Prevalence, prognostic value, pathophysiology, and management of hyponatraemia in children and adolescents with COVID-19
Keywords:
hyponatraemia, SIADH, sodium, COVID-19, SARS-CoV-2Abstract
Hyponatraemia is frequently encountered in adults with coronavirus disease 2019 (COVID-19) and is associated with poor prognosis. This review aims to describe for the first time the prevalence, aetiology, prognostic value, pathophysiology, and management of hyponatraemia in children and adolescents with COVID-19, taking into account all relevant studies published in PubMed and Cochrane Library studies until 26th September 2021. Literature search did not detect any studies evaluating the prevalence and prognostic value of sodium disorders in paediatric patients with COVID-19. A broader literature review showed a high prevalence of hyponatraemia in children with bacterial pneumonia, while some studies have reported that hyponatraemia is relatively common in Multisystem Inflammatory Syndrome in Children (MIS-C). In adults with COVID-19, an inverse association between sodium and interleukin-6 levels has been found, indicating that hyponatraemia could be used as a surrogate marker for the risk of cytokine storm and may facilitate the identification of patients who could benefit from immunomodulatory agents. Studies are urgently needed to evaluate the frequency and prognostic impact of electrolyte abnormalities in children with COVID-19. In the meantime, clinicians are urged to consider hyponatraemia in children with COVID-19 as a potential red flag, investigate the cause and administer fluids and other therapies accordingly.
References
Moritz ML, Ayus JC. Disorders of water metabolism in children: hyponatremia and hypernatremia. Pediatr Rev. 2002;23:371-380.
Carandang F, Anglemyer A, Longhurst CA, et al. Association between maintenance fluid tonicity and hospital-acquired hyponatremia. J Pediatr. 2013;163:1646-1651.
Wald R, Jaber BL, Price LL, et al. Impact of hospital-associated hyponatremia on selected outcomes. Arch Intern Med. 2010;170:294-302.
Tzoulis P, Bagkeris E, Bouloux PM. A case-control study of hyponatraemia as an independent risk factor for inpatient mortality. Clin Endocrinol (Oxf). 2014;81:401-407.
Whelan B, Bennett K, O'Riordan D, et al. Serum sodium as a risk factor for in-hospital mortality in acute unselected general medical patients. QJM. 2009;102:175-182.
Moritz ML, Ayus JC. New aspects in the pathogenesis, prevention, and treatment of hyponatremic encephalopathy in children. Pediatr Nephrol. 2010;25:1225-1238.
Ayus JC, Achinger SG, Arieff A. Brain cell volume regulation in hyponatremia: role of sex, age, vasopressin, and hypoxia. Am J Physiol Renal Physiol. 2008;295:F619-624.
Park SW, Shin SM, Jeong M, et al. Hyponatremia in children with respiratory infections: a cross-sectional analysis of a cohort of 3938 patients. Sci Rep. 2018;8:16494.
Tagarro A, Martin MD, Del-Amo N, et al. Hyponatremia in children with pneumonia rarely means SIADH. Paediatr Child Health. 2018;23:e126-e133.
Sakellaropoulou A, Hatzistilianou M, Eboriadou M, et al. Hyponatraemia in cases of children with pneumonia. Arch Med Sci. 2010;6:578-583.
Kruger S, Ewig S, Giersdorf S, et al. Dysnatremia, vasopressin, atrial natriuretic peptide and mortality in patients with community-acquired pneumonia: results from the german competence network CAPNETZ. Respir Med. 2014;108:1696-1705.
Cuesta M, Slattery D, Goulden EL, et al. Hyponatraemia in patients with community-acquired pneumonia; prevalence and aetiology, and natural history of SIAD. Clin Endocrinol (Oxf). 2019;90:744-752.
Nair V, Niederman MS, Masani N, et al. Hyponatremia in community-acquired pneumonia. Am J Nephrol. 2007;27:184-190.
Muller M, Schefold JC, Guignard V, et al. Hyponatraemia is independently associated with in-hospital mortality in patients with pneumonia. Eur J Intern Med. 2018; 54:46-52.
Zilberberg MD, Exuzides A, Spalding J, et al. Hyponatremia and hospital outcomes among patients with pneumonia: a retrospective cohort study. BMC Pulm Med. 2008;8:16.
Zhu N, Zhang D, Wang W, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020;382:727-733.
Gandhi RT, Lynch JB, Del Rio C. Mild or Moderate Covid-19. N Engl J Med. 2020.
