Associations between vitamin D and antimicrobial peptide LL-37 in children with respiratory syncytial virus pneumonia

doi:10.21203/rs.3.rs-2577440/v1

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Associations between vitamin D and antimicrobial peptide LL-37 in children with respiratory syncytial virus pneumonia

https://doi.org/10.21203/rs.3.rs-2577440/v1

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Objective

We investigated the effects of serum vitamin D and antimicrobial peptide LL-37 levels on the respiratory syncytial virus (RSV) pneumonia in children.

Methods

From January 2021 to December 2021, 81 children with RSV pneumonia (case group) were divided into severe group (n = 29) and normal group (n = 52) according to the 2019 edition of the expert consensus on childhood pneumonia, while 45 health clinic checkup children were selected as controls. Serum 25-(OH)D levels were measured by electrochemiluminescence and serum LL-37 levels were measured by enzyme-linked immunosorbent assay. Levels and correlations between groups were then statistically analyzed.

Results

25-(OH)D levels in the case group (91.25 ± 24.80 nmol/L) were significantly lower than in the healthy controls (104.91 ± 22.23 nmol/L, P < 0.01). LL-37 levels in the case group (323.81 ± 91.51 pg/mL) were higher than levels in the healthy controls (260.85 ± 38.48 pg/mL, P < 0.001). We identified a correlation between 25-(OH)D and LL-37 levels in the case group (r = 0.231, P = 0.04). We observed no significant differences in 25-(OH)D and LL-37 levels between affected children in winter and spring periods, and affected children in summer and autumn periods (P > 0.05). When common group compared with the severe group of RSV pneumonia, there were significant differences in LL-37 levels (t = -3.611, P = 0.001), white blood cell (WBC) ≥ 10×10⁹/L (χ2 = 7.89, P < 0.01) and C-reaction protein (CRP) < 10 mg/L (χ2 = 4.71, P = 0.03) and there was no significant difference in the 25-(OH)D levels (t = -1.08, P > 0.05). Receiver-operating characteristic (ROC) curve analyses showed that the optimal critical serum LL-37 value was 384.24 pg/mL, and corresponding specificity and sensitivity values were 90.4% and 58.6%, respectively. Severe RSV pneumonia risk of LL-37 ≥ 384.24 pg/mL was significantly higher than that of the LL-37 < 384.24 pg/mL group (χ2 = 22.60, P < 0.001). Using multivariate logistic regression analysis, serum LL-37 ≥ 384.24 pg/mL (odds ratio (OR) = 17.127, P < 0.001), WBC ≥ 10×10⁹/L (OR = 7.399, P < 0.01), and CRP < 10 mg/L (OR = 12.393, P = 0.02) may be risk factors for severe RSV pneumonia in children.

Conclusions

25-(OH)D and LL-37 levels are involved in RSV pneumonia, with little seasonal correlations. High LL-37, WBC ≥ 10×10⁹/L, and CRP < 10 mg/L levels are probably related to disease severity and may be used for disease evaluation.

Health sciences/Diseases/Respiratory tract diseases

Health sciences/Biomarkers/Prognostic markers

Respiratory syncytial virus

25-hydroxy vitamin D

Antimicrobial peptide

LL-37

Globally, respiratory syncytial virus (RSV) is a key pathogen implicated in lower respiratory tract infections in infants and young children, and is the main cause of hospitalization for infants with pneumonia ^[1]. Annual RSV epidemics cause high infant morbidity and mortality ^[1], and currently, there is a dearth of effective antiviral drugs against the pathogen. Vitamin D is required during childhood growth and development, and plays important roles in innate immunity and anti-infection mechanisms ^[2]. Studies have shown that vitamin D functions in innate immunity are mediated by the up-regulated expression of the human antimicrobial peptide LL-37 gene, cathelicidin antimicrobial peptide^[3]. LL-37 is the only cathelicidin class antimicrobial peptide found in the human body ^[4]. As a component of the human innate immune system, the peptide contains 37 amino acids and has a broad spectrum of antimicrobial functions ^[4]. Studies have reported that children with severe vitamin D deficiency and RSV are more likely to have severe disease ^[5], and serum LL-37 levels were higher in critically ill children ^[6]; however, Mansbach et al.^[7] showed that vitamin D deficiency was not correlated with severe disease, and that low serum LL-37 levels were more likely to be severe. Therefore, controversy persist regarding vitamin D and LL-37 associations with RSV pneumonia. In this study, we measured vitamin D and LL-37 levels in children with RSV pneumonia to investigate their effects on disease occurrence, development, and severity.

