Prevalence and Clinical Impact of Hypocalcemia in Pediatric COVID-19 Patients: A Cross-Sectional Study in Iran

Prevalence and Clinical Impact of Hypocalcemia in Pediatric COVID-19 Patients: A Cross-Sectional Study in Iran | 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 Research Article Prevalence and Clinical Impact of Hypocalcemia in Pediatric COVID-19 Patients: A Cross-Sectional Study in Iran Farzaneh Abbasi, Asal Khalili Dehkordi, Yasaman Ramezankhani, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8068078/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction and Objectives: The global COVID-19 pandemic has had a significant impact on pediatric populations, with varying clinical presentations. Hypocalcemia is a prevalent biochemical abnormality observed in hospitalized patients and is linked to poorer outcomes in infectious diseases, including COVID-19. However, the prevalence and prognostic significance of this condition in pediatric COVID-19 cases remain unclear. This study examines the prevalence of hypocalcemia among pediatric COVID-19 patients and its association with clinical outcomes. Materials and Methods This cross-sectional study analyzed medical records of 1,259 pediatric patients hospitalized with COVID-19 at Children's Medical Center Hospital in Tehran, from March 2020 to March 2021. Serum calcium levels and their correlations with demographic, clinical, and biochemical parameters were assessed using SPSS software. Results Hypocalcemia was observed in 15.1% of patients, with no significant differences in incidence based on gender or age. Hypocalcemic patients experienced longer hospital stays (p < 0.001) and higher oxygen dependency (p < 0.001) compared to normocalcemic patients. Other biochemical parameters, except calcium, remained within normal ranges. Conclusions Hypocalcemia is a prevalent condition in pediatric COVID-19 patients and correlates with disease severity markers, such as extended hospitalization and increased oxygen requirements. Early identification and management of hypocalcemia could improve clinical outcomes. Further research, including randomized controlled trials, is recommended to explore targeted interventions. COVID-19 Hypocalcemia Hospitalized Children Disease Severity Calcium Introduction Coronavirus disease 2019 (COVID-19), initially identified in late 2019, is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has had a pronounced clinical impact on pediatric populations.[ 1 ] The American Academy of Pediatrics (AAP) documented around 234,000 pediatric COVID-19 hospitalizations in the United States from 2020 to early 2024, with 58% of these cases involving children aged 0 to 4.[ 2 ] COVID-19 in pediatric patients can manifest with various respiratory and systemic symptoms, such as fever, cough, and gastrointestinal issues, although children often experience milder symptoms than adults. In some cases, children may develop a multisystem inflammatory syndrome (MIS-C), which is a severe inflammatory condition that may result in organ damage.[ 1 , 3 ] The clinical presentation in children ranges from asymptomatic or mild cases to severe manifestations that require intensive care, particularly in individuals with underlying conditions like chronic respiratory disease.[ 4 ] Various risk factors, such as ethnicity, renal dysfunction, diabetes, hypertension, obesity, e lectrolyte abnormalities, and cardiovascular diseases, influence the risk of COVID-19 in pediatric patients.[ 5 – 8 ] Each factor impacts the severity, prognosis, and mortality risk.[ 9 , 10 ] Serum calcium levels are another important prognostic indicator. Hypocalcemia, commonly seen in COVID-19 patients, correlates with adverse outcomes; individuals with serum calcium levels below 2.0 mmol/L are more prone to severe complications. This condition disrupts the balance of vitamin D and parathyroid hormone (PTH), compromising immune response and exacerbating disease severity.[ 11 ] Hypocalcemia has been consistently associated with increased risks of ICU admission, multi-organ failure, and mortality in adult COVID-19 cohorts.[ 11 – 13 ] Addressing calcium deficiency may improve immune response and alleviate some of the more serious COVID-19 complications. However, research on hypocalcemia in pediatric COVID-19 cases is limited, especially among Middle Eastern populations, highlighting the need for regional studies. The purpose of this cross-sectional study is to investigate the prevalence of hypocalcemia and its link to the severity and consequences of COVID-19 in pediatric hospitalized patients in Iran. Patients and Methods This cross-sectional, single-center study was performed at Children's Medical Center Hospital, a referral and specialized pediatric hospital in Tehran Province, Iran. The study was conducted in accordance with the relevant guidelines, with informed consent obtained from all patients. Ethical approval was obtained from the Ethical Council of Tehran University of Medical Sciences (IR.TUMS.CHMC.REC.1401.108). This study included all consecutive patients aged 0 to 18 years