Castagnoli R, Votto M, Licari A, et al. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection in Children and Adolescents: A Systematic Review. JAMA Pediatr. 2020;174:882-889.
Riphagen S, Gomez X, Gonzalez-Martinez C, et al. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet. 2020;395:1607-1608.
Feldstein LR, Rose EB, Horwitz SM, et al. Multisystem Inflammatory Syndrome in U.S. Children and Adolescents. N Engl J Med. 2020;383:334-346.
Feldstein LR, Tenforde MW, Friedman KG, et al. Characteristics and Outcomes of US Children and Adolescents With Multisystem Inflammatory Syndrome in Children (MIS-C) Compared With Severe Acute COVID-19. JAMA. 2021;325:1074-1087.
Tzoulis P, Waung JA, Bagkeris E, et al. Dysnatremia is a predictor for morbidity and mortality in hospitalized patients with COVID-19. J Clin Endocrinol Metab. 2021;106:1637-1648.
Tzoulis P, Grossman AB, Baldeweg SE, et al. MANAGEMENT OF ENDOCRINE DISEASE: Dysnatraemia in COVID-19: prevalence, prognostic impact, pathophysiology, and management. Eur J Endocrinol. 2021;185:R103-R111.
Frontera JA, Valdes E, Huang J, et al. Prevalence and Impact of Hyponatremia in Patients With Coronavirus Disease 2019 in New York City. Crit Care Med. 2021; 96:e575-e586.
Ruiz-Sanchez JG, Nunez-Gil IJ, Cuesta M, et al. Prognostic Impact of Hyponatremia and Hypernatremia in COVID-19 Pneumonia. A HOPE-COVID-19 (Health Outcome Predictive Evaluation for COVID-19) Registry Analysis. Front Endocrinol (Lausanne). 2020;11:599255.
Cui X, Zhang T, Zheng J, et al. Children with coronavirus disease 2019: A review of demographic, clinical, laboratory, and imaging features in pediatric patients. J Med Virol. 2020;92:1501-1510.
Henry BM, Lippi G, Plebani M. Laboratory abnormalities in children with novel coronavirus disease 2019. Clin Chem Lab Med. 2020;58:1135-1138.
Henry BM, Benoit SW, de Oliveira MHS, et al. Laboratory abnormalities in children with mild and severe coronavirus disease 2019 (COVID-19): A pooled analysis and review. Clin Biochem. 2020;81:1-8.
Singhi S, Dhawan A. Frequency and significance of electrolyte abnormalities in pneumonia. Indian Pediatr. 1992;29:735-740.
Wrotek A, Jackowska T. Hyponatremia in children hospitalized due to pneumonia. Adv Exp Med Biol. 2013;788:103-108.
Don M, Valerio G, Korppi M, et al. Hyponatremia in pediatric community-acquired pneumonia. Pediatr Nephrol. 2008;23:2247-2253.
Shann F, Germer S. Hyponatraemia associated with pneumonia or bacterial meningitis. Arch Dis Child. 1985;60:963-966.
Hu W, Lv X, Li C, et al. Disorders of sodium balance and its clinical implications in COVID-19 patients: a multicenter retrospective study. Intern Emerg Med. 2021;16:853-862.
Tezcan ME, Dogan Gokce G, Sen N, et al. Baseline electrolyte abnormalities would be related to poor prognosis in hospitalized COVID-19 patients. New Microbes New Infect. 2021;16:853-862.
Atila C, Sailer CO, Bassetti S, et al. Prevalence and outcome of dysnatremia in patients with COVID-19 compared to controls. Eur J Endocrinol. 2021;184:409-418.
Hirsch JS, Uppal NN, Sharma P, et al. Prevalence and outcomes of hyponatremia and hypernatremia in patients hospitalized with COVID-19. Nephrol Dial Transplant. 2021; 36:1135-1138.
De Carvalho H, Letellier T, Karakachoff M, et al. Hyponatremia is associated with poor outcome in COVID-19. J Nephrol. 2021;34:991-998.
Sjostrom A, Rysz S, Sjostrom H, et al. Electrolyte and acid-base imbalance in severe COVID-19. Endocr Connect. 2021;10:805-814.
Berni A, Malandrino D, Corona G, et al. Serum sodium alterations in SARS CoV-2 (COVID-19) infection: impact on patient outcome. Eur J Endocrinol. 2021;185:137-144.