Patients and clinical information

Between January 1 and December 31, 2021, patients were selected from the Department of Pediatrics, Affiliated Hospital of Hangzhou Normal University. In total, 81 children (29 cases in the severe group and 52 cases in the common group) were diagnosed with RSV pneumonia (case group) using nasopharyngeal wipes. Severe group diagnoses include: onset outside the hospital or within 48 hours of hospitalization, fever, cough and expectoration, wheezing and shortness of breath, pulmonary moist rales, plus etiological basis, with chest imaging findings ^[8]. RSV nucleic acid was detected using the Respiratory Syncytial Virus Nucleic Acid Detection Test Kit (Polymerase chain reaction assays ). The test kits were produced by Hangzhou Genesis Biodetection & Biocontrol Ltd, China. Patients included 45 males and 36 females, with an average age of 3.71 ± 0.96 years. Concomitantly, 45 healthy children (from outpatients) were selected during the same period and included 17 males and 28 females, with a mean age of 3.98 ± 1.24 years. No significant differences in age and gender were observed between groups. We excluded participants with autoimmune diseases, inherited metabolic diseases, liver, kidney, and gastrointestinal diseases, lymphoma, and granulomatous diseases (e.g., tuberculosis, acquired immunodeficiency syndrome, and sarcoidosis). This study was approved by the Medical Ethics Committee of the Affiliated Hospital of Hangzhou Normal University [approval number: 2021-(E2)-KS-025]. It was conducted according to the Declaration of Helsinki. Guardians of all children provided informed consent and signed informed consent sheets.

LL-37 and 25(OH)D Assays

We collected 2 mL of fasting peripheral venous blood into ethylenediaminetetraacetic acid blood tubes (containing anticoagulants) from healthy children on the day of physical examination, and from children with RSV pneumonia at admission. Tubes were centrifuged for 10 min at 3000 rpm, after which serum was removed and stored at -80°C. LL-37 levels were determined by enzyme-linked immunosorbent assay (Shanghai Keshun Biotechnology Co., Ltd). Optical density values in 96-well plates were measured using a microplate reader at 450 nm, after which a standard curve was generated to calculate LL-37 levels. 25(OH)D levels were determined using an electrochemiluminescence analyzer (Roche Diagnostics GmbH, Mannheim, Germany).

Statistical analysis

Data were entered into Excel spreadsheets and statistically analyzed using SPSS 25.0 software (IBM Corp, Armonk, NY, USA). Enumeration data were described using cases (%), and the χ2 test was used for comparisons between groups. Measurement data were described by the mean ± standard deviation (x ± s). When data conformed to a normal distribution and showed equal variance, independent sample t tests were used for comparisons between groups.

Bivariate correlation analysis was used for correlation analyses, and Pearson correlation analyses for normal data. Multivariate analysis was performed using logistic regression stepwise regression. Differences were statistically significant at P < 0.05. Receiver operating characteristic (ROC) curves were used to analyze the diagnostic efficacy of LL-37 levels in severe RSV pneumonia, and determine the optimal cut-off value.

