem\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/em\u003e\u003c/sup\u003e: \u003cem\u003e0.296; Durbin-Watson: 1.959; F\u0026thinsp;=\u0026thinsp;5.153 with p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Abbreviation: B: unstandardized coefficients, Beta: standardized coefficients, IQ: intelligence quotient\u003c/em\u003e\u003c/p\u003e\u003cp\u003eAccuracy of tests\u003c/p\u003e\u003cp\u003eTesting of recurrent CrP elevations on the outcome FEV\u003csub\u003e1\u003c/sub\u003e z-score\u0026thinsp;\u0026lt;\u0026thinsp;5th percentile demonstrated a sensitivity of 71.9%. Specificity was 60.9%. The positive predictive value (PPV) was 19.8% and negative predictive value (NPV) was 94.2%.\u003c/p\u003e\u003cp\u003eSupplementary analyses\u003c/p\u003e\u003cp\u003eFrequency of CrP determinations grouped by recurrent elevations\u0026thinsp;\u0026gt;\u0026thinsp;10 mg/l against all other infants with single and no CrP elevation is given in supplementary Fig.\u0026nbsp;1. Highest frequencies of CrP determination are found within the first days of life. Infants with recurrent CrP elevations have continuously higher values of CrP during the first 28 days of life (supplementary Fig.\u0026nbsp;2) and higher values of inflammatory markers in the white blood count (supplementary table 3), indicating a higher systemic inflammatory impact. Furthermore, infants with worse respiratory long-term outcome show higher median CrP levels over the first 28 days of life (supplementary Figs.\u0026nbsp;3 and 4). However, median levels of CrP were not associated with worse respiratory outcome (supplementary table 4a and 4b). Independent from early diagnosis of BPD, frequencies for long-term respiratory sequalae are increased represented in the group of recurrent CrP elevations (supplementary table 5).\u003c/p\u003e\u003cp\u003eThe ROC analysis evaluated the predictive power of neonatal clinical parameters on long-term respiratory outcome prediction (supplementary table 6 and 7). Among the tested variables, CrP elevations\u0026thinsp;\u0026gt;\u0026thinsp;10 mg/L within the first 28 days of life emerged as a significant predictor of z-scores of FEV1 and FVC\u0026thinsp;\u0026lt;\u0026thinsp;5th percentile. In addition, ventilation duration and diagnosis of BPD showed a significant predictive relationship. Concerning the prediction of lower FVC values, other variables such as gestational age and birth weight also demonstrated significant, albeit weaker, associations.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study investigated the association between elevated CrP levels within the first 28 days of life in VLBWI and long-term respiratory function at the age of five to six years. Our findings revealed a significant correlation between recurrent elevation of CrP during the neonatal period and adverse respiratory outcomes in later life. We could further show that the absence of recurrent CrP elevations has potential at correctly excluding individuals without reduced lung function. However, the low sensitivity indicates a considerable proportion of true cases are missed and limits its utility as a standalone diagnostic tool for identifying all positive cases. Furthermore, regarding our ROC analysis, our findings highlight the multifactorial nature of long-term pulmonary outcomes in preterm infants. Systemic inflammation, as evidenced by CrP elevations, prolonged mechanical ventilation, and the diagnosis of BPD, represent key contributors to reduced respiratory parameters at 5 years of age. We here used the measurement of FEV\u003csub\u003e1\u003c/sub\u003e and FVC via spirometry as a standard pulmonary function test for neonatal outcome-measurement \u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eOur study aligns with previous research linking early inflammation or immune-dysregulation \u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e