Inflammatory and coagulation marker profiles in severe pediatric COVID-19 patients: a systematic review

Tartila Fathan; Antonius Hocky Pudjiadi; Nina Dwi Putri; Nindya Permata; Yosilia Nursakina

doi:10.14238/pi62.6.2022.411-21

Tartila Fathan Department of Child Health, Universitas Indonesia Medical School/Dr. Cipto Mangunkusumo Hospital, Jakarta
Antonius Hocky Pudjiadi Department of Child Health, Universitas Indonesia/Cipto Mangunkusumo Hospital, Jakarta
Nina Dwi Putri Department of Child Health, Universitas Indonesia/Cipto Mangunkusumo Hospital, Jakarta
Nindya Permata Faculty of Medicine, Universitas Indonesia, Jakarta
Yosilia Nursakina Faculty of Medicine, Universitas Indonesia, Jakarta

DOI: https://doi.org/10.14238/pi62.6.2022.411-21

Keywords: inflammatory marker; coagulation marker; severe pediatric COVID-19

Abstract

Background Children are susceptible to SARS-CoV-2 infection and often present mild manifestations. However, severe and critical cases have also been reported. The inflammation and coagulation marker profile pattern in these patients along with the white blood cell differential count in critical PICU cases with non-COVID-19 etiology is not entirely clear.

Objective To evaluate the inflammation and coagulation profiles in children presenting with severe/critical SARS-CoV-2 infection.

Methods A systematic search and review of scientific literature was conducted following the PRISMA guidelines using ProQuest, SCOPUS, EBSCOHost, ScienceDirect, Cochrane, EMBASE, and Pubmed databases. All relevant original studies until March 11, 2021, were included. The risk of bias was appraised using the Modified Newcastle Ottawa Scale and JBI Critical Appraisal Checklist tools.

Results We identified 14 studies across 6 countries, including a total sample of 159 severe and critically ill pediatric COVID-19 patients. Most of the subjects showed normal leukocytes, but increased CRP, procalcitonin, ferritin, and IL-6. Studies on coagulation profiles showed normal thrombocytes, PT, aPTT, and inconsistent D-dimer results.

Conclusion Inflammation and coagulation parameters in severe/critically ill children with COVID-19 are atypical. Several inflammatory markers were elevated, including CRP, ferritin, procalcitonin, and IL-6. However, the elevated marker values are still lower compared to non-COVID infection patients. Further investigation of the parameters need to be done in serial examination multicenter studies, which include control subjects.