Voets PJ, Frolke SC, Vogtlander NP, et al. COVID-19 and dysnatremia: A comparison between COVID-19 and non-COVID-19 respiratory illness. SAGE Open Med. 2021;9:20503121211027778.
Martino M, Falcioni P, Giancola G, et al. Sodium alterations impair the prognosis of hospitalized patients with COVID-19 pneumonia. Endocr Connect. 2021:EC-21-0411.R1.
Christ-Crain M, Hoorn EJ, Sherlock M, et al. ENDOCRINOLOGY IN THE TIME OF COVID-19-2021 UPDATES: The management of diabetes insipidus and hyponatraemia. Eur J Endocrinol. 2021;185:G35-G42.
Akbar MR, Pranata R, Wibowo A, et al. The Prognostic Value of Hyponatremia for Predicting Poor Outcome in Patients With COVID-19: A Systematic Review and Meta-Analysis. Front Med (Lausanne). 2021;8:666949.
Mardi P, Esmaeili M, Iravani P, et al. Characteristics of Children With Kawasaki Disease-Like Signs in COVID-19 Pandemic: A Systematic Review. Front Pediatr. 2021;9: 625377.
Grimaud M, Starck J, Levy M, et al. Acute myocarditis and multisystem inflammatory emerging disease following SARS-CoV-2 infection in critically ill children. Ann Intensive Care. 2020;10:69.
Toubiana J, Poirault C, Corsia A, et al. Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: prospective observational study. BMJ. 2020;369:m2094.
Tolunay O, Celik U, Arslan I, et al. Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with COVID-19: A Case Series Experience in a Tertiary Care Hospital of Southern Turkey. J Trop Pediatr. 2021;67:fmab050.
Reiff DD, Mannion ML, Samuy N, et al. Distinguishing active pediatric COVID-19 pneumonia from MIS-C. Pediatr Rheumatol Online J. 2021;19:21.
Zieg J. Pathophysiology of Hyponatremia in Children. Front Pediatr. 2017;5:213.
Park SJ, Shin JI. Inflammation and hyponatremia: an underrecognized condition? Korean J Pediatr. 2013;56:519-522.
Mills T, Trivedi A, Tremoulet AH, et al. Hyponatremia in Patients With Multisystem Inflammatory Syndrome in Children. Pediatr Infect Dis J. 2021;40:e344-e346.
Yousaf Z, Al-Shokri SD, Al-Soub H, et al. Covid-19 associated SIADH; a clue in the times of pandemic! Am J Physiol Endocrinol Metab. 2020;318:E882-E885.
Garrahy A, Thompson CJ. Glucocorticoid deficiency and syndrome of inappropriate antidiuresis: an underdiagnosed association? Ann Clin Biochem. 2018;55:4-6.
Tan T, Khoo B, Mills EG, et al. Association between high serum total cortisol concentrations and mortality from COVID-19. Lancet Diabetes Endocrinol. 2020;8:659-660.
Arlt W, Baldeweg SE, Pearce SHS, et al. ENDOCRINOLOGY IN THE TIME OF COVID-19: Management of adrenal insufficiency. Eur J Endocrinol. 2020;183:G25-G32.
Verbalis JG, Goldsmith SR, Greenberg A, et al. Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. Am J Med. 2013;126 (Suppl 1):S1-42.
Spasovski G, Vanholder R, Allolio B, et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Eur J Endocrinol. 2014;170:G1-47.
Feld LG, Neuspiel DR, Foster BA, et al. Clinical Practice Guideline: Maintenance Intravenous Fluids in Children. Pediatrics. 2018;142:e20183083.
Hoorn EJ, Geary D, Robb M, et al. Acute hyponatremia related to intravenous fluid administration in hospitalized children: an observational study. Pediatrics. 2004;113:1279-1284.
Friedman JN, Canadian Paediatric Society ACC. Risk of acute hyponatremia in hospitalized children and youth receiving maintenance intravenous fluids. Paediatr Child Health. 2013;18:102-107.
Park SJ, Oh YS, Choi MJ, et al. Hyponatremia may reflect severe inflammation in children with febrile urinary tract infection. Pediatr Nephrol. 2012;27:2261-2267.
Dixon BN, Daley RJ, Buie LW, et al. Correlation of IL-6 secretion and hyponatremia with the use of CD19+ chimeric antigen receptor T-cells. Clin Nephrol. 2020;93:42-46.