to adverse respiratory outcomes. Stimulation of inflammatory cascades, involving cytokines and pattern recognition receptors, can lead to endothelial cell activation, oxidative stress, cell death, and microvascular complications, contributing to lung injury in neonates \u003csup\u003e\u003cspan additionalcitationids=\"CR24 CR25\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. Studies have shown associations between elevated levels of serum eosinophil chemotactic factors, TNF-α, IL-1β, IL-6, IL-8, and other pro-inflammatory markers with the occurrence and prognosis of BPD \u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. Furthermore, reductions in neonatal sepsis prevalence appear to correlate with a decreased incidence of BPD, suggesting a potential link between postnatal sepsis and the risk of BPD in premature infants \u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. Rodent models of postnatal sepsis-induced lung injury using systemic LPS exposure in newborn mice highlight the vulnerability and an ontogenic window in early lung development to inflammation-induced disruptions, affecting lung morphogenic pathways critical for distal acinar development \u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e,\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. These data underscore the role of endothelial cells in both developmental angiogenesis and sepsis-induced dysmorphic angiogenesis, indicating that factors like vascular endothelial growth factor (VEGF), angiopoietins, and FOSL1 play complex roles in this process \u003csup\u003e\u003cspan additionalcitationids=\"CR31\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. An altered elastic fibre assembly, mesenchymal and fibroblast growth factor downregulation, and protease-mediated lung extracellular matrix degradation also play an important role in sepsis-induced lung injury \u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e,\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eInduction of CrP expression is significantly influenced by IL-6 and IL-1, leading to activation of phagocytic cells, production of inflammatory cytokines, and regulation of the complement pathway, potentially resulting in adverse vascular events when elevated \u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. In clinical settings, monitoring of CrP levels is one of the most widely used detection methods for neonatal sepsis. The relationship between CrP and diseases, particularly in premature infants, has garnered significant attention as it may aid to early detect a risk for respiratory long-term complication and may guide future interventions for BPD to improve prognoses. Studies have consistently linked elevated CrP levels with bronchopulmonary dysplasia (BPD) in preterm infants \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Elevated CrP levels, particularly on day 28 of life, have been associated with BPD and increased mortality risk, indicating a systemic inflammatory response \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Notably, elevated CrP levels have been observed early before clinical symptoms of BPD manifestation, highlighting its potential as an early diagnostic marker \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eOne strength of this study is that results of respiratory outcome are adjusted for several risk factors impacting respiratory outcome, like gestational age, birth weight and mechanical ventilation. Besides these variables, increased recurrent CrP values are associated with poor expiratory airflow at age five to six years. Furthermore, evaluation of lung function parameters assessed by a consistent team of physicians and nurses suggests a high consistency of the data. Despite its strengths, our study might have limitations worth considering. For instance, the focus on expiratory airflow as an outcome