who were hospitalized at Children's Medical Center Hospital in Tehran with a confirmed positive COVID-19 result by RT-PCR between March 2020 and March 2021. Individuals between the ages of 0 and 18 were required to be included. The serum calcium concentration of all eligible patients was assessed at admission. Exclusion criteria were: (i) conditions known to affect calcium metabolism, such as fat malabsorption diseases (e.g., celiac disease), conditions associated with urinary calcium excretion and reabsorption, and the taking of medications that induce hypocalcemia, and (ii) any past medical history of chronic diseases known to affect COVID-19 severity (e.g., chronic respiratory disease, congenital heart disease, diabetes, or immunodeficiency). After applying these criteria, a total of 1,259 patients were included in the final analysis. Clinical and laboratory data were retrospectively collected from electronic medical records by a single researcher using a standardized data collection form to ensure consistency and completeness of the data. Hypocalcemia in pediatric patients was defined as total serum calcium levels below 8.0 mg/dL (2.0 mmol/L), as per clinical guidelines. The prevalence of hypocalcemia among positive COVID-19 inpatients, as well as the relationship between hypocalcemia and age, gender, disease severity, complications, oxygen requirements, hospitalization duration, and ICU admission, were investigated. Calcium, phosphorus, alkaline phosphatase, magnesium, albumin, vitamin D, and parathyroid hormone (PTH) plasma levels are reported as means ± standard deviations. A p-value below 0.05 was considered statistically significant for all statistical analyses. Statistical analysis was conducted using SPSS software version 16.0. Due to data limitations, multivariable regression models were not applied, which means that potential confounding factors such as nutritional status, baseline vitamin D levels, and comorbidities were not considered in the analysis. Results A total of 1,259 patients with confirmed COVID-19 were hospitalized and their serum calcium concentrations were assessed during the study period. Hypocalcemia was noted in 190 patients (15.1%), while the remaining 1,069 patients did not exhibit hypocalcemia. In this study, demographic analysis revealed that within the hypocalcemic group, 53.7% (102 patients) were male, whereas 54.7% (585 patients) of those with normal calcium levels were male, with no statistically significant difference in gender distribution between the groups (P = 0.791). The mean age in the hypocalcemic group was 7.34 ± 4.28 years, compared to 7.32 ± 4.42 years in the non-hypocalcemic group. ( Table 1 ) The age distribution also showed no significant differences: in the hypocalcemic group, 14.2% were under 3 years old, 42.1% were between 3 and 6 years old, and 43.7% were over 6 years old. The non-hypocalcemic group consisted of 16.1% of individuals under 3 years, 41.2% between 3 and 6 years, and 42.7% over 6 years (P = 0.541). Table 1 Epidemiological Characteristics and COVID-19 Severity Indicators Hypocalcemic n = 190 Normocalcemic n = 1069 P-value Male gender n (%) 102 (53.7) 585(54.7) 0.791 a Age (years) 7.34 ± 4.28 7.32 ± 4.42 0.446 b Hospitalization duration (days) 23.13 ± 10.27 17.14 ± 11.70 < 0.00 b Oxygen requirement n (%) 184(96.8) 931(87.1) < 0.001 a Hospitalized in ICU department n (%) 4(2.1) 12(1.1) 0.265 a Data are shown in frequency (%) or Mean ± Standard Deviation. a: derived from Chi-square b: derived from Independent T-test The analysis revealed significant differences between the hypocalcemic and normocalcemic groups in terms of both hospital stay duration and oxygen requirement. Patients with hypocalcemia had a longer mean hospital stay (23.13 ± 10.27 days) compared to those with normal calcium levels (17.14 ± 11.70 days) (P < 0.001, Cohen's d effect size: 0.52). Additionally, oxygen support was required for 96.8% of hypocalcemic patients, compared to 87.1% of non-hypocalcemic patients (P < 0.001), indicating a significantly higher dependency on oxygen in the hypocalcemic group. These findings suggest a greater severity of illness among patients with hypocalcemia. Nevertheless, ICU admission was required for 2.1% of hypocalcemic patients and 1.1% of normocalcemic patients, with no statistically significant difference observed between the groups. ( Table 1 ) Discussion COVID-19, caused by SARS-CoV-2, was a global health crisis characterized by respiratory symptoms ranging from mild to severe, including fever, cough, and shortness of breath. Severe cases may progress to pneumonia and multi-organ failure, with a variable mortality rate between 1% and 5%, influenced by age and comorbidities.[ 4 ] This study aimed to investigate the prevalence of hypocalcemia and its association with disease severity and outcomes in hospitalized pediatric patients with COVID-19, providing significant insights into the disease. Hypocalcemia is a serum calcium level lower than 8.0 mg/dL. In many viral infections, serum calcium levels considerably decline without medical intervention.