References

1. Ryan GA, Purandare NC, McAuliffe FM, Hod M, Purandare CN. Clinical update on COVID-19 in pregnancy: a review article. J Obstet Gynaecol Res. 2020;46:1235–45. DOI: https://doi.org/10.1111/jog.14321.
2. Rasmussen SA, Smulian JC, Lednicky JA, Wen TS, Jamieson DJ. Coronavirus Disease 2019 (COVID-19) and pregnancy: what obstetricians need to know. Am J Obstet Gynecol. 2020;222:415–26. DOI: https://doi.org/10.1016/j.ajog.2020.02.017.
3. World Health Organization. WHO coronavirus disease (COVID-19) dashboard. Geneva. 2020. [cited 2021 March 11]. Available from: https://covid19.who.int.
4. Yuki K, Fujiogi M, Koutsogiannaki S. COVID-19 pathophysiology: A review Clin Immunol. 2020: 108427. DOI: https://doi.org/10.1016/j.clim.2020.108427.
5. Magro C, Mulvey JJ, Berlin D, Nuovo G, Salvatore S, Harp J, Baxter-Stoltzfus A, Laurence J. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases. Transl Res. 2020 Jun;220:1-13. DOI: https://doi.org/10.1016/j.trsl.2020.04.007.
6. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021; n71. DOI: https://doi.org/10.1136/bmj.n71.
7. Wells G, Shea B, O’Connell D, Peterson J, Welch V, Losos M, & Tugwell P. Newcastle-Ottawa quality assessment scale cohort studies. University of Ottawa. [Cited 2021 Mar 11]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK99082/bin/appb-fm4.pdf.
8. Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. [cited 2021 March 11]. Available from: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.
9. Luchini C, Stubbs B, Solmi M, Veronese N. Assessing the quality of studies in meta-analyses: Advantages and limitations of the Newcastle Ottawa Scale. World Journal of Meta-Analysis. 2017;5(4): 80–84. DOI: https://doi.org/10.13105/wjma.v5.i4.80.
10. Munn Z, Barker TH, Moola S, Tufanaru C, Stern C, McArthur A, et al. Methodological quality of case series studies: an introduction to the JBI critical appraisal tool. JBI Evidence Synthesis. 2020;18(10): 2127–2133. DOI: https://doi.org/10.11124/JBISRIR-D-19-00099.
11. Alfraij A, Bin Alamir A, Al-Otaibi A, Alsharrah D, Aldaithan A, Kamel A et al. Characteristics and outcomes of coronavirus disease 2019 (COVID-19) in critically ill pediatric patients admitted to the intensive care unit: A multicenter retrospective cohort study. Journal of Infection and Public Health. 2021;14:193-200. DOI: https://doi.org/10.1016/j.jiph.2020.12.010.
12. Fisler G, Izard S, Shah S, Lewis D, Kainth M, Hagmann S et al. Characteristics and risk factors associated with critical illness in pediatric COVID-19. Annals of Intensive Care. 2020;10. DOI: https://doi.org/10.1186/s13613-020-00790-5.
13. Chao J, Derespina K, Herold B, Goldman D, Aldrich M, Weingarten J et al. Clinical Characteristics and Outcomes of Hospitalized and Critically Ill Children and Adolescents with Coronavirus Disease 2019 at a Tertiary Care Medical Center in New York City. The Journal of Pediatrics. 2020;223:14-19.e2. DOI: https://doi.org/10.1016/j.jpeds.2020.05.006.
14. Storch-de-Gracia P, Leoz-Gordillo I, Andina D, Flores P, Villalobos E, Escalada-Pellitero S et al. Clinical spectrum and risk factors for complicated disease course in children admitted with SARS-CoV-2 infection. Anales de Pediatría (English Edition). 2020;93:323-33. DOI: https://doi.org/10.1016/j.anpede.2020.07.005.
15. Ren G, Wang X, Xu J, Li J, Meng Q, Xie G et al. Comparison of acute pneumonia caused by SARS-COV-2 and other respiratory viruses in children: a retrospective multi-center cohort study during COVID-19 outbreak. Military Medical Research. 2021;8. DOI: https://doi.org/10.1186/s40779-021-00306-7.
16. Lu W, Lu W, Yang L, Yang L, Li X, Li X et al. Early Immune Responses and Prognostic Factors in Children with COVID-19: A Single-center Retrospective Analysis. 2020;. DOI: https://doi.org/10.21203/rs.3.rs-101151/v1.
17. Al Yazidi L, Al Hinai Z, Al Waili B, Al Hashami H, Al Reesi M, Al Othmani F et al. Epidemiology, characteristics and outcome of children hospitalized with COVID-19 in Oman: A multicenter cohort study. International Journal of Infectious Diseases. 2021;104:655-660. DOI: https://doi.org/10.1016/j.ijid.2021.01.036.
18. Zachariah P, Johnson C, Halabi K, Ahn D, Sen A, 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):e202430. DOI: https://doi.org/10.1001/jamapediatrics.2020.2430.
19. Diorio C, McNerney K, Lambert M, Paessler M, Anderson E, Henrickson S et al. Evidence of thrombotic microangiopathy in children with SARS-CoV-2 across the spectrum of clinical presentations. Blood Advances. 2020;4:6051-6063. DOI: https://doi.org/10.1182/bloodadvances.2020003471.
20. Sun D, Li H, Lu X, Xiao H, Ren J, Zhang F et al. Clinical features of severe pediatric patients with coronavirus disease 2019 in Wuhan: a single center’s observational study. World Journal of Pediatrics. 2020;16:251-259. DOI: https://doi.org/10.1007/s12519-020-00354-4.