might not encompass the entirety of respiratory function. Additionally, the absence of detailed mechanistic insights or direct causality between long-term lung impairment and increased CrP values might warrant further investigations. Furthermore, studies have indicated a systemic inflammatory response associated with Ureaplasma spp. in premature neonates, leading to elevated CrP levels. This chronic systemic inflammatory response may be linked to the development and persistence of lung injury. We here also cannot control for potential effects as the presence for \u003cem\u003eureaplasma spp\u003c/em\u003e. is not recorded in our data set. The retrospective nature of our study may introduce bias and limit the establishment of causal relationships. The absence of planned blood samples in the GNN dataset constrained the availability of CrP data, potentially affecting the representativeness of the sample. Additionally, the study's reliance on CrP as a sole inflammatory marker may overlook the contribution of other inflammatory factors. Our follow-up cohort has a risk of selection bias. For the follow-up, we chose a random invitation practice. However, it is possible that the invitation process and voluntary participation in the follow-up studies resulted in a bias towards presenting an incompletely balanced group. Furthermore, while efforts are made to adjust for confounding variables, residual confounders might influence the observed associations. Further studies should therefore take additional factors as environmental exposures like genetic predispositions, histologic proved chorioamnionitis, hemodynamic relevant factors during prematurity, respiratory infections, parental smoking or vaccination status into account \u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. From our data it can be assumed, that infections detected by increased CrP levels increase the risk for developing respiratory complications. From our data we cannot distinguish between recurrent infections reflected by different CrP elevations or a possible underlying sustained inflammation leading to a continuous process of inflammatory process.\u003c/p\u003e\u003cp\u003eIn conclusion, our study conveys information about the impact of systemic inflammation on respiratory outcomes in preterm infants. Our findings highlight the importance of early inflammatory markers in predicting long-term respiratory health and warrant further research to explore interventions for mitigating the impact of inflammation on neonatal lung injury and subsequent respiratory complications. Our findings emphasize the need for individualized approaches to monitoring neonatal inflammation and its progression. This perspective aligns with the growing interest in tailoring treatment strategies based on endotype classification \u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e. Interventions targeting the inflammatory pathways, such as IL-1 receptor antagonists like anakinra, hold promise in mitigating inflammation-driven lung injury \u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e,\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e. While BPD has traditionally been used as a predictor, it is now recognized as a relatively poor measure of neonatal lung injury \u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e. Therefore, there is a need for new and feasible diagnostic methods to better understand lung injury in these vulnerable infants and to predict their future respiratory health accurately. This knowledge is essential for assessing interventions aimed at early prevention and treatment of lung disease in preterm infants. The measurement of recurrent CrP elevations in a combined model with other risk factors such as mechanical ventilation could be a clinical tool for further risk assessment studies. Further research is warranted to elucidate the mechanisms linking early inflammation to CLD development and to evaluate the feasibility of integrating inflammatory monitoring into clinical practice.