[ 14 ] Hypocalcemia is notably prevalent in COVID-19, occurring in 60% or more of patients during hospital stays.[ 15 , 16 ] The exact pathophysiological mechanisms responsible for hypocalcemia in severely affected COVID-19 patients remain uncertain. The condition often presents as multifactorial, indicating critical illness physiology and systemic inflammation rather than just one hormonal defect.[ 17 ] However, several factors have been suggested, including malnutrition, low serum albumin, vitamin D deficiency, proinflammatory cytokines suppressing PTH secretion, and increased unsaturated fatty acids binding to calcium.[ 11 , 18 ] In our cohort, similar to the findings of Raesi et al., calcium levels were decreased despite normal vitamin D and PTH values. Because malnutrition and chronic comorbid conditions were excluded at baseline, these mechanisms are unlikely to fully explain the observed hypocalcemia.[ 19 ] In our cohort of 1,259 pediatric patients, hypocalcemia was identified in 15.1% of cases, with no gender difference. Moreover, hypocalcemia was significantly associated with prolonged hospitalization and higher oxygen demand, but not with ICU admission. These findings align with prior evidence that low calcium levels are a marker of a worse clinical course in COVID-19, even though the reported prevalence varies across studies, depending on the age groups and populations examined. [ 10 , 20 – 22 ] Systematic reviews by Martha et al. and Filippo et al. suggest that hypocalcemia correlates with poorer prognoses and severe complications, including cardiovascular and neurological effects. Similarly, other studies have linked hypocalcemia to increased mortality, ICU admissions, and extended hospitalization, aligning with our findings.[ 16 , 21 ] While variations in study populations, methodologies, and analytical approaches may account for observed differences in prevalence and statistical associations, our study underscores the need for proactive monitoring and tailored management strategies in affected patients. It reinforces the utility of hypocalcemia as an indicator of COVID-19 severity. This study has several limitations that should be taken into consideration. As a retrospective analysis, it relied on existing medical records, which may include inconsistencies or missing data that could impact the accuracy of the findings. Furthermore, the retrospective design limited our ability to account for potential confounding variables or to further stratify disease severity beyond oxygen requirements and ICU admissions. Finally, as a single-center study conducted in a tertiary referral hospital, the findings may not be generalizable to all pediatric populations. Future research should focus on addressing these limitations to enhance understanding of the relationship between hypocalcemia and COVID-19 outcomes in pediatric populations. Conclusion In conclusion, hypocalcemia may serve as a valuable predictive marker for severity and complications in pediatric COVID-19 cases, highlighting the need for targeted therapeutic interventions to improve clinical outcomes. While our study provides important insights, it has some limitations. Unlike previous research, which primarily focused on adults, our study emphasizes the significance of hypocalcemia in children. However, our data were derived from retrospective medical records, so potential errors cannot be ruled out. We recommend conducting randomized controlled trials to determine whether managing hypocalcemia can effectively mitigate disease severity and improve outcomes in pediatric patients with COVID-19. Declarations Human Ethics and Consent to Participate This study was conducted in accordance with the ethical standards of the institutional and national research committees, as well as the 1964 Helsinki Declaration and its subsequent amendments or comparable ethical standards. The study protocol was approved by the Research Ethics Committee of Tehran University of Medical Sciences, the IR.TUMS.CHMC.REC.1401.108, and written informed consent was obtained from the parents or legal guardians of all pediatric participants prior to inclusion in the study. Competing interests: The authors have no competing interests to declare that are relevant to the content of this article. Patient consent Not applicable. This manuscript does not contain any data related to an individual person, including personal information, images, or videos. Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Author Contribution Conception: S. A. & F. A. Design: F. A.& MR. A. Drafting the manuscript: A. K. & Y. R. Supervision: R. M. & M. M. Data collection and/or processing: Y. R. Analysis and/or interpretation: A. K. & M. D. Literature review: A. K. & P. R. Critical review: R. M. & A. A. Acknowledgements: The authors would like to acknowledge Dr. Parastoo Rostami, Dr. Mohammad Reza Abdolsalehi and Dr. Mastaneh Moghtaderi for their valuable contributions and support to this work. Data Availability The data supporting the findings of this study can be accessed from the corresponding author upon reasonable request. References Hoang A, Chorath K, Moreira A, Evans M, Burmeister-Morton F, Burmeister F, et al. COVID-19 in 7780 pediatric patients: A systematic review. EClinicalMedicine. 