Serum 25-(OH)D and LL-37 levels

We observed that 25-(OH)D levels were significantly lower, while serum LL-37 levels were significantly higher in children with RSV patients when compared with healthy children.**P < 0.01, ****P < 0.0001. (Fig. 1 ).

we observed no significant differences in 25-(OH)D and LL-37 levels between affected children in winter and spring periods, and affected children in summer and autumn periods. ns: P > 0.05.(Fig. 2).

Clinical RSV data

We observed no significant differences in serum 25-(OH)D levels, lactate dehydrogenase, and blood glucose ≥ 6.1 mmol/L levels between severe and common RSV groups (P > 0.05). When compared with the common group, significant differences in serum LL-37 levels, white blood cells (WBC) ≥ 10 × 10⁹/L, and CRP < 10 mg/L levels were observed in the severe group (P < 0.05) (Table 1).

Table 1

Serum 25-(OH)D and LL-37 levels, and clinical data in common and severe RSV groups
Clinical data	Common group (n = 52)	Severe group (n = 29)	t/χ2	P
WBC ≥ 10×10⁹/L	11 (21.15)	15 (51.72)	χ2 = 7.89	< 0.01
CRP < 10 mg/L	38 (73.08)	27 (93.10)	χ2 = 4.71	0.03
LDH (ng/mL)	362.58 ± 99.35	362.34 ± 131.10	t = 0.009	0.99
Blood glucose ≥ 6.1 mmol/L	15 (28.85)	14 (48.28)	χ2 = 3.06	0.08
25-(OH)D (nmol/L)	89.02 ± 24.53	95.24 ± 25.21	t = -1.075	0.29
LL-37 (pg/mL)	295.32 ± 66.73	374.90 ± 107.73	t = -3.611	0.001
LL-37 ≥ 384.24 pg/mL	5 (9.62)	17 (58.62)	χ2 = 22.60	< 0.001
WBC: white blood cell; CRP: C-reaction protein; LDH: lactate dehydrogenase;

ROC analysis of LL-37 levels in RSV pneumonia

Using ROC analysis, the area under the serum LL-37 curve was 0.712, and the optimal cut-off value was 384.24 pg/mL, which corresponded to a sensitivity of 58.6% and a specificity of 90.4% (Fig. 3).

According to cut-off serum LL-37 values, 81 children in the case group were divided into low (serum LL-37 < 384.24 pg/mL) and high serum LL-37 groups (serum LL-37 ≥ 384.24 pg/mL), showing that the risk of severe RSV pneumonia was higher in high serum LL-37 levels than in low serum LL-37, and the difference was statistically significant (P < 0.05) (Table 1).

Multivariate logistic regression analysis in RSV

Serum LL-37 ≥ 384.24 pg/mL, WBC ≥ 10 × 10⁹/L, and CRP < 10 mg/L levels, with statistical significance (P < 0.05) in univariate analyses, underwent multivariate logistic regression analyses, and showed significant differences across these values (P < 0.05) (Table 2).

Table 2

Multivariate logistic regression analysis of severe RSV
Related factors	β	P	OR	95% CI
LL-37 ≥ 384.24 pg/mL	2.841	< 0.001	17.127	4.353–67.386
WBC ≥ 10×10⁹/L	2.001	< 0.01	7.399	1.981–27.634
CRP < 10 mg/L	2.517	0.02	12.393	1.529–100.425
β: regression coefficient; OR: odds ratio; 95% CI: 95% confidence interval

Correlation of serum LL-37 levels with serum 25-(OH)D levels

From correlation analysis between serum LL-37 and 25-(OH)D levels, we observed a positive correlation between serum LL-37 and 25-(OH)D levels in cases (r = 0.231, P = 0.038), but no correlation in controls (r = − 0.057, P = 0.709) (Table 3 and Fig. 4).