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e5YFU five to six year follow-up examination\u003c/p\u003e\n\u003cp\u003eAUC area under the curve\u003c/p\u003e\n\u003cp\u003eBPD bronchopulmonary dysplasia\u003c/p\u003e\n\u003cp\u003eCrP C-reactive protein\u003c/p\u003e\n\u003cp\u003eEDTA ethylene diamine tetraacetic acid\u003c/p\u003e\n\u003cp\u003eFEV\u003csub\u003e1\u003c/sub\u003e forced expiratory volume in one second\u003c/p\u003e\n\u003cp\u003eFEV\u003csub\u003e1\u003c/sub\u003e% forced expiratory volume in one second as a percentage of predicted\u003c/p\u003e\n\u003cp\u003eFVC forced vital capacity\u003c/p\u003e\n\u003cp\u003eFVC% forced vital capacity as a percentage of predicted\u003c/p\u003e\n\u003cp\u003eg gram\u003c/p\u003e\n\u003cp\u003eGMFCS gross motor function scale\u003c/p\u003e\n\u003cp\u003eGNN German Neonatal Network\u003c/p\u003e\n\u003cp\u003eICH intracerebral hemorrhage\u003c/p\u003e\n\u003cp\u003eIQ intelligence quotient\u003c/p\u003e\n\u003cp\u003ekg kilogram\u003c/p\u003e\n\u003cp\u003eNEC necrotizing enterocolitis\u003c/p\u003e\n\u003cp\u003ePVL periventricular leukomalacia\u003c/p\u003e\n\u003cp\u003eROC receiver operating characteristic\u003c/p\u003e\n\u003cp\u003es seconds\u003c/p\u003e\n\u003cp\u003eSGA small for gestational age\u003c/p\u003e\n\u003cp\u003eSIP spontaneous intestinal perforation\u003c/p\u003e\n\u003cp\u003eVLBWI Very low birthweight infants\u003c/p\u003e\n\u003cp\u003eWPPSI Wechsler Preschool and Primary Scale of Intelligence \u0026ndash; Third Edition\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCompeting Interests: All authors declare no financial competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the University of L\u0026uuml;beck (file numbers 08-022 and 14-220) and the ethics committees of all participating centres. Informed consent was obtained from the parents or legal guardians of all participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of Data and Materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRaw data were generated at the University of Luebeck and the University of Muenster. Derived data supporting the findings of this study are available from the corresponding author on request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe German Neonatal Network was funded by the German Ministry for Education and Research (BMBF-grant-No: 01ER0805 and 01ER1501).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMF, RD and AH wrote the manuscript; RD, WG and AH performed the analytic calculations; AH, CH EH and WG planned the study; MF, RD, CR, MK, AW, CH, JS and AH performed the data acquisition, MF, RD, CR, AW, CH, EH, WG, AH contributed to the design and implementation of the research.\u003c/p\u003e\n\u003cp\u003eAll authors discussed the results and commented on the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003ePatel R. Short- and Long-Term Outcomes for Extremely Preterm Infants. \u003cem\u003eAm J Perinatol\u003c/em\u003e 2016; \u003cstrong\u003e33\u003c/strong\u003e: 318\u0026ndash;328.\u003c/li\u003e\n\u003cli\u003eGalderisi A, Calabrese F, Fortarezza F, Abman S, Baraldi E. Airway Histopathology of Adolescent Survivors of Bronchopulmonary Dysplasia. \u003cem\u003eJ Pediatr\u003c/em\u003e 2019; \u003cstrong\u003e211\u003c/strong\u003e: 215\u0026ndash;218.\u003c/li\u003e\n\u003cli\u003eTh\u0026eacute;baud B, Goss KN, Laughon M, Whitsett JA, Abman SH, Steinhorn RH \u003cem\u003eet al.\u003c/em\u003e Bronchopulmonary dysplasia. \u003cem\u003eNat Rev Dis Prim\u003c/em\u003e 2019; \u003cstrong\u003e5\u003c/strong\u003e: 78.