2020;24:100433. GROUP C-W. Successes and Lessons Learned in Responding to the Needs of Pediatricians, Children, and Families During the COVID-19 Pandemic. Pediatrics. 2024;153(6). Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet. 2020;395(10237):1607–8. Zachariah P, Johnson CL, Halabi KC, Ahn D, Sen AI, Fischer A et al. Epidemiology, Clinical Features, and Disease Severity in Patients With Coronavirus Disease 2019 (COVID-19) in a Children’s Hospital in New York City, New York. JAMA Pediatrics. 2020;174(10):e202430–e. Raisi-Estabragh Z, McCracken C, Bethell MS, Cooper J, Cooper C, Caulfield MJ, et al. Greater risk of severe COVID-19 in Black, Asian and Minority Ethnic populations is not explained by cardiometabolic, socioeconomic or behavioural factors, or by 25(OH)-vitamin D status: study of 1326 cases from the UK Biobank. J Public Health (Oxf). 2020;42(3):451–60. Council E-E, Group EW. Chronic kidney disease is a key risk factor for severe COVID-19: a call to action by the ERA-EDTA. Nephrol Dialysis Transplantation. 2020;36(1):87–94. di Filippo L, Allora A, Doga M, Formenti AM, Locatelli M, Rovere Querini P, et al. Vitamin D Levels Are Associated With Blood Glucose and BMI in COVID-19 Patients, Predicting Disease Severity. J Clin Endocrinol Metab. 2022;107(1):e348–60. Cooper ID, Crofts CAP, DiNicolantonio JJ, Malhotra A, Elliott B, Kyriakidou Y et al. Relationships between hyperinsulinaemia, magnesium, vitamin D, thrombosis and COVID-19: rationale for clinical management. Open Heart. 2020;7(2). Xu Y, Baylink DJ, Chen CS, Reeves ME, Xiao J, Lacy C, et al. The importance of vitamin d metabolism as a potential prophylactic, immunoregulatory and neuroprotective treatment for COVID-19. J Transl Med. 2020;18(1):322. Bennouar S, Cherif AB, Kessira A, Bennouar DE, Abdi S. Vitamin D Deficiency and Low Serum Calcium as Predictors of Poor Prognosis in Patients with Severe COVID-19. J Am Coll Nutr. 2021;40(2):104–10. Sun JK, Zhang WH, Zou L, Liu Y, Li JJ, Kan XH, et al. Serum calcium as a biomarker of clinical severity and prognosis in patients with coronavirus disease 2019. Aging. 2020;12(12):11287–95. Lippi G, South AM, Henry BM. Electrolyte imbalances in patients with severe coronavirus disease 2019 (COVID-19). Ann Clin Biochem. 2020;57(3):262–5. Raesi A, Saedi Dezaki E, Moosapour H, Saeidifard F, Habibi Z, Rahmani F, et al. Hypocalcemia in Covid-19: A Prognostic Marker for Severe Disease. Iran J Pathol. 2021;16(2):144–53. Crespi B, Alcock J. Conflicts over calcium and the treatment of COVID-19. Evol Med Public Health. 2021;9(1):149–56. Guan W-j, Ni Z-y, Hu Y, Liang W-h, Ou C-q, He J-x, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020;382(18):1708–20. Martha JW, Wibowo A, Pranata R. Hypocalcemia is associated with severe COVID-19: A systematic review and meta-analysis. Diabetes Metab Syndr. 2021;15(1):337–42. Mikhail N, Wali S. Clinical significance of hypocalcemia in COVID-19. Clin Res Diabetes Endocrinol. 2020;3(01):1–3. Cappellini F, Brivio R, Casati M, Cavallero A, Contro E, Brambilla P. Low levels of total and ionized calcium in blood of COVID-19 patients. Clin Chem Lab Med. 2020;58(9):e171–3. Raesi A, Saedi Dezaki E, Moosapour H, Saeidifard F, Habibi Z, Rahmani F, et al. Hypocalcemia in Covid-19: A Prognostic Marker for Severe Disease. Iran J Pathol. 2020;16(2):144–53. Liu J, Han P, Wu J, Gong J, Tian D. Prevalence and predictive value of hypocalcemia in severe COVID-19 patients. J Infect Public Health. 2020;13(9):1224–8. Di Filippo L, Formenti AM, Rovere-Querini P, Carlucci M, Conte C, Ciceri F, et al. Hypocalcemia is highly prevalent and predicts hospitalization in patients with COVID-19. Endocrine. 2020;68(3):475–8. Wu Y, Hou B, Liu J, Chen Y, Zhong P. Risk Factors Associated With Long-Term Hospitalization in Patients With COVID-19: A Single-Centered, Retrospective Study. Front Med. 2020;7. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted 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. 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2024, with 58% of these cases involving children aged 0 to 4.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eCOVID-19 in pediatric patients can manifest with various respiratory and systemic symptoms, such as fever, cough, and gastrointestinal issues, although children often experience milder symptoms than adults. In some cases, children may develop a multisystem inflammatory syndrome (MIS-C), which is a severe inflammatory condition that may result in organ damage.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] The clinical presentation in children ranges from asymptomatic or mild cases to severe manifestations that require intensive care, particularly in individuals with underlying conditions like chronic respiratory disease.