21. Wang Y, Zhu F, Wang C, Wu J, Liu J, Chen X et al. Children Hospitalized With Severe COVID-19 in Wuhan. Pediatric Infectious Disease Journal. 2020;39:e91-e94. DOI: https://doi.org/10.1097/inf.0000000000002739.
22. Ozenen G, Sahbudak Bal Z, Umit Z, Bilen N, Yildirim Arslan S, Yurtseven A et al. Demographic, clinical, and laboratory features of COVID?19 in children: The role of mean platelet volume in predicting hospitalization and severity. Journal of Medical Virology. 2021;. DOI: https://doi.org/10.1002/jmv.26902.
23. Du H, Dong X, Zhang J, Cao Y, Akdis M, Huang P et al. Clinical characteristics of 182 pediatric COVID?19 patients with different severities and allergic status. Allergy. 2020;76:510-32. DOI: https://doi.org/10.1111/all.14452.
24. Zheng F, Liao C, Fan Q, Chen H, Zhao X, Xie Z et al. Clinical Characteristics of Children with Coronavirus Disease 2019 in Hubei, China. Current Medical Science. 2020;40:275-80. DOI: https://doi.org/10.1007/s11596-020-2172-6.
25. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395:1054-62. DOI: https://doi.org/10.1016/S0140-6736(20)30566-3.
26. Peckham H, Gruijter NM, Raine C, Radziszewska A, Clurtin C, Wedderburn L, et al. Male sex identified by global COVID-19 meta-analysis as a risk factor for death and ITU admission 2020;11:6317. DOI: https://doi.org/10.1038/s41467-020-19741-6.
27. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020;46:846–8. DOI: https://doi.org/10.1007/s00134-020-05991-x.
28. 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 Pediatr. 2020;174:e202430. DOI: https://doi.org/10.1001/jamapediatrics.2020.2430.
29. Carcillo JA, Sward K, Halstead ES, Telford R, Jimenez-Bacardi A, Shakoory B, et al. A systemic inflammation mortality risk assessment contingency table for severe sepsis. Pediatr Crit Care Med. 2017;18:143–50. DOI: https://doi.org/10.1097/PCC.0000000000001029.
30. Khattab AA, El- Mekkawy MS, Shehatab AM, Whdan NA. Clinical study of serum interleukin-6 in children with community-acquired pneumonia. Egyptian Pediatric Association Gazette. 2018;66:43-8. DOI: https://doi.org/10.1016/j.epag.2018.03.003.
31. Guervilly C, Coisel Y, Botelho-Nevers E, Dizier S, Castanier M, Lepaul-Ercole R, et al. Significance of high levels of procalcitonin in patients with influenza A (H1N1) pneumonia. J Infect. 2010;61:355–8. DOI: https://doi.org/10.1016/j.jinf.2010.07.013.
32. Almazeedi S, Al-Youha S, Jamal MH, Al-Haddad M, Al-Muhaini A, Al-Ghimlas F, et al. Characteristics, risk factors and outcomes among the first consecutive 1096 patients diagnosed with COVID-19 in Kuwait. EClinicalMedicine. 2020;24:100448. DOI: https://doi.org/10.1016/j.eclinm.2020.100448.
33. Leteurtre S, Duhamel A, Salleron J, Grandbastien B, Lacroix J, Leclerc F, et al. PELOD-2: an update of the PEdiatric logistic organ dysfunction score. Crit Care Med. 2013;41:1761–73. DOI: https://doi.org/10.1097/CCM.0b013e31828a2bbd.
34. Carcillo J, Halstead ES, Hall M W, Nguyen TC, Reeder R, Aneja R, et al. Three hypothetical inflammation pathobiology phenotypes and pediatric sepsis-induced multiple organ failure outcomes. Pediatr Crit Care Med. 2017;18: 513–3. DOI: https://doi.org/10.1097/PCC.000000000000112230.Cao B, Li XW, Mao Y, Wang J, Lu HZ, Chen YS, et al. Clinical features of the initial cases of 2009 pandemic influenza A (H1N1) virus infection in China. N Engl J Med. 2009;361:2507–17. DOI: https://doi.org/10.1056/NEJMoa090661.
35. Russell CD, Parajuli A, Gale HJ, Bulteel NS, Schuetz P, de Jager CPC, et al. The utility of peripheral blood leucocyte ratios as biomarkers in infectious diseases: a systematic review and meta-analysis. J Infect. 2019;78:339-48. DOI: https://doi.org/10.1016/j.jinf.2019.02.006.
36. Jesenak M, Brndiarova M, Urbancikova I, Rennerova Z, Vojtkova J, Bobcakova A, et al. Immune parameters and COVID-19 infection - associations with clinical severity and disease prognosis. Front Cell Infect Microbiol 2020;10:364. DOI: https://doi.org/10.3389/fcimb.2020.00364.
37. Huang CL, Wang YM, Li XW, Ren LL, Zhao JP, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497 –506. DOI: https://doi.org/10.1016/S0140-6736(20)30183-5.
38. Dhar SK, K V, Damodar S, Gujar S, Das M. IL-6 and IL-10 as predictors of disease severity in COVID-19 patients: results from meta-analysis and regression. Heliyon. 2021;7(2): e06155. DOI: https://doi.org/10.1016/j.heliyon.2021.e06155.
39. Li L, Li J, Gao M, Fan H, Wang Y, Xu X, et al. Interleukin-8 as a biomarker for disease prognosis of coronavirus disease-2019 patients. Frontiers in Immunology. 2021;11: 602395. DOI: https://doi.org/10.3389/fimmu.2020.602395.