\u003c/li\u003e\n\u003cli\u003ePierro M, Van Mechelen K, van Westering-Kroon E, Villamor-Mart\u0026iacute;nez E, Villamor E. Endotypes of Prematurity and Phenotypes of Bronchopulmonary Dysplasia: Toward Personalized Neonatology. \u003cem\u003eJ Pers Med\u003c/em\u003e 2022; \u003cstrong\u003e12\u003c/strong\u003e: 687.\u003c/li\u003e\n\u003cli\u003eDing KL, Smith C, Seedorf G, Abman SH. Nintedanib preserves lung growth and prevents pulmonary hypertension in a hyperoxia-induced lung injury model. \u003cem\u003ePediatr Res\u003c/em\u003e 2025; \u003cstrong\u003e97\u003c/strong\u003e: 1676\u0026ndash;1683.\u003c/li\u003e\n\u003cli\u003eHengst JM. The Role of C-reactive protein in the evaluation and management of infants with suspected sepsis. \u003cem\u003eAdv Neonatal Care\u003c/em\u003e 2003; \u003cstrong\u003e3\u003c/strong\u003e: 3\u0026ndash;13.\u003c/li\u003e\n\u003cli\u003eAmbalavanan N, Ross AC, Carlo WA. Retinol-Binding Protein, Transthyretin, and C-Reactive Protein in Extremely Low Birth Weight (ELBW) Infants. \u003cem\u003eJ Perinatol\u003c/em\u003e 2005; \u003cstrong\u003e25\u003c/strong\u003e: 714\u0026ndash;719.\u003c/li\u003e\n\u003cli\u003eD\u0026rsquo;Angio CT, Ambalavanan N, Carlo WA, McDonald SA, Skogstrand K, Hougaard DM \u003cem\u003eet al.\u003c/em\u003e Blood Cytokine Profiles Associated with Distinct Patterns of Bronchopulmonary Dysplasia among Extremely Low Birth Weight Infants. \u003cem\u003eJ Pediatr\u003c/em\u003e 2016; \u003cstrong\u003e174\u003c/strong\u003e: 45-51.e5.\u003c/li\u003e\n\u003cli\u003eLeroy S, Caumette E, Waddington C, H\u0026eacute;bert A, Brant R, Lavoie PM. A Time-Based Analysis of Inflammation in Infants at Risk of Bronchopulmonary Dysplasia. \u003cem\u003eJ Pediatr\u003c/em\u003e 2018; \u003cstrong\u003e192\u003c/strong\u003e: 60-65.e1.\u003c/li\u003e\n\u003cli\u003eYang Y, Li J, Mao J. Early diagnostic value of C-reactive protein as an inflammatory marker for moderate-to-severe bronchopulmonary dysplasia in premature infants with birth weight less than 1500 g. \u003cem\u003eInt Immunopharmacol\u003c/em\u003e 2022; \u003cstrong\u003e103\u003c/strong\u003e: 108462.\u003c/li\u003e\n\u003cli\u003eSanchez-Solis M, Perez-Fernandez V, Bosch-Gimenez V, Quesada JJ, Garcia-Marcos L. Lung function gain in preterm infants with and without bronchopulmonary dysplasia. \u003cem\u003ePediatr Pulmonol\u003c/em\u003e 2016; \u003cstrong\u003e51\u003c/strong\u003e: 936\u0026ndash;942.\u003c/li\u003e\n\u003cli\u003eLombardi E, Fainardi V, Calogero C, Puglia M, Voller F, Cuttini M \u003cem\u003eet al.\u003c/em\u003e Lung function in a cohort of 5‐year‐old children born very preterm. \u003cem\u003ePediatr Pulmonol\u003c/em\u003e 2018; \u003cstrong\u003e53\u003c/strong\u003e: 1633\u0026ndash;1639.\u003c/li\u003e\n\u003cli\u003eHagman C, Bj\u0026ouml;rklund LJ, Bjermer L, Hansen‐Pupp I, Tufvesson E. Perinatal inflammation relates to early respiratory morbidity and lung function at 12 years of age in children born very preterm. \u003cem\u003eActa Paediatr\u003c/em\u003e 2021; \u003cstrong\u003e110\u003c/strong\u003e: 2084\u0026ndash;2092.\u003c/li\u003e\n\u003cli\u003eHjalmarson O, Brynjarsson H, Nilsson S, Sandberg KL. Persisting hypoxaemia is an insufficient measure of adverse lung function in very immature infants. \u003cem\u003eArch Dis Child - Fetal Neonatal Ed\u003c/em\u003e 2014; \u003cstrong\u003e99\u003c/strong\u003e: F257\u0026ndash;F262.\u003c/li\u003e\n\u003cli\u003ePriante E, Moschino L, Mardegan V, Manzoni P, Salvadori S, Baraldi E. Respiratory Outcome after Preterm Birth: A Long and Difficult Journey. Am. J. Perinatol. 2016; \u003cstrong\u003e33\u003c/strong\u003e: 1040\u0026ndash;1042.\u003c/li\u003e\n\u003cli\u003eVolls\u0026aelig;ter M, Skromme K, Satrell E, Clemm H, R\u0026oslash;ksund O, \u0026Oslash;ymar K \u003cem\u003eet al.\u003c/em\u003e Children Born Preterm at the Turn of the Millennium Had Better Lung Function Than Children Born Similarly Preterm in the Early 1990s. \u003cem\u003ePLoS One\u003c/em\u003e 2015; \u003cstrong\u003e10\u003c/strong\u003e: e0144243.