[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eVarious risk factors, such as ethnicity, renal dysfunction, diabetes, hypertension, obesity, \u003cb\u003ee\u003c/b\u003electrolyte abnormalities, and cardiovascular diseases, influence the risk of COVID-19 in pediatric patients.[\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] Each factor impacts the severity, prognosis, and mortality risk.[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eSerum calcium levels are another important prognostic indicator. Hypocalcemia, commonly seen in COVID-19 patients, correlates with adverse outcomes; individuals with serum calcium levels below 2.0 mmol/L are more prone to severe complications. This condition disrupts the balance of vitamin D and parathyroid hormone (PTH), compromising immune response and exacerbating disease severity.[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] Hypocalcemia has been consistently associated with increased risks of ICU admission, multi-organ failure, and mortality in adult COVID-19 cohorts.[\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eAddressing calcium deficiency may improve immune response and alleviate some of the more serious COVID-19 complications. However, research on hypocalcemia in pediatric COVID-19 cases is limited, especially among Middle Eastern populations, highlighting the need for regional studies. The purpose of this cross-sectional study is to investigate the prevalence of hypocalcemia and its link to the severity and consequences of COVID-19 in pediatric hospitalized patients in Iran.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cp\u003eThis cross-sectional, single-center study was performed at Children's Medical Center Hospital, a referral and specialized pediatric hospital in Tehran Province, Iran. The study was conducted in accordance with the relevant guidelines, with informed consent obtained from all patients. Ethical approval was obtained from the Ethical Council of Tehran University of Medical Sciences (IR.TUMS.CHMC.REC.1401.108). This study included all consecutive patients aged 0 to 18 years who were hospitalized at Children's Medical Center Hospital in Tehran with a confirmed positive COVID-19 result by RT-PCR between March 2020 and March 2021. Individuals between the ages of 0 and 18 were required to be included. The serum calcium concentration of all eligible patients was assessed at admission.\u003c/p\u003e \u003cp\u003eExclusion criteria were: (i) conditions known to affect calcium metabolism, such as fat malabsorption diseases (e.g., celiac disease), conditions associated with urinary calcium excretion and reabsorption, and the taking of medications that induce hypocalcemia, and (ii) any past medical history of chronic diseases known to affect COVID-19 severity (e.g., chronic respiratory disease, congenital heart disease, diabetes, or immunodeficiency). After applying these criteria, a total of 1,259 patients were included in the final analysis.\u003c/p\u003e \u003cp\u003eClinical and laboratory data were retrospectively collected from electronic medical records by a single researcher using a standardized data collection form to ensure consistency and completeness of the data. Hypocalcemia in pediatric patients was defined as total serum calcium levels below 8.0 mg/dL (2.0 mmol/L), as per clinical guidelines. The prevalence of hypocalcemia among positive COVID-19 inpatients, as well as the relationship between hypocalcemia and age, gender, disease severity, complications, oxygen requirements, hospitalization duration, and ICU admission, were investigated. Calcium, phosphorus, alkaline phosphatase, magnesium, albumin, vitamin D, and parathyroid hormone (PTH) plasma levels are reported as means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviations. A p-value below 0.05 was considered statistically significant for all statistical analyses. Statistical analysis was conducted using SPSS software version 16.0. Due to data limitations, multivariable regression models were not applied, which means that potential confounding factors such as nutritional status, baseline vitamin D levels, and comorbidities were not considered in the analysis.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 1,259 patients with confirmed COVID-19 were hospitalized and their serum calcium concentrations were assessed during the study period. Hypocalcemia was noted in 190 patients (15.1%), while the remaining 1,069 patients did not exhibit hypocalcemia.\u003c/p\u003e \u003cp\u003eIn this study, demographic analysis revealed that within the hypocalcemic group, 53.7% (102 patients) were male, whereas 54.7% (585 patients) of those with normal calcium levels were male, with no statistically significant difference in gender distribution between the groups (P\u0026thinsp;=\u0026thinsp;0.791). The mean age in the hypocalcemic group was 7.34\u0026thinsp;\u0026plusmn;\u0026thinsp;4.28 years, compared to 7.32\u0026thinsp;\u0026plusmn;\u0026thinsp;4.42 years in the non-hypocalcemic group. \u003cem\u003e(\u003c/em\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cem\u003e)\u003c/em\u003e The age distribution also showed no significant differences: in the hypocalcemic group, 14.2% were under 3 years old, 42.1% were between 3 and 6 years old, and 43.7% were over 6 years old. The non-hypocalcemic group consisted of 16.1% of individuals under 3 years, 41.2% between 3 and 6 years, and 42.7% over 6 years (P\u0026thinsp;=\u0026thinsp;0.541).