Table 3

Correlation of serum LL-37 levels with serum 25-(OH)D levels
	r	r²	P	(95% CI)
RSV patients (n = 81)	0.231	0.053	0.04	0.85 (0.05 ~ 1.66)
Healthy controls (n = 45)	-0.057	0.003	0.71	-
r²: Coefficient of determination; 95% CI: 95% confidence interval

Vitamin D regulates calcium and phosphorus metabolism to promote bone growth, and regulate cell growth, differentiation, and immunoregulatory effects. In a mouse vitamin D deficiency model, Zosky et al. reported that vitamin D deficiency decreased lung volume, alveoli numbers, and lung compliance in mouse offspring, thereby increasing the chance of infection with viral pneumonia ^[9]. Vitamin D also reduces mortality associated with influenza and severe respiratory tract infections ^[10]. Appropriate serum vitamin D concentrations or vitamin D supplementation in individuals with vitamin D deficiency may reduce the occurrence of respiratory viral infections ^{[11, 12]}. In our study, we showed that serum 25-(OH)D levels in the case group were significantly lower than in controls, which may have affected innate immunity regulation and caused decreased resistance in children, thereby increasing viral infection risks. Previous studies reported an inverse correlation between serum 25-(OH)D levels and severity of bronchiolitis ^[13]. Hurwitz et al. reported that children with RSV, with severe vitamin D deficiency, were more likely to be admitted to an intensive care unit and mechanically ventilated ^[5]. However, the authors identified no associations between vitamin D and RSV pneumonia severity in children, consistent with Mansbach et al.^[7] and may alter the effect of vitamin D levels on disease and/or the effect of disease on vitamin D levels due to different ethnic, geographical, growth environment, and dietary characteristics. Okan et al. investigated relationships between the seasons and vitamin D levels, and found that winter had the lowest 25-(OH)D levels in all subjects, and this was followed by spring, while summer recorded the highest levels ^[14]. However, this study reported that 25-(OH)D levels were associated with season onset, which may be related to sufficient sunshine times in this region, therefore, larger samples will be required for future studies.

LL-37 is an endogenous antimicrobial peptide which disrupts viral membranes, attenuates viral replication, and reduces viral infection severity ^[15]. Silke et al. observed that the exogenous application of LL-37 exerted protective effects against RSV-mediated disease in vivo in a mouse pulmonary RSV infection model; LL-37 directly damaged the viral capsule, destroyed viral particles, reduced viral binding to human epithelial cells and infection in vitro, exerted significant antiviral activity against RSV, and prevented RSV infection ^[16–18]. Mansbach et al. examined 82 infants with viral bronchiolitis (62 were diagnosed with RSV infection) and found that infants with serum LL-37 levels < 218 ng/mL were more likely to be hospitalized within 24 h ^[7]. A further 2017 study by the same authors showed that the incidence of severe bronchiolitis was significantly higher in infants with low serum LL-37 levels (< 34 ng/mL) than infants with high serum LL-37 levels (> 60 ng/mL) ^[19]. However, Gad et al. showed that serum LL-37 levels in neonates with congenital pneumonia (pathogens included both viruses and bacteria) were significantly higher than levels in healthy controls, and neonates with high LL-37 levels were more likely to be treated with mechanical ventilation ^[20]. Gedik et al. examined 63 children with post-infectious bronchiolitis obliterans, and showed that serum LL-37 levels were significantly higher when compared with healthy children ^[21]. Chen et al. reported that serum LL-37 levels were significantly higher in children with severe lower respiratory tract infections when compared with children with mild disease ^[6].Therefore, it remains controversial to assess the risk of severe RSV disease against LL-37 serum levels.

We showed that LL-37 levels were significantly increased in children with RSV pneumonia, and this increase was more significant in severe RSV pneumonia, indicating that increased LL-37 serum levels may be related to RSV pneumonia occurrence and progression. Our ROC analysis of serum LL-37 levels in children with RSV infections suggested that the risk of severe RSV may occur when serum LL-37 levels were ≥ 384.24 pg/mL. We also performed correlation analysis for other risk factors related to severe viral pneumonia: increased peripheral WBC counts ^[22], increased blood glucose ^[23], decreased serum CRP ^[24], and increased lactate dehydrogenase levels ^[25] showed that increased blood glucose and lactate dehydrogenase levels were not associated with severe RSV infection, while peripheral WBCs ≥ 10 × 10⁹/L and CRP < 10 mg/L could cause severe disease. However, the confidence interval for CRP < 10 mg/L was wide, thus sample size must be increased for future, comprehensive analyses.