\u003c/li\u003e\n\u003cli\u003eHumberg A, H\u0026auml;rtel C, Rausch TK, Stichtenoth G, Jung P, Wieg C \u003cem\u003eet al.\u003c/em\u003e Active perinatal care of preterm infants in the German Neonatal Network. \u003cem\u003eArch Dis Child Fetal Neonatal Ed\u003c/em\u003e 2020; \u003cstrong\u003e105\u003c/strong\u003e: 190\u0026ndash;195.\u003c/li\u003e\n\u003cli\u003eNissen G, Hinsenbrock S, Rausch TK, Stichtenoth G, Ricklefs I, Weckmann M \u003cem\u003eet al.\u003c/em\u003e Lung Function of Preterm Children Parsed by a Polygenic Risk Score for Adult COPD. \u003cem\u003eNEJM Evid\u003c/em\u003e 2023; \u003cstrong\u003e2\u003c/strong\u003e. doi:10.1056/EVIDoa2200279.\u003c/li\u003e\n\u003cli\u003eQuanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH \u003cem\u003eet al.\u003c/em\u003e Multi-ethnic reference values for spirometry for the 3\u0026ndash;95-yr age range: the global lung function 2012 equations. \u003cem\u003eEur Respir J\u003c/em\u003e 2012; \u003cstrong\u003e40\u003c/strong\u003e: 1324\u0026ndash;1343.\u003c/li\u003e\n\u003cli\u003eHunter JD. Matplotlib: A 2D Graphics Environment. \u003cem\u003eComput Sci Eng\u003c/em\u003e 2007; \u003cstrong\u003e9\u003c/strong\u003e: 90\u0026ndash;95.\u003c/li\u003e\n\u003cli\u003eMerino‐Hern\u0026aacute;ndez A, Mu\u0026ntilde;oz‐Cutillas A, Ramos‐Navarro C, Bell\u0026oacute;n‐Alonso S, Rodr\u0026iacute;guez‐Cimadevilla JL, Gonz\u0026aacute;lez‐Pacheco N \u003cem\u003eet al.\u003c/em\u003e Long‐term lung function follow‐up of preterm infants less than 32 weeks of gestational age. \u003cem\u003ePediatr Pulmonol\u003c/em\u003e 2024; \u003cstrong\u003e59\u003c/strong\u003e: 2922\u0026ndash;2931.\u003c/li\u003e\n\u003cli\u003ePagel J, Twisselmann N, Rausch TK, Waschina S, Hartz A, Steinbeis M \u003cem\u003eet al.\u003c/em\u003e Increased Regulatory T Cells Precede the Development of Bronchopulmonary Dysplasia in Preterm Infants. \u003cem\u003eFront Immunol\u003c/em\u003e 2020; \u003cstrong\u003e11\u003c/strong\u003e.\u003c/li\u003e\n\u003cli\u003eKurata H, Ochiai M, Inoue H, Kusuda T, Fujiyoshi J, Ichiyama M \u003cem\u003eet al.\u003c/em\u003e Inflammation in the neonatal period and intrauterine growth restriction aggravate bronchopulmonary dysplasia. \u003cem\u003ePediatr Neonatol\u003c/em\u003e 2019; \u003cstrong\u003e60\u003c/strong\u003e: 496\u0026ndash;503.\u003c/li\u003e\n\u003cli\u003eMai J, Virtue A, Shen J, Wang H, Yang X-F. An evolving new paradigm: endothelial cells \u0026ndash; conditional innate immune cells. \u003cem\u003eJ Hematol Oncol\u003c/em\u003e 2013; \u003cstrong\u003e6\u003c/strong\u003e: 61.\u003c/li\u003e\n\u003cli\u003eChoi CW, Lee J, Oh JY, Lee SH, Lee HJ, Kim B Il. Protective effect of chorioamnionitis on the development of bronchopulmonary dysplasia triggered by postnatal systemic inflammation in neonatal rats. \u003cem\u003ePediatr Res\u003c/em\u003e 2016; \u003cstrong\u003e79\u003c/strong\u003e: 287\u0026ndash;294.\u003c/li\u003e\n\u003cli\u003eShrestha AK, Bettini ML, Menon RT, Gopal VYN, Huang S, Edwards DP \u003cem\u003eet al.\u003c/em\u003e Consequences of early postnatal lipopolysaccharide exposure on developing lungs in mice. \u003cem\u003eAm J Physiol Cell Mol Physiol\u003c/em\u003e 2019; \u003cstrong\u003e316\u003c/strong\u003e: L229\u0026ndash;L244.\u003c/li\u003e\n\u003cli\u003eAmbalavanan N, Carlo WA, D\u0026rsquo;Angio CT, McDonald SA, Das A, Schendel D \u003cem\u003eet al.\u003c/em\u003e Cytokines Associated With Bronchopulmonary Dysplasia or Death in Extremely Low Birth Weight Infants. \u003cem\u003ePediatrics\u003c/em\u003e 2009; \u003cstrong\u003e123\u003c/strong\u003e: 1132\u0026ndash;1141.\u003c/li\u003e\n\u003cli\u003eLapcharoensap W, Kan P, Powers RJ, Shaw GM, Stevenson DK, Gould JB \u003cem\u003eet al.