\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\u003eEpidemiological Characteristics and COVID-19 Severity Indicators\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\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=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHypocalcemic\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;190\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNormocalcemic\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;1069\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\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\u003eMale gender n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e102 (53.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e585(54.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.791\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7.34\u0026thinsp;\u0026plusmn;\u0026thinsp;4.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7.32\u0026thinsp;\u0026plusmn;\u0026thinsp;4.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.446 \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHospitalization duration (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23.13\u0026thinsp;\u0026plusmn;\u0026thinsp;10.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e17.14\u0026thinsp;\u0026plusmn;\u0026thinsp;11.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.00 \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOxygen requirement n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e184(96.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e931(87.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHospitalized in ICU department n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4(2.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12(1.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.265 \u003csup\u003ea\u003c/sup\u003e\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\u003eData are shown in frequency (%) or Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;Standard Deviation.\u003c/p\u003e \u003cp\u003ea: derived from Chi-square\u003c/p\u003e \u003cp\u003eb: derived from Independent T-test\u003c/p\u003e \u003cp\u003eThe analysis revealed significant differences between the hypocalcemic and normocalcemic groups in terms of both hospital stay duration and oxygen requirement. Patients with hypocalcemia had a longer mean hospital stay (23.13\u0026thinsp;\u0026plusmn;\u0026thinsp;10.27 days) compared to those with normal calcium levels (17.14\u0026thinsp;\u0026plusmn;\u0026thinsp;11.70 days) (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Cohen's d effect size: 0.52). Additionally, oxygen support was required for 96.8% of hypocalcemic patients, compared to 87.1% of non-hypocalcemic patients (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), indicating a significantly higher dependency on oxygen in the hypocalcemic group. These findings suggest a greater severity of illness among patients with hypocalcemia.\u003c/p\u003e \u003cp\u003eNevertheless, ICU admission was required for 2.1% of hypocalcemic patients and 1.1% of normocalcemic patients, with no statistically significant difference observed between the groups. \u003cem\u003e(\u003c/em\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cem\u003e)\u003c/em\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eCOVID-19, caused by SARS-CoV-2, was a global health crisis characterized by respiratory symptoms ranging from mild to severe, including fever, cough, and shortness of breath. Severe cases may progress to pneumonia and multi-organ failure, with a variable mortality rate between 1% and 5%, influenced by age and comorbidities.[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] This study aimed to investigate the prevalence of hypocalcemia and its association with disease severity and outcomes in hospitalized pediatric patients with COVID-19, providing significant insights into the disease.\u003c/p\u003e \u003cp\u003eHypocalcemia is a serum calcium level lower than 8.0 mg/dL. In many viral infections, serum calcium levels considerably decline without medical intervention.[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] Hypocalcemia is notably prevalent in COVID-19, occurring in 60% or more of patients during hospital stays.[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThe exact pathophysiological mechanisms responsible for hypocalcemia in severely affected COVID-19 patients remain uncertain. The condition often presents as multifactorial, indicating critical illness physiology and systemic inflammation rather than just one hormonal defect.[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eHowever, several factors have been suggested, including malnutrition, low serum albumin, vitamin D deficiency, proinflammatory cytokines suppressing PTH secretion, and increased unsaturated fatty acids binding to calcium.