Swart RM, Hoorn EJ, Betjes MG, et al. Hyponatremia and inflammation: the emerging role of interleukin-6 in osmoregulation. Nephron Physiol. 2011;118:45-51.
Berni A, Malandrino D, Parenti G, et al. Hyponatremia, IL-6, and SARS-CoV-2 (COVID-19) infection: may all fit together? J Endocrinol Invest. 2020;43:1137-1139.
Sinha P, Matthay MA, Calfee CS. Is a "Cytokine Storm" Relevant to COVID-19? JAMA Intern Med. 2020;180:1152-1154.
Cao X. COVID-19: immunopathology and its implications for therapy. Nat Rev Immunol. 2020;20:269-270.
Zhu Z, Cai T, Fan L, et al. Clinical value of immune-inflammatory parameters to assess the severity of coronavirus disease 2019. Int J Infect Dis. 2020;95:332-339.
Fajgenbaum DC, June CH. Cytokine Storm. N Engl J Med. 2020;383:2255-2273.
Parr JB. Time to Reassess Tocilizumab's Role in COVID-19 Pneumonia. JAMA Intern Med. 2021;181:12-15.
Gupta S, Wang W, Hayek SS, et al. Association Between Early Treatment With Tocilizumab and Mortality Among Critically Ill Patients With COVID-19. JAMA Intern Med. 2021;181:41-51.
REMAP-CAP, Gordon AC, Mouncey PR, et al. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19. N Engl J Med. 2021;384:1491-1502.
Rubin EJ, Longo DL, Baden LR. Interleukin-6 Receptor Inhibition in Covid-19 - Cooling the Inflammatory Soup. N Engl J Med. 2021;384:1564-1565.
Liu B, Li M, Zhou Z, et al. Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)? J Autoimmun. 2020;111:102452.
Zieg J. Evaluation and management of hyponatraemia in children. Acta Paediatr. 2014;103:1027-1034.
Musch W, Thimpont J, Vandervelde D, et al. Combined fractional excretion of sodium and urea better predicts response to saline in hyponatremia than do usual clinical and biochemical parameters. Am J Med. 1995;99:348-355.
Chung HM, Kluge R, Schrier RW, et al. Clinical assessment of extracellular fluid volume in hyponatremia. Am J Med. 1987;83:905-908.
Grant P, Ayuk J, Bouloux PM, et al. The diagnosis and management of inpatient hyponatraemia and SIADH. Eur J Clin Invest. 2015;45:888-894.
Miles BE, Paton A, De Wardener HE. Maximum urine concentration. Br Med J. 1954;2:901-905.
Wang S, Ma P, Zhang S, et al. Fasting blood glucose at admission is an independent predictor for 28-day mortality in patients with COVID-19 without previous diagnosis of diabetes: a multi-centre retrospective study. Diabetologia. 2020;63:2102-2111.
Hillier TA, Abbott RD, Barrett EJ. Hyponatremia: evaluating the correction factor for hyperglycemia. Am J Med. 1999;106:399-403.
Brenkert TE, Estrada CM, McMorrow SP, et al. Intravenous hypertonic saline use in the pediatric emergency department. Pediatr Emerg Care. 2013;29:71-73.
Sterns RH, Nigwekar SU, Hix JK. The treatment of hyponatremia. Semin Nephrol. 2009;29:282-299.
Koenig MA, Bryan M, Lewin JL, 3rd, et al. Reversal of transtentorial herniation with hypertonic saline. Neurology. 2008;70:1023-1029.
Christ Crain M, Hoorn EJ, Sherlock M, et al. Endocrinology in the time of COVID-19: Management of Hyponatraemia and Diabetes Insipidus. Eur J Endocrinol. 2020 ;183:G9-G15.
Fernandez Martinez A, Barajas Galindo D, Ruiz Sanchez J. Management of hyponatraemia and hypernatraemia during the Covid-19 pandemic: a consensus statement of the Spanish Society for Endocrinology (Acqua Neuroendocrinology Group). Rev Endocr Metab Disord. 2021;22:317-324.
Downloads
Published
Issue
Section
License
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Transfer of Copyright and Permission to Reproduce Parts of Published Papers.
Authors retain the copyright for their published work. No formal permission will be required to reproduce parts (tables or illustrations) of published papers, provided the source is quoted appropriately and reproduction has no commercial intent. Reproductions with commercial intent will require written permission and payment of royalties.
How to Cite