\u003c/em\u003e The Relationship of Nosocomial Infection Reduction to Changes in Neonatal Intensive Care Unit Rates of Bronchopulmonary Dysplasia. \u003cem\u003eJ Pediatr\u003c/em\u003e 2017; \u003cstrong\u003e180\u003c/strong\u003e: 105-109.e1.\u003c/li\u003e\n\u003cli\u003eShrestha AK, Menon RT, El-Saie A, Barrios R, Reynolds C, Shivanna B. Interactive and independent effects of early lipopolysaccharide and hyperoxia exposure on developing murine lungs. \u003cem\u003eAm J Physiol Cell Mol Physiol\u003c/em\u003e 2020; \u003cstrong\u003e319\u003c/strong\u003e: L981\u0026ndash;L996.\u003c/li\u003e\n\u003cli\u003eNitkin CR, Xia S, Menden H, Yu W, Xiong M, Heruth DP \u003cem\u003eet al.\u003c/em\u003e FOSL1 is a novel mediator of endotoxin/lipopolysaccharide-induced pulmonary angiogenic signaling. \u003cem\u003eSci Rep\u003c/em\u003e 2020; \u003cstrong\u003e10\u003c/strong\u003e: 13143.\u003c/li\u003e\n\u003cli\u003eMenden H, Welak S, Cossette S, Ramchandran R, Sampath V. Lipopolysaccharide (LPS)-mediated Angiopoietin-2-dependent Autocrine Angiogenesis Is Regulated by NADPH Oxidase 2 (Nox2) in Human Pulmonary Microvascular Endothelial Cells. \u003cem\u003eJ Biol Chem\u003c/em\u003e 2015; \u003cstrong\u003e290\u003c/strong\u003e: 5449\u0026ndash;5461.\u003c/li\u003e\n\u003cli\u003eSyed MA, Choo-Wing R, Homer RJ, Bhandari V. Role of Nitric Oxide Isoforms in Vascular and Alveolar Development and Lung Injury in Vascular Endothelial Growth Factor Overexpressing Neonatal Mice Lungs. \u003cem\u003ePLoS One\u003c/em\u003e 2016; \u003cstrong\u003e11\u003c/strong\u003e: e0147588.\u003c/li\u003e\n\u003cli\u003eDavey A, McAuley DF, O\u0026rsquo;Kane CM. Matrix metalloproteinases in acute lung injury: mediators of injury and drivers of repair. \u003cem\u003eEur Respir J\u003c/em\u003e 2011; \u003cstrong\u003e38\u003c/strong\u003e: 959\u0026ndash;970.\u003c/li\u003e\n\u003cli\u003eAldridge AJ. Role of the Neutrophil in Septic Shock and the Adult Respiratory Distress Syndrome. \u003cem\u003eEur J Surg\u003c/em\u003e 2002; \u003cstrong\u003e168\u003c/strong\u003e: 204\u0026ndash;214.\u003c/li\u003e\n\u003cli\u003eVolanakis J. Human C-reactive protein: expression, structure, and function. \u003cem\u003eMol Immunol\u003c/em\u003e 2001; \u003cstrong\u003e38\u003c/strong\u003e: 189\u0026ndash;197.\u003c/li\u003e\n\u003cli\u003eDankhara N, Holla I, Ramarao S, Kalikkot Thekkeveedu R. Bronchopulmonary Dysplasia: Pathogenesis and Pathophysiology. \u003cem\u003eJ Clin Med\u003c/em\u003e 2023; \u003cstrong\u003e12\u003c/strong\u003e: 4207.\u003c/li\u003e\n\u003cli\u003eDurlak W, Th\u0026eacute;baud B. BPD: Latest Strategies of Prevention and Treatment. \u003cem\u003eNeonatology\u003c/em\u003e 2024; \u003cstrong\u003e121\u003c/strong\u003e: 596\u0026ndash;607.\u003c/li\u003e\n\u003cli\u003eNold MF, Mangan NE, Rudloff I, Cho SX, Shariatian N, Samarasinghe TD \u003cem\u003eet al.\u003c/em\u003e Interleukin-1 receptor antagonist prevents murine bronchopulmonary dysplasia induced by perinatal inflammation and hyperoxia. \u003cem\u003eProc Natl Acad Sci U S A\u003c/em\u003e 2013; \u003cstrong\u003e110\u003c/strong\u003e: 14384\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eGreen EA, Metz D, Galinsky R, Atkinson R, Skuza EM, Clark M \u003cem\u003eet al.\u003c/em\u003e Anakinra Pilot - a clinical trial to demonstrate safety, feasibility and pharmacokinetics of interleukin 1 receptor antagonist in preterm infants. \u003cem\u003eFront Immunol\u003c/em\u003e 2022; \u003cstrong\u003e13\u003c/strong\u003e: 1022104.\u003c/li\u003e\n\u003cli\u003eBentsen MH, Markestad T, \u0026Oslash;ymar K, Halvorsen T. Lung function at term in extremely preterm-born infants: a regional prospective cohort study. \u003cem\u003eBMJ Open\u003c/em\u003e 2017; \u003cstrong\u003e7\u003c/strong\u003e: e016868.