[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] In our cohort, similar to the findings of Raesi et al., calcium levels were decreased despite normal vitamin D and PTH values. Because malnutrition and chronic comorbid conditions were excluded at baseline, these mechanisms are unlikely to fully explain the observed hypocalcemia.[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eIn our cohort of 1,259 pediatric patients, hypocalcemia was identified in 15.1% of cases, with no gender difference. Moreover, hypocalcemia was significantly associated with prolonged hospitalization and higher oxygen demand, but not with ICU admission. These findings align with prior evidence that low calcium levels are a marker of a worse clinical course in COVID-19, even though the reported prevalence varies across studies, depending on the age groups and populations examined. [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eSystematic reviews by Martha et al. and Filippo et al. suggest that hypocalcemia correlates with poorer prognoses and severe complications, including cardiovascular and neurological effects. Similarly, other studies have linked hypocalcemia to increased mortality, ICU admissions, and extended hospitalization, aligning with our findings.[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eWhile variations in study populations, methodologies, and analytical approaches may account for observed differences in prevalence and statistical associations, our study underscores the need for proactive monitoring and tailored management strategies in affected patients. It reinforces the utility of hypocalcemia as an indicator of COVID-19 severity.\u003c/p\u003e \u003cp\u003eThis study has several limitations that should be taken into consideration. As a retrospective analysis, it relied on existing medical records, which may include inconsistencies or missing data that could impact the accuracy of the findings. Furthermore, the retrospective design limited our ability to account for potential confounding variables or to further stratify disease severity beyond oxygen requirements and ICU admissions. Finally, as a single-center study conducted in a tertiary referral hospital, the findings may not be generalizable to all pediatric populations. Future research should focus on addressing these limitations to enhance understanding of the relationship between hypocalcemia and COVID-19 outcomes in pediatric populations.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, hypocalcemia may serve as a valuable predictive marker for severity and complications in pediatric COVID-19 cases, highlighting the need for targeted therapeutic interventions to improve clinical outcomes. While our study provides important insights, it has some limitations. Unlike previous research, which primarily focused on adults, our study emphasizes the significance of hypocalcemia in children. However, our data were derived from retrospective medical records, so potential errors cannot be ruled out. We recommend conducting randomized controlled trials to determine whether managing hypocalcemia can effectively mitigate disease severity and improve outcomes in pediatric patients with COVID-19.\u003c/p\u003e"},{"header":"Declarations","content":" \u003cp\u003e \u003cstrong\u003eHuman Ethics and Consent to Participate\u003c/strong\u003e \u003cp\u003e This study was conducted in accordance with the ethical standards of the institutional and national research committees, as well as the 1964 Helsinki Declaration and its subsequent amendments or comparable ethical standards. The study protocol was approved by the Research Ethics Committee of Tehran University of Medical Sciences, the IR.TUMS.CHMC.REC.1401.108, and written informed consent was obtained from the parents or legal guardians of all pediatric participants prior to inclusion in the study.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCompeting interests:\u003c/strong\u003e \u003cp\u003eThe authors have no competing interests to declare that are relevant to the content of this article.\u003c/p\u003e\u003cp\u003e \u003cstrong\u003ePatient consent\u003c/strong\u003e \u003cp\u003eNot applicable. This manuscript does not contain any data related to an individual person, including personal information, images, or videos.\u003c/p\u003e \u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eConception: S. A. \u0026amp;amp; F. A. Design: F. A.\u0026amp;amp; MR. A. Drafting the manuscript: A. K. \u0026amp;amp; Y. R. Supervision: R. M. \u0026amp;amp; M. M. Data collection and/or processing: Y. R. Analysis and/or interpretation: A. K. \u0026amp;amp; M. D. Literature review: A. K. \u0026amp;amp; P. R. Critical review: R. M. \u0026amp;amp; A. A.\u003c/p\u003e\u003ch2\u003eAcknowledgements:\u003c/h2\u003e \u003cp\u003eThe authors would like to acknowledge Dr. Parastoo Rostami, Dr. Mohammad Reza Abdolsalehi and Dr. Mastaneh Moghtaderi for their valuable contributions and support to this work.