Pretreatment of primary human bronchial epithelial cells with 1,25 (OH)₂D increased the RSV-induced mRNA expression of the antimicrobial peptide cathelicidin in a dose-dependent manner ^[26]. Bhan et al. reported a significant correlation between 25-(OH)D and LL-37 levels in healthy adults when 25-(OH)D levels were ≤ 80 nmol/L ^[27]. Papadaki et al. observed no relationship between serum 25-(OH)D and LL-37 levels in children with bronchiolitis ^[28]. We identified no correlations between serum 25-(OH)D and serum LL-37 levels in healthy children, but during RSV infection, serum LL-37 levels increased concomitant with increased 25-(OH)D levels in a positively correlated manner, thereby indicating that 25-(OH)D deficiency may decrease LL-37 levels. Thus, vitamin D levels can exert immunoregulatory roles in the 50–125 nmol/L range ^[29], and our data showed that the serum 25-(OH)D levels in children with RSV pneumonia are higher than the range of 50 nmol/L, so children can maintain higher LL-37 levels to resist RSV infection.

In summary, deficient serum vitamin D levels during RSV pneumonia are common, with little seasonal correlations. Clinically, it is important to supplement vitamin D to children to prevent and treat pneumonia. Serum LL-37 levels were increased in RSV pneumonia, and positively correlated with vitamin D levels. Serum LL-37 levels ≥ 384.24 pg/mL, WBCs ≥ 10 × 10⁹/L, and CRP levels < 10 mg/L may be factors indicating severe RSV. However, due to the small sample size of this study, differences in vitamin D and LL-37 levels, and their relationship with disease severity remain unclear, thus future studies are required to comprehensively explore this relationship.

RSV Respiratory syncytial virus

WBC White blood cell

CRP C-reaction protein

ROC Receiver-operating characteristic

OR Odds ratio

Authors’ contributions

Yixiu He , Shaojie Zhao and Yafei Zhu conceived and designed research; Yixiu He , Shaojie Zhao , Menglan Pan, Bingzhang Chen and Yufeng Zhang collected data and conducted research; Yixiu He and Yafei Zhu analyzed and interpreted data; Yixiu He wrote the initial paper; Yafei Zhu revised the paper; Yafei Zhu had primary responsibility for final content. All authors read and approved the final manuscript.

Funding This study was supported by the Hangzhou Agricultural and Social Development Scientific Research Independent Application Project (20191293B107).

Ethics approval The study confirmed informed consent from all participants and/or their legal guardians and was approved by the Medical Ethics Committee of the Affiliated Hospital of Hangzhou Normal University [approval number: 2021-(E2)-KS-025].

Consent to participate applicable.

Consent for publication Not applicable.

Conflict of Interests The authors declare no competing interests.

Availability of Data and Materials All data generated or analysed during this study are included in this published article [and its supplementary information files].

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No competing interests reported.

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Associations between vitamin D and antimicrobial peptide LL-37 in children with respiratory syncytial virus pneumonia

Status:

Version 1

Abstract

Objective

Methods

Results

Conclusions

Figures

Introduction

Methodology

Patients and clinical information

LL-37 and 25(OH)D Assays

Statistical analysis

Results

Serum 25-(OH)D and LL-37 levels

Clinical RSV data

ROC analysis of LL-37 levels in RSV pneumonia

Multivariate logistic regression analysis in RSV

Correlation of serum LL-37 levels with serum 25-(OH)D levels

Discussion

Conclusion

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

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