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Bronchopulmonary dysplasia, chronic lung disease, very low birthweight, preterm, lung function, neonatal sepsis, C-reactive protein, VLBWI, FEV1","lastPublishedDoi":"10.21203/rs.3.rs-7358959/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7358959/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe multifactorial pathophysiology of chronic lung disease in very low birthweight infants (VLBWI) includes inflammatory driven trauma of the lungs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMulticentre observational study to evaluate the predictive value of C-reactive protein (CrP) levels in VLBWI within the first 28 days of life on forced expiratory volume (FEV\u003csub\u003e1\u003c/sub\u003e) at 5-6 years of age. A CrP level exceeding 10 mg/l was considered as elevated, with recurrent elevations defined as at least two values \u0026gt;10 mg/l at intervals of 14 days or more. Univariate analyses, linear regression models, and predictive models with adjustments for gestational age, birth weight, born small-for-gestational age, antenatal steroid usage, cerebral haemorrhage, periventricular leukomalacia, cerebral palsy, surgical treatment of necrotizing enterocolitis, duration of mechanical ventilation, duration of oxygen therapy within the first 28 days, presence of BPD, intelligence quotient, and weight at five year follow-up were used.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResult\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e353 VLBWI born between 2009 and 2015 with median gestational age of 27.6 (25.7-29.4) weeks were included. Infants with recurrent CrP elevations demonstrated significantly higher rates of bronchopulmonary dysplasia (BPD) (59.5% vs. 17.3%, p \u0026lt; 0.001) and z-scores of FEV\u003csub\u003e1\u003c/sub\u003e \u0026lt; 5\u003csup\u003eth\u003c/sup\u003e percentile at five to six years (71.9% vs. 35.3%, p \u0026lt; 0.001). Absence of recurrent CrP elevations showed a negative predictive value of 94.2%, but the positive predictive value was only 19.8%.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe absence of recurrent CRP elevations in VLBWI seems to be associated with better long-term pulmonary outcome, highlighting the potential utility of inflammatory biomarkers in risk stratification for chronic lung disease.\u003c/p\u003e","manuscriptTitle":"Predictive value of increased C-reactive protein levels in preterm infants on respiratory function at five to six years of age: a cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-09 12:49:58","doi":"10.21203/rs.3.rs-7358959/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"communications-medicine","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"commsmed","sideBox":"Learn more about [Communications Medicine](http://www.nature.com/commsmed)","snPcode":"43856","submissionUrl":"https://mts-commsmed.nature.com/cgi-bin/main.plex","title":"Communications Medicine","twitterHandle":"@commsmedicine","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Communications Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"883af13f-4e4c-4ea3-b871-a58eded50d00","owner":[],"postedDate":"September 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":53191903,"name":"Health sciences/Medical research"},{"id":53191904,"name":"Health sciences/Health care"}],"tags":[],"updatedAt":"2026-04-03T07:12:14+00:00","versionOfRecord":{"articleIdentity":"rs-7358959","link":"https://doi.org/10.1038/s43856-026-01569-8","journal":{"identity":"communications-medicine","isVorOnly":false,"title":"Communications Medicine"},"publishedOn":"2026-04-01 04:00:00","publishedOnDateReadable":"April 1st, 2026"},"versionCreatedAt":"2025-09-09 12:49:58","video":"","vorDoi":"10.1038/s43856-026-01569-8","vorDoiUrl":"https://doi.org/10.1038/s43856-026-01569-8","workflowStages":[]},"version":"v1","identity":"rs-7358959","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7358959","identity":"rs-7358959","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}