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe data supporting the findings of this study can be accessed from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHoang A, Chorath K, Moreira A, Evans M, Burmeister-Morton F, Burmeister F, et al. 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JAMA Pediatrics. 2020;174(10):e202430\u0026ndash;e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRaisi-Estabragh Z, McCracken C, Bethell MS, Cooper J, Cooper C, Caulfield MJ, et al. Greater risk of severe COVID-19 in Black, Asian and Minority Ethnic populations is not explained by cardiometabolic, socioeconomic or behavioural factors, or by 25(OH)-vitamin D status: study of 1326 cases from the UK Biobank. J Public Health (Oxf). 2020;42(3):451\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCouncil E-E, Group EW. Chronic kidney disease is a key risk factor for severe COVID-19: a call to action by the ERA-EDTA. Nephrol Dialysis Transplantation. 2020;36(1):87\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003edi Filippo L, Allora A, Doga M, Formenti AM, Locatelli M, Rovere Querini P, et al. Vitamin D Levels Are Associated With Blood Glucose and BMI in COVID-19 Patients, Predicting Disease Severity. 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Clin Chem Lab Med. 2020;58(9):e171\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRaesi A, Saedi Dezaki E, Moosapour H, Saeidifard F, Habibi Z, Rahmani F, et al. Hypocalcemia in Covid-19: A Prognostic Marker for Severe Disease. Iran J Pathol. 2020;16(2):144\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu J, Han P, Wu J, Gong J, Tian D. Prevalence and predictive value of hypocalcemia in severe COVID-19 patients. J Infect Public Health. 2020;13(9):1224\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDi Filippo L, Formenti AM, Rovere-Querini P, Carlucci M, Conte C, Ciceri F, et al. Hypocalcemia is highly prevalent and predicts hospitalization in patients with COVID-19. Endocrine. 2020;68(3):475\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu Y, Hou B, Liu J, Chen Y, Zhong P. Risk Factors Associated With Long-Term Hospitalization in Patients With COVID-19: A Single-Centered, Retrospective Study. Front Med. 2020;7.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"COVID-19, Hypocalcemia, Hospitalized Children, Disease Severity, Calcium","lastPublishedDoi":"10.21203/rs.3.rs-8068078/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8068078/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eIntroduction and Objectives:\u003c/h2\u003e \u003cp\u003eThe global COVID-19 pandemic has had a significant impact on pediatric populations, with varying clinical presentations. Hypocalcemia is a prevalent biochemical abnormality observed in hospitalized patients and is linked to poorer outcomes in infectious diseases, including COVID-19. However, the prevalence and prognostic significance of this condition in pediatric COVID-19 cases remain unclear. This study examines the prevalence of hypocalcemia among pediatric COVID-19 patients and its association with clinical outcomes.\u003c/p\u003e\u003ch2\u003eMaterials and Methods\u003c/h2\u003e \u003cp\u003eThis cross-sectional study analyzed medical records of 1,259 pediatric patients hospitalized with COVID-19 at Children's Medical Center Hospital in Tehran, from March 2020 to March 2021. Serum calcium levels and their correlations with demographic, clinical, and biochemical parameters were assessed using SPSS software.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eHypocalcemia was observed in 15.1% of patients, with no significant differences in incidence based on gender or age. Hypocalcemic patients experienced longer hospital stays (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and higher oxygen dependency (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) compared to normocalcemic patients. Other biochemical parameters, except calcium, remained within normal ranges.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eHypocalcemia is a prevalent condition in pediatric COVID-19 patients and correlates with disease severity markers, such as extended hospitalization and increased oxygen requirements. Early identification and management of hypocalcemia could improve clinical outcomes. Further research, including randomized controlled trials, is recommended to explore targeted interventions.\u003c/p\u003e","manuscriptTitle":"Prevalence and Clinical Impact of Hypocalcemia in Pediatric COVID-19 Patients: A Cross-Sectional Study in Iran","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-06 11:25:20","doi":"10.21203/rs.3.rs-8068078/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8b6ec1dc-8188-4130-8eff-b14d418f5fb1","owner":[],"postedDate":"January 6th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-10T08:39:10+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-06 11:25:20","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8068078","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8